ORGANIC CHEMISTRY

Vollhardt and Schore

LibreTexts Textmap
LibreTexts Textmap
Organic Chemistry

Vollhardt and Schore

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This text was compiled on 12/05/2021

TABLE OF CONTENTS
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

1: STRUCTURE AND BONDING IN ORGANIC MOLECULES

1.1: THE SCOPE OF ORGANIC CHEMISTRY
1.2: COULOMB FORCES - A SIMPLIFIED VIEW OF BONDING
1.3: IONIC AND COVALENT BONDS - THE OCTET RULE
1.4: ELECTRON-DOT MODEL OF BONDING - LEWIS STRUCTURES
1.5: RESONANCE FORMS
1.6: ATOMIC ORBITALS: A QUANTUM MECHANICAL DESCRIPTION OF ELECTRONS AROUND THE NUCLEUS
1.7: MOLECULAR ORBITALS AND COVALENT BONDING
1.8: HYBRID ORBITALS: BONDING IN COMPLEX MOLECULES AND PRACTICE PROBLEMS
1.9: STRUCTURES AND FORMULAS OF ORGANIC MOLECULES
1.E: STRUCTURE AND BONDING IN ORGANIC MOLECULES (EXERCISES)

2: STRUCTURE AND REACTIVITY: ACIDS AND BASES, POLAR AND

NONPOLAR MOLECULES
2.1: KINETICS AND THERMODYNAMICS OF SIMPLE CHEMICAL PROCESSES
2.2: KEYS TO SUCCESS: USING CURVED "ELECTRON PUSHING" ARROWS TO DESCRIBE CHEMICAL
REACTIONS
2.3: ACIDS AND BASES; ELECTROPHILES AND NUCLEOPHILES
2.4: FUNCTIONAL GROUPS: CENTERS OF REACTIVITY
2.5: STRAIGHT-CHAIN AND BRANCHED ALKANES
2.6: NAMING THE ALKANES
2.7: STRUCTURAL AND PHYSICAL PROPERTIES OF ALKANES
2.8: ROTATION ABOUT SINGLE BONDS: CONFORMATIONS
2.9: ROTATION IN SUBSTITUTED ETHANES
2.E: STRUCTURE AND REACTIVITY: ACIDS AND BASES, POLAR AND NONPOLAR MOLECULES (EXERCISES)

3: REACTIONS OF ALKANES: BOND-DISSOCIATION ENERGIES, RADICAL

HALOGENATION, AND RELATIVE REACTIVITY
3.1: STRENGTH OF ALKANE BONDS: RADICALS
3.2: STRUCTURE OF ALKYL RADICALS: HYPERCONJUGATION
3.3: CONVERSION OF PETROLEUM: PYROLYSIS
3.4: CHLORINATION OF METHANE: THE RADICAL CHAIN MECHANISM
3.5: OTHER RADICAL HALOGENATIONS OF METHANE
3.6: KEYS TO SUCCESS: USING THE "KNOWN" MECHANISM AS A MODEL FOR THE "UNKNOWN"
3.7: CHLORINATION OF HIGHER ALKANES: RELATIVE REACTIVITY AND SELECTIVITY
3.8: SELECTIVITY IN RADICAL HALOGENATION WITH FLUORINE AND BROMINE
3.9: SYNTHETIC RADICAL HALOGENATION
3.10: SYNTHETIC CHLORINE COMPOUNDS AND THE STRATOSPHERIC OZONE LAYER
3.11: COMBUSTION AND THE RELATIVE STABILITIES OF ALKANES
3.E: REACTIONS OF ALKANES (EXERCISES)

4: CYCLOALKANES
4.1: NAMES AND PHYSICAL PROPERTIES OF CYCLOALKANES
4.2: RING STRAIN AND THE STRUCTURE OF CYCLOALKANES
4.3: CYCLOHEXANE: A STRAIN-FREE CYCLOALKANE
4.4: SUBSTITUTED CYCLOHEXANES
4.5: LARGER CYCLOALKANES
4.6: POLYCYCLIC ALKANES
4.7: CARBOCYCLIC PRODUCTS IN NATURE

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4.E: CYCLOALKANES (EXERCISES)

5: STEREOISOMERS
5.1: CHIRAL MOLECULES
5.2: OPTICAL ACTIVITY
5.3: ABSOLUTE CONFIGURATION: R-S SEQUENCE RULES
5.4: FISCHER PROJECTIONS
5.5: MOLECULES INCORPORATING SEVERAL STEREOCENTERS: DIASTEREOMERS
5.6: MESO COMPOUNDS
5.7: STEREOCHEMISTRY IN CHEMICAL REACTIONS
5.8: RESOLUTION: SEPARATION OF ENANTIOMERS
5.E: STEREOISOMERS (EXERCISES)

6: BIMOLECULAR NUCLEOPHILIC SUBSTITUTION IN HALOALKANES

6.1: PHYSICAL PROPERTIES OF HALOALKANES
6.2: NUCLEOPHILIC SUBSTITUTION
6.3: REACTION MECHANISMS INVOLVING POLAR FUNCTIONAL GROUPS: USING "ELECTRON-PUSHING'"
ARROWS
6.4: A CLOSER LOOK AT THE NUCLEOPHILIC SUBSTITUTION MECHANISM: KINETICS
6.5: FRONTSIDE OR BACKSIDE ATTACK? STEREOCHEMISTRY OF THE SN2 REACTION
6.6: CONSEQUENCES OF INVERSION IN SN2 REACTIONS
6.7: STRUCTURE AND SN 2 REACTIVITY: THE LEAVING GROUP
6.8: STRUCTURE AND SN2 REACTIVITY: THE NUCLEOPHILE
6.9: KEYS TO SUCCESS: CHOOSING AMONG MULTIPLE MECHANISTIC PATHWAYS
6.3: REACTION MECHANISMS INVOLVING POLAR FUNCTIONAL GROUPS: USING "ELECTRON-PUSHING\\'"
ARROWS
6.10: STRUCTURE AND SN2 REACTIVITY: THE SUBSTRATE
6.11: THE SN2 REACTION AT A GLANCE
6.E: PROPERTIES AND REACTIONS OF HALOALKANES: BIMOLECULAR NUCLEOPHILIC SUBSTITUTION
(EXERCISES)

7: FURTHER REACTIONS OF HALOALKANES: UNIMOLECULAR

SUBSTITUTION AND PATHWAYS OF ELIMINATION
7.1: SOLVOLYSIS OF TERTIARY AND SECONDARY HALOALKANES
7.2: UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION
7.3: STEREOCHEMICAL CONSEQUENCES OF SN1 REACTIONS
7.4: EFFECTS OF SOLVENT, LEAVING GROUP, AND NUCLEOPHILE ON UNIMOLECULAR SUBSTITUTION
7.5: EFFECT OF THE ALKYL GROUP ON THE SN 1 REACTION: CARBOCATION STABILITY
7.6: UNIMOLECULAR ELIMINATION: E1
7.7: BIMOLECULAR ELIMINATION: E2
7.8: KEYS TO SUCCESS: SUBSTITUTIN VERSUS ELIMINATION-STRUCTURE DETERMINES FUNCTION
7.9: SUMMARY OF REACTIVITY OF HALOALKANES
7.E: FURTHER REACTIONS OF HALOALKANES: UNIMOLECULAR SUBSTITUTION (EXERCISES)

8: HYDROXY OF FUNCTIONAL GROUP: ALCOHOLS: PROPERTIES,

PREPARATION, AND STRATEGY OF SYNTHESIS
8.1: NAMING THE ALCOHOLS
8.2: STRUCTURAL AND PHYSICAL PROPERTIES OF ALCOHOLS
8.3: ALCOHOLS AS ACIDS AND BASES
8.4: INDUSTRIAL SOURCES OF ALCOHOLS: CARBON MONOXIDE AND ETHENE
8.5: SYNTHESIS OF ALCOHOLS BY NUCLEOPHILIC SUBSTITUTION
8.6: SYNTHESIS OF ALCOHOLS: OXIDATION-REDUCTION RELATION BETWEEN ALCOHOLS AND CARBONYL
COMPOUNDS
8.7: ORGANOMETALLIC REAGENTS: SOURCES OF NUCLEOPHILIC CARBON FOR ALCOHOL SYNTHESIS
8.8: ORGANOMETALLIC REAGENTS IN THE SYNTHESIS OF ALCOHOLS
8.9: KEYS TO SUCCESS: AN INTRODUCTION TO SYNTHETIC STRATEGY

9: FURTHER REACTIONS OF ALCOHOLS AND THE CHEMISTRY OF ETHERS

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9.1: REACTIONS OF ALCOHOLS WITH BASE: PREPARATION OF ALKOXIDES
9.2: REACTIONS OF ALCOHOLS WITH STRONG ACIDS: ALKYLOXONIUM IONS IN SUBSTITUTION AND
ELIMINATION REACTIONS OF ALCOHOLS
9.3: CARBOCATION REARRANGEMENTS
9.4: ORGANIC AND INORGANIC ESTERS FROM ALCOHOLS
9.5: NAMES AND PHYSICAL PROPERTIES OF ETHERS
9.6: WILLIAMSON ETHER SYNTHESIS
9.7: SYNTHESIS OF ETHERS: ALCOHOLS AND MINERAL ACIDS
9.8: REACTIONS OF ETHERS
9.9: REACTIONS OF OXACYCLOPROPANES
9.10: SULFUR ANALOGS OF ALCOHOLS AND ETHERS
9.11: PHYSIOLOGICAL PROPERTIES AND USES OF ALCOHOLS AND ETHERS

10: USING NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY TO

DEDUCE STRUCTURE
10.1: PHYSICAL AND CHEMICAL TESTS
10.2: DEFINING SPECTROSCOPY
10.3: HYDROGEN NUCLEAR MAGNETIC RESONANCE
10.4: USING NMR SPECTRA TO ANALYZE MOLECULAR STRUCTURE: THE PROTON CHEMICAL SHIFT
10.5: TESTS FOR CHEMICAL EQUIVALENCE
10.6: INTEGRATION
10.7: SPIN-SPIN SPLITTING: THE EFFECT OF NONEQUIVALENT NEIGHBORING HYDROGENS
10.8: SPIN-SPIN SPLITTING: SOME COMPLICATIONS
10.9: CARBON-13 NUCLEAR MAGNETIC RESONANCE
BACK MATTER

INDEX

11: ALKENES: INFRARED SPECTROSCOPY AND MASS SPECTROMETRY

11.1: NAMING THE ALKENES
11.2: STRUCTURE AND BONDING IN ETHENE: THE PI BOND
11.3: PHYSICAL PROPERTIES OF ALKENES
11.4: NUCLEAR MAGNETIC RESONANCE OF ALKENES
11.5: CATALYTIC HYDROGENATIN OF ALKENES: RELATIVE STABILITY OF DOUBLE BONDS
11.6: PREPARATION OF ALKENES FROM HALOALKANES AND ALKYL SUFONATES: BIMOLECULAR ELIMINATION
REVISITED
11.7: PREPARATION OF ALKENES BY DEHYDRATION OF ALCOHOLS
11.8: INFRARED SPECTROSCOPY
11.9: MEASURING THE MOLECULAR MASS OF ORGANIC COMPOUNDS: MASS SPECTROMETRY
11.10: FRAGMENTATION PATTERNS OF ORGANIC MOLECULES
11.11: DEGREE OF UNSATURATION: ANOTHER AID TO IDENTIFYING MOLECULAR STRUCTURE

12: REACTIONS TO ALKENES

12.1: WHY ADDITION REACTIONS PROCEED: THERMODYNAMIC FEASIBILITY
12.2: CATALYTIC HYDROGENATION
12.3: NUCLEOPHILIC CHARACTER OF THE PI BOND: ELECTROPHILIC ADDITION OF HYDROGEN HALIDES
12.4: ALCOHOL SYNTHESIS BY ELECTROPHILIC HYDRATION: THERMODYNAMIC CONTROL
12.5: ELECTROPHILIC ADDITION OF HALOGENS TO ALKENES
12.6: THE GENERALITY OF ELECTROPHILIC ADDITION
12.7: OXYMNCURATION-DEMERCURATION: A SPECIAL ELCCTROPHILIC ADDITION
12.8: HYDROBORATION-OXIDATION: A STEREOSPECIFIC ANTI-MARKOVNIKOV HYDRATION
12.9: DIAZOMETHANE, CARBENES, AND CYCLOPROPANE SYNTHESIS
12.10: OXACYCLOPROPANE ( EPOXIDE) SYNTHESIS: EPOXIDATION BY PEROXYCARBOXYLIC ACIDS
12.11: VICINAL SYN DIHYDROXYLATION WITH OSMIUM TETROXIDE
12.12: OXIDATIVE CLEAVAGE: OZONOLYSIS
12.13: RADICAL ADDITIONS: ANTI-MARKOVNIKOV PRODUCT FORMATION
12.14: DIMERIZATION, OLIGOMERIZATION. AND POLYMERIZATION OF ALKENES
12.15: SYNTHESIS OF POLYMERS
12.16: ETHENE: AN IMPORTANT INDUSTRIAL FEEDSTOCK
12.17: ALKENES IN NATURE - INSECT PHEROMONES

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13: ALKYNES: THE CARBON
13.1: NAMING THE ALKYNES
13.2: PROPERTIES AND BONDING IN THE ALKYNES
13.3: SPECTROSCOPY OF THE ALKYNES
13.4: PREPARATION OF ALKYNES BY DOUBLE ELIMINATION
13.5: PREPARATION OF ALKYNES FROM ALKYNYL ANIONS
13.6: REDUCTION OF ALKYNES: THE RELATIVE REACTIVITY OF THE TWO π BONDS
13.7: ELECTROPHILIC ADDITION REACTIONS OF ALKYNES
13.8: ANTI-MARKOVNIKOV ADDITIONS TO TRIPLE BONDS
13.9: CHEMISTRY OF ALKENYL HALIDES
13.10: ETHYNE AS AN INDUSTRIAL STARTING MATERIAL
13.11: NATURALLY OCCURRING AND PHYSIOLOGICALLY ACTIVE ALKYNES

14: DELOCALIZED PI SYSTEMS: INVESTIGATION BY ULTRAVIOLET AND

VISIBLE SPECTROSCOPY
14.1: OVERLAP OF THREE ADJACENT P ORBITALS: ELECTRON DELOCALIZATION IN THE 2-PROPENYL (ALLYL)
SYSTEM
14.2: RADICAL ALLYLIC HALOGENATION
14.3: NUCLEOPHILIC SUBSTITUTION OF ALLYLIC HALIDES: SN1 AND SN2
14.4: ALLYLIC ORGANOMETALLIC REAGENTS: USEFUL THREE-CARBON NUCLEOPHILES
14.5: TWO NEIGHBORING DOUBLE BONDS: CONJUGATED DIENES
14.6: ELECTROPHILIC ATTACK ON CONJUGATED DIENES: KINETIC AND THERMODYNAMIC CONTROL
14.7: DELOCALIZATION AMONG MORE THAN TWO PI BONDS: EXTENDED CONJUGATION AND BENZENE
14.8: A SPECIAL TRANSFORMATION OF CONJUGATED DIENES: DIELS-ALDER CYCLOADDITION
14.9: ELECTROCYCLIC REACTIONS
14.10: POLYMERIZATION OF CONJUGATED DIENES: RUBBER
14.11: ELECTRONIC SPECTRA: ULTRAVIOLET AND VISIBLE SPECTROSCOPY

15: BENZENE AND AROMATICITY: ELECTROPHILIC AROMATIC

SUBSTITUTION
15.1: NAMING THE BENZENES
15.2: STRUCTURE AND RESONANCE ENERGY OF BENZENE: A FIRST LOOK AT AROMATICITY
15.3: PI MOLECULAR ORBITALS OF BENZENE
15.4: SPECTRAL CHARACTERISTICS OF THE BENZENE RING
15.5: POLYCYCLIC AROMATIC HYDROCARBONS
15.6: OTHER CYCLIC POLYENES: HUCKEL 'S RULE
15.7: HUCKEL'S RULE AND CHARGED MOLECULES
15.8: SYNTHESIS OF BENZENE DERIVATIVES: ELECTROPHILIC AROMATIC SUBSTITUTION
15.9: HALOGENATION OF BENZENE: THE NEED FOR A CATALYST
15.10: NITRATION AND SULFONATION OF BENZENE
15.11: FRIEDEL-CRAFTS ALKYLATION
15.12: LIMITATIONS OF FRIEDEL-CRAFTS ALKYLATIONS
15.13: FRIEDEL-CRAFTS ALKANOYLATION (ACYLATION)

16: ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE:

SUBSTITUENTS CONTROL REGIOSELECTIVITY
16.1: ACTIVATION OR DEACTIVATION BY SUBSTITUENTS ON A BENZENE RING
16.2: DIRECTING INDUCTIVE EFFECTS OF ALKYL GROUPS
16.3: DIRECTING EFFECTS OF SUBSTITUENTS IN CONJUGATION WITH THE BENZENE RING
16.4: ELECTROPHILIC ATTACK ON DISUBSTITUTED BENZENES
16.5: SYNTHETIC STRATEGIES TOWARD SUBSTITUTED BENZENES
16.6: REACTIVITY OF POLYCYCLIC BENZENOID HYDROCARBONS
16.7: POLYCYCLIC AROMATIC HYDROCARBONS AND CANCER

17: ALDEHYDES AND KETONES - THE CARBONYL GROUP

17.1: NAMING THE ALDEHYDES AND KETONES
17.2: STRUCTURE OF THE CARBONYL GROUP

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17.3: SPECTROSCOPIC PROPERTIES OF ALDEHYDES AND KETONES
17.4: PREPARATION OF ALDEHYDES AND KETONES
17.5: REACTIVITY OF THE CARBONYL GROUP: MECHANISMS OF ADDITION
17.6: ADDITION OF WATER TO FORM HYDRATES
17.7: ADDITION OF ALCOHOLS TO FORM HEMIACETALS AND ACETALS
17.8: ACETALS AS PROTECTING GROUPS
17.9: NUCLEOPHILIC ADDITION OF AMMONIA AND ITS DERIVATIVES
17.10: DEOXYGENATION OF THE CARBONYL GROUP
17.11: ADDITION OF HYDROGEN CYANIDE TO GIVE CYANOHYDRINS
17.12: ADDITION OF PHOSPHORUS YLIDES: THE WITTIG REACTION
17.13: OXIDATION BY PEROXYCARBOXYLIC ACIDS: THE BAEYER- VILLIGER OXIDATION
17.14: OXIDATIVE CHEMICAL TESTS FOR ALDEHYDES

18: ENOLS, ENOLATES, AND THE ALDOL CONDENSATION: A,B-

UNSATURATED ALDEHYDES AND KETONES
18.1: ACIDITY OF ALDEHYDES AND KETONES: ENOLATE IONS
18.2: KETO-ENOL EQUILIBRIA
18.3: HALOGENATION OF ALDEHYDES AND KETONES
18.4: ALKYLATION OF ALDEHYDES AND KETONES
18.5: ATTACK BY ENOLATES ON THE CARBONYL FUNCTION: ALDOL CONDENSATION
18.6: CROSSED ALDOL CONDENSATION
18.7: KEYS TO SUCCESS: COMPETITIVE RECTION PATHWAYS AND THE INTRAMOLECULAR ALDOL
CONDENSATION
18.8: PROPERTIES OF A,B-UNSATURATED ALDEHYDES AND KETONES
18.9: CONJUGATE ADDITIONS TO A,B-UNSATURATED ALDEHYDES AND KETONES
18.10: 1,2- AND 1,4-ADDITIONS OF ORGANOMETALLIC REAGENTS
18.11: CONJUGATE ADDITIONS OF ENOLATE IONS: MICHAEL ADDITION AND ROBINSON ANNULATION

19: CARBOXYLIC ACIDS

19.1: NAMING THE CARBOXYLIC ACIDS
19.2: STRUCTURAL AND PHYSICAL PROPERTIES OF CARBOXYLIC ACIDS
19.3: SPECTROSCOPY AND MASS SPECTROMETRY OF CARBOXYLIC ACIDS
19.4: ACIDIC AND BASIC CHARACTER OF CARBOXYLIC ACIDS
19.5: CARBOXYLIC ACID SYNTHESIS IN INDUSTRY
19.6: METHODS FOR INTRODUCING THE CARBOXY FUNCTIONAL GROUP
19.7: SUBSTITUTION AT THE CARBOXY CARBON: THE ADDITION-ELIMINATION MECHANISM
19.8: CARBOXYLIC ACID DERIVATIVES: ALKANOYL (ACYL) HALIDES AND ANHYDRIDES
19.9: CARBOXYLIC ACID DERIVATIVES: ESTERS
19.10: CARBOXYLIC ACID DERIVATIVES: AMIDES
19.11: REDUCTION OF CARBOXYLIC ACIDS BY LITHIUM ALUMINUM HYDRIDE
19.12: BROMINATION NEXT TO THE CARBOXY GROUP: THE HELL-VOLHARD-ZELINSKY REACTION
19.13: BIOLOGICAL ACTIVITY OF CARBOXYLIC ACIDS

20: CARBOXYLIC ACID DERIVATIVES

20.1: RELATIVE REACTIVITIES, STRUCTURES, AND SPECTRA OF CARBOXYLIC ACID DERIVATIVES
20.2: CHEMISTRY OF ALKANOYL HALIDES
20.3: CHEMISTRY OF CARBOXYLIC ANHYDRIDES
20.4: CHEMISTRY OF ESTERS
20.5: ESTERS IN NATURE: WAXES, FATS, OILS, AND LIPIDS
20.6: AMIDES: THE LEAST REACTIVE CARBOXYLIC ACID DERIVATIVES
20.7: AMIDATES AND THEIR HALOGENATION: THE HOFMANN REARRANGEMENT
20.8: ALKANENITRILES: A SPECIAL CLASS OF CARBOXYLIC

21: AMINES AND THEIR DERIVATIVES

21.1: NAMING THE AMINES
21.2: STRUCTURAL AND PHYSICAL PROPERTIES OF AMINES
21.3: SPECTROSCOPY OF THE AMINE GROUP
21.4: ACIDITY AND BASICITY OF AMINES
21.5: SYNTHESIS OF AMINES BY ALKYLATION

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21.6: SYNTHESIS OF AMINES BY REDUCTIVE AMINATION
21.7: SYNTHESIS OF AMINES FROM CARBOXYLIC AMIDES
21.8: QUATERNARY AMMONIUM SALTS: HOFMANN ELIMINATION
21.9: MANNICH REACTION: ALKYLATION OF ENOLS BY IMINIUM IONS
21.10: NITROSATION OF AMINES

22: CHEMISTRY OF THE BENZENE SUBSTITUENTS: ALKYLBENZENES,

PHENOLS, AND BENZENAMINES
22.1: REACTIVITY AT THE PHENYLMETHYL (BENZYL) CARBON: BENZYLIC RESONANCE STABILIZATION
22.2: BENZYLIC OXIDATIONS AND REDUCTIONS
22.3: NAMES AND PROPERTIES OF PHENOLS
22.4: PREPARATION OF PHENOLS: NUCLEOPHILIC AROMATIC SUBSTITUTION
22.5: ALCOHOL CHEMISTRY OF PHENOLS
22.6: ELECTROPHILIC SUBSTITUTION OF PHENOLS
22.7: AN ELECTROCYCLIC REACTION OF THE BENZENE RING: THE CLAISEN REARRANGEMENT
22.8: OXIDATION OF PHENOLS: BENZOQUINONES
22.9: OXIDATION-REDUCTION PROCESSES IN NATURE
22.10: ARENEDIAZONIUM SALTS
22.11: ELECTROPHILIC SUBSTITUTION WITH ARENEDIAZONIUM SALTS: DIAZO COUPLING

23: ESTER ENOLATES AND THE CLAISEN CONDENSATION

23.1: B-DICARBONYL COMPOUNDS: CLAISEN CONDENSATIONS
23.2: B-DICARBONYL COMPOUNDS AS SYNTHETIC INTERMEDIATES
23.3: B-DICARBONYL ANION CHEMISTRY: MICHAEL ADDITIONS
23.4: ALKANOYL (ACYL) ANION EQUIVALENTS: PREPARATION OF A-HYDROXYKETONES

24: CARBOHYDRATES: POLYFUNCTIONAL COMPOUNDS IN NATURE

24.1: NAMES AND STRUCTURES OF CARBOHYDRATES
24.2: CONFORMATIONS AND CYCLIC FORMS OF SUGARS
24.3: ANOMERS OF SIMPLE SUGARS - MUTAROTATION OF GLUCOSE
24.4: POLYFUNCTIONAL CHEMISTRY OF SUGARS: OXIDATION TO CARBOXYLIC ACIDS
24.5: OXIDATIVE CLEAVAGE OF SUGARS
24.6: REDUCTION OF MONOSACCHARIDES TO ALDITOLS
24.7: CARBONYL CONDENSATIONS WITH AMINE DERIVATIVES
24.8: ESTER AND ETHER FORMATION: GLYCOSIDES
24.9: STEP-BY-STEP BUILDUP AND DEGRADATION OF SUGARS
24.10: RELATIVE CONFIGURATIONS OF THE ALDOSES: AN EXERCISE IN STRUCTURE DETERMINATION
24.11: COMPLEX SUGARS IN NATURE: DISACCHARIDES
24.12: POLYSACCHARIDES AND OTHER SUGARS IN NATURE

25: HETEROCYCLES: HETEROATOMS IN CYCLIC ORGANIC COMPOUNDS

25.1: NAMING THE HETEROCYCLES
25.2: NONAROMATIC HETEROCYCLES
25.3: STRUCTURE AND PROPERTIES OF AROMATIC HETEROCYCLOPENTADIENES
25.4: REACTIONS OF THE AROMATIC HETEROCYCLOPENTADIENES
25.5: STRUCTURE AND PREPARATION OF PYRIDINE: AN AZABENZENE
25.6: REACTIONS OF PYRIDINE
25.7: QUINOLINE AND ISOQUINOLINE: THE BENZOPYRIDINES
25.8: ALKALOIDS: PHYSIOLOGICALLY POTENT NITROGEN HETEROCYCLES IN NATURE

26: AMINO ACIDS, PEPTIDES, PROTEINS, AND NUCLEIC ACIDS: NITROGEN-

CONTAINING POLYMERS IN NATURE
26.1: STRUCTURE AND PROPERTIES OF AMINO ACIDS
26.2: SYNTHESIS OF AMINO ACIDS: A COMBINATION OF AMINE AND CARBOXYLIC ACID CHEMISTRY
26.3: SYNTHESIS OF ENANTIOMERICALLY PURE AMINO ACIDS
26.4: PEPTIDES AND PROTEINS: AMINO ACID OLIGOMERS AND POLYMERS
26.5: DETERMINATION OF PRIMARY STRUCTURE: AMINO ACID SEQUENCING

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26.6: SYNTHESIS OF POLYPEPTIDES: A CHALLENGE IN THE APPLICATION OF PROTECTING GROUPS
26.7: MERRIFIELD SOLID-PHASE PEPTIDE SYNTHESIS
26.8: POLYPEPTIDES IN NATURE: OXYGEN TRANSPORT BY THE PROTEINS MYOGLOBIN AND HEMOGLOBIN
26.9: BIOSYNTHESIS OF PROTEINS: NUCLEIC ACIDS
26.10: PROTEIN SYNTHESIS THROUGH RNA
26.11: DNA SEQUENCING AND SYNTHESIS: CORNERSTONES OF GENE TECHNOLOGY

BACK MATTER
INDEX
GLOSSARY
BACK MATTER
INDEX

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CHAPTER OVERVIEW
1: STRUCTURE AND BONDING IN ORGANIC MOLECULES
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

1.1: THE SCOPE OF ORGANIC CHEMISTRY

The job of a synthetic chemist is akin to that of an architect (or civil engineer). While the architect could actually see the building he
is constructing, a molecular architect called Chemist is handicapped by the fact that the molecule he is synthesizing is too small to be
seen even through the most powerful microscope developed to date. With such a limitation, how does he ‘see’ the developing
structure?

1.2: COULOMB FORCES - A SIMPLIFIED VIEW OF BONDING

Through various experiments, Charles Augustin de Coulomb found a way to explain the interactions between charged particles, which
in turn helped to explain where the stabilities and instabilities of various particles come from. While the entities that hold atoms
together within a molecule can be attributed to bonds, the forces that create these bonds can be explained by Coulomb Forces. Thus,
the physical basis behind the bonding of two atoms can be explained.

1.3: IONIC AND COVALENT BONDS - THE OCTET RULE

There are many types of chemical bonds and forces that bind molecules together. The two most basic types of bonds are characterized
as either ionic or covalent. In ionic bonding, atoms transfer electrons to each other. Ionic bonds require at least one electron donor and
one electron acceptor. In contrast, atoms with the same electronegativity share electrons in covalent bonds, because neither atom
preferentially attracts or repels the shared electrons.

1.4: ELECTRON-DOT MODEL OF BONDING - LEWIS STRUCTURES

1.5: RESONANCE FORMS
1.6: ATOMIC ORBITALS: A QUANTUM MECHANICAL DESCRIPTION OF ELECTRONS AROUND THE NUCLEUS
1.7: MOLECULAR ORBITALS AND COVALENT BONDING
1.8: HYBRID ORBITALS: BONDING IN COMPLEX MOLECULES AND PRACTICE PROBLEMS
1.9: STRUCTURES AND FORMULAS OF ORGANIC MOLECULES
1.E: STRUCTURE AND BONDING IN ORGANIC MOLECULES (EXERCISES)

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1.1: The Scope of Organic Chemistry
Wöhler synthesis of Urea in 1828 heralded the birth of modern chemistry. The Art of synthesis is as old as Organic
chemistry itself. Natural product chemistry is firmly rooted in the science of degrading a molecule to known smaller
molecules using known chemical reactions and conforming the assigned structure by chemical synthesis from small, well
known molecules using well established synthetic chemistry techniques. Once this art of synthesizing a molecule was
mastered, chemists attempted to modify bioactive molecules in an attempt to develop new drugs and also to unravel the
mystery of biomolecular interactions. Until the middle of the 20th Century, organic chemists approached the task of
synthesis of molecules as independent tailor made projects, guided mainly by chemical intuition and a sound knowledge of
chemical reactions. During this period, a strong foundation was laid for the development of mechanistic principles of
organic reactions, new reactions and reagents. More than a century of such intensive studies on the chemistry of
carbohydrates, alkaloids, terpenes and steroids laid the foundation for the development of logical approaches for the
synthesis of molecules.
Organic chemistry encompasses a very large number of compounds (many millions), and our previous discussion and
illustrations have focused on their structural characteristics. Now that we can recognize these actors (compounds), we turn
to the roles they are inclined to play in the scientific drama staged by the multitude of chemical reactions that define
organic chemistry.
If you scan any organic textbook you will encounter what appears to be a very large, often intimidating, number of
reactions. These are the "tools" of a chemist, and to use these tools effectively, we must organize them in a sensible manner
and look for patterns of reactivity that permit us make plausible predictions. Most of these reactions occur at special sites
of reactivity known as functional groups, and these constitute one organizational scheme that helps us catalog and
remember reactions.
Ultimately, the best way to achieve proficiency in organic chemistry is to understand how reactions take place, and
to recognize the various factors that influence their course.
First, we identify four broad classes of reactions based solely on the structural change occurring in the reactant molecules.
This classification does not require knowledge or speculation concerning reaction paths or mechanisms. The four main
reaction classes are additions, eliminations, substitutions, and rearrangements.
The job of a synthetic chemist is akin to that of an architect (or civil engineer). While the architect could actually see the
building he is constructing, a molecular architect called Chemist is handicapped by the fact that the molecule he is
synthesizing is too small to be seen even through the most powerful microscope developed to date. With such a limitation,
how does he ‘see’ the developing structure? For this purpose, a chemist makes use of spectroscopic tools. How does this
chemist cut, tailor and glue the components on a molecule that cannot be seen with the naked eye? For this purpose
chemists have developed molecular level tools called Reagents and Reactions. How does he clean the debris and produce
pure molecules? This feat is achieved by crystallization, distillation and extensive use of chromatography techniques. A
mastery over several such techniques enables the molecular architect (popularly known as organic chemist) to achieve the
challenging task of synthesizing the mirade molecular structures encountered in Natural Products Chemistry, Drug
Chemistry and modern Molecular Materials.

Contributors and Attributions

William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

William Reusch 1.1.1 11/14/2021 https://chem.libretexts.org/@go/page/32321

1.2: Coulomb Forces - A Simplified View of Bonding

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1.3: Ionic and Covalent Bonds - The Octet Rule
There are many types of chemical bonds and forces that bind molecules together. The two most basic types of bonds are
characterized as either ionic or covalent. In ionic bonding, atoms transfer electrons to each other. Ionic bonds require at
least one electron donor and one electron acceptor. In contrast, atoms with the same electronegativity share electrons in
covalent bonds, because neither atom preferentially attracts or repels the shared electrons.

Introduction
Ionic bonding is the complete transfer of valence electron(s) between atoms. It is a type of chemical bond that generates
two oppositely charged ions. In ionic bonds, the metal loses electrons to become a positively charged cation, whereas the
nonmetal accepts those electrons to become a negatively charged anion. Ionic bonds require an electron donor, often a
metal, and an electron acceptor, a nonmetal.
Ionic bonding is observed because metals have few electrons in their outer-most orbitals. By losing those electrons, these
metals can achieve noble gas configuration and satisfy the octet rule. Similarly, nonmetals that have close to 8 electrons in
their valence shells tend to readily accept electrons to achieve noble gas configuration. In ionic bonding, more than 1
electron can be donated or received to satisfy the octet rule. The charges on the anion and cation correspond to the number
of electrons donated or received. In ionic bonds, the net charge of the compound must be zero.

This sodium molecule donates the lone electron in its valence orbital in order to achieve octet configuration. This creates a
positively charged cation due to the loss of electron.

This chlorine atom receives one electron to achieve its octet configuration, which creates a negatively charged anion.
The predicted overall energy of the ionic bonding process, which includes the ionization energy of the metal and electron
affinity of the nonmetal, is usually positive, indicating that the reaction is endothermic and unfavorable. However, this
reaction is highly favorable because of the electrostatic attraction between the particles. At the ideal interatomic distance,
attraction between these particles releases enough energy to facilitate the reaction. Most ionic compounds tend to
dissociate in polar solvents because they are often polar. This phenomenon is due to the opposite charges on each ion.

Example 1.3.1 : Chloride Salts

In this example, the sodium atom is donating its 1 valence electron to the chlorine atom. This creates a sodium cation
and a chlorine anion. Notice that the net charge of the resulting compound is 0.

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 In this example, the magnesium atom is donating both of its valence electrons to chlorine atoms. Each chlorine atom
can only accept 1 electron before it can achieve its noble gas configuration; therefore, 2 atoms of chlorine are required
to accept the 2 electrons donated by the magnesium. Notice that the net charge of the compound is 0.

Covalent Bonding
Covalent bonding is the sharing of electrons between atoms. This type of bonding occurs between two atoms of the same
element or of elements close to each other in the periodic table. This bonding occurs primarily between nonmetals;
however, it can also be observed between nonmetals and metals.
If atoms have similar electronegativities (the same affinity for electrons), covalent bonds are most likely to occur. Because
both atoms have the same affinity for electrons and neither has a tendency to donate them, they share electrons in order to
achieve octet configuration and become more stable. In addition, the ionization energy of the atom is too large and the
electron affinity of the atom is too small for ionic bonding to occur. For example: carbon does not form ionic bonds
because it has 4 valence electrons, half of an octet. To form ionic bonds, Carbon molecules must either gain or lose 4
electrons. This is highly unfavorable; therefore, carbon molecules share their 4 valence electrons through single, double,
and triple bonds so that each atom can achieve noble gas configurations. Covalent bonds include interactions of the sigma
and pi orbitals; therefore, covalent bonds lead to formation of single, double, triple, and quadruple bonds.

Example 1.3.2 : P Cl 3

In this example, a phosphorous atom is sharing its three unpaired electrons with three chlorine atoms. In the end
product, all four of these molecules have 8 valence electrons and satisfy the octet rule.

Bonding in Organic Chemistry

Ionic and covalent bonds are the two extremes of bonding. Polar covalent is the intermediate type of bonding between the
two extremes. Some ionic bonds contain covalent characteristics and some covalent bonds are partially ionic. For example,
most carbon-based compounds are covalently bonded but can also be partially ionic. Polarity is a measure of the separation
of charge in a compound. A compound's polarity is dependent on the symmetry of the compound and on differences in
electronegativity between atoms. Polarity occurs when the electron pushing elements, found on the left side of the periodic
table, exchanges electrons with the electron pulling elements, on the right side of the table. This creates a spectrum of
polarity, with ionic (polar) at one extreme, covalent (nonpolar) at another, and polar covalent in the middle.
Both of these bonds are important in organic chemistry. Ionic bonds are important because they allow the synthesis of
specific organic compounds. Scientists can manipulate ionic properties and these interactions in order to form desired
products. Covalent bonds are especially important since most carbon molecules interact primarily through covalent
bonding. Covalent bonding allows molecules to share electrons with other molecules, creating long chains of compounds
and allowing more complexity in life.

References
1. Vollhardt, K. Peter C., and Neil E. Schore. Organic Chemistry Structure and Function. New York: W. H. Freeman,
2007.
2. Petrucci, Ralph H. General Chemistry: Principles and Modern Applications. Upper Saddle River, NJ: Pearson
Education, 2007.

1.3.2 10/31/2021 https://chem.libretexts.org/@go/page/32323

 3. Brown, Theodore L., Eugene H. Lemay, and Bruce E. Bursten. Chemistry: The Central Science. 6th ed. Englewood
Cliffs, NJ: Prentice Hall, 1994.

Problems
1. Are these compounds ionic or covalent?

2. In the following reactions, indicate whether the reactants and products are ionic or covalently bonded.
a)

b) Clarification: What is the nature of the bond between sodium and amide? What kind of bond forms between the anion
carbon chain and sodium?

c)

Solutions
1) From left to right: Covalent, Ionic, Ionic, Covalent, Covalent, Covalent, Ionic.
2a) All products and reactants are ionic.
2b) From left to right: Covalent, Ionic, Ionic, Covalent, Ionic, Covalent, Covalent, Ionic.
2c) All products and reactants are covalent.

Further Reading
Michigan State Virtual Textbook of Organic Chemistry
Chemical Bonding and Valence
MasterOrganicChemistry
Chemical Bonding
Understanding Periodic Trends
Carey 4th Edition On-Line Activity

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Bond Types
Khan Academy
Leah4Sci
Intro to Organic Chemistry 3
Lewis Dots and the Octet Rule
Cliffs Notes
Covalent Bonding and Electronegativity
Slide Presentations
Web Pages
Counting Valence Electrons
The Octet Rule Rules!
*Exceptions to the Octet Rule
Videos
Video on Octet rule and Valance charges

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1.4: Electron-Dot Model of Bonding - Lewis Structures
Using Lewis Dot Symbols to Describe Covalent Bonding
This sharing of electrons allowing atoms to "stick" together is the basis of covalent bonding. There is some intermediate
distant, generally a bit longer than 0.1 nm, or if you prefer 100 pm, at which the attractive forces significantly outweigh the
repulsive forces and a bond will be formed if both atoms can achieve a completen s2np6 configuration. It is this behavior
that Lewis captured in his octet rule. The valence electron configurations of the constituent atoms of a covalent compound
are important factors in determining its structure, stoichiometry, and properties. For example, chlorine, with seven valence
electrons, is one electron short of an octet. If two chlorine atoms share their unpaired electrons by making a covalent bond
and forming Cl2, they can each complete their valence shell:

Each chlorine atom now has an octet. The electron pair being shared by the atoms is called a bonding pair ; the other three
pairs of electrons on each chlorine atom are called lone pairs. Lone pairs are not involved in covalent bonding. If both
electrons in a covalent bond come from the same atom, the bond is called a coordinate covalent bond.
We can illustrate the formation of a water molecule from two hydrogen atoms and an oxygen atom using Lewis dot
symbols:

The structure on the right is the Lewis electron structure, or Lewis structure, for H2O. With two bonding pairs and two lone
pairs, the oxygen atom has now completed its octet. Moreover, by sharing a bonding pair with oxygen, each hydrogen
atom now has a full valence shell of two electrons. Chemists usually indicate a bonding pair by a single line, as shown here
for our two examples:

The following procedure can be used to construct Lewis electron structures for more complex molecules and ions:

1. Arrange the atoms to show specific connections. When there is a central atom, it is usually the least electronegative
element in the compound. Chemists usually list this central atom first in the chemical formula (as in CCl4 and CO32−,
which both have C as the central atom), which is another clue to the compound’s structure. Hydrogen and the halogens
are almost always connected to only one other atom, so they are usually terminal rather than central.
Note
The central atom is usually the least electronegative element in the molecule or ion; hydrogen and the halogens are
usually terminal.

1. Determine the total number of valence electrons in the molecule or ion. Add together the valence electrons from
each atom. (Recall from Chapter 2 that the number of valence electrons is indicated by the position of the element in
the periodic table.) If the species is a polyatomic ion, remember to add or subtract the number of electrons necessary to
give the total charge on the ion. For CO32−, for example, we add two electrons to the total because of the −2 charge.
2. Place a bonding pair of electrons between each pair of adjacent atoms to give a single bond. In H O, for example,
2

there is a bonding pair of electrons between oxygen and each hydrogen.

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 3. Beginning with the terminal atoms, add enough electrons to each atom to give each atom an octet (two for
hydrogen). These electrons will usually be lone pairs.
4. If any electrons are left over, place them on the central atom. Some atoms are able to accommodate more than eight
electrons.
5. If the central atom has fewer electrons than an octet, use lone pairs from terminal atoms to form multiple
(double or triple) bonds to the central atom to achieve an octet. This will not change the number of electrons on the
terminal atoms.

Now let’s apply this procedure to some particular compounds, beginning with one we have already discussed.

H2O
1. Because H atoms are almost always terminal, the arrangement within the molecule must be HOH.
2. Each H atom (group 1) has 1 valence electron, and the O atom (group 16) has 6 valence electrons, for a total of 8
valence electrons.
3. Placing one bonding pair of electrons between the O atom and each H atom gives H:O:H, with 4 electrons left over.
4. Each H atom has a full valence shell of 2 electrons.
5. Adding the remaining 4 electrons to the oxygen (as two lone pairs) gives the following structure:

This is the Lewis structure we drew earlier. Because it gives oxygen an octet and each hydrogen two electrons, we do not
need to use step 6.

OCl−
1. With only two atoms in the molecule, there is no central atom.
2. Oxygen (group 16) has 6 valence electrons, and chlorine (group 17) has 7 valence electrons; we must add one more for
the negative charge on the ion, giving a total of 14 valence electrons.
3. Placing a bonding pair of electrons between O and Cl gives O:Cl, with 12 electrons left over.
4. If we place six electrons (as three lone pairs) on each atom, we obtain the following structure:

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Each atom now has an octet of electrons, so steps 5 and 6 are not needed. The Lewis electron structure is drawn within
brackets as is customary for an ion, with the overall charge indicated outside the brackets, and the bonding pair of electrons
is indicated by a solid line. OCl− is the hypochlorite ion, the active ingredient in chlorine laundry bleach and swimming
pool disinfectant.

CH2O
1. Because carbon is less electronegative than oxygen and hydrogen is normally terminal, C must be the central atom. One
possible arrangement is as follows:

2. Each hydrogen atom (group 1) has one valence electron, carbon (group 14) has 4 valence electrons, and oxygen (group
16) has 6 valence electrons, for a total of [(2)(1) + 4 + 6] = 12 valence electrons.
3. Placing a bonding pair of electrons between each pair of bonded atoms gives the following:

Six electrons are used, and 6 are left over.

4. Adding all 6 remaining electrons to oxygen (as three lone pairs) gives the following:

Although oxygen now has an octet and each hydrogen has 2 electrons, carbon has only 6 electrons.
5. There are no electrons left to place on the central atom.
6. To give carbon an octet of electrons, we use one of the lone pairs of electrons on oxygen to form a carbon–oxygen
double bond:

Both the oxygen and the carbon now have an octet of electrons, so this is an acceptable Lewis electron structure. The O
has two bonding pairs and two lone pairs, and C has four bonding pairs. This is the structure of formaldehyde, which is
used in embalming fluid.
An alternative structure can be drawn with one H bonded to O. Formal charges, discussed later in this section, suggest that
such a structure is less stable than that shown previously.
Example
Write the Lewis electron structure for each species.
1. NCl3
2. S22−
3. NOCl
Given: chemical species
Asked for: Lewis electron structures
Strategy:
Use the six-step procedure to write the Lewis electron structure for each species.
Solution:
Nitrogen is less electronegative than chlorine, and halogen atoms are usually terminal, so nitrogen is the central atom.
The nitrogen atom (group 15) has 5 valence electrons and each chlorine atom (group 17) has 7 valence electrons, for a

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total of 26 valence electrons. Using 2 electrons for each N–Cl bond and adding three lone pairs to each Cl account for
(3 × 2) + (3 × 2 × 3) = 24 electrons. Rule 5 leads us to place the remaining 2 electrons on the central N:

Nitrogen trichloride is an unstable oily liquid once used to bleach flour; this use is now prohibited in the United States.

1.
2. In a diatomic molecule or ion, we do not need to worry about a central atom. Each sulfur atom (group 16) contains 6
valence electrons, and we need to add 2 electrons for the −2 charge, giving a total of 14 valence electrons. Using 2
electrons for the S–S bond, we arrange the remaining 12 electrons as three lone pairs on each sulfur, giving each S
atom an octet of electrons:

3. Because nitrogen is less electronegative than oxygen or chlorine, it is the central atom. The N atom (group 15) has 5
valence electrons, the O atom (group 16) has 6 valence electrons, and the Cl atom (group 17) has 7 valence
electrons, giving a total of 18 valence electrons. Placing one bonding pair of electrons between each pair of bonded
atoms uses 4 electrons and gives the following:

Adding three lone pairs each to oxygen and to chlorine uses 12 more electrons, leaving 2 electrons to place as a lone
pair on nitrogen:

4. Because this Lewis structure has only 6 electrons around the central nitrogen, a lone pair of electrons on a terminal
atom must be used to form a bonding pair. We could use a lone pair on either O or Cl. Because we have seen many
structures in which O forms a double bond but none with a double bond to Cl, it is reasonable to select a lone pair
from O to give the following:

All atoms now have octet configurations. This is the Lewis electron structure of nitrosyl chloride, a highly
corrosive, reddish-orange gas.

Exercise
Write Lewis electron structures for CO2 and SCl2, a vile-smelling, unstable red liquid that is used in the manufacture of
rubber.
Answer:

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 1.

2.

Formal Charges
It is sometimes possible to write more than one Lewis structure for a substance that does not violate the octet rule, as we
saw for CH2O, but not every Lewis structure may be equally reasonable. In these situations, we can choose the most stable
Lewis structure by considering the formal charge on the atoms, which is the difference between the number of valence
electrons in the free atom and the number assigned to it in the Lewis electron structure. The formal charge is a way of
computing the charge distribution within a Lewis structure; the sum of the formal charges on the atoms within a molecule
or an ion must equal the overall charge on the molecule or ion. A formal charge does not represent a true charge on an
atom in a covalent bond but is simply used to predict the most likely structure when a compound has more than one valid
Lewis structure.
To calculate formal charges, we assign electrons in the molecule to individual atoms according to these rules:
Nonbonding electrons are assigned to the atom on which they are located.
Bonding electrons are divided equally between the bonded atoms.
For each atom, we then compute a formal charge:

To illustrate this method, let’s calculate the formal charge on the atoms in ammonia (NH3) whose Lewis electron structure
is as follows:

A neutral nitrogen atom has five valence electrons (it is in group 15). From its Lewis electron structure, the nitrogen atom
in ammonia has one lone pair and shares three bonding pairs with hydrogen atoms, so nitrogen itself is assigned a total of
five electrons [2 nonbonding e− + (6 bonding e−/2)]. Substituting into Equation 5.3.1, we obtain

A neutral hydrogen atom has one valence electron. Each hydrogen atom in the molecule shares one pair of bonding
electrons and is therefore assigned one electron [0 nonbonding e− + (2 bonding e−/2)]. Using Equation 4.4.1 to calculate
the formal charge on hydrogen, we obtain

The hydrogen atoms in ammonia have the same number of electrons as neutral hydrogen atoms, and so their formal charge
is also zero. Adding together the formal charges should give us the overall charge on the molecule or ion. In this example,
the nitrogen and each hydrogen has a formal charge of zero. When summed the overall charge is zero, which is consistent
with the overall charge on the NH3 molecule.

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Typically, the structure with the most charges on the atoms closest to zero is the more stable Lewis structure. In cases
where there are positive or negative formal charges on various atoms, stable structures generally have negative formal
charges on the more electronegative atoms and positive formal charges on the less electronegative atoms. The next
example further demonstrates how to calculate formal charges.
Example
Calculate the formal charges on each atom in the NH4+ ion.
Given: chemical species
Asked for: formal charges
Strategy:
Identify the number of valence electrons in each atom in the NH4+ ion. Use the Lewis electron structure of NH4+ to
identify the number of bonding and nonbonding electrons associated with each atom and then use Equation 4.4.1 to
calculate the formal charge on each atom.
Solution:
The Lewis electron structure for the NH4+ ion is as follows:

The nitrogen atom shares four bonding pairs of electrons, and a neutral nitrogen atom has five valence electrons. Using
Equation 4.4.1, the formal charge on the nitrogen atom is therefore

Each hydrogen atom in has one bonding pair. The formal charge on each hydrogen atom is therefore

The formal charges on the atoms in the NH4+ ion are thus

Adding together the formal charges on the atoms should give us the total charge on the molecule or ion. In this case, the
sum of the formal charges is 0 + 1 + 0 + 0 + 0 = +1.

Exercise
Write the formal charges on all atoms in BH4−.
Answer:

If an atom in a molecule or ion has the number of bonds that is typical for that atom (e.g., four bonds for carbon), its
formal charge is zero.

Using Formal Charges to Distinguish between Lewis Structures

As an example of how formal charges can be used to determine the most stable Lewis structure for a substance, we can
compare two possible structures for CO2. Both structures conform to the rules for Lewis electron structures.

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CO2
1. C is less electronegative than O, so it is the central atom.

2. C has 4 valence electrons and each O has 6 valence electrons, for a total of 16 valence electrons.

3. Placing one electron pair between the C and each O gives O–C–O, with 12 electrons left over.

4. Dividing the remaining electrons between the O atoms gives three lone pairs on each atom:

This structure has an octet of electrons around each O atom but only 4 electrons around the C atom.

5. No electrons are left for the central atom.

6. To give the carbon atom an octet of electrons, we can convert two of the lone pairs on the oxygen atoms to bonding
electron pairs. There are, however, two ways to do this. We can either take one electron pair from each oxygen to form a
symmetrical structure or take both electron pairs from a single oxygen atom to give an asymmetrical structure:

Both Lewis electron structures give all three atoms an octet. How do we decide between these two possibilities? The
formal charges for the two Lewis electron structures of CO2 are as follows:

Both Lewis structures have a net formal charge of zero, but the structure on the right has a +1 charge on the more
electronegative atom (O). Thus the symmetrical Lewis structure on the left is predicted to be more stable, and it is, in fact,
the structure observed experimentally. Remember, though, that formal charges do not represent the actual charges on atoms
in a molecule or ion. They are used simply as a bookkeeping method for predicting the most stable Lewis structure for a
compound.
Note
The Lewis structure with the set of formal charges closest to zero is usually the most stable.

Example
The thiocyanate ion (SCN−), which is used in printing and as a corrosion inhibitor against acidic gases, has at least two
possible Lewis electron structures. Draw two possible structures, assign formal charges on all atoms in both, and decide
which is the preferred arrangement of electrons.
Given: chemical species
Asked for: Lewis electron structures, formal charges, and preferred arrangement
Strategy:
A Use the step-by-step procedure to write two plausible Lewis electron structures for SCN−.
B Calculate the formal charge on each atom using Equation 4.4.1.

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 C Predict which structure is preferred based on the formal charge on each atom and its electronegativity relative to the
other atoms present.
Solution:
A Possible Lewis structures for the SCN− ion are as follows:

B We must calculate the formal charges on each atom to identify the more stable structure. If we begin with carbon, we
notice that the carbon atom in each of these structures shares four bonding pairs, the number of bonds typical for
carbon, so it has a formal charge of zero. Continuing with sulfur, we observe that in (a) the sulfur atom shares one
bonding pair and has three lone pairs and has a total of six valence electrons. The formal charge on the sulfur atom is
therefore In (c), nitrogen has a formal charge of −2.
C Which structure is preferred? Structure (b) is preferred because the negative charge is on the more electronegative
atom (N), and it has lower formal charges on each atom as compared to structure (c): 0, −1 versus +1, −2.

Exercise
Salts containing the fulminate ion (CNO−) are used in explosive detonators. Draw three Lewis electron structures for
CNO− and use formal charges to predict which is more stable. (Note: N is the central atom.)
Answer:

The second structure is predicted to be more stable.

Drawing isomers of Lewis Structures

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Contributors
Anonymous
Layne Morsch (University of Illinois Springfield)
Three cases can be constructed that do not follow the octet rule, and as such, they are known as the exceptions to the octet
rule. Following the Octet Rule for Lewis Dot Structures leads to the most accurate depictions of stable molecular and
atomic structures and because of this we always want to use the octet rule when drawing Lewis Dot Structures. However, it
is hard to imagine that one rule could be followed by all molecules. There is always an exception, and in this case, three
exceptions. The octet rule is violated in these three scenarios:
1. When there are an odd number of valence electrons
2. When there are too few valence electrons
3. When there are too many valence electrons

Exception 1: Species with Odd Numbers of Electrons

The first exception to the Octet Rule is when there are an odd number of valence electrons. An example of this would be
Nitrogen (II) Oxide (NO ,refer to figure one). Nitrogen has 5 valence electrons while Oxygen has 6. The total would be 11
valence electrons to be used. The Octet Rule for this molecule is fulfilled in the above example, however that is with 10
valence electrons. The last one does not know where to go. The lone electron is called an unpaired electron. But where
should the unpaired electron go? The unpaired electron is usually placed in the Lewis Dot Structure so that each element in
the structure will have the lowest formal charge possible. The formal charge is the perceived charge on an individual atom
in a molecule when atoms do not contribute equal numbers of electrons to the bonds they participate in. The formula to
find a formal charge is:
Formal Charge= [# of valence e- the atom would have on its own] - [# of lone pair electrons on that atom]
- [# of bonds that atom participates in]
No formal charge at all is the most ideal situation. An example of a stable molecule with an odd number of valence
electrons would be nitrogen monoxide. Nitrogen monoxide has 11 valence electrons. If you need more information about
formal charges, see Lewis Structures. If we were to imagine nitrogen monoxide had ten valence electrons we would come
up with the Lewis Structure (Figure 8.7.1):

Figure 8.7.1. This is if Nitrogen monoxide has only ten valence electrons, which it does not.
Let's look at the formal charges of Figure 8.7.2 based on this Lewis structure. Nitrogen normally has five valence
electrons. In Figure 8.7.1, it has two lone pair electrons and it participates in two bonds (a double bond) with oxygen. This
results in nitrogen having a formal charge of +1. Oxygen normally has six valence electrons. In Figure 8.7.1, oxygen has
four lone pair electrons and it participates in two bonds with nitrogen. Oxygen therefore has a formal charge of 0. The
overall molecule here has a formal charge of +1 (+1 for nitrogen, 0 for oxygen. +1 + 0 = +1). However, if we add the
eleventh electron to nitrogen (because we want the molecule to have the lowest total formal charge), it will bring both the
nitrogen and the molecule's overall charges to zero, the most ideal formal charge situation. That is exactly what is done to
get the correct Lewis structure for nitrogen monoxide (Figure 8.7.2):

Figure 8.7.2. The proper Lewis structure for NO molecule

Free Radicals

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There are actually very few stable molecules with odd numbers of electrons that exist, since that unpaired electron is
willing to react with other unpaired electrons. Most odd electron species are highly reactive, which we call Free Radicals.
Because of their instability, free radicals bond to atoms in which they can take an electron from in order to become stable,
making them very chemically reactive. Radicals are found as both reactants and products, but generally react to form more
stable molecules as soon as they can. In order to emphasize the existence of the unpaired electron, radicals are denoted
with a dot in front of their chemical symbol as with , the hydroxyl radical. An example of a radical you may by
familiar with already is the gaseous chlorine atom, denoted . Interestingly, odd Number of Valence Electrons will result
in the molecule being paramagnetic.

Exception 2: Incomplete Octets

The second exception to the Octet Rule is when there are too few valence electrons that results in an incomplete Octet.
There are even more occasions where the octet rule does not give the most correct depiction of a molecule or ion. This is
also the case with incomplete octets. Species with incomplete octets are pretty rare and generally are only found in some
beryllium, aluminum, and boron compounds including the boron hydrides. Let's take a look at one such hydride, BH3
(Borane).
If one was to make a Lewis structure for BH3 following the basic strategies for drawing Lewis structures, one would
probably come up with this structure (Figure 8.7.3):

Figure 8.7.3
The problem with this structure is that boron has an incomplete octet; it only has six electrons around it. Hydrogen atoms
can naturally only have only 2 electrons in their outermost shell (their version of an octet), and as such there are no spare
electrons to form a double bond with boron. One might surmise that the failure of this structure to form complete octets
must mean that this bond should be ionic instead of covalent. However, boron has an electronegativity that is very similar
to hydrogen, meaning there is likely very little ionic character in the hydrogen to boron bonds, and as such this Lewis
structure, though it does not fulfill the octet rule, is likely the best structure possible for depicting BH3 with Lewis theory.
One of the things that may account for BH3's incomplete octet is that it is commonly a transitory species, formed
temporarily in reactions that involve multiple steps.
Let's take a look at another incomplete octet situation dealing with boron, BF3 (Boron trifluorine). Like with BH3, the
initial drawing of a Lewis structure of BF3 will form a structure where boron has only six electrons around it (Figure
8.7.4).

Figure 8.7.4
If you look Figure 8.7.4, you can see that the fluorine atoms possess extra lone pairs that they can use to make additional
bonds with boron, and you might think that all you have to do is make one lone pair into a bond and the structure will be
correct. If we add one double bond between boron and one of the fluorines we get the following Lewis Structure (Figure
8.7.5):

Figure 8.7.5

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Each fluorine has eight electrons, and the boron atom has eight as well! Each atom has a perfect octet, right? Not so fast.
We must examine the formal charges of this structure. The fluorine that shares a double bond with boron has six electrons
around it (four from its two lone pairs of electrons and one each from its two bonds with boron). This is one less electron
than the number of valence electrons it would have naturally (Group Seven elements have seven valence electrons), so it
has a formal charge of +1. The two flourines that share single bonds with boron have seven electrons around them (six
from their three lone pairs and one from their single bonds with boron). This is the same amount as the number of valence
electrons they would have on their own, so they both have a formal charge of zero. Finally, boron has four electrons around
it (one from each of its four bonds shared with fluorine). This is one more electron than the number of valence electrons
that boron would have on its own, and as such boron has a formal charge of -1.
This structure is supported by the fact that the experimentally determined bond length of the boron to fluorine bonds in
BF3 is less than what would be typical for a single bond (see Bond Order and Lengths). However, this structure contradicts
one of the major rules of formal charges: Negative formal charges are supposed to be found on the more electronegative
atom(s) in a bond, but in the structure depicted in Figure 8.7.5, a positive formal charge is found on fluorine, which not
only is the most electronegative element in the structure, but the most electronegative element in the entire periodic table (
). Boron on the other hand, with the much lower electronegativity of 2.0, has the negative formal charge in this
structure. This formal charge-electronegativity disagreement makes this double-bonded structure impossible.
However the large electronegativity difference here, as opposed to in BH3, signifies significant polar bonds between boron
and fluorine, which means there is a high ionic character to this molecule. This suggests the possibility of a semi-ionic
structure such as seen in Figure 8.7.6:

Figure 8.7.6
None of these three structures is the "correct" structure in this instance. The most "correct" structure is most likely a
resonance of all three structures: the one with the incomplete octet (Figure 8.7.4), the one with the double bond (Figure
8.7.5), and the one with the ionic bond (Figure 8.7.6). The most contributing structure is probably the incomplete octet
structure (due to Figure 8.7.5 being basically impossible and Figure 8.7.6 not matching up with the behavior and properties
of BF3). As you can see even when other possibilities exist, incomplete octets may best portray a molecular structure.
As a side note, it is important to note that BF3 frequently bonds with a F- ion in order to form BF4- rather than staying as
BF3. This structure completes boron's octet and it is more common in nature. This exemplifies the fact that incomplete
octets are rare, and other configurations are typically more favorable, including bonding with additional ions as in the case
of BF3 .
Example 8.7.1:

Draw the Lewis structure for boron trifluoride (BF3).

SOLUTION
1. Add electrons (3*7) + 3 = 24
2. Draw connectivities:

3. Add octets to outer atoms:

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4. Add extra electrons (24-24=0) to central atom:

5. Does central electron have octet?

NO. It has 6 electrons
Add a multiple bond (double bond) to see if central atom can achieve an octet:

6. The central Boron now has an octet (there would be three resonance Lewis structures)
However...
In this structure with a double bond the fluorine atom is sharing extra electrons with the boron.
The fluorine would have a '+' partial charge, and the boron a '-' partial charge, this is inconsistent with the electronegativities of fluorine
and boron.
Thus, the structure of BF3, with single bonds, and 6 valence electrons around the central boron is the most likely structure
BF3 reacts strongly with compounds which have an unshared pair of electrons which can be used to form a bond with the boron:

Exception 3: Expanded Valence Shells

More common than incomplete octets are expanded octets where the central atom in a Lewis structure has more than eight
electrons in its valence shell. In expanded octets, the central atom can have ten electrons, or even twelve. Molecules with
expanded octets involve highly electronegative terminal atoms, and a nonmetal central atom found in the third period or
below, which those terminal atoms bond to. For example, is a legitimate compound (whereas ) is not:

Note

Expanded valence shells are observed only for elements in period 3 (i.e. n=3) and beyond

The 'octet' rule is based upon available ns and np orbitals for valence electrons (2 electrons in the s orbitals, and 6 in the p
orbitals). Beginning with the n=3 principle quantum number, the d orbitals become available (l=2). The orbital diagram for
the valence shell of phosphorous is:

Hence, the third period elements occasionally exceed the octet rule by using their empty d orbitals to accommodate
additional electrons. Size is also an important consideration:

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 The larger the central atom, the larger the number of electrons which can surround it
Expanded valence shells occur most often when the central atom is bonded to small electronegative atoms, such as F,
Cl and O.
There is currently much scientific exploration and inquiry into the reason why expanded valence shells are found. The top
area of interest is figuring out where the extra pair(s) of electrons are found. Many chemists think that there is not a very
large energy difference between the 3p and 3d orbitals, and as such it is plausible for extra electrons to easily fill the 3d
orbital when an expanded octet is more favorable than having a complete octet. This matter is still under hot debate,
however and there is even debate as to what makes an expanded octet more favorable than a configuration that follows the
octet rule.
One of the situations where expanded octet structures are treated as more favorable than Lewis structures that follow the
octet rule is when the formal charges in the expanded octet structure are smaller than in a structure that adheres to the octet
rule, or when there are less formal charges in the expanded octet than in the structure a structure that adheres to the octet
rule.
Example 8.7.2: The ion

Such is the case for the sulfate ion, SO4-2. A strict adherence to the octet rule forms the following Lewis structure:

Figure 8.7.12
If we look at the formal charges on this molecule, we can see that all of the oxygen atoms have seven electrons around them (six from the
three lone pairs and one from the bond with sulfur). This is one more electron than the number of valence electrons then they would have
normally, and as such each of the oxygens in this structure has a formal charge of -1. Sulfur has four electrons around it in this structure (one
from each of its four bonds) which is two electrons more than the number of valence electrons it would have normally, and as such it carries a
formal charge of +2.
If instead we made a structure for the sulfate ion with an expanded octet, it would look like this:

Figure 8.7.13
Looking at the formal charges for this structure, the sulfur ion has six electrons around it (one from each of its bonds). This is the same
amount as the number of valence electrons it would have naturally. This leaves sulfur with a formal charge of zero. The two oxygens that
have double bonds to sulfur have six electrons each around them (four from the two lone pairs and one each from the two bonds with sulfur).
This is the same amount of electrons as the number of valence electrons that oxygen atoms have on their own, and as such both of these
oxygen atoms have a formal charge of zero. The two oxygens with the single bonds to sulfur have seven electrons around them in this
structure (six from the three lone pairs and one from the bond to sulfur). That is one electron more than the number of valence electrons that
oxygen would have on its own, and as such those two oxygens carry a formal charge of -1. Remember that with formal charges, the goal is to
keep the formal charges (or the difference between the formal charges of each atom) as small as possible. The number of and values of the
formal charges on this structure (-1 and 0 (difference of 1) in Figure 8.7.12, as opposed to +2 and -1 (difference of 3) in Figure 8.7.12) is
significantly lower than on the structure that follows the octet rule, and as such an expanded octet is plausible, and even preferred to a normal
octet, in this case.

Example 8.7.3: The Ion

Draw the Lewis structure for ion.

SOLUTION
1. Count up the valence electrons: 7+(4*7)+1 = 36 electrons

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2. Draw the connectivities:

3. Add octet of electrons to outer atoms:

4. Add extra electrons (36-32=4) to central atom:

5. The ICl4- ion thus has 12 valence electrons around the central Iodine (in the 5d orbitals)

Expanded Lewis structures are also plausible depictions of molecules when experimentally determined bond lengths
suggest partial double bond characters even when single bonds would already fully fill the octet of the central atom.
Despite the cases for expanded octets, as mentioned for incomplete octets, it is important to keep in mind that, in general,
the octet rule applies.

Contributors
Mike Blaber (Florida State University)

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1.5: Resonance Forms
Resonance Structures
Sometimes, even when formal charges are considered, the bonding in some molecules or ions cannot be described by a
single Lewis structure. Such is the case for ozone (O3), an allotrope of oxygen with a V-shaped structure and an O–O–O
angle of 117.5°.

O3

1. We know that ozone has a V-shaped structure, so one O atom is central:

2. Each O atom has 6 valence electrons, for a total of 18 valence electrons.

3. Assigning one bonding pair of electrons to each oxygen–oxygen bond gives

with 14 electrons left over.

4. If we place three lone pairs of electrons on each terminal oxygen, we obtain

and have 2 electrons left over.

5. At this point, both terminal oxygen atoms have octets of electrons. We therefore place the last 2 electrons on the central
atom:

6. The central oxygen has only 6 electrons. We must convert one lone pair on a terminal oxygen atom to a bonding pair of
electrons—but which one? Depending on which one we choose, we obtain either

Which is correct? In fact, neither is correct. Both predict one O–O single bond and one O=O double bond. As you will
learn in Section 4.8, if the bonds were of different types (one single and one double, for example), they would have
different lengths. It turns out, however, that both O–O bond distances are identical, 127.2 pm, which is shorter than a
typical O–O single bond (148 pm) and longer than the O=O double bond in O2 (120.7 pm).
Equivalent Lewis dot structures, such as those of ozone, are called resonance structures . The position of the atoms is the
same in the various resonance structures of a compound, but the position of the electrons is different. Double-headed
arrows link the different resonance structures of a compound:

Before the development of quantum chemistry it was thought that the double-headed arrow indicates that the actual
electronic structure is an average of those shown, or that the molecule oscillates between the two structures. Today we

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know that the electrons involved in the double bonds occupy an orbital that extends over all three oxygen molecules,
combining p orbitals on all three.

Figure 5.3.4 The resonance structure of ozone involves a molecular orbital extending all three oxygen atoms. In ozone, a
molecular orbital extending over all three oxygen atoms is formed from three atom centered pz orbitals. Similar molecular
orbitals are found in every resonance structure.

We will discuss the formation of these molecular orbitals in the next chapter but it is important to understand that
resonance structures are based on molecular orbitals not averages of different bonds between atoms. We describe the
electrons in such molecular orbitals as being delocalized, that is they cannot be assigned to a bond between two atoms.

Note the Pattern

When it is possible to write more than one equivalent resonance structure for a molecule or ion, the actual structure
involves a molecular orbital which is a linear combination of atomic orbitals from each of the atoms.

CO32−
Like ozone, the electronic structure of the carbonate ion cannot be described by a single Lewis electron structure. Unlike
O3, though, the Lewis structures describing CO32− has three equivalent representations.
1. Because carbon is the least electronegative element, we place it in the central position:

2. Carbon has 4 valence electrons, each oxygen has 6 valence electrons, and there are 2 more for the −2 charge. This gives
4 + (3 × 6) + 2 = 24 valence electrons.
3. Six electrons are used to form three bonding pairs between the oxygen atoms and the carbon:

4. We divide the remaining 18 electrons equally among the three oxygen atoms by placing three lone pairs on each and
indicating the −2 charge:

5. No electrons are left for the central atom.

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6. At this point, the carbon atom has only 6 valence electrons, so we must take one lone pair from an oxygen and use it to
form a carbon–oxygen double bond. In this case, however, there are three possible choices:

As with ozone, none of these structures describes the bonding exactly. Each predicts one carbon–oxygen double bond and
two carbon–oxygen single bonds, but experimentally all C–O bond lengths are identical. We can write resonance structures
(in this case, three of them) for the carbonate ion:

As the case for ozone, the actual structure involves the formation of a molecular orbital from pz orbitals centered on each
atom and sitting above and below the plane of the CO32− ion.

Example
Benzene is a common organic solvent that was previously used in gasoline; it is no longer used for this purpose, however,
because it is now known to be a carcinogen. The benzene molecule (C6H6) consists of a regular hexagon of carbon atoms,
each of which is also bonded to a hydrogen atom. Use resonance structures to describe the bonding in benzene.
Given: molecular formula and molecular geometry
Asked for: resonance structures
Strategy:
A Draw a structure for benzene illustrating the bonded atoms. Then calculate the number of valence electrons used in this
drawing.
B Subtract this number from the total number of valence electrons in benzene and then locate the remaining electrons such
that each atom in the structure reaches an octet.
C Draw the resonance structures for benzene.
Solution:
A Each hydrogen atom contributes 1 valence electron, and each carbon atom contributes 4 valence electrons, for a total of
(6 × 1) + (6 × 4) = 30 valence electrons. If we place a single bonding electron pair between each pair of carbon atoms and
between each carbon and a hydrogen atom, we obtain the following:

Each carbon atom in this structure has only 6 electrons and has a formal charge of +1, but we have used only 24 of the 30
valence electrons.
B If the 6 remaining electrons are uniformly distributed pairwise on alternate carbon atoms, we obtain the following:

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Three carbon atoms now have an octet configuration and a formal charge of −1, while three carbon atoms have only 6
electrons and a formal charge of +1. We can convert each lone pair to a bonding electron pair, which gives each atom an
octet of electrons and a formal charge of 0, by making three C=C double bonds.
C There are, however, two ways to do this:

Each structure has alternating double and single bonds, but experimentation shows that each carbon–carbon bond in
benzene is identical, with bond lengths (139.9 pm) intermediate between those typically found for a C–C single bond (154
pm) and a C=C double bond (134 pm). We can describe the bonding in benzene using the two resonance structures, but the
actual electronic structure is an average of the two. The existence of multiple resonance structures for aromatic
hydrocarbons like benzene is often indicated by drawing either a circle or dashed lines inside the hexagon:

This combination of p orbitals for benzene can be visualized as a ring with a node in the plane of the carbon atoms.
Exercise
The sodium salt of nitrite is used to relieve muscle spasms. Draw two resonance structures for the nitrite ion (NO2−).
Answer:

Resonance structures are particularly common in oxoanions of the p-block elements, such as sulfate and phosphate, and in
aromatic hydrocarbons, such as benzene and naphthalene.

Rules for estimating stability of resonance

structures
1. The greater the number of covalent bonds, the greater the stability since more atoms will have complete octets
2. The structure with the least number of formal charges is more stable
3. The structure with the least separation of formal charge is more stable
4. A structure with a negative charge on the more electronegative atom will be more stable
5. Positive charges on the least electronegative atom (most electropositive) is more stable
6. Resonance forms that are equivalent have no difference in stability and contribute equally. (eg. benzene)

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The above resonance structures show that the electrons are delocalized within the molecule and through this process the
molecule gains extra stability. Ozone with both of its opposite charges creates a neutral molecule and through resonance it
is a stable molecule. The extra electron that created the negative charge on either terminal oxygen can be delocalized by
resonance through the terminal oxygens.
Benzene is an extremely stable molecule and it is accounted for its geometry and molecular orbital interaction, but most
importantly it's due to its resonance structures. The delocalized electrons in the benzene ring make the molecule very stable
and with its characteristics of a nucleophile, it will react with a strong electrophile only and after the first reactivity, the
substituted benzene will depend on its resonance to direct the next position for the reaction to add a second substituent.
The next molecule, the Amide, is a very stable molecule that is present in most biological systems, mainly in proteins. By
studies of NMR spectroscopy and X-Ray crystallography it is confirmed that the stability of the amide is due to resonance
which through molecular orbital interaction creates almost a double bond between the Nitrogen and the carbon.
Example: Multiple Resonance of other Molecules

Molecules with more than one resonance form

Some structural resonance conformations are the major contributor or the dominant forms that the molecule exists. For example, if we look at
the above rules for estimating the stability of a molecule, we see that for the third molecule the first and second forms are the major
contributors for the overall stability of the molecule. The nitrogen is more electronegative than carbon so, it can handle the negative charge
more than carbon. A carbon with a negative charge is the least favorable conformation for the molecule to exist, so the last resonance form
contributes very little for the stability of the Ion.

The Hybrid Resonance forms show the different Lewis structures with the electron been delocalized. This is very important for the reactivity
of chloro-benzene because in the presence of an electrophile it will react and the formation of another bond will be directed and determine by
resonance. The long pair of electrons delocalized in the aromatic substituted ring is where it can potentially form a new bond with an
electrophile, as it is shown there are three possible places that reactivity can take place, the first to react will take place at the para position
with respect to the chloro substituent and then to either ortho position.

Contributors
Sharon Wei (UCD), Liza Chu (UCD)

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1.6: Atomic Orbitals: A Quantum Mechanical Description of Electrons Around
the Nucleus
Objectives

After completing this section, you should be able to

1. describe the physical significance of an orbital.
2. list the atomic orbitals from 1s to 3d in order of increasing energy.
3. sketch the shapes of s and p orbitals.

Key Terms
Make certain that you can define, and use in context, the key terms below.
nodal plane
node
orbital
quantum mechanics
wave function

Atomic Orbitals
An orbital is the quantum mechanical refinement of Bohr’s orbit. In contrast to his concept of a simple circular orbit with a
fixed radius, orbitals are mathematically derived regions of space with different probabilities of having an electron.
One way of representing electron probability distributions was illustrated in Figure 6.5.2 for the 1s orbital of hydrogen.
Because Ψ2 gives the probability of finding an electron in a given volume of space (such as a cubic picometer), a plot of
Ψ2 versus distance from the nucleus (r) is a plot of the probability density. The 1s orbital is spherically symmetrical, so the
probability of finding a 1s electron at any given point depends only on its distance from the nucleus. The probability
density is greatest at r = 0 (at the nucleus) and decreases steadily with increasing distance. At very large values of r, the
electron probability density is very small but not zero.
In contrast, we can calculate the radial probability (the probability of finding a 1s electron at a distance r from the nucleus)
by adding together the probabilities of an electron being at all points on a series of x spherical shells of radius r1, r2, r3,…,
rx − 1, rx. In effect, we are dividing the atom into very thin concentric shells, much like the layers of an onion (part (a) in
Figure 1.2.1), and calculating the probability of finding an electron on each spherical shell. Recall that the electron
probability density is greatest at r = 0 (part (b) in Figure 1.2.1), so the density of dots is greatest for the smallest spherical
shells in part (a) in Figure 1.2.1. In contrast, the surface area of each spherical shell is equal to 4πr2, which increases very
rapidly with increasing r (part (c) in Figure 1.2.1). Because the surface area of the spherical shells increases more rapidly
with increasing r than the electron probability density decreases, the plot of radial probability has a maximum at a
particular distance (part (d) in Figure 1.2.1). Most important, when r is very small, the surface area of a spherical shell is so
small that the total probability of finding an electron close to the nucleus is very low; at the nucleus, the electron
probability vanishes (part (d) in Figure 1.2.1).

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 Figure 1.2.1 Most Probable Radius for the Electron in the Ground State of the Hydrogen Atom. (a) Imagine dividing the
atom’s total volume into very thin concentric shells as shown in the onion drawing. (b) A plot of electron probability
density Ψ2 versus r shows that the electron probability density is greatest at r = 0 and falls off smoothly with increasing r.
The density of the dots is therefore greatest in the innermost shells of the onion. (c) The surface area of each shell, given by
4πr2, increases rapidly with increasing r. (d) If we count the number of dots in each spherical shell, we obtain the total
probability of finding the electron at a given value of r. Because the surface area of each shell increases more rapidly with
increasing r than the electron probability density decreases, a plot of electron probability versus r (the radial probability)
shows a peak. This peak corresponds to the most probable radius for the electron, 52.9 pm, which is exactly the radius
predicted by Bohr’s model of the hydrogen atom.
For the hydrogen atom, the peak in the radial probability plot occurs at r = 0.529 Å (52.9 pm), which is exactly the radius
calculated by Bohr for the n = 1 orbit. Thus the most probable radius obtained from quantum mechanics is identical to the
radius calculated by classical mechanics. In Bohr’s model, however, the electron was assumed to be at this distance 100%
of the time, whereas in the Schrödinger model, it is at this distance only some of the time. The difference between the two
models is attributable to the wavelike behavior of the electron and the Heisenberg uncertainty principle.
Figure 1.2.2 compares the electron probability densities for the hydrogen 1s, 2s, and 3s orbitals. Note that all three are
spherically symmetrical. For the 2s and 3s orbitals, however (and for all other s orbitals as well), the electron probability
density does not fall off smoothly with increasing r. Instead, a series of minima and maxima are observed in the radial
probability plots (part (c) in Figure 1.2.2). The minima correspond to spherical nodes (regions of zero electron probability),
which alternate with spherical regions of nonzero electron probability.

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 Figure 1.2.2: Probability Densities for the 1s, 2s, and 3s Orbitals of the Hydrogen Atom. (a) The electron probability
density in any plane that contains the nucleus is shown. Note the presence of circular regions, or nodes, where the
probability density is zero. (b) Contour surfaces enclose 90% of the electron probability, which illustrates the different
sizes of the 1s, 2s, and 3s orbitals. The cutaway drawings give partial views of the internal spherical nodes. The orange
color corresponds to regions of space where the phase of the wave function is positive, and the blue color corresponds to
regions of space where the phase of the wave function is negative. (c) In these plots of electron probability as a function of
distance from the nucleus (r) in all directions (radial probability), the most probable radius increases as n increases, but
the 2s and 3s orbitals have regions of significant electron probability at small values of r.

s Orbitals
Three things happen to s orbitals as n increases (Figure 1.2.2): Edit section

1. They become larger, extending farther from the nucleus.

2. They contain more nodes. This is similar to a standing wave that has regions of significant amplitude separated by
nodes, points with zero amplitude.
3. For a given atom, the s orbitals also become higher in energy as n increases because of their increased distance from
the nucleus.
Orbitals are generally drawn as three-dimensional surfaces that enclose 90% of the electron density, as was shown for the
hydrogen 1s, 2s, and 3s orbitals in part (b) in Figure 1.2.2. Although such drawings show the relative sizes of the orbitals,
they do not normally show the spherical nodes in the 2s and 3s orbitals because the spherical nodes lie inside the 90%
surface. Fortunately, the positions of the spherical nodes are not important for chemical bonding.

p Orbitals Edit section

Only s orbitals are spherically symmetrical. As the value of l increases, the number of orbitals in a given subshell
increases, and the shapes of the orbitals become more complex. Because the 2p subshell has l = 1, with three values of ml
(−1, 0, and +1), there are three 2p orbitals.

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 Figure 1.2.3: Electron Probability Distribution for a Hydrogen 2p Orbital. The nodal plane of zero electron density
separates the two lobes of the 2p orbital. As in Figure 1.2.2, the colors correspond to regions of space where the phase of
the wave function is positive (orange) and negative (blue).
The electron probability distribution for one of the hydrogen 2p orbitals is shown in Figure 1.2.3. Because this orbital has
two lobes of electron density arranged along the z axis, with an electron density of zero in the xy plane (i.e., the xy plane is
a nodal plane), it is a 2pz orbital. As shown in Figure 1.2.4, the other two 2p orbitals have identical shapes, but they lie
along the x axis (2px) and y axis (2py), respectively. Note that each p orbital has just one nodal plane. In each case, the
phase of the wave function for each of the 2p orbitals is positive for the lobe that points along the positive axis and
negative for the lobe that points along the negative axis. It is important to emphasize that these signs correspond to the
phase of the wave that describes the electron motion, not to positive or negative charges.

Figure 1.2.4 The Three Equivalent 2p Orbitals of the Hydrogen Atom

The surfaces shown enclose 90% of the total electron probability for the 2px, 2py, and 2pz orbitals. Each orbital is oriented
along the axis indicated by the subscript and a nodal plane that is perpendicular to that axis bisects each 2p orbital. The
phase of the wave function is positive (orange) in the region of space where x, y, or z is positive and negative (blue) where
x, y, or z is negative.
Just as with the s orbitals, the size and complexity of the p orbitals for any atom increase as the principal quantum number
n increases. The shapes of the 90% probability surfaces of the 3p, 4p, and higher-energy p orbitals are, however, essentially
the same as those shown in Figure 1.2.4.
he electron configuration of an atom is the representation of the arrangement of electrons distributed among the orbital
shells and subshells. Commonly, the electron configuration is used to describe the orbitals of an atom in its ground state,
but it can also be used to represent an atom that has ionized into a cation or anion by compensating with the loss of or gain
of electrons in their subsequent orbitals. Many of the physical and chemical properties of elements can be correlated to
their unique electron configurations. The valence electrons, electrons in the outermost shell, are the determining factor for
the unique chemistry of the element.

Electron Configurations Edit section

Before assigning the electrons of an atom into orbitals, one must become familiar with the basic concepts of electron
configurations. Every element on the periodic table consists of atoms, which are composed of protons, neutrons, and
electrons. Electrons exhibit a negative charge and are found around the nucleus of the atom in electron orbitals, defined as
the volume of space in which the electron can be found within 95% probability. The four different types of orbitals (s,p,d,

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and f) have different shapes, and one orbital can hold a maximum of two electrons. The p, d, and f orbitals have different
sublevels, thus can hold more electrons.
As stated, the electron configuration of each element is unique to its position on the periodic table. The energy level is
determined by the period and the number of electrons is given by the atomic number of the element. Orbitals on different
energy levels are similar to each other, but they occupy different areas in space. The 1s orbital and 2s orbital both have the
characteristics of an s orbital (radial nodes, spherical volume probabilities, can only hold two electrons, etc.) but, as they
are found in different energy levels, they occupy different spaces around the nucleus. Each orbital can be represented by
specific blocks on the periodic table. The s-block is the region of the alkali metals including helium (Groups 1 & 2), the d-
block are the transition metals (Groups 3 to 12), the p-block are the main group elements from Groups 13 to 18, and the f-
block are the lanthanides and actinides series.

Using the periodic table to determine the electron configurations of atoms is key, but also keep in mind that there are
certain rules to follow when assigning electrons to different orbitals. The periodic table is an incredibly helpful tool in
writing electron configurations. For more information on how electron configurations and the periodic table are linked,
visit the Connecting Electrons to the Periodic Table module.

Rules for Assigning Electron Orbitals Edit section

Occupation of Orbitals Edit section

Electrons fill orbitals in a way to minimize the energy of the atom. Therefore, the electrons in an atom fill the principal
energy levels in order of increasing energy (the electrons are getting farther from the nucleus). The order of levels filled
looks like this:
1s, 2s, 2p, 3s, 3p, 4s, 3d, 4p, 5s, 4d, 5p, 6s, 4f, 5d, 6p, 7s, 5f, 6d, and 7p
One way to remember this pattern, probably the easiest, is to refer to the periodic table and remember where each orbital
block falls to logically deduce this pattern. Another way is to make a table like the one below and use vertical lines to
determine which subshells correspond with each other.

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The number of valence electrons
The number of valence electrons of an element can be determined by the periodic table group (vertical column) in which
the element is categorized. With the exception of groups 3–12 (the transition metals), the units digit of the group number
identifies how many valence electrons are associated with a neutral atom of an element listed under that particular column.

The periodic table of the chemical elements

Periodic table group Valence electrons

Group 1: alkali metals 1

Group 2: alkaline earth metals 2

Groups 3-12: transition metals 2* (The 4s shell is complete and cannot hold any more electrons)
Group 13: boron group 3
Group 14: carbon group 4
Group 15: pnictogens 5
Group 16: chalcogens 6
Group 17: halogens 7
Group 18: noble gases 8**

* The general method for counting valence electrons is generally not useful for transition metals. Instead the modified d
electron count method is used.
** Except for helium, which has only two valence electrons.

Exercises
Questions

Q1.2.1
Label the following orbitals:

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Solutions

S1.2.1

1 = 3s ; 2 = 2pz

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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1.7: Molecular Orbitals and Covalent Bonding
Learning Objectives
To use molecular orbital theory to predict bond order

None of the approaches we have described so far can adequately explain why some compounds are colored and others are
not, why some substances with unpaired electrons are stable, and why others are effective semiconductors. These
approaches also cannot describe the nature of resonance. Such limitations led to the development of a new approach to
bonding in which electrons are not viewed as being localized between the nuclei of bonded atoms but are instead
delocalized throughout the entire molecule. Just as with the valence bond theory, the approach we are about to discuss is
based on a quantum mechanical model.
Previously, we described the electrons in isolated atoms as having certain spatial distributions, called orbitals, each with a
particular orbital energy. Just as the positions and energies of electrons in atoms can be described in terms of atomic
orbitals (AOs), the positions and energies of electrons in molecules can be described in terms of molecular orbitals (MOs)
A particular spatial distribution of electrons in a molecule that is associated with a particular orbital energy.—a spatial
distribution of electrons in a molecule that is associated with a particular orbital energy. As the name suggests, molecular
orbitals are not localized on a single atom but extend over the entire molecule. Consequently, the molecular orbital
approach, called molecular orbital theory is a delocalized approach to bonding.

Molecular Orbital Theory: A Delocalized Bonding Approach

Although the molecular orbital theory is computationally demanding, the principles on which it is based are similar to
those we used to determine electron configurations for atoms. The key difference is that in molecular orbitals, the electrons
are allowed to interact with more than one atomic nucleus at a time. Just as with atomic orbitals, we create an energy-level
diagram by listing the molecular orbitals in order of increasing energy. We then fill the orbitals with the required number of
valence electrons according to the Pauli principle. This means that each molecular orbital can accommodate a maximum of
two electrons with opposite spins.

Molecular Orbitals Involving Only ns Atomic Orbitals

We begin our discussion of molecular orbitals with the simplest molecule, H2, formed from two isolated hydrogen atoms,
each with a 1s1 electron configuration. As we explained in Chapter 9, electrons can behave like waves. In the molecular
orbital approach, the overlapping atomic orbitals are described by mathematical equations called wave functions. The 1s
atomic orbitals on the two hydrogen atoms interact to form two new molecular orbitals, one produced by taking the sum of
the two H 1s wave functions, and the other produced by taking their difference:
M O(1) = AO(atom A) + AO(atomB)
(1.7.1)
M O(1) = AO(atom A) − AO(atomB)

The molecular orbitals created from Equation 1.7.1 are called linear combinations of atomic orbitals (LCAOs) Molecular
orbitals created from the sum and the difference of two wave functions (atomic orbitals). A molecule must have as many
molecular orbitals as there are atomic orbitals.

A molecule must have as many molecular orbitals as there are atomic orbitals.

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 Figure 1.7.1 : Molecular Orbitals for the H2 Molecule. (a) This diagram shows the formation of a bonding σ1s molecular
orbital for H2 as the sum of the wave functions (Ψ) of two H 1s atomic orbitals. (b) This plot of the square of the wave
function (Ψ2) for the bonding σ1s molecular orbital illustrates the increased electron probability density between the two
hydrogen nuclei. (Recall that the probability density is proportional to the square of the wave function.) (c) This diagram
shows the formation of an antibonding σ molecular orbital for H2 as the difference of the wave functions (Ψ) of two H 1s
∗
1s

atomic orbitals. (d) This plot of the square of the wave function (Ψ2) for the σ antibonding molecular orbital illustrates
∗
1s

the node corresponding to zero electron probability density between the two hydrogen nuclei.
Adding two atomic orbitals corresponds to constructive interference between two waves, thus reinforcing their intensity;
the internuclear electron probability density is increased. The molecular orbital corresponding to the sum of the two H 1s
orbitals is called a σ1s combination (pronounced “sigma one ess”) (part (a) and part (b) in Figure 1.7.1). In a sigma (σ)
orbital, (i.e., a bonding molecular orbital in which the electron density along the internuclear axis and between the nuclei
has cylindrical symmetry), the electron density along the internuclear axis and between the nuclei has cylindrical
symmetry; that is, all cross-sections perpendicular to the internuclear axis are circles. The subscript 1s denotes the atomic
orbitals from which the molecular orbital was derived: The ≈ sign is used rather than an = sign because we are ignoring
certain constants that are not important to our argument.
σ1s ≈ 1s (A) + 1s (B) (1.7.2)

Conversely, subtracting one atomic orbital from another corresponds to destructive interference between two waves, which
reduces their intensity and causes a decrease in the internuclear electron probability density (part (c) and part (d) in Figure
1.7.1). The resulting pattern contains a node where the electron density is zero. The molecular orbital corresponding to the

difference is called σ (“sigma one ess star”). In a sigma star (σ*) orbital An antibonding molecular orbital in which there
∗
1s

is a region of zero electron probability (a nodal plane) perpendicular to the internuclear axis., there is a region of zero
electron probability, a nodal plane, perpendicular to the internuclear axis:
⋆
σ ≈ 1s (A) − 1s (B) (1.7.3)
1s

The electron density in the σ1s molecular orbital is greatest between the two positively charged nuclei, and the resulting
electron–nucleus electrostatic attractions reduce repulsions between the nuclei. Thus the σ1s orbital represents a bonding
molecular orbital. A molecular orbital that forms when atomic orbitals or orbital lobes with the same sign interact to give
increased electron probability between the nuclei due to constructive reinforcement of the wave functions. In contrast,
electrons in the σ orbital are generally found in the space outside the internuclear region. Because this allows the
⋆
1s

positively charged nuclei to repel one another, the σ orbital is an antibonding molecular orbital (a molecular orbital that
⋆
1s

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forms when atomic orbitals or orbital lobes of opposite sign interact to give decreased electron probability between the
nuclei due to destructive reinforcement of the wave functions).

Antibonding orbitals contain a node perpendicular to the internuclear axis;

bonding orbitals do not.
Energy-Level Diagrams
Because electrons in the σ1s orbital interact simultaneously with both nuclei, they have a lower energy than electrons that
interact with only one nucleus. This means that the σ1s molecular orbital has a lower energy than either of the hydrogen 1s
atomic orbitals. Conversely, electrons in the σ orbital interact with only one hydrogen nucleus at a time. In addition, they
⋆
1s

are farther away from the nucleus than they were in the parent hydrogen 1s atomic orbitals. Consequently, the σ ⋆
1s

molecular orbital has a higher energy than either of the hydrogen 1s atomic orbitals. The σ1s (bonding) molecular orbital is
stabilized relative to the 1s atomic orbitals, and the σ (antibonding) molecular orbital is destabilized. The relative energy
⋆
1s

levels of these orbitals are shown in the energy-level diagram (a schematic drawing that compares the energies of the
molecular orbitals (bonding, antibonding, and nonbonding) with the energies of the parent atomic orbitals) in Figure 1.7.2

Figure 1.7.2 : Molecular Orbital Energy-Level Diagram for H2. The two available electrons (one from each H atom) in this
diagram fill the bonding σ1s molecular orbital. Because the energy of the σ1s molecular orbital is lower than that of the two
H 1s atomic orbitals, the H2 molecule is more stable (at a lower energy) than the two isolated H atoms.

A bonding molecular orbital is always lower in energy (more stable) than the
component atomic orbitals, whereas an antibonding molecular orbital is always
higher in energy (less stable).
To describe the bonding in a homonuclear diatomic molecule (a molecule that consists of two atoms of the same element)
such as H2, we use molecular orbitals; that is, for a molecule in which two identical atoms interact, we insert the total
number of valence electrons into the energy-level diagram (Figure 1.7.2). We fill the orbitals according to the Pauli
principle and Hund’s rule: each orbital can accommodate a maximum of two electrons with opposite spins, and the orbitals
are filled in order of increasing energy. Because each H atom contributes one valence electron, the resulting two electrons
are exactly enough to fill the σ1s bonding molecular orbital. The two electrons enter an orbital whose energy is lower than
that of the parent atomic orbitals, so the H2 molecule is more stable than the two isolated hydrogen atoms. Thus molecular
orbital theory correctly predicts that H2 is a stable molecule. Because bonds form when electrons are concentrated in the
space between nuclei, this approach is also consistent with our earlier discussion of electron-pair bonds.

Bond Order in Molecular Orbital Theory

In the Lewis electron structures, the number of electron pairs holding two atoms together was called the bond order. In the
molecular orbital approach, bond order One-half the net number of bonding electrons in a molecule. is defined as one-half
the net number of bonding electrons:
number of bonding electrons − number of antibonding electrons
bond order = (1.7.4)
2

To calculate the bond order of H2, we see from Figure 1.7.2 that the σ1s (bonding) molecular orbital contains two
electrons, while the σ (antibonding) molecular orbital is empty. The bond order of H2 is therefore
⋆
1s

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 2 −0
=1 (1.7.5)
2

This result corresponds to the single covalent bond predicted by Lewis dot symbols. Thus molecular orbital theory and the
Lewis electron-pair approach agree that a single bond containing two electrons has a bond order of 1. Double and triple
bonds contain four or six electrons, respectively, and correspond to bond orders of 2 and 3. We can use energy-level
diagrams such as the one in Figure 1.7.2 to describe the bonding in other pairs of atoms and ions where n = 1, such as the
H2+ ion, the He2+ ion, and the He2 molecule. Again, we fill the lowest-energy molecular orbitals first while being sure not
to violate the Pauli principle or Hund’s rule.

Figure 1.7.3 : Molecular Orbital Energy-Level Diagrams for Diatomic Molecules with Only 1s Atomic Orbitals. (a) The
H2+ ion, (b) the He2+ ion, and (c) the He2 molecule are shown here.
Figure 1.7.3a shows the energy-level diagram for the H2+ ion, which contains two protons and only one electron. The
single electron occupies the σ1s bonding molecular orbital, giving a (σ1s)1 electron configuration. The number of electrons
in an orbital is indicated by a superscript. In this case, the bond order is
1 −0
= 1/2 (1.7.6)
2

Because the bond order is greater than zero, the H2+ ion should be more stable than an isolated H atom and a proton. We
can therefore use a molecular orbital energy-level diagram and the calculated bond order to predict the relative stability of
species such as H2+. With a bond order of only 1/2 the bond in H2+ should be weaker than in the H2 molecule, and the H–H
bond should be longer. As shown in Table 1.7.1, these predictions agree with the experimental data.
Figure 1.7.3b is the molecular orbital energy-level diagram for He2+. This ion has a total of three valence electrons.
Because the first two electrons completely fill the σ1s molecular orbital, the Pauli principle states that the third electron
1
must be in the σ
1s
⋆
antibonding orbital, giving a 2
(σ1s ) (σ
⋆
1s
) electron configuration. This electron configuration gives a
bond order of
2 −1
= 1/2 (1.7.7)
2

As with H2+, the He2+ ion should be stable, but the He–He bond should be weaker and longer than in H2. In fact, the He2+
ion can be prepared, and its properties are consistent with our predictions (Table 1.7.1).
Table 1.7.1 : Molecular Orbital Electron Configurations, Bond Orders, Bond Lengths, and Bond Energies for some Simple Homonuclear
Diatomic Molecules and Ions
Molecule or Ion Electron Configuration Bond Order Bond Length (pm) Bond Energy (kJ/mol)

H2+ (σ1s)1 1/2 106 269

H2 (σ1s)2 1 74 436

He2+
1
2
(σ1s ) (σ
1s
⋆
) 1/2 108 251
2
He2 2
(σ1s ) (σ
1s
⋆
) 0 not observed not observed

Finally, we examine the He2 molecule, formed from two He atoms with 1s2 electron configurations. Figure 1.7.3c is the
molecular orbital energy-level diagram for He2. With a total of four valence electrons, both the σ1s bonding and σ ⋆
1s
2 2
antibonding orbitals must contain two electrons. This gives a (σ ) (σ ) electron configuration, with a predicted bond
1s
⋆
1s

order of (2 − 2) ÷ 2 = 0, which indicates that the He2 molecule has no net bond and is not a stable species. Experiments
show that the He2 molecule is actually less stable than two isolated He atoms due to unfavorable electron–electron and
nucleus–nucleus interactions.

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In molecular orbital theory, electrons in antibonding orbitals effectively cancel the stabilization resulting from electrons in
bonding orbitals. Consequently, any system that has equal numbers of bonding and antibonding electrons will have a bond
order of 0, and it is predicted to be unstable and therefore not to exist in nature. In contrast to Lewis electron structures and
the valence bond approach, molecular orbital theory is able to accommodate systems with an odd number of electrons,
such as the H2+ ion.

In contrast to Lewis electron structures and the valence bond approach, molecular
orbital theory can accommodate systems with an odd number of electrons.

Molecular Orbital Theory

Example 1.7.1

Use a molecular orbital energy-level diagram, such as those in Figure 1.7.2, to predict the bond order in the He22+ ion.
Is this a stable species?
Given: chemical species
Asked for: molecular orbital energy-level diagram, bond order, and stability
Strategy:
A. Combine the two He valence atomic orbitals to produce bonding and antibonding molecular orbital
B. s. Draw the molecular orbital energy-level diagram for the system.
C. Determine the total number of valence electrons in the He22+ ion. Fill the molecular orbitals in the energy-level
diagram beginning with the orbital with the lowest energy. Be sure to obey the Pauli principle and Hund’s rule
while doing so.
D. Calculate the bond order and predict whether the species is stable.
Solution:
A Two He 1s atomic orbitals combine to give two molecular orbitals: a σ1s bonding orbital at lower energy than the
atomic orbitals and a σ antibonding orbital at higher energy. The bonding in any diatomic molecule with two He
⋆
1s

atoms can be described using the following molecular orbital diagram:

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 B The He22+ ion has only two valence electrons (two from each He atom minus two for the +2 charge). We can also
view He22+ as being formed from two He+ ions, each of which has a single valence electron in the 1s atomic orbital.
We can now fill the molecular orbital diagram:

The two electrons occupy the lowest-energy molecular orbital, which is the bonding (σ1s) orbital, giving a (σ1s)2
electron configuration. To avoid violating the Pauli principle, the electron spins must be paired. C So the bond order is
2 −0
=1 (1.7.8)
2

He22+ is therefore predicted to contain a single He–He bond. Thus it should be a stable species.

Exercise 1.7.1

Use a molecular orbital energy-level diagram to predict the valence-electron configuration and bond order of the H22−
ion. Is this a stable species?

Answer
H22− has a valence electron configuration of
2
2
(σ1s ) (σ
⋆
1s
) with a bond order of 0. It is therefore predicted to be
unstable.

So far, our discussion of molecular orbitals has been confined to the interaction of valence orbitals, which tend to lie
farthest from the nucleus. When two atoms are close enough for their valence orbitals to overlap significantly, the filled
inner electron shells are largely unperturbed; hence they do not need to be considered in a molecular orbital scheme. Also,
when the inner orbitals are completely filled, they contain exactly enough electrons to completely fill both the bonding and
antibonding molecular orbitals that arise from their interaction. Thus the interaction of filled shells always gives a bond
order of 0, so filled shells are not a factor when predicting the stability of a species. This means that we can focus our
attention on the molecular orbitals derived from valence atomic orbitals.
A molecular orbital diagram that can be applied to any homonuclear diatomic molecule with two identical alkali metal
atoms (Li2 and Cs2, for example) is shown in part (a) in Figure 1.7.4, where M represents the metal atom. Only two energy
levels are important for describing the valence electron molecular orbitals of these species: a σns bonding molecular orbital
and a σ*ns antibonding molecular orbital. Because each alkali metal (M) has an ns1 valence electron configuration, the M2
molecule has two valence electrons that fill the σns bonding orbital. As a result, a bond order of 1 is predicted for all
homonuclear diatomic species formed from the alkali metals (Li2, Na2, K2, Rb2, and Cs2). The general features of these M2
diagrams are identical to the diagram for the H2 molecule in Figure 1.7.4. Experimentally, all are found to be stable in the
gas phase, and some are even stable in solution.

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 Figure 1.7.4 : Molecular Orbital Energy-Level Diagrams for Alkali Metal and Alkaline Earth Metal Diatomic (M2)
Molecules. (a) For alkali metal diatomic molecules, the two valence electrons are enough to fill the σns (bonding) level,
giving a bond order of 1. (b) For alkaline earth metal diatomic molecules, the four valence electrons fill both the σns
(bonding) and the σns* (nonbonding) levels, leading to a predicted bond order of 0.
Similarly, the molecular orbital diagrams for homonuclear diatomic compounds of the alkaline earth metals (such as Be2),
in which each metal atom has an ns2 valence electron configuration, resemble the diagram for the He2 molecule in part (c)
in Figure 1.7.2. As shown in part (b) in Figure 1.7.4, this is indeed the case. All the homonuclear alkaline earth diatomic
molecules have four valence electrons, which fill both the σns bonding orbital and the σns* antibonding orbital and give a
bond order of 0. Thus Be2, Mg2, Ca2, Sr2, and Ba2 are all expected to be unstable, in agreement with experimental data.In
the solid state, however, all the alkali metals and the alkaline earth metals exist as extended lattices held together by
metallic bonding. At low temperatures, Be is stable.
2

Example 1.7.2

Use a qualitative molecular orbital energy-level diagram to predict the valence electron configuration, bond order, and
likely existence of the Na2− ion.
Given: chemical species
Asked for: molecular orbital energy-level diagram, valence electron configuration, bond order, and stability
Strategy:
A. Combine the two sodium valence atomic orbitals to produce bonding and antibonding molecular orbitals. Draw the
molecular orbital energy-level diagram for this system.
B. Determine the total number of valence electrons in the Na2− ion. Fill the molecular orbitals in the energy-level
diagram beginning with the orbital with the lowest energy. Be sure to obey the Pauli principle and Hund’s rule
while doing so.
C. Calculate the bond order and predict whether the species is stable.
Solution:
A Because sodium has a [Ne]3s1 electron configuration, the molecular orbital energy-level diagram is qualitatively
identical to the diagram for the interaction of two 1s atomic orbitals. B The Na2− ion has a total of three valence
electrons (one from each Na atom and one for the negative charge), resulting in a filled σ3s molecular orbital, a half-
1
filled σ3s* and a (σ ) (σ ) electron configuration.
3s
2 ⋆
3s

C The bond order is (2-1)÷2=1/2 With a fractional bond order, we predict that the Na2− ion exists but is highly
reactive.

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 Exercise 1.7.2

Use a qualitative molecular orbital energy-level diagram to predict the valence electron configuration, bond order, and
likely existence of the Ca2+ ion.

Answer

Ca2+ has a (σ
2 1

4s ) (σ
4s
⋆
) electron configurations and a bond order of 1/2 and should exist.

Molecular Orbitals Formed from ns and np Atomic Orbitals

Atomic orbitals other than ns orbitals can also interact to form molecular orbitals. Because individual p, d, and f orbitals
are not spherically symmetrical, however, we need to define a coordinate system so we know which lobes are interacting
in three-dimensional space. Recall that for each np subshell, for example, there are npx, npy, and npz orbitals. All have the
same energy and are therefore degenerate, but they have different spatial orientations.

σnp = npz (A) − npz (B) (1.7.9)

z

Just as with ns orbitals, we can form molecular orbitals from np orbitals by taking their mathematical sum and difference.
When two positive lobes with the appropriate spatial orientation overlap, as illustrated for two npz atomic orbitals in part
(a) in Figure 1.7.5, it is the mathematical difference of their wave functions that results in constructive interference, which
in turn increases the electron probability density between the two atoms. The difference therefore corresponds to a
molecular orbital called a σ bonding molecular orbital because, just as with the σ orbitals discussed previously, it is
npz

symmetrical about the internuclear axis (in this case, the z-axis):

σnp = npz (A) − npz (B) (1.7.10)

z

The other possible combination of the two npz orbitals is the mathematical sum:

σnp = npz (A) + npz (B) (1.7.11)

z

In this combination, shown in part (b) in Figure 1.7.5, the positive lobe of one npz atomic orbital overlaps the negative
lobe of the other, leading to destructive interference of the two waves and creating a node between the two atoms. Hence
this is an antibonding molecular orbital. Because it, too, is symmetrical about the internuclear axis, this molecular orbital is
called a σ = np (A) − np (B) antibonding molecular orbital. Whenever orbitals combine, the bonding combination
npz z z

is always lower in energy (more stable) than the atomic orbitals from which it was derived, and the antibonding
combination is higher in energy (less stable).

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 Figure 1.7.5 Formation of Molecular Orbitals from npz Atomic Orbitals on Adjacent Atoms.(a) By convention, in a linear
molecule or ion, the z-axis always corresponds to the internuclear axis, with +z to the right. As a result, the signs of the
lobes of the npz atomic orbitals on the two atoms alternate − + − +, from left to right. In this case, the σ (bonding)
molecular orbital corresponds to the mathematical difference, in which the overlap of lobes with the same sign results in
increased probability density between the nuclei. (b) In contrast, the σ* (antibonding) molecular orbital corresponds to the
mathematical sum, in which the overlap of lobes with opposite signs results in a nodal plane of zero probability density
perpendicular to the internuclear axis.

Overlap of atomic orbital lobes with the same sign produces a bonding molecular orbital, regardless of whether it
corresponds to the sum or the difference of the atomic orbitals.

The remaining p orbitals on each of the two atoms, npx and npy, do not point directly toward each other. Instead, they are
perpendicular to the internuclear axis. If we arbitrarily label the axes as shown in Figure 1.7.6, we see that we have two
pairs of np orbitals: the two npx orbitals lying in the plane of the page, and two npy orbitals perpendicular to the plane.
Although these two pairs are equivalent in energy, the npx orbital on one atom can interact with only the npx orbital on the
other, and the npy orbital on one atom can interact with only the npy on the other. These interactions are side-to-side rather
than the head-to-head interactions characteristic of σ orbitals. Each pair of overlapping atomic orbitals again forms two
molecular orbitals: one corresponds to the arithmetic sum of the two atomic orbitals and one to the difference. The sum of
these side-to-side interactions increases the electron probability in the region above and below a line connecting the nuclei,
so it is a bonding molecular orbital that is called a pi (π) orbital (a bonding molecular orbital formed from the side-to-side
interactions of two or more parallel np atomic orbitals). The difference results in the overlap of orbital lobes with opposite
signs, which produces a nodal plane perpendicular to the internuclear axis; hence it is an antibonding molecular orbital,
called a pi star (π*) orbital An antibonding molecular orbital formed from the difference of the side-to-side interactions of
two or more parallel np atomic orbitals, creating a nodal plane perpendicular to the internuclear axis..
πnp = npx (A) + npx (B) (1.7.12)
x

⋆
πnp = npx (A) − npx (B) (1.7.13)
x

The two npy orbitals can also combine using side-to-side interactions to produce a bonding π molecular orbital and an
npy

antibonding π ⋆
molecular orbital. Because the npx and npy atomic orbitals interact in the same way (side-to-side) and
npy

have the same energy, the π and π molecular orbitals are a degenerate pair, as are the π
npx npy and π molecular
⋆
npx
⋆
npy

orbitals.

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 Figure 1.7.6 : Formation of π Molecular Orbitals from npx and npy Atomic Orbitals on Adjacent Atoms.(a) Because the
signs of the lobes of both the npx and the npy atomic orbitals on adjacent atoms are the same, in both cases the
mathematical sum corresponds to a π (bonding) molecular orbital. (b) In contrast, in both cases, the mathematical
difference corresponds to a π* (antibonding) molecular orbital, with a nodal plane of zero probability density perpendicular
to the internuclear axis.

Figure 1.7.7 is an energy-level diagram that can be applied to two identical interacting atoms that have three np atomic
orbitals each. There are six degenerate p atomic orbitals (three from each atom) that combine to form six molecular
orbitals, three bonding and three antibonding. The bonding molecular orbitals are lower in energy than the atomic orbitals
because of the increased stability associated with the formation of a bond. Conversely, the antibonding molecular orbitals
are higher in energy, as shown. The energy difference between the σ and σ* molecular orbitals is significantly greater than
the difference between the two π and π* sets. The reason for this is that the atomic orbital overlap and thus the strength of
the interaction are greater for a σ bond than a π bond, which means that the σ molecular orbital is more stable (lower in
energy) than the π molecular orbitals.

Figure 1.7.7 : The Relative Energies of the σ and π Molecular Orbitals Derived from npx, npy, and npz Orbitals on Identical
Adjacent Atoms. Because the two npz orbitals point directly at each other, their orbital overlap is greater, so the difference
in energy between the σ and σ* molecular orbitals is greater than the energy difference between the π and π* orbitals.
Although many combinations of atomic orbitals form molecular orbitals, we will discuss only one other interaction: an ns
atomic orbital on one atom with an npz atomic orbital on another. As shown in Figure 1.7.8, the sum of the two atomic
wave functions (ns + npz) produces a σ bonding molecular orbital. Their difference (ns − npz) produces a σ* antibonding
molecular orbital, which has a nodal plane of zero probability density perpendicular to the internuclear axis.

Figure 1.7.8 : Formation of Molecular Orbitals from an ns Atomic Orbital on One Atom and an npz Atomic Orbital on an
Adjacent Atom.(a) The mathematical sum results in a σ (bonding) molecular orbital, with increased probability density
between the nuclei. (b) The mathematical difference results in a σ* (antibonding) molecular orbital, with a nodal plane of
zero probability density perpendicular to the internuclear axis.

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Summary
Molecular orbital theory, a delocalized approach to bonding, can often explain a compound’s color, why a compound with
unpaired electrons is stable, semiconductor behavior, and resonance, none of which can be explained using a localized
approach. A molecular orbital (MO) is an allowed spatial distribution of electrons in a molecule that is associated with a
particular orbital energy. Unlike an atomic orbital (AO), which is centered on a single atom, a molecular orbital extends
over all the atoms in a molecule or ion. Hence the molecular orbital theory of bonding is a delocalized approach.
Molecular orbitals are constructed using linear combinations of atomic orbitals (LCAOs), which are usually the
mathematical sums and differences of wave functions that describe overlapping atomic orbitals. Atomic orbitals interact to
form three types of molecular orbitals.
A completely bonding molecular orbital contains no nodes (regions of zero electron probability) perpendicular to the
internuclear axis, whereas a completely antibonding molecular orbital contains at least one node perpendicular to the
internuclear axis. A sigma (σ) orbital (bonding) or a sigma star (σ*) orbital (antibonding) is symmetrical about the
internuclear axis. Hence all cross-sections perpendicular to that axis are circular. Both a pi (π) orbital (bonding) and a pi
star (π*) orbital (antibonding) possess a nodal plane that contains the nuclei, with electron density localized on both sides
of the plane.
The energies of the molecular orbitals versus those of the parent atomic orbitals can be shown schematically in an energy-
level diagram. The electron configuration of a molecule is shown by placing the correct number of electrons in the
appropriate energy-level diagram, starting with the lowest-energy orbital and obeying the Pauli principle; that is, placing
only two electrons with opposite spin in each orbital. From the completed energy-level diagram, we can calculate the bond
order, defined as one-half the net number of bonding electrons. In bond orders, electrons in antibonding molecular orbitals
cancel electrons in bonding molecular orbitals, while electrons in nonbonding orbitals have no effect and are not counted.
Bond orders of 1, 2, and 3 correspond to single, double, and triple bonds, respectively. Molecules with predicted bond
orders of 0 are generally less stable than the isolated atoms and do not normally exist.

Contributors and Attributions

Modified by Joshua Halpern (Howard University)
1. Orbitals or orbital lobes with the same sign interact to give increased electron probability along the plane of the
internuclear axis because of constructive reinforcement of the wave functions. Consequently, electrons in such
molecular orbitals help to hold the positively charged nuclei together. Such orbitals are bonding molecular orbitals,
and they are always lower in energy than the parent atomic orbitals.
2. Orbitals or orbital lobes with opposite signs interact to give decreased electron probability density between the nuclei
because of destructive interference of the wave functions. Consequently, electrons in such molecular orbitals are
primarily located outside the internuclear region, leading to increased repulsions between the positively charged nuclei.
These orbitals are called antibonding molecular orbitals, and they are always higher in energy than the parent atomic
orbitals.
3. Some atomic orbitals interact only very weakly, and the resulting molecular orbitals give essentially no change in the
electron probability density between the nuclei. Hence electrons in such orbitals have no effect on the bonding in a
molecule or ion. These orbitals are nonbonding molecular orbitals, and they have approximately the same energy as
the parent atomic orbitals.

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1.8: Hybrid Orbitals: Bonding in Complex Molecules and Practice Problems
Formation of sigma bonds: the H2 molecule
The simplest case to consider is the hydrogen molecule, H2. When we say that the two electrons from each of the hydrogen
atoms are shared to form a covalent bond between the two atoms, what we mean in valence bond theory terms is that the
two spherical 1s orbitals overlap, allowing the two electrons to form a pair within the two overlapping orbitals.

These two electrons are now attracted to the positive charge of both of the hydrogen nuclei, with the result that they serve
as a sort of ‘chemical glue’ holding the two nuclei together.

Bonding in Methane

Now let’s turn to methane, the simplest organic molecule. Recall the valence electron configuration of the central carbon:

This picture, however, is problematic. How does the carbon form four bonds if it has only two half-filled p orbitals
available for bonding? A hint comes from the experimental observation that the four C-H bonds in methane are arranged
with tetrahedral geometry about the central carbon, and that each bond has the same length and strength. In order to
explain this observation, valence bond theory relies on a concept called orbital hybridization. In this picture, the four
valence orbitals of the carbon (one 2s and three 2p orbitals) combine mathematically (remember: orbitals are described by
equations) to form four equivalent hybrid orbitals, which are named sp3 orbitals because they are formed from mixing
one s and three p orbitals. In the new electron configuration, each of the four valence electrons on the carbon occupies a
single sp3 orbital.

The sp3 hybrid orbitals, like the p orbitals of which they are partially composed, are oblong in shape, and have two lobes of
opposite sign. Unlike the p orbitals, however, the two lobes are of very different size. The larger lobes of the sp3 hybrids
are directed towards the four corners of a tetrahedron, meaning that the angle between any two orbitals is 109.5o.

This geometric arrangement makes perfect sense if you consider that it is precisely this angle that allows the four orbitals
(and the electrons in them) to be as far apart from each other as possible.This is simply a restatement of the Valence Shell
Electron Pair Repulsion (VSEPR) theory that you learned in General Chemistry: electron pairs (in orbitals) will arrange
themselves in such a way as to remain as far apart as possible, due to negative-negative electrostatic repulsion.
Each C-H bond in methane, then, can be described as an overlap between a half-filled 1s orbital in a hydrogen atom and
the larger lobe of one of the four half-filled sp3 hybrid orbitals in the central carbon. The length of the carbon-hydrogen
bonds in methane is 1.09 Å (1.09 x 10-10 m).

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While previously we drew a Lewis structure of methane in two dimensions using lines to denote each covalent bond, we
can now draw a more accurate structure in three dimensions, showing the tetrahedral bonding geometry. To do this on a
two-dimensional page, though, we need to introduce a new drawing convention: the solid / dashed wedge system. In this
convention, a solid wedge simply represents a bond that is meant to be pictured emerging from the plane of the page. A
dashed wedge represents a bond that is meant to be pictured pointing into, or behind, the plane of the page. Normal lines
imply bonds that lie in the plane of the page.

This system takes a little bit of getting used to, but with practice your eye will learn to immediately ‘see’ the third
dimension being depicted.

Example

Imagine that you could distinguish between the four hydrogens in a methane molecule, and labeled them Ha through Hd. In the images below,
the exact same methane molecule is rotated and flipped in various positions. Draw the missing hydrogen atom labels. (It will be much easier
to do this if you make a model.)

Example

Describe, with a picture and with words, the bonding in chloroform, CHCl3.
Solutions

The bonding arrangement here is also tetrahedral: the three N-H bonds of ammonia can be pictured as forming the base of
a trigonal pyramid, with the fourth orbital, containing the lone pair, forming the top of the pyramid.

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Recall from your study of VSEPR theory in General Chemistry that the lone pair, with its slightly greater repulsive effect,
‘pushes’ the three N-H sbonds away from the top of the pyramid, meaning that the H-N-H bond angles are slightly less
than tetrahedral, at 107.3˚ rather than 109.5˚.
VSEPR theory also predicts, accurately, that a water molecule is ‘bent’ at an angle of approximately 104.5˚. It would seem
logical, then, to describe the bonding in water as occurring through the overlap of sp3-hybrid orbitals on oxygen with
1sorbitals on the two hydrogen atoms. In this model, the two nonbonding lone pairs on oxygen would be located in sp3
orbitals.

Some experimental evidence, however, suggests that the bonding orbitals on the oxygen are actually unhybridized 2p
orbitals rather than sp3 hybrids. Although this would seem to imply that the H-O-H bond angle should be 90˚ (remember
that p orbitals are oriented perpendicular to one another), it appears that electrostatic repulsion has the effect of distorting
this p-orbital angle to 104.5˚. Both the hybrid orbital and the nonhybrid orbital models present reasonable explanations for
the observed bonding arrangement in water, so we will not concern ourselves any further with the distinction.

Example

Draw, in the same style as the figures above, an orbital picture for the bonding in methylamine.
Solution

Formation of π bonds - sp and sp hybridization

2

The valence bond theory, along with the hybrid orbital concept, does a very good job of describing double-bonded
compounds such as ethene. Three experimentally observable characteristics of the ethene molecule need to be accounted
for by a bonding model:
1. Ethene is a planar (flat) molecule.
2. Bond angles in ethene are approximately 120o, and the carbon-carbon bond length is 1.34 Å, significantly shorter than
the 1.54 Å single carbon-carbon bond in ethane.
3. There is a significant barrier to rotation about the carbon-carbon double bond.

Clearly, these characteristics are not consistent with an sp3 hybrid bonding picture for the two carbon atoms. Instead, the
bonding in ethene is described by a model involving the participation of a different kind of hybrid orbital. Three atomic
orbitals on each carbon – the 2s, 2px and 2py orbitals – combine to form three sp2 hybrids, leaving the 2pz orbital
unhybridized.

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The three sp2 hybrids are arranged with trigonal planar geometry, pointing to the three corners of an equilateral triangle,
with angles of 120°between them. The unhybridized 2pz orbital is perpendicular to this plane (in the next several figures,
sp2 orbitals and the sigma bonds to which they contribute are represented by lines and wedges; only the 2pz orbitals are
shown in the 'space-filling' mode).

The carbon-carbon double bond in ethene consists of one sbond, formed by the overlap of two sp2 orbitals, and a second
bond, calleda π (pi) bond, which is formed by the side-by-side overlap of the two unhybridized 2pz orbitals from each
carbon.

spacefilling image of bonding in ethene

The pi bond does not have symmetrical symmetry. Because they are the result of side-by-side overlap (rather then end-to-
end overlap like a sigma bond), pi bonds are not free to rotate. If rotation about this bond were to occur, it would involve
disrupting the side-by-side overlap between the two 2pz orbitals that make up the pi bond. The presence of the pi bond thus
‘locks’ the six atoms of ethene into the same plane. This argument extends to larger alkene groups: in each case, the six
atoms of the group form a single plane.

Conversely, sbonds such as the carbon-carbon single bond in ethane (CH3CH3) exhibit free rotation, and can assume many
different conformations, or shapes - this is one of the main subjects of Chapter 3.

Example 1.20

Circle the six atoms in the molecule below that are ‘locked’ into the same plane.

Example

What kinds of orbitals are overlapping in bonds a-d indicated below?

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Example

What is wrong with the way the following structure is drawn?

Solutions

A similar picture can be drawn for the bonding in carbonyl groups, such as formaldehyde. In this molecule, the carbon is
sp2-hybridized, and we will assume that the oxygen atom is also sp2 hybridized. The carbon has three sigma bonds: two are
formed by overlap between two of its sp2 orbitals with the 1sorbital from each of the hydrogens, and the third sigma bond
is formed by overlap between the remaining carbon sp2 orbital and an sp2 orbital on the oxygen. The two lone pairs on
oxygen occupy its other two sp2 orbitals.

The pi bond is formed by side-by-side overlap of the unhybridized 2pz orbitals on the carbon and the oxygen. Just like in
alkenes, the 2pz orbitals that form the pi bond are perpendicular to the plane formed by the sigma bonds.
Example

Describe and draw the bonding picture for the imine group shown below. Use the drawing of formaldehyde above as your guide.

Solution

Contributors
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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1.9: Structures and Formulas of Organic Molecules
It is necessary to draw structural formulas for organic compounds because in most cases a molecular formula does not
uniquely represent a single compound. Different compounds having the same molecular formula are called isomers, and
the prevalence of organic isomers reflects the extraordinary versatility of carbon in forming strong bonds to itself and to
other elements. When the group of atoms that make up the molecules of different isomers are bonded together in
fundamentally different ways, we refer to such compounds as constitutional isomers. There are seven constitutional
isomers of C4H10O, and structural formulas for these are drawn in the following table. These formulas represent all known
and possible C4H10O compounds, and display a common structural feature. There are no double or triple bonds and no
rings in any of these structures.
Structural Formulas for C4H10O isomers

Kekulé Formula Condensed Formula Shorthand Formula

Simplification of structural formulas may be achieved without any loss of the information they convey. In condensed
structural formulas the bonds to each carbon are omitted, but each distinct structural unit (group) is written with subscript
numbers designating multiple substituents, including the hydrogens. Shorthand (line) formulas omit the symbols for
carbon and hydrogen entirely. Each straight line segment represents a bond, the ends and intersections of the lines are
carbon atoms, and the correct number of hydrogens is calculated from the tetravalency of carbon. Non-bonding valence
shell electrons are omitted in these formulas.
Developing the ability to visualize a three-dimensional structure from two-dimensional formulas requires practice, and in
most cases the aid of molecular models. As noted earlier, many kinds of model kits are available to students and
professional chemists, and the beginning student is encouraged to obtain one.

Kekulé Formula
A structural formula displays the atoms of the molecule in the order they are bonded. It also depicts how the atoms are
bonded to one another, for example single, double, and triple covalent bond. Covalent bonds are shown using lines. The
number of dashes indicate whether the bond is a single, double, or triple covalent bond. Structural formulas are helpful
because they explain the properties and structure of the compound which empirical and molecular formulas cannot always
represent.

Ex. Kekulé Formula for Ethanol:

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Condensed Formula
Condensed structural formulas show the order of atoms like a structural formula but are written in a single line to save
space and make it more convenient and faster to write out. Condensed structural formulas are also helpful when showing
that a group of atoms is connected to a single atom in a compound. When this happens, parenthesis are used around the
group of atoms to show they are together.
Ex. Condensed Structural Formula for Ethanol: CH3CH2OH (Molecular Formula for Ethanol C2H6O).

Shorthand Formula
Because organic compounds can be complex at times, line-angle formulas are used to write carbon and hydrogen atoms
more efficiently by replacing the letters with lines. A carbon atom is present wherever a line intersects another line.
Hydrogen atoms are then assumed to complete each of carbon's four bonds. All other atoms that are connected to carbon
atoms are written out. Line angle formulas help show structure and order of the atoms in a compound making the
advantages and disadvantages similar to structural formulas.

Ex.Shorthand Formula for Ethanol:

Contributors
Jean Kim (UCD), Kristina Bonnett (UCD)

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1.E: Structure and Bonding in Organic Molecules (Exercises)
These are homework exercises to accompany Chapter 1 of Vollhardt and Schore's "Organic Chemistry" Textmap.

1.1: The Scope of Organic Chemistry: An Overview

1.2: Coulomb Forces: A Simplified View of Bonding

1.3: Ionic and Covalent Bonds: The Octet Rule

1.4: Electron-Dot Model of Bonding: Lewis Structures

1.5: Resonance Forms

1.6: Atomic Orbitals: A Quantum Mechanical Description of Electrons Around the Nucleus

1.7: Molecular Orbitals and Covalent Bonding

1.8: Hybrid Orbitals: Bonding in Complex Molecules and Practice Problems
Q25
Draw the Lewis Structures of the following molecules, and if necessary assign charges.
a. BrF
b. ClCN
c. SOCl2
d. CH3CH2NH2
e. CH3CH2OCH2CH3
f. (CH3)2NNH2
g. CH3NCNCH3
h. CH3COOH
i. N2O4

Q26
In problem 25 identify the polar covalent bonds with δ+ and δ- on the atoms according to their electronegativity.

Q27
Draw the Lewis Structures of the following species, and if necessary assign charges.
a. H3O+
b. NH4+
c. CH3CH2-
d. CH3CH2+
e. CH3CH2
f. CH3CH
g. H-
h. CH3COO-

Q28
Add charges to the following Lewis Structures, if neutral do not add any charges.

(a) (b) (c)

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(d) (e) (f)

Q29
Sulfuric Acid is a known strong acid, it's deprotonated form SO42-, has several resonance structures. Draw the remaining
two using electron pushing arrows.

Acetic acid is a common household acid once deprotonated it forms an anion with resonance structures possible. Draw
these with electron-pushing arrows.

Q30
In problem 25 several of the species have possible resonance structures. Draw the electron-pushing arrows and resulting
resonance structures for 25.c, 25.h, 25.i. Identify the major contributor, and give reasons.

Q31
Draw all possible resonance structures of the following species.
a. CH2COCH3-
b. CH2N2
c. CO
d. CH2ON(CH3)2
e. SCN-
f. NO32-
g. O3

Q32
Draw all possible resonance structures of the following. Based on the resonance structures, which carbonyl carbon, marked
in red, would be the most electron deficient?

Q33
Draw the Lewis structure for each compound.
a. Fluorine and the Fluoride anion
b. GeH4 and GeO
c. H2O2 (Hydrogen Peroxide)
d. Phosphine (PH3) and Ammonia (NH3)

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Q34
Draw the molecular orbital diagrams of H2+, He22+, and He2, and indicate the bond order. Compare and contrast the
molecular orbital diagrams of He2+ and He2, which is more favorable?

Q35
Predict the geometry for each red-highlighted atom and give the hybridization of that center.

(a) (b) (c) (d) (e)

(f)

Q36
In problem 35 indicate the hybrid orbitals' interactions (sp3, sp2, sp) and the atomic orbitals used (s, p).

Q37
Draw the hybridized orbitals for each of the highlighted carbons in problem 35.

Q38
Determine the hybridization of each carbon based on the shape of each molecule.
(a) CH3Br (b) CH3CH2OH (c) H3CHCCH (d) CH3- (e) NH4+

Q39
Draw the Kekule structures for the following molecules, an example is given below.
Example. CH3CH2CH2CH3

(a) CH3CH2OH (b) (CH3)2CH2OH (c) (CH3)2NCHO (d) CH2ClCH2Cl (e) HOOCCH2COOH

Q40
Draw the Kekule structures for the following molecules.

(a) (b) (c) (d) (e)

(f)

Q41
Convert the following structures into condensed formulas

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(a) (b) (c)

Q42
Give the condensed structures for the following Kekulé structures.

(a) (b) (c) (d) (e)

(f)

Q43
In the previous problem, 42, draw the Kekulé structures as bond line structures.

Q44
Draw the following condensed formulas as hashed-wedged line structures.
a. CH3CH2OCH2CN
b. CH2Cl2
c. (CH3CH2)3P
d. CH2CHCH2SiH3

Q45
Draw all possible constitutional isomers, in bond-line form, ofIthe following molecules.
(a) C3H8 (b) C6H14 (c) C4H10

Q46
Draw line-bond structures of the following pairs of species and include all charges. Are any of the pairs resonance forms of
the other species in the pair? If not explain the difference
(a) H3CCHCCH2 and H2CCCHCH3 (b) HCN and H3CNH2 (c) CH3CH2COH and CH3CH2CHOH

Q47
The following boron-halogen compounds have resonance structures possible. Draw them and in each compound indicate
which structure is favored (hint: the octet rule takes precedent). Also, compare the relative energy levels of the three
favored resonance structures, which is favored/lowest in energy?
(a) (CH3)2BF (b) (CH3)2BCl (c) (CH3)2BBr

Q48
Using the formula for the degrees of each angle, [(n-2)*180]/n, where n equals the number of sides, determine the angles
in each of the following shapes. If the given shapes were considered bond-line structures, order them from highest to

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lowest favorability based on the angles (The best overlap in sp3 hybridized carbon is at 104.5o). Compare this answer to
the following ring strain energies of each: cyclopropane (triangle)- 27.5 kcal/mol cyclobutane (square)- 26.3 kcal/mol
cyclopentane (pentagon)- 6.2 kcal/mol cyclohexane (hexagon)-0.1 kcal/mol.

Q49
Give the hybridization orbital that the lone pair of each of the following species belongs in. Also, given that the 2p orbitals
are higher in energy than the 2s orbitals, order the species from lowest to highest energy according to the s/p character.
(sp3= 1/4s and 3/4p) (sp2= 1/3s and 2/3p) (sp= 1/2s and 1/2p).
(a) CH3CH2CH2- (b) CH3CHCH- (c) CH3CC-
Based on their relative energy, which species would it be most favorable to undergo the following dissociation (HA
represents the neutral hydrocarbon)?

Q50
In each set which of the following positively polarized carbon bond atoms is the most electropositive?
(a) (i)CHCl3 (ii) CHCl2 (iii) CCl4
(b) (i) ClCH2OCH2Cl (ii) CH3OCH2Cl
(c) (i) (CH3)3C+ (ii) (CH3CH2)3C+

Q51
The following molecule is a common insecticide, cyfluthrin. It is known to be very effective against invertibrates, but it is
not nearly as toxic to mammals. In the following highlight one (a) highly polarized covalent single bond (b) one highly
polarized double bond (c) one sp2 hybridized carbon atom (d) one sp hybridized carbon atom and (e) one conjugated
system.

Q52
In the following reaction does the hybridization of the highlighted carbon atom change? Give the hybridization before and
after.

Q53
A combustion elemental analysis finds that a compound is made up of 84% carbon and 16% hydrogen (C=12.0, H=1.0,
O=16.0). Which of the following could be the compound tested?

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(a) CH4O (b) C6H14O2 (c) C14H22 (d) C7H16

Q54
As drawn, which of the following is a correct formal charge assignment?

(a) +1 on F (b) -1 on N (c) +2 on N (d) -1 on B (e) +1 on B

Q55
The highlighted bond is formed by the interaction between what two orbitals?

Q56
Which highlighted carbon center has the smallest bond angles?
(a) CO2 (b) CH2Cl2 (c) HCCH (d) CO

Q57
Which pair of structures are resonance hybrids?

(a) (b) (c) (d)

Solutions
S25.

(a) (b) (c) (d)

(e) (f) The lone pair is shared between the two N atoms.

(g) (h) (i)

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S26

(a) (b) (c) (d)

(e) (f) (g)

(h) (i)

S27

(a) (b) (c) (d)

(e) (f) (g) (h)

S28

(a) (b) (c)

(d) (e) neutral (f)

S29
Sulfuric acid has two more possible resonance structures. Later, resonance/charge distribution will be mentioned; the
resonance structures possible for the deprotonated sulfuric acid are one reason for why it is so strongly acidic.

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Acetic acid has one additional resonance structure possible, again a reason for its moderate acidity.

S30

(c) The resonance structure with no charges is the major contributor.

(h) Again, the resonance structure with no charges is the major contributor.

(i) Each resonance structure is equivalent, so there is no "major contributor".

S31

(a) (b)

(c) (d)

(e) (f)

(g)

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S32

The first structure has two possible resonance structures, further distributing electrons more among the carbonyl carbon.
However, the second structure only has one possible resonance structure. This distributes electrons to a lesser extent
among the carbonyl carbon. Thus, in the second structure, the aldehyde, the carbon marked in red is more electron
deficient than in the carboxylic acid.

S33

(a) (b) (c) (d)

S34

H2+ has a bond order of 1/2, He2+ has a bond order of 1/2, and He2 has a bond order of 0. The zero bond order indicates
that He2 is not favorable.

S35
a. dichloroethane: The highlighted carbon center is tetrahedral with a hybridization of sp3; it is bonded to four other
groups.
b. acetic acid: The carbon center is trigonal planar with a hybridization of sp2; it is bonded to three groups and has no lone
pairs.
c. propene: The carbon center is trigonal planar with a hybridization sp2; it is bonded to three groups and has no lone
pairs.
d. acetylene: The carbon center is linear with a hybridization of sp; it is bonded to two groups with no lone pairs.
e. triethylamine: The nitrogen center is tetrahedral with a hybridization of sp3; it is bonded to three groups with one lone
pair.
f. triethylammonium ion: The nitrogen center is tetrahedral with a hybridization of sp3; it is bonded to four groups with
no lone pairs. All are sigma bonds.

S36
a. The highlighted carbon forms bonds with one chlorine, two hydrogen atoms, and one other carbon. Each of these atoms
connect to the central carbon forming sp3-sp3 hybridized orbitals. The carbon and hydrogen both use electrons from the
s orbital, while the bonding electrons from the chlorine are from the p orbitals. All are sigma bonds.

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 b. The central carbon is sp2 hybridized, and it is bonded to one carbon and two oxygen atoms. The bond to the carbon
involves an sp3-sp2 overlap with the s orbital on the adjacent carbon involved in bonding, sigma bonding. The carbon
oxygen double bond is slightly more complicated. The oxygen is less likely to undergo orbital hybridization. So, the
C(sp2)-O(p) sigma bond is formed along with the interaction of the second oxygen p orbital with the carbon p orbital to
yield a pi bond. The carbon oxygen bond is similar forming a sigma bond through the C(sp2)-O(p) interaction.
c. The central carbon is sp2 hybridized and bonded to two other carbons and one hydrogen atom. The bond between the
hydrogen atom involves the C(sp2)-H(s) interaction yielding a sigma bond. The C=C double bond involves the C(sp2)-
C(sp2) interaction creating a pi bond. The C-C single bond is a sigma bond involving the C(sp2)-C(sp3) hybrid orbitals.
d. The highlighted carbon is bonded to one hydrogen and one carbon atom. The C-H single bond is made up of the C(sp)-
H(s) interaction yielding a sigma bond. The C-C triple bond is made up of the C(sp)-C(sp) hybrid orbitals yielding a
sigma bond, s orbitals, and two pi bonds, using the two p orbitals.
e. The highlighted nitrogen is bonded to three identical carbon groups and has one lone pair. Each of the carbon atoms is
sp3 hybridized. So, a N(sp3)-C(sp3) yields a sigma bond.
f. The highlighted nitrogen is bonded to three identical carbon atoms and one hydrogen. There are no lone pairs on the
nitrogen, and it is sp3 hybridized. The N-C bonds are the same as in part (e), N(sp3)-C(sp3) yielding a sigma bond. The
N-H bond is formed from the N(sp3)-H(s) interaction, also a sigma bond.

S37

(a) (b) (c)

(d) (e) (f)

S38
Each carbon's hybridization is listed from left to right in the chemical formula.
a. tetrahedral, sp3
b. tetrahedral, sp3 ; tetrahedral, sp3
c. tetrahedral, sp3 ; linear, sp ; linear, sp
d. tetrahedral, sp3
e. tetrahedral, sp3

S39

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(a) (b) (c) (d) (e)

S40

(a) (b) (c) (d)

(e) (f)

S41
(a) (CH3)2CHNH2 (b) CClH2CH2Cl (c) CH3I

S42
(a) CH3CH2NH2 (b) CH3 C=O CH3 (c) CH3SCH2C2OH (d) CF3CHOHCF3 (e) CH2CCH2 (f) CH2CH C=O OCH3

S43

(a) (b) (c) (d) (e) (f)

S44

(a) (b) (c) (d)

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S45

(a) (b) (c)

S46

(a) the two structures are identical (b) These are not

resonance structures; there additional H atoms. (c) These are not resonance
structures; there are three additional H atoms.

S47

In each case the double bonded resonance structure is preferred, due to the octet rule
being fulfilled.
The lowest energy structure can be determined by thinking about the electronegativity of each halogen atom. The higher
the electronegativity, the less favorable a positive charge is. The order of the electronegativity is as follows, F>Cl>Br, and
so the reverse is the order of favorability. (CH3)2BF (b) (CH3)2BCl (c) (CH3)2BBr

S48
Triangle- 60o Square- 90o Pentagon- 108o Hexagon- 120o
This would lead to the expectation that the order of favorability is Pentagon>Square>Hexagon>Triangle. However, the
order differs and is in fact Hexagon>Pentagon>Square>Triangle.
In reality this is due to different conformations of the shapes, so that the hexagon and pentagon are no longer flat/planar.
This will be covered in more detail later on.

S49
CH3CH2CH2- - sp3 CH3CHCH- - sp2 CH3CC- - sp
The order of energy is as follows, or increasing p character. CH3CC-<CH3CHCH-<CH3CH2CH2-
The reaction would be most favorable if the A- is lowest in energy, so, the order of favorability is the reverse of above.
CH3CH2CH2-<CH3CHCH-<CH3CC-

S50
(a) CCl4

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(b) ClCH2OCH2Cl
(c) (CH3)3C+ The additional hydrocarbons on the ethyl group do marginally hyperconjugate and donate electrons to the
center carbon, making it less electropositive.

S51

(a) In this structure any sp3 carbon connected to a heteroatom would be a polarized bond.

(b) In this structure this is the only highly polarized double bond.

(c) Any double bonded carbon could be considered sp2 hybridized.

(d) This is the only sp hybridized carbon.

(e) These two benzene rings are conjugated system.

S52
The hybridization changes from sp2 to sp3.

S53
(d) 84/12=7 Carbon and 14/1=14 Hydrogen

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S54
(d) is correct, boron typically has 3 valence electrons. It currently is bonded to four different atoms; it has an octet. 8/2=4
electrons, and 3-4=-1 formal charge.

S55
The bond is formed by the interaction between the s orbital of the hydrogen and the sp2 orbital of the carbon.

S56
(b) This is the only sp3 hybridized highlighted carbon, characterized by bond angles of 104.5o. Which is less than both sp2
and sp, 120o and 180o respectively.

S57
(c) The number of electrons is the same and all atoms are in the same locations. Placement of charges is important to look
at; in the pairs with no charges present then some atoms were moved around.

1.9: Structures and Formulas of Organic Molecules

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CHAPTER OVERVIEW
2: STRUCTURE AND REACTIVITY: ACIDS AND BASES, POLAR AND
NONPOLAR MOLECULES
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

2.1: KINETICS AND THERMODYNAMICS OF SIMPLE CHEMICAL PROCESSES

2.2: KEYS TO SUCCESS: USING CURVED "ELECTRON PUSHING" ARROWS TO DESCRIBE CHEMICAL
REACTIONS
2.3: ACIDS AND BASES; ELECTROPHILES AND NUCLEOPHILES
2.4: FUNCTIONAL GROUPS: CENTERS OF REACTIVITY
2.5: STRAIGHT-CHAIN AND BRANCHED ALKANES
2.6: NAMING THE ALKANES
2.7: STRUCTURAL AND PHYSICAL PROPERTIES OF ALKANES
2.8: ROTATION ABOUT SINGLE BONDS: CONFORMATIONS
Conformational isomerism involves rotation about sigma bonds, and does not involve any differences in the connectivity or geometry
of bonding. Two or more structures that are categorized as conformational isomers, or conformers, are really just two of the exact
same molecule that differ only in terms of the angle about one or more sigma bonds.

2.9: ROTATION IN SUBSTITUTED ETHANES

2.E: STRUCTURE AND REACTIVITY: ACIDS AND BASES, POLAR AND NONPOLAR MOLECULES (EXERCISES)

1 12/5/2021
2.1: Kinetics and Thermodynamics of Simple Chemical Processes
Equilibrium Constant
For the hypothetical chemical reaction:
aA + bB ⇌ cC + dD (6.5.1)

the equilibrium constant is defined as:

c d
[C ] [D]
KC = (6.5.2)
a b
[A] [B]

The notation [A] signifies the molar concentration of species A. An alternative expression for the equilibrium constant involves partial
pressures:
c d
P P
C D
KP = (6.5.3)
a b
P P
A B

Note that the expression for the equilibrium constant includes only solutes and gases; pure solids and liquids do not appear in the
expression. For example, the equilibrium expression for the reaction

C aH2 (s) + 2 H2 O(g) ⇌ C a(OH )2 (s) + 2 H2 (g) (6.5.4)

is the following:
2
[H2 ]
KC = (6.5.5)
[ H2 O]2

Observe that the gas-phase species H2O and H2 appear in the expression but the solids CaH2 and Ca(OH)2 do not appear.

The equilibrium constant is most readily determined by allowing a reaction to reach equilibrium, measuring the concentrations of the
various solution-phase or gas-phase reactants and products, and substituting these values into the Law of Mass Action.

Gibbs Energy
The interaction between enthalpy and entropy changes in chemical reactions is best observed by studying their influence on the
equilibrium constants of reversible reactions. To this end a new thermodynamic function called Free Energy (or Gibbs Free Energy),
symbol ΔG, is defined as shown in the first equation below. Two things should be apparent from this equation. First, in cases where the
entropy change is small, ΔG ≅ ΔH. Second, the importance of ΔS in determining ΔG increases with increasing temperature.
º º
ΔG = ΔH – T ΔS º (6.5.6)

where T is the absolute temperature measured in kelvin.

The free energy function provides improved insight into the thermodynamic driving forces that influence reactions. A negative ΔGº is
characteristic of an exergonic reaction, one which is thermodynamically favorable and often spontaneous, as is the melting of ice at 1
ºC. Likewise a positive ΔGº is characteristic of an endergonic reaction, one which requires an input of energy from the surroundings.
Example 6.5.1: Decomposition of Cyclobutane
For an example of the relationship of free energy to enthalpy consider the decomposition of cyclobutane to ethene, shown in the
following equation. The standard state for all the compounds is gaseous.

This reaction is endothermic, but the increase in number of molecules from one (reactants) to two (products) results in a large positive
ΔSº.
At 25 ºC (298 ºK), ΔGº = 19 kcal/mol – 298(43.6) cal/mole = 19 – 13 kcal/mole = +6 kcal/mole. Thus, the entropy change opposes
the enthalpy change, but is not sufficient to change the sign of the resulting free energy change, which is endergonic. Indeed,
cyclobutane is perfectly stable when kept at room temperature.
Because the entropy contribution increases with temperature, this energetically unfavorable transformation can be made favorable by
raising the temperature. At 200 ºC (473 ºK), ΔGº = 19 kcal/mol – 473(43.6) cal/mole = 19 – 20.6 kcal/mole = –1.6 kcal/mole. This is
now an exergonic reaction, and the thermal cracking of cyclobutane to ethene is known to occur at higher temperatures.
º
ΔG =– RT ln K =– 2.303RT log K (2.1.1)

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 with
R = 1.987 cal/ ºK mole
T = temperature in ºK
K = equilibrium constant
A second equation, shown above, is important because it demonstrates the fundamental relationship of ΔGº to the equilibrium
constant, K. Because of the negative logarithmic relationship between these variables, a negative ΔGº generates a K>1, whereas a
positive ΔGº generates a K<1. When ΔGº = 0, K = 1. Furthermore, small changes in ΔGº produce large changes in K. A change of 1.4
kcal/mole in ΔGº changes K by approximately a factor of 10. This interrelationship may be explored with the calculator on the right.
Entering free energies outside the range -8 to 8 kcal/mole or equilibrium constants outside the range 10-6 to 900,000 will trigger an
alert, indicating the large imbalance such numbers imply.

Substituted Cyclohexanes
A Values
Substituents on a cyclohexane prefer to be in the equatorial position. When a substituent is in the axial position, there are two gauche
butane interactions more than when a substituent is in the equatorial position. We quantify the energy difference between the axial and
equatorial conformations as the A-value, which is equivalent to the negative of the ∆G°, for the equilibrium shown below. Therefore the
A-value, or -∆G°, is the preference for the substituent to sit in the equatorial position.

Recall that the equilibrium constant is related to the change in Gibbs Energies for the reaction:
o
ΔG = −RT ln Keq (2.1.2)

The balance between reactants and products in a reaction will be determined by the free energy difference between the two sides of the
reaction. The greater the free energy difference, the more the reaction will favor one side or the other (Table 6.5.1).
Table 6.5.1: Below is a table of A-values for some common substituents.
Substituent ∆G° (kcal/mol) A-value

-F -0.28-0.24 0.24-0.28

-Cl -0.53 0.53

-Br -0.48 0.48

-I -0.47 0.47

-CH3 (-Me) -1.8 1.8

-CH2CH3 (-Et) -1.8 1.8

-CH(CH3)2 (-i-Pr) -2.1 2.1

-C(CH3)3 (-t-Bu) <-4.5 >4.5

-CHCH2 -1.7 1.7

-CCH -0.5 0.5

-CN -0.25-0.15 0.15-0.25

-C6H5 (-Ph) -2.9 2.9

Polysubstituted Cyclohexanes

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1,4-disubstitution
The A-values of the substituents are roughly additive in either the cis- or trans-diastereomers.

1,3-disubstitution
A-values are only additive in the trans-diastereomer:

When there are cis-substituents on the chair, there is a new interaction in the di-axial conformation:
In the above example, each methyl group has one 1,3-diaxial interaction with a hydrogen. The methyl groups also interact with each
other. This new diaxial interaction is extremely unfavorable based on their steric interaction (see: double-gauche pentane conformation).

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
You may recall from general chemistry that it is often convenient to describe chemical reactions with energy diagrams. In an energy
diagram, the vertical axis represents the overall energy of the reactants, while the horizontal axis is the ‘reaction coordinate’, tracing
from left to right the progress of the reaction from starting compounds to final products. The energy diagram for a typical one-step
reaction might look like this:

Despite its apparent simplicity, this energy diagram conveys some very important ideas about the thermodynamics and kinetics of the
reaction. Recall that when we talk about the thermodynamics of a reaction, we are concerned with the difference in energy between
reactants and products, and whether a reaction is ‘downhill’ (exergonic, energy releasing) or ‘uphill (endergonic, energy absorbing).
When we talk about kinetics, on the other hand, we are concerned with the rate of the reaction, regardless of whether it is uphill or
downhill thermodynamically.
First, let’s review what this energy diagram tells us about the thermodynamics of the reaction illustrated by the energy diagram above.
The energy level of the products is lower than that of the reactants. This tells us that the change in standard Gibbs Free Energy for the
reaction (ΔG˚rnx) is negative. In other words, the reaction is exergonic, or ‘downhill’. Recall that the ΔG˚rnx term encapsulates both
ΔH˚rnx, the change in enthalpy (heat) and ΔS˚rnx , the change in entropy (disorder):
ΔG˚ = ΔH ˚ − T ΔS˚ (2.1.3)

where T is the absolute temperature in Kelvin. For chemical processes where the entropy change is small (~0), the enthalpy change is
essentially the same as the change in Gibbs Free Energy. Energy diagrams for these processes will often plot the enthalpy (H) instead of

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Free Energy for simplicity.
The standard Gibbs Free Energy change for a reaction can be related to the reaction's equilibrium constant (\(K_{eq}\_) by a simple
equation:

ΔG˚ = −RT ln Keq (2.1.4)

where:
Keq = [product] / [reactant] at equilibrium
R = 8.314 J×K-1×mol-1 or 1.987 cal× K-1×mol-1
T = temperature in Kelvin (K)
If you do the math, you see that a negative value for ΔG˚rnx (an exergonic reaction) corresponds - as it should by intuition - to Keq being
greater than 1, an equilibrium constant which favors product formation.
In a hypothetical endergonic (energy-absorbing) reaction the products would have a higher energy than reactants and thus ΔG˚rnx would
be positive and Keq would be less than 1, favoring reactants.

Now, let's move to kinetics. Look again at the energy diagram for exergonic reaction: although it is ‘downhill’ overall, it isn’t a straight
downhill run.

First, an ‘energy barrier’ must be overcome to get to the product side. The height of this energy barrier, you may recall, is called the
‘activation energy’ (ΔG‡). The activation energy is what determines the kinetics of a reaction: the higher the energy hill, the slower the
reaction. At the very top of the energy barrier, the reaction is at its transition state (TS), which is the point at which the bonds are in the
process of breaking and forming. The transition state is an ‘activated complex’: a transient and dynamic state that, unlike more stable
species, does not have any definable lifetime. It may help to imagine a transition state as being analogous to the exact moment that a
baseball is struck by a bat. Transition states are drawn with dotted lines representing bonds that are in the process of breaking or forming,
and the drawing is often enclosed by brackets. Here is a picture of a likely transition state for a substitution reaction between hydroxide
and chloromethane:
− −
C H3 C l + H O → C H3 OH + C l (2.1.5)

This reaction involves a collision between two molecules: for this reason, we say that it has second order kinetics. The rate expression
for this type of reaction is:
rate = k[reactant 1][reactant 2]

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. . . which tells us that the rate of the reaction depends on the rate constant k as well as on the concentration of both reactants. The rate
constant can be determined experimentally by measuring the rate of the reaction with different starting reactant concentrations. The rate
constant depends on the activation energy, of course, but also on temperature: a higher temperature means a higher k and a faster
reaction, all else being equal. This should make intuitive sense: when there is more heat energy in the system, more of the reactant
molecules are able to get over the energy barrier.
Here is one more interesting and useful expression. Consider a simple reaction where the reactants are A and B, and the product is AB
(this is referred to as a condensation reaction, because two molecules are coming together, or condensing). If we know the rate constant
k for the forward reaction and the rate constant kreverse for the reverse reaction (where AB splits apart into A and B), we can simply take
the quotient to find our equilibrium constant K :
eq

This too should make some intuitive sense; if the forward rate constant is higher than the reverse rate constant, equilibrium should lie
towards products.

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Further Reading

MasterOrganicChemistry
Equilibria

Websites
Reversible and irreversible reactions
Activation Energy
Since exothermic reactions are energetically (thermodynamically) favored, a careless thinker might conclude that all such reactions will
proceed spontaneously to their products. Were this true, no life would exist on Earth, because the numerous carbon compounds that are
present in and essential to all living organisms would spontaneously combust in the presence of oxygen to give carbon dioxide-a more
stable carbon compound. The combustion of methane (eq.1), for example, does not occur spontaneously, but requires an initiating energy
in the form of a spark or flame. The flaw in this careless reasoning is that we have focused only on the initial (reactant) and final
(product) states of reactions. To understand why some reactions occur readily (almost spontaneously), whereas other reactions are slow,
even to the point of being unobservable, we need to consider the intermediate stages of reactions.
Exothermic Endothermic Exothermic
Single Step Reaction Single Step Reaction Two Step Reaction

Every reaction in which bonds are broken will have a high energy transition state that must be reached before products can form. In
order for the reactants to reach this transition state, energy must be supplied and reactant molecules must orient themselves in a suitable
fashion. The energy needed to raise the reactants to the transition state energy level is called the activation energy, ΔE‡. An example of
a single-step exothermic reaction profile is shown on the left above, and a similar single-step profile for an endothermic reaction is in the
center. The activation energy is drawn in red in each case, and the overall energy change (ΔE) is in green.
The profile becomes more complex when a multi-step reaction path is described. An example of a two-step reaction proceeding by way
of a high energy intermediate is shown on the right above. Here there are two transition states, each with its own activation energy. The
overall activation energy is the difference in energy between the reactant state and the highest energy transition state. We see now why
the rate of a reaction may not correlate with its overall energy change. In the exothermic diagram on the left, a significant activation
energy must be provided to initiate the reaction. Since the reaction is strongly exothermic, it will probably generate enough heat to keep
going as long as reactants remain. The endothermic reaction in the center has a similar activation energy, but this will have to be supplied
continuously for the reaction to proceed to completion.

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What is the source of the activation energy that enables a chemical reaction to occur? Often it is heat, as noted above in reference to the
flame or spark that initiates methane combustion. At room temperature, indeed at any temperature above absolute zero, the molecules of
a compound have a total energy that is a combination of translational (kinetic) energy, internal vibrational and rotational energies, as well
as electronic and nuclear energies. The temperature of a system is a measure of the average kinetic energy of all the atoms and molecules
present in the system. As shown in the following diagram, the average kinetic energy increases and the distribution of energies broadens
as the temperature is raised from T1 to T2. Portions of this thermal or kinetic energy provide the activation energy for many reactions, the
concentration of suitably activated reactant molecules increasing with temperature, e.g. orange area for T1 and yellow plus orange for T2.
(Note that the area under a curve or a part of a curve is proportional to the number of molecules represented.)

Distribution of Molecular Kinetic Energy

at Two Different Temperatures, T1 & T2

Reaction Rates and Kinetics

Chemical reactivity is the focus of chemistry, and the study of reaction rates provides essential information about this subject. Some
reactions proceed so rapidly they seem to be instantaneous, whereas other reactions are so slow they are nearly unobservable. Most of
the reactions described in this text take place in from 0.2 to 12 hours at 25 ºC. Temperature is important, since fast reactions may be
slowed or stopped by cooling, and slow reactions are accelerated by heating. When a reaction occurs between two reactant species, it
proceeds faster at higher concentrations of the reactants. These facts lead to the following general analysis of reaction rates.

Number of Collisions Fraction of Collisions an Orientational

between Reactant Molecules with Sufficient Energy or Probability
Reaction Rate = per Unit of Time • to pass the Transition State • Factor

Since reacting molecules must collide to interact, and the necessary activation energy must come from the kinetic energy of the colliding
molecules, the first two factors are obvious. The third (probability) factor incorporates the orientational requirements of the reaction. For
example, the addition of bromine to a double bond at the end of a six-carbon chain (1-hexene) could only occur if the colliding
molecules came together in a way that allowed the bromine molecule to interact with the pi-electrons of the double bond.
The collision frequency of reactant molecules will be proportional to their concentration in the reaction system. This aspect of a reaction
rate may be incorporated in a rate equation, which may take several forms depending on the number of reactants. Three general
examples are presented in the following table.

Reaction Type Rate Equation Reaction Order

A ——> B Reaction Rate = k•[A] First Order Reaction (no collision needed)

A+B ——> C + D Reaction Rate = k•[A]*[B] Second Order Reaction

A+A ——> D Reaction Rate = k•[A]2 Second Order Reaction

These rate equations take the form Reaction Rate = k[X] n[Y] m, where the proportionality constant k reflects the unique characteristics
of a specific reaction, and is called the rate constant. The concentrations of reactants X and Y are [X] and [Y] respectively, and n & m
are exponential numbers used to fit the rate equation to the experimental data. The sum n + m is termed the kinetic order of a reaction.
The first example is a simple first order process. The next two examples are second order reactions, since n + m = 2. The kinetic order of
a reaction is usually used to determine its molecularity.
In writing a rate equation we have disconnected the collision frequency term from the activation energy and probability factors defined
above, which are necessarily incorporated in the rate constant k. This is demonstrated by the following equation.

The complex parameter A incorporates the probability factor. Because of the exponential relationship of k and the activation energy
small changes in ΔE ‡ will cause relatively large changes in reaction rate. An increase in temperature clearly acts to increase k, but of
greater importance is the increase in average molecular kinetic energy such an increase produces. This was illustrated in a previous

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diagram, increase in temperature from T1 to T2 producing a larger proportion of reactant molecules having energies equal or greater than
the activation energy (designated by the red line.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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2.2: Keys to Success: Using Curved "Electron Pushing" Arrows to Describe Chemical Reactions
The Arrow Notation in Mechanisms
Since chemical reactions involve the breaking and making of bonds, a consideration of the movement of bonding ( and non-bonding ) valence shell electrons is
essential to this understanding. It is now common practice to show the movement of electrons with curved arrows, and a sequence of equations depicting the
consequences of such electron shifts is termed a mechanism. In general, two kinds of curved arrows are used in drawing mechanisms:

A full head on the arrow indicates the movement or shift of an electron pair:

A partial head (fishhook) on the arrow indicates the shift of a single electron:

The use of these symbols in bond-breaking and bond-making reactions is illustrated below. If a covalent single bond is broken so that one electron of the
shared pair remains with each fragment, as in the first example, this bond-breaking is called homolysis. If the bond breaks with both electrons of the shared
pair remaining with one fragment, as in the second and third examples, this is called heterolysis.

Bond-Breaking Bond-Making

Other Arrow Symbols

Chemists also use arrow symbols for other purposes, and it is essential to use them correctly.

The Reaction Arrow The Equilibrium Arrow The Resonance Arrow

The following equations illustrate the proper use of these symbols:

Reactive Intermediates
The products of bond breaking, shown above, are not stable in the usual sense, and cannot be isolated for prolonged study. Such species are referred to as
reactive intermediates, and are believed to be transient intermediates in many reactions. The general structures and names of four such intermediates are
given below.

A pair of widely used terms, related to the Lewis acid-base notation, should also be introduced here.
Electrophile: An electron deficient atom, ion or molecule that has an affinity for an electron pair, and will bond to a base or nucleophile.
Nucleophile: An atom, ion or molecule that has an electron pair that may be donated in bonding to an electrophile (or Lewis acid).
Using these definitions, it is clear that carbocations ( called carbonium ions in the older literature ) are electrophiles and carbanions are nucleophiles. Carbenes
have only a valence shell sextet of electrons and are therefore electron deficient. In this sense they are electrophiles, but the non-bonding electron pair also
gives carbenes nucleophilic character. As a rule, the electrophilic character dominates carbene reactivity. Carbon radicals have only seven valence electrons,
and may be considered electron deficient; however, they do not in general bond to nucleophilic electron pairs, so their chemistry exhibits unique differences
from that of conventional electrophiles. Radical intermediates are often called free radicals.
The importance of electrophile / nucleophile terminology comes from the fact that many organic reactions involve at some stage the bonding of a nucleophile
to an electrophile, a process that generally leads to a stable intermediate or product. Reactions of this kind are sometimes called ionic reactions, since ionic
reactants or products are often involved. Some common examples of ionic reactions and their mechanisms may be examined by Clicking Here

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The shapes ideally assumed by these intermediates becomes important when considering the stereochemistry of reactions in which they play a role. A simple
tetravalent compound like methane, CH4, has a tetrahedral configuration. Carbocations have only three bonds to the charge bearing carbon, so it adopts a
planar trigonal configuration. Carbanions are pyramidal in shape ( tetrahedral if the electron pair is viewed as a substituent ), but these species invert rapidly at
room temperature, passing through a higher energy planar form in which the electron pair occupies a p-orbital. Radicals are intermediate in configuration, the
energy difference between pyramidal and planar forms being very small. Since three points determine a plane, the shape of carbenes must be planar; however,
the valence electron distribution varies.

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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2.3: Acids and Bases; Electrophiles and Nucleophiles
☰
In 1923, chemists Johannes Brønsted and Martin Lowry independently developed definitions of acids and bases based on
compounds abilities to either donate or accept protons (H+ ions). Here, acids are defined as being able to donate protons in
the form of hydrogen ions; whereas bases are defined as being able to accept protons. This took the Arrhenius definition
one step further as water is no longer required to be present in the solution for acid and base reactions to occur.

Brønsted-Lowery Definition
J.N. Brønsted and T.M. Lowry independently developed the theory of proton donors and proton acceptors in acid-base
reactions, coincidentally in the same region and during the same year. The Arrhenius theory where acids and bases are
defined by whether the molecule contains hydrogen and hydroxide ion is too limiting. The main effect of the Brønsted-
Lowry definition is to identify the proton (H+) transfer occurring in the acid-base reaction. This is best illustrated in the
following equation:
− +
HA + Z ⇌ A + HZ (2.3.1)

Acid Base

Donates hydrogen ions Accepts hydrogen ions.

HCl+ HOH → H3O+ + Cl-

HOH+ NH3→ NH4+ + OH-

The determination of a substance as a Brønsted-Lowery acid or base can only be done by observing the reaction. In the
case of the HOH it is a base in the first case and an acid in the second case.

To determine whether a substance is an acid or a base, count the hydrogens on each substance before and after the reaction.
If the number of hydrogens has decreased that substance is the acid (donates hydrogen ions). If the number of hydrogens
has increased that substance is the base (accepts hydrogen ions). These definitions are normally applied to the reactants on
the left. If the reaction is viewed in reverse a new acid and base can be identified. The substances on the right side of the
equation are called conjugate acid and conjugate base compared to those on the left. Also note that the original acid turns
in the conjugate base after the reaction is over.

Acids are Proton Donors and Bases are Proton Acceptors

For a reaction to be in equilibrium a transfer of electrons needs to occur. The acid will give an electron away and the base
will receive the electron. Acids and Bases that work together in this fashion are called a conjugate pair made up of
conjugate acids and conjugate bases.
− +
HA + Z ⇌ A + HZ (2.3.2)

A stands for an Acidic compound and Z stands for a Basic compound

A Donates H to form HZ+.
Z Accepts H from A which forms HZ+

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 A- becomes conjugate base of HA and in the reverse reaction it accepts a H from HZ to recreate HA in order to remain
☰ in equilibrium
HZ+ becomes a conjugate acid of Z and in the reverse reaction it donates a H to A- recreating Z in order to remain in
equilibrium

Questions
1. Why is H A an Acid?
2. Why is Z a Base?
−

3. How can A- be a base when HA was and Acid?

4. How can HZ+ be an acid when Z used to be a Base?
Now that we understand the concept, let's look at an an example with actual compounds!
+ ¯
H C l + H2 O ⇌ H3 O + Cl (2.3.3)

HCL is the acid because it is donating a proton to H2O

H2O is the base because H2O is accepting a proton from HCL
H3O+ is the conjugate acid because it is donating an acid to CL turn into it's conjugate acid H2O
Cl¯ is the conjugate base because it accepts an H from H3O to return to it's conjugate acid HCl
How can H2O be a base? I thought it was neutral?

Answers
1. It has a proton that can be transferred
2. It receives a proton from HA
3. A- is a conjugate base because it is in need of a H in order to remain in equilibrium and return to HA
4. HZ+ is a conjugate acid because it needs to donate or give away its proton in order to return to it's previous state of Z
5. In the Brønsted-Lowry Theory what makes a compound an element or a base is whether or not it donates or accepts
protons. If the H2O was in a different problem and was instead donating an H rather than accepting an H it would be
an acid!

Conjugate Acid–Base Pairs

In aqueous solutions, acids and bases can be defined in terms of the transfer of a proton from an acid to a base. Thus for
every acidic species in an aqueous solution, there exists a species derived from the acid by the loss of a proton. These two
species that differ by only a proton constitute a conjugate acid–base pair.

All acid–base reactions contain two conjugate acid–base pairs.

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For example, in the reaction of HCl with water, HCl, the parent acid, donates a proton to a water molecule, the parent base,
☰
thereby forming Cl-. Thus HCl and Cl- constitute a conjugate acid–base pair. By convention, we always write a conjugate
acid–base pair as the acid followed by its conjugate base. In the reverse reaction, the Cl- ion in solution acts as a base to
accept a proton from H2O and HCl. Thus H3O+ and H2O constitute a second conjugate acid–base pair. In general, any
acid–base reaction must contain two conjugate acid–base pairs, which in this case are HCl/Cl- and H3O+/H2O.

Similarly, in the reaction of acetic acid with water, acetic acid donates a proton to water, which acts as the base. In the
reverse reaction, H O is the acid that donates a proton to the acetate ion, which acts as the base. Once again, we have
3
+

two conjugate acid–base pairs: the parent acid and its conjugate base (CH3CO2H/CH3CO2-) and the parent base and
its conjugate acid (H3O+/H2O).

Figure 2.3.2
In the reaction of ammonia with water to give ammonium ions and hydroxide ions (Figure 16.3), ammonia acts as a base
by accepting a proton from a water molecule, which in this case means that water is acting as an acid. In the reverse
reaction, an ammonium ion acts as an acid by donating a proton to a hydroxide ion, and the hydroxide ion acts as a base.
The conjugate acid–base pairs for this reaction are NH4+/NH3 and H2O/OH-.

Figure 2.3.3 : The Relative Strengths of Some Common Conjugate Acid–Base Pairs
Some common conjugate acid–base pairs are shown in Figure 2.3.4.

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☰

Figure 2.3.4 : The strongest acids are at the bottom left, and the strongest bases are at the top right. The conjugate base of a
strong acid is a very weak base, and, conversely, the conjugate acid of a strong base is a very weak acid.

Contributors
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne A. Morsch (University of Illinois Springfield)

The Brønsted-Lowry definition of acidity

We’ll begin our discussion of acid-base chemistry with a couple of essential definitions. The first of these definitions was
proposed in 1923 by the Danish chemist Johannes Brønsted and the English chemist Thomas Lowry, and has come to be
known as the Brønsted-Lowry definition of acids and bases. An acid, by the Brønsted-Lowry definition, is a species which
is able to donate a proton (H+), while a base is a proton acceptor. We have already discussed in the previous chapter one of
the most familiar examples of a Brønsted-Lowry acid-base reaction, between hydrochloric acid and hydroxide ion:

In this reaction, a proton is transferred from HCl (the acid, or proton donor) to hydroxide (the base, or proton acceptor). As
we learned in the previous chapter, curved arrows depict the movement of electrons in this bond-breaking and bond-
forming process.
After a Brønsted-Lowry acid donates a proton, what remains – in this case, a chloride ion – is called the conjugate base.
Chloride is thus the conjugate base of hydrochloric acid. Conversely, when a Brønsted-Lowry base accepts a proton it is
converted into its conjugate acid form: water is thus the conjugate acid of hydroxide.
We can also talk about conjugate acid/base pairs: the two acid/base pairs involved in our first reaction are hydrochloric
acid/chloride and hydroxide/water.In this next acid-base reaction, the two pairs involved are acetate/acetic acid and methyl
ammonium/methylamine:

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☰

Throughout this text, we will often use the abbreviations HA and :B in order to refer in a general way to acidic and basic
reactants:

In order to act as a proton acceptor, a base must have a reactive pair of electrons. In all of the examples we shall see in
this chapter, this pair of electrons is a non-bonding lone pair, usually (but not always) on an oxygen, nitrogen, sulfur, or
halogen atom. When acetate acts as a base in the reaction shown above, for example, one of its oxygen lone pairs is used to
form a new bond to a proton. The same can be said for an amine acting as a base. Clearly, methyl ammonium ion cannot
act as a base – it does not have a reactive pair of electrons with which to accept a new bond to a proton.

Later, in chapter 15, we will see several examples where the (relatively) reactive pair of electrons in a pi bond act in a basic
fashion.

In this chapter, we will concentrate on those bases with non-bonding (lone pair) electrons.

Example

Exercise 7.1: Draw structures for the missing conjugate acids or conjugate bases in the reactions below.

Solution

Contributors
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
You are no doubt aware that some acids are stronger than others. Sulfuric acid is strong enough to be used as a drain
cleaner, as it will rapidly dissolve clogs of hair and other organic material.

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☰

Not surprisingly, concentrated sulfuric acid will also cause painful burns if it touches your skin, and permanent damage if
it gets in your eyes (there’s a good reason for those safety goggles you wear in chemistry lab!). Acetic acid (vinegar), will
also burn your skin and eyes, but is not nearly strong enough to make an effective drain cleaner. Water, which we know
can act as a proton donor, is obviously not a very strong acid. Even hydroxide ion could theoretically act as an acid – it
has, after all, a proton to donate – but this is not a reaction that we would normally consider to be relevant in anything but
the most extreme conditions.
The relative acidity of different compounds or functional groups – in other words, their relative capacity to donate a proton
to a common base under identical conditions – is quantified by a number called the dissociation constant, abbreviated Ka.
The common base chosen for comparison is water.
We will consider acetic acid as our first example. When a small amount of acetic acid is added to water, a proton-transfer
event (acid-base reaction) occurs to some extent.

Notice the phrase ‘to some extent’ – this reaction does not run to completion, with all of the acetic acid converted to
acetate, its conjugate base. Rather, a dynamic equilibrium is reached, with proton transfer going in both directions (thus the
two-way arrows) and finite concentrations of all four species in play. The nature of this equilibrium situation, as you recall
from General Chemistry, is expressed by an equilibrium constant, Keq. The equilibrium constant is actually a ratio of
activities (represented by the symbol a ), but activities are rarely used in courses other than analytical or physical
chemistry. To simplify the discussion for general chemistry and organic chemistry courses, the activities of all of
the solutes are replaced with molarities, and the activity of the solvent (usually water) is defined as having the value of 1.
In our example, we added a small amount of acetic acid to a large amount of water: water is the solvent for this reaction.
Therefore, in the course of the reaction, the concentration of water changes very little, and the water can be treated as a
pure solvent, which is always assigned an activity of 1. The acetic acid, acetate ion and hydronium ion are all solutes, and
so their activities are approximated with molarities. The acid dissociation constant, or Ka, for acetic acid is therefore
defined as:
− +
a − ⋅a +
[C H3 C OO ][ H3 O ]
C H3 C OO H3 O
Keq = ≈ (2.3.4)
aC H3 C OOH ⋅ aH2 O [C H3 C OOH ][1]

Because dividing by 1 does not change the value of the constant, the "1" is usually not written, and Ka is written as:
− +
[C H3 C OO ][ H3 O ]
−5
Keq = Ka = = 1.75 × 10 (2.3.5)
[C H3 C OOH ]

In more general terms, the dissociation constant for a given acid is expressed as:
− +
[A ][ H3 O ]
Ka = (2.3.6)
[H A]

or
+
[A][ H3 O ]
Ka = (2.3.7)
+
[H A ]

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☰
The first expression applies to a neutral acid such as like HCl or acetic acid, while the second applies to a cationic acid like
ammonium (NH4+).
The value of Ka = 1.75 x 10-5 for acetic acid is very small - this means that very little dissociation actually takes place, and
there is much more acetic acid in solution at equilibrium than there is acetate ion. Acetic acid is a relatively weak acid, at
least when compared to sulfuric acid (Ka = 109) or hydrochloric acid (Ka = 107), both of which undergo essentially
complete dissociation in water.
A number like 1.75 x 10- 5 is not very easy either to say or to remember. Chemists have therefore come up with a more
convenient term to express relative acidity: the pKa value.
pKa = -log Ka
Doing the math, we find that the pKa of acetic acid is 4.8. The use of pKa values allows us to express the acidity of
common compounds and functional groups on a numerical scale of about –10 (very strong acid) to 50 (not acidic at all).
Table 7 at the end of the text lists exact or approximate pKa values for different types of protons that you are likely to
encounter in your study of organic and biological chemistry. Looking at Table 7, you see that the pKa of carboxylic acids
are in the 4-5 range, the pKa of sulfuric acid is –10, and the pKa of water is 14. Alkenes and alkanes, which are not acidic
at all, have pKa values above 30. The lower the pKa value, the stronger the acid.
It is important to realize that pKa is not at all the same thing as pH: the former is an inherent property of a compound or
functional group, while the latter is the measure of the hydronium ion concentration in a particular aqueous solution:
pH = -log [H3O+]
Any particular acid will always have the same pKa (assuming that we are talking about an aqueous solution at room
temperature) but different aqueous solutions of the acid could have different pH values, depending on how much acid is
added to how much water.
Our table of pKa values will also allow us to compare the strengths of different bases by comparing the pKavalues of their
conjugate acids. The key idea to remember is this: the stronger the conjugate acid, the weaker the conjugate base. Sulfuric
acid is the strongest acid on our list with a pKa value of –10, so HSO4- is the weakest conjugate base. You can see that
hydroxide ion is a stronger base than ammonia (NH3), because ammonium (NH4+, pKa = 9.2) is a stronger acid than water
(pKa = 14.0).
While Table 7 provides the pKa values of only a limited number of compounds, it can be very useful as a starting point for
estimating the acidity or basicity of just about any organic molecule. Here is where your familiarity with organic functional
groups will come in very handy. What, for example, is the pKaof cyclohexanol? It is not on the table, but as it is an alcohol
it is probably somewhere near that of ethanol (pKa = 16). Likewise, we can use Table 7 to predict that para-hydroxyphenyl
acetaldehyde, an intermediate compound in the biosynthesis of morphine, has a pKa in the neighborhood of 10, close to
that of our reference compound, phenol.

Notice in this example that we need to evaluate the potential acidity at four different locations on the molecule.

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☰

Aldehyde and aromatic protons are not at all acidic (pKavalues are above 40 – not on our table). The two protons on the
carbon next to the carbonyl are slightly acidic, with pKa values around 19-20 according to the table. The most acidic
proton is on the phenol group, so if the compound were to be subjected to a single molar equivalent of strong base, this is
the proton that would be donated.
As you continue your study of organic chemistry, it will be a very good idea to commit to memory the approximate pKa
ranges of some important functional groups, including water, alcohols, phenols, ammonium, thiols, phosphates, carboxylic
acids and carbons next to carbonyl groups (so-called a-carbons). These are the groups that you are most likely to see acting
as acids or bases in biological organic reactions.
A word of caution: when using the pKa table, be absolutely sure that you are considering the correct conjugate acid/base
pair. If you are asked to say something about the basicity of ammonia (NH3) compared to that of ethoxide ion
(CH3CH2O-), for example, the relevant pKa values to consider are 9.2 (the pKa of ammonium ion) and 16 (the pKa of
ethanol). From these numbers, you know that ethoxide is the stronger base. Do not make the mistake of using the pKa
value of 38: this is the pKa of ammonia acting as an acid, and tells you how basic the NH2- ion is (very basic!)

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☰

Example

Exercise 7.2: Using the pKa table, estimate pKa values for the most acidic group on the compounds below, and draw the structure of the
conjugate base that results when this group donates a proton.

Solution

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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2.4: Functional Groups: Centers of Reactivity
 Objectives

After completing this section, you should be able to

1. explain why the properties of a given organic compound are largely dependent on the functional group or groups
present in the compound.
2. identify the functional groups present in each of the following compound types: alkenes, alkynes, arenes, (alkyl and
aryl) halides, alcohols, ethers, aldehydes, ketones, esters, carboxylic acids, (carboxylic) acid chlorides, amides,
amines, nitriles, nitro compounds, sulfides and sulfoxides.
3. identify the functional groups present in an organic compound, given its structure.
4. Given the structure of an organic compound containing a single functional group, identify which of the compound
types listed under Objective 2, above, it belongs to.
5. draw the structure of a simple example of each of the compound types listed in Objective 2.

 Key Terms

Make certain that you can define, and use in context, the key term below.
functional group

 Study Notes

The concept of functional groups is a very important one. We expect that you will need to refer back to tables at the
end of Section 3.1 quite frequently at first, as it is not really feasible to learn the names and structures of all the
functional groups and compound types at one sitting. Gradually they will become familiar, and eventually you will
recognize them automatically.

Functional groups are small groups of atoms that exhibit a characteristic reactivity. A particular functional group will
almost always display its distinctive chemical behavior when it is present in a compound. Because of their importance in
understanding organic chemistry, functional groups have specific names that often carry over in the naming of individual
compounds incorporating the groups.
As we progress in our study of organic chemistry, it will become extremely important to be able to quickly recognize the
most common functional groups, because they are the key structural elements that define how organic molecules react. For
now, we will only worry about drawing and recognizing each functional group, as depicted by Lewis and line structures.
Much of the remainder of your study of organic chemistry will be taken up with learning about how the different
functional groups tend to behave in organic reactions.

Drawing abbreviated organic structures

Often when drawing organic structures, chemists find it convenient to use the letter 'R' to designate part of a molecule
outside of the region of interest. If we just want to refer in general to a functional group without drawing a specific
molecule, for example, we can use 'R groups' to focus attention on the group of interest:
H H O O
R C OH R C OH C C
H R H R R R

a primary a secondary an aldehyde a ketone

alcohol alcohol

The 'R' group is a convenient way to abbreviate the structures of large biological molecules,
especially when we are interested in something that is occurring specifically at one location on the
molecule.

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Common Functional Groups
In the following sections, many of the common functional groups found in organic chemistry will be described. Tables of
these functional groups can be found at the bottom of the page.

Hydrocarbons
The simplest functional group in organic chemistry (which is often ignored when listing functional groups) is called an
alkane, characterized by single bonds between two carbons and between carbon and hydrogen. Some examples of alkanes
include methane, CH4, is the natural gas you may burn in your furnace or on a stove. Octane, C8H18, is a component of
gasoline.

Alkanes
H H H H H H H H
H C C C C C C C C H
H H H H H H H H H
H C H

=
H

methane

octane

Alkenes (sometimes called olefins) have carbon-carbon double bonds, and alkynes have carbon-carbon triple bonds.
Ethene, the simplest alkene example, is a gas that serves as a cellular signal in fruits to stimulate ripening. (If you
want bananas to ripen quickly, put them in a paper bag along with an apple - the apple emits ethene gas, setting off the
ripening process in the bananas). Ethyne, commonly called acetylene, is used as a fuel in welding blow torches.
Alkenes and alkynes

H H
C C H C C H
H H
ethene ethyne
(an alkene) (an alkyne)

Alkenes have trigonal planar electron geometry (due to sp2 hybrid orbitals at the alkene carbons) while alkynes
have linear geometry (due to sp hybrid orbitals at the alkyne carbons). Furthermore, many alkenes can take two
geometric forms: cis or trans (or Z and E which will be explained in detail in Chapter 7). The cis and trans
forms of a given alkene are different molecules with different physical properties there is a very high energy
barrier to rotation about a double bond. In the example below, the difference between cis and trans alkenes is
readily apparent.
H 3C CH3 H3C H
C C C C
H H H CH3

cis -alkene trans -alkene

CH3 groups on CH3 groups on
the same side opposite sides

Alkanes, alkenes, and alkynes are all classified as hydrocarbons, because they are composed solely of carbon
and hydrogen atoms. Alkanes are said to be saturated hydrocarbons, because the carbons are bonded to the
maximum possible number of hydrogens - in other words, they are saturated with hydrogen atoms. The double
and triple-bonded carbons in alkenes and alkynes have fewer hydrogen atoms bonded to them - they are thus
referred to as unsaturated hydrocarbons. As we will see in Chapter 7, hydrogen can be added to double and
triple bonds, in a type of reaction called 'hydrogenation'.

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The aromatic group is exemplified by benzene (which used to be a commonly used solvent on the organic lab,
but which was shown to be carcinogenic), and naphthalene, a compound with a distinctive 'mothball' smell.
Aromatic groups are planar (flat) ring structures, and are widespread in nature. We will learn more about the
structure and reactions of aromatic groups in Chapter 15.

Aromatics
H
H C H
C C
=
C C
H C H
H
benzene naphthalene

Functional Groups with Carbon Single Bonds to other Atoms

Halides
When the carbon of an alkane is bonded to one or more halogens, the group is referred to as a alkyl halide
or haloalkane. The presence of a halogen atom (F, Cl, Br, or I), is often represented by X due to the similar
chemistry of halogens. Chloroform is a useful solvent in the laboratory, and was one of the earlier anesthetic
drugs used in surgery. Chlorodifluoromethane was used as a refrigerant and in aerosol sprays until the late
twentieth century, but its use was discontinued after it was found to have harmful effects on the ozone layer.
Bromoethane is a simple alkyl halide often used in organic synthesis. Alkyl halides groups are quite rare in
biomolecules.
H Cl H H
Cl C Cl F C Cl H C C Br
Cl F H H

trichloromethane dichlorodifluoromethane bromoethane

(chloroform) (Freon-12)

Alcohols and Thiols

In the alcohol functional group, a carbon is single-bonded to an OH group (the OH group, by itself, is
referred to as a hydroxyl). Except for methanol, all alcohols can be classified as primary, secondary, or
tertiary. In a primary alcohol, the carbon bonded to the OH group is also bonded to only one other carbon.
In a secondary alcohol and tertiary alcohol, the carbon is bonded to two or three other carbons,
respectively. When the hydroxyl group is directly attached to an aromatic ring, the resulting group is called
a phenol.
H
H H H CH3 H C OH
C C
H C OH H3C C OH H3C C OH H3C C OH
C C
H H CH3 CH3 H C H

methanol a primary a secondary a tertiary H

alcohol alcohol alcohol a phenol

The sulfur analog of an alcohol is called a thiol (the prefix thio, derived from the Greek, refers to sulfur).
H H CH3
H 3C C SH H 3C C SH H 3C C SH
H CH3 CH3

a primary a secondary a tertiary

thiol thiol thiol

Ethers and sulfides

In an ether functional group, a central oxygen is bonded to two carbons. Below are the line and Lewis
structures of diethyl ether, a common laboratory solvent and also one of the first medical anaesthesia agents.

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 H H H H
O H C C O C C H
H H H H

In sulfides, the oxygen atom of an ether has been replaced by a sulfur atom.

S
S

Amines

Amines are characterized by nitrogen atoms with single bonds to hydrogen and carbon. Just as there are
primary, secondary, and tertiary alcohols, there are primary, secondary, and tertiary amines. Ammonia is a
special case with no carbon atoms.

H N H H N CH3 H N CH3 H3 C N CH3

H H CH3 CH3

ammonia a primary a secondary a tertiary

amine amine amine

One of the most important properties of amines is that they are basic, and are readily protonated to form
ammonium cations. In the case where a nitrogen has four bonds to carbon (which is somewhat unusual in
biomolecules), it is called a quaternary ammonium ion.

H N H H N CH3 H N CH3 H3 C N CH3

H H CH3 CH3

ammonia a primary a secondary a tertiary

amine amine amine

H H CH3
H N H H N CH3 H 3C N CH3
H H CH3
ammonium a primary a quaternary
ion ammonium ion ammonium ion

Note: Do not be confused by how the terms 'primary', 'secondary', and 'tertiary' are applied to alcohols and
amines - the definitions are different. In alcohols, what matters is how many other carbons the alcohol
carbon is bonded to, while in amines, what matters is how many carbons the nitrogen is bonded to.
carbon is bonded to nitrogen is bonded to
three carbons one carbon

CH3
H 3C C OH H N CH3

CH3 H

a tertiary a primary
alcohol amine

Carbonyl Containing Functional Groups

Aldehydes and Ketones
There are a number of functional groups that contain a carbon-oxygen double bond, which is commonly
referred to as a carbonyl. Ketones and aldehydes are two closely related carbonyl-based functional groups
that react in very similar ways. In a ketone, the carbon atom of a carbonyl is bonded to two other carbons.
In an aldehyde, the carbonyl carbon is bonded on one side to a hydrogen, and on the other side to a carbon.
The exception to this definition is formaldehyde, in which the carbonyl carbon has bonds to two hydrogens.
O O O
C C C
H H H CH3 H3C CH3

formaldehyde an aldehyde a ketone

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Carboxylic acids and acid derivatives
If a carbonyl carbon is bonded on one side to a carbon (or hydrogen) and on the other side to a heteroatom
(in organic chemistry, this term generally refers to oxygen, nitrogen, sulfur, or one of the halogens), the
functional group is considered to be one of the ‘carboxylic acid derivatives’, a designation that describes a
grouping of several functional groups. The eponymous member of this grouping is the carboxylic acid
functional group, in which the carbonyl is bonded to a hydroxyl (OH) group.
O O
C C
H OH H 3C OH

formic acid acetic acid

(vinegar)

As the name implies, carboxylic acids are acidic, meaning that they are readily deprotonated to form the
conjugate base form, called a carboxylate (much more about carboxylic acids in Chapter 20).
O O
C C
H O H 3C O

formate acetate

In amides, the carbonyl carbon is bonded to a nitrogen. The nitrogen in an amide can be bonded either to
hydrogens, to carbons, or to both. Another way of thinking of an amide is that it is a carbonyl bonded to an
amine.
O O O
C H C CH3 C CH3
H3C N H3C N H 3C N
H H CH3

In esters, the carbonyl carbon is bonded to an oxygen which is itself bonded to another carbon. Another
way of thinking of an ester is that it is a carbonyl bonded to an alcohol. Thioesters are similar to esters,
except a sulfur is in place of the oxygen.
O O
C CH3 C CH3
H 3C O H 3C S

an ester a thioester

In an acid anhydride, there are two carbonyl carbons with an oxygen in between. An acid anhydride is
formed from combination of two carboxylic acids with the loss of water (anhydride).
O O
C C
H3C O CH3

an anhydride

In an acyl phosphate, the carbonyl carbon is bonded to the oxygen of a phosphate, and in an acid chloride,
the carbonyl carbon is bonded to a chlorine.
O
O O
C
H 3C O P O C
H3C Cl
O
an acyl an acid
phosphate chloride

Nitriles and Imines

In a nitrile group, a carbon is triple-bonded to a nitrogen. Nitriles are also often referred to as cyano
groups.
H 3C C N

a nitrile

Molecules with carbon-nitrogen double bonds are called imines, or Schiff bases.

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 H CH3
N N
C C
H3 C CH3 H3 C CH3

imines

Phosphates
Phosphorus is a very important element in biological organic chemistry, and is found as the central atom in
the phosphate group. Many biological organic molecules contain phosphate, diphosphate, and triphosphate
groups, which are linked to a carbon atom by the phosphate ester functionality.
O
O O O
O P O O
O P O P O
O OH O P O
O O
O

inorganic an organic an organic

phosphate phosphate ester diphosphate ester

Because phosphates are so abundant in biological organic chemistry, it is convenient to depict them with the
abbreviation 'P'. Notice that this 'P' abbreviation includes the oxygen atoms and negative charges associated
with the phosphate groups.
O O

O
=
OH O P O OH OP
O

O O
O P O P O = PPO
O O

Molecules with Multiple Functional Groups

A single compound may contain several different functional groups. The six-carbon sugar molecules
glucose and fructose, for example, contain aldehyde and ketone groups, respectively, and both contain five
alcohol groups (a compound with several alcohol groups is often referred to as a ‘polyol’).
OH OH O OH OH OH

H
OH OH OH OH OH O

glucose fructose

Capsaicin, the compound responsible for the heat in hot peppers, contains phenol, ether, amide, and alkene
functional groups.
HO
H
N
O
O
capsaicin

The male sex hormone testosterone contains ketone, alkene, and secondary alcohol groups, while
acetylsalicylic acid (aspirin) contains aromatic, carboxylic acid, and ester groups.

OH O OH

O CH3

O
acetylsalicylic acid
testosterone (aspirin)

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While not in any way a complete list, this section has covered most of the important functional groups that
we will encounter in biological and laboratory organic chemistry. The table found below provides a
summary of all of the groups listed in this section, plus a few more that will be introduced later in the text.

Exercise 2.4.1

Identify the functional groups in the following organic compounds. State whether alcohols and amines
are primary, secondary, or tertiary.

Answer
a) carboxylate, sulfide, aromatic, two amide groups (one of which is cyclic)
b) tertiary alcohol, thioester
c) carboxylate, ketone
d) ether, primary amine, alkene

2: Draw one example each (there are many possible correct answers) of compounds fitting the descriptions
below, using line structures. Be sure to designate the location of all non-zero formal charges. All atoms
should have complete octets (phosphorus may exceed the octet rule).
a) a compound with molecular formula C6H11NO that includes alkene, secondary amine, and primary
alcohol functional groups
b) an ion with molecular formula C3H5O6P 2- that includes aldehyde, secondary alcohol, and phosphate
functional groups.
c) A compound with molecular formula C6H9NO that has an amide functional group, and does not have an
alkene group.

Functional Group Tables

Exclusively Carbon Functional Groups
Group Formula Class Name Specific Example IUPAC Name Common Name

C C alkene H2C=CH2 ethene ethylene

C C alkyne HC≡CH ethyne acetylene

arene C6H6 benzene benzene

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Functional Groups with Single Bonds to Heteroatoms
Group Formula Class Name Specific Example IUPAC Name Common Name

C X halide H3C-I iodomethane methyl iodide

C OH alcohol CH3CH2OH ethanol ethyl alcohol
C O C ether CH3CH2OCH2CH3 diethyl ether ether

C N
amine H3C-NH2 aminomethane methylamine

O
C N
O
nitro compound H3C-NO2 nitromethane

C SH thiol H3C-SH methanethiol methyl mercaptan

C S C sulfide H3C-S-CH3 dimethyl sulfide

Functional Groups with Multiple Bonds to Heteroatoms

Group Formula Class Name Specific Example IUPAC Name Common Name

C C N nitrile H3C-CN ethanenitrile acetonitrile

O
C C aldehyde H3CCHO ethanal acetaldehyde
H

O
C C ketone H3CCOCH3 propanone acetone
C

O
C C
OH
carboxylic acid H3CCO2H ethanoic Acid acetic acid

O
C C
O C
ester H3CCO2CH2CH3 ethyl ethanoate ethyl acetate

O
C C
X
acid halide H3CCOCl ethanoyl chloride acetyl chloride

O
C C
N
amide H3CCON(CH3)2 N,N-dimethylethanamide N,N-dimethylacetamide

O acid Anhydride (H3CCO)2O ethanoic anhydride acetic anhydride

C C O
O C
C

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Exercises
Questions

Q3.1.1
The following is the molecule for ATP, or the molecule responsible for energy in human cells. Identify the
functional groups for ATP.

Solutions
S3.1.1

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham

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2.5: Straight-Chain and Branched Alkanes
Alkanes are organic compounds that consist entirely of single-bonded carbon and hydrogen atoms and lack any other
functional groups. Alkanes have the general formula C H n and can be subdivided into the following three groups: the
2n+2

linear straight-chain alkanes, branched alkanes, and cycloalkanes. Alkanes are also saturated hydrocarbons.
Cycloalkanes are cyclic hydrocarbons, meaning that the carbons of the molecule are arranged in the form of a ring.
Cycloalkanes are also saturated, meaning that all of the carbons atoms that make up the ring are single bonded to other
atoms (no double or triple bonds). There are also polycyclic alkanes, which are molecules that contain two or more
cycloalkanes that are joined, forming multiple rings.

Molecular Formulas
Alkanes are the simplest family of hydrocarbons - compounds containing carbon and hydrogen only. Alkanes only
contain carbon-hydrogen bonds and carbon-carbon single bonds. The first six alkanes are as follows:

methane CH4
ethane C2H6
propane C3H8
butane C4H10
pentane C5H12
hexane C6H14

You can work out the formula of any of the alkanes using the general formula CnH2n+2

Isomerism
Isomers are molecules that have the same molecular formula, but have a different arrangement of the atoms in space. That
excludes any different arrangements which are simply due to the molecule rotating as a whole, or rotating about particular
bonds. For example, both of the following are the same molecule. They are not isomers. Both are butane.

All of the alkanes containing four or more carbon atoms show structural isomerism, meaning that there are two or more
different structural formulae that you can draw for each molecular formula.
Example 1: Butane or MethylPropane
C4H10 could be either of these two different molecules:

These are different molecules named butane (left) and 2-methylpropane (right).

There are also endless other possible ways that this molecule could twist itself. There is completely free rotation around all
the carbon-carbon single bonds. If you had a model of a molecule in front of you, you would have to take it to pieces and
rebuild it if you wanted to make an isomer of that molecule. If you can make an apparently different molecule just by
rotating single bonds, it's not different - it's still the same molecule. In structural isomerism, the atoms are arranged in a
completely different order. This is easier to see with specific examples. What follows looks at some of the ways that
structural isomers can arise.

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Constitutional isomers arise because of the possibility of branching in carbon chains. For example, there are two isomers
of butane, C4H10. In one of them, the carbon atoms lie in a "straight chain" whereas in the other the chain is branched.

Be careful not to draw "false" isomers which are just twisted versions of the original molecule. For example, this structure
is just the straight chain version of butane rotated about the central carbon-carbon bond.

You could easily see this with a model. This is the example we've already used at the top of this page.

Example 2: Constitutional Isomers in Pentane

Pentane, C5H12, has three chain isomers. If you think you can find any others, they are simply twisted versions of the
ones below. If in doubt make some models.

Classification of Carbon and Hydrogen Atoms

Carbons have a special terminology to describe how many other carbons they are attached to.

Primary carbons (1o) attached to one other C atom

Secondary carbons (2o) are attached to two other C’s
Tertiary carbons (3o) are attached to theree other C’s
Quaternary carbons (4o) are attached to four C's
For example, each of the three types of carbons are found in the 2,2 -dimethyl, 4-methylpentane molecule

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Hydrogen atoms are also classified in this manner. A hydrogen atom attached to a primary carbon atom is called a primary
hydrogen; thus, isobutane, has nine primary hydrogens and one tertiary hydrogen.

Primary hydrogens (1o) are attached to carbons bonded to one other C atom
Secondary hydrogens (2o) are attached to carbons bonded to two other C’s
Tertiary hydrogens (3o) are attached to carbons bonded to theree other C’s
Each of the three types of carbons are found in the 2,2 -dimethyl, 4-methylpentane molecule

Contributors
Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Steven Farmer (Sonoma State University)

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2.6: Naming the Alkanes
 Objectives

After completing this section, you should be able to

1. provide the correct IUPAC name for any given alkane structure (Kekulé, condensed or shorthand).
2. draw the Kekulé, condensed or shorthand structure of an alkane, given its IUPAC name.

 Key Terms

Make certain that you can define, and use in context, the key term below.
IUPAC system

 Study Notes

The IUPAC system of nomenclature aims to ensure

1. that every organic compound has a unique, unambiguous name.
2. that the IUPAC name of any compound conveys the structure of that compound to a person familiar with the
system.
One way of checking whether the name you have given to an alkane is reasonable is to count the number of carbon
atoms implied by the chosen name. For example, if you named a compound 3‑ethyl-4‑methylheptane, you have
indicated that the compound contains a total of 10 carbon atoms—seven carbon atoms in the main chain, two carbon
atoms in an ethyl group, and one carbon atom in a methyl group. If you were to check the given structure and find 11
carbon atoms, you would know that you had made a mistake. Perhaps the name you should have written was 3‑ethyl-
4,4‑dimethylheptane!
When naming alkanes, a common error of beginning students is a failure to pick out the longest carbon chain. For
example, the correct name for the compound shown below is 3‑methylheptane, not 2‑ethylhexane.
H 3C CH2 CH2 CH2 CH CH3
CH2
CH3

Remember that every substituent must have a number, and do not forget the prefixes: di, tri, tetra, etc.
You must use commas to separate numbers, and hyphens to separate numbers and substituents. Notice that
3‑methylhexane is one word.

Hydrocarbons having no double or triple bond functional groups are classified as alkanes or cycloalkanes, depending on
whether the carbon atoms of the molecule are arranged only in chains or also in rings. Although these hydrocarbons have
no functional groups, they constitute the framework on which functional groups are located in other classes of compounds,
and provide an ideal starting point for studying and naming organic compounds. The alkanes and cycloalkanes are also
members of a larger class of compounds referred to as aliphatic. Simply put, aliphatic compounds are compounds that do
not incorporate any aromatic rings in their molecular structure.
The following table lists the IUPAC names assigned to simple continuous-chain alkanes from C-1 to C-10. A common
"ane" suffix identifies these compounds as alkanes. Longer chain alkanes are well known, and their names may be found
in many reference and text books. The names methane through decane should be memorized, since they constitute the
root of many IUPAC names. Fortunately, common numerical prefixes are used in naming chains of five or more carbon
atoms.
Table 3.4.1 : Simple Unbranched Alkanes

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 Molecular Structural Molecular Structural
Name Isomers Name Isomers
Formula Formula Formula Formula

CH3(CH2)4C
methane CH4 CH4 1 hexane C6H14 5
H3
CH3(CH2)5C
ethane C2H6 CH3CH3 1 heptane C7H16 9
H3
CH3(CH2)6C
propane C3H8 CH3CH2CH3 1 octane C8H18 18
H3
CH3CH2CH2 CH3(CH2)7C
butane C4H10 2 nonane C9H20 35
CH3 H3
pentane C5H12 CH3(CH2)3CH3 3 decane C10H22 CH3(CH2)8CH3 75

 Some important behavior trends and terminologies

1. The formulas and structures of these alkanes increase uniformly by a CH2 increment.
2. A uniform variation of this kind in a series of compounds is called homologous.
3. These formulas all fit the CnH2n+2 rule. This is also the highest possible H/C ratio for a stable hydrocarbon.
4. Since the H/C ratio in these compounds is at a maximum, we call them saturated (with hydrogen).

Beginning with butane (C4H10), and becoming more numerous with larger alkanes, we note the existence of alkane
isomers. For example, there are five C6H14 isomers, shown below as abbreviated line formulas (A through E):

A B C D E

Although these distinct compounds all have the same molecular formula, only one (A) can be called hexane. How then are
we to name the others?
The IUPAC system requires first that we have names for simple unbranched chains, as noted above, and second that we
have names for simple alkyl groups that may be attached to the chains. Examples of some common alkyl groups are given
in the following table. Note that the "ane" suffix is replaced by "yl" in naming groups. The symbol R is used to designate a
generic (unspecified) alkyl group.
Table 3.4.2 : Alkyl Groups Names
Group CH3– C2H5– CH3CH2CH2– (CH3)2CH– CH3CH2CH2CH
(CH
2–3)2CHCH2CH
– 3CH2CH(CH(CH
3)– 3)3C– R–

Name Methyl Ethyl Propyl Isopropyl Butyl Isobutyl sec-Butyl tert-Butyl Alkyl

IUPAC Rules for Alkane Nomenclature

1. Find and name the longest continuous carbon chain.
2. Identify and name groups attached to this chain.
3. Number the chain consecutively, starting at the end nearest a substituent group.
4. Designate the location of each substituent group by an appropriate number and name.
5. Assemble the name, listing groups in alphabetical order.
6. The prefixes di, tri, tetra etc., used to designate several groups of the same kind, are not considered when alphabetizing.

 Example 3.4.1 : Alkanes

A B C D E

The IUPAC names of the isomers of hexane are: A hexane B 2-methylpentane C 3-methylpentane D 2,2-
dimethylbutane E 2,3-dimethylbutane

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Halogen Groups
Halogen substituents are easily accommodated, using the names: fluoro (F-), chloro (Cl-), bromo (Br-) and iodo (I-).

 Example 3.4.2 : Halogen Substitution

For example, (CH3)2CHCH2CH2Br would be named 1-bromo-3-methylbutane. If the halogen is bonded to a simple
alkyl group an alternative "alkyl halide" name may be used. Thus, C2H5Cl may be named chloroethane (no locator
number is needed for a two carbon chain) or ethyl chloride.

Alkyl Groups
Alkanes can be described by the general formula CnH2n+2. An alkyl group is formed by removing one hydrogen from the
alkane chain and is described by the formula CnH2n+1. The removal of this hydrogen results in a stem change from -ane to
-yl. Take a look at the following examples.
CH4 CH3 R
methane methyl

CH3CH2CH3 CH3CH2CH2 R
propane propyl

The same concept can be applied to any of the straight chain alkane names provided in the table below.

Name Molecular Formula Condensed Structural Formula

Methane CH4 CH4

Ethane C2H6 CH3CH3

Propane C3H8 CH3CH2CH3
Butane C4H10 CH3(CH2)2CH3
Pentane C5H12 CH3(CH2)3CH3
Hexane C6H14 CH3(CH2)4CH3
Heptane C7H16 CH3(CH2)5CH3
Octane C8H18 CH3(CH2)6CH3
Nonane C9H20 CH3(CH2)7CH3
Decane C10H22 CH3(CH2)8CH3
Undecane C11H24 CH3(CH2)9CH3
Dodecane C12H26 CH3(CH2)10CH3
Tridecane C13H28 CH3(CH2)11CH3
Tetradecane C14H30 CH3(CH2)12CH3
Pentadecane C15H32 CH3(CH2)13CH3
Hexadecane C16H34 CH3(CH2)14CH3
Heptadecane C17H36 CH3(CH2)15CH3
Octadecane C18H38 CH3(CH2)16CH3
Nonadecane C19H40 CH3(CH2)17CH3
Eicosane C20H42 CH3(CH2)18CH3

Three Rules for Naming Alkanes

1. Choose the longest, most substituted carbon chain containing a functional group.

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2. A carbon bonded to a functional group must have the lowest possible carbon number. If there are no functional groups,
then any substituent present must have the lowest possible number.
3. Take the alphabetical order into consideration; that is, after applying the first two rules given above, make sure that
your substituents and/or functional groups are written in alphabetical order.

 Example 3.4.3

What is the name of the follow molecule?

Solution
Rule #1: Choose the longest, most substituted carbon chain containing a functional group. This example does not
contain any functional groups, so we only need to be concerned with choosing the longest, most substituted carbon
chain. The longest carbon chain has been highlighted in blue and consists of eight carbons.

Rule #2: Carbons bonded to a functional group must have the lowest possible carbon number. If there are no
functional groups, then any substitute present must have the lowest possible number. Because this example does not
contain any functional groups, we only need to be concerned with the two substitutes present, that is, the two methyl
groups. If we begin numbering the chain from the left, the methyls would be assigned the numbers 4 and 7,
respectively. If we begin numbering the chain from the right, the methyls would be assigned the numbers 2 and 5.
Therefore, to satisfy the second rule, numbering begins on the right side of the carbon chain as shown below. This
gives the methyl groups the lowest possible numbering.

8 7 6 5 4 3 2 1

Rule 3: In this example, there is no need to utilize the third rule. Because the two substitutes are identical, neither takes
alphabetical precedence with respect to numbering the carbons. This concept will become clearer in the following
examples.
The name of this molecule is 2,5-dimethyloctane

 Example 3.4.4

What is the name of the follow molecule?

Br Cl

Solution
Rule #1: Choose the longest, most substituted carbon chain containing a functional group. This example contains two
functional groups, bromine and chlorine. The longest carbon chain has been highlighted in blue and consists of seven
carbons.
Br Cl

Rule #2: Carbons bonded to a functional group must have the lowest possible carbon number. If there are no
functional groups, then any substituent present must have the lowest possible number. In this example, numbering the

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chain from either the left or the right would satisfy this rule. If we number the chain from the left, bromine and
chlorine would be assigned the second and sixth carbon positions, respectively. If we number the chain from the right,
chlorine would be assigned the second position and bromine would be assigned the sixth position. In other words,
whether we choose to number from the left or right, the functional groups occupy the second and sixth positions in the
chain. To select the correct numbering scheme, we need to utilize the third rule.
Br Cl Br Cl

7 6 5 4 3 2 1 1 2 3 4 5 6 7

Rule #3: After applying the first two rules, take the alphabetical order into consideration. Alphabetically, bromine
comes before chlorine. Therefore, bromine is assigned the second carbon position, and chlorine is assigned the sixth
carbon position.
Br Cl

1 2 3 4 5 6 7

The name of this molecule is: 2-bromo-6-chloroheptane

 Example 3.4.5
What is the name of the follow molecule?
Br Cl

Solution
Rule #1: Choose the longest, most substituted carbon chain containing a functional group. This example contains two
functional groups, bromine and chlorine, and one substitute, the methyl group. The longest carbon chain has been
highlighted in blue and consists of seven carbons.
Br Cl

Rule #2: Carbons bonded to a functional group must have the lowest possible carbon number. After taking functional
groups into consideration, any substitutes present must have the lowest possible carbon number. This particular
example illustrates the point of difference principle. If we number the chain from the left, bromine, the methyl group
and chlorine would occupy the second, fifth and sixth positions, respectively. This concept is illustrated in the second
drawing below. If we number the chain from the right, chlorine, the methyl group and bromine would occupy the
second, third and sixth positions, respectively, which is illustrated in the first drawing below. The position of the
methyl, therefore, becomes a point of difference. In the first drawing, the methyl occupies the third position. In the
second drawing, the methyl occupies the fifth position. To satisfy the second rule, we want to choose the numbering
scheme that provides the lowest possible numbering of this substitute. Therefore, the first of the two carbon chains
shown below is correct.
Br Cl

7 6 5 4 3 2 1

Br Cl

1 2 3 4 5 6 7

Therefore, the first numbering scheme is the appropriate one to use.

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 Br Cl

7 6 5 4 3 2 1

Once you have determined the correct numbering of the carbons, it is often useful to make a list, including the
functional groups, substitutes, and the name of the parent chain.
Rule #3: After applying the first two rules, take the alphabetical order into consideration. Alphabetically, bromine
comes before chlorine. Therefore, bromine is assigned the second carbon position, and chlorine is assigned the sixth
carbon position.
Parent chain: heptane Substitutents: 2-chloro 3-methyl 6-bromo
The name of this molecule is: 6-bromo-2-chloro-3-methylheptane

Exercises

 Exercise 3.4.1

Give the proper IUPAC names of the following compounds.

a)

b)

c)

Answer
a) Since this structure is an unbranched alkane (all single bonds) with a 5 carbon chain length, its name would be
pentane.
b) This alkane has a 7 carbon longest continuous chain length that we number from right to left to get the first
methyl substituent we encounter to have the lowest possible number (3 versus being 4 if numbering from left to
right). This causes it to have 2 methyl substituents at positions 3 & 4 so we would name it indicating those numbers
and the prefix dimethyl which gives a proper IUPAC name of 3,4-dimethylheptane.
c) This alkane has a 5 carbon longest continuous chain length (which could be numbered from left to right or right
to left due to the symmetry at C-3). It has two methyl substituents off of C-3 so the proper IUPAC name is 3,3-
dimethylpentane.
1 2
a) 4
3
5

7 5 3 1
b) 4
6 2

2 4
c) 3
5
1

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 Exercise 3.4.2

Give the proper IUPAC names of the following compounds.

a)

b)

c)

Answer
a) This alkane has a 9 carbon longest continuous chain length that we number from left to right (structure on left
numbered in blue) to make the ethyl substituent be number 4. For the structure on the right (numbered in red) going
from right to left, the methyl substituent is number 4. Since ethyl is higher in the alphabetical order, you want to
make it have the lower number so the structure on the left (blue numbering) takes priority and the name is 4-ethyl-
6-methylnonane.
b) This alkane has a 6 carbon longest continuous chain length that we number from right to left to make the first
methyl be C-2 (versus the opposite direction which would make the first methyl C-3). Since there are 3 methyl
substituents at positions 2,3, & 4, this compound would have the name 2,3,4-trimethylhexane.
c) This 6 carbon alkane can be numbered along different chains (see below) as well as in the opposite directions.
This shows the two different chains that can be drawn (making the first substituent in that chain the lowest
number). The structure on the left (numbered in blue) is the correct choice since it causes more substituents to be
on the longest continuous chain (3 vs 2 in the structure on the right). This would make the IUPAC name of the
structure 3-ethyl-2,4-dimethylhexane. (Notice how ethyl takes priority over methyl and the di- is not considered
for alphabetizing.)

2 8 vs 8 2
a) 1 1
4 6 9 6 4
3 5 7 9 7 5 3

b) 5 1
6 4
3
2

c) 4
3 6 vs 2 4
3 6
5
1 5
1 2

 Exercise 3.4.3

All of the following names represent a compound that has been named improperly. Draw out the structure from the
name and give the proper IUPAC name for the compounds.

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 a) 1,3-dimethylbutane
b) 4-ethylpentane
c) 2-ethyl-3-methylpentane

Answer
a) The structure that can be drawn for the improper name is shown below on the left. When you renumber it
properly (structure on the right), the correct name should be 2-methylpentane.

1
a)
3 4 2
2 4 5 3 1

b) The structure that can be drawn for the improper name is shown below on the left. When you renumber it
properly (structure on the right), notice that the longest chain is 6 C’s and we start the numbering on the end to the
right to make the methyl substituent come off at C-3 (instead of beong at C-4 if we numbered it the opposite
direction) the correct name should be 3-methyl hexane.

b) 2 1
5
2 4 3
3 5 6 4
1

c) The structure that can be drawn for the improper name is shown below on the left. When you renumber it
properly (structure on the right), notice that the longest chain is 6 C’s and since this molecule is symmetrical
(between carbon 3 & 4), you can start the numbers from either end. In this case, we have methyl substituents
coming off of carbons 3 & 4 so the proper name is 3,4-dimethyl hexane.

c) 1
2
3 3 5
2 4 4
5 6
1

 Exercise 3.4.4

All of the following names represent a compound that has been named improperly. Draw out the structure from the
name and give the proper IUPAC name for the compounds.
a) 2,2-diethylheptane
b) 2-propylpentane
c) 4,4-diethylbutane

Answer
a) The structure that can be drawn for the improper name is shown below on the left. When you renumber it
properly (structure on the right), notice that the longest chain is now 8 C’s and you have an ethyl substituent at C-3
and a methyl substituent also at C-3 so the proper name is 3- ethyl-3-methyloctane.
1
a)
2
7
2 4 6 3 5
1 3 5 7 8
4 6

b) The structure that can be drawn for the improper name is shown below on the left. When you renumber it
properly (structure on the right), notice that the longest chain is now 7 C’s and since this molecule is symmetrical
(at carbon 4), you can start the numbers from either end. There is a methyl substituent at C-4 so the proper name is
4-methylheptane.

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 1
b)
2 3
6
2 4 7
3 5 4
1 5

c) The structure that can be drawn for the improper name is shown below on the left. When you renumber it
properly (structure on the right) going from right to left (to make the ethyl substituent have the lowest number
possible), the correct name is 3-ethylhexane

c) 5 3 1
2 4
1 3 6 4 2

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Dr. Krista Cunningham
Dr. Zachary Sharrett (Sonoma State University)

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2.7: Structural and Physical Properties of Alkanes
☰
Alkanes are not very reactive and have little biological activity; all alkanes are colorless and odorless.

Boiling Points
The boiling points shown are for the "straight chain" isomers of which there is more than one. The first four alkanes are
gases at room temperature, and solids do not begin to appear until about C H , but this is imprecise because different
17 36

isomers typically have different melting and boiling points. By the time you get 17 carbons into an alkane, there are
unbelievable numbers of isomers!

Cycloalkanes have boiling points that are approximately 20 K higher than the corresponding straight chain alkane.
There is not a significant electronegativity difference between carbon and hydrogen, thus, there is not any significant bond
polarity. The molecules themselves also have very little polarity. A totally symmetrical molecule like methane is
completely non-polar, meaning that the only attractions between one molecule and its neighbors will be Van der Waals
dispersion forces. These forces will be very small for a molecule like methane but will increase as the molecules get
bigger. Therefore, the boiling points of the alkanes increase with molecular size.
Where you have isomers, the more branched the chain, the lower the boiling point tends to be. Van der Waals dispersion
forces are smaller for shorter molecules and only operate over very short distances between one molecule and its
neighbors. It is more difficult for short, fat molecules (with lots of branching) to lie as close together as long, thin
molecules.

Example

For example, the boiling points of the three isomers of C

5 H12 are:
pentane: 309.2 K
2-methylbutane: 301.0 K
2,2-dimethylpropane: 282.6 K
The slightly higher boiling points for the cycloalkanes are presumably because the molecules can get closer together because the ring
structure makes them tidier and less "wriggly"!

Solubility
Alkanes (both alkanes and cycloalkanes) are virtually insoluble in water, but dissolve in organic solvents. However, liquid
alkanes are good solvents for many other non-ionic organic compounds.

Solubility in Water
When a molecular substance dissolves in water, the following must occur:
break the intermolecular forces within the substance. In the case of the alkanes, these are the Van der Waals dispersion
forces.
break the intermolecular forces in the water so that the substance can fit between the water molecules. In water, the
primary intermolecular attractions are hydrogen bonds.
Breaking either of these attractions requires energy, although the amount of energy to break the Van der Waals dispersion
forces in something like methane is relatively negligible; this is not true of the hydrogen bonds in water.

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As something of a simplification, a substance will dissolve if there is enough energy released when new bonds are made
☰
between the substance and the water to compensate for what is used in breaking the original attractions. The only new
attractions between the alkane and the water molecules are Van der Waals forces. These forces do not release a sufficient
amount of energy to compensate for the energy required to break the hydrogen bonds in water. The alkane does not
dissolve.
Note: This is a simplification because entropic effects are important when things dissolve.

Solubility in organic solvents

In most organic solvents, the primary forces of attraction between the solvent molecules are Van der Waals - either
dispersion forces or dipole-dipole attractions. Therefore, when an alkane dissolves in an organic solvent, the Van der Waals
forces are broken and are replaced by new Van der Waals forces. The two processes more or less cancel each other out
energetically; thus, there is no barrier to solubility.

Contributors
Jim Clark (Chemguide.co.uk)

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2.8: Rotation about Single Bonds: Conformations
 Objectives

After completing this section, you should be able to

1. explain the concept of free rotation about a carbon-carbon single bond.
2. explain the difference between conformational isomerism and structural isomerism.
3. draw the conformers of ethane using both sawhorse representation and Newman projection.
4. sketch a graph of energy versus bond rotation for ethane, and discuss the graph in terms of torsional strain.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
conformation (conformer, conformational isomer)
dihedral angle
eclipsed conformation
Newman projection
staggered conformation
strain energy
torsional strain (eclipsing strain)

 Study Notes

You should be prepared to sketch various conformers using both sawhorse representations and Newman projections.
Each method has its own advantages, depending upon the circumstances. Notice that when drawing the Newman
projection of the eclipsed conformation of ethane, you cannot clearly draw the rear hydrogens exactly behind the front
ones. This is an inherent limitation associated with representing a 3-D structure in two dimensions.

Conformational isomerism involves rotation about sigma bonds, and does not involve any differences in the connectivity
of the atoms or geometry of bonding. Two or more structures that are categorized as conformational isomers, or
conformers, are really just two of the exact same molecule that differ only in rotation of one or more sigma bonds.

Ethane Conformations
Although there are seven sigma bonds in the ethane molecule, rotation about the six carbon-hydrogen bonds does not result
in any change in the shape of the molecule because the hydrogen atoms are essentially spherical. Rotation about the
carbon-carbon bond, however, results in many different possible molecular conformations.
rotating bond

H H H HH H H
180° rotation 90° rotation
C C C C C C H
HH H HH H HH H
H

In order to better visualize these different conformations, it is convenient to use a drawing convention called the Newman
projection. In a Newman projection, we look lengthwise down a specific bond of interest – in this case, the carbon-carbon
bond in ethane. We depict the ‘front’ atom as a dot, and the ‘back’ atom as a larger circle.
H HH H
looking down the H H
C C carbon-carbon bond
HH H H
H H
“staggered” conformation
(Newman projection)

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The six carbon-hydrogen bonds are shown as solid lines protruding from the two carbons at 120°angles, which is what the
actual tetrahedral geometry looks like when viewed from this perspective and flattened into two dimensions.
Figure 3.6.1: A 3D Model of Staggered Ethane.
The lowest energy conformation of ethane, shown in the figure above, is called the ‘staggered’ conformation. In the
staggered conformation, all of the C-H bonds on the front carbon are positioned at an angle of 60° relative to the C-H
bonds on the back carbon. This angle between a sigma bond on the front carbon compared to a sigma bond on the back
carbon is called the dihedral angle. In this conformation, the distance between the bonds (and the electrons in them) is
maximized. Maximizing the distance between the electrons decreases the electrostatic repulsion between the electrons and
results in a more stable structure.
If we now rotate the front CH3 group 60° clockwise, the molecule is in the highest energy ‘eclipsed' conformation, and the
hydrogens on the front carbon are as close as possible to the hydrogens on the back carbon.
H H HH
C C H
H H
HH HH H
“eclipsed” conformation

This is the highest energy conformation because of unfavorable electrostatic repulsion between the electrons in the front
and back C-H bonds. The energy of the eclipsed conformation is approximately 3 kcal/mol (12 kJ/mol) higher than that of
the staggered conformation. Torsional strain (or eclipsing strain) is the name give to the energy difference caused by the
increased electrostatic repulsion of eclipsing bonds.
Another 60° rotation returns the molecule to a second eclipsed conformation. This process can be continued all around the
360° circle, with three possible eclipsed conformations and three staggered conformations, in addition to an infinite
number of variations in between. We will focus on the staggered and eclipsed conformers since they are, respectively, the
lowest and highest energy conformers.

Unhindered (Free) Rotations Do Not Exist in Ethane

The carbon-carbon bond is not completely free to rotate – the 3 kcal/mol torsional strain in ethane creates a barrier to
rotation that must be overcome for the bond to rotate from one staggered conformation to another. This rotational barrier is
not large enough to prevent rotation except at extremely cold temperatures. So at normal temperatures, the carbon-carbon
bond is constantly rotating. However, at any given moment the molecule is more likely to be in a staggered conformation -
one of the rotational ‘energy valleys’ - than in any other conformer. The potential energy associated with the various
conformations of ethane varies with the dihedral angle of the bonds, as shown in Figure 3.6.2.

Figure 3.6.2: The potential energy associated with the various conformations of ethane varies with the dihedral angle of the
bonds. Valleys in the graph represent the low energy staggered conformers, while peaks represent the higher energy
eclipsed conformers.

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Although the conformers of ethane are in rapid equilibrium with each other, the 3 kcal/mol energy difference leads to a
substantial preponderance of staggered conformers (> 99.9%) at any given time. The animation below illustrates the
relationship between ethane's potential energy and its dihedral angle

Figure 3.6.2: Animation of potential energy vs. dihedral angle in ethane

Exercises
1) What is the most stable rotational conformation of ethane and explain why it is preferred over the other conformation?

Solutions
1) Staggered, as there is less repulsion between the hydrogen atoms.
Questions
Q3.6.1
What is the most stable rotational conformation of ethane and explain why it is preferred over the other conformation?
Solutions
S3.6.1
Staggered, as there is less repulsion between the hydrogen atoms.

Contributors and Attributions

William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Dr. Krista Cunningham

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2.9: Rotation in Substituted Ethanes
 Objectives

After completing this section, you should be able to

1. depict the staggered and eclipsed conformers of propane (or a similar compound) using sawhorse representations
and Newman projections.
2. sketch a graph of energy versus bond rotation for propane (or a similar compound) and discuss the graph in terms
of torsional strain.
3. depict the anti, gauche, eclipsed and fully eclipsed conformers of butane (or a similar compound), using sawhorse
representations and Newman projections.
4. sketch a graph of energy versus C2-C3 bond rotation for butane (or a similar compound), and discuss it in terms of
torsional and steric repulsion.
5. assess which of two (or more) conformers of a given compound is likely to predominate at room temperature from
a semi-quantitative knowledge of the energy costs of the interactions involved.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
anti conformation
gauche conformation
eclipsed conformation
steric repulsion (strain)

In butane, there are three rotating carbon-carbon sigma bonds to consider, but we will focus on the middle bond between
C2 and C3. Below are two representations of butane in a conformation which puts the two CH3 groups (C1 and C4) in the
eclipsed position.
H3C CH3 H3C CH3
C C H
H H
HH HH H
“eclipsed” (A)

Eclipsed interaction Energy (kcal/mol) Energy (kJ/mol)

H-H 1.0 4.0

H-CH3 1.4 6.0

CH3-CH3 2.6 11.0

The CH3-CH3 groups create the significantly larger eclipsed interaction of 11.0 kJ/mol. There are also two H-H eclipsed
interactions at 4.0 kJ/mol each to create a total of 2(4.0 kJ/mol) + 11.0 kJ/mol = 19.0 kJ/mol of strain. This is the highest
energy conformation for butane, due to torsional strain caused by the electrostatic repulsion of electrons in the eclipsed
bonds, but also because of another type of strain called ‘steric repulsion’, between the two rather bulky methyl groups.
Steric strain comes about when two large groups, such as two methyl groups, try to occupy the same space. What results is
a repulsive non-covalent interaction caused by their respective electron densities.
If we rotate the front, (blue) carbon by 60°clockwise, the butane molecule is now in a staggered conformation.
H 3C HCH CH3
3 H CH3
C C
HH H H
H H
gauche

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This is more specifically referred to as the ‘gauche’ conformation of butane. Notice that although they are staggered, the
two methyl groups are not as far apart as they could possibly be. There is still significant steric repulsion between the two
bulky groups.
A further rotation of 60° gives us a second eclipsed conformation (B) in which both methyl groups are lined up with
hydrogen atoms.
H3 C H H3 C H
C C H
HH H H CH3
CH3 H
“eclipsed” (B)

Due to steric repulsion between methyl and hydrogen substituents, this eclipsed conformation B is higher in energy than
the gauche conformation. However, because there is no methyl-to-methyl eclipsing, it is lower in energy than eclipsed
conformation A. One more 60° rotation produces the ‘anti’ conformation, where the two methyl groups are positioned
opposite each other and steric repulsion is minimized.
H3C HH CH3
H H
C C
HH H H
CH3 CH3
anti

The anti conformation is the lowest energy conformation for butane. The diagram below summarizes the relative energies
for the various eclipsed, staggered, and gauche conformations.
Figure 2.9.1 : A 3D Structure of the Anti Butane Conformer.

Figure 2.9.2 : Potential curve vs dihedral angle of the C2-C3 bond of butane.

Figure 2.9.2 : Newman projections of butane conformations & their relative energy differences (not total energies).
Conformations form when butane rotates about one of its single covalent bond. Torsional/dihedral angle is shown on x-
axis. Torsional/dihedral angle is shown on x-axis. Conformation names (according to IUPAC): A: anti-periplanar, anti or
trans B: synclinal or gauche C: anticlinal or eclipsed D: syn-periplanar or cis. Source for conformation names & conformer
classification: Pure & Appl. Chem., Vol. 68, No. 12, pp. 2193-2222, 1996. (Public Domain; Keministi).
At room temperature, butane is most likely to be in the lowest-energy anti conformation at any given moment in time,
although the energy barrier between the anti and eclipsed conformations is not high enough to prevent constant rotation
except at very low temperatures. For this reason (and also simply for ease of drawing), it is conventional to draw straight-

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chain alkanes in a zigzag form, which implies the anti conformation at all carbon-carbon bonds. For example octane is
commonly drawn as:
H H H H H H
C C C CH3 =
H3 C C C C
H H H H H H

octane

Drawing Newman Projections

Newman projections are a valuable method for viewing the relative positions of groups within molecule. Being able to
draw the Newman projection for a given molecule is a valuable skill and will be used repeatedly throughout organic
chemistry. Because organic molecules often contain multiple carbon-carbon bonds it is important to precisely know which
bond and which direction is being sighted for the Newman projection. The details of the Newman projection change given
the molecule but for typical alkanes a full conformational analysis involves a full 360o rotation in 60o increments. This will
produce three staggered conformers and three eclipsed conformers. Typically, the staggered conformers are more stable
and the eclipsed conformers are less stable. The least stable conformer will have the largest groups eclipsed while the most
stable conformer will have the largest groups anti (180o) to each other.

Example
Draw the Newman projection of 2,3 dimethylbutane along the C2-C3 bond. Then determine the least stable
conformation.
First draw the molecule and locate the indicated bond:
H3 C CH3
H C C H
H3 C CH3

Because the question asks for the least stable conformation, focus on the three possible eclipsed Newman projections.
Draw out three eclipsed Newman projections as a template. Because it is difficult to draw a true staggered Newman
projection, it is common to show the bonds slightly askew.

Place the substituents attached to the second carbon (C3) on the back bonds of all three Newman projections. In this
example they are 2 CH3s and an H. Place the substituents in the same position on all three Newman projections.
The groups are filled in on the three Newman projections.

Then place the substituents attached to the first carbon (C2) on the front bonds of the Newman projection. In this example,
the substituents are also 2 CH3s and an H. Move the substituents through two 60o rotations to create the remaining two
eclipsed Newman projections. Leave the substituents on the back carbon in place. Attempting to rotate the front and back
carbons simultaneously is a common mistake and often leads to incorrect Newman projections.
The groups are filled in on the three Newman projections.

Compare the Newman projections by looking the eclipsed interactions. Remember that the order of torsional strain
interactions are CH3-CH3 > CH3-H > H-H. The third structure has two CH3-CH3 torsional interactions which will make it
the least stable conformer of 2,3 dimethyl butane.
H3C CH3
CH3
H CH3
H

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 Example 2.9.1

Draw Newman projections of the eclipsed and staggered conformations of propane, as if viewed down the C1-C2 bond.

Answer
H 3C H H 3C H
C C H
H H
HH HH H
highest energy
(eclipsed)

H 3C HH CH3
H H
C C
HH H H
H H
lowest energy
(staggered)

 Example 2.9.2

Draw a Newman projection, looking down the C2-C3 bond, of 1-butene in the conformation shown below.

Answer

H H 3C H
H C CH3 H
C C
H CH2
H H H

Exercises
Questions
Q3.7.1
Draw the energy diagram for the rotation of the bond highlighted in pentane.

Solutions
S3.7.1

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Dr. Krista Cunningham

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2.E: Structure and Reactivity: Acids and Bases, Polar and Nonpolar Molecules
(Exercises)
These are homework exercises to accompany Chapter 2 of Vollhardt and Schore's "Organic Chemistry" Textmap.

2.1: Kinetics and Thermodynamics of Simple Chemical Processes

2.2: Keys to Success: Using Curved "Electron Pushing" Arrows to Describe Chemical
Reactions
2.3: Acids and Bases; Electrophiles and Nucleophiles

2.4: Functional Groups: Centers of Reactivity

2.5: Straight-Chain and Branched Alkanes

2.6: Naming the Alkanes

2.7: Structural and Physical Properties of Alkanes

2.8: Rotation about Single Bonds: Conformations

2.9: Rotation in Substituted Ethanes
Problems
Q26
A tray of ice cubes is left out on the counter in a room, and the ice cubes melt. If the room is a closed system, what is the
total enthalpy of the system (room + ice)? The entropy of the system? What about the free energy? Is this process
thermodynamically favorable? How would the temperature of the ice, now water, and the room compare?

Q27
(a) Using the following bond strengths, calculate the ∆Ho for each of the reactions.
Bond Average Strength (kcal mol-1)

C-C 83

C=C 146
C-H 99
Cl-Cl 57
H-Cl 102
C-Cl 78

(i) CH3-CH=CH2 + Cl2 → CH3-CHCl-CH2Cl

(ii) CH3-CH=CH2 + Cl2 → CH2Cl-CH=CH2 + HCl
(b) One of these reactions as a ∆So <0 (-35 cal mol-1) and the other has a ∆So=0. Assign the two to the equations, and give
your reasoning.
(c) Based on both ∆So and ∆Ho calculate ∆Go for each reaction at 30oC and 800oC. Are the reactions favorable at these
temperatures?

Q28
I. In each of the following equations label the Brønsted acid and base, on both sides.
II. Also, determine which way the equilibrium lies, left or right.

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III. From the given pKa of each acid calculate the equilibrium constant, Keq. (pKa H3O+ = -1.7)

a.

b.

c.

d.

Q29
In problem 28 use electron pushing arrows to show what is occurring, looking from left to right.

Q30
Determine whether each of the following species is a Lewis acid or Lewis base. Demonstrate this ability with an electron
arrow pushing mechanism.
(a) AlCl3 (b) H2O (c) ZnCl2 (d) ScCl3 (e) N3- (f) CH3CH2O-

Q31
For each of the following molecules denote the bond polarities, δ+ or δ-.

(a) (b) (c) (d) (e)

Q32
Identify whether each species is nucleophilic or electrophilic
(a) Fluoride anion, F- (b) Hydride anion, H- (c) acid chloride, CH3COCl (d) ScCl3 (e) N,N'-diethylcarbodiimide

Q33
Identify the functional groups present in each molecule below.

(a) (b) (c) (d) (e) (f)

Q34
Determine, based on Coulombic interaction, if the following are likely to react. No reaction is a possibility.
(a) ammonia (NH3) and cyclohexanone (b) H+ and ethanol (c) azide (N3-) and bromoethane (d) nitrogen (N2) and propane
(e) triethylamine and H+

Q35
Draw the electron arrow pushing mechanism of the potential interaction in problem 34

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Q36
Name each of the following compounds according to IUPAC.

(a) (b) (c) (d) (e)

(f)

Q37
Draw the following structures from the name
a. 2,3,4-trimethylpentane
b. 4-ethyl-3,4,5,5-tetramethylnonane
c. neopentane
d. 2,2,4,4-tetramethylpentane
e. 7-pentyltridecane
f. 2,3,4,5,6-pentamethylheptane

Q38
Draw the structures that correspond to the following names, correct any names that are not in accord with the rules of
systematic nomenclature.
a. 3-methyl-2-fluoropentane
b. 1-chloro-3-bromo-2,2-dimethylbutane
c. 2-ethyl-2-chloro-4,5-methylhexane
d. 3-methylpentane

Q39
Draw all possible isomers of C6H14

Q40
In each of the following compounds identify each carbon as either primary (1o), secondary (2o), tertiary (3o), or quaternary
(4o).
(a) cyclopentane (b) 3,3,5,5-tetraethylheptane (c) methylcyclopentane (d) 2,3,4-trimethylpentane

Q41
Identify each of the following alkyl groups as primary, secondary, tertiary, or quaternary. This is based off of the 1 position
in the alkyl group, connected to the dashed bond. Also, give its IUPAC name.

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(a) (b) (c) (d)

Q42
Does the molecule in (a) contain a tertiary carbon? Does the molecule in (b)? Explain why.

(a) (b)

Q43
Based on the following structures, think about the London dispersion forces and how that would affect the boiling point.
Rank the following compounds in order from lowest to highest boiling point.
(a) 2,3,4-trimethylhexane (b) nonane (c) 2,3-dimethylpentane (d) 3-methylheptane

Q44
Draw the lowest energy Newman projection of the following:
a. 2,3-dimethylbutane C2-C3
b. 2,2-dimethylbutane C2-C3
c. 2-methylpentane C2-C3
d. 2-methylpropane

Q45
Draw the energy diagram, Energy vs. Torsional angle of the C2-C3 bond of butane, rotating increments of 60o starting at
the lowest energy conformation. Also draw the Newman projection of each.

Q46
Given that 85% of all molecules are anti- and 15% of all molecules are eclipsed conformation along a certain C-C bond,
take for example C2-C3 of butane, draw the two Newman projections. Calculate the ΔGo value using ΔGo=-RTln(K), at
25oC where R=1.986 cal deg-1 mol-1. Does the given information make sense? If not, in what ways?

Q47
Identify the functional groups in each compound.

(a) (aspirin) (b) (dopamine) (c) (erythritol- sweetener)

(d) (limonene- in oranges and lemons, subtle differences in stereochemistry make a difference in the
smell)

Q48
Name the alkyl group as if the dashed line were where it was connect to the rest of the molecule, state whether it is
primary, secondary, or tertiary.

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(a) (b) (c) (d)

Q49
Calculate the new value of k, relative to the initial value, using the Arrhenius equation with increases of 10, 25, and 60oC.
Assume the initial temperature is 300oC.
Where Ea is the following
(a) 10 kcal mol-1 (b) 25 kcal mol-1 (c) 50 kcal mol-1

Q50
An alternate form of the Arrhenius equation involves taking the natural logarithm of the equation giving the following.
lnk=lnA-(Ea/RT)
What plot involving both k and T would yield a straight line? Give some characteristics of the line, slope and intercept.

Q51
For question 35 draw the product that would result from the arrow pushing mechanism. Make sure not to draw a
pentavalent carbon in (a) (use the oxygen atom) and (b) (substitute the bromine and have it leave).

Q52
Given that the Gibbs free energy is given by the following equation ΔG=ΔH-TΔS, fill in the table that yield a spontaneous
process (ΔG<0)

ΔH ΔS

Less than Zero ???

??? Greater than Zero

Q53
Under certain conditions the two following reactions are second order, proportional to both reactants concentrations. Write
the rate law for each reaction, and similar to in problem 35 draw the structures with any electrostatic interactions.

(a)

(b)

Q54
Which of the following is true about 2,3-dimethylbutane?
a. There are 10 primary H's
b. There are 6 times as many primary H's as there are tertiary H's
c. There are 3 tertiary C's
d. There are no primary C's

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Q55
Using ΔG=ΔH-TΔS, where ΔH=-1000 cal/mol and ΔS=-2cal/mol at T=200K, which of the following is true.
a. The reaction is endothermic
b. The reaction is not spontaneous
c. The reaction is exergonic
d. It is likely that the reaction involves one reactant and yields two products.

Q56
In 2-methylbutane what bond angles exist?
a. 90o
b. 120o
c. 180o
d. 109.5o

Q57
Which conformation describes the following Newman projection? Which one would be the lowest in energy?

a. anti eclipsed
b. anti gauche
c. gauche staggered
d. anti staggered

Q58
The following molecule, isatin, has all of the following functional groups except for:

a. aromatic ring
b. ketone
c. aldehyde
d. amide

Solutions
S26
The enthalpy of the system is zero, since the change is cancelled out by the ice gaining heat and the room losing heat.
However, the entropy does increase and so the free energy decreases. This process is thermodynamically favorable as the
free energy decreases. The end temperature of the ice and water would be equal.

S27
(a) ∆Ho= Bonds Broken - Bonds Formed
(i) ∆Ho= (C=C + Cl-Cl) - (2 C-Cl + C-C)
= (146 + 57) - (2(78) + 83) = -36 kcal mol-1
(ii) ∆Ho= (C-H + Cl-Cl) - (C-Cl + H-Cl)

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=(99 + 57) - (78 + 102) = -24 kcal mol-1
(b) Reaction (i) involves the combination of two molecules into one. Fewer numbers of products concentrates the energy,
and therefor leads to a negative ∆So value. Reaction (ii) starts with two molecules and results in two molecules. There is no
change in the entropy, and so ∆So=0.
(c) The two above values can be used to find the change in the Gibbs Free Energy using the following equation.
∆Go= ∆Ho - T∆So
(i) at 30oC, or (30 + 273.15)=303.15 K
∆Go= -36 - 303.15(-35x10-3) = -25 kcal mol-1 Favorable
at 800oC, or 973.15 K
∆Go= -36 - 1073.15(-35x10-3) = +1 kcal mol-1 Not Favorable
(ii) at 30oC
∆Go= -24 - 303.15(0) = -24 kcal mol-1 Favorable
at 700oC
∆Go= -24 - 1073.15(0) = -24 kcal mol-1 Favorable

S28
(a) (i) H2O=Weaker Base HF= Weaker Acid; H3O+= Stronger Acid F-=Stronger Base
(ii) From above, the equilibrium would lie to the left
(iii) Using the pKa we can find the Ka for each acid, Ka=10-pKa HF Ka=10-3.45 and H3O+ Ka= 101.7
Ka HF= [F-][H+]/[HF] and Ka H3O+ =[H+][H2O]/[H3O+] and Keq= [H3O+][F-]/[H2O][HF], from this we can see that Keq= Ka
-3.45
HF/Ka H3O+ or 10 /101.7= 7.08x10-6. This makes sense because the favors the left, so calculating the equilibrium to the
right would mean a very small equilibrium constant.
(b) (i) H2O=Weaker Base HCN=Weaker Acid; H3O+=Stronger Acid CN-=Stronger Base
(ii) From part (i), the equilibrium would lie to the left.
(iii) Ka H3O+= [H+][H2O]/[H3O+]= 101.7 and Ka HCN= [CN-][H+]/[HCN]= 10-9.2 and the Keq= Ka HCN/Ka H3O+ = 10-9.2/101.7
= 1.26x10-11 , the case is the same as the previous problem. The equilbrium constant for the reaction as drawn, left to right,
is very small.
(c) (i) CH3COOH=Weaker Acid F-=Weaker Base; CH3COO-=Stronger Base HF=Stronger Acid
(ii) Due to part (i), the equilibrium would lie to the left.
(iii) Ka CH3COOH= [H+][CH3COO-]/[CH3COOH]=10-4.7 KHF= [H+][F-]/[HF]=10-3.45 This results in Keq=Ka CH3COOH/KHF=
10-4.7/10-3.45 =5.62x10-2
(d) (i) H3BO3= Equally Acid NH3=Equally Basic; H2BO3-=Equally Basic NH4+=Equally Acidic
(ii) The reaction equilibrium does not lie to either side. H3BO3 and NH4+ are equally acidic according to their pKa
(iii) If the Keq were calculated it be equal to 1. 10-9.3/10-9.3=1.

S29

(a) (b)

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(c) (c)

S30
(a) AlCl3 is a Lewis acid. Aluminum is electron deficient, and with three electronegative halogens attached, the Aluminum
center is an electron acceptor.

(b) H2O is a Lewis base. The oxygen has two lone pairs of electrons, and is thus an electron donor.

(c) ZnCl2 is a Lewis acid. The zinc center is Zn2+, losing two electrons from the 4s orbitals leaving it with a full 3d orbital.
It is in a positive oxidation state and has two electronegative halogens attached, and so the zinc center is an electron
acceptor.

(d) ScCl3 is a Lewis acid. The scandium center is Sc3+, lacking two electrons in the 4s orbitals and one from the 3d orbital,
leaving it with a full 3p orbital. It is in a positive oxidation state hand has three electronegative halogens attached, and so
the scandium center is an electron acceptor.

(e) N3- is a Lewis base. There are two possible resonance structures for this species, and in both there are lone pair
electrons on the front nitrogen. It is an electron donor.

for simplicity, only one resonance structure was shown as the

Lewis acid/base adduct.
(f) CH3CH2O- is a Lewis base. The oxygen has three lone pairs of electrons, it is an electron donor. Even if it was not
negatively charged it would still be a Lewis base, with two lone pairs.

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S31

(a) (b) (c) (d) (e)

S32
(a) The fluoride anion is negatively charged, and it is nucleophilic. (b) The hydride anion is negatively charged, and it is
nucleophilic. (c) Acid chlorides are similar to esters and ketones in that there is an electrophilic carbon double bonded to
the oxygen, but acid chlorides are typically much more reactive. (d) ScCl3 was seen earlier to be Lewis acidic, and it is
electrophilic. (e) The central carbon in N,N'-diethylcarbodiimide is electrophilic due to the bond polarizations between the
two nitrogen atoms.

S33
(a) An aromatic ring and a carboxylic acid are present. (b) Alcohol (c) ester (d) haloalkane (e) anhydride, this is similar to
an ester, but the difference is the oxygen atom placement. (f) amide

S34
a. The ketone provides an electrophilic carbon.
b. The alcohol has two lone pairs of electrons, and with a positive charge there is a Coulombic attraction.
c. The important thing here is the polarization of the C-Br bond, making the carbon electrophilic. The azide has an overall
negative charge, and a Coulombic attraction is present.
d. There is no large polarization in bonds present. Both of these gases are not known for being nucleophilic or
electrophilic.
e. This is a standard acid base reaction, but it can be explained by the Coulombic attraction between the positively
charged hydrogen ion and the lone pair on the nitrogen.

S35

(a) (b) (c) (d) No reaction (e)

S36

(a) (b) (c)

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(d) (e) (f)

S37

(a) (b) (c) (d)

(e) (f)

S38

(a) (b) (c) (d)

or 2-methylpentane

S39

S40

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(a) (b) (c) (d)

S41
(a) primary, 2,2-dimethylbutyl (b) tertiary, 1-ethyl-1-methylbutyl (c) secondary, 1,3-dimethylbutyl (d) tertiary, 1,1,2,2-
tetramethylethyl

S42
Molecule (a) does not contain a tertiary carbon, it is only bonded to two other carbon atoms. An oxygen atom does not
affect this. Compound (b) does contain a tertiary carbon, as it is bonded to three other carbon atoms.

S43
2,3,4-trimethylpentane<2,3-dimethylhexane<3-methylheptane<nonane
This is a combination of both molecular weight and how branched the molecule is (affect the strength of the London
dispersion forces). The higher the molecular weight the higher the boiling point, but also the more branched a molecule is
the lower the boiling point.

S44

(a) (b) (c) (d)

S45

S46

ΔGo=-(1.986)(273+25)ln(85/15)= -1027 cal or -1.027 kcal

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The given information makes sense in that a larger percentage of the molecules are present in the Anti conformation due to
its lower energy. However, other conformations are not included, some lower in energy than the eclipsed form such as
staggered. These are likely to also make a contribution.

S47

(a) (b) (c) (d)

S48
(a) 1,6,6-trimethylhexyl, secondary (b) 1,1,2,2-tetramethylbutyl, tertiary (c) 2,2-dimethylbutyl, primary (d) 2-methylethyl
or isopropyl, primary

S49
The Arrhenius equation is k=Ae-(Ea/RT) where A is a constant. To calculate the new k value use the following k2/k1=Ae-
(Ea/RT2)
/Ae-(Ea/RT1) and the constant, A, cancels.
k2=[e-(Ea/RT2)/e-(Ea/RT1)]k1 also remember to convert the Ea from kcal to cal.
(a) 10oC - k2=[e-(10,000/(1.986)(310))/e-(10,000/(1.986)(300))]k1= 1.71k1
25oC - k2= 3.64k1
60oC - k2=16.4k1
(b) 10oC - k2=3.87k1
25oC - k2=25.2k1
60oC - k2=1090k1
(c) 10oC- k2=15.0k1
25oC- k2=636k1
60oC- k2=1.19x106k1
Note the increase in affect of the temperature the larger the activation energy.

S50
lnk=lnA-(Ea/RT)
A plot of lnk vs. 1/T would yield a straight line. The slope of this line would be -(Ea/R) with an x-intercept of Ea/(R(lnA))
and a y-intercept of lnA.

S51

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(a) (b) (c) This is an example of a substitution reaction,
which you'll learn about later.

(d) No Reaction (e)

S52
ΔG=ΔH-TΔS
ΔH ΔS

ΔS can either be any positive value, or a negative value such that

Less than Zero
|TΔS|<|ΔH|
ΔH can either be any negative value, or a positive value such that |
Greater than Zero
ΔH|<|TΔS|

S53
(a) Rate=k[CH3CH2O-][alkyl bromide]

(b) Rate=k[CHC-][alkyl bromide]

S54

(b) is correct, there are 12 primary H's and 2 tertiary H's.

(a) There are 10 primary H's - incorrect, there are 12 primary H's
(c) There are 3 tertiary C's - incorrect, there are 2 tertiary C's
(d) There are no primary C's - There are 4 primary C's

S55
ΔG=ΔH-TΔS=-1000-(200)(-2)=-600 cal/mol, so (c) is true. exergonic means that ΔG<0.
(a) The reaction is endothermic - incorrect, ΔH<0
(b) The reaction is not spontaneous - incorrect, ΔG<0

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(d) It is likely that the reaction involves one reactant and yields two products. - incorrect, with a negative change in
entropy, it is more likely that two reactants yielded one product.

S56
This molecule is entirely sp3 hybridized, so all angles are 109.5o, (d).

S57
(c) - gauche staggered is the conformation. The two CH3 groups are separated by 60o and no group is eclipsed. The lowest
energy conformation would be (d) anti staggered, where the larger CH3 groups are anti and there is no eclipsed group.

S58
(c), aldehyde is not in the molecule. There is a ketone, but no aldehyde.

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CHAPTER OVERVIEW
3: REACTIONS OF ALKANES: BOND-DISSOCIATION ENERGIES, RADICAL
HALOGENATION, AND RELATIVE REACTIVITY
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

3.1: STRENGTH OF ALKANE BONDS: RADICALS

3.2: STRUCTURE OF ALKYL RADICALS: HYPERCONJUGATION
3.3: CONVERSION OF PETROLEUM: PYROLYSIS
3.4: CHLORINATION OF METHANE: THE RADICAL CHAIN MECHANISM
3.5: OTHER RADICAL HALOGENATIONS OF METHANE
3.6: KEYS TO SUCCESS: USING THE "KNOWN" MECHANISM AS A MODEL FOR THE "UNKNOWN"
3.7: CHLORINATION OF HIGHER ALKANES: RELATIVE REACTIVITY AND SELECTIVITY
3.8: SELECTIVITY IN RADICAL HALOGENATION WITH FLUORINE AND BROMINE
3.9: SYNTHETIC RADICAL HALOGENATION
3.10: SYNTHETIC CHLORINE COMPOUNDS AND THE STRATOSPHERIC OZONE LAYER
3.11: COMBUSTION AND THE RELATIVE STABILITIES OF ALKANES
3.E: REACTIONS OF ALKANES (EXERCISES)

1 12/5/2021
3.1: Strength of Alkane Bonds: Radicals
In chemistry, a radical (more precisely, a free radical) is an atom, molecule, or ion that has unpaired valence electrons or
an open electron shell, and therefore may be seen as having one or more "dangling" covalent bonds.
With some exceptions, these "dangling" bonds make free radicals highly chemically reactive towards other substances, or
even towards themselves: their molecules will often spontaneously dimerize or polymerize if they come in contact with
each other. Most radicals are reasonably stable only at very low concentrations in inert media or in a vacuum.
Free radicals may be created in a number of ways, including synthesis with very dilute or rarefied reagents, reactions at
very low temperatures, or breakup of larger molecules. The latter can be affected by any process that puts enough energy
into the parent molecule, such as ionizing radiation, heat, electrical discharges, electrolysis, and chemical reactions.
Indeed, radicals are intermediate stages in many chemical reactions.

History
The first organic free radical identified was triphenylmethyl radical. This species was discovered by Moses Gomberg in
1900 at the University of Michigan USA. Historically, the term radical in radical theory was also used for bound parts of
the molecule, especially when they remain unchanged in reactions. These are now called functional groups. For example,
methyl alcohol was described as consisting of a methyl "radical" and a hydroxyl "radical". Neither are radicals in the
modern chemical sense, as they are permanently bound to each other, and have no unpaired, reactive electrons; however,
they can be observed as radicals in mass spectrometry when broken apart by irradiation with energetic electrons.

Depiction in chemical reactions

In this chapter, we will learn about some reactions in which the key steps involve the movement of single electrons. You
may recall from way back in section 6.1A that single electron movement is depicted by a single-barbed'fish-hook' arrow
(as opposed to the familiar double-barbed arrows that we have been using throughout the book to show two-electron
movement).

Single-electron mechanisms involve the formation and subsequent reaction of free radical species, highly unstable
intermediates that contain an unpaired electron. We will learn in this chapter how free radicals are often formed from
homolytic cleavage, an event where the two electrons in a breaking covalent bond move in opposite directions.

(In contrast, essentially all of the reactions we have studied up to now involve bond-breaking events in which both
electrons move in the same direction: this is called heterolytic cleavage).
We will also learn that many single-electron mechanisms take the form of a radical chain reaction, in which one radical
causes the formation of a second radical, which in turn causes the formation of a third radical, and so on.

The high reactivity of free radical species and their ability to initiate chain reactions is often beneficial - we will learn in
this chapter about radical polymerization reactions that form useful materials such as plexiglass and polyproylene fabric.
We will also learn about radical reactions that are harmful, such as the degradation of atmospheric ozone by freon, and the
oxidative damage done to lipids and DNA in our bodies by free radicals species. Finally, we will see how some enzymes
use bound metals to catalyze high e

The geometry and relative stability of carbon radicals

As organic chemists, we are particularly interested in radical intermediates in which the unpaired electron resides on a
carbon atom. Experimental evidence indicates that the three bonds in a carbon radical have trigonal planar geometry, and

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therefore the carbon is considered to be sp2-hybridized with the unpaired electron occupying the perpendicular,
unhybridized 2pzorbital. Contrast this picture with carbocation and carbanion intermediates, which are both also trigonal
planar but whose 2pz orbitals contain zero or two electrons, respectively.

The trend in the stability of carbon radicals parallels that of carbocations (section 8.4B): tertiary radicals, for example, are
more stable than secondary radicals, followed by primary and methyl radicals. This should make intuitive sense, because
radicals, like carbocations, can be considered to be electron deficient, and thus are stabilized by the electron-donating
effects of nearby alkyl groups. Benzylic and allylic radicals are more stable than alkyl radicals due to resonance effects -
an unpaired electron can be delocalized over a system of conjugated pi bonds. An allylic radical, for example, can be
pictured as a system of three parallel 2pz orbitals sharing three electrons.

Trends in radical stability

Allyic & Benzlic > 3o > 2o > 1o > Methyl

Template:ExampleStart
Exercise 17.1: Draw the structure of a benzylic radical compound, and then draw a resonance form showing how the
radical is stabilized.
Template:ExampleEnd
With enough resonance stabilization, radicals can be made that are quite unreactive. One example of an inert organic
radical structure is shown below.

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In this molecule, the already extensive resonance stabilization is further enhanced by the ability of the chlorine atoms to
shield the radical center from external reagents. The radical is, in some sense, inside a protective 'cage'.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Prof. Steven Farmer (Sonoma State University)

The Relationship between Bond Order and Bond Energy

Triple bonds between like atoms are shorter than double bonds, and because more energy is required to completely break
all three bonds than to completely break two, a triple bond is also stronger than a double bond. Similarly, double bonds
between like atoms are stronger and shorter than single bonds. Bonds of the same order between different atoms show a
wide range of bond energies, however. Table 8.6 lists the average values for some commonly encountered bonds. Although
the values shown vary widely, we can observe four trends:

Table 8.6 Average Bond Energies (kJ/mol) for Commonly Encountered Bonds at 273 K
Single Bonds Multiple Bonds

H–H 432 C–C 346 N–N ≈167 O–O ≈142 F–F 155 C=C 602

H–C 411 C–Si 318 N–O 201 O–F 190 F–Cl 249 C≡C 835

H–Si 318 C–N 305 N–F 283 O–Cl 218 F–Br 249 C=N 615

H–N 386 C–O 358 N–Cl 313 O–Br 201 F–I 278 C≡N 887

H–P ≈322 C–S 272 N–Br 243 O–I 201 Cl–Cl 240 C=O 749

H–O 459 C–F 485 P–P 201 S–S 226 Cl–Br 216 C≡O 1072

H–S 363 C–Cl 327 S–F 284 Cl–I 208 N=N 418

H–F 565 C–Br 285 S–Cl 255 Br–Br 190 N≡N 942

H–Cl 428 C–I 213 S–Br 218 Br–I 175 N=O 607

H–Br 362 Si–Si 222 I–I 149 O=O 494

H–I 295 Si–O 452 S=O 532

Source: Data from J. E. Huheey, E. A. Keiter, and R. L. Keiter, Inorganic Chemistry, 4th ed. (1993).
1. Bonds between hydrogen and atoms in the same column of the periodic table decrease in strength as we go down the
column. Thus an H–F bond is stronger than an H–I bond, H–C is stronger than H–Si, H–N is stronger than H–P, H–O is
stronger than H–S, and so forth. The reason for this is that the region of space in which electrons are shared between
two atoms becomes proportionally smaller as one of the atoms becomes larger (part (a) in Figure 8.11).

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2. Bonds between like atoms usually become weaker as we go down a column (important exceptions are noted later). For
example, the C–C single bond is stronger than the Si–Si single bond, which is stronger than the Ge–Ge bond, and so
forth. As two bonded atoms become larger, the region between them occupied by bonding electrons becomes
proportionally smaller, as illustrated in part (b) in Figure 8.11. Noteworthy exceptions are single bonds between the
period 2 atoms of groups 15, 16, and 17 (i.e., N, O, F), which are unusually weak compared with single bonds between
their larger congeners. It is likely that the N–N, O–O, and F–F single bonds are weaker than might be expected due to
strong repulsive interactions between lone pairs of electrons on adjacent atoms. The trend in bond energies for the
halogens is therefore
Cl–Cl > Br–Br > F–F > I–I
Similar effects are also seen for the O–O versus S–S and for N–N versus P–P single bonds.
Note

Bonds between hydrogen and atoms in a given column in the periodic table are weaker down the column; bonds between like atoms usually
become weaker down a column.

3. Because elements in periods 3 and 4 rarely form multiple bonds with themselves, their multiple bond energies are not
accurately known. Nonetheless, they are presumed to be significantly weaker than multiple bonds between lighter atoms of
the same families. Compounds containing an Si=Si double bond, for example, have only recently been prepared, whereas
compounds containing C=C double bonds are one of the best-studied and most important classes of organic compounds.

Figure 8.11 The Strength of Covalent Bonds Depends on the Overlap between the Valence Orbitals of the Bonded Atoms.
The relative sizes of the region of space in which electrons are shared between (a) a hydrogen atom and lighter (smaller)
vs. heavier (larger) atoms in the same periodic group; and (b) two lighter versus two heavier atoms in the same group.
Although the absolute amount of shared space increases in both cases on going from a light to a heavy atom, the amount of
space relative to the size of the bonded atom decreases; that is, the percentage of total orbital volume decreases with
increasing size. Hence the strength of the bond decreases.
4. Multiple bonds between carbon, oxygen, or nitrogen and a period 3 element such as phosphorus or sulfur tend to be
unusually strong. In fact, multiple bonds of this type dominate the chemistry of the period 3 elements of groups 15 and 16.
Multiple bonds to phosphorus or sulfur occur as a result of d-orbital interactions, as we discussed for the SO42− ion in
Section 8.6. In contrast, silicon in group 14 has little tendency to form discrete silicon–oxygen double bonds.
Consequently, SiO2 has a three-dimensional network structure in which each silicon atom forms four Si–O single bonds,
which makes the physical and chemical properties of SiO2 very different from those of CO2.

Note

Bond strengths increase as bond order increases, while bond distances decrease.

Table: Average bond energies:

Bond (kJ/mol)

C-F 485
C-Cl 328
C-Br 276
C-I 240

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 C-C 348
C-N 293
C-O 358
C-F 485

C-C 348
C=C 614
C=C 839

Contributors
Kim Song (UCD), Donald Le (UCD)

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3.2: Structure of Alkyl Radicals: Hyperconjugation
☰
Trend in Radical Stability

3o > 2o > 1o > Methyl

In order to understand the reason for this ordering in radical stability we must first look at the structure of a alkyl radical.

Experimental data have shown that radicals have a trigonal planar geometry associated with sp2 hybridization.
The unpaired electron is contained in a p orbital which is perpendicular to the molecular plane.

This trigonal planar geometry allows for sigma on adjacent carbons to align and overlap with the p orbital. The alignment
allows for the electrons in the sigma bond to donate electrons into the electron deficient p orbital. This process is called
hyperconjugation.

The more alkyl substituents, and therefore more sigma bonds, the electron density is donated into the p orbitals. This is
why the general trend in radical stability is true 3o > 2o > 1o > Methyl.

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3.3: Conversion of Petroleum: Pyrolysis
Objectives
After completing this section, you should be able to
1. describe the general nature of petroleum deposits, and recognize why petroleum is such an important source of
organic compounds.
2. explain, in general terms, the processes involved in the refining of petroleum.
3. define the octane number of a fuel, and relate octane number to chemical structure.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
catalytic cracking
catalytic reforming
fractional distillation
octane number (octane rating)

 Study Notes

The refining of petroleum into usable fractions is a very important industrial process. In the laboratory component of
this course, you will have the opportunity to compare this industrial process to the distillation procedure as it is
performed in the student laboratory.

Petroleum
The petroleum that is pumped out of the ground is a complex mixture of several thousand organic compounds, including
straight-chain alkanes, cycloalkanes, alkenes, and aromatic hydrocarbons with four to several hundred carbon atoms. The
identities and relative abundance of the components vary depending on the source - Texas crude oil is somewhat different
from Saudi Arabian crude oil. In fact, the analysis of petroleum from different deposits can produce a “fingerprint” of
each, which is useful in tracking down the sources of spilled crude oil. For example, Texas crude oil is “sweet,” meaning
that it contains a small amount of sulfur-containing molecules, whereas Saudi Arabian crude oil is “sour,” meaning that it
contains a relatively large amount of sulfur-containing molecules.

Gasoline
Petroleum is converted to useful products such as gasoline in three steps: distillation, cracking, and reforming. Recall from
Chapter 1 that distillation separates compounds on the basis of their relative volatility, which is usually inversely
proportional to their boiling points. Part (a) in Figure 3.8.1 shows a cutaway drawing of a column used in the petroleum
industry for separating the components of crude oil. The petroleum is heated to approximately 400°C (750°F) and becomes
a mixture of liquid and vapor. This mixture, called the feedstock, is introduced into the refining tower. The most volatile
components (those with the lowest boiling points) condense at the top of the column where it is cooler, while the less
volatile components condense nearer the bottom. Some materials are so nonvolatile that they collect at the bottom without
evaporating at all. Thus the composition of the liquid condensing at each level is different. These different fractions, each
of which usually consists of a mixture of compounds with similar numbers of carbon atoms, are drawn off separately. Part
(b) in Figure 3.8.1 shows the typical fractions collected at refineries, the number of carbon atoms they contain, their
boiling points, and their ultimate uses. These products range from gases used in natural and bottled gas to liquids used in
fuels and lubricants to gummy solids used as tar on roads and roofs.

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 Figure 3.8.1: The Distillation of Petroleum. (a) This is a diagram of a distillation column used for separating petroleum
fractions. (b) Petroleum fractions condense at different temperatures, depending on the number of carbon atoms in the
molecules, and are drawn off from the column. The most volatile components (those with the lowest boiling points)
condense at the top of the column, and the least volatile (those with the highest boiling points) condense at the bottom. (CC
BY-NC-SA; anonymous)
The economics of petroleum refining are complex. For example, the market demand for kerosene and lubricants is much
lower than the demand for gasoline, yet all three fractions are obtained from the distillation column in comparable
amounts. Furthermore, most gasolines and jet fuels are blends with very carefully controlled compositions that cannot vary
as their original feedstocks did. To make petroleum refining more profitable, the less volatile, lower-value fractions are
converted to more volatile, higher-value mixtures that have carefully controlled formulas. The first process used to
accomplish this transformation is cracking, in which the larger and heavier hydrocarbons in the kerosene and higher-
boiling-point fractions are heated to temperatures as high as 900°C. High-temperature reactions cause the carbon–carbon
bonds to break, which converts the compounds to lighter molecules similar to those in the gasoline fraction. Thus in
cracking, a straight-chain alkane with a number of carbon atoms corresponding to the kerosene fraction is converted to a
mixture of hydrocarbons with a number of carbon atoms corresponding to the lighter gasoline fraction. The second process
used to increase the amount of valuable products is called reforming; it is the chemical conversion of straight-chain
alkanes to either branched-chain alkanes or mixtures of aromatic hydrocarbons. Using metals such as platinum brings
about the necessary chemical reactions. The mixtures of products obtained from cracking and reforming are separated by
fractional distillation.

Octane Ratings
The quality of a fuel is indicated by its octane rating, which is a measure of its ability to burn in a combustion engine
without knocking or pinging. Knocking and pinging signal premature combustion (Figure 3.8.2), which can be caused
either by an engine malfunction or by a fuel that burns too fast. In either case, the gasoline-air mixture detonates at the
wrong point in the engine cycle, which reduces the power output and can damage valves, pistons, bearings, and other
engine components. The various gasoline formulations are designed to provide the mix of hydrocarbons least likely to
cause knocking or pinging in a given type of engine performing at a particular level.

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 Figure 3.8.2: The Burning of Gasoline in an Internal Combustion Engine. (a) Normally, fuel is ignited by the spark plug,
and combustion spreads uniformly outward. (b) Gasoline with an octane rating that is too low for the engine can ignite
prematurely, resulting in uneven burning that causes knocking and pinging. (CC BY-NC-SA; anonymous)
The octane scale was established in 1927 using a standard test engine and two pure compounds: n-heptane and isooctane
(2,2,4-trimethylpentane). n-Heptane, which causes a great deal of knocking on combustion, was assigned an octane rating
of 0, whereas isooctane, a very smooth-burning fuel, was assigned an octane rating of 100. Chemists assign octane ratings
to different blends of gasoline by burning a sample of each in a test engine and comparing the observed knocking with the
amount of knocking caused by specific mixtures of n-heptane and isooctane. For example, the octane rating of a blend of
89% isooctane and 11% n-heptane is simply the average of the octane ratings of the components weighted by the relative
amounts of each in the blend. Converting percentages to decimals, we obtain the octane rating of the mixture:

0.89(100) + 0.11(0) = 89 (3.3.1)

As shown in Table 3.3.1, many compounds that are now available have octane ratings greater than 100, which means they
are better fuels than pure isooctane. In addition, anti-knock agents, also called octane enhancers, have been developed. One
of the most widely used for many years was tetraethyl lead [(C2H5)4Pb], which at approximately 3 g/gal gives a 10–15-
point increase in octane rating. Since 1975, however, lead compounds have been phased out as gasoline additives because
they are highly toxic. Other enhancers, such as methyl t-butyl ether (MTBE), have been developed to take their place.
They combine a high octane rating with minimal corrosion to engine and fuel system parts. Unfortunately, when gasoline
containing MTBE leaks from underground storage tanks, the result has been contamination of the groundwater in some
locations, resulting in limitations or outright bans on the use of MTBE in certain areas. As a result, the use of alternative
octane enhancers such as ethanol, which can be obtained from renewable resources such as corn, sugar cane, and,
eventually, corn stalks and grasses, is increasing.
Table 3.3.1 : The Octane Ratings of Some Hydrocarbons and Common Additives
Condensed Structural Condensed Structural
Name Octane Rating Name Octane Rating
Formula Formula

CH3CH2CH2CH2CH skeletal structure of

n-heptane 0 o-xylene 107
2CH2CH3 o-xylene.cdxml
CH3CH2CH2CH2CH
n-hexane 25 ethanol CH3CH2OH 108
2CH3

CH3CH2CH2CH2CH
n-pentane 62 t-butyl alcohol (CH3)3COH 113
3
CH3
(CH3)3CCH2CH(CH3
isooctane 100 p-xylene 116
)2 H3 C

benzene 106 methyl t-butyl ether H3COC(CH3)3 116

CH3

methanol CH3OH 107 toluene 118

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Dr. Krista Cunningham

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3.4: Chlorination of Methane: The Radical Chain Mechanism
 Objectives

After completing this section, you should be able to

1. explain why the radical halogenation of alkanes is not usually a particularly good method of preparing pure
samples of alkyl halides.
2. use C– H bond energies to account for the fact that in radical chlorinations, the reactivity of hydrogen atoms
decreases in the order

tertiary > secondary > primary. (3.4.1)

3. predict the approximate ratio of the expected products from the monochlorination of a given alkane.

 Study Notes

The following terms are synonymous:

1. methyl hydrogens, primary hydrogens, and 1° hydrogens.
2. methylene hydrogens, secondary hydrogens, and 2° hydrogens.
3. methine hydrogens, tertiary hydrogens, and 3° hydrogens.
Note that in radical chlorination reactions, the reactivity of methine, methylene and methyl hydrogens decreases in the
ratio of approximately 5 : 3.5 : 1. This will aid in the prediction of expected products from the monochlorination of a
given alkane.

Radical Halogenation
Alkanes (the simplest of all organic compounds) undergo very few reactions. One of these reactions is halogenation, or the
substitution of a single hydrogen on the alkane for a single halogen (Cl2 or Br2) to form a haloalkane. This reaction is very
important in organic chemistry because it functionalizes alkanes which opens a gateway to further chemical reactions.

General Reaction
C H4 + C l2 + energy → C H3 C l + H C l (3.4.2)

Radical Chain Mechanism

The reaction proceeds through the radical chain mechanism which is characterized by three steps: initiation, propagation,
and termination. Initiation requires an input of energy but after that the reaction is self-sustaining.
Step 1: Initiation
During the initiation step free radicals are created when ultraviolet light or heat causes the X-X halogen bond to undergo
homolytic to create two halogen free radicals. It is important to note that this step is not energetically favorable and cannot
occur without some external energy input. After this step, the reaction can occur continuously (as long as reactants
provide) without input of more energy.

Step 2: Propagation
The next two steps in the mechanism are called propagation steps. In the first propagation step, a chlorine radical abstracts
hydrogen atom from methane. This gives hydrochloric acid (HCl, the inorganic product of this reaction) and the methyl
radical. In the second propagation step, the methyl radical reacts with more of the chlorine starting material (Cl2). One of
the chlorine atoms becomes a radical and the other combines with the methyl radical to form the alkyl halide product.

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Step 3: Termination
In the three termination steps of this mechanism, radicals produced in the mechanism an undergo radical coupling to form
a sigma bond. These are called termination steps because a free radical is not produced as a product, which prevents the
reaction from continuing. Combining the two types of radicals produced can be combined to from three possible
products. Two chlorine radicals and couple to form more halogen reactant (Cl2). A chlorine radical and a methyl radical
can couple to form more product (CH3Cl). An finally, two methyl radicals can couple to form a side product of ethane
(CH3CH3).

This reaction is a poor synthetic method due to the formation of polyhalogenated side products. The desired product occurs
when one of the hydrogen atoms in the methane has been replaced by a chlorine atom. However, the reaction doesn't stop
there, and all the hydrogens in the methane can in turn be replaced by chlorine atoms to produce a mixture of
chloromethane, dichloromethane, trichloromethane and tetrachloromethane.

Energetics
Why do these reactions occur? Is the reaction favorable? A way to answer these questions is to look at the change in
enthalpy ΔH that occurs when the reaction takes place.
ΔH = (Energy put into reaction) – (Energy given off from reaction)
If more energy is put into a reaction than is given off, the ΔH is positive, the reaction is endothermic and not energetically
favorable. If more energy is given off in the reaction than was put in, the ΔH is negative, the reaction is said to be
exothermic and is considered favorable. The figure below illustrates the difference between endothermic and exothermic
reactions.

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ΔH can also be calculated using bond dissociation energies (ΔH°):
∘ ∘
ΔH = ∑ ΔH  of bonds broken − ∑ ΔH  of bonds formed (3.4.3)

Let’s look at our specific example of the chlorination of methane to determine if it is endothermic or exothermic:

Since, the ΔH for the chlorination of methane is negative, the reaction is exothermic. Energetically this reaction is
favorable. In order to better understand this reaction we need to look at the mechanism ( a detailed step by step look at the
reaction showing how it occurs) by which the reaction occurs.

Chlorination of Other Alkanes

When alkanes larger than ethane are halogenated, isomeric products are formed. Thus chlorination of propane gives both
1-chloropropane and 2-chloropropane as mono-chlorinated products. The halogenation of propane discloses an interesting
feature of these reactions. All the hydrogens in a complex alkane do not exhibit equal reactivity. For example, propane
has eight hydrogens, six of them being structurally equivalent primary, and the other two being secondary. If all these
hydrogen atoms were equally reactive, halogenation should give a 3:1 ratio of 1-halopropane to 2-halopropane mono-
halogenated products, reflecting the primary/secondary numbers. This is not what we observe. Light-induced gas phase
chlorination at 25 ºC gives 45% 1-chloropropane and 55% 2-chloropropane.

CH3-CH2-CH3 + Cl2 → 45% CH3-CH2-CH2Cl + 55% CH3-CHCl-CH3

These results suggest strongly that 2º-hydrogens are inherently more reactive than 1º-hydrogens, by a factor of about 3.5:1.
Further experiments showed that 3º-hydrogens are about 5 times more toward halogen atoms 1º-hydrogens. Thus, light-
induced chlorination of 2-methylpropane gave predominantly (65%) 2-chloro-2-methylpropane, the substitution product of
the sole 3º-hydrogen, despite the presence of nine 1º-hydrogens in the molecule.

(CH3)3CH + Cl2 → 65% (CH3)3CCl + 35% (CH3)2CHCH2Cl

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 The Relative Reactivity of Hydrogens to
Radical Chlorination

This difference in reactivity can only be attributed to differences in C-H bond dissociation energies. In our previous
discussion of bond energy we assumed average values for all bonds of a given kind, but now we see that this is not strictly
true. In the case of carbon-hydrogen bonds, there are significant differences, and the specific dissociation energies (energy
required to break a bond homolytically) for various kinds of C-H bonds have been measured. These values are given in the
following table.

R (in R–H) methyl ethyl i-propyl t-butyl

Bond Dissociation Energy

103 98 95 93
(kcal/mole)

This data shows that a tertiary C-H bond (93 kcal/mole) is easier to break than a secondary (95 kcal/mole) and primary (98
kcal/mole) C-H bond. These bond dissociation energies can be used to estimate the relative stability of the radicals formed
after homolytic cleavage. Because a tertiary C-H bond requires less energy to undergo homolytic cleavage than a
secondary or primary C-H bond, it can be inferred that a tertiary radical is more stable than secondary or primary.

Relative Stability of Free Radicals

 Exercise 3.4.1

Write out the complete mechanism for the chlorination of methane.

Answer
The answer to this problem is actually above in the initiation, propagation and termination descriptions.

 Exercise 3.4.2

Explain, in your own words, how the first propagation step can occur without input of energy if it is energetically
unfavorable.

Answer
Since the second step in propagation is energetically favorable and fast, it drives the equilibrium toward products,
even though the first step is not favorable.

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 Exercise 3.4.3

Which step of the radical chain mechanism requires outside energy? What can be used as this energy?

Answer
Initiation step requires energy which can be in the form of light or het.

 Exercise 3.4.4

Having learned how to calculate the change in enthalpy for the chlorination of methane apply your knowledge and
using the table provided below calculate the change in enthalpy for the bromination of ethane.

Compound Bond Dissociation Energy (kcal/mol)

CH3CH2-H 101

CH3CH2-Br 70

H-Br 87

Br2 46

Answer
To calculate the enthalpy of reaction, you subtract the BDE of the bonds formed from the BDE of the bonds
broken.
Bonds broken are C-H and Br-Br.
Bonds formed are H-Br adn C-Br.
Bonds broken - bonds formed = change in enthalpy
(101 kcal/mol + 46 kcal/mol) - (87 kcal/mol + 70 kcal/mol) = change in enthalpy
-10 kcal/mol = change in enthalpy for bromination of ethane.

Exercise 3.4.5

1) Predict the mono-substituted halogenated product(s) of chlorine gas reacting with 2-methylbutane.
2) Predict the relative amount of each mono-brominated product when 3-methylpentane is reacted with Br2. Consider
1°, 2°, 3° hydrogen.
3) For the following compounds, give all possible monochlorinated derivatives.

Answer
1)

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 2)

.
3)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Jim Clark (Chemguide.co.uk)
Kristen Kelley and Britt Farquharson
Layne Morsch (University of Illinois Springfield)

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3.5: Other Radical Halogenations of Methane
For the radical halogenation of methane, fluorine is the most reactive and iodine is the least reactive. The reason for this
can be seen in the enthalpy for the first propagation step in the different halognations of methane. For fluorine the step is
exothermic, however, for chlorine, bromine, and iodine the step is endothermic. This trend comes from the relative bond
strengths of the H-X bond which is formed. The H-F bond is strong which causes the high reactivity of fluorine in these
reactions. Correspondingly, reactions with fluorine have a relatively small activation energy and Iodine have relatively
large activation energy. In the case of Iodine the energy of activation is so high that Iodination of methane does not occur.

Enthalpy of the Propagation Steps for the Halogenation of Methane

F: -130 Kj/mol

Cl: +8 Kj/mol

Br: +75 Kj/mol

I: +142 Kj/mol

Relative reactivity of X. in Hydrogen Abstraction reactions

F. > C. > Br. > I.

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3.6: Keys to Success: Using the "Known" Mechanism as a model for the
"Unknown"
Alkanes (the most basic of all organic compounds) undergo very few reactions. One of these reactions is halogenation, or
the substitution of a single hydrogen on the alkane for a single halogen to form a haloalkane. This reaction is very
important in organic chemistry because it opens a gateway to further chemical reactions.

Introduction
While the reactions possible with alkanes are few, there are many reactions that involve haloalkanes. In order to better
understand the mechanism (a detailed look at the step by step process through which a reaction occurs), we will closely
examine the chlorination of methane. When methane (CH4) and chlorine (Cl2) are mixed together in the absence of light at
room temperature nothing happens. However, if the conditions are changed, so that either the reaction is taking place at
high temperatures (denoted by Δ) or there is ultra violet irradiation, a product is formed, chloromethane (CH3Cl).

Energetics
Why does this reaction occur? Is the reaction favorable? A way to answer these questions is to look at the change in
enthalpy (ΔH ) that occurs when the reaction takes place.
ΔH = (Energy put into reaction) – (Energy given off from reaction)
If more energy is put into a reaction than is given off, the ΔH is positive, the reaction is endothermic and not energetically
favorable. If more energy is given off in the reaction than was put in, the ΔH is negative, the reaction is said to be
exothermic and is considered favorable. The figure below illustrates the difference between endothermic and exothermic
reactions.

ΔH can also be calculated using bond dissociation energies (ΔH°):

∘ ∘
ΔH = ∑ ΔH  of bonds broken − ∑ ΔH  of bonds formed (3.6.1)

Let’s look at our specific example of the chlorination of methane to determine if it is endothermic or exothermic:

Since, the ΔH for the chlorination of methane is negative, the reaction is exothermic. Energetically this reaction is
favorable. In order to better understand this reaction we need to look at the mechanism ( a detailed step by step look at the
reaction showing how it occurs) by which the reaction occurs.

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Radical Chain Mechanism
The reaction proceeds through the radical chain mechanism. The radical chain mechanism is characterized by three steps:
initiation, propagation and termination. Initiation requires an input of energy but after that the reaction is self-sustaining.
The first propagation step uses up one of the products from initiation, and the second propagation step makes another one,
thus the cycle can continue until indefinitely.

Step 1: Initiation
Initiation breaks the bond between the chlorine molecule (Cl2). For this step to occur energy must be put in, this step is not
energetically favorable. After this step, the reaction can occur continuously (as long as reactants provide) without input of
more energy. It is important to note that this part of the mechanism cannot occur without some external energy input,
through light or heat.

Step 2: Propagation
The next two steps in the mechanism are called propagation steps. In the first propagation step, a chlorine radical combines
with a hydrogen on the methane. This gives hydrochloric acid (HCl, the inorganic product of this reaction) and the methyl
radical. In the second propagation step more of the chlorine starting material (Cl2) is used, one of the chlorine atoms
becomes a radical and the other combines with the methyl radical.

The first propagation step is endothermic, meaning it takes in heat (requires 2 kcal/mol) and is not energetically favorable.
In contrast the second propagation step is exothermic, releasing 27 kcal/mol. Since the second propagation step is so
exothermic, it occurs very quickly. The second propagation step uses up a product from the first propagation step (the
methyl radical) and following Le Chatelier's principle, when the product of the first step is removed the equilibrium is
shifted towards it's products. This principle is what governs the unfavorable first propagation step's occurance.

Step 3: Termination
In the termination steps, all the remaining radicals combine (in all possible manners) to form more product (CH3Cl), more
reactant (Cl2) and even combinations of the two methyl radicals to form a side product of ethane (CH3CH3).

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Problems with the Chlorination of Methane
The chlorination of methane does not necessarily stop after one chlorination. It may actually be very hard to get a
monosubstituted chloromethane. Instead di-, tri- and even tetra-chloromethanes are formed. One way to avoid this problem
is to use a much higher concentration of methane in comparison to chloride. This reduces the chance of a chlorine radical
running into a chloromethane and starting the mechanism over again to form a dichloromethane. Through this method of
controlling product ratios one is able to have a relative amount of control over the product.

References
1. Matyjaszewski, Krzysztof, Wojciech Jakubowski, Ke Min, Wei Tang, Jinyu Huang, Wade A. Braunecker, and Nicolay
V. Tsarevsky. "Diminishing Catalyst Concentration in Atom Transfer Radical Polymerization with Reducing Agents."
Proceedings of the National Academy of Sciences of the United States of America 103 (2006): 15309-5314.
2. Morgan, G. T. "A State Experiment in Chemical Research." Science 72 (1930): 379-90.
3. Phillips, Francis C. "# Researches upon the Chemical Properties of Gases." Researches upon the Chemical Properties
of Gases 17 (1893): 149-236.

Outside Links
Video of Mechanism: http://www.jbpub.com/organic-online/...s/chlormet.htm
Wikipedia of Radical Chain Mechanism: http://en.wikipedia.org/wiki/Free_ra...l_halogenation
Wikipedia of Le Chatelier's Principle: http://en.wikipedia.org/wiki/Le_Chat...#Concentration

Problems
Answers to these questions are in an attached slide
1. Write out the complete mechanism for the chlorination of methane.
2. Explain, in your own words, how the first propagation step can occur without input of energy if it is energetically
unfavorable.
3. Compounds other than chlorine and methane go through halogenation with the radical chain mechanism. Write out a
generalized equation for the halogenation of RH with X2including all the different steps of the mechanism.
4. Which step of the radical chain mechanism requires outside energy? What can be used as this energy?
5. Having learned how to calculate the change in enthalpy for the chlorination of methane apply your knowledge and
using the table provided below calculate the change in enthalpy for the bromination of ethane.

Compound Bond Dissociation Energy (kcal/mol)

CH3CH2-H 101

CH3CH2-Br 70

H-Br 87

Br2 46

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Contributors
Kristen Kelley and Britt Farquharson

Further Reading

Wikipedia
Free radical halogenation
Khan Academy
Free radical reactions

Carey 5th Ed Online

Radical substitution reactions

Chemtube3D
Radical Chlorination of alkanes
MasterOrganicChemistry
Free radical halogenation
Selectivity in free radical reactions

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3.7: Chlorination of Higher Alkanes: Relative Reactivity and Selectivity

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3.8: Selectivity in Radical Halogenation with Fluorine and Bromine
☰

 Objectives

After completing this section, you should be able to

1. explain why the radical halogenation of alkanes is not usually a particularly good method of preparing pure
samples of alkyl halides.
2. use C– H bond energies to account for the fact that in radical chlorinations, the reactivity of hydrogen atoms
decreases in the order

tertiary > secondary > primary. (3.8.1)

3. predict the approximate ratio of the expected products from the monochlorination of a given alkane.

 Study Notes

The following terms are synonymous:

1. methyl hydrogens, primary hydrogens, and 1° hydrogens.
2. methylene hydrogens, secondary hydrogens, and 2° hydrogens.
3. methine hydrogens, tertiary hydrogens, and 3° hydrogens.
Note that in radical chlorination reactions, the reactivity of methine, methylene and methyl hydrogens decreases in the
ratio of approximately 5 : 3.5 : 1. This will aid in the prediction of expected products from the monochlorination of a
given alkane.

Methane and chlorine

If a mixture of methane and chlorine is exposed to a flame, it explodes - producing carbon and hydrogen chloride. This is
not a very useful reaction! The reaction we are going to explore is a more gentle one between methane and chlorine in the
presence of ultraviolet light - typically sunlight. This is a good example of a photochemical reaction - a reaction brought
about by light.
C H4 + C l2 + energy → C H3 C l + H C l (3.8.2)

The organic product is chloromethane. One of the hydrogen atoms in the methane has been replaced by a chlorine atom, so
this is a substitution reaction. However, the reaction doesn't stop there, and all the hydrogens in the methane can in turn be
replaced by chlorine atoms.
Substitution reactions happen in which hydrogen atoms in the methane are replaced one at a time by chlorine atoms. You
end up with a mixture of chloromethane, dichloromethane, trichloromethane and tetrachloromethane.

The original mixture of a colorless and a green gas would produce steamy fumes of hydrogen chloride and a mist of
organic liquids. All of the organic products are liquid at room temperature with the exception of the chloromethane which
is a gas.
If you were using bromine, you could either mix methane with bromine vapor, or bubble the methane through liquid
bromine - in either case, exposed to UV light. The original mixture of gases would, of course, be red-brown rather than
green.

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You wouldn't choose to use these reactions as a means of preparing these organic compounds in the lab because the
☰
mixture of products would be too tedious to separate. The mechanisms for the reactions are explained on separate pages.
Alkanes (the most basic of all organic compounds) undergo very few reactions. One of these reactions is halogenation, or
the substitution of a single hydrogen on the alkane for a single halogen to form a haloalkane. This reaction is very
important in organic chemistry because it opens a gateway to further chemical reactions.

Halogenation Reaction
While the reactions possible with alkanes are few, there are many reactions that involve haloalkanes. In order to better
understand the mechanism (a detailed look at the step by step process through which a reaction occurs), we will closely
examine the chlorination of methane. When methane (CH4) and chlorine (Cl2) are mixed together in the absence of light at
room temperature nothing happens. However, if the conditions are changed, so that either the reaction is taking place at
high temperatures (denoted by Δ) or there is ultra violet irradiation, a product is formed, chloromethane (CH3Cl).

Energetics
Why does this reaction occur? Is the reaction favorable? A way to answer these questions is to look at the change in
enthalpy (ΔH ) that occurs when the reaction takes place.
ΔH = (Energy put into reaction) – (Energy given off from reaction)
If more energy is put into a reaction than is given off, the ΔH is positive, the reaction is endothermic and not energetically
favorable. If more energy is given off in the reaction than was put in, the ΔH is negative, the reaction is said to be
exothermic and is considered favorable. The figure below illustrates the difference between endothermic and exothermic
reactions.

ΔH can also be calculated using bond dissociation energies (ΔH°):

∘ ∘
ΔH = ∑ ΔH  of bonds broken − ∑ ΔH  of bonds formed (3.8.3)

Let’s look at our specific example of the chlorination of methane to determine if it is endothermic or exothermic:

Since, the ΔH for the chlorination of methane is negative, the reaction is exothermic. Energetically this reaction is
favorable. In order to better understand this reaction we need to look at the mechanism ( a detailed step by step look at the
reaction showing how it occurs) by which the reaction occurs.

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Radical Chain Mechanism
☰
The reaction proceeds through the radical chain mechanism. The radical chain mechanism is characterized by three steps:
initiation, propagation and termination. Initiation requires an input of energy but after that the reaction is self-sustaining.
The first propagation step uses up one of the products from initiation, and the second propagation step makes another one,
thus the cycle can continue until indefinitely.

Step 1: Initiation
Initiation breaks the bond between the chlorine molecule (Cl2). For this step to occur energy must be put in, this step is not
energetically favorable. After this step, the reaction can occur continuously (as long as reactants provide) without input of
more energy. It is important to note that this part of the mechanism cannot occur without some external energy input,
through light or heat.

Step 2: Propagation
The next two steps in the mechanism are called propagation steps. In the first propagation step, a chlorine radical combines
with a hydrogen on the methane. This gives hydrochloric acid (HCl, the inorganic product of this reaction) and the methyl
radical. In the second propagation step more of the chlorine starting material (Cl2) is used, one of the chlorine atoms
becomes a radical and the other combines with the methyl radical.

The first propagation step is endothermic, meaning it takes in heat (requires 2 kcal/mol) and is not energetically favorable.
In contrast the second propagation step is exothermic, releasing 27 kcal/mol. Since the second propagation step is so
exothermic, it occurs very quickly. The second propagation step uses up a product from the first propagation step (the
methyl radical) and following Le Chatelier's principle, when the product of the first step is removed the equilibrium is
shifted towards it's products. This principle is what governs the unfavorable first propagation step's occurance.

Step 3: Termination
In the termination steps, all the remaining radicals combine (in all possible manners) to form more product (CH3Cl), more
reactant (Cl2) and even combinations of the two methyl radicals to form a side product of ethane (CH3CH3).

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☰

Problems with the Chlorination of Methane

The chlorination of methane does not necessarily stop after one chlorination. It may actually be very hard to get a
monosubstituted chloromethane. Instead di-, tri- and even tetra-chloromethanes are formed. One way to avoid this problem
is to use a much higher concentration of methane in comparison to chloride. This reduces the chance of a chlorine radical
running into a chloromethane and starting the mechanism over again to form a dichloromethane. Through this method of
controlling product ratios one is able to have a relative amount of control over the product.

Chlorination of other alkanes

When alkanes larger than ethane are halogenated, isomeric products are formed. Thus chlorination of propane gives both
1-chloropropane and 2-chloropropane as mono-chlorinated products. Four constitutionally isomeric dichlorinated products
are possible, and five constitutional isomers exist for the trichlorinated propanes. Can you write structural formulas for
the four dichlorinated isomers?
C H3 C H2 C H3 + 2C l2 → Four C3 H6 C l2 isomers + 2H C l (3.8.4)

The halogenation of propane discloses an interesting feature of these reactions. All the hydrogens in a complex alkane
do not exhibit equal reactivity. For example, propane has eight hydrogens, six of them being structurally equivalent
primary, and the other two being secondary. If all these hydrogen atoms were equally reactive, halogenation should give
a 3:1 ratio of 1-halopropane to 2-halopropane mono-halogenated products, reflecting the primary/secondary numbers. This
is not what we observe. Light-induced gas phase chlorination at 25 ºC gives 45% 1-chloropropane and 55% 2-
chloropropane.
CH3-CH2-CH3 + Cl2 → 45% CH3-CH2-CH2Cl + 55% CH3-CHCl-CH3
The results of bromination (light-induced at 25 ºC) are even more suprising, with 2-bromopropane accounting for 97% of
the mono-bromo product.
CH3-CH2-CH3 + Br2 → 3% CH3-CH2-CH2Br + 97% CH3-CHBr-CH3
These results suggest strongly that 2º-hydrogens are inherently more reactive than 1º-hydrogens, by a factor of about 3:1.
Further experiments showed that 3º-hydrogens are even more reactive toward halogen atoms. Thus, light-induced
chlorination of 2-methylpropane gave predominantly (65%) 2-chloro-2-methylpropane, the substitution product of the sole
3º-hydrogen, despite the presence of nine 1º-hydrogens in the molecule.
(CH3)3CH + Cl2 → 65% (CH3)3CCl + 35% (CH3)2CHCH2Cl
It should be clear from a review of the two steps that make up the free radical chain reaction for halogenation that the first
step (hydrogen abstraction) is the product determining step. Once a carbon radical is formed, subsequent bonding to a
halogen atom (in the second step) can only occur at the radical site. Consequently, an understanding of the preference for
substitution at 2º and 3º-carbon atoms must come from an analysis of this first step.
First Step: R3CH + X· → R3C· + H-X
Second Step: R3C· + X2 → R3CX + X·
Since the H-X product is common to all possible reactions, differences in reactivity can only be attributed to differences in
C-H bond dissociation energies. In our previous discussion of bond energy we assumed average values for all bonds of a

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given kind, but now we see that this is not strictly true. In the case of carbon-hydrogen bonds, there are significant
☰
differences, and the specific dissociation energies (energy required to break a bond homolytically) for various kinds of C-H
bonds have been measured. These values are given in the following table.
R (in R–H) methyl ethyl i-propyl t-butyl phenyl benzyl allyl vinyl

Bond
Dissociation
103 98 95 93 110 85 88 112
Energy
(kcal/mole)

The difference in C-H bond dissociation energy reported for primary (1º), secondary (2º) and tertiary (3º) sites agrees with
the halogenation observations reported above, in that we would expect weaker bonds to be broken more easily than are
strong bonds. By this reasoning we would expect benzylic and allylic sites to be exceptionally reactive in free radical
halogenation, as experiments have shown. The methyl group of toluene, C6H5CH3, is readily chlorinated or brominated in
the presence of free radical initiators (usually peroxides), and ethylbenzene is similarly chlorinated at the benzylic location
exclusively. The hydrogens bonded to the aromatic ring (referred to as phenyl hydrogens above) have relatively high bond
dissociation energies and are not substituted.
C6H5CH2CH3 + Cl2 → C6H5CHClCH3 + HCl

 Exercise 3.8.1
Write out the complete mechanism for the chlorination of methane.

Answer
The answer to this problem is actually above in the initiation, propagation and termination descriptions.

 Exercise 3.8.2

Explain, in your own words, how the first propagation step can occur without input of energy if it is energetically
unfavorable.

Answer
Since the second step in propagation is energetically favorable and fast, it drives the equilibrium toward products,
even though the first step is not favorable.

 Exercise 3.8.3
Which step of the radical chain mechanism requires outside energy? What can be used as this energy?

Answer
Initiation step requires energy which can be in the form of light or het.

 Exercise 3.8.4

Having learned how to calculate the change in enthalpy for the chlorination of methane apply your knowledge and
using the table provided below calculate the change in enthalpy for the bromination of ethane.

Compound Bond Dissociation Energy (kcal/mol)

CH3CH2-H 101

CH3CH2-Br 70

H-Br 87

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 Br2 46
☰
Answer
To calculate the enthalpy of reaction, you subtract the BDE of the bonds formed from the BDE of the bonds
broken.
Bonds broken are C-H and Br-Br.
Bonds formed are H-Br adn C-Br.
Bonds broken - bonds formed = change in enthalpy
(101 kcal/mol + 46 kcal/mol) - (87 kcal/mol + 70 kcal/mol) = change in enthalpy
-10 kcal/mol = change in enthalpy for bromination of ethane.

Problems
1. Compounds other than chlorine and methane go through halogenation with the radical chain mechanism. Write out a
generalized equation for the halogenation of RH with X2including all the different steps of the mechanism.

Exercises
Questions
Q10.2.1
Predict the mono-substituted halogenated product(s) of chlorine gas reacting with 2-methylbutane.
Q10.2.2
Predict the relative amount of each mono-brominated product when 3-methylpentane is reacted with Br2. Consider 1°, 2°,
3° hydrogen.
Solutions
S10.2.1

S10.2.2

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Contributors and Attributions
☰
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Jim Clark (Chemguide.co.uk)
Kristen Kelley and Britt Farquharson
Layne Morsch (University of Illinois Springfield)

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3.9: Synthetic Radical Halogenation

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3.10: Synthetic Chlorine Compounds and the Stratospheric Ozone Layer
☰
The high reactivity of free radicals and the multiplicative nature of radical chain reactions can be useful in the synthesis of
materials such as polyethylene plastic - but these same factors can also result in dangerous consequences. You are probably
aware of the danger posed to the earth's protective stratospheric ozone layer by the use of chlorofluorocarbons (CFCs) as
refrigerants and propellants in aerosol spray cans. Freon-11, or CFCl3, is a typical CFC that was widely used until fairly
recently. It can take months or years for a CFC molecule to drift up into the stratosphere from the surface of the earth, and
of course the concentration of CFCs at this altitude is very low. Ozone, on the other hand, is continually being formed in
the stratosphere. Why all the concern, then, about destruction of the ozone layer - how could such a small amount of CFCs
possibly do significant damage? The problem lies in the fact that the process by which ozone is destroyed is a chain
reaction, so that a single CFC molecule can initiate the destruction of many ozone molecules before a chain termination
event occurs.
Although there are several different processes by which the ozone destruction process might occur, the most important is
believed to be the chain reaction shown below.

To address the problem of ozone destruction, scientists are developing new organohalogen refrigerant compounds that are
less stable than the older CFCs like Freon-11, in the hope that the new compounds will break down in the lower
atmosphere before they reach an altitude where they can harm the ozone layer. Most of the new compounds contain
carbon-hydrogen bonds, which are subject to homolytic cleavage initiated by hydroxide radicals present in the lower
atmosphere.

This degradation occurs before the refrigerant molecules have a chance to drift up to the stratosphere where the ozone
plays its important protective role. The degradation products are quite unstable and quickly degrade further, by a variety of
mechanisms, into relatively harmless by-products. The hydroxide radical is sometimes referred to as an atmospheric
'detergent' due to its ability to degrade refrigerants and other volatile organic pollutants which have escaped into the
atmosphere.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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3.11: Combustion and the Relative Stabilities of Alkanes
☰
Alkane Heats of Combustion

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3.E: Reactions of Alkanes (Exercises)
These are homework exercises to accompany Chapter 3 of Vollhardt and Schore's "Organic Chemistry" Textmap.

3.1: Strength of Alkane Bonds: Radicals

3.2: Structure of Alkyl Radicals: Hyperconjugation

3.3: Conversion of Petroleum: Pyrolysis

3.4: Chlorination of Methane: The Radical Chain Mechanism

3.5: Other Radical Halogenations of Methane
3.6: Keys to Success: Using the "Known" Mechanism as a model for the "Unknown"

3.7: Chlorination of Higher Alkanes: Relative Reactivity and Selectivity

3.8: Selectivity in Radical Halogenation with Fluorine and Bromine
3.9: Synthetic Radical Halogenation

3.10: Synthetic Chlorine Compounds and the Stratospheric Ozone Layer

3.11: Combustion and the Relative Stabilities of Alkanes
Problems
Q15
Indicate whether each Hydrogen present is primary, secondary, or tertiary. Why is quaternary not an option?
(a) ethane (b) 2,2-dimethylpropane (c) 1-methylcyclobutane

Q16
In each pair of radicals, determine whether the radical is primary, secondary, or tertiary and also decide which radical is more favorable. Give the general reason why for all of the cases.

(a) (b) (c)

Q17
Draw the electron pushing arrow mechanism for all possible pyrolysis radicals that can form from butane, assuming only C-C bonds are broken. What type of bond cleavage is this,
heterolytic or homolytic?

Q18
Draw all the possible pyrolysis radical products for 2-methylbutane, and determine which bond is most likely to be broken.

Q19
Calculate the ΔHo (kJ/mol) of the following reactions using the given bond dissociation energies.
Bond Dissociation Energies (Homolytic) ΔHo (kJ/mol)

CH3-H (methane) 439

C2H5-H (ethane) 423

(CH3)3C-H 404
H-H 435
H-Cl 431
H-Br 364
CH3-Cl 356
CH3-Br 293
C2H5-Cl 352
C2H5-Br 293
(CH3)3C-Cl 356
(CH3)3C-Br 297
Cl-Cl 242
Br-Br 192

(a) CH4 + Cl2 → CH3Cl + HCl (b) CH4 + Br2 → CH3Br + HBr
(c) C2H6 + Cl2 → C2H5Cl + HCl (d) C2H6 + Br2 → C2H5Br + HBr
(e) (CH3)3CH + Cl2 → (CH3)3CCl + HCl (f) (CH3)3CH + Br2 → (CH3)3CBr + HBr
(g) H2 + Cl2 → 2HCl

Q20
Predict all possible constitutional isomers possible if monohalogenation were performed on the molecules in problem 15 with Br2. Give the name of the haloalkane.

Q21
Given the following alkanes, draw the most likely product to form upon monohalogenation with Br2 (keep in mind that this may not be the only product to form though). If the reaction was
performed with Cl2 would there be more or less selectivity in the desired product formation? Why?

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(a) (b) (c)

Q22
Draw out the full mechanism of the monochlorination of ethane with electron-pushing arrows. Label the three overall steps of the mechanism.

Q23
Calculate the statistical probablity of monobromination of propane on each unique carbon, and discuss why this is not likely. Given that the experimental monobromination produces two
products, 97% one and 3% the other, assign these percentages to the corresponding product.

Q24
Draw the mechanism of the bromination of propene using Br2, on the carbon adjacent to the double bond. Can you draw any resonance structures for the intermediates in the propagation
steps? Would you expect this to make the radical more or less stable?

Q25
Based on the previous question, how do you think the ∆Ho to form the propene radical would compare to that of a propane radical?

Q26
Similar to problem 21, describe the resemblence to products and reactants of an early and a late transition state. In a monohalogenation, what step is early what step is late (propagation and
termination)?

Q27
Draw the line-bond structure of the major product for the following reaction, if a reaction occurs, assume monohalogenation.

(a) (b) (c)

(d) (e)

Q28
For problem 27.c, calculate the product ratios using the following information (hint use the number of hydrogens in each category present to calculate the ratios).
Chlorination: 1o Reactivity=1 2o Reactivity=4 3o Reactivity=5

Q29
Halo alkanes are synthetically useful compounds as you'll learn later. However, the radical halogenation is not always selective as seen in problem 27. If any of the products of the reactions
were to be used as subsequent reagents, which would be more useful, 27.c or 27.d?

Q30
What are potential problems of trying to brominate the second carbon in hexane? If however, this does form draw the Newman Projection of the most favorable staggered conformation
looking down the C2-C3 axis.

Q31
Calculate the ΔHo value for the bromination and iodination of propene, on the secondary carbon, assume monohalogenation. The bond dissociation values are as follows. What is the major
difference between the two values? (Note this problem uses kcal mol-1)
Bond Bond Dissociation Energy (kcal mol-1)

Br-Br 46

I-I 36
(CH3)2CH-H 98.5
H-Br 87
H-I 71
Secondary C-I 56
Secondary C-Br 71

Q32
Draw the bond polarity present of chloroethane, explain how this affects the electronics of the carbon attached to the chloro group.

Q33
Write a balanced combustion reaction for the following hydrocarbons, sugars, and alchols. Assume complete combustion, what is one typical product of incomplete combustion?
(a) butane (b) octane (c) glucose (C6H12O6) (d) methanol

Q34
At 25oC the heat of combustion of 2-butanone, CH3CHOCH2CH3, is 2444.1 kJ mol-1 and the heat of combustion of butanal, CHOCH2CH2CH3, is 2470.3 kJ mol-1. Which combustion is
more endothermic? What does this tell us about the relative stability of the two compounds?

Q35
Often times NBS, N-bromosuccinimide, is substituted for Br2 in radical halogenation reactions to keep the concentration of Br2 low. This low concentration favors the radical halogenation
and not other alkene reactions, that you will learn later on. Using NBS, drawn below, draw the radical bromination of propene.

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 N-bromosuccinimide

Q36
Peroxides are also good initiators for radical reactions. Given the peroxide, RO-OR, draw the initiation step of the general peroxide and the propagation of that radical to create bromine
radicals with HBr.

Q37
One radical inhibitor BHT, butylated hydroxytoluene, is often added to diethylether, CH3CH2OCH2CH3, to prevent explosive peroxides from forming. Given BHT's structure below, draw
the radical formation on the oxygen of BHT with a general radical, R. . The phenoxy radical is stabilized/made unreactive by steric hindrance of the tertbutyl groups and also resonance.

Q38
Draw the two radical halogenation products of 2-methylpropane, also known as isobutane, with Cl2. Given the percentages of the two products are 37% and 63%, calculate the reactivity of
each hydrogen and the ratio between the two.

Q39
Given the following reactions and the relative ΔHo, what is most likely the rate limiting step of the radical halogenation mechanism?
1) X-X → 2X. ΔH1o>0
2) R-CH3 + X. → R-CH2. + HX ΔH2o>ΔH1o
3) R-CH2. + X. → R-CH2X ΔH3o<0

Q40
Explain or use a mechanism to show how BHT, or other radical inhibitors, could cause a radical halogenation to come to a stop?

Q41
Given the following heats of combustion; propane ΔH= -2202 kJ/mol, gasoline ΔH=-44,000 kJ/kg, diesel ΔH=-45,000 kJ/kg; what fuel could potentially provide the most miles per weight
of fuel?

Q42
Write out the reactions for the complete combustion of propane and gasoline, assuming gasoline is completely C8H18 (gasoline is actually a mixture of smaller and larger hydrocarbons).

Q43
Draw the transition states of the reaction of Cl. and Br. with a secondary carbon, compare the radical character of that carbon between the two transition states.

Q44
CFC's, chlorofluorocarbons (CF2Cl2), saw widespread use as refrigerants and as aerosols. However, due to their low boiling point, when sprayed into the air they rise up to the atmosphere
and are exposed to large amounts of uv radiation. This light, often seen as hv in chemical equations, provides the energy needed to break the CFC's into radicals. Chlorine radicals are
formed and this degrades the protective layer of ozone into oxygen, O2. Draw the formation of the chlorine radical from a CFC.

Q45
N-bromosuccinimide, NBS, is a reagent with what purpose?
(a) a strong base (b) a strong acid (c) radical initiator (d) radical inhibitor

Q46
Name the following compound.

Q47
A polymer scientist is trying to perform a halogenation on the following polymer to perform a subsequent reaction (the structure repeats itself to form a length of n units). She/he has been
using Cl2 to perform the radical halogenation, but cannot obtain a uniformly halogenated product. What suggestion would you give her/him to try and achieve a more uniformly halogenated
product?

Q48
Given that a radical halogenation with chlorine yields an early transition state, as defined in Hammond's Postulate, is the halogenation likely to be endothermic or exothermic?

Solutions
S15

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(a) (b) (c)
There can be no quaternary Hydrogen because a Carbon can only have four covalent bonds. In (b) the central carbon has no attached Hydrogen, but it is a quaternary carbon.

S16
(a) left- tertiary right-secondary; the left is more favorable (b) left-primary right-tertiary; the right is more favorable (c) left- primary right- secondary; the right is more favorable
For all of theses cases the more favorable radical is as follows 3o>2o>1o. Since the radical is electron deficient, the more carbon substituents the more hyperconjugation that can occur. This
stabilizes the radical, this "rule" is also true for carbocations as you will see later.

S17

Make sure to draw single electron arrows. Also, this is homolytic bond cleavage because one electron goes to each atom involved in
bonding.

S18

The stability of radicals is as follows: 3o>2o>1o>CH3, and so the second pair of radicals is most likely to form. A secondary and a
primary radical are formed, compared to the other products that contain a methyl radical.

S19
ΔHo=(ΔHo Bonds Broken)-(ΔHo Bonds Formed)
(a) CH4 + Cl2 → CH3Cl + HCl ΔHo=(CH3-H + Cl-Cl)-(CH3-Cl + H-Cl)=(439+242)-(356+431)=-106 kJ mol-1
(b) CH4 + Br2 → CH3Br + HBr ΔHo=(CH3-H + Br-Br)-(CH3-Br + H-Br)=(439+192)-(293+364)=-26 kJ mol-1
(c) C2H6 + Cl2 → C2H5Cl + HCl ΔHo=(C2H5-H + Cl-Cl)-(C2H5-Cl + H-Cl)=(423+242)-(352+431)=-118 kJ mol-1
(d) C2H6 + Br2 → C2H5Br + HBr ΔHo=(C2H5-H + Br-Br)-(C2H5-Br + H-Br)=(423+192)-(293+364)=-42 kJ mol-1
(e) (CH3)3CH + Cl2 → (CH3)3CCl + HCl ΔHo=((CH3)3C-H + Cl-Cl)-((CH3)3C-Cl + H-Cl)=(404+242)-(356+431)=-141 kJ mol-1
(f) (CH3)3CH + Br2 → (CH3)3CBr + HBr ΔHo=((CH3)3C-H + Br-Br)-((CH3)3C-Br + H-Br)=(404+192)-(297+364)=-65 kJ mol-1
(g) H2 + Cl2 → 2HCl ΔHo=(H-H + Cl-Cl)-2(H-Cl)=(435+242)-2(431)=-185 kJ mol-1

S20
(a) ethane; bromethane (b) 2,2-dimethylpropane; 1-bromo-2,2-dimethylpropane (c) 1-methylcyclobutane; (bromomethyl)cyclobutane, 1-bromo-1-methylcyclobutane, 1-bromo-2-
methylcyclobutane, 1-bromo-3-methylcyclobutane

S21

a.

b.

c.
If the reaction were performed with Cl2 the product formation would not likely be as selective. This is due to the fact that the radical formation with chlorine is exothermic and the radical
formation with bromine is endothermic. Hammond's postulate explains that the transition state of exothermic reaction will be more similar to the reactants, less like a radical, leading to a
less selective radical formation. Whereas the transition state of an endothermic reaction will be more similar to the products, more radical like, leading to a selective radical formation.

S22

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S23

The statistical distribution is calculated from the following: Total Carbons=3, Two external carbons are not unique, so probability=2/3 x
100% The center carbon probability is 1/3 x 100%. However, this is not likely, because the secondary carbon forms a much more stable radical than a primary radical.

S24

As you'll learn, this is not the only reaction that can occur. Alkene chemistry will be discussed later on.

S25
Since the propene radical is more favorable than the propane radical, the ∆Ho would be lower than that of propane.

S26
An early transition state resembles the reactants, and a late transition state resembles the products (Hammond's postulate). The formation of the alkyl radical, propagation, is an early
transition state (if you draw the reaction coordinate diagram for this step it should be endothermic), and the formation of the alkyl halide, termination, is a late transition state (if you draw
the reaction coordinate diagram for this step it should be exothermic).

S27

(a) (b)

(c) (d) Notice how the chlorination is not as selective as the bromination.

(e)

S28
Assuming there is no primary chlorination, which in reality is likely not the case, only 2o and 3o hydrogen atoms are taken into account.
# 2o=2 Multiply by reactivity=Relative Yield => 8 Ratio= 8/(5+8) x 100%=62% 2o
# 3o=1 Multiply by reactivity=Relative Yield => 5 Ratio=5/(5+8) x 100%=38% 3o

S29
27.d produces a much more pure mixture of products, and thus is more likely to be useful. Whereas, the chlorination, 27.c, of the same alkane potentially yields a mixture of products. This
mixture would require a difficult separation, and is much less likely to be synthetically useful.
However, if a different haloalkane were desired, then this could be useful after purification. As you see later on, though, there are other methods of creating haloalkanes that are more
selective.

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S30
The problem with this is that there are several secondary carbons, all about as equally likely to form a radical. There are three groups of unique hydrogens on the molecule, the two primary,
the adjacent secondary, and the most interior secondary. Statistically speaking the inner two and second most outer two are equally likely to be brominated, there are equal number of
hydrogens. If however, the second carbon is brominated, the following is the most favorable conformation.
Since the methyl group is much larger than the bromine, the rest of the carbon chain is adjacent to the bromine to reduce the steric interaction. It is also anti to the methyl group to further
reduce steric interaction.

S31
This problem could be broken up into the individual steps of the mechanism, and the ΔHo values for each step could be summed together to get the same value.
Bromination:
ΔHo=Bonds Broken - Bonds Made = (Br-Br + Secondary C-H) - (Secondary C-Br + H-Br) = (46 + 98.5) - (71 + 87)= -13.5 kcal mol-1
Iodination:
ΔHo=Bonds Broken - Bonds Made = (I-I + Secondary C-H) - (Secondary C-I + H-I) = (36 + 98.5) - (56 + 71)= +7.5 kcal mol-1
The main difference between the two is that the bromination is exothermic, whereas the iodination is endothermic. This explains why no reaction occurs in 27.b

S32

The connectivity to a chlorine atom produces a highly polarized bond. This chlorination has further reactivity as you will see later on, taking advantage of the electron
deficient carbon.

S33
With any complete combustion reaction the only products are CO2 and H2O.
(a) butane 2C4H10 + 13O2 → 8CO2 + 10H2O
(b) octane 2C8H18 + 17O2 → 16CO2 + 18H2O
(c) glucose C6H12O6 + 6O2 → 6CO2 + 6H2O
(d) methanol 4CH3 + 7O2 → 4CO2 + 6H2O
If any incomplete combustion occurred, carbon monoxide, CO, would be produced.

S34
Butanal's combustion is more exothermic than that of 2-butanone. The heats of combustion tell us that 2-butanone is more stable, as it has a lower heat of combustion an thus less potential
combustion energy in the compound.

S35

S36

S37

S38

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 Total number of abstractable Hydrogens=(3x3)+1=10
Relative Reactivity=[(Percentage)/(Number of Hydrogens)]
Tertiary Reactivity = 63/1=63
Primary Reactivity =37/9=4.1
The ratio between the two is 63/4.1=15

S39
The most endothermic step, most postive value of ΔHo, is most likely to be the rate limiting step. So, (2) is the rate limiting step.

S40
The inihibitor stops interrupts the propagation step, effectively terminating the reaction. If a carbon or halogen radical does form, it will react with the BHT to form the radical in problem
37. The phenoxy radical in BHT is unreactive, and the reaction stops there.

S41
First, convert the 2202 kJ/mol to kJ/kg.
(-2202 kJ/mol) x (1 mol/44.1 g) x (1000g / 1kg) = -49,931 kJ/mol ~ 50,000 kJ/kg
Since propane has the largest, most negative, heat of combustion it is likely to yield the best mileage. It, and natural gas, is commonly used as a fuel in buses.

S42
Propane: C3H8 + 5O2 → 3CO2 + 4H2O
"Gasoline": 2C8H18 + 27O2 → 16CO2 + 18H2O

S43

The transition state with the chlorine radical is considered an early transition state and more similar to the reactants. The transition state with the bromine radical is considered a late
transition state and more similar to the products.

S44

S45
(c) NBS is a radical initiator.

S46

S47
As you may have seen in previous problems, radical halogenation with chlorine is less selective than with bromine. A good suggestion would be to use Br2, as it will almost exclusively be
added to the tertiary carbon if used in a 1:1 stoichiometric ratio. Wheras, the chlorine will also be added to the secondary carbons, thus producing a non-uniform product.

S48
From Hammond's Postulate, an early transition state indicates an endothermic reaction.

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CHAPTER OVERVIEW
4: CYCLOALKANES
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

Cycloalkanes are cyclic hydrocarbons with the carbons of the molecule arranged in the form of one or more rings. Cycloalkanes are
saturated hydrocarbons, meaning that all of the carbons atoms that make up the ring are single bonded to other atoms (no double or
triple bonds).

4.1: NAMES AND PHYSICAL PROPERTIES OF CYCLOALKANES

4.2: RING STRAIN AND THE STRUCTURE OF CYCLOALKANES
4.3: CYCLOHEXANE: A STRAIN-FREE CYCLOALKANE
4.4: SUBSTITUTED CYCLOHEXANES
4.5: LARGER CYCLOALKANES
4.6: POLYCYCLIC ALKANES
4.7: CARBOCYCLIC PRODUCTS IN NATURE
4.E: CYCLOALKANES (EXERCISES)

1 12/5/2021
4.1: Names and Physical Properties of Cycloalkanes
Objectives
After completing this section, you should be able to
1. name a substituted or unsubstituted cycloalkane, given its Kekulé structure, shorthand structure or condensed
structure.
2. draw the Kekulé, shorthand or condensed structure for a substituted or unsubstituted cycloalkane, given its IUPAC
name.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
cycloalkane

 Study Notes

Provided that you have mastered the IUPAC system for naming alkanes, you should find that the nomenclature of
cycloalkanes does not present any particular difficulties.

Many organic compounds found in nature contain rings of carbon atoms. These compounds are known as cycloalkanes.
Cycloalkanes only contain carbon-hydrogen bonds and carbon-carbon single bonds. The simplest examples of this class
consist of a single, un-substituted carbon ring, and these form a homologous series similar to the unbranched alkanes.
Like alkanes, cycloalkane molecules are often drawn as skeletal structures in which each intersection between two lines is
assumed to have a carbon atom with its corresponding number of hydrogens. Cyclohexane, one of the most common
cycloalkanes is shown below as an example.
H2 H H
H H
C
H 2C CH2 H H
= =
H 2C CH2 H H
C
H2 H H
H H

Cyclic hydrocarbons have the prefix "cyclo-". The IUPAC names, molecular formulas, and skeleton structures of the
cycloalkanes with 3 to 10 carbons are given in Table 4.1.1. Note that the general formula for a cycloalkane composed of n
carbons is CnH2n, and not CnH2n+2 as for alkanes. Although a cycloalkane has two fewer hydrogens than the equivalent
alkane, each carbon is bonded to four other atoms so are still considered to be saturated with hydrogen.
Table 4.1.1 : Examples of Simple Cycloalkanes
Cycloalkane Molecular Formula Skeleton Structure

Cyclopropane C3H6
Cyclobutane C4H8
Cyclopentane C5H10
Cyclohexane C6H12

Cycloheptane C7H14

Cyclooctane C8H16

Cyclononane C9H18

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 Cycloalkane Molecular Formula Skeleton Structure

Cyclodecane C10H20

IUPAC Rules for Nomenclature

The naming of substituted cycloalkanes follows the same basic steps used in naming alkanes.
1. Determine the parent chain.
2. Number the substituents of the ring so that the sum of the numbers is the lowest possible.
3. Name the substituents and place them in alphabetical order.
More specific rules for naming substituted cycloalkanes with examples are given below.
1. Determine the cycloalkane to use as the parent. If there is an alkyl straight chain that has a greater number of carbons
than the cycloalkane, then the alkyl chain must be used as the primary parent chain. Cycloalkanes substituents have an
ending "-yl". If there are two cycloalkanes in the molecule, use the cycloalkane with the higher number of carbons as
the parent.

 Example 4.1.1

5
6

8 7 4 3
2
10 9

The longest straight chain contains 10 carbons, compared with cyclopropane, which only contains 3 carbons. The
parent chain in this molecule is decane and cyclopropane is a substituent. The name of this molecule is 3-cyclopropyl-
6-methyldecane.

 Example 4.1.2

Name the cycloalkane structure.

Solution
There are two different cycloalkanes in this molecule. Because it contains more carbons, the cyclopentane ring will be
named as the parent chain. The smaller ring, cyclobutane, is named as a substituent on the parent chain. The name of
this molecule is cyclobutylcyclopentane.

2) When there is only one substituent on the ring, the ring carbon attached to the substituent is automatically carbon #1.
Indicating the number of the carbon with the substituent in the name is optional.

 Example 4.1.3
6
Cl 5
1
2
1
4 2
4 3
3

1-chlorocyclobutane or cholorocyclobutane 1-propylcyclohexane or propylcyclohexane

3) If there are multiple substituents on the ring, number the carbons of the cycloalkane so that the carbons with substituents
have the lowest possible number. A carbon with multiple substituents should have a lower number than a carbon with only

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one substituent or functional group. One way to make sure that the lowest number possible is assigned is to number the
carbons so that when the numbers corresponding to the substituents are added, their sum is the lowest possible.
4) When naming the cycloalkane, the substituents must be placed in alphabetical order. Remember the prefixes di-, tri-,
etc. , are not used for alphabetization.

 Example 4.1.4

1 1
6 2 2 6

5 3 3 5
4 4

1-ethyl-3-methylcyclohexane NOT 1-ethyl-5-methylcyclohexane

(1 + 3 = 4) (1 + 5 = 6)

In this example, the ethyl or the methyl subsistent could be attached to carbon one. The ethyl group attachment is
assigned carbon 1 because ethyl comes before methyl alphabetically. After assigning carbon 1 the cyclohexane ring
can be numbered going clockwise or counterclockwise. When looking at the numbers produced going clockwise
produces lower substituents numbers (4) than when numbered counterclockwise (6).

 Example 4.1.5

Name the following structure using IUPAC rules.

Br

CH3
CH3

Solution
Remember when dealing with cycloalkanes with more than two substituents, finding the lowest possible substituent
numbering takes prescient. Consider a numbering system with each substituent attachment point as being carbon one.
Compare them and whichever produces the lowest numbering will be correct.
NOT
Br
1
6 2

5 3
Br 4 CH3
4
CH3
5 3
1-bromo-3,4-dimethylcyclohexane
6 2 (1 + 3 + 4 = 8)
1 CH3
OR
CH3

4-bromo-1,2-dimethylcyclohexane Br
(4 + 1 + 2 = 7) 5
4 6

3 1
2 CH3
CH3
5-bromo-1,2-dimethylcyclohexane
(5 + 1 + 2 = 8)

Because there are three substituents there are three possible numbering systems. The one shown to the left allows for a
distinctly lower numbering system. Note, that alphabetical prioritizing was not used to make this assessment. The
correct name for the molecule is 4-Bromo-1,2-dimethylcyclohexane.

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 Example 4.1.6
Cl
1
5
Br
2

4 3
CH3

2-bromo-1-chloro-3-methylcyclopentane
Notice that "b" of bromo alphabetically precedes the "m" of methyl. Also, notice that the chlorine attachment point is
assigned carbon 1 because it comes first alphabetically and the overall sum of numbers would be the same if the
methyl attachment carbon was assigned as 1 and the chlorine attachment as 3.

 Example 4.1.7

CH3
6
CH3
1
5
2
Br
4 3

(2-bromo-1,1-dimethylcyclohexane)
Although "di" alphabetically precedes "f", "di" is not used in determining the alphabetical order.

 Example 4.1.8
6 CH3
5 1 CH3
4
2
3 F

(2-fluoro-1,1,-dimethylcyclohexane NOT 1,1-dimethyl-2-fluorocyclohexane)

also
2-fluoro-1,1,-dimethylcyclohexane (2+1+1 = 4) NOT 1-fluoro-2,2-dimethylcyclohexane (2+2+1 = 5)
Although "di" alphabetically precedes "f", "di" is not used in determining the alphabetical order of the substitutents.
Notice that the attachment point of the two methyl groups is assigned carbon 1 despite the fact that fluorine comes first
alphabetically. This is because this assignment allows for a lower overall numbering of substituents, so assigning
alphabetical priority is not necessary.

Polycyclic Compounds
Hydrocarbons having more than one ring are common, and are referred to as bicyclic (two rings), tricyclic (three rings)
and in general, polycyclic compounds. The molecular formulas of such compounds have H/C ratios that decrease with the
number of rings. In general, for a hydrocarbon composed of n carbon atoms associated with m rings the formula is:
CnH
2 n+2 −2 m
. The structural relationship of rings in a polycyclic compound can vary. They may be separate and
independent, or they may share one or two common atoms. Some examples of these possible arrangements are shown in
the following table.
Table 4.1.2 : Examples of Isomeric C 8
H
14
Bicycloalkanes
Isolated Rings Spiro Rings Fused Rings Bridged Rings

No common atoms One common atom One common bond Two common atoms

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Polycyclic compounds, like cholesterol shown below, are biologically important and typically have common names
accepted by IUPAC. However, the common names do not generally follow the basic IUPAC nomenclature rules, and will
not be covered here.

H H
HO

Cholesterol (polycyclic)

Contributors and Attributions

Pwint Zin
Jim Clark (ChemGuide)
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Dr. Kelly Matthews (Senior Professor of Chemistry, Harrisburg Area Community College)
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham

Objectives

After completing this section, you should be able to

1. draw structural formulas that distinguish between cis and trans disubstituted cycloalkanes.
2. construct models of cis and trans disubstituted cycloalkanes using ball-and-stick molecular models.

 Key Terms
Make certain that you can define, and use in context, the key terms below.
constitutional isomer
stereoisomer
cis-trans isomers

Previously, constitutional isomers have been defined as molecules that have the same molecular formula, but different
atom connectivity. In this section, a new class of isomers, stereoisomers, will be introduced. Stereoisomers are molecules
that have the same molecular formula, the same atom connectivity, but they differ in the relative spatial orientation of the
atoms.
Cycloalkanes are similar to open-chain alkanes in many respects. They both tend to be nonpolar and relatively inert. One
important difference, is that cycloalkanes have much less freedom of movement than open-chain alkanes. As discussed in
Sections 3.6 and 3.7, open-chain alkanes are capable of rotation around their carbon-carbon sigma bonds. The ringed
structures of cycloalkanes prevent such free rotation, causing them to be more rigid and somewhat planar.
Di-substituted cycloalkanes are one class of molecules that exhibit stereoisomerism. 1,2-dibromocyclopentane can exist as
two different stereoisomers: cis-1,2-dibromocyclopentane and trans-1,2-dibromocyclopentane. The cis-1,2-
dibromocyclopentane and trans-1,2-dibromocyclopentane stereoisomers of 1,2-dibromocyclopentane are shown below.
Both molecules have the same molecular formula and the same atom connectivity. They differ only in the relative spatial
orientation of the two bromines on the ring. In cis-1,2-dibromocyclopentane, both bromine atoms are on the same "face" of
the cyclopentane ring, while in trans-1,2-dibromocyclopentane, the two bromines are on opposite faces of the ring.

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Stereoisomers require an additional nomenclature prefix be added to the IUPAC name in order to indicate their spatial
orientation. Di-substituted cycloalkane stereoisomers are designated by the nomenclature prefixes cis (Latin, meaning on
this side) and trans (Latin, meaning across).

H
Br Br Br
= cis -1,2-dibromocyclopentane
H
Br H
H

H
Br H Br
= trans -1,2-dibromocyclopentane
H
H Br
Br

The 3D Structure of cis-1,2-dibromocyclopentane

The 3D Structure of trans-1,2-dibromocyclopentane

Representing 3D Structures
By convention, chemists use heavy, wedge-shaped bonds to indicate a substituent located above the plane of the ring
(coming out of the page), a dashed line for bonds to atoms or groups located below the ring (going back into the page), and
solid lines for bonds in the plane of the page.
CH3
CH3

H 3C
CH3
Br

cis -1,3-dimethylcyclobutane trans -5-bromo-1,4,6-trimethyl-1,3-cycloheptadiene

CH3
CH3

Cl Cl

trans -2,4-dichloro-1,1-dimethylcyclohexane cis -3,5-divinylcyclopentene

In general, if any two sp3 carbons in a ring have two different substituent groups (not counting other ring atoms) cis/trans
stereoisomerism is possible. However, the cis/trans designations are not used if both groups are on the same carbon. For
example, the chlorine and the methyl group are on the same carbon in 1-chloro-1-methylcyclohexane and the trans prefix
should not be used.
Cl
CH3

1-chloro-1-methylcyclohexane

If more than two ring carbons have substituents, the stereochemical notation distinguishing the various isomers becomes
more complex and the prefixes cis and trans cannot be used to formally name the molecule. However, the relationship of
any two substituents can be informally described using cis or trans. For example, in the tri-substituted cyclohexane below,
the methyl group is cis to the ethyl group, and also trans to the chlorine. However, the entire molecule cannot be
designated as either a cis or trans isomer. Later sections will describe how to name these more complex molecules (5.5:
Sequence Rules for Specifying Configuration)
CH3

Cl CH2CH3

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 Example 4.1.1

Name the following cycloalkanes:

a) Br b)
H3C H
H
Br H CH3
H

Solution
These two example represent the two main ways of showing spatial orientation in cycloalkanes.
a) In example "a" the cycloalkane is shown as being flat and in the plane of the page. The positioning of the
substituents is shown by using dash-wedge bonds. Cis/trans positioning can be determined by looking at the type of
bonds attached to the substituents. If the substituents are both on the same side of the ring (Cis) they would both have
either dash bonds or wedge bonds. If the the substituents are on opposite side of the ring (Trans) one substituent would
have a dash bond and the other a wedge bond. Because both bromo substituents have a wedge bond they are one the
same side of the ring and are cis. The name of this molecule is cis-1,4-Dibromocyclohexane.
b) Example "b" shows the cycloalkane ring roughly perpendicular to the plane of the page. When this is done, the
upper and lower face of the ring is defined and each carbon in the ring will have a bond one the upper face and a bond
on the lower face. Cis substituents will either both be on the upper face or the lower face. Trans substituents will have
one on the upper face and one one the lower face. In example "b", one of the methyl substituents is on the upper face
of the ring and one is on the lower face which makes them trans to each other. The name of this molecule is trans-1,2-
Dimethylcyclopropane.

Exercises

 Exercise 4.1.1

Draw the following molecules:

trans-1,3-dimethylcyclohexane
trans-1,2-dibromocyclopentane
cis-1,3-dichlorocyclobutane

Answer

2) Cis/Trans nomenclature can be used to describe the relative positioning of substituents on molecules with more complex
ring structures. The molecule below is tesosterone, the primary male sex hormone. Is the OH and the adjacent methyl

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group cis or trans to each other? What can you deduce about the relative positions of the indicated hydrogens?

3) Name the following compounds:

Solutions
2) Both the OH and the methyl group have wedge bonds. This implies that they are both on the same side of the
testosterone ring making them cis. Two of the hydrogens have wedge bonds while one has a wedge. This means two of the
hydrogens are on one side of the testosterone ring while one is on the other side.
3)
Cis-1-Bromo-3-Chlorocyclobutane
Trans-1,4-Dimethylcyclooctane
Trans-1-Bromo-3-ethylcyclopentane

Exercises
Questions
Q4.2.1
Draw the following molecules:
trans-1,3-dimethylcyclohexane
trans-1,2-dibromocyclopentane
cis-1,3-dichlorocyclobutane
Solutions
S4.2.1

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Dr. Krista Cunningham

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4.2: Ring Strain and the Structure of Cycloalkanes
Objectives
After completing this section, you should be able to
1. describe the Baeyer strain theory.
2. describe how the measurement of heats of combustion provides information about the amount of strain present in a
cycloalkane ring.
3. determine the relative stability of cyclic compounds, by assessing such factors as angle strain, torsional strain and
steric strain.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
angle strain
steric strain
torsional strain
ring strain
heat of combustion

Heat of Combustion as a Measure of Bond Strength

The combustion of carbon compounds, especially hydrocarbons, has been the most important source of heat energy for
human civilizations throughout recorded history. The practical importance of this reaction cannot be denied, but the
massive and uncontrolled chemical changes that take place in combustion make it difficult to deduce mechanistic paths.
Using the combustion of propane as an example, we see from the following equation that every covalent bond in the
reactants has been broken and an entirely new set of covalent bonds have formed in the products. No other common
reaction involves such a profound and pervasive change, and the mechanism of combustion is so complex that chemists are
just beginning to explore and understand some of its elementary features.
C H3 C H2 C H3 + 5 O2 → 3C O2 + 4 H2 O + heat (4.2.1)

Since all the covalent bonds in the reactant molecules are broken, the quantity of heat evolved in this reaction, and any
other combustion reaction, is related to the strength of these bonds (and, of course, the strength of the bonds formed in the
products). Precise heat of combustion measurements can provide useful information about the structure of molecules and
their relative stability.
For example, heat of combustion is useful in determining the relative stability of isomers. Pentane has a heat of
combustion of -782 kcal/mol, while that of its isomer, 2,2-dimethylpropane (neopentane), is –777 kcal/mol. These values
indicate that 2,3-dimethylpentane is 5 kcal/mol more stable than pentane, since it has a lower heat of combustion.

Ring Strain
Table 4.2.1 lists the heat of combustion data for some simple cycloalkanes. These cycloalkanes do not have the same
molecular formula, so the heat of combustion per each CH2 unit present in each molecule is calculated (the fourth column)
to provide a useful comparison. From the data, cyclopropane and cyclobutane have significantly higher heats of
combustion per CH2, while cyclohexane has the lowest heat of combustion. This indicates that cyclohexane is more stable
than cyclopropane and cyclobutane, and in fact, that cyclohexane has a same relative stability as long chain alkanes that
are not cyclic. This difference in stability is seen in nature where six membered rings are by far the most common. What
causes the difference in stability or the strain in small cycloalkanes?
Table 4.2.1 : Heats of combustion of select hydrocarbons
Cycloalkane CH2 Units ΔH25º ΔH25º Ring Strain
(CH2)n n kcal/mol per CH2 Unit kcal/mol

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 Cycloalkane CH2 Units ΔH25º ΔH25º Ring Strain
(CH2)n n kcal/mol per CH2 Unit kcal/mol

Cyclopropane n=3 468.7 156.2 27.6

Cyclobutane n=4 614.3 153.6 26.4

Cyclopentane n=5 741.5 148.3 6.5
Cyclohexane n=6 882.1 147.0 0.0
Cycloheptane n=7 1035.4 147.9 6.3
Cyclooctane n=8 1186.0 148.2 9.6
Cyclononane n=9 1335.0 148.3 11.7
Cyclodecane n = 10 1481 148.1 11.0
CH3(CH2)mCH3 m = large — 147.0 0.0

The Baeyer Theory on the Strain in Cycloalkane Rings

In 1890, the famous German organic chemist, A. Baeyer, suggested that cyclopropane and cyclobutane are less stable than
cyclohexane, because the the smaller rings are more "strained". There are many different types of strain that contribute to
the overall ring strain in cycloalkanes, including angle strain, torsional strain, and steric strain. Torsional strain and steric
strain were previously defined in the discussion of conformations of butane. Angle Strain occurs when the sp3 hybridized
carbons in cycloalkanes do not have the expected ideal bond angle of 109.5o, causing an increase in the potential energy.
An example of angle strain can be seen in the diagram of cyclopropane below in which the bond angle is 60o between the
carbons. The compressed bond angles causes poor overlap of the hybrid orbitals forming the carbon-carbon sigma bonds
which in turn creates destabilization.

H2
C

109.5° 60°
H 2C CH2

The C-C-C bond angles in cyclopropane (diagram above) (60o) and cyclobutane (90o) are much different than the ideal
bond angle of 109.5o. This bond angle causes cyclopropane and cyclobutane to be less stable than molecules such as
cyclohexane and cyclopentane, which have a much lower ring strain because the bond angle between the carbons is much
closer to 109.5o. Changes in chemical reactivity as a consequence of angle strain are dramatic in the case of cyclopropane,
and are also evident for cyclobutane.
In addition to angle strain, there is also steric (transannular) strain and torsional strain in many cycloalkanes. Transannular
strain exists when there is steric repulsion between atoms.
H3 C
CH3
steric repulsion
CH3

transannular strain

Because cycloalkane lack the ability to freely rotate, torsional (eclipsing) strain exists when a cycloalkane is unable to
adopt a staggered conformation around a C-C bond. Torsional strain is especially prevalent in small cycloalkanes, such as
cyclopropane, whose structures are nearly planar.

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 The Eclipsed C-H Bonds in Cyclopropane
Larger rings like cyclohexane, deal with torsional strain by forming conformers in which the rings are not planar. A
conformer is a stereoisomer in which molecules of the same connectivity and formula exist as different isomers, in this
case, to reduce ring strain. The ring strain is reduced in conformers due to the rotations around the sigma bonds, which
decreases the angle and torsional strain in the ring. The non-planar structures of cyclohexane are very stable compared to
cyclopropane and cyclobutane, and will be discussed in more detail in the next section.
H
HH
H
H
H H
H
H
HH
H
cyclohexane cyclohexane chair conformer
(more stable)

The Types of Strain Which Contribute to Ring Strain in Cycloalkanes

Angle Strain The strain caused by the increase or reduction of bond angles

Torsional Strain The strain caused by eclipsing bonds on adjacent atoms

The strain caused by the repulsive interactions of atoms trying to

Steric Strain
occupy the same space

Exercise 4.2.1

trans-1,2-Dimethylcyclobutane is more stable than cis-1,2-dimethylcyclobutane. Explain this observation.

Answer
The trans form does not have eclipsing methyl groups, therefore lowering the energy within the molecule. It does
however have hydrogen-methyl eclipsing interactions which are not as high in energy as methyl-methyl
interactions.

Exercise 4.2.2

Cyclobutane has more torsional stain than cyclopropane. Explain this observation.

Answer
Cyclobutane has 4 CH2 groups while cyclopropane only has 3. More CH2 groups means cyclobutane has more
eclipsing H-H interactions and therefore has more torsional strain.

Questions
Q4.3.1
trans-1,2-Dimethylcyclobutane is more stable than cis-1,2-dimethylcyclobutane. Explain this observation.
Solutions
S4.3.1
The trans form does not have eclipsing methyl groups, therefore lowering the energy within the molecule. It does however
have hydrogen-methyl interactions, but are not as high in energy than methyl-methyl interactions.

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Contributors

William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Kelly Matthews, Senior Professor of Chemistry (Harrisburg Area Community College)
Steven Farmer, Professor of Chemistry (Sonoma State University)
Dr. Krista Cunningham

Objectives

After completing this section, you should be able to

1. describe, and sketch the conformation of cyclopropane, cyclobutane, and cyclopentane.
2. describe the bonding in cyclopropane, and use this to account for the high reactivity of this compound.
3. analyze the stability of cyclobutane, cyclopentane and their substituted derivatives in terms of angular strain,
torsional strain and steric interactions.

 Study Notes
Notice that in both cyclobutane and cyclopentane, torsional strain is reduced at the cost of increasing angular (angle)
strain.

Although the customary line drawings of simple cycloalkanes are geometrical polygons, the actual shape of these
compounds in most cases is very different.

cyclopropane cyclobutane cyclopentane cyclohexane cycloheptane cyclooctane

Cyclopropane is necessarily planar (flat), with the carbon atoms at the corners of an equilateral triangle. The 60º bond
angles are much smaller than the optimum 109.5º angles of a normal tetrahedral carbon atom, and the resulting angle strain
dramatically influences the chemical behavior of this cycloalkane. Cyclopropane also suffers substantial eclipsing strain,
since all the carbon-carbon bonds are fully eclipsed. Cyclobutane reduces some bond-eclipsing strain by folding (the out-
of-plane dihedral angle is about 25º), but the total eclipsing and angle strain remains high. Cyclopentane has very little
angle strain (the angles of a pentagon are 108º), but its eclipsing strain would be large (about 40 kJ/mol) if it remained
planar. Consequently, the five-membered ring adopts non-planar puckered conformations whenever possible.
Rings larger than cyclopentane would have angle strain if they were planar. However, this strain, together with the
eclipsing strain inherent in a planar structure, can be relieved by puckering the ring. Cyclohexane is a good example of a
carbocyclic system that virtually eliminates eclipsing and angle strain by adopting non-planar conformations.
Cycloheptane and cyclooctane have greater strain than cyclohexane, in large part due to transannular crowding (steric
hindrance by groups on opposite sides of the ring).
Cyclic systems are a little different from open-chain systems. In an open chain, any bond can be rotated 360º, going
through many different conformations. That complete rotation isn't possible in a cyclic system, because the parts that
would be trying to twist away from each other would still be connected together. Thus cyclic systems have fewer "degrees
of freedom" than aliphatic systems; they have "restricted rotation".
Because of the restricted rotation of cyclic systems, most of them have much more well-defined shapes than their aliphatic
counterparts. Let's take a look at the basic shapes of some common rings. Many biologically important compounds are
built around structures containing rings, so it's important that we become familiar with them. In nature, three- to six-
membered rings are frequently encountered, so we'll focus on those.

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Cyclopropane
A three membered ring has no rotational freedom whatsoever. A plane is defined by three points, so the three carbon atoms
in cyclopropane are all constrained to lie in the same plane. This lack of flexibility does not allow cyclopropane to form
more stable conformers which are non-planar.
H H
H
H H
cyclopropane H

The main source of ring strain in cyclopropane is angle strain. All of the carbon atoms in cyclopropane are tetrahedral and
would prefer to have a bond angle of 109.5o The angles in an equilateral triangle are actually 60o, about half as large as the
optimum angle. The large deviation from the optimal bond angle means that the C-C sigma bonds forming the
cyclopropane ring are bent. Maximum bonding occurs when the overlapping orbitals are pointing directly toward each
other. The severely strained bond angles in cyclopropane means that the orbitals forming the C-C bonds overlap at a slight
angle making them weaker. This strain is partially overcome by using so-called “banana bonds”, where the overlap
between orbitals is no longer directly in a line between the two nuclei, as shown here in three representations of the
bonding in cyclopropane:
HH
C

H C C H
H H

The constrained nature of cyclopropane causes neighboring C-H bonds to all be held in eclipsed conformations.
Cyclopropane is always at maximum torsional strain. This strain can be illustrated in a Newman projections of
cyclopropane as shown from the side.
HH

HH

Newman Projection of cyclopropane

Cyclopropane isn't large enough to introduce any steric strain. Steric strain does not become a factor until we reach six
membered rings. Before that point, rings are not flexible enough to allow for two ring substituents to interact with each
other.
The combination of torsional and angle strain creates a large amount of ring strain in cyclopropane which weakens the C-C
ring bonds (255 kJ/mol) when compared to C-C bonds in open-chain propane (370 kJ/mol).

Cyclobutane
Cyclobutane is a four membered ring. The larger number of ring hydrogens would cause a substantial amount of torsional
strain if cyclobutane were planar.

cyclobutane

In three dimensions, cyclobutane is flexible enough to buckle into a "puckered" shape which causes the C-H ring
hydrogens to slightly deviate away from being completely eclipsed. This conformation relives some of the torsional strain
but increases the angle strain because the ring bond angles decreases to 88o.
In a line drawing, this butterfly shape is usually shown from the side, with the near edges drawn using darker lines.
H H
H
H H
H
H
H

The deviation of cyclobutane's ring C-H bonds away from being fully eclipsed can clearly be seen when viewing a
Newman projections signed down one of the C-C bond.

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 HH

HH

Newman projection of cyclobutane

With bond angles of 88 rather than 109.5o degrees, cyclobutane has significant amounts of angle strain, but less than
o

in cyclopropane.
Although torsional strain is still present, the neighboring C-H bonds are not exactly eclipsed in the cyclobutane's
puckered conformation.
Steric strain is very low. Cyclobutane is still not large enough that substituents can reach around to cause crowding.
Overall the ring strain in cyclobutane (110 kJ/mol) is slightly less than cyclopropane (115 kJ/mol).

Cyclopentane
Cyclopentanes are even more stable than cyclobutanes, and they are the second-most common cycloalkane ring in nature,
after cyclohexanes. Planar cyclopentane has virtually no angle strain but an immense amount of torsional strain. To reduce
torsional strain, cyclopentane addops a non-planar conformation even though it slightly increases angle strain.

cyclopentane

The lowest energy conformation of cyclopentane is known as the ‘envelope’, with four of the ring atoms in the same plane
and one out of plane (notice that this shape resembles an envelope with the flap open). The out-of-plane carbon is said to
be in the endo position (‘endo’ means ‘inside’). The envelope removes torsional strain along the sides and flap of the
envelope. However, the neighboring carbons are eclipsed along the "bottom" of the envelope, away from the flap.
H
HH H
H
H
H
H HH

3D structure of cyclopentane (notice that the far top right carbon is the endo position).
At room temperature, cyclopentane undergoes a rapid bond rotation process in which each of the five carbons takes turns
being in the endo position.
rotate up
1
2
4 5 4 5
etc.
3 2 3
1
rotate down

Cyclopentane distorts only very slightly into an "envelope" shape in which one corner of the pentagon is lifted up above
the plane of the other four. The envelope removes torsional strain along the sides and flap of the envelope by allowing the
bonds to be in an almost completely staggered position. However, the neighboring bonds are eclipsed along the "bottom"
of the envelope, away from the flap. Viewing a Newman projections of cyclopentane signed down one of the C-C bond
show the staggered C-H bonds.
HH

HH

Newman projection of cyclopentane

The angle strain in the envelope conformation of cyclopentane is low. The ideal angle in a regular pentagon is about
107o, very close to the preferred 109.5o tetrahedral bond angle.
There is some torsional strain in cyclopentane. The envelope conformation reduces torsional strain by placing some
bonds in nearly staggered positions. However, other bonds are still almost fully eclipsed.
Cyclopentane is not large enough to allow for steric strain to be created.
Overall, cyclopentane has very little ring strain (26 kJ/mol) when compared to cyclopropane and cyclobutane.

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C3-C5 Cycloalkanes in Nature
If one of the carbon-carbon bonds is broken in cyclopropane or cyclobutane, the ring will ‘spring’ open, releasing energy
as the bonds reassume their preferred tetrahedral geometry. The effectiveness of two antibiotic drugs, fosfomycin and
penicillin, is due in large part to the high reactivity of the three- and four-membered rings in their structures.
H
O N S
H H O CH3
O N CH3
H3C O P O
O
O O
O
fosfomycin penicillin G

One of the most important five-membered rings in nature is a sugar called ribose – DNA and RNA are both constructed
upon ‘backbones’ derived from ribose. Pictured below is one thymidine (T) deoxy-nucleotide from a stretch of DNA.
Since the ribose has lost one of the OH groups (at carbon 2 of the ribose ring), this is part of a deoxyribonucleic acid
(DNA). If the OH at carbon 2 of the ribose ring was present, this would be part of a ribonucleic acid (RNA).
DNA

O H
O
HO N
O P O O
O OH O
O N
CH3
HO OH O
(no OH group
here in DNA)
ribose DNA

The lowest-energy conformations for ribose are envelope forms in which either C3 or C2 are endo, on the same side as the
C5 substituent.
OH

HO
O OH

OH

Exercises
1) If cyclobutane were to be planar, how many H-H eclipsing interactions would there be? Assuming 4 kJ/mol per H-H
eclipsing interaction what would the strain be on this “planar” molecule?
2) In the two conformations of trans-1,2-Dimethylcyclopentane one is more stable than the other. Explain why this is.

3) In methylcyclopentane, which carbon would most likely be in the endo position?

Solutions
1) There are 8 eclipsing interactions (two per C-C bond). The extra strain on this molecule would be 32 kJ/mol (4 kJ/mol x
8).
2) The first conformation is more stable. Even though the methyl groups are trans in both models, they are anti to one
another in the first structure (which is lower energy) while they are gauche in the second structure increasing strain within
the molecule.
3) The ring carbon attached to the methyl group would most likely be the endo carbon. The large methyl group would
create the most torsional strain if eclipsed. Being in the endo position would place the bonds is a more staggered position
which would reduce strain.

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Questions
Q4.4.1
If cyclobutane were to be planar how many H-H eclipsing interactions would there be, and assuming 4 kJ/mol per H-H
eclipsing interaction what is the strain on this “planar” molecule?
Q4.4.2
In the two conformations of trans-cyclopentane one is more stable than the other. Explain why this is.

Solutions
S4.4.1
There are 8 eclipsing interactions (two per C-C bond). The extra strain on this molecule would be 32 kJ/mol (4 kJ/mol x
8).
S4.4.2
The first conformation is more stable. Even though the methyl groups are trans in both models, in the second
structure they are eclipsing one another, therefore increasing the strain within the molecule compared to the first structure
where the larger methyl groups are anti to one another.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Chris P Schaller, Ph.D., (College of Saint Benedict / Saint John's University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham

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4.3: Cyclohexane: A Strain-Free Cycloalkane
☰
Objectives
After completing this section, you should be able to
1. explain why cyclohexane rings are free of angular strain.
2. draw the structure of a cyclohexane ring in the chair conformation.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
chair conformation
twist-boat conformation

We will find that cyclohexanes tend to have the least angle strain and consequently are the most common cycloalkanes
found in nature. A wide variety of compounds including, hormones, pharmaceuticals, and flavoring agents have substituted
cyclohexane rings.
OH

H H
O

testosterone, which contains three cyclohexane rings and one cyclopentane ring
Rings larger than cyclopentane would have angle strain if they were planar. However, this strain, together with the
eclipsing strain inherent in a planar structure, can be relieved by puckering the ring. Cyclohexane is a good example of a
carbocyclic system that virtually eliminates eclipsing and angle strain by adopting non-planar conformations.
Cycloheptane and cyclooctane have greater strain than cyclohexane, in large part due to transannular crowding (steric
hindrance by groups on opposite sides of the ring). Cyclohexane has the possibility of forming multiple conformations
each of which have structural differences which lead to different amounts of ring strain.
H H
H H H H H
H
H H H H
H H H H H H
H H H H
H H H H
H H H H
H H H H H
H
H
H HH H H H
H H

boat conformation twist boat conformation chair conformation

planar structure
slight angle strain slight angle strain no angle strain
severe angle strain (120°)
eclipsing strain at two bonds small eclipsing strain no eclipsing strain
severe eclipsing strain (all bonds)
steric crowding of two hydrogens small steric strain small steric strain
small steric strain

Conformations of Cyclohexane
A planar structure for cyclohexane is clearly improbable. The bond angles would necessarily be 120º, 10.5º larger than the
ideal tetrahedral angle. Also, every carbon-hydrogen bond in such a structure would be eclipsed. The resulting angle and
eclipsing strains would severely destabilize this structure. The ring strain of planar cyclohexane is in excess of 84 kJ/mol
so it rarely discussed other than in theory.

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☰

Cyclohexane in the strained planar configuration showing how the hydrogens become eclipsed.
Chair Conformation of Cyclohexane
The flexibility of cyclohexane allows for a conformation which is almost free of ring strain. If two carbon atoms on
opposite sides of the six-membered ring are bent out of the plane of the ring, a shape is formed that resembles a reclining
beach chair. This chair conformation is the lowest energy conformation for cyclohexane with an overall ring strain of 0
kJ/mol. In this conformation, the carbon-carbon ring bonds are able to assume bonding angles of ~111o which is very near
the optimal tetrahedral 109.5o so angle strain has been eliminated.
H H
H H
H C C C H =
H C
C C H
H H
H H

Also, the C-H ring bonds are staggered so torsional strain has also been eliminated. This is clearly seen when looking at a
Newman projection of chair cyclohexane sighted down the two central C-C bonds.
H H2 H
H C H
H C H
H H2 H

Newman projection of cyclohexane

How to Draw the Chair Conformation

To draw a chair: 1) Draw two 2) Draw another pair of 3) Connect with

slightly offset parallel lines from the a third set of
parallel lines. ends of the first pair. parallel lines.

To draw its ring-flip conformer, just start the first pair of lines at the opposite angle.

Boat Conformation of Cyclohexane

The Boat Conformation of cyclohexane is created when two carbon atoms on opposite sides of the six-membered ring are
both lifted up out of the plane of the ring creating a shape which slightly resembles a boat. The boat conformation is less
stable than the chair form for two major reasons. The boat conformation has unfavorable steric interactions between a pair
of 1,4 hydrogens (the so-called "flagpole" hydrogens) that are forced to be very close together (1.83Å). This steric
hindrance creates a repulsion energy of about 12 kJ/mol. An additional cause of the higher energy of the boat conformation
is that adjacent hydrogen atoms on the 'bottom of the boat' are forced into eclipsed positions. For these reasons, the boat
conformation about 30 kJ/mol less stable than the chair conformation.
H H
H H

A boat structure of cyclohexane (the interfering "flagpole" hydrogens are shown in red)

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Twist-Boat Conformation of Cyclohexane
☰
The boat form is quite flexible and by twisting it at the bottom created the twist-boat conformer. This conformation
reduces the strain which characterized the boat conformer. The flagpole hydrogens move farther apart (the carbons they are
attached to are shifted in opposite directions, one forward and one back) and the eight hydrogens along the sides become
largely but not completely staggered. Though more stable than the boat conformation, the twist-boat (sometimes skew-
boat) conformation is roughly 23 kJ/mol less stable than the chair conformation.
H H
H
H

A twist-boat structure of cyclohexane

Half Chair Conformation of Cyclohexane
Cyclohexane can obtain a partially plane conformation called "half chair" but with only with excessive amounts of ring
strain. The half chair conformation is formed by taking planar cyclohexane and lifting one carbon out of the plane of the
ring. The half chair conformation has much of the same strain effects predicted by the fully planar cyclohexane. In the
planar portion of half chair cyclohexane the C-C bond angles are forced to 120o which creates significant amounts of angle
strain. Also, the corresponding C-H bonds are fully eclipsed which create torsional strain. The out-of-plane carbon allows
for some of the ring's bond angles to reach 109.5o and for some of C-H bonds to not be fully eclipsed. Overall, the half
chair conformation is roughly 45 kJ/mol less stable than the chair conformation.

Conformation Changes in Cyclohexane - "Ring Flips"

Cyclohexane is rapidly rotating between the two most stable conformations known as the chair conformations in what is
called the "ring flip" shown below. The importance of the ring flip will be discussed in the next section.

"Ring flip" describes the rapid equilibrium of cyclohexane rings between the two chair conformations
rotate this carbon down

rotate this carbon up

axial
H H UP H H
H H H H
H H H H equatorial
H H H H UP
H H H H
equatorial axial
H H DOWN H H
DOWN

It is important to note that one chair does not immediately become the other chair, rather the ring must travel through the
higher energy conformations as transitions. At room temperature the energy barrier created by the half chair conformation
is easily overcome allowing for equilibration between the two chair conformation on the order of 80,000 times per second.
Although cyclohexane is continually converting between these different conformations, the stability of the chair
conformation causes it to comprises more than 99.9% of the equilibrium mixture at room temperature.

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☰

1" id="MathJax-Element-12-Frame" role="presentation" style="position:relative;" tabindex="0">Image of energy diagram

of cyclohexane conformations
1" role="presentation" style="position:relative;" tabindex="0">

Exercises
1) Consider the conformations of cyclohexane: half chair, chair, boat, twist boat. Order them in increasing ring strain in the
molecule.

Solutions
1) Chair < Twist Boat < Boat < half chair (most ring strain)
Questions
Q4.5.1
Consider the conformations of cyclohexane, chair, boat, twist boat. Order them in increasing strain in the molecule.
Solutions
S4.5.1
Chair < Twist Boat < Boat (most strain)

Contributors and Attributions

>Robert Bruner (http://bbruner.org)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Steven Farmer (Sonoma State University)
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham

Objectives
After completing this section, you should be able to
1. Draw the chair conformation of cyclohexane, with axial and equatorial hydrogen atoms clearly shown and
identified.
2. identify the axial and equatorial hydrogens in a given sketch of the cyclohexane molecule.
3. explain how chair conformations of cyclohexane and its derivatives can interconvert through the process of ring
flip.

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 Key Terms
☰
Make certain that you can define, and use in context, the key terms below.
axial position
equatorial position
ring flip

Axial and Equatorial Positions in Cyclohexane

Careful examination of the chair conformation of cyclohexane, shows that the twelve hydrogens are not structurally
equivalent. Six of them are located about the periphery of the carbon ring, and are termed equatorial. The other six are
oriented above and below the approximate plane of the ring (three in each location), and are termed axial because they are
aligned parallel to the symmetry axis of the ring.
H Hax
H H
H Heq
H H
H H
H H

In the figure above, the equatorial hydrogens are colored blue, and the axial hydrogens are black. Since there are two
equivalent chair conformations of cyclohexane in rapid equilibrium, all twelve hydrogens have 50% equatorial and 50%
axial character.

How To Draw Axial and Equatorial Bonds

corner pointing
down, so axial
bond goes down

corner pointing
up, so axial
bond goes up

Draw axial bonds straight Draw equatorial bonds up

up or straight down. and out or down and out.

How not to draw the chair:

H
H H
H H
H H

Incorrect. Incorrect. Incorrect.

Incorrect.
Equatorial bond Axial bond Axial bond should be
Ring should be
should be down should be straight down, equatorial
tilted slightly.
and out. straight up. bond should be up and out.

Aside from drawing the basic chair, the key points are:
Axial bonds alternate up and down, and are shown "vertical".
Equatorial groups are approximately horizontal, but actually somewhat distorted from that (slightly up or slightly
down), so that the angle from the axial group is a bit more than a right angle -- reflecting the common 109.5o bond
angle.
Each carbon has an axial and an equatorial bond.
Each face of the cyclohexane ring has three axial and three equatorial bonds.
Each face alternates between axial and equatorial bonds. Then looking at the "up" bond on each carbon in the
cyclohexane ring they will alternate axial-equatorial-axial ect.
When looking down at a cyclohexane ring:
the equatorial bonds will form an "equator" around the ring.
The axial bonds will either face towards you or away. These will alternate with each axial bond. The first axial bond
will be coming towards with the next going away. There will be three of each type.
Note! The terms cis and trans in regards to the stereochemistry of a ring are not directly linked to the terms axial and
equatorial. It is very common to confuse the two. It typically best not to try and directly inter convert the two naming

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 systems.
☰
Axial vs. Equatorial Substituents
When a substituent is added to cyclohexane, the ring flip allows for two distinctly different conformations. One will have
the substituent in the axial position while the other will have the substituent in the equatorial position. In the next section
will discuss the energy differences between these two possible conformations. Below are the two possible chair
conformations of methylcyclohexane created by a ring-flip. Although the conformation which places the methyl group in
the equatorial position is more stable by 7 kJ/mol, the energy provided by ambient temperature allows the two
conformations to rapidly interconvert.
CH3
Keq > 1
H
CH3

H
methyl group axial methyl group equatorial
(more stable by 7 kJ/mol)

The figure below illustrates how to convert a molecular model of cyclohexane between two different chair conformations -
this is something that you should practice with models. Notice that a 'ring flip' causes equatorial groups to become axial,
and vice-versa.
rotate this carbon down

rotate this carbon up

axial
H H UP H H
H H H H
H H H H equatorial
H H H H UP
H H H H
equatorial axial
H H DOWN H H
DOWN

 Example 4.3.1

For the following please indicate if the substituents are in the axial or equatorial positions.
Br Cl

CH3

Solution
Due to the large number of bonds in cyclohexane it is common to only draw in the relevant ones (leaving off the
hydrogens unless they are involved in a reaction or are important for analysis). It is still possible to determine axial and
equatorial positioning with some thought. With problems such as this it is important to remember that each carbon in a
cyclohexane ring has one axial and one equatorial bond. Also, remember that axial bonds are perpendicular with the
ring and appear to be going either straight up or straight down. Equatorial bonds will be roughly in the plane of the
cyclohexane ring (only slightly up or down). Sometimes it is valuable to draw in the additional bonds on the carbons
of interest.
H H

Br Cl
H

CH3

With this it can be concluded that the bromine and chlorine substituents are attached in equatorial positions and the
CH3 substituent is attached in an axial position.

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Exercises
☰
1) Draw two conformations of cyclohexyl amine (C6H11NH2). Indicate axial and equatorial positions.
2) Draw the two isomers of 1,4-dihydroxylcyclohexane, identify which are equatorial and axial.
3) In the following molecule, label which are equatorial and which are axial, then draw the chair flip (showing labels
1,2,3).

Solutions
1)

2)

3) Original conformation: 1 = axial, 2 = equatorial, 3 = axial

Flipped chair now looks like this.

Questions

Q4.6.1
Draw two conformations of cyclohexyl amine (C6H11NH2). Indicate axial and equatorial positions.
Q4.6.2
Draw the two isomers of 1,4-dihydroxylcyclohexane, identify which are equatorial and axial.
Q4.6.3

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In the following molecule, label which are equatorial and which are axial, then draw the chair flip (showing labels 1,2,3).
☰

Solutions
S4.6.1

S4.6.2

S4.6.3
Original conformation: 1 = axial, 2 = equatorial, 3 = axial
Flipped chair now looks like this.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Dr. Kelly Matthews, Harrisburg Area Community College
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham

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4.4: Substituted Cyclohexanes
Objectives
After completing this section, you should be able to
1. account for the greater stability of the equatorial conformers of monosubstituted cyclohexanes compared to their
axial counterparts, using the concept of 1,3‑diaxial interaction.
2. compare the gauche interactions in butane with the 1,3‑diaxial interactions in the axial conformer of
methylcyclohexane.
3. arrange a given list of substituents in increasing or decreasing order of 1,3‑diaxial interactions.

 Key Terms

Make certain that you can define, and use in context, the key term below.
1,3‑diaxial interaction

 Study Notes

1,3-Diaxial interactions are steric interactions between an axial substituent located on carbon atom 1 of a cyclohexane
ring and the hydrogen atoms (or other substituents) located on carbon atoms 3 and 5.
Be prepared to draw Newman-type projections for cyclohexane derivatives as the one shown for methylcyclohexane.
Note that this is similar to the Newman projections from chapter 3 such as n-butane.
H CH3 CH3
H H H3 C H
H H H H
H H H
methylcyclohexane n-butane

Newman projections of methylcyclohexane and n‑butane

When a substituent is added to a cyclohexane ring, the two possible chair conformations created during a ring flip are not
equally stable. In the example of methylcyclohexane the conformation where the methyl group is in the equatorial position
is more stable than the axial conformation by 7.6 kJ/mol at 25o C. The percentages of the two different conformations at
equilibrium can be determined by solving the following equation for K (the equilibrium constant): ΔE = -RTlnK. In this
equation ΔE is the energy difference between the two conformations, R is the gas constant (8.314 J/mol•K), T is the
temperature in Kelvin, and K is the equilibrium constant for the ring flip conversion. Using this equation, we can calculate
a K value of 21 which means about 95% methylcyclohexane molecules have the methyl group in the equatorial position at
25o C.
CH3
Keq > 1
H
CH3

H
methyl group axial methyl group equatorial
(more stable by 7 kJ/mol)

The energy difference between the two conformations comes from strain, called 1,3-diaxial interactions, created when the
axial methyl group experiences steric crowding with the two axial hydrogens located on the same side of the cyclohexane
ring. Because axial bonds are parallel to each other, substituents larger than hydrogen experience greater steric crowding
when they are oriented axial rather than equatorial. Consequently, substituted cyclohexanes will preferentially adopt
conformations in which the larger substituents are in the equatorial orientation. When the methyl group is in the
equatorial position this strain is not present which makes the equatorial conformer more stable and favored in the ring flip
equilibrium.

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 steric repulsion H
H
H C
5 H H 1

6
H
3
4 2

Actually, 1,3-diaxial steric strain is directly related to the steric strain created in the gauche conformer of butane discussed
in Section: 3-7. When butane is in the gauche conformation 3.8 kJ/mol of strain was created due the steric crowding of two
methyl group with a 60o dihedral angle. When looking at the a Newman projection of axial methylcyclohexane the methyl
group is at a 60o dihedral angle with the ring carbon in the rear. This creates roughly the same amount of steric strain as the
gauche conformer of butante. Given that there is actually two such interactions in axial methylcyclohexane, it makes sense
that there is 2(3.8 kJ/mol) = 7.6 kJ/mol of steric strain in this conformation. The Newman projection of equatorial
methylcyclohexane shows no such interactions and is therefore more stable.
H CH3 CH3
H H H3 C H
H H H H
H H H
methylcyclohexane n-butane

Newman projections of methyl cyclohexane and butane showing similarity of 1,3-diaxial and gauche interactions.
Strain values for other cyclohexane substituents can also be considered. The relative steric hindrance experienced by
different substituent groups oriented in an axial versus equatorial location on cyclohexane determined the amount of strain
generated. The strain generated can be used to evaluate the relative tendency of substituents to exist in an equatorial or
axial location. Looking at the energy values in this table, it is clear that as the size of the substituent increases, the 1,3-
diaxial energy tends to increase, also. Note that it is the size and not the molecular weight of the group that is important.
Table 4.7.1 summarizes some of these strain values values.
Table 4.7.1: A Selection of ΔG° Values for the Change from Axial to Equatorial Orientation of Substituents for Monosubstituted
Cyclohexanes
Substituent -ΔG° (kcal/mol) Substituent -ΔG° (kcal/mol)

CH −
3
1.7 O N−
2
1.1

CH H −
2 5
1.8 N≡C− 0.2

(CH ) CH−
3 2
2.2 CH O−
3
0.5

(CH ) C−
3 3
≥ 5.0 HO C−
2
0.7

F− 0.3 H C=CH−
2
1.3

Cl− 0.5 C H −
6 5
3.0

Br− 0.5

I− 0.5

Exercises
1) In the molecule, cyclohexyl ethyne there is little steric strain, why?

2) Calculate the energy difference between the axial and equatorial conformations of bromocyclohexane?
3) Using your answer from Question 2) estimate the percentages of axial and equatorial conformations of
bromocyclohexane at 25o C.

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4) There very little in 1,3-diaxial strain when going from a methyl substituent (3.8 kJ/mol) to an ethyl substituent (4.0
kJ/mol), why? It may help to use molecular model to answer this question.

Solutions
1) The ethyne group is linear and therefore does not affect the hydrogens in the 1,3 positions to say to the extent as a
bulkier or a bent group (e.g. ethene group) would. This leads to less of a strain on the molecule.

2) The equatorial conformation of bromocyclohexane will have two 1,3 diaxial interactions. The table above states that
each interaction accounts for 1.2 kJ/mol of strain. The total strain in equatorial bromocyclohexane will be 2(1.2 kJ/mol) =
2.4 kJ/mol.
3) Remembering that the axial conformation is higher in energy, the energy difference between the two conformations is
ΔE = (E equatorial - E axial) = (0 - 2.4 kJ/mol) = -2.4 kJ/mol. After converting oC to Kelvin and kJ/mol to J/mol we can
use the equation ΔE = -RT lnK to find that -ΔE/RT = lnK or (2.4 x 103 J/mol) / (8.313 kJ/mol K • 298 K) = lnK. From this
we calculate that K = 2.6. Because the ring flip reaction is an equilibrium we can say that K = [Equatorial] / [Axial]. If
assumption is made that [Equatorial] = X then [Axial] must be 1-X. Plugging these values into the equilibrium expression
produces K = [X] / [1-X]. After plugging in the calculated value for K, X can be solved algebraically. 2.6 = [X] / [1-X] →
2.6 - 2.6X = X → 2.6 = 3.6X → 2.6/3.6 = X = 0.72. This means that bromocyclohexane is in the equatorial position 72%
of the time and in the axial position 28% of the time.

4) The fact that C-C sigma bonds can freely rotate allows the ethyl subsistent to obtain a conformation which places the
bulky CH3 group away from the cyclohexane ring. This forces the ethyl substituent to have only have 1,3- diaxial
interactions between hydrogens, which only provides a slight difference to a methyl group.

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Exercises
Questions
Q4.7.1
In the molecule, cyclohexyl ethyne there is little steric strain, why?
Solutions

S4.7.1
The ethyne group is linear and therefore does not affect the hydrogens in the 1,3 positions to say to the extent as a bulkier
or a bent group (e.g. ethene group) would. This leads to less of a strain on the molecule.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
>Robert Bruner (http://bbruner.org)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham

 Objective
After completing this section, you should be able to use conformational analysis to determine the most stable
conformation of a given disubstituted cyclohexane.

 Key Terms

Make certain that you can define, and use in context, the key term below.
conformational analysis

 Study Notes

When faced with the problem of trying to decide which of two conformers of a given disubstituted cyclohexane is the
more stable, you may find the following generalizations helpful.
1. A conformation in which both substituents are equatorial will always be more stable than a conformation with both
groups axial.

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 2. When one substituent is axial and the other is equatorial, the most stable conformation will be the one with the
bulkiest substituent in the equatorial position. Steric bulk decreases in the order
tert-butyl > isopropyl > ethyl > methyl > hydroxyl > halogens

Monosubstituted Cyclohexanes
In the previous section, it was stated that the chair conformation in which the methyl group is equatorial is more stable
because it minimizes steric repulsion, and thus the equilibrium favors the more stable conformer. This is true for all
monosubstituted cyclohexanes. The chair conformation which places the substituent in the equatorial position will be the
most stable and be favored in the ring flip equilibrium.
CH3
Keq > 1
H
CH3

H
methyl group axial methyl group equatorial
(more stable by 7 kJ/mol)

steric repulsion H
H
H C
5 H H 1

6
H
3
4 2

Disubstituted Cyclohexanes
Determining the more stable chair conformation becomes more complex when there are two or more substituents attached
to the cyclohexane ring. To determine the stable chair conformation, the steric effects of each substituent, along with any
additional steric interactions, must be taken into account for both chair conformations.
In this section, the effect of conformations on the relative stability of disubstituted cyclohexanes is examined using the two
principles:
i. Substituents prefer equatorial rather than axial positions in order to minimize the steric strain created of 1,3-diaxial
interactions.
ii. The more stable conformation will place the larger substituent in the equatorial position.

1,1-Disubstituted Cyclohexanes
The more stable chair conformation can often be determined empirically or by using the energy values of steric
interactions previously discussed in this chapter. Note, in some cases there is no discernable energy difference between the
two chair conformations which means they are equally stable.
1,1-dimethylcyclohexane does not have cis or trans isomers, because both methyl groups are on the same ring carbon.
Both chair conformers have one methyl group in an axial position and one methyl group in an equatorial position giving
both the same relative stability. The steric strain created by the 1,3-diaxial interactions of a methyl group in an axial
position (versus equatorial) is 7.6 kJ/mol (from Table 4.7.1), so both conformers will have equal amounts of steric strain.
Thus, the equilibrium between the two conformers does not favor one or the other. Note, that both methyl groups cannot be
equatorial at the same time without breaking bonds and creating a different molecule.
CH3
CH3

1,1-dimethylcyclohexane
1,3-diaxial interactions (7.6 kJ/mol)

H CH3 H
H
H CH3 H CH3
H
H H CH3
1,3-diaxial interactions (7.6 kJ/mol)

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 However, if the two groups are different, as in 1-tert-butyl-1-methylcyclohexane, then the equilibrium favors the
conformer in which the larger group (tert-butyl in this case) is in the more stable equatorial position. The energy cost of
having one tert-butyl group axial (versus equatorial) can be calculated from the values in table 4.7.1 and is approximately
22.8 kJ/mol. The conformer with the tert-butyl group axial is approximately 15.2 kJ/mol (22.8 kJ/mol - 7.6 kJ/mol) less
stable then the conformer with the tert-butyl group equatorial. Solving for the equilibrium constant K shows that the
equatorial is preferred about 460:1 over axial. This means that 1-tert-butyl-1-methylcyclohexane will spend the majority of
its time in the more stable conformation, with the tert-butyl group in the equatorial position.
C(CH3)3
CH3

1-(tert-butyl)-1-methylcyclohexane
1,3-diaxial interactions (22.8 kJ/mol)

H C(CH3)3 H
H
H CH3 H C(CH3)3
H
H H CH3
1,3-diaxial interactions (7.6 kJ/mol)

Cis and trans stereoisomers of 1,2-dimethylcyclohexane

In cis-1,2-dimethylcyclohexane, both chair conformations have one methyl group equatorial and one methyl group axial.
As previously discussed, the axial methyl group creates 7.6 kJ/mol of steric strain due to 1,3-diaxial interactions. It is
important to note, that both chair conformations also have an additional 3.8 kJ/mol of steric strain created by a gauche
interaction between the two methyl groups. Overall, both chair conformations have 11.4 kJ/mol of steric strain and are of
equal stability.
CH3

CH3
cis -1,2-dimethylcyclohexane

gauche
CH3
1,3-diaxial + gauche interactions (11.4 kJ/mol) CH3
H H ring CH3
H CH3 HH C gauche CH3 ring H
3
H H gauche H
H CH3
H CH3
1,3-diaxial + gauche interactions (11.4 kJ/mol)

In trans-1,2-dimethylcyclohexane, one chair conformer has both methyl groups axial and the other conformer has both
methyl groups equatorial. The conformer with both methyl groups equatorial has no 1,3-diaxial interactions however there
is till 3.8 kJ/mol of strain created by a gauche interaction. The conformer with both methyl groups axial has four 1,3-
Diaxial interactions which creates 2 x 7.6 kJ/mol (15.2 kJ/mol) of steric strain. This conformer is (15.2 kJ/mol -3.8 kJ/mol)
11.4 kJ/mol less stable than the other conformer. The equilibrium will therefore favor the conformer with both methyl
groups in the equatorial position.
CH3

CH3
trans -1,2-dimethylcyclohexane

two 1,3-diaxial interactions (15.2 kJ/mol)

H CH3 H
H H H H H
H CH3 ring CH3
H H gauche
CH3 gauche H CH3
H ring CH3
H CH3 CH3 H
gauche interaction (3.8 kJ/mol)

Cis and trans stereoisomers of 1,3-dimethylcyclohexane

A similar conformational analysis can be made for the cis and trans stereoisomers of 1,3-dimethylcyclohexane. For cis-
1,3-dimethylcyclohexane one chair conformation has both methyl groups in axial positions creating 1,3-diaxial
interactions. The other conformer has both methyl groups in equatorial positions thus creating no 1,3-diaxial interaction.

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Because the methyl groups are not on adjacent carbons in the cyclohexane rings gauche interactions are not possible. Even
without energy calculations it is simple to determine that the conformer with both methyl groups in the equatorial position
will be the more stable conformer.
CH3 CH3
CH3
H 3C CH3

CH3 both methyl groups axial both methyl groups equatorial

1,3-diaxial interactions no interactions
more stable conformer

For trans-1,3-dimethylcyclohexane both conformations have one methyl axial and one methyl group equatorial. Each
conformer has one methyl group creating a 1,3-diaxial interaction so both are of equal stability.
CH3 CH3

CH3
H 3C
CH3 CH3
one methyl group axial one methyl group axial
and one equatorial and one equatorial

both conformers have equal stability

Summary of Disubstitued Cyclohexane Chair Conformations

When considering the conformational analyses discussed above a pattern begins to form. There are only two possible
relationships which can occur between ring-flip chair conformations:
1) AA/EE: One chair conformation places both substituents in axial positions creating 1,3-diaxial interactions. The other
conformer places both substituents in equatorial positions creating no 1,3-diaxial interactions. This diequatorial conformer
is the more stable regardless of the substituents.
2) AE/EA: Each chair conformation places one substituent in the axial position and one substituent in the equatorial
position. If the substituents are the same, there will be equal 1,3-diaxial interactions in both conformers making them equal
in stability. However, if the substituents are different then different 1,3-diaxial interactions will occur. The chair
conformation which places the larger substituent in the equatorial position will be favored.

Substitution type Chair Conformation Relationship

cs-1,2-disubstituted cyclohexanes AE/EA

trans-1,2-disubstituted cyclohexanes AA/EE

cis-1,3-disubstituted cyclohexanes AA/EE

trans-1,3-disubstituted cyclohexanes AE/EA

cis-1,4-disubstituted cyclohexanes AE/EA

trans-1,4-disubstituted cyclohexanes AA/EE

 Example 4.4.1
For cis-1-chloro-4-methylcyclohexane, draw the most stable chair conformation and determine the energy difference
between the two chair conformers.
Solution
Based on the table above, cis-1,4-disubstitued cyclohexanes should have two chair conformations each with one
substituent axial and one equatorial. Based on this, we can surmise that the energy difference of the two chair
conformations will be based on the difference in the 1,3-diaxial interactions created by the methyl and chloro
substituents.

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 1,3-diaxial interactions (7.6 kJ/mol)

H CH3 Cl H
H H H H
Cl H H CH3

1,3-diaxial interactions (2.0 kJ/mol)

As predicted, each chair conformer places one of the substituents in the axial position. Because the methyl group is
larger and has a greater 1,3-diaxial interaction than the chloro, the most stable conformer will place it the equatorial
position, as shown in the structure on the right. Using the 1,3-diaxial energy values given in the previous sections we
can calculate that the conformer on the right is (7.6 kJ/mol - 2.0 kJ/mol) 5.6 kJ/mol more stable than the other.

 Example 4.4.2

For trans-1-chloro-2-methylcyclohexane, draw the most stable chair conformation and determine the energy difference
between the two chair conformers.
Solution
Based on the table above, trans-1,2-disubstitued cyclohexanes should have one chair conformation with both
substituents axial and one conformation with both substituents equatorial. Based on this, we can predict that the
conformer which places both substituents equatorial will be the more stable conformer. The energy difference of the
two chair conformations will be based on the 1,3-diaxial interactions created by both the methyl and chloro
substituents.
H CH3
H H
H H
H CH3
H Cl
H Cl
both groups are axial both groups are equatorial
1,3-diaxial interactions (9.6 kJ/mol) no 1,3-diaxial interactions

As predicted, one chair conformer places both substituents in the axial position and other places both substituents
equatorial. The more stable conformer will place both substituents in the equatorial position, as shown in the structure
on the right. Using the 1,3-diaxial energy values given in the previous sections we can calculate that the conformer on
the right is (7.6 kJ/mol + 2.0 kJ/mol) 9.6 kJ/mol more stable than the other.

Conformational Analysis of Complex Six Membered Ring Structures

Cyclohexane can have more than two substituents. Also, there are multiple six membered rings which contain atoms other
than carbon. All of these systems usually form chair conformations and follow the same steric constraints discussed in this
section. Because the most commonly found rings in nature are six membered, conformational analysis can often help in
understanding the usual shapes of some biologically important molecules. In complex six membered ring structures a
direct calculation of 1,3-diaxial energy values may be difficult. In these cases a determination of the more stable chair
conformer can be made by empirically applying the principles of steric interactions.
A later chapter will discuss how many sugars can exist in cyclic forms which are often six remembered rings. When in an
aqueous solution the six carbon sugar, glucose, is usually a six membered ring adopting a chair conformation. When
looking at the two possible ring-clip chair conformations, one has all of the substituents axial and the other has all the
substutents equatorial. Even without a calculation, it is clear that the conformation with all equatorial substituents is the
most stable and glucose will most commonly be found in this conformation.
HO OH
OH
OH Keq >> 1
O HO O
HO OH
OH OH OH

glucose
(β-glucopyranose form)

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  Example 4.4.3
The six carbon sugar, fructose, in aqueous solution is also a six-membered ring in a chair conformation. Which of the
two possible chair conformations would be expected to be the most stable?
OH
OH OH
O HO O
OH OH
HO
OH OH
OH
fructose
(β-fructopyranose form)

Solution
The lower energy chair conformation is the one with three of the five substituents (including the bulky –CH2OH
group) in the equatorial position (pictured on the right). The left structure has 3 equatorial substituents while the
structure on the right only has two equatorial substituents.

Exercises
1. Draw the two chair conformations for cis-1-ethyl-2-methylcyclohexane using bond-line structures and indicate the more
energetically favored conformation.
2. Draw the most stable conformation for trans-1-ethyl-3-methylcyclohexane using bond-line structures.
3. Draw the most stable conformation for trans-1-t-butyl-4-methylcyclohexane using bond-line structures.
4. Draw the most stable conformation fo trans-1-isopropyl-3-methylcyclohexane.
5. Can a ‘ring flip’ change a cis-disubstituted cyclohexane to trans? Explain.
6. Draw the two chair conformations of the six-carbon sugar mannose, being sure to clearly show each non-hydrogen
substituent as axial or equatorial. Predict which conformation is likely to be more stable, and explain why.

Solutions

4.

The bulkier isopropyl groups is in the equatorial position.

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5. No. In order to change the relationship of two substituents on a ring from cis to trans, you would need to break and
reform two covalent bonds. Ring flips involve only rotation of single bonds.
6.

Exercises
Questions
Q4.8.1
For the following molecules draw the most stable chair conformation and explain why you chose this as an answer
1 = trans-1,2-dimethylcyclohexane
2 = cis-1,3-dimethylcyclohexane
Solutions
S4.8.1
1 – The most stable conformation would be to have the methyl groups equatorial reducing steric interaction
2 – The most stable conformation would be to have the groups equatorial this would reduce the strain if they were axial

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
>Robert Bruner (http://bbruner.org)
Kelly Matthews, Senior Professor of Chemistry, Harrisburg Area Community College
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham

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4.5: Larger Cycloalkanes
The Baeyer strain theory suggested that the larger cycloalkanes ring are difficult to synthesize because of angle strain
associated with planar rings, as calculated in Table 12-3. We now know that, except for cyclopropane, none of the
cycloalkanes have planar carbon rings and that the higher cycloalkanes have normal or nearly normal bond angles. The
reason that the higher cycloalkanes are generally difficult to synthesize from open-chain compounds is not so much angle
strain, as Baeyer hypothesized, but the low probability of having reactive groups on the two fairly remote ends of a long
hydrocarbon chain come together to effect cyclization. Usually, coupling of reactive groups on the ends of different
molecules occurs in preference to cyclization, unless the reactions are carried out in very dilute solutions. This is called the
high-dilution technique for achieving ring formation when the ring-forming reaction has to compete with rapid inter-
molecular reactions.
With regard to conformations of the larger cycloalkanes, we first note that the chair form of cyclohexane is a “perfect”
conformation for a cycloalkane. The C−C−C bond angles are close to their normal values, all the adjacent hydrogens are
staggered with respect to one another, and the 1,3-axial hydrogens are not close enough together to experience nonbonded
repulsions. About the only qualification one could put on the ideality of the chair form is that the trans conformation of
butane is somewhat more stable than the gauche conformation (Section 5-2), and that all of the C−C−C−C segments of
cyclohexane have the gauche arrangement. Arguing from this, J. Dale has suggested that large cycloalkane rings would
6

tend to have trans C−C−C−C segments to the degree possible and, indeed, cyclotetradecane seems to be most stable in a
rectangular conformation with trans C−C−C−C bond segments (Figure 12-16). This conformation has a number of
possible substituent positions, but because only single isomers of monosubstituted cyclotetradecanes have been isolated,
rapid equilibration of the various conformational isomers must occur. Other evidence indicates that the barrier to
interconversion of these conformations is about 7 kcal mol . −1

Figure 12-16 Favored conformation of cyclotetradecane as proposed by Dale. For comparison, the trans and gauche forms
of butane are shown by the same convention. (The convention implies that the wedged lines are C−C or C−H bonds
projecting out of the plane of the paper, with the wide end closest to you, and the broken lines are C−H bonds projecting
behind the plane of the paper. The result is an “aerial” view of the molecule in the most stable staggered conformation.)
With the cycloalkanes having 7 to 10 carbons, there are problems in trying to make either trans or gauche C−C−C−C
segments, because the sizes of these rings do not allow the proper bond angles or torsional angles, or else there are more or
less serious nonbonded repulsions. Consequently each of these rings assumes a compromise conformation with some
eclipsing, some nonbonded repulsions, and some angle distortions. Brief comments on some of these conformations
follow. It will be useful to use molecular models to see the interactions involved.

Cycloheptane
Possible conformations for cycloheptane include the “comfortable” appearing chair form, 7. However, this form has
eclipsed hydrogens at C and C as well as nonbonded interactions between the axial-like hydrogens on C and C . The
4 5 3 6

best compromise conformation is achieved by a 30 -40 rotation around the C −C bond to relieve the eclipsing of the
o o
4 5

hydrogens. This spreads the interfering hydrogens at C and C and results in a somewhat less strained conformation
3 6

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called the twist chair. The twist chair, 8, is very flexible and probably only about 3 kcal mol−1
of activation is required to
interconvert the various possible monosubstituted cycloheptane conformations.

Cyclooctane
There are several more or less reasonable looking cyclooctane conformations. After much research it now is clear that the
favored conformation is the boat-chair, 9, which is in equilibrium with a few tenths percent of the crown conformation, 10
:

The activation energy for interconversion of these two forms is about 10 kcal mol . The boat-chair conformation 9 is
−1

quite flexible and movement of its CH groups between the various possible positions occurs with an activation energy of
2

only about 5 kcal mol .

−1

Cyclononane
Several more or less reasonable conformations of cyclononane also can be developed, but the most favorable one is called
the twist-boat-chair, which has three-fold symmetry (Figure 12-17). The activation energy for inversion of the ring is
about 6 kcal mol .
−1

Figure 12-17: Twist boat-chair conformation of cyclononane (Public Domain; Jynto). IColor code: Carbon, C: black
Hydrogen, H: white

Cyclodecane
The stable conformation of cyclodecane (Figure 12-18) is similar to that of cyclotetradecane (Figure 12-16). However,
there are relatively short H ⋅ ⋅ ⋅ ⋅H distances and the C−C−C bond angles are somewhat distorted because of cross-ring
hydrogen-hydrogen repulsions. The most stable position for a substituent on the cyclodecane ring is the one indicated in
Figure 12-18. The least stable positions are those in which a substituent replaces any of the six hydrogens shown, because
nonbonded interactions are particularly strong at these positions. The activation energy for interconversion of substituent
positions is about 6 kcal mol .
−1

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Most stable conformation of cyclodecane; Dale and sawhorse representations. The shaded area in the sawhorse convention
indicates substantial nonbonded H ⋅ ⋅ ⋅ ⋅H interactions.

Figure 12-16).
6
Pronounced Dalluh.

Contributors and Attributions

John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin,
Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions, "You are granted
permission for individual, educational, research and non-commercial reproduction, distribution, display and performance
of this work in any format."

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4.6: Polycyclic Alkanes
Objective
After completing this section, you should be able to draw the structures and construct molecular models of simple
polycyclic molecules.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
bridgehead carbon atom
polycyclic molecule

 Study Notes

A bridgehead carbon atom is a carbon atom which is shared by at least two rings. The hydrogen atom which is
attached to a bridgehead carbon may be referred to as a bridgehead hydrogen.
Note that bicyclo[2.2.1]heptane is the systematic name of norborane. You need not be concerned over the IUPAC
name of norbornane. The nomenclature of compounds of this type is beyond the scope of this course.

Nomenclature of Bicyclic Ring Systems

There are many hydrocarbons and hydrocarbon derivatives with two rings having common carbon atoms. There are three
main ways that the two rings can be connected. The first is called a fused bicyclic ring structure where the two rings share
a covalent bond and a have two bridgehead carbons (marked in red on the structures below). A bridgehead is defined as a
carbon that is part of two or more rings. Hydrogens attached to bridge head carbons are often referred to as bridge head
hydrogens. The two rings can also be connected by a bridge containing one or more carbons to form a bridged bicyclic
molecule. Lastly, the two rings can be joined with a singe bridge head carbon to form spiro bicyclic molecules.

fused bridged spiro

= bridgehead carbons

Bicyclic Isomers of C10H18

Naming Fused and Bridged Compounds

Fused and bridged bicyclic compounds are follow similar naming conventions:
1. Count the total number of carbons in both rings. This is the parent name. (eg. ten carbons in the system would be
decane)
2. Count the number of carbons between the bridgeheads, then place the numbers in square brackets in descending order
separated by periods. Fused and bridged bycyclic compounds should have three numbers such as [2.2.0]. For fused
compounds one of the numbers should be zero.
3. Place the word bicyclo at the beginning of the name.
1 1 1
1 2
2 2
0 2 1
3 3
3 3
4 4 4

bicyclo[4.4.0]decane bicyclo[4.3.1]decane

Examples with carbons and hydrogens explicitly shown:

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 H
H C H
C H 2C CH2 C
H 2C CH2 H 2C H 2C CH2
CH2 H 2C CH C
H 2C CH2 C H
H2
bicyclo[2.2.1]heptane bicyclo[3.1.1]heptane bicyclo[1.1.0]butane

Naming Spiro Compounds

Spiro bicyclics are named using the same basic rules. Because there is only one bridgehead carbon only two numbers will
be required in the brackets. Also, the word spiro is placed at the beginning.
2 1 1
2
3
3
4 5 4

spiro[5.4]decane

Examples

spiro[4.4]nonane spiro[3.2]hexane

Conformations in Bicyclic Ring Systems

As expected, the connection of two rings has defined effects on the possible conformations. However, the ideas previously
discussed in this chapter can be used for conformational analysis. Fused rings have the possibility of two isomers where
the bridgehead hydrogens are either cis or trans along the shared bond. These two isomers have significant differences in
flexibility and stability as seen in bicyclo[4,4,0]decane more commonly known as decalin. If the positioning of the
bridgehead hydrogens are shown in a fused ring the prefix cis or trans should be included in the name.
The trans-isomer is the easiest to describe because the fusion of the two rings creates a rigid, roughly planar, structure
made up of two chair conformations. Unlike cyclohexane, the two rings cannot flip from one chair form to another.
Accordingly, the orientation of the any substituents is fixed in either an axial or equatorial position in trans-decalin. This
means that the C-C bonds coming away from the fused edge are held in equatorial positions relative to each ring thus
preventing the possibility of any 1,3-diaxial interactions occurring between ring atoms.
H H

H H
trans -decalin
(rigid)

2kcal mol&#x2212;1" id="MathJax-Element-1-Frame" role="presentation" style="position:relative;" tabindex="0">

The two rings in cis-decalin are also both held in a chair conformations. In comparison, the chair-chair forms of cis-decalin
are relatively flexible, and inversion of both rings at once occurs fairly easily.
H H H
H
H

H
cis -decalin
(more flexible)

The flexibility of cis-decalin allows for a substituent to interconvert between axial and equatorial conformations. In much
the same fashion as cyclohexane, equatorial substituents tend to create less steric strain and create a more stable conformer.

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 CH3 CH3
2 3 4
1 3
2
1 6 5
6 5 4

(Note: atoms are mapped in blue for clarity.)

A major difference in cis-decalin is the fact that one of C-C bonds coming away from the fused edge is held an an axial
position. This is true in both ring-flip conformations. This axial C-C bond causes 1,3-diaxial interactions to occur in cis-
decalin making it roughly 8.4 kJ/mol less stable than trans-decalin. This amount of 1,3-diaxial steric strain is roughly
equivalent to that of an ethyl substituent attached to a cyclohexane ring (8.0 kJ/mol)

H H
H H

= steric strain

Bicyclic compounds with a bridge typically have very little flexibility and are often held in a ridged conformation. The
molecule norbornane represent a cyclohexane ring connected by a single carbon bridge.

norbornane, or
bicyclo[2.2.1]heptane

Norbornane is estimated to have 72 kJ/mol of ring strain which can be understood when viewing the contained rings. The
carbon bridge in norbornane holds the cyclohexane ring at the bottom in a boat conformation creating torsional strain from
eclipsing bonds along the edge.

H H
H H
H H
H H
(green arrows used to illustrate
eclipsing hydrogens)

Also, the carbon bridge forms a cyclopentane ring (shown in red below making up the right side of the structure) with
increased angle strain throughout the whole molecule.

Polycyclic Systems in Nature

Fused ring systems like decalin are very common in natural products. In fact, similar ring systems are found in steroids,
which are an important class of lipids. Steroids generally have structures that include three six-membered rings and a five-
membered ring connected by three fused bonds. Most natural steroids have a trans configuration at all three fusion points.
This tends to give steroids a rigid and semi-flat structure.
H
H H

H H
H

basic steroid ring confguration trans-trans-trans

(fused bonds highlighted in purple)

Sex hormones are an example of steroids. The primary male hormone, testosterone, is responsible for the development of
secondary sex characteristics. Two female sex hormones, progesterone and estrogen (or estradiol) control the ovulation
cycle. Notice that the male and female hormones have only slight differences in structures, but yet have very different
physiological effects. Testosterone promotes the normal development of male genital organs and is synthesized from
cholesterol in the testes. It also promotes secondary male sexual characteristics such as deep voice, facial and body hair.

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 OH OH

H H

H H H H
O HO
testosterone estradiol

The best known and most abundant steroid in the body is cholesterol. Cholesterol is formed in brain tissue, nerve tissue,
and the blood stream. It is the major compound found in gallstones and bile salts. Cholesterol also contributes to the
formation of deposits on the inner walls of blood vessels. These deposits harden and obstruct the flow of blood. This
condition, known as atherosclerosis, results in various heart diseases, strokes, and high blood pressure.

H H
HO
cholesterol

Exercises
1)

i)

j)

3) The following molecule is cholic acid. Determine if the three fused bonds have a cis or trans configuration.

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Solutions
1)
a) Bicyclo[2.1.1]hexane
b) Bicyclo[3.2.1]octane
c) Bicyclo[2.1.0]pentane (more commonly called "housane")
d) Bicyclo[2.2.2]octane
e) cis-Bicyclo[3.3.0]octane
f) cis-Bicyclo[1.1.0]butane
g) Bicyclo[1.1.1]pentane
h) Bicyclo[4.3.3]dodecane
i) Spiro[5.2]octane
j) Spiro[3.3]heptane
2)

Questions

Q4.9.1
Someone stated that trans-decalin is more stable than cis-decalin. Explain why this is incorrect.
Solutions
S4.9.1
Cis-decalin has fewer steric interactions than trans-decalin.

Contributors and Attributions

Gamini Gunawardena from the OChemPal site (Utah Valley University)
John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin,
Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions, "You are granted
permission for individual, educational, research and non-commercial reproduction, distribution, display and performance
of this work in any format."
Prof. Steven Farmer (Sonoma State University)
Layne Morsch (University of Illinois Springfield)
Chris P Schaller, Ph.D., (College of Saint Benedict / Saint John's University)
Dr. Krista Cunningham

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4.7: Carbocyclic Products in Nature
The important class of lipids called steroids are actually metabolic derivatives of terpenes, but they are customarily treated
as a separate group. Steroids may be recognized by their tetracyclic skeleton, consisting of three fused six-membered and
one five-membered ring, as shown in the diagram to the right. The four rings are designated A, B, C & D as noted, and the
peculiar numbering of the ring carbon atoms (shown in red) is the result of an earlier misassignment of the structure. The
substituents designated by R are often alkyl groups, but may also have functionality. The R group at the A:B ring fusion is
most commonly methyl or hydrogen, that at the C:D fusion is usually methyl. The substituent at C-17 varies considerably,
and is usually larger than methyl if it is not a functional group. The most common locations of functional groups are C-3,
C-4, C-7, C-11, C-12 & C-17. Ring A is sometimes aromatic. Since a number of tetracyclic triterpenes also have this
tetracyclic structure, it cannot be considered a unique identifier.

Steroids are widely distributed in animals, where they are associated with a number of physiological processes. Examples
of some important steroids are shown in the following diagram. Norethindrone is a synthetic steroid, all the other examples
occur naturally. A common strategy in pharmaceutical chemistry is to take a natural compound, having certain desired
biological properties together with undesired side effects, and to modify its structure to enhance the desired characteristics
and diminish the undesired. This is sometimes accomplished by trial and error.
The generic steroid structure drawn above has seven chiral stereocenters (carbons 5, 8, 9, 10, 13, 14 & 17), which means
that it may have as many as 128 stereoisomers. With the exception of C-5, natural steroids generally have a single common
configuration. This is shown in the last of the toggled displays, along with the preferred conformations of the rings.

Chemical studies of the steroids were very important to our present understanding of the configurations and conformations
of six-membered rings. Substituent groups at different sites on the tetracyclic skeleton will have axial or equatorial
orientations that are fixed because of the rigid structure of the trans-fused rings. This fixed orientation influences chemical

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reactivity, largely due to the greater steric hindrance of axial groups versus their equatorial isomers. Thus an equatorial
hydroxyl group is esterified more rapidly than its axial isomer.
It is instructive to examine a simple bicyclic system as a model for the fused rings of the steroid molecule. Decalin, short
for decahydronaphthalene, exists as cis and trans isomers at the ring fusion carbon atoms. Planar representations of these
isomers are drawn at the top of the following diagram, with corresponding conformational formulas displayed underneath.
The numbering shown for the ring carbons follows IUPAC rules, and is different from the unusual numbering used for
steroids. For purposes of discussion, the left ring is labeled A (colored blue) and the right ring B (colored red). In the
conformational drawings the ring fusion and the angular hydrogens are black.

The trans-isomer is the easiest to describe because the fusion of the A & B rings creates a rigid, roughly planar, structure
made up of two chair conformations. Each chair is fused to the other by equatorial bonds, leaving the angular hydrogens
(Ha) axial to both rings. Note that the bonds directed above the plane of the two rings alternate from axial to equatorial and
back if we proceed around the rings from C-1 to C-10 in numerical order. The bonds directed below the rings also alternate
in a complementary fashion.
Conformational descriptions of cis- decalin are complicated by the fact that two energetically equivalent fusions of chair
cyclohexanes are possible, and are in rapid equilibrium as the rings flip from one chair conformation to the other. In each
of these all chair conformations the rings are fused by one axial and one equatorial bond, and the overall structure is bent at
the ring fusion. In the conformer on the left, the red ring (B) is attached to the blue ring (A) by an axial bond to C-1 and an
equatorial bond to C-6 (these terms refer to ring A substituents). In the conformer on the right, the carbon bond to C-1 is
equatorial and the bond to C-6 is axial. Each of the angular hydrogens (Hae or Hea) is oriented axial to one of the rings and
equatorial to the other. This relationship reverses when double ring flipping converts one cis-conformer into the other.
Cis-decalin is less stable than trans-decalin by about 2.7 kcal/mol (from heats of combustion and heats of isomerization
data). This is due to steric crowding (hindrance) of the axial hydrogens in the concave region of both cis-conformers, as
may be seen in the model display activated by the following button. This difference is roughly three times the energy of a
gauche butane conformer relative to its anti conformer. Indeed three gauche butane interactions may be identified in each
of the cis-decalin conformations, as will be displayed by clicking on the above conformational diagram. These gauche
interactions are also shown in the model.
Steroids in which rings A and B are fused cis, such as the example on the right, do not have the sameconformational
mobility exhibited by cis-decalin. The fusion of ring C to ring B in a trans configuration prevents ring B from undergoing a

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conformational flip to another chair form. If this were to occur, ring C would have to be attached to ring B by two adjacent
axial bonds directed 180º apart. This is too great a distance to be bridged by the four carbon atoms making up ring C.
Consequently, the steroid molecule is locked in the all chair conformation shown here. Of course, all these steroids and
decalins may have one or more six-membered rings in a boat conformation. However the high energy of boat conformers
relative to chairs would make such structures minor components in the overall ensemble of conformations available to
these molecules.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Compounds classified as terpenes constitute what is arguably the largest and most diverse class of natural products. A
majority of these compounds are found only in plants, but some of the larger and more complex terpenes (e.g. squalene &
lanosterol) occur in animals. Terpenes incorporating most of the common functional groups are known, so this does not
provide a useful means of classification. Instead, the number and structural organization of carbons is a definitive
characteristic. Terpenes may be considered to be made up of isoprene (more accurately isopentane) units, an empirical
feature known as the isoprene rule. Because of this, terpenes usually have 5n carbon atoms (n is an integer), and are
subdivided as follows:
Classification Isoprene Units Carbon Atoms

monoterpenes 2 C10

sesquiterpenes 3 C15

diterpenes 4 C20

sesterterpenes 5 C25

triterpenes 6 C30

Isoprene itself, a C5H8 gaseous hydrocarbon, is emitted by the leaves of various plants as a natural byproduct of plant
metabolism. Next to methane it is the most common volatile organic compound found in the atmosphere. Examples of C10
and higher terpenes, representing the four most common classes are shown in the following diagrams. Most terpenes may
be structurally dissected into isopentane segments. How this is done can be seen in the diagram directly below.

Figure: Monoterpenes and diterpenes

The isopentane units in most of these terpenes are easy to discern, and are defined by the shaded areas. In the case of the
monoterpene camphor, the units overlap to such a degree it is easier to distinguish them by coloring the carbon chains.
This is also done for alpha-pinene. In the case of the triterpene lanosterol we see an interesting deviation from the isoprene
rule. This thirty carbon compound is clearly a terpene, and four of the six isopentane units can be identified. However, the
ten carbons in center of the molecule cannot be dissected in this manner. Evidence exists that the two methyl groups
circled in magenta and light blue have moved from their original isoprenoid locations (marked by small circles of the same

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color) to their present location. This rearrangement is described in the biosynthesis section. Similar alkyl group
rearrangements account for other terpenes that do not strictly follow the isoprene rule.

Figure: Triterpenes
Polymeric isoprenoid hydrocarbons have also been identified. Rubber is undoubtedly the best known and most widely used
compound of this kind. It occurs as a colloidal suspension called latex in a number of plants, ranging from the dandelion to
the rubber tree (Hevea brasiliensis). Rubber is a polyene, and exhibits all the expected reactions of the C=C function.
Bromine, hydrogen chloride and hydrogen all add with a stoichiometry of one molar equivalent per isoprene unit.
Ozonolysis of rubber generates a mixture of levulinic acid ( C H C OC H C H C O H ) and the corresponding aldehyde.
3 2 2 2

Pyrolysis of rubber produces the diene isoprene along with other products.

The double bonds in rubber all have a Z-configuration, which causes this macromolecule to adopt a kinked or coiled
conformation. This is reflected in the physical properties of rubber. Despite its high molecular weight (about one million),
crude latex rubber is a soft, sticky, elastic substance. Chemical modification of this material is normal for commercial
applications. Gutta-percha (structure above) is a naturally occurring E-isomer of rubber. Here the hydrocarbon chains
adopt a uniform zig-zag or rod like conformation, which produces a more rigid and tough substance. Uses of gutta-percha
include electrical insulation and the covering of golf balls.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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4.E: Cycloalkanes (Exercises)
These are homework exercises to accompany Chapter 4 of Vollhardt and Schore's "Organic Chemistry" Textmap.

4.1: Names and Physical Properties of Cycloalkanes

4.2: Ring Strain and the Structure of Cycloalkanes

4.3: Cyclohexane: A Strain-Free Cycloalkane

4.4: Substituted Cyclohexanes

4.5: Larger Cycloalkanes

4.6: Polycyclic Alkanes

4.7: Carbocyclic Products in Nature

Practice Problems
Q21
Draw all of the different structures with the formula C6H12 with only one ring and name them.

Q22
Draw all of the different structures with the formula C7H14 with only one ring and name them.

Q23
Name each of the following structures.

Q24
Draw the following structures, and if the name is not in accordance with IUPAC naming, give the proper name.
(a) isopropylcyclohexane (b) 1,1-dimethylcyclobutane (c) cyclobutylcyclopentane (d) cyclopropylpropane (e) 1-iodo-4-
chlorocyclohexane (f) 1-ethyl-2-cyclobutane

Q25
Draw the following structures, no indication of the ring conformation is necessary.
a. trans-1-bromo-2-methylcyclohexane
b. cis-1-bromo-2-methylcyclohexane
c. trans-1-bromo-2-iodocyclopropane
d. 1-bromo-2-iodocyclopropane
e. 1-fluoro-4-methylcycloheptane

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Q26
Given that the ideal bond angle for an sp3 hybrdized carbon is 109.5o and that the ideal angle for an sp2 hybridized carbon
is 120o, what radical is the most stable based on the angle strain? Is the radical more stable than the previous cycloalkane,
again based on angle strain alone? (Hint, a transition from an sp3 hybridized to an sp2 hybridized carbon occurs).
(a) cyclobutane (angle=88o) (b) cyclopropane (angle=60o) (c) cyclohexane (angle ~ 109.5o)

Solutions

S21

S22
Notice how many more different structures that can be drawn for C7H14 than C6H12. If more than one ring were an option,
even more structures could be drawn.

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S23

S24

S25

S26
Given that the ideal bond angle for an sp3 hybrdized carbon is 109.5o and that the ideal angle for an sp2 hybridized carbon
is 120o, what radical is the most stable based on the angle strain? Is the radical more stable than the previous cycloalkane,
again based on angle strain alone? (Hint, a transition from an sp3 hybridized to an sp2 hybridized carbon occurs).
(a) cyclobutane (angle=88o)
Before the radical forms: 109.5-88= 21.5o
After the radical forms: 120-88= 32o
The radical creates more ring strain
(b) cyclopropane (angle=60o)
Before the radical forms: 109.5-60=49.5o

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 After the radical forms: 120-60=60o
The radical creates more ring strain
(c) cyclohexane (angle ~ 109.5o)
Before the radical forms: 109.5-109.5=0
After the radical forms: 120-109.5=10.5o The radical creates more ring strain
The cyclohexane radical is the most stable based on angle strain alone

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CHAPTER OVERVIEW
5: STEREOISOMERS
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

Stereoisomers are isomers that differ in spatial arrangement of atoms, rather than order of atomic connectivity. One of their most
interesting type of isomer is the mirror-image stereoisomers, a non-superimposable set of two molecules that are mirror image of one
another. The existence of these molecules are determined by concept known as chirality.

5.1: CHIRAL MOLECULES

5.2: OPTICAL ACTIVITY
5.3: ABSOLUTE CONFIGURATION: R-S SEQUENCE RULES
5.4: FISCHER PROJECTIONS
5.5: MOLECULES INCORPORATING SEVERAL STEREOCENTERS: DIASTEREOMERS
5.6: MESO COMPOUNDS
5.7: STEREOCHEMISTRY IN CHEMICAL REACTIONS
5.8: RESOLUTION: SEPARATION OF ENANTIOMERS
5.E: STEREOISOMERS (EXERCISES)

1 12/5/2021
5.1: Chiral Molecules
Objectives
After completing this section, you should be able to
1. use molecular models to show that only a tetrahedral carbon atom satisfactorily accounts for the lack of isomerism in
molecules of the type CH2XY, and for the existence of optical isomerism in molecules of the type CHXYZ.
2. determine whether two differently oriented wedge-and-broken-line structures are identical or represent a pair of
enantiomers.

 Key Terms
Make certain that you can define, and use in context, the key term below.
enantiomer

 Study Notes

Stereoisomers are isomers that differ in spatial arrangement of atoms, rather than order of atomic connectivity. One of the
most interesting types of isomer is the mirror-image stereoisomer, a non-superimposable set of two molecules that are mirror
images of one another. The existence of these molecules are determined by a a concept known as chirality. The word
“chiral” was derived from the Greek word for hand, because our hands are a good example of chirality since they are non-
superimposable mirror images of each other.

Chiral Molecules
The term chiral, from the Greek work for 'hand', refers to anything which cannot be superimposed on its own mirror image.
Certain organic molecules are chiral meaning that they are not superimposable on their mirror image. Chiral molecules contain
one or more chiral centers, which are almost always tetrahedral (sp3-hybridized) carbons with four different substituents.
Consider the molecule A below: a tetrahedral carbon, with four different substituents denoted by balls of four different colors.

The mirror image of A, which we will call B, is drawn on the right side of the figure, and an imaginary mirror is in the middle.
Notice that every point on A lines up through the mirror with the same point on B: in other words, if A looked in the mirror, it
would see B looking back.
Now, if we flip compound A over and try to superimpose it point for point on compound B, we find that we cannot do it: if we
superimpose any two colored balls, then the other two are misaligned.

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A is not superimposable on its mirror image (B), thus by definition A is a chiral molecule. It follows that B also is not
superimposable on its mirror image (A), and thus it is also a chiral molecule.
A and B are called stereoisomers or optical isomers: molecules with the same molecular formula and the same bonding
arrangement, but a different arrangement of atoms in space. Enantiomers are pairs of stereoisomers which are mirror images of
each other: thus, A and B are enantiomers. It should be self-evident that a chiral molecule will always have one (and only one)
enantiomer: enantiomers come in pairs. Enantiomers have identical physical properties (melting point, boiling point, density, and
so on). However, enantiomers do differ in how they interact with polarized light (we will learn more about this soon) and they
may also interact in very different ways with other chiral molecules - proteins, for example. We will begin to explore this last
idea in later in this chapter, and see many examples throughout the remainder of our study of biological organic chemistry.

 The Many Synonyms of the Chiral Carbon

Be aware - all of the following terms can be used to describe a chiral carbon.
chiral carbon = asymmetric carbon = optically active carbon = stereo carbon = stereo center = chiral center

Let's apply our chirality discussion to real molecules.

Consider 2-butanol, drawn in two dimensions below.

Carbon #2 is a chiral center: it is sp3-hybridized and tetrahedral (even though it is not drawn that way above), and the four
substituents attached to is are different: a hydrogen (H) , a methyl (-CH3) group, an ethyl (-CH2CH3) group, and a hydroxyl
(OH) group. If the bonding at C2 of 2-butanol is drawn in three dimensions and this structure called A. Then the mirror image of
A can be drawn to form structure B.

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When we try to superimpose A onto B, we find that we cannot do it. Because structure A and B are not superimposable on their
mirror image they are both chiral molecules. Because A and B are different due only to the arrangement of atoms in space they
are stereoisomers. Because A and B are mirror images of each other they are also enantiomers. When looking at simplified line
structures is clear that there are two distinct ways of drawing 2-butanol which only differ in their spatial arrangement around a
chiral carbon.

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 GLmol

GLmol
The 3D Structures of the Two Enantiomers of 2-Butanol
For comparison, 2-propanol, is an achiral molecule because is lacks a chiral carbon. Carbon #2 is bonded to two identical
substituents (methyl groups), and so it is not a chiral carbon. Being achiral means that 2-propanol should be superimposable on
its mirror image which is shown in the figure below. A more detailed explaination on why 2-propanol is achiral will be given in
the next section.

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Stereoisomers
Stereoisomers have been defined as molecules with the same connectivity but different arrangements of the atoms in space. It is
important to note that there are two types of stereoisomers: geometric and optical.
Optical isomers are molecules whose structures are mirror images but cannot be superimposed on one another in any
orientation. Optical isomers have identical physical properties, although their chemical properties may differ in asymmetric
environments. Molecules that are nonsuperimposable mirror images of each other are said to be chiral.
25.7.1a" id="MathJax-Element-1-Frame" role="presentation" style="position:relative;" tabindex="0">
Geometric isomers differ in the relative position(s) of substituents in a rigid molecule. Simple rotation about a C–C σ bond in
an alkene, for example, cannot occur because of the presence of the π bond. The substituents are therefore rigidly locked into a
particular spatial arrangement. Thus a carbon–carbon multiple bond, or in some cases a ring, prevents one geometric isomer
from being readily converted to the other. The members of an isomeric pair are identified as either cis or trans, and
interconversion between the two forms requires breaking and reforming one or more bonds. Because their structural difference
causes them to have different physical and chemical properties, cis and trans isomers are actually two distinct chemical
compounds.mers have the same connectivity, but different arrangements of atoms in space. Geometric isomers will be discussed
in more detain in Sections 7.4 and 7.5.

 Exercise 5.1.1

Identify the following molecules as chiral or achiral.

Br H3 C H3CH2C
a) H b) CH3 c) OH
F I F I H3CH2C I

d) e) f)

OH OH

Answer
a) chiral (4 different groups off C)
b) achiral (2 identical -CH3 substituents off central C)
c) achiral (2 identical -CH2CH3 substituents off central C)
d) achiral (2 identical CH3 substituents off carbon 2)
e) chiral (4 different groups off carbon 2)
f) achiral (2 identical CH3 substituents off central C)

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 Exercise 5.1.2
Determine if the following sets of compounds in each group are enantiomers or the same compound.
Br Br
a) OH & H
Cl H Cl OH

Br H
b) OH Br
&
Cl H Cl OH

c) H Br
Cl & H
HO Br Cl OH

d)
&

OH OH

Answer
a) enantiomers – non superimposable mirror images
b) same compound – when you rotate the molecule on the right it is identical to the one on the left
c) enantiomers – non superimposable mirror images
d) enantiomers – non superimposable mirror images

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
Dr. Zachary Sharrett (Sonoma State University)

Objectives
After completing this section, you should be able to
1. determine whether or not a compound is chiral, given its Kelulé, condensed or shorthand structure, with or without the
aid of molecular models.
2. label the chiral centres (carbon atoms) in a given Kelulé, condensed or shorthand structure.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
achiral
chiral
chiral (stereogenic) centre
plane of symmetry

Symmetry and Chirality

Molecules that are nonsuperimposable mirror images of each other are said to be chiral (pronounced “ky-ral,” from the Greek
cheir, meaning “hand”). Examples of some familiar chiral objects are your hands. Your left and right hands are

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nonsuperimposable mirror images. (Try putting your right shoe on your left foot—it just doesn’t work.) An achiral object is one
that can be superimposed on its mirror image, as shown by the superimposed flasks
25.7.1b" id="MathJax-Element-2-Frame" role="presentation" style="position:relative;" tabindex="0">in the figure
. below.

An an important questions is why is one chiral and the other not? The answer is that the flask has a plane of symmetry and your
hand does not. A plane of symmetry is a plane or a line through an object which divides the object into two halves that are
mirror images of each other. When looking at the flask, a line can be drawn down the middle which separates it into two mirror
image halves. However, a similar line down the middle of a hand separates it into two non-mirror image halves. This idea can be
used to predict chirality. If an object or molecule has a plane of symmetry it is achiral. If if lacks a plane of symmetry it is chiral.

Symmetry can be used to explain why a carbon bonded to four different substituents is chiral. When a carbon is bonded to fewer
than four different substituents it will have a plane of symmetry making it achiral. A carbon atom that is bonded to four different
substituents loses all symmetry, and is often referred to as an asymmetric carbon. The lack of a plane of symmetry makes the
carbon chiral. The presence of a single chiral carbon atom sufficient to render the molecule chiral, and modern terminology
refers to such groupings as chiral centers or stereo centers.
An example is shown in the bromochlorofluoromethane molecule shown in part (a) of the figure below. This carbon, is attached
to four different substituents making it chiral. which is often designated by an asterisk in structural drawings. If the bromine
atom is replaced by another chlorine to make dichlorofluoromethane, as shown in part (b) below, the molecule and its mirror
image can now be superimposed by simple rotation. Thus the carbon is no longer a chiral center. Upon comparison,
bromochlorofluoromethane lacks a plane of symmetry while dichlorofluoromethane has a plane of symmetry.

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 Plane of Symmetry No Plane of Symmetry
(Achiral) (Chiral)

H H
Cl C Cl Br C Cl
F F

Dichloro Bromochloro
fluoromethane fluoromethane

Identifying Chiral carbons

Identifying chiral carbons in a molecule is an important skill for organic chemists. The presence of a chiral carbon presents the
possibility of a molecule having multiple stereoisomers. Most of the chiral centers we shall discuss in this chapter are
asymmetric carbon atoms, but it should be recognized that other tetrahedral or pyramidal atoms may become chiral centers if
appropriately substituted. Also, when more than one chiral center is present in a molecular structure, care must be taken to
analyze their relationship before concluding that a specific molecular configuration is chiral or achiral. This aspect of
stereoisomerism will be treated later. Because an carbon requires four different substituents to become asymmertric, it can be
said, with few exceptions, that sp2 and sp hybridized carbons involved in multiple bonds are achiral. Also, any carbon with more
than one hydrogen, such as a -CH3 or -CH2- group, are also achiral.
Looking for planes of symmetry in a molecule is useful, but often difficult in practice. It is difficult to illustrate on the two
dimensional page, but you will see if you build models of these achiral molecules that, in each case, there is at least one plane of
symmetry, where one side of the plane is the mirror image of the other. In most cases, the easiest way to decide whether a
molecule is chiral or achiral is to look for one or more stereocenters - with a few rare exceptions, the general rule is that
molecules with at least one stereocenter are chiral, and molecules with no stereocenters are achiral.
Determining if a carbon is bonded to four distinctly different substituents can often be difficult to ascertain. Remember even the
slightest difference makes a substituent unique. Often these difference can be distant from the chiral carbon itself. Careful
consideration and often the building of molecular models may be required. A good example is shown below. It may appear that
the molecule is achiral, however, when looking at the groups directly attached to the possible chiral carbon, it is clear that they
all different. The two alkyl groups are differ by a single -CH2- group which is enough to consider them different.

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 Substituent
H2
C CH3 Butyl
C C
H2 H2
H2 HO H H2
C C* C CH3 H2
H 3C C C C C Propyl
H2 H2 H2 C CH3
H2

OH Hydroxyl

H Hydrogen

 Example 5.1.1
Predict if the following molecule would be chiral or achiral:

Answer
Achiral. When determinig the chirality of a molecule, it best to start by locating any chiral carbons. An obvious candidate
is the ring carbon attached to the methyl substituent. The question then becomes: does the ring as two different
substituents making the substituted ring carbon chiral? With an uncertantity such as this, it is then helpful try to identify
any planes of symmetry in the molecule. This molecule does have a plane of symmetry making the molecul achiral. The
plane of symmetry would be easier see if the molecule were view from above. Typically, monosubstitued cycloalkanes
have a similar plane of symmetry making them all achiral.

 Exercise 5.2.1

Determine if each of the following molecules are chiral or achiral. For chiral molecules indicate any chiral carbons.
OH
Br OH

OH
a b c d

Cl Cl H
Cl O

O CH3 O
H
e f g h

Answer

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 *
Br * OH
* * * *
*
OH
a b c d

Cl Cl H
Cl O
* *
*
O CH3 O
H
e f g h

Explanation
Structures F and G are achiral. The former has a plane of symmetry passing through the chlorine atom and bisecting the
opposite carbon-carbon bond. The similar structure of compound E does not have such a symmetry plane, and the carbon
bonded to the chlorine is a chiral center (the two ring segments connecting this carbon are not identical). Structure G is
essentially flat. All the carbons except that of the methyl group are sp2 hybridized, and therefore trigonal-planar in
configuration. Compounds C, D & H have more than one chiral center, and are also chiral.

Something Extra
In the 1960’s, a drug called thalidomide was widely prescribed in the Western Europe to alleviate morning sickness in pregnant
women.

Thalidomide had previously been used in other countries as an antidepressant, and was believed to be safe and effective for both
purposes. The drug was not approved for use in the U.S.A. It was not long, however, before doctors realized that something had
gone horribly wrong: many babies born to women who had taken thalidomide during pregnancy suffered from severe birth
defects.
Researchers later realized the problem lay in the fact that thalidomide was being provided as a mixture of two different isomeric
forms.

One of the isomers is an effective medication, the other caused the side effects. Both isomeric forms have the same molecular
formula and the same atom-to-atom connectivity, so they are not constitutional isomers. Where they differ is in the arrangement
in three-dimensional space about one tetrahedral, sp3-hybridized carbon. These two forms of thalidomide are stereoisomers. If
you make models of the two stereoisomers of thalidomide, you will see that they too are mirror images, and cannot be
superimposed.

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As a historical note, thalidomide was never approved for use in the United States. This was thanks in large part to the efforts of
Dr. Frances Kelsey, a Food and Drug officer who, at peril to her career, blocked its approval due to her concerns about the lack
of adequate safety studies, particularly with regard to the drug's ability to enter the bloodstream of a developing fetus.
Unfortunately, though, at that time clinical trials for new drugs involved widespread and unregulated distribution to doctors and
their patients across the country, so families in the U.S. were not spared from the damage caused.
Very recently a close derivative of thalidomide has become legal to prescribe again in the United States, with strict safety
measures enforced, for the treatment of a form of blood cancer called multiple myeloma. In Brazil, thalidomide is used in the
treatment of leprosy - but despite safety measures, children are still being born with thalidomide-related defects.

 Example 5.2.2

Label the molecules below as chiral or achiral, and locate all stereocenters.

Answer

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 Exercise 5.2.2
1) For the following compounds, star (*) each chiral center, if any.

2) Explain why the following compound is chiral.

3) Determine which of the following objects is chiral.

a) A Glove.
b) A nail.
c) A pair of sunglasses.
d) The written word "Chiral".
4) Place an "*" by all of the chrial carbons in the following molecules.
a)
Erythrose, a four carbon sugar.

b) Isoflurane, an anestetic. Bright green = Chlorine, Pale green = Fluorine.

Answer
1)

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 2) Though the molecule does not contain a chiral carbon, it is chiral as it is non-superimposable on its mirror image due
to its twisted nature (the twist comes from the structure of the double bonds needing to be at 90° angles to each other,
preventing the molecule from being planar).
3)
a) Just as hands are chiral a glove must also be chiral.
b) A nail has a plane of symmetry which goes down the middle making it a achiral.
c) A pair of sunglasses has a plane of symmetry which goes through the nose making it achiral.
d) Most written words are chiral. Look one in a mirror to confirm this.
4
a)

H OH H
HO *C * C
C C O
H
H HO H
b)

F F
F F
C * O
F C C
Cl H H

 Exercise 5.2.3
Circle all of the carbon stereocenters in the molecules below.
OH O
a) O OH b) c) H3 N
O O
O OH H3 N
O OH

mevalonate serine threonine

Answer
OH O
a) O OH b) c) H3 N
O O
O OH H3 N
O OH

mevalonate serine threonine

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 Exercise 5.2.4
Circle all of the carbon stereocenters in the molecules below.
a)
OH
O
HO
O P O
OH O
2-methylerythritol-4-phopshate

O
b)
H N H
N CO2

S
biotin
c)
O
H
N
O
O N
H O
dihydroorotate

Answer
a)
OH
O
HO
O P O
OH O
2-methylerythritol-4-phopshate

O
b)
H N H
N CO2

S
biotin
c)
O
H
N
O
O N
H O
dihydroorotate

Here are some more examples of chiral molecules that exist as pairs of enantiomers. In each of these examples, there is a single
stereocenter, indicated with an arrow. (Many molecules have more than one stereocenter, but we will get to that that a little
later!)

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Here are some examples of molecules that are achiral (not chiral). Notice that none of these molecules has a stereocenter.

It is difficult to illustrate on the two dimensional page, but you will see if you build models of these achiral molecules that, in
each case, there is at least one plane of symmetry, where one side of the plane is the mirror image of the other. Chirality is tied
conceptually to the idea of asymmetry, and any molecule that has a plane of symmetry cannot be chiral. When looking for a
plane of symmetry, however, we must consider all possible conformations that a molecule could adopt. Even a very simple
molecule like ethane, for example, is asymmetric in many of its countless potential conformations – but it has obvious symmetry
in both the eclipsed and staggered conformations, and for this reason it is achiral.
Looking for planes of symmetry in a molecule is useful, but often difficult in practice. In most cases, the easiest way to decide
whether a molecule is chiral or achiral is to look for one or more stereocenters - with a few rare exceptions (see section 3.7B),
the general rule is that molecules with at least one stereocenter are chiral, and molecules with no stereocenters are achiral.
Carbon stereocenters are also referred to quite frequently as chiral carbons.
When evaluating a molecule for chirality, it is important to recognize that the question of whether or not the dashed/solid wedge
drawing convention is used is irrelevant. Chiral molecules are sometimes drawn without using wedges (although obviously this
means that stereochemical information is being omitted). Conversely, wedges may be used on carbons that are not stereocenters
– look, for example, at the drawings of glycine and citrate in the figure above. Just because you see dashed and solid wedges in a
structure, do not automatically assume that you are looking at a stereocenter.
Other elements in addition to carbon can be stereocenters. The phosphorus center of phosphate ion and organic phosphate esters,
for example, is tetrahedral, and thus is potentially a stereocenter.

We will see in chapter 10 how researchers, in order to investigate the stereochemistry of reactions at the phosphate center,
incorporated sulfur and/or 17O and 18O isotopes of oxygen (the ‘normal’ isotope is 16O) to create chiral phosphate groups.
Phosphate triesters are chiral if the three substituent groups are different.
Asymmetric quaternary ammonium groups are also chiral. Amines, however, are not chiral, because they rapidly invert, or turn
‘inside out’, at room temperature.

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 Exercise 5.2.5

Label the molecules below as chiral or achiral, and circle all stereocenters.
a) fumarate (a citric acid cycle intermediate)
O
O
O
O

b) malate (a citric acid cycle intermediate)

O
O
O
OH O

b) malate (a citric acid cycle intermediate)

O OH

Answer
a) achiral (no stereocenters)
O
O
O
O

b) chiral
O
O
O
OH O

c) chiral
O OH

 Exercise 5.2.6

Label the molecules below as chiral or achiral, and circle all stereocenters.
a) acetylsalicylic acid (aspirin)

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 O OH

O O

b) acetaminophen (active ingredient in Tylenol)

H
N

O
HO

c) thalidomide (drug that caused birth defects in pregnant mothers in the 1960’s)
O

N O
NH
O O

Answer
a) achiral (no stereocenters)
O OH

O O

b) achiral (no stereocenters)

H
N

O
HO

c) chiral
O

N O
NH
O O

 Exercise 5.2.7

Draw both enantiomers of the following chiral amino acids.

O

HS OH

a) Cysteine NH2

N OH
b) Proline H

Answer

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 O O

a) HS OH HS OH
NH2 NH2

O O
b)
N OH N OH
H H

 Exercise 5.2.8
Draw both enantiomers of the following compounds from the given names.
a) 2-bromobutane
b) 2,3-dimethyl-3-pentanol

Answer
Br Br
a)

HO HO
b)

 Exercise 5.2.9
Which of the following body parts are chiral?
a) Hands b) Eyes c) Feet d) Ears

Answer
a) Hands- chiral since the mirror images cannot be superimposed (think of the example in the beginning of the section)
b) Eyes- achiral since mirror images that are superimposable
c) Feet- chiral since the mirror images cannot be superimposed (Does your right foot fit in your left shoe?)
d) Ears- chiral since the mirror images cannot be superimposed

 Exercise 5.2.10

Circle the chiral centers in the following compounds.

a) b) c)
OH
HO
NH Br

Answer
a) b) c)
OH
HO
NH
Br

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 Exercise 5.2.11

Identify the chiral centers in the following compounds.

a) H
H2 N CO2H
CH2CH2CO2-Na+

CH3
H3C
b)
CH3
O

c)

HO

Answer
H
a)
H2 N CO2H
CH2CH2CO2-Na+

CH3
H3C
b)
CH3
O

c)

HO

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
Dr. Zachary Sharrett (Sonoma State University)
Layne Morsch (University of Illinois Springfield)

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5.2: Optical Activity
Objectives
After completing this section, you should be able to
1. describe the nature of plane-polarized light.
2. describe the features and operation of a simple polarimeter.
3. calculate the specific rotation of a compound, given the relevant experimental data.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
analyzer
dextrorotatory
levorotatory
optically active
plane-polarized light
polarimeter
polarizer
specific rotation, $\ce{\sf{[\alpha]_{D}}}$

 Study Notes

A polarizer is a device through which only light waves oscillating in a single plane may pass. A polarimeter is an
instrument used to determine the angle through which plane-polarized light has been rotated by a given sample. You
will have the opportunity to use a polarimeter in the laboratory component of the course. An analyzer is the component
of a polarimeter that allows the angle of rotation of plane-polarized light to be determined.
Specific rotations are normally measured at 20°C, and this property may be indicated by the symbol
$\ce{\sf{[\alpha]^20_{D}}}$. Sometimes the solvent is specified in parentheses behind the specific rotation value, for
example,
$\ce{\sf{[\alpha]^20_{D} = +12}}$° (chloroform)
For liquids, the specific rotation may be obtained using the neat liquid rather than a solution; in such cases the formula
is
temp
α
[α] (neat) =
D
l×d

where α is the observed rotation, l is the path length of the cell (measured in decimetres, dm), and d is the density of
the liquid.

Identifying and distinguishing enantiomers is inherently difficult, since their physical and chemical properties are largely
identical. Fortunately, a nearly two hundred year old discovery by the French physicist Jean-Baptiste Biot has made this
task much easier. This discovery disclosed that the right- and left-handed enantiomers of a chiral compound perturb plane-
polarized light in opposite ways. This perturbation is unique to chiral molecules, and has been termed optical activity.

Polarimetry
Plane-polarized light is created by passing ordinary light through a polarizing device, which may be as simple as a lens
taken from polarizing sun-glasses. Such devices transmit selectively only that component of a light beam having electrical
and magnetic field vectors oscillating in a single plane. The plane of polarization can be determined by an instrument
called a polarimeter, shown in the diagram below.

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Monochromatic (single wavelength) light, is polarized by a fixed polarizer next to the light source. A sample cell holder is
located in line with the light beam, followed by a movable polarizer (the analyzer) and an eyepiece through which the light
intensity can be observed. In modern instruments an electronic light detector takes the place of the human eye. In the
absence of a sample, the light intensity at the detector is at a maximum when the second (movable) polarizer is set parallel
to the first polarizer (α = 0º). If the analyzer is turned 90º to the plane of initial polarization, all the light will be blocked
from reaching the detector.
Chemists use polarimeters to investigate the influence of compounds (in the sample cell) on plane polarized light. Samples
composed only of achiral molecules (e.g. water or hexane), have no effect on the polarized light beam. However, if a single
enantiomer is examined (all sample molecules being right-handed, or all being left-handed), the plane of polarization is
rotated in either a clockwise (positive) or counter-clockwise (negative) direction, and the analyzer must be turned an
appropriate matching angle, α, if full light intensity is to reach the detector. In the above illustration, the sample has rotated
the polarization plane clockwise by +90º, and the analyzer has been turned this amount to permit maximum light
transmission.
The observed rotations (α ) of enantiomers are opposite in direction. One enantiomer will rotate polarized light in a
clockwise direction, termed dextrorotatory or (+), and its mirror-image partner in a counter-clockwise manner, termed
levorotatory or (–). The prefixes dextro and levo come from the Latin dexter, meaning right, and laevus, for left, and are
abbreviated d and l respectively. If equal quantities of each enantiomer are examined , using the same sample cell, then the
magnitude of the rotations will be the same, with one being positive and the other negative. To be absolutely certain
whether an observed rotation is positive or negative it is often necessary to make a second measurement using a different
amount or concentration of the sample. In the above illustration, for example, α might be –90º or +270º rather than +90º. If
the sample concentration is reduced by 10%, then the positive rotation would change to +81º (or +243º) while the negative
rotation would change to –81º, and the correct α would be identified unambiguously.
Since it is not always possible to obtain or use samples of exactly the same size, the observed rotation is usually corrected
to compensate for variations in sample quantity and cell length. Thus it is common practice to convert the observed
rotation, α, to a specific rotation, by the following formula:
α
[α ]D = (5.3.1)
lc

where
[α]D is the specific rotation
lis the cell length in dm
c is the concentration in g/ml

D designates that the light used is the 589 line from a sodium lamp

Compounds that rotate the plane of polarized light are termed optically active. Each enantiomer of a stereoisomeric pair is
optically active and has an equal but opposite-in-sign specific rotation. Specific rotations are useful in that they are
experimentally determined constants that characterize and identify pure enantiomers. For example, the lactic acid and
carvone enantiomers discussed earlier have the following specific rotations.

Carvone from caraway: [α]D = +62.5º this isomer may be referred to as (+)-carvone or d-carvone

Carvone from spearmint: [α]D = –62.5º this isomer may be referred to as (–)-carvone or l-carvone

Lactic acid from muscle tissue: [α]D = +2.5º this isomer may be referred to as (+)-lactic acid or d-lactic acid

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Lactic acid from sour milk: [α]D = –2.5º this isomer may be referred to as (–)-lactic acid or l-lactic acid

A 50:50 mixture of enantiomers has no observable optical activity. Such mixtures are called racemates or racemic
modifications, and are designated (±). When chiral compounds are created from achiral compounds, the products are
racemic unless a single enantiomer of a chiral co-reactant or catalyst is involved in the reaction. The addition of HBr to
either cis- or trans-2-butene is an example of racemic product formation (the chiral center is colored red in the following
equation).

CH3CH=CHCH3 + HBr (±) CH3CH2CHBrCH3

Chiral organic compounds isolated from living organisms are usually optically active, indicating that one of the
enantiomers predominates (often it is the only isomer present). This is a result of the action of chiral catalysts we call
enzymes, and reflects the inherently chiral nature of life itself. Chiral synthetic compounds, on the other hand, are
commonly racemates, unless they have been prepared from enantiomerically pure starting materials.
There are two ways in which the condition of a chiral substance may be changed:
1. A racemate may be separated into its component enantiomers. This process is called resolution.
2. A pure enantiomer may be transformed into its racemate. This process is called racemization.

Enantiomeric Excess
The "optical purity" is a comparison of the optical rotation of a pure sample of unknown stereochemistry versus the optical
rotation of a sample of pure enantiomer. It is expressed as a percentage. If the sample only rotates plane-polarized light
half as much as expected, the optical purity is 50%.

Because R and S enantiomers have equal but opposite optical activity, it naturally follows that a 50:50 racemic mixture of
two enantiomers will have no observable optical activity. If we know the specific rotation for a chiral molecule, however,
we can easily calculate the ratio of enantiomers present in a mixture of two enantiomers, based on its measured optical
activity. When a mixture contains more of one enantiomer than the other, chemists often use the concept of enantiomeric
excess (ee) to quantify the difference. Enantiomeric excess can be expressed as:

For example, a mixture containing 60% R enantiomer (and 40% S enantiomer) has a 20% enantiomeric excess of R: ((60-
50) x 100) / 50 = 20 %.

 Exercise 5.2.1

The specific rotation of (S)-carvone is (+)61°, measured 'neat' (pure liquid sample, no solvent). The optical rotation of
a neat sample of a mixture of R and S carvone is measured at (-)23°. Which enantiomer is in excess, and what is its ee?
What are the percentages of (R)- and (S)-carvone in the sample?

Answer
The observed rotation of the mixture is levorotary (negative, counter-clockwise), and the specific rotation of the
pure S enantiomer is given as dextrorotary (positive, clockwise), meaning that the pure R enantiomer must be
levorotary, and the mixture must contain more of the R enantiomer than of the S enantiomer.
Rotation (R/S Mix) = [Fraction(S) × Rotation (S)] + [Fraction(R) × Rotation (R)]
Let Fraction (S) = x, therefore Fraction (R) = 1 – x.
Rotation (R/S Mix) = x[Rotation (S)] + (1 – x)[Rotation (R)].
–23 = x(+61) + (1 – x)(–61)

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 Solve for x: x = 0.3114 and (1 – x) = 0.6885
Therefore the percentages of (R)- and (S)-carvone in the sample are 68.9% and 31.1%, respectively.
ee = [(% more abundant enantiomer – 50) × 100]/50. = [68.9 – 50) × 100]/50 = 37.8%.
Chiral molecules are often labeled according to the sign of their specific rotation, as in (S)-(+)-carvone and (R)-(-)-
carvone, or (±)-carvone for the racemic mixture. However, there is no relationship whatsoever between a
molecule's R/S designation and the sign of its specific rotation. Without performing a polarimetry experiment or
looking in the literature, we would have no idea that (-)-carvone has the R configuration and (+)-carvone has the S
configuration

Chiral molecules are often labeled according to the sign of their specific rotation, as in (S)-(+)-carvone and (R)-(-)-
carvone, or (±)-carvone for the racemic mixture. However, there is no relationship whatsoever between a molecule's R/S
designation and the sign of its specific rotation. Without performing a polarimetry experiment or looking in the literature,
we would have no idea that (-)-carvone has the R configuration and (+)-carvone has the S configuration.

Separation of Chiral Compounds

As noted earlier, chiral compounds synthesized from achiral starting materials and reagents are generally racemic (i.e. a
50:50 mixture of enantiomers). Separation of racemates into their component enantiomers is a process called resolution.
Since enantiomers have identical physical properties, such as solubility and melting point, resolution is extremely difficult.
Diastereomers, on the other hand, have different physical properties, and this fact is used to achieve resolution of
racemates. Reaction of a racemate with an enantiomerically pure chiral reagent gives a mixture of diastereomers, which
can be separated. For example, if a racemic mixture of a chiral alcohol is reacted with a enantiomerically pure carboxylic
acid, the result is a mixture of diastereomers: in this case, because the pure (R) entantiomer of the acid was used, the
product is a mixture of (R-R) and (R-S) diastereomeric esters, which can, in theory, be separated by their different physical
properties. Subsequent hydrolysis of each separated ester will yield the 'resolved' (enantiomerically pure) alcohols. The
used of this technique is known as chiral resolution.

 Exercise 5.2.2

A 3.20 g sample of morphine ([α]D = -132) was dissolved in 10.0 mL of acetic acid ([α]D = 0). If it is put into a sample
tube with a path length of 2.00 cm, what would be its observed rotation (α)?

Answer
The specific rotation, [α]D = (observed rotation, α (degrees))/ [(pathlength, l (dm)) x (concentration, c (g/cm3))] =
α/(l x c)
Solving for α, α = [α]D x l x c
([α]D = -132) x (l = 2.00 cm = 0.200 dm) x (c = 3.20 g / 10.0 cm3 = 0.320 g/cm3)
α = -132 x 0.200 dm x 0.320 g/cm3 = -8.45 o

 Exercise 5.2.3

Is the morphine in the previous excercise dextrorotatory or levorotatory?

Answer
Since morphine has a (-) rotation, it indicates that it rotates light to the left (counterclockwise) and morphine is
levorotatory.

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 Exercise 5.2.4

Label the following compounds as dextrorotatory or levorotatory.

a) sucrose ([α]D = + 66.7)
b) cholesterol ([α]D = - 31.5)
c) cocaine ([α]D = - 16)
d) chloroform ([α]D = 0)

Answer
a) sucrose ([α]D = + 66.7) dextrorotatory
b) cholesterol ([α]D = - 31.5) levorotatory
c) cocaine ([α]D = - 16) levorotatory
d) chloroform ([α]D = 0) neither, not optically active

 Exercise 5.2.5a

The specific rotation of (S)-carvone is (+) 61o when measured neat (pure liquid sample with no solvent). The optical
rotation of a neat sample of a mixture of R and S carvone is measured at (-) 23 o.
a) Which enantiomer is in excess?

Answer
Since the pure S enantiomer ((+) 61o) is dextrorotatory (positive, clockwise), the R enantiomer must be
levorotatory. The observed rotation of the mixture is levorotatory since its negative (counterclockwise). This means
the mixture must contain more of the R enantiomer than the S enantiomer.

 Exercise 5.2.5b

b) What are the percentages of (S)- and (R)- carvone in the sample mixture?

Answer
Optical rotation (α) of the (R/S mixture) = [fraction (S) x [α]D (S)] + [fraction (R) x [α]D (R)]
To determine the fraction of S and R, we make y = fraction (S) and 1 – y = fraction (R)
-23o = y x (61o) + (1 – y) x (-61o) solving for y: y = 0.3114 and (1-y) = 0.6885
Therefore the percentage of (S)-carvone is 31.1 % and (R)-carvone is 68.9 %

 Exercise 5.2.5c

c) What is the ee (enantiomeric excess)?

Answer
ee = [(% more abundant isomer – 50) x 100]/50 = [(68.9 – 50) x100]/50 = 37.8 % ee

 Exercise 5.2.6a
Determine the ee’s of the following from the percentages
a) 95 % (R)- tartaric acid and 5.0 % (S)- tartaric acid

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 Answer
[(95 – 50) x 100] / 50 = 90 % ee (R)-tartaric acid

 Exercise 5.2.6b

b) 75 % (S)- limonene and 25 % (R)- limonene

Answer
[(75 – 50) x 100] / 50 = 50 % ee (S)- limonene

 Exercise 5.2.6c

c) 85 % (R) cysteine

Answer
(85 – 50) x 100] / 50 = 70 % ee (R)-cysteine

 Exercise 5.2.6d

d) 50 % (S) alanine

Answer
(50 – 50) x 100] / 50 = 0 % ee, racemic mixture

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Dr. Zachary Sharrett (Sonoma State University)

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5.3: Absolute Configuration: R-S Sequence Rules
Objectives
After completing this section, you should be able to
1. assign Cahn-Ingold-Prelog priorities to a given set of substituents.
2. determine whether a given wedge-and-broken-line structure corresponds to an R or an S configuration, with or
without the aid of molecular models.
3. draw the wedge-and-broken-line structure for a compound, given its IUPAC name, complete with R or S
designation.
4. construct a stereochemically accurate model of a given enantiomer from either a wedge-and-broken-line structure
or the IUPAC name of the compound, complete with R or S designation.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
absolute configuration
R configuration
S configuration

 Study Notes

When designating a structure as R or S, you must ensure that the atom or group with the lowest priority is pointing
away from you, the observer. The easiest way to show this is to use the wedge-and-broken-line representation. You can
then immediately determine whether you are observing an R configuration or an S configuration.

To name the enantiomers of a compound unambiguously, their names must include the "handedness" of the molecule. The
method for this is formally known as R/S nomenclature.

Introduction
The method of unambiguously assigning the handedness of molecules was originated by three chemists: R.S. Cahn, C.
Ingold, and V. Prelog and, as such, is also often called the Cahn-Ingold-Prelog rules. In addition to the Cahn-Ingold
system, there are two ways of experimentally determining the absolute configuration of an enantiomer:
1. X-ray diffraction analysis. Note that there is no correlation between the sign of rotation and the structure of a particular
enantiomer.
2. Chemical correlation with a molecule whose structure has already been determined via X-ray diffraction.
However, for non-laboratory purposes, it is beneficial to focus on the R/S system. The sign of optical rotation, although
different for the two enantiomers of a chiral molecule,at the same temperature, cannot be used to establish the absolute
configuration of an enantiomer; this is because the sign of optical rotation for a particular enantiomer may change when
the temperature changes.

Stereocenters are labeled R or S

The "right hand" and "left hand" nomenclature is used to name the enantiomers of a chiral compound. The stereocenters
are labeled as R or S.
The Cahn-Ingold-Prelog rules of assign priorities the groups directly bonded to the chiral carbon. Having ranked the four
groups attached to a chiral carbon, we describe the stereochemical configuration around the carbon by orienting the
molecule so that the group with the lowest ranking (4) is given a dash bond to indicate it points directly away from us. We
then look at the three remaining substituents, which now appear to radiate toward us which is shown by using wedge
bonds. If a curved arrow drawn from the highest to second-highest to third-highest ranked substituent is clockwise, we say
that the chirality center has the R configuration (Latin rectus, meaning “right”). If an arrow from is counterclockwise, the

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chirality center has the S configuration (Latin sinister, meaning “left”). To remember these assignments, think of a car’s
steering wheel when making a Right (clockwise) turn. Note, the R or S configurations represent the two enantiomers of a
chiral molecule. The R or S configuration is often added as a prefix, in parenthesis, to a chiral molecule's name to indicate
which enantiomer is being discussed. Ex: (R)-2-Bromobutane. If more than chiral carbon is present in a chiral molecule,
each carbon's number is included before the R or S configuration. Ex: (2R,4S,6R)-2-bromo-6-chloro-4-methylheptane.
Mirror
4 4

C C
1 3 3 1

2 2
Reorient to place Reorient to place
the lowest priority the lowest priority
substituent (4) substituent (4)
going away going away
4 4
1 2 2 1
C C

3 3

R Configuration S Configuration
(Clockwise) (Counterclockwise)

Sequence Rules to Assign Priorities to Substituents

Before applying the R and S nomenclature to a stereocenter, the substituents must be prioritized according to the following
rules:

Rule 1
First, examine at the atoms directly attached to the stereocenter of the compound. A atom with a higher atomic number
takes precedence over a atom with a lower atomic number. Hydrogen is the lowest possible priority atom, because it has
the lowest atomic number.
1. The atom with higher atomic number has higher priority (I > Br > Cl > S > P > F > O > N > C > H).
2. When comparing isotopes, the atom with the higher mass number has higher priority [18O > 16O or 15N > 14N or 13C >
12
C or T (3H) > D (2H) > H].

Rule 2
If there are two or more substituents which have the same element directly attached to chiral carbon, proceed along the
substituent chains until a point of difference is found. Determine which of the chains has the first connection to an atom
with the highest priority (the highest atomic number). That chain has the higher priority.
For example: an ethyl substituent takes priority over a methyl substituent. At the connectivity of the stereocenter, both
have a carbon atom, which are equal in rank. Going down the chains, a methyl has only has hydrogen atoms attached to it,
whereas the ethyl has two hydrogen atoms and a carbon atom. The carbon atom on the ethyl is the first point of difference
and has a higher atomic number than hydrogen; therefore the ethyl takes priority over the methyl.

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 Example 5.3.1

H H H H H
C C H C O H C O H C Br
H H H H H
Lower Higher Lower Higher

H H H H H H H H
C C Br C O H C C H C C C H
H H H H H H H H

Lower Higher Lower Higher

 Worked Exercise 5.3.1

For the following pairs of substituents, determine which would have the higher and lower priority based on the Cahn-
Ingold-Prelog rules. Explain your answer.
CH3 CH3 Br
H2
C CH3 C CH3 C CH3 C CH3
H H
H

CH2CH3 CH2CH3
CH3 H2
H2 H2 H2
C C Cl C CH3 C C OH C C O CH3
H H H

Answer
A 1-methylethyl substituent takes precedence over an ethyl substituent. Connected to the first carbon atom, ethyl
only has one other carbon, whereas the 1-methylethyl has two carbon atoms attached to the first; this is the first
point of difference. Therefore, 1-methylethyl ranks higher in priority than ethyl, as shown below:

However:

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 Caution!!
Keep in mind that priority is determined by the first point of difference along the two similar substituent chains.
After the first point of difference, the rest of the chain is irrelevant.

When looking for the first point of difference on similar substituent chains, one may encounter branching. If there
is branching, choose the branch that is higher in priority. If the two substituents have similar branches, rank the
elements within the branches until a point of difference.

Rule 3
For assigning priority, multiple bonds are treated as if each bond of the multiple bond is bonded to a unique atom. For
example, an alkene substituent (CH2=CH-) has higher priority than an ethyl substituent (CH3CH2-). The alkene carbon
priority is "two" bonds to carbon atoms and one bond to a hydrogen atom compared with the ethyl carbon that has only
one bond to a carbon atom and two bonds to two hydrogen atoms. Similarly, alkyne substituent (HCC-) would have an
even higher priority because the alkyne carbon is treated as if it is bonded to three carbons. This method remains the same
with compounds containing a carbonyl (C=O) group. The carbon of an aldehyde substituent (O=CH-) is treated as if it is
bonded to a hydrogen and two oxygen atoms.

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 H H C C
H
C C Is prioritized as C C H
H H
Alkene

C C
C C H Is prioritized as C C H

Alkyne C C

H O C
H
C O Is prioritized as C O
C
Aldehyde

Determining R or S Configuration Using a Molecular Model

In order to demonstrate how to determine the R/S configuration of the chiral carbon in the following molecule using
molecular models, first construct a model of the bromoethanol structure:

H3C Br
C
HO H
First make a molecular model of a tetrahedral carbon with four different substituents. In many cases, this will appear as a
carbon with four bonds with a different colored ball attached to each bond.
For the molecule in question, determine the location of the chiral carbon and assign CIP priorities to the substituents. In
this case, Br gets the highest priority because it has the highest atomic number. The O in the OH substituent gets priority 2
and the C in CH3 gets priority 3. Lastly, H gets the lowest priority, 4, because it has the smallest atomic number.

H3C Br
C
HO H
Now take your molecular model and orientate it to match the molecule in question. Remember in the dash/wedge
representation, two regular bonds are in the plane of the page. The wedge bond is coming toward you and the dashed bond
is going away from you. If you were to hold a piece of paper directly in front of you, the substituents with the regular bond
should both be touching the piece of paper. The dashed bond should be pointing behind the piece of paper and the wedge
bond should be pointing in front.

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 Br

CH3
H3 C Br
C C
HO HO H

In this structure, the bromine is going away from you, the hydrogen is coming toward you and the
hydroxide and methyl groups are in the plane of the page.
Then based on the position, assign each substituent on the chiral carbon a colored ball on your molecular model. In this
case, bromine is going away so it is assigned the green ball. The hydrogen is coming toward you so it is assigned the blue
ball. The last two substituents are in the plane of the page, however, the CH3 is positioned higher so it is assigned the red
ball which leaves OH being assigned the black ball.
Lastly, grab onto the ball for the lowest priority substitutent, in this case the blue one, and point the other three substituents
towards you. The three bonds should be angled towards you as if they all have wedge bonds. Assign the original
substituents and their corresponding CIP priorities to the three colored balls. The green ball was assigned to Bromine
which was given priority one. The OH was assigned to the black ball and given prioirty two. The CH3 was assigned to the
red ball and given priority three. In this case the priorities are going counter clockwise so the chiral carbon has an S
configuration.

CH3 3

Br OH 1 2

S Configuration

Determining R or S Configuration Without a Molecular Model

If a molecular model cannot be used there are a couple of simple methods which can be applied if the dash/wedge bond
system is being used.
After assigning CIP priorities, if the lowest priority substituent (4) is on the dash bond the configuration of substituents 1-3
can be assigned directly. As shown in the figure below, the configuration of substituents 1-3 does not change when moving
to sight down the bond of substituent 4. In both cases, substituents 1-3 are ordered in a counterclockwise fashion which
gives the chiral carbon an S configuration.

1 4 1 4 3
C C
2 3 2

Counterclockwise Counterclockwise
(S Configuration) (S Configuration)

The opposite is true if the lowest priority substituent (4) is on the wedge bond. As shown in the figure below, the
configuration of substituents 1-3 is inverted when moving to sight down the bond of substituent 4. When the lowest
priority substituent is on the wedge bond, the configuration of substituents 1-3 can be assigned directly only if the direction
is inverted. i.e. clockwise = S and counterclockwise = R.

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 1 3 1 4 2
C C
2 4 3

Counterclockwise Clockwise
(R Configuration)

With the lowest priority group in front, drawing an arc from 1 to 2 to 3 gives the reverse of the configuration.
However, if the lowest priority substituent is on one of the regular bonds when the dash/wedge system is being used then
configurations are best assigned by changing perspectives. This method can also be used if the three-demensional
configuration of the chiral carbon is represented. First, locate the chiral carbon and assign CIP priorities to its substituents.
Then while perceiving the drawn molecule as a three-dimensional image, mentally change your perspective such that you
are looking down the bond between the chiral carbon and the lowest CIP ranked substituent (#4). If done correctly, the
bonds for substituents 1-3 should be coming towards you as wedge bonds. You can then follow the direction of the CIP
priority numbers to determine the R/S configuration of the chiral carbon.
O O
(1)
C CH C CH (3)
2 CH3 2 CH3
H H
C *C
H CH2 H CH2
(4) (2)
CH3 CH3

Locate the chiral carbon and assign CIP priorities to its substituents.

Mentally sight down the bond between the chiral carbon and the lowest CIP
ranked substituent.
This bond is shown in Red.

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 H O
(3) C
(1)
H3C H CH2

CH2
H3C (2)
Clockwise
(R Configuration)

Follow the direction of the CIP priority numbers to determine the R/S
configuration.
Drawing the Structure of a Chiral Molecule from its Name
Draw the structure of (S)-2-Bromobutane:
1) Draw the basic structure of the molecule and determine the location of the chiral carbon.

H
H3CH2C *C CH3
Br
2) Determine the chiral carbon's substituents and assign them a CIP priority.
-H (Priority 4)
-CH3 (Priority 3)
-CH2CH3 (Priority 2)
-Br (Priority 1)
3) Draw the chiral carbon in a dash/wedge form and add the lowest priority substituent to the wedge bond. In this case, the
lowest priority substituent is -H.

H
*
C

4) Add the remaining substituents in a clockwise fashion for R and a counterclockwise fashion for S.

1 H 1 H
*
C *
C
3 2 2 3

Clockwise Counterclockwise
(R Configuration) (S Configuration)

The molecule posed in this question has an S configuration so the remaining substituents are added in a counterclockwise
fashion.

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 1 H Br H
* *
C
C
2 3 H3CH2C CH3

Counterclockwise (S)-2-Bromobutane
(S Configuration)

 Exercise 5.3.1

1) Orient the following so that the least priority (4) atom is paced behind, then assign stereochemistry (R or S).

2) Draw (R)-2-bromobutan-2-ol.

3) Assign R/S to the following molecule.

4) Which in the following pairs would have a higher CIP priority?

a) -H or -Cl
b) -Br or -I
c) -CH2OH or -OCH3
d) -CH2CH3 or -CH=CH2
e) -NH2 or -OH
5) Rank the following substituents in order of their CIP priority:
a) -H, -OCH3, -CH2OH, -OH
b) -OH, -CO2H, -CH=O, -CH2OH
c) -CN, -NH2, -CH=O, -NHCH3
d) -SH, -SCH3, -OH, -OOCH3
6) Determine if the chiral carbon in the following molecules have an R or S configuration. Red = Oxygen & Blue =
Nitrogen.
a)

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 GLmol
b)

GLmol
Answer
1) A is S and B is R.

2)

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 3) The stereocenter is R.
4)
a) -Cl
b) -I
c) -OCH3
d) -CH=CH2
e) -OH
5) Rank the following substituents in order of their CIP priority:
a) -OCH3, -OH, -CH2OH, -H,
b) -OH, -CO2H, -CH=O, -CH2OH
c) -NHCH3, -NH2, -CH=O, -CN
d) -SCH3, -SH, -OOCH3, -OH
6)
a) The chiral carbon is R. The four substituents of the chiral carbon are -OH (1), -NH2 (2), -CH3 (3), and -H (4).
Then looking down the lowest priority bond, you should roughly see what appears in the picture below. The
substituents with priorities 1-3 are ordered in a clockwise fashion so the chiral carbon is R.

b) The chiral carbon is S. The four substituents of the chiral carbon are -CO2H (1), -OH (2), -CH2CH2CH3 (3), and
-H (4). Then looking down the lowest priority bond, you should roughly see what appears in the picture below. The
substituents with priorities 1-3 are ordered in a counterclockwise fashion so the chiral carbon is S.

 Exercise 5.3.2
Identify which substituent in the following sets has a higher ranking.
a) -H or -CH3
b) -CH2CH2CH3 or CH2CH3
c) -CH2Cl or CH2OH

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 Answer
a) -CH3
b) -CH2CH2CH3
c) -CH2Cl

 Exercise 5.3.3

Identify which substituent in the following sets has a higher ranking.

a) -NH2 or -N=NH
b) -CH2CH2OH or -CH2OH
c) -CH=CH2 or -CH2CH3

Answer
a) -N=NH
b) -CH2OH
c) -CH=CH2

 Exercise 5.3.4

Place the following sets of substituents in each group in order of lowest priority (1st) to highest priority (4th)
a) -NH2, -F, -Br, -CH3
b) -SH, -NH2, -F, -H

Answer
a) -CH3 < -NH2 < -F, < -Br
b) -H < -NH2 < -F, < -SH

 Exercise 5.3.5
Place the following sets of substituents in each group in order of lowest priority (1st) to highest priority (4th)
a) -CH2CH3, -CN, -CH2CH2OH, -CH2CH2CH2OH
b) -CH2NH2, -CH2SH, -C(CH3)3, -CN

Answer
a) -CH2CH3 < -CH2CH2OH < -CH2CH2CH2OH, < -CN
b) -C(CH3)3 < -CH2NH2 < -CN < -CH2SH

 Exercise 5.3.6
Assign the following chiral centers as R or S.

a) Br H b) H Br c) SHH

F I Cl CH3 H CH3

Answer

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 a) S: I > Br > F > H. The lowest priority substituent is going backwards so following the highest priority, it goes
left (counterclockwise).
b) R: Br > Cl > CH3 > H. Using a model kit, you need to rotate the H to the back position where the Br is. This
causes the priority to go to the left (clockwise) when looking at it with the H in the back position. Alternatively, if
you do not have a model kit, you can imagine the structure 3-dimensionally and since the lowest priority (H) is
facing up (as drawn), if you look at it from below, starting with Br (1st priority) and moving towards Cl (2nd
priority), you are moving right (clockwise) which represents R stereochemistry.
c) Neither R or S: Since there are two identical substituents (H’s) the molecule is achiral and cannot be assigned R
or S.

 Exercise 5.3.7
Assign the following chiral centers as R or S.
CH
a) CNCH NH b) c) OHCH
2 2 C COOH 3
C C
H OH C H 2N Br
HOH2C H

Answer
a) R: OH > CN (C triple bonded to N) > CH2NH2 > H. The H needs to be moved to the back position which causes
the priority to go to the right (clockwise) which indicates R.
b) S: COOH > CH2OH > C CH > H. Since the H is coming forward, you can assign the priority and it goes to the
right (clockwise which would be R) but since the lowest priority is forward, you have to switch it to S.
Alternatively, you can rotate the molecule to put the lowest priority to the back and you’ll see that it rotates left (or
counterclockwise) for S.
c) S: Br > OH > NH2 > CH3. Since the lowest priority is going back, you can follow the priority and see that it is
going left (counterclockwise) and therefore S.

 Exercise 5.3.8
Draw the structure of (R)-2-bromohexane.

Answer
Br H

 Exercise 5.3.9

Draw the structure of (S)-2-methyl-3-pentanol.

Answer

H OH

Outside links
http://www.youtube.com/watch?v=EphUiPiQiCo
http://en.Wikipedia.org/wiki/Absolute_configuration

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References
1. Schore and Vollhardt. Organic Chemistry Structure and Function. New York:W.H. Freeman and Company, 2007.
2. McMurry, John and Simanek, Eric. Fundamentals of Organic Chemistry. 6th Ed. Brooks Cole, 2006.

Contributors and Attributions

Ekta Patel (UCD), Ifemayowa Aworanti (University of Maryland Baltimore County)
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Dr. Zachary Sharrett (Sonoma State University)
Layne Morsch (University of Illinois Springfield)

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5.4: Fischer Projections
Objectives
After completing this section, you should be able to
1. draw the Fischer projection of a monosaccharide, given its wedge‑and‑broken‑line structure or a molecular model.
2. draw the wedge‑and‑broken‑line structure of a monosaccharide, given its Fischer projection or a molecular model.
3. construct a molecular model of a monosaccharide, given its Fischer projection or wedge‑and‑broken‑line structure.

Key Terms
Make certain that you can define, and use in context, the key term below.
Fischer projection

Study Notes

When studying this section, use your molecular model set to assist you in visualizing the structures of the compounds
that are discussed. It is important that you be able to determine whether two apparently different Fischer projections
represent two different structures or one single structure. Often the simplest way to check is to construct a molecular
model corresponding to each projection formula, and then compare the two models.

The problem of drawing three-dimensional configurations on a two-dimensional surface, such as a piece of paper, has been
a long-standing concern of chemists. The wedge and hatched line notations we have been using are effective, but can be
troublesome when applied to compounds having many chiral centers. As part of his Nobel Prize-winning research on
carbohydrates, the great German chemist Emil Fischer, devised a simple notation that is still widely used. In a Fischer
projection drawing, the four bonds to a chiral carbon make a cross with the carbon atom at the intersection of the
horizontal and vertical lines. The two horizontal bonds are directed toward the viewer (forward of the stereogenic carbon).
The two vertical bonds are directed behind the central carbon (away from the viewer). Since this is not the usual way in
which we have viewed such structures, the following diagram shows how a stereogenic carbon positioned in the common
two-bonds-in-a-plane orientation ( x–C–y define the reference plane ) is rotated into the Fischer projection orientation (the
far right formula). When writing Fischer projection formulas it is important to remember these conventions. Since the
vertical bonds extend away from the viewer and the horizontal bonds toward the viewer, a Fischer structure may only be
turned by 180º within the plane, thus maintaining this relationship. The structure must not be flipped over or rotated by
90º.

In the above diagram, if x = CO2H, y = CH3, a = H & b = OH, the resulting formula describes (R)-(–)-lactic acid. The
mirror-image formula, where x = CO2H, y = CH3, a = OH & b = H, would, of course, represent (S)-(+)-lactic acid.
The Fischer Projection consists of both horizontal and vertical lines, where the horizontal lines represent the atoms that are
pointed toward the viewer while the vertical line represents atoms that are pointed away from the viewer. The point of
intersection between the horizontal and vertical lines represents the central carbon.

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Using the Fischer projection notation, the stereoisomers of 2-methylamino-1-phenylpropanol are drawn in the following
manner. Note that it is customary to set the longest carbon chain as the vertical bond assembly.

The usefulness of this notation to Fischer, in his carbohydrate studies, is evident in the following diagram. There are eight
stereoisomers of 2,3,4,5-tetrahydroxypentanal, a group of compounds referred to as the aldopentoses. Since there are three
chiral centers in this constitution, we should expect a maximum of 23 stereoisomers. These eight stereoisomers consist of
four sets of enantiomers. If the configuration at C-4 is kept constant (R in the examples shown here), the four
stereoisomers that result will be diastereomers. Fischer formulas for these isomers, which Fischer designated as the "D"-
family, are shown in the diagram. Each of these compounds has an enantiomer, which is a member of the "L"-family so, as
expected, there are eight stereoisomers in all. Determining whether a chiral carbon is R or S may seem difficult when using
Fischer projections, but it is actually quite simple. If the lowest priority group (often a hydrogen) is on a vertical bond, the
configuration is given directly from the relative positions of the three higher-ranked substituents. If the lowest priority
group is on a horizontal bond, the positions of the remaining groups give the wrong answer (you are in looking at the
configuration from the wrong side), so you simply reverse it.

The aldopentose structures drawn above are all diastereomers. A more selective term, epimer, is used to designate
diastereomers that differ in configuration at only one chiral center. Thus, ribose and arabinose are epimers at C-2, and
arabinose and lyxose are epimers at C-3. However, arabinose and xylose are not epimers, since their configurations differ
at both C-2 and C-3.

How to make Fischer Projections

To make a Fischer Projection, it is easier to show through examples than through words. Lets start with the first example,
turning a 3D structure of ethane into a 2D Fischer Projection.

Example 25.2.1
Start by mentally converting a 3D structure into a Dashed-Wedged Line Structure. Remember, the atoms that are
pointed toward the viewer would be designated with a wedged lines and the ones pointed away from the viewer are
designated with dashed lines.

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 Figure A Figure B
Notice the red balls (atoms) in Figure A above are pointed away from the screen. These atoms will be designated with
dashed lines like those in Figure B by number 2 and 6. The green balls (atoms) are pointed toward the screen. These
atoms will be designated with wedged lines like those in Figure B by number 3 and 5. The blue atoms are in the plane
of the screen so they are designated with straight lines.
Now that we have our Dashed- Wedged Line Structure, we can convert it to a Fischer Projection. However, before we
can convert this Dashed-Wedged Line Structure into a Fischer Projection, we must first convert it to a “flat” Dashed-
Wedged Line Structure. Then from there we can draw our Fischer Projection. Lets start with a more simpler example.
Instead of using the ethane shown in Figure A and B, we will start with a methane. The reason being is that it allows us
to only focus on one central carbon, which make things a little bit easier.

Figure C Figure D
Lets start with this 3D image and work our way to a dashed-wedged image. Start by imagining yourself looking
directly at the central carbon from the left side as shown in Figure C. It should look something like Figure D. Now take
this Figure D and flatten it out on the surface of the paper and you should get an image of a cross.

As a reminder, the horizontal line represents atoms that are coming out of the paper and the vertical line represents
atoms that are going into the paper. The cross image to the right of the arrow is a Fischer projection.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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5.5: Molecules Incorporating Several Stereocenters: Diastereomers
Objectives
After completing this section, you should be able to
1. calculate the maximum number of stereoisomers possible for a compound containing a specified number of chiral
carbon atoms.
2. draw wedge-and-broken-line structures for all possible stereoisomers of a compound containing two chiral carbon
atoms, with or without the aid of molecular models.
3. assign R,S configurations to wedge-and-broken-line structures containing two chiral carbon atoms, with or without
the aid of molecular models.
4. determine, with or without the aid of molecular models, whether two wedge-and-broken-line structures containing
two chiral carbon atoms are identical, represent a pair of enantiomers, or represent a pair of diastereomers.
5. draw the wedge-and-broken-line structure of a specific stereoisomer of a compound containing two chiral carbon
atoms, given its IUPAC name and R,S configuration.

 Key Terms

Make certain that you can define, and use in context, the key term below.
diastereomer

Diastereomers are two molecules which are stereoisomers (same molecular formula, same connectivity, different
arrangement of atoms in space) but are not enantiomers. Unlike enatiomers which are mirror images of each other and
non-sumperimposable, diastereomers are not mirror images of each other and non-superimposable. Diastereomers can
have different physical properties and reactivity. They have different melting points and boiling points and different
densities. In order for diastereomer stereoisomers to occur, a compound must have two or more stereocenters.

Introduction
So far, we have been analyzing compounds with a single chiral center. Next, we turn our attention to those which have
multiple chiral centers. We'll start with some stereoisomeric four-carbon sugars with two chiral centers.

We will start with a common four-carbon sugar called D-erythrose.

A note on sugar nomenclature: biochemists use a special system to refer to the stereochemistry of sugar molecules,
employing names of historical origin in addition to the designators 'D' and 'L'. You will learn about this system if you take
a biochemistry class. We will use the D/L designations here to refer to different sugars, but we won't worry about learning
the system.
As you can see, D-erythrose is a chiral molecule: C2 and C3 are stereocenters, both of which have the R configuration. In
addition, you should make a model to convince yourself that it is impossible to find a plane of symmetry through the
molecule, regardless of the conformation. Does D-erythrose have an enantiomer? Of course it does – if it is a chiral

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molecule, it must. The enantiomer of erythrose is its mirror image, and is named L-erythrose (once again, you should use
models to convince yourself that these mirror images of erythrose are not superimposable).

Notice that both chiral centers in L-erythrose both have the S configuration. To avoid confusion, we will simply refer to the
different stereoisomers by capital letters.
Now let's consider all the possible stereoisomers
Look first at compound A below. Both chiral centers in have the R configuration (you should confirm this for yourself!).
The mirror image of Compound A is compound B, which has the S configuration at both chiral centers. If we were to pick
up compound A, flip it over and put it next to compound B, we would see that they are not superimposable (again, confirm
this for yourself with your models!). A and B are nonsuperimposable mirror images: in other words, enantiomers.

Now, look at compound C, in which the configuration is S at chiral center 1 and R at chiral center 2. Compounds A and C
are stereoisomers: they have the same molecular formula and the same bond connectivity, but a different arrangement of
atoms in space (recall that this is the definition of the term 'stereoisomer). However, they are not mirror images of each
other (confirm this with your models!), and so they are not enantiomers. By definition, they are diastereomers of each
other.
Notice that compounds C and B also have a diastereomeric relationship, by the same definition.
So, compounds A and B are a pair of enantiomers, and compound C is a diastereomer of both of them. Does compound C
have its own enantiomer? Compound D is the mirror image of compound C, and the two are not superimposable.
Therefore, C and D are a pair of enantiomers. Compound D is also a diastereomer of compounds A and B.
This can also seem very confusing at first, but there some simple shortcuts to analyzing stereoisomers:

Stereoisomer Shortcuts
If all of the chiral centers are of opposite R/S configuration between two stereoisomers, they are enantiomers.
If at least one, but not all of the chiral centers are opposite between two stereoisomers, they are diastereomers.

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(Note: these shortcuts to not take into account the possibility of additional stereoisomers due to alkene groups: we will
come to that later)
Here's another way of looking at the four stereoisomers, where one chiral center is associated with red and the other blue.
Pairs of enantiomers are stacked together.

We know, using the shortcut above, that the enantiomer of RR must be SS - both chiral centers are different. We also know
that RS and SR are diastereomers of RR, because in each case one - but not both - chiral centers are different.

Determining the Maximun Number of Stereoisomers for a Compound

In general, a structure with n stereocenters will have a maximum of 2n different stereoisomers. (We are not considering, for
the time being, the stereochemistry of double bonds – that will come later). For example, let's consider the glucose
molecule in its open-chain form (recall that many sugar molecules can exist in either an open-chain or a cyclic form).
There are two enantiomers of glucose, called D-glucose and L-glucose. The D-enantiomer is the common sugar that our
bodies use for energy. It has n = 4 stereocenters, so therefore there are 2n = 24 = 16 possible stereoisomers (including D-
glucose itself).

In L-glucose, all of the stereocenters are inverted relative to D-glucose. That leaves 14 diastereomers of D-glucose: these
are molecules in which at least one, but not all, of the stereocenters are inverted relative to D-glucose. One of these 14
diastereomers, a sugar called D-galactose, is shown above: in D-galactose, one of four stereocenters is inverted relative to
D-glucose. Diastereomers which differ in only one stereocenter (out of two or more) are called epimers. D-glucose and D-
galactose can therefore be refered to as epimers as well as diastereomers.

 Example 5.5.1

Draw the structure of L-galactose, the enantiomer of D-galactose.

Draw the structure of two more diastereomers of D-glucose. One should be an epimer.

Answer

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Erythronolide B, a precursor to the 'macrocyclic' antibiotic erythromycin, has 10 stereocenters. It’s enantiomer is that
molecule in which all 10 stereocenters are inverted.

In total, there are 210 = 1024 stereoisomers in the erythronolide B family: 1022 of these are diastereomers of the structure
above, one is the enantiomer of the structure above, and the last is the structure above.
We know that enantiomers have identical physical properties and equal but opposite degrees of specific rotation.
Diastereomers, in theory at least, have different physical properties – we stipulate ‘in theory’ because sometimes the
physical properties of two or more diastereomers are so similar that it is very difficult to separate them. In addition, the
specific rotations of diastereomers are unrelated – they could be the same sign or opposite signs, and similar in magnitude
or very dissimilar.

 Exercise 5.5.1

Determine the number of stereoisomers a molecule can have with…

a) 3 chiral centers
b) 1 chiral center
c) 6 chiral centers

Answer
Since a molecule with n chiral centers can have 2n stereoisomers…

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 a) 23 = 8 possible stereoisomers
b) 21 = 2 possible stereoisomers
c) 26 = 64 possible stereoisomers

 Exercise 5.5.2a

a) What is the relationship between enantiomers?

Answer
a) They are mirror images of each other and when 2 or more chiral centers are present, every stereocenter is the
opposite in its enantiomer.

 Exercise 5.5.2b

b) How does the stereochemistry in diastereomers differ from each other?

Answer
b) In diastereomers, one or more of the chiral centers is the opposite but they all can’t be the opposite or else they’d
be enantiomers.

 Exercise 5.5.2c

c) What are epimers?

Answer
c) Epimers are when only one chiral center is the opposite (in molecules with 2 or more chiral centers) in its
diastereomer.

 Exercise 5.5.3a

a) Draw the structure of (2R,3R) 2-fluoro-3-methylhexane.

Answer
H
F
H
2R,3R

 Exercise 5.5.3b

b) Draw both diastereomers of (2R,3R) 2-fluoro-3-methylhexane.

Answer
H
H
F H
H F
2R,3S 2S,3R

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 Exercise 5.5.3c

c) Draw the enantiomer of (2R,3R) 2-fluoro-3-methylhexane.

Answer

H
H
F
2S,3S

 Exercise 5.5.4a

a) Draw the structure of L-galactose, the enantiomer of D-galactose.

OH OH O
HO
H
OH OH

S, R, R, S
D-galactose

Answer
OH OH O
HO
H
OH OH

S, R, R, S
L-galactose

 Exercise 5.5.4b

b) Draw a diastereomer of D-galactose that is an epimer.

Answer
You can draw an epimer by drawing D-galactose with 1 (and only 1) of its chiral centers reversed. Here’s an
example when you switch only the first chiral center (in red). (There are 3 other epimers that could be drawn as
long as you only swap a single chiral center in the diastereomer that you use.)
OH OH O
HO
H
OH OH

R, R, R, S

 Exercise 5.5.4c

c) Identify if the following diastereomer of galactose is an epimer of D- galactose or L- galactose.

OH OH O
HO
H
OH OH

Answer

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 OH OH O
HO
H
OH OH

S, R, S, S

Since the diastereomer above only varies from L-galactose by 1 chiral center, the above is an epimer in relationship
to L-galactose. Since it varies from D-galactose by 3 chiral centers, it is not an epimer but a diastereomer. Since not
all of the chiral centers are swapped, it is not an enantiomer!

 Exercise 5.5.5a
a) For the compound shown below, label each chiral center as R or S.
OH

Answer
S OH

R F
S

 Exercise 5.5.5b

b) How many stereoisomers are possible for the compound in part a)?

Answer
Since there are 3 chiral centers, 23 = 8 possible stereoisomers.

 Exercise 5.5.6

Consider the stereoisomers below.

OH OH OH OH

i ii iii iv

a) Which is/are an enantiomer of i?

b) Which is/are a diastereomer of ii?
b) Which is/are an epimer of i?

Answer
a) iv is an enantiomer of i since both chiral centers are switched and they are non superimposable mirror images.
b) i & iv are diastereomers of ii since they are stereoisomers that are not mirror images.
c) ii and iii are epimers of i since they are diastereomers with only 1 chiral center switched and the other one the
same.

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 Exercise 5.5.7

Consider the 8 stereoisomers below.

OH OH OH
OH

OH OH OH
OH
i ii iii iv

OH OH OH
OH

OH OH OH
OH
v vi vii viii

a) Which is/are an enantiomer of i?

b) Which is/are a diastereomer of i?
b) Which is/are an epimer of i?

Answer
a) v is an enantiomer since all three chiral centers are switched and they are non superimposable mirror images.
b) ii, iii, iv, vi, vii & viii are diastereomers of i since they are stereoisomers that are not mirror images.
c) ii,iii & viii are epimers of i since they are diastereomers with only 1 chiral center switched and the other chiral
centers the same.

Contributors and Attributions

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Dr. Zachary Sharrett (Sonoma State University
Prof. Steven Farmer (Sonoma State University)

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5.6: Meso Compounds
 Objectives

After completing this section, you should be able to

1. determine whether or not a compound containing two chiral carbon atoms will have a meso form, given its Kekulé,
condensed or shorthand structure, or its IUPAC name.
2. draw wedge-and-broken-line structures for the enantiomers and meso form of a compound such as tartaric acid,
given its IUPAC name, or its Kekulé, condensed or shorthand structure.
3. make a general comparison of the physical properties of the enantiomers, meso form and racemic mixture of a
compound such as tartaric acid.

 Key Terms

Make certain that you can define, and use in context, the key term below.
meso compound

 Study Notes

You may be confused by the two sets of structures showing “rotations.” Of course in each case the two structures
shown are identical, they represent the same molecule looked at from two different perspectives. In the first case, there
is a 120° rotation around the single carbon-carbon bond. In the second, the whole molecule is rotated 180° top to
bottom.

Introduction
A meso compound is an achiral compound that has chiral centers. A meso compound contains an internal plane of
symmetry which makes it superimposable on its mirror image and is optically inactive although it contains two or more
stereocenters. Remember, an internal plane of symmetry was shown to make a molecule achiral in Section 5.2.
In general, a meso compound should contain two or more identical substituted stereocenters. Also, it has an internal
symmetry plane that divides the compound in half. These two halves reflect each other by the internal mirror. The
stereochemistry of reflected stereocenters should "cancel out". What it means here is that when we have an internal plane
that splits the compound into two symmetrical sides, the stereochemistry of both left and right side should be opposite to
each other, and therefore, resulting the molecule being optically inactive.

Identification
A meso compound must have:
1. Two or more stereocenters.
2. An internal plane of symmetry, or internal mirror, that lies in the compound.
3. Stereochemistry that cancels out. This means reflected stereocenter should have the same substituents and be inverted.
For instance, in a meso compound with two stereocenters one should be R and the other S.
The compounds 2,3-dichlorobutane contains two chiral carbons and therefore would be expected to provide 22 = 4
different stereoisomers. These stereoisomers should be made up of two pairs of enantiomers.
Cl Cl
H3C C* C* CH3
H H
2,3-Dichlorobutane

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After drawing out all the possible stereoisomers of 2,3-dichlorobutane, the pair on the right in the figure below are mirror
images. Also, they are non-superimposable because they have distinctly different conformation (R,R & S,S). This makes
the pair enantiomers of each other. However, the pair on the left represent a meso compound, they both are identical
despite being mirror images.

Upon further investigation, the meso compound has an internal plane of symmetry which is not present in the pair of
enantiomers. The plane of symmetry in the meso compound comes about because there are two chiral carbons present,
both chiral carbons are identically substituted (Cl, H, CH3), and one chiral carbon is R and the other is S. Despite being
represented as mirror images, both structures represent the same compound. This is best proven by making molecular
models of both representations and then superimposing them. Overall, 2,3-dichlorobutane only has three possible
stereosiomers, the pair of enantiomers and the meso compound.

H3C H H CH3
S C Cl Cl C R Internal plane
R C Cl Cl C S of symmetry
H3C H H CH3
Identical
(Meso)

When looking for an internal plane of symmetry, it is important to remember that sigma bonds (single bonds) can rotate.
Just because the immediate representation of a molecule does not have a plane of symmetry does not mean that one cannot
be obtained through rotation. Often the substituents attached to a stereocenter need to be rotated to recognize the internal
plane of symmetry. As the stereocenter is rotated, its configuration does not change. Building a molecular model when
considering a possible meso compound is an invaluable tool because it allows for easy rotation of chiral carbons. An
example of how rotation of a chiral carbon can reveal an internal plane of symmetry is shown below.

Rotated

CH3 H
Cl H 3C
C H C Cl Internal plane
C Cl C Cl of symmetry
H 3C H H3 C H
Meso
Compound

 Example 5.6.1

Below are the two mirror images of (meso)-2,3-Butanediol. Because it is a meso compound, the two structures are
identical. Show that both mirror images can be obtained by simply rotating the three-dimensional structure provided
belwo.

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 Mirror

H 3C OH HO CH3
C H H C
H C C H
HO CH3 H 3C OH

(meso)-2,3-Butanediol

GLmol
 Example 5.6.2

1 has a plane of symmetry (the horizontal plane going through the red broken line) and, therefore, is achiral; 1 has
chiral centers. Thus, 1 is a meso compound.

 Example 5.6.3

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 This molecules has a plane of symmetry (the vertical plane going through the red broken line perpendicular to the
plane of the ring) and, therefore, is achiral, but has has two chiral centers. Thus, its is a meso compound.

Other Examples of Meso Compounds

Meso compounds can exist in many different forms such as pentane, butane, heptane, and even cycloalkanes. Although
two chiral carbons must be present, meso compounds can have many more. Notice that in every case a plane of symmetry
is present.

In general, a disubstituted cycloalkane is meso if the two substituents are the same and they are in a cis conformation.
Trans disubstituted cycloalkanes are not meso regardless if the two substituents are the same.

Optical Activity Analysis of a Meso Compound

When the optical activity of a meso compound is attempted to be determined with a polarimeter, the indicator will not
show (+) or (-). It simply means there is no certain direction of rotation of the polarized light, neither levorotatory (-) and
dexorotatory (+) because a meso compound is achiral (optically inactive). Investigations of isomeric tartaric acid (2,3-
dihydroxybutanedioic acid), carried out by Louis Pasteur in the mid 19th century, were instrumental in elucidating some of
the subtleties of stereochemistry. Tartaric acid, has two chiral but only three stereoisomers. Two of these stereoisomers are
enantiomers and the third is an achiral a meso compound. Some physical properties of these stereoisomers of tartaric acid
are given in the table below. Notice that the enantiomers have the same amount of optical rotation but in different
directons. Meso-tartaric acid produces no optical rotation because it is achiral and not optically active. Meso-tartaric acid is
actually a diastereomer of both (-) and (+)-tartaric acid, which gives it a distinctly different melting point.

(+)-tartaric acid: [α]D = +13º m.p. 172 ºC

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(–)-tartaric acid: [α]D = –13º m.p. 172 ºC

meso-tartaric acid: [α]D = 0º m.p. 140 ºC

 Exercise 5.6.1

1) Determine which of the following molecules are meso.

2) Explain why 2,3-dibromobutane has the possibility of being a meso compound while 2,3-dibromopentane does not.
3) Observe the following compound and determine if it is a meso compound. If so indicate the plane of symmetry. Red
= oxygen. Remember sigma bonds are able to rotate.

GLmol
Answer
1) A C, D, E are meso compounds.

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 2) One of the requirements of a meso compound is that the reflected chiral carbons have the same substituents. The
compound 2,3-dibromobutane, fulfills this requirement (Br, H, CH3) and can possibly be a meso compound if the
two chiral carbons have the appropriate configuration (R & S). The substituents of the two chiral carbons in 2,3-
dibromopentane do not have the same substituents (Br, H, CH3 vs. Br, H, CH2CH3). This 2,3-dibromopentane
cannot form a meso compound regardless of the configurations of its chiral carbons.
Possible plane
of symmetry

Br Br Br Br
H3C C* C* CH3 H3C C* C* CH2CH3
H H H H
2,3-Dibromobutane 2,3-Dibromopentane

3) The compound is meso.

Plane of Symmetry

H3 C CH3

OH

Exercise 5.6.1
Which of the following are meso compounds?
a) H H b) H H c) H OH
HO OH HO Cl HO Cl
Cl Cl Cl OH Cl H

Answer
a) This is a meso compound. There is an internal plane of symmetry (dashed line shown in red) between the C’s
(and it has stereochemistry of S & R).

H H
HO OH
Cl Cl

b) This is not a meso compound. No matter how you rotate the C-C bond, you do not see a plane of symmetry (and
its stereochemistry is S & S)
c) This is a meso compound. There is an internal plane of symmetry (dashed line shown in red) that can be seen
when you rotate the C-C bond (and it has stereochemistry of S & R).

H OH H H
HO Cl HO OH
Cl H Cl Cl

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 Exercise 5.6.2

Which of the following are meso compounds?

a) Br Br b) Br Br c) Br

Br

Answer
a) This is not a meso compound. There is no plane of symmetry and has stereochemistry of S & S.
Br Br
S S

b) This is a meso compound. There is an internal plane of symmetry (dashed line shown in red) and it has
stereochemistry of R & S.

Br Br
R S

c) This is not a meso compound (even though it has planes of symmetry). The plane of symmetry shown in red
makes it so that both chiral centers have symmetrical groups (the ring) and thus the compound is not chiral (so it
can’t be a meso compound).

Br

Br

 Exercise 5.6.3
Which of the following are meso compounds?

a) OH b) c)
Cl CH2CH3
HO Cl
CH2CH3

Answer
a) This is a meso compound. If you rotate between the C-C bond, you can see that it has a mirror plane between the
C’s (shown in red on the structure to the right). Notice how rotating a C-C bond doesn’t change the stereochemistry
of the molecule (S & R).
OH OH
S S
Cl CH2CH3 Cl CH2CH3
HO Cl Cl CH2CH3
R R
CH2CH3 OH

b) This is a meso compound. You can see the plane of symmetry in red and the compound has stereochemistry of S
& R.

S R

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 c) This is not a meso compound. There is no plane of symmetry and it has stereochemistry of S & S.

S S

 Exercise 5.6.4

Determine (and draw) if any of the forms of 3,4-dichlorohexane are a meso compound.

Answer
Looking at the 4 different possibilities below, i & ii are equivalent structures (with R & S stereochemistry) so it is a
meso compound. iii & iv are not meso compounds but are enantiomers to each other.
Cl Cl Cl Cl
=
R S S R R R S S
Cl Cl Cl Cl

i ii iii iv

Contributors and Attributions

Duy Dang
Gamini Gunawardena from the OChemPal site (Utah Valley University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Dr. Zachary Sharrett (Sonoma State University)

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5.7: Stereochemistry in Chemical Reactions
 Objectives

After completing this section, you should be able to

1. identify a compound as being prochiral.
2. identify the Re and Si faces of prochiral sp2 centre.
3. identify atoms (or groups of atoms) as pro-R or pro-S on a prochiral sp3 centre.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
prochiral
pro-R
pro-S
Re
Si

Prochiral Carbons
When a tetrahedral carbon can be converted to a chiral center by changing only one of the attached groups, it is referred to
as a ‘prochiral' carbon. The two hydrogens on the prochiral carbon can be described as 'prochiral hydrogens'.

Note that if, in a 'thought experiment', we were to change either one of the prochiral hydrogens on a prochiral carbon
center to a deuterium (the 2H isotope of hydrogen), the carbon would now have four different substituents and thus would
be a chiral center.
Prochirality is an important concept in biological chemistry, because enzymes can distinguish between the two ‘identical’
groups bound to a prochiral carbon center due to the fact that they occupy different regions in three-dimensional space.
Consider the isomerization reaction below, which is part of the biosynthesis of isoprenoid compounds. We do not need to
understand the reaction itself (it will be covered in chapter 14); all we need to recognize at this point is that the isomerase
enzyme is able to distinguish between the prochiral 'red' and the 'blue' hydrogens on the isopentenyl diphosphate (IPP)
substrate. In the course of the left to right reaction, IPP specifically loses the 'red' hydrogen and keeps the 'blue' one.

Prochiral hydrogens can be unambiguously designated using a variation on the R/S system for labeling chiral centers. For
the sake of clarity, we'll look at a very simple molecule, ethanol, to explain this system. To name the 'red' and 'blue'
prochiral hydrogens on ethanol, we need to engage in a thought experiment. If we, in our imagination, were to arbitrarily
change red H to a deuterium, the molecule would now be chiral and the chiral carbon would have the R configuration (D
has a higher priority than H).

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For this reason, we can refer to the red H as the pro-R hydrogen of ethanol, and label it HR. Conversely, if we change the
blue H to D and leave red H as a hydrogen, the configuration of the molecule would be S, so we can refer to blue H as the
pro-S hydrogen of ethanol, and label it HS.
Looking back at our isoprenoid biosynthesis example, we see that it is specifically the pro-R hydrogen that the isopentenyl
diphosphate substrate loses in the reaction.

Prochiral hydrogens can be designated either enantiotopic or diastereotopic. If either HR or HS on ethanol were replaced by
a deuterium, the two resulting isomers would be enantiomers (because there are no other stereocenters anywhere on the
molecule).

Thus, these two hydrogens are referred to as enantiotopic.

In (R)-glyceraldehyde-3-phosphate ((R)-GAP), however, we see something different:

R)-GAP already has one chiral center. If either of the prochiral hydrogens HR or HS is replaced by a deuterium, a second
chiral center is created, and the two resulting molecules will be diastereomers (one is S,R, one is R,R). Thus, in this
molecule, HR and HS are referred to as diastereotopic hydrogens.
Finally, hydrogens that can be designated neither enantiotopic nor diastereotopic are called homotopic. If a homotopic
hydrogen is replaced by deuterium, a chiral center is not created. The three hydrogen atoms on the methyl (CH3) group of
ethanol (and on any methyl group) are homotopic. An enzyme cannot distinguish among homotopic hydrogens.

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 Example 5.7.1

Identify in the molecules below all pairs/groups of hydrogens that are homotopic, enantiotopic, or diastereotopic.
When appropriate, label prochiral hydrogens as HR or HS.

Answer

Groups other than hydrogens can be considered prochiral. The alcohol below has two prochiral methyl groups - the red one
is pro-R, the blue is pro-S. How do we make these designations? Simple - just arbitrarily assign the red methyl a higher
priority than the blue, and the compound now has the R configuration - therefore red methyl is pro-R.

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Citrate is another example. The central carbon is a prochiral center with two 'arms' that are identical except that one can be
designated pro-R and the other pro-S.

In an isomerization reaction of the citric acid (Krebs) cycle, a hydroxide is shifted specifically to the pro-R arm of citrate to
form isocitrate: again, the enzyme catalyzing the reaction distinguishes between the two prochiral arms of the substrate
(we will study this reaction in chapter 13).

 Exercise 5.7.1

Assign pro-R and pro-S designations to all prochiral groups in the amino acid leucine. (Hint: there are two pairs of
prochiral groups!). Are these prochiral groups diastereotopic or enantiotopic?

Answer

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Prochiral Carbonyl and Imine Groups
Trigonal planar, sp2-hybridized carbons are not, as we well know, chiral centers– but they can be prochiral centers if they
are bonded to three different substitutuents. We (and the enzymes that catalyze reactions for which they are substrates) can
distinguish between the two planar ‘faces’ of a prochiral sp2 - hybridized group. These faces are designated by the terms re
and si. To determine which is the re and which is the si face of a planar organic group, we simply use the same priority
rankings that we are familiar with from the R/S system, and trace a circle: re is clockwise and si is counterclockwise.

When the two groups adjacent to a carbonyl (C=O) are not the same, we can distinguish between the re and si 'faces' of the
planar structure. The concept of a trigonal planar group having two distinct faces comes into play when we consider the
stereochemical outcome of a nucleophilic addition reaction. Nucleophilic additions to carbonyls will be covered in greater
detail in Chapter 19. Notice that in the course of a carbonyl addition reaction, the hybridization of the carbonyl carbon
changes from sp2 to sp3, meaning that the bond geometry changes from trigonal planar to tetrahedral. If the two R groups
are not equivalent, then a chiral center is created upon addition of the nucleophile. The configuration of the new chiral
center depends upon which side of the carbonyl plane the nucleophile attacks from. Reactions of this type often result in a
50:50 racemic mixture of stereoisomers, but it is also possible that one stereoisomer may be more abundant, depending on
the structure of the reactants and the conditions under which the reaction takes place.
R is higher priority than R'

H A OH OH H A

O C R' R' C Nu O
Nu
Nu C R R C Nu
R' R R' R
Enantiomers
Attack at re face Attack at si face

Below, for example, we are looking down on the re face of the ketone group in pyruvate. If we flipped the molecule over,
we would be looking at the si face of the ketone group. Note that the carboxylate group does not have re and si faces,
because two of the three substituents on that carbon are identical (when the two resonance forms of carboxylate are taken
into account).

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As we will see in chapter 10, enzymes which catalyze reactions at carbonyl carbons act specifically from one side or the
other.

We need not worry about understanding the details of the reaction pictured above at this point, other than to notice the
stereochemistry involved. The pro-R hydrogen (along with the two electrons in the C-H bond) is transferred to the si face
of the ketone (in green), forming, in this particular example, an alcohol with the R configuration. If the transfer had taken
place at the re face of the ketone, the result would have been an alcohol with the S configuration.

 Exercise 5.7.2

For each of the carbonyl groups in uracil, state whether we are looking at the re or the si face in the structural drawing
below.

Answer

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  Exercise 5.7.3

a) State which of the following hydrogen atoms are pro-R or pro-S.

b) Identify which side is Re or Si.

Answer
a) Left compound: Ha = pro-S and Hb = pro-R; Right compound: Ha = pro-R and Hb = pro-S
b) A – Re; B – Si; C – Re; D – Si

\)

 Exercise 5.7.4

State whether the H's indicated below are pro-R or pro-S for the following structures.

a) b) Ha Hb
Ha Hb

HO H O

Answer
a) Ha is pro-R; Hb is pro-S b) Ha is pro-R; Hb is pro-S

 Exercise 5.7.5
In the structures below, determine if the H's are homotopic, enantiotopic, or diastereotopic.

a) b) Ha Hb
Ha Hb

HO H O

Answer
In a), the CH2 is diastereotopic since there is another chiral center on the molecule. Both CH3's are homotopic since
replacing one of them doesn't create a chiral center.
IN b), the CH2's are enantiotopic since it would create the only chiral center on the molecule. Both CH3's are
homotopic since replacing one of them doesn't create a chiral center.

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 diastereotopic enantiotopic enantiotopic
a) b) H
Ha Hb CH3 H2 b Hb
homotopic C
H3 C CH3
H3C HO H
homotopic O homotopic
homotopic

 Exercise 5.7.6

State whether you are looking down at the molecule from the re face or si face.
a) b)
O HOH2C H

HOH2C CH2CH3 H H

Answer
a) You are looking at the si face. The re face would be if you were facing the molecule from the back.
b) You are looking at the re face. The si face would be if you were facing the molecule from the back.

Template.Soderberg() }}

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)

Prof. Steven Farmer (Sonoma State University)
Dr. Zachary Sharrett (Sonoma State University)

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5.8: Resolution: Separation of Enantiomers
 Objectives

After completing this section, you should be able to

1. describe a common process for separating a mixture of enantiomers.
2. explain why racemic mixtures do not rotate plane-polarized light.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
racemic mixture (or racemate)
resolve

 Study Notes

A racemic mixture is a 50:50 mixture of two enantiomers. Because they are mirror images, each enantiomer rotates
plane-polarized light in an equal but opposite direction and is optically inactive. If the enantiomers are separated, the
mixture is said to have been resolved. A common experiment in the laboratory component of introductory organic
chemistry involves the resolution of a racemic mixture.
The dramatic biochemical consequences of chirality are illustrated by the use, in the 1950s, of the drug Thalidomide, a
sedative given to pregnant women to relieve morning sickness. It was later realized that while the (+)‑form of the
molecule, was a safe and effective sedative, the (−)‑form was an active teratogen. The drug caused numerous birth
abnormalities when taken in the early stages of pregnancy because it contained a mixture of the two forms.

As noted earlier, chiral compounds synthesized from achiral starting materials and reagents are generally racemic (i.e. a
50:50 mixture of enantiomers). Separation of racemates into their component enantiomers is a process called resolution.
Since enantiomers have identical physical properties, such as solubility and melting point, resolution is extremely difficult.
Diastereomers, on the other hand, have different physical properties, and this fact is used to achieve resolution of
racemates. Reaction of a racemate with an enantiomerically pure chiral reagent gives a mixture of diastereomers, which
can be separated. For example, if a racemic mixture of a chiral alcohol is reacted with a enantiomerically pure carboxylic
acid, the result is a mixture of diastereomers: in this case, because the pure (R) entantiomer of the acid was used, the
product is a mixture of (R-R) and (R-S) diastereomeric esters, which can, in theory, be separated by their different physical
properties. Subsequent hydrolysis of each separated ester will yield the 'resolved' (enantiomerically pure) alcohols. The
used in this technique are known as 'Moscher's esters', after Harry Stone Moscher, a chemist who pioneered the method at
Stanford University.
As noted earlier, chiral compounds synthesized from achiral starting materials and reagents are generally racemic (i.e. a
50:50 mixture of enantiomers). Separation of racemates into their component enantiomers is a process called resolution.
Since enantiomers have identical physical properties, such as solubility and melting point, resolution is extremely difficult.
Diastereomers, on the other hand, have different physical properties, and this fact is used to achieve resolution of
racemates. Reaction of a racemate with an enantiomerically pure chiral reagent gives a mixture of diastereomers, which
can be separated. Reversing the first reaction then leads to the separated enantiomers plus the recovered reagent.

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 Figure 5.8.1:
Many kinds of chemical and physical reactions, including salt formation, may be used to achieve the diastereomeric
intermediates needed for separation. Figure 5.8.1 illustrates this general principle by showing how a nut having a right-
handed thread (R) could serve as a "reagent" to discriminate and separate a mixture of right- and left-handed bolts of
identical size and weight. Only the two right-handed partners can interact to give a fully-threaded intermediate, so
separation is fairly simple. The resolving moiety, i.e. the nut, is then removed, leaving the bolts separated into their right
and left-handed forms. Chemical reactions of enantiomers are normally not so dramatically different, but a practical
distinction is nevertheless possible.
Because the physical properties of enantiomers are identical, they seldom can be separated by simple physical methods,
such as fractional crystallization or distillation. It is only under the influence of another chiral substance that enantiomers
behave differently, and almost all methods of resolution of enantiomers are based upon this fact. We include here a
discussion of the primary methods of resolution.

Chiral Amines as Resolving Agents and Resolution of Racemic Acids

The most commonly used procedure for separating enantiomers is to convert them to a mixture of diastereomers that will
have different physical properties: melting point, boiling point, solubility, and so on (Section 5-5). For example, if you
have a racemic or R, S mixture of enantiomers of a carboxylic acid and convert this to a salt with a chiral amine base
having the R configuration, the salt will be a mixture of two diastereomers, (R acid . R base) and (S acid . R base). These
diastereomeric salts are not identical and they are not mirror images. Therefore they will differ to some degree in their
physical properties, and a separation by physical methods, such as crystallization, may be possible. If the diastereomeric
salts can be completely separated, the carboxylic acid regenerated from each salt will be either exclusively the R or the S
enantiomer.
R-Acid · R-Base Pure R-Carboxylic Acid

R-Carboxylic Acid R-Amine Base R-Acid · R-Base

Resolution
S-Carboxylic Acid S-Acid · R-Base Regeneration

Racemic Mixture Diastereomers

S-Acid · R-Base Pure S-Carboxylic Acid

Resolution of chiral acids through the formation of diastereomeric salts requires adequate supplies of suitable chiral bases.
Brucine, strychnine, and quinine frequently are used for this purpose because they are readily available, naturally occurring
chiral bases. Simpler amines of synthetic origin, such as 2-amino- 1 -butanol, amphetamine, and 1 -phenylethanamine, also
can be used, but first they must be resolved themselves.

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  Worked Example 5.8.1

Show how (S)-1-phenylethylamine can be used to resolve a racemic mixture of lactic acid. Please draw all the
structures involved.

Answer
CH3
O O O OH
C C H C
CH3 H3 N
O OH C H C H
C C H H 3C H3C
H 2N OH OH
(S)
C H
H 3C S,R Diastereomeric Pure (S)-Lactic Acid
OH
ammonium salt
+
CH3
O OH (S)-1-Phenylethylamine
C O O C H
(R) C H3 N
C OH O OH
H 3C C OH C
H H3C
H C OH
Racemic Mixture H3C
R,R Diastereomeric H
of lactic acid
ammonium salt Pure (R)-Lactic Acid

Resolution of Racemic Bases

Chiral acids, such as (+)-tartaric acid, (-)-malic acid, (-)-mandelic acid, and (+)-camphor- 10-sulfonic acid, are used for the
resolution of a racemic base.

The principle is the same as for the resolution of a racemic acid with a chiral base, and the choice of acid will depend both
on the ease of separation of the diastereomeric salts and, of course, on the availability of the acid for the scale of the
resolution involved. Resolution methods of this kind can be tedious, because numerous recrystallizations in different

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solvents may be necessary to progressively enrich the crystals in the less-soluble diastereomer. To determine when the
resolution is complete, the mixture of diastereomers is recrystallized until there is no further change in the measured
optical rotation of the crystals. At this stage it is hoped that the crystalline salt is a pure diastereomer from which one pure
enantiomer can be recovered. The optical rotation of this enantiomer will be a maximum value if it is "optically" pure
because any amount of the other enantiomer could only reduce the magnitude of the measured rotation α .

Resolution of Racemic Alcohols

To resolve a racemic alcohol, a chiral acid can be used to convert the alcohol to a mixture of diastereomeric esters. This is
not as generally useful as might be thought because esters tend to be liquids unless they are very high-molecularweight
compounds. If the diastereomeric esters are not crystalline, they must be separated by some other method than fractional
crystallization (for instance, by chromatography methods, Section 9-2). Two chiral acids that are useful resolving agents
for alcohols are:

The most common method of resolving an alcohol is to convert it to a half-ester of a dicarboxylic acid, such as butanedioic
(succinic) or 1,2-benzenedicarboxylic (phthalic) acid, with the corresponding anhydride. The resulting half-ester has a free
carboxyl function and may then be resolvable with a chiral base, usually brucine:

Other Methods of Resolution

One of the major goals in the field of organic chemistry is the development of reagents with the property of "chiral
recognition" such that they can affect a clean separation of enantiomers in one operation without destroying either of the
enantiomers. We have not achieved that ideal yet, but it may not be far in the future. Chromatographic methods, whereby
the stationary phase is a chiral reagent that adsorbs one enantiomer more strongly than the other, have been used to resolve
racemic compounds, but such resolutions seldom have led to both pure enantiomers on a preparative scale. Other methods,
called kinetic resolutions, are excellent when applicable. The procedure takes advantage of differences in reaction rates of
enantiomers with chiral reagents. One enantiomer may react more rapidly, thereby leaving an excess of the other
enantiomer behind. For example, racemic tartaric acid can be resolved with the aid of certain penicillin molds that
consume the dextrorotatory enantiomer faster than the levorotatory enantiomer. As a result, almost pure (-)-tartaric acid
can be recovered from the mixture:
(±)-tartaric acid + mold → (-)-tartaric acid + more mold
The crystallization procedure employed by Pasteur for his classical resolution of (±)-tartaric acid (Section 5.4) has been
successful only in a very few cases. This procedure depends on the formation of individual crystals of each enantiomer.
Thus if the crystallization of sodium ammonium tartrate is carried out below 27", the usual racemate salt does not form; a
mixture of crystals of the (+) and (-) salts forms instead. The two different kinds of crystals, which are related as an object
to its mirror image, can be separated manually with the aid of a microscope and subsequently may be converted to the

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tartaric acid enantiomers by strong acid. A variation on this method of resolution is the seeding of a saturated solution of a
racemic mixture with crystals of one pure enantiomer in the hope of causing crystallization of just that one enantiomer,
thereby leaving the other in solution. Unfortunately, very few practical resolutions have been achieved in this way.

Predicating the Chirality of the Product of a Reaction

It important to understand the changes in chirality which occur during the formation of product during a reaction. A chiral
reaction product, has the possibility of forming multiple stereoisomers which all need to be considered. Changes in
chirality, if possible, will be discussed with each individual reaction as this textbook moves forward. Some possible
situations which can occur are:
A new chiral carbon is formed during a reaction. This commonly occurs when an sp2 hybridized carbon in the
reactant is converted to sp3 hybridized chiral carbon in the product. When this occurs, a racemic mixture of the new
chiral carbon is formed.
A chiral carbon is lost during a reaction. This commonly occurs when an sp3 hybridized chiral carbon in the reactant
is converted to either a sp2 or sp hybridized carbon in the product.
An enantiomerically pure starting material is converted to a racemic mixture in the product. This commonly
occurs when a sp3 hybridized chiral carbon is temporarily converted to an sp2 hybrized carbon during a reaction's
mechanism. The chiral carbon is reformed as a racemic mixture.
Chiral carbons remain unchanged during a reaction. If a chiral carbon is not directly involved in a reaction, it will
move from a reactant to a product unchanged.
Determining if a chiral carbon is involved in a given reaction is vital for determining which of these four situations is
occurring.

 Worked Example 5.8.2

The following reaction involves the conversion of a carboxylic acid reacting with an alcohol to form an ester. If a pure
sample of (R)-2-methylbutanoic acid is reacted with methanol to form an ester, what would be the stereochemistry of
the product?
O Acid O
C + HO R' C R' + H2O
R OH R O

Carboxylic Alcohol Ester

Acid

Answer
First it is important to identify the location of the chiral carbon and determine if it is directly involved in the
reaction. In this case, the chiral carbon is not involved so the stereochemistry will be carried over into the product
unchanged.
O O
H2 Acid H2
H3 C
C * C
C OH + HO CH3
H3 C
C * C
C O
CH3 + H2O
H CH3 H CH3

(R)-2-methyl Methanol Methyl (R)-2-methyl

butanoic acid butanoate

 Exercise 5.8.1
Indicate the reagents you could use to resolve the following compounds. Show the reactions involved and specify the
physical method you believe would be the best to separate the diastereomers of 1 -phenyl-2-propanamine.

Answer

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 You could react the 1-phenyl-2-propanamine racemic mixture with a chiral acid such as (+)-tartaric acid (R, R). The
reaction will produce a mixture of diastereomeric salts (i.e. R, R, R and S, R, R). You can separate the diastereomers
through crystallization and treat the salt with a strong base (e.g. KOH) to recover the pure enantiomeric amine.

 Exercise 5.8.2

Indicate the reagents you would use to resolve the following and discuss the reactions involved and specify the
physical method you believe would be the best to separate the diastereomers of 2,3-pentadienedioic acid.

Answer
You could react the 2,3-pentadienedioic acid mixture with a chiral base such as (R)‑1‑phenylethylamine. The
reaction will produce a mixture of diastereomeric salts. Separate the diastereomers through crystallization and treat
the resulting salt with strong acid (e.g. HCl) to recover the pure enantiomeric acid.

 Exercise 5.8.3

Indicate the reagents you would use to resolve the following and discuss the reactions involved and specify the
physical method you believe would be the best to separate the diastereomers of 1 -phenylethanol.

Answer
You could react the 1-phenylethanol mixture with 1,2-benzenedicarboxylic anhydride. The reaction will produce a
mixture of diastereomeric salts. You could then separate the diastereomers through crystallization and then alkaline
hydrolysis treatment should recover the pure enantiomeric alcohol.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A.
Benjamin, Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions,
"You are granted permission for individual, educational, research and non-commercial reproduction, distribution,
display and performance of this work in any format."
Dr. Zachary Sharrett (Sonoma State University)
Layne A. Morsch (University of Illinois Springfield)

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5.E: Stereoisomers (Exercises)
☰
These are homework exercises to accompany Chapter 5 of Vollhardt and Schore's "Organic Chemistry" Textmap.

5.1: Chiral Molecules

5.2: Optical Activity

5.3: Absolute Configuration: R-S Sequence Rules

5.4: Fischer Projections

5.5: Molecules Incorporating Several Stereocenters: Diastereomers

5.6: Meso Compounds

5.7: Stereochemistry in Chemical Reactions

5.8: Resolution: Separation of Enantiomers

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CHAPTER OVERVIEW
6: BIMOLECULAR NUCLEOPHILIC SUBSTITUTION IN HALOALKANES
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

6.1: PHYSICAL PROPERTIES OF HALOALKANES

6.2: NUCLEOPHILIC SUBSTITUTION
6.3: REACTION MECHANISMS INVOLVING POLAR FUNCTIONAL GROUPS: USING "ELECTRON-PUSHING'"
ARROWS
6.4: A CLOSER LOOK AT THE NUCLEOPHILIC SUBSTITUTION MECHANISM: KINETICS
6.5: FRONTSIDE OR BACKSIDE ATTACK? STEREOCHEMISTRY OF THE SN2 REACTION
6.6: CONSEQUENCES OF INVERSION IN SN2 REACTIONS
6.7: STRUCTURE AND SN 2 REACTIVITY: THE LEAVING GROUP
6.8: STRUCTURE AND SN2 REACTIVITY: THE NUCLEOPHILE
6.9: KEYS TO SUCCESS: CHOOSING AMONG MULTIPLE MECHANISTIC PATHWAYS
6.3: REACTION MECHANISMS INVOLVING POLAR FUNCTIONAL GROUPS: USING "ELECTRON-PUSHING\\'"
ARROWS
6.10: STRUCTURE AND SN2 REACTIVITY: THE SUBSTRATE
6.11: THE SN2 REACTION AT A GLANCE
6.E: PROPERTIES AND REACTIONS OF HALOALKANES: BIMOLECULAR NUCLEOPHILIC SUBSTITUTION
(EXERCISES)

1 12/5/2021
6.1: Physical Properties of Haloalkanes
 Objectives

After completing this section, you should be able to

1. write the IUPAC name of a halogenated aliphatic hydrocarbon, given its Kekulé, condensed or shorthand structure.
2. draw the Kekulé, condensed or shorthand structure of a halogenated aliphatic hydrocarbon, given it IUPAC name.
3. write the IUPAC name and draw the Kekulé, condensed or shorthand structure of a simple alkyl halide, given a
systematic, non-IUPAC name (e.g., sec-butyl iodide).
4. arrange a given series of carbon-halogen bonds in order of increasing or decreasing length and strength.

 Study Notes

This section contains little that is new. If you mastered the IUPAC nomenclature of alkanes, you should have little
difficulty in naming alkyl halides. Notice that when a group such as CH2Br must be regarded as a substituent, rather
than as part of the main chain, we may use terms such as bromomethyl.
You will find it easier to understand the reactions of the alkyl halides if you keep the polarity of the C-X bond fixed
permanently in your mind (see ”The Polar C-X Bond” shown in the reading below).

Alkyl halides are also known as haloalkanes. This page explains what they are and discusses their physical properties.
alkyl halides are compounds in which one or more hydrogen atoms in an alkane have been replaced by halogen atoms
(fluorine, chlorine, bromine or iodine). For example:

Halide Designations
Alkyl halides fall into different classes depending on how many alkyl groups are attached to the carbon which holds the
halogen. There are some chemical differences between the various types. When there are no alkyl groups attached to the
carbon holding the halogen, these are considered methyl halides (CH3X).

Primary alkyl halides

In a primary (1°) haloalkane, the carbon which carries the halogen atom is only attached to one other alkyl group. Some
examples of primary alkyl halides include:

Notice that it doesn't matter how complicated the attached alkyl group is. In each case there is only one linkage to an alkyl
group from the CH2 group holding the halogen. There is an exception to this: CH3Br and the other methyl halides are often
counted as primary alkyl halides even though there are no alkyl groups attached to the carbon with the halogen on it.

Secondary alkyl halides

In a secondary (2°) haloalkane, the carbon with the halogen attached is joined directly to two other alkyl groups, which
may be the same or different. Examples:

Tertiary alkyl halides

In a tertiary (3°) haloalkane, the carbon atom holding the halogen is attached directly to three alkyl groups, which may be
any combination of same or different. Examples:

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Example 6.1.1

Please indicate if the following haloalkanes are methyl, 1o, 2o, or 3o:
a) CH3I
b) CH3CH2Br
c)

d)

e)

f)

Solution
a) methyl
b) 1o
c) 2o
d) 3o
e) 1o
f) 2o

Nomenclature of Alkyl Halides

Alkyl halides are systematically named as alkanes (Section 3-4) where the halogen is a substituent on the parent alkane
chain. To summarize the rules discussed in detail in Section 3-4, there are three basic steps to naming alkyl halides.
1) Find and name the longest carbon chain and name it as the parent. Remember is an alkene or alkyne is present, the
parent chain must contain both carbons of the multiple bond.

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2) Number the parent chain consecutively, starting at the end nearest a substituent group. Then assign each substituent a
number. Remember the IUPAC system uses prefix to indicate the halogen followed by the suffix -ide. The prefixes are
fluoro- for fluorine, chloro- for chlorine, bromo- from bromine, and iodo- for iodine. The name of a halogen is preceded by
a number indicating the substituent’s location on the parent chain.

CH3 CH3 Br CH3

CH3CHCH CHCH2CH3 CH3CHCH CHCH2CH3
1 2 3 4 5 6 1 2 3 4 5 6
Br H3C
3-Bromo-2,4-Dimethylhexane 2-Bromo-3,4-Dimethylhexane

CH3
BrCH3CH2CH CHCH2CH2CH3
1 2 3 4 5 6 7
Cl
1-Bromo-3-Chloro-4-methylheptane

3) If there is an ambiguity in numbering the parent chain, begin on the end which is closer to the substituent which comes
first alphabetically.

Cl CH3
CH3CHCH2 CH2CHCH3
1 2 3 4 5 6
2-Chloro-5-methylhexane
(Not 5-Chloro-2-methylhexane)

Common Names of Alkyl Halides

Alkyl halides with simple alkyl groups are often called by common names. Those with a larger number of carbon atoms
are usually given IUPAC names. The common names of alkyl halides consist of two parts: the name of the alkyl group plus
the first syllable of the name of the halogen, with the ending -ide. The names of common alkyl groups are listed in Section
3.3.

I
CH3Br CH3CHCH3 Cl
IUPAC Name: Bromomethane 2-Iodopropane Chlorocyclohexane
Common Name: Methyl bromide Isopropy iodide Cyclohexyl chloride

Exercise 6.1.1

1) Give the common and IUPAC names for each compound.

a) CH3CH2CH2Br
b) (CH3)2CHCl
c) CH3CH2I
d) CH3CH2CH2CH2F
2) Give the IUPAC name for each compound.
a)

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 b)
c)

d)

Answer
1) a) The alkyl group (CH3CH2CH2–) is a propyl group, and the halogen is bromine (Br). The common name is
therefore propyl bromide. For the IUPAC name, the prefix for bromine (bromo) is combined with the name for a
three-carbon chain (propane), preceded by a number identifying the carbon atom to which the Br atom is attached,
so the IUPAC name is 1-bromopropane.
b) The alkyl group [(CH3)2CH–] has three carbon atoms, with a chlorine (Cl) atom attached to the middle carbon
atom. The alkyl group is therefore isopropyl, and the common name of the compound is isopropyl chloride. For the
IUPAC name, the Cl atom (prefix chloro-) attached to the middle (second) carbon atom of a propane chain results
in 2-chloropropane.
c) The alkyl group (CH3CH2–) is a ethyl group, and the halogen is iodide (I). The common name is therefore ethyl
iodide. For the IUPAC name, the prefix for Iodide (Iodod) is combined with the name for a two-carbon chain
(ethane), preceded by a number identifying the carbon atom to which the I atom is attached, so the IUPAC name is
1-bromoethane
d) The alkyl group (CH3CH2CH2CH2–) is a butyl group, and the halogen is fluorine (F). The common name is
therefore butyl fluoride. For the IUPAC name, the prefix for Fluorine (Fluoro) is combined with the name for a
four-carbon chain (butane), preceded by a number identifying the carbon atom to which the Br atom is attached, so
the IUPAC name is 1-fluorobutane.
2) a) The parent alkane has five carbon atoms in the longest continuous chain; it is pentane. A bromo (Br) group is
attached to the second carbon atom of the chain. The IUPAC name is 2-bromopentane.
b) The parent alkane is hexane. Methyl (CH3) and bromo (Br) groups are attached to the second and fourth carbon
atoms, respectively. Listing the substituents in alphabetical order gives the name 4-bromo-2-methylhexane.
c) 2-Chloro-3-methylbutane
d) 1-Bromo-2-chloro-4-methylpentane rine (F). The common name is therefore butyl fluoride. For the IUPAC
name, the prefix for Fluorine (Fluoro) is combined with the name for a four-carbon chain (butane), preceded by a
number identifying the carbon atom to which the Br atom is attached, so the IUPAC name is 1-fluorobutane.

There is a fairly large distinction between the structural and physical properties of haloalkanes and the structural and
physical properties of alkanes. As mentioned above, the structural differences are due to the replacement of one or more

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hydrogens with a halogen atom. The differences in physical properties are a result of factors such as electronegativity,
bond length, bond strength, and molecular size.

Halogens and the Character of the Carbon-Halogen Bond

As discussed in Section 6. 4, halogens are more electronegative than carbon. This results in a carbon-halogen bond that is
polarized with the carbon atom bearing a partial positive charge and the halogen a partial negative charge. This polarity
can be distinctly seen when viewing the electrostatic potential map of a methyl halide. Electron density is shown by a
red/yellow color which is almost exclusively around the halogen atom. The methyl portion of the compound lacks electron
density which is shown by a blue/green color.

The following image shows the relationship between the halogens and electronegativity. Notice, as we move up the
periodic table from iodine to fluorine, electronegativity increases.

The following image shows the relationships between bond length, bond strength, and molecular size. As we progress
down the periodic table from fluorine to iodine, molecular size increases. As a result, we also see an increase in bond
length. Conversely, as molecular size increases and we get longer bonds, the strength of those bonds decreases.

Haloalkanes Have Higher Boiling Points than Alkanes

When comparing alkanes and haloalkanes, we will see that haloalkanes have higher boiling points than alkanes containing
the same number of carbons. London dispersion forces are the first of two types of forces that contribute to this physical
property. You might recall from general chemistry that London dispersion forces increase with molecular surface area. In
comparing haloalkanes with alkanes, haloalkanes exhibit an increase in surface area due to the substitution of a halogen for
hydrogen. The increase in surface area leads to an increase in London dispersion forces, which then results in a higher
boiling point.
Dipole-dipole interaction is the second type of force that contributes to a higher boiling point. As you may recall, this type
of interaction is a coulombic attraction between the partial positive and partial negative charges that exist between carbon-
halogen bonds on separate haloalkane molecules. Similar to London dispersion forces, dipole-dipole interactions establish
a higher boiling point for haloalkanes in comparison to alkanes with the same number of carbons.

The table below illustrates how boiling points are affected by some of these properties. Notice that the boiling point
increases when hydrogen is replaced by a halogen, a consequence of the increase in molecular size, as well as an increase

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in both London dispersion forces and dipole-dipole attractions. The boiling point also increases as a result of increasing the
size of the halogen, as well as increasing the size of the carbon chain.

Solubility
Solubility in water
The alkyl halides are at best only slightly soluble in water. For a haloalkane to dissolve in water you have to break
attractions between the haloalkane molecules (van der Waals dispersion and dipole-dipole interactions) and break the
hydrogen bonds between water molecules. Both of these cost energy. Energy is released when new intermolecular forces
are generated between the haloalkane molecules and water molecules. These will only be dispersion forces and dipole-
dipole interactions. These are not as strong as the original hydrogen bonds in the water, and so not as much energy is
released as was used to separate the water molecules. The energetics of the change are sufficiently "unprofitable" that very
little dissolves.

Solubility in organic solvents

Alkyl halides tend to dissolve in organic solvents because the new intermolecular attractions have much the same strength
as the ones being broken in the separate haloalkane and solvent.

Chemical Reactivity
The pattern in strengths lies in the strength of the bond between the carbon atom and the halogen atom. Previously in this
section, it was noted that the trend for bond strength increases from C-I to C-Br to C-Cl with C-F bonds being the
strongest. To react with the alkyl halides, the carbon-halogen bond has got to be broken. Because that gets easier as you go
from fluoride to chloride to bromide to iodide, the compounds get more reactive in that order. Iodoalkanes are the most
reactive and fluoroalkanes are the least. In fact, fluoroalkanes are so unreactive that we will ignore them completely from
now on in this section!

Exercise 6.1.2

1) Give the names of the following organohalides:

2) Draw the structures of the following compounds:

a) 2-Chloro-3,3-dimethylpentane

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 b) 1,1-Dichloro-4-isopropylcyclohexane
c) 3-bromo-3-ethylhexane

Answer
1)
a) 5-ethyl-4-iodo-3methyl-octane
b) 1-bromo-2,3,4-trimethyl-pentane
c) 4-bromo-5-chloro-2-methyl-heptane
2)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Jim Clark (Chemguide.co.uk)
Rachael Curtis (UC Davis)
Layne Morsch (University of Illinois Springfield)

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6.2: Nucleophilic Substitution
Halogens and the Character of the Carbon-Halogen Bond
With respect to electronegativity, halogens are more electronegative than carbons. This results in a carbon-halogen bond
that is polarized. As shown in the image below, carbon atom has a partial positive charge, while the halogen has a partial
negative charge.

The following image shows the relationship between the halogens and electronegativity. Notice, as we move up the
periodic table from iodine to fluorine, electronegativity increases.

The following image shows the relationships between bond length, bond strength, and molecular size. As we progress
down the periodic table from fluorine to iodine, molecular size increases. As a result, we also see an increase in bond
length. Conversely, as molecular size increases and we get longer bonds, the strength of those bonds decreases.

The influence of bond polarity

Of the four halogens, fluorine is the most electronegative and iodine the least. That means that the electron pair in the
carbon-fluorine bond will be dragged most towards the halogen end. Looking at the methyl halides as simple
examples:

The electronegativities of carbon and iodine are equal and so there will be no separation of charge on the bond.
One of the important set of reactions of alkyl halides involves replacing the halogen by something else - substitution
reactions. These reactions involve either:
the carbon-halogen bond breaking to give positive and negative ions. The ion with the positively charged carbon
atom then reacts with something either fully or slightly negatively charged.
something either fully or negatively charged attracted to the slightly positive carbon atom and pushing off the
halogen atom.
You might have thought that either of these would be more effective in the case of the carbon-fluorine bond with the
quite large amounts of positive and negative charge already present. But that's not so - quite the opposite is true! The
thing that governs the reactivity is the strength of the bonds which have to be broken. If is difficult to break a carbon-
fluorine bond, but easy to break a carbon-iodine one.

Contributors
Rachael Curtis (UC Davis)
Jim Clark (Chemguide.co.uk)

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In many ways, the proton transfer process in a Brønsted-Lowry acid-base reaction can be thought of as simply a special
kind of nucleophilic substitution reaction, one in which the electrophile is a hydrogen rather than a carbon.

In both reaction types, we are looking at very similar players: an electron-rich species (the nucleophile/base) attacks an
electron-poor species (the electrophile/proton), driving off the leaving group/conjugate base.
In the next few sections, we are going to be discussing some general aspects of nucleophilic substitution reactions, and in
doing so it will simplify things greatly if we can use some abbreviations and generalizations before we dive into real
examples.
Instead of showing a specific nucleophile like hydroxide, we will simply refer to the nucleophilic reactant as 'Nu'. In a
similar fashion, we will call the leaving group 'X'. We will see as we study actual reactions that leaving groups are
sometimes negatively charged, sometimes neutral, and sometimes positively charged. We will also see some examples of
nucleophiles that are negatively charged and some that are neutral. Therefore, in this general picture we will not include a
charge designation on the 'X' or 'Nu' species. In the same way, we will see later that nucleophiles and leaving groups are
sometimes protonated and sometimes not, so for now, for the sake of simplicity, we will not include protons on 'Nu' or 'X'.
We will generalize the three other groups bonded on the electrophilic central carbon as R1, R2, and R3: these symbols
could represent hydrogens as well as alkyl groups. Finally, in order to keep figures from becoming too crowded, we will
use in most cases the line structure convention in which the central, electrophilic carbon is not drawn out as a 'C'.
Here, then, is the generalized picture of a concerted (single-step) nucleophilic substitution reaction:

The functional group of alkyl halides is a carbon-halogen bond, the common halogens being fluorine, chlorine, bromine
and iodine. With the exception of iodine, these halogens have electronegativities significantly greater than carbon.
Consequently, this functional group is polarized so that the carbon is electrophilic and the halogen is nucleophilic, as
shown in the drawing on the right. Two characteristics other than electronegativity also have an
important influence on the chemical behavior of these compounds. The first of these is covalent bond
strength. The strongest of the carbon-halogen covalent bonds is that to fluorine. Remarkably, this is
the strongest common single bond to carbon, being roughly 30 kcal/mole stronger than a carbon-carbon bond and about 15
kcal/mole stronger than a carbon-hydrogen bond. Because of this, alkyl fluorides and fluorocarbons in general are
chemically and thermodynamically quite stable, and do not share any of the reactivity patterns shown by the other alkyl
halides. The carbon-chlorine covalent bond is slightly weaker than a carbon-carbon bond, and the bonds to the other
halogens are weaker still, the bond to iodine being about 33% weaker. The second factor to be considered is the relative
stability of the corresponding halide anions, which is likely the form in which these electronegative atoms will be replaced.
This stability may be estimated from the relative acidities of the H-X acids, assuming that the strongest acid releases the
most stable conjugate base (halide anion). With the exception of HF (pKa = 3.2), all the hydrohalic acids are very strong,
small differences being in the direction HCl < HBr < HI.
In order to understand why some combinations of alkyl halides and nucleophiles give a substitution reaction, whereas
other combinations give elimination, and still others give no observable reaction, we must investigate systematically the

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way in which changes in reaction variables perturb the course of the reaction. The following general equation summarizes
the factors that will be important in such an investigation.

One conclusion, relating the structure of the R-group to possible products, should be immediately obvious. If R- has no
beta-hydrogens an elimination reaction is not possible, unless a structural rearrangement occurs first. The first four
halides shown on the left below do not give elimination reactions on treatment with base, because they have no β-
hydrogens. The two halides on the right do not normally undergo such reactions because the potential elimination products
have highly strained double or triple bonds.
It is also worth noting that sp2 hybridized C–X compounds, such as the three on the right, do not normally undergo
nucleophilic substitution reactions, unless other functional groups perturb the double bond(s).

Using the general reaction shown above as our reference, we can identify the following variables and observables.
R change α-carbon from 1º to 2º to 3º
if the α-carbon is a chiral center, set as (R) or (S)
X change from Cl to Br to I (F is relatively unreactive)
Variables
Nu: change from anion to neutral; change basicity; change
polarizability
Solvent polar vs. non-polar; protic vs. non-protic
Products substitution, elimination, no reaction.
Stereospecificity if the α-carbon is a chiral center what happens to its
Observables
configuration?
Reaction Rate measure as a function of reactant concentration.

When several reaction variables may be changed, it is important to isolate the effects of each during the course of study. In
other words: only one variable should be changed at a time, the others being held as constant as possible. For example,
we can examine the effect of changing the halogen substituent from Cl to Br to I, using ethyl as a common R–group,
cyanide anion as a common nucleophile, and ethanol as a common solvent. We would find a common substitution product,
C2H5–CN, in all cases, but the speed or rate of the reaction would increase in the order: Cl < Br < I. This reactivity order
reflects both the strength of the C–X bond, and the stability of X(–) as a leaving group, and leads to the general conclusion
that alkyl iodides are the most reactive members of this functional class.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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6.3: Reaction Mechanisms Involving Polar Functional Groups: Using "Electron-
Pushing'" Arrows
Objectives

After completing this section, you should be able to

1. explain the difference between heterolytic and homolytic bond breakage, and between heterogenic and homogenic
bond formation.
2. state the two reaction types involved in symmetrical and unsymmetrical processes.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
heterogenic
heterolytic
homogenic
homolytic
polar reaction
radical reaction
reaction mechanism

 Study Notes

Upon first reading first four key terms, it is easy to be puzzled. The ending of the word tells you whether a bond is
being formed (‑genic) or broken (‑lytic), while the root of the word describes the nature of that formation or
decomposition. So hetero (meaning different) reactions involve asymmetrical bond making (or breaking) and homo
(meaning same) involve symmetrical processes.
Because one pair of electrons constitutes a single bond, the unsymmetrical making or breaking of that bond in a hetero
processes are described as polar reactions. Similarly, symmetrical homo processes of bond making and breaking are
called radical reactions. Radicals (sometimes referred to as free radicals) are highly reactive neutral chemical species
with one unpaired electron. In later sections we discuss radical and polar reactions in more detail.

The Arrow Notation in Mechanisms

Since chemical reactions involve the breaking and making of bonds, a consideration of the movement of bonding (and
non-bonding) valence shell electrons is essential to this understanding. It is now common practice to show the movement
of electrons with curved arrows, and a sequence of equations depicting the consequences of such electron shifts is termed a
mechanism. In general, two kinds of curved arrows are used in drawing mechanisms:

A full head on the arrow indicates the A B A + B

both electrons
movement or shift of an electron pair: transfer to B

A partial head (fishhook) on the arrow A B A + B

indicates the shift of a single electron: one electron goes to A;
the other electron to B

The use of these symbols in bond-breaking and bond-making reactions is illustrated below. If a covalent single bond is
broken so that one electron of the shared pair remains with each fragment, as in the first example, this bond-breaking is
called homolysis. If the bond breaks with both electrons of the shared pair remaining with one fragment, as in the second
and third examples, this is called heterolysis.

Bond-Breaking Bond-Making

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 R R R R
homolysis
R C Y R C + Y R C + Y R C Y
R R R R

R R R R
heterolysis
R C Y R C + Y R C + Y R C Y
R R R R

R R R R
heterolysis
R C Y R C + Y R C + Y R C Y
R R R R

Other Arrow Symbols

Chemists also use arrow symbols for other purposes, and it is essential to use them correctly.

The Reaction Arrow The Equilibrium Arrow The Resonance Arrow

The following equations illustrate the proper use of these symbols:

CH4 + 2O2 CO2 + H 2O + energy

O O
H 3C C + H 2O H 3C C + H 3O
O H O

H H
H2 C C CH2 H2C C CH2

Reactive Intermediates
The products of bond breaking, shown above, are not stable in the usual sense, and cannot be isolated for prolonged study.
Such species are referred to as reactive intermediates, and are believed to be transient intermediates in many reactions.
The general structures and names of four such intermediates are given below.
Charged Intermediates Uncharged Intermediates
R R
R C R C
R R

a carbocation a radical
R R
R C C
R R

a carbanion a carbene

A pair of widely used terms, related to the Lewis acid-base notation, should also be introduced here.
Electrophile: An electron deficient atom, ion or molecule that has an affinity for an electron pair, and will bond to a
base or nucleophile.
Nucleophile: An atom, ion or molecule that has an electron pair that may be donated in bonding to an electrophile (or
Lewis acid).
Using these definitions, it is clear that carbocations ( called carbonium ions in the older literature ) are electrophiles and
carbanions are nucleophiles. Carbenes have only a valence shell sextet of electrons and are therefore electron deficient. In
this sense they are electrophiles, but the non-bonding electron pair also gives carbenes nucleophilic character. As a rule,
the electrophilic character dominates carbene reactivity. Carbon radicals have only seven valence electrons, and may be
considered electron deficient; however, they do not in general bond to nucleophilic electron pairs, so their chemistry
exhibits unique differences from that of conventional electrophiles. Radical intermediates are often called free radicals.

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The importance of electrophile / nucleophile terminology comes from the fact that many organic reactions involve at some
stage the bonding of a nucleophile to an electrophile, a process that generally leads to a stable intermediate or product.
Reactions of this kind are sometimes called ionic reactions, since ionic reactants or products are often involved. Some
common examples of ionic reactions and their mechanisms may be examined below.
The shapes ideally assumed by these intermediates becomes important when considering the stereochemistry of reactions
in which they play a role. A simple tetravalent compound like methane, CH4, has a tetrahedral configuration. Carbocations
have only three bonds to the charge bearing carbon, so it adopts a planar trigonal configuration. Carbanions are pyramidal
in shape ( tetrahedral if the electron pair is viewed as a substituent), but these species invert rapidly at room temperature,
passing through a higher energy planar form in which the electron pair occupies a p-orbital. Radicals are intermediate in
configuration, the energy difference between pyramidal and planar forms being very small. Since three points determine a
plane, the shape of carbenes must be planar; however, the valence electron distribution varies.

Ionic Reactions
The principles and terms introduced in the previous sections can now be summarized and illustrated by the following three
examples. Reactions such as these are called ionic or polar reactions, because they often involve charged species and the
bonding together of electrophiles and nucleophiles. Ionic reactions normally take place in liquid solutions, where solvent
molecules assist the formation of charged intermediates.

CH3 CH3
H 3C C O + H Cl H 3C C Cl + H2O
CH3 H CH3 The substitution reaction shown on the left can be viewed as taking
place in three steps. The first is an acid-base equilibrium, in which
HCl protonates the oxygen atom of the alcohol. The resulting
conjugate acid then loses water in a second step to give a carbocation
CH3 H CH3
H 3C C O Cl H 3C C Cl +
intermediate. Finally, this electrophile combines with the chloride
H 2O
CH3 H CH3 anion nucleophile to give the final product.
conjugate conjugate electrophile nucleophile
acid base

H H
H H The addition reaction shown on the left can be viewed as taking place
H C C Br
C C + H Br in two steps. The first step can again be considered an acid-base
H H H H
equilibrium, with the pi-electrons of the carbon-carbon double bond
functioning as a base. The resulting conjugate acid is a carbocation,
H H
and this electrophile combines with the nucleophilic bromide anion.
H C C Br
H H
electrophile nucleophile

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 CH3 H CH3
H 3C C Cl + KOH C C + H 2O + KCl
H CH3
The elimination reaction shown on the left takes place in one step.
CH3
The bond breaking and making operations that take place in this step
are described by the curved arrows. The initial stage may also be
H CH3 H CH3 viewed as an acid-base interaction, with hydroxide ion serving as the
+ H 2O + KCl
H C C Cl + K OH C C base and a hydrogen atom component of the alkyl chloride as an acid.
H CH3 H CH3

rearrangement (tautomerism)
There are many kinds of molecular rearrangements. The examples
H
H O O shown on the left are from an important class called tautomerization
C C C C or, more specifically, keto-enol tautomerization. Tautomers are
R R
keto enol rapidly interconverted constitutional isomers, usually distinguished
tautomer tautomer
by a different bonding location for a labile hydrogen atom (colored
red here) and a differently located double bond. The equilibrium
H
H N R N R between tautomers is not only rapid under normal conditions, but it
C C
R
C C often strongly favors one of the isomers (acetone, for example, is
R
imine
tautomer
enamine
tautomer
99.999% keto tautomer). Even in such one-sided equilibria, evidence
for the presence of the minor tautomer comes from the chemical
H behavior of the compound. Tautomeric equilibria are catalyzed by
H O
O traces of acids or bases that are generally present in most chemical
C N
C N
samples.
nitroso oxime
tautomer tautomer

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)

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 Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Dr. Krista Cunningham

The Brønsted-Lowry definition of acidity

We’ll begin our discussion of acid-base chemistry with a couple of essential definitions. The first of these definitions was
proposed in 1923 by the Danish chemist Johannes Brønsted and the English chemist Thomas Lowry, and has come to be
known as the Brønsted-Lowry definition of acids and bases. An acid, by the Brønsted-Lowry definition, is a species which
is able to donate a proton (H+), while a base is a proton acceptor. We have already discussed in the previous chapter one of
the most familiar examples of a Brønsted-Lowry acid-base reaction, between hydrochloric acid and hydroxide ion:

In this reaction, a proton is transferred from HCl (the acid, or proton donor) to hydroxide (the base, or proton acceptor). As
we learned in the previous chapter, curved arrows depict the movement of electrons in this bond-breaking and bond-
forming process.
After a Brønsted-Lowry acid donates a proton, what remains – in this case, a chloride ion – is called the conjugate base.
Chloride is thus the conjugate base of hydrochloric acid. Conversely, when a Brønsted-Lowry base accepts a proton it is
converted into its conjugate acid form: water is thus the conjugate acid of hydroxide.
We can also talk about conjugate acid/base pairs: the two acid/base pairs involved in our first reaction are hydrochloric
acid/chloride and hydroxide/water.In this next acid-base reaction, the two pairs involved are acetate/acetic acid and methyl
ammonium/methylamine:

Throughout this text, we will often use the abbreviations HA and :B in order to refer in a general way to acidic and basic
reactants:

In order to act as a proton acceptor, a base must have a reactive pair of electrons. In all of the examples we shall see in
this chapter, this pair of electrons is a non-bonding lone pair, usually (but not always) on an oxygen, nitrogen, sulfur, or
halogen atom. When acetate acts as a base in the reaction shown above, for example, one of its oxygen lone pairs is used to
form a new bond to a proton. The same can be said for an amine acting as a base. Clearly, methyl ammonium ion cannot
act as a base – it does not have a reactive pair of electrons with which to accept a new bond to a proton.

Later, in chapter 15, we will see several examples where the (relatively) reactive pair of electrons in a pi bond act in a basic
fashion.

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In this chapter, we will concentrate on those bases with non-bonding (lone pair) electrons.

Example

Exercise 7.1: Draw structures for the missing conjugate acids or conjugate bases in the reactions below.

Solution

Contributors
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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6.4: A Closer Look at the Nucleophilic Substitution Mechanism: Kinetics
☰
Objectives
After completing this section, you should be able to
1. write an expression relating reaction rate to the concentration of reagents for a second-order reaction.
2. determine the order of a chemical reaction from experimentally obtained rate data.
3. describe the essential features of the SN2 mechanism, and draw a generalized transition state for such a reaction.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
bimolecular
kinetics
rate coefficient
rate equation
reaction rate
second-order reaction
SN2

 Study Notes

Most of the key terms introduced in this section should already be familiar to you from your previous general
chemistry course.
Reaction rate refers to the change in concentration of a reactant or product per unit of time. Using strict SI units,
reaction rates are expressed in mol · L−1 · s−1, but in some textbooks you will find this value written as M/s. In general,
the reaction rate of a given reaction changes with time, as it is dependent on the concentration of one or more of the
reactants.
An equation which shows the relationship between the reaction rate and the concentrations of the reactants is known as
the rate equation. All rate equations contain a proportionality constant, usually given the symbol k, which is known as
the rate coefficient. Some textbooks refer to this value as the “rate constant,” but this name is a little misleading as it is
not a true constant. The rate coefficient of a given reaction depends on such factors as temperature and the nature of
the solvent.
SN2 is short for “bimolecular nucleophilic substitution.” You will encounter abbreviations for other types of reactions
later in this chapter.
If you are unclear on the point about the inversion of configuration during an SN2 reaction, construct a molecular
model of a chiral alkyl halide, the transition state formed when this substance reacts with a nucleophile in an SN2
process, and the product obtained from this reaction.

In many ways, the proton transfer process in a Brønsted-Lowry acid-base reaction can be thought of as simply a special
kind of nucleophilic substitution reaction, one in which the electrophile is a hydrogen rather than a carbon.

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☰

In both reaction types, we are looking at very similar players: an electron-rich species (the nucleophile/base) attacks an
electron-poor species (the electrophile/proton), driving off the leaving group/conjugate base.
In the next few sections, we are going to be discussing some general aspects of nucleophilic substitution reactions, and in
doing so it will simplify things greatly if we can use some abbreviations and generalizations before we dive into real
examples.
Instead of showing a specific nucleophile like hydroxide, we will simply refer to the nucleophilic reactant as 'Nu'. In a
similar fashion, we will call the leaving group 'X'. We will see as we study actual reactions that leaving groups are
sometimes negatively charged, sometimes neutral, and sometimes positively charged. We will also see some examples of
nucleophiles that are negatively charged and some that are neutral. Therefore, in this general picture we will not include a
charge designation on the 'X' or 'Nu' species. In the same way, we will see later that nucleophiles and leaving groups are
sometimes protonated and sometimes not, so for now, for the sake of simplicity, we will not include protons on 'Nu' or 'X'.
We will generalize the three other groups bonded on the electrophilic central carbon as R1, R2, and R3: these symbols
could represent hydrogens as well as alkyl groups. Finally, in order to keep figures from becoming too crowded, we will
use in most cases the line structure convention in which the central, electrophilic carbon is not drawn out as a 'C'.
Here, then, is the generalized picture of a concerted (single-step) nucleophilic substitution reaction:

The functional group of alkyl halides is a carbon-halogen bond, the common halogens being fluorine, chlorine, bromine
and iodine. With the exception of iodine, these halogens have electronegativities significantly greater than carbon.
Consequently, this functional group is polarized so that the carbon is electrophilic and the halogen is nucleophilic..

Two characteristics other than electronegativity also have an important influence on the chemical behavior of these
compounds.
1) The first of these is covalent bond strength. The strongest of the carbon-halogen covalent bonds is that to fluorine.
Remarkably, this is the strongest common single bond to carbon, being roughly 30 kcal/mole stronger than a carbon-
carbon bond and about 15 kcal/mole stronger than a carbon-hydrogen bond. Because of this, alkyl fluorides and
fluorocarbons in general are chemically and thermodynamically quite stable, and do not share any of the reactivity
patterns shown by the other alkyl halides. The carbon-chlorine covalent bond is slightly weaker than a carbon-carbon
bond, and the bonds to the other halogens are weaker still, the bond to iodine being about 33% weaker.
2) The second factor to be considered is the relative stability of the corresponding halide anions, which is likely the form
of the leaving group when these electronegative atoms are replaced. This stability may be estimated from the relative
acidities of the H-X acids, assuming that the strongest acid releases the most stable conjugate base (halide anion). With the

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exception of HF (pKa = 3.2), all the hydrohalic acids are very strong, small differences being in the direction HCl < HBr <
☰
HI.
In order to understand why some combinations of alkyl halides and nucleophiles give a substitution reaction, whereas
other combinations give elimination, and still others give no observable reaction, we must investigate systematically the
way in which changes in reaction variables perturb the course of the reaction. The following general equation summarizes
the factors that will be important in such an investigation.

One conclusion, relating the structure of the R-group to possible products, should be immediately obvious. If R- has no
beta-hydrogens an elimination reaction is not possible, unless a structural rearrangement occurs first. The first four
halides shown on the left below do not give elimination reactions on treatment with base, because they have no β-
hydrogens. The two halides on the right do not normally undergo such reactions because the potential elimination products
have highly strained double or triple bonds.
It is also worth noting that sp2 hybridized C–X compounds, such as the three on the right, do not normally undergo
nucleophilic substitution reactions, unless other functional groups perturb the double bond(s).

Using the general reaction shown above as our reference, we can identify the following variables and observables.

R change α-carbon from 1º to 2º to 3º

if the α-carbon is a chiral center, set as (R) or (S)
X change from Cl to Br to I (F is relatively unreactive)
Variables
Nu: change from anion to neutral; change basicity; change
polarizability
Solvent polar vs. non-polar; protic vs. non-protic
Products substitution, elimination, no reaction.
Stereospecificity if the α-carbon is a chiral center what happens to its
Observables
configuration?
Reaction Rate measure as a function of reactant concentration.

When several reaction variables may be changed, it is important to isolate the effects of each during the course of study. In
other words: only one variable should be changed at a time, the others being held as constant as possible. For example,
we can examine the effect of changing the halogen substituent from Cl to Br to I, using ethyl as a common R–group,
cyanide anion as a common nucleophile, and ethanol as a common solvent. We would find a common substitution product,
C2H5–CN, in all cases, but the speed or rate of the reaction would increase in the order: Cl < Br < I. This reactivity order
reflects both the strength of the C–X bond, and the stability of X(–) as a leaving group, and leads to the general conclusion
that alkyl iodides are the most reactive members of this functional class.

The SN2 mechanism

There are two mechanistic models for how an alkyl halide can undergo nucleophilic substitution. In the first picture, the
reaction takes place in a single step, and bond-forming and bond-breaking occur simultaneously. (In all figures in this
section, 'X' indicates a halogen substituent).

This is called an 'SN2' mechanism. In the term SN2, S stands for 'substitution', the subscript N stands for 'nucleophilic', and
the number 2 refers to the fact that this is a bimolecular reaction: the overall rate depends on a step in which two separate

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molecules (the nucleophile and the electrophile) collide. A potential energy diagram for this reaction shows the transition
☰
state (TS) as the highest point on the pathway from reactants to products.

If you look carefully at the progress of the SN2 reaction, you will realize something very important about the outcome. The
nucleophile, being an electron-rich species, must attack the electrophilic carbon from the back side relative to the location
of the leaving group. Approach from the front side simply doesn't work: the leaving group - which is also an electron-rich
group - blocks the way.

The result of this backside attack is that the stereochemical configuration at the central carbon inverts as the reaction
proceeds. In a sense, the molecule is turned inside out. At the transition state, the electrophilic carbon and the three 'R'
substituents all lie on the same plane.

What this means is that SN2 reactions whether enzyme catalyzed or not, are inherently stereoselective: when the
substitution takes place at a stereocenter, we can confidently predict the stereochemical configuration of the product.
Below is an animation illustrating the principles we have just learned, showing the SN2 reaction between hydroxide ion
and methyl iodide. Notice how backside attack by the hydroxide nucleophile results in inversion at the tetrahedral carbon
electrophile.

 Exercise

Predict the structure of the product in this SN2 reaction. Be sure to specify stereochemistry.

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We will be contrasting about two types of nucleophilic substitution reactions. One type is referred to as unimolecular
☰
nucleophilic substitution (SN1), whereby the rate determining step is unimolecular and bimolecular nucleophilic
substitution (SN2), whereby the rate determining step is bimolecular. We will begin our discussion with SN2 reactions, and
discuss SN1 reactions elsewhere.

Bimolecular Nucleophilic Substitution Reactions and Kinetics

In the term SN2, (as previously stated) the number two stands for bimolecular, meaning there are two molecules involved
in the rate determining step. The rate of bimolecular nucleophilic substitution reactions depends on the concentration of
both the haloalkane and the nucleophile. To understand how the rate depends on the concentrations of both the haloalkane
and the nucleophile, let us look at the following example. The hydroxide ion is the nucleophile and methyl iodide is the
haloalkane.

If we were to double the concentration of either the haloalkane or the nucleophile, we can see that the rate of the reaction
would proceed twice as fast as the initial rate.

If we were to double the concentration of both the haloalkane and the nucleophile, we can see that the rate of the reaction
would proceed four times as fast as the initial rate.

The bimolecular nucleophilic substitution reaction follows second-order kinetics; that is, the rate of the reaction depends
on the concentration of two first-order reactants. In the case of bimolecular nucleophilic substitution, these two reactants
are the haloalkane and the nucleophile. For further clarification on reaction kinetics, the following links may facilitate your
understanding of rate laws, rate constants, and second-order kinetics:
Definition of a Reaction Rate
Rate Laws and Rate Constants
The Determination of the Rate Law
Second-Order Reactions

Frontside vs. Backside Attacks

A bimolecular nucleophilic substitution (SN2) reaction is a type of nucleophilic substitution whereby a lone pair of
electrons on a nucleophile attacks an electron deficient electrophilic center and bonds to it, resulting in the expulsion of a
leaving group. It is possible for the nucleophile to attack the electrophilic center in two ways.
Frontside Attack: In a frontside attack, the nucleophile attacks the electrophilic center on the same side as the leaving
group. When a frontside attack occurs, the stereochemistry of the product remains the same; that is, we have retention
of configuration.
Backside Attack: In a backside attack, the nucleophile attacks the electrophilic center on the side that is opposite to the
leaving group. When a backside attack occurs, the stereochemistry of the product does not stay the same. There is
inversion of configuration.
The following diagram illustrates these two types of nucleophilic attacks, where the frontside attack results in retention of
configuration; that is, the product has the same configuration as the substrate. The backside attack results in inversion of
configuration, where the product's configuration is opposite that of the substrate.

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☰

Experimental Observation: All SN2 Reactions Proceed With Backside Attacks

Experimental observation shows that all SN2 reactions proceed with inversion of configuration; that is, the nucleophile will
always attack from the backside in all SN2 reactions. To think about why this might be true, remember that the nucleophile
has a lone pair of electrons to be shared with the electrophilic center, and the leaving group is going to take a lone pair of
electrons with it upon leaving. Because like charges repel each other, the nucleophile will always proceed by a backside
displacement mechanism.

SN2 Reactions Are Stereospecific

The SN2 reaction is stereospecific. A stereospecific reaction is one in which different stereoisomers react to give different
stereoisomers of the product. For example, if the substrate is an R enantiomer, a frontside nucleophilic attack results in
retention of configuration, and the formation of the R enantiomer. A backside nucleophilic attack results in inversion of
configuration, and the formation of the S enantiomer.

Conversely, if the substrate is an S enantiomer, a frontside nucleophilic attack results in retention of configuration, and the
formation of the S enantiomer. A backside nucleophilic attack results in inversion of configuration, and the formation of
the R enantiomer.

In conclusion, SN2 reactions that begin with the R enantiomer as the substrate will form the S enantiomer as the product.
Those that begin with the S enantiomer as the substrate will form the R enantiomer as the product. This concept also
applies to substrates that are cis and substrates that are trans. If the cis configuration is the substrate, the resulting product
will be trans. Conversely, if the trans configuration is the substrate, the resulting product will be cis.

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Exercises
☰1. In an experiment to investigate the kinetics of the reaction
$\ce{\sf{CH3Cl + OH^{−} -> CH3OH + Cl^{−}}}$
the following results were obtained:
initial concentration of chloromethane = 0.01 mol · L−1
initial concentration of hydroxide ion = 0.01 mol · L−1
initial rate of reaction = 6 × 10−10 mol · L−1 · s−1
Assuming the reaction to be second order:
a. determine the value of the rate coefficient, k.
b. calculate the initial rate of the reaction if [CH3Cl]0 = 0.02 mol · L−1 and [OH−]0 = 0.005 mol · L−1.

Answer
If this reaction is an SN2 reaction as indicated in the question,
−
Rate = k[ CH3 Cl][ OH ]

a. Substituting the given values of the initial rate and concentrations

−10 -1 -1 -1 -1
6 × 10 mol ⋅ L ⋅s = k(0.01 mol ⋅ L )(0.01 mol ⋅ L )

or
−10
6 × 10  
k = mol× L −1 ⋅ s −1 (0.01 mol⋅ L −1 )(0.01 mol⋅ L −1 ) =6× 10 −6 mol× L −1 ⋅ s −1

b. Initial rate
−6 −1 −1 −1 −1
= (6 × 10  mol ⋅ L ⋅s )(0.02 mol ⋅ L )(0.005 mol ⋅ L )

−10 −1 −1
= (6 × 10  mol ⋅ L ⋅s )

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne Morsch (University of Illinois Springfield)

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6.5: Frontside or Backside Attack? Stereochemistry of the SN2 Reaction

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6.6: Consequences of Inversion in SN2 Reactions
Objectives
After completing this section, you should be able to
1. write an equation to represent the Walden inversion.
2. write a short paragraph describing the Walden inversion.
3. describe, using equations, a series of reactions interconverting two enantiomers of 1-phenyl-2-propanol which led
to the conclusion that nucleophilic substitution of primary and secondary alkyl halides proceeds with inversion of
configuration.

 Study Notes

The IUPAC name for malic acid is 2-hydroxybutanedioic acid. This acid is produced by apples, a fact which seems to
have been appreciated by the British novelist Thomas Hardy in The Woodlanders:
Up, upward they crept, a stray beam of the sun alighting every now and then like a star on the blades of the
pomace-shovels, which had been converted to steel mirrors by the action of the malic acid.

In 1896, the German chemist Paul Walden discovered that he could interconvert pure enantiomeric (+) and (-) malic acids
through a series of reactions. This conversion meant that there was some kind of change in the stereo chemistry made
during the reaction.

These reactions are currently referred to as nucleophilic substitution reactions because each step involves the substitution
of one nucleophile by another. These are among the most common and versatile reaction types in organic chemistry.

Further investigations into these reaction were undertaken during the 1920's and 1930's to clarify the mechanism and
clarify how the inversion of configurations occur. These reactions involved nucleophilic substitution of an alkyl p-
toluenesulfonate (called a tosylate group). For this purpose the tosylate groups act similarly to a halogen substituent. In the
series of reactions (+)-1-phenyl-2-propanol is interconverted with (-)-1-phenyl-2-propanol.

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It was determined that the reaction with acetate was causing the stereochemical configuration to be inverted.

Exercises
Questions
Q11.1.1
Predict the product of a nucleophilic substitution of (S)-2-bromopentane reacting with CH3CO2-, Show stereochemistry.
Solutions
S11.1.1

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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6.7: Structure and S N 2 SN2 Reactivity: The Leaving Group
Our general discussion of nucleophilic substitution reactions, we have until now been designating the leaving group simply
as “X". As you may imagine, however, the nature of the leaving group is an important consideration: if the C-X bond does
not break, the new bond between the nucleophile and electrophilic carbon cannot form, regardless of whether the
substitution is SN1 or SN2. In this module, we are focusing on substitution reactions in which the leaving group is a
halogen ion, although many reactions are known, both in the laboratory and in biochemical processes, in which the leaving
group is something other than a halogen.
In order to understand the nature of the leaving group, it is important to first discuss factors that help determine whether a
species will be a strong base or weak base. If you remember from general chemistry, a Lewis base is defined as a species
that donates a pair of electrons to form a covalent bond. The factors that will determine whether a species wants to share its
electrons or not include electronegativity, size, and resonance.
As Electronegativity Increases, Basicity Decreases: In general, if we move from the left of the periodic table to the right
of the periodic table as shown in the diagram below, electronegativity increases. As electronegativity increases, basicity
will decrease, meaning a species will be less likely to act as base; that is, the species will be less likely to share its
electrons.

As Size Increases, Basicity Decreases: In general, if we move from the top of the periodic table to the bottom of the
periodic table as shown in the diagram below, the size of an atom will increase. As size increases, basicity will decrease,
meaning a species will be less likely to act as a base; that is, the species will be less likely to share its electrons.

Resonance Decreases Basicity:The third factor to consider in determining whether or not a species will be a strong or
weak base is resonance. As you may remember from general chemistry, the formation of a resonance stabilized structure
results in a species that is less willing to share its electrons. Since strong bases, by definition, want to share their electrons,
resonance stabilized structures are weak bases. Edit section
Now that we understand how electronegativity, size, and resonance affect basicity, we can combine these concepts with the
fact that weak bases make the best leaving groups. Think about why this might be true. In order for a leaving group to
leave, it must be able to accept electrons. A strong bases wants to donate electrons; therefore, the leaving group must be a
weak base. We will now revisit electronegativity, size, and resonance, moving our focus to the leaving group, as well
providing actual examples.
Note
As the Electronegativity of the group Increases, The propensity of the Leaving Group to Leave Increases

As mentioned previously, if we move from left to right on the periodic table, electronegativity increases. With an increase
in electronegativity, basisity decreases, and the ability of the leaving group to leave increases. This is because an increase
in electronegativity results in a species that wants to hold onto its electrons rather than donate them. The following
diagram illustrates this concept, showing -CH3 to be the worst leaving group and F- to be the best leaving group. This
particular example should only be used to facilitate your understanding of this concept. In real reaction mechanisms, these

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groups are not good leaving groups at all. For example, fluoride is such a poor leaving group that SN2 reactions of
fluoroalkanes are rarely observed.

As Size Increases, The Ability of the Leaving Group to Leave Increases:Here we revisit the effect size has on basicity.
If we move down the periodic table, size increases. With an increase in size, basicity decreases, and the ability of the
leaving group to leave increases. The relationship among the following halogens, unlike the previous example, is true to
what we will see in upcoming reaction mechanisms.

Example 7.7.1
In each pair (A and B) below, which electrophile would be expected to react more rapidly in an SN2 reaction with the
thiol group of cysteine as the common nucleophile?

Solution (8.13)

Contributor
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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6.8: Structure and SN2 Reactivity: The Nucleophile
What is a nucleophile?
Nucleophilic functional groups are those which have electron-rich atoms able to donate a pair of electrons to form a new
covalent bond. In both laboratory and biological organic chemistry, the most relevant nucleophilic atoms are oxygen,
nitrogen, and sulfur, and the most common nucleophilic functional groups are water, alcohols, phenols, amines, thiols, and
occasionally carboxylates. More specifically in laboratory reactions, halide and azide (N3-) anions are commonly seen
acting as nucleophiles.
Of course, carbons can also be nucleophiles - otherwise how could new carbon-carbon bonds be formed in the synthesis of
large organic molecules like DNA or fatty acids? Enolate ions (section 7.5) are the most common carbon nucleophiles in
biochemical reactions, while the cyanide ion (CN-) is just one example of a carbon nucleophile commonly used in the
laboratory. Reactions with carbon nucleophiles will be dealt with in chapters 13 and 14, however - in this chapter and the
next, we will concentrate on non-carbon nucleophiles.
When thinking about nucleophiles, the first thing to recognize is that, for the most part, the same quality of 'electron-
richness' that makes a something nucleophilic also makes it basic: nucleophiles can be bases, and bases can be
nucleophiles. It should not be surprising, then, that most of the trends in basicity that we have already discussed also apply
to nucleophilicity.

Protonation states and nucleophilicity

The protonation state of a nucleophilic atom has a very large effect on its nucleophilicity. This is an idea that makes
intuitive sense: a hydroxide ion is much more nucleophilic (and basic) than a water molecule, because the negatively
charged oxygen on the hydroxide ion carries greater electron density than the oxygen atom of a neutral water molecule. In
practical terms, this means that a hydroxide nucleophile will react in an SN2 reaction with methyl bromide much faster (
about 10,000 times faster) than a water nucleophile.

Periodic trends and solvent effects in nucleophilicity

There are predictable periodic trends in nucleophilicity. Moving horizontally across the second row of the table, the trend
in nucleophilicity parallels the trend in basicity:

The reasoning behind the horizontal nucleophilicity trend is the same as the reasoning behind the basicity trend: more
electronegative elements hold their electrons more tightly, and are less able to donate them to form a new bond.
This horizontal trends also tells us that amines are more nucleophilic than alcohols, although both groups commonly act as
nucleophiles in both laboratory and biochemical reactions.
Recall that the basicity of atoms decreases as we move vertically down a column on the periodic table: thiolate ions are
less basic than alkoxide ions, for example, and bromide ion is less basic than chloride ion, which in turn is less basic than
fluoride ion. Recall also that this trend can be explained by considering the increasing size of the 'electron cloud' around
the larger ions: the electron density inherent in the negative charge is spread around a larger area, which tends to increase
stability (and thus reduce basicity).
The vertical periodic trend for nucleophilicity is somewhat more complicated that that for basicity: depending on the
solvent that the reaction is taking place in, the nucleophilicity trend can go in either direction. Let's take the simple
example of the SN2 reaction below:

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. . .where Nu- is one of the halide ions: fluoride, chloride, bromide, or iodide, and the leaving group I* is a radioactive
isotope of iodine (which allows us to distinguish the leaving group from the nucleophile in that case where both are
iodide). If this reaction is occurring in a protic solvent (that is, a solvent that has a hydrogen bonded to an oxygen or
nitrogen - water, methanol and ethanol are the most important examples), then the reaction will go fastest when iodide is
the nucleophile, and slowest when fluoride is the nucleophile, reflecting the relative strength of the nucleophile.

Relative nucleophilicity in a protic solvent

This of course, is opposite that of the vertical periodic trend for basicity, where iodide is the least basic. What is going on
here? Shouldn't the stronger base, with its more reactive unbonded valence electrons, also be the stronger nucleophile?
As mentioned above, it all has to do with the solvent. Remember, we are talking now about the reaction running in a protic
solvent like ethanol. Protic solvent molecules form very strong ion-dipole interactions with the negatively-charged
nucleophile, essentially creating a 'solvent cage' around the nucleophile:

In order for the nucleophile to attack the electrophile, it must break free, at least in part, from its solvent cage. The lone
pair electrons on the larger, less basic iodide ion interact less tightly with the protons on the protic solvent molecules - thus
the iodide nucleophile is better able to break free from its solvent cage compared the smaller, more basic fluoride ion,
whose lone pair electrons are bound more tightly to the protons of the cage.
The picture changes if we switch to a polar aprotic solvent, such as acetone, in which there is a molecular dipole but no
hydrogens bound to oxygen or nitrogen. Now, fluoride is the best nucleophile, and iodide the weakest.

Relative nucleophilicity in a polar aprotic solvent

The reason for the reversal is that, with an aprotic solvent, the ion-dipole interactions between solvent and nucleophile are
much weaker: the positive end of the solvent's dipole is hidden in the interior of the molecule, and thus it is shielded from
the negative charge of the nucleophile.

A weaker solvent-nucleophile interaction means a weaker solvent cage for the nucleophile to break through, so the solvent
effect is much less important, and the more basic fluoride ion is also the better nucleophile.
Why not use a completely nonpolar solvent, such as hexane, for this reaction, so that the solvent cage is eliminated
completely? The answer to this is simple - the nucleophile needs to be in solution in order to react at an appreciable rate
with the electrophile, and a solvent such as hexane will not solvate an a charged (or highly polar) nucleophile at all. That is
why chemists use polar aprotic solvents for nucleophilic substitution reactions in the laboratory: they are polar enough to

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solvate the nucleophile, but not so polar as to lock it away in an impenetrable solvent cage. In addition to acetone, three
other commonly used polar aprotic solvents are acetonitrile, dimethylformamide (DMF), and dimethyl sulfoxide (DMSO).

In biological chemistry, where the solvent is protic (water), the most important implication of the periodic trends in
nucleophilicity is that thiols are more powerful nucleophiles than alcohols. The thiol group in a cysteine amino acid, for
example, is a powerful nucleophile and often acts as a nucleophile in enzymatic reactions, and of course negatively-
charged thiolates (RS-) are even more nucleophilic. This is not to say that the hydroxyl groups on serine, threonine, and
tyrosine do not also act as nucleophiles - they do.

Resonance effects on nucleophilicity

Resonance effects also come into play when comparing the inherent nucleophilicity of different molecules. The reasoning
involved is the same as that which we used to understand resonance effects on basicity. If the electron lone pair on a
heteroatom is delocalized by resonance, it is inherently less reactive - meaning less nucleophilic, and also less basic. An
alkoxide ion, for example, is more nucleophilic and more basic than a carboxylate group, even though in both cases the
nucleophilic atom is a negatively charged oxygen. In the alkoxide, the negative charge is localized on a single oxygen,
while in the carboxylate the charge is delocalized over two oxygen atoms by resonance.

The nitrogen atom on an amide is less nucleophilic than the nitrogen of an amine, due to the resonance stabilization of the
nitrogen lone pair provided by the amide carbonyl group.

Steric effects on nucleophilicity

Steric hindrance is an important consideration when evaluating nucleophility. For example, tert-butanol is less potent as a
nucleophile than methanol. This is because the comparatively bulky methyl groups on the tertiary alcohol effectively block
the route of attack by the nucleophilic oxygen, slowing the reaction down considerably (imagine trying to walk through a
narrow doorway while carrying three large suitcases!).

It is not surprising that it is more common to observe serines acting as nucleophiles in enzymatic reactions compared to
threonines - the former is a primary alcohol, while the latter is a secondary alcohol.
Example 7.8.1
Which is the better nucleophile - a cysteine side chain or a methionine side chain? Explain.

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 Example 7.8.2
In each of the following pairs of molecules/ions, which is the better nucleophile in a reaction with CH3Br in acetone
solvent? Explain your choice.
a. phenolate ion (deprotonated phenol) or benzoate ion (deprotonated benzoic acid)
b. water and hydronium ion
c. trimethylamine and triethylamine
d. chloride anion and iodide anion
e. CH3NH- and CH3CH2NH

Contributors
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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6.9: Keys to Success: Choosing Among Multiple Mechanistic Pathways
☰
Predicting SN1 vs. SN2 mechanisms; competition between nucleophilic substitution and
elimination reactions
When considering whether a nucleophilic substitution is likely to occur via an SN1 or SN2 mechanism, we really need to
consider three factors:
1. The electrophile: when the leaving group is attached to a methyl group or a primary carbon, an SN2 mechanism is
favored (here the electrophile is unhindered by surrounded groups, and any carbocation intermediate would be high-
energy and thus unlikely). When the leaving group is attached to a tertiary, allylic, or benzylic carbon, a carbocation
intermediate will be relatively stable and thus an SN1 mechanism is favored.
2. The nucleophile: powerful nucleophiles, especially those with negative charges, favor the SN2 mechanism. Weaker
nucleophiles such as water or alcohols favor the SN1 mechanism.
3. The solvent: Polar aprotic solvents favor the SN2 mechanism by enhancing the reactivity of the nucleophile. Polar
protic solvents favor the SN1 mechanism by stabilizing the carbocation intermediate. SN1 reactions are frequently
solvolysis reactions.
For example, the reaction below has a tertiary alkyl bromide as the electrophile, a weak nucleophile, and a polar protic
solvent (we’ll assume that methanol is the solvent). Thus we’d confidently predict an SN1 reaction mechanism. Because
substitution occurs at a chiral carbon, we can also predict that the reaction will proceed with racemization.

In the reaction below, on the other hand, the electrophile is a secondary alkyl bromide – with these, both SN1 and SN2
mechanisms are possible, depending on the nucleophile and the solvent. In this example, the nucleophile (a thiolate anion)
is strong, and a polar protic solvent is used – so the SN2 mechanism is heavily favored. The reaction is expected to proceed
with inversion of configuration.

Example 7.17.1
Determine whether each substitution reaction shown below is likely to proceed by an SN1 or SN2 mechanism.

Solution

Contributors
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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6.3: Reaction Mechanisms Involving Polar Functional Groups: Using "Electron-
Pushing\\'" Arrows
Objectives

After completing this section, you should be able to

1. explain the difference between heterolytic and homolytic bond breakage, and between heterogenic and homogenic
bond formation.
2. state the two reaction types involved in symmetrical and unsymmetrical processes.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
heterogenic
heterolytic
homogenic
homolytic
polar reaction
radical reaction
reaction mechanism

 Study Notes

Upon first reading first four key terms, it is easy to be puzzled. The ending of the word tells you whether a bond is
being formed (‑genic) or broken (‑lytic), while the root of the word describes the nature of that formation or
decomposition. So hetero (meaning different) reactions involve asymmetrical bond making (or breaking) and homo
(meaning same) involve symmetrical processes.
Because one pair of electrons constitutes a single bond, the unsymmetrical making or breaking of that bond in a hetero
processes are described as polar reactions. Similarly, symmetrical homo processes of bond making and breaking are
called radical reactions. Radicals (sometimes referred to as free radicals) are highly reactive neutral chemical species
with one unpaired electron. In later sections we discuss radical and polar reactions in more detail.

The Arrow Notation in Mechanisms

Since chemical reactions involve the breaking and making of bonds, a consideration of the movement of bonding (and
non-bonding) valence shell electrons is essential to this understanding. It is now common practice to show the movement
of electrons with curved arrows, and a sequence of equations depicting the consequences of such electron shifts is termed a
mechanism. In general, two kinds of curved arrows are used in drawing mechanisms:

A full head on the arrow indicates the A B A + B

both electrons
movement or shift of an electron pair: transfer to B

A partial head (fishhook) on the arrow A B A + B

indicates the shift of a single electron: one electron goes to A;
the other electron to B

The use of these symbols in bond-breaking and bond-making reactions is illustrated below. If a covalent single bond is
broken so that one electron of the shared pair remains with each fragment, as in the first example, this bond-breaking is
called homolysis. If the bond breaks with both electrons of the shared pair remaining with one fragment, as in the second
and third examples, this is called heterolysis.

Bond-Breaking Bond-Making

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 R R R R
homolysis
R C Y R C + Y R C + Y R C Y
R R R R

R R R R
heterolysis
R C Y R C + Y R C + Y R C Y
R R R R

R R R R
heterolysis
R C Y R C + Y R C + Y R C Y
R R R R

Other Arrow Symbols

Chemists also use arrow symbols for other purposes, and it is essential to use them correctly.

The Reaction Arrow The Equilibrium Arrow The Resonance Arrow

The following equations illustrate the proper use of these symbols:

CH4 + 2O2 CO2 + H 2O + energy

O O
H 3C C + H 2O H 3C C + H 3O
O H O

H H
H2 C C CH2 H2C C CH2

Reactive Intermediates
The products of bond breaking, shown above, are not stable in the usual sense, and cannot be isolated for prolonged study.
Such species are referred to as reactive intermediates, and are believed to be transient intermediates in many reactions.
The general structures and names of four such intermediates are given below.
Charged Intermediates Uncharged Intermediates
R R
R C R C
R R

a carbocation a radical
R R
R C C
R R

a carbanion a carbene

A pair of widely used terms, related to the Lewis acid-base notation, should also be introduced here.
Electrophile: An electron deficient atom, ion or molecule that has an affinity for an electron pair, and will bond to a
base or nucleophile.
Nucleophile: An atom, ion or molecule that has an electron pair that may be donated in bonding to an electrophile (or
Lewis acid).
Using these definitions, it is clear that carbocations ( called carbonium ions in the older literature ) are electrophiles and
carbanions are nucleophiles. Carbenes have only a valence shell sextet of electrons and are therefore electron deficient. In
this sense they are electrophiles, but the non-bonding electron pair also gives carbenes nucleophilic character. As a rule,
the electrophilic character dominates carbene reactivity. Carbon radicals have only seven valence electrons, and may be
considered electron deficient; however, they do not in general bond to nucleophilic electron pairs, so their chemistry
exhibits unique differences from that of conventional electrophiles. Radical intermediates are often called free radicals.

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The importance of electrophile / nucleophile terminology comes from the fact that many organic reactions involve at some
stage the bonding of a nucleophile to an electrophile, a process that generally leads to a stable intermediate or product.
Reactions of this kind are sometimes called ionic reactions, since ionic reactants or products are often involved. Some
common examples of ionic reactions and their mechanisms may be examined below.
The shapes ideally assumed by these intermediates becomes important when considering the stereochemistry of reactions
in which they play a role. A simple tetravalent compound like methane, CH4, has a tetrahedral configuration. Carbocations
have only three bonds to the charge bearing carbon, so it adopts a planar trigonal configuration. Carbanions are pyramidal
in shape ( tetrahedral if the electron pair is viewed as a substituent), but these species invert rapidly at room temperature,
passing through a higher energy planar form in which the electron pair occupies a p-orbital. Radicals are intermediate in
configuration, the energy difference between pyramidal and planar forms being very small. Since three points determine a
plane, the shape of carbenes must be planar; however, the valence electron distribution varies.

Ionic Reactions
The principles and terms introduced in the previous sections can now be summarized and illustrated by the following three
examples. Reactions such as these are called ionic or polar reactions, because they often involve charged species and the
bonding together of electrophiles and nucleophiles. Ionic reactions normally take place in liquid solutions, where solvent
molecules assist the formation of charged intermediates.

CH3 CH3
H 3C C O + H Cl H 3C C Cl + H2O
CH3 H CH3 The substitution reaction shown on the left can be viewed as taking
place in three steps. The first is an acid-base equilibrium, in which
HCl protonates the oxygen atom of the alcohol. The resulting
conjugate acid then loses water in a second step to give a carbocation
CH3 H CH3
H 3C C O Cl H 3C C Cl +
intermediate. Finally, this electrophile combines with the chloride
H 2O
CH3 H CH3 anion nucleophile to give the final product.
conjugate conjugate electrophile nucleophile
acid base

H H
H H The addition reaction shown on the left can be viewed as taking place
H C C Br
C C + H Br in two steps. The first step can again be considered an acid-base
H H H H
equilibrium, with the pi-electrons of the carbon-carbon double bond
functioning as a base. The resulting conjugate acid is a carbocation,
H H
and this electrophile combines with the nucleophilic bromide anion.
H C C Br
H H
electrophile nucleophile

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 CH3 H CH3
H 3C C Cl + KOH C C + H 2O + KCl
H CH3
The elimination reaction shown on the left takes place in one step.
CH3
The bond breaking and making operations that take place in this step
are described by the curved arrows. The initial stage may also be
H CH3 H CH3 viewed as an acid-base interaction, with hydroxide ion serving as the
+ H 2O + KCl
H C C Cl + K OH C C base and a hydrogen atom component of the alkyl chloride as an acid.
H CH3 H CH3

rearrangement (tautomerism)
There are many kinds of molecular rearrangements. The examples
H
H O O shown on the left are from an important class called tautomerization
C C C C or, more specifically, keto-enol tautomerization. Tautomers are
R R
keto enol rapidly interconverted constitutional isomers, usually distinguished
tautomer tautomer
by a different bonding location for a labile hydrogen atom (colored
red here) and a differently located double bond. The equilibrium
H
H N R N R between tautomers is not only rapid under normal conditions, but it
C C
R
C C often strongly favors one of the isomers (acetone, for example, is
R
imine
tautomer
enamine
tautomer
99.999% keto tautomer). Even in such one-sided equilibria, evidence
for the presence of the minor tautomer comes from the chemical
H behavior of the compound. Tautomeric equilibria are catalyzed by
H O
O traces of acids or bases that are generally present in most chemical
C N
C N
samples.
nitroso oxime
tautomer tautomer

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)

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Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Dr. Krista Cunningham

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6.10: Structure and SN2 Reactivity: The Substrate
☰
The SN2 mechanism
There are two mechanistic models for how an alkyl halide can undergo nucleophilic substitution. In the first picture, the
reaction takes place in a single step, and bond-forming and bond-breaking occur simultaneously. (In all figures in this
section, 'X' indicates a halogen substituent).

This is called an 'SN2' mechanism. In the term SN2, S stands for 'substitution', the subscript N stands for 'nucleophilic', and
the number 2 refers to the fact that this is a bimolecular reaction: the overall rate depends on a step in which two separate
molecules (the nucleophile and the electrophile) collide. A potential energy diagram for this reaction shows the transition
state (TS) as the highest point on the pathway from reactants to products.

If you look carefully at the progress of the SN2 reaction, you will realize something very important about the outcome. The
nucleophile, being an electron-rich species, must attack the electrophilic carbon from the back side relative to the location
of the leaving group. Approach from the front side simply doesn't work: the leaving group - which is also an electron-rich
group - blocks the way.

The result of this backside attack is that the stereochemical configuration at the central carbon inverts as the reaction
proceeds. In a sense, the molecule is turned inside out. At the transition state, the electrophilic carbon and the three 'R'
substituents all lie on the same plane.

What this means is that SN2 reactions whether enzyme catalyzed or not, are inherently stereoselective: when the
substitution takes place at a stereocenter, we can confidently predict the stereochemical configuration of the product.
Below is an animation illustrating the principles we have just learned, showing the SN2 reaction between hydroxide ion
and methyl iodide. Notice how backside attack by the hydroxide nucleophile results in inversion at the tetrahedral carbon
electrophile.

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☰

Exercise

Predict the structure of the product in this SN2 reaction. Be sure to specify stereochemistry.

We will be contrasting about two types of nucleophilic substitution reactions. One type is referred to as unimolecular
nucleophilic substitution (SN1), whereby the rate determining step is unimolecular and bimolecular nucleophilic
substitution (SN2), whereby the rate determining step is bimolecular. We will begin our discussion with SN2 reactions, and
discuss SN1 reactions elsewhere.

Biomolecular Nucleophilic Substitution Reactions and Kinetics

In the term SN2, the S stands for substitution, the N stands for nucleophilic, and the number two stands for bimolecular,
meaning there are two molecules involved in the rate determining step. The rate of bimolecular nucleophilic substitution
reactions depends on the concentration of both the haloalkane and the nucleophile. To understand how the rate depends on
the concentrations of both the haloalkane and the nucleophile, let us look at the following example. The hydroxide ion is
the nucleophile and methyl iodide is the haloalkane.

If we were to double the concentration of either the haloalkane or the nucleophile, we can see that the rate of the reaction
would proceed twice as fast as the initial rate.

If we were to double the concentration of both the haloalkane and the nucleophile, we can see that the rate of the reaction
would proceed four times as fast as the initial rate.

The bimolecular nucleophilic substitution reaction follows second-order kinetics; that is, the rate of the reaction depends
on the concentration of two first-order reactants. In the case of bimolecular nucleophilic substitution, these two reactants
are the haloalkane and the nucleophile. For further clarification on reaction kinetics, the following links may facilitate your
understanding of rate laws, rate constants, and second-order kinetics:
Definition of a Reaction Rate
Rate Laws and Rate Constants
The Determination of the Rate Law
Second-Order Reactions

Bimolecular Nucleophilic Substitution Reactions Are Concerted

Bimolecular nucleophilic substitution (SN2) reactions are concerted, meaning they are a one step process. This means
that the process whereby the nucleophile attacks and the leaving group leaves is simultaneous. Hence, the bond-making

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between the nucleophile and the electrophilic carbon occurs at the same time as the bond-breaking between the electophilic
☰
carbon and the halogen.
The potential energy diagram for an SN2 reaction is shown below. Upon nucleophilic attack, a single transition state is
formed. A transition state, unlike a reaction intermediate, is a very short-lived species that cannot be isolated or directly
observed. Again, this is a single-step, concerted process with the occurrence of a single transition state.

Sterrically Hindered Substrates Will Reduce the SN2 Reaction Rate

Now that we have discussed the effects that the leaving group, nucleophile, and solvent have on biomolecular nucleophilic
substitution (SN2) reactions, it's time to turn our attention to how the substrate affects the reaction. Although the substrate,
in the case of nucleophilic substitution of haloalkanes, is considered to be the entire molecule circled below, we will be
paying particular attention to the alkyl portion of the substrate. In other words, we are most interested in the electrophilic
center that bears the leaving group.

In the section Kinetics of Nucleophilic Substitution Reactions, we learned that the SN2 transition state is very crowded.
Recall that there are a total of five groups around the electrophilic center, the nucleophile, the leaving group, and three
substituents.

If each of the three substituents in this transition state were small hydrogen atoms, as illustrated in the first example below,
there would be little steric repulsion between the incoming nucleophile and the electrophilic center, thereby increasing the
ease at which the nucleophilic substitution reaction can occur. Remember, for the SN2 reaction to occur, the nucleophile
must be able to attack the electrophilic center, resulting in the expulsion of the leaving group. If one of the hydrogens,
however, were replaced with an R group, such as a methyl or ethyl group, there would be an increase in steric repulsion
with the incoming nucleophile. If two of the hydrogens were replaced by R groups, there would be an even greater
increase in steric repulsion with the incoming nucleophile.

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☰

How does steric hindrance affect the rate at which an SN2 reaction will occur? As each hydrogen is replaced by an R
group, the rate of reaction is significantly diminished. This is because the addition of one or two R groups shields the
backside of the electrophilic carbon, impeding nucleophilic attack.
The diagram below illustrates this concept, showing that electrophilic carbons attached to three hydrogen atoms results in
faster nucleophilic substitution reactions, in comparison to primary and secondary haloalkanes, which result in
nucleophilic substitution reactions that occur at slower or much slower rates, respectively. Notice that a tertiary haloalkane,
that which has three R groups attached, does not undergo nucleophilic substitution reactions at all. The addition of a third
R group to this molecule creates a carbon that is entirely blocked.

Substitutes on Neighboring Carbons Slow Nucleophilic Substitution Reactions

Previously we learned that adding R groups to the electrophilic carbon results in nucleophilic substitution reactions that
occur at a slower rate. What if R groups are added to neighboring carbons? It turns out that the addition of substitutes on
neighboring carbons will slow nucleophilic substitution reactions as well.
In the example below, 2-methyl-1-bromopropane differs from 1-bromopropane in that it has a methyl group attached to the
carbon that neighbors the electrophilic carbon. The addition of this methyl group results in a significant decrease in the rate
of a nucleophilic substitution reaction.

If R groups were added to carbons farther away from the electrophilic carbon, we would still see a decrease in the reaction
rate. However, branching at carbons farther away from the electrophilic carbon would have a much smaller effect.

Frontside vs. Backside Attacks

A biomolecular nucleophilic substitution (SN2) reaction is a type of nucleophilic substitution whereby a lone pair of
electrons on a nucleophile attacks an electron deficient electrophilic center and bonds to it, resulting in the expulsion of a
leaving group. It is possible for the nucleophile to attack the electrophilic center in two ways.
Frontside Attack: In a frontside attack, the nucleophile attacks the electrophilic center on the same side as the leaving
group. When a frontside attack occurs, the stereochemistry of the product remains the same; that is, we have retention
of configuration.
Backside Attack: In a backside attack, the nucleophile attacks the electrophilic center on the side that is opposite to the
leaving group. When a backside attack occurs, the stereochemistry of the product does not stay the same. There is
inversion of configuration.
The following diagram illustrates these two types of nucleophilic attacks, where the frontside attack results in retention of
configuration; that is, the product has the same configuration as the substrate. The backside attack results in inversion of
configuration, where the product's configuration is opposite that of the substrate.

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☰

Experimental Observation: All SN2 Reactions Proceed With Nucleophilic Backside Attacks
Experimental observation shows that all SN2 reactions proceed with inversion of configuration; that is, the nucleophile will
always attack from the backside in all SN2 reactions. To think about why this might be true, remember that the nucleophile
has a lone pair of electrons to be shared with the electrophilic center, and the leaving group is going to take a lone pair of
electrons with it upon leaving. Because like charges repel each other, the nucleophile will always proceed by a backside
displacement mechanism.

SN2 Reactions Are Stereospecific

The SN2 reaction is stereospecific. A stereospecific reaction is one in which different stereoisomers react to give different
stereoisomers of the product. For example, if the substrate is an R enantiomer, a frontside nucleophilic attack results in
retention of configuration, and the formation of the R enantiomer. A backside nucleophilic attack results in inversion of
configuration, and the formation of the S enantiomer.

Conversely, if the substrate is an S enantiomer, a frontside nucleophilic attack results in retention of configuration, and the
formation of the S enantiomer. A backside nucleophilic attack results in inversion of configuration, and the formation of
the R enantiomer.

In conclusion, SN2 reactions that begin with the R enantiomer as the substrate will form the S enantiomer as the product.
Those that begin with the S enantiomer as the substrate will form the R enantiomer as the product. This concept also
applies to substrates that are cis and substrates that are trans. If the cis configuration is the substrate, the resulting product
will be trans. Conversely, if the trans configuration is the substrate, the resulting product will be cis.

6.10.5 10/17/2021 https://chem.libretexts.org/@go/page/32375

Contributors
☰
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin,
Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions, "You are granted
permission for individual, educational, research and non-commercial reproduction, distribution, display and performance
of this work in any format."

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6.11: The Sn2 Reaction at a Glance
In many ways, the proton transfer process in a Brønsted-Lowry acid-base reaction can be thought of as simply a special
kind of nucleophilic substitution reaction, one in which the electrophile is a hydrogen rather than a carbon.

In both reaction types, we are looking at very similar players: an electron-rich species (the nucleophile/base) attacks an
electron-poor species (the electrophile/proton), driving off the leaving group/conjugate base.
In the next few sections, we are going to be discussing some general aspects of nucleophilic substitution reactions, and in
doing so it will simplify things greatly if we can use some abbreviations and generalizations before we dive into real
examples.
Instead of showing a specific nucleophile like hydroxide, we will simply refer to the nucleophilic reactant as 'Nu'. In a
similar fashion, we will call the leaving group 'X'. We will see as we study actual reactions that leaving groups are
sometimes negatively charged, sometimes neutral, and sometimes positively charged. We will also see some examples of
nucleophiles that are negatively charged and some that are neutral. Therefore, in this general picture we will not include a
charge designation on the 'X' or 'Nu' species. In the same way, we will see later that nucleophiles and leaving groups are
sometimes protonated and sometimes not, so for now, for the sake of simplicity, we will not include protons on 'Nu' or 'X'.
We will generalize the three other groups bonded on the electrophilic central carbon as R1, R2, and R3: these symbols
could represent hydrogens as well as alkyl groups. Finally, in order to keep figures from becoming too crowded, we will
use in most cases the line structure convention in which the central, electrophilic carbon is not drawn out as a 'C'.
Here, then, is the generalized picture of a concerted (single-step) nucleophilic substitution reaction:

The functional group of alkyl halides is a carbon-halogen bond, the common halogens being fluorine, chlorine, bromine
and iodine. With the exception of iodine, these halogens have electronegativities significantly greater than carbon.
Consequently, this functional group is polarized so that the carbon is electrophilic and the halogen is nucleophilic, as
shown in the drawing on the right. Two characteristics other than electronegativity also have an
important influence on the chemical behavior of these compounds. The first of these is covalent bond
strength. The strongest of the carbon-halogen covalent bonds is that to fluorine. Remarkably, this is
the strongest common single bond to carbon, being roughly 30 kcal/mole stronger than a carbon-carbon bond and about 15
kcal/mole stronger than a carbon-hydrogen bond. Because of this, alkyl fluorides and fluorocarbons in general are
chemically and thermodynamically quite stable, and do not share any of the reactivity patterns shown by the other alkyl
halides. The carbon-chlorine covalent bond is slightly weaker than a carbon-carbon bond, and the bonds to the other
halogens are weaker still, the bond to iodine being about 33% weaker. The second factor to be considered is the relative
stability of the corresponding halide anions, which is likely the form in which these electronegative atoms will be replaced.
This stability may be estimated from the relative acidities of the H-X acids, assuming that the strongest acid releases the
most stable conjugate base (halide anion). With the exception of HF (pKa = 3.2), all the hydrohalic acids are very strong,
small differences being in the direction HCl < HBr < HI.

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In order to understand why some combinations of alkyl halides and nucleophiles give a substitution reaction, whereas
other combinations give elimination, and still others give no observable reaction, we must investigate systematically the
way in which changes in reaction variables perturb the course of the reaction. The following general equation summarizes
the factors that will be important in such an investigation.

One conclusion, relating the structure of the R-group to possible products, should be immediately obvious. If R- has no
beta-hydrogens an elimination reaction is not possible, unless a structural rearrangement occurs first. The first four
halides shown on the left below do not give elimination reactions on treatment with base, because they have no β-
hydrogens. The two halides on the right do not normally undergo such reactions because the potential elimination products
have highly strained double or triple bonds.
It is also worth noting that sp2 hybridized C–X compounds, such as the three on the right, do not normally undergo
nucleophilic substitution reactions, unless other functional groups perturb the double bond(s).

Using the general reaction shown above as our reference, we can identify the following variables and observables.
R change α-carbon from 1º to 2º to 3º
if the α-carbon is a chiral center, set as (R) or (S)
X change from Cl to Br to I (F is relatively unreactive)
Variables
Nu: change from anion to neutral; change basicity; change
polarizability
Solvent polar vs. non-polar; protic vs. non-protic
Products substitution, elimination, no reaction.
Stereospecificity if the α-carbon is a chiral center what happens to its
Observables
configuration?
Reaction Rate measure as a function of reactant concentration.

When several reaction variables may be changed, it is important to isolate the effects of each during the course of study. In
other words: only one variable should be changed at a time, the others being held as constant as possible. For example,
we can examine the effect of changing the halogen substituent from Cl to Br to I, using ethyl as a common R–group,
cyanide anion as a common nucleophile, and ethanol as a common solvent. We would find a common substitution product,
C2H5–CN, in all cases, but the speed or rate of the reaction would increase in the order: Cl < Br < I. This reactivity order
reflects both the strength of the C–X bond, and the stability of X(–) as a leaving group, and leads to the general conclusion
that alkyl iodides are the most reactive members of this functional class.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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6.E: Properties and Reactions of Haloalkanes: Bimolecular Nucleophilic
Substitution (Exercises)
These are homework exercises to accompany Chapter 6 of Vollhardt and Schore's "Organic Chemistry" Textmap.

6.1: Physical Properties of Haloalkanes

6.2: Nucleophilic Substitution

6.3: Reaction Mechanisms Involving Polar Functional Groups: Using "Electron-Pushing'"

Arrows

6.4: A Closer Look at the Nucleophilic Substitution Mechanism: Kinetics

6.5: Frontside or Backside Attack? Stereochemistry of the SN2 Reaction

6.6: Consequences of Inversion in SN2 Reactions

6.7: Structure and SN2SN2 Reactivity: The Leaving Group

6.8: Structure and SN2 Reactivity: The Nucleophile

6.9: Keys to Success: Choosing Among Multiple Mechanistic Pathways

6.3: Reaction Mechanisms Involving Polar Functional Groups: Using "Electron-Pushing\\'"

Arrows

6.10: Structure and SN2 Reactivity: The Substrate

6.11: The Sn2 Reaction at a Glance

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CHAPTER OVERVIEW
7: FURTHER REACTIONS OF HALOALKANES: UNIMOLECULAR
SUBSTITUTION AND PATHWAYS OF ELIMINATION
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

7.1: SOLVOLYSIS OF TERTIARY AND SECONDARY HALOALKANES

7.2: UNIMOLECULAR NUCLEOPHILIC SUBSTITUTION
7.3: STEREOCHEMICAL CONSEQUENCES OF SN1 REACTIONS
7.4: EFFECTS OF SOLVENT, LEAVING GROUP, AND NUCLEOPHILE ON UNIMOLECULAR SUBSTITUTION
7.5: EFFECT OF THE ALKYL GROUP ON THE SN 1 REACTION: CARBOCATION STABILITY
7.6: UNIMOLECULAR ELIMINATION: E1
7.7: BIMOLECULAR ELIMINATION: E2
7.8: KEYS TO SUCCESS: SUBSTITUTIN VERSUS ELIMINATION-STRUCTURE DETERMINES FUNCTION
7.9: SUMMARY OF REACTIVITY OF HALOALKANES
7.E: FURTHER REACTIONS OF HALOALKANES: UNIMOLECULAR SUBSTITUTION (EXERCISES)

1 12/5/2021
7.1: Solvolysis of Tertiary and Secondary Haloalkanes
Just as with SN2 reactions, the nucleophile, solvent and leaving group also affect SN1 (Unimolecular Nucleophilic
Substitution) reactions. Polar protic solvents have a hydrogen atom attached to an electronegative atom so the hydrogen is
highly polarized. Polar aprotic solvents have a dipole moment, but their hydrogen is not highly polarized. Polar aprotic
solvents are not used in SN1 reactions because some of them can react with the carbocation intermediate and give you an
unwanted product. Rather, polar protic solvents are preferred.
Introduction

Since the hydrogen atom in a polar protic solvent is highly positively charged, it can interact with the anionic nucleophile
which would negatively affect an SN2, but it does not affect an SN1 reaction because the nucleophile is not a part of the
rate-determining step (See SN2 Nucleophile). Polar protic solvents actually speed up the rate of the unimolecular
substitution reaction because the large dipole moment of the solvent helps to stabilize the transition state. The highly
positive and highly negative parts interact with the substrate to lower the energy of the transition state. Since the
carbocation is unstable, anything that can stabilize this even a little will speed up the reaction.

Sometimes in an SN1 reaction the solvent acts as the nucleophile. This is called a solvolysis reaction (see example below).
The polarity and the ability of the solvent to stabilize the intermediate carbocation is very important as shown by the
relative rate data for the solvolysis (see table below). The dielectric constant of a solvent roughly provides a measure of the
solvent's polarity. A dielectric constant below 15 is usually considered non-polar. Basically, the dielectric constant can be
thought of as the solvent's ability to reduce the internal charge of the solvent. So for our purposes, the higher the dielectric
constant the more polar the substance and in the case of SN1 reactions, the faster the rate.

Below is the same reaction conducted in two different solvents and the relative rate that corresponds with it.

The figure below shows the mechanism of an SN1 reaction of an alkyl halide with water. Since water is also the solvent,
this is an example of a solvolysis reaction.

Examples of polar protic solvents are: acetic acid, isopropanol, ethanol, methanol, formic acid, water, etc.

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Effects of Nucleophile

The strength of the nucleophile does not affect the reaction rate of SN1 because, as stated above, the nucleophile is not
involved in the rate-determining step. However, if you have more than one nucleophile competing to bond to the
carbocation, the strengths and concentrations of those nucleophiles affects the distribution of products that you will get.
For example, if you have (CH3)3CCl reacting in water and formic acid where the water and formic acid are competing
nucleophiles, you will get two different products: (CH3)3COH and (CH3)33COCOH. The relative yields of these products
depend on the concentrations and relative reactivities of the nucleophiles.

Effects of Leaving Group

An SN1 reaction speeds up with a good leaving group. This is because the leaving group is involved in the rate-
determining step. A good leaving group wants to leave so it breaks the C-Leaving Group bond faster. Once the bond
breaks, the carbocation is formed and the faster the carbocation is formed, the faster the nucleophile can come in and the
faster the reaction will be completed.
A good leaving group is a weak base because weak bases can hold the charge. They're happy to leave with both electrons
and in order for the leaving group to leave, it needs to be able to accept electrons. Strong bases, on the other hand, donate
electrons which is why they can't be good leaving groups. As you go from left to right on the periodic table, electron
donating ability decreases and thus ability to be a good leaving group increases. Halides are an example of a good leaving
group whos leaving-group ability increases as you go down the column.

The two reactions below is the same reaction done with two different leaving groups. One is significantly faster than the
other. This is because the better leaving group leaves faster and thus the reaction can proceed faster.

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Other examples of good leaving groups are sulfur derivatives such as methyl sulfate ion and other sulfonate ions (See
Figure below)

Methyl Sulfate Ion Mesylate Ion Triflate Ion Tosylate Ion

References
Uggerud E. "Reactivity trends and stereospecificity in nucleophilic substitution reactions." J. Phys. Org. Chem. 2006;
19; 461-466.
Vollhardt, K. Peter C., and Neil E. Schore. Organic Chemistry Structure and Function. New York: W. H. Freeman,
2007.
Petrucci, Ralph H. General Chemistry: Principles and Modern Applications. Upper Saddle River, NJ: Pearson
Education, 2007.
Suggs, William J. Organic Chemistry. Canada: Barron's Educational Series Inc., 2002.
Outside Links
http://en.wikipedia.org/wiki/Sn1
http://www.youtube.com/watch?v=FuFpjx_ZeT0 (Pretty good summary of SN1 reaction)

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Problems
1. Put the following leaving groups in order of decreasing leaving group ability

2. Which solvent would an SN1 reaction occur faster in? H2O or CH3CN
3. What kind of conditions disfavor SN1 reactions?
4. What are the products of the following reaction and does it proceed via SN1 or SN2?

5. How could you change the reactants in the problem 4 to favor the other substitution reaction?
6. Indicate the expected product and list why it occurs through SN1 instead of SN2?

Answers

1.
2. An SN1 reaction would occur faster in H2O because it's polar protic and would stailize the carbocation and CH3CN is
polar aprotic.
3. Polar aprotic solvents, a weak leaving group and primary substrates disfavor SN1 reactions.

4.
Reaction proceeds via SN1 because a tertiary carbocation was formed, the solvent is polar protic and Br- is a good leaving
group.
5. You could change the solvent to something polar aprotic like CH3CN or DMSO and you could use a better base for a
nucleophile such as NH2- or OH-.

6.
This reaction occurs via SN1 because Cl- is a good leaving group and the solvent is polar protic. This is an example of a
solvolysis reaction because the nucleophile is also the solvent.

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Contributors
Ashiv Sharma

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7.2: Unimolecular Nucleophilic Substitution
The SN1 mechanism
A second model for a nucleophilic substitution reaction is called the 'dissociative', or 'SN1' mechanism: in this picture, the
C-X bond breaks first, before the nucleophile approaches:

This results in the formation of a carbocation: because the central carbon has only three bonds, it bears a formal charge of
+1. Recall that a carbocation should be pictured as sp2 hybridized, with trigonal planar geometry. Perpendicular to the
plane formed by the three sp2 hybrid orbitals is an empty, unhybridized p orbital.

In the second step of this two-step reaction, the nucleophile attacks the empty, 'electron hungry' p orbital of the carbocation
to form a new bond and return the carbon to tetrahedral geometry.

We saw that SN2 reactions result specifically in inversion of stereochemistry at the electrophilic carbon center. What about
the stereochemical outcome of SN1 reactions? In the model SN1 reaction shown above, the leaving group dissociates
completely from the vicinity of the reaction before the nucleophile begins its attack. Because the leaving group is no
longer in the picture, the nucleophile is free to attack from either side of the planar, sp2-hybridized carbocation
electrophile. This means that about half the time the product has the same stereochemical configuration as the starting
material (retention of configuration), and about half the time the stereochemistry has been inverted. In other words,
racemization has occurred at the carbon center. As an example, the tertiary alkyl bromide below would be expected to
form a racemic mix of R and S alcohols after an SN1 reaction with water as the incoming nucleophile.

Exercise

Draw the structure of the intermediate in the two-step nucleophilic substitution reaction above.

The SN1 reaction we see an example of a reaction intermediate, a very important concept in the study of organic reaction
mechanisms that was introduced earlier in the module on organic reactivity Recall that many important organic reactions
do not occur in a single step; rather, they are the sum of two or more discreet bond-forming / bond-breaking steps, and
involve transient intermediate species that go on to react very quickly. In the SN1 reaction, the carbocation species is a
reaction intermediate. A potential energy diagram for an SN1 reaction shows that the carbocation intermediate can be
visualized as a kind of valley in the path of the reaction, higher in energy than both the reactant and product but lower in
energy than the two transition states.

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Exercise

Draw structures representing TS1 and TS2 in the reaction above. Use the solid/dash wedge convention to show three dimensions.

Recall that the first step of the reaction above, in which two charged species are formed from a neutral molecule, is much
the slower of the two steps, and is therefore rate-determining. This is illustrated by the energy diagram, where the
activation energy for the first step is higher than that for the second step. Also recall that an SN1 reaction has first order
kinetics, because the rate determining step involves one molecule splitting apart, not two molecules colliding.
Exercise

Consider two nucleophilic substitutions that occur uncatalyzed in solution. Assume that reaction A is SN2, and reaction B is SN1. Predict, in
each case, what would happen to the rate of the reaction if the concentration of the nucleophile were doubled, while all other conditions
remained constant.

Influence of the solvent in an SN1 reaction

Since the hydrogen atom in a polar protic solvent is highly positively charged, it can interact with the anionic nucleophile
which would negatively affect an SN2, but it does not affect an SN1 reaction because the nucleophile is not a part of the
rate-determining step. Polar protic solvents actually speed up the rate of the unimolecular substitution reaction because the
large dipole moment of the solvent helps to stabilize the transition state. The highly positive and highly negative parts
interact with the substrate to lower the energy of the transition state. Since the carbocation is unstable, anything that can
stabilize this even a little will speed up the reaction.
Sometimes in an SN1 reaction the solvent acts as the nucleophile. This is called a solvolysis reaction.The SN1 reaction of
allyl bromide in methanol is an example of what we would call methanolysis, while if water is the solvent the reaction
would be called hydrolysis:

The polarity and the ability of the solvent to stabilize the intermediate carbocation is very important as shown by the
relative rate data for the solvolysis (see table below). The dielectric constant of a solvent roughly provides a measure of the
solvent's polarity. A dielectric constant below 15 is usually considered non-polar. Basically, the dielectric constant can be
thought of as the solvent's ability to reduce the internal charge of the solvent. So for our purposes, the higher the dielectric
constant the more polar the substance and in the case of SN1 reactions, the faster the rate.

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Below is the same reaction conducted in two different solvents and the relative rate that corresponds with it.

Exercise

Draw a complete curved-arrow mechanism for the methanolysis reaction of allyl bromide shown above.

One more important point must be made before continuing: nucleophilic substitutions as a rule occur at sp3-hybridized
carbons, and not where the leaving group is attached to an sp2-hybridized carbon::

Bonds on sp2-hybridized carbons are inherently shorter and stronger than bonds on sp3-hybridized carbons, meaning that it
is harder to break the C-X bond in these substrates. SN2 reactions of this type are unlikely also because the (hypothetical)
electrophilic carbon is protected from nucleophilic attack by electron density in the p bond. SN1 reactions are highly
unlikely, because the resulting carbocation intermediate, which would be sp-hybridized, would be very unstable (we’ll
discuss the relative stability of carbocation intermediates in a later section of this module).
Before we look at some real-life nucleophilic substitution reactions in the next chapter, we will spend some time in the
remainder of this module focusing more closely on the three principal partners in the nucleophilic substitution reaction: the
nucleophile, the electrophile, and the leaving group.

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota,

Morris)

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7.3: Stereochemical Consequences of SN1 Reactions
The SN1 mechanism
A second model for a nucleophilic substitution reaction is called the 'dissociative', or 'SN1' mechanism: in this picture, the
C-X bond breaks first, before the nucleophile approaches:

This results in the formation of a carbocation: because the central carbon has only three bonds, it bears a formal charge of
+1. Recall that a carbocation should be pictured as sp2 hybridized, with trigonal planar geometry. Perpendicular to the
plane formed by the three sp2 hybrid orbitals is an empty, unhybridized p orbital.

In the second step of this two-step reaction, the nucleophile attacks the empty, 'electron hungry' p orbital of the carbocation
to form a new bond and return the carbon to tetrahedral geometry.

We saw that SN2 reactions result specifically in inversion of stereochemistry at the electrophilic carbon center. What about
the stereochemical outcome of SN1 reactions? In the model SN1 reaction shown above, the leaving group dissociates
completely from the vicinity of the reaction before the nucleophile begins its attack. Because the leaving group is no
longer in the picture, the nucleophile is free to attack from either side of the planar, sp2-hybridized carbocation
electrophile. This means that about half the time the product has the same stereochemical configuration as the starting
material (retention of configuration), and about half the time the stereochemistry has been inverted. In other words,
racemization has occurred at the carbon center. As an example, the tertiary alkyl bromide below would be expected to
form a racemic mix of R and S alcohols after an SN1 reaction with water as the incoming nucleophile.

Exercise

Draw the structure of the intermediate in the two-step nucleophilic substitution reaction above.

The SN1 reaction we see an example of a reaction intermediate, a very important concept in the study of organic reaction
mechanisms that was introduced earlier in the module on organic reactivity Recall that many important organic reactions
do not occur in a single step; rather, they are the sum of two or more discreet bond-forming / bond-breaking steps, and
involve transient intermediate species that go on to react very quickly. In the SN1 reaction, the carbocation species is a
reaction intermediate. A potential energy diagram for an SN1 reaction shows that the carbocation intermediate can be
visualized as a kind of valley in the path of the reaction, higher in energy than both the reactant and product but lower in
energy than the two transition states.

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Exercise

Draw structures representing TS1 and TS2 in the reaction above. Use the solid/dash wedge convention to show three dimensions.

Recall that the first step of the reaction above, in which two charged species are formed from a neutral molecule, is much
the slower of the two steps, and is therefore rate-determining. This is illustrated by the energy diagram, where the
activation energy for the first step is higher than that for the second step. Also recall that an SN1 reaction has first order
kinetics, because the rate determining step involves one molecule splitting apart, not two molecules colliding.
Exercise

Consider two nucleophilic substitutions that occur uncatalyzed in solution. Assume that reaction A is SN2, and reaction B is SN1. Predict, in
each case, what would happen to the rate of the reaction if the concentration of the nucleophile were doubled, while all other conditions
remained constant.

Influence of the solvent in an SN1 reaction

Since the hydrogen atom in a polar protic solvent is highly positively charged, it can interact with the anionic nucleophile
which would negatively affect an SN2, but it does not affect an SN1 reaction because the nucleophile is not a part of the
rate-determining step. Polar protic solvents actually speed up the rate of the unimolecular substitution reaction because the
large dipole moment of the solvent helps to stabilize the transition state. The highly positive and highly negative parts
interact with the substrate to lower the energy of the transition state. Since the carbocation is unstable, anything that can
stabilize this even a little will speed up the reaction.
Sometimes in an SN1 reaction the solvent acts as the nucleophile. This is called a solvolysis reaction.The SN1 reaction of
allyl bromide in methanol is an example of what we would call methanolysis, while if water is the solvent the reaction
would be called hydrolysis:

The polarity and the ability of the solvent to stabilize the intermediate carbocation is very important as shown by the
relative rate data for the solvolysis (see table below). The dielectric constant of a solvent roughly provides a measure of the
solvent's polarity. A dielectric constant below 15 is usually considered non-polar. Basically, the dielectric constant can be
thought of as the solvent's ability to reduce the internal charge of the solvent. So for our purposes, the higher the dielectric
constant the more polar the substance and in the case of SN1 reactions, the faster the rate.

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Below is the same reaction conducted in two different solvents and the relative rate that corresponds with it.

Exercise

Draw a complete curved-arrow mechanism for the methanolysis reaction of allyl bromide shown above.

One more important point must be made before continuing: nucleophilic substitutions as a rule occur at sp3-hybridized
carbons, and not where the leaving group is attached to an sp2-hybridized carbon::

Bonds on sp2-hybridized carbons are inherently shorter and stronger than bonds on sp3-hybridized carbons, meaning that it
is harder to break the C-X bond in these substrates. SN2 reactions of this type are unlikely also because the (hypothetical)
electrophilic carbon is protected from nucleophilic attack by electron density in the p bond. SN1 reactions are highly
unlikely, because the resulting carbocation intermediate, which would be sp-hybridized, would be very unstable (we’ll
discuss the relative stability of carbocation intermediates in a later section of this module).
Before we look at some real-life nucleophilic substitution reactions in the next chapter, we will spend some time in the
remainder of this module focusing more closely on the three principal partners in the nucleophilic substitution reaction: the
nucleophile, the electrophile, and the leaving group.

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota,

Morris)

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7.4: Effects of Solvent, Leaving Group, and Nucleophile on Unimolecular
Substitution
 Objectives

After completing this section, you should be able to

1. discuss how the structure of the substrate affects the rate of a reaction occurring by the SN1 mechanism.
2. arrange a given list of carbocations (including benzyl and allyl) in order of increasing or decreasing stability.
3. explain the high stability of the allyl and benzyl carbocations.
4. arrange a given series of compounds in order of increasing or decreasing reactivity in SN1 reactions, and discuss
this order in terms of the Hammond postulate.
5. discuss how the nature of the leaving group affects the rate of an SN1 reaction, and in particular, explain why SN1
reactions involving alcohols are carried out under acidic conditions.
6. explain why the nature of the nucleophile does not affect the rate of an SN1 reaction.
7. discuss the role played by the solvent in an SN1 reaction, and hence determine whether a given solvent will
promote reaction by this mechanism.
8. compare the roles played by the solvent in SN1 and in SN2 reactions.
9. determine which of two SN1 reactions will occur faster, by taking into account factors such as the structure of the
substrate and the polarity of the solvent.
10. determine whether a given reaction is most likely to occur by an SN1 or SN2 mechanism, based on factors such as
the structure of the substrate, the solvent used, etc.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
benzylic
dielectric constant
polarity

SN1 Mechanism
The first order kinetics of SN1 reactions suggests a two-step mechanism in which the rate-determining step consists of the
ionization of the alkyl halide, as shown in the diagram below. In this mechanism, a carbocation is formed as a high-energy
intermediate, and this species bonds immediately to nearby nucleophiles. If the nucleophile is a neutral molecule, the
initial product is an "onium" cation, as drawn above for t-butyl chloride, and presumed in the energy diagram. In
evaluating this mechanism, we may infer several outcomes from its function.
The only reactant that is undergoing change in the first (rate-determining) step is
the alkyl halide, so we expect such reactions would be unimolecular and follow a
first-order rate equation. Hence the name SN1 is applied to this mechanism.
1. Since nucleophiles only participate in the fast second step, their relative molar
concentrations rather than their nucleophilicities should be the primary product-
determining factor. If a nucleophilic solvent such as water is used, its high
concentration will assure that alcohols are the major product. Recombination of
the halide anion with the carbocation intermediate simply reforms the starting
compound. Note that SN1 reactions in which the nucleophile is also the solvent are commonly called solvolysis
reactions. The hydrolysis of t-butyl chloride is an example.
2. The activation energy of the rate-determining first step will be proportional to the stability of the carbocation
intermediate (more stable carbocations will reduce activation evergy). The stability of carbocations was discussed
earlier, and a qualitative relationship is given below.

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 Benzyl Carbocation

Carbocatio
(CH3)2CH( CH2=CH- C6H5CH2(+
n CH3(+) < CH3CH2(+) < +)
≈ < ≈ (CH3)3C(+)
CH2(+) )
Stability

Consequently, we expect that 3º-alkyl halides will be more reactive than their 2º and 1º-counterparts in reactions that
follow an SN1 mechanism. This is opposite to the reactivity order observed for the SN2 mechanism. Allylic and benzylic
halides are exceptionally reactive by either mechanism.
3. In order to facilitate the charge separation of an ionization reaction, as required by the first step, a good ionizing solvent
will be needed. Two solvent characteristics will be particularly important in this respect. The first is the ability of solvent
molecules to orient themselves between ions so as to attenuate the electrostatic force one ion exerts on the other. This
characteristic is related to the dielectric constant, ε, of the solvent. Solvents having high dielectric constants, such as
water (ε=81), formic acid (ε=58), dimethyl sulfoxide (ε=45) & acetonitrile (ε=39) are generally considered better ionizing
solvents than are some common organic solvents such as ethanol (ε=25), acetone (ε=21), methylene chloride (ε=9) & ether
(ε=4). The second factor is solvation, which refers to the solvent's ability to stabilize ions by encasing them in a sheath of
weakly bonded solvent molecules. Anions are solvated by hydrogen-bonding solvents, as noted earlier. Cations are often
best solvated by nucleophilic sites on a solvent molecule (e.g. oxygen & nitrogen atoms), but in the case of carbocations
these nucleophiles may form strong covalent bonds to carbon, thus converting the intermediate to a substitution product.
This is what happens in the hydrolysis reactions described above.
4. The stereospecificity of these reactions may vary. The positively-charged carbon atom of a carbocation has a trigonal
planar (flat) configuration (it prefers to be sp2 hybridized), and can bond to a nucleophile equally well from either face. If
the intermediate from a chiral alkyl halide survives long enough to encounter a random environment, the products are
expected to be racemic (a 50:50 mixture of enantiomers). On the other hand, if the departing halide anion temporarily
blocks the front side, or if a nucleophile is oriented selectively at one or the other face, then the substitution might occur
with predominant inversion or even retention of configuration.
5. Just as with SN2 reactions, the nucleophile, solvent and leaving group also affect SN1 (Unimolecular Nucleophilic
Substitution) reactions. Polar protic solvents have a hydrogen atom attached to an electronegative atom so the hydrogen is
highly polarized. Polar aprotic solvents have a dipole moment, but their hydrogen is not highly polarized. Polar aprotic
solvents are not used in SN1 reactions because some of them can react with the carbocation intermediate and give you an
unwanted product. Rather, polar protic solvents are preferred.
The strength of the nucleophile does not affect the reaction rate of SN1 because, as stated above, the nucleophile is not
involved in the rate-determining step. However, if you have more than one nucleophile competing to bond to the
carbocation, the strengths and concentrations of those nucleophiles affects the distribution of products that you will get.
For example, if you have (CH3)3CCl reacting in water and formic acid where the water and formic acid are competing
nucleophiles, you will get two different products: (CH3)3COH and (CH3)3COCOH. The relative yields of these products
depend on the concentrations and relative reactivities of the nucleophiles.

Solvent Effects on the SN1 Reaction

Since the hydrogen atom in a polar protic solvent is highly positively charged, it can interact with the anionic nucleophile
which would negatively affect an SN2 , but it does not affect an SN1 reaction because the nucleophile is not a part of the
rate-determining step. Polar protic solvents actually speed up the rate of the unimolecular substitution reaction because the
large dipole moment of the solvent helps to stabilize the transition state. The highly positive and highly negative parts

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interact with the substrate to lower the energy of the transition state. Since the carbocation is unstable, anything that can
stabilize this even a little will speed up the reaction.
Sometimes in an SN1 reaction the solvent acts as the nucleophile. This is called a solvolysis reaction.The SN1 reaction of
allyl bromide in methanol is an example of what we would call methanolysis, while if water is the solvent the reaction
would be called hydrolysis:

The polarity and the ability of the solvent to stabilize the intermediate carbocation is very important as shown by the
relative rate data for the solvolysis (see table below). The dielectric constant of a solvent roughly provides a measure of the
solvent's polarity. A dielectric constant below 15 is usually considered non-polar. Basically, the dielectric constant can be
thought of as the solvent's ability to reduce the internal charge of the solvent. So for our purposes, the higher the dielectric
constant the more polar the substance and in the case of SN1 reactions, the faster the rate.

Below is the same reaction conducted in two different solvents and the relative rate that corresponds with it.

The figure below shows the mechanism of an SN1 reaction of an alkyl halide with water. Since water is also the solvent,
this is an example of a solvolysis reaction.

Examples of polar protic solvents are: acetic acid, isopropanol, ethanol, methanol, formic acid, water, etc.

Effects of Nucleophile
The strength of the nucleophile does not affect the reaction rate of SN1 because, as stated above, the nucleophile is not
involved in the rate-determining step. However, if you have more than one nucleophile competing to bond to the
carbocation, the strengths and concentrations of those nucleophiles affects the distribution of products that you will get.
For example, if you have (CH3)3CCl reacting in water and formic acid where the water and formic acid are competing
nucleophiles, you will get two different products: (CH3)3COH and (CH3)3COCOH. The relative yields of these products
depend on the concentrations and relative reactivities of the nucleophiles.

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Effects of Leaving Group
An SN1 reaction speeds up with a good leaving group. This is because the leaving
group is involved in the rate-determining step. A good leaving group wants to leave so
it breaks the C-Leaving Group bond faster. Once the bond breaks, the carbocation is
formed and the faster the carbocation is formed, the faster the nucleophile can come in
and the faster the reaction will be completed.
A good leaving group is a weak base because weak bases can hold the charge. They're
happy to leave with both electrons and in order for the leaving group to leave, it needs
to be able to accept electrons. Strong bases, on the other hand, donate electrons which is
why they can't be good leaving groups. As you go from left to right on the periodic
table, electron donating ability decreases and thus ability to be a good leaving group
increases. Halides are an example of a good leaving group whos leaving-group ability
increases as you go down the column.

The two reactions below is the same reaction done with two different leaving groups. One is significantly faster than the
other. This is because the better leaving group leaves faster and thus the reaction can proceed faster.

Figure below)

Predicting SN1 vs. SN2 mechanisms; competition between nucleophilic substitution and
elimination reactions
When considering whether a nucleophilic substitution is likely to occur via an SN1 or SN2 mechanism, we really need to
consider three factors:
1) The electrophile: when the leaving group is attached to a methyl group or a primary carbon, an SN2
mechanism is favored (here the electrophile is unhindered by surrounded groups, and any carbocation
intermediate would be high-energy and thus unlikely). When the leaving group is attached to a tertiary, allylic,
or benzylic carbon, a carbocation intermediate will be relatively stable and thus an SN1 mechanism is favored.

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 2) The nucleophile: powerful nucleophiles, especially those with negative charges, favor the SN2 mechanism.
Weaker nucleophiles such as water or alcohols favor the SN1 mechanism.
3) The solvent: Polar aprotic solvents favor the SN2 mechanism by enhancing the reactivity of the nucleophile.
Polar protic solvents favor the SN1 mechanism by stabilizing the carbocation intermediate. SN1 reactions are
frequently solvolysis reactions.
For example, the reaction below has a tertiary alkyl bromide as the electrophile, a weak nucleophile, and a polar protic
solvent (we’ll assume that methanol is the solvent). Thus we’d confidently predict an SN1 reaction mechanism. Because
substitution occurs at a chiral carbon, we can also predict that the reaction will proceed with racemization.

In the reaction below, on the other hand, the electrophile is a secondary alkyl bromide – with these, both SN1 and SN2
mechanisms are possible, depending on the nucleophile and the solvent. In this example, the nucleophile (a thiolate anion)
is strong, and a polar aprotic solvent is used – so the SN2 mechanism is heavily favored. The reaction is expected to
proceed with inversion of configuration.

Exercise 8.15: Determine whether each substitution reaction shown below is likely to proceed by an SN1 or SN2
mechanism.

Solution

 Exercise 7.4.1

1. Put the following leaving groups in order of decreasing leaving group ability

2. Which solvent would an SN1 reaction occur faster in? H2O or CH3CN
3. What kind of conditions disfavor SN1 reactions?
4. What are the products of the following reaction and does it proceed via SN1 or SN2?

5. How could you change the reactants in the problem 4 to favor the other substitution reaction?
6. Indicate the expected product and list why it occurs through SN1 instead of SN2?

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 Answers

2. An SN1 reaction would occur faster in H2O because it's polar protic and would stailize the carbocation and
CH3CN is polar aprotic.
3. Polar aprotic solvents, a weak leaving group and primary substrates disfavor SN1 reactions.

4.
Reaction proceeds via SN1 because a tertiary carbocation was formed, the solvent is polar protic and Br- is a good
leaving group.
5. You could change the solvent to something polar aprotic like CH3CN or DMSO and you could use a better base
for a nucleophile such as NH2- or OH-.

6.
This reaction occurs via SN1 because Cl- is a good leaving group and the solvent is polar protic. This is an example
of a solvolysis reaction because the nucleophile is also the solvent.

Exercises
Questions
Q11.5.1
Rank the following by increasing reactivity in an SN1 reaction.

Q11.5.2
3-bromo-1-pentene and 1-bromo-2-pentene undergo SN1 reaction at almost the same rate, but one is a secondary halide
while the other is a primary halide. Explain why this is.
Q11.5.3

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Label the following reactions as most likely occuring by an SN1 or SN2 mechanism. Suggest why.

Solutions

S11.5.1
Consider the stability of the intermediate, the carbocation.
A < D < B < C (most reactive)
S11.5.2
They have the same intermediates when you look at the resonance forms.

S11.5.3
A – SN1 *poor leaving group, protic solvent, secondary cation intermediate
B – SN2 *good leaving group, polar solvent, primary position.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Ashiv Sharma
Layne Morsch (University of Illinois Springfield)

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7.5: Effect of the Alkyl Group on the SN 1 Reaction: Carbocation Stability
Stability of carbocation intermediates
We know that the rate-limiting step of an SN1 reaction is the first step - formation of the this carbocation intermediate. The
rate of this step – and therefore, the rate of the overall substitution reaction – depends on the activation energy for the
process in which the bond between the carbon and the leaving group breaks and a carbocation forms. According to
Hammond’s postulate (section 6.2B), the more stable the carbocation intermediate is, the faster this first bond-breaking
step will occur. In other words, the likelihood of a nucleophilic substitution reaction proceeding by a dissociative (SN1)
mechanism depends to a large degree on the stability of the carbocation intermediate that forms.
The critical question now becomes, what stabilizes a carbocation?
So if it takes an electron withdrawing group to stabilize a negative charge, what will stabilize a positive charge? An
electron donating group!

A positively charged species such as a carbocation is very electron-poor, and thus anything which donates electron density
to the center of electron poverty will help to stabilize it. Conversely, a carbocation will be destabilized by an electron
withdrawing group.
Alkyl groups – methyl, ethyl, and the like – are weak electron donating groups, and thus stabilize nearby carbocations.
What this means is that, in general, more substituted carbocations are more stable: a tert-butyl carbocation, for example, is
more stable than an isopropyl carbocation. Primary carbocations are highly unstable and not often observed as reaction
intermediates; methyl carbocations are even less stable.

Alkyl groups are electron donating and carbocation-stabilizing because the electrons around the neighboring carbons are
drawn towards the nearby positive charge, thus slightly reducing the electron poverty of the positively-charged carbon.
It is not accurate to say, however, that carbocations with higher substitution are always more stable than those with less
substitution. Just as electron-donating groups can stabilize a carbocation, electron-withdrawing groups act to destabilize
carbocations. Carbonyl groups are electron-withdrawing by inductive effects, due to the polarity of the C=O double bond.
It is possible to demonstrate in the laboratory (see section 16.1D) that carbocation A below is more stable than carbocation
B, even though A is a primary carbocation and B is secondary.

The difference in stability can be explained by considering the electron-withdrawing inductive effect of the ester carbonyl.
Recall that inductive effects - whether electron-withdrawing or donating - are relayed through covalent bonds and that the
strength of the effect decreases rapidly as the number of intermediary bonds increases. In other words, the effect decreases
with distance. In species B the positive charge is closer to the carbonyl group, thus the destabilizing electron-withdrawing
effect is stronger than it is in species A.

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In the next chapter we will see how the carbocation-destabilizing effect of electron-withdrawing fluorine substituents can
be used in experiments designed to address the question of whether a biochemical nucleophilic substitution reaction is SN1
or SN2.
Stabilization of a carbocation can also occur through resonance effects, and as we have already discussed in the acid-base
chapter, resonance effects as a rule are more powerful than inductive effects. Consider the simple case of a benzylic
carbocation:

This carbocation is comparatively stable. In this case, electron donation is a resonance effect. Three additional resonance
structures can be drawn for this carbocation in which the positive charge is located on one of three aromatic carbons. The
positive charge is not isolated on the benzylic carbon, rather it is delocalized around the aromatic structure: this
delocalization of charge results in significant stabilization. As a result, benzylic and allylic carbocations (where the
positively charged carbon is conjugated to one or more non-aromatic double bonds) are significantly more stable than even
tertiary alkyl carbocations.

Because heteroatoms such as oxygen and nitrogen are more electronegative than carbon, you might expect that they would
by definition be electron withdrawing groups that destabilize carbocations. In fact, the opposite is often true: if the oxygen
or nitrogen atom is in the correct position, the overall effect is carbocation stabilization. This is due to the fact that
although these heteroatoms are electron withdrawing groups by induction, they are electron donating groups by resonance,
and it is this resonance effect which is more powerful. (We previously encountered this same idea when considering the
relative acidity and basicity of phenols and aromatic amines in section 7.4). Consider the two pairs of carbocation species
below:

In the more stable carbocations, the heteroatom acts as an electron donating group by resonance: in effect, the lone pair on
the heteroatom is available to delocalize the positive charge. In the less stable carbocations the positively-charged carbon is
more than one bond away from the heteroatom, and thus no resonance effects are possible. In fact, in these carbocation
species the heteroatoms actually destabilize the positive charge, because they are electron withdrawing by induction.
Finally, vinylic carbocations, in which the positive charge resides on a double-bonded carbon, are very unstable and thus
unlikely to form as intermediates in any reaction.

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Example 8.10

Exercise 8.10: In which of the structures below is the carbocation expected to be more stable? Explain.

Solution

For the most part, carbocations are very high-energy, transient intermediate species in organic reactions. However, there
are some unusual examples of very stable carbocations that take the form of organic salts. Crystal violet is the common
name for the chloride salt of the carbocation whose structure is shown below. Notice the structural possibilities for
extensive resonance delocalization of the positive charge, and the presence of three electron-donating amine groups.

Example 8.11

Draw a resonance structure of the crystal violet cation in which the positive charge is delocalized to one of the nitrogen atoms.
Solution

When considering the possibility that a nucleophilic substitution reaction proceeds via an SN1 pathway, it is critical to
evaluate the stability of the hypothetical carbocation intermediate. If this intermediate is not sufficiently stable, an SN1
mechanism must be considered unlikely, and the reaction probably proceeds by an SN2 mechanism. In the next chapter we
will see several examples of biologically important SN1 reactions in which the positively charged intermediate is stabilized
by inductive and resonance effects inherent in its own molecular structure.

Example 8.12

State which carbocation in each pair below is more stable, or if they are expected to be approximately equal. Explain your reasoning.

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Solution

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Now, back to transition states. Chemists are often very interested in trying to learn about what the transition state for a
given reaction looks like, but addressing this question requires an indirect approach because the transition state itself
cannot be observed. In order to gain some insight into what a particular transition state looks like, chemists often invoke
the Hammond postulate, which states that a transition state resembles the structure of the nearest stable species. For an
exergonic reaction, therefore, the transition state resembles the reactants more than it does the products.

If we consider a hypothetical exergonic reaction between compounds A and B to form AB, the distance between A and B
would be relatively large at the transition state, resembling the starting state where A and B are two isolated species. In the
hypothetical endergonic reaction between C and D to form CD, however, the bond formation process would be much
further along at the TS point, resembling the product.

The Hammond Postulate is a very simplistic idea, which relies on an assumption that potential energy surfaces are
parabolic. Although such an assumption is not rigorously true, it is fairly reliable and allows chemists to make energetic
arguments about transition states by employing arguments about the stability of a related species. Since the formation of a
reactive intermediate is very reliably endergonic, arguments about the stability of reactive intermediates can serve as
proxy arguments about transition state stability.

The Hammond Postulate and the SN1 Reaction

the Hammond postulate suggests that the activation energy of the rate-determining first step will be inversely proportional
to the stability of the carbocation intermediate. The stability of carbocations was discussed earlier, and a qualitative
relationship is given below:

Carbocati CH3(+) < CH3CH2( < (CH3)2C ≈ CH2=CH < C6H5CH2 ≈ (CH3)3C(

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on +) H(+) -CH2(+) (+) +)

Stability

Consequently, we expect that 3º-alkyl halides will be more reactive than their 2º and 1º-counterparts in reactions that
follow an SN1 mechanism. This is opposite to the reactivity order observed for the SN2 mechanism. Allylic and benzylic
halides are exceptionally reactive by either mechanism.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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7.6: Unimolecular Elimination: E1
Unimolecular Elimination (E1) is a reaction in which the removal of an HX substituent results in the formation of a double
bond. It is similar to a unimolecular nucleophilic substitution reaction (SN1) in various ways. One being the formation of a
carbocation intermediate. Also, the only rate determining (slow) step is the dissociation of the leaving group to form a
carbocation, hence the name unimolecular. Thus, since these two reactions behave similarly, they compete against each
other. Many times, both these reactions will occur simultaneously to form different products from a single reaction.
However, one can be favored over another through thermodynamic control. Although Elimination entails two types of
reactions, E1 and E2, we will focus mainly on E1 reactions with some reference to E2.

General Reaction
An E1 reaction involves the deprotonation of a hydrogen nearby (usually one carbon away, or the beta position) the
carbocation resulting in the formation of an alkene product. In order to accomplish this, a Lewis base is required. For a
simplified model, we’ll take B to be a Lewis base, and LG to be a halogen leaving group.

As can be seen above, the preliminary step is the leaving group (LG) leaving on its own. Because it takes the electrons in
the bond along with it, the carbon that was attached to it loses its electron, making it a carbocation. Once it becomes a
carbocation, a Lewis Base (B ) deprotonates the intermediate carbocation at the beta position, which then donates its
−

electrons to the neighboring C-C bond, forming a double bond. Unlike E2 reactions, which require the proton to be anti to
the leaving group, E1 reactions only require a neighboring hydrogen. This is due to the fact that the leaving group has
already left the molecule. The final product is an alkene along with the HB byproduct.

Reactivity
Due to the fact that E1 reactions create a carbocation intermediate, rules present in S
N 1 reactions still apply.

As expected, tertiary carbocations are favored over secondary, primary and methyl’s. This is due to the phenomena of
hyperconjugation, which essentially allows a nearby C-C or C-H bond to interact with the p orbital of the carbon to bring
the electrons down to a lower energy state. Thus, this has a stabilizing effect on the molecule as a whole. In general,
primary and methyl carbocations do not proceed through the E1 pathway for this reason, unless there is a means of
carbocation rearrangement to move the positive charge to a nearby carbon. Secondary and Tertiary carbons form more
stable carbocations, thus this formation occurs quite rapidly.
Secondary carbocations can be subject to the E2 reaction pathway, but this generally occurs in the presence of a good /
strong base. Adding a weak base to the reaction disfavors E2, essentially pushing towards the E1 pathway. In many
instances, solvolysis occurs rather than using a base to deprotonate. This means heat is added to the solution, and the
solvent itself deprotonates a hydrogen. The medium can effect the pathway of the reaction as well. Polar protic solvents
may be used to hinder nucleophiles, thus disfavoring E2 / Sn2 from occurring.

Acid catalyzed dehydration of secondary / tertiary alcohols

We’ll take a look at a mechanism involving solvolysis during an E1 reaction of Propanol in Sulfuric Acid.

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 Step 1: The OH group on the pentanol is hydrated by H2SO4. This allows the OH to become an H2O, which is a better
leaving group.
Step 2: Once the OH has been hydrated, the H2O molecule leaves, taking its electrons with it. This creates a
carbocation intermediate on the attached carbon.
Step 3: Another H2O molecule comes in to deprotonate the beta carbon, which then donates its electrons to the
neighboring C-C bond. The carbons are rehybridized from sp3 to sp2, and thus a pi bond is formed between them.

Mechanism for Alkyl Halides

This mechanism is a common application of E1 reactions in the synthesis of an alkene.

Once again, we see the basic 2 steps of the E1 mechanism.

1. The leaving group leaves along with its electrons to form a carbocation intermediate.
2. A base deprotonates a beta carbon to form a pi bond.
In this case we see a mixture of products rather than one discrete one. This is the case because the carbocation has two
nearby carbons that are capable of being deprotonated, but that only one forms a major product (more stable).

How are Regiochemistry & Stereochemistry involved?

In terms of regiochemistry, Zaitsev's rule states that although more than one product can be formed during alkene
synthesis, the more substituted alkene is the major product. This infers that the hydrogen on the most substituted carbon is
the most probable to be deprotonated, thus allowing for the most substituted alkene to be formed.
Unlike E2 reactions, E1 is not stereospecific. Thus, a hydrogen is not required to be anti-periplanar to the leaving group.

In this mechanism, we can see two possible pathways for the reaction. One in which the methyl on the right is
deprotonated, and another in which the CH2 on the left is deprotonated. Either one leads to a plausible resultant product,
however, only one forms a major product. As stated by Zaitsev's rule, deprotonation of the most substituted carbon results
in the most substituted alkene. This then becomes the most stable product due to hyperconjugation, and is also more
common than the minor product.

Contributors
Satish Balasubramanian
The E1 mechanism is nearly identical to the SN1 mechanism, differing only in the course of reaction taken by the
carbocation intermediate. As shown by the following equations, a carbocation bearing beta-hydrogens may function either

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as a Lewis acid (electrophile), as it does in the SN1 reaction, or a Brønsted acid, as in the E1 reaction.

Thus, hydrolysis of tert-butyl chloride in a mixed solvent of water and acetonitrile gives a mixture of 2-methyl-2-propanol
(60%) and 2-methylpropene (40%) at a rate independent of the water concentration. The alcohol is the product of an SN1
reaction and the alkene is the product of the E1 reaction. The characteristics of these two reaction mechanisms are similar,
as expected. They both show first order kinetics; neither is much influenced by a change in the nucleophile/base; and both
are relatively non-stereospecific.

(CH3)3C–Cl + H2O ——> [ (CH3)3C(+) ] + Cl(–) + H2O ——> (CH3)3C–OH + (CH3)2C=CH2 + HCl + H2O
To summarize, when carbocation intermediates are formed one can expect them to react further by one or more of the
following modes:
1. The cation may bond to a nucleophile to give a substitution product.
2. The cation may transfer a beta-proton to a base, giving an alkene product.
3. The cation may rearrange to a more stable carbocation, and then react by mode #1 or #2.
Since the SN1 and E1 reactions proceed via the same carbocation intermediate, the product ratios are difficult to control
and both substitution and elimination usually take place.
Having discussed the many factors that influence nucleophilic substitution and elimination reactions of alkyl halides, we
must now consider the practical problem of predicting the most likely outcome when a given alkyl halide is reacted with a
given nucleophile. As we noted earlier, several variables must be considered, the most important being the structure of
the alkyl group and the nature of the nucleophilic reactant. The nature of the halogen substituent on the alkyl halide is
usually not very significant if it is Cl, Br or I. In cases where both SN2 and E2 reactions compete, chlorides generally give
more elimination than do iodides, since the greater electronegativity of chlorine increases the acidity of beta-hydrogens.
Indeed, although alkyl fluorides are relatively unreactive, when reactions with basic nucleophiles are forced, elimination
occurs (note the high electronegativity of fluorine).

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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7.7: Bimolecular Elimination: E2
E2, bimolecular elimination, was proposed in the 1920s by British chemist Christopher Kelk Ingold. Unlike E1 reactions,
E2 reactions remove two subsituents with the addition of a strong base, resulting in an alkene.

Introduction
E2 reactions are typically seen with secondary and tertiary alkyl halides, but a hindered base is necessary with a primary
halide. The mechanism by which it occurs is a single step concerted reaction with one transition state. The rate at which
this mechanism occurs is second order kinetics, and depends on both the base and alkyl halide. A good leaving group is
required because it is involved in the rate determining step. The leaving groups must be coplanar in order to form a pi
bond; carbons go from sp3 to sp2 hybridization states.
To get a clearer picture of the interplay of these factors involved in a a reaction between a nucleophile/base and an alkyl
halide, consider the reaction of a 2º-alkyl halide, isopropyl bromide, with two different nucleophiles. In one pathway, a
methanethiolate nucleophile substitutes for bromine in an SN2 reaction. In the other (bottom) pathway, methoxide ion acts
as a base (rather than as a nucleophile) in an elimination reaction. As we will soon see, the mechanism of this reaction is
single-step, and is referred to as the E2 mechanism.

General Reaction
Below is a mechanistic diagram of an elimination reaction by the E2 pathway:
.

In this reaction Ba represents the base and Br representents a leaving group, typically a halogen. There is one transition
state that shows the concerted reaction for the base attracting the hydrogen and the halogen taking the electrons from the
bond. The product be both eclipse and staggered depending on the transition states. Eclipsed products have a synperiplanar
transition states, while staggered products have antiperiplanar transition states. Staggered conformation is usually the
major product because of its lower energy confirmation.
An E2 reaction has certain requirements to proceed:
A strong base is necessary especially necessary for primary alkyl halides. Secondary and tertirary primary halides will
procede with E2 in the precesence of a base (OH-, RO-, R2N-)
Both leaving groups should be on the same plane, this allows the double bond to form in the reaction. In the reaction
above you can see both leaving groups are in the plane of the carbons.
Follows Zaitsev's rule, the most substituted alkene is usually the major product.
Hoffman Rule, if a strically hindered base will result in the least substituted product.

E2 Reaction Coordinate

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The Leaving Group Effect in E2 Reactions
As Size Increases, The Ability of the Leaving Group to Leave Increases: Here we revisit the effect size has on basicity.
If we move down the periodic table, size increases. With an increase in size, basicity decreases, and the ability of the
leaving group to leave increases. The relationship among the following halogens, unlike the previous example, is true to
what we will see in upcoming reaction mechanisms.

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota,

Morris)
Stereochemistry of the E2 Reaction
E2 elimination reactions of certain isomeric cycloalkyl halides show unusual rates and regioselectivity that are not
explained by the principles thus far discussed. For example, trans-2-methyl-1-chlorocyclohexane reacts with alcoholic
KOH at a much slower rate than does its cis-isomer. Furthermore, the product from elimination of the trans-isomer is 3-
methylcyclohexene (not predicted by the Zaitsev rule), whereas the cis-isomer gives the predicted 1-methylcyclohexene as
the chief product. These differences are described by the first two equations in the following diagram.
Unlike open chain structures, cyclic compounds generally restrict the spatial orientation of ring substituents to relatively
few arrangements. Consequently, reactions conducted on such substrates often provide us with information about the
preferred orientation of reactant species in the transition state. Stereoisomers are particularly suitable in this respect, so the
results shown here contain important information about the E2 transition state.

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The most sensible interpretation of the elimination reactions of 2- and 4-substituted halocyclohexanes is that this reaction
prefers an anti orientation of the halogen and the beta-hydrogen which is attacked by the base. These anti orientations are
colored in red in the above equations. The compounds used here all have six-membered rings, so the anti orientation of
groups requires that they assume a diaxial conformation. The observed differences in rate are the result of a steric
preference for equatorial orientation of large substituents, which reduces the effective concentration of conformers having
an axial halogen. In the case of the 1-bromo-4-tert-butylcyclohexane isomers, the tert-butyl group is so large that it will
always assume an equatorial orientation, leaving the bromine to be axial in the cis-isomer and equatorial in the trans.
Because of symmetry, the two axial beta-hydrogens in the cis-isomer react equally with base, resulting in rapid elimination
to the same alkene (actually a racemic mixture). This reflects the fixed anti orientation of these hydrogens to the chlorine
atom. To assume a conformation having an axial bromine the trans-isomer must tolerate serious crowding distortions. Such
conformers are therefore present in extremely low concentration, and the rate of elimination is very slow. Indeed,
substitution by hydroxide anion predominates.
A similar analysis of the 1-chloro-2-methylcyclohexane isomers explains both the rate and
regioselectivity differences. Both the chlorine and methyl groups may assume an equatorial orientation in
a chair conformation of the trans-isomer, as shown in the top equation. The axial chlorine needed for the
E2 elimination is present only in the less stable alternative chair conformer, but this structure has only one
axial beta-hydrogen (colored red), and the resulting elimination gives 3-methylcyclohexene. In the cis-
isomer the smaller chlorine atom assumes an axial position in the more stable chair conformation, and
here there are two axial beta hydrogens. The more stable 1-methylcyclohexene is therefore the predominant product, and
the overall rate of elimination is relatively fast.
An orbital drawing of the anti-transition state is shown on the right. Note that the base attacks the alkyl halide from the
side opposite the halogen, just as in the SN2 mechanism. In this drawing the α and β carbon atoms are undergoing a
rehybridization from sp3 to sp2 and the developing π-bond is drawn as dashed light blue lines. The symbol R represents an
alkyl group or hydrogen. Since both the base and the alkyl halide are present in this transition state, the reaction is
bimolecular and should exhibit second order kinetics. We should note in passing that a syn-transition state would also
provide good orbital overlap for elimination, and in some cases where an anti-orientation is prohibited by structural
constraints syn-elimination has been observed.
Instead, in an E2 reaction, stereochemistry of the double bond -- that is, whether the E or Z isomer results -- is dictated by
the stereochemistry of the starting material, if it is diastereomeric. In other words, if the carbon with the hydrogen and the
carbon with the halogen are both chiral, then one diastereomer will lead to one product, and the other diastereomer will
lead to the other product.
The following reactions of potassium ethoxide with dibromostilbene (1,2-dibromo-1,2-diphenylethane) both occurred via
an E2 mechanism. Two different diastereomers were used. Two different stereoisomers (E vs. Z) resulted.

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Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Steven Farmer (Sonoma State University)

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7.8: Keys to Success: Substitutin Versus Elimination-Structure Determines
Function
Having discussed the many factors that influence nucleophilic substitution and elimination reactions of alkyl halides, we must
now consider the practical problem of predicting the most likely outcome when a given alkyl halide is reacted with a given
nucleophile. As we noted earlier, several variables must be considered, the most important being the structure of the alkyl
group and the nature of the nucleophilic reactant.In general, in order for an SN1 or E1 reaction to occur, the relevant
carbocation intermediate must be relatively stable. Strong nucleophile favor substitution, and strong bases, especially strong
hindered bases (such as tert-butoxide) favor elimination.
The nature of the halogen substituent on the alkyl halide is usually not very significant if it is Cl, Br or I. In cases where both
SN2 and E2 reactions compete, chlorides generally give more elimination than do iodides, since the greater electronegativity
of chlorine increases the acidity of beta-hydrogens. Indeed, although alkyl fluorides are relatively unreactive, when reactions
with basic nucleophiles are forced, elimination occurs (note the high electronegativity of fluorine).
The following table summarizes the expected outcome of alkyl halide reactions with nucleophiles. It is assumed that the alkyl
halides have one or more beta-hydrogens, making elimination possible; and that low dielectric solvents (e.g. acetone, ethanol,
tetrahydrofuran & ethyl acetate) are used. When a high dielectric solvent would significantly influence the reaction this is
noted in red. Note that halogens bonded to sp2 or sp hybridized carbon atoms do not normally undergo substitution or
elimination reactions with nucleophilic reagents.

Nucleophile Anionic Nucleophiles

Anionic Nucleophiles Neutral Nucleophiles
( Weak Bases: I–, Br–, SCN–, N3–,
( Strong Bases: HO–, RO– ) ( H2O, ROH, RSH, R3N )
CH3CO2– , RS–, CN– etc. )
Alkyl Group pKa's > 15 pKa's ranging from -2 to 11
pKa's from -9 to 10 (left to right)
Rapid SN2 substitution. E2 elimination
Rapid SN2 substitution. The rate may be may also occur. e.g.
Primary reduced by substitution of β-carbons, as SN2 substitution. (N ≈ S >>O)
RCH2– in the case of neopentyl. ClCH2CH2Cl + KOH ——>
CH2=CHCl
SN2 substitution and / or E2 elimination
(depending on the basicity of the SN2 substitution. (N ≈ S >>O)
nucleophile). Bases weaker than acetate In high dielectric ionizing solvents, such as
Secondary (pKa = 4.8) give less elimination. The E2 elimination will dominate. water, dimethyl sulfoxide & acetonitrile,
R2CH– rate of substitution may be reduced by SN1 and E1 products may be formed
branching at the β-carbons, and this will slowly.
increase elimination.
E2 elimination will dominate with most
nucleophiles (even if they are weak
E2 elimination will dominate. No SN2 E2 elimination with nitrogen nucleophiles
bases). No SN2 substitution due to steric
substitution will occur. In high (they are bases). No SN2 substitution. In
Tertiary hindrance. In high dielectric ionizing
dielectric ionizing solvents SN1 and E1 high dielectric ionizing solvents SN1 and
R3C– solvents, such as water, dimethyl
products may be formed. E1 products may be formed.
sulfoxide & acetonitrile, SN1 and E1
products may be expected.
Nitrogen and sulfur nucleophiles will give
Rapid SN2 substitution for 1º and 2º-
Rapid SN2 substitution for 1º halides. SN2 substitution in the case of 1º and 2º-
halides. For 3º-halides a very slow SN2
E2 elimination will compete with halides. 3º-halides will probably give E2
substitution or, if the nucleophile is
substitution in 2º-halides, and dominate elimination with nitrogen nucleophiles
Allyl moderately basic, E2 elimination. In
in the case of 3º-halides. In high (they are bases). In high dielectric ionizing
H2C=CHCH2– high dielectric ionizing solvents, such as
dielectric ionizing solvents SN1 and E1 solvents SN1 and E1 products may be
water, dimethyl sulfoxide & acetonitrile,
products may be formed. formed. Water hydrolysis will be favorable
SN1 and E1 products may be observed.
for 2º & 3º-halides.
Rapid SN2 substitution for 1º and 2º- Rapid SN2 substitution for 1º halides Nitrogen and sulfur nucleophiles will give
Benzyl halides. For 3º-halides a very slow SN2 (note there are no β hydrogens). E2 SN2 substitution in the case of 1º and 2º-
C6H5CH2– substitution or, if the nucleophile is elimination will compete with halides. 3º-halides will probably give E2
moderately basic, E2 elimination. In substitution in 2º-halides, and dominate elimination with nitrogen nucleophiles
high dielectric ionizing solvents, such as in the case of 3º-halides. In high (they are bases). In high dielectric ionizing

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 water, dimethyl sulfoxide & acetonitrile, dielectric ionizing solvents SN1 and E1 solvents SN1 and E1 products may be
SN1 and E1 products may be observed. products may be formed. formed. Water hydrolysis will be favorable
for 2º & 3º-halides.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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7.9:
☰ Summary of Reactivity of Haloalkanes
Having discussed the many factors that influence nucleophilic substitution and elimination reactions of alkyl halides, we must
now consider the practical problem of predicting the most likely outcome when a given alkyl halide is reacted with a given
nucleophile. As we noted earlier, several variables must be considered, the most important being the structure of the alkyl
group and the nature of the nucleophilic reactant.In general, in order for an SN1 or E1 reaction to occur, the relevant
carbocation intermediate must be relatively stable. Strong nucleophile favor substitution, and strong bases, especially strong
hindered bases (such as tert-butoxide) favor elimination.
The nature of the halogen substituent on the alkyl halide is usually not very significant if it is Cl, Br or I. In cases where both
SN2 and E2 reactions compete, chlorides generally give more elimination than do iodides, since the greater electronegativity
of chlorine increases the acidity of beta-hydrogens. Indeed, although alkyl fluorides are relatively unreactive, when reactions
with basic nucleophiles are forced, elimination occurs (note the high electronegativity of fluorine).
The following table summarizes the expected outcome of alkyl halide reactions with nucleophiles. It is assumed that the alkyl
halides have one or more beta-hydrogens, making elimination possible; and that low dielectric solvents (e.g. acetone, ethanol,
tetrahydrofuran & ethyl acetate) are used. When a high dielectric solvent would significantly influence the reaction this is
noted in red. Note that halogens bonded to sp2 or sp hybridized carbon atoms do not normally undergo substitution or
elimination reactions with nucleophilic reagents.

Nucleophile Anionic Nucleophiles

Anionic Nucleophiles Neutral Nucleophiles
( Weak Bases: I–, Br–, SCN–, N3–,
( Strong Bases: HO–, RO– ) ( H2O, ROH, RSH, R3N )
CH3CO2– , RS–, CN– etc. )
Alkyl Group pKa's > 15 pKa's ranging from -2 to 11
pKa's from -9 to 10 (left to right)
Rapid SN2 substitution. E2 elimination
Rapid SN2 substitution. The rate may be may also occur. e.g.
Primary reduced by substitution of β-carbons, as SN2 substitution. (N ≈ S >>O)
RCH2– in the case of neopentyl. ClCH2CH2Cl + KOH ——>
CH2=CHCl
SN2 substitution and / or E2 elimination
(depending on the basicity of the SN2 substitution. (N ≈ S >>O)
nucleophile). Bases weaker than acetate In high dielectric ionizing solvents, such as
Secondary (pKa = 4.8) give less elimination. The E2 elimination will dominate. water, dimethyl sulfoxide & acetonitrile,
R2CH– rate of substitution may be reduced by SN1 and E1 products may be formed
branching at the β-carbons, and this will slowly.
increase elimination.
E2 elimination will dominate with most
nucleophiles (even if they are weak
E2 elimination will dominate. No SN2 E2 elimination with nitrogen nucleophiles
bases). No SN2 substitution due to steric
substitution will occur. In high (they are bases). No SN2 substitution. In
Tertiary hindrance. In high dielectric ionizing
dielectric ionizing solvents SN1 and E1 high dielectric ionizing solvents SN1 and
R3C– solvents, such as water, dimethyl
products may be formed. E1 products may be formed.
sulfoxide & acetonitrile, SN1 and E1
products may be expected.
Nitrogen and sulfur nucleophiles will give
Rapid SN2 substitution for 1º and 2º-
Rapid SN2 substitution for 1º halides. SN2 substitution in the case of 1º and 2º-
halides. For 3º-halides a very slow SN2
E2 elimination will compete with halides. 3º-halides will probably give E2
substitution or, if the nucleophile is
substitution in 2º-halides, and dominate elimination with nitrogen nucleophiles
Allyl moderately basic, E2 elimination. In
in the case of 3º-halides. In high (they are bases). In high dielectric ionizing
H2C=CHCH2– high dielectric ionizing solvents, such as
dielectric ionizing solvents SN1 and E1 solvents SN1 and E1 products may be
water, dimethyl sulfoxide & acetonitrile,
products may be formed. formed. Water hydrolysis will be favorable
SN1 and E1 products may be observed.
for 2º & 3º-halides.
Rapid SN2 substitution for 1º and 2º- Rapid SN2 substitution for 1º halides Nitrogen and sulfur nucleophiles will give
Benzyl halides. For 3º-halides a very slow SN2 (note there are no β hydrogens). E2 SN2 substitution in the case of 1º and 2º-
C6H5CH2– substitution or, if the nucleophile is elimination will compete with halides. 3º-halides will probably give E2
moderately basic, E2 elimination. In substitution in 2º-halides, and dominate elimination with nitrogen nucleophiles
high dielectric ionizing solvents, such as in the case of 3º-halides. In high (they are bases). In high dielectric ionizing
water, dimethyl sulfoxide & acetonitrile, dielectric ionizing solvents SN1 and E1 solvents SN1 and E1 products may be
SN1 and E1 products may be observed. products may be formed.

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 formed. Water hydrolysis will be favorable
☰ for 2º & 3º-halides.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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7.E: Further Reactions of Haloalkanes: Unimolecular Substitution (Exercises)
These are homework exercises to accompany Chapter 7 of Vollhardt and Schore's "Organic Chemistry" Textmap.

7.1: Solvolysis of Tertiary and Secondary Haloalkanes

7.2: Unimolecular Nucleophilic Substitution

7.3: Stereochemical Consequences of S N 1 Reactions

7.4: Effects of Solvent, Leaving Group, and Nucleophile on Unimolecular Substitution

7.5: Effect of the Alkyl Group on the S N 1 Reaction: Carbocation Stability

7.6: Unimolecular Elimination: E1

7.7: Bimolecular Elimination: E2

7.8: Keys to Success: Substitutin Versus Elimination-Structure Determines Function

7.9: Summary of Reactivity of Haloalkanes

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CHAPTER OVERVIEW
8: HYDROXY OF FUNCTIONAL GROUP: ALCOHOLS: PROPERTIES,
PREPARATION, AND STRATEGY OF SYNTHESIS
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

8.1: NAMING THE ALCOHOLS

8.2: STRUCTURAL AND PHYSICAL PROPERTIES OF ALCOHOLS
8.3: ALCOHOLS AS ACIDS AND BASES
8.4: INDUSTRIAL SOURCES OF ALCOHOLS: CARBON MONOXIDE AND ETHENE
8.5: SYNTHESIS OF ALCOHOLS BY NUCLEOPHILIC SUBSTITUTION
8.6: SYNTHESIS OF ALCOHOLS: OXIDATION-REDUCTION RELATION BETWEEN ALCOHOLS AND CARBONYL
COMPOUNDS
8.7: ORGANOMETALLIC REAGENTS: SOURCES OF NUCLEOPHILIC CARBON FOR ALCOHOL SYNTHESIS
8.8: ORGANOMETALLIC REAGENTS IN THE SYNTHESIS OF ALCOHOLS
8.9: KEYS TO SUCCESS: AN INTRODUCTION TO SYNTHETIC STRATEGY

1 12/5/2021
8.1: Naming the Alcohols
Objectives
After completing this section, you should be able to
1. identify an alcohol as being primary, secondary or tertiary, given its structure, its IUPAC name or its trivial name.
2. write the IUPAC name of an alcohol or phenol given its Kekulé, condensed or shorthand structure.
3. draw the structure of an alcohol or phenol given its IUPAC name.
4. identify a number of commonly occurring alcohols (e.g., benzyl alcohol, tert‑butyl alcohol) by their trivial names.

Study Notes
The following are common names of some alcohols (with IUPAC name).

Primary alcohols
In a primary (1°) alcohol, the carbon which carries the -OH group is only attached to one alkyl group. Some examples of
primary alcohols include:

Notice that it doesn't matter how complicated the attached alkyl group is. In each case there is only one linkage to an alkyl
group from the CH2 group holding the -OH group. There is an exception to this. Methanol, CH3OH, is counted as a
primary alcohol even though there are no alkyl groups attached to the carbon with the -OH group on it.

Secondary alcohols
In a secondary (2°) alcohol, the carbon with the -OH group attached is joined directly to two alkyl groups, which may be
the same or different. Examples:

Tertiary alcohols
In a tertiary (3°) alcohol, the carbon atom holding the -OH group is attached directly to three alkyl groups, which may be
any combination of same or different. Examples:

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Naming Alcohols Edit section

1. Find the longest chain containing the hydroxy group (OH). If there is a chain with more carbons than the one
containing the OH group it will be named as a subsitutent.
2. Place the OH on the lowest possible number for the chain. With the exception of carbonyl groups such as ketones and
aldehydes, the alcohol or hydroxy groups have first priority for naming.
3. When naming a cyclic structure, the -OH is assumed to be on the first carbon unless the carbonyl group is present, in
which case the later will get priority at the first carbon.
4. When multiple -OH groups are on the cyclic structure, number the carbons on which the -OH groups reside.
5. Remove the final e from the parent alkane chain and add -ol. When multiple alcohols are present use di, tri, et.c before
the ol, after the parent name. ex. 2,3-hexandiol. If a carbonyl group is present, the -OH group is named with the prefix
"hydroxy," with the carbonyl group attached to the parent chain name so that it ends with -al or -one.
Examples

Ethane: CH3CH3 ----->Ethanol: (the alcohol found in beer, wine and other consumed sprits)

Secondary alcohol: 2-propanol

Other functional groups on an alcohol: 3-bromo-2-pentanol

Cyclic alcohol (two -OH groups): cyclohexan-1,4-diol

Other functional group on the cyclic structure: 3-hexeneol (the alkene is in bold and indicated by numbering
the carbon closest to the alcohol)

A complex alcohol: 4-ethyl-3hexanol (the parent chain is in red and the substituent is in blue)
In the IUPAC system of nomenclature, functional groups are normally designated in one of two ways. The presence of the
function may be indicated by a characteristic suffix and a location number. This is common for the carbon-carbon double
and triple bonds which have the respective suffixes -ene and -yne. Halogens, on the other hand, do not have a suffix and
are named as substituents, for example: (CH3)2C=CHCHClCH3 is 4-chloro-2-methyl-2-pentene.
Alcohols are usually named by the first procedure and are designated by an -ol suffix, as in ethanol, CH3CH2OH (note that
a locator number is unnecessary on a two-carbon chain). On longer chains the location of the hydroxyl group determines
chain numbering. For example: (CH3)2C=CHCH(OH)CH3 is 4-methyl-3-penten-2-ol. Other examples of IUPAC
nomenclature are shown below, together with the common names often used for some of the simpler compounds. For the
mono-functional alcohols, this common system consists of naming the alkyl group followed by the word alcohol.
Alcohols may also be classified as primary, 1º, secondary, 2º, and tertiary, 3º, in the same manner as alkyl halides. This
terminology refers to alkyl substitution of the carbon atom bearing the hydroxyl group (colored blue in the illustration).

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Many functional groups have a characteristic suffix designator, and only one such suffix (other than "-ene" and "-yne")
may be used in a name. When the hydroxyl functional group is present together with a function of higher nomenclature
priority, it must be cited and located by the prefix hydroxy and an appropriate number. For example, lactic acid has the
IUPAC name 2-hydroxypropanoic acid.

Naming phenols
Phenols are named using the rules for aromatic compounds discussed in seciton 15.1 Note! that -phenol is used rather than
-benzene.

Exercises
Questions
Q17.1.1
Give IUPAC names for the following structures.

(a) (b) Indicate stereochemistry (c) (d)

Q17.1.2
Name the following structures.

Q17.1.3

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Draw and name all the alcohol isomers of C3H9O

Q17.1.4
Oleic acid, a commonly occurring fatty acid in vegetable oils, has the following structure. Name the compound, making
sure to give the correct alkene geometry.

Q17.1.5
Creosols are naturally occurring compounds used building blocks for many molecules, they occur as three different
isomers. Name each of the following isomers.

Solutions
S17.1.1

(a) (b) (c) (d)

S17.1.2

S17.1.3

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 or, 1-propanol and 2-propanol
S17.1.4
(9Z)-Octadec-9-enoic acid

S17.1.5

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Jim Clark (Chemguide.co.uk)

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8.2: Structural and Physical Properties of Alcohols
Objectives
After completing this section, you should be able to
1. explain why the boiling points of alcohols and phenols are much higher than those of alkanes, ethers, etc., of
similar molecular mass.
2. discuss the factors that are believed to determine the acidity of alcohols and phenols.
3. list a given series of alcohols or phenols in order of increasing or decreasing acidity.
4. explain the difference in acidity between two given alcohols or phenols.
5. explain why phenols are more acidic than alcohols.
6. explain, in terms of inductive and resonance effects, why a given substituted phenol is more or less acidic than
phenol itself.
7. write equations for the reactions of given alcohols and phenols with strong bases, such as sodium hydride and
sodium amide.

Key Terms
Make certain that you can define, and use in context, the key terms below.
acid ionization constant (Ka)
alkoxide ion (RO−)
phenoxide ion (ArO−)

Study Notes

You may wish to review the concept of hydrogen bonding, which should have been discussed in your first‑year general
chemistry course.

Boiling Points
The chart below shows the boiling points of the following simple primary alcohols with up to 4 carbon atoms:

These boiling points are compared with those of the equivalent alkanes (methane to butane) with the same
number of carbon atoms.

Notice that:
The boiling point of an alcohol is always significantly higher than that of the analogous alkane.
The boiling points of the alcohols increase as the number of carbon atoms increases.
The patterns in boiling point reflect the patterns in intermolecular attractions.

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Hydrogen bonding
Hydrogen bonding occurs between molecules in which a hydrogen atom is attached to a strongly
electronegative element: fluorine, oxygen or nitrogen. In the case of alcohols, hydrogen bonds occur between
the partially-positive hydrogen atoms and lone pairs on oxygen atoms of other molecules.

The hydrogen atoms are slightly positive because the bonding electrons are pulled toward the very
electronegative oxygen atoms. In alkanes, the only intermolecular forces are van der Waals dispersion forces.
Hydrogen bonds are much stronger than these, and therefore it takes more energy to separate alcohol
molecules than it does to separate alkane molecules. This the main reason for higher boiling points in alcohols.

The effect of van der Waals forces

Boiling points of the alcohols: Hydrogen bonding is not the only intermolecular force alcohols experience.
There are also van der Waals dispersion forces and dipole-dipole interactions. The hydrogen bonding and
dipole-dipole interactions are much the same for all alcohols, but dispersion forces increase as the alcohols
get bigger. These attractions get stronger as the molecules get longer and have more electrons. This
increases the sizes of the temporary dipoles formed. This is why the boiling points increase as the number
of carbon atoms in the chains increases. It takes more energy to overcome the dispersion forces, and thus
the boiling points rise.
Comparison between alkanes and alcohols: Even without any hydrogen bonding or dipole-dipole
interactions, the boiling point of the alcohol would be higher than the corresponding alkane with the same
number of carbon atoms.
Compare ethane and ethanol:

Ethanol is a longer molecule, and the oxygen atom brings with it an extra 8 electrons. Both of these increase
the size of the van der Waals dispersion forces, and subsequently the boiling point. A more accurate
measurement of the effect of the hydrogen bonding on boiling point would be a comparison of ethanol with
propane rather than ethane. The lengths of the two molecules are more similar, and the number of electrons is
exactly the same.

Solubility of alcohols in water

Small alcohols are completely soluble in water; mixing the two in any proportion generates a single solution.
However, solubility decreases as the length of the hydrocarbon chain in the alcohol increases. At four carbon
atoms and beyond, the decrease in solubility is noticeable; a two-layered substance may appear in a test tube
when the two are mixed.
Consider ethanol as a typical small alcohol. In both pure water and pure ethanol the main intermolecular
attractions are hydrogen bonds.

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In order to mix the two, the hydrogen bonds between water molecules and the hydrogen bonds between ethanol molecules
must be broken. Energy is required for both of these processes. However, when the molecules are mixed, new hydrogen
bonds are formed between water molecules and ethanol molecules.

The energy released when these new hydrogen bonds form approximately compensates for the energy needed
to break the original interactions. In addition, there is an increase in the disorder of the system, an increase in
entropy. This is another factor in deciding whether chemical processes occur. Consider a hypothetical situation
involving 5-carbon alcohol molecules.

The hydrocarbon chains are forced between water molecules, breaking hydrogen bonds between those water
molecules. The -OH ends of the alcohol molecules can form new hydrogen bonds with water molecules, but the
hydrocarbon "tail" does not form hydrogen bonds. This means that many of the original hydrogen bonds being
broken are never replaced by new ones.
In place of those original hydrogen bonds are merely van der Waals dispersion forces between the water and
the hydrocarbon "tails." These attractions are much weaker, and unable to furnish enough energy to
compensate for the broken hydrogen bonds. Even allowing for the increase in disorder, the process becomes
less feasible. As the length of the alcohol increases, this situation becomes more pronounced, and thus the
solubility decreases.

Acid/Base properties of alcohols

Several important chemical reactions of alcohols involving the O-H bond or oxygen-hydrogen bond only and leave the
carbon-oxygen bond intact. An important example is salt formation with acids and bases. Alcohols, like water, are both
weak bases and weak acids. The acid ionization constant (Ka) of ethanol is about 10~18, slightly less than that of water.
Ethanol can be converted to its conjugate base by the conjugate base of a weaker acid such as ammonia {Ka — 10~35), or
hydrogen (Ka ~ 10-38). It is convenient to employ sodium metal or sodium hydride, which react vigorously but
controllably with alcohols:

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The order of acidity of various liquid alcohols generally is water > primary > secondary > tertiary ROH. By this we mean
that the equilibrium position for the proton-transfer reaction (Equation 15-1) lies more on the side of ROH and OHe as R is
changed from primary to secondary to tertiary; therefore, tert-butyl alcohol is considered less acidic than ethanol:
− −
ROH + OH ⇌ RO + H OH (8.2.1)

However, in the gas phase the order of acidity is reversed, and the equilibrium position for Equation 15-1 lies increasingly
on the side of ROGas R is changed from primary to secondary to tertiary, terf-Butyl alcohol is therefore more acidic than
ethanol in the gas phase. This seeming contradiction appears more reasonable when one considers what effect solvation (or
the lack of it) has on equilibria expressed by Equation 15-1. In solution, the larger anions of alcohols, known as alkoxide
ions, probably are less well solvated than the smaller ions, because fewer solvent molecules can be accommodated around
the negatively charged oxygen in the larger ions:

Acidity of alcohols therefore decreases as the size of the conjugate base increases. However, “naked” gaseous ions are
more stable the larger the associated R groups, probably because the larger R groups can stabilize the charge on the oxygen
atom better than the smaller R groups. They do this by polarization of their bonding electrons, and the bigger the group,
the more polarizable it is. (Also see Section 11-8A, which deals with the somewhat similar situation encountered with
respect to the relative acidities of ethyne and water.)

Chemical Reactions of Alcohols involving the O-H bond of Compounds with Basic Properties
Alcohols are bases similar in strength to water and accept protons from strong acids. An example is the reaction of
methanol with hydrogen bromide to give methyloxonium bromide, which is analogous to the formation of hydroxonium
bromide with hydrogen bromide and water:

Acidity of Phenol
Compounds like alcohols and phenol which contain an -OH group attached to a hydrocarbon are very weak acids.
Alcohols are so weakly acidic that, for normal lab purposes, their acidity can be virtually ignored. However, phenol is
sufficiently acidic for it to have recognizably acidic properties - even if it is still a very weak acid. A hydrogen ion can
break away from the -OH group and transfer to a base. For example, in solution in water:

Phenol is a very weak acid and the position of equilibrium lies well to the left. Phenol can lose a hydrogen ion because the
phenoxide ion formed is stabilised to some extent. The negative charge on the oxygen atom is delocalised around the ring.
The more stable the ion is, the more likely it is to form. One of the lone pairs on the oxygen atom overlaps with the
delocalised electrons on the benzene ring.

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This overlap leads to a delocalization which extends from the ring out over the oxygen atom. As a result, the negative
charge is no longer entirely localized on the oxygen, but is spread out around the whole ion.

Spreading the charge around makes the ion more stable than it would be if all the charge remained on the oxygen.
However, oxygen is the most electronegative element in the ion and the delocalized electrons will be drawn towards it.
That means that there will still be a lot of charge around the oxygen which will tend to attract the hydrogen ion back again.
That is why phenol is only a very weak acid.
Why is phenol a much stronger acid than cyclohexanol? To answer this question we must evaluate the manner in which an
oxygen substituent interacts with the benzene ring. As noted in our earlier treatment of electrophilic aromatic substitution
reactions, an oxygen substituent enhances the reactivity of the ring and favors electrophile attack at ortho and para sites. It
was proposed that resonance delocalization of an oxygen non-bonded electron pair into the pi-electron system of the
aromatic ring was responsible for this substituent effect. A similar set of resonance structures for the phenolate anion
conjugate base appears below the phenol structures.
The resonance stabilization in these two cases is very different. An important principle of resonance is that charge
separation diminishes the importance of canonical contributors to the resonance hybrid and reduces the overall
stabilization. The contributing structures to the phenol hybrid all suffer charge separation, resulting in very modest
stabilization of this compound. On the other hand, the phenolate anion is already charged, and the canonical contributors
act to disperse the charge, resulting in a substantial stabilization of this species. The conjugate bases of simple alcohols are
not stabilized by charge delocalization, so the acidity of these compounds is similar to that of water. An energy diagram
showing the effect of resonance on cyclohexanol and phenol acidities is shown on the right. Since the resonance
stabilization of the phenolate conjugate base is much greater than the stabilization of phenol itself, the acidity of phenol
relative to cyclohexanol is increased. Supporting evidence that the phenolate negative charge is delocalized on the ortho
and para carbons of the benzene ring comes from the influence of electron-withdrawing substituents at those sites.

In this reaction, the hydrogen ion has been removed by the strongly basic hydroxide ion in the sodium hydroxide solution.
Acids react with the more reactive metals to give hydrogen gas. Phenol is no exception - the only difference is the slow
reaction because phenol is such a weak acid. Phenol is warmed in a dry tube until it is molten, and a small piece of sodium
added. There is some fizzing as hydrogen gas is given off. The mixture left in the tube will contain sodium phenoxide.

Acidity of Substituted Phenols

Substitution of the hydroxyl hydrogen atom is even more facile with phenols, which are roughly a million times more
acidic than equivalent alcohols. This phenolic acidity is further enhanced by electron-withdrawing substituents ortho and

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para to the hydroxyl group, as displayed in the following diagram. The alcohol cyclohexanol is shown for reference at the
top left. It is noteworthy that the influence of a nitro substituent is over ten times stronger in the para-location than it is
meta, despite the fact that the latter position is closer to the hydroxyl group. Furthermore additional nitro groups have an
additive influence if they are positioned in ortho or para locations. The trinitro compound shown at the lower right is a
very strong acid called picric acid.

Why is phenol a much stronger acid than cyclohexanol? To answer this question we must evaluate the manner in which an
oxygen substituent interacts with the benzene ring. As noted in our earlier treatment of electrophilic aromatic substitution
reactions, an oxygen substituent enhances the reactivity of the ring and favors electrophile attack at ortho and para sites. It
was proposed that resonance delocalization of an oxygen non-bonded electron pair into the pi-electron system of the
aromatic ring was responsible for this substituent effect. Formulas illustrating this electron delocalization will be displayed
when the "Resonance Structures" button beneath the previous diagram is clicked. A similar set of resonance structures for
the phenolate anion conjugate base appears below the phenol structures.

The resonance stabilization in these two cases is very different. An important principle of resonance is that charge
separation diminishes the importance of canonical contributors to the resonance hybrid and reduces the overall
stabilization. The contributing structures to the phenol hybrid all suffer charge separation, resulting in very modest
stabilization of this compound. On the other hand, the phenolate anion is already charged, and the canonical contributors

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act to disperse the charge, resulting in a substantial stabilization of this species. The conjugate bases of simple alcohols are
not stabilized by charge delocalization, so the acidity of these compounds is similar to that of water. An energy diagram
showing the effect of resonance on cyclohexanol and phenol acidities is shown on the right. Since the resonance
stabilization of the phenolate conjugate base is much greater than the stabilization of phenol itself, the acidity of phenol
relative to cyclohexanol is increased. Supporting evidence that the phenolate negative charge is delocalized on the ortho
and para carbons of the benzene ring comes from the influence of electron-withdrawing substituents at those sites.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Jim Clark (Chemguide.co.uk)
John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin,
Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions, "You are granted
permission for individual, educational, research and non-commercial reproduction, distribution, display and performance
of this work in any format."

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8.3: Alcohols as Acids and Bases
Alcohols are very weak Brønsted acids with pKa values generally in the range of 15 - 20. Because the hydroxyl proton is
the most electrophilic site, proton transfer is the most important reaction to consider with nucleophiles. There are small
differences in the acidities of aliphatic alcohols in aqueous solution, which are due to differences in structure and, more
importantly, solvation.

General Assessment of Acidities

When considering alcohols as organic reagents, pKas are often used because they reflect reactivity in aqueous solution. In
general, alcohols in aqueous solution are slightly less acidic than water. However, the differences among the pKas of the
alcohols are not large. This is not surprising because all alcohols are oxy-acids (OH), and the differences in acidities are
due to the effect of substituents in the 1-position removed from the acidic site. Moreover, the more highly substituted
alcohols vary only in the structure two positions removed from the acidic site. The marginal effects of additional
substituents at the carbon tow positions removed from the acidic site are even evident in the gas-phase enthalpies of
reaction for the reaction
− +
ROH → RO +H (1)

The pKas and gas-phase enthalpies of reaction for various alcohols, ROH, with various substituents (R) are shown in Table
1 below.
Table 1: pKas and gas-phase enthalpies of reaction
R Name pKa1 ΔHacid kJ/mo l
2

H water 14.0 1633.1

CH3 methanol 15.5 1597 ± 6

CH3CH2 ethanol 15.9 1587 ± 4

(CH3)2CH propan-2-ol (isopropyl alcohol) 16.5 1569 ± 4

(CH3)3C 2-methylpropan-2-ol (t-butanol) 17 1568 ± 4

C6H5 (phenyl) phenol 9.95 1462 ± 10

Interpretation of the Relative Acidities of Alcohols

There are many sites on the internet with explanations of the relative ordering of alcohol acidities in aqueous solution.
The general explanation is that the larger substituents are better electron donors, which destabilize the resulting alkoxide
anions. Because hydrogen is least donating of the substituents, water is the strongest acid. Unfortunately, although this
belief persists, it is incomplete because it does not account for the gas-phase results. The problem with the electron
donation explanation is that it suggests that the order of acidity is due solely to the intrinsic electronic effects of the
substituents. However, if that were the case, the electron donating effect should also be evident in the gas-phase data.
However, the relative acidities in the gas phase are opposite to those in aqueous solution. Consequently, any interpretation
of the acidities of alcohols must take the gas phase data into account.
The inversion of the acidities of alcohols between the gas phase and aqueous solution was pointed out by Brauman and
Blair in 1968.3 They proposed that the ordering of acidities of alcohols in solution is predominantly due to the
combination of a) polarizibility and b) solvation, and that the electron donating ability of the substituent does not play a
significant role.4

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Polarizibility almost completely accounts for the trend in gas-phase acidities. As the size of the substituent increases, the
acid becomes stronger due to the ability for the charge to be distributed over a larger volume, thereby reducing the charge
density and, consequently, the Coulombic repulsion. Therefore, in the gas-phase, t-butanol is the most acidic alcohol, more
acidic than isopropanol, followed by ethanol and methanol. In the gas phase, water is much less acidic than methanol,
which is consistent with the difference in polarizibility between a proton and a methyl group. As before, the fact that water
is less acidic than methanol in the gas phase is not consistent with the expected electronic donating capabilities of the two
substituents. Given the absence of a solvent, the gas-phase properties reflect the instrinsic effects on the acidities.
In solution, however, the ions can be stabilized by solvation, and this is what leads to the inversion of acidity ordering.
Brauman and Blair3 showed that smaller ions are better stabilized by solvation, which is consistent with the Born equation.
Therefore, methanol is more acidic than t-butanol because the smaller methoxide ion has a shorter radius of solvation,
leading to a larger solvation energy, which overcomes the stabilization that results from polarization of the charge. Because
the solvation energy of hydroxide is even larger than that of methoxide, water is more acidic than methanol.
Note: Phenol
Discussions of acidities of alcohols usually include phenol in which the enhanced acidity is generally attributed to
stabilization of the phenoxide ion by resonance delocalization. In this case, the gas-phase results agree with the solution
trend that phenol is a much stronger acid than the aliphatic alcohols, and the difference is certainly due to electronic
effects. However, this commonly encountered explanation is incomplete because it ignores the role that inductive
effects have on acidities of oxy-acids. However, it is true that the acidity of phenol is much more a result of resonance
stabilization than, for example, the acidities of carboxylic acids.

Practical Considerations
With pKa values in the 15.5 - 20.0 range, useful concentrations of alkoxides cannot be formed by proton transfer with
hydroxide:
− −
ROH + OH → RO + H2 O (2)

-2 -5
The equilibrium constant for the proton transfer reaction is on the order of 10 -10 . Phenoxide can be formed almost
completely by reaction with aqueous alkaline base because the value of the equilibrium constant is roughly 104. The
acidity of alcohols also indicates that it will react by proton transfer with any base more basic than hydroxide, which
includes most organic bases, such as acetylide ions, cyanide, and vinyl/phenyl/alkyl anions. Therefore, alcohols will
protonate most organic nucleophiles and effectively destroy most organometallic reagents, including Grignard or
organolithium reagents.

Formation of alkoxide ions

Alkoxide ions can be formed by deprotonating alcohols with an extremely strong base such as an amide ion, NH2-.
However, this method is rarely used. Alkoxides are more often formed by reaction of an alkali metal such as sodium with
the pure alcohol:
− +
2ROH + 2N a → 2RO + 2N a + H2 (3)

Conclusions
Relative acidities of all acids depend on many factors, including intrinsic electronic factors such as electronegativity,
inductive and resonance effects, and polarizibility, as well as extrinsic factors such as solvation. For aliphatic alcohols, the
most important effects are polarizibility and solvation, not electronic donation, as is generally assumed. In systems where
the intrinsic factors are large, their effects are manifested in the overall properties, regardless of the medium.

References
1. http://research.chem.psu.edu/brpgrou...ompilation.pdf with correction for pKa of water
2. http://webbook.nist.gov/chemistry/ accessing Reaction Thermochemistry Data for each compound
3. Brauman,J.I.; Blair,L.K. J. Am. Chem. Soc. 1968, 90, 6561.
4. Brauman,J.I.; Blair,L.K. J. Am. Chem. Soc. 1970, 92, 5986.

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8.4: Industrial Sources of Alcohols: Carbon Monoxide and Ethene
This page looks at the manufacture of alcohols by the direct hydration of alkenes, concentrating mainly on the hydration of ethene to make ethanol. It then compares that method with
making ethanol by fermentation.

Manufacturing alcohols from alkenes

Ethanol is manufactured by reacting ethene with steam. The catalyst used is solid silicon dioxide coated with phosphoric(V) acid. The reaction is reversible.

Only 5% of the ethene is converted into ethanol at each pass through the reactor. By removing the ethanol from the equilibrium mixture and recycling the ethene, it is possible to achieve an
overall 95% conversion. A flow scheme for the reaction looks like this:

The manufacture of other alcohols from alkenes

Some - but not all - other alcohols can be made by similar reactions. The catalyst used and the reaction conditions will vary from alcohol to alcohol. The reason that there is a problem with
some alcohols is well illustrated with trying to make an alcohol from propene, CH3CH=CH2. In principle, there are two different alcohols which might be formed:

You might expect to get either propan-1-ol or propan-2-ol depending on which way around the water adds to the double bond. In practice what you get is propan-2-ol. If you add a molecule
H-X across a carbon-carbon double bond, the hydrogen nearly always gets attached to the carbon with the most hydrogens on it already - in this case the CH2 rather than the CH. The effect
of this is that there are bound to be some alcohols which it is impossible to make by reacting alkenes with steam because the addition would be the wrong way around.

Making ethanol by fermentation

This method only applies to ethanol and you cannot make any other alcohol this way. The starting material for the process varies widely, but will normally be some form of starchy plant
material such as maize (US: corn), wheat, barley or potatoes. Starch is a complex carbohydrate, and other carbohydrates can also be used - for example, in the lab sucrose (sugar) is
normally used to produce ethanol. Industrially, this wouldn't make sense. It would be silly to refine sugar if all you were going to use it for was fermentation. There is no reason why you
should not start from the original sugar cane, though.
The first step is to break complex carbohydrates into simpler ones. For example, if you were starting from starch in grains like wheat or barley, the grain is heated with hot water to extract
the starch and then warmed with malt. Malt is germinated barley which contains enzymes which break the starch into a simpler carbohydrate called maltose, C H O . Maltose has the 12 22 11

same molecular formula as sucrose but contains two glucose units joined together, whereas sucrose contains one glucose and one fructose unit.
Yeast is then added and the mixture is kept warm (say 35°C) for perhaps several days until fermentation is complete. Air is kept out of the mixture to prevent oxidation of the ethanol
produced to ethanoic acid (vinegar). Enzymes in the yeast first convert carbohydrates like maltose or sucrose into even simpler ones like glucose and fructose, both C H O , and then 6 12 6

convert these in turn into ethanol and carbon dioxide. You can show these changes as simple chemical equations, but the biochemistry of the reactions is much, much more complicated than
this suggests.
C12 H22 O11 + H2 O ⟶ 2 C6 H12 O6 (8.4.1)

C6 H12 O6 ⟶ 2C H3 C H2 OH + 2C O2 (8.4.2)

Yeast is killed by ethanol concentrations in excess of about 15%, and that limits the purity of the ethanol that can be produced. The ethanol is separated from the mixture by fractional
distillation to give 96% pure ethanol. For theoretical reasons (minimum boiling point azeotrope), it is impossible to remove the last 4% of water by fractional distillation.
Table 1.1.1: A comparison of fermentation with the direct hydration of ethene
Fermentation Hydration of e

A batch process. Everything is put into a container and then left until fermentation is complete. That A continuous flow process. A stream of reactants is passed cont
Type of process
batch is then cleared out and a new reaction set up. This is inefficient. doing thin
Rate of reaction Very slow. Very rapi
Quality of product Produces very impure ethanol which needs further processing Produces much pur
Reaction conditions Uses gentle temperatures and atmospheric pressure. Uses high temperatures and pressures
Use of resources Uses renewable resources based on plant material. Uses finite resources ba

Contributors
Jim Clark (Chemguide.co.uk)

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8.5: Synthesis of Alcohols by Nucleophilic Substitution
☰
Synthesis of Alcohols by Substitution of Alkyl Halides
Synthesis of alcohols from alkyl halides
Formation of alcohols from alkenes

Additional Resources
Carey 4th Edition On-Line Activity
Hydration of alkenes
Hydroboration-Oxidation of Alkenes
Oxymercuration-Demercuration of Alkenes
Hydrolysis of Alkyl halides
Cliffs Notes
Synthesis of alcohols
Slide Presentations
Properties and preps of alcohols
Synthesis and structure of alcohol presentation

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8.6: Synthesis of Alcohols: Oxidation-Reduction Relation Between Alcohols
and Carbonyl Compounds
Objectives

After completing this section, you should be able to

1. determine whether a given reaction should be classified as an oxidation or a reduction.
2. write an equation to represent the reduction of an aldehyde or ketone using sodium borohydride or lithium
aluminum hydride.
a. discuss the relative advantages and disadvantages of using sodium borohydride or lithium aluminum hydride to
reduce aldehydes or ketones to alcohols.
b. identify the product formed from the reduction of a given aldehyde or ketone.
c. identify the aldehyde or ketone that should be used to produce a given alcohol in a reduction reaction.
d. identify the best reagent to carry out the reduction of a given aldehyde or ketone.
3. write an equation to represent the reduction of an ester or a carboxylic acid to an alcohol.
a. identify the product formed from the reduction of a given ester or carboxylic acid.
b. identify the esters or carboxylic acids that could be reduced to form a given alcohol.

Key Terms

Make certain that you can define, and use in context, the key terms below.
(organic) oxidation
(organic) reduction

Study Notes
In your course in first‑year general chemistry, you probably discussed oxidation‑reduction reactions in terms of the
transfer of electrons and changes in oxidation numbers (oxidation states). In organic chemistry, it is often more
convenient to regard reduction as the gain of hydrogen or loss of oxygen, and oxidation as the gain of oxygen or the
loss of hydrogen. There is no contradiction in using these various definitions. For example, when hydrogen is added
across the double bond of ethene to reduce it to ethane, the oxidation number of the doubly bonded carbon atoms
decreases from −II to −III. Similarly, when 2‑propanol

is oxidized to acetone

hydrogen is removed from the compound and the oxidation number of the central carbon atom increases from 0 to +II.
If necessary, review the concept of oxidation number.

Reduction of Aldehydes and Ketones

The most common sources of the hydride Nucleophile are lithium aluminum hydride (LiAlH4) and sodium borohydride
(NaBH4). Note! The hydride anion is not present during this reaction; rather, these reagents serve as a source of hydride
due to the presence of a polar metal-hydrogen bond. Because aluminum is less electronegative than boron, the Al-H bond
in LiAlH4 is more polar, thereby, making LiAlH4 a stronger reducing agent.

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Addition of a hydride anion (H:-) to an aldehyde or ketone gives an alkoxide anion, which on protonation yields the
corresponding alcohol. Aldehydes produce 1º-alcohols and ketones produce 2º-alcohols.

In metal hydrides reductions the resulting alkoxide salts are insoluble and need to be hydrolyzed (with care) before the
alcohol product can be isolated. In the sodium borohydride reduction the methanol solvent system achieves this hydrolysis
automatically. In the lithium aluminum hydride reduction water is usually added in a second step. The lithium, sodium,
boron and aluminum end up as soluble inorganic salts at the end of either reaction. Note! LiAlH4 and NaBH4 are both
capable of reducing aldehydes and ketones to the corresponding alcohol.

Example 17.4.1

Mechanism
This mechanism is for a LiAlH4 reduction. The mechanism for a NaBH4 reduction is the same except methanol is the
proton source used in the second step.
1) Nucleopilic attack by the hydride anion

2) The alkoxide is protonated

Biological Reduction
Addition to a carbonyl by a semi-anionic hydride, such as NaBH4, results in conversion of the carbonyl compound to an
alcohol. The hydride from the BH4- anion acts as a nucleophile, adding H- to the carbonyl carbon. A proton source can
then protonate the oxygen of the resulting alkoxide ion, forming an alcohol.
Formally, that process is referred to as a reduction. Reduction generally means a reaction in which electrons are added to a
compound; the compound that gains electrons is said to be reduced. Because hydride can be thought of as a proton plus

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two electrons, we can think of conversion of a ketone or an aldehyde to an alcohol as a two-electron reduction. An
aldehyde plus two electrons and two protons becomes an alcohol.
Aldehydes, ketones and alcohols are very common features in biological molecules. Converting between these compounds
is a frequent event in many biological pathways. However, semi-anionic compounds like sodium borohydride don't exist in
the cell. Instead, a number of biological hydride donors play a similar role.
NADH is a common biological reducing agent. NADH is an acronym for nicotinamide adenine dinucleotide hydride.
Insetad of an anionic donor that provides a hydride to a carbonyl, NADH is actually a neutral donor. It supplies a hydride
to the carbonyl under very specific circumstances. In doing so, it forms a cation, NAD+. However, NAD+ is stabilized by
the fact that its nicotinamide ring is aromatic; it was not aromatic in NADH.

Reduction of Carboxylic Acids and Esters

Carboxylic acids can be converted to 1o alcohols using Lithium aluminum hydride (LiAlH4). Note that NaBH4 is not
strong enough to convert carboxylic acids or esters to alcohols. An aldehyde is produced as an intermediate during this
reaction, but it cannot be isolated because it is more reactive than the original carboxylic acid.

Esters can be converted to 1o alcohols using LiAlH4, while sodium borohydride (N aBH ) is not a strong enough reducing
4

agent to perform this reaction.

Exercises
Questions

Q17.4.1
Give the aldehyde, ketone, or carboxyllic acid (there can be multiple answers) that could be reduced to form the following
alcohols.

(a) (b) (c) (d)

Q17.4.2
Given the following alcohol, draw the structure from which it could be derived using only NaBH4

(a) (b) (c) (d)

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Solutions
S17.4.1

(a) (b) (c) (d)

S17.4.2
Note, NaBH4 is only a strong enough reducing agent to reduce ketones and aldehydes.

(a) (b) (c) (d)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Chris P Schaller, Ph.D., (College of Saint Benedict / Saint John's University)

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8.7: Organometallic Reagents: Sources of Nucleophilic Carbon for Alcohol
Synthesis
The alkali metals (Li, Na, K etc.) and the alkaline earth metals (Mg and Ca, together with Zn) are good reducing agents,
the former being stronger than the latter. These same metals reduce the carbon-halogen bonds of alkyl halides. The halogen
is converted to a halide anion, and the carbon bonds to the metal which has characteristics similar to a carbanion (R:-).

Formation of Organometallic Reagents

Many organometallic reagents are commercially available, however, it is often necessary to make then. The following
equations illustrate these reactions for the commonly used metals lithium and magnesium (R may be hydrogen or alkyl
groups in any combination).
An Alkyl Lithium Reagent

R C−X + 2 Li → R C−Li + LiX (8.7.1)

3 3

A Grignard Regent

R C−X + Mg → R C−MgX (8.7.2)

3 3

Halide reactivity in these reactions increases in the order: Cl < Br < I and Fluorides are usually not used. The alkyl
magnesium halides described in the second reaction are called Grignard Reagents after the French chemist, Victor
Grignard, who discovered them and received the Nobel prize in 1912 for this work. The other metals mentioned above
react in a similar manner, but Grignard and Alky Lithium Reagents most widely used. Although the formulas drawn here
for the alkyl lithium and Grignard reagents reflect the stoichiometry of the reactions and are widely used in the chemical
literature, they do not accurately depict the structural nature of these remarkable substances. Mixtures of polymeric and
other associated and complexed species are in equilibrium under the conditions normally used for their preparation.
A suitable solvent must be used. For alkyl lithium formation pentane or hexane are usually used. Diethyl ether can also be
used but the subsequent alkyl lithium reagent must be used immediately after preparation due to an interaction with the
solvent. Ethyl ether or THF are essential for Grignard reagent formation. Lone pair electrons from two ether molecules
form a complex with the magnesium in the Grignard reagent (As pictured below). This complex helps stabilize the
organometallic and increases its ability to react.

These reactions are obviously substitution reactions, but they cannot be classified as nucleophilic substitutions, as were the
earlier reactions of alkyl halides. Because the functional carbon atom has been reduced, the polarity of the resulting
functional group is inverted (an originally electrophilic carbon becomes nucleophilic). This change, shown below, makes
alkyl lithium and Grignard reagents excellent nucleophiles and useful reactants in synthesis.

Example 8.7.1 :

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Common Organometallic Reagents

Reaction of Organometallic Reagents with Various Carbonyls

Because organometallic reagents react as their corresponding carbanion, they are excellent nucleophiles. The basic reaction
involves the nucleophilic attack of the carbanionic carbon in the organometallic reagent with the electrophilic carbon in the
carbonyl to form alcohols.

Both Grignard and Organolithium Reagents will perform these reactions.

Addition to formaldehyde gives 1° alcohols

Addition to aldehydes gives 2° alcohols

Addition to ketones gives 3° alcohols

Addition to carbon dioxide (CO2) forms a carboxylic acid

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 Example 8.7.1 :

Going from Reactants to Products Simplified

Mechanism for the Addition to Carbonyls

The mechanism for a Grignard agent is shown; the mechanism for an organometallic reagent is the same.
1) Nucleophilic attack

2) Protonation

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Organometallic Reagents as Bases
These reagents are very strong bases (pKa's of saturated hydrocarbons range from 42 to 50). Although not usually done
with Grignard reagents, organolithium reagents can be used as strong bases. Both Grignard reagents and organolithium
reagents react with water to form the corresponding hydrocarbon. This is why so much care is needed to insure dry
glassware and solvents when working with organometallic reagents.

In fact, the reactivity of Grignard reagents and organolithium reagents can be exploited to create a new method for the
conversion of halogens to the corresponding hydrocarbon (illustrated below). The halogen is converted to an
organometallic reagent and then subsequently reacted with water to from an alkane.

Limitation of Organometallic Reagents

As discussed above, Grignard and organolithium reagents are powerful bases. Because of this they cannot be used as
nucleophiles on compounds which contain acidic hydrogens. If they are used they will act as a base and deprotonate the
acidic hydrogen rather than act as a nucleophile and attack the carbonyl. A partial list of functional groups which cannot be
used are: alcohols, amides, 1o amines, 2o amines, carboxylic acids, and terminal alkynes.

Problems
1) Please write the product of the following reactions.

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2) Please indicate the starting material required to produce the product.

3) Please give a detailed mechanism and the final product of this reaction

4) Please show two sets of reactants which could be used to synthesize the following molecule using a Grignard reaction.

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Answers
1)

2)

3)
Nucleophilic attack

Protonation

4)

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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8.8: Organometallic Reagents in the Synthesis of Alcohols
The alkali metals (Li, Na, K etc.) and the alkaline earth metals (Mg and Ca, together with Zn) are good reducing agents,
the former being stronger than the latter. These same metals reduce the carbon-halogen bonds of alkyl halides. The halogen
is converted to a halide anion, and the carbon bonds to the metal which has characteristics similar to a carbanion (R:-).

Formation of Organometallic Reagents

Many organometallic reagents are commercially available, however, it is often necessary to make then. The following
equations illustrate these reactions for the commonly used metals lithium and magnesium (R may be hydrogen or alkyl
groups in any combination).
An Alkyl Lithium Reagent

R C−X + 2 Li → R C−Li + LiX (8.8.1)

3 3

A Grignard Regent

R C−X + Mg → R C−MgX (8.8.2)

3 3

Halide reactivity in these reactions increases in the order: Cl < Br < I and Fluorides are usually not used. The alkyl
magnesium halides described in the second reaction are called Grignard Reagents after the French chemist, Victor
Grignard, who discovered them and received the Nobel prize in 1912 for this work. The other metals mentioned above
react in a similar manner, but Grignard and Alky Lithium Reagents most widely used. Although the formulas drawn here
for the alkyl lithium and Grignard reagents reflect the stoichiometry of the reactions and are widely used in the chemical
literature, they do not accurately depict the structural nature of these remarkable substances. Mixtures of polymeric and
other associated and complexed species are in equilibrium under the conditions normally used for their preparation.
A suitable solvent must be used. For alkyl lithium formation pentane or hexane are usually used. Diethyl ether can also be
used but the subsequent alkyl lithium reagent must be used immediately after preparation due to an interaction with the
solvent. Ethyl ether or THF are essential for Grignard reagent formation. Lone pair electrons from two ether molecules
form a complex with the magnesium in the Grignard reagent (As pictured below). This complex helps stabilize the
organometallic and increases its ability to react.

These reactions are obviously substitution reactions, but they cannot be classified as nucleophilic substitutions, as were the
earlier reactions of alkyl halides. Because the functional carbon atom has been reduced, the polarity of the resulting
functional group is inverted (an originally electrophilic carbon becomes nucleophilic). This change, shown below, makes
alkyl lithium and Grignard reagents excellent nucleophiles and useful reactants in synthesis.

Example 8.8.1 :

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Common Organometallic Reagents

Reaction of Organometallic Reagents with Various Carbonyls

Because organometallic reagents react as their corresponding carbanion, they are excellent nucleophiles. The basic reaction
involves the nucleophilic attack of the carbanionic carbon in the organometallic reagent with the electrophilic carbon in the
carbonyl to form alcohols.

Both Grignard and Organolithium Reagents will perform these reactions.

Addition to formaldehyde gives 1° alcohols

Addition to aldehydes gives 2° alcohols

Addition to ketones gives 3° alcohols

Addition to carbon dioxide (CO2) forms a carboxylic acid

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 Example 8.8.1 :

Going from Reactants to Products Simplified

Mechanism for the Addition to Carbonyls

The mechanism for a Grignard agent is shown; the mechanism for an organometallic reagent is the same.
1) Nucleophilic attack

2) Protonation

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Organometallic Reagents as Bases
These reagents are very strong bases (pKa's of saturated hydrocarbons range from 42 to 50). Although not usually done
with Grignard reagents, organolithium reagents can be used as strong bases. Both Grignard reagents and organolithium
reagents react with water to form the corresponding hydrocarbon. This is why so much care is needed to insure dry
glassware and solvents when working with organometallic reagents.

In fact, the reactivity of Grignard reagents and organolithium reagents can be exploited to create a new method for the
conversion of halogens to the corresponding hydrocarbon (illustrated below). The halogen is converted to an
organometallic reagent and then subsequently reacted with water to from an alkane.

Limitation of Organometallic Reagents

As discussed above, Grignard and organolithium reagents are powerful bases. Because of this they cannot be used as
nucleophiles on compounds which contain acidic hydrogens. If they are used they will act as a base and deprotonate the
acidic hydrogen rather than act as a nucleophile and attack the carbonyl. A partial list of functional groups which cannot be
used are: alcohols, amides, 1o amines, 2o amines, carboxylic acids, and terminal alkynes.

Problems
1) Please write the product of the following reactions.

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2) Please indicate the starting material required to produce the product.

3) Please give a detailed mechanism and the final product of this reaction

4) Please show two sets of reactants which could be used to synthesize the following molecule using a Grignard reaction.

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Answers
1)

2)

3)
Nucleophilic attack

Protonation

4)

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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8.9: Keys to Success: An Introduction to Synthetic Strategy
This section needs to be better incorporated as the original text below is from a source that is no longer available.
For this summer, you can read more about synthesis on Dr. William Reusch's website
I am leaving the text below to remind myself to replace it, but without images it may not be very valuable.
‘There could be ART in Organic Synthesis’ declared the inimitable monarch of organic synthesis, Professor R.B. Woodward. His school unveiled several elegant approaches covering a
variety of complex structures and broke new grounds to define the art of organic synthesis. ‘If organic synthesis is a branch of science, what is the LOGIC of organic synthesis?’
marveled several others. The development of the concept of logical approaches towards synthesis has been evolving over the past several decades. A few stalwarts focused their
attention on this theme and attempted to evolve a pattern to define this logic. There is no doubt that all of us who dabble with synthesis contribute our small bit in the magnificent
direction. A few names stand out in our minds for their outstanding contributions. Notable contributions came from the schools of J.A. Marshal, E.J. Wenkert, G. Stork, S Hanessian,
E.E. van Tamalen, S. Masamune, R.B. Woodward, E.J. Corey and several others. More focused on this theme were the contributions from the school of E.J. Corey.
The period 1960 – 1990 witnessed the evolution of this thought and the concept bloomed into a full-fledged topic that now merits a separate space in college curriculum. Earlier
developments focused on the idea of ANTITHETIC APPROACHES and perfected the art of DISCONNECTION via RETROSYNTHESIS. This led to logical approaches for the
construction of SYNTHETIC TREES that summarized various possible approaches for the proposed Target structure. All disconnections may not lead to good routes for synthesis. Once
the synthetic tree was constructed, the individual branches were analyzed critically. The reactions involved were looked into, to study their feasibility in the laboratory, their mechanistic
pathways were analyzed to understand the conformational and stereochemical implications on the outcome of each step involved and the time / cost factors of the proposed routes were
also estimated. The possible areas of pitfall were identified and the literature was critically scanned to make sure that the steps contemplated were already known or feasible on the basis
of known chemistry. In some cases, model compounds were first constructed to study the feasibility of the particular reaction, before embarking on the synthesis of the complex
molecular architecture. Thus a long process of logical planning is now put in place before the start of the actual synthetic project. In spite of all these careful and lengthy preparations, an
experienced chemist is still weary of the Damocles Sword of synthesis viz., the likely failure of a critical step in the proposed route(s), resulting in total failure of the entire project. All
achievements are 10% inspiration and 90% perspiration. For these brave molecular engineers, sometimes also called chemists, these long-drawn programs and possible perils of failures
are still worth, for the perspiration is enough reward.
A sound knowledge of mechanistic organic chemistry, detailed information on the art and science of functional group transformations, bond formation and cleavage reactions, mastery
over separation and purification techniques and a sound knowledge of spectroscopic analysis are all essential basics for the synthesis of molecules. A synthetic chemist should also be
aware of developments in synthetic strategies generated over the years for different groups of compounds, which include Rules and guidelines governing synthesis. Since organic
chemistry has a strong impact on the development of other sister disciplines like pharmacy, biochemistry and material science, an ability to understand one or more of these areas and
interact with them using their terminologies is also an added virtue for a synthetic chemist. With achievements from synthesis of strained molecules (once considered difficult (if not
impossible) to synthesize, to the synthesis of complex, highly functionalized and unstable molecules, an organic chemist could now confidently say that he could synthesize any
molecule that is theoretically feasible. This is the current status of the power of organic synthesis. Based on the task assigned to the chemist, he would select a Target molecule for
investigation and devise suitable routes for synthesis.

Disconnection of bonds
Having chosen the TARGET molecule for synthesis, the next exercise is to draw out synthetic plans that would summarize all reasonable routes for its synthesis. During the past few
decades, chemists have been working on a process called RETROSYNTHESIS. Retrosynthesis could be described as a logical Disconnection at strategic bonds in such a way that the
process would progressively lead to easily available starting material(s) through several synthetic plans. Each plan thus evolved, describes a ‘ROUTE’ based on a retrosynthesis. Each
disconnection leads to a simplified structure. The logic of such disconnections forms the basis for the retroanalysis of a given target molecule. Natural products have provided chemists
with a large variety of structures, having complex functionalities and stereochemistry. This area has provided several challenging targets for development of these concepts. The
underlining principle in devising logical approaches for synthetic routes is very much akin to the following simple problem. Let us have a look of the following big block, which is made
by assembling several small blocks (Fig 1.4.2.1). You could easily see that the large block could be broken down in different ways and then reassembled to give the same original block.

Fig 1.4.2.1
Now let us try and extend the same approach for the synthesis of a simple molecule. Let us look into three possible ‘disconnections’ for a cyclohexane ring as shown in Fig 1.4.2.2.

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Fig 1.4.2.2
In the above analysis we have attempted to develop three ways of disconnecting the six membered ring. Have we thus created three pathways for the synthesis of cyclohexane ring? Do
such disconnections make chemical sense? The background of an organic chemist should enable him to read the process as a chemical reaction in the reverse (or ‘retro-‘) direction. The
dots in the above structures could represent a carbonium ion, a carbanion, a free radical or a more complex reaction (such as a pericyclic reaction or a rearrangement). Applying such
chemical thinking could open up several plausible reactions. Let us look into path b, which resulted from cleavage of one sigma bond. An anionic cyclisation route alone exposes several
candidates as suitable intermediates for the formation of this linkage. The above analysis describes only three paths out of the large number of alternate cleavage routes that are
available. An extended analysis shown below indicates more such possibilities (Fig 1.4.2.3). Each such intermediate could be subjected to further disconnection process and the process
continued until we reach a reasonably small, easily available starting materials. Thus, a complete ‘SYNTHETIC TREE’ could be constructed that would summarize all possible routes
for the given target molecule.

Fig 1.4.2.3

Efficiency of a route
A route is said to be efficient when the ‘overall yield’ of the total process is the best amongst all routes investigated. This would depend not only on the number of steps involved in the
synthesis, but also on the type of strategy followed. The strategy could involve a ‘linear syntheses’ involving only consequential steps or a ‘convergent syntheses’ involving fewer
consequential steps. Fig 1.4.3.1 shown below depicts a few patterns that could be recognized in such synthetic trees. When each disconnection process leads to only one feasible
intermediate and the process proceeds in this fashion

Fig 1.4.3.1
all the way to one set of starting materials (SM), the process is called a Linear Synthesis. On the other hand, when an intermediate could be disconnected in two or more ways leading to
different intermediates, branching occurs in the plan. The processes could be continued all the way to SMs. In such routes different branches of the synthetic pathways converge towards
an intermediate. Such schemes are called Convergent Syntheses.
The flow charts shown below (Fig 1.4.3.2) depicts a hypothetical 5-step synthesis by the above two strategies. Assuming a very good yield (90%) at each step (this is rarely seen in real
projects), a linier synthesis gives 59% overall yield, whereas a convergent synthesis gives 73% overall yield for the same number of steps..

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Contributors
Prof. R Balaji Rao (Department of Chemistry, Banaras Hindu University, Varanasi) as part of Information and Communication Technology

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CHAPTER OVERVIEW
9: FURTHER REACTIONS OF ALCOHOLS AND THE CHEMISTRY OF ETHERS
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

9.1: REACTIONS OF ALCOHOLS WITH BASE: PREPARATION OF ALKOXIDES

9.2: REACTIONS OF ALCOHOLS WITH STRONG ACIDS: ALKYLOXONIUM IONS IN SUBSTITUTION AND
ELIMINATION REACTIONS OF ALCOHOLS
9.3: CARBOCATION REARRANGEMENTS
9.4: ORGANIC AND INORGANIC ESTERS FROM ALCOHOLS
9.5: NAMES AND PHYSICAL PROPERTIES OF ETHERS
9.6: WILLIAMSON ETHER SYNTHESIS
9.7: SYNTHESIS OF ETHERS: ALCOHOLS AND MINERAL ACIDS
9.8: REACTIONS OF ETHERS
9.9: REACTIONS OF OXACYCLOPROPANES
9.10: SULFUR ANALOGS OF ALCOHOLS AND ETHERS
9.11: PHYSIOLOGICAL PROPERTIES AND USES OF ALCOHOLS AND ETHERS

1 12/5/2021
9.1: Reactions of Alcohols with Base: Preparation of Alkoxides
This page describes the reaction between alcohols and metallic sodium,and introduces the properties of the alkoxide that is formed.
We will look at the reaction between sodium and ethanol as being typical, but you could substitute any other alcohol and the
reaction would be the same.

The Reaction between Sodium Metal and Ethanol

If a small piece of sodium is dropped into ethanol, it reacts steadily to give off bubbles of hydrogen gas and leaves a colorless
solution of sodium ethoxide: C H C H ON a . The anion component is an alkoxide.
3 2

− +
2C H3 C H2 O H(l) + 2N a(s) → 2C H3 C H2 O + 2N a + H2(g) (9.1.1)
(aq) (aq)

If the solution is evaporated carefully to dryness, then sodium ethoxide (C H C H ON a ) is left behind as a white solid. Although
3 2

initially this appears as something new and complicated, in fact, it is exactly the same (apart from being a more gentle reaction) as
the reaction between sodium and water - something you have probably known about for years.
− +
2H2 O(l) + 2N a(s) → 2O H + 2N a + H2(g) (9.1.2)
(aq) (aq)

If the solution is evaporated carefully to dryness, then the sodium hydroxide (N aOH ) is left behind as a white solid.
We normally, of course, write the sodium hydroxide formed as N aOH rather than HON a - but that's the only difference. Sodium
ethoxide is just like sodium hydroxide, except that the hydrogen has been replaced by an ethyl group. Sodium hydroxide contains
OH
−
ions; sodium ethoxide contains C H C H O ions.
3 2
−

Note
The reason that the ethoxide formula is written with the oxygen on the right unlike the hydroxide ion is simply a matter
of clarity. If you write it the other way around, it doesn't immediately look as if it comes from ethanol. You will find the
same thing happens when you write formulae for organic salts like sodium ethanoate, for example.

There are two simple uses for this reaction:

To safely dispose of small amounts of sodium: If you spill some sodium on the bench or have a
small amount left over from a reaction you cannot simply dispose of it in the sink. It tends to react explosively with the water -
and comes flying back out at you again! It reacts much more gently with ethanol. Ethanol is, therefore, used to dissolve small
quantities of waste sodium. The solution formed can be washed away without problems (provided you remember that sodium
ethoxide is strongly alkaline - see below).
To test for the -OH group in alcohols: Because of the dangers involved in handling sodium, this is
not the best test for an alcohol at this level. Because sodium reacts violently with acids to produce a salt and hydrogen,
you would first have to be sure that the liquid you were testing was neutral. You would also have to be confident that
there was no trace of water present because sodium reacts with the -OH group in water even better than with the one in
an alcohol. With those provisos, if you add a tiny piece of sodium to a neutral liquid free of water and get bubbles of
hydrogen produced, then the liquid is an alcohol.

Ethoxide Ions are Strongly Basic

If you add water to sodium ethoxide, it dissolves to give a colorless solution with a high pH. The solution is strongly alkaline
because ethoxide ions are Brønsted-Lowry bases and remove hydrogen ions from water molecules to produce hydroxide ions,
which increase the pH.
− −
C H3 C H2 O + H2 O → C H3 C H2 OH + O H (9.1.3)

Ethoxide Ions are Good Nucleophiles

A nucleophile is a chemical species that carries a negative or partial negative charge that it uses to attack positive centers in other
molecules or ions. Hydroxide ions are good nucleophiles, and you may have come across the reaction between a halogenoalkane
(also called a haloalkane or alkyl halide) and sodium hydroxide solution. The hydroxide ions replace the halogen atom.

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 − −
C H3 C H2 C H2 Br + OH → C H3 C H2 C H2 OH + Br (9.1.4)

In this case, an alcohol is formed. The ethoxide ion behaves in exactly the same way. If you knew the mechanism for the hydroxide
ion reaction, you could work out exactly what happens in the reaction between a halogenoalkane and ethoxide ion.
Compare this equation with the last one.
−
C H3 C H2 C H2 OH + C H3 C H2 Br → C H3 C H2 C H2 OC H2 C H3 + Br (9.1.5)

The only difference is that where there was a hydrogen atom at the right-hand end of the product molecule, an alkyl group is now
present. Two alkyl (or other hydrocarbon) groups bridged by an oxygen atom is called an ether. This particular one is 1-
ethoxypropane or ethyl propyl ether. This reaction is known as the Williamson Ether Synthesis and is a good method of
synthesizing ethers in the lab.

Contributors

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9.2: Reactions of Alcohols with Strong Acids: Alkyloxonium Ions in Substitution and
Elimination Reactions of Alcohols

Purdue CHM 26100: Organic

Chemistry for Engineers (1st Semester)
Fall 2014: Prof. Paul Wenthold

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9.3: Carbocation Rearrangements
☰
09.9 Carbocation Rearrangements

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9.4: Organic and Inorganic Esters from Alcohols
Nucleophilic Substitution of the Hydroxyl Group
The chemical behavior of alkyl halides can be used as a reference in discovering analogous substitution and elimination reactions of
alcohols. The chief difference, of course, is a change in the leaving anion from halide to hydroxide. Because oxygen is slightly more
electronegative than chlorine (3.5 vs. 2.8 on the Pauling scale), the C-O bond is expected to be more polar than a C-Cl bond.
Furthermore, an independent measure of the electrophilic characteristics of carbon atoms from their NMR chemical shifts (both 13C
and alpha protons) indicates that oxygen and chlorine substituents exert a similar electron-withdrawing influence when bonded to sp3
hybridized carbon atoms. Despite this promising background evidence, alcohols do not undergo the same SN2 reactions commonly
observed with alkyl halides. For example, the rapid SN2 reaction of 1-bromobutane with sodium cyanide, shown below, has no
parallel when 1-butanol is treated with sodium cyanide. In fact, ethyl alcohol is often used as a solvent for alkyl halide substitution
reactions such as this.
CH3CH2CH2CH2–Br + Na(+) CN(–) CH3CH2CH2CH2–CN + Na(+) Br(–)
CH3CH2CH2CH2–OH + Na(+) CN(–) No Reaction

The key factor here is the stability of the leaving anion (bromide vs. hydroxide). HBr is a much stronger acid than water (by more
than 18 orders of magnitude), and this difference is reflected in reactions that generate their respective conjugate bases. The weaker
base, bromide, is more stable, and its release in a substitution or elimination reaction is much more favorable than that of hydroxide
ion, a stronger and less stable base.
A clear step toward improving the reactivity of alcohols in SN2 reactions would be to modify the –OH functional group in a way that
improves its stability as a leaving anion. One such modification is to conduct the substitution reaction in a strong acid, converting –
OH to –OH2(+). Because the hydronium ion (H3O(+)) is a much stronger acid than water, its conjugate base (H2O) is a better leaving
group than hydroxide ion. The only problem with this strategy is that many nucleophiles, including cyanide, are deactivated by
protonation in strong acids, effectively removing the nucleophilic co-reactant required for the substitution. The strong acids HCl, HBr
and HI are not subject to this difficulty because their conjugate bases are good nucleophiles and are even weaker bases than alcohols.
The following equations illustrate some substitution reactions of alcohols that may be affected by these acids. As with alkyl halides,
the nucleophilic substitution of 1º-alcohols proceeds by an SN2 mechanism, whereas 3º-alcohols react by an SN1 mechanism.
Reactions of 2º-alcohols may occur by both mechanisms and often produce some rearranged products. The numbers in parentheses
next to the mineral acid formulas represent the weight percentage of a concentrated aqueous solution, the form in which these acids
are normally used.
CH3CH2CH2CH2–OH + HBr (48%) CH3CH2CH2CH2–OH2(+) Br(–) CH3CH2CH2CH2–Br + H2O SN2
(CH3)3C–OH + HCl (37%) (CH3)3C–OH2(+) Cl(–) (CH3)3C(+) Cl(–) + H2O (CH3)3C–Cl + H2O SN1

Although these reactions are sometimes referred to as "acid-catalyzed," this is not strictly correct. In the overall transformation, a
strong HX acid is converted to water, a very weak acid, so at least a stoichiometric quantity of HX is required for a complete
conversion of alcohol to alkyl halide. The necessity of using equivalent quantities of very strong acids in this reaction limits its
usefulness to simple alcohols of the type shown above. Alcohols with acid-sensitive groups do not, of course, tolerate such treatment.
Nevertheless, the idea of modifying the -OH functional group to improve its stability as a leaving anion can be pursued in other
directions. The following diagram shows some modifications that have proven effective. In each case the hydroxyl group is converted
to an ester of a strong acid. The first two examples show the sulfonate esters described earlier. The third and fourth examples show
the formation of a phosphite ester (X represents the remaining bromines or additional alcohol substituents) and a chlorosulfite ester,
respectively. All of these leaving groups (colored blue) have conjugate acids that are much stronger than water (by 13 to 16 powers of
ten); thus, the leaving anion is correspondingly more stable than the hydroxide ion. The mesylate and tosylate compounds are
particularly useful because they may be used in substitution reactions with a wide variety of nucleophiles. The intermediates produced
in reactions of alcohols with phosphorus tribromide and thionyl chloride (last two examples) are seldom isolated, and these reactions
continue to produce alkyl bromide and chloride products.

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The importance of sulfonate ester intermediates in general nucleophilic substitution reactions of alcohols may be illustrated by the
following conversion of 1-butanol to pentanenitrile (butyl cyanide), a reaction that does not occur with the alcohol alone. The
phosphorus and thionyl halides, on the other hand, only act to convert alcohols to the corresponding alkyl halides.
pyridine Na(+) CN(–)
CH3CH2CH2CH2–OH + CH3SO2Cl CH3CH2CH2CH2–OSO2CH3 CH3CH2CH2CH2–CN + CH3SO2

Some examples of alcohol substitution reactions using this approach to activating the hydroxyl group are shown in the following
diagram. The first two cases serve to reinforce the fact that sulfonate ester derivatives of alcohols may replace alkyl halides in a
variety of SN2 reactions. The next two cases demonstrate the use of phosphorus tribromide in converting alcohols to bromides. This
reagent may be used without added base (e.g. pyridine) because the phosphorous acid product is a weaker acid than HBr. Phosphorus
tribromide is best used with 1º-alcohols because 2º-alcohols often yield rearrangement by-products resulting from competing SN1
reactions. Note that the ether oxygen in reaction 4 is not affected by this reagent, whereas the alternative synthesis using concentrated
HBr cleaves ethers. Phosphorus trichloride (PCl3) converts alcohols to alkyl chlorides in a similar manner, but thionyl chloride is
usually preferred for this transformation because the inorganic products are gases (SO2 & HCl). Phosphorus triiodide is not stable but
may be generated in situ from a mixture of red phosphorus and iodine and acts to convert alcohols to alkyl iodides. The last example
shows the reaction of thionyl chloride with a chiral 2º-alcohol. The presence of an organic base such as pyridine is important because
it provides a substantial concentration of chloride ion required for the final SN2 reaction of the chlorosufite intermediate. In the
absence of a base, chlorosufites decompose upon heating to yield the expected alkyl chloride with retention of configuration
Tertiary alcohols are not commonly used for substitution reactions of the type discussed here because SN1 and E1 reaction paths are
dominant and are difficult to control.

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The importance of sulfonate esters as intermediates in many substitution reactions cannot be overstated. A rigorous proof of the
configurational inversion that occurs at the substitution site in SN2 reactions makes use of such reactions. An example of such a proof
is displayed below. Abbreviations for the more commonly used sulfonyl derivatives are given in the following table.
Sulfonyl Group CH3SO2– CH3C6H4SO2– BrC6H4SO2– CF3SO2–

Name & Abbrev. Mesyl or Ms Tosyl or Ts Brosyl or Bs Trifyl or Tf

Inversion Proof

For a more complete discussion of hydroxyl substitution reactions and a description of other selective methods for this
transformation, Click Here.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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9.5: Names and Physical Properties of Ethers
Ethers are compounds having two alkyl or aryl groups bonded to an oxygen atom, as in the formula R1–O–R2. The ether functional group does not have
a characteristic IUPAC nomenclature suffix, so it is necessary to designate it as a substituent. To do so the common alkoxy substituents are given names
derived from their alkyl component (below):
Na
Alkyl Group Name Alkoxy Group m
e

M
C
et
H3 Methyl CH3O–
ho
–
xy
C
H3 Et
C Ethyl CH3CH2O– ho
H2 xy
–
(C
H3
)2
Isopropyl (CH3)2CHO– Isoprop
C
H
–
(C ter
H3 t-
)3 tert-Butyl (CH3)3CO– Bu
C to
– xy
Ph
C6
en
H5 Phenyl C6H5O–
ox
–
y

Ethers can be named by naming each of the two carbon groups as a separate word followed by a space and the word ether. The -OR group can also be
named as a substituent using the group name, alkox

Example 9.5.1
CH3-CH2-O-CH3 is called ethyl methyl ether or methoxyethane.

The smaller, shorter alkyl group becomes the alkoxy substituent. The larger, longer alkyl group side becomes the alkane base name. Each alkyl group on
each side of the oxygen is numbered separately. The numbering priority is given to the carbon closest to the oxgen. The alkoxy side (shorter side) has an
"-oxy" ending with its corresponding alkyl group. For example, CH3CH2CH2CH2CH2-O-CH2CH2CH3 is 1-propoxypentane. If there is cis or trans
stereochemistry, the same rule still applies.

Examples 9.5.2
C H3 C H2 OC H2 C H3 , diethyl ether (sometimes referred to as just ether)
C H3 OC H2 C H2 OC H3 , ethylene glycol dimethyl ether (glyme).

Exercises 9.5.2
Try to name the following compounds using these conventions:

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 Try to draw structures for the following compounds:
2-pentyl 1-propyl ether J
1-(2-propoxy)cyclopentene J

Common names
Simple ethers are given common names in which the alkyl groups bonded to the oxygen are named in alphabetical order followed by the word "ether".
The top left example shows the common name in blue under the IUPAC name. Many simple ethers are symmetrical, in that the two alkyl substituents
are the same. These are named as "dialkyl ethers".
anisole (try naming anisole by the other two conventions. J )

oxirane

1,2-epoxyethane, ethylene oxide, dimethylene oxide, oxacyclopropane,

furan (this compound is aromatic)

tetrahydrofuran

oxacyclopentane, 1,4-epoxybutane, tetramethylene oxide,

dioxane

1,4-dioxacyclohexane

Exercise 9.5.2
Try to draw structures for the following compounds-
3-bromoanisole J
2-methyloxirane J
3-ethylfuran J

Heterocycles
In cyclic ethers (heterocycles), one or more carbons are replaced with oxygen. Often, it's called heteroatoms, when carbon is replaced by an oxygen or
any atom other than carbon or hydrogen. In this case, the stem is called the oxacycloalkane, where the prefix "oxa-" is an indicator of the replacement of
the carbon by an oxygen in the ring. These compounds are numbered starting at the oxygen and continues around the ring. For example,

If a substituent is an alcohol, the alcohol has higher priority. However, if a substituent is a halide, ether has higher priority. If there is both an alcohol
group and a halide, alcohol has higher priority. The numbering begins with the end that is closest to the higher priority substituent. There are ethers that
are contain multiple ether groups that are called cyclic polyethers or crown ethers. These are also named using the IUPAC system.

Sulfides
Sulfur analogs of ethers (R–S–R') are called sulfides, e.g., (CH3)3C–S–CH3 is tert-butyl methyl sulfide. Sulfides are chemically more reactive than
ethers, reflecting the greater nucleophilicity of sulfur relative to oxygen.

References
1. Schore, Neil E. and Vollhardt, K. Peter C. Organic Chemistry: Structure and Function. New York: Bleyer, Brennan, 2007.
2. Winter, Arthur. Organic Chemistry for Dummies. Hoboken, New Jersey: Wiley, 2005.
3. Pellegrini, Frank. Cliffs QuickReview Organic Chemistry II. Foster City, CA: Wiley, 2000

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Problems
Name the following ethers:

(Answers to problems above: 1. diethyl ether; 2. 2-ethoxy-2-methyl-1-propane; 3. cis-1-ethoxy-2-methoxycyclopentane; 4. 1-ethoxy-1-

methylcyclohexane; 5. oxacyclopropane; 6. 2,2-Dimethyloxacyclopropane)

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Richard Banks (Boise State University)

 Objectives
After completing this section, you should be able to
1. write the normally accepted name for a crown ether, given its structure.
2. draw the structure of a crown ether, given its normally accepted name.
3. describe, briefly, the uses of crown ethers.

 Key Terms

Make certain that you can define, and use in context, the key term below.
crown ether

 Study Notes

A “crown ether ” is a cyclic ether containing several (i.e., 4, 5, 6 or more) oxygen atoms. As we have indicated in the objectives above, a detailed
knowledge of these compounds is not required in this course.

It is possible to dissolve ionic compounds in organic solvents using crown ethers. Cyclic polyether with four or more oxygen atoms separated by two or
three carbon atoms. All crown ethers have a central cavity that can accommodate a metal ion coordinated to the ring of oxygen atoms., cyclic
compounds with the general formula (OCH2CH2)n. Crown ethers are named using both the total number of atoms in the ring and the number of oxygen
atoms. Thus 18-crown-6 is an 18-membered ring with six oxygen atoms (part (a) in Figure 18.7.1 ). The cavity in the center of the crown ether molecule
is lined with oxygen atoms and is large enough to be occupied by a cation, such as K+. The cation is stabilized by interacting with lone pairs of electrons
on the surrounding oxygen atoms. Thus crown ethers solvate cations inside a hydrophilic cavity, whereas the outer shell, consisting of C–H bonds, is
hydrophobic. Crown ethers are useful for dissolving ionic substances such as KMnO4 in organic solvents such as isopropanol [(CH3)2CHOH] (Figure
18.7.1). The availability of crown ethers with cavities of different sizes allows specific cations to be solvated with a high degree of selectivity.

Figure 18.7.1: Crown Ethers and Cryptands (a) The potassium complex of the crown ether 18-crown-6. Note how the cation is nestled within the central
cavity of the molecule and interacts with lone pairs of electrons on the oxygen atoms. (b) The potassium complex of 2,2,2-cryptand, showing how the
cation is almost hidden by the cryptand. Cryptands solvate cations via lone pairs of electrons on both oxygen and nitrogen atoms.

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 Purple benzene

Figure 18.7.2: Effect of a Crown Ether on the Solubility of KMnO4 in Benzene. Normally which is intensely purple, is completely insoluble in
benzene which has a relatively low dielectric constant. In the presence of a small amount of crown ether, KMnO4 dissolves in benzene as shown by the
reddish purple color caused by the permanganate ions in solution.
Cryptands (from the Greek kryptós, meaning “hidden”) are compounds that can completely surround a cation with lone pairs of electrons on oxygen and
nitrogen atoms (Figure 18.7.1b). The number in the name of the cryptand is the number of oxygen atoms in each strand of the molecule. Like crown
ethers, cryptands can be used to prepare solutions of ionic compounds in solvents that are otherwise too nonpolar to dissolve them.

Figure 18.7.3: Ion–Dipole Interactions in the Solvation of Li+ Ions by Acetone, a Polar Solvent

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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9.6: Williamson Ether Synthesis
Objectives
After completing this section, you should be able to
1. write an equation to illustrate the industrial preparation of simple symmetrical ethers.
2. write an equation to illustrate the Williamson synthesis of ethers.
a. identify the ether obtained from the reaction of a given alkyl halide with a given alkoxide ion.
b. identify the reagents needed to prepare a given ether through a Williamson synthesis.
c. identify the limitations of the Williamson synthesis, and make the appropriate choices when deciding how best
to synthesize a given ether.
d. write an equation to describe the formation of an alkoxide from an alcohol.
e. identify silver(I) oxide as a reagent which can be used in a Williamson synthesis.
3. write an equation to show how an ether can be prepared by the alkoxymercuration‑demercuration of an alkene.
a. identify the product formed from the alkoxymercuration‑ demercuration of a given alkene.
b. identify the alkene, the reagents, or both, needed to prepare a given ether by the
alkoxymercuration‑demercuration process.
c. write the detailed mechanism of the reaction between an alkene, an alcohol and mercury(II) trifluoroacetate.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
alkoxymercuration
oxymercuration
Williamson ether synthesis

 Study Notes

We studied oxymercuration as a method of converting an alkene to an alcohol in Section 8.5. “Alkoxymercuration” is

a very similar process, except that we are now converting an alkene into an ether. The two processes are compared
below.

Description oxymercuration alkoxymercuration

we react an alkene alkene

with water an alcohol
in the presence of Hg(O2CCH3)2 Hg(O2CCF3)2
followed by treatment with NaBH4 NaBH4
to produce an alcohol ether

Review the mechanism of the oxymercuration reaction in Section 8.5, paying particular attention to the regiochemistry
and the stereochemistry of the reaction. The mechanism is identical to alkoxymercuration.

Ethers are usually prepared from alcohols or their conjugate bases. One important procedure, known as the Williamson
Ether Synthesis, proceeds by an SN2 reaction of an alkoxide nucleophile with an alkyl halide. Reactions 1 and 2 below
are two examples of this procedure. When applied to an unsymmetrical ether, as in this case, there are two different
combinations of reactants are possible. Of these one is usually better than the other. Since alkoxide anions are strong bases,
the possibility of a competing E2 elimination must always be considered. Bearing in mind the factors that favor
substitution over elimination, a 1º-alkyl halide should be selected as a preferred reactant whenever possible. Thus, reaction
1 gives a better and cleaner yield of benzyl isopropyl ether than does reaction 2, which generates considerable elimination
product.

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A second general ether synthesis, alkoxymercuration, is patterned after the oxymercuration reaction. Reactions 3 and 4
are examples of this two-step procedure. Note that the alcohol reactant is used as the solvent, and a trifluoroacetate
mercury (II) salt is used in preference to the acetate (trifluoroacetate anion is a poorer nucleophile than acetate). The
mechanism of alkoxymercuration is similar to that of oxymercuration, with an initial anti-addition of the mercuric species
and alcohol being followed by reductive demercuration.
Acid-catalyzed dehydration of small 1º-alcohols constitutes a specialized industrial method of preparing symmetrical
ethers. As shown in the following two equations, the success of this procedure depends on the temperature. At 110º to 130
ºC an SN2 reaction of the alcohol conjugate acid leads to an ether product.
o
130 C

2 CH CH −OH + H SO −−−−→ CH CH −O−CH CH +H O (18.2.1)

3 2 2 4 3 2 2 3 2

At higher temperatures (over 150 ºC) an E2 elimination takes place.

o
150 C

CH CH −OH + H SO −−−−→ CH =CH +H O (18.2.2)

3 2 2 4 2 2 2

This reaction cannot be employed to prepare unsymmetrical ethers. It is because a mixture of products is likely to be
obtained.

Exercises
Questions
Q18.2.1
When preparing ethers using the Williamson ether synthesis, what factors are important when considering the nucleophile
and the electrophile?
Q18.2.2
How would you synthesize the following ethers? Keep in mind there are multiple ways. The Williamson ether synthesis,
alkoxymercuration of alkenes, and also the acid catalyzed substitution.

(a) (b) (c) (d)

(e)
Q18.2.3
Draw the electron arrow pushing mechanism for the formation of diethyl ether in the previous problem.
Q18.2.4

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Ether C from problem 26 can also be prepared from an alkene and an alcohol, draw these two. (There are two possibilities
for the alcohol and alkene)
Q18.2.5
Epoxides are often formed intramolecularly. Take for example this large ring, in a publication from 2016 [J. Org. Chem.,
2016, 81 (20), pp 10029–10034]. If subjected to base, what epoxide would be formed? (Include stereochemistry)

Q18.2.6
What reagents would you use to perform the following transformations?

(a) (b)

(c)

(d)
Q18.2.7
Predict the product of the following.

Q18.2.8
If the following epoxide were subjected to a general nucleophile, Nu, what would be the major product?

Solutions
S18.2.1
The nucleophile ideally should be very basic, yet not sterically hindered. This will minimize any elimination reactions
from occuring. The electrophile should have the characteristics of a good Sn2 electrophile, preferably primary to minimize
any elimination reactions from occuring.
S18.2.2

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The Williamson ether syntheses require added catalytic base. Also, most of the halides can be interchanged, say for
example for a -Br or a -Cl. Although, typically -I is the best leaving group.

(a)

(b)

(c)

(d)
Note, there is only one ether (also called a silyl ether, and often used as an alcohol protecting group.) The other group is an
ester.

(e)
S18.2.3

S18.2.4

While both are possible, the top route is likely easier because
both starting materials are a liquid.
S18.2.5

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S18.2.6

(a) (b) Note the cis addition

(c)
An oxidation to an alcohol through hydroboration, and subsequent substitution with 2-bromopropane could also work, but
this route provides the least likelihood of an elimination reaction occurring.

(d)
Lindlar's catalyst reduces alkynes to cis/Z alkenes. This stereochemistry is retained after epoxidation.
S18.2.7

The result is the production of dioxane, a common solvent.

S18.2.8

The regiochemistry is determined by the slight electron withdrawing effect of the adjacent benzene
ring. The stereochemistry is determined by the stereospecific Sn2 mechanism.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Layne Morsch (University of Illinois Springfield)

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9.7: Synthesis of Ethers: Alcohols and Mineral Acids
Objectives
After completing this section, you should be able to
1. write an equation to illustrate the industrial preparation of simple symmetrical ethers.
2. write an equation to illustrate the Williamson synthesis of ethers.
a. identify the ether obtained from the reaction of a given alkyl halide with a given alkoxide ion.
b. identify the reagents needed to prepare a given ether through a Williamson synthesis.
c. identify the limitations of the Williamson synthesis, and make the appropriate choices when deciding how best
to synthesize a given ether.
d. write an equation to describe the formation of an alkoxide from an alcohol.
e. identify silver(I) oxide as a reagent which can be used in a Williamson synthesis.
3. write an equation to show how an ether can be prepared by the alkoxymercuration‑demercuration of an alkene.
a. identify the product formed from the alkoxymercuration‑ demercuration of a given alkene.
b. identify the alkene, the reagents, or both, needed to prepare a given ether by the
alkoxymercuration‑demercuration process.
c. write the detailed mechanism of the reaction between an alkene, an alcohol and mercury(II) trifluoroacetate.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
alkoxymercuration
oxymercuration
Williamson ether synthesis

 Study Notes

We studied oxymercuration as a method of converting an alkene to an alcohol in Section 8.5. “Alkoxymercuration” is

a very similar process, except that we are now converting an alkene into an ether. The two processes are compared
below.

Description oxymercuration alkoxymercuration

we react an alkene alkene

with water an alcohol
in the presence of Hg(O2CCH3)2 Hg(O2CCF3)2
followed by treatment with NaBH4 NaBH4
to produce an alcohol ether

Review the mechanism of the oxymercuration reaction in Section 8.5, paying particular attention to the regiochemistry
and the stereochemistry of the reaction. The mechanism is identical to alkoxymercuration.

Ethers are usually prepared from alcohols or their conjugate bases. One important procedure, known as the Williamson
Ether Synthesis, proceeds by an SN2 reaction of an alkoxide nucleophile with an alkyl halide. Reactions 1 and 2 below
are two examples of this procedure. When applied to an unsymmetrical ether, as in this case, there are two different
combinations of reactants are possible. Of these one is usually better than the other. Since alkoxide anions are strong bases,
the possibility of a competing E2 elimination must always be considered. Bearing in mind the factors that favor
substitution over elimination, a 1º-alkyl halide should be selected as a preferred reactant whenever possible. Thus, reaction
1 gives a better and cleaner yield of benzyl isopropyl ether than does reaction 2, which generates considerable elimination
product.

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A second general ether synthesis, alkoxymercuration, is patterned after the oxymercuration reaction. Reactions 3 and 4
are examples of this two-step procedure. Note that the alcohol reactant is used as the solvent, and a trifluoroacetate
mercury (II) salt is used in preference to the acetate (trifluoroacetate anion is a poorer nucleophile than acetate). The
mechanism of alkoxymercuration is similar to that of oxymercuration, with an initial anti-addition of the mercuric species
and alcohol being followed by reductive demercuration.
Acid-catalyzed dehydration of small 1º-alcohols constitutes a specialized industrial method of preparing symmetrical
ethers. As shown in the following two equations, the success of this procedure depends on the temperature. At 110º to 130
ºC an SN2 reaction of the alcohol conjugate acid leads to an ether product.
o
130 C

2 CH CH −OH + H SO −−−−→ CH CH −O−CH CH +H O (18.2.1)

3 2 2 4 3 2 2 3 2

At higher temperatures (over 150 ºC) an E2 elimination takes place.

o
150 C

CH CH −OH + H SO −−−−→ CH =CH +H O (18.2.2)

3 2 2 4 2 2 2

This reaction cannot be employed to prepare unsymmetrical ethers. It is because a mixture of products is likely to be
obtained.

Exercises
Questions
Q18.2.1
When preparing ethers using the Williamson ether synthesis, what factors are important when considering the nucleophile
and the electrophile?
Q18.2.2
How would you synthesize the following ethers? Keep in mind there are multiple ways. The Williamson ether synthesis,
alkoxymercuration of alkenes, and also the acid catalyzed substitution.

(a) (b) (c) (d)

(e)
Q18.2.3
Draw the electron arrow pushing mechanism for the formation of diethyl ether in the previous problem.
Q18.2.4

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Ether C from problem 26 can also be prepared from an alkene and an alcohol, draw these two. (There are two possibilities
for the alcohol and alkene)
Q18.2.5
Epoxides are often formed intramolecularly. Take for example this large ring, in a publication from 2016 [J. Org. Chem.,
2016, 81 (20), pp 10029–10034]. If subjected to base, what epoxide would be formed? (Include stereochemistry)

Q18.2.6
What reagents would you use to perform the following transformations?

(a) (b)

(c)

(d)
Q18.2.7
Predict the product of the following.

Q18.2.8
If the following epoxide were subjected to a general nucleophile, Nu, what would be the major product?

Solutions
S18.2.1
The nucleophile ideally should be very basic, yet not sterically hindered. This will minimize any elimination reactions
from occuring. The electrophile should have the characteristics of a good Sn2 electrophile, preferably primary to minimize
any elimination reactions from occuring.
S18.2.2

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The Williamson ether syntheses require added catalytic base. Also, most of the halides can be interchanged, say for
example for a -Br or a -Cl. Although, typically -I is the best leaving group.

(a)

(b)

(c)

(d)
Note, there is only one ether (also called a silyl ether, and often used as an alcohol protecting group.) The other group is an
ester.

(e)
S18.2.3

S18.2.4

While both are possible, the top route is likely easier because
both starting materials are a liquid.
S18.2.5

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S18.2.6

(a) (b) Note the cis addition

(c)
An oxidation to an alcohol through hydroboration, and subsequent substitution with 2-bromopropane could also work, but
this route provides the least likelihood of an elimination reaction occurring.

(d)
Lindlar's catalyst reduces alkynes to cis/Z alkenes. This stereochemistry is retained after epoxidation.
S18.2.7

The result is the production of dioxane, a common solvent.

S18.2.8

The regiochemistry is determined by the slight electron withdrawing effect of the adjacent benzene
ring. The stereochemistry is determined by the stereospecific Sn2 mechanism.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Layne Morsch (University of Illinois Springfield)

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9.8: Reactions of Ethers
Objectives
After completing this section, you should be able to
1. write an equation to illustrate the acidic cleavage of an ether.
2. identify the products formed when a given ether is cleaved by a strong acid.
3. identify the reagent needed to bring about cleavage of a given ether.
4. deduce the structure of an unknown ether, given the products of acidic cleavage of the ether.
5. write the detailed mechanism for the acidic cleavage of a given ether.

 Study Notes

There are a number of points in this section that require additional explanations.
First, if an excess of HI (or HBr) is used in the cleavage reaction, the alcohol formed is converted by a nucleophilic
substitution reaction to the appropriate alkyl halide:
ROH + HI → RI + H2O
In view of this substitution, some textbooks simplify the overall cleavage process as:
R$\ce{-}$O$\ce{-}$R′ + 2HI → RI + R′I + H2O
Second, we should consider in detail how certain ethers (those containing tertiary alkyl, benzyl or allyl groups) cleave
by an SN1 mechanism:

Finally, notice that an aryl alkyl ether will always produce a phenol and an alkyl halide, never an aryl halide and an
alcohol. This is because we rarely see a nucleophile attacking an aromatic ring carbon in preference to an aliphatic
carbon:

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 As phenols do not undergo nucleophilic substitution reactions, even if an excess of HX is used, the products from the
cleavage of an aryl alkyl ether are a phenol and an alkyl halide. Diaryl ethers are not cleaved by acids.

The most common reaction of ethers is cleavage of the C–O bond by strong acids. This may occur by SN1 or E1
mechanisms for 3º-alkyl groups or by an SN2 mechanism for 1º-alkyl groups. Some examples are shown in the following
diagram. The conjugate acid of the ether is an intermediate in all these reactions, just as conjugate acids were intermediates
in certain alcohol reactions.

The first two reactions proceed by a sequence of SN2 steps in which the iodide or bromide anion displaces an alcohol in
the first step, and then converts the conjugate acid of that alcohol to an alkyl halide in the second. Since SN2 reactions are
favored at least hindered sites, the methyl group in example #1 is cleaved first. The 2º-alkyl group in example #3 is
probably cleaved by an SN2 mechanism, but the SN1 alternative cannot be ruled out. The phenol formed in this reaction
does not react further, since SN2, SN1 and E1 reactions do not take place on aromatic rings. The last example shows the
cleavage of a 3º-alkyl group by a strong acid. Acids having poorly nucleophilic conjugate bases are often chosen for this
purpose so that E1 products are favored. The reaction shown here (#4) is the reverse of the tert-butyl ether preparation
described earlier.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

Objectives
After completing this section, you should be able to
1. explain what is meant by “protecting” a functional group during an organic synthesis.
2. describe one common method for protecting the hydroxy group of an alcohol, and give an example of its use (e.g.,
in the preparation of a Grignard reagent).

Often during the synthesis of complex molecules on functional group in a molecule interferes with an intended reaction on
a second functional group on the same molecule. An excellent example is the fact that a Grignard reagent can't be prepared
from halo alcohol because the C-Mg bond is not compatible with the acidic -OH group.
When situations like this occurs chemists circumvent eh problem by protecting the interfering functional group. Functional
group protection involves three steps:
1. Blocking the interfering functionality by introducing a protecting group.
2. Performing the intended reaction.
3. Removing the protecting group and reforming the original functional group.
There are several methods for protecting an alcohol, however, the most common is the reaction with a chlorotrialkylsilane,
Cl-SiR3 This reactions forms a trialkylsilyl ether, R'-O-SiR3. Chlorotrimethylsilane is often used in conjuction with a base,
such as triethylamine, The base helps to form the alkoxide anion and remove the HCl produced by the reaction.

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General Reaction

Example

The silyl ether protecting group can be removed by reaction with an aqueous acid or the fluoride ion.

By utilizing a protecting group a Grignad reagent can be formed and reacted on a halo alcohol.
1) Protect the Alcohol

2) Form the Grignard Reagent

3) Perform the Grignard Reaction

4) Deprotection

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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9.9: Reactions of Oxacyclopropanes
 Objectives

After completing this section, you should be able to

1. write an equation to describe the opening of an epoxide ring under mildly acidic conditions.
a. identify the product formed from the hydrolysis of an epoxide.
b. write the mechanism for the opening of an epoxide ring by an aqueous acid, paying particular attention to the
stereochemistry of the product.
c. identify the product formed when an epoxide ring is opened by a hydrogen halide under anhydrous conditions.
2. predict the major product from the acidic cleavage of a given unsymmetrical epoxide.
3. write an equation to illustrate the cleavage of an epoxide ring by a base.
a. identify the product formed from the reaction of a given epoxide with given base.
b. explain why epoxides are susceptible to cleavage by bases, whereas other cyclic ethers are not.

 Study Notes

In the discussion on base‑catalyzed epoxide opening, the mechanism is essentially SN2. While oxygen is a poor
leaving group, the ring strain of the epoxide really helps to drive this reaction to completion. Indeed, larger cyclic
ethers would not be susceptible to either acid‑catalyzed or base‑catalyzed cleavage under the same conditions because
the ring strain is not as great as in the three‑membered epoxide ring.

Epoxide ring-opening reactions - SN1 vs. SN2, regioselectivity, and stereoselectivity

The nonenzymatic ring-opening reactions of epoxides provide a nice overview of many of the concepts we have seen
already in this chapter. Ring-opening reactions can proceed by either SN2 or SN1 mechanisms, depending on the nature of
the epoxide and on the reaction conditions. If the epoxide is asymmetric, the structure of the product will vary according to
which mechanism dominates. When an asymmetric epoxide undergoes solvolysis in basic methanol, ring-opening occurs
by an SN2 mechanism, and the less substituted carbon is the site of nucleophilic attack, leading to what we will refer to as
product B:

Conversely, when solvolysis occurs in acidic methanol, the reaction occurs by a mechanism with substantial SN1 character,
and the more substituted carbon is the site of attack. As a result, product A predominates.

These are both good examples of regioselective reactions. In a regioselective reaction, two (or more) different
constitutional isomers are possible as products, but one is formed preferentially (or sometimes exclusively).
Let us examine the basic, SN2 case first. The leaving group is an alkoxide anion, because there is no acid available to
protonate the oxygen prior to ring opening. An alkoxide is a poor leaving group, and thus the ring is unlikely to open
without a 'push' from the nucleophile.

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The nucleophile itself is potent: a deprotonated, negatively charged methoxide ion. When a nucleophilic substitution
reaction involves a poor leaving group and a powerful nucleophile, it is very likely to proceed by an SN2 mechanism.
What about the electrophile? There are two electrophilic carbons in the epoxide, but the best target for the nucleophile in
an SN2 reaction is the carbon that is least hindered. This accounts for the observed regiochemical outcome. Like in other
SN2 reactions, nucleophilic attack takes place from the backside, resulting in inversion at the electrophilic carbon.
Probably the best way to depict the acid-catalyzed epoxide ring-opening reaction is as a hybrid, or cross, between an SN2
and SN1 mechanism. First, the oxygen is protonated, creating a good leaving group (step 1 below) . Then the carbon-
oxygen bond begins to break (step 2) and positive charge begins to build up on the more substituted carbon (recall the
discussion from section 8.4B about carbocation stability).

Unlike in an SN1 reaction, the nucleophile attacks the electrophilic carbon (step 3) before a complete carbocation
intermediate has a chance to form.

Attack takes place preferentially from the backside (like in an SN2 reaction) because the carbon-oxygen bond is still to
some degree in place, and the oxygen blocks attack from the front side. Notice, however, how the regiochemical outcome
is different from the base-catalyzed reaction: in the acid-catalyzed process, the nucleophile attacks the more substituted
carbon because it is this carbon that holds a greater degree of positive charge.

 Example 18.6.1
Predict the major product(s) of the ring opening reaction that occurs when the epoxide shown below is treated with:
a. ethanol and a small amount of sodium hydroxide
b. ethanol and a small amount of sulfuric acid

Hint: be sure to consider both regiochemistry and stereochemistry!

Answer

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Anti Dihydroxylation
Epoxides may be cleaved by aqueous acid to give glycols that are often diastereomeric with those prepared by the syn-
hydroxylation reaction described above. Proton transfer from the acid catalyst generates the conjugate acid of the epoxide,
which is attacked by nucleophiles such as water in the same way that the cyclic bromonium ion described above undergoes
reaction. The result is anti-hydroxylation of the double bond, in contrast to the syn-stereoselectivity of the earlier method.
In the following equation this procedure is illustrated for a cis-disubstituted epoxide, which, of course, could be prepared
from the corresponding cis-alkene. This hydration of an epoxide does not change the oxidation state of any atoms or
groups.

Addition of HX
Epoxides can also be opened by other anhydrous acids (HX) to form a trans halohydrin. When both the epoxide carbons
are either primary or secondary the halogen anion will attack the less substituted carbon and an SN2 like reaction.
However, if one of the epoxide carbons is tertiary, the halogen anion will primarily attack the tertialy cabon in a SN1 like
reaction.

 Example 18.6.2

Exercises
Questions
Q18.6.1
Given the following, predict the product assuming only the epoxide is affected. (Remember stereochemistry)

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Q18.6.2
Predict the product of the following, similar to above but a different nucleophile is used and not in acidic conditions.
(Remember stereochemistry)

Q18.6.3
Epoxides are often very useful reagents to use in synthesis when the desired product is a single stereoisomer. If the
following alkene were reacted with an oxyacid to form an epoxide, would the result be a enantiomerically pure? If not,
what would it be?

Solutions
S18.6.1

Note that the stereochemistry has been inverted

S18.6.2

S18.6.3
First, look at the symmetry of the alkene. There is a mirror plane, shown here.

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 Then, think about the mechanism of epoxidation with an oxyacid, take for example mCPBA. The
mechanism is concerted, so the original cis stereochemistry is not changed. This leads to "two" epoxides.

However, these two mirror images are actually identical due to the mirror plane of the cis
geometry. It is a meso compound, so the final result is a single stereoisomer, but not a single enantiomer.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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9.10: Sulfur Analogs of Alcohols and Ethers
 Objectives

After completing this section, you should be able to

1. a. write the IUPAC name of a thiol, given its Kekulé, condensed or shorthand structure.
b. draw the structure of a thiol, given its IUPAC name.
c. write an equation to represent the formation of a thiol by the reaction of hydrosulfide anion with an alkyl halide.
d. write an equation to illustrate the preparation of a thiol by the reaction of thiourea with an alkyl halide.
2. write an equation to show the interconversion between thiols and disulfides.
3. a. write the name of a sulfide, given its structure.
b. draw the structure of a sulfide, given its name.
c. write an equation showing how a sulfide may be prepared by the reaction of a thiolate anion on an alkyl halide.
d. identify the product from the reaction of a given alkyl halide with a given thiolate anion.
e. identify the reagents necessary to prepare a given sulfide.
f. write an equation to illustrate the formation of a trialkylsulfonium salt from a sulfide and an alkyl halide.

 Key Terms

Note: All of these terms are defined in the “Study Notes,” below.
disulfide
mercapto group
(organic) sulfide
sulfone
sulfoxide
thiol
thiolate anion
trialkylsulfonium ion (trialkylsulfonium salt)

 Study Notes

The chemistry of sulfur‑containing organic compounds is often omitted from introductory organic chemistry courses.
However, we have included a short section on these compounds, not for the sake of increasing the amount of material
to be digested, but because much of the chemistry of these substances can be predicted from a knowledge of their
oxygen‑containing analogues.
A thiol is a compound which contains an $\ce{-}$SH functional group. The $\ce{-}$SH group itself is called a
mercapto group. A disulfide is a compound containing an $\ce{-}$S$\ce{-}$S$\ce{-}$ linkage.
(Organic) sulfides have the structure R$\ce{-}$S$\ce{-}$R′, and are therefore the sulfur analogues of ethers. The
nomenclature of sulfides can be easily understood if one understands the nomenclature of the corresponding ethers.
Notice that the term “thio” is also used in inorganic chemistry. For example, SO42− is the sulfate ion; while S2O32−, in
which one of the oxygen atoms of a sulfate ion has been replaced by a sulfur atom, is called thiosulfate.
Thiolate anions, RS$\ce{-}$, are analogous to alkoxy anions, RO$\ce{-}$. Thiolate anions are better nucleophiles than
are alkoxy anions.
If you have trouble understanding why trialkylsulfonium ions are formed, think of them as being somewhat similar to
the hydronium ions that are formed by protonating water:

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 Later we shall see examples of tetraalkylammonium ions, R4N+, which again may be regarded as being similar to
hydronium ions.
Sulfoxides and sulfones are obtained by oxidizing organic sulfides. You need not memorize the methods used to carry
out these oxidations.

Table 18.1, below, provides a quick comparison of oxygen‑containing and sulfur‑containing organic compounds.
Table 18.1 Comparison of compounds containing oxygen and sulfur
Oxygen‑containing Compound Sulfur Analogue

ether, R$\ce{-}$O$\ce{-}$R′ sulfide, R$\ce{-}$S$\ce{-}$R′

R$\ce{-}$O$\ce{-}$, alkoxy group R$\ce{-}$S$\ce{-}$, alkylthio group

−
R$\ce{-}$O , alkoxy anion R$\ce{-}$S−, thiolate anion
alcohol, R$\ce{-}$OH thiol, R$\ce{-}$SH
$\ce{-}$OH, hydroxy group $\ce{-}$SH, mercapto group
R$\ce{-}$O$\ce{-}$O$\ce{-}$R′, peroxide R$\ce{-}$S$\ce{-}$S$\ce{-}$R′, disulfide

Note that when we name thiols, we include the “e” of the alkane name. Thus, CH3CH2SH is called “ethanethiol,” not
“ethanthiol.”

Thiols and sulfides are the "sulfur equivalent" of alcohols and ethers. You can replace the oxygen atom of an alcohol with
a sulfur atom to make a thiol; similarly, you can replace the oxygen atom in an ether with S to make the corresponding
alkyl sulfide. This is because thiols contain the C-S-H functional group, while sulfides contain the C-S-C group.

Oxidation States of Sulfur Compounds

Oxygen assumes only two oxidation states in its organic compounds (–1 in peroxides and –2 in other compounds). Sulfur,
on the other hand, is found in oxidation states ranging from –2 to +6, as shown in the following table (some simple
inorganic compounds are displayed in orange).

Thiols
Thiols are often called “mercaptans,” a reference to the Latin term mercurium captans(capturing mercury), since the -SH
group forms strong bonds with mercury and its ions. Thiols are analogous to alcohols. They are named in a similar fashion
as alcohols except the suffix -thiol is used in place of -ol. By itself the -SH group is called a mercapto group.

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Thiols are usually prepared by using the hydrosulfide anion (-SH) as a nucleophile in an SN2 reaction with alkyl halides.

One problem with this reaction is that the thiol product can undergo a second SN2 reaction with an additional alkyl halide
to produce a sulfide side product. This problem can be solved by using thiourea, (NH2)2C=S, as the nucleophile. The
reaction first produces an alkyl isothiourea salt and an intermediate. This salt is then hydrolyzed by a reaction with
aqueous base.

Disulfides
Oxidation of thiols and other sulfur compounds changes the oxidation state of sulfur rather than carbon. We see some
representative sulfur oxidations in the following examples. In the first case, mild oxidation converts thiols to disufides. An
equivalent oxidation of alcohols to peroxides is not normally observed. The reasons for this different behavior are not hard
to identify. The S–S single bond is nearly twice as strong as the O–O bond in peroxides, and the O–H bond is more than 25
kcal/mole stronger than an S–H bond. Thus, thermodynamics favors disulfide formation over peroxide.

Disulfide bridges in proteins

Disulfide (sulfur-sulfur) linkages between two cysteine residues are an integral component of the three-dimensional
structure of many proteins. The interconversion between thiols and disulfide groups is a redox reaction: the thiol is the
reduced state, and the disulfide is the oxidized state.

Notice that in the oxidized (disulfide) state, each sulfur atom has lost a bond to hydrogen and gained a bond to a sulfur -
this is why the disulfide state is considered to be oxidized relative to the thiol state. The redox agent that mediates the
formation and degradation of disulfide bridges in most proteins is glutathione, a versatile coenzyme that we have met
before in a different context (section 14.2A). Recall that the important functional group in glutathione is the thiol,
highlighted in blue in the figure below. In its reduced (free thiol) form, glutathione is abbreviated 'GSH'.

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In its oxidized form, glutathione exists as a dimer of two molecules linked by a disulfide group, and is abbreviated 'GSSG'.
A new disulfide in a protein forms via a 'disulfide exchange' reaction with GSSH, a process that can be described as a
combination of two SN2-like attacks. The end result is that a new cysteine-cysteine disulfide forms at the expense of the
disulfide in GSSG.

In its reduced (thiol) state, glutathione can reduce disulfides bridges in proteins through the reverse of the above reaction.
Disulfide bridges exist for the most part only in proteins that are located outside the cell. Inside the cell, cysteines are kept
in their reduced (free thiol) state by a high intracellular concentration of GSH, which in turn is kept in a reduced state (ie.
GSH rather than GSSG) by a flavin-dependent enzyme called glutathione reductase.
Disulfide bridges in proteins can also be directly reduced by another flavin-dependent enzyme called 'thioredoxin'. In both
cases, NADPH is the ultimate electron donor, reducing FAD back to FADH2 in each catalytic cycle.
In the biochemistry lab, proteins are often maintained in their reduced (free thiol) state by incubation in buffer containing
an excess concentration of b-mercaptoethanol (BME) or dithiothreitol (DTT). These reducing agents function in a manner
similar to that of GSH, except that DTT, because it has two thiol groups, forms an intramolecular disulfide in its oxidized
form.

Sulfides
Sulfur analogs of ethers are called sulfides. Sulfides are less common than thiols as naturally occurring compounds.
However, sulfides—especially disulfides (C-S-S-C)—have important biological functions, mainly in reducing agents
(antioxidants). The chemical behavior of sulfides contrasts with that of ethers in some important ways. Since hydrogen
sulfide (H2S) is a much stronger acid than water (by more than ten million fold), we expect, and find, thiols to be stronger
acids than equivalent alcohols and phenols. Thiolate conjugate bases are easily formed, and have proven to be excellent
nucleophiles in SN2 reactions of alkyl halides and tosylates.
R–S(–) Na(+) + (CH3)2CH–Br (CH3)2CH–S–R + Na(+) Br(–)
Although the basicity of ethers is roughly a hundred times greater than that of equivalent sulfides, the nucleophilicity of
sulfur is much greater than that of oxygen, leading to a number of interesting and useful electrophilic substitutions of
sulfur that are not normally observed for oxygen. Sulfides, for example, react with alkyl halides to give ternary sulfonium
salts (equation # 1) in the same manner that 3º-amines are alkylated to quaternary ammonium salts. Although equivalent
oxonium salts of ethers are known, they are only prepared under extreme conditions, and are exceptionally reactive.

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sulfides are named using the same rules as ethers except sulfide is used in the place of ether. For more complex substance
alkylthio is used instead of alkoxy.

SAM methyltransferases
The most common example of sulfonium ions in a living organism is the reaction of S-Adenosylmethionine. Some of the
most important examples of SN2 reactions in biochemistry are those catalyzed by S-adenosyl methionine (SAM) –
dependent methyltransferase enzymes. We have already seen, in chapter 6 and again in chapter 8, how a methyl group is
transferred in an SN2 reaction from SAM to the amine group on the nucleotide base adenosine:

(Nucleic Acids Res. 2000, 28, 3950).

Another SAM-dependent methylation reaction is catalyzed by an enzyme called catechol-O-methyltransferase. The
substrate here is epinephrine, also known as adrenaline.

Notice that in this example, the attacking nucleophile is an alcohol rather than an amine (that’s why the enzyme is called
an O-methyltransferase). In both cases, though, a basic amino acid side chain is positioned in the active site in just the right
place to deprotonate the nucleophilic group as it attacks, increasing its nucleophilicity. The electrophile in both reactions is
a methyl carbon, so there is little steric hindrance to slow down the nucleophilic attack. The methyl carbon is electrophilic
because it is bonded to a positively-charged sulfur, which is a powerful electron withdrawing group. The positive charge
on the sulfur also makes it an excellent leaving group, as the resulting product will be a neutral and very stable sulfide. All
in all, in both reactions we have a reasonably good nucleophile, an electron-poor, unhindered electrophile, and an excellent
leaving group.
Because the electrophilic carbon in these reactions is a methyl carbon, a stepwise SN1-like mechanism is extremely
unlikely: a methyl carbocation is very high in energy and thus is not a reasonable intermediate to propose. We can
confidently predict that this reaction is SN2. Does this SN2 reaction occur, as expected, with inversion of stereochemistry?
Of course, the electrophilic methyl carbon in these reactions is achiral, so inversion is not apparent. To demonstrate
inversion, the following experiment has been carried out with catechol-O-methyltransferase:

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Here, the methyl group of SAM was made to be chiral by incorporating hydrogen isotopes tritium (3H, T) and deuterium
(2H, D). The researchers determined that the reaction occurred with inversion of configuration, as expected for an SN2
displacement (J. Biol. Chem. 1980, 255, 9124).
Sulfides can be easily oxidized. Reacting a sulfide with hydrogen peroxide, H2O2, as room termpeature produces a
sulfoxide (R2SO). The oxidation can be continued by reaction with a peroxyacid to produce the sulfone (R2SO2)

A common example of a sulfoxide is the solvent dimethyl sulfoxide (DMSO). DMSO is polar aprotic solvent.

Figure AB16.3. DMSO is a very polar, aprotic solvent.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Chris P Schaller, Ph.D., (College of Saint Benedict / Saint John's University)

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9.11: Physiological Properties and Uses of Alcohols and Ethers

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CHAPTER OVERVIEW
10: USING NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY TO
DEDUCE STRUCTURE
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

10.1: PHYSICAL AND CHEMICAL TESTS

10.2: DEFINING SPECTROSCOPY
10.3: HYDROGEN NUCLEAR MAGNETIC RESONANCE
10.4: USING NMR SPECTRA TO ANALYZE MOLECULAR STRUCTURE: THE PROTON CHEMICAL SHIFT
10.5: TESTS FOR CHEMICAL EQUIVALENCE
10.6: INTEGRATION
10.7: SPIN-SPIN SPLITTING: THE EFFECT OF NONEQUIVALENT NEIGHBORING HYDROGENS
10.8: SPIN-SPIN SPLITTING: SOME COMPLICATIONS
10.9: CARBON-13 NUCLEAR MAGNETIC RESONANCE
BACK MATTER
INDEX

1 12/5/2021
CHAPTER OVERVIEW
FRONT MATTER

TITLEPAGE
INFOPAGE

1 12/5/2021
Contents
Readability
Resources

10: Using Nuclear Magnetic Resonance

Libraries

Spectroscopy to Deduce Structure

Tools
Community
Developers
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10.1: Physical and Chemical Tests
This page explains what structural isomerism is, and looks at some of the various ways that structural isomers can arise.

What is structural isomerism?

Isomers are molecules that have the same molecular formula, but have a different arrangement of the atoms in space. That
excludes any different arrangements which are simply due to the molecule rotating as a whole, or rotating about particular
bonds. For example, both of the following are the same molecule. They are not isomers. Both are butane.

There are also endless other possible ways that this molecule could twist itself. There is completely free rotation around all
the carbon-carbon single bonds. If you had a model of a molecule in front of you, you would have to take it to pieces and
rebuild it if you wanted to make an isomer of that molecule. If you can make an apparently different molecule just by
rotating single bonds, it's not different - it's still the same molecule.
In structural isomerism, the atoms are arranged in a completely different order. This is easier to see with specific examples.
What follows looks at some of the ways that structural isomers can arise. The names of the various forms of structural
isomerism probably don't matter all that much, but you must be aware of the different possibilities when you come to draw
isomers.

Chain Isomerism
These isomers arise because of the possibility of branching in carbon chains. For example, there are two isomers of butane,
C H
4 10. In one of them, the carbon atoms lie in a "straight chain" whereas in the other the chain is branched.

Be careful not to draw "false" isomers which are just twisted versions of the original molecule. For example, this structure
is just the straight chain version of butane rotated about the central carbon-carbon bond.

You could easily see this with a model. This is the example we've already used at the top of this page.

Example 1: Chain Isomers in Pentane

Pentane, C5H12, has three chain isomers. If you think you can find any others, they are simply twisted versions of the
ones below. If in doubt make some models.

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Position isomerism
In position isomerism, the basic carbon skeleton remains unchanged, but important groups are moved around on that
skeleton.
Example 2: Positional Isomers in C5H12
For example, there are two structural isomers with the molecular formula C3H7Br. In one of them the bromine atom is
on the end of the chain, whereas in the other it's attached in the middle.

If you made a model, there is no way that you could twist one molecule to turn it into the other one. You would have to
break the bromine off the end and re-attach it in the middle. At the same time, you would have to move a hydrogen
from the middle to the end.

Another similar example occurs in alcohols such as C 4 H9 OH

These are the only two possibilities provided you keep to a four carbon chain, but there is no reason why you should do
that. You can easily have a mixture of chain isomerism and position isomerism - you aren't restricted to one or the other.
So two other isomers of butanol are:

You can also get position isomers on benzene rings. Consider the molecular formula C H C l. There are four different
7 7

isomers you could make depending on the position of the chlorine atom. In one case it is attached to the side-group carbon
atom, and then there are three other possible positions it could have around the ring - next to the C H group, next-but-one
3

to the C H group, or opposite the C H group.

3 3

Functional group isomerism

In this variety of structural isomerism, the isomers contain different functional groups - that is, they belong to different
families of compounds (different homologous series).
Example 3: Isomers in C3H6O
A molecular formula C 3 H6 O could be either propanal (an aldehyde) or propanone (a ketone).

There are other possibilities as well for this same molecular formula - for example, you could have a carbon-carbon double
bond (an alkene) and an -OH group (an alcohol) in the same molecule.

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Another common example is illustrated by the molecular formula C H 3 6 O2 . Amongst the several structural isomers of this
are propanoic acid (a carboxylic acid) and methyl ethanoate (an ester).

Contributors
Jim Clark (Chemguide.co.uk)

Further Reading

Khan Academy
Constitutional Isomers
Cliffs Notes
Structural Isomers and Stereoisomers

Web Pages
Information on Isomers
Organizing Isomers
Difference Between Isomers and Resonance Structures
Lewis Formulas, Structural Isomerism, Resonance
Structural Isomerism
Videos
Isomers Video
Isomers Video
Tutorial
Drawing Isomers
Drawing Isomers tutorial

Practice Problems
Isomer quiz
Isomer quiz

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10.2: Defining Spectroscopy
The electromagnetic spectrum
Electromagnetic radiation, as you may recall from a previous chemistry or physics class, is composed of electrical and
magnetic waves which oscillate on perpendicular planes. Visible light is electromagnetic radiation. So are the gamma rays
that are emitted by spent nuclear fuel, the x-rays that a doctor uses to visualize your bones, the ultraviolet light that causes
a painful sunburn when you forget to apply sun block, the infrared light that the army uses in night-vision goggles, the
microwaves that you use to heat up your frozen burritos, and the radio-frequency waves that bring music to anybody who
is old-fashioned enough to still listen to FM or AM radio.
Just like ocean waves, electromagnetic waves travel in a defined direction. While the speed of ocean waves can vary,
however, the speed of electromagnetic waves – commonly referred to as the speed of light – is essentially a constant,
approximately 300 million meters per second. This is true whether we are talking about gamma radiation or visible light.
Obviously, there is a big difference between these two types of waves – we are surrounded by the latter for more than half
of our time on earth, whereas we hopefully never become exposed to the former to any significant degree. The different
properties of the various types of electromagnetic radiation are due to differences in their wavelengths, and the
corresponding differences in their energies: shorter wavelengths correspond to higher energy.

High-energy radiation (such as gamma- and x-rays) is composed of very short waves – as short as 10-16 meter from crest to
crest. Longer waves are far less energetic, and thus are less dangerous to living things. Visible light waves are in the range
of 400 – 700 nm (nanometers, or 10-9 m), while radio waves can be several hundred meters in length.
The notion that electromagnetic radiation contains a quantifiable amount of energy can perhaps be better understood if we
talk about light as a stream of particles, called photons, rather than as a wave. (Recall the concept known as ‘wave-particle
duality’: at the quantum level, wave behavior and particle behavior become indistinguishable, and very small particles
have an observable ‘wavelength’). If we describe light as a stream of photons, the energy of a particular wavelength can be
expressed as:
hc
E = (4.1.1)
λ

where E is energy in kJ/mol, λ (the Greek letter lambda) is wavelength in meters, c is 3.00 x 108 m/s (the speed of light),
and h is 3.99 x 10-13 kJ·s·mol-1, a number known as Planck’s constant.
Because electromagnetic radiation travels at a constant speed, each wavelength corresponds to a given frequency, which is
the number of times per second that a crest passes a given point. Longer waves have lower frequencies, and shorter waves
have higher frequencies. Frequency is commonly reported in hertz (Hz), meaning ‘cycles per second’, or ‘waves per
second’. The standard unit for frequency is s-1.
When talking about electromagnetic waves, we can refer either to wavelength or to frequency - the two values are
interconverted using the simple expression:
λν = c (4.1.2)

-1
where ν (the Greek letter ‘nu’) is frequency in s . Visible red light with a wavelength of 700 nm, for example, has a
frequency of 4.29 x 1014 Hz, and an energy of 40.9 kcal per mole of photons. The full range of electromagnetic radiation
wavelengths is referred to as the electromagnetic spectrum.

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 (Image from Wikipedia commons)
Notice that visible light takes up just a narrow band of the full spectrum. White light from the sun or a light bulb is a
mixture of all of the visible wavelengths. You see the visible region of the electromagnetic spectrum divided into its
different wavelengths every time you see a rainbow: violet light has the shortest wavelength, and red light has the longest.

Exercise 4.4: Visible light has a wavelength range of about 400-700 nm. What is the corresponding frequency range?
What is the corresponding energy range, in kJ/mol of photons?
Solutions

Overview of a molecular spectroscopy experiment

In a spectroscopy experiment, electromagnetic radiation of a specified range of wavelengths is allowed to pass through a
sample containing a compound of interest. The sample molecules absorb energy from some of the wavelengths, and as a
result jump from a low energy ‘ground state’ to some higher energy ‘excited state’. Other wavelengths are not absorbed by
the sample molecule, so they pass on through. A detector on the other side of the sample records which wavelengths were
absorbed, and to what extent they were absorbed.
Here is the key to molecular spectroscopy: a given molecule will specifically absorb only those wavelengths which have
energies that correspond to the energy difference of the transition that is occurring. Thus, if the transition involves the
molecule jumping from ground state A to excited state B, with an energy difference of ΔE, the molecule will specifically
absorb radiation with wavelength that corresponds to ΔE, while allowing other wavelengths to pass through unabsorbed.

By observing which wavelengths a molecule absorbs, and to what extent it absorbs them, we can gain information about
the nature of the energetic transitions that a molecule is able to undergo, and thus information about its structure.
These generalized ideas may all sound quite confusing at this point, but things will become much clearer as we begin to
discuss specific examples.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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10.3: Hydrogen Nuclear Magnetic Resonance
Objectives
After completing this section, you should be able to
1. discuss the principles of NMR spectroscopy.
2. identify the two magnetic nuclei that are most important to an organic chemist.

 Key Terms

Make certain that you can define, and use in context, the key term below.
resonance

 Study Notes

Notice that the word “resonance” has a different meaning when we are discussing nuclear magnetic resonance
spectroscopy than it does when discussing molecular structures.

Introduction
Some types of atomic nuclei act as though they spin on their axis similar to the Earth. Since they are positively charged
they generate an electromagnetic field just as the Earth does. So, in effect, they will act as tiny bar magnetics. Not all
nuclei act this way, but fortunately both 1H and 13C do have nuclear spins and will respond to this technique.

NMR Spectrometer
In the absence of an external magnetic field the direction of the spin of the nuclei will be randomly oriented (see figure
below left). However, when a sample of these nuclei is place in an external magnetic field, the nuclear spins will adopt
specific orientations much as a compass needle responses to the Earth’s magnetic field and aligns with it. Two possible
orientations are possible, with the external field (i.e. parallel to and in the same direction as the external field) or against
the field (i.e. antiparallel to the external field). See figure below right.

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 Figure 1: (Left) Random nuclear spin without an external magnetic field. (Right)Ordered nuclear spin in an external
magnetic field
If the ordered nuclei are now subjected to EM radiation of the proper frequency the nuclei aligned with the field will
absorb energy and "spin-flip" to align themselves against the field, a higher energy state. When this spin-flip occurs the
nuclei are said to be in "resonance" with the field, hence the name for the technique, Nuclear Magentic Resonance or
NMR.
The amount of energy, and hence the exact frequency of EM radiation required for resonance to occur is dependent on both
the strength of the magnetic field applied and the type of the nuclei being studied. As the strength of the magnetic field
increases the energy difference between the two spin states increases and a higher frequency (more energy) EM radiation
needs to be applied to achieve a spin-flip (see image below).

Superconducting magnets can be used to produce very strong magnetic field, on the order of 21 tesla (T). Lower field
strengths can also be used, in the range of 4 - 7 T. At these levels the energy required to bring the nuclei into resonance is
in the MHz range and corresponds to radio wavelength energies, i.e. at a field strength of 4.7 T 200 MHz bring 1H nuclei
into resonance and 50 MHz bring 13C into resonance. This is considerably less energy then is required for IR spectroscopy,
~10-4 kJ/mol versus ~5 - ~50 kJ/mol.

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1
H and 13C are not unique in their ability to undergo NMR. All nuclei with an odd number of protons (1H, 2H, 14N, 19F, 31P
...) or nuclei with an odd number of neutrons (i.e. 13C) show the magnetic properties required for NMR. Only nuclei with
even number of both protons and neutrons (12C and 16O) do not have the required magnetic properties.

Exercise
Questions
Q13.1.1
If in a field strength of 4.7 T, H1 requires 200 MHz of energy to maintain resonance. If atom X requires 150 MHz,
calculate the amount of energy required to spin flip atom X’s nucleus. Is this amount greater than the energy required for
hydrogen?
Q13.1.2
Calculate the energy required to spin flip at 400 MHz. Does changing the frequency to 500 MHz decrease or increase the
energy required? What about 300 MHz.
Solutions
S13.1.1
E = hυ
E = (6.62 × 10−34)(150 MHz)
E = 9.93 × 10−26 J
The energy is equal to 9.93x10-26 J. This value is smaller than the energy required for hydrogen (1.324 × 10−25 J).
S13.1.2
E = hυ
E = (6.62 × 10−34)(400 MHz)
E = 2.648 × 10−25 J
The energy would increase if the frequency would increase to 500 MHz, and decrease if the frequency would decrease to
300 MHz.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Dr. Richard Spinney (The Ohio State University)

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10.4: Using NMR Spectra to Analyze Molecular Structure: The Proton
Chemical Shift
 Objectives

After completing this section, you should be able to

1. explain, in general terms, the origin of shielding effects in NMR spectroscopy.
2. explain the number of peaks occurring in the 1H or 13C NMR spectrum of a simple compound, such as methyl
acetate.
3. describe, and sketch a diagram of, a simple NMR spectrometer.
4. explain the difference in time scales of NMR and infrared spectroscopy.
5. predict the number of peaks expected in the 1H or 13C NMR spectrum of a given compound.

 Study Notes

Before you go on, make sure that you understand that each signal in the 1H NMR spectrum shown for methyl acetate is
due to a different proton environment. The three protons on the same methyl group are equivalent and appear in the
spectrum as one signal. However, the two methyl groups are in two different environments (one is more deshielded)
and so we see two signals in the whole spectrum (aside from the TMS reference peak).
Methyl acetate has a very simple 1H NMR spectrum, because there is no proton-proton coupling, and therefore no
splitting of the signals. In later sections, we discuss splitting patterns in 1H NMR spectra and how they help a chemist
determine the structure of organic compounds.

Nuclear precession, spin states, and the resonance condition

When a sample of an organic compound is sitting in a flask on a laboratory benchtop, the magnetic moments of its
hydrogen atoms are randomly oriented. When the same sample is placed within the field of a very strong magnet in an
NMR instrument (this field is referred to by NMR spectroscopists as the applied field, abbreviated B0 ) each hydrogen
will assume one of two possible spin states. In what is referred to as the +½ spin state, the hydrogen's magnetic moment is
aligned with the direction of B0, while in the -½ spin state it is aligned opposed to the direction of B0.

Because the +½ spin state is slightly lower in energy, in a large population of organic molecules slightly more than half of
the hydrogen atoms will occupy this state, while slightly less than half will occupy the –½ state. The difference in energy
between the two spin states increases with increasing strength of B0.This last statement is in italics because it is one of the
key ideas in NMR spectroscopy, as we shall soon see.
At this point, we need to look a little more closely at how a proton spins in an applied magnetic field. You may recall
playing with spinning tops as a child. When a top slows down a little and the spin axis is no longer completely vertical, it
begins to exhibit precessional motion, as the spin axis rotates slowly around the vertical. In the same way, hydrogen
atoms spinning in an applied magnetic field also exhibit precessional motion about a vertical axis. It is this axis (which is
either parallel or antiparallel to B0) that defines the proton’s magnetic moment. In the figure below, the proton is in the
+1/2 spin state.

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The frequency of precession (also called the Larmour frequency, abbreviated ωL) is simply the number of times per
second that the proton precesses in a complete circle. A proton`s precessional frequency increases with the strength of B0.
If a proton that is precessing in an applied magnetic field is exposed to electromagnetic radiation of a frequency ν that
matches its precessional frequency ωL, we have a condition called resonance. In the resonance condition, a proton in the
lower-energy +½ spin state (aligned with B0) will transition (flip) to the higher energy –½ spin state (opposed to B0). In
doing so, it will absorb radiation at this resonance frequency ν = ωL. This frequency, as you might have already guessed,
corresponds to the energy difference between the proton’s two spin states. With the strong magnetic fields generated by the
superconducting magnets used in modern NMR instruments, the resonance frequency for protons falls within the radio-
wave range, anywhere from 100 MHz to 800 MHz depending on the strength of the magnet.

The basics of an NMR experiment

So far, you may have the impression that all 1H nuclei in a molecule would absorb the same frequency. However, this
would be of little use to organic chemists if that were the case. It turns out that not all 1H nuclei absorb the same frequency
and this is the same for all other NMR active nuclei. It turns out that chemically nonequivalent protons (or other nuclei)
have different resonance frequencies in the same applied magnetic field. Nonequivalent protons are in different chemical
environments. This allows NMR spectroscopy to provide us with useful information about the structure of an organic
molecule. A full explanation of how a modern NMR instrument functions is beyond the scope of this text, but here is what
happens. First, a sample compound (we'll use methyl acetate) is placed inside a very strong applied magnetic field (B0).
There are two types of protons in methyl acetate. Ha are bonded to a C that is then bonded to a carbonyl, whereas Hb are
bonded to a carbon that is then bonded to an oxygen atom. This difference in bonding leads to different types of
environments for Ha and Hb. All the Ha protons are the same since they all have the same type of bonding and will be in
the same chemical environment and the same is true for Hb.

The basic arrangement of an NMR spectrometer is displayed below. A sample (in a small glass tube, where the methyl
acetate is in solution) is placed between the poles of a strong magnet. A radio frequency generator pulses the sample and
excites the nuclei causing a spin-flip. The spin flip is detected by the detector and the signal sent to a computer where it is
processed.

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In the magnet, all of the protons begin to precess: the Ha protons at precessional frequency ωa, the Hb protons at ωb. At
first, the magnetic moments of (slightly more than) half of the protons are aligned with B0, and half (slightly less than half)
are aligned against B0. Then, the sample is hit with electromagnetic radiation in the radio frequency range. The two
specific frequencies which match ωa and ωb (i.e. the resonance frequencies) cause those Ha and Hb protons which are
aligned with B0 to 'flip' so that they are now aligned against B0. In doing so, the protons absorb radiation at the two
resonance frequencies. The NMR instrument records which frequencies were absorbed, as well as the intensity of each
absorbance.
In most cases, a sample being analyzed by NMR is in solution. If we used a common laboratory solvent (diethyl ether,
acetone, dichloromethane, ethanol, water, etc.) to dissolve our NMR sample, however, we run into a problem – there many
more solvent protons in solution than there are sample protons, therefore the signals from the sample protons will be
overwhelmed. To get around this problem, we use special NMR solvents in which all protons have been replaced by
deuterium. Recall that deuterium is NMR-active, but its resonance frequency is very different from that of protons, and
thus it is `invisible` in 1H-NMR. Some common NMR solvents are shown below. There are multiple deuterated solvents
since molecules have different solubilities, so one molecule may dissolve in deuterated chloroform while others may not.

The Chemical Shift

Let's look at an actual 1H-NMR plot for methyl acetate. Just as in IR and UV-vis spectroscopy, the vertical axis
corresponds to intensity of absorbance, the horizontal axis to frequency (typically the vertical axis is not shown in an NMR
spectrum).

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We see three absorbance signals: two of these correspond to Ha and Hb, while the peak at the far right of the spectrum
corresponds to the 12 chemically equivalent protons in tetramethylsilane (TMS), a standard reference compound that was
added to our sample.

You may be wondering about a few things at this point - why is TMS necessary, and what is the meaning of the `ppm (δ)`
label on the horizontal axis? Shouldn't the frequency units be in Hz? Keep in mind that NMR instruments of many
different applied field strengths are used in organic chemistry laboratories, and that the proton's resonance frequency range
depends on the strength of the applied field. The spectrum above was generated on an instrument with an applied field of
approximately 7.1 Tesla, at which strength protons resonate in the neighborhood of 300 million Hz (chemists refer to this
as a 300 MHz instrument). If our colleague in another lab takes the NMR spectrum of the same molecule using an
instrument with a 2.4 Tesla magnet, the protons will resonate at around 100 million Hz (so we’d call this a 100 MHz
instrument). It would be inconvenient and confusing to always have to convert NMR data according to the field strength of
the instrument used. Therefore, chemists report resonance frequencies not as absolute values in Hz, but rather as values
relative to a common standard, generally the signal generated by the protons in TMS. This is where the ppm – parts per
million – term comes in. Regardless of the magnetic field strength of the instrument being used, the resonance frequency
of the 12 equivalent protons in TMS is defined as a zero point. The resonance frequencies of protons in the sample
molecule are then reported in terms of how much higher they are, in ppm, relative to the TMS signal (almost all protons in
organic molecules have a higher resonance frequency than those in TMS, for reasons we shall explore quite soon).
The two proton groups in our methyl acetate sample are recorded as resonating at frequencies 2.05 and 3.67 ppm higher
than TMS. One-millionth (1.0 ppm) of 300 MHz is 300 Hz. Thus 2.05 ppm, on this instrument, corresponds to 615 Hz, and
3.67 ppm corresponds to 1101 Hz. If the TMS protons observed by our 7.1 Tesla instrument resonate at exactly
300,000,000 Hz, this means that the protons in our ethyl acetate samples are resonating at 300,000,615 and 300,001,101
Hz, respectively. Likewise, if the TMS protons in our colleague's 2.4 Tesla instrument resonate at exactly 100 MHz, the
methyl acetate protons in her sample resonate at 100,000,205 and 100,000,367 Hz (on the 100 MHz instrument, 1.0 ppm
corresponds to 100 Hz). The absolute frequency values in each case are not very useful – they will vary according to the
instrument used – but the difference in resonance frequency from the TMS standard, expressed in parts per million, should
be the same regardless of the instrument.
Expressed this way, the resonance frequency for a given proton in a molecule is called its chemical shift. A frequently
used symbolic designation for chemical shift in ppm is the lower-case Greek letter delta (δ). Most protons in organic
compounds have chemical shift values between 0 and 12 ppm from TMS, although values below zero and above 12 are
occasionally observed. By convention, the left-hand side of an NMR spectrum (higher chemical shift) is called downfield,
and the right-hand direction is called upfield.

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In our methyl acetate example we included for illustrative purposes a small amount of TMS standard directly in the
sample, as was the common procedure for determining the zero point with older NMR instruments That practice is
generally no longer necessary, as modern NMR instruments are designed to use the deuterium signal from the solvent as a
standard reference point, then to extrapolate the 0 ppm baseline that corresponds to the TMS proton signal (in an applied
field of 7.1 Tesla, the deuterium atom in CDCl3 resonates at 32 MHz, compared to 300 MHz for the protons in TMS). In
the remaining NMR spectra that we will see in this text we will not see an actual TMS signal, but we can always assume
that the 0 ppm point corresponds to where the TMS protons would resonate if they were present.

 Example

A proton has a chemical shift (relative to TMS) of 4.56 ppm.

a. a) What is its chemical shift, expressed in Hz, in a 300 MHz instrument? On a 200 MHz instrument?
b. b) What is its resonance frequency, expressed in Hz, in a 300 MHz instrument? On a 200 MHz instrument?
(Assume that in these instruments, the TMS protons resonate at exactly 300 or 200 MHz, respectively)
Solution

Diamagnetic shielding and deshielding

We come now to the question of why nonequivalent protons have different chemical shifts. The chemical shift of a given
proton is determined primarily by its immediate electronic environment. Consider the methane molecule (CH4), in which
the protons have a chemical shift of 0.23 ppm. The valence electrons around the methyl carbon, when subjected to B0, are
induced to circulate and thus generate their own very small magnetic field that opposes B0. This induced field, to a small
but significant degree, shields the nearby protons from experiencing the full force of B0, an effect known as local
diamagnetic shielding. The methane protons therefore do not experience the full force of B0 - what they experience is
called Beff, or the effective field, which is slightly weaker than B0.

Therefore, their resonance frequency is slightly lower than what it would be if they did not have electrons nearby to shield
them.
Now consider methyl fluoride, CH3F, in which the protons have a chemical shift of 4.26 ppm, significantly higher than that
of methane. This is caused by something called the deshielding effect. Because fluorine is more electronegative than
carbon, it pulls valence electrons away from the carbon, effectively decreasing the electron density around each of the
protons. For the protons, lower electron density means less diamagnetic shielding, which in turn means a greater overall
exposure to B0, a stronger Beff, and a higher resonance frequency. Put another way, the fluorine, by pulling electron density
away from the protons, is deshielding them, leaving them more exposed to B0. As the electronegativity of the substituent
increases, so does the extent of deshielding, and so does the chemical shift. This is evident when we look at the chemical
shifts of methane and three halomethane compounds (remember that electronegativity increases as we move up a column
in the periodic table).

To a large extent, then, we can predict trends in chemical shift by considering how much deshielding is taking place near a
proton. The chemical shift of trichloromethane is, as expected, higher than that of dichloromethane, which is in turn higher
than that of chloromethane.

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The deshielding effect of an electronegative substituent diminishes sharply with increasing distance:

The presence of an electronegative oxygen, nitrogen, sulfur, or sp2-hybridized carbon also tends to shift the NMR signals
of nearby protons slightly downfield:

Table 2 lists typical chemical shift values for protons in different chemical environments.
Armed with this information, we can finally assign the two peaks in the the 1H-NMR spectrum of methyl acetate that we
saw a few pages back. The signal at 3.65 ppm corresponds to the methyl ester protons (Hb), which are deshielded by the
adjacent oxygen atom. The upfield signal at 2.05 ppm corresponds to the acetate protons (Ha), which is deshielded - but to
a lesser extent - by the adjacent carbonyl group.

Finally, a note on the use of TMS as a standard in NMR spectroscopy: one of the main reasons why the TMS proton signal
was chosen as a zero-point is that the TMS protons are highly shielded: silicon is slightly less electronegative than carbon,
and therefore donates some additional shielding electron density. Very few organic molecules contain protons with
chemical shifts that are negative relative to TMS.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Lauren Reutenauer (Amherst College)

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10.5: Tests for Chemical Equivalence
 Objectives

After completing this section, you should be able to

1. identify those protons which are equivalent in a given chemical structure.
2. use the 1H NMR spectrum of a simple organic compound to determine the number of equivalent sets of protons
present.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
diastereotopic
enantiotopic
homotopic

 Study Notes

It is important at this stage to be able to identify equivalent protons in any organic compound given the structure of
that compound. Once you know the number of different groups of equivalent protons in a compound, you can predict
the number (before coupling) and relative strength of signals. Look at the following examples and make sure you
understand how the number and intensity ratio of signals are derived from the structure shown.
Structure Number of Signals Ratio of Signals

$\ce{\sf{CH3OCH2CH2Br}}$ 3 A:B:C 3:2:2

3 A:B:C 2 : 2 : 6 (or 1 : 1 : 3)

3 A:B:C 2 : 4 : 2 (or 1 : 2 : 1)

4 A:B:C:D 3:2:2:3

5 A:B:C:D:E 3:1:1:1:1

If all protons in all organic molecules had the same resonance frequency in an external magnetic field of a given strength,
the information in the previous paragraph would be interesting from a theoretical standpoint, but would not be terribly
useful to organic chemists. Fortunately for us, however, resonance frequencies are not uniform for all protons in a
molecule. In an external magnetic field of a given strength, protons in different locations in a molecule have different
resonance frequencies, because they are in non-identical electronic environments. In methyl acetate, for example, there are
two ‘sets’ of protons. The three protons labeled Ha have a different - and easily distinguishable – resonance frequency than
the three Hb protons, because the two sets of protons are in non-identical environments: they are, in other words,
chemically nonequivalent.

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On the other hand, the three Ha protons are all in the same electronic environment, and are chemically equivalent to one
another. They have identical resonance frequencies. The same can be said for the three Hb protons. These protons are
considered to be homotopic. Homotopic protons are chemically identical, so electronically equivalent, thus show up as
identical NMR absorptions.
The ability to recognize chemical equivalency and nonequivalency among atoms in a molecule will be central to
understanding NMR. In each of the molecules below, all protons are chemically equivalent, and therefore will have the
same resonance frequency in an NMR experiment.

You might expect that the equitorial and axial hydrogens in cyclohexane would be non-equivalent, and would have
different resonance frequencies. In fact, an axial hydrogen is in a different electronic environment than an equitorial
hydrogen. Remember, though, that the molecule rotates rapidly between its two chair conformations, meaning that any
given hydrogen is rapidly moving back and forth between equitorial and axial positions. It turns out that, except at
extremely low temperatures, this rotational motion occurs on a time scale that is much faster than the time scale of an
NMR experiment.

In this sense, NMR is like a camera that takes photographs of a rapidly moving object with a slow shutter speed - the result
is a blurred image. In NMR terms, this means that all 12 protons in cyclohexane are equivalent.
Each the molecules in the next figure contains two sets of protons, just like our previous example of methyl acetate, and
again in each case the resonance frequency of the Ha protons will be different from that of the Hb protons.

Notice how the symmetry of para-xylene results in there being only two different sets of protons.
Most organic molecules have several sets of protons in different chemical environments, and each set, in theory, will have
a different resonance frequency in 1H-NMR spectroscopy.

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When stereochemistry is taken into account, the issue of equivalence vs nonequivalence in NMR starts to get a little more
complicated. It should be fairly intuitive that hydrogens on different sides of asymmetric ring structures and double bonds
are in different electronic environments, and thus are non-equivalent and have different resonance frequencies. In the
alkene and cyclohexene structures below, for example, Ha is trans to the chlorine substituent, while Hb is cis to chlorine.

What is not so intuitive is that diastereotopic hydrogens (section 3.10) on chiral molecules are also non-equivalent:

However, enantiotopic and homotopic hydrogens are chemically equivalent. To determine if protons are homotopic or
enantiotopic, you can do a thought experiment by replacing one H with X followed by the other H by X. In pyruvate
below, if you replace any of the Hs with an X, then you would get the same molecule. These protons are homotopic. In
dihydroxyacetone phosphate, this is not quite the case. If you exchange HR for X, then you would create a stereocenter
with R configuration. If you exchange HS for X, then you would create a stereocenter with S configuration. The two "new
molecules" would have the relationship of being enantiomers. Therefore HR and HS are enantiotopic protons. The only
way these protons will show up different under NMR experimental conditions would be if you used a solvent that was
chiral. Since most common solvents are all achiral, the enantiotopic protons are NMR equivalent and will show up as if
they were the same proton.

 Example 13.6.1

How many different sets of protons do the following molecules contain? (count diastereotopic protons as non-
equivalent).

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 Solution

Exercises
Questions
Q13.8.1
How many non-equivalent hydrogen are in the following molecules; how many different signals will you see in a H1 NMR
spectrum.
A. CH3CH2CH2Br
B. CH3OCH2C(CH3)3
C. Ethyl Benzene
D. 2-methyl-1-hexene
Solutions

S13.8.1
A. 3; B. 3; C. 5; D. 7

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Lauren Reutenauer (Amherst College)

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10.6: Integration
Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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10.7: Spin-Spin Splitting: The Effect of Nonequivalent Neighboring Hydrogens
Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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10.8: Spin-Spin Splitting: Some Complications
☰

 Objectives

After completing this section, you should be able to

1. explain how multiple coupling can give rise to complex-looking 1H NMR spectra.
2. predict the splitting pattern expected in the 1H NMR spectrum of an organic compound in which multiple coupling
is possible.
3. interpret 1H NMR spectra in which multiple coupling is evident.

 Key Terms

Make certain that you can define, and use in context, the key term below.
tree diagram

 Study Notes

We saw the effects of spin-spin coupling on the appearance of a 1H NMR signal. These effects can be further
complicated when that signal is coupled to several different protons. For example, BrCH2CH2CH2Cl would produce
three signals. The hydrogens at C1 and C3 would each be triplets because of coupling to the two hydrogens on C2.
However, the hydrogen on C2 “sees” two different sets of neighboring hydrogens, and would therefore produce a
triplet of triplets.
Another effect that can complicate a spectrum is the “closeness” of signals. If signals accidently overlap they can be
difficult to identify. In the example above, we expected a triplet of triplets. However, if the coupling is identical (or
almost identical) between the hydrogens on C2 and the hydrogens on both C1 and C3, one would observe a quintet in
the 1H NMR spectrum. [You can try this yourself by drawing a tree diagram of a triplet of triplets assuming, first,
different coupling constants, and then, identical coupling constants.] Keep this point in mind when interpreting real 1H
NMR spectra.
Also, when multiplets are well separated, they form patterns. However, when multiplets approach each other in the
spectrum they sometimes become distorted. Usually, the inner peaks become larger than the outer peaks. Note the
following examples:

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☰

Aromatic ring protons quite commonly have overlapping signals and multiplet distortions. Sometimes you cannot
distinguish between individual signals, and one or more messy multiplets often appear in the aromatic region.
It is much easier to rationalize the observed 1H NMR spectrum of a known compound than it is to determine the
structure of an unknown compound from its 1H NMR spectrum. However, rationalizations can be a useful learning
technique as you try to improve your proficiency in spectral interpretation. Remember that when a chemist tries to
interpret the 1H NMR spectrum of an unknown compound, he or she usually has additional information available to
make the task easier. For example, the chemist will almost certainly have an infrared spectrum of the compound and
possibly a mass spectrum too. Details of how the compound was synthesized may be available, together with some
indication of its chemical properties, its physical properties, or both.
In examinations, you will be given a range of information (IR, MS, UV data and empirical formulae) to aid you with
your structural determination using 1H NMR spectroscopy. For example, you may be asked to determine the structure
of C6H12O given the following spectra:
Infrared spectrum: 3000 cm−1 and 1720 cm−1 absorptions are both strong
1H NMR δ (ppm) Protons Multiplicity

0.87 6 doublet
1.72 1 broad multiplet
2.00 3 singlet
2.18 2 doublet

To answer this question, you note that the infrared spectrum of C6H12O shows $\ce{\sf{C-H}}$ stretching (3000
cm−1) and $\ce{\sf{C-O}}$ stretching (1720 cm−1). Now you have to piece together the information from the 1H NMR
spectrum. Notice the singlet with three protons at 2.00 ppm. This signal indicates a methyl group that is not coupled to
other protons. It could possibly mean the presence of a methyl ketone functional group.

The signal at 1.72 ppm is a broad multiplet, suggesting that a carbon with a single proton is beside carbons with
several different protons.

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☰

The doublet signal at 2.18 ppm implies that a $\ce{\sf{-CH2-}}$ group is attached to a carbon having only one proton.

The six protons showing a doublet at 0.87 ppm indicate two equivalent methyl groups attached to a carbon with one
proton.

Whenever you see a signal in the 0.7-1.3 ppm range that is a multiplet of three protons (3, 6, 9) it is most likely caused
by equivalent methyl groups.
Using trial and error, and with the above observations, you should come up with the correct structure.

Complex coupling
In all of the examples of spin-spin coupling that we have seen so far, the observed splitting has resulted from the coupling
of one set of hydrogens to just one neighboring set of hydrogens. When a set of hydrogens is coupled to two or more sets
of nonequivalent neighbors, the result is a phenomenon called complex coupling. A good illustration is provided by the
1
H-NMR spectrum of methyl acrylate:

First, let's first consider the Hc signal,

which is centered at 6.21 ppm. Here is a closer look:

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☰

With this enlargement, it becomes evident that the Hc signal is actually composed of four sub-peaks. Why is this? Hc is
coupled to both Ha and Hb , but with two different coupling constants. Once again, a splitting diagram (or tree diagram)
can help us to understand what we are seeing. Ha is trans to Hc across the double bond, and splits the Hc signal into a
doublet with a coupling constant of 3Jac = 17.4 Hz. In addition, each of these Hc doublet sub-peaks is split again by Hb
(geminal coupling) into two more doublets, each with a much smaller coupling constant of 2Jbc = 1.5 Hz.

The result of this `double splitting` is a pattern referred to as a doublet of doublets, abbreviated `dd`.
The signal for Ha at 5.95 ppm is also a doublet of doublets, with coupling constants 3Jac= 17.4 Hz and 3Jab = 10.5 Hz.

The signal for Hb at 5.64 ppm is split into a doublet by Ha, a cis coupling with 3Jab = 10.4 Hz. Each of the resulting sub-
peaks is split again by Hc, with the same geminal coupling constant 2Jbc = 1.5 Hz that we saw previously when we looked
at the Hc signal. The overall result is again a doublet of doublets, this time with the two `sub-doublets` spaced slightly
closer due to the smaller coupling constant for the cis interaction. Here is a blow-up of the actual Hbsignal:

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 Example 10.8.1
☰
Construct a splitting diagram for the Hb signal in the 1H-NMR spectrum of methyl acrylate. Show the chemical shift
value for each sub-peak, expressed in Hz (assume that the resonance frequency of TMS is exactly 300 MHz).
Solution

 Note

When constructing a splitting diagram to analyze complex coupling patterns, it is usually easier to show the larger
splitting first, followed by the finer splitting (although the reverse would give the same end result).

When a proton is coupled to two different neighboring proton sets with identical or very close coupling constants, the
splitting pattern that emerges often appears to follow the simple `n + 1 rule` of non-complex splitting. In the spectrum of
1,1,3-trichloropropane, for example, we would expect the signal for Hb to be split into a triplet by Ha, and again into
doublets by Hc, resulting in a 'triplet of doublets'.

Ha and Hc are not equivalent (their chemical shifts are different), but it turns out that 3Jab is very close to 3Jbc. If we
perform a splitting diagram analysis for Hb, we see that, due to the overlap of sub-peaks, the signal appears to be a quartet,
and for all intents and purposes follows the n + 1 rule.

For similar reasons, the Hc peak in the spectrum of 2-pentanone appears as a sextet, split by the five combined Hb and Hd
protons. Technically, this 'sextet' could be considered to be a 'triplet of quartets' with overlapping sub-peaks.

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☰

 Example 10.8.2

What splitting pattern would you expect for the signal coresponding to Hb in the molecule below? Assume that Jab ~
Jbc. Draw a splitting diagram for this signal, and determine the relative integration values of each subpeak.

Solution

In many cases, it is difficult to fully analyze a complex splitting pattern. In the spectrum of toluene, for example, if we
consider only 3-bond coupling we would expect the signal for Hb to be a doublet, Hd a triplet, and Hc a triplet.

In practice, however, all three aromatic proton groups have very similar chemical shifts and their signals overlap
substantially, making such detailed analysis difficult. In this case, we would refer to the aromatic part of the spectrum as a
multiplet.
When we start trying to analyze complex splitting patterns in larger molecules, we gain an appreciation for why scientists
are willing to pay large sums of money (hundreds of thousands of dollars) for higher-field NMR instruments. Quite simply,
the stronger our magnet is, the more resolution we get in our spectrum. In a 100 MHz instrument (with a magnet of
approximately 2.4 Tesla field strength), the 12 ppm frequency 'window' in which we can observe proton signals is 1200 Hz
wide. In a 500 MHz (~12 Tesla) instrument, however, the window is 6000 Hz - five times wider. In this sense, NMR
instruments are like digital cameras and HDTVs: better resolution means more information and clearer pictures (and
higher price tags!)

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Exercises
☰1. Given the information below, draw the structures of compounds A through D.
a. An unknown compound A was prepared as follows:

Mass spectrum:
base peak m/e = 39
parent peak m/e = 54
1
H NMR spectrum:

δ (ppm) Relative Area Multiplicity

1.0 2 triplet
5.4 1 quintet

b. Unknown compound B has the molecular formula C7H6O2.

Infrared spectrum:
3200 cm−1 (broad) and 1747 cm−1 (strong) absorptions
1
H NMR spectrum:

δ (ppm) Protons

6.9 2
7.4 2
9.8 1
10.9 1

Hint: Aromatic ring currents deshield all proton signals just outside the ring.
c. Unknown compound C shows no evidence of unsaturation and contains only carbon and hydrogen.
Mass spectrum:
parent peak m/e = 68
1
H NMR spectrum:
δ (ppm) Relative Area Multiplicity

1.84 3 triplet
2.45 1 septet

Hint: Think three dimensionally!

d. Unknown compound D (C15H14O) has the following spectral properties.
Infrared spectrum:
3010 cm−1 (medium)
1715 cm−1 (strong)
1610 cm−1 (strong)
1500 cm−1 (strong)
1
H NMR spectrum:

δ (ppm) Relative Area Multiplicity

3.00 2 triplet

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 3.07 2 triplet
☰ 7.1-7.9 10 Multiplets

Answers
1. a.

b.

c.

d.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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10.9: Carbon-13 Nuclear Magnetic Resonance
☰

 Objectives

After completing this section, you should be able to

Determine the number of distinct C atoms in a molecule.
Use the chemical shifts table to determine functional groups present in a molecule.
Assign a chemical shift to each carbon in a given molecule.

The basics of 13C-NMR spectroscopy

Unlike 1H-NMR signals, the area under a 13C-NMR signal cannot be used to determine the number of carbons to which it
corresponds. This is because the signals for some types of carbons are inherently weaker than for other types – peaks
corresponding to carbonyl carbons, for example, are much smaller than those for methyl or methylene (CH2) peaks. Peak
integration is generally not useful in 13C-NMR spectroscopy, except when investigating molecules that have been enriched
with 13C isotope.
The resonance frequencies of 13C nuclei are lower than those of protons in the same applied field - in a 7.05 Tesla
instrument, protons resonate at about 300 MHz, while carbons resonate at about 75 MHz. This is fortunate, as it allows us
to look at 13C signals using a completely separate 'window' of radio frequencies. This means you will only see the 13C
nuclei in a 13C NMR experiment like in the 1H NMR experiments we just looked at, we only saw hydrogens. Just like in
1H-NMR, the standard used in 13C-NMR experiments to define the 0 ppm point is tetramethylsilane (TMS), although of

course in 13C-NMR it is the signal from the four equivalent carbons in TMS that serves as the standard. Chemical shifts
for 13C nuclei in organic molecules are spread out over a much wider range than for protons – up to 200 ppm for 13C
compared to 12 ppm for protons (see Table 3 for a list of typical 13C-NMR chemical shifts). This is also fortunate, because
it means that the signal from each carbon in a compound can almost always be seen as a distinct peak, without the
overlapping that often plagues 1H-NMR spectra. The chemical shift of a 13C nucleus is influenced by essentially the same
factors that influence a proton's chemical shift: bonds to electronegative atoms and diamagnetic anisotropy effects tend to
shift signals downfield (higher resonance frequency). In addition, sp2 hybridization results in a large downfield shift. The
13C-NMR signals for carbonyl carbons are generally the furthest downfield (170-220 ppm), due to both sp2 hybridization

and to the double bond to oxygen.

 Example 10.9.1

a) How many sets of non-equivalent carbons are there in each of the molecules shown in exercise 5.1?
b) How many sets of non-equivalent carbons are there in:
a. toluene
b. 2-pentanone
c. para-xylene
d. triclosan
(all structures are shown earlier in this chapter)
Solution
a
a) 8 signals (each carbon is different)
b) 11 signals (the two enantiotopic CH2CH3 groups are NMR-equivalent)
c) 6 signals (each carbon is different)
d) 16 signals (the fluorobenzene group only contributes 4 signals due to symmetry)
b
a) 5 signals

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 b) 5 signals
☰
c) 3 signals

d) 6 signals

Because of the low natural abundance of 13C nuclei, it is very unlikely to find two 13C atoms near each other in the same
molecule, and thus we do not see spin-spin coupling between neighboring carbons in a 13C-NMR spectrum. There is,
however, heteronuclear coupling between 13C carbons and the hydrogens to which they are bound. Carbon-proton
coupling constants are very large, on the order of 100 – 250 Hz. For clarity, chemists generally use a technique called
broadband decoupling, which essentially 'turns off' C-H coupling, resulting in a spectrum in which all carbon signals are
singlets. Below is the proton-decoupled13C-NMR spectrum of ethyl acetate, showing the expected four signals, one for
each of the carbons.

One of the greatest advantages of 13C-NMR compared to 1H-NMR is the breadth of the spectrum - recall that carbons
resonate from 0-220 ppm relative to the TMS standard, as opposed to only 0-12 ppm for protons. Because of this, 13C
signals rarely overlap, and we can almost always distinguish separate peaks for each carbon, even in a relatively large
compound containing carbons in very similar environments. In the proton spectrum of 1-heptanol, for example, only the
signals for the alcohol proton (Ha) and the two protons on the adjacent carbon (Hb) are easily analyzed. The other proton
signals overlap, making analysis difficult.

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In the 13C spectrum of the same molecule, however, we can easily distinguish each carbon signal, and we know from this
☰
data that our sample has seven non-equivalent carbons. (Notice also that, as we would expect, the chemical shifts of the
carbons get progressively smaller as they get farther away from the deshielding oxygen.)

This property of 13C-NMR makes it very helpful in the elucidation of larger, more complex structures.
13
C NMR Chemical Shifts
The Carbon NMR is used for determining functional groups using characteristic shift values. 13C chemical shifts
are greatly affected by electronegative effects. If a H atom in an alkane is replaced by substituent X,
electronegative atoms (O, N, halogen), 13C signals for nearby carbons shift downfield (left; increase in ppm)
with the effect diminishing with distance from the electron withdrawing group. Figure 13.11.1 shows typical 13C
chemical shift regions of the major chemical class.

Figure 10.9.1 : 13C Chemical shift range for organic compound

Spin-Spin splitting
Comparing the 1H NMR, there is a big difference thing in the 13C NMR. The 13C-13Cspin-spin splitting rarely exit
between adjacent carbons because 13C is naturally lower abundant (1.1%)
13
C-1H Spin coupling: 13C-1H Spin coupling provides useful information about the number of protons attached a
carbon atom. In case of one bond coupling (1JCH), -CH, -CH2, and CH3 have respectively doublet, triplet, quartets for

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 the 13C resonances in the spectrum. However, 13C-1H Spin coupling has an disadvantage for 13C spectrum
☰ interpretation. 13C-1H Spin coupling is hard to analyze and reveal structure due to a forest of overlapping peaks that
result from 100% abundance of 1H.
Decoupling: Decoupling is the process of removing 13C-1H coupling interaction to simplify a spectrum and
identify which pair of nuclei is involved in the J coupling. The decoupling 13C spectra shows only one
peak(singlet) for each unique carbon in the molecule (Fig 13.11.2). Decoupling is performed by irradiating at
the frequency of one proton with continuous low-power RF.

Fig 10.9.2: Decoupling in the 13C NMR

Contributors and Attributions

Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Chris P Schaller, Ph.D., (College of Saint Benedict / Saint John's University)
Layne Morsch (University of Illinois Springfield)
Lauren Reutenauer (Amherst College)

 Objectives
After completing this section, you should be able to use data from 13C NMR spectra to distinguish between two (or
more) possible structures for an unknown organic compound.

Features of a 13C NMR spectrum

Butane shows two different peaks in the 13C NMR spectrum, below. Note that: the chemical shifts of these peaks are not
very different from methane. The carbons in butane are in a similar environment to the one in methane.
there are two distinct carbons in butane: the methyl, or CH3, carbon, and the methylene, or CH2, carbon.
the methyl carbon absorbs slightly upfield, or at lower shift, around 10 ppm.
the methylene carbon absorbs at slightly downfield, or at higher shift, around 20 ppm.
other factors being equal, methylene carbons show up at slightly higher shift than methyl carbons.

Figure 10.9.1 . Simulated 13C NMR spectrum of butane (showing only the upfield portion of the spectrum).
In the 13C NMR spectrum of pentane (below), you can see three different peaks, even though pentane just contains methyl
carbons and methylene carbons like butane. As far as the NMR spectrometer is concerned, pentane contains three different
kinds of carbon, in three different environments. That result comes from symmetry.

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☰

Figure 10.9.2 .13C NMR spectrum of pentane. Source: SDBSWeb : http://riodb01.ibase.aist.go.jp/sdbs/ (National Institute
of Advanced Industrial Science and Technology of Japan, 15 August 2008)
Symmetry is an important factor in spectroscopy. Nature says:
atoms that are symmetry-inequivalent can absorb at different shifts.
atoms that are symmetry-equivalent must absorb at the same shift.
To learn about symmetry, take a model of pentane and do the following:
make sure the model is twisted into the most symmetric shape possible: a nice "W".
choose one of the methyl carbons to focus on.
rotate the model 180 degrees so that you are looking at the same "W" but from the other side.
note that the methyl you were focusing on has simply switched places with the other methyl group. These two carbons
are symmetry-equivalent via two-fold rotation.
By the same process, you can see that the second and fourth carbons along the chain are also symmetry-equivalent.
However, the middle carbon is not; it never switches places with the other carbons if you rotate the model. There are three
different sets of inequivalent carbons; these three groups are not the same as each other according to symmetry.

 Example 10.9.1
Determine how many inequivalent carbons there are in each of the following compounds. How many peaks do you
expect in each 13C NMR spectrum?

Practically speaking, there is only so much room in the spectrum from one end to the other. At some point, peaks can
get so crowded together that you can't distinguish one from another. You might expect to see ten different peaks in
eicosane, a twenty-carbon alkane chain, but when you look at the spectrum you can only see seven different peaks.
That may be frustrating, because the experiment does not seem to agree with your expectation. However, you will be
using a number of methods together to minimize the problem of misleading data.
Solution
a) Three inequivalent carbons/three peaks. There is a plane of symmetry that bisects the cyclohexene horizontally. The
three different carbons are one of the alkene (C1), the CH2 next to alkene (C3) and C4.

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 b) Six inequivalent carbons/six peaks. The two methyl groups attached to the alkene are identical.
☰
c) Four inequivalent carbons/four peaks. This molecule has a plane of symmetry through the molecule, including the
methyl group. The two carbons adjacent to the methyl group are equivalent (C2 and C5). C3 and C4 are also
equivalent.
d) Five inequivalent carbons/five peaks. This molecule has a plane of symmetry that passes through the ring carbon
between the two methyl groups. The two methyl carbons are identical. The two ring carbons with the methyl groups
attached are identical (C1 and C3). C4 and C6 are also equivalent.
e) Six inequivalent carbons/six peaks. The three methyl groups at the end of the molecule are equivalent.
f) Ten inequivalent carbons/ten peaks. There is no symmetry for the carbons in this molecule.

The 13C NMR spectrum for ethanol

This is a simple example of a 13C NMR spectrum. Don't worry about the scale for now - we'll look at that in a minute.

 Note

Note: The NMR spectra on this page have been produced from graphs taken from the Spectral Data Base System for
Organic Compounds (SDBS) at the National Institute of Materials and Chemical Research in Japan.

There are two peaks because there are two different environments for the carbons. The carbon in the CH3 group is attached
to 3 hydrogens and a carbon. The carbon in the CH2 group is attached to 2 hydrogens, a carbon and an oxygen. The two
lines are in different places in the NMR spectrum because they need different external magnetic fields to bring them in to
resonance at a particular radio frequency.

The 13C NMR spectrum for a more complicated compound

13
This is the C NMR spectrum for 1-methylethyl propanoate (also known as isopropyl propanoate or isopropyl
propionate).

This time there are 5 lines in the spectrum. That means that there must be 5 different environments for the carbon atoms in
the compound. Is that reasonable from the structure?

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If you count the carbon atoms, there are 6 of them. So why only 5 lines? In this case, two of the carbons are in exactly the
☰
same environment. They are attached to exactly the same things. Look at the two CH3 groups on the right-hand side of the
molecule.
You might reasonably ask why the carbon in the CH3 on the left is not also in the same environment. Just like the ones on
the right, the carbon is attached to 3 hydrogens and another carbon. But the similarity is not exact - you have to chase the
similarity along the rest of the molecule as well to be sure.
The carbon in the left-hand CH3 group is attached to a carbon atom which in turn is attached to a carbon with two oxygens
on it - and so on down the molecule. That's not exactly the same environment as the carbons in the right-hand CH3 groups.
They are attached to a carbon which is attached to a single oxygen - and so on down the molecule. We'll look at this
spectrum again in detail on the next page - and look at some more similar examples as well. This all gets easier the more
examples you look at.
For now, all you need to realize is that each line in a 13C NMR spectrum recognizes a carbon atom in one particular
environment in the compound. If two (or more) carbon atoms in a compound have exactly the same environment, they will
be represented by a single line.

 Note

You might wonder why all this works, since only about 1% of carbon atoms are 13C. These are the only ones picked up
by this form of NMR. If you had a single molecule of ethanol, then the chances are only about 1 in 50 of there being
one 13C atom in it, and only about 1 in 10,000 of both being 13C.
But you have got to remember that you will be working with a sample containing huge numbers of molecules. The
instrument can pick up the magnetic effect of the 13C nuclei in the carbon of the CH3 group and the carbon of the CH2
group even if they are in separate molecules. There's no need for them to be in the same one.

Contributors and Attributions

Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne Morsch (University of Illinois Springfield)
Lauren Reutenauer (Amherst College)

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Back Matter

Index

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Index
C L P
Coulombic force Lewis structures pheromones
1.4: Electron-Dot Model of Bonding - Lewis 12.17: Alkenes in Nature - Insect Pheromones
1.2: Coulomb Forces - A Simplified View of
Structures
Bonding
S
O solvolysis
octet rule 7.1: Solvolysis of Tertiary and Secondary
1.3: Ionic and Covalent Bonds - The Octet Rule Haloalkanes
CHAPTER OVERVIEW
11: ALKENES: INFRARED SPECTROSCOPY AND MASS SPECTROMETRY
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

11.1: NAMING THE ALKENES

11.2: STRUCTURE AND BONDING IN ETHENE: THE PI BOND
11.3: PHYSICAL PROPERTIES OF ALKENES
11.4: NUCLEAR MAGNETIC RESONANCE OF ALKENES
11.5: CATALYTIC HYDROGENATIN OF ALKENES: RELATIVE STABILITY OF DOUBLE BONDS
11.6: PREPARATION OF ALKENES FROM HALOALKANES AND ALKYL SUFONATES: BIMOLECULAR ELIMINATION
REVISITED
11.7: PREPARATION OF ALKENES BY DEHYDRATION OF ALCOHOLS
11.8: INFRARED SPECTROSCOPY
11.9: MEASURING THE MOLECULAR MASS OF ORGANIC COMPOUNDS: MASS SPECTROMETRY
11.10: FRAGMENTATION PATTERNS OF ORGANIC MOLECULES
11.11: DEGREE OF UNSATURATION: ANOTHER AID TO IDENTIFYING MOLECULAR STRUCTURE

1 12/5/2021
11.1: Naming the Alkenes
 Objectives

After completing this section, you should be able to

1. provide the correct IUPAC name for an acyclic or cyclic alkene, given its Kekulé, condensed or shorthand structure.
2. draw the Kekulé, condensed or shorthand structure of an alkene (cyclic or acyclic), given its IUPAC name.
3. give the IUPAC equivalent of the following trivial names: ethylene, propylene, isobutylene and isoprene.
4. draw the structure of a vinyl (ethenyl) and allyl (2-propenyl) group, and use these names in alkene nomenclature.

 Study Notes

This course uses IUPAC nomenclature; therefore, you need not usually memorize a large number of trivial names.
However, you will encounter some trivial names so frequently in books and articles that they soon become familiar.
An alkene that can exhibit geometric isomerism has not been properly named unless its name specifies whether the double
bond (or bonds) is (or are) cis or trans. The most effective way of giving this information is discussed, and more details of
cis and trans follow in Section 7.4.

Introduction
Alkenes contain carbon-carbon double bonds and are unsaturated hydrocarbons with the molecular formula is CnH2n; this is
also the same molecular formula as cycloalkanes. The parent chain of an alkene is the longest chain containing both carbon
atoms of the double bond. Alkenes are named by dropping the -ane ending of the parent and adding -ene. Also, the position of
double bond in the parent chain of the alkene is indicated with a number.

The Basic Rules for Naming Alkenes

For straight chain alkenes, it is the same basic rules as nomenclature of alkanes apply except the -ane suffix is changed to -
ene.
1) Find the longest carbon chain that contains both carbons of the double bond.
H3CH2C H H3CH2C H
C C C C
H3CH2C H H3CH2C H

This compound is NOT This compound is named

named as an pentene as a butene because the
double bond is contained in
the four carbon chain

2) Start numbering from the end of the parent chain which gives the lowest possible number to the double bond. If the double
bond is equidistant from both ends of the parent chain, number from the end which gives the substituents the lowest possible
number. The double bond in cycloalkenes do not need to number because it is understood that they are in the one position.

CH3
CH3CH2CH CHCH3 CH3CHCH CHCH2CH3
5 4 3 2 1 1 2 3 4 5 6

3) Place the location number of the double bond directly before the parent name. The location number indicates the position of
the first carbon of the double bond. Add substituents and their position to the alkene as prefixes. Remember substituents are
written in alphabetical order.
The presence of multiple double bonds is indicated by using the appropriate suffix such as -diene, -triene, ect. Each of the
multiple bonds receives a location number. Also, only -ne is removed from the parent alkane chain name leaving an "a" in the

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name.
Overall, the name of an alkene should look like:
(Location number of substituent)-(Name of substituent)-(Location number of double bond)-(Name of parent chain) + ene
CH3
CH3CH2CH CHCH3 CH3CHCH CHCH2CH3
5 4 3 2 1 1 2 3 4 5 6

2-Pentene 2-Methyl-3-hexene

CH3
H3CH2C H
C C CH3CHCH CH CH CH2
2 1 6 5 4 3 2 1
H3CH2C H
4 3
3-Ethyl-1-butene 5-Methyl-1,3-hexadiene

Newer IUPAC Nomenclature

In 1993 IUPAC updated their naming recommendation to place the location number of the double bond before the -ene suffix
of alkene names. The provides names such as hex-2-ene rather than 2-hexene. The newer system is slowly being accepted so it
may occasionally be encountered.
CH3 CH3 CH3 CH3
CH3CHCH CHCH2CH3 CH3CHCH CH C CH CH3
1 2 3 4 5 6 7 6 5 4 3 2 1

Older Numbering System: 2,5-Dimethyl-3-hexene 5-Methyl-1,3-hexadiene

Newer Numbering System: 2,5-Dimethylhex-3-ene 5-Methylhexa-1,3-diene

Naming Cycloalkenes
Because there are no chain ends in cycloalkenes, the double bond is assumed to numbered C1 and C2 and its location number
is not required in the name. The direction of the numbering is determined by which will give the substituent closest to the
double bond the lowest number. If multiple double bonds are present, it may be necessary to include their location numbers in
the name. One of the double bonds will be number C1 and C2 and the numbering direction is determined by which gives the
remaining double bonds the lowest possible number.
6 1
2 H 3C 5 1 CH3
3 6 2
H3C 1
4 2 5 3
4 5
3 4

3-Methylcyclopentene 1,5-Dimethylcyclohexene 1,3-Cyclohexadiene

(New:Cyclohexa-1,3-diene)

Endocyclic vs. Exocyclic Alkenes

Endocyclic double bonds have both carbons in the ring and exocyclic double bonds have only one carbon as part of the ring.

cycloalkane:
a type of alkane
which has one
or more rings of
carbon atoms in
its chemical
structure

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Cyclopentene is an example of an endocyclic double bond.

Methylenecylopentane is an example of an exocyclic double bond.

Name the following compounds...

1-methylcyclobutene. The methyl group places the double bond. It is correct to also name this compound as 1-methylcyclobut-
1-ene.

1-ethenylcyclohexene, the methyl group places the double bond. It is correct to also name this compound as 1-
ethenylcyclohex-1-ene. A common name would be 1-vinylcyclohexene.
Try to draw structures for the following compounds...
3-allylcyclohex-1-ene

2-vinyl-1,3-cyclohexadiene

Common Names of Alkene Fragments

Some alkene containing fragments have common names which should be recognized. These common names can be used to
simplify naming much the alkyl fragments discussed in Section: 3.3. Some of these fragments are the methylene group
(H2C=), the vinyl group (H2C=CH-), and the allyl group (H2C=CH-CH2-).

H H H H H
C C C C C
H H H H2 C

Methylene Group Vinyl Group Allyl Group

In addition, the common name some small alkene compounds are still accepted by IUPAC. It is important to be able to identify
them.
CH3 H
H H H CH3 H CH3
C C C C C C H C C
C C H
H H H H H CH3
H H

Common Name: Ethylene Propylene Isobutylene Isoprene

IUPAC Name: Ethene Propene 2-Methylpropene 2-Methyl-1,3-butadiene

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 Exercise 11.1.1

Name the following compounds using common fragment names.

a) b) C)

Answer
a) 2-Vinyl-1,3-cyclohexadiene
b) Methylenecylopentane
c) 3-Allylcyclohexene

Examples
CH3
H CH3
H3 C 2 C C4 (CH3)2C=CHCH2C(CH3)3
(1) C C 5 CH3 ≣ ≣
1 3
2,5,5-trimethyl-2-hexene
H2 6
CH3

1 CH2
H2 H2
(CH3CH2CH2)2C=CH2
(2) C C 3 C 5 ≣ ≣
H3 C C 2 C 4 CH3 2-propyl-1-pentene
H2 H2

Both these compounds have double bonds, making them alkenes. In example (1) the longest chain consists of six carbons, so
the root name of this compound will be hexene. Three methyl substituents (colored red) are present. Numbering the six-carbon
chain begins at the end nearest the double bond (the left end), so the methyl groups are located on carbons 2 & 5. The IUPAC
name is therefore: 2,5,5-trimethyl-2-hexene.
In example (2) the longest chain incorporating both carbon atoms of the double bond has a length of five. There is a seven-
carbon chain, but it contains only one of the double bond carbon atoms. Consequently, the root name of this compound will be
pentene. There is a propyl substituent on the inside double bond carbon atom (#2), so the IUPAC name is: 2-propyl-1-pentene.
H2 H 6
C 3 C H CH3
H3 C 2 C 4 C5 (CH3CH2)2C=CHCH(CH3)2
(3) ≣ ≣
1 4-ethyl-2-methyl-3-hexene
CH2 CH3
H3 C

1
CH3 CH2
5 C H C CH3 CH2=C(CH3)CH(CH3)C(C2H5)=CH2
(4) H2 C C3 2 C ≣ ≣
4 2-ethyl-3,4-dimethyl-1,4-pentadiene
H2
CH3

The double bond in example (3) is located in the center of a six-carbon chain. The double bond would therefore have a locator
number of 3 regardless of the end chosen to begin numbering. The right hand end is selected because it gives the lowest first-
substituent number (2 for the methyl as compared with 3 for the ethyl if numbering were started from the left). The IUPAC
name is assigned as shown.
Example (4) is a diene (two double bonds). Both double bonds must be contained in the longest chain, which is therefore five-
rather than six-carbons in length. The second and fourth carbons of this 1,4-pentadiene are both substituted, so the numbering
begins at the end nearest the alphabetically first-cited substituent (the ethyl group).
2 3
CH3
(5) ≣ H 3C 1 4 CH ≣ 4-isopropyl-1-methylcyclohexene
CH3

CH3
1 2 3
(6) ≣ C C CH ≣ 1-cyclobutyl-3-methyl-1-butyne
4 CH
3

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 1

(7) ≣ 2 ≣ 1-cyclodecen-4-yne
C C 3
5 4

3 4
Cl H Cl
C 2 5
(8) Cl ≣ H 2C Cl ≣ 5,5-dichloro-2-vinyl-1,3,6-cyclooctatriene
1 6

8 7

These examples include rings of carbon atoms as well as some carbon-carbon triple bonds. Example (6) is best named as an
alkyne bearing a cyclobutyl substituent. Example (7) is simply a ten-membered ring containing both a double and a triple
bond. The double bond is cited first in the IUPAC name, so numbering begins with those two carbons in the direction that
gives the triple bond carbons the lowest locator numbers. Because of the linear geometry of a triple bond, a-ten membered ring
is the smallest ring in which this functional group is easily accommodated. Example (8) is a cyclooctatriene (three double
bonds in an eight-membered ring). The numbering must begin with one of the end carbons of the conjugated diene moiety
(adjacent double bonds), because in this way the double bond carbon atoms are assigned the smallest possible locator numbers
(1, 2, 3, 4, 6 & 7). Of the two ways in which this can be done, we choose the one that gives the vinyl substituent the lower
number.

References
1. Vollhardt, Peter, and Neil E. Schore. Organic Chemistry: Structure and Function. 5th Edition. New York: W. H. Freeman &
Company, 2007.

Problems
1. Try to name the following compounds...

2. Try to draw structures for the following compounds...

2-pentene
3-heptene
3. Give the double bond the lowest possible numbers regardless of substituent placement.
• Try to draw a structure for the following compound...
4-methyl-2-pentene
4. Name the following structures:
5. Draw (Z)-5-Chloro-3-ethly-4-hexen-2-ol

Answers
1. 1-pentene or pent-1-ene; 2-ethyl-1-hexene or 2-ethylhex-1-ene
2. CH3–CH=CH–CH2–CH3; CH3–CH2–CH=CH–CH2–CH2–CH3
3. CH3–CH=CH–CH(CH3)–CH3
4. (I) trans-8-ethyl-3-undecene; (II) E-5-bromo-4-chloro-7,7-dimethyl-4-undecene;
(III) Z-1,2-difluoro-cyclohexene; (IV) 4-ethenylcyclohexanol
5.

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
S. Devarajan (UCD)
Prof. Steven Farmer (Sonoma State University)
Richard Banks (Boise State University)
Dr. Krista Cunningham

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11.2: Structure and Bonding in Ethene: The Pi Bond
This is an introductory page about alkenes such as ethene, propene and the rest. It deals with their formulae and
isomerism, their physical properties, and an introduction to their chemical reactivity.

What are alkenes?

Alkenes are a family of hydrocarbons (compounds containing carbon and hydrogen only) containing a carbon-carbon
double bond. The first two are:

ethene C2H4
propene C3H6

You can work out the formula of any of them using: CnH2n The table is limited to the first two, because after that
there are isomers which affect the names.

Isomerism in the alkenes

Structural isomerism
All the alkenes with 4 or more carbon atoms in them show structural isomerism. This means that there are two or more
different structural formulae that you can draw for each molecular formula.
For example, with C4H8, it isn't too difficult to come up with these three structural isomers:

There is, however, another isomer. But-2-ene also exhibits geometric isomerism.

Geometric (cis-trans) isomerism

The carbon-carbon double bond doesn't allow any rotation about it. That means that it is possible to have the CH3
groups on either end of the molecule locked either on one side of the molecule or opposite each other.
These are called cis-but-2-ene (where the groups are on the same side) or trans-but-2-ene (where they are on
opposite sides).

Cis-but-2-ene is also known as (Z)-but-2-ene; trans-but-2-ene is also known as (E)-but-2-ene. For an explanation of
the two ways of naming these two compounds, follow the link in the box below..

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Chemical Reactivity
Bonding in the alkenes
We just need to look at ethene, because what is true of C=C in ethene will be equally true of C=C in more complicated
alkenes. Ethene is often modeled like this:

The double bond between the carbon atoms is, of course, two pairs of shared electrons. What the diagram doesn't
show is that the two pairs aren't the same as each other.

One of the pairs of electrons is held on the line between the two carbon nuclei as you would expect, but the other is
held in a molecular orbital above and below the plane of the molecule. A molecular orbital is a region of space within
the molecule where there is a high probability of finding a particular pair of electrons.

In this diagram, the line between the two carbon atoms represents a normal bond - the pair of shared electrons lies in a
molecular orbital on the line between the two nuclei where you would expect them to be. This sort of bond is called a
sigma bond.
The other pair of electrons is found somewhere in the shaded part above and below the plane of the molecule. This
bond is called a pi bond. The electrons in the pi bond are free to move around anywhere in this shaded region and can
move freely from one half to the other.

The pi electrons are not as fully under the control of the carbon nuclei as the electrons in the sigma bond and, because
they lie exposed above and below the rest of the molecule, they are relatively open to attack by other things.

Contributors
Jim Clark (Chemguide.co.uk)

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11.3: Physical Properties of Alkenes
Physical state
Ethene, Propene, and Butene exists as colorless gases. Members of the 5 or more carbons such as Pentene, Hexene, and
Heptene are liquid, and members of the 15 carbons or more are solids.

Density
Alkenes are lighter than water, therefore, are insoluble in water. Alkenes are only soluble in nonpolar solvent.

Solubility
Alkenes are virtually insoluble in water, but dissolve in organic solvents. The reasons for this are exactly the same as for
the alkanes.

Boiling Points
The boiling point of each alkene is very similar to that of the alkane with the same number of carbon atoms. Ethene,
propene and the various butenes are gases at room temperature. All the rest that you are likely to come across are liquids.
Boiling points of alkenes depends on more molecular mass (chain length). The more intermolecular mass is added, the
higher the boiling point. Intermolecular forces of alkenes gets stronger with increase in the size of the molecules.

Compound Boiling points (oC)

Ethene -104
Propene -47
Trans-2-Butene 0.9
Cis-2-butene 3.7
Trans 1,2-dichlorobutene 155
Cis 1,2-dichlorobutene 152
1-Pentene 30
Trans-2-Pentene 36
Cis-2-Pentene 37
1-Heptene 115
3-Octene 122
3-Nonene 147
5-Decene 170

In each case, the alkene has a boiling point which is a small number of degrees lower than the corresponding alkane. The
only attractions involved are Van der Waals dispersion forces, and these depend on the shape of the molecule and the
number of electrons it contains. Each alkene has 2 fewer electrons than the alkane with the same number of carbons.

Melting Points
Melting points of alkenes depends on the packaging of the molecules. Alkenes have similar melting points to that of
alkanes, however, in cis isomers molecules are package in a U-bending shape, therefore, will display a lower melting
points to that of the trans isomers.

Compound Melting Points (0C)

Ethene -169
Propene -185
Butene -138

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1-Pentene -165
Trans-2-Pentene -135
Cis-2-Pentene -180
1-Heptene -119
3-Octene -101.9
3-Nonene -81.4
5-Decene -66.3

Polarity
Chemical structure and fuctional groups can affect the polarity of alkenes compounds. The sp2 carbon is much more
electron-withdrawing than the sp3 hybridize orbitals, therefore, creates a weak dipole along the substituent weak alkenly
carbon bond. The two individual dipoles together form a net molecular dipole. In trans-subsituted alkenes, the dipole
cancel each other out. In cis-subsituted alkenes there is a net dipole, therefore contributing to higher boiling in cis-isomers
than trans-isomers.

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Contributors
Trung Nguyen
Jim Clark (Chemguide.co.uk)

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11.4: Nuclear Magnetic Resonance of Alkenes

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11.5: Catalytic hydrogenatin of Alkenes: Relative Stability of Double Bonds

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11.6: Preparation of Alkenes from Haloalkanes and Alkyl Sufonates:
Bimolecular Elimination Revisited
E2 Reaction
E2 reactions are typically seen with secondary and tertiary alkyl halides, but a hindered base is necessary with a primary
halide. The mechanism by which it occurs is a single step concerted reaction with one transition state. The rate at which
this mechanism occurs is second order kinetics, and depends on both the base and alkyl halide. A good leaving group is
required because it is involved in the rate determining step. The leaving groups must be coplanar in order to form a pi
bond; carbons go from sp3 to sp2 hybridization states.
To get a clearer picture of the interplay of these factors involved in a a reaction between a nucleophile/base and an alkyl
halide, consider the reaction of a 2º-alkyl halide, isopropyl bromide, with two different nucleophiles. In one pathway, a
methanethiolate nucleophile substitutes for bromine in an SN2 reaction. In the other (bottom) pathway, methoxide ion acts
as a base (rather than as a nucleophile) in an elimination reaction. As we will soon see, the mechanism of this reaction is
single-step, and is referred to as the E2 mechanism.
.

E1 Reaction
An E1 reaction involves the deprotonation of a hydrogen nearby (usually one carbon away, or the beta position) the
carbocation resulting in the formation of an alkene product. In order to accomplish this, a Lewis base is required. For a
simplified model, we’ll take B to be a Lewis base, and LG to be a halogen leaving group.

As can be seen above, the preliminary step is the leaving group (LG) leaving on its own. Because it takes the electrons in
the bond along with it, the carbon that was attached to it loses its electron, making it a carbocation. Once it becomes a
carbocation, a Lewis Base ( ) deprotonates the intermediate carbocation at the beta position, which then donates its
electrons to the neighboring C-C bond, forming a double bond. Unlike E2 reactions, which require the proton to be anti to
the leaving group, E1 reactions only require a neighboring hydrogen. This is due to the fact that the leaving group has
already left the molecule. The final product is an alkene along with the HB byproduct.

Dehydration
One way to synthesize alkenes is by dehydration of alcohols, a process in which alcohols undergo E1 or E2 mechanisms to
lose water and form a double bond.
The dehydration reaction of alcohols to generate alkene proceeds by heating the alcohols in the presence of a strong acid,
such as sulfuric or phosphoric acid, at high temperatures.

Primary alcohol dehydrates through the E2 mechanism

Oxygen donates two electrons to a proton from sulfuric acid H2SO4, forming an alkyloxonium ion. Then the nucleophile
HSO4– back-side attacks one adjacent hydrogen and the alkyloxonium ion leaves in a concerted process, making a double

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bond.

Secondary and tertiary alcohols dehydrate through the E1 mechanism

Similarly to the reaction above, secondary and tertiary –OH protonate to form alkyloxonium ions. However, in this case
the ion leaves first and forms a carbocation as the reaction intermediate. The water molecule (which is a stronger base than
the HSO4- ion) then abstracts a proton from an adjacent carbon, forming a double bond. Notice in the mechanism below
that the aleke formed depends on which proton is abstracted: the red arrows show formation of the more substituted 2-
butene, while the blue arrows show formation of the less substituted 1-butene. Recall the general rule that more substituted
alkenes are more stable than less substituted alkenes, and trans alkenes are more stable than cis alkenes. Thereore, the
trans diastereomer of the 2-butene product is most abundant.

Zaitsev's Rule
Zaitsev’s or Saytzev’s (anglicized spelling) rule is an empirical rule used to predict regioselectivity of 1,2-elimination
reactions occurring via the E1 or E2 mechanisms. It states that in a regioselective E1 or E2 reaction the major product is
the more stable alkene, (i.e., the alkene with the more highly substituted double bond). For example:

If two or more structurally distinct groups of beta-hydrogens are present in a given reactant, then several constitutionally
isomeric alkenes may be formed by an E2 elimination. This situation is illustrated by the 2-bromobutane and 2-bromo-2,3-
dimethylbutane elimination examples given below.

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Gamini Gunawardena from the OChemPal site (Utah Valley University)

 Objectives

After completing this section, you should be able to

1. write the mechanism of a typical E2 reaction.
2. sketch the transition state of a typical E2 reaction.
3. discuss the kinetic evidence that supports the proposed E2 mechanism.

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 4. discuss the stereochemistry of an E2 reaction, and explain why the anti periplanar geometry is preferred.
5. determine the structure of the alkene produced from the E2 reaction of a substrate containing two chiral carbon
atoms.
6. describe the deuterium isotope effect, and discuss how it can be used to provide evidence in support of the E2
mechanism.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
anti periplanar
deuterium isotope effect
E2 reaction
periplanar
syn periplanar

 Study Notes

An E2 reaction is a bimolecular elimination reaction; thus, two molecules are involved in the rate-limiting step. In this
section, we are concerned with E2 reactions involving an alkyl halide and a base.
Use molecular models to assist you to understand the difference between syn periplanar and anti periplanar, and to
appreciate why E2 eliminations are stereospecific.
Note that when deuterium is used the kinetic isotope effect (KIE) is referred to as the deuterium isotope effect. A C–H
bond is about 5 kJ/mol weaker than a C–D bond. So if the rate-limiting step involves a breaking of this bond as it does
at the E2 transition state there will be a substantial difference in reaction rates when comparing deuterated and non-
deuterated analogues. Indeed, the reaction of 2-bromopropane with sodium ethoxide (NaOEt) is 6.7 times faster than
its deuterated counterpart, providing evidence consistent with an E2 mechanism.

Content
E2, bimolecular elimination, was proposed in the 1920s by British chemist Christopher Kelk Ingold. Unlike E1 reactions,
E2 reactions remove two subsituents in a single concerted reaction step, also resulting in an alkene.

Introduction
E2 reactions are typically seen with secondary and tertiary alkyl halides, but a hindered base is necessary with a primary
halide. The mechanism by which it occurs is a single step concerted reaction with one transition state. The rate at which
this mechanism occurs is second order kinetics, and depends on both the base and alkyl halide. A good leaving group is
required because it is involved in the rate determining step. The leaving groups must be coplanar in order to form a pi
bond; carbons go from sp3 to sp2 hybridization states.
To get a clearer picture of the interplay of these factors involved in a a reaction between a nucleophile/base and an alkyl
halide, consider the reaction of a 2º-alkyl halide, isopropyl bromide, with two different nucleophiles. In one pathway, a
methanethiolate nucleophile substitutes for bromine in an SN2 reaction. In the other (bottom) pathway, methoxide ion acts

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as a base (rather than as a nucleophile) in an elimination reaction. As we will soon see, the mechanism of this reaction is
single-step, and is referred to as the E2 mechanism.

General Reaction
Below is a mechanistic diagram of an elimination reaction by the E2 pathway:

An E2 reaction has certain requirements to proceed:

A strong base is necessary especially necessary for primary alkyl halides. Secondary and tertirary primary halides will
procede with E2 in the precesence of a base (OH-, RO-, R2N-)
Both leaving groups should be on the same plane, this allows the double bond to form in the reaction. In the reaction
above you can see both leaving groups are in the plane of the carbons.
Follows Zaitsev's rule, the most substituted alkene is usually the major product.
Hofmann's Rule, if a sterically hindered base will result in the least substituted product.

E2 Reaction Coordinate
In this reaction Ba represents the base and Br representents a leaving group, typically a halogen. There is one transition
state that shows the concerted reaction for the base attracting the hydrogen and the halogen taking the electrons from the
bond. The product be both eclipse and staggered depending on the transition states. Eclipsed products have a synperiplanar
transition states, while staggered products have antiperiplanar transition states. Staggered conformation is usually the
major product because of its lower energy confirmation.

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The Leaving Group Effect in E2 Reactions
As Size Increases, The Ability of the Leaving Group to Leave Increases: Here we revisit the effect size has on basicity.
If we move down the periodic table, size increases. With an increase in size, basicity decreases, and the ability of the
leaving group to leave increases. The relationship among the following halogens, unlike the previous example, is true to
what we will see in upcoming reaction mechanisms.

Kinetic Isotope Effects

Kinetic Isotope Effects (KIEs) are used to determine reaction mechanisms by determining rate limiting steps and transition
states and are commonly measured using NMR to detect isotope location or GC/MS to detect mass changes. In a KIE
experiment an atom is replaced by its isotope and the change in rate of the reaction is observed. A very common isotope
substitution is when hydrogen is replaced by deuterium. This is known as a deuterium effect and is expressed by the ratio
kH/kD (as explained above). Normal KIEs for the deuterium effect are around 1 to 7 or 8. Large effects are seen because
the percentage mass change between hydrogen and deuterium is great. Heavy atom isotope effects involve the substitution
of carbon, oxygen, nitrogen, sulfur, and bromine, with effects that are much smaller and are usually between 1.02 and 1.10.
The difference in KIE magnitude is directly related to the percentage change in mass. Large effects are seen when
hydrogen is replaced with deuterium because the percentage mass change is very large (mass is being doubled) while
smaller percent mass changes are present when an atom like sulfur is replaced with its isotope (increased by two mass
units).

Primary KIEs
Primary kinetic isotope effects are rate changes due to isotopic substitution at a site of bond breaking in the rate
determining step of a reaction.

 Example
Consider the bromination of acetone: kinetic studies have been performed that show the rate of this reaction is
independent of the concentration of bromine. To determine the rate determining step and mechanism of this reaction
the substitution of a deuterium for a hydrogen can be made.

When hydrogen was replaced with deuterium in this reaction a kH/kD of 7 was found. Therefore the rate determining
step is the tautomerization of acetone and involves the breaking of a C-H bond. Since the breaking of a C-H bond is
involved, a substantial isotope effect is expected.

Exercises
Questions
Q11.8.1
What is the product of the following molecule in an E2 reaction? What is the stereochemistry?

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Solutions
S11.8.1
The stereochemistry is (Z) for the reaction.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne Morsch (University of Illinois Springfield)

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11.7: Preparation of Alkenes by Dehydration of Alcohols
One way to synthesize alkenes is by dehydration of alcohols, a process in which alcohols undergo E1 or E2 mechanisms to
lose water and form a double bond.

Introduction
The dehydration reaction of alcohols to generate alkene proceeds by heating the alcohols in the presence of a strong acid, such
as sulfuric or phosphoric acid, at high temperatures.

The required range of reaction temperature decreases with increasing substitution of the hydroxy-containing carbon:
1° alcohols: 170° - 180°C
2° alcohols: 100°– 140 °C
3° alcohols: 25°– 80°C
If the reaction is not sufficiently heated, the alcohols do not dehydrate to form alkenes, but react with one another to form
ethers (e.g., the Williamson Ether Synthesis).

Alcohols are amphoteric; they can act both as acid or base. The lone pair of electrons on oxygen atom makes the –OH group
weakly basic. Oxygen can donate two electrons to an electron-deficient proton. Thus, in the presence of a strong acid, R—OH
acts as a base and protonates into the very acidic alkyloxonium ion +OH2 (The pKa value of a tertiary protonated alcohol can
go as low as -3.8). This basic characteristic of alcohol is essential for its dehydration reaction with an acid to form alkenes.

Mechanism for the Dehydration of Alcohol into Alkene

Different types of alcohols may dehydrate through a slightly different mechanism pathway. However, the general idea behind
each dehydration reaction is that the –OH group in the alcohol donates two electrons to H+ from the acid reagent, forming an
alkyloxonium ion. This ion acts as a very good leaving group which leaves to form a carbocation. The deprotonated acid (the
nucleophile) then attacks the hydrogen adjacent to the carbocation and form a double bond.
Primary alcohols undergo bimolecular elimination (E2 mechanism) while secondary and tertiary alcohols undergo
unimolecular elimination (E1 mechanism). The relative reactivity of alcohols in dehydration reaction is ranked as the
following
Methanol < primary < secondary < tertiary

Primary alcohol dehydrates through the E2 mechanism

Oxygen donates two electrons to a proton from sulfuric acid H2SO4, forming an alkyloxonium ion. Then the nucleophile
HSO4– back-side attacks one adjacent hydrogen and the alkyloxonium ion leaves in a concerted process, making a double
bond.

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Secondary and tertiary alcohols dehydrate through the E1 mechanism
Similarly to the reaction above, secondary and tertiary –OH protonate to form alkyloxonium ions. However, in this case the
ion leaves first and forms a carbocation as the reaction intermediate. The water molecule (which is a stronger base than the
HSO4- ion) then abstracts a proton from an adjacent carbon, forming a double bond. Notice in the mechanism below that the
aleke formed depends on which proton is abstracted: the red arrows show formation of the more substituted 2-butene, while
the blue arrows show formation of the less substituted 1-butene. Recall the general rule that more substituted alkenes are more
stable than less substituted alkenes, and trans alkenes are more stable than cis alkenes. Therefore, the trans diastereomer of the
2-butene product is most abundant.

Dehydration reaction of secondary alcohol: The dehydration mechanism for a tertiary alcohol is analogous to that shown
above for a secondary alcohol.
When more than one alkene product are possible, the favored product is usually the thermodynamically most stable alkene.
More-substituted alkenes are favored over less-substituted ones; and trans-substituted alkenes are preferred compared to cis-
substituted ones.
1. Since the C=C bond is not free to rotate, cis-substituted alkenes are less stable than trans-subsituted alkenes because of
steric hindrance (spatial interfererence) between two bulky substituents on the same side of the double bond (as seen in the
cis product in the above figure). Trans-substituted alkenes reduce this effect of spatial interference by separating the two
bulky substituents on each side of the double bond (for further explanation on the rigidity of C=C bond, see Structure and
Bonding in Ethene- The pi Bond).
2. Heats of hydrogenation of differently-substituted alkene isomers are lowest for more-substituted alkenes, suggesting that
they are more stable than less-substituted alkenes and thus are the major products in an elimination reaction. This is partly
because in more --substituted alkenes, the p orbitals of the pi bond are stabilized by neighboring alkyl substituents, a
phenomenon similar to hyperconjugation.

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Hydride and Alkyl Shifts
Since the dehydration reaction of alcohol has a carbocation intermediate, hydride or alkyl shifts can occur which relocates the
carbocation to a more stable position. The dehydrated products therefore are a mixture of alkenes, with and without
carbocation rearrangement. Tertiary cation is more stable than secondary cation, which in turn is more stable than primary
cation due to a phenomenon known as hyperconjugation, where the interaction between the filled orbitals of neighboring
carbons and the singly occupied p orbital in the carbocation stabilizes the positive charge in carbocation.
In hydride shifts, a secondary or tertiary hydrogen from a carbon next to the original carbocation takes both of its electrons
to the cation site, swapping place with the carbocation and renders it a more stable secondary or tertiary cation.

Similarly, when there is no hydride available for hydride shifting, an alkyl group can take its bonding electrons and swap place
with an adjacent cation, a process known as alkyl shift.

Practice Problems
Test your understanding by predicting what product(s) will be formed in each of the following reactions:

1.

2.

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Solutions
1. Did you notice the reaction temperature? It is only 25°, which is much lower than the required temperature of 170°C for
dehydration of primary alcohol. This reaction will not produce any alkene but will form ether.

2. . Notice that the reactant is a secondary -OH group, which will form a relatively unstable secondary carbocation in the
intermediate. Thus hydride shift from an adjacent hydrogen will occur to make the carbocation tertiary, which is much more
stable. The products are a mixture of alkenes that are formed with or without carbocation rearrangement (A number of
products are formed faster than hydride shift can occur).

References
1. Vollhart, K. Peter C. and Neil Schore. Organic Chemistry, Structure and Function. 5th Ed. W. H. Freeman and Company,
2007
2. McMurry, John. Fundamentals of Organic Chemistry. 3rd Ed. Cornell University. Pacific Grove, CA: Brooks/ Cole
Publishing Company, 1994.

Contributors
Thuy Hoang

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11.8: Infrared Spectroscopy
☰

 Objectives

After completing this section, you should be able to

1. identify (by wavelength, wavenumber, or both) the region of the electromagnetic spectrum which is used in
infrared (IR) spectroscopy.
2. interconvert between wavelength and wavenumber.
3. discuss, in general terms, the effect that the absorption of infrared radiation can have on a molecule.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
infrared spectrum
wavenumber (reciprocal centimetres)

 Study Notes

Notice that the scale at the bottom of the infrared spectrum for 2-hexanone shown is calibrated in wavenumbers
(cm−1). A wavenumber is the reciprocal of a wavelength (1/λ); thus, a wavenumber of 1600 cm−1 corresponds to a
wavelength of
1 −4
= 6.25 × 10 cm or6.25 μ m
1600 cm−1

Organic chemists find it more convenient to deal with wavenumbers rather than wavelengths when discussing infrared
spectra.
You will obtain infrared spectra for a number of the compounds you will synthesize in the laboratory component of
this course.
The inverted peaks observed in the spectra correspond to molecular stretching and bending vibrations that only occur
at certain quantized frequencies. When infrared radiation matching these frequencies falls on the molecule, the
molecule absorbs energy and becomes excited. Eventually the molecule returns to its original (ground) state, and the
energy which was absorbed is released as heat.

Infrared Spectroscopy
The full range of electromagnetic radiation wavelengths is referred to as the electromagnetic spectrum.

Notice in the figure above that infrared light is lower energy than visible light. The wavelengths of infrared radiation are
between 0.8 and 250 μm. The units that are typically used for infrared spectroscopy are wavenumbers (which is cm-1). IR

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spectroscopy analyzes radiation between 40 to 13,000 cm-1. But what type of excitation is occurring when infrared
☰
radiation is absorbed by a molecule?
Covalent bonds in organic molecules are not rigid sticks – rather, they behave more like springs. At room temperature,
organic molecules are always in motion, as their bonds stretch, bend, and twist. These complex vibrations can be broken
down mathematically into individual vibrational modes, a few of which are illustrated below.

The energy of molecular vibration is quantized rather than continuous, meaning that a molecule can only stretch and bend
at certain 'allowed' frequencies. If a molecule is exposed to electromagnetic radiation that matches the frequency of one of
its vibrational modes, it will in most cases absorb energy from the radiation and jump to a higher vibrational energy state -
what this means is that the amplitude of the vibration will increase, but the vibrational frequency will remain the same. The
difference in energy between the two vibrational states is equal to the energy associated with the wavelength of radiation
that was absorbed. It turns out that it is the infrared region of the electromagnetic spectrum which contains frequencies
corresponding to the vibrational frequencies of organic bonds.
Let's take 2-hexanone as an example. Picture the carbonyl bond of the ketone group as a spring. This spring is constantly
bouncing back and forth, stretching and compressing, pushing the carbon and oxygen atoms further apart and then pulling
them together. This is the stretching mode of the carbonyl bond. In the space of one second, the spring 'bounces' back and
forth 5.15 x 1013 times - in other words, the ground-state frequency of carbonyl stretching for a the ketone group is about
5.15 x 1013 Hz.
If our ketone sample is irradiated with infrared light, the carbonyl bond will specifically absorb light with this same
frequency, which by equations 4.1 and 4.2 corresponds to a wavelength of 5.83 x 10-6 m and an energy of 4.91 kcal/mol.
When the carbonyl bond absorbs this energy, it jumps up to an excited vibrational state.

The value of ΔE - the energy difference between the low energy (ground) and high energy (excited) vibrational states - is
equal to 4.91 kcal/mol, the same as the energy associated with the absorbed light frequency. The molecule does not remain
in its excited vibrational state for very long, but quickly releases energy to the surrounding environment in form of heat,
and returns to the ground state.

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With an instrument called an infrared spectrophotometer, we can 'see' this vibrational transition. In the spectrophotometer,
☰
infrared light with frequencies ranging from about 1013 to 1014 Hz is passed though our sample of cyclohexane. Most
frequencies pass right through the sample and are recorded by a detector on the other side.

Our 5.15 x 1013 Hz carbonyl stretching frequency, however, is absorbed by the 2-hexanone sample, and so the detector
records that the intensity of this frequency, after having passed through the sample, is something less than 100% of its
initial intensity.
The vibrations of a 2-hexanone molecule are not, of course, limited to the simple stretching of the carbonyl bond. The
various carbon-carbon bonds also stretch and bend, as do the carbon-hydrogen bonds, and all of these vibrational modes
also absorb different frequencies of infrared light.
The power of infrared spectroscopy arises from the observation that different functional groups have different
characteristic absorption frequencies. The carbonyl bond in a ketone, as we saw with our 2-hexanone example, typically
absorbs in the range of 5.11 - 5.18 x 1013 Hz, depending on the molecule. The carbon-carbon triple bond of an alkyne, on
the other hand, absorbs in the range 6.30 - 6.80 x 1013 Hz. The technique is therefore very useful as a means of identifying
which functional groups are present in a molecule of interest. If we pass infrared light through an unknown sample and
find that it absorbs in the carbonyl frequency range but not in the alkyne range, we can infer that the molecule contains a
carbonyl group but not an alkyne.
Some bonds absorb infrared light more strongly than others, and some bonds do not absorb at all. In order for a vibrational
mode to absorb infrared light, it must result in a periodic change in the dipole moment of the molecule. Such vibrations are
said to be infrared active. In general, the greater the polarity of the bond, the stronger its IR absorption. The carbonyl
bond is very polar, and absorbs very strongly. The carbon-carbon triple bond in most alkynes, in contrast, is much less
polar, and thus a stretching vibration does not result in a large change in the overall dipole moment of the molecule.
Alkyne groups absorb rather weakly compared to carbonyls.
Some kinds of vibrations are infrared inactive. The stretching vibrations of completely symmetrical double and triple
bonds, for example, do not result in a change in dipole moment, and therefore do not result in any absorption of light (but
other bonds and vibrational modes in these molecules do absorb IR light).

Now, let's look at some actual output from IR spectroscopy experiments. Below is the IR spectrum for 2-hexanone.

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☰

There are a number of things that need to be explained in order for you to understand what it is that we are looking at. On
the horizontal axis we see IR wavelengths expressed in terms of a unit called wavenumber (cm-1), which tells us how
many waves fit into one centimeter. On the vertical axis we see ‘% transmittance’, which tells us how strongly light was
absorbed at each frequency (100% transmittance means no absorption occurred at that frequency). The solid line traces the
values of % transmittance for every wavelength – the ‘peaks’ (which are actually pointing down) show regions of strong
absorption. For some reason, it is typical in IR spectroscopy to report wavenumber values rather than wavelength (in
meters) or frequency (in Hz). The ‘upside down’ vertical axis, with absorbance peaks pointing down rather than up, is also
a curious convention in IR spectroscopy. We wouldn’t want to make things too easy for you!

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne Morsch (University of Illinois Springfield)

 Objectives

After completing this section, you should be able to

1. describe how the so-called “fingerprint region” of an infrared spectrum can assist in the identification of an
unknown compound.
2. identify the functional group or groups present in a compound, given a list of the most prominent absorptions in the
infrared spectrum and a table of characteristic absorption frequencies.
3. identify the broad regions of the infrared spectrum in which occur absorptions caused by
a. $\ce{\sf{N-H}}$, $\ce{\sf{C-H}}$, and $\ce{\sf{O-H}}$
b. $\ce{\sf{C#C}}$ and $\ce{\sf{C#N}}$
c. $\ce{\sf{C=O}}$, $\ce{\sf{C=N}}$, and $\ce{\sf{C=C}}$

 Key Terms

Make certain that you can define, and use in context, the key term below.
fingerprint region

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 Study Notes
☰
When answering assignment questions, you may use this IR table to find the characteristic infrared absorptions of the
various functional groups. However, you should be able to indicate in broad terms where certain characteristic
absorptions occur. You can achieve this objective by memorizing the following table.

Region of Spectrum (cm−1) Absorption

2500-4000 $\ce{\sf{N−H}}$, $\ce{\sf{O−H}}$, $\ce{\sf{C−H}}$

2000-2500 $\ce{\sf{C#C}}$, $\ce{\sf{C#N}}$
1500-2000 $\ce{\sf{C=O}}$, $\ce{\sf{C=N}}$, $\ce{\sf{C=C}}$
below 1500 Fingerprint region

The Origin of Group Frequencies

An important observation made by early researchers is that many functional group absorb infrared radiation at about the
same wavenumber, regardless of the structure of the rest of the molecule. For example, C-H stretching vibrations usually
appear between 3200 and 2800cm-1 and carbonyl(C=O) stretching vibrations usually appear between 1800 and 1600cm-1.
This makes these bands diagnostic markers for the presence of a functional group in a sample. These types of infrared
bands are called group frequencies because they tell us about the presence or absence of specific functional groups in a
sample.

Figure 2. Group frequency and fingerprint regions of the mid-infrared spectrum

The region of the infrared spectrum from 1200 to 700 cm-1 is called the fingerprint region. This region is notable for the
large number of infrared bands that are found there. Many different vibrations, including C-O, C-C and C-N single bond
stretches, C-H bending vibrations, and some bands due to benzene rings are found in this region. The fingerprint region is
often the most complex and confusing region to interpret, and is usually the last section of a spectrum to be interpreted.
However, the utility of the fingerprint region is that the many bands there provide a fingerprint for a molecule.

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☰

The key absorption peak in this spectrum is that from the carbonyl double bond, at 1716 cm-1 (corresponding to a
wavelength of 5.86 mm, a frequency of 5.15 x 1013 Hz, and a ΔE value of 4.91 kcal/mol). Notice how strong this peak is,
relative to the others on the spectrum: a strong peak in the 1650-1750 cm-1 region is a dead giveaway for the presence of a
carbonyl group. Within that range, carboxylic acids, esters, ketones, and aldehydes tend to absorb in the shorter
wavelength end (1700-1750 cm-1), while conjugated unsaturated ketones and amides tend to absorb on the longer
wavelength end (1650-1700 cm-1).
The jagged peak at approximately 2900-3000 cm-1 is characteristic of tetrahedral carbon-hydrogen bonds. This peak is not
terribly useful, as just about every organic molecule that you will have occasion to analyze has these bonds. Nevertheless,
it can serve as a familiar reference point to orient yourself in a spectrum.
You will notice that there are many additional peaks in this spectrum in the longer-wavelength 400 -1400 cm-1 region. This
part of the spectrum is called the fingerprint region. While it is usually very difficult to pick out any specific functional
group identifications from this region, it does, nevertheless, contain valuable information. The reason for this is suggested
by the name: just like a human fingerprint, the pattern of absorbance peaks in the fingerprint region is unique to every
molecule, meaning that the data from an unknown sample can be compared to the IR spectra of known standards in order
to make a positive identification. In the mid-1990's, for example, several paintings were identified as forgeries because
scientists were able to identify the IR footprint region of red and yellow pigment compounds that would not have been
available to the artist who supposedly created the painting (for more details see Chemical and Engineering News, Sept 10,
2007, p. 28).
Now, let’s take a look at the IR spectrum for 1-hexanol.

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☰

As you can see, the carbonyl peak is gone, and in its place is a very broad ‘mountain’ centered at about 3400 cm-1. This
signal is characteristic of the O-H stretching mode of alcohols, and is a dead giveaway for the presence of an alcohol
group. The breadth of this signal is a consequence of hydrogen bonding between molecules.
In the spectrum of octanoic acid we see, as expected, the characteristic carbonyl peak, this time at 1709 cm-1.

We also see a low, broad absorbance band that looks like an alcohol, except that it is displaced slightly to the right (long-
wavelength) side of the spectrum, causing it to overlap to some degree with the C-H region. This is the characteristic
carboxylic acid O-H single bond stretching absorbance.
The spectrum for 1-octene shows two peaks that are characteristic of alkenes: the one at 1642 cm-1 is due to stretching of
the carbon-carbon double bond, and the one at 3079 cm-1 is due to stretching of the s bond between the alkene carbons and
their attached hydrogens.

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☰

Alkynes have characteristic IR absorbance peaks in the range of 2100-2250 cm-1 due to stretching of the carbon-carbon
triple bond, and terminal alkenes can be identified by their absorbance at about 3300 cm-1, due to stretching of the bond
between the sp-hybridized carbon and the terminal hydrogen.
It is possible to identify other functional groups such as amines and ethers, but the characteristic peaks for these groups are
considerably more subtle and/or variable, and often are overlapped with peaks from the fingerprint region. For this reason,
we will limit our discussion here to the most easily recognized functional groups, which are summarized in this table.
As you can imagine, obtaining an IR spectrum for a compound will not allow us to figure out the complete structure of
even a simple molecule, unless we happen to have a reference spectrum for comparison. In conjunction with other
analytical methods, however, IR spectroscopy can prove to be a very valuable tool, given the information it provides about
the presence or absence of key functional groups. IR can also be a quick and convenient way for a chemist to check to see
if a reaction has proceeded as planned. If we were to run a reaction in which we wished to convert cyclohexanone to
cyclohexanol, for example, a quick comparison of the IR spectra of starting compound and product would tell us if we had
successfully converted the ketone group to an alcohol.

More examples of IR spectra

To illustrate the usefulness of infrared absorption spectra, examples for five C4H8O isomers are presented below their
corresponding structural formulas. Try to associate each spectrum with one of the isomers in the row above it.

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☰

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Exercises
☰
Questions
Q12.7.1
What functional groups give the following signals in an IR spectrum?
A) 1700 cm-1
B) 1550 cm-1
C) 1700 cm-1 and 2510-3000 cm-1
Q12.7.2
How can you distinguish the following pairs of compounds through IR analysis?
A) CH3OH (Methanol) and CH3CH2OCH2CH3 (Diethylether)
B) Cyclopentane and 1-pentene.
C)

Solutions
S12.7.1

S12.7.2
A) A OH peak will be present around 3300 cm-1 for methanol and will be absent in the ether.
B) 1-pentene will have a alkene peak around 1650 cm-1 for the C=C and there will be another peak around 3100 cm-1 for
the sp2 C-H group on the alkene
C) Cannot distinguish these two isomers. They both have the same functional groups and therefore would have the same
peaks on an IR spectra.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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 William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
☰
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

 Objective

After completing this section, you should be able to use an infrared spectrum to determine the presence of functional
groups, such as alcohols, amines and carbonyl groups, in an unknown compound, given a list of infrared absorption
frequencies.

 Study Notes

In Chapter 12.7 you should have learned, in broad terms, where a few key absorptions occur. Otherwise, to find the
characteristic infrared absorptions of the various functional groups, refer to this IR table.

Spectral Interpretation by Application of Group Frequencies

One of the most common application of infrared spectroscopy is to the identification of organic compounds. The major
classes of organic molecules are shown in this category and also linked on the bottom page for the number of collections of
spectral information regarding organic molecules.

Hydrocarbons
Hydrocarbons compounds contain only C-H and C-C bonds, but there is plenty of information to be obtained from the
infrared spectra arising from C-H stretching and C-H bending.
In alkanes, which have very few bands, each band in the spectrum can be assigned:
C–H stretch from 3000–2850 cm-1
C–H bend or scissoring from 1470-1450 cm-1
C–H rock, methyl from 1370-1350 cm-1
C–H rock, methyl, seen only in long chain alkanes, from 725-720 cm-1
Figure 3. shows the IR spectrum of octane. Since most organic compounds have these features, these C-H vibrations are
usually not noted when interpreting a routine IR spectrum. Note that the change in dipole moment with respect to distance
for the C-H stretching is greater than that for others shown, which is why the C-H stretch band is the more intense.

Figure 3. Infrared Spectrum of Octane

In alkenes compounds, each band in the spectrum can be assigned:
C=C stretch from 1680-1640 cm-1
=C–H stretch from 3100-3000 cm-1
=C–H bend from 1000-650 cm-1
Figure 4. shows the IR spectrum of 1-octene. As alkanes compounds, these bands are not specific and are generally not
noted because they are present in almost all organic molecules.

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☰

Figure 4. Infrared Spectrum of 1-Octene

In alkynes, each band in the spectrum can be assigned:

–C≡C– stretch from 2260-2100 cm-1

–C≡C–H: C–H stretch from 3330-3270 cm-1
–C≡C–H: C–H bend from 700-610 cm-1
The spectrum of 1-hexyne, a terminal alkyne, is shown below.

Figure 5. Infrared Spectrum of 1-Hexyne

In aromatic compounds, each band in the spectrum can be assigned:
C–H stretch from 3100-3000 cm-1
overtones, weak, from 2000-1665 cm-1
C–C stretch (in-ring) from 1600-1585 cm-1
C–C stretch (in-ring) from 1500-1400 cm-1
C–H "oop" from 900-675 cm-1
Note that this is at slightly higher frequency than is the –C–H stretch in alkanes. This is a very useful tool for interpreting
IR spectra. Only alkenes and aromatics show a C–H stretch slightly higher than 3000 cm-1.
Figure 6. shows the spectrum of toluene.

Figure 6. Infrared Spectrum of Toluene

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Functional Groups Containing the C-O Bond
☰
Alcohols have IR absorptions associated with both the O-H and the C-O stretching vibrations.
O–H stretch, hydrogen bonded 3500-3200 cm-1
C–O stretch 1260-1050 cm-1 (s)
Figure 7. shows the spectrum of ethanol. Note the very broad, strong band of the O–H stretch.

Figure 7. Infrared Spectrum of Ethanol

The carbonyl stretching vibration band C=O of saturated aliphatic ketones appears:
C=O stretch - aliphatic ketones 1715 cm-1

α, β -unsaturated ketones 1685-1666 cm-1

Figure 8. shows the spectrum of 2-butanone. This is a saturated ketone, and the C=O band appears at 1715.

Figure 8. Infrared Spectrum of 2-Butanone

If a compound is suspected to be an aldehyde, a peak always appears around 2720 cm-1 which often appears as a shoulder-
type peak just to the right of the alkyl C–H stretches.
H–C=O stretch 2830-2695 cm-1
C=O stretch:
aliphatic aldehydes 1740-1720 cm-1

α, β -unsaturated aldehydes 1710-1685 cm-1

Figure 9. shows the spectrum of butyraldehyde.

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☰

Figure 9. Infrared Spectrum of Butyraldehyde

The carbonyl stretch C=O of esters appears:
C=O stretch
aliphatic from 1750-1735 cm-1

α, β -unsaturated from 1730-1715 cm-1

C–O stretch from 1300-1000 cm-1
Figure 10. shows the spectrum of ethyl benzoate.

Figure 10. Infrared Spectrum of Ethyl benzoate

The carbonyl stretch C=O of a carboxylic acid appears as an intense band from 1760-1690 cm-1. The exact position of this
broad band depends on whether the carboxylic acid is saturated or unsaturated, dimerized, or has internal hydrogen
bonding.
O–H stretch from 3300-2500 cm-1
C=O stretch from 1760-1690 cm-1
C–O stretch from 1320-1210 cm-1
O–H bend from 1440-1395 and 950-910 cm-1
Figure 11. shows the spectrum of hexanoic acid.

Figure 11. Infrared Spectrum of Hexanoic acid

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Organic Nitrogen Compounds
☰ N–O asymmetric stretch from 1550-1475 cm-1
N–O symmetric stretch from 1360-1290 cm-1

Figure 12. Infrared Spectrum of Nitomethane

Organic Compounds Containing Halogens
Alkyl halides are compounds that have a C–X bond, where X is a halogen: bromine, chlorine, fluorene, or iodine.
C–H wag (-CH2X) from 1300-1150 cm-1
C–X stretches (general) from 850-515 cm-1
C–Cl stretch 850-550 cm-1
C–Br stretch 690-515 cm-1
The spectrum of 1-chloro-2-methylpropane are shown below.

Figure 13. Infrared Spectrum of 1-chloro-2-methylpropane

For more Infrared spectra Spectral database of organic molecules is introduced to use free database. Also, the infrared
spectroscopy correlation table is linked on bottom of page to find other assigned IR peaks.

Exercises
Questions
Q12.8.1
The following spectra is for the accompanying compound. What are the peaks that you can I identify in the spectrum?

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☰

Source: SDBSWeb : http://sdbs.db.aist.go.jp (National Institute of Advanced Industrial Science and Technology, 2
December 2016)
Q12.8.2
What absorptions would the following compounds have in an IR spectra?

Solutions
S12.8.1
Frequency (cm-1) Functional Group
3200 C≡C-H
2900-3000 C-C-H, C=C-H
2100 C≡C
1610 C=C
(There is also an aromatic undertone region between 2000-1600 which describes the substitution on the phenyl ring.)
S12.8.2
A)
Frequency (cm-1) Functional Group
2900-3000 C-C-H, C=C-H
1710 C=O
1610 C=C
1100 C-O

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☰
B)
Frequency (cm-1) Functional Group
3200 C≡C-H
2900-3000 C-C-H, C=C-H
2100 C≡C
1710 C=O

C)
Frequency (cm-1) Functional Group
3300 (broad) O-H
2900-3000 C-C-H, C=C-H
2000-1800 Aromatic Overtones
1710 C=O
1610 C=C

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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11.9: Measuring the Molecular Mass of Organic Compounds: Mass
Spectrometry
 Objectives

After completing this section, you should be able to

1. describe, briefly, how a mass spectrometer works.
2. sketch a simple diagram to show the essential features of a mass spectrometer.
3. identify peaks in a simple mass spectrum, and explain how they arise.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
base peak
parent peak (molecular ion peak)
cation radical
relative abundance
mass spectrometer
mass spectroscopy
mass spectrum
molecular ion (M+·)
mass-to-charge ratio (m/z)

 Study Notes

You may remember from general first-year chemistry how mass spectroscopy has been used to establish the atomic
mass and abundance of isotopes.
Mass spectrometers are large and expensive, and usually operated only by fully trained personnel, so you may not have
the opportunity to use such an instrument as part of this course. Research chemists often rely quite heavily on mass
spectra to assist them in the identification of compounds, and you will be required to interpret simple mass spectra
both in assignments and on examinations. Note that in most attempts to identify an unknown compound, chemists do
not rely exclusively on the results obtained from a single spectroscopic technique. A combination of chemical and
physical properties and spectral evidence is usually employed.

The Mass Spectrometer

In order to measure the characteristics of individual molecules, a mass spectrometer converts them to ions so that they can
be moved about and manipulated by external electric and magnetic fields. The three essential functions of a mass
spectrometer, and the associated components, are:
1. A small sample is ionized, usually to cations by loss of an electron. The Ion Source
2. The ions are sorted and separated according to their mass and charge. The Mass Analyzer
3. The separated ions are then measured, and the results displayed on a chart. The Detector
Because ions are very reactive and short-lived, their formation and manipulation must be conducted in a vacuum.
Atmospheric pressure is around 760 torr (mm of mercury). The pressure under which ions may be handled is roughly 10-5
to 10-8 torr (less than a billionth of an atmosphere). Each of the three tasks listed above may be accomplished in different
ways. In one common procedure, ionization is effected by a high energy beam of electrons, and ion separation is achieved
by accelerating and focusing the ions in a beam, which is then bent by an external magnetic field. The ions are then
detected electronically and the resulting information is stored and analyzed in a computer. A mass spectrometer operating
in this fashion is outlined in the following diagram. The heart of the spectrometer is the ion source. Here molecules of the
sample (black dots) are bombarded by electrons (light blue lines) issuing from a heated filament. This is called an EI

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(electron-ionization) source. Gases and volatile liquid samples are allowed to leak into the ion source from a reservoir (as
shown). Non-volatile solids and liquids may be introduced directly. Cations formed by the electron bombardment (red
dots) are pushed away by a charged repellor plate (anions are attracted to it), and accelerated toward other electrodes,
having slits through which the ions pass as a beam. Some of these ions fragment into smaller cations and neutral
fragments. A perpendicular magnetic field deflects the ion beam in an arc whose radius is inversely proportional to the
mass of each ion. Lighter ions are deflected more than heavier ions. By varying the strength of the magnetic field, ions of
different mass can be focused progressively on a detector fixed at the end of a curved tube (also under a high vacuum).

When a high energy electron collides with a molecule it often ionizes it by knocking away one of the molecular electrons
(either bonding or non-bonding). This leaves behind a molecular ion (colored red in the following diagram). Residual
energy from the collision may cause the molecular ion to fragment into neutral pieces (colored green) and smaller
fragment ions (colored pink and orange). The molecular ion is a radical cation, but the fragment ions may either be radical
cations (pink) or carbocations (orange), depending on the nature of the neutral fragment. An animated display of this
ionization process will appear if you click on the ion source of the mass spectrometer diagram.

Below is typical output for an electron-ionization MS experiment (MS data below is derived from the Spectral Database
for Organic Compounds, a free, web-based service provided by AIST in Japan.

The sample is acetone. On the horizontal axis is the value for m/z, which is the mass to charge ratio (as we stated above,
the charge z is almost always +1, so in practice this is the same as mass). On the vertical axis is the relative abundance of
each ion detected. On this scale, the most abundant ion, called the base peak, is set to 100%, and all other peaks are
recorded relative to this value. For acetone, the base peak corresponds to a fragment with m/z = 43 - . The molecular
weight of acetone is 58, so we can identify the peak at m/z = 58 as that corresponding to the molecular ion peak, or

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parent peak. Notice that there is a small peak at m/z = 59: this is referred to as the M+1 peak. How can there be an ion
that has a greater mass than the molecular ion? Simple: a small fraction - about 1.1% - of all carbon atoms in nature are
actually the 13C rather than the 12C isotope. The 13C isotope is, of course, heavier than 12C by 1 mass unit. In addition,
about 0.015% of all hydrogen atoms are actually deuterium, the 2H isotope. So the M+1 peak represents those few acetone
molecules in the sample which contained either a 13C or 2H.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Layne Morsch (University of Illinois Springfield)

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11.10: Fragmentation Patterns of Organic Molecules
Objectives
After completing this section, you should be able to
1. suggest possible molecular formulas for a compound, given the m/z value for the molecular ion, or a mass spectrum
from which this value can be obtained.
2. predict the relative heights of the M+·, (M + 1)+·, etc., peaks in the mass spectrum of a compound, given the
natural abundance of the isotopes of carbon and the other elements present in the compound.
3. interpret the fragmentation pattern of the mass spectrum of a relatively simple, known compound (e.g., hexane).
4. use the fragmentation pattern in a given mass spectrum to assist in the identification of a relatively simple,
unknown compound (e.g., an unknown alkane).

 Study Notes

When interpreting fragmentation patterns, you may find it helpful to know that, as you might expect, the weakest
carbon-carbon bonds are the ones most likely to break. You might wish to refer to the table of bond dissociation
energies when attempting problems involving the interpretation of mass spectra.

This page looks at how fragmentation patterns are formed when organic molecules are fed into a mass spectrometer, and
how you can get information from the mass spectrum.

The Origin of Fragmentation Patterns

When the vaporized organic sample passes into the ionization chamber of a mass spectrometer, it is bombarded by a
stream of electrons. These electrons have a high enough energy to knock an electron off an organic molecule to form a
positive ion. This ion is called the molecular ion - or sometimes the parent ion and is often given the symbol M+ or .
The dot in this second version represents the fact that somewhere in the ion there will be a single unpaired electron. That's
one half of what was originally a pair of electrons - the other half is the electron which was removed in the ionization
process.
The molecular ions are energetically unstable, and some of them will break up into smaller pieces. The simplest case is that
a molecular ion breaks into two parts - one of which is another positive ion, and the other is an uncharged free radical.

The uncharged free radical will not produce a line on the mass spectrum. Only charged particles will be accelerated,
deflected and detected by the mass spectrometer. These uncharged particles will simply get lost in the machine -
eventually, they get removed by the vacuum pump.
The ion, X+, will travel through the mass spectrometer just like any other positive ion - and will produce a line on the stick
diagram. All sorts of fragmentations of the original molecular ion are possible - and that means that you will get a whole
host of lines in the mass spectrum. For example, the mass spectrum of pentane looks like this:

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 Note
The pattern of lines in the mass spectrum of an organic compound tells you something quite different from the pattern
of lines in the mass spectrum of an element. With an element, each line represents a different isotope of that element.
With a compound, each line represents a different fragment produced when the molecular ion breaks up.

In the stick diagram showing the mass spectrum of pentane, the line produced by the heaviest ion passing through the
machine (at m/z = 72) is due to the molecular ion. The tallest line in the stick diagram (in this case at m/z = 43) is called
the base peak. This is usually given an arbitrary height of 100, and the height of everything else is measured relative to
this. The base peak is the tallest peak because it represents the commonest fragment ion to be formed - either because there
are several ways in which it could be produced during fragmentation of the parent ion, or because it is a particularly stable
ion.

Using Fragmentation Patterns

This section will ignore the information you can get from the molecular ion (or ions). That is covered in three other pages
which you can get at via the mass spectrometry menu. You will find a link at the bottom of the page.

 Example 12.2.1: Pentane

Let's have another look at the mass spectrum for pentane:

What causes the line at m/z = 57?

How many carbon atoms are there in this ion? There cannot be 5 because 5 x 12 = 60. What about 4? 4 x 12 = 48. That
leaves 9 to make up a total of 57. How about C4H9+ then?
C4H9+ would be [CH3CH2CH2CH2]+, and this would be produced by the following fragmentation:

The methyl radical produced will simply get lost in the machine.
The line at m/z = 43 can be worked out similarly. If you play around with the numbers, you will find that this
corresponds to a break producing a 3-carbon ion:

The line at m/z = 29 is typical of an ethyl ion, [CH3CH2]+:

The other lines in the mass spectrum are more difficult to explain. For example, lines with m/z values 1 or 2 less than
one of the easy lines are often due to loss of one or more hydrogen atoms during the fragmentation process.

 Example 12.2.2: Pentan-3-one

This time the base peak (the tallest peak - and so the commonest fragment ion) is at m/z = 57. But this is not produced
by the same ion as the same m/z value peak in pentane.

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 If you remember, the m/z = 57 peak in pentane was produced by [CH3CH2CH2CH2]+. If you look at the structure of
pentan-3-one, it's impossible to get that particular fragment from it.
Work along the molecule mentally chopping bits off until you come up with something that adds up to 57. With a
small amount of patience, you'll eventually find [CH3CH2CO]+ - which is produced by this fragmentation:

You would get exactly the same products whichever side of the CO group you split the molecular ion. The m/z = 29
peak is produced by the ethyl ion - which once again could be formed by splitting the molecular ion either side of the
CO group.

Peak Heights and Stability

The more stable an ion is, the more likely it is to form. The more of a particular sort of ion that's formed, the higher its
peak height will be. We'll look at two common examples of this.

Carbocations (carbonium ions)

Summarizing the most important conclusion from the page on carbocations:
Order of stability of carbocations
primary < secondary < tertiary
Applying the logic of this to fragmentation patterns, it means that a split which produces a secondary
carbocation is going to be more successful than one producing a primary one. A split producing a tertiary
carbocation will be more successful still. Let's look at the mass spectrum of 2-methylbutane. 2-methylbutane is
an isomer of pentane - isomers are molecules with the same molecular formula, but a different spatial
arrangement of the atoms.

Look first at the very strong peak at m/z = 43. This is caused by a different ion than the corresponding peak in
the pentane mass spectrum. This peak in 2-methylbutane is caused by:

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The ion formed is a secondary carbocation - it has two alkyl groups attached to the carbon with the positive
charge. As such, it is relatively stable. The peak at m/z = 57 is much taller than the corresponding line in
pentane. Again a secondary carbocation is formed - this time, by:

You would get the same ion, of course, if the left-hand CH3 group broke off instead of the bottom one as we've
drawn it. In these two spectra, this is probably the most dramatic example of the extra stability of a secondary
carbocation.

Acylium ions, [RCO]+

Ions with the positive charge on the carbon of a carbonyl group, C=O, are also relatively stable. This is fairly
clearly seen in the mass spectra of ketones like pentan-3-one.

The base peak, at m/z=57, is due to the [CH3CH2CO]+ ion. We've already discussed the fragmentation that
produces this.

 Note

The more stable an ion is, the more likely it is to form. The more of a particular ion that is formed, the higher will be
its peak height.

Using mass spectra to distinguish between compounds

Suppose you had to suggest a way of distinguishing between pentan-2-one and pentan-3-one using their mass spectra.

pentan-2-one CH3COCH2CH2CH3

pentan-3-one CH3CH2COCH2CH3

Each of these is likely to split to produce ions with a positive charge on the CO group. In the pentan-2-one case, there are
two different ions like this:
[CH3CO]+
[COCH2CH2CH3]+
That would give you strong lines at m/z = 43 and 71. With pentan-3-one, you would only get one ion of this kind:
[CH3CH2CO]+
In that case, you would get a strong line at 57. You don't need to worry about the other lines in the spectra - the 43, 57 and
71 lines give you plenty of difference between the two. The 43 and 71 lines are missing from the pentan-3-one spectrum,
and the 57 line is missing from the pentan-2-one one.
The two mass spectra look like this:

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As you've seen, the mass spectrum of even very similar organic compounds will be quite different because of the different
fragmentation patterns that can occur. Provided you have a computer data base of mass spectra, any unknown spectrum
can be computer analyzed and simply matched against the data base.

Exercises
Questions
Q12.2.1
Caffeine has a mass of 194.19 amu, determined by mass spectrometry, and contains C, N, H, O. What is a molecular
formula for this molecule?
Q12.2.2
The following are the spectra for 2-methyl-2-hexene and 2-heptene, which spectra belongs to the correct molecule.
Explain.
A:

B:

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Source: SDBSWeb : http://sdbs.db.aist.go.jp (National Institute of Advanced Industrial Science and Technology, 2
December 2016)
Solutions
S12.2.1
C8H10N4O2
C = 12 × 8 = 96
N = 14 × 4 = 56
H = 1 × 10 = 10
O = 2 × 16 = 32
96+56+10+32 = 194 g/mol
S12.2.2
The (A) spectrum is 2-methyl-2-hexene and the (B) spectrum is 2-heptene. Looking at (A) the peak at 68 m/z is the
fractioned molecule with just the tri-substituted alkene present. While (B) has a strong peak around the 56 m/z, which in
this case is the di-substituted alkene left behind from the linear heptene.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)

Objective
After completing this section, you should be able to predict the expected fragmentation for common functional groups,
such as alcohols, amines, and carbonyl compounds.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
alpha (α) cleavage
McLafferty rearrangement

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Much of the utility in electron-ionization MS comes from the fact that the radical cations generated in the electron-
bombardment process tend to fragment in predictable ways. Detailed analysis of the typical fragmentation patterns of
different functional groups is beyond the scope of this text, but it is worthwhile to see a few representative examples, even
if we don’t attempt to understand the exact process by which the fragmentation occurs. We saw, for example, that the base
peak in the mass spectrum of acetone is m/z = 43. This is the result of cleavage at the ‘alpha’ position - in other words, at
the carbon-carbon bond adjacent to the carbonyl. Alpha cleavage results in the formation of an acylium ion (which
accounts for the base peak at m/z = 43) and a methyl radical, which is neutral and therefore not detected.

After the parent peak and the base peak, the next largest peak, at a relative abundance of 23%, is at m/z = 15. This, as you
might expect, is the result of formation of a methyl cation, in addition to an acyl radical (which is neutral and not detected).

A common fragmentation pattern for larger carbonyl compounds is called the McLafferty rearrangement:

The mass spectrum of 2-hexanone shows a 'McLafferty fragment' at m/z = 58, while the propene fragment is not observed
because it is a neutral species (remember, only cationic fragments are observed in MS). The base peak in this spectrum is
again an acylium ion.

When alcohols are subjected to electron ionization MS, the molecular ion is highly unstable and thus a parent peak is often
not detected. Often the base peak is from an ‘oxonium’ ion.

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Other functional groups have predictable fragmentation patterns as well. By carefully analyzing the fragmentation
information that a mass spectrum provides, a knowledgeable spectrometrist can often ‘put the puzzle together’ and make
some very confident predictions about the structure of the starting sample.
Click here for examples of compounds listed by functional group, which demonstrate patterns which can be seen in mass
spectra of compounds ionized by electron impact ionization.

 Example 12.3.1

The mass spectrum of an aldehyde gives prominent peaks at m/z = 59 (12%, highest value of m/z in the spectrum), 58
(85%), and 29 (100%), as well as others. Propose a structure, and identify the three species whose m/z values were
listed.
Solution

Exercises
Questions
Q12.3.1
What are the masses of all the components in the following fragmentations?

Solutions
S12.3.1

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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11.11: Degree of Unsaturation: Another Aid to Identifying Molecular Structure
 Objectives

After completing this section, you should be able to

1. determine the degree of unsaturation of an organic compound, given its molecular formula, and hence determine
the number of double bonds, triple bonds and rings present in the compound.
2. draw all the possible isomers that correspond to a given molecular formula containing only carbon (up to a
maximum of six atoms) and hydrogen.
3. draw a specified number of isomers that correspond to a given molecular formula containing carbon, hydrogen, and
possibly other elements, such as oxygen, nitrogen and the halogens.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
degree of unsaturation
saturated
unsaturated

There are many ways one can go about determining the structure of an unknown organic molecule. Although, nuclear
magnetic resonance (NMR) and infrared radiation (IR) are the primary ways of determining molecular structures,
calculating the degrees of unsaturation is useful information because it easily provides information about molecular
structure.

Saturated and Unsaturated Molecules

Because alkanes have the maximum number of H atoms possible according to the rules of covalent bonds, alkanes are also
referred to as saturated hydrocarbons. The presence of a double bond causes alkenes to have less hydrogens than an
alkane with the same number of carbons. Likewise, compounds containing a carbon-to-carbon triple bonds (R–C≡C–R)
called alkynes (Discussed in Chapter 9), also have fewer hydrogens than the corresponding alkane. Collectively,
compounds which have fewer hydrogen atoms than an alkane with the same number of carbon atoms are called
unsaturated hydrocarbons. The relationship between the number of carbons (n) and hydrogens in the molecular formula
for alkanes, alkenes, and alkynes are listed below.

For example, the three carbon alkane, propane has the molecular formula of C3H8. While the unsaturated compounds
propene (C3H6) and propyne (C3H4) both have fewer hydrogens. Also, it is important to note that cycloalkanes with one
ring have a general molecular formula of CnH2n just like alkenes. Because they also have fewer than maximum number of
hydrogens possible, cyclic compounds are also considered unsaturated.

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 H H H H H H
H
H C H C C C
C C H C C C H H H
H C H C C
H H H H H
H H H H
Propane Propene Propyne Cyclopropane
(C3H8) (C3H6) (C3H4) (C3H6)
Saturated Unaturated Unaturated Unaturated

Identifying Degrees of Unsaturation

Every ring or pi bond in a compound is said to represent one degree of unsaturation. Being able to determine the degrees of
unsaturation in a given compound is an important skill. Each of the following compounds are isomers of C5H7 and contain
two degrees of unsaturation.

1,3-Pentadiene Cyclopentene Bycyclo[2.1.0]pentane 2-Pentyne

(Two double bonds) (One double bond (Two rings) (One triple bond)
and one ring)

 Exercise 11.11.1

How many degrees of unsaturation do the following compounds have?

a) , b) CH3CH=CHCH3, c) , d) , e) 3-chloro-5-octyne, f)

Answer
a) 0
b) 1
c) 1
d) 2)
e) 2
f) 2

Calculating the Degree of Unsaturation (DoU)

As noted above, every degree of unsaturation causes the loss of two hydrogens from a compound's molecular formula
when compared to an alkane with the same number of carbons. Understanding this relationship allows for the degrees of
unsaturation of a compound to be calculated from its molecular formula. First, the maximum number of hydrogens
possible for a given compound (2C + 2) is calculated and then the actual number of hydrogens present in the compound
(H) is subtracted. If this difference is then divided by 2 the answer will be equal to the degrees of unsaturation for the
compound.
For a compound which only contains carbon and hydrogen:
DoU = (2C + 2) - H / 2

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As an example, for the molecular formula C3H4 the number of actual hydrogens needed for the compound to be saturated
is 8 [2C+2=(2x3)+2=8]. Because the compound only has 4 hydrogens in its molecular formula, it would have to gain 4
more hydrogens in order to be fully saturated (8-4 = 4). Degrees of unsaturation is equal to half the number of hydrogens
the molecule needs to be fully saturated. This compound has 2 degrees of unsaturation (4/2 = 2).
The DoU of compounds containing elements other than carbon and hydrogen can also be calculated in a similar fashion.
However, different elements can affect the formula used to calculate DoU.
For a compound which contains elements other than carbon and hydrogen:
2C + 2 + N − X − H
DoU = (7.2.1)
2

C is the number of carbons

N is the number of nitrogens
X is the number of halogens (F, Cl, Br, I)

H is the number of hydrogens

A halogen (X) replaces a hydrogen in a compound because both form one single bond. Therefore the DoU formula
subtracts the number of halogens (X) present in a compound. For instance, 1,1-dichloroethene (C2H2Cl2) has two fewer
hydrogens than ethene (C2H4) yet they both have one degree of unsaturation.

H Cl H H
C C C C
H Cl H H

1,1-Dichloroethene Ethene
(C2H2Cl2) (C2H4)

One Degree of Unsaturation

Oxygen and sulfur are not included in the DoU formula because saturation is unaffected by these elements. The inclusion
of an alcohol or sulfur in a compound does not change the number of hydrogens to obtain saturation. As seen in alcohols,
the number of hydrogens in cyclohexanol (C6H12O) matches the number of hydrogens in cyclohexane (C6H12) and they
both have one degree of unsaturation.

OH

Cyclohexanol Cyclohexane
(C6H12O) (C6H12)

One Degree of Unsaturation

When a nitrogen is present in a compound one more hydrogen is required to reach saturation. Therefore, we add the
number of nitrogens (N). Propyl amine (C3H9N) has one more hydrogen compared to propane (C3H8) both of which are
saturated compounds with 0 DoU.

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 NH2

Propyl Amine Propane

(C3H9N) (C3H8)

Zero Degrees of Unsaturation

With the degrees of unsaturation comes information about the possible number of rings and multiple bonds in a given
compound. Remember, the degrees of unsaturation only gives the sum of pi bonds and/or rings.
One degree of unsaturation is equivalent to 1 ring or 1 double bond (1 π bond).
Two degrees of unsaturation is equivalent to 2 double bonds, 1 ring and 1 double bond, 2 rings, or 1 triple bond (2 π
bonds).

 Example 7.2.1: Benzene

What is the Degree of Unsaturation for Benzene?

Solution
The molecular formula for benzene is C6H6. Thus,
DoU= 4, where C=6, N=0,X=0, and H=6. 1 DoB can equal 1 ring or 1 double bond. This corresponds to benzene
containing 1 ring and 3 double bonds.

However, when given the molecular formula C6H6, benzene is only one of many possible structures (isomers). The
following structures all have DoB of 4 and have the same molecular formula as benzene.

References
1. Vollhardt, K. P.C. & Shore, N. (2007). Organic Chemistry (5thEd.). New York: W. H. Freeman. (473-474)
2. Shore, N. (2007). Study Guide and Solutions Manual for Organic Chemistry (5th Ed.). New York: W.H. Freeman. (201)

Exercise 11.11.1

Are the following molecules saturated or unsaturated:

(a.) (b.) (c.) (d.) C10H6N4

Answer
(a.) unsaturated (Even though rings only contain single bonds, rings are considered unsaturated.)
(b.) unsaturated
(c.) saturated
(d.) unsaturated

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Problems
1. Are the following molecules saturated or unsaturated:

1. (b.) (c.) (d.) C10H6N4

2. Using the molecules from 1., give the degrees of unsaturation for each.
3. Calculate the degrees of unsaturation for the following molecular formulas:
1. (a.) C9H20 (b.) C7H8 (c.) C5H7Cl (d.) C9H9NO4
4. Using the molecular formulas from 3, are the molecules unsaturated or saturated.
5. Using the molecular formulas from 3, if the molecules are saturated, how many rings/double bonds/triple bonds are
predicted?
6. 5.
(a.) 0 (Remember-a saturated molecule only contains single bonds)
(b.) The molecule can contain any of these combinations (i) 4 double bonds (ii) 4 rings (iii) 2 double bonds+2 rings
(iv) 1 double bond+3 rings (v) 3 double bonds+1 ring (vi) 1 triple bond+2 rings (vii) 2 triple bonds (viii) 1 triple
bond+1 double bond+1 ring (ix) 1 triple bond+2 double bonds
(c.) (i) 1 triple bond (ii) 1 ring+1 double bond (iii) 2 rings (iv) 2 double bonds
(d.) (i) 3 triple bonds (ii) 2 triple bonds+2 double bonds (iii) 2 triple bonds+1 double bond+1 ring (iv)... (As you
can see, the degrees of unsaturation only gives the sum of double bonds, triple bonds and/or ring. Thus, the formula
may give numerous possible structures for a given molecular formula.)

Answers
1.
(a.) unsaturated (Even though rings only contain single bonds, rings are considered unsaturated.)
(b.) unsaturated
(c.) saturated
(d.) unsaturated
2. If the molecular structure is given, the easiest way to solve is to count the number of double bonds, triple bonds and/or
rings. However, you can also determine the molecular formula and solve for the degrees of unsaturation by using the
formula.
(a.) 2
(b.) 2 (one double bond and the double bond from the carbonyl)
(c.) 0
(d.) 10
3. Use the formula to solve
(a.) 0
(b.) 4
(c.) 2
(d.) 6
4.
(a.) saturated
(b.) unsaturated

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(c.) unsaturated

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Kim Quach (UCD)
Dr. Krista Cunningham

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CHAPTER OVERVIEW
12: REACTIONS TO ALKENES
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

12.1: WHY ADDITION REACTIONS PROCEED: THERMODYNAMIC FEASIBILITY

12.2: CATALYTIC HYDROGENATION
12.3: NUCLEOPHILIC CHARACTER OF THE PI BOND: ELECTROPHILIC ADDITION OF HYDROGEN HALIDES
12.4: ALCOHOL SYNTHESIS BY ELECTROPHILIC HYDRATION: THERMODYNAMIC CONTROL
12.5: ELECTROPHILIC ADDITION OF HALOGENS TO ALKENES
12.6: THE GENERALITY OF ELECTROPHILIC ADDITION
12.7: OXYMNCURATION-DEMERCURATION: A SPECIAL ELCCTROPHILIC ADDITION
12.8: HYDROBORATION-OXIDATION: A STEREOSPECIFIC ANTI-MARKOVNIKOV HYDRATION
12.9: DIAZOMETHANE, CARBENES, AND CYCLOPROPANE SYNTHESIS
12.10: OXACYCLOPROPANE ( EPOXIDE) SYNTHESIS: EPOXIDATION BY PEROXYCARBOXYLIC ACIDS
12.11: VICINAL SYN DIHYDROXYLATION WITH OSMIUM TETROXIDE
12.12: OXIDATIVE CLEAVAGE: OZONOLYSIS
12.13: RADICAL ADDITIONS: ANTI-MARKOVNIKOV PRODUCT FORMATION
12.14: DIMERIZATION, OLIGOMERIZATION. AND POLYMERIZATION OF ALKENES
12.15: SYNTHESIS OF POLYMERS
12.16: ETHENE: AN IMPORTANT INDUSTRIAL FEEDSTOCK
12.17: ALKENES IN NATURE - INSECT PHEROMONES
Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to impact the behavior of the
receiving individuals.

1 12/5/2021
12.1: Why Addition Reactions Proceed: Thermodynamic Feasibility

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12.2: Catalytic Hydrogenation
 Objectives

After completing this section, you should be able to

1. write an equation for the catalytic hydrogenation of an alkene.
2. identify the product obtained from the hydrogenation of a given alkene.
3. identify the alkene, the reagents, or both, required to prepare a given alkane by catalytic hydrogenation.
4. describe the mechanism of the catalytic hydrogenation of alkenes.
5. explain the difference between a heterogeneous reaction and a homogeneous reaction.
6. recognize that other types of compounds containing multiple bonds, such as ketones, esters, nitriles and aromatic
compounds, do not react with hydrogen under the conditions used to hydrogenate alkenes.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
Adams’ catalyst
hydrogenation

 Study Notes

Chemical reactions that are heterogeneous have reactants that are in at least two different phases (e.g. gas with a solid),
whereas homogeneous reactions occur in a single phase (e.g. gas with another gas).
Some confusion may arise from the description of the catalyst used in the reaction between alkenes and hydrogen.
Three metals—nickel, platinum and palladium—are commonly used, but a chemist cannot simply place a piece of one
of these metals in a mixture of the alkene and hydrogen and get a reaction. Each metal catalyst must be prepared in a
special way:
nickel is usually used in a finely divided form called “Raney nickel.” It is prepared by reacting a Ni-Al alloy with
NaOH.
palladium is obtained commercially “supported” on an inert substance, such as charcoal, (Pd/C). The alkene is
usually dissolved in ethanol when Pd/C is used as the catalyst.
platinum is used as PtO2, Adams’ catalyst, although it is actually platinum metal that is the catalyst. The hydrogen
used to add to the carbon-carbon double bond also reduces the platinum(IV) oxide to finely divided platinum
metal. Ethanol or acetic acid is used as the solvent for the alkene.
Other types of compounds containing multiple bonds, such as ketones, esters, and nitriles, do not react with hydrogen
under the conditions used to hydrogenate alkenes. The examples below show reduction of an alkene, but the ketone
and nitrile groups present remain intact and are not reduced.

Aromatic rings are also not reduced under the conditions used to reduce alkenes, although these rings appear to contain
three carbon-carbon double bonds. As you will see later, aromatic rings do not really contain any double bonds, and
many chemists prefer to represent the benzene ring as a hexagon with a circle inside it

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 rather than as a hexagon with three alternating double bonds.

The representation of the benzene ring will be discussed further in Section 15.2.
The reaction between carbon-carbon double bonds and hydrogen provides a method of determining the number of
double bonds present in a compound. For example, one mole of cyclohexene reacts with one mole of hydrogen to
produce one mole of cyclohexane:

but one mole of 1,4-cyclohexadiene reacts with two moles of hydrogen to form one mole of cyclohexane:

A chemist would say that cyclohexene reacts with one equivalent of hydrogen, and 1,4-cyclohexadiene reacts with two
equivalents of hydrogen. If you take a known amount of an unknown, unsaturated hydrocarbon and determine how
much hydrogen it will absorb, you can readily determine the number of double bonds present in the hydrocarbon (see
question 2, below).

Addition of hydrogen to a carbon-carbon double bond is called hydrogenation. The overall effect of such an addition is the
reductive removal of the double bond functional group. Regioselectivity is not an issue, since the same group (a hydrogen
atom) is bonded to each of the double bond carbons. The simplest source of two hydrogen atoms is molecular hydrogen
(H2), but mixing alkenes with hydrogen does not result in any discernible reaction. Although the overall hydrogenation
reaction is exothermic, a high activation energy prevents it from taking place under normal conditions. This restriction may
be circumvented by the use of a catalyst, as shown in the reaction coordinate diagram below.
An example of an alkene addition reaction is a process called hydrogenation. In a hydrogenation reaction, two hydrogen
atoms are added across the double bond of an alkene, resulting in a saturated alkane. Hydrogenation of a double bond is a
thermodynamically favorable reaction because it forms a more stable (lower energy) product. In other words, the energy of
the product is lower than the energy of the reactant; thus it is exothermic (heat is released). The heat released is called the
heat of hydrogenation, which is an indicator of a molecule’s stability.

Catalysts are substances that changes the rate (velocity) of a chemical reaction without being consumed or appearing as
part of the product. Catalysts act by lowering the activation energy of reactions, but they do not change the relative
potential energy of the reactants and products. Finely divided metals, such as platinum, palladium and nickel, are among
the most widely used hydrogenation catalysts. Catalytic hydrogenation takes place in at least two stages, as depicted in the
diagram. First, the alkene must be adsorbed on the surface of the catalyst along with some of the hydrogen. Next, two
hydrogens shift from the metal surface to the carbons of the double bond, and the resulting saturated hydrocarbon, which is
more weakly adsorbed, leaves the catalyst surface. The exact nature and timing of the last events is not well understood.

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As shown in the energy diagram, the hydrogenation of alkenes is exothermic, and heat is released corresponding to the ΔH
in the diagram. This heat of reaction can be used to evaluate the thermodynamic stability of alkenes having different
numbers of alkyl substituents on the double bond. For example, the following table lists the heats of hydrogenation for
three C5H10 alkenes which give the same alkane product (2-methylbutane). Since a larger heat of reaction indicates a
higher energy reactant, these heats are inversely proportional to the stabilities of the alkene isomers. To a rough
approximation, we see that each alkyl substituent on a double bond stabilizes this functional group by a bit more than 1
kcal/mole.
(CH3)2CHCH=CH2 CH2=C(CH3)CH2CH3 (CH3)2C=CHCH3
Alkene Isomer
3-methyl-1-butene 2-methyl-1-butene 2-methyl-2-butene

Heat of Reaction
–30.3 kcal/mole –28.5 kcal/mole –26.9 kcal/mole
( ΔHº )

From the mechanism shown here we would expect the addition of hydrogen to occur with syn-stereoselectivity. This is
often true, but the hydrogenation catalysts may also cause isomerization of the double bond prior to hydrogen addition, in
which case stereoselectivity may be uncertain.

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 Exercise 1
1. In the reaction

a. 0.500 mol of ethene reacts with _______ mol of hydrogen. Thus a chemist might say that ethene reacts with one
_______ of hydrogen.
b. ethene is being _______; while _______ is being oxidized.
c. the oxidation number of carbon in ethene is _______; in ethane it is _______.

Answer
a. 0.500 mol of ethene reacts with 0.500 mol of hydrogen. Thus a chemist might say that ethene reacts with one
equivalent of hydrogen.
b. ethene is being reduced; while hydrogen is being oxidized.
c. the oxidation number of carbon in ethene is −2; in ethane it is −3.

 Exercise 2

When 1.000 g of a certain triglyceride (fat) is treated with hydrogen gas in the presence of Adams’ catalyst, it is found
that the volume of hydrogen gas consumed at 99.8 kPa and 25.0°C is 162 mL. A separate experiment indicates that the
molar mass of the fat is 914 g mol−1. How many carbon-carbon double bonds does the compound contain?

Answer
Amount of hydrogen consumed
= n mol

PV
=
RT

99.8 kPa × 0.162 L
=
−1 −1
8.31 kPa ⋅ mol ⋅K × 298 K
−3
= 6.53 × 10  mol H2

Amount of fat used

(1.000 g) × (1 mol)
=
(914 g)

−3
= 1.09 × 10  mol fat

Ratio of moles of hydrogen consumed to moles of fat

−3 −3
= 6.53 × 10 : 1.09 × 10

=6 : 1

Thus, the fat contains six carbon-carbon double bonds per molecule.

Questions
Q8.6.1
Predict the products if the following alkenes were reacted with catalytic hydrogen.

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Solutions

S8.6.1

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne Morsch (University of Illinois Springfield)

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12.3: Nucleophilic Character of the Pi Bond: Electrophilic Addition of Hydrogen
Halides
 Objectives

After completing this section, you should be able to

1. explain the term “electrophilic addition reaction,” using the reaction of a protic acid, HX, with an alkene as an
example.
2. write the mechanism for the reaction of a protic acid, HX, with an alkene.
3. sketch a reaction energy diagram for the electrophilic addition of an acid, HX, to an alkene.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
carbocation (carbonium ion)
electrophilic addition reaction

 Study Notes

An electrophilic addition reaction is a reaction in which a substrate is initially attacked by an electrophile, and the
overall result is the addition of one or more relatively simple molecules across a multiple bond.
The mechanism for the addition of hydrogen halide to propene shown in the reading is quite detailed. Normally, an
organic chemist would write the reaction scheme as follows:
H H CH3 CH3
H X
C C C H C X
H3C H H CH3 CH3

However, the more detailed mechanism shown in the reading does allow you to see the exact fate of all the electrons
involved in the reaction.
In your previous chemistry course, you were probably taught the importance of balancing chemical equations. It may
come as a surprise to you that organic chemists usually do not balance their equations, and often represent reactions
using a format which is quite different from the carefully written, balanced equations encountered in general chemistry
courses. In fact, organic chemists are rarely interested in the inorganic products of their reactions; furthermore, most
organic reactions are non-quantitative in nature.
In many of the reactions in this course, the percentage yield is indicated beneath the products: you are not expected to
memorize these figures. The question of yield is very important in organic chemistry, where two, five, ten or even
twenty reactions may be needed to synthesize a desired product. For example, if a chemist wishes to prepare
compound D by the following reaction sequence:
A → B → C → D (12.3.1)

and each of the individual steps gives only a 50% yield, one mole of A would give only
50% 50% 50%
1 mol × × × = 0.125 mol of D
100% 100% 100%

You will gain first-hand experience of such situations in the laboratory component of this course.

Introduction
One of the most important reactions for alkenes is called electrophilic addition. In this chapter several variations of the
electrophilic addition reaction will be discussed. Each case will have aspects common among all electrophilic addition. In

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this section, the electrophilic addition reaction will be discussed in general to provide a better understanding of subsequent
alkene reactions.
As discussed in Section 6-5, the double bond in alkenes is electron rich due to the prescience of 4 electrons instead of the
two in a single bond. Also, the pi electrons are positioned above and below the double bond making them more accessibly
for reactions. Overall, double bonds can easily donate lone pair electrons to act like a nucleophile (nucleus-loving, electron
rich, a Lewis acid). During an electrophilic addition reactions double bonds donate lone pair electrons to an electrophile
(Electron-loving, electron poor, a Lewis base). There are many types of electrophilic addition, but this section will focus
on the addition of hydrogen halides (HX). Many of the basic ideas discussed will aplicable to subsequent electrophilic
addition reactions.

General Reaction
Overall during this reaction the pi bond of the alkene is broken to form two single, sigma bonds. As shown in the reaction
mechanism, one of these sigma bonds is connected to the H and the other to the X of the hydrogen halide. This reaction
works well with HBr and HCl. HI can also but used but is is usually generated during the reaction by reacting potassium
iodidie (KI) with phosphoric acid (H3PO4).
X H
Ether
C C + HX C C

Alkene Hydrogen Alkyl Halide

Halide

 Example 12.3.1

H3C H Br H
Ether
C C + HBr H3C C C H
H3C H H 3C H

Cl H
Ether
H3CH2CH2CH CH2 + HCl H3 C C C H
H3C H

I
KI
H3PO4

Addition to symmetrical alkenes

What happens?
All alkenes undergo addition reactions with the hydrogen halides. A hydrogen atom joins to one of the carbon atoms
originally in the double bond, and a halogen atom to the other.
For example, with ethene and hydrogen chloride, you get chloroethane:

H 2C CH2 + HCl H 3C CH2Cl

Figure 12.3.1 Electrophilic addition of HCl to ethene.

With but-2-ene you get 2-chlorobutane:

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 H H
H 3C C C CH3 + HCl H3C CH2 C CH3
H
Cl

Figure 12.3.2 Electrophilic addition of HCl to but-2-ene.

What happens if you add the hydrogen to the carbon atom at the right-hand end of the double bond, and the chlorine to the
left-hand end? You would still have the same product. The chlorine would be on a carbon atom next to the end of the chain
- you would simply have drawn the molecule flipped over in space. That would be different of the alkene was
unsymmetrical - that's why we have to look at them separately.

Mechanism
Step 1) Electrophilic Attack
During the first step of the mechanism, the 2 pi electrons from the double bond attack the H in the HBr electrophile which
is shown by a curved arrow. The two pi electrons form a C-H sigma bond between the hydrogen from HBr and a carbon
from the double bond. Simultaneously the electrons from the H-X bond move onto the halogen to form a halide anion. The
removal of pi electrons form the double bond makes one of the carbons become an electron deficient carbocation
intermediate. This carbon is sp2 hybridized and the positive charge is contained in an unhybridized p orbital.
Step 2) Nucleophilic attack by halide anion
The formed carbocation now can act as an electrophile and accept an electron pair from the nucleophilic halide anion. The
electron pair becomes a X-C sigma bond to create the neutral alkyl halide product of electrophilic addition.

H X X

H H H H H X
C C H C C H C C H
1 - electrophilic 2 - nucleophilic
H H attack H H trapping H H

Figure 12.3.3 Mechanism of Electrophilic Addition of Hydrogen Halide to Ethene

H X X

H H H H X H
C C C C H H C C H
1 - electrophilic 2 - nucleophilic
H3 C H attack H3C H trapping H H

Figure 12.3.4 Mechanism of Electrophilic Addition of Hydrogen Halide to Propene

All of the halides (HBr, HCl, HI, HF) can participate in this reaction and add on in the same manner. Although different
halides do have different rates of reaction, due to the H-X bond getting weaker as X gets larger (poor overlap of orbitals)s.

Reaction Energy Diagram

An energy diagram for the two-step electrophilic addition mechanism is shown below. The energy diagram has two peaks
which represent the transition state for each mechanistic step. The peaks are separated by a valley which represents the
high energy carbocation reaction intermediate. Because the energy of activation for the first step of the mechanism (ΔE ‡ 1)
is much larger than the second (ΔE‡1), the first step of the mechanism is the rate-determining step. Both the alkene and the
hydrogen halide are reactants in the first step of the mechanism, this electrophilic addition is a second order reaction and
the rate law expression can be written rate = k[Alkene][HX]. Also, any structural feature which can stabilize the transition
state between the reactants the carbocation intermediate will lower ΔE‡1 and thereby increase the reaction rate. Overall, the
alkyl halide product of this reaction more stable than the reactants making the reaction exothermic.

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Reaction rates
Variation of rates when you change the halogen
Reaction rates increase in the order HF - HCl - HBr - HI. Hydrogen fluoride reacts much more slowly than the other three,
and is normally ignored in talking about these reactions.
When the hydrogen halides react with alkenes, the hydrogen-halogen bond has to be broken. The bond strength falls as you
go from HF to HI, and the hydrogen-fluorine bond is particularly strong. Because it is difficult to break the bond between
the hydrogen and the fluorine, the addition of HF is bound to be slow.
Variation of rates when you change the alkene
This applies to unsymmetrical alkenes as well as to symmetrical ones. For simplicity the examples given below are all
symmetrical ones- but they don't have to be.
Reaction rates increase as the alkene gets more complicated - in the sense of the number of alkyl groups (such as methyl
groups) attached to the carbon atoms at either end of the double bond. For example:
H H H CH3 H3C CH3
C C C C C C
H H H3C H H3C CH3

reactivity increases

There are two ways of looking at the reasons for this - both of which need you to know about the mechanism for the
reactions.
Alkenes react because the electrons in the pi bond attract things with any degree of positive charge. Anything which
increases the electron density around the double bond will help this.
Alkyl groups have a tendency to "push" electrons away from themselves towards the double bond. The more alkyl groups
you have, the more negative the area around the double bonds becomes.
The more negatively charged that region becomes, the more it will attract molecules like hydrogen chloride.
The more important reason, though, lies in the stability of the intermediate ion formed during the reaction. The three
examples given above produce these carbocations (carbonium ions) at the half-way stage of the reaction:
H H H H
C C H C C
H H H H
a primary carbocation

H CH3 H CH3 ions getting

C C H C C more
energetically
H 3C H H 3C H stable and so
a secondary carbocation easier to form

H 3C CH3 H CH3
C C H 3C C C
H 3C CH3 H 3C CH3
a tertiary carbocation

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The stability of the intermediate ions governs the activation energy for the reaction. As you go towards the more
complicated alkenes, the activation energy for the reaction falls. That means that the reactions become faster.

Representing Organic Reactions

Organic reaction equations are often written in one of two ways. The reactant for the reaction is written to the left of the
reaction arrow. The products are written to the right of the arrow. The reagent for the reaction is written above the arrow.
Other reaction conditions such as the solvent or the temperature can be written above or below the reaction arrow.

Reaction solvent

H3 C H Br H
Ether
C C + HBr H3 C C C H
H H 25 oC H
H
Reactant Reagent Product
Reaction temperature

Alternativley the reactant and reagent can both be written to the left of the reaction arrow. This is typically done to
highlight the importance of the reactant. The solvent and reaction temperature are still written above or below the reaction
arrow. The reaction products are still written to the right of the reaction arrow.

Reagent Reaction solvent

H 3C H HBr, Ether Br H
C C H 3C C C H
25 oC H
H H H
Reactant Product
Reaction temperature

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A.
Benjamin, Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions,
"You are granted permission for individual, educational, research and non-commercial reproduction, distribution,
display and performance of this work in any format."
Dr. Krista Cunningham
very important regarding electrophilic addition reactions is that if the starting alkene is asymmetrical, there are two
possible courses that could be followed, depending on which of the two alkene carbons forms the new sigma bond in the
first step.

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Of course, the two reaction courses involve two different carbocation intermediates, which may have different energy
levels. Two different products are possible, and in general the product which predominates will be the one that is derived
from the lower-energy carbocation intermediate.
This important regiochemical principle is nicely illustrated by a simple electrophilic addition that is commonly carried out
in the organic laboratory: the conversion of an alkene to an alkyl bromide by electrophilic addition of HBr to the double
bond. Let's look at a hypothetical addition of HBr to 2-methyl-2-butene, pictured below. Two different regiochemical
outcomes are possible:

The initial protonation step could follow two different pathways, resulting in two different carbocation intermediates:
pathway 'a' gives a tertiary carbocation intermediate (Ia), while pathway 'b' gives a secondary carbocation intermediate (Ib)
We know already that the tertiary carbocation is more stable (in other words, lower in energy). According to the Hammond
postulate, this implies that the activation energy for pathway a is lower than in pathway b, meaning in turn that Ia forms
faster.

Because the protonation step is the rate determining step for the reaction, the tertiary alkyl bromide A will form much
faster than the secondary alkyl halide B, and thus A will be the predominant product observed in this reaction. This is a
good example of a non-enzymatic organic reaction that is highly regiospecific.
In the example above, the difference in carbocation stability can be accounted for by the electron-donating effects of the
extra methyl group on one side of the double bond. It is generally observed that, in electrophilic addition of acids
(including water) to asymmetrical alkenes, the more substituted carbon is the one that ends up bonded to the heteroatom of
the acid, while the less substituted carbon is protonated.

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This rule of thumb is known as Markovnikov's rule, after the Russian chemist Vladimir Markovnikov who proposed it in
1869.
While it is useful in many cases, Markovikov's rule does not apply to all possible electrophilic additions. It is more
accurate to use the more general principle that has already been stated above:
When an asymmetrical alkene undergoes electrophilic addition, the product that predominates is the one that results from
the more stable of the two possible carbocation intermediates.
How is this different from Markovnikov's original rule? Consider the following hypothetical reaction, which is similar to
the HBr addition shown above except that the six methyl hydrogens on the left side of the double bond have been replaced
by highly electron-withdrawing fluorines.

Now when HBr is added, it is the less substituted carbocation that forms faster in the rate-determining protonation step,
because in this intermediate the carbon bearing the positive charge is located further away from the electron-withdrawing,
cation-destabilizing fluorines. As a result, the predominant product is the secondary rather than the tertiary bromoalkane.
This would be referred to as an 'anti-Markovnikov' addition product, because it 'breaks' Markovnikov's rule.

Example

Predict the product of the following reaction:

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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12.4: Alcohol Synthesis by Electrophilic Hydration: Thermodynamic Control
Electrophilic hydration is the act of adding electrophilic hydrogen from a non-nucleophilic strong acid (a reusable catalyst,
examples of which include sulfuric and phosphoric acid) and applying appropriate temperatures to break the alkene's
double bond. After a carbocation is formed, water bonds with the carbocation to form a 1º, 2º, or 3º alcohol on the alkane.

What Is Electrophilic Hydration?

Electrophilic hydration is the reverse dehydration of alcohols and has practical application in making alcohols for fuels and
reagents for other reactions. The basic reaction under certain temperatures (given below) is the following:

The phrase "electrophilic" literally means "electron loving" (whereas "nucleophilic" means "nucleus loving"). Electrophilic
hydrogen is essentially a proton: a hydrogen atom stripped of its electrons. Electrophilic hydrogen is commonly used to
help break double bonds or restore catalysts (see SN2 for more details).

How Does Electrophilic Hydration Work?

Mechanism for 3º Alcohol (1º and 2º mechanisms are similar):

Temperatures for Types of Alcohol Synthesis

Heat is used to catalyze electrophilic hydration; because the reaction is in equilibrium with the dehydration of an alcohol,
which requires higher temperatures to form an alkene, lower temperatures are required to form an alcohol. The exact
temperatures used are highly variable and depend on the product being formed.
Primary Alcohol: Less than 170ºC
Secondary Alcohol: Less than 100ºC
Tertiary Alcohol: Less than 25ºC

But...Why Does Electrophilic Hydration Work?

An alkene placed in an aqueous non-nucleophilic strong acid immediately "reaches out" with its double bond and
attacks one of the acid's hydrogen atoms (meanwhile, the bond between oxygen and hydrogen performs heterolytic
cleavage toward the oxygen—in other words, both electrons from the oxygen/hydrogen single bond move onto the
oxygen atom).
A carbocation is formed on the original alkene (now alkane) in the more-substituted position, where the oxygen end of
water attacks with its 4 non-bonded valence electrons (oxygen has 6 total valence electrons because it is found in
Group 6 on the periodic table and the second row down: two electrons in a 2s-orbital and four in 2p-orbitals. Oxygen
donates one valence electron to each bond it forms, leaving four 4 non-bonded valence electrons).

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 After the blue oxygen atom forms its third bond with the more-substituted carbon, it develops a positive charge (3
bonds and 2 valence electrons give the blue oxygen atom a formal charge of +1).
The bond between the green hydrogen and the blue oxygen undergoes heterolytic cleavage, and both the electrons from
the bond move onto the blue oxygen. The now negatively-charged strong acid picks up the green electrophilic
hydrogen.
Now that the reaction is complete, the non-nucleophilic strong acid is regenerated as a catalyst and an alcohol forms on
the most substituted carbon of the current alkane. At lower temperatures, more alcohol product can be formed.

What is Regiochemistry and How Does It Apply?

Regiochemistry deals with where the substituent bonds on the product. Zaitsev's and Markovnikov's rules address
regiochemistry, but Zaitsev's rule applies when synthesizing an alkene while Markovnikov's rule describes where the
substituent bonds onto the product. In the case of electrophilic hydration, Markovnikov's rule is the only rule that directly
applies. See the following for an in-depth explanation of regiochemistry Markovnikov explanation: Radical Additions--
Anti-Markovnikov Product Formation
In the mechanism for a 3º alcohol shown above, the red H is added to the least-substituted carbon connected to the
nucleophilic double bonds (it has less carbons attached to it). This means that the carbocation forms on the 3º carbon,
causing it to be highly stabilized by hyperconjugation—electrons in nearby sigma (single) bonds help fill the empty p-
orbital of the carbocation, which lessens the positive charge. More substitution on a carbon means more sigma bonds are
available to "help out" (by using overlap) with the positive charge, which creates greater carbocation stability. In other
words, carbocations form on the most substituted carbon connected to the double bond. Carbocations are also
stabilized by resonance, but resonance is not a large factor in this case because any carbon-carbon double bonds are used to
initiate the reaction, and other double bonded molecules can cause a completely different reaction.
If the carbocation does originally form on the less substituted part of the alkene, carbocation rearrangements occur to form
more substituted products:
Hydride shifts: a hydrogen atom bonded to a carbon atom next to the carbocation leaves that carbon to bond with the
carbocation (after the hydrogen has taken both electrons from the single bond, it is known as a hydride). This changes
the once neighboring carbon to a carbocation, and the former carbocation becomes a neighboring carbon atom.

Alkyl shifts: if no hydrogen atoms are available for a hydride shift, an entire methyl group performs the same shift.

The nucleophile attacks the positive charge formed on the most substituted carbon connected to the double bond, because
the nucleophile is seeking that positive charge. In the mechanism for a 3º alcohol shown above, water is the nucleophile.
When the green H is removed from the water molecule, the alcohol attached to the most substituted carbon. Hence,
electrophilic hydration follows Markovnikov's rule.

What is Stereochemistry and How Does It Apply?

Stereochemistry deals with how the substituent bonds on the product directionally. Dashes and wedges denote
stereochemistry by showing whether the molecule or atom is going into or out of the plane of the board. Whenever the
bond is a simple single straight line, the molecule that is bonded is equally likely to be found going into the plane of the
board as it is out of the plane of the board. This indicates that the product is a racemic mixture.

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Electrophilic hydration adopts a stereochemistry wherein the substituent is equally likely to bond pointing into the plane of
the board as it is pointing out of the plane of the board. The 3º alcohol product could look like either of the following
products:

Note: Whenever a straight line is used along with dashes and wedges on the same molecule, it could be denoting that the
straight line bond is in the same plane as the board. Practice with a molecular model kit and attempting the practice
problems at the end can help eliminate any ambiguity.

Is this a Reversible Synthesis?

Electrophilic hydration is reversible because an alkene in water is in equilibrium with the alcohol product. To sway the
equilibrium one way or another, the temperature or the concentration of the non-nucleophilic strong acid can be changed.
For example:
Less sulfuric or phosphoric acid and an excess of water help synthesize more alcohol product.
Lower temperatures help synthesize more alcohol product.

Is There a Better Way to Add Water to Synthesize an Alcohol From an Alkene?

A more efficient pathway does exist: see Oxymercuration - Demercuration: A Special Electrophilic Addition.
Oxymercuration does not allow for rearrangements, but it does require the use of mercury, which is highly toxic.
Detractions for using electrophilic hydration to make alcohols include:
Allowing for carbocation rearrangements
Poor yields due to the reactants and products being in equilibrium
Allowing for product mixtures (such as an (R)-enantiomer and an (S)-enantiomer)
Using sulfuric or phosphoric acid

Problems
Predict the product of each reaction.
1)

2) How does the cyclopropane group affect the reaction?

3) (Hint: What is different about this problem?)

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4) (Hint: Consider stereochemistry.)

5) Indicate any shifts as well as the major product:

Answers to Practice Problems

1) This is a basic electrophilic hydration.

2) The answer is additional side products, but the major product formed is still the same (the product shown).
Depending on the temperatures used, the cyclopropane may open up into a straight chain, which makes it unlikely that the
major product will form (after the reaction, it is unlikely that the 3º carbon will remain as such).

3) A hydride shift actually occurs from the top of the 1-methylcyclopentane to where the carbocation had formed.

4) This reaction will have poor yields due to a very unstable intermediate. For a brief moment, carbocations can form
on the two center carbons, which are more stable than the outer two carbons. The carbocations have an sp2 hybridization,

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and when the water is added on, the carbons change their hybridization to sp3. This makes the methyl and alcohol groups
equally likely to be found going into or out of the plane of the paper- the product is racemic.

5) In the first picture shown below, an alkyl shift occurs but a hydride shift (which occurs faster) is possible. Why doesn't a
hydride shift occur? The answer is because the alkyl shift leads to a more stable product. There is a noticeable amount
of side product that forms where the two methyl groups are, but the major product shown below is still the most significant
due to the hyperconjugation that occurs by being in between the two cyclohexanes.

References
1. Vollhardt and Schore. Organic Chemistry, Structure and Function- Fifth Edition. New York: W. H. Freeman and
Company, 2007.
2. Krow, Grant. "Sulfuric Acid." Encyclopedia of Reagents for Organic Synthesis. Philadelphia, Pennsylvania: John
Wiley & Sons, 2001.

Outside Links
http://en.wikipedia.org/wiki/Electrophile
http://www.youtube.com/watch?v=Z7xskJnGDEM
For more on Hyperconjugation: http://en.wikipedia.org/wiki/Hyperconjugation
For more on Markovnikov's Rule: http://en.wikipedia.org/wiki/Markovnikov_rule
For more on Zaitsev's Rule: http://en.wikipedia.org/wiki/Zaitsev%27s_rule

Contributors
Lance Peery (UCD)

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12.5: Electrophilic Addition of Halogens to Alkenes
 Objectives

After completing this section, you should be able to

1. write the equation for the reaction of chlorine or bromine with a given alkene.
2. identify the conditions under which an addition reaction occurs between an alkene and chlorine or bromine.
3. draw the structure of the product formed when a given alkene undergoes an addition reaction with chlorine or
bromine.
4. write the mechanism for the addition reaction that occurs between an alkene and chlorine or bromine, and account
for the stereochemistry of the product.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
anti stereochemistry
bromonium ion

 Study Notes

In the laboratory you will test a number of compounds for the presence of a carbon-carbon double bond. A common
test is the decolourization of a reddish-brown bromine solution by an alkene.
The two-step mechanism shown in the LibreText pages gives you an idea of how the reaction between an alkene and a
halogen occurs. Note the formation of the bridged bromonium ion intermediate and the anti stereochemistry of the
final product because the two bromine atoms come from opposite faces of the double bond.
Additional evidence in support of the bromonium ion mechanism comes from the results obtained when an alkene
(such as cyclopentene) reacts with bromine in the presence of sodium chloride (see Figure 8.2: Reaction of an alkene
with bromine in the presence of sodium chloride, below).
Br2
+
NaCl
Br H Br H
H Br H Cl
Figure 8.2: Reaction of an alkene with bromine in the presence of sodium chloride
Once formed, the bromonium ion is susceptible to attack by two nucleophiles—chloride ion and bromide ion—and, in
fact, a mixture of two products (both produced by anti attack) is formed.

Halogens can act as electrophiles to which can be attacked by a pi bond from an alkene. Pi bonds represents a region of
electron density and therefore function as a nucleophiles. How is it possible for a halogen to obtain positive charge to be an
electrophile?

Introduction
A halogen molecule, for example Br2, approaches a double bond of the alkene, electrons in the double bond repel electrons
in the bromine molecule causing polarization of the halogen-halogen bond. This creates a dipole moment in the halogen-
halogen bond. Heterolytic bond cleavage occurs and one of the halogens obtains a positive charge and reacts as an
electrophile. The reaction of the addition is not regioselective but is stereoselective. Stereochemistry of this addition can be
explained by the mechanism of the reaction. In the first step, the electrophilic halogen (with the positive charge)
approaches the pi bond and 2p orbitals of the halogen bond with two carbon atoms creating a cyclic ion with a halogen as
the intermediate. In the second step, the remaining halide ion (halogen with the negative charge) attacks either of the two
carbons in the cyclic ion from the back side of the cycle as in the SN2 reaction. Therefore stereochemistry of the product is
anti addition of vicinal dihalides.

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 R C=CR +X → R CX−CR X (8.2.1)
2 2 2 2 2

Step 1: In the first step of the addition the Br-Br bond polarizes, heterolytic cleavage occurs and Br with the positive
charge forms a cyclic intermediate with the two carbons from the alkene.

Br Br

Br
C C + Br
C C

Step 2: In the second step, bromide anion attacks either carbon of the bridged bromonium ion from the back side of the
ring. The bromine atom in the bromonium ion acts as a shield in a way, forcing the bromonium anion to attack from the
opposite side as it. The result of this is the ring opening up with the two halogens on opposite sides as each other. This is
anti stereochemistry, which is defined as the two bromine atoms come from opposite faces of the double bond. The
product is that the bromines add on trans to each other.

Br Br
C C C C
Br

Br

Halogens that are commonly used in this type of the reaction are: Br and C l. In thermodynamical terms I is too slow for
this reaction because of the size of its atom, and F is too vigorous and explosive.
Because the halide ion can attack any carbon from the opposite side of the ring it creates a mixture of steric products.
Optically inactive starting material produce optically inactive achiral products (meso) or a racemic mixture.

Electrophilic addition mechanism consists of two steps.

Before constructing the mechanism let us summarize conditions for this reaction. We will use Br2 in our example for
halogenation of ethylene.

Nucleophile Double bond in alkene

Electrophile Br2, Cl2

Regiochemistry not relevant

Stereochemistry ANTI

Summary
Halogens can act as electrophiles due to polarizability of their covalent bond. Addition of halogens is stereospecific and
produces vicinal dihalides with anti addition.

References
1. Vollhard,K.Peter C., and Neil E.Schore.Organic Chemistry:Structure and Function.New Yourk: W.H.Freeman and
Company 2007
2. Chemestry-A Europian Journal 9 (2003) :1036-1044

Problems
1.What is the mechanism of adding Cl2 to the cyclohexene?

2.A reaction of Br2 molecule in an inert solvent with alkene follows?

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a) syn addition
b) anti addition
c) Morkovnikov rule

3)

4)
Key:
1.

2. b

3. enantiomer

4.

Exercises
Questions
Q8.2.1
Predict the products for 1,2-dimethylcyclopentene reacting with Br2 with proper
stereochemistry.
Q8.2.2
Predict the products for 1,2-dimethylcyclpentene reacting with HCl, give the proper
stereochemistry. What is the relationship between the two products?
Solutions
S8.2.1

S8.2.2

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These compounds are enantiomers.
Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Jim Clark (Chemguide.co.uk)
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham
Lauren Reutenauer (Amherst College)

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12.6: The Generality of Electrophilic Addition
The proton is not the only electrophilic species that initiates addition reactions to the double bond of alkenes. Lewis acids
like the halogens, boron hydrides and certain transition metal ions are able to bond to the alkene pi-electrons, and the
resulting complexes rearrange or are attacked by nucleophiles to give addition products.The electrophilic character of the
halogens is well known. Chlorine (Cl2) and bromine(Br2) react selectively with the double bond of alkenes, and these
reactions are what we will focus on. Fluorine adds uncontrollably with alkenes,and the addition of iodine is unfavorable, so
these are not useful preparative methods.
The addition of chlorine and bromine to alkenes, as shown below, proceeds by an initial electrophilic attack on the pi-
electrons of the double bond. Dihalo-compounds in which the halogens are bound to adjacent carbons are called vicinal,
from the Latin vicinalis, meaning neighboring.

R2C=CR2 + X2 ——> R2CX-CR2X

Other halogen-containing reagents which add to double bonds include hypohalous acids, HOX, and sulfenyl chlorides,
RSCl. These reagents are unsymmetrical, so their addition to unsymmetrical double bonds may in principle take place in
two ways. In practice, these addition reactions are regioselective, with one of the two possible constitutionally isomeric
products being favored. The electrophilic moiety in both of these reagents is the halogen.

(CH3)2C=CH2 + HOBr ——> (CH3)2COH-CH2Br

(CH3)2C=CH2 + C6H5SCl ——> (CH3)2CCl-CH2SC6H5

The regioselectivity of the above reactions may be explained by the same mechanism we used to rationalize the
Markovnikov rule. Thus, bonding of an electrophilic species to the double bond of an alkene should result in preferential
formation of the more stable (more highly substituted) carbocation, and this intermediate should then combine rapidly with
a nucleophilic species to produce the addition product.

To apply this mechanism we need to determine the electrophilic moiety in each of the reagents. By using electronegativity
differences we can dissect common addition reagents into electrophilic and nucleophilic moieties, as shown on the right.
In the case of hypochlorous and hypobromous acids (HOX), these weak Brønsted acids (pKa's ca. 8) do not react as proton
donors; and since oxygen is more electronegative than chlorine or bromine, the electrophile will be a halide cation. The
nucleophilic species that bonds to the intermediate carbocation is then hydroxide ion, or more likely water (the usual
solvent for these reagents), and the products are called halohydrins. Sulfenyl chlorides add in the opposite manner because
the electrophile is a sulfur cation, RS(+), whereas the nucleophilic moiety is chloride anion (chlorine is more
electronegative than sulfur).
Below are some examples illustrating the addition of various electrophilic halogen reagents to alkene groups. Notice the
specific regiochemistry of the products, as explained above.

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Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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12.7: Oxymncuration-Demercuration: A Special Elcctrophilic Addition
Objectives
After completing this section, you should be able to
1. write an equation for the hydration of an alkene with sulfuric acid.
2. write an equation for the formation of an alcohol from an alkene by the oxymercuration-demercuration process.
3. identify the alkene, the reagents, or both, that should be used to produce a given alcohol by the oxymercuration-
demercuration process.
4. write the mechanism for the reaction of an alkene with mercury(II) acetate in aqueous tetrahydrofuran (THF).

 Key Terms

Make certain that you can define, and use in context, the key terms below.
hydration
oxymercuration

 Study Notes

Oxymercuration is the reaction of an alkene with mercury(II) acetate in aqueous THF, followed by reduction with
sodium borohydride. The final product is an alcohol.
It is important that you recognize the similarity between the mechanisms of bromination and oxymercuration.
Recognizing these similarities helps you to reduce the amount of factual material that you need to remember.
Mercuric acetate, or mercury(II) acetate, to give it the preferred IUPAC name, is written as Hg(OAc)2; by comparing
this formula with the formula Hg(O2CCH3)2, you can equate Ac with -COCH3. In fact, Ac is an abbreviation used for
the acetyl group with the structure shown below as are other similar abbreviations that you will encounter.
O
Ac (acetyl)
CH3

Me (methyl) CH3

Et (ethyl) CH2CH3

Prn (n-propyl) CH2CH2CH3

CH3
Pri (isopropyl)
CH3

CH3
But (tert-butyl) CH3
CH3

Ph (phenyl) or

What Is Electrophilic Hydration?

Electrophilic hydration is the act of adding electrophilic hydrogen from a non-nucleophilic strong acid (a reusable catalyst,
examples of which include sulfuric and phosphoric acid) and applying appropriate temperatures to break the alkene's
double bond. After a carbocation is formed, water bonds with the carbocation to form a 1º, 2º, or 3º alcohol on the alkane.
Electrophilic hydration is the reverse dehydration of alcohols and has practical application in making alcohols for fuels and
reagents for other reactions. The basic reaction under certain temperatures (given below) is the following:

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 R R’’ H OH
H2SO4
C C + H2 O R C C R’’’
R’ R’’’ R’ R’’

Electrophilic hydrogen is essentially a proton: a hydrogen atom stripped of its electrons. Electrophilic hydrogen is
commonly used to help break double bonds or restore catalysts (see SN2 for more details).

How Does Electrophilic Hydration Work?

Mechanism for 3º Alcohol (1º and 2º mechanisms are similar):
Hydration is the process where water is added to an alkene to yield an alcohol. Acid-catalyzed hydration is when a strong
acid is used as a catalyst to begin the reaction, but let's look at the mechanism below and break down the steps.
H3C H O H H 3C H O H
Δ
C C + O S O C C H + O S O
H3C H H O H 3C H O

O
H H

O H H H O
H O H O H H
Δ
O S O + H3C C C H H3C C C H + O S O
H O O
H 3C H H3C H

Step 1: A hydrogen atom from the acid is attacked by the nucleophilic Pi-electrons in the double bond. This is similar to
the other alkene reactions we have seen so far. In this process, a new C-H bond is formed to create the more stable
carbocation.
Step 2: A nucleophilic water attacks or donates a lone pair to the positively charged carbon in the carbocation intermediate
created in the first step. There is new C-O bond with the O having a formal charge of +1. The product is a protonated
alcohol.
Step 3: To obtain the neutral alcohol product, the final step is to deprotonate the oxygen atom with the +1 formal charge
using the acid. This final step regenerates the acid catalyst and yields the neutral alcohol product.

Temperatures for Types of Alcohol Synthesis

Heat is used to catalyze electrophilic hydration; because the reaction is in equilibrium with the dehydration of an alcohol,
which requires higher temperatures to form an alkene, lower temperatures are required to form an alcohol. The exact
temperatures used are highly variable and depend on the product being formed.

What is Regiochemistry and How Does It Apply?

Regiochemistry deals with where the substituent bonds on the product. Zaitsev's and Markovnikov's rules address
regiochemistry, but Zaitsev's rule applies when synthesizing an alkene while Markovnikov's rule describes where the
substituent bonds onto the product. In the case of electrophilic hydration, Markovnikov's rule is the only rule that directly
applies. See the following for an in-depth explanation of regiochemistry Markovnikov explanation: Radical Additions--
Anti-Markovnikov Product Formation
In the mechanism for a 3º alcohol shown above, the H is added to the least-substituted carbon connected to the
nucleophilic double bonds (it has less carbons attached to it). This means that the carbocation forms on the 3º carbon,
causing it to be highly stabilized by hyperconjugation—electrons in nearby sigma (single) bonds help fill the empty p-
orbital of the carbocation, which lessens the positive charge. More substitution on a carbon means more sigma bonds are
available to "help out" (by using overlap) with the positive charge, which creates greater carbocation stability. In other
words, carbocations form on the most substituted carbon connected to the double bond. Carbocations are also
stabilized by resonance, but resonance is not a large factor in this case because any carbon-carbon double bonds are used to
initiate the reaction, and other double bonded molecules can cause a completely different reaction.

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If the carbocation does originally form on the less substituted part of the alkene, carbocation rearrangements occur to form
more substituted products:
Hydride shifts: a hydrogen atom bonded to a carbon atom next to the carbocation leaves that carbon to bond with the
carbocation (after the hydrogen has taken both electrons from the single bond, it is known as a hydride). This changes
the once neighboring carbon to a carbocation, and the former carbocation becomes a neighboring carbon atom.
CH3 CH3 H3 C CH3
H3 C C C C C H
H H H3 C H

Alkyl shifts: if no hydrogen atoms are available for a hydride shift, an entire methyl group performs the same shift.
H3C CH3 CH3 CH3
C C CH3 H C C
H CH3 CH3 CH3

The nucleophile attacks the positive charge formed on the most substituted carbon connected to the double bond, because
the nucleophile is seeking that positive charge. In the mechanism for a 3º alcohol shown above, water is the nucleophile.
After one H atom is removed from the water molecule, the alcohol is attached to the most substituted carbon. Hence,
electrophilic hydration follows Markovnikov's rule.

What is Stereochemistry and How Does It Apply?

Stereochemistry deals with how the substituent bonds on the product directionally. Dashes and wedges denote
stereochemistry by showing whether the molecule or atom is going into or out of the plane of the board. Whenever the
bond is a simple single straight line, the molecule that is bonded is equally likely to be found going into the plane of the
board as it is out of the plane of the board. This indicates that the product is a racemic mixture.
Electrophilic hydration adopts a stereochemistry wherein the substituent is equally likely to bond pointing into the plane of
the board as it is pointing out of the plane of the board. The 3º alcohol product of the following reaction could look like
either of the following products:
OH OH
H2SO4 H H
H +
H 2O H H
H H H

There is no stereochemical control in acid-catalyzed hydration reactions. This is due to the trigonal planar, sp2 nature of the
carbocation intermediate. Water can act as a nucleophile to form a bond to either face of the carbocation, resulting in a
mixture of stereochemical outcomes.

H H
H H 2O or H H 2O
H H

Note: Whenever a straight line is used along with dashes and wedges on the same molecule, it could be denoting that the
straight line bond is in the same plane as the board. Practice with a molecular model kit and attempting the practice
problems at the end can help eliminate any ambiguity.

Is this a Reversible Synthesis?

Electrophilic hydration is reversible because an alkene in water is in equilibrium with the alcohol product. To sway the
equilibrium one way or another, the temperature or the concentration of the non-nucleophilic strong acid can be changed.
For example:
Less sulfuric or phosphoric acid and an excess of water help synthesize more alcohol product.
Lower temperatures help synthesize more alcohol product.

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Is There a Better Way to Add Water to Synthesize an Alcohol From an Alkene?
A more efficient pathway does exist: Oxymercuration - Demercuration, a special type of electrophilic addition.
Oxymercuration does not allow for rearrangements, but it does require the use of mercury, which is highly toxic.
Detractions for using electrophilic hydration to make alcohols include:
Allowing for carbocation rearrangements
Poor yields due to the reactants and products being in equilibrium
Allowing for product mixtures (such as an (R)-enantiomer and an (S)-enantiomer)
Using sulfuric or phosphoric acid
Oxymercuration is a special electrophilic addition. It is anti-stereospecific and regioselective. Regioselectivity is a process
in which the substituents choses one direction it prefers to be attached to over all the other possible directions. The good
thing about this reaction is that there are no carbocation rearrangement due to stabilization of the reactive intermediate.
Similar stabilization is also seen in bromination addition to alkenes.

Introduction to Oxymercuration
One of the major advantages to oxymercuration is that carbocation rearrangements cannot occur under these conditions
(Hg(OAc)2, H2O). Carbocation rearrangement is a process in which the carbocation intermediate can undergo a methyl or
alkyl shift to form a more stable ion. Due to a possible carbocation rearrangement, the reaction below would not generate
the product shown in high yields. In contrast, the oxymercuration reaction would proceed to form the desired product.
OH
H2SO4, H2O

(racemic mixture)

OH
1. HgOAc2, H2O
2. NaBH4, NaOH
H 2O
(racemic mixture)

This reaction involves a mercury acting as a reagent attacking the alkene double bond to form a Mercurinium Ion Bridge.
A water molecule will then attack the most substituted carbon to open the mercurium ion bridge, followed by proton
transfer to solvent water molecule.
OAc
Hg OAc OAc
Ac
Hg
H H Hg H H
C C H C C H C C
R H R H OH2 R H
O
H H
+ OAc
water attacks the more
substituted carbon
OH2

OAc

H H Hg
H NaBH4 H H
C C C C
R H R H
OH O
H

The organomercury intermediate is then reduced by sodium borohydride - the mechanism for this final step is beyond the
scope of our discussion here. Notice that overall, the oxymercuration - demercuration mechanism follows Markovnikov's
regioselectivity with the OH group is attached to the most substituted carbon and the H is attach to the least substituted
carbon. The reaction is useful, however, because strong acids are not required, and carbocation rearrangements are avoided
because no discreet carbocation intermediate forms.
It is important to note that for the mechanism shown above, the enantiomer of the product shown is also formed. This is
the result of formation of the mercurium ion below the alkene in the first step.

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References
1. Vollhardt, K. Peter C. Organic chemistry structure and function. New York: W.H. Freeman, 2007.
2. Smith, Michael B., and Jerry March. March's Advanced Organic Chemistry Reactions, Mechanisms, and Structure
(March's Advanced Organic Chemistry). New York: Wiley-Interscience, 2007 2007.
3. Roderic P. Quirk , Robert E. Lea, Reductive demercuration of hex-5-enyl-1-mercuric bromide by metal hydrides.
Rearrangement, isotope effects, and mechanism, J. Am. Chem. Soc., 1976, 98 (19), pp 5973–5978.

Some Practice Problems

 Practice problems

What are the end products of these reactants?

Answer

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 The end product to these practice problems are pretty much very similar. First, you locate where the double bond is
on the reactant side. Then, you look at what substituents are attached to each side of the double bond and add the
OH group to the more substituent side and the hydrogen on the less substituent side.

 More Problems

Predict the product of each reaction.

1)

2) How does the cyclopropane group affect the reaction?

3) (Hint: What is different about this problem?)

4) (Hint: Consider stereochemistry.)

5) Indicate any shifts as well as the major product:

Answer
1) This is a simple electrophilic hydration.

2) The answer is additional side products, but the major product formed is still the same (the product shown).
Depending on the temperatures used, the cyclopropane may open up into a straight chain, which makes it unlikely
that the major product will form (after the reaction, it is unlikely that the 3º carbon will remain as such).

3) A hydride shift actually occurs from the 3 carbon of the 3-methylcyclopentene to where the carbocation had
formed.

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 4) This reaction will have poor yields due to a very unstable intermediate. For a brief moment, carbocations
can form on the two center carbons, which are more stable than the outer two carbons. The carbocations have an
sp2 hybridization, and when the water is added on, the carbons change their hybridization to sp3. This makes the
methyl and alcohol groups equally likely to be found going into or out of the plane of the paper- the product is
racemic.

5) In the first picture shown below, an alkyl shift occurs but a hydride shift (which occurs faster) is possible. Why
doesn't a hydride shift occur? The answer is because the alkyl shift leads to a more stable product. There is a
noticeable amount of side product that forms where the two methyl groups are, but the major product shown below
is still the most significant due to the hyperconjugation that occurs by being in between the two cyclohexanes.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Lance Peery (UCD), Duyen Dao-Tran (UCD)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
Prof. Steven Farmer (Sonoma State University)
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham
Lauren Reutenauer (Amherst College)

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12.8: Hydroboration-Oxidation: A Stereospecific Anti-Markovnikov Hydration
 Objectives

After completing this section, you should be able to

1. identify hydroboration (followed by oxidation) as a method for bringing about the (apparently) non-Markovnikov
addition of water to an alkene.
2. write an equation for the formation of a trialkylborane from an alkene and borane.
3. write an equation for the oxidation of a trialkylborane to an alcohol.
4. draw the structure of the alcohol produced by the hydroboration, and subsequent oxidation, of a given alkene.
5. determine whether a given alcohol should be prepared by oxymercuration-demercuration or by hydroboration-
oxidation, and identify the alkene and reagents required to carry out such a synthesis.
6. write the detailed mechanism for the addition of borane to an alkene, and explain the stereochemistry and
regiochemistry of the reaction.

 Key Terms

Make certain that you can define, and use in context, the key term below.
hydroboration

 Study Notes

The two most important factors influencing organic reactions are polar (or electronic) effects and steric effects.

Hydroboration-oxidation is a two step pathway used to produce alcohols. The reaction proceeds in an anti-Markovnikov
manner, where the hydrogen (from BH3 or BHR2) attaches to the more substituted carbon and the boron attaches to the
least substituted carbon in the alkene double bond. Furthermore, the borane acts as a Lewis acid by accepting two electrons
in its empty p orbital from an alkene that is electron rich. This process allows boron to have an electron octet. A very
interesting characteristic of this process is that it does not require any activation by a catalyst. The hydroboration
mechanism has the elements of both hydrogenation and electrophilic addition and it is a stereospecific (syn addition),
meaning that the hydroboration takes place on the same face of the double bond, this leads cis stereochemistry.

Introduction
Hydroboration-oxidation of alkenes has been a very valuable laboratory method for the stereoselectivity and
regioselectivity of alkenes. An additional feature of this reaction is that it occurs without rearrangement.

The Borane Complex

First off it is very important to understand little bit about the structure and the properties of the borane molecule. Borane
exists naturally as a very toxic gas and it exists as dimer of the general formula B2H6 (diborane). Additionally, the dimer
B2H6 ignites spontaneously in air. Borane is commercially available in ether and tetrahydrofuran (THF), in these solutions
the borane can exist as a Lewis acid-base complex, which allows boron to have an electron octet.

2 O + B 2H 6 2 O BH3

tetrahydrofuran (THF) (BH3 • THF)

The Mechanism

Step 1
Part 1: Hydroboration of the alkene. In this first step the addition of the borane to the alkene is initiated and proceeds as
a concerted reaction because bond breaking and bond formation occurs at the same time. This part consists of the

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 vacant 2p orbital of the boron electrophile pairing with the electron pair of the pi bond of the nucleophile.

H
B
H H

Transition state
‡
H
H

BH2
H H

* Note that a carbocation is not formed. Therefore, no rearrangement takes place.

Part 2: The Anti Markovnikov addition of Boron. The boron adds to the less substituted carbon of the alkene, which
then places the hydrogen on the more substituted carbon. Both, the boron and the hydrogen add simultaneously on the
same face of the double bond (syn addition).
BH2
H

Oxidation of the Trialkylborane by Hydrogen Peroxide

Step 2
Part 1: The first part of this mechanism deals with the donation of a pair of electrons from the hydrogen peroxide ion.
the hydrogen peroxide is the nucleophile in this reaction because it is the electron donor to the newly formed
trialkylborane that resulted from hydroboration.
H H
O O + OH O O + H 2O
H
hydrogen hydrogen
peroxide peroxide ion

H R
R R
B + O O R B O
R R O H

trialkylborane hydrogen
(electrophile) peroxide ion
(nucleophile)

Part 2: In this second part of the mechanism, a rearrangement of an R group with its pair of bonding electrons to an
adjacent oxygen results in the removal of a hydroxide ion.
R R
R B O B R + OH
O H R O
R

Two more of these reactions with hydroperoxide will occur in order give a trialkylborate
R R R
H 2O 2 O H 2O 2 O
B R B R R B R
R O NaOH R O NaOH O O

trialkylborate

Part 3: This is the final part of the oxidation process. In this part the trialkylborate reacts with aqueous NaOH to give
the alcohol and sodium borate.
(RO)3B + 3 NaOH 3 ROH + Na3BO3
trialkylborate sodium borate

If you need additional visuals to aid you in understanding the mechanism, click on the outside links provided here that will
take you to other pages and media that are very helpful as well.

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Stereochemistry of Hydroboration
The hydroboration reaction is among the few simple addition reactions that proceed cleanly in a syn fashion. As noted
above, this is a single-step reaction. Since the bonding of the double bond carbons to boron and hydrogen is concerted, it
follows that the geometry of this addition must be syn. Furthermore, rearrangements are unlikely inasmuch as a discrete
carbocation intermediate is never formed. These features are illustrated for the hydroboration of α-pinene.
H3 C CH3 H3 C CH3 H3 C CH3 H3 C CH3
6 6 H 6 H 6
H H O
R2 B H C H2O2 HO BH C
H3 C 3 R 3
NaOH
R2 B R
R2 B H3 C H H
H
H

H3 C CH3 H3C CH3

H 6 H 6

RO
2 ROH + HO H C NaO2H BH C
3 3
+ repeat 2x
R
B(OH)3 H H
+ OH

Since the hydroboration procedure is most commonly used to hydrate alkenes in an anti-Markovnikov fashion, we also
need to know the stereoselectivity of the second oxidation reaction, which substitutes a hydroxyl group for the boron atom.
Independent study has shown this reaction takes place with retention of configuration so the overall addition of water is
also syn.
The hydroboration of α-pinene also provides a nice example of steric hindrance control in a chemical reaction. In the less
complex alkenes used in earlier examples the plane of the double bond was often a plane of symmetry, and addition
reagents could approach with equal ease from either side. In this case, one of the methyl groups bonded to C-6 (colored
purple in the equation) covers one face of the double bond, blocking any approach from that side. All reagents that add to
this double bond must therefore approach from the side opposite this methyl.

Outside links
http://en.Wikipedia.org/wiki/Hydroboration-oxidation
bcs.whfreeman.com/vollhardtsc...2/12010-03.htm
http://www.chemhelper.com/hydroboration.html
www.cartage.org.lb/en/themes/...roboration.htm
http://www.organic-chemistry.org/nam...oboration.shtm

References
1. Vollhardt, Peter, and Neil Shore. Organic Chemistry: Structure and Function. 5th. New York: W.H. Freeman and
Company, 2007.
2. Foote, S. Christopher, and William H. Brown. Organic Chemistry. 5th. Belmont, CA: Brooks/Cole Cengage Learning,
2005.
3. Bruice, Paula Yurkanis. Oragnic Chemistry. 5th. CA. Prentice Hall, 2006.
4. Bergbreiter E. David , and David P. Rainville. Stereochemistry of hydroboration-oxidation of terminal alkenes. J. Org.
Chem., 1976, 41 (18), pp 3031–3033
5. Ilich, Predrag-Peter; Rickertsen, Lucas S., and Becker Erienne. Polar Addition to C=C Group: Why Is Anti-
Markovnikov Hydroboration-Oxidation of Alkenes Not "Anti-"? Journal of Chemical Education., 2006, v83, n11, pg
1681-1685

 Problems

What are the products of these following reactions?

1.

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2.

3.

Draw the structural formulas for the alcohols that result from hydroboration-oxidation of the alkenes shown.
4.

5. (E)-3-methyl-2-pentene
If you need clarification or a reminder on the nomenclature of alkenes refer to the link below on naming the alkenes.

Answer
1.

2.

3.

4.

5.

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Exercises
Questions
Q8.5.1
Write out the reagents or products (A–D) shown in the following reaction schemes.

Solutions
S8.5.1

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Layne Morsch (University of Illinois Springfield)
Dr. Krista Cunningham

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12.9: Diazomethane, Carbenes, and Cyclopropane Synthesis
 Objectives

After completing this section, you should be able to

1. describe, and write the detailed mechanism for, the formation of a carbene, such as dichlorocarbene.
2. describe the structure of a carbene in terms of the hybridization of the central carbon atom.
3. write an equation for the formation of a substituted cyclopropane from an alkene and a carbene.
4. identify the reagents, the alkene, or both, needed to prepare a given substituted cyclopropane by addition of a
carbene to a double bond.
5. identify the substituted cyclopropane formed from the reaction of a given alkene with the reagents necessary to
form a carbene.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
carbene (R2C:)
carbenoid
Simmons-Smith reaction
stereospecific

 Study Notes

A carbenoid is best considered to be a reagent which, while not actually a carbene, behaves as if it were an
intermediate of this type.
Dichlorocarbenes can also form cyclopropane structures and are created in situ from reagents such as chloroform and
KOH.

The detailed mechanism of the formation of dichlorocarbene is given below. Note that the deprotonation of chloroform
generates the trichloromethanide anion, which spontaneously expels the chloride anion.

The highly strained nature of cyclopropane compounds makes them very reactive and interesting synthetic targets.
Additionally cyclopropanes are present in numerous biological compounds. One common method of cyclopropane

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synthesis is the reaction of carbenes with the double bond in alkenes or cycloalkenes. Methylene, H2C, is simplest carbene,
and in general carbenes have the formula R2C. Other species that will also react with alkenes to form cyclopropanes but do
not follow the formula of carbenes are referred to as carbenoids.

Introduction
Carbenes were once only thought of as short lived intermediates. The reactions of this section only deal with these short
lived carbenes which are mostly prepared in situ, in conjunction with the main reaction. However, there do exist so called
persistent carbenes. These persistent carbenes are stabilized by a variety of methods often including aromatic rings or
transition metals. In general a carbene is neutral and has 6 valence electrons, 2 of which are non bonding. These electrons
can either occupy the same sp2 hybridized orbital to form a singlet carbene (with paired electrons), or two different sp2
orbitals to from a triplet carbene (with unpaired electrons). The chemistry of triplet and singlet carbenes is quite different
but can be oversimplified to the statement: singlet carbenes usually retain stereochemistry while triplet carbenes do not.
The carbenes discussed in this section are singlet and thus retain stereochemistry.
The reactivity of a singlet carbene is concerted and similar to that of electrophilic or nucleophilic addition wheras, triplet
carbenes react like biradicals, explaining why sterochemistry is not retained. The highly reactive nature of carbenes leads
to very fast reactions in which the rate determining step is generally carbene formation.

Preparation of methylene
The preparation of methylene starts with the yellow gas diazomethane, CH2N2. Diazomethane can be exposed to light, heat
or copper to facilitate the loss of nitrogen gas and the formation of the simplest carbene methylene. The process is driven
by the formation of the nitrogen gas which is a very stable molecule.

Carbene reaction with alkenes

A carbene such as methlyene will react with an alkene which will break the double bond and result with a cyclopropane.
The reaction will usually leave stereochemistry of the double bond unchanged. As stated before, carbenes are generally
formed along with the main reaction; hence the starting material is diazomethane not methylene.

In the above case cis-2-butene is converted to cis-1,2-dimethylcyclopropane. Likewise, below the trans configuration is
maintained. This shows that the reactions are stereospecific, only a single stereoisomer is obtained as the product.

Additional Types of Carbenes and Carbenoids

In addition to the general carbene with formula R2C there exist a number of other compounds that behave in much the
same way as carbenes in the synthesis of cyclopropane. Halogenated carbenes are formed from halomethanes. An
example is dicholorcarbene, Cl2C. The mechanism for the formation of dichlorocarbene is above in the study notes. These
halogenated carbenes will form cyclopropanes in the same manner as methylene but with the interesting presence of two
halogen atoms in place of the hydrogen atoms.
Carbenoids are substances that form cyclopropanes like carbenes but are not technically carbenes. One common example
is the stereospecific Simmon-Smith reaction which utilizes the carbenoid - ICH2ZnI. The (iodomethyl) zinc iodide is
formed in situ via the mixing of Zn-Cu with CH2I2. If this ICH2ZnI is in the presence of an alkene, a CH2 group is

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transferred to the double bond to create cyclopropane. Since this reacts as a carbene, the same methods can be applied to
determine the product.

Outside links
http://en.Wikipedia.org/wiki/Simmons-Smith_reaction
http://en.Wikipedia.org/wiki/Carbene

Problems
1. Knowing that cycloalkenes react much the same as regular alkenes what would be the expected structure of the product
of cyclohexene and diazomethane facilitated by copper metal?
2. What would be the result of a Simmons-Smith reaction that used trans-3-pentene as a reagent?
3. What starting material could be used to form cis-1,2-diethylcyclopropane?
4. What would the following reaction yield?

5. Draw the product of this reaction. What type of reaction is this?

Answers
1. The product will be a bicyclic ring, Bicyclo[4.1.0]heptane.

2. The stereochemistry will be retained making a cyclopropane with trans methyl and ethyl groups. Trans-1-ethyl-2-
methylcyclopropane
3. The cis configuration will be maintained from reagent to product so we would want to start with cis-3-hexene. A
Simmons Smith reagent, or methylene could be used as the carbene or carbenoid.
4. The halogenated carbene will react the same as methylene yielding, cis-1,1-dichloro-2,3dimethylcyclopropane.

5. This is a Simmons-Smith reaction which uses the carbenoid formed by the CH2I2 and Zu-Cu. The reaction results in the
same product as if methylene was used and retains stereospecificity. Iodine metal and the Zn-Cu are not part of the
product. The product is trans-1,2-ethyl-methylcyclopropane.

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References
1. Vollhardt, K. Peter C. and Schore, Neil E. Organic Chemistry: Structure and Function. New York: Bleyer, Brennan,
2007.
2. Abdel-Wahab, Aboel-Magd A. Ahmed, Saleh A. and Dürr, Heinz. "Carbene Formation by Extrusion of Nitrogen" in
CRC Handbook of Organic Photochemistry and Photobiology. CRC Press, 2004.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Paul Tisher
Lauren Reutenauer (Amherst College)

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12.10: Oxacyclopropane ( Epoxide) Synthesis: Epoxidation by Peroxycarboxylic
Acids
 Objectives

After completing this section, you should be able to

1. write the equation for the epoxidation of an alkene using meta-chloroperoxybenzoic acid.
2. identify the alkene, reagents, or both, that must be used to prepare a given epoxide.
3. write the equation for the hydroxylation of an alkene using osmium tetroxide, and draw the structure of the cyclic
intermediate.
4. draw the structure of the diol formed from the reaction of a given alkene with osmium tetroxide.
5. identify the alkene, the reagents, or both, that must be used to prepare a given 1,2-diol.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
diol
glycol
hydroxylation

The previous section discussed the reduction of a double bond, so adding hydrogen to the the double bond. This section will
discuss oxidation. In organic chemistry, this is a reaction that where the carbon atom loses electron density, which happens
when new bond to a more electronegative atom occurs or when a double bond is broken between a carbon and a less
electronegative atom. A simplified to say this is in organic chemistry a reduction is more bonds to hydrogen and oxidation is
more bonds to oxygen often.

Oxacyclopropane Synthesis by Peroxycarboxylic Acid

One way to oxidized a double bond is to produce an oxacyclopropane ring. Oxacyclopropane rings, also called epoxide rings,
are useful reagents that may be opened by further reaction to form anti vicinal diols. One way to synthesize oxacyclopropane
rings is through the reaction of an alkene with peroxycarboxylic acid. Oxacyclopropane synthesis by peroxycarboxylic acid
requires an alkene and a peroxycarboxylic acid as well as an appropriate solvent. The peroxycarboxylic acid has the unique
property of having an electropositive oxygen atom on the COOH group. The reaction is initiated by the electrophilic oxygen
atom reacting with the nucleophilic carbon-carbon double bond. The mechanism involves a concerted reaction with a four-
part, circular transition state. The result is that the originally electropositive oxygen atom ends up in the oxacyclopropane ring
and the COOH group becomes COH.

Mechanism
Peroxycarboxylic acids are generally unstable. An exception is meta-chloroperoxybenzoic acid, shown in the mechanism
above. Often abbreviated MCPBA, it is a stable crystalline solid. Consequently, MCPBA is popular for laboratory use.
However, MCPBA can be explosive under some conditions.

Peroxycarboxylic acids are sometimes replaced in industrial applications by monoperphthalic acid, or the
monoperoxyphthalate ion bound to magnesium, which gives magnesium monoperoxyphthalate (MMPP). In either case, a
nonaqueous solvent such as chloroform, ether, acetone, or dioxane is used. This is because in an aqueous medium with any
acid or base catalyst present, the epoxide ring is hydrolyzed to form a vicinal diol, a molecule with two OH groups on

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neighboring carbons. (For more explanation of how this reaction leads to vicinal diols, see below.) However, in a nonaqueous
solvent, the hydrolysis is prevented and the epoxide ring can be isolated as the product. Reaction yields from this reaction are
usually about 75%. The reaction rate is affected by the nature of the alkene, with more nucleophilic double bonds resulting in
faster reactions.

 Example 8.7.1

Since the transfer of oxygen is to the same side of the double bond, the resulting oxacyclopropane ring will have the same
stereochemistry as the starting alkene. A good way to think of this is that the alkene is rotated so that some constituents are
coming forward and some are behind. Then, the oxygen is inserted on top. (See the product of the above reaction.) One
way the epoxide ring can be opened is by an acid catalyzed oxidation-hydrolysis. Oxidation-hydrolysis gives a vicinal
diol, a molecule with OH groups on neighboring carbons. For this reaction, the dihydroxylation is anti since, due to steric
hindrance, the ring is attacked from the side opposite the existing oxygen atom. Thus, if the starting alkene is trans, the
resulting vicinal diol will have one S and one R stereocenter. But, if the starting alkene is cis, the resulting vicinal diol will
have a racemic mixture of S, S and R, R enantiomers.

 Epoxidation exercises

1. Predict the product of the reaction of cis-2-hexene with MCPBA (meta-chloroperoxybenzoic acid)
a) in acetone solvent.

b) in an aqueous medium with acid or base catalyst present.

2. Predict the product of the reaction of trans-2-pentene with magnesium monoperoxyphthalate (MMPP) in a chloroform
solvent.

3. Predict the product of the reaction of trans-3-hexene with MCPBA in ether solvent.

4. Predict the reaction of propene with MCPBA.

a) in acetone solvent

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 b) after aqueous work-up.

5. Predict the reaction of cis-2-butene in chloroform solvent.

Answers
1. a) Cis-2-methyl-3-propyloxacyclopropane

b) Racemic (2R,3R)-2,3-hexanediol and (2S,3S)-2,3-hexanediol

2. Trans-3-ethyl-2-methyloxacyclopropane.

3. Trans-3,4-diethyloxacyclopropane.

4. a) 2-methyl-oxacyclopropane

b) Racemic (2S)-1,2-propandiol and (2R)-1,2-propanediol

5. Cis-2,3-dimethyloxacyclopropane

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Anti Dihydroxylation
Epoxides may be cleaved by aqueous acid to give glycols that are often diastereomeric with those prepared by the syn-
hydroxylation reaction described above. Proton transfer from the acid catalyst generates the conjugate acid of the epoxide,
which is attacked by nucleophiles such as water in the same way that the cyclic bromonium ion described above undergoes
reaction. The result is anti-hydroxylation of the double bond, in contrast to the syn-stereoselectivity of the earlier method. In
the following equation this procedure is illustrated for a cis-disubstituted epoxide, which, of course, could be prepared from
the corresponding cis-alkene. This hydration of an epoxide does not change the oxidation state of any atoms or groups.

Syn Dihydroxylation
Osmium tetroxide oxidizes alkenes to give glycols through syn addition. A glycol, also known as a vicinal diol, is a compound
with two -OH groups on adjacent carbons.

Introduction
The reaction with OsO is a concerted process that has a cyclic intermediate and no rearrangements. Vicinal syn
4

dihydroxylation complements the epoxide-hydrolysis sequence which constitutes an anti dihydroxylation of an alkene. When
an alkene reacts with osmium tetroxide, stereocenters can form in the glycol product. Cis alkenes give meso products and trans
alkenes give racemic mixtures.

OsO4 is formed slowly when osmium powder reacts with gasoues O at ambient temperature. Reaction of bulk solid requires
2

heating to 400 °C:

Os(s) + 2 O2 (g) → OS4 (12.10.1)

Since Osmium tetroxide is expensive and highly toxic, the reaction with alkenes has been modified. Catalytic amounts of
OsO4 and stoichiometric amounts of an oxidizing agent such as hydrogen peroxide are now used to eliminate some hazards.
Also, an older reagent that was used instead of OsO4 was potassium permanganate, KM nO . Although syn diols will result
4

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from the reaction of KMnO4 and an alkene, potassium permanganate is less useful since it gives poor yields of the product
because of overoxidation.

Mechanism
Electrophilic attack on the alkene
Pi bond of the alkene acts as the nucleophile and reacts with osmium (VIII) tetroxide (OsO4)
2 electrons from the double bond flows toward the osmium metal
In the process, 3 electron pairs move simultaneously
Cyclic ester with Os (VI) is produced
Reduction
H2S reduces the cyclic ester
NaHSO4 with H2O may be used
Forms the syn-1,2-diol (glycol)
Example: Dihydroxylation of 1-ethyl-1-cycloheptene

Hydroxylation of alkenes
Dihydroxylated products (glycols) are obtained by reaction with aqueous potassium permanganate (pH > 8) or osmium
tetroxide in pyridine solution. Both reactions appear to proceed by the same mechanism (shown below); the metallocyclic
intermediate may be isolated in the osmium reaction. In basic solution the purple permanganate anion is reduced to the green
manganate ion, providing a nice color test for the double bond functional group. From the mechanism shown here we would
expect syn-stereoselectivity in the bonding to oxygen, and regioselectivity is not an issue.

When viewed in context with the previously discussed addition reactions, the hydroxylation reaction might seem implausible.
Permanganate and osmium tetroxide have similar configurations, in which the metal atom occupies the center of a tetrahedral
grouping of negatively charged oxygen atoms. How, then, would such a species interact with the nucleophilic pi-electrons of a
double bond? A possible explanation is that an empty d-orbital of the electrophilic metal atom extends well beyond the
surrounding oxygen atoms and initiates electron transfer from the double bond to the metal, in much the same fashion noted
above for platinum. Back-bonding of the nucleophilic oxygens to the antibonding π*-orbital completes this interaction. The
result is formation of a metallocyclic intermediate, as shown above.

Chemical Highlight
Antitumor drugs have been formed by using dihydroxylation. This method has been applied to the enantioselective synthesis
of ovalicin, which is a class of fungal-derived products called antiangiogenesis agents. These antitumor products can cut off
the blood supply to solid tumors. A derivative of ovalicin, TNP-470, is chemically stable, nontoxic, and noninflammatory.

12.10.5 10/10/2021 https://chem.libretexts.org/@go/page/32437

TNP-470 has been used in research to determine its effectiveness in treating cancer of the breast, brain, cervix, liver, and
prostate.

Outside links
http://en.Wikipedia.org/wiki/Osmium_tetroxide
http://www.chm.bris.ac.uk/motm/oso4/oso4v.htm
http://www.organic-chemistry.org/chemicals/oxidations/osmiumtetroxide.shtm

References
1. Dehestani, Ahmad et al. (2005). Ligand-assisted reduction of osmium tetroxide with molecular hydrogen via a [3+2]
mechanism. Journal of the American Chemical Society, 2005, 127 (10), 3423-3432.
2. Sorrell, Thomas, N. Organic Chemistry. New York: University Science Books, 2006.
3. Vollhardt, Peter, and Neil E. Schore. Organic Chemistry: Structure and Function. 5th Edition. New York: W. H. Freeman &
Company, 2007.

 Dihydroxylation Exercises

1. Give the major product.

2. What is the product in the dihydroxylation of (Z)-3-hexene?

3. What is the product in the dihydroxylation of (E)-3-hexene?

4. Draw the intermediate of this reaction.

5. Fill in the missing reactants, reagents, and product.

Answers
1. A syn-1,2-ethanediol is formed. There is no stereocenter in this particular reaction. The OH groups are on the same
side.

2. Meso-3,4-hexanediol is formed. There are 2 stereocenters in this reaction.

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 3. A racemic mixture of 3,4-hexanediol is formed. There are 2 stereocenters in both products.

4. A cyclic osmic ester is formed.

5. The Diels-Alder cycloaddition reaction is needed in the first box to form the cyclohexene. The second box needs a
reagent to reduce the intermediate cyclic ester (not shown). The third box has the product: 1,2-cyclohexanediol.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Shivam Nand
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Kristen Perano
Layne Morsch (University of Illinois Springfield)
Lauren Reutenauer (Amherst College)

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12.11: Vicinal SYn Dihydroxylation with Osmium Tetroxide
 Objectives

After completing this section, you should be able to

1. write the equation for the epoxidation of an alkene using meta-chloroperoxybenzoic acid.
2. identify the alkene, reagents, or both, that must be used to prepare a given epoxide.
3. write the equation for the hydroxylation of an alkene using osmium tetroxide, and draw the structure of the cyclic
intermediate.
4. draw the structure of the diol formed from the reaction of a given alkene with osmium tetroxide.
5. identify the alkene, the reagents, or both, that must be used to prepare a given 1,2-diol.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
diol
glycol
hydroxylation

The previous section discussed the reduction of a double bond, so adding hydrogen to the the double bond. This section
will discuss oxidation. In organic chemistry, this is a reaction that where the carbon atom loses electron density, which
happens when new bond to a more electronegative atom occurs or when a double bond is broken between a carbon and a
less electronegative atom. A simplified to say this is in organic chemistry a reduction is more bonds to hydrogen and
oxidation is more bonds to oxygen often.

Oxacyclopropane Synthesis by Peroxycarboxylic Acid

One way to oxidized a double bond is to produce an oxacyclopropane ring. Oxacyclopropane rings, also called epoxide
rings, are useful reagents that may be opened by further reaction to form anti vicinal diols. One way to synthesize
oxacyclopropane rings is through the reaction of an alkene with peroxycarboxylic acid. Oxacyclopropane synthesis by
peroxycarboxylic acid requires an alkene and a peroxycarboxylic acid as well as an appropriate solvent. The
peroxycarboxylic acid has the unique property of having an electropositive oxygen atom on the COOH group. The reaction
is initiated by the electrophilic oxygen atom reacting with the nucleophilic carbon-carbon double bond. The mechanism
involves a concerted reaction with a four-part, circular transition state. The result is that the originally electropositive
oxygen atom ends up in the oxacyclopropane ring and the COOH group becomes COH.

Mechanism
Peroxycarboxylic acids are generally unstable. An exception is meta-chloroperoxybenzoic acid, shown in the mechanism
above. Often abbreviated MCPBA, it is a stable crystalline solid. Consequently, MCPBA is popular for laboratory use.
However, MCPBA can be explosive under some conditions.

Peroxycarboxylic acids are sometimes replaced in industrial applications by monoperphthalic acid, or the
monoperoxyphthalate ion bound to magnesium, which gives magnesium monoperoxyphthalate (MMPP). In either case, a
nonaqueous solvent such as chloroform, ether, acetone, or dioxane is used. This is because in an aqueous medium with any
acid or base catalyst present, the epoxide ring is hydrolyzed to form a vicinal diol, a molecule with two OH groups on
neighboring carbons. (For more explanation of how this reaction leads to vicinal diols, see below.) However, in a

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nonaqueous solvent, the hydrolysis is prevented and the epoxide ring can be isolated as the product. Reaction yields from
this reaction are usually about 75%. The reaction rate is affected by the nature of the alkene, with more nucleophilic double
bonds resulting in faster reactions.

 Example 8.7.1

Since the transfer of oxygen is to the same side of the double bond, the resulting oxacyclopropane ring will have the
same stereochemistry as the starting alkene. A good way to think of this is that the alkene is rotated so that some
constituents are coming forward and some are behind. Then, the oxygen is inserted on top. (See the product of the
above reaction.) One way the epoxide ring can be opened is by an acid catalyzed oxidation-hydrolysis. Oxidation-
hydrolysis gives a vicinal diol, a molecule with OH groups on neighboring carbons. For this reaction, the
dihydroxylation is anti since, due to steric hindrance, the ring is attacked from the side opposite the existing oxygen
atom. Thus, if the starting alkene is trans, the resulting vicinal diol will have one S and one R stereocenter. But, if the
starting alkene is cis, the resulting vicinal diol will have a racemic mixture of S, S and R, R enantiomers.

 Epoxidation exercises

1. Predict the product of the reaction of cis-2-hexene with MCPBA (meta-chloroperoxybenzoic acid)
a) in acetone solvent.

b) in an aqueous medium with acid or base catalyst present.

2. Predict the product of the reaction of trans-2-pentene with magnesium monoperoxyphthalate (MMPP) in a
chloroform solvent.

3. Predict the product of the reaction of trans-3-hexene with MCPBA in ether solvent.

4. Predict the reaction of propene with MCPBA.

a) in acetone solvent

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 b) after aqueous work-up.

5. Predict the reaction of cis-2-butene in chloroform solvent.

Answers
1. a) Cis-2-methyl-3-propyloxacyclopropane

b) Racemic (2R,3R)-2,3-hexanediol and (2S,3S)-2,3-hexanediol

2. Trans-3-ethyl-2-methyloxacyclopropane.

3. Trans-3,4-diethyloxacyclopropane.

4. a) 2-methyl-oxacyclopropane

b) Racemic (2S)-1,2-propandiol and (2R)-1,2-propanediol

5. Cis-2,3-dimethyloxacyclopropane

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Anti Dihydroxylation
Epoxides may be cleaved by aqueous acid to give glycols that are often diastereomeric with those prepared by the syn-
hydroxylation reaction described above. Proton transfer from the acid catalyst generates the conjugate acid of the epoxide,
which is attacked by nucleophiles such as water in the same way that the cyclic bromonium ion described above undergoes
reaction. The result is anti-hydroxylation of the double bond, in contrast to the syn-stereoselectivity of the earlier method.
In the following equation this procedure is illustrated for a cis-disubstituted epoxide, which, of course, could be prepared
from the corresponding cis-alkene. This hydration of an epoxide does not change the oxidation state of any atoms or
groups.

Syn Dihydroxylation
Osmium tetroxide oxidizes alkenes to give glycols through syn addition. A glycol, also known as a vicinal diol, is a
compound with two -OH groups on adjacent carbons.

Introduction
The reaction with OsO is a concerted process that has a cyclic intermediate and no rearrangements. Vicinal syn
4

dihydroxylation complements the epoxide-hydrolysis sequence which constitutes an anti dihydroxylation of an alkene.
When an alkene reacts with osmium tetroxide, stereocenters can form in the glycol product. Cis alkenes give meso
products and trans alkenes give racemic mixtures.

OsO4 is formed slowly when osmium powder reacts with gasoues O2 at ambient temperature. Reaction of bulk solid
requires heating to 400 °C:
Os(s) + 2 O2 (g) → OS4 (12.11.1)

Since Osmium tetroxide is expensive and highly toxic, the reaction with alkenes has been modified. Catalytic amounts of
OsO4 and stoichiometric amounts of an oxidizing agent such as hydrogen peroxide are now used to eliminate some
hazards. Also, an older reagent that was used instead of OsO4 was potassium permanganate, KM nO . Although syn diols
4

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will result from the reaction of KMnO4 and an alkene, potassium permanganate is less useful since it gives poor yields of
the product because of overoxidation.

Mechanism
Electrophilic attack on the alkene
Pi bond of the alkene acts as the nucleophile and reacts with osmium (VIII) tetroxide (OsO4)
2 electrons from the double bond flows toward the osmium metal
In the process, 3 electron pairs move simultaneously
Cyclic ester with Os (VI) is produced
Reduction
H2S reduces the cyclic ester
NaHSO4 with H2O may be used
Forms the syn-1,2-diol (glycol)
Example: Dihydroxylation of 1-ethyl-1-cycloheptene

Hydroxylation of alkenes
Dihydroxylated products (glycols) are obtained by reaction with aqueous potassium permanganate (pH > 8) or osmium
tetroxide in pyridine solution. Both reactions appear to proceed by the same mechanism (shown below); the metallocyclic
intermediate may be isolated in the osmium reaction. In basic solution the purple permanganate anion is reduced to the
green manganate ion, providing a nice color test for the double bond functional group. From the mechanism shown here
we would expect syn-stereoselectivity in the bonding to oxygen, and regioselectivity is not an issue.

When viewed in context with the previously discussed addition reactions, the hydroxylation reaction might seem
implausible. Permanganate and osmium tetroxide have similar configurations, in which the metal atom occupies the center
of a tetrahedral grouping of negatively charged oxygen atoms. How, then, would such a species interact with the
nucleophilic pi-electrons of a double bond? A possible explanation is that an empty d-orbital of the electrophilic metal
atom extends well beyond the surrounding oxygen atoms and initiates electron transfer from the double bond to the metal,
in much the same fashion noted above for platinum. Back-bonding of the nucleophilic oxygens to the antibonding π*-
orbital completes this interaction. The result is formation of a metallocyclic intermediate, as shown above.

Chemical Highlight
Antitumor drugs have been formed by using dihydroxylation. This method has been applied to the enantioselective
synthesis of ovalicin, which is a class of fungal-derived products called antiangiogenesis agents. These antitumor products
can cut off the blood supply to solid tumors. A derivative of ovalicin, TNP-470, is chemically stable, nontoxic, and

12.11.5 11/28/2021 https://chem.libretexts.org/@go/page/32438

noninflammatory. TNP-470 has been used in research to determine its effectiveness in treating cancer of the breast, brain,
cervix, liver, and prostate.

Outside links
http://en.Wikipedia.org/wiki/Osmium_tetroxide
http://www.chm.bris.ac.uk/motm/oso4/oso4v.htm
http://www.organic-chemistry.org/chemicals/oxidations/osmiumtetroxide.shtm

References
1. Dehestani, Ahmad et al. (2005). Ligand-assisted reduction of osmium tetroxide with molecular hydrogen via a [3+2]
mechanism. Journal of the American Chemical Society, 2005, 127 (10), 3423-3432.
2. Sorrell, Thomas, N. Organic Chemistry. New York: University Science Books, 2006.
3. Vollhardt, Peter, and Neil E. Schore. Organic Chemistry: Structure and Function. 5th Edition. New York: W. H.
Freeman & Company, 2007.

 Dihydroxylation Exercises

1. Give the major product.

2. What is the product in the dihydroxylation of (Z)-3-hexene?

3. What is the product in the dihydroxylation of (E)-3-hexene?

4. Draw the intermediate of this reaction.

5. Fill in the missing reactants, reagents, and product.

Answers
1. A syn-1,2-ethanediol is formed. There is no stereocenter in this particular reaction. The OH groups are on the
same side.

2. Meso-3,4-hexanediol is formed. There are 2 stereocenters in this reaction.

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 3. A racemic mixture of 3,4-hexanediol is formed. There are 2 stereocenters in both products.

4. A cyclic osmic ester is formed.

5. The Diels-Alder cycloaddition reaction is needed in the first box to form the cyclohexene. The second box needs
a reagent to reduce the intermediate cyclic ester (not shown). The third box has the product: 1,2-cyclohexanediol.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Shivam Nand
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Kristen Perano
Layne Morsch (University of Illinois Springfield)
Lauren Reutenauer (Amherst College)

12.11.7 11/28/2021 https://chem.libretexts.org/@go/page/32438

12.12: Oxidative Cleavage: Ozonolysis
☰

 Objective

After completing this section, you should be able to

1. write an equation to describe the cleavage of an alkene by ozone, followed by reduction of the ozonide so formed
with either sodium borohydride or zinc and acetic acid.
2. predict the products formed from the ozonolysis-reduction of a given alkene.
3. write an equation to describe the cleavage of an alkene by potassium permanganate.
4. predict the products from the oxidative cleavage of a given alkene by potassium permanganate.
5. use the results of ozonolysis-reduction, or cleavage with permanganate, to deduce the structure of an unknown
alkene.
6. identify the reagents that should be used in the oxidative cleavage of an alkene to obtain a given product or
products.
7. write the equation for the cleavage of a 1,2-diol by periodic acid, and draw the structure of the probable
intermediate.
8. predict the product or products that will be formed from the treatment of a given 1,2-diol with periodic acid.
9. use the results of hydroxylation/1,2-diol cleavage to deduce the structure of an unknown alkene.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
molozonide
ozonide
ozonolysis

 Study Notes

Ozonolysis, or ozonolysis-reduction, refers to the treatment of an alkene with ozone followed by a suitable reducing
agent to break down complex double-bond-containing compounds into smaller, more easily identified products. From
the identity of the products formed, it may be possible to deduce the structure of the original double-bond-containing
substance. Ozonolysis will feature prominently in many of the road-map problems that you will encounter in this
course.
A molozonide is an unstable, cyclic intermediate that is initially formed when an alkene reacts with ozone.
Alkenes can also be cleaved by other oxidizing agents such as potassium permanganate. However, KMnO4 will carry
the oxidation further than ozonolysis, so products can be slightly different. Note within the summary of the following
reactions that ozonolysis produces aldehydes and ketones, while KMnO4 can oxidize all the way to to carbon dioxide
and carboxylic acid.

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☰

Diol cleavage is another example of a redox reaction; periodic acid, HIO4, is reduced to iodic acid, HIO3.

Ozonolysis is a method of oxidatively cleaving alkenes or alkynes using ozone (O ), a reactive allotrope of oxygen. The
3

process allows for carbon-carbon double or triple bonds to be replaced by double bonds with oxygen. This reaction is often
used to identify the structure of unknown alkenes. by breaking them down into smaller, more easily identifiable pieces.
Ozonolysis also occurs naturally and would break down repeated units used in rubber and other polymers. On an industrial
scale, azelaic acid and pelargonic acids are produced from ozonolysis.

Introduction
The gaseous ozone is first passed through the desired alkene solution in either methanol or dichloromethane. The first
intermediate product is an ozonide molecule which is then further reduced to carbonyl products. This results in the
breaking of the Carbon-Carbon double bond and is replaced by a Carbon-Oxygen double bond instead.

Reaction Mechanism
Step 1:

The first step in the mechanism of ozonolysis is the initial electrophilic addition of ozone to the Carbon-Carbon double
bond, which then form the molozonide intermediate. Due to the unstable molozonide molecule, it continues further with
the reaction and breaks apart to form a carbonyl and a carbonyl oxide molecule.
Step 2:

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☰

The carbonyl and the carbonyl oxide rearranges itself and reforms to create the stable ozonide intermediate. Since some
ozonides are explosive, it is immediately reacted with a reductive workup to then convert the ozonide molecule into the
desired carbonyl products. A typical reductive workup is zinc metal in acetic acid. A variety of carbonyl products could
result depending on the starting alkene. For example, a tetrasubstituted alkene would yield two ketone products, while a
trisubstituted alkene would yield one ketone product and one aldehyde product.
While there are other options for oxidative cleavage of the double bond, this is the most commonly used reaction.

References
1. Vollhardt, K., Schore, N. Organic Chemistry: Structure and Function. 5th ed. New York, NY: W. H. Freeman and
Company, 2007.
2. Shore, N. Study Guide and Solutions Manual for Organic Chemistry. 5th ed. New York, NY: W.H. Freeman and
Company, 2007.

 Exercise 12.12.1

Answer

Exercises
1. Draw the structure of the product or products obtained in each of the following reactions:
a. cis-2-butene $\ce{\sf{->[\displaystyle{1. ~~ \textrm{O}_3}][\displaystyle{2. ~~ \textrm{Zn/H}^+}]}}$

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 b. trans-2-butene $\ce{\sf{->[\displaystyle{1. ~~ \textrm{O}_3}][\displaystyle{2. ~~ \textrm{Zn/H}^+}]}}$
☰ c. 2-methylpropene $\ce{\sf{->[\displaystyle{1. ~~ \textrm{O}_3}][\displaystyle{2. ~~ \textrm{Zn/H}^+}]}}$
d. 2-methyl-1-pentene $\ce{\sf{->[\displaystyle{\textrm{hot, acidic}}][\displaystyle{\textrm{KMnO}_4}]}}$
2. What important point did you learn from questions 1(a) and 1(b), above?
Answers:
1. a.

b.

c.

d.

2. Exercises 1(a) and 1(b), above, indicate that it is not possible to distinguish between cis and trans isomers of alkenes
using oxidative cleavage. Both isomers give the same product or products.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A.
Benjamin, Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions,
"You are granted permission for individual, educational, research and non-commercial reproduction, distribution,
display and performance of this work in any format."
Lauren Reutenauer (Amherst College)

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12.13: Radical Additions: Anti-Markovnikov Product Formation
☰
Protons and other electrophiles are not the only reactive species that initiate addition reactions to carbon-carbon double
bonds. Curiously, this first became evident as a result of conflicting reports concerning the regioselectivity of HBr
additions. As noted earlier, the acid-induced addition of HBr to 1-butene gave predominantly 2-bromobutane, the
Markovnikov Rule product. However, in some early experiments in which peroxide contaminated reactants were used, 1-
bromobutane was the chief product. Further study showed that an alternative radical chain-reaction, initiated by peroxides,
was responsible for the anti-Markovnikov product. This is shown by the following equations.

The weak O–O bond of a peroxide initiator is broken homolytically by thermal or hight energy. The resulting alkoxy
radical then abstracts a hydrogen atom from HBr in a strongly exothermic reaction. Once a bromine atom is formed it adds
to the π-bond of the alkene in the first step of a chain reaction. This addition is regioselective, giving the more stable
carbon radical as an intermediate. The second step is carbon radical abstraction of another hydrogen from HBr, generating
the anti-Markovnikov alkyl bromide and a new bromine atom. Each of the steps in this chain reaction is exothermic, so
once started the process continues until radicals are lost to termination events.
This free radical chain addition competes very favorably with the slower ionic addition of HBr described earlier, especially
in non-polar solvents. It is important to note, however, that HBr is unique in this respect. The radical addition process is
unfavorable for HCl and HI because one of the chain steps becomes endothermic (the second for HCl & the first for HI).
Other radical addition reactions to alkenes have been observed, one example being the peroxide induced addition of carbon
tetrachloride shown in the following equation

RCH=CH2 + CCl4 (peroxide initiator) —> RCHClCH2CCl3

The best known and most important use of free radical addition to alkenes is probably polymerization. Since the addition
of carbon radicals to double bonds is energetically favorable, concentrated solutions of alkenes are prone to radical-
initiated polymerization, as illustrated for propene by the following equation. The blue colored R-group represents an
initiating radical species or a growing polymer chain; the propene monomers are colored maroon. The addition always
occurs so that the more stable radical intermediate is formed.

RCH2(CH3)CH· + CH3CH=CH2 —>RCH2(CH3)CH-CH2(CH3)CH· + CH3CH=CH2 —>RCH2(CH3)CHCH2(CH3)CH-

CH2(CH3)CH· —> etc.

Anti-Markovnikov rule describes the regiochemistry where the substituent is bonded to a less substituted carbon, rather
than the more substitued carbon. This process is quite unusual, as carboncations which are commonly formed during
alkene, or alkyne reactions tend to favor the more substitued carbon. This is because substituted carbocation allow more
hyperconjugation and indution to happen, making the carbocation more stable.

Introduction
This process was first explained by Morris Selig Karasch in his paper: 'The Addition of Hydrogen Bromide to Allyl
Bromide' in 1933.1 Examples of Anti-Markovnikov includes Hydroboration-Oxidation and Radical Addition of HBr. A
free radical is any chemical substance with unpaired electron. The more substituents the carbon is connected to, the more
substituted is that carbon. For example: Tertiary carbon (most substituted), Secondary carbon (medium substituted),
primary carbon (least substituted)

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Anti-Markovnikov Radical Addition of Haloalkane can ONLY happen to HBr and there MUST be presence of Hydrogen
☰
Peroxide (H2O2). Hydrogen Peroxide is essential for this process, as it is the chemical which starts off the chain reaction in
the initiation step. HI and HCl cannot be used in radical reactions, because in their radical reaction one of the radical
reaction steps: Initiation is Endothermic, as recalled from Chem 118A, this means the reaction is unfavorable. To
demonstrate the anti-Markovnikov regiochemistry, I will use 2-Methylprop-1-ene as an example below:

Initiation Steps
Hydrogen Peroxide is an unstable molecule, if we heat it, or shine it with sunlight,
two free radicals of OH will be formed. These OH radicals will go on and attack
HBr, which will take the Hydrogen and create a Bromine radical. Hydrogen radical
do not form as they tend to be extremely unstable with only one electron, thus
bromine radical which is more stable will be readily formed.

Propagation Steps

The Bromine Radical will go on and attack the LESS

SUBSTITUTED carbon of the alkene. This is because after the
bromine radical attacked the alkene a carbon radical will be
formed. A carbon radical is more stable when it is at a more
substituted carbon due to induction and hyperconjugation.
Thus, the radical will be formed at the more substituted carbon,
while the bromine is bonded to the less substituted carbon.
After a carbon radical is formed, it will go on and attack the
hydrogen of a HBr, which a bromine radical will be formed again.

Termination Steps
There are also Termination Steps, but we do not concern about the termination steps as they are just the radicals combining
to create waste products. For example two bromine radical combined to give bromine. This radical addition of bromine to
alkene by radical addition reaction will go on until all the alkene turns into bromoalkane, and this process will take some
time to finish.

References
1. K. Peter C. Vollhardt, Neil E. Schore; Organic Chemistry: Structure and Function Fifth Edition; W. H. Freeman and
Campany, 2007
2. Micheal Vokin; Nuffield Advance Chemistry Student's Book Forth Edition; Person Education Limited, 2004

Outside Links
1. http://en.wikipedia.org/wiki/Morris_S._Kharasch

Problems
Please give the product(s) of the reactions below:
1. CH3-C(CH3)=CH-CH3 + HBr + H2O2 ==> ?
2. CH3-C(CH3)=CH-CH3 + HI + H2O2 ==> ?
3. CH3-C(CH3)=CH-CH3 + HCl + H2O2 ==> ?
4. CH3-CH=CH-CH3 + HBr + H2O2 ==> ?
5. CH3-C(CH3)=CH-CH3 + HBr ==> ?

Answers
1. CH3-CH(CH3)-CHBr-CH3 (Anti-Markovnikov)
2. CH3-C(CH3)I-CH2-CH3 (Markovnikov)
3. CH3-C(CH3)Cl-CH2-CH3 (Markovnikov)

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 4. CH3-CHBr-CH-CH3 or CH3-CH-CHBr-CH3 (Both molecules are the same)
☰5. CH3-C(CH3)Br-CH2-CH3 (Markovnikov)

References
1. http://uncyclopedia.wikia.com/wiki/Organic_chemistry
2. http://uncyclopedia.wikia.com/wiki/Chemistry

Contributors
Kelvin Kan (UCD)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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12.14: Dimerization, Oligomerization. and Polymerization of Alkenes
All the monomers from which addition polymers are made are alkenes or functionally substituted alkenes. The most
common and thermodynamically favored chemical transformations of alkenes are addition reactions. Many of these
addition reactions are known to proceed in a stepwise fashion by way of reactive intermediates, and this is the mechanism
followed by most polymerizations. A general diagram illustrating this assembly of linear macromolecules, which supports
the name chain growth polymers, is presented here. Since a pi-bond in the monomer is converted to a sigma-bond in the
polymer, the polymerization reaction is usually exothermic by 8 to 20 kcal/mol. Indeed, cases of explosively uncontrolled
polymerizations have been reported.

It is useful to distinguish four polymerization procedures fitting this general description.

• Radical Polymerization The initiator is a radical, and the propagating site of reactivity (*) is a carbon radical.
• Cationic Polymerization The initiator is an acid, and the propagating site of reactivity (*) is a carbocation.
• Anionic Polymerization The initiator is a nucleophile, and the propagating site of reactivity (*) is a carbanion.
• Coordination Catalytic Polymerization The initiator is a transition metal complex, and the propagating site of reactivity
(*) is a terminal catalytic complex.

Radical Chain-Growth Polymerization

Virtually all of the monomers described above are subject to radical polymerization. Since this can be initiated by traces of
oxygen or other minor impurities, pure samples of these compounds are often "stabilized" by small amounts of radical
inhibitors to avoid unwanted reaction. When radical polymerization is desired, it must be started by using a radical
initiator, such as a peroxide or certain azo compounds. The formulas of some common initiators, and equations showing
the formation of radical species from these initiators are presented below.

By using small amounts of initiators, a wide variety of monomers can be polymerized. One example of this radical
polymerization is the conversion of styrene to polystyrene, shown in the following diagram. The first two equations
illustrate the initiation process, and the last two equations are examples of chain propagation. Each monomer unit adds to
the growing chain in a manner that generates the most stable radical. Since carbon radicals are stabilized by substituents of
many kinds, the preference for head-to-tail regioselectivity in most addition polymerizations is understandable. Because
radicals are tolerant of many functional groups and solvents (including water), radical polymerizations are widely used in
the chemical industry.

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In principle, once started a radical polymerization might be expected to continue unchecked, producing a few extremely
long chain polymers. In practice, larger numbers of moderately sized chains are formed, indicating that chain-terminating
reactions must be taking place. The most common termination processes are Radical Combination and Disproportionation.
These reactions are illustrated by the following equations. The growing polymer chains are colored blue and red, and the
hydrogen atom transferred in disproportionation is colored green. Note that in both types of termination two reactive
radical sites are removed by simultaneous conversion to stable product(s). Since the concentration of radical species in a
polymerization reaction is small relative to other reactants (e.g. monomers, solvents and terminated chains), the rate at
which these radical-radical termination reactions occurs is very small, and most growing chains achieve moderate length
before termination.

The relative importance of these terminations varies with the nature of the monomer undergoing polymerization. For
acrylonitrile and styrene combination is the major process. However, methyl methacrylate and vinyl acetate are terminated
chiefly by disproportionation.
Another reaction that diverts radical chain-growth polymerizations from producing linear macromolecules is called chain
transfer. As the name implies, this reaction moves a carbon radical from one location to another by an intermolecular or
intramolecular hydrogen atom transfer (colored green). These possibilities are demonstrated by the following equations

Chain transfer reactions are especially prevalent in the high pressure radical polymerization of ethylene, which is the
method used to make LDPE (low density polyethylene). The 1º-radical at the end of a growing chain is converted to a
more stable 2º-radical by hydrogen atom transfer. Further polymerization at the new radical site generates a side chain

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radical, and this may in turn lead to creation of other side chains by chain transfer reactions. As a result, the morphology of
LDPE is an amorphous network of highly branched macromolecules.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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12.15: Synthesis of Polymers
Polymers are long chain giant organic molecules are assembled from many smaller molecules called monomers.
Polymers consist of many repeating monomer units in long chains. A polymer is analogous to a necklace made from many
small beads (monomers). Many monomers are alkenes or other molecules with double bonds which react by addition to
their unsaturated double bonds.

Introduction
The electrons in the double bond are used to bond two monomer molecules together. This is represented by the red arrows
moving from one molecule to the space between two molecules where a new bond is to form. The formation of
polyethylene from ethylene (ethene) may be illustrated in the graphic on the left as follows. In the complete polymer, all of
the double bonds have been turned into single bonds. No atoms have been lost and you can see that the monomers have
just been joined in the process of addition. A simple representation is -[A-A-A-A-A]-. Polyethylene is used in plastic bags,
bottles, toys, and electrical insulation.
LDPE - Low Density Polyethylene: The first commercial polyethylene process used peroxide catalysts at a
temperature of 500 C and 1000 atmospheres of pressure. This yields a transparent polymer with highly branched chains
which do not pack together well and is low in density. LDPE makes a flexible plastic. Today most LDPE is used for
blow-molding of films for packaging and trash bags and flexible snap-on lids. LDPE is recyclable plastic #4.
HDPE - High Density Polyethylene: An alternate method is to use Ziegler-Natta aluminum titanium catalysts to make
HDPE which has very little branching, allows the strands to pack closely, and thus is high density. It is three times
stronger than LDPE and more opaque. About 45% of the HDPE is blow molded into milk and disposable consumer
bottles. HDPE is also used for crinkly plastic bags to pack groceries at grocery stores. HDPE is recyclable plastic #2.

Other Addition Polymers

PVC (polyvinyl chloride), which is found in plastic wrap, simulated leather, water pipes, and garden hoses, is formed
from vinyl chloride (H2C=CHCl). The reaction is shown in the graphic on the left. Notice how every other carbon must
have a chlorine attached.
Polypropylene: The reaction to make polypropylene (H2C=CHCH3) is illustrated in the middle reaction of the graphic.
Notice that the polymer bonds are always through the carbons of the double bond. Carbon #3 already has saturated
bonds and cannot participate in any new bonds. A methyl group is on every other carbon.
Polystyrene: The reaction is the same for polystrene where every other carbon has a benzene ring attached.
Polystyrene (PS) is recyclable plastic #6. In the following illustrated example, many styrene monomers are
polymerized into a long chain polystyrene molecule. The squiggly lines indicate that the polystyrene molecule extends
further at both the left and right ends.

Blowing fine gas bubbles into liquid polystyrene and letting it solidify produces expanded polystyrene, called
Styrofoam by the Dow Chemical Company.
Polystyrene with DVB: Cross-linking between polymer chains can be introduced into polystyrene by copolymerizing
with p-divinylbenzene (DVB). DVB has vinyl groups (-CH=CH2) at each end of its molecule, each of which can be
polymerized into a polymer chain like any other vinyl group on a styrene monomer.

Other addition polymers

Table 1: Links to various polymers with Chime molecule - Macrogalleria at U. Southern Mississippi
Monomer Polymer Name Trade Name Uses

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Monomer Polymer Name Trade Name Uses

Non-stick coating for cooking

F2C=CF2 polytetrafluoroethylene Teflon utensils, chemically-resistant
specialty plastic parts, Gore-Tex
H2C=CCl2 polyvinylidene dichloride Saran Clinging food wrap
Fibers for textiles, carpets,
H2C=CH(CN) polyacrylonitrile Orlon, Acrilan, Creslan
upholstery
H2C=CH(OCOCH3) polyvinyl acetate Elmer's glue - Silly Putty Demo
H2C=CH(OH) polyvinyl alcohol Ghostbusters Demo
Stiff, clear, plastic sheets, blocks,
H2C=C(CH3)COOCH3 polymethyl methacrylate Plexiglass, Lucite
tubing, and other shapes

Addition polymers from conjugated dienes

Polymers from conjugated dienes usually give elastomer polymers having rubber-like properties.
Table 2. Addition homopolymers from conjugated dienes
Monomer Polymer name Trade name Uses

applications similar to natural

H2C=CH-C(CH3)=CH2 polyisoprene natural or some synthetic rubber
rubber
select synthetic rubber
H2C=CH-CH=CH2 polybutadiene polybutadiene synthetic rubber
applications
H2C=CH-CCl=CH2 polychloroprene Neoprene chemically-resistant rubber

All the monomers from which addition polymers are made are alkenes or functionally substituted alkenes. The most
common and thermodynamically favored chemical transformations of alkenes are addition reactions. Many of these
addition reactions are known to proceed in a stepwise fashion by way of reactive intermediates, and this is the mechanism
followed by most polymerizations. A general diagram illustrating this assembly of linear macromolecules, which supports
the name chain growth polymers, is presented here. Since a pi-bond in the monomer is converted to a sigma-bond in the
polymer, the polymerization reaction is usually exothermic by 8 to 20 kcal/mol. Indeed, cases of explosively uncontrolled
polymerizations have been reported.

It is useful to distinguish four polymerization procedures fitting this general description.

• Radical Polymerization The initiator is a radical, and the propagating site of reactivity (*) is a carbon radical.
• Cationic Polymerization The initiator is an acid, and the propagating site of reactivity (*) is a carbocation.
• Anionic Polymerization The initiator is a nucleophile, and the propagating site of reactivity (*) is a carbanion.
• Coordination Catalytic Polymerization The initiator is a transition metal complex, and the propagating site of reactivity
(*) is a terminal catalytic complex.

Radical Chain-Growth Polymerization

Virtually all of the monomers described above are subject to radical polymerization. Since this can be initiated by traces of
oxygen or other minor impurities, pure samples of these compounds are often "stabilized" by small amounts of radical
inhibitors to avoid unwanted reaction. When radical polymerization is desired, it must be started by using a radical
initiator, such as a peroxide or certain azo compounds. The formulas of some common initiators, and equations showing
the formation of radical species from these initiators are presented below.

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By using small amounts of initiators, a wide variety of monomers can be polymerized. One example of this radical
polymerization is the conversion of styrene to polystyrene, shown in the following diagram. The first two equations
illustrate the initiation process, and the last two equations are examples of chain propagation. Each monomer unit adds to
the growing chain in a manner that generates the most stable radical. Since carbon radicals are stabilized by substituents of
many kinds, the preference for head-to-tail regioselectivity in most addition polymerizations is understandable. Because
radicals are tolerant of many functional groups and solvents (including water), radical polymerizations are widely used in
the chemical industry.

In principle, once started a radical polymerization might be expected to continue unchecked, producing a few extremely
long chain polymers. In practice, larger numbers of moderately sized chains are formed, indicating that chain-terminating
reactions must be taking place. The most common termination processes are Radical Combination and Disproportionation.
These reactions are illustrated by the following equations. The growing polymer chains are colored blue and red, and the
hydrogen atom transferred in disproportionation is colored green. Note that in both types of termination two reactive
radical sites are removed by simultaneous conversion to stable product(s). Since the concentration of radical species in a
polymerization reaction is small relative to other reactants (e.g. monomers, solvents and terminated chains), the rate at
which these radical-radical termination reactions occurs is very small, and most growing chains achieve moderate length
before termination.

The relative importance of these terminations varies with the nature of the monomer undergoing polymerization. For
acrylonitrile and styrene combination is the major process. However, methyl methacrylate and vinyl acetate are terminated

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chiefly by disproportionation.
Another reaction that diverts radical chain-growth polymerizations from producing linear macromolecules is called chain
transfer. As the name implies, this reaction moves a carbon radical from one location to another by an intermolecular or
intramolecular hydrogen atom transfer (colored green). These possibilities are demonstrated by the following equations

Chain transfer reactions are especially prevalent in the high pressure radical polymerization of ethylene, which is the
method used to make LDPE (low density polyethylene). The 1º-radical at the end of a growing chain is converted to a
more stable 2º-radical by hydrogen atom transfer. Further polymerization at the new radical site generates a side chain
radical, and this may in turn lead to creation of other side chains by chain transfer reactions. As a result, the morphology of
LDPE is an amorphous network of highly branched macromolecules.

Chain topology
Polymers may also be classified as straight-chained or branched, leading to forms such as these:

The monomers can be joined end-to-end, and they can also be cross-linked to provide a harder material:

If the cross-links are fairly long and flexible, adjacent chains can move with respect to each other, producing an elastic
polymer or

Cationic Chain-Growth Polymerization

Polymerization of isobutylene (2-methylpropene) by traces of strong acids is an example of cationic polymerization. The
polyisobutylene product is a soft rubbery solid, Tg = _70º C, which is used for inner tubes. This process is similar to
radical polymerization, as demonstrated by the following equations. Chain growth ceases when the terminal carbocation
combines with a nucleophile or loses a proton, giving a terminal alkene (as shown here).

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Monomers bearing cation stabilizing groups, such as alkyl, phenyl or vinyl can be polymerized by cationic processes.
These are normally initiated at low temperature in methylene chloride solution. Strong acids, such as HClO4 , or Lewis
acids containing traces of water (as shown above) serve as initiating reagents. At low temperatures, chain transfer reactions
are rare in such polymerizations, so the resulting polymers are cleanly linear (unbranched).

Anionic Chain-Growth Polymerization

Treatment of a cold THF solution of styrene with 0.001 equivalents of n-butyllithium causes an immediate polymerization.
This is an example of anionic polymerization, the course of which is described by the following equations. Chain growth
may be terminated by water or carbon dioxide, and chain transfer seldom occurs. Only monomers having anion stabilizing
substituents, such as phenyl, cyano or carbonyl are good substrates for this polymerization technique. Many of the
resulting polymers are largely isotactic in configuration, and have high degrees of crystallinity.

Species that have been used to initiate anionic polymerization include alkali metals, alkali amides, alkyl lithiums and
various electron sources. A practical application of anionic polymerization occurs in the use of superglue. This material is
methyl 2-cyanoacrylate, CH2=C(CN)CO2CH3. When exposed to water, amines or other nucleophiles, a rapid
polymerization of this monomer takes place.

Ring opening polymerization

In this kind of polymerization, molecular rings are opened in the formation of a polymer. Here epsilon-caprolactam, a 6-
carbon cyclic monomer, undergoes ring opening to form a Nylon 6 homopolymer, which is somewhat similar to but not the
same as Nylon 6,6 alternating copolymer.

Addition Copolymerization
Most direct copolymerizations of equimolar mixtures of different monomers give statistical copolymers, or if one
monomer is much more reactive a nearly homopolymer of that monomer. The copolymerization of styrene with methyl
methacrylate, for example, proceeds differently depending on the mechanism. Radical polymerization gives a statistical
copolymer. However, the product of cationic polymerization is largely polystyrene, and anionic polymerization favors
formation of poly(methyl methacrylate). In cases where the relative reactivities are different, the copolymer composition
can sometimes be controlled by continuous introduction of a biased mixture of monomers into the reaction.
Formation of alternating copolymers is favored when the monomers have different polar substituents (e.g. one electron
withdrawing and the other electron donating), and both have similar reactivities toward radicals. For example, styrene and
acrylonitrile copolymerize in a largely alternating fashion.
Some Useful Copolymers
Monomer A Monomer B Copolymer Uses
H2C=CHCl H2C=CCl2 Saran films & fibers
SBR
H2C=CHC6H5 H2C=C-CH=CH2 tires
styrene butadiene rubber
adhesives
H2C=CHCN H2C=C-CH=CH2 Nitrile Rubber
hoses

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H2C=C(CH3)2 H2C=C-CH=CH2 Butyl Rubber inner tubes
F2C=CF(CF3) H2C=CHF Viton gaskets

A terpolymer of acrylonitrile, butadiene and styrene, called ABS rubber, is used for high-impact containers, pipes and
gaskets.

Block Copolymerization
Several different techniques for preparing block copolymers have been developed, many of which use condensation
reactions (next section). At this point, our discussion will be limited to an application of anionic polymerization. In the
anionic polymerization of styrene described above, a reactive site remains at the end of the chain until it is quenched. The
unquenched polymer has been termed a living polymer, and if additional styrene or a different suitable monomer is added a
block polymer will form. This is illustrated for methyl methacrylate in the following diagram.

Contributors
Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Symmetrical monomers such as ethylene and tetrafluoroethylene can join together in only one way. Monosubstituted
monomers, on the other hand, may join together in two organized ways, described in the following diagram, or in a third
random manner. Most monomers of this kind, including propylene, vinyl chloride, styrene, acrylonitrile and acrylic esters,
prefer to join in a head-to-tail fashion, with some randomness occurring from time to time. The reasons for this
regioselectivity will be discussed in the synthetic methods section.

If the polymer chain is drawn in a zig-zag fashion, as shown above, each of the substituent groups (Z) will necessarily be
located above or below the plane defined by the carbon chain. Consequently we can identify three configurational isomers
of such polymers. If all the substituents lie on one side of the chain the configuration is called isotactic. If the substituents
alternate from one side to another in a regular manner the configuration is termed syndiotactic. Finally, a random
arrangement of substituent groups is referred to as atactic. Examples of these configurations are shown here.

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Many common and useful polymers, such as polystyrene, polyacrylonitrile and poly(vinyl chloride) are atactic as normally
prepared. Customized catalysts that effect stereoregular polymerization of polypropylene and some other monomers have
been developed, and the improved properties associated with the increased crystallinity of these products has made this an
important field of investigation. The following values of Tg have been reported.

Polymer Tg atactic Tg isotactic Tg syndiotactic

PP –20 ºC 0 ºC –8 ºC

PMMA 100 ºC 130 ºC 120 ºC

The properties of a given polymer will vary considerably with its tacticity. Thus, atactic polypropylene is useless as a solid
construction material, and is employed mainly as a component of adhesives or as a soft matrix for composite materials. In
contrast, isotactic polypropylene is a high-melting solid (ca. 170 ºC) which can be molded or machined into structural
components.

Ziegler-Natta Catalytic Polymerization

An efficient and stereospecific catalytic polymerization procedure was developed by Karl Ziegler (Germany) and Giulio
Natta (Italy) in the 1950's. Their findings permitted, for the first time, the synthesis of unbranched, high molecular weight
polyethylene (HDPE), laboratory synthesis of natural rubber from isoprene, and configurational control of polymers from
terminal alkenes like propene (e.g. pure isotactic and syndiotactic polymers). In the case of ethylene, rapid polymerization
occurred at atmospheric pressure and moderate to low temperature, giving a stronger (more crystalline) product (HDPE)
than that from radical polymerization (LDPE). For this important discovery these chemists received the 1963 Nobel Prize
in chemistry.
Ziegler-Natta catalysts are prepared by reacting certain transition metal halides with organometallic reagents such as alkyl
aluminum, lithium and zinc reagents. The catalyst formed by reaction of triethylaluminum with titanium tetrachloride has
been widely studied, but other metals (e.g. V & Zr) have also proven effective. The following diagram presents one
mechanism for this useful reaction. Others have been suggested, with changes to accommodate the heterogeneity or
homogeneity of the catalyst. Polymerization of propylene through action of the titanium catalyst gives an isotactic product;
whereas, a vanadium based catalyst gives a syndiotactic product.

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Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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12.16: Ethene: An Important Industrial Feedstock
Ethene
Cracking is the name given to breaking up large hydrocarbon molecules into smaller and more useful bits. This is
achieved by using high pressures and temperatures without a catalyst, or lower temperatures and pressures in the
presence of a catalyst. The source of the large hydrocarbon molecules is often the naphtha fraction or the gas oil
fraction from the fractional distillation of crude oil (petroleum). These fractions are obtained from the distillation process
as liquids, but are re-vaporized before cracking.
There is not any single unique reaction happening in the cracker. The hydrocarbon molecules are broken up in a fairly
random way to produce mixtures of smaller hydrocarbons, some of which have carbon-carbon double bonds. One
possible reaction involving the hydrocarbon C15H32 might be:

Or, showing more clearly what happens to the various atoms and bonds:

This is only one way in which this particular molecule might break up. The ethene and propene are important materials
for making plastics or producing other organic chemicals. You will remember that during the polymeriation of ethene,
thousands of ethene molecules join together to make poly(ethene) - commonly called polythene. The reaction is done at
high pressures in the presence of a trace of oxygen as an initiator.

Beta-Carotene
The long chain of alternating double bonds (conjugated) is responsible for the orange color of beta-carotene. The
conjugated chain in carotenoids means that they absorb in the visible region - green/blue part of the spectrum. So β-
carotene appears orange, because the red/yellow colors are reflected back to us.

Vitamin A
Vitamin A has several functions in the body. The most well known is its role in vision - hence carrots "make you able to
see in the dark". The retinol is oxidized to its aldehyde, retinal, which complexes with a molecule in the eye called opsin.
When a photon of light hits the complex, the retinal changes from the 11-cis form to the all-trans form, initiating a chain of

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events which results in the transmission of an impulse up the optic nerve. A more detailed explanation is in Photochemical
Events.

Other roles of vitamin A are much less well understood. It is known to be involved in the synthesis of certain
glycoproteins, and that deficiency leads to abnormal bone development, disorders of the reproductive system,
xerophthalmia (a drying condition of the cornea of the eye) and ultimately death.
Vitamin A is required for healthy skin and mucus membranes, and for night vision. Its absence from diet leads to a loss in
weight and failure of growth in young animals, to the eye diseases; xerophthalmia, and night blindness, and to a general
susceptibility to infections. It is thought to help prevent the development of cancer. Good sources of carotene, such as
green vegetables are good potential sources of vitamin A. Vitamin A is also synthetically manufactured by extraction from
fish-liver oil and by synthesis from beta-ionone.

Contributors
Jim Clark (Chemguide.co.uk)
Charles Ophardt, Professor Emeritus, Elmhurst College; Virtual Chembook

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12.17: Alkenes in Nature - Insect Pheromones
Pheromones are chemicals capable of acting like hormones outside the body of the secreting individual, to impact the
behavior of the receiving individuals. Pheromones of certain pest insect species, such as the Japanese beetle, acrobat ant,
and the gypsy moth, can be used to trap the respective insect for monitoring purposes, to control the population by creating
confusion, to disrupt mating, and to prevent further egg laying.

Figure 12.17.1: (S)-Ipsdienol is a terpene alcohol and is one of the major aggregation pheromones of the bark beetle. It
was first identified from Ips confusus, in which it is believed to be a principle sex attractant
When a female bark beetle produces and secretes a sex pheromone in order to attract a mate, the pheromone can be carried
on currents of air to male bark beetles, whose antennae can intercept individual pheromone molecules, completely intact,
still in the same form as when they were secreted by the female, no matter how far away she is. The male recognizes the
structure of the molecule; it can clearly tell if it has just intercepted the proper pheromone or some subtle imposter that also
happens to have the formula C10H16O.

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CHAPTER OVERVIEW
13: ALKYNES: THE CARBON
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

13.1: NAMING THE ALKYNES

13.2: PROPERTIES AND BONDING IN THE ALKYNES
13.3: SPECTROSCOPY OF THE ALKYNES
13.4: PREPARATION OF ALKYNES BY DOUBLE ELIMINATION
13.5: PREPARATION OF ALKYNES FROM ALKYNYL ANIONS
13.6: REDUCTION OF ALKYNES: THE RELATIVE REACTIVITY OF THE TWO π BONDS
13.7: ELECTROPHILIC ADDITION REACTIONS OF ALKYNES
13.8: ANTI-MARKOVNIKOV ADDITIONS TO TRIPLE BONDS
13.9: CHEMISTRY OF ALKENYL HALIDES
13.10: ETHYNE AS AN INDUSTRIAL STARTING MATERIAL
13.11: NATURALLY OCCURRING AND PHYSIOLOGICALLY ACTIVE ALKYNES

1 12/5/2021
13.1: Naming the Alkynes
 Objectives

After completing this section, you should be able to

1. provide the correct IUPAC name of an alkyne, given its Kekulé, condensed or shorthand structure.
2. provide the correct IUPAC name of a compound containing both double and triple bonds, given its Kekulé,
condensed or shorthand structure.
3. draw the structure of a compound containing one or more triple bonds, and possibly one or more double bonds,
given its IUPAC name.
4. name and draw the structure of simple alkynyl groups, and where appropriate, use these names as part of the
IUPAC system of nomenclature.

 Study Notes

Simple alkynes are named by the same rules that are used for alkenes (see Section 7.3), except that the ending is -yne
instead of -ene. Alkynes cannot exhibit E,Z (cis‑trans) isomerism; hence, in this sense, their nomenclature is simpler
than that of alkenes.

Alkynes are organic molecules made of the functional group carbon-carbon triple bonds and are written in the empirical
formula of C H
n 2n−2 . They are unsaturated hydrocarbons. Like alkenes have the suffix –ene, alkynes use the ending –yne;
this suffix is used when there is only one alkyne in the molecule.

Introduction
Here are the molecular formulas and names of the first ten carbon straight chain alkynes.
Name Molecular Formula

Ethyne C2H2

Propyne C3H4
1-Butyne C4H6
1-Pentyne C5H8
1-Hexyne C6H10
1-Heptyne C7H12
1-Octyne C8H14
1-Nonyne C9H16
1-Decyne C10H18

The more commonly used name for ethyne is acetylene, which used industrially.

Naming Alkynes
Like previously mentioned, the IUPAC rules are used for the naming of alkynes.

Rule 1
Find the longest carbon chain that includes both carbons of the triple bond.

Rule 2
Number the longest chain starting at the end closest to the triple bond. A 1-alkyne is referred to as a terminal alkyne and
alkynes at any other position are called internal alkynes.

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For example:

Rule 3
After numbering the longest chain with the lowest number assigned to the alkyne, label each of the substituents at its
corresponding carbon. While writing out the name of the molecule, arrange the substituents in alphabetical order. If there
are more than one of the same substituent use the prefixes di, tri, and tetra for two, three, and four substituents respectively.
These prefixes are not taken into account in the alphabetical order.
For example:

If there is an alcohol present in the molecule, number the longest chain starting at the end closest to it, and follow the same
rules. However, the suffix would be –ynol, because the alcohol group takes priority over the triple bond.

When there are two triple bonds in the molecule, find the longest carbon chain including both the triple bonds. Number the
longest chain starting at the end closest to the triple bond that appears first. The suffix that would be used to name this
molecule would be –diyne.
For example:

Rule 4
Substituents containing a triple bond are called alkynyl.
For example:

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Here is a table with a few of the alkynyl substituents:
Name Molecule

Ethynyl -C≡CH

2- Propynyl -CH2C≡CH
2-Butynyl -CH3C≡CH2CH3

Rule 5
A molecule that contains both double and triple bonds is called an alkenyne. The chain can be numbered starting with the
end closest to the functional group that appears first. For example:

If both functional groups are the exact same distance from the ending of the parent chain, the alkene takes precedence in
the numbering.

Hex-1-en-5-yne
.

 Exercise 13.1.1

1) Name the following compounds:

2) How many isomers are possible for C5H8? Draw them.

3) Draw the following compounds:
a) 4,4-dimethyl-2-pentyne
b) 3-octyne
c) 3-methyl-1-hexyne
d) trans 3-hepten-1-yne
4) Do alkynes show cis-trans isomerism? Explain.

Answer
1)

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 A – 3,6-diethyl-4-octyne
B – 3-methylbutyne
C – 4-ethyl-2-heptyne
D – cyclodecyne
2) 2 possible isomers

3)

4) No. A triply bonded carbon atom can form only one other bond and has linear electron geometry so there are no
"sides". Allkenes have two groups attached to each inyl carbon with a trigonal planar electron geometry that creates
the possibility of cis-trans isomerism.

Reference
1. Vollhardt, Peter, and Neil E. Schore. Organic Chemistry: Structure and Function. 5th Edition. New York: W. H.
Freeman & Company, 2007.

Exercises
Questions

Q9.1.1
Name the following compounds:

Q9.1.2
How many isomers are possible for C5H8? Draw them.
Q9.1.3
Draw the following compounds:
A) 4,4-dimethyl-2-pentyne

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B) 3-octyne
C) 3-methyl-1-hexyne
D) trans 3-hepten-1-yne
Q9.1.4
Do alkynes show cis-trans isomerism? Explain.
Solutions
S9.1.1
A – 3,6-diethyl-4-octyne
B – 3-methylbutyne
C – 4-ethyl-2-heptyne
D – cyclodecyne
S9.1.2
2 possible isomers

S9.1.3

S9.1.4
No. A triply bonded carbon atom can form only one other bond and has linear electron geometry so there are no "sides".
Allkenes have two groups attached to each inyl carbon with a trigonal planar electron geometry that creates the possibility
of cis-trans isomerism.

Contributors and Attributions

A. Sheth and S. Sujit (UCD)
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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13.2: Properties and Bonding in the Alkynes
The simplest alkyne—a hydrocarbon with carbon-to-carbon triple bond—has the molecular formula C2H2 and is known by
its common name—acetylene. Its structure is H–C≡C–H.

Terminal Alkyne: Internal Alkyne:

3-chloro-1-propyne 4,4-dichloro-2-pentyne

Bonding and Hybridization

Bond Name Location Overlap

Formed between 2 sp
Bond 1 s (? bond) bond orbitals of carbon and End-on overlap
hydrogen atoms
Formed between the 2 sp
Bond 2 S (? bond) bond orbital of 2 unsaturated End-on overlap
Carbon atoms.
Formed between the 2 p-
Bond 3 p-bonds (? bonds) orbitals among the carbon Side-on overlap
atoms

Orbital Name Location

Orbital 1 sp hybrid orbitals Formed in the linear structure model of carbon atom

Orbital 2 p-orbitals Formed on each carbon

Contributors
Jim Clark (Chemguide.co.uk)
The characteristic of the triple bond helps to explain the properties and bonding in the alkynes.

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Importance of Triple Bonds
Hybridization due to triple bonds allows the uniqueness of alkyne structure. This
triple bond contributes to the nonpolar bonding strength, linear, and the acidity of
alkynes. Physical Properties include nonpolar due to slight solubility in polar
solvents and insoluble in water. This solubility in water and polar solvents is a
characteristic feature to alkenes as well. Alkynes dissolve in organic solvents.

Boiling Points
Compared to alkanes and alkenes, alkynes have a slightly higher boiling point. Ethane has a boiling point of -88.6 ?C,
while Ethene is -103.7 ?C and Ethyne has a higher boiling point of -84.0 ?C.

Alkynes are High In Energy

Alkynes are involved in a high release of energy because of repulsion of electrons. The content of energy involved in the
alkyne molecule contributes to this high amount of energy. The pi-bonds however, do not encompass a great amount of
energy even though the concentration is small within the molecule. The combustion of Ethyne is a major contributor from
CO2, water, and the ethyne molecule

??H = -311 kcal/mol

To help understand the relative stabilities of alkyne isomers, heats of hydrogenation must be used. Hydrogenation of the
least energy, results in the release of the internal alkyne. With the result of the production of butane, the stability of internal
versus terminal alkynes has significant relative stability due to hyperconjugation.

Outside links
http://www.ucc.ie/academic/chem/dolc...t/alkynes.html
http://www.cliffsnotes.com/WileyCDA/...eId-22631.html

References
1. Bloch, D.R. Organic chemistry demystified, New York : McGraw-Hill, 2006.
2. Vollhardt. Schore, Organic Chemistry Structure and Function Fifth Edition, New York: W.H. Freeman and Company,
2007.

Problems
1. What is the carbon-carbon, carbon-hydrogen bond length for alkyne? Is it shorter or longer than alkane and alkene?
2. Which is the most acidic and most stable, alkane, alkene, or alkyne? And depends on what?
3. How many pi bonds and sigma bonds are involved in the structure of ethyne?
4. Why is the carbon-hydrogen bond so short?
5. What is the alkyne triple bond characterizes by? How is this contribute to the weakness of the pi bonds?
6. How is heat of hydrogenation effects the stability of the alkyne?

Contributors
Bao Kha Nguyen, Garrett M. Chin

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13.3: Spectroscopy of the Alkynes

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13.4: Preparation of Alkynes by Double Elimination
☰

 Objectives

After completing this section, you should be able to

1. write an equation to describe the preparation of an alkyne by the dehydrohalogenation of a vicinal dihalide or
vinylic halide.
2. identify the alkyne produced from the dehydrohalogenation of a given vicinal dihalide or vinylic halide.
3. write a reaction sequence to show how the double bond of an alkene can be transformed into a triple bond.
4. identify the vicinal dihalide (or vinylic halide) needed to synthesize a given alkyne by dehydrohalogenation.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
vicinal dihalide
vinylic halide

Alkynes can be a useful functional group to synthesize due to some of their antibacterial, antiparasitic, and antifungal
properties. One simple method for alkyne synthesis is by double elimination from a dihaloalkane.

E2 Mechanism
Section 8.2 discussed that alkenes can be formed through an elimination reaction. In particular, the synthesis of alkynes
will utilize the E2 elimination reaction. During the mechanism of an E2 reaction, a strong base removes a hydrogen
adjacent to a halogen. The electrons from the broken C-H bond more to form the C=C double bond. Doing this causes the
halogen to be ejected from the compound. Overall, a hydrogen and a halogen a eliminated from the compound to form an
alkene. During this mechanism there is a stereoelectronic requirement that the adjacent hydrogen and the halogen be
adjacent to each other.
E2 reaction will be discussed in greater detail in Section 11.10.

Alkyne Formation Through Dihaloalkane Elimination

Alkynes are frequently prepared through a double E2 reaction using 2 halides that are vicinal (meaning on adjacent
carbons) or geminal (meaning on the same carbon). Because the E2 reaction takes place twice 2 π bonds are formed thus
creating an Alkyne. Although hydroxide and alkoxide bases could be used for the strong base required for an E2 reaction,
their used opens the possibility of position rearrangement in the alkyne product. Because of this, the stronger base sodium
amide in ammonia (NaNH2/NH3) is commonly used.

General Reaction

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 Vicinal dihalide converted to an alkyne
☰
or

Geminal dihalide converted to an alkyne

Note! If a terminal alkyne is formed during the reaction, 3 equivalents of base are required instead of 2 as discussed below.

Mechanism
The following mechanism represents the reaction between 2,3-Dibromopentane with sodium amide in liquid ammonia to
form pent-2-yne. During this mechanism an intermediate alkene is formed. Notice that in the alkene intermediate, the
remaining hydrogen and halogen are anti to each other due to the stereoelectronic requirements of the E2 mechanism. The
intermediate alkene is converted to an alkyne by a second E2 elimination of a hydrogen and halogen.

Terminal Alkynes
The acidity of terminal alkynes also plays a role in product determination when vicinal (or geminal) dihalides undergo base
induced dielimination reactions. The following example illustrates eliminations of this kind starting from 1,2-
dibromopentane, prepared from 1-pentene by addition of bromine. The initial elimination presumably forms 1-bromo-1-
pentene, since base attack at the more acidic and less hindered 1º-carbon should be favored. The second elimination then
produces 1-pentyne. If the very strong base such as sodium amide is used, the terminal alkyne is trapped as its sodium salt,
from which it may be released by mild acid treatment. However, if the weaker base KOH with heat is used for the
elimination, the terminal alkyne salt is not formed, or is formed reversibly, and the initially generated 1-pentyne rearranges
to the more stable 2-pentyne via an allene intermediate. Even though terminal alkynes can be generated using sodium
amide as a base, most chemists will prefer to use SN2 nucleophilic substitution instead of elimination when trying to form
a terminal alkyne.

Preparation of Alkynes from Alkenes

An simple method for the preparation of alkynes utilizes alkenes as starting material. The process begins with the
electrophilic addition of a halogen to the alkene bond to form the dihaloalkane. Then the double E2 elimination process is
used to form the 2 π bonds of an alkyne.
This first process is gone over in much greater detail in the page on halogenation of an alkene. In general, chlorine or
bromine is used with an inert halogenated solvent like chloromethane to create a vicinal dihalide from an alkene. The
vicinal dihalide formed is the reactant needed to produce the alkyene using double elimination, as covered previously on
this page.

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☰

 Exercise 13.4.1

1) Why would we need 3 bases for every terminal dihaloalkane instead of 2 in order to form an alkyne?

2) What are the major products of the following reactions:

a.) 1,2-Dibromopentane with sodium amide in liquid ammonia
b.) 1-Pentene first with Br2 and chloromethane, followed by sodium ethoxide (Na+ -O-CH2CH3)
3) What would be good starting molecules for the synthesis of the following molecules:

4) Use a 6 carbon diene to synthesize a 6 carbon molecule with 2 terminal alkynes.

5) Identify the vinyl halide or halides and the vicinal dihalide or dihalides that could be used in the synthesis of:
a) 2,2,5,5-Tetramethyl-3-hexyne.
b) 4-Methyl-2-hexyne.

Answer
1) Remember that hydrogen atoms on terminal alkynes make the alkyne acidic. One of the base molecules
will pull off the terminal hydrogen instead of one of the halides like we want.
2)
a) 1-Pentyne
b) 1-Pentyne
3)

4) Bromine or chlorine can be used with different inert solvents for the halogenation. This can be done using
many different bases. Liquid ammonia is used as a solvent and needs to be followed by an aqueous work-up.

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☰

5)
a)

b)

References
1. Vollhardt, Peter, and Neil Shore. Organic Chemistry: Structure and Function. 5th. New York: W.H. Freeman and
Company, 2007.
2. Daley, Richard, and Sally Daley. "13.8 Elimination of Organohalogens." Organic Chemistry. Daley. 5 July 2005. 21
Feb. 2009. <https://studylib.net/doc/8721401/13-elimination-reactions>.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Layne Morsch (University of Illinois Springfield)
Prof. Steven Farmer (Sonoma State University)

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13.5: Preparation of Alkynes from Alkynyl Anions
 Objectives

After completing this section, you should be able to

1. write an equation for the reaction that occurs between a terminal alkyne and a strong base, such as sodamide,
NaNH2.
2. rank a given list of compounds, including water, acetylene and ammonia, in order of increasing or decreasing
acidity.
3. rank a given list of hydrocarbons, such as acetylene, ethylene and ethane, in order of increasing or decreasing
acidity.
4. describe a general method for determining which of two given compounds is the stronger acid.
5. provide an acceptable explanation of why terminal alkynes are more acidic than alkanes or alkenes.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
acetylide anion
acidity order

 Study Notes

An acetylide anion is an anion formed by removing the proton from the end carbon of a terminal alkyne:

An acidity orderis a list of compounds arranged in order of increasing or decreasing acidity.

The general ideas discussed in this section should already be familiar to you from your previous exposure to chemistry
and from the review in Section 2.8. A slightly different account of why terminal alkynes are stronger acids than are
alkenes or alkanes is given below. However, the argument is still based on the differences between sp-, sp2- and sp3-
hybrid orbitals.
The carbons of a triple bond are sp-hybridized. An sp‑hybrid orbital has a 50% s character and a 50% p character,
whereas an sp2‑hybrid orbital is 33% s and 67% p, and an sp3‑hybrid orbital is 25% s and 75% p. The greater the s
character of the orbital, the closer the electrons are to the nucleus. Thus in a C(sp)$\ce{-}$H bond, the bonding
electrons are closer to the carbon nucleus than they are in a C(sp2)$\ce{-}$H bond. In other words, compared to a
C(sp2)$\ce{-}$H bond (or a C(sp3)$\ce{-}$H bond), a C(sp)$\ce{-}$H bond is very slightly polar: Cδ−$\ce{-}$Hδ+.
This slight polarity makes it easier for a base to remove a proton from a terminal alkyne than from a less polar or non-
polar alkene or alkane.
As you will appreciate, the reaction between sodium amide and a terminal alkyne is an acid-base reaction. The sodium
acetylide product is, of course, a salt. Terminal alkynes can also form salts with certain heavy-metal cations, notably
silver(I) and copper(I). In the laboratory component of this course, you will use the formation of an insoluble silver
acetylide as a method for distinguishing terminal alkynes from alkenes and non-terminal alkynes:

Metal acetylides are explosive when dry. They should be destroyed while still wet by warming with dilute nitric acid:

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Acidity of Terminal Alkynes: Formation of Acetylide Anions
Terminal alkynes are much more acidic than most other hydrocarbons. Removal of the terminal proton leads to the
formation of an acetylide anion, RC=C:-.

R C C H + Na NH2 R C C Na + NH3

Terminal Alkyne Sodium Amide Acetylide Anion Ammonia

As discussed in Section 2.10, acidity typically increases with the stability of the corresponding conjugate base. The origin
of the enhanced acidity of terminal alkynes can be attributed to the stability of the acetylide anion, which has the unpaired
electrons in an sp hybridized orbital. The hybridization of an orbital affects its electronegativity. Within a shell, the s
orbitals occupy the region closer to the nucleus than the p orbitals. Therefore, the spherical s orbitals are more
electronegative than the lobed p orbitals. The relative electronegativity of hybridized orbitals increases as the percent s
character increases and follows the order sp > sp2 > sp3. This trend indicates the sp hybridized orbitals of the acetylide
anion are more electronegative and better able to stabilize a negative charge than sp2 or sp3 hybridized orbitals. There is a
strong correlation between s-character in the orbital containing the non-bonding electrons in the anion and the acidity of
hydrocarbons. The table below shows how orbital hybridization compares with the identity of the atom when predicting
relative acidity. Remember that as the pKa of a compound decreases its acidity increases.

H
H sp3 H C sp2 sp
H C
C H C C
H
H
Alkyl Anion Vinyl Anion Acetylide Anion
(25% s) (33% s) (50% s)

Stability
Table 9.7.1: Akynes
Compound Conjugate Base Hybridization "s Character" pKa C-H BDE (kJ/mol)

CH3CH3 CH3CH2- sp3 25% 50 410

CH2CH2 CH2CH- sp2 33% 44 473

HCCH HCC- sp 50% 25 523

Acetylene, with a pKa of 25 is shown to be much more acidic than ethylene (pKa = 44) or ethane (pKa = 50).
Consequently, acetylide anions can be readily formed by deprotonation of a terminal alkynes with a sufficiently strong
base. The amide anion (NH2-), in the form of sodium amide (NaNH2) is commonly used for the formation of acetylide
anions.

 Example 13.5.1

NaNH2
C C H C C Na

NaNH2
C C H C C Na

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 Exercise 9.7.1
1. Given that the pKa of water is 14.00, would you expect hydroxide ion to be capable of removing a proton from
each of the substances listed below? Justify your answers, briefly.
a. ethanol (pKa = 16)
b. acetic acid (pKa = 4.72)
c. acetylene (pKa = 25)

Answer
1.
a. No, not very well. The pKa of ethanol is greater than that of water, thus the equilibrium lies to the left rather than
to the right.Add texts here. Do not delete this text first.

b. Yes, very well. There is a difference of 11 pKa units between the pKa of water and the pKa of acetic acid. The
equilibrium lies well to the right.

c. No, hardly at all. The hydroxide ion is too weak a base to remove a proton from acetylene. The equilibrium lies
well to the left.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Paul G. Wenthold (Purdue University)

Layne Morsch (University of Illinois Springfield)

 Objectives

After completing this section, you should be able to

1. write an equation to describe the reaction of an acetylide ion with an alkyl halide.
2. discuss the importance of the reaction between acetylide ions and alkyl halides as a method of extending a carbon
chain.
3. identify the alkyne (and hence the acetylide ion) and the alkyl halide needed to synthesize a given alkyne.
4. determine whether or not the reaction of an acetylide ion with a given alkyl halide will result in substitution or
elimination, and draw the structure of the product formed in either case.

 Key Terms

Make certain that you can define, and use in context, the key term below.
alkylation

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 Study Notes

The alkylation of acetylide ions is important in organic synthesis because it is a reaction in which a new carbon-carbon
bond is formed; hence, it can be used when an organic chemist is trying to build a complicated molecule from much
simpler starting materials.
The alkyl halide used in this reaction must be primary. Thus, if you were asked for a suitable synthesis of 2,2-
dimethyl-3-hexyne, you would choose to attack iodoethane with the anion of 3,3- dimethyl-1-butyne

rather than to attack 2-iodo-2-methylpropane with the anion of 1-butyne.

The reasons will be made clear in Chapter 11.

Nucleophilic Substitution Reactions of Acetylides

The presence of lone pair electrons and a negative charge on a carbon, makes acetylide anions are strong bases and strong
nucleophiles. Therefore, acetylide anions can attack electrophiles such as alkyl halides to cause a substitution reaction.
These substitution reactions will be discussed in detail in Chapter 11.

Mechanism
The C-X bonds in 1o alkyl halides are polarized due to the high electronegativity of the halogen. The electrons of the C-X
sigma bond are shifted towards the halogen giving it a partial negative charge. This also causes electrons to be shifted
away from the carbon giving it a partial positive and making it electrophilic. During this reaction, the lone pair electrons
on the acetylide anion attack the electrophilic carbon in the 1o alkyl halide forming a new C-C bond. The formation of this
new bond causes the expulsion of the halogen as what is called a leaving group. Overall, this reaction forms a C-C bond
and converts a terminal alkyne into a internal alkyne. Because a new alkyl group is added to the alkyne during this
reaction, it is commonly called an alkylation.

SN2
R C C Na + R' X R C C R' + NaX

Acetylide Anion 1o Halide Internal Alkyne

This substitution reaction is often coupled with the acetylide formation, discussed in the previous section, and shown as a
single reaction.

 Example 13.5.1

Terminal alkynes can be generated through the reaction of acetylene and a 1o alkyl halide.

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 NaNH2 RCH2X H2
H C C H H C C H C C C R
Acetylene Acetylide Anion Terminal Alkyne

 Example 13.5.2

1) NaNH2
H C C H H C CCH2CH2CH3
2) CH3CH2CH2Br
Acetylene Pent-1-yne

Because the acetylide anion is a very strong base, this substitution reaction is most efficient with methyl or primary
halides. Secondary, tertiary, or even bulky primary halogens will give alkenes by the E2 elimination mechanism discussed
in Section 11.10. An example of this effect is seen in the reaction of bromocyclopentane with a propyne anion. The
reaction produces the elimination product cyclopentene rather than the substitution product 1-propynylcyclopentane.
H
+ HC CCH3 + NaBr
H
H Cyclopentene
Br
+ Na C CCH3
H
H H CH3
Bromocyclopentane C C
(2o Alkyl Halide)
H
H
Not Formed

Nucleophilic Addition of Acetylides to Carbonyls

Acetylide anions also add to the electrophilic carbon in aldehydes and ketones to form alkoxides, which, upon protonation,
give propargyl alcohols. With aldehydes and non-symmetric ketones, in the absence of chiral catalyst, the product will be a
racemic mixture of the two enantiomers. These types of reaction will be discussed in more detail in Chapter 19.

 Exercise 13.5.1
1) The pKa of ammonia is 35. Estimate the equilibrium constant for the deprotonation of pent-1-yne by sodium amide,
as shown below.

H3CH2CH2C C H + NaNH2 H3CH2CH2C C Na + NH3

2) Give the possible reactants which could form the following molecules by an alkylation.

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3) Propose a synthetic route to produce 2-pentene from propyne and an alkyl halide.
4) Using acetylene as the starting material, show how you would synthesize the following compounds

a)
b) but-2-yne

c)

d)
5) Show how you would accomplish the following synthetic transformation.

Answer
1) Assuming the pKa of pent-1-yne is about 25, then the difference in pKas is 10. Since pentyne is more acidic, the
formation of the acetylide will be favored at equilibrium, so the equilibrium constant for the reaction is about 1010.
2)

3)

4)
a)

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 b)

c)

d)

5)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Paul G. Wenthold (Purdue University)

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13.6: Reduction of Alkynes: The Relative Reactivity of the Two \(\pi\) Bonds
☰

 Objectives

After completing this section, you should be able to

1. write equations for the catalytic hydrogenation of alkynes to alkanes and cis alkenes.
2. identify the reagent and catalyst required to produce a given alkane or cis alkene from a given alkyne.
3. identify the product formed from the reaction of a given alkyne with hydrogen and a specified catalyst.
4. identify the alkyne that must be used to produce a given alkane or cis alkene by catalytic hydrogenation.
5. write the equation for the reduction of an alkyne with an alkali metal and liquid ammonia.
6. predict the structure of the product formed when a given alkyne is reduced with an alkali metal and liquid
ammonia.
7. identify the alkyne that must be used to produce a given alkene by reduction with an alkali metal and ammonia.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
anion radical
Lindlar catalyst

 Study Notes

The Lindlar catalyst allows a chemist to reduce a triple bond in the presence of a double bond.
Thus

but

Hydrogenation and the Relative Stability of Hydrocarbons

Like alkenes, alkynes readily undergo catalytic hydrogenation partially to cis- or trans- alkenes or fully to alkanes
depending on the reaction employed.

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The catalytic addition of hydrogen to 2-butyne provides heat of reaction data that reflect the relative thermodynamic
☰
stabilities of these hydrocarbons, as shown above. From the heats of hydrogenation, shown in blue in units of kcal/mole, it
would appear that alkynes are thermodynamically less stable than alkenes to a greater degree than alkenes are less stable
than alkanes. The standard bond energies for carbon-carbon bonds confirm this conclusion. Thus, a double bond is stronger
than a single bond, but not twice as strong. The difference ( 63 kcal/mole ) may be regarded as the strength of the π-bond
component. Similarly, a triple bond is stronger than a double bond, but not 50% stronger. Here the difference ( 54
kcal/mole ) may be taken as the strength of the second π-bond. The 9 kcal/mole weakening of this second π-bond is
reflected in the heat of hydrogenation numbers ( 36.7 - 28.3 = 8.4 ).

Overview of Reduction of Alkynes

Alkynes can undergo reductive hydrogenation reactions similar to alkenes. With the presence of two pi bonds within
alkynes, the reduction reactions can be partial to form an alkene or complete to form an alkane. Since partial reduction of
an alkyne produces an alkene, the stereochemistry provided by the reaction's mechanism determines whether a cis- or
trans- alkene is formed. The three most significant alkyne reduction reactions are summarized below:

R H
2 H2 H
C C Full Reduction
Pt, Pd, or Ni H R'
H
Alkane
H2 H H
Partial Reduction
R C C R' C C
Lindlar's Cat. (Syn Addition)
Alkyne R R'
Cis-Alkene

Na/NH3 H R'
Partial Reduction
C C
(Anti Addition)
R H
Trans-Alkene

Catalytic Hydrogenation of an Alkyne

Much like alkenes, alkynes can be fully hydrogenated into alkanes with the help of a platinum, paladium, or nickel
catalyst. Because the reaction is catalyzed on the surface of the metal, it is common for these catalysts to dispersed on
carbon (Pd/C) or finely dispersed as nickel (Raney-Ni). The presence of two pi bonds in the alkyne cause two equivalents
of H2 to be added during the reaction. During the reaction an alkene intermediate is form but not isolated.

H3 C H
2 H2 H
H3C C C CH3 C C
Pt, Pd, or Ni H CH3
H
2-Butyne Butane

Hydrogenation of an Alkyne to a Cis-Alkene

For catalytic hydrogenation, the Pt, Pd, or Ni catalysts are so effective in promoting addition of hydrogen to both double
and triple carbon-carbon bonds that the alkene intermediate formed by hydrogen addition to an alkyne cannot be isolated.
A less efficient catalyst, Lindlar's catalyst permits alkynes to be converted to alkenes without further reduction to an
alkane. Lindlar’s Catalyst transforms an alkyne to a cis-alkene because the hydrogenation reaction is occurring on the
surface of the metal. Both hydrogen atoms are added to the same side of the alkyne as shown in the syn-addition
mechanism for hydrogenation of alkenes in the previous chapter.

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 H2 H H
☰
H3C C C CH4 C C
Lindlar's Cat. H3C CH3
2-Butyne Cis-2-Butene

Lindlar's catalyst is prepared by deactivating (or poisoning) a conventional palladium catalyst. Lindlar’s catalyst has three
components: palladium-calcium carbonate, lead acetate, and quinoline. The quinoline serves to prevent complete
hydrogenation of the alkyne to an alkane.

5% Pd-CaCO3 + Pb(OCOCH3)2 + = Lindlar's Catalyst

N
Palladium- Lead acetate Quinoline
calcium carbonate

Hydrogenation of an Alkyne to a Trans-Alkene

The anti-addition of hydrogen to an alkyne pi bond occurs when reacted with sodium or lithium metal dissolved in
ammonia. This reaction, also called dissolving metal reduction, involves radicals in its mechanism and produces a trans-
alkene as it product.

H CH3
Na/NH3
H3C C C CH4 C C
H 3C H
2-Butyne Trans-2-Butene

Mechanism
Sodium metal is a powerful reducing agent due to the presence of a 3s1 electron in its valence. Sodium metal easily gives
up this electron to become Na+. The mechanism start with a sodium atom donating an electron to the alkyne creating an
intermediate with a negative charge and an unpaired electron called a radical anion. Next the amine solvent protonates the
anion to create a vinyl radical. A second sodium atom then donates an electron to pair the radical converting it to a vinyl
anion. This vinyl anion intermediate rapid interconverts between cis and trans conformations and determines the
stereochemistry of the reaction. The trans-vinyl anion is more stable due to reduced steric crowding and is preferentially
formed. Finally, the protonation of the trans-vinyl anion creates the trans-alkene product.
1) Electron Donation

Na R
R C C R C C + Na+
R
Radical Anion

2) Protonation
R R
C C C C + -
NH2
R R H
H NH2 Vinyl Radical

3) Electron Donation

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 Na R
☰ R
C C C C + Na+
R H R H
Trans-Vinyl Anion

4) Protonation
R H R
C C C C + -
NH2
H2 N H R H R H
Trans-Alkene

 Exercise

Using any alkyne how would you prepare the following compounds: pentane, trans-4-methyl-2-pentene, cis-4-methyl-
2-pentene.

Answer

Contributors and Attributions

Ravjot Takhar (UCD)
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Layne A. Morsch - University of Illinois Springfield

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13.7: Electrophilic Addition Reactions of Alkynes
Contributors and Attributions
•
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)

Prof. Steven Farmer (Sonoma State University)

William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

Jim Clark (Chemguide.co.uk)

 Objectives

After completing this section, you should be able to

1. write the equation for the reaction of water with an alkyne in the presence of sulfuric acid and mercury(II) sulfate.
2. describe keto-enol tautomerism.
3. predict the structure of the ketone formed when a given alkyne reacts with sulfuric acid in the presence of
mercury(II) sulfate.
4. identify the reagents needed to convert a given alkyne to a given ketone.
5. identify the alkyne needed to prepare a given ketone by hydration of the triple bond.
6. write an equation for the reaction of an alkyne with borane.
7. write the equation for the reaction of a vinylic borane with basic hydrogen peroxide or hot acetic acid.
8. identify the reagents, the alkyne, or both, needed to prepare a given ketone or a given cis alkene through a vinylic
borane intermediate.
9. identify the ketone produced when a given alkyne is reacted with borane followed by basic hydrogen peroxide.
10. identify the cis alkene produced when a given alkyne is reacted with borane followed by hot acetic acid.
11. explain why it is necessary to use a bulky, sterically hindered borane when preparing vinylic boranes from terminal
alkynes.
12. predict the product formed when the vinylic borane produced from a terminal alkyne is treated with basic hydrogen
peroxide.
13. identify the alkyne needed to prepare a given aldehyde by a vinylic borane.

 Key Terms
Make certain that you can define, and use in context, the key terms below.
enol
keto-enol tautomeric equilibrium
tautomerism
tautomers

 Study Notes

Rapid interconversion between tautomers is called tautomerism; however, as the two tautomers are in equilibrium, the
term tautomeric equilibrium may be used. This section demonstrates the equilibrium between a ketone and an enol;
hence, the term keto-enol tautomeric equilibrium is appropriate. The term “enol” indicates the presence of a carbon-

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 carbon double bond and a hydroxyl (i.e., alcohol) group. Later in the course, you will see the importance of keto-enol
tautomerism in discussions of the reactions of ketones, carbohydrates and nucleic acids.
It is important to note that tautomerism is not restricted to keto-enol systems. Other examples include imine-enamine
tautomerism

and nitroso-oxime tautomerism

However, at the moment you need only concern yourself with keto-enol tautomerism.
Notice how hydroboration complements hydration in the chemistry of both alkenes and alkynes.

Mercury(II)-Catalyzed Hydration of Alkynes

As with alkenes, hydration (addition of water) of alkynes requires a strong acid, usually sulfuric acid, and is facilitated by
the mercuric ion (Hg2+). However, the hydration of alkynes gives ketone products while the hydration of alkenes gives
alcohol products. Notice that the addition of oxygen in both reactions follows Markovnikov rule.

H H 1) Hg(OAc)2, H2O/THF HO H
H
C C
H C C
R H 2) NaBH4 R H
Terminal 2o Alcohol
Alkene

H2O, H2SO4 O
R C C H C
HgSO4 R CH3
Terminal Ketone
Alkyne

During the hydration of an alkyne, the initial product is an enol intermediate (a compound having a hydroxyl substituent
attached to a double-bond), which immediately rearranges to the more stable ketone through a process called enol-keto
tautomerization.

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 O
HO H Tautomerization
H2O, H2SO4 C H
R C C H C C R C
HgSO4 R H H
H
Terminal Enol Ketone
Alkyne

Tautomers are defined as rapidly inter-converted constitutional isomers, usually distinguished by a different bonding
location for a labile hydrogen atom and a differently located double bond. The keto and enol tautomers are in equilibrium
with each other and with few exceptions the keto tautomer is more thermodynamically stable and therefor favored by the
equilibrium. This mechanism for tautomerization will be discussed in greater detail in Section 22-1.
O
HO Tautomerization
C H
C C C
R

Enol Keto
Tautomer Tautomer
(Favored)

General Reaction
For terminal alkynes, the addition of water follows the Markovnikov rule, and the final product is a methyl ketone. For
internal alkynes the addition of water is not regioselective. Hydration of symmetrical internal alkynes produces a single
ketone product. However, hydration of asymmetrical alkynes, (i.e. if R & R' are not the same ) produces two isomeric
ketone products.
O
C H
H2O, H2SO4
R C
R C C H H
HgSO4 H
Terminal Methylketone
Alkyne

O
C R
H2O, H2SO4
R C
R C C R H
HgSO4 H
Symmetrical Internal Single Ketone Product
Alkyne

O O
H2O, H2SO4 R' R C
R C C R' R
C
C + C R'
HgSO4 H H
H H

Asymmetrical Internal Mixture of Ketone Products

Alkyne

Mechanism

The mechanism starts with the eletrophilic addition of the mercuric ion (Hg2+) to the alkyne producing a mercury-
containing vinylic carbocation intermediate. Nucleophilic attack of water on the vinylic carbocation forms a C-O bond to
produce a protonated enol. Deprotonation of the enol by water then produces a organomurcury enol. The murcury is
substituted with H+ to produced a neutral enol and regenerate the Hg2+ catalyst. The enol is converted to the ketone
product through keto-enol tautomerization the mechanism of which is provided in Section 22-1.

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1) Electrophilic addition of Hg2+
H
R C C H C C
R Hg+SO42-
Hg2+ SO42-

2) Nucleophilic attack by water

H
H
H O
H H O H
C C C C
R Hg+SO42- R Hg+SO42-

3) Deprotonation
H
O H
H
H O H H O H
C C C C + H3 O +
R Hg+SO42- R Hg+SO42-

4) Substitution
H O H H O H
H 3O +
C C C C + H 2O + HgSO4
R Hg+SO42- R H

5) Tautomerization
H O H O H
C C C C H
R H R H

Hydroboration–Oxidation of Alkynes
The hydroboration-oxidation of alkynes is analagous to the reaction with alkenes. However, where alkenes for alcohol
products, alkynes for aldehyde or ketone products. In both cases the addition is anti-Markovnikov and an oxygen is placed
on the less alkyl substituted carbon. With the hydroboration of an alkyne the presences of a second pi bond allows the
initial product to under tautomerization to become the final aldehyde product.
H H 1) BH3 H OH
C C
H C C H
R H 2) H2O2, OH- R H
Terminal 1o Alcohol
Alkene

1) BH3 H OH Tautomerization H O
R C C H C C H C C
2) H2O2, OH- R H R H

Terminal Enol Aldehyde

Alkyne

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Alkynes have two pi bonds both of which are capable of reacting with borane (BH3). To limit the reactivity to only one
alkyne pi bond, a dialkyl borane reagent (R2BH) is used. Replacing two of the hydrogens on the borane with alkyl groups
also creates steric hindrance which enhances the anti-Markovnikov regioselective of the reaction. Disiamylborane
(Sia2BH) and 9-borabicyclo[3.3.1]nonane (9-BBN) are two common reagents for this hydroboration reaction. The
oxidation reagents (a basic hydrogen peroxide solution) are the same for both alkenes and alkynes.
H
H B
B

Disiamylborane 9-Borabicyclo[3.3.1]nonane
(Sia2BH) (9-BBN)

General Reaction
The hydroboration of terminal alkynes produces aldehyde products while internal alkynes produce ketone products. The
hydroboration of symmetrical alkynes produces one ketone product and asymmetrical alkynes produce a mixture of
product ketones.

1) Sia2BH or 9-BBN H O
R C C H H C C
2) H2O2, OH- R H
Terminal Aldehyde
Alkyne

O
1) Sia2BH or 9-BBN H
C C H C C
2) H2O2, OH-

Internal Ketone
Alkyne

Mechanism
The mechanism starts with the electrophilic addition of the B-H bond of the borane. The hydrogen atom and the borane all
on the same side of the alkyne creating a syn addition configuration in the alkene poduct. Also, the addition is anti-
Markovnikov regioselective which means the borane adds to the less substituted carbon of the alkyne and the hydrogen
atom adds to the more substituted. The oxidative work-up replaces the borane with a hydroxy group (-OH) creating an enol
intermediate. The enol immediately tautomerizes to the product aldehyde for terminal alkynes and the product ketone for
internal alkynes.
Sia
H B
Sia Sia
H B Sia H OH H O
Syn H2O2, OH- Tautomerization
R C C H C C C C H C C
Anti-Mark R H R H R H
Alkyne Enol Aldehyde

Comparison of Mercury(II)-Catalyzed Hydration and Hydroboration–Oxidation of Alkynes

These two reactions are complementary for the reaction of a terminal alkyne because the produce distinctly different
products. The mercury(II) catalyzed hydration of a terminal alkyne produces a methyl ketone, while the hydroboration-

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oxidation produces an aldehyde.

1) Sia2BH or 9-BBN H O
H C C
2) H2O2, OH- R H
Aldehyde
R C C H
Terminal O
Alkyne H2O, H2SO4 H
C
R C
HgSO4 H
H
Methylketone

For internal alkynes, the regioslectivity of these reactions are rendered ineffective. The reactions are redundant in that they
both produce the same ketone products.

1) Sia2BH or 9-BBN H O
H C C
2) H2O2, OH- R R
Ketone
R C C R
Internal
Alkyne H O
H2O, H2SO4
H C C
HgSO4 R R
Ketone

 Exercise 13.7.1

1) Draw the structure of the product formed when each of the substances below is treated with H2O/H2SO4 in the
presence of HgSO4.
a)

b)

2) Draw the structure of the keto form of the compound shown below. Which form would you expect to be the most
stable?

3) What alkyne would you start with to gain the following products?

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4) What alkyne would you start with to gain the following product?

5) Draw the product(s) of the following reactions:

Answer
Answers:
1)
a)

b)

2.

The keto form should be the most stable.

3)

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 4)

5)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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13.8: Anti-Markovnikov Additions to Triple Bonds
 Objectives

After completing this section, you should be able to

1. write the equation for the reaction of water with an alkyne in the presence of sulfuric acid and mercury(II) sulfate.
2. describe keto-enol tautomerism.
3. predict the structure of the ketone formed when a given alkyne reacts with sulfuric acid in the presence of
mercury(II) sulfate.
4. identify the reagents needed to convert a given alkyne to a given ketone.
5. identify the alkyne needed to prepare a given ketone by hydration of the triple bond.
6. write an equation for the reaction of an alkyne with borane.
7. write the equation for the reaction of a vinylic borane with basic hydrogen peroxide or hot acetic acid.
8. identify the reagents, the alkyne, or both, needed to prepare a given ketone or a given cis alkene through a vinylic
borane intermediate.
9. identify the ketone produced when a given alkyne is reacted with borane followed by basic hydrogen peroxide.
10. identify the cis alkene produced when a given alkyne is reacted with borane followed by hot acetic acid.
11. explain why it is necessary to use a bulky, sterically hindered borane when preparing vinylic boranes from terminal
alkynes.
12. predict the product formed when the vinylic borane produced from a terminal alkyne is treated with basic hydrogen
peroxide.
13. identify the alkyne needed to prepare a given aldehyde by a vinylic borane.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
enol
keto-enol tautomeric equilibrium
tautomerism
tautomers

 Study Notes

Rapid interconversion between tautomers is called tautomerism; however, as the two tautomers are in equilibrium, the
term tautomeric equilibrium may be used. This section demonstrates the equilibrium between a ketone and an enol;
hence, the term keto-enol tautomeric equilibrium is appropriate. The term “enol” indicates the presence of a carbon-
carbon double bond and a hydroxyl (i.e., alcohol) group. Later in the course, you will see the importance of keto-enol
tautomerism in discussions of the reactions of ketones, carbohydrates and nucleic acids.
It is important to note that tautomerism is not restricted to keto-enol systems. Other examples include imine-enamine
tautomerism

and nitroso-oxime tautomerism

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 However, at the moment you need only concern yourself with keto-enol tautomerism.
Notice how hydroboration complements hydration in the chemistry of both alkenes and alkynes.

Mercury(II)-Catalyzed Hydration of Alkynes

As with alkenes, hydration (addition of water) of alkynes requires a strong acid, usually sulfuric acid, and is facilitated by
the mercuric ion (Hg2+). However, the hydration of alkynes gives ketone products while the hydration of alkenes gives
alcohol products. Notice that the addition of oxygen in both reactions follows Markovnikov rule.

H H 1) Hg(OAc)2, H2O/THF HO H
H
C C C C
H
R H 2) NaBH4 R H
Terminal 2o Alcohol
Alkene

H2O, H2SO4 O
R C C H C
HgSO4 R CH3
Terminal Ketone
Alkyne

During the hydration of an alkyne, the initial product is an enol intermediate (a compound having a hydroxyl substituent
attached to a double-bond), which immediately rearranges to the more stable ketone through a process called enol-keto
tautomerization.
O
HO H Tautomerization
H2O, H2SO4 C H
R C C H C C R C
HgSO4 R H H
H
Terminal Enol Ketone
Alkyne

Tautomers are defined as rapidly inter-converted constitutional isomers, usually distinguished by a different bonding
location for a labile hydrogen atom and a differently located double bond. The keto and enol tautomers are in equilibrium
with each other and with few exceptions the keto tautomer is more thermodynamically stable and therefor favored by the
equilibrium. This mechanism for tautomerization will be discussed in greater detail in Section 22-1.

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 O
HO Tautomerization
C H
C C C
R

Enol Keto
Tautomer Tautomer
(Favored)

General Reaction
For terminal alkynes, the addition of water follows the Markovnikov rule, and the final product is a methyl ketone. For
internal alkynes the addition of water is not regioselective. Hydration of symmetrical internal alkynes produces a single
ketone product. However, hydration of asymmetrical alkynes, (i.e. if R & R' are not the same ) produces two isomeric
ketone products.
O
C H
H2O, H2SO4
R C
R C C H H
HgSO4 H
Terminal Methylketone
Alkyne

O
C R
H2O, H2SO4
R C
R C C R H
HgSO4 H
Symmetrical Internal Single Ketone Product
Alkyne

O O
H2O, H2SO4 R' R C
R C C R' R
C
C + C R'
HgSO4 H H
H H

Asymmetrical Internal Mixture of Ketone Products

Alkyne

Mechanism

The mechanism starts with the eletrophilic addition of the mercuric ion (Hg2+) to the alkyne producing a mercury-
containing vinylic carbocation intermediate. Nucleophilic attack of water on the vinylic carbocation forms a C-O bond to
produce a protonated enol. Deprotonation of the enol by water then produces a organomurcury enol. The murcury is
substituted with H+ to produced a neutral enol and regenerate the Hg2+ catalyst. The enol is converted to the ketone
product through keto-enol tautomerization the mechanism of which is provided in Section 22-1.
1) Electrophilic addition of Mg2+
H
R C C H C C
R Hg+SO42-
Hg2+ SO42-

2) Nucleophilic attack by water

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 H
H
H O
H H O H
C C C C
+ 2-
R Hg SO4 R Hg+SO42-

3) Deprotonation
H
O H
H
H O H H O H
C C C C + H3 O +
+ 2- + 2-
R Hg SO4 R Hg SO4

4) Substitution
H O H H O H
H 3O +
C C C C + H 2O + HgSO4
+ 2-
R Hg SO4 R H

5) Tautomerization
H O H O H
C C C C H
R H R H

Hydroboration–Oxidation of Alkynes
The hydroboration-oxidation of alkynes is analagous to the reaction with alkenes. However, where alkenes for alcohol
products, alkynes for aldehyde or ketone products. In both cases the addition is anti-Markovnikov and an oxygen is placed
on the less alkyl substituted carbon. With the hydroboration of an alkyne the presences of a second pi bond allows the
initial product to under tautomerization to become the final aldehyde product.

H H 1) BH3 H OH
C C
H C C H
R H 2) H2O2, OH- R H
Terminal 1o Alcohol
Alkene

1) BH3 H OH Tautomerization H O
R C C H C C H C C
2) H2O2, OH- R H R H

Terminal Enol Aldehyde

Alkyne

Alkynes have two pi bonds both of which are capable of reacting with borane (BH3). To limit the reactivity to only one
alkyne pi bond, a dialkyl borane reagent (R2BH) is used. Replacing two of the hydrogens on the borane with alkyl groups
also creates steric hindrance which enhances the anti-Markovnikov regioselective of the reaction. Disiamylborane
(Sia2BH) and 9-borabicyclo[3.3.1]nonane (9-BBN) are two common reagents for this hydroboration reaction. The
oxidation reagents (a basic hydrogen peroxide solution) are the same for both alkenes and alkynes.

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 H
H B
B

Disiamylborane 9-Borabicyclo[3.3.1]nonane
(Sia2BH) (9-BBN)

General Reaction
The hydroboration of terminal alkynes produces aldehyde products while internal alkynes produce ketone products. The
hydroboration of symmetrical alkynes produces one ketone product and asymmetrical alkynes produce a mixture of
product ketones.

1) Sia2BH or 9-BBN H O
R C C H H C C
2) H2O2, OH- R H
Terminal Aldehyde
Alkyne

O
1) Sia2BH or 9-BBN H
C C H C C
2) H2O2, OH-

Internal Ketone
Alkyne

Mechanism
The mechanism starts with the electrophilic addition of the B-H bond of the borane. The hydrogen atom and the borane all
on the same side of the alkyne creating a syn addition configuration in the alkene poduct. Also, the addition is anti-
Markovnikov regioselective which means the borane adds to the less substituted carbon of the alkyne and the hydrogen
atom adds to the more substituted. The oxidative work-up replaces the borane with a hydroxy group (-OH) creating an enol
intermediate. The enol immediately tautomerizes to the product aldehyde for terminal alkynes and the product ketone for
internal alkynes.
Sia
H B
Sia Sia
H B Sia H OH H O
Syn H2O2, OH- Tautomerization
R C C H C C C C H C C
Anti-Mark R H R H R H
Alkyne Enol Aldehyde

Comparison of Mercury(II)-Catalyzed Hydration and Hydroboration–Oxidation of Alkynes

These two reactions are complementary for the reaction of a terminal alkyne because the produce distinctly different
products. The mercury(II) catalyzed hydration of a terminal alkyne produces a methyl ketone, while the hydroboration-
oxidation produces an aldehyde.

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 1) Sia2BH or 9-BBN H O
H C C
2) H2O2, OH- R H
Aldehyde
R C C H
Terminal O
Alkyne H2O, H2SO4 H
C
R C
HgSO4 H
H
Methylketone

For internal alkynes, the regioslectivity of these reactions are rendered ineffective. The reactions are redundant in that they
both produce the same ketone products.

1) Sia2BH or 9-BBN H O
H C C
2) H2O2, OH- R R
Ketone
R C C R
Internal
Alkyne H O
H2O, H2SO4
H C C
HgSO4 R R
Ketone

 Exercise 13.8.1

1) Draw the structure of the product formed when each of the substances below is treated with H2O/H2SO4 in the
presence of HgSO4.
a)

b)

2) Draw the structure of the keto form of the compound shown below. Which form would you expect to be the most
stable?

3) What alkyne would you start with to gain the following products?

4) What alkyne would you start with to gain the following product?

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5) Draw the product(s) of the following reactions:

Answer
Answers:
1)
a)

b)

2.

The keto form should be the most stable.

3)

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 4)

5)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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13.9: Chemistry of Alkenyl Halides

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13.10: Ethyne as an Industrial Starting Material

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13.11: Naturally Occurring and Physiologically Active Alkynes
The important class of lipids called steroids are actually metabolic derivatives of terpenes, but they are customarily treated as
a separate group. Steroids may be recognized by their tetracyclic skeleton, consisting of three fused six-membered and one
five-membered ring.
Steroids are widely distributed in animals, where they are associated with a number of physiological processes. Examples of
some important steroids are shown in the following diagram. Norethindrone is a synthetic steroid, all the other examples occur
naturally. A common strategy in pharmaceutical chemistry is to take a natural compound, having certain desired biological
properties together with undesired side effects, and to modify its structure to enhance the desired characteristics and diminish
the undesired. This is sometimes accomplished by trial and error.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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CHAPTER OVERVIEW
14: DELOCALIZED PI SYSTEMS: INVESTIGATION BY ULTRAVIOLET AND
VISIBLE SPECTROSCOPY
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

14.1: OVERLAP OF THREE ADJACENT P ORBITALS: ELECTRON DELOCALIZATION IN THE 2-PROPENYL (ALLYL)
SYSTEM
14.2: RADICAL ALLYLIC HALOGENATION
14.3: NUCLEOPHILIC SUBSTITUTION OF ALLYLIC HALIDES: SN1 AND SN2
14.4: ALLYLIC ORGANOMETALLIC REAGENTS: USEFUL THREE-CARBON NUCLEOPHILES
14.5: TWO NEIGHBORING DOUBLE BONDS: CONJUGATED DIENES
14.6: ELECTROPHILIC ATTACK ON CONJUGATED DIENES: KINETIC AND THERMODYNAMIC CONTROL
14.7: DELOCALIZATION AMONG MORE THAN TWO PI BONDS: EXTENDED CONJUGATION AND BENZENE
14.8: A SPECIAL TRANSFORMATION OF CONJUGATED DIENES: DIELS-ALDER CYCLOADDITION
14.9: ELECTROCYCLIC REACTIONS
14.10: POLYMERIZATION OF CONJUGATED DIENES: RUBBER
14.11: ELECTRONIC SPECTRA: ULTRAVIOLET AND VISIBLE SPECTROSCOPY

1 12/5/2021
14.1: Overlap of Three Adjacent p Orbitals: Electron Delocalization in the 2-
Propenyl (Allyl) System
Have you ever wondered why color exists? If you know it is because of molecules, do you know what makes the different
colors appear? Most of it can be explained by the presence of the π bonds, and how many there are. When photons hit the
atoms and excite the electrons, the bonds that the electrons are in affect the frequency of light that is reflected when the
electrons go back to th ground state and is perceived by our eyes.

Introduction
π-Bonds are formed from the overlap of two adjacent parallel p orbitals (Fig.1). π bonds are important in the addition
reactions. It is vital in synthesising many products like the polymers we use in modern day society. These systems have
incredibly unique thermodynamic and photochemical properties. In this section we discover the special properties that
three adjacent p orbitals (a π double bond and a p orbital) can have on the reactivity of a carbon center. We call a carbon
next to a double bonded carbon an allylic carbon. The electrons that are shared between all the atomic centers are
commonly said to be delocalized.

Figure 1 A π Bond is the interaction between the two p orbitals of the bonded carbons.

Allylic Carbocations
Lets take a look at the energy required to homolytically cleave (bond enthalpies) a covalent bond fig.2

Figure 2: shows the decreasing energy required to a cleave a bond as we add methyl groups (for stabilization)

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As you can see, the more stable the carbocation, the easier it is to form. The tertiary carbocation takes less energy to cleave
than the primary carbocation. This is due to hyperconjugation which stabilizes the free electron by the slight interaction
with nearby bond orbitals in the methyl groups.
Now we look at a propene molecule Figure 3.

Figure 3: propene radical formation

Even though the carbocation is a primary one, the energy required to cleave the bond is even lower than that of a
seemingly stable tertiary structure. Also, the pKa of propene is about 40, compared to propane, which is about 50. This
means the propene is much more willing to form the propenyl anion, about ten orders of magnitude more. Let's take a look
at why:

Resonance
One way to explain the stability is in terms of resonance, the allylic effect can be shown in all carbon center forms: Cation,
Radical, and Anion in figure 4. The double bond's ability to shift in between different carbons gives it extra resonance
forms, which lends extra stability.

Figure 4: Each type of center is stabilized through resonance because double bond

Molecular Orbitals
It can also be clearly shown through orbitals in figure 5.

Figure 5. A conjugated ? electron system

The stability of the carbocation of propene is due to a conjugated π electron system. A "double bond" doesn't really exist.
Instead, it is a group of 3 adjacent, overlapping, non-hybridized p orbitals we call a conjugated π electron system. You
can clearly see the interactions between all three of the p orbitals from the three carbons resulting in a really stable cation.
It all comes down to where the location of the electron-deficient carbon is.
Molecular orbital descriptions can explain allylic stability in yet another way using 2-propenyl. Fig.6

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 Figure 6: Shows the 3 possible Molecular orbitals of 2-propenyl
If we just take the π molecular orbital and not any of the s, we get three of them. π1 is bonding with no nodes, π2 is
nonbonding (In other words, the same energy as a regular p-orbital) with a node, and π3 is antibonding with 2 nodes (none
of the orbitals are interacting). The first two electrons will go into the π1 molecular orbital, regardless of whether it is a
cation, radical, or anion. If it is a radical or anion, the next electron goes into the π2 molecular orbital. The last anion
electron goes into the nonbonding orbital also. So no matter what kind of carbon center exists, no electron will ever go into
the antibonding orbital.
The Bonding orbitals are the lowest energy orbitals and are favorable, which is why they are filled first. Even though the
nonbonding orbitals can be filled, the overall energy of the system is still lower and more stable due to the filled bonding
molecular orbitals.
This figure also shows that π2 is the only molecular orbital where the electrion differs, and it is also where a single node
passes through the middle. Because of this, the charges of the molecule are mainly on the two terminal carbons and not the
middle carbon.
This molecular orbital description can also illustrate the stability of allylic carbon centers in figure 7.

Fig.7 diagram showing how the electrons fill based on the Aufbau principle.
The π bonding orbital is lower in energy than the nonbonding p orbital. Since every carbon center shown has two electrons
in the lower energy, bonding π orbitals, the energy of each system is lowered overall (and thus more stable), regardless of
cation, radical, or anion.

Ultraviolet and Visible Spectroscopy

An electronic spectra can indicate the relative amounts of delocalization in a π electron system. The more conjugated π
bonds there are, the longer the wavelength is reflected. Ethene has a maximum wavelength of 171 nm compared to 1,4-
Pentadiene, which has a maximum wavelength of 178 nm and 1,3-Butadiene which has a maximum wavelength of 217

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nm. The higher wavelength of the 1,3-Butadiene compared to only 178 nm for 1,4-Pentadiene shows the unique difference
between a conjugated an non conjugated system.

References
1. Kent, Doug. 2009. Lecture on February 4, General assistance in Chem 118B workshop. University of California, Davis.
2. Loudon, G. Marc. Organic Chemistry. 4th ed. New York: Oxford University Press, 2002.
3. Vollhardt, Peter, and Neil Shore. Organic Chemistry: Structure and Function. 5th. New York: W.H. Freeman and
Company, 2007.

Problems
1. Given 1-bromopropane and water, or 1-bromopropene, which one would react and why?
2. Order these in terms of free radical stability, 1 being most stable: tertiary alkyl, primary alkyl, secondary allylic, tertiary
.
allylic, CH3, primary allylic, secondary alkyl.
3. Order these molecules in terms of relative wavelength, from longest, to shortest.
4. 1,3-Cyclopentene; 2-Methyl-1,3-Pentadiene; Pyrrole; 2-Methyl-1,4-Pentadiene; trans-1,3,5-Hexatriene.
5. Draw out the resonance structures of the arenium ion during a general electrophilic aromatic substitution of a Benzene
ring.

Answers
1. 1-bromopropane would have no reaction because water is a poor nucleophile, and a primary carbocation would form.
1-bromopropene is allylic and so stabilizes the carbon attached to the bromine. The water can then successfully react
with it through an SN2 reaction.
.
2. 1 tertiary allylic, 2 secondary allylic~tertiary alkyl, 3 primary allylic~secondary alkyl, 4 primary alkyl, 5 CH3
3. Long wavelength Pyrrole>1,3-Cyclopentadiene>trans-1,3,5-Hexatriene>2-Methyl-1,3-Pentadiene>2-Methyl-1,4-
Pentadiene short wavelength
4.

Contributors
Jeffrey Hu

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14.2: Radical Allylic Halogenation
When halogens are in the presence of unsaturated molecules such as alkenes, the expected reaction is addition to the
double bond carbons resulting in a vicinal dihalide (halogens on adjacent carbons). However, when the halogen
concentration is low enough, alkenes containing allylic hydrogens undergo substitution at the allylic position rather than
addition at the double bond. The product is an allylic halide (halogen on carbon next to double bond carbons), which is
acquired through a radical chain mechanism.

Why Substitution of Allylic Hydrogens?

As the table below shows, the dissociation energy for the allylic C-H bond is lower than the dissociation energies for the
C-H bonds at the vinylic and alkylic positions. This is because the radical formed when the allylic hydrogen is removed is
resonance-stabilized. Hence, given that the halogen concentration is low, substitution at the allylic position is favored over
competing reactions. However, when the halogen concentration is high, addition at the double bond is favored because a
polar reaction outcompetes the radical chain reaction.

Radical Allylic Bromination (Wohl-Ziegler Reaction)

Preparation of Bromine (low concentration)
NBS (N-bromosuccinimide) is the most commonly used reagent to produce low concentrations of bromine. When
suspended in tetrachloride (CCl4), NBS reacts with trace amounts of HBr to produce a low enough concentration of
bromine to facilitate the allylic bromination reaction.

Allylic Bromination Mechanism

Step 1: Initiation
Once the pre-initiation step involving NBS produces small quantities of Br2, the bromine molecules are homolytically
cleaved by light to produce bromine radicals.

Step 2: Propagation
One bromine radical produced by homolytic cleavage in the initiation step removes an allylic hydrogen of the alkene
molecule. A radical intermediate is generated, which is stabilized by resonance. The stability provided by delocalization of

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the radical in the alkene intermediate is the reason that substitution at the allylic position is favored over competing
reactions such as addition at the double bond.

The intermediate radical then reacts with a Br2 molecule to generate the allylic bromide product and regenerate the
bromine radical, which continues the radical chain mechanism. If the alkene reactant is asymmetric, two distinct product
isomers are formed.

Step 3: Termination
The radical chain mechanism of allylic bromination can be terminated by any of the possible steps shown below.

Radical Allylic Chlorination

Like bromination, chlorination at the allylic position of an alkene is achieved when low concentrations of Cl2 are present.
The reaction is run at high temperatures to achieve the desired results.

Industrial Uses
Allylic chlorination has important practical applications in industry. Since chlorine is inexpensive, allylic chlorinations of
alkenes have been used in the industrial production of valuable products. For example, 3-chloropropene, which is
necessary for the synthesis of products such as epoxy resin, is acquired through radical allylic chlorination (shown below).

Problems (Answers are attached as a file)

1. Cyclooctene undergoes radical allylic bromination. Write out the complete mechanism including reactants,
intermediates and products.
2. Predict the two products of the allylic chlorination reaction of 1-heptene.
3. What conditions are required for allylic halogenation to occur? Why does this reaction outcompete other possible
reactions such as addition when these conditions are met?
4. Predict the product of the allylic bromination reaction of 2-benzylheptane. (Hint: How are benzylic hydrogens similar
to allylic hydrogens?)
5. The reactant 5-isopropyl-1-hexene generates the products 3-bromo-5-isopropyl-1-hexene and 1-bromo-5-isopropyl-2-
hexene. What reagents were used in this reaction?

References
1. Djerassi, Carl. "Brominations with N-Bromosuccinimide and Related Compounds - The Wohl-Ziegler Reaction."
Chemical Reviews 43 (1948):271-314.
2. Easton, Christopher J., Alison J. Edwards, Stephen B. McNabb, Martin C. Merrett, Jenny L. O'Connell, Gregory W.
Simpson, Jamie S. Simpson, and Anthony C. Willis. "Allylic halogenation of unsaturated amino acids." Organic and
Biomolecular Chemistry (2003). RSC Publishing. 9 June 2003. Royal Society of Chemistry. 25 Feb. 2009.
3. Kent, Doug. Allylic Bromination. Chem 118B Workshop. Learning Skills Center. 3 Feb. 2009.

14.2.2 12/5/2021 https://chem.libretexts.org/@go/page/32458

4. Li, Chao-Jun, and Tak-Hang Chan. Comprehensive Organic Reactions in Aqueous Media. New York: Wiley-
Interscience, 2007.
5. Vollhardt, Peter C., and Neil E. Schore. Organic Chemistry: Structure and Function. 5th ed. New York: W.H. Freeman
and Company, 2007.

Outside Links
http://en.wikipedia.org/wiki/N-Bromo...de#Preparation
http://en.wikipedia.org/wiki/Wohl-Ziegler_reaction
http://www.mhhe.com/physsci/chemistr...10allylic.html

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14.3: Nucleophilic Substitution of Allylic Halides: SN1 and SN2

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14.4: Allylic Organometallic Reagents: Useful Three-Carbon Nucleophiles

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14.5: Two Neighboring Double Bonds: Conjugated Dienes
 Objectives

After completing this section, you should be able to

1. write a reaction sequence to show a convenient method for preparing a given conjugated diene from an alkene,
allyl halide, alkyl dihalide or alcohol (diol).
2. identify the reagents needed to prepare a given diene from one of the starting materials listed in Objective 1, above.
3. compare the stabilities of conjugated and non-conjugated dienes, using evidence obtained from hydrogenation
experiments.
4. discuss the bonding in a conjugated diene, such as 1,3-butadiene, in terms of the hybridization of the carbon atoms
involved.
5. discuss the bonding in 1,3-butadiene in terms of the molecular orbital theory, and draw a molecular orbital for this
and similar compounds.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
delocalized electrons
node

 Study Notes

The two most frequent ways to synthesize conjugated dienes are dehydration of alcohols and dehydrohalogenation of
organohalides, which were introduced in the preparation of alkenes (Section 8.1). The following scheme illustrates
some of the routes to preparing a conjugated diene.

The formation of synthetic polymers from dienes such as 1,3-butadiene and isoprene is discussed in Section 14.6.
Synthetic polymers are large molecules made up of smaller repeating units. You are probably somewhat familiar with a
number of these polymers; for example, polyethylene, polypropylene, polystyrene and poly(vinyl chloride).
As the hydrogenation of 1,3-butadiene releases less than the predicted amount of energy, the energy content of 1,3-
butadiene must be lower than we might have expected. In other words, 1,3-butadiene is more stable than its formula
suggests.

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 Figure 14.1: Energy diagram for the hydrogenation of 1,3-butadiene (not to scale).
Some university-level general chemistry courses do not introduce the subject of molecular orbitals. If you have taken
such a course, or forgotten what is meant by the term “molecular orbital,” combine a review of Section 1.11 with your
study of this section.

1,3-Dienes
Conjugated double bonds are separated by a single bond. 1,3-dienes are an excellent example of a conjugated system. Each
carbon in 1,3 dienes are sp2 hybridized and therefore have one p orbital. The four p orbitals in 1,3-butadiene overlap to
form a conjugated system.

Conjugated vs. Non-conjugated Dienes

Conjugated dienes are two double bonds separated by a single bond

Non-conjugated (Isolated) dienes are two double bonds are separated by more than one single bond.

When using electrostatic potential maps, it is observed that the pi electron density overlap is closer together and
delocalized in conjugated dienes, while in non- conjugated dienes the pi electron density is located differently across the
molecule. Since having more electron density delocalized makes the molecule more stable conjugated dienes are more
stable than non-conjugated

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For example in 1,3-butadiene the carbons with the single bond are sp2 hybridized unlike in non-conjugated dienes where
the carbons with single bonds are sp3 hybridized. This difference in hybridization shows that the conjugated dienes have
more 's' character and draw in more of the pi electrons, thus making the single bond stronger and shorter than an ordinary
alkane C-C bond (1.54Å).

Stability of Conjugated Dienes

Conjugated dienes are more stable than non-conjugated dienes (both isolated and cumulated) due to factors such as
delocalization of charge through resonance and hybridization energy. This is all due to the positioning of the pi orbitals and
ability for overlap to occur to strengthen the single bond between the two double bonds.
The resonance structure shown below gives a good understanding of how the charge is delocalized across the four carbons
in this conjugated diene. This delocalization of charges stablizes the conjugated diene:

Along with resonance, hybridization energy effect the stability of the compound. For example in 1,3-butadiene the carbons
with the single bond are sp2 hybridized unlike in non-conjugated dienes where the carbons with single bonds are sp3
hybridized. This difference in hybridization shows that the conjugated dienes have more 's' character and draw in more of
the pi electrons, thus making the single bond stronger and shorter than an ordinary alkane C-C bond (1.54Å).

Another useful resource to consider are the heats of hydrogenation of different arrangements of double bonds. Since the
higher the heat of hydrogenation the less stable the compound, it is shown below that conjugated dienes (~54 kcal) have a
lower heat of hydrogenation than their isolated (~60 kcal) and cumulated diene (~70 kcal) counterparts.
Here is an energy diagram comparing different types of bonds with their heats of hydrogenation to show relative stability
of each molecule:

The stabilization of dienes by conjugation is less dramatic than the aromatic stabilization of benzene. Nevertheless, similar
resonance and molecular orbital descriptions of conjugation may be written.

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Molecular Orbitals of 1,3 Dienes
A molecular orbital model for 1,3-butadiene is shown below. Note that the lobes of the four p-orbital components in each
pi-orbital are colored differently and carry a plus or minus sign. This distinction refers to different phases, defined by the
mathematical wave equations for such orbitals. Regions in which adjacent orbital lobes undergo a phase change are called
nodes. Orbital electron density is zero in such regions. Thus a single p-orbital has a node at the nucleus, and all the pi-
orbitals shown here have a nodal plane that is defined by the atoms of the diene. This is the only nodal surface in the
lowest energy pi-orbital, π1. Higher energy pi-orbitals have an increasing number of nodes.

Allylic Carbocation
Conjugation occurs when p orbital on three or more adjacent atoms can overlap Conjugation tends to stabilize molecules.
Allylic carbocations are a common conjugated system.

The positive charge of a carbocation is contained in a P orbital of a sp2 hybrizied carbon. This allows for overlap with
double bonds. The positive charge is more stable because it is spread over 2 carbons.

This delocalization can also explain why allylic radicals are much more stable than secondary or even tertiary radicals.

Molecular Orbitals of an Allylic Carbocation

The stability of the carbocation of propene is due to a conjugated π electron system. A "double bond" doesn't really exist.
Instead, it is a group of 3 adjacent, overlapping, non-hybridized p orbitals we call a conjugated π electron system. You
can clearly see the interactions between all three of the p orbitals from the three carbons resulting in a really stable cation.
It all comes down to where the location of the electron-deficient carbon is.
Molecular orbital descriptions can explain allylic stability in yet another way using the 2-propenyl cation.

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If we just take the π molecular orbital and not any of the s, we get three of them. π1 is bonding with no nodes, π2 is
nonbonding (In other words, the same energy as a regular p-orbital) with a node, and π3 is antibonding with 2 nodes (none
of the orbitals are interacting). The first two electrons will go into the π1 molecular orbital, regardless of whether it is a
cation, radical, or anion. If it is a radical or anion, the next electron goes into the π2 molecular orbital. The last anion
electron goes into the nonbonding orbital also. So no matter what kind of carbon center exists, no electron will ever go into
the antibonding orbital.
The Bonding orbitals are the lowest energy orbitals and are favorable, which is why they are filled first. Even though the
nonbonding orbitals can be filled, the overall energy of the system is still lower and more stable due to the filled bonding
molecular orbitals.
This figure also shows that π2 is the only molecular orbital where the electrion differs, and it is also where a single node
passes through the middle. Because of this, the charges of the molecule are mainly on the two terminal carbons and not the
middle carbon.
This molecular orbital description can also illustrate the stability of allylic carbon centers.

diagram showing how the electrons fill based on the Aufbau principle.
The π bonding orbital is lower in energy than the nonbonding p orbital. Since every carbon center shown has two electrons
in the lower energy, bonding π orbitals, the energy of each system is lowered overall (and thus more stable), regardless of
cation, radical, or anion.

Exercise
Questions
Q14.1.1
The heat of hydrogenation for allene is about 300 kJ/mol. Order a conjugated diene, a non-conjugated diene, and allene in
increasing stability.

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Solutions
S14.1.1
allene < non-conjugated diene < conjugated diene (most stable)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne Morsch (University of Illinois Springfield)

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14.6: Electrophilic Attack on Conjugated Dienes: Kinetic and Thermodynamic
Control
Objectives

After completing this section, you should be able to

1. write an equation for the addition of one or two mole equivalents of a halogen or a hydrogen halide to a
nonconjugated diene.
2. write an equation for the addition of one or two mole equivalents of a halogen or a hydrogen halide to a conjugated
diene.
3. write the mechanism for the addition of one mole equivalent of hydrogen halide to a conjugated diene, and hence
account for the formation of 1,2- and 1,4-addition products.
4. explain the stability of allylic carbocations in terms of resonance.
5. draw the resonance contributors for a given allylic carbocation.
6. predict the products formed from the reaction of a given conjugated diene with one mole equivalent of halogen or
hydrogen halide.
7. predict which of the possible 1,2- and 1,4-addition products is likely to predominate when one mole equivalent of a
hydrogen halide is reacted with a given conjugated diene.
8. use the concept of carbocation stability to explain the ratio of the products obtained when a given conjugated diene
is reacted with one mole equivalent of hydrogen halide.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
1,2-addition
1,4-addition

 Study Notes

Notice that the numbers used in the expressions 1,2-addition and 1,4-addition do not refer to the positions of the
carbon atoms in the diene molecule. Here, 1,2 indicates two neighbouring carbon atoms, while 1,4 indicates two
carbon atoms which are separated in the carbon chain by two additional carbon atoms. Thus in 1,2- and 1,4-additions
to 2,4-hexadiene, the additions actually occur at carbons 2 and 3, and 2 and 5, respectively.
The term “monoadduct” should be interpreted as meaning the product or products formed when one mole of reagent
adds to one mole of substrate. In the objectives above, this process is referred to as the addition of one mole equivalent
(or one mol equiv).
In Section 7.9 we saw that electrophilic addition to a simple alkene would follow Markovnikov’s rule, where the
stability of the carbocation intermediate would increase: primary < secondary < tertiary. With conjugated dienes the
allylic carbocation intermediately generated has different resonance forms. The following scheme represents the
mechanism for the addition of HBr to 1,3-butadiene (at 0°C). Note the resonance contributors for the allylic
carbocation intermediate and that the product resulting from the secondary cation is generated in higher yield than
from the primary cation as you might expect from our discussions until now. However, in the next section you will see
that the resulting product ratio can be drastically affected by a number of reaction conditions, including temperature.

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The reactions of 1,3-butadiene are reasonably typical of conjugated dienes. The compound undergoes the usual reactions
of alkenes, such as catalytic hydrogenation or radical and polar additions, but it does so more readily than most alkenes or
dienes that have isolated double bonds. Furthermore, the products frequently are those of 1,2 and 1,4 addition:

Formation of both 1,2- and 1,4-addition products occurs not only with halogens, but also with other electrophiles such as
the hydrogen halides. The mechanistic course of the reaction of 1,3-butadiene with hydrogen chloride is shown in Equation
13-1. The first step, as with alkenes, is formation of a carbocation. However, with 1,3-butadiene, if the proton is added to
C (but not C ), the resulting cation has a substantial delocalization energy, with the charge distributed over two carbons
1 2

(review Sections 6-5 and 6-5C if this is not clear to you). Attack of Cl as a nucleophile at one or the other of the positive
⊖

carbons yields the 1,2- or the 1,4- addition product:

An important feature of reactions in which 1,2 and 1,4 additions occur in competition with one another is that the ratio of
the products can depend on the temperature, the solvent, and also on the total time of reaction.

Exercises
Questions
Q14.2.1
Give the 1,2 and the 1,4 products of the addition of one equivalent of HBr to 1,3-hexa-diene.
Q14.2.2
Look at the previous addition reaction of HBr with a diene. Consider the transition states, predict which of them would be
the major products and which will be the minor.
Solutions
S14.2.1

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S14.2.2
The products i-iii all show a secondary cation intermediate which is more stable than primary. Therefore those would be
major products and the iv product would be the minor product.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A.
Benjamin, Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions,
"You are granted permission for individual, educational, research and non-commercial reproduction, distribution,
display and performance of this work in any format."

 Objectives

After completing this section, you should be able to

1. explain the difference between thermodynamic and kinetic control of a chemical reaction; for example, the reaction
of a conjugated diene with one equivalent of hydrogen halide.
2. draw a reaction energy diagram for a reaction which can result in both a thermodynamically controlled product and
a kinetically controlled product.
3. explain how reaction conditions can determine the product ratio in a reaction in which there is competition between
thermodynamic and kinetic control.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
kinetic control
thermodynamic control

Like non-conjugated dienes, conjugated dienes are subject to attack by electrophiles. In fact, conjugated dienes experience
relatively greater kinetic reactivity when reacted with electrophiles than non-conjugated dienes do. The reaction

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mechanism is similar to other electrophilic addition reactions to alkenes (Section 7.9). However there are two possibile
outcomes once the carbocation intermediate is formed. The allyl carbocation is stabilized by resonance structures that vary
in the position of the carbocation. This allows the bromide ion to add to either of these carbons leading to two different
products. In the kinetic product, the bromide adds on the carbon adjacent to the one that the hydrogen added to (1,2
addition). If the bromide adds to the other carbon (after drawing the resonance structure) then the 1,4 (thermodynamic)
product will form.
The reaction of one equivalent of hydrogen bromide with 1,3-butadiene gives different products under different reaction
conditions and is a classic example of the concept of thermodynamic versus kinetic control of a reaction

The ratio of products is determined by the conditions of reaction. A reaction yielding more thermodynamic product is said
to be under thermodynamic control, and likewise, a reaction that yields more kinetic product is under kinetic control.
Take a look at this energy profile diagram in Figure 14.6.1. In this scenario, the starting material A can react to form either
B (to the left) or C (to the right). The formation of the product B involves overcoming barriers with lower activation

energies, which means that it will form faster (ignoring the pre-exponential constant effects).

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 Figure 14.6.1 : Energy profile diagram for A → B (left) and A → C (right). The horizontal axis is a reaction coordinate,
and the vertical axis represents Gibbs energy. The delocalized carbocation intermediate (A) is the protonated form of 1,3-
butadiene (first step of the reaction of 1,3-butadiene with HBr).
If we keep the temperature sufficiently low, the molecules of B , which are inevitably formed faster, will probably not have
enough energy to overcome the reverse activation barrier (i.e., B → A ) to regenerate A (Table 14.6.1). The forward
reactions A ⟶ B and A ⟶ C are, under such conditions, effectively irreversible. Since the formation of B is faster, it
will predominate, and the major product formed will be B . This is known as kinetic control and B is the kinetic product.
At elevated temperatures, B is still going to be the product that is formed faster. However, it also means that all the
reactions will be reversible. This means that molecules of B can revert back to A . Since the system is no longer limited by
temperature, the system will minimize its Gibbs free energy, which is the thermodynamic criterion for chemical
equilibrium. This means that, as the most thermodynamically stable molecule, C will be predominantly formed.2 The
reaction is said to be under thermodynamic control and C is the thermodynamic product.
Table 14.6.1 : Conjugated Dienes: Kinetic vs. Thermodynamic Conditions
Kinetic or Thermodynamically 1,2-adduct (B) : 1,4-adduct (C)
Temperature Speed of Reaction
Controlled Ratio

-15 °C Kinetic Fast 70:30

0 °C Kinetic Fast 60:40

40 °C Thermodynamic Slow 15:85
60 °C Thermodynamic Slow 10:90

A simple definition is that the kinetic product is the product that is formed faster,
and the thermodynamic product is the product that is more stable. This is precisely
what is happening here. The kinetic product is 3-bromobut-1-ene, and the
thermodynamic product is 1-bromobut-2-ene (specifically, the trans isomer).

 A Warning: Not every reaction has different thermodynamic and kinetic products!

Note that not every reaction has an energy profile diagram like Figure 14.6.1, and not every reaction has different
thermodynamic and kinetic products! If the transition states leading to the formation of C (e.g., TC1, and TC2) were to
be higher in energy than that leading to B (e.g., TB1, and TB2), then B would simultaneously be both the

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 thermodynamic and kinetic product. There are plenty of reactions in which the more stable product (thermodynamic) is
also formed faster (kinetic).

The Reaction Mechanism

The first step is the protonation of one of the C=C double bonds. In butadiene (1), both double bonds are the same, so it
does not matter which one is protonated. The protonation occurs regioselectively to give the more stable carbocation (i.e.,
IB=IC in Figure 14.6.11):

The more stable cation is not only secondary, but also allylic, and therefore enjoys stabilization via resonance (or
conjugation). This is depicted in the resonance forms 2a and 2b above. This allylic carbocation, more properly denoted as
the resonance hybrid 2, has two carbons which have significant positive charge, and the bromide ion (here denoted as X ) −

can attack either carbon. Attacking the central carbon, adjacent to the site of protonation, leads to the kinetic product 3
(called the 1,2-adduct); attacking the terminal carbon, distant from the site of protonation, leads to the thermodynamic
product 4 (called the 1,4-adduct).

 A Common Mistake: Resonance Structures do not Independently Exist

There are some people who write that 3 results from attack of X on resonance form 2a, and 4 from attack of X on
− −

resonance form 2b. This is not correct! Resonance forms do not separately exist, and they are not distinct species that
rapidly interconvert. As such, one cannot speak of one single resonance form undergoing a reaction.

Now, why 4 is the thermodynamic product, and why 3 is the kinetic product for this reaction?

The thermodynamic product: trans-1-bromobut-2-ene

It is perhaps simple enough to see why 4 is more stable than 3. It has an internal, disubstituted double bond, and we know
that as a general rule of thumb, the thermodynamic stability of an alkene increases with increasing substitution. So,
compared to the terminal, monosubstituted alkene 3, 4 is more stable.

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Both the trans isomer 4 as well as the cis isomer 5 can be formed via attack of the nucleophile at the terminal carbon, and
both are disubstituted alkenes. However, the trans isomer 4 is more stable than the cis isomer 5, because there is less steric
repulsion between the two substituents on the double bond. As such, 4 is the thermodynamic product.

The kinetic product: 3-bromobut-1-ene

Several explanations may be proposed to explain the nature of the kinetic product.
The worst possible argument argues that the resonance form 2a, being an allylic secondary carbocation, is more stable than
resonance form 2b, which is an allylic primary carbocation. Therefore, resonance form 2a exists in greater relative
proportion (i.e., more molecules will look like 2a than 2b), and the nucleophile preferentially reacts with this specific
carbocation, leading to the formation of 3. However, this is incorrect, since individual resonance forms do not exist.
Moreover, such an argument suggests that we are looking for the more stable intermediate (IB or IC in Figure 14.6.1). In
fact, we should be looking for the more stable transition states (TB1, TB2, TC1, and TC2 in Figure 14.6.1). The carbocation
is an intermediate, and not a transition state.
The most common argument is since resonance form 2a is more stable than 2b, is that it contributes more towards the
resonance hybrid 2. As such, the positive charge on the internal carbon is greater than the positive charge on the terminal
carbon. The nucleophile, being negatively charged, is more strongly attracted to the more positively charged or more
electrophilic carbon, and therefore attack there occurs faster (the transition state being stabilized by greater electrostatic
interactions). That's actually a very sensible explanation; with only the data that has been presented so far, we would not be
able to disprove it, and it was indeed the accepted answer for quite a while.

Experimental Results
In 1979, Nordlanderet al. carried out a similar investigation on the addition of \(\ce{DCl}\) to a
different substrate, 1,3-pentadiene.4 This experiment was ingenious, because it was designed to
proceed via an almost symmetrical intermediate:

Resonance forms 7a and 7b are both allylic and secondary. There is a very minor difference in their stabilities arising from
the different hyperconjugative ability of C−D vs C−H bonds, but in any case, it is not very large. Therefore, if we adopt
the explanation in the previous section, one would expect there not to be any major kinetic pathway, and both 1,2- and 1,4-
addition products (8 and 9) would theoretically be formed roughly equally.

Instead, it was found that the 1,2-addition product was favored over the 1,4-addition product. For example, at −78  C in ∘

the absence of solvent, there was a roughly 75 : 25 ratio of 1,2- to 1,4-addition products. Clearly, there is a factor that
favors 1,2-addition that does not depend on the electrophilicity of the carbon being attacked! The authors attributed this
effect to an ion pair mechanism. This means that, after the double bond is protonated (deuterated in this case), the chloride
counterion remains in close proximity to the carbocation generated. Immediately following dissociation of DCl, the
chloride ion is going to be much closer to C−2 than it is to C−4, and therefore attack at C−2 is much faster. In fact,
normal electrophilic addition of HX to conjugated alkenes in polar solvents can also proceed via similar ion pair
mechanisms. This is reflected by the greater proportion of syn addition products to such substrates.7

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 The mechanism that favors 1,2-addition clearly does not depend on the
electrophilicity of the carbon being attacked.
This ion pair mechanism is a pre-exponential constant effects that is attributed to the proximity and frequency of collision
rather than a activation barrier effect.

Conclusion
The reactivity of conjugated dienes (hydrocarbons that contain two double bonds) varies depending on the location of
double bonds and temperature of the reaction.These reactions can produce both thermodynamic and kinetic products.
Isolated double bonds provide dienes with less stability thermodynamically than conjugated dienes. However, they are
more reactive kinetically in the presence of electrophiles and other reagents. This is a result of Markovnikov addition to
one of the double bonds. A carbocation is formed after a double bond is opened. This carbocation has two resonance
structures and addition can occur at either of the positive carbons.

References
1. Smith, M. B. March's Advanced Organic Chemistry, 7th ed., p 272
2. This does not mean that all of A will be converted to B ; the reaction is still an equilibrium, and equilibria always go
forward and backward. In general, the minimum system Gibbs free energy (G ) will occur at a certain proportion of
syst

A , B , and C . However, since B has the lowest Gibbs free energy, it will be formed in a greater proportion than C .

3. http://www.ochempal.org/index.php/alphabetical/a-b/14-addition/
4. J. Am. Chem. Soc. 1979, 101 (5), 1288–1289
5. Because of the larger reduced mass and lower zero-point energy, a $\ce{C-D}$ bond is stronger and therefore less
willing to donate electron density into an adjacent empty $\mathrm{p}$ orbital. This is the origin of some secondary
kinetic isotope effects; in our case, it means that 7a is marginally less stable than 7b.
6. J. Am. Chem. Soc. 1969, 91 (14), 3865–3869
7. Addition of HX to butadiene in the gas phase gives approximately a 1 : 1 ratio of 1,2- to 1,4-addition product,
suggesting that an ion pair mechanism (which would favor the 1,2-addition product) does not operate: J. Org. Chem.,
1991, 56 (2), 595–601

Practice Problems
1. Write out the products of 1,2 addition and 1,4- addition of a) HBr and Br. b) DBr to 1,3-cyclo-hexadiene. What is
unusual about the products of 1,2- and 1,4- addition of HX to unsubstituted cyclic 1,3-dienes?
2. Is the 1,2-addition product formed more rapidly at higher temperatures, even though it is the 1,4-addition product that
predominates under these conditions?
3. Why is the 1,4-addition product the thermodynamically more stable product?
4. Out of the following radical cations which one is not a reasonable resonance structure?

5. Addition of 1 equivalent of Bromine to 2,4-hexadiene at 0 degrees C gives 4,5-dibromo-2-hexene plus an isomer. Which
of the following is that isomer:
a. 5,5-dibromo-2-hexene
b. 2,5-dibromo-3-hexene
c. 2,2-dibromo-3-hexene
d. 2,3-dibromo-4-hexene
6. Which of the following will be the kinetically favored product from the depicted reaction?

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7. Addition of HBr to 2,3-dimethyl-1,3-cyclohexadiene may occur in the absence or presence of peroxides. In each case
two isomeric C8H13Br products are obtained. Which of the following is a common product from both reactions?

8. and 9.

8. The kinetically controlled product in the above reaction is:

a. 3-Chloro-1-Butene
b. 1-Chloro-2-Butene
9. For the reaction in question 8, which one is the result of 1,4-addition?
a. 3-Chloro-1-Butene
b. 1-Chloro-2-Butene

Answers to Problems
1. A) Same product for both modes of addition.

B) Both cis and trans isomers will form.

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Addition of the HX to unsubstituted cycloalka-1,3-dienes in either 1,2- or 1,4- manner gives the same product becasuse of
symmetry.
2. Yes. the Kinetic Product will still form faster but in this case there will be enough energy to form the thermodynamic
product because the thermodynamic product is still more stable.
3. The 1,4- product is more thermodynamically stable because there are two alkyl groups on each side of the double bond.
This form offers stability to the overall structure.
4. All of these isomers are viable.
5. B
6. C
7. D
8. A
9. B

Exercises
Questions
Q14.3.1
Consider the reaction with 1,3-buta-diene reacting with HCl. Propose a mechanism for the reaction.
Q14.3.2
Predict why the 1,4 adduct is the major product in this reaction compared to the 1,2.
Solutions

S14.3.1

S14.3.2
Even though the cation would prefer to be in a secondary position in the transition state, the final product is less stable with
a terminal alkene. Therefore the major product will be the 1,4 adduct.

Contributors and Attributions

Orthocresol (@chemistry StackExchange)
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Natasha Singh

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14.7: Delocalization among More than Two Pi Bonds: Extended Conjugation
and Benzene
Among the many distinctive features of benzene, its aromaticity is the major contributor to why it is so unreactive. This
section will try to clarify the theory of aromaticity and why aromaticity gives unique qualities that make these conjugated
alkenes inert to compounds such as Br2 and even hydrochloric acid. It will also go into detail about the unusually large
resonance energy due to the six conjugated carbons of benzene.

The delocalization of the p-orbital carbons on the sp2 hybridized carbons is what gives the aromatic qualities of benzene.

This diagram shows one of the molecular orbitals containing two of the delocalized electrons, which may be found
anywhere within the two "doughnuts". The other molecular orbitals are almost never drawn.
Benzene, C6H6, is a planar molecule containing a ring of six carbon atoms, each with a hydrogen atom attached.

The six carbon atoms form a perfectly regular hexagon. All of the carbon-carbon bonds have exactly the same
lengths - somewhere between single and double bonds.
There are delocalized electrons above and below the plane of the ring.
The presence of the delocalized electrons makes benzene particularly stable.

Benzene resists addition reactions because those reactions would involve breaking the delocalization and losing
that stability.
Benzene is represented by this symbol, where the circle represents the delocalized electrons, and each corner of the hexagon
has a carbon atom with a hydrogen attached.

Basic Structure of Benzene

Because of the aromaticity of benzene, the resulting molecule is planar in shape

with each C-C bond being 1.39 Å in length and each bond angle being 120°.
You might ask yourselves how it's possible to have all of the bonds to be the
same length if the ring is conjugated with both single (1.47 Å) and double (1.34
Å), but it is important to note that there are no distinct single or double bonds
within the benzene. Rather, the delocalization of the ring makes each count as
one and a half bonds between the carbons which makes sense because
experimentally we find that the actual bond length is somewhere in between a
single and double bond. Finally, there are a total of six p-orbital electrons that
form the stabilizing electron clouds above and below the aromatic ring.

Contributors
Jim Clark (Chemguide.co.uk)

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14.8: A Special Transformation of Conjugated Dienes: Diels-Alder
Cycloaddition
 Objectives

After completing this section, you should be able to

1. write an equation to represent a typical Diels-Alder reaction.
2. draw the structure of the product formed when a given conjugated diene reacts with a given dienophile in a Diels-
Alder reaction.
3. identify the diene and dienophile that must be used to prepare a given compound by a Diels-Alder reaction.
4. explain the general mechanism of the Diels-Alder reaction, without necessarily being able to describe it in detail.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
Diels-Alder cycloaddition
pericyclic reaction

 Study Notes

The Diels-Alder reaction is an example of an organic chemical reaction which does not proceed by either a polar or a
free radical pathway, but rather a pericyclic reaction.
Although we do not expect you to be able to provide a detailed account of the mechanism of this reaction, you should
learn enough about the Diels-Alder reaction to fulfil the objectives stated above. You will find it useful to contrast the
mechanism of the Diels-Alder reaction with the polar and radical mechanisms studied earlier.

The unique character of conjugated dienes manifests itself dramatically in the Diels-Alder Cycloaddition Reaction. A
cycloaddition reaction is the concerted bonding together of two independent pi-electron systems to form a new ring of
atoms. When this occurs, two pi-bonds are converted to two sigma-bonds, the simplest example being the hypothetical
combination of two ethene molecules to give cyclobutane. This does not occur under normal conditions, but the
cycloaddition of 1,3-butadiene to cyanoethene (acrylonitrile) does, and this is an example of the Diels-Alder reaction. The
following diagram illustrates two cycloadditions, and introduces several terms that are useful in discussing reactions of this
kind.

In the hypothetical ethylene dimerization on the left, each reactant molecule has a pi-bond (colored orange) occupied by
two electrons. The cycloaddition converts these pi-bonds into new sigma-bonds (colored green), and this transformation is
then designated a [2+2] cycloaddition, to enumerate the reactant pi-electrons that change their bonding location.
The Diels-Alder reaction is an important and widely used method for making six-membered rings, as shown on the right.
The reactants used in such reactions are a conjugated diene, simply referred to as the diene, and a double or triple bond
coreactant called the dienophile, because it combines with (has an affinity for) the diene. The Diels-Alder cycloaddition is
classified as a [4+2] process because the diene has four pi-electrons that shift position in the reaction and the dienophile
has two.
The Diels-Alder reaction is a single step process, so the diene component must adopt an s-cisconformation in order for the
end carbon atoms (#1 & #4) to bond simultaneously to the dienophile. For many acyclic dienes the s-trans conformer is

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more stable than the s-cis conformer (due to steric crowding of the end groups), but the two are generally in rapid
equilibrium, permitting the use of all but the most hindered dienes as reactants in Diels-Alder reactions. In its usual form,
the diene component is electron rich, and the best dienophiles are electron poor due to electron withdrawing substituents
such as CN, C=O & NO2. The initial bonding interaction reflects this electron imbalance, with the two new sigma-bonds
being formed simultaneously, but not necessarily at equal rates.

Mechanism
We end this chapter with a discussion of a type of reaction that is different from anything we have seen before. In the
Diels-Alder cycloaddition reaction, a conjugated diene reacts with an alkene to form a ring structure.

In a Diels-Alder reaction, the alkene reacting partner is referred to as the dienophile. Essentially, this process involves
overlap of the 2p orbitals on carbons 1 and 4 of the diene with 2p orbitals on the two sp2-hybridized carbons of the
dienophile. Both of these new overlaps end up forming new sigma bonds, and a new pi bond is formed between carbon 2
and 3 of the diene. Three electron pairs move at the same time, one pi bond from the diene breaks with the electrons
forming a new sigma bond with one end of the dienophile. The dienophile pi bond breaks forming a new sigma bond with
the opposite end of the diene and the last pi bond of the diene breaks forming a new pi bond between C2 and C3 of the
diene. The result is a cyclohexene molecule.
One of the most important things to understand about this process is that it is concerted – all of the electron rearrangement
takes place at once, with no carbocation intermediates.

Problems

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Answers

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Amar Patel (UCD)

 Objectives

After completing this section, you should be able to

1. determine whether or not a given compound would behave as a reactive dienophile in a Diels-Alder reaction.
2. predict the stereochemistry of the product obtained from the reaction of a given diene with a given dienophile.
3. recognize that in order to undergo a Diels-Alder reaction, a diene must be able to assume ans-cis geometry, and
determine whether or not a given diene can assume this geometry.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
dienophile
dimerization

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  Study Notes

Make sure that you understand that the s-cis and s-trans forms of a diene such as 1,3-butadiene are conformers, not
isomers. Note that some textbooks can confuse the issue further by referring to a compound such as (2Z, 4Z)-
hexadiene as cis, cis-2,4-hexadiene, and saying that the most stable form of this compound is its s-trans conformer!
In fulfilling Objective 2, above, you must recognize that the Diels-Alder reaction is stereospecific.
Finally, note reaction B in the reading shows 1,3-cyclopentadiene reacting with another molecule of 1,3-
cyclopentadiene. When the same compound acts as both diene and dienophile in a Diels-Alder reaction to couple it is a
dimerization.

The Diels-Alder reaction is enormously useful for synthetic organic chemists, not only because ring-forming reactions are
useful in general but also because in many cases two new stereocenters are formed, and the reaction is inherently
stereospecific. A cis dienophile will generate a ring with cis substitution, while a trans dienophile will generate a ring with
trans substitution:

In order for a Diels-Alder reaction to occur, the diene molecule must adopt what is called the s-cis conformation:

The s-cis conformation is higher in energy than the s-trans conformation, due to steric hindrance. For some dienes, extreme
steric hindrance causes the s-cis conformation to be highly strained, and for this reason such dienes do not readily undergo
Diels-Alder reactions.

Cyclic dienes, on the other hand, are ‘locked’ in the s-cis conformation, and are especially reactive. The result of a Diels-
Alder reaction involving a cyclic diene is a bicyclic structure:

Here, we see another element of stereopecificity: Diels-Alder reactions with cyclic dienes favor the formation of bicyclic
structures in which substituents are in the endo position.

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The endo position on a bicyclic structure refers to the position that is inside the concave shape of the larger (six-
membered) ring. As you might predict, the exo position refers to the outside position.
The rate at which a Diels-Alder reaction takes place depends on electronic as well as steric factors. A particularly rapid
Diels-Alder reaction takes place between cyclopentadiene and maleic anhydride.

We already know that cyclopentadiene is a good diene because of its inherent s-cis conformation. Maleic anhydride is also
a very good dienophile, because the electron-withdrawing effect of the carbonyl groups causes the two alkene carbons to
be electron-poor, and thus a good target for attack by the pi electrons in the diene.
In general, Diels-Alder reactions proceed fastest with electron-donating groups on the diene (eg. alkyl groups) and
electron-withdrawing groups on the dienophile.
Alkynes can also serve as dienophiles in Diels-Alder reactions:

Below are just three examples of Diels-Alder reactions that have been reported in recent years:

link

link

link
The Diels-Alder reaction is just one example of a pericyclic reaction: this is a general term that refers to concerted
rearrangements that proceed though cyclic transition states. Two well-studied intramolecular pericyclic reactions are
known as the Cope rearrangement . . .

. . .and the Claisen rearrangement (when an oxygen is involved):

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Notice that the both of these reactions require compounds in which two double bonds are separated by three single bonds.
Pericyclic reactions are rare in biological chemistry, but here is one example: the Claisen rearrangement catalyzed by
chorismate mutase in the aromatic amino acid biosynthetic pathway.

The study of pericyclic reactions is an area of physical organic chemistry that blossomed in the mid-1960s, due mainly to
the work of R.B. Woodward, Roald Hoffman, and Kenichi Fukui. The Woodward-Hoffman rules for pericyclic reactions
(and a simplified version introduced by Fukui) use molecular orbital theory to explain why some pericyclic processes take
place and others do not. A full discussion is beyond the scope of this text, but if you go on to study organic chemistry at
the advanced undergraduate or graduate level you are sure to be introduced to this fascinating area of inquiry.

Stereochemistry of the Diels-Alder reaction

We noted earlier that addition reactions of alkenes often exhibited stereoselectivity, in that the reagent elements in some
cases added syn and in other cases anti to the the plane of the double bond. Both reactants in the Diels-Alder reaction may
demonstrate stereoisomerism, and when they do it is found that the relative configurations of the reactants are preserved in
the product (the adduct). The following drawing illustrates this fact for the reaction of 1,3-butadiene with (E)-
dicyanoethene. The trans relationship of the cyano groups in the dienophile is preserved in the six-membered ring of the
adduct. Likewise, if the terminal carbons of the diene bear substituents, their relative configuration will be retained in the
adduct. Using the earlier terminology, we could say that bonding to both the diene and the dienophile is syn. An alternative
description, however, refers to the planar nature of both reactants and terms the bonding in each case to be suprafacial (i.e.
to or from the same face of each plane). This stereospecificity also confirms the synchronous nature of the 1,4-bonding that
takes place.

The essential characteristics of the Diels-Alder cycloaddition reaction may be summarized as follows:
i. The reaction always creates a new six-membered ring. When intramolecular, another ring may also be formed.
ii. The diene component must be able to assume a s-cis conformation.
iii. Electron withdrawing groups on the dienophile facilitate reaction.
iv. Electron donating groups on the diene facilitate reaction.
v. Steric hindrance at the bonding sites may inhibit or prevent reaction.
vi. The reaction is stereospecific with respect to substituent configuration in both the dienophile and the diene.
These features are illustrated by the following eight examples, one of which does not give a Diels-Alder cycloaddition.

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There is no reaction in example D because this diene cannot adopt an s-cis orientation. In examples B, C, F, G & H at least
one of the reactants is cyclic so that the product has more than one ring, but the newly formed ring is always six-
membered. In example B the the same cyclic compound acts as both the diene colored blue) and the dienophile (colored
red). The adduct has three rings, two of which are the five-membered rings present in the reactant, and the third is the new
six-membered ring (shaded light yellow). Example C has an alkyne as a dienophile (colored red), so the adduct retains a
double bond at that location. This double bond could still serve as a dienophile, but in the present case the diene is
sufficiently hindered to retard a second cycloaddition. The quinone dienophile in reaction F has two dienophilic double
bonds. However, the double bond with two methyl substituents is less reactive than the unsubstituted dienophile due in part
to the electron donating properties of the methyl groups and in part to steric hindrance. The stereospecificity of the Diels-
Alder reaction is demonstrated by examples A, E & H. In A & H the stereogenic centers lie on the dienophile, whereas in
E these centers are on the diene. In all cases the configuration of the reactant is preserved in the adduct.

Exercises
Questions
Q14.5.1
Of the following dienes, which are S-trans and which are s-cis? Of those that are s-trans, are they able to rotate to become
s-cis?

Q14.5.2
Predict the product of the following reaction.

Solutions

S14.5.1
A) s-trans, unable to rotate to become s-cis

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B) s-cis
C) s-trans, can rotate to become s-cis.
S14.5.2

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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14.9: Electrocyclic Reactions
An electrocyclic reaction is the concerted cyclization of a conjugated π-electron system by converting one π-bond to a ring
forming σ-bond. The reverse reaction may be called electrocyclic ring opening. Two examples are shown on the right. The
electrocyclic ring closure is designated by blue arrows, and the ring opening by red arrows. Once again, the number of
curved arrows that describe the bond reorganization is half the total number of electrons involved in the process.

In the first case, trans,cis,trans-2,4,6-octatriene undergoes thermal ring closure to cis-5,6-dimethyl-1,3-cyclohexadiene.

The sterospecificity of this reaction is demonstrated by closure of the isomeric trans,cis,cis-triene to trans-5,6-dimethyl-
1,3-cyclohexadiene, as noted in the second example.

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By clicking on this diagram two examples of thermal electrocyclic opening of cyclobutenes to conjugated butadienes will
be displayed. This mode of reaction is favored by relief of ring strain, and the reverse ring closure (light blue arrows) is not
normally observed. Photochemical ring closure can be effected, but the stereospecificity is opposite to that of thermal ring
opening.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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14.10: Polymerization of Conjugated Dienes: Rubber
Conjugated dienes (alkenes with two double bonds and a single bond in between) can be polymerized to form important
compounds like rubber. This takes place, in different forms, both in nature and in the laboratory. Interactions between
double bonds on multiple chains leads to cross-linkage which creates elasticity within the compound.

Polymerization of 1,3-Butadiene
For rubber compounds to be synthesized, 1,3-butadiene must be polymerized. Below is a simple illustration of how this
compound is formed into a chain. The 1,4 polymerization is much more useful to polymerization reactions.

Above, the green structures represent the base units of the polymers that are synthesized and the red represents the bonds
between these units which form these polymers. Whether the 1,3 product or the 1,4 product is formed depends on whether
the reaction is thermally or kinetically controlled.

Synthetic Rubber
The most important synthetic rubber is Neoprene which is produced by the polymerization of 2-chloro-1,3-butadiene.

In this illustration, the dashed lines represent repetition of the same base units, so both the products and reactants are
polymers. The reaction proceeds with a mechanism similar to the Friedel-Crafts mechanism. Cross-linkage between the
chlorine atom of one chain and the double bond of another contributes to the overall elasticity of neoprene. This cross-
linkage occurs as the chains lie next to each other at random angles, and the attractions between double bonds prevent
them from sliding back and forth.

Colored molecules
The counjugated double bonds in beta-carotene produce the orange color in carrots. The conjugated double bons in
lycopene produce the red color in tomatoes.

ß carotene

lycopene

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Outside links
"Dienes," http://en.wikipedia.org/wiki/Diene
"Rubber," http://en.wikipedia.org/wiki/Rubber
"Neoprene," http://en.wikipedia.org/wiki/Neoprene

References
1. Vollhardt, Peter, and Neil E. Schore. Organic Chemistry: Structure and Function. New York: W. H. Freeman &
Company, 2007.
2. Buehr, Walter. Rubber: Natural and Synthetic. Morrow, 1964.

Problem
Draw out the mechanism for the natural synthesis of rubber from 3-methyl-3-butenyl pyrophosphate and 2-methyl-1,3-
butadiene. Show the movement of electrons with arrows.

Answer

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14.11: Electronic Spectra: Ultraviolet and Visible Spectroscopy
☰

 Objectives

After completing this section, you should be able to

1. identify the ultraviolet region of the electromagnetic spectrum which is of most use to organic chemists.
2. interpret the ultraviolet spectrum of 1,3-butadiene in terms of the molecular orbitals involved.
3. describe in general terms how the ultraviolet spectrum of a compound differs from its infrared and NMR spectra.

 Key Terms

Make certain that you can define, and use in context, the key term below.
ultraviolet (UV) spectroscopy

 Study Notes

Ultraviolet spectroscopy provides much less information about the structure of molecules than do the spectroscopic
techniques studied earlier (infrared spectroscopy, mass spectroscopy, and NMR spectroscopy). Thus, your study of this
technique will be restricted to a brief overview. You should, however, note that for an organic chemist, the most useful
ultraviolet region of the electromagnetic spectrum is that in which the radiation has a wavelength of between 200 and
400 nm.

Violet: 400 - 420 nm

Indigo: 420 - 440 nm
Blue: 440 - 490 nm
Green: 490 - 570 nm
Yellow: 570 - 585 nm
Orange: 585 - 620 nm
Red: 620 - 780 nm
When white light passes through or is reflected by a colored substance, a characteristic portion of the mixed wavelengths is
absorbed. The remaining light will then assume the complementary color to the wavelength(s) absorbed. This relationship
is demonstrated by the color wheel shown below. Here, complementary colors are diametrically opposite each other. Thus,
absorption of violet (400-440 nm) light renders a substance yellow, and absorption of 490-560 nm (green) light makes it
red. Green is unique in that it can be created by absorption close to 400 nm as well as absorption near 800 nm.

Early humans valued colored pigments, and used them for decorative purposes. Many of these were inorganic minerals,
but several important organic dyes were also known. These included the crimson pigment, kermesic acid, the blue dye,
indigo, and the yellow saffron pigment, crocetin. A rare dibromo-indigo derivative, punicin, was used to color the robes of
the royal and wealthy. The deep orange hydrocarbon carotene is widely distributed in plants, but is not sufficiently stable

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to be used as permanent pigment, other than for food coloring. A common feature of all these colored compounds,
☰
displayed below, is a system of extensively conjugated π-electrons.

The Electromagnetic Spectrum

The visible spectrum constitutes but a small part of the total radiation spectrum. Most of the radiation that surrounds us
cannot be seen, but can be detected by dedicated sensing instruments. This electromagnetic spectrum ranges from very
short wavelengths (including gamma and x-rays) to very long wavelengths (including microwaves and broadcast radio
waves). The following chart displays many of the important regions of this spectrum, and demonstrates the inverse
relationship between wavelength and frequency (shown in the top equation below the chart).

The energy associated with a given segment of the spectrum is proportional to its frequency. The bottom equation
describes this relationship, which provides the energy carried by a photon of a given wavelength of radiation.

To obtain specific frequency, wavelength and energy values use this calculator.

UV-Visible Absorption Spectra

To understand why some compounds are colored and others are not, and to determine the relationship of conjugation to
color, we must make accurate measurements of light absorption at different wavelengths in and near the visible part of the
spectrum. Commercial optical spectrometers enable such experiments to be conducted with ease, and usually survey both
the near ultraviolet and visible portions of the spectrum.
The visible region of the spectrum comprises photon energies of 36 to 72 kcal/mole, and the near ultraviolet region, out to
200 nm, extends this energy range to 143 kcal/mole. Ultraviolet radiation having wavelengths less than 200 nm is difficult
to handle, and is seldom used as a routine tool for structural analysis.

The energies noted above are sufficient to promote or excite a molecular electron to a higher energy orbital. Consequently,
absorption spectroscopy carried out in this region is sometimes called "electronic spectroscopy". A diagram showing the
various kinds of electronic excitation that may occur in organic molecules is shown on the left. Of the six transitions
outlined, only the two lowest energy ones (left-most, colored blue) are achieved by the energies available in the 200 to 800
nm spectrum. As a rule, energetically favored electron promotion will be from the highest occupied molecular orbital
(HOMO) to the lowest unoccupied molecular orbital (LUMO), and the resulting species is called an excited state.
When sample molecules are exposed to light having an energy that matches a possible electronic transition within the
molecule, some of the light energy will be absorbed as the electron is promoted to a higher energy orbital. An optical

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spectrometer records the wavelengths at which absorption occurs, together with the degree of absorption at each
☰
wavelength. The resulting spectrum is presented as a graph of absorbance (A) versus wavelength, as in the isoprene
spectrum shown below. Since isoprene is colorless, it does not absorb in the visible part of the spectrum and this region is
not displayed on the graph. Absorbance usually ranges from 0 (no absorption) to 2 (99% absorption), and is precisely
defined in context with spectrometer operation.

Electronic transitions
Let’s take as our first example the simple case of molecular hydrogen, H2. As you may recall from section 2.1A, the
molecular orbital picture for the hydrogen molecule consists of one bonding σ MO, and a higher energy antibonding σ*
MO. When the molecule is in the ground state, both electrons are paired in the lower-energy bonding orbital – this is the
Highest Occupied Molecular Orbital (HOMO). The antibonding σ* orbital, in turn, is the Lowest Unoccupied Molecular
Orbital (LUMO).

If the molecule is exposed to light of a wavelength with energy equal to ΔE, the HOMO-LUMO energy gap, this
wavelength will be absorbed and the energy used to bump one of the electrons from the HOMO to the LUMO – in other
words, from the σ to the σ* orbital. This is referred to as a σ - σ* transition. ΔE for this electronic transition is 258
kcal/mol, corresponding to light with a wavelength of 111 nm.
When a double-bonded molecule such as ethene (common name ethylene) absorbs light, it undergoes a π - π* transition.
Because π- π* energy gaps are narrower than σ - σ* gaps, ethene absorbs light at 165 nm - a longer wavelength than
molecular hydrogen.

The electronic transitions of both molecular hydrogen and ethene are too energetic to be accurately recorded by standard
UV spectrophotometers, which generally have a range of 220 – 700 nm. Where UV-vis spectroscopy becomes useful to
most organic and biological chemists is in the study of molecules with conjugated pi systems. In these groups, the energy
gap for π -π* transitions is smaller than for isolated double bonds, and thus the wavelength absorbed is longer. Molecules
or parts of molecules that absorb light strongly in the UV-vis region are called chromophores.

Next, we'll consider the 1,3-butadiene molecule. From valence orbital theory alone we might
expect that the C2-C3 bond in this molecule, because it is a sigma bond, would be able to rotate
freely.

Experimentally, however, it is observed that there is a significant barrier to rotation about the C2-C3 bond, and that the
entire molecule is planar. In addition, the C2-C3 bond is 148 pm long, shorter than a typical carbon-carbon single bond

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(about 154 pm), though longer than a typical double bond (about 134 pm).
☰
Molecular orbital theory accounts for these observations with the concept of delocalized π bonds. In this picture, the four
p atomic orbitals combine mathematically to form four pi molecular orbitals of increasing energy. Two of these - the
bonding pi orbitals - are lower in energy than the p atomic orbitals from which they are formed, while two - the
antibonding pi orbitals - are higher in energy.

The lowest energy molecular orbital, pi1, has only constructive interaction and zero nodes. Higher in energy, but still lower
than the isolated p orbitals, the pi2 orbital has one node but two constructive interactions - thus it is still a bonding orbital
overall. Looking at the two antibonding orbitals, pi3* has two nodes and one constructive interaction, while pi4* has three
nodes and zero constructive interactions.
By the aufbau principle, the four electrons from the isolated 2pz atomic orbitals are placed in the bonding pi1 and pi2
MO’s. Because pi1 includes constructive interaction between C2 and C3, there is a degree, in the 1,3-butadiene molecule,
of pi-bonding interaction between these two carbons, which accounts for its shorter length and the barrier to rotation. The
valence bond picture of 1,3-butadiene shows the two pi bonds as being isolated from one another, with each pair of pi
electrons ‘stuck’ in its own pi bond. However, molecular orbital theory predicts (accurately) that the four pi electrons are
to some extent delocalized, or ‘spread out’, over the whole pi system.

space-filling view
1,3-butadiene is the simplest example of a system of conjugated pi bonds. To be considered conjugated, two or more pi
bonds must be separated by only one single bond – in other words, there cannot be an intervening sp3-hybridized carbon,
because this would break up the overlapping system of parallel p orbitals. In the compound below, for example, the C1-C2
and C3-C4 double bonds are conjugated, while the C6-C7 double bond is isolated from the other two pi bonds by sp3-
hybridized C5.

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A very important concept to keep in mind is that there is an inherent thermodynamic stability associated with conjugation.
☰
This stability can be measured experimentally by comparing the heat of hydrogenation of two different dienes.
(Hydrogenation is a reaction type that we will learn much more about in chapter 15: essentially, it is the process of adding
a hydrogen molecule - two protons and two electrons - to a p bond). When the two conjugated double bonds of 1,3-
pentadiene are 'hydrogenated' to produce pentane, about 225 kJ is released per mole of pentane formed. Compare that to
the approximately 250 kJ/mol released when the two isolated double bonds in 1,4-pentadiene are hydrogenated, also
forming pentane.

The conjugated diene is lower in energy: in other words, it is more stable. In general, conjugated pi bonds are more stable
than isolated pi bonds.
Conjugated pi systems can involve oxygen and nitrogen atoms as well as carbon. In the metabolism of fat molecules, some
of the key reactions involve alkenes that are conjugated to carbonyl groups.

In molecules with extended pi systems, the HOMO-LUMO energy gap becomes so small that absorption occurs in the
visible rather then the UV region of the electromagnetic spectrum. Beta-carotene, with its system of 11 conjugated double
bonds, absorbs light with wavelengths in the blue region of the visible spectrum while allowing other visible wavelengths
– mainly those in the red-yellow region - to be transmitted. This is why carrots are orange.

 Exercise 2.2.1

Identify all conjugated and isolated double bonds in the structures below. For each conjugated pi system, specify the
number of overlapping p orbitals, and how many pi electrons are shared among them.

Exercise 2.2.2
Identify all isolated and conjugated pi bonds in lycopene, the red-colored compound in tomatoes. How many pi
electrons are contained in the conjugated pi system?

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Exercises
☰
Questions
Q14.7.1
What is the energy range for 300 nm to 500 nm in the ultraviolet spectrum? How does this compare to energy values from
NMR and IR spectroscopy?
Solutions

S14.7.1
E = hc/λ
E = (6.62 × 10−34 Js)(3.00 × 108 m/s)/(3.00 × 10−7 m)
E = 6.62 × 10−19 J
The range of 3.972 × 10-19 to 6.62 × 10-19 joules. This energy range is greater in energy than the in NMR and IR.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

 Objective

After completing this section, you should be able to use data from ultraviolet spectra to assist in the elucidation of
unknown molecular structures.

 Study Notes

It is important that you recognize that the ultraviolet absorption maximum of a conjugated molecule is dependent upon
the extent of conjugation in the molecule.

When a double-bonded molecule such as ethene (common name ethylene) absorbs light, it undergoes a π - π* transition.
Because π- π* energy gaps are narrower than σ - σ* gaps, ethene absorbs light at 165 nm - a longer wavelength than
molecular hydrogen.

The electronic transitions of both molecular hydrogen and ethene are too energetic to be accurately recorded by standard
UV spectrophotometers, which generally have a range of 220 – 700 nm. Where UV-vis spectroscopy becomes useful to
most organic and biological chemists is in the study of molecules with conjugated pi systems. In these groups, the energy
gap for π -π* transitions is smaller than for isolated double bonds, and thus the wavelength absorbed is longer. Molecules
or parts of molecules that absorb light strongly in the UV-vis region are called chromophores.
Let’s revisit the MO picture for 1,3-butadiene, the simplest conjugated system (see section 2.1B). Recall that we can draw
a diagram showing the four pi MO’s that result from combining the four 2pz atomic orbitals. The lower two orbitals are
bonding, while the upper two are antibonding.

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☰

Comparing this MO picture to that of ethene, our isolated pi-bond example, we see that the HOMO-LUMO energy gap is
indeed smaller for the conjugated system. 1,3-butadiene absorbs UV light with a wavelength of 217 nm.
As conjugated pi systems become larger, the energy gap for a π - π* transition becomes increasingly narrow, and the
wavelength of light absorbed correspondingly becomes longer. The absorbance due to the π - π* transition in 1,3,5-
hexatriene, for example, occurs at 258 nm, corresponding to a ΔE of 111 kcal/mol.

In molecules with extended pi systems, the HOMO-LUMO energy gap becomes so small that absorption occurs in the
visible rather then the UV region of the electromagnetic spectrum. Beta-carotene, with its system of 11 conjugated double
bonds, absorbs light with wavelengths in the blue region of the visible spectrum while allowing other visible wavelengths
– mainly those in the red-yellow region - to be transmitted. This is why carrots are orange.

The conjugated pi system in 4-methyl-3-penten-2-one gives rise to a strong UV absorbance at 236 nm due to a π - π*
transition. However, this molecule also absorbs at 314 nm. This second absorbance is due to the transition of a non-
bonding (lone pair) electron on the oxygen up to a π* antibonding MO:

This is referred to as an n - π* transition. The nonbonding (n) MO’s are higher in energy than the highest bonding p
orbitals, so the energy gap for an n - π* transition is smaller that that of a π - π* transition – and thus the n - π* peak is at a
longer wavelength. In general, n - π* transitions are weaker (less light absorbed) than those due to π - π* transitions.

Looking at UV-vis spectra

We have been talking in general terms about how molecules absorb UV and visible light – now let's look at some actual
examples of data from a UV-vis absorbance spectrophotometer. The basic setup is the same as for IR spectroscopy:
radiation with a range of wavelengths is directed through a sample of interest, and a detector records which wavelengths
were absorbed and to what extent the absorption occurred. Below is the absorbance spectrum of an important biological

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molecule called nicotinamide adenine dinucleotide, abbreviated NAD+ (we'll learn what it does in section 16.4) This
☰
compound absorbs light in the UV range due to the presence of conjugated pi-bonding systems.

You’ll notice that this UV spectrum is much simpler than the IR spectra we saw earlier: this one has only one peak,
although many molecules have more than one. Notice also that the convention in UV-vis spectroscopy is to show the
baseline at the bottom of the graph with the peaks pointing up. Wavelength values on the x-axis are generally measured in
nanometers (nm) rather than in cm-1 as is the convention in IR spectroscopy.
Peaks in UV spectra tend to be quite broad, often spanning well over 20 nm at half-maximal height. Typically, there are
λmax, which is the wavelength at maximal
two things that we look for and record from a UV-Vis spectrum.. The first is
light absorbance. As you can see, NAD has λmax, = 260 nm. We also want to record how much light is absorbed at λmax.
+

Here we use a unitless number called absorbance, abbreviated 'A'. This contains the same information as the 'percent
transmittance' number used in IR spectroscopy, just expressed in slightly different terms. To calculate absorbance at a
given wavelength, the computer in the spectrophotometer simply takes the intensity of light at that wavelength before it
passes through the sample (I0), divides this value by the intensity of the same wavelength after it passes through the
sample (I), then takes the log10 of that number:
A = log I0/I
You can see that the absorbance value at 260 nm (A260) is about 1.0 in this spectrum.

 Example 14.8.1

Express A = 1.0 in terms of percent transmittance (%T, the unit usually used in IR spectroscopy (and sometimes in
UV-vis as well).
Solution

Here is the absorbance spectrum of the common food coloring Red #3:

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☰

Here, we see that the extended system of conjugated pi bonds causes the molecule to absorb light in the visible range.
Because the λmax of 524 nm falls within the green region of the spectrum, the compound appears red to our eyes.
Now, take a look at the spectrum of another food coloring, Blue #1:

Here, maximum absorbance is at 630 nm, in the orange range of the visible spectrum, and the compound appears blue.

 Example 14.8.2
How large is the π - π* transition in 4-methyl-3-penten-2-one?
Solution

 Example 14.8.3

Which of the following molecules would you expect absorb at a longer wavelength in the UV region of the
electromagnetic spectrum? Explain your answer.

Solution

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Exercise
☰
Questions
Q14.8.1
Which of the following would show UV absorptions in the 200-300 nm range?

Solutions
S14.8.1
B and D would be in that range.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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CHAPTER OVERVIEW
15: BENZENE AND AROMATICITY: ELECTROPHILIC AROMATIC
SUBSTITUTION
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

15.1: NAMING THE BENZENES

15.2: STRUCTURE AND RESONANCE ENERGY OF BENZENE: A FIRST LOOK AT AROMATICITY
15.3: PI MOLECULAR ORBITALS OF BENZENE
15.4: SPECTRAL CHARACTERISTICS OF THE BENZENE RING
15.5: POLYCYCLIC AROMATIC HYDROCARBONS
15.6: OTHER CYCLIC POLYENES: HUCKEL 'S RULE
15.7: HUCKEL'S RULE AND CHARGED MOLECULES
15.8: SYNTHESIS OF BENZENE DERIVATIVES: ELECTROPHILIC AROMATIC SUBSTITUTION
15.9: HALOGENATION OF BENZENE: THE NEED FOR A CATALYST
15.10: NITRATION AND SULFONATION OF BENZENE
15.11: FRIEDEL-CRAFTS ALKYLATION
15.12: LIMITATIONS OF FRIEDEL-CRAFTS ALKYLATIONS
15.13: FRIEDEL-CRAFTS ALKANOYLATION (ACYLATION)

1 12/5/2021
15.1: Naming the Benzenes
 Objectives

After completing this section, you should be able to

1. draw the structure of each of the common aromatic compounds in Figure 16 (Common benzene derived
compounds with various substituents), given their IUPAC-accepted trivial names.
2. write the IUPAC-accepted trivial name for each of the compounds in Figure 16, given the appropriate Kekulé,
condensed or shorthand structure.
3. identify the ortho, meta and para positions in a monosubstituted benzene ring.
4. use the ortho/meta/para system to name simple disubstituted aromatic compounds.
5. draw the structure of a simple disubstituted aromatic compound, given its name according to the ortho/meta/para
system.
6. provide the IUPAC name of a given aromatic compound containing any number of the following substituents:
alkyl, alkenyl or alkynyl groups; halogens; nitro groups; carboxyl groups; amino groups; hydroxyl groups.
7. draw the structure of an aromatic compound containing any number of the substituents listed in Objective 6, above,
given the IUPAC name.
8. provide the IUPAC name of a given aromatic compound in which the phenyl group is regarded as a substituent.
9. draw the Kekulé, condensed or shorthand structure of an aromatic compound in which the phenyl group is regarded
as a substituent, given its IUPAC name.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
arene
benzyl group
phenyl group

 Study Notes

You should already know the names and structures of several of the hydrocarbons shown in Figure 15.1. A compound
containing a benzene ring which has one or more alkyl substituents is called an arene.
A phenyl group consists of a benzene ring with one of its hydrogens removed.

Figure 15.1.1 : Two ways of representing a phenyl group

You should memorize the structures and formulas shown in Figure 16. You will meet these compounds frequently
throughout the remainder of this course.
Note that the ortho/meta/para system cannot be used when more than two substituents are present in the benzene ring.
The “numbering system” can be used instead of the ortho/meta/para system in most cases when only two substituents
are present.

Sources of Aromatic Compounds

Initially aromatic compounds were isolated from coal tar. Coal tar, which is a distillate obtained when heating coal at 1000
o
C in the absence of air, is a source of an amazing number of aromatic compounds. Many simple aromatic compounds,
some of which includes nitrogen, oxygen, and sulfur, as well as hydrocarbons are obtained.

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 Some of the Aromatic Compounds Obtained from Coal Tar
Prior to World War II, coal tar was the only important source of aromatic hydrocarbons, but during the war the demand for
benzene and toluene, a precursor to the explosive TNT, rose so sharply that other sources had to be found. Today, most of
the benzene and almost all of the toluene produced in the United States are derived from petroleum. Although petroleum
does contain some aromatic compound, it primarily made up of alkanes of various chain lengths. Aromatic compounds are
synthesized from petroleum the by a process referred to in the petroleum industry as catalytic re-forming or hydroforming.
This involves heating a C6-C10 alkane fraction of petroleum with hydrogen in the presence of a catalyst to modify the
molecular structure of its components. Some amazing transformations take place, and the C6-C7 alkanes can be converted
to cycloalkanes, which, in turn, are converted to arenes. Benzene, and methylbenzene (toluene) are produced primarily in
this way.

Nomenclature of Mono-Substituted Benzenes

Unlike aliphatic organics, nomenclature of benzene-derived compounds can be confusing because a single aromatic
compound can have multiple possible names (such as common and systematic names) be associated with its structure.
Common names are often used in the nomenclature of aromatic compounds. IUPAC still allows for some of the more
widely used common name to be used. A partial list of these common name is shown in Figure 15.1.2 and there are
numerous others. These common names take the place of the benzene base name. Methylbenzene is commonly known
with the base name toluene, hydroxyphenol is known as phenol etc. It is very important to be able to identify these
structures as they will be utilized in the nomenclature of more complex compounds.

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 Figure 15.1.2 : Common Names for Mono-Substituted Benzenes
Mono-substituted benzene rings, with a substituent not on the list above, are named with benzene being the parent name.
These compounds are named as such: Name of the substituent + Benzene.
Br NO2
CH2CH2CH3

Bromobenzene Propylbenzene Nitrobenzene

The use of Phenyl and Benzyl in Nomenclature

If the alkyl group attached to the benzene contains seven or more carbons the compounds is named as a phenyl substituted
alkane. The name phenyl (C6H5-)is often abbreviated (Ph) and comes from the Greek word pheno which means "I bear
light". This name commemorates the fact that benzene was first isolated by Michael Faraday in 1925 from the residue left
in London street lamps which burned coal gas. If the alkyl substituent is smaller than the benzene ring (six or fewer
carbons), the compound is named as an alkyl-substituted benzene following the rules listed above.

1 CH3 Ph
CHCH2CH2CH2CH2CH2CH3
2 3 4 5 6 7 8

Phenyl group 2-Phenyloctane Phenylcycloheptane

The benzyl group (abbv. Bn), similar to the phenyl group and can be written as C6H5CH2-R, PhCH2-R, or Bn-R.
Nomenclature of benzyl group based compounds are very similar to the phenyl group compounds. For example, a chlorine
attached to a benzyl group would simply be called benzyl chloride, whereas an OH group attached to a benzyl group would
simply be called benzyl alcohol.
H2
C

Benzyl group

Nomenclature of Disubstituted Benzenes

With disubstituted benzenes there are three distinct positional isomers which can occur and must be identified in the
compounds name. Although numbering can be used to indicate the position of the two subsituents it is much more
common for the compounds to be named using prefixes. These prefixes are italicized and are often abbreviated with a
single letter. They are defined as the following:

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 ortho- (o-): 1,2- (next to each other in a benzene ring)
meta- (m): 1,3- (separated by one carbon in a benzene ring)
para- (p): 1,4- (across from each other in a benzene ring)
X
X X 1
1 1 2
X
2
2 3
3
X 4
X
ortho-Disubstituted meta-Disubstituted para-Disubstituted
(1,2) (1,3) (1,4)
Figure 15.1.2 . If any do appear then the compound is not named as a benzene but with a different parent name. These
compounds are named as such: Position prefix-Name of the substituent + Name of parent chain.

O OH CH3
Cl
OH

NO2 CH3

ortho-Chlorophenol meta-Nitrobenzoic acid para-Xylene

Figure 15.1.2 the compound is named as such: Position prefix-Names of the substituents in alphabetical order + benzene.
Remember if two of the same substituent appears then the prefix di- is used before the substituent's name.
CH2CH2CH3
Cl Br
NO2

Br
Br
ortho-Chloronitrobenzene meta-Dibromobenzene para-Bromopropylbenzene

Nomenclature of Benzenes with Three or more Substituents

When three or more substituents are present the ortho, meta, para positional prefixes become inadequate and a numbering
system for the ring must be applied. Here again it is important to check if any of the substituents are listed in Figure
15.1.2 . If a substituent from Figure 15.1.2 is present it is given the parent name in the nomenclature. Also, this

substituent is given position one in the numbering system. The other substituents are numbered such that they get the
lowest possible sum. In the compound's name the subsituents are given their position number and listed alphabetically.
Remember that di-, tri, tetra- prefixes are still used to indicate multiple of the same substituent being present but are
ignored for alphabetical listing.
OH NH2
1 1
2 CH2CH2CH3
2
3
Br 4 O 2N 5 3
4
Br

3,4-Dibromophenol 5-Nitro-2-propylaniline
Figure 15.1.2 , the benzene ring is name in the same fashion as cycloalkanes. The lowest possible number is given to the
substituents present. This is best done by arbitrarily giving a substituent position one and then numbering the rest of the
substituents. Then this process is repeated with the other substituents. Which ever iteration provides the lowest overall sum
of numbers will be used in the compound's name. The substituents are assigned a location number, listed alphabetically
and the suffix -benzene is added.

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 NO2 NO2 NO2
5 4 1
4 3 2
1 2 3
3
Br 2 Br Br 4
1
Br Br Br

1,2-Dibromo-5-nitrobenzene 1,2-Dibromo-4-nitrobenzene 3,4-Dibromo-1-nitrobenzene

This numbering provides

the lowest numbers to the
substituents

References
1. Nicolaou, K. C., & Montagnon, T. (2008). Molecules That Changed the World. KGaA, Weinheim: Wiley-VCH. p. 54
2. Pitman, V. (2004). Aromatherapy. Great Britain, UK: Nelson Thornes. p.135-136
3. Burton, G. (2000). Chemical Ideas. Bicester, Oxon: Heinemann. p.290-292
4. Vollhardt, K. P.C. & Shore, N. (2007). Organic Chemistry (5th Ed.). New York: W. H. Freeman. p. 667-669
5. Schnaubelt, K. (1999). Medical Aromatherapy. Berkeley, CA: Frog Books. p. 211-213
6. Patrick, G. L. (2004). Organic Chemistry. New York, NY: Taylor & Francis. p. 135-136
7. Talbott, S. M. (2002). A Guide to Understanding Dietary Supplements. Binghamton, NY: Haworth Press. p. 616-619
8. Lifton, R. J. (2000). The Nazi doctors. New York, NY: Basic Books. p. 255-261
9. Myers, R. L., & Myers, R. L. (2007). The 100 most important chemical compounds. Westport, CT: Greenwood
Publishing Group. p. 281-282

Exercises

 Exercise 15.1.1
OH

(True/False) The compound above contains a benzene ring and thus is aromatic.

Answer
False, this compound does not contain a benzene ring in its structure.

 Exercise 15.1.2
Benzene unusual stability is caused by how many conjugated pi bonds in its cyclic ring? ____

Answer
3

 Exercise 15.1.3

Menthol, a topical analgesic used in many ointments for the relief of pain, releases a peppermint aroma upon exposure
to the air. Based on this conclusion, can you imply that a benzene ring is present in its chemical structure? Why or why
not?

Answer
No, a substance that is fragrant does not imply a benzene ring is in its structure. See camphor example (figure 1)

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 Exercise 15.1.4
Pd/C
+ H2 ?

Answer
No reaction, benzene requires a special catalyst to be hydrogenated due to its unusual stability given by its three
conjugated pi bonds.

 Exercise 15.1.5

At normal conditions, benzene has ___ resonance structures.

Answer
2

 Exercise 15.1.6

Which of the following name(s) is/are correct for the following compound?
NH2

a) nitrohydride benzene
b) phenylamine
c) phenylamide
d) aniline
e) nitrogenhydrogen benzene
f) All of the above is correct

Answer
b, d

 Exercise 15.1.7

Convert 1,4-dimethylbenzene into its common name.

Answer
p-Xylene

 Exercise 15.1.8

TNT's common name is: ______________________________

Answer
2,4,6-trinitrotoluene

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 Exercise 15.1.9

Name the following compound using OMP nomenclature:

Cl

NO2

Answer
p-chloronitrobenzene

 Exercise 15.1.10

Draw the structure of 2,4-dinitrotoluene.

Answer
NO2
H3 C

NO2

 Exercise 15.1.11
Name the following compound:

Answer
4-phenylheptane

 Example 15.1.12

Which of the following is the correct name for the following compound?
F

Br
F

a) 3,4-difluorobenzyl bromide
b) 1,2-difluorobenzyl bromide
c) 4,5-difluorobenzyl bromide
d) 1,2-difluoroethyl bromide
e) 5,6-difluoroethyl bromide
f) 4,5-difluoroethyl bromide
Solution
a

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 Exercise 15.1.13

(True/False) Benzyl chloride can be abbreviated Bz-Cl.

Answer
False, the correct abbreviation for the benzyl group is Bn, not Bz. The correct abbreviation for Benzyl chloride is
Bn-Cl.

 Exercise 15.1.14

Benzoic Acid has what R group attached to its phenyl functional group?

Answer
COOH

 Exercise 15.1.15

(True/False) A single aromatic compound can have multiple names indicating its structure.

Answer
True. TNT, for example, has the common name 2,4,6-trinitrotoluene and its systematic name is 2-methyl-1,3,5-
trinitrobenzene.

 Exercise 15.1.16

List the corresponding positions for the OMP system (o-, m-, p-).

Answer
Ortho - 1,2 ; Meta - 1,3 ; Para - 1,4

 Exercise 15.1.17

A scientist has conducted an experiment on an unknown compound. He was able to determine that the unknown
compound contains a cyclic ring in its structure as well as an alcohol (-OH) group attached to the ring. What is the
unknown compound?
a) Cyclohexanol
b) Cyclicheptanol
c) Phenol
d) Methanol
e) Bleach
f) Cannot determine from the above information

Answer
The correct answer is f). We cannot determine what structure this is since the question does not tell us what kind of
cyclic ring the -OH group is attached on. Just as cyclohexane can be cyclic, benzene and cycloheptane can also be
cyclic.

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 Exercise 15.1.18
Which of the following statements is false for the compound, phenol?
a) Phenol is a benzene derived compound.
b) Phenol can be made by attaching an -OH group to a phenyl group.
c) Phenol is highly toxic to the body even in small doses.
d) Phenol can be used as a catalyst in the hydrogenation of benzene into cyclohexane.
e) Phenol is used as an antiseptic in minute doses.
f) Phenol is amongst one of the three common names retained in the IUPAC nomenclature.

Answer
d

 Exercise 15.1.19

State wither the following is para, meta, or ortho substituted.

O H Cl

NH2

A B C

Answer
A – meta; B – para; C – ortho

 Exercise 15.1.20
Name the following compounds.
Br Br
A) B)

O 2N NO2
Cl
C) D)
Cl
NO2

Answer
a. 1,3-Dibromobenzene
b. 1-phenyl-4-methylhexane
c. 1,4-Dichloro-2,5-dimethylbenzene
d. 2-methyl-1,3,5-trinitrobenzene. (Also known as trinitrotoluene, or TNT)

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 Exercise 15.1.21

Draw the following structures

a. p-chloroiodobenzene
b. m-bromotoluene
c. p-chloroaniline
d. 1,3,5-trimethylbenzene

Answer

I
A) C)
Cl Br

Cl

B) D)

NH2

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
David Lam
James Kabrhel (University of Wisconsin - Green Bay, Sheboygan Campus)

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15.2: Structure and Resonance Energy of Benzene: A First Look at Aromaticity
☰
Objectives
After completing this section, you should be able to
1. compare the reactivity of a typical alkene with that of benzene.
2. Use the heat of hydrogenation data to show that benzene is more stable than might be expected for
“cyclohexatriene.”
3. state the length of the carbon-carbon bonds in benzene, and compare this length with those of bonds found in other
hydrocarbons.
4. describe the geometry of the benzene molecule.
5. describe the structure of benzene in terms of resonance.
6. describe the structure of benzene in terms of molecular orbital theory.
7. draw a molecular orbital diagram for benzene.

 Key Terms

Make certain that you can define, and use in context, the key term below.
degenerate

 Study Notes

You may wish to review Sections 1.5 and 14.1 before you begin to study this section.
Note that the figure showing the molecular orbitals of benzene has two bonding (π2 and π3) and two anti-bonding (π*
and π5*) orbital pairs at the same energy levels. Orbitals with the same energy are described as degenerate orbitals.

Structure of Benzene
When benzene (C6H6) was first discovered its low hydrogen to carbon ratio (1:1) led chemists to believed it contained
double or triple bonds. Since double and triple bonds rapidly add bromine (Br2), this reactions were applied to benzene.
Surprisingly, benzene was entirely unreactive toward bromine. In addition, if benzene is forced to react with bromine
through the addition of a catalyst, it undergoes substitution reactions rather than the addition reactions that are typical of
alkenes. These experiments suggested that the six-carbon benzene core is unusually stable to chemical modification. '

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 H
☰ Br
Br2

Br
H
Cyclohexene Addition Product

H
Br2 Br

Br
H
Benzene Addition Product
(Not Formed!)

Br2 Br

Fe Catalyst
+ HBr

Benzene Substitution Product

The conceptual contradiction presented by a high degree of unsaturation (low H:C ratio) and high chemical stability for
benzene and related compounds remained an unsolved puzzle for many years. Eventually, the presently accepted structure
of benene as a hexagonal, planar ring of carbons with alternating single and double bonds was adopted, and the exceptional
chemical stability of this system was attributed to a special resonance stabilization of the conjugated cyclic triene. No
single structure provides an accurate representation of benzene as it is a combination of two structurally and energetically
equivalent resonance forms representing the continuous cyclic conjugation of the double bonds. In the past the benzene
resonance hybrid was represented by a hexagon with a circle in the center to represent the benzene's pi-electron
delocalization. This method has largely been abandoned because it does not show the pi electrons contained in benzene.
Currently, the structure of benzene is usually represented by drawing one resonance form with the understanding that it
does not completely represent the true structure of benzene.

The six-membered ring in benzene is a perfect hexagon with all carbon-carbon bonds have an identical length of 140 pm.
The 140 pm bond length is roughly in between those of a C=C double bond (134 pm) and a C-C single (154 pm) which
agrees with benzene ring being a resonance hybrid made up of 1.5 C-C bonds. Each carbon in the benzene ring is sp2
hybridized which makes all the C-C-C and H-C-C bond angles in benzene 120o and makes the overall molecule planar.

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 1.5 Bonds Each
☰ (139 pm)

120o

The High Stability of Benzene

In previous polyalkene, examples the electron delocalization described by resonance enhanced the stability of the
molecule. However, benzene's stability goes beyond this. Evidence for the enhanced thermodynamic stability of benzene
was obtained from measurements of the heat released when double bonds in a six-carbon ring are hydrogenated (hydrogen
is added catalytically) to give cyclohexane as a common product. In the following diagram cyclohexane represents a low-
energy reference point. Addition of hydrogen to cyclohexene produces cyclohexane and releases heat amounting to 28.6
kcal per mole. If we take this value to represent the energy cost of introducing one double bond into a six-carbon ring, we
would expect a cyclohexadiene to release 57.2 kcal per mole on complete hydrogenation, and 1,3,5-cyclohexatriene to
release 85.8 kcal per mole. These heats of hydrogenation would reflect the relative thermodynamic stability of the
compounds. In practice, 1,3-cyclohexadiene is slightly more stable than expected, by about 2 kcal, presumably due to
conjugation of the double bonds. Benzene, however, is an extraordinary 36 kcal/mole more stable than expected. This
sort of stability enhancement is called aromaticity and molecules with aromaticity are called aromatic compounds.
Benzene is the most common aromatic compound but there are many others. Aromatic stabilization explains benzene's
lack of reactivity compared to typical alkenes.

Atomic Orbitals of Benzene

Also, each of benzene's six carbon atoms are sp2 hybridized and have an unhybrized p orbital perpendicular to plane of the
ring. Because each of the six carbon atoms and their corresponding p orbitals are equivalent, it is impossible for them to
only overlap with one adjacent p orbital to create three defined double bonds. Instead each p orbtial overlaps equally with
both adjacent orbitals creating a cyclic overlap involving all six p orbitals. This allows the p orbitals to be delocalized in
molecular orbitals that extend all the way around the ring allowing for more overlap than would be obtained from the
linear 1,3,5-hexatriene equivalent. For this to happen, of course, the ring must be planar – otherwise the p orbitals couldn’t
overlap properly and benzene is known to be a flat molecule. An electrostatic potential map of benzene, shown below,
shows that the pi electrons are evenly distributed around the ring and that every carbon equivalent.

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☰

Each carbon in the benzene ring is sp2 hybrized with a p orbital perpendicular to the ring plane (Left)
Being planar and cyclic allows benzene's p orbitals to undergo cyclic overlap (Right)

An electrostatic potential map of benzene

The Molecular Orbitals of Benzene

A molecular orbital description of benzene provides a more satisfying and more general treatment of "aromaticity". We
know that benzene has a planar hexagonal structure in which all the carbon atoms are sp2 hybridized, and all the carbon-
carbon bonds are equal in length. As shown below, the remaining cyclic array of six p-orbitals ( one on each carbon)
overlap to generate six molecular orbitals, three bonding and three antibonding. The plus and minus signs shown in the
diagram do not represent electrostatic charge, but refer to phase signs in the equations that describe these orbitals (in the
diagram the phases are also color coded). When the phases correspond, the orbitals overlap to generate a common region
of like phase, with those orbitals having the greatest overlap (e.g. π1) being lowest in energy. The remaining carbon
valence electrons then occupy these molecular orbitals in pairs, resulting in a fully occupied (6 electrons) set of bonding
molecular orbitals. It is this completely filled set of bonding orbitals, or closed shell, that gives the benzene ring its
thermodynamic and chemical stability, just as a filled valence shell octet confers stability on the inert gases.

To better see source of the stabilizing aromaticity effect created by the cyclic p orbitals of benzene, the molecular orbitals
of 1,3,5-hexatriene must be investigated. The molecule 1,3,5-hexatriene contains six p orbitals which all overlap but in a
linear fashion. As with benzene, this overlap creates 3 stabilized bonding molecular which are completely filled with six p
electron. As expected, the conjugation creates a marked increase of stability in 1,3,5-hexatriene but not as much as in
benzene.

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☰

The main difference in stability can be seen when comparing the lowest energy molecular orbital of 1,3,5-hexatriene and
benzne: pi1. In pi1 molecular orbital of 1,3,5-hexatriene there are 5 stabilizing bonding interactions where there are 6
stabilizing bonding interactions in the pi1 of benzne. The sixth bonding interaction is made possible by benzene's p orbitals
being in a ring. Because benzene's pi1 molecular orbital has more stabilizing bonding interactions it is lower in energy than
the pi1 molecular orbital of 1,3,5-hexatriene. This gives benzene the additional aromatic stability not seen in the acyclic
1,3,5-hexatriene.

The pi1 molecular obrital of benzene (Left) has 6 stabilizing bonding interaction
where 1,3,5-hexatriene's (Right) only has 5

Exercises

 Exercise 15.2.1

1) The molecule, pyridine, is planar with bond angles of 120o. Pyridine has many other characteristics similar to
benzene. Draw a diagram showing the p orbitals in pyridine and use it to explain its similarity to benzene.

Answer
The nitrogen and each carbon in the pyridine ring is sp2 hybridized. In the bonding picture for pyridine, the
nitrogen is sp2-hybridized, with two of the three sp2 orbitals forming sigma overlaps with the sp2 orbitals of

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 neighboring carbon atoms, and the third nitrogen sp2 orbital containing the lone pair electrons. The unhybridized p
☰ orbital contains a single electron, which is part of the 6 pi-electron system delocalized around the ring. Pyridine is
most likely aromatic which gives it its planar shape and 120o bond angles.

 Exercise 15.2.2

The molecule shown, p-methylpyridine, has similar properties to benzene (flat, 120° bond angles). Draw the pi-orbitals
for this compound.

Answer

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
James Kabrhel (University of Wisconsin - Green Bay, Sheboygan Campus)

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15.3: Pi Molecular Orbitals of Benzene
Objectives
After completing this section, you should be able to
1. compare the reactivity of a typical alkene with that of benzene.
2. Use the heat of hydrogenation data to show that benzene is more stable than might be expected for
“cyclohexatriene.”
3. state the length of the carbon-carbon bonds in benzene, and compare this length with those of bonds found in other
hydrocarbons.
4. describe the geometry of the benzene molecule.
5. describe the structure of benzene in terms of resonance.
6. describe the structure of benzene in terms of molecular orbital theory.
7. draw a molecular orbital diagram for benzene.

 Key Terms

Make certain that you can define, and use in context, the key term below.
degenerate

 Study Notes

You may wish to review Sections 1.5 and 14.1 before you begin to study this section.
Note that the figure showing the molecular orbitals of benzene has two bonding (π2 and π3) and two anti-bonding (π*
and π5*) orbital pairs at the same energy levels. Orbitals with the same energy are described as degenerate orbitals.

Structure of Benzene
When benzene (C6H6) was first discovered its low hydrogen to carbon ratio (1:1) led chemists to believed it contained
double or triple bonds. Since double and triple bonds rapidly add bromine (Br2), this reactions were applied to benzene.
Surprisingly, benzene was entirely unreactive toward bromine. In addition, if benzene is forced to react with bromine
through the addition of a catalyst, it undergoes substitution reactions rather than the addition reactions that are typical of
alkenes. These experiments suggested that the six-carbon benzene core is unusually stable to chemical modification. '

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 H
Br2 Br

Br
H
Cyclohexene Addition Product

H
Br2 Br

Br
H
Benzene Addition Product
(Not Formed!)

Br2 Br

Fe Catalyst
+ HBr

Benzene Substitution Product

The conceptual contradiction presented by a high degree of unsaturation (low H:C ratio) and high chemical stability for
benzene and related compounds remained an unsolved puzzle for many years. Eventually, the presently accepted structure
of benene as a hexagonal, planar ring of carbons with alternating single and double bonds was adopted, and the exceptional
chemical stability of this system was attributed to a special resonance stabilization of the conjugated cyclic triene. No
single structure provides an accurate representation of benzene as it is a combination of two structurally and energetically
equivalent resonance forms representing the continuous cyclic conjugation of the double bonds. In the past the benzene
resonance hybrid was represented by a hexagon with a circle in the center to represent the benzene's pi-electron
delocalization. This method has largely been abandoned because it does not show the pi electrons contained in benzene.
Currently, the structure of benzene is usually represented by drawing one resonance form with the understanding that it
does not completely represent the true structure of benzene.

The six-membered ring in benzene is a perfect hexagon with all carbon-carbon bonds have an identical length of 140 pm.
The 140 pm bond length is roughly in between those of a C=C double bond (134 pm) and a C-C single (154 pm) which
agrees with benzene ring being a resonance hybrid made up of 1.5 C-C bonds. Each carbon in the benzene ring is sp2
hybridized which makes all the C-C-C and H-C-C bond angles in benzene 120o and makes the overall molecule planar.

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 1.5 Bonds Each
(139 pm)

120o

The High Stability of Benzene

In previous polyalkene, examples the electron delocalization described by resonance enhanced the stability of the
molecule. However, benzene's stability goes beyond this. Evidence for the enhanced thermodynamic stability of benzene
was obtained from measurements of the heat released when double bonds in a six-carbon ring are hydrogenated (hydrogen
is added catalytically) to give cyclohexane as a common product. In the following diagram cyclohexane represents a low-
energy reference point. Addition of hydrogen to cyclohexene produces cyclohexane and releases heat amounting to 28.6
kcal per mole. If we take this value to represent the energy cost of introducing one double bond into a six-carbon ring, we
would expect a cyclohexadiene to release 57.2 kcal per mole on complete hydrogenation, and 1,3,5-cyclohexatriene to
release 85.8 kcal per mole. These heats of hydrogenation would reflect the relative thermodynamic stability of the
compounds. In practice, 1,3-cyclohexadiene is slightly more stable than expected, by about 2 kcal, presumably due to
conjugation of the double bonds. Benzene, however, is an extraordinary 36 kcal/mole more stable than expected. This
sort of stability enhancement is called aromaticity and molecules with aromaticity are called aromatic compounds.
Benzene is the most common aromatic compound but there are many others. Aromatic stabilization explains benzene's
lack of reactivity compared to typical alkenes.

Atomic Orbitals of Benzene

Also, each of benzene's six carbon atoms are sp2 hybridized and have an unhybrized p orbital perpendicular to plane of the
ring. Because each of the six carbon atoms and their corresponding p orbitals are equivalent, it is impossible for them to
only overlap with one adjacent p orbital to create three defined double bonds. Instead each p orbtial overlaps equally with
both adjacent orbitals creating a cyclic overlap involving all six p orbitals. This allows the p orbitals to be delocalized in
molecular orbitals that extend all the way around the ring allowing for more overlap than would be obtained from the
linear 1,3,5-hexatriene equivalent. For this to happen, of course, the ring must be planar – otherwise the p orbitals couldn’t
overlap properly and benzene is known to be a flat molecule. An electrostatic potential map of benzene, shown below,
shows that the pi electrons are evenly distributed around the ring and that every carbon equivalent.

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 Each carbon in the benzene ring is sp2 hybrized with a p orbital perpendicular to the ring plane (Left)
Being planar and cyclic allows benzene's p orbitals to undergo cyclic overlap (Right)

An electrostatic potential map of benzene

The Molecular Orbitals of Benzene

A molecular orbital description of benzene provides a more satisfying and more general treatment of "aromaticity". We
know that benzene has a planar hexagonal structure in which all the carbon atoms are sp2 hybridized, and all the carbon-
carbon bonds are equal in length. As shown below, the remaining cyclic array of six p-orbitals ( one on each carbon)
overlap to generate six molecular orbitals, three bonding and three antibonding. The plus and minus signs shown in the
diagram do not represent electrostatic charge, but refer to phase signs in the equations that describe these orbitals (in the
diagram the phases are also color coded). When the phases correspond, the orbitals overlap to generate a common region
of like phase, with those orbitals having the greatest overlap (e.g. π1) being lowest in energy. The remaining carbon
valence electrons then occupy these molecular orbitals in pairs, resulting in a fully occupied (6 electrons) set of bonding
molecular orbitals. It is this completely filled set of bonding orbitals, or closed shell, that gives the benzene ring its
thermodynamic and chemical stability, just as a filled valence shell octet confers stability on the inert gases.

To better see source of the stabilizing aromaticity effect created by the cyclic p orbitals of benzene, the molecular orbitals
of 1,3,5-hexatriene must be investigated. The molecule 1,3,5-hexatriene contains six p orbitals which all overlap but in a
linear fashion. As with benzene, this overlap creates 3 stabilized bonding molecular which are completely filled with six p
electron. As expected, the conjugation creates a marked increase of stability in 1,3,5-hexatriene but not as much as in
benzene.

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The main difference in stability can be seen when comparing the lowest energy molecular orbital of 1,3,5-hexatriene and
benzne: pi1. In pi1 molecular orbital of 1,3,5-hexatriene there are 5 stabilizing bonding interactions where there are 6
stabilizing bonding interactions in the pi1 of benzne. The sixth bonding interaction is made possible by benzene's p orbitals
being in a ring. Because benzene's pi1 molecular orbital has more stabilizing bonding interactions it is lower in energy than
the pi1 molecular orbital of 1,3,5-hexatriene. This gives benzene the additional aromatic stability not seen in the acyclic
1,3,5-hexatriene.

The pi1 molecular obrital of benzene (Left) has 6 stabilizing bonding interaction
where 1,3,5-hexatriene's (Right) only has 5

Exercises

 Exercise 15.3.1

1) The molecule, pyridine, is planar with bond angles of 120o. Pyridine has many other characteristics similar to
benzene. Draw a diagram showing the p orbitals in pyridine and use it to explain its similarity to benzene.

Answer
The nitrogen and each carbon in the pyridine ring is sp2 hybridized. In the bonding picture for pyridine, the
nitrogen is sp2-hybridized, with two of the three sp2 orbitals forming sigma overlaps with the sp2 orbitals of

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 neighboring carbon atoms, and the third nitrogen sp2 orbital containing the lone pair electrons. The unhybridized p
orbital contains a single electron, which is part of the 6 pi-electron system delocalized around the ring. Pyridine is
most likely aromatic which gives it its planar shape and 120o bond angles.

 Exercise 15.3.2

The molecule shown, p-methylpyridine, has similar properties to benzene (flat, 120° bond angles). Draw the pi-orbitals
for this compound.

Answer

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
James Kabrhel (University of Wisconsin - Green Bay, Sheboygan Campus)

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15.4: Spectral Characteristics of the Benzene Ring
Objectives
After completing this section, you should be able to
1. determine whether an unknown compound contains an aromatic ring by inspection of its infrared spectrum, given a
table of characteristic infrared absorptions.
2. state the approximate chemical shift of aryl protons in a proton NMR spectrum.
3. explain why signals resulting from the presence of aryl protons are found downfield from those caused by vinylic
protons in a proton NMR spectrum.
4. propose possible structures for an unknown aromatic compound, given its proton NMR spectrum, other
spectroscopic data (such as a 13C NMR or infrared spectrum), or both.

 Key Terms

Make certain that you can define, and use in context, the key term below.
ring current

 Study Notes

It is not necessary that you memorize detailed spectroscopic data. In the laboratory, on assignments and when writing
examinations, you will be provided with a table of characteristic infrared absorptions to assist you in interpreting
infrared spectra.
The important points to note about the proton NMR of aromatic compounds are the approximate chemical shifts of
such protons and the complex splitting pattern that is sometimes observed. You are advised not to spend too long
trying to understand why the signal for an aryl proton is found downfield from the signal for a vinylic proton. In
general, we want you to be able to interpret NMR spectra, and leave the underlying theory for subsequent chemistry
courses.

The chemical shifts of aromatic protons

Some protons resonate much further downfield than can be accounted for simply by the deshielding effect of nearby
electronegative atoms. Vinylic protons (those directly bonded to an alkene carbon) and aromatic (benzylic) protons are
dramatic examples.

We'll consider the aromatic proton first. Recall that in benzene and many other aromatic structures, a sextet of p electrons
is delocalized around the ring. When the molecule is exposed to B0, these p electrons begin to circulate in a ring current,

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generating their own induced magnetic field that opposes B0. In this case, however, the induced field of the p electrons
does not shield the benzylic protons from B0 as you might expect– rather, it causes the protons to experience a stronger
magnetic field in the direction of B0 – in other words, it adds to B0 rather than subtracting from it.
To understand how this happens, we need to understand the concept of diamagnetic anisotropy (anisotropy means `non-
uniformity`). So far, we have been picturing magnetic fields as being oriented in a uniform direction. This is only true over
a small area. If we step back and take a wider view, however, we see that the lines of force in a magnetic field are actually
anisotropic. They start in the 'north' direction, then loop around like a snake biting its own tail.
If we are outside the ring in the figure above, we feel a magnetic field pointing in a northerly direction. If we are inside the
ring, however, we feel a field pointing to the south.
In the induced field generated by the aromatic ring current, the benzylic protons are outside the ring – this means that the
induced current in this region of space is oriented in the same direction as B0.
In total, the benzylic protons are subjected to three magnetic fields: the applied field (B0) and the induced field from the
electrons pointing in one direction, and the induced field of the non-aromatic electrons pointing in the opposite (shielding)
direction. The end result is that benzylic protons, due to the anisotropy of the induced field generated by the ring current,
appear to be highly de-shielded. Their chemical shift is far downfield, in the 6.5-8 ppm region.
The presence of anisotropy effects is often used to indicate aromaticity in a molecule. An example is the nonaromatic 8 pi
electron cyclooctatetraene. In order to avoid anti-aromatic destabilization, the molecule takes a non-planar conformation
which prevents conjugation and ring currents. Consequently, the molecule's protons absorbed at 5.8 ppm which is within
the alkene region of 1H NMR.

Exercise 15.4.1

The 1H-NMR spectrum of [18] annulene has two peaks, at 8.9 ppm and -1.8 ppm (upfield of TMS!) with an
integration ratio of 2:1. Explain the unusual chemical shift of the latter peak.

Answer
The molecule contains two groups of equivalent protons: the twelve pointing to the outside of the ring, and the six
pointing into the center of the ring. The molecule is aromatic, as evidenced by the chemical shift of the ‘outside’
protons’ (and the fact that there are 18 pelectrons, a Hückel number). The inside protons are shielded by the
induced field of the aromatic ring current, because inside the ring this field points in the opposite direction of B0.
This is the source of the unusually low (negative relative to TMS) chemical shift for these protons.

Characteristic 1H NMR Absorptions of Aromatic Compounds

Protons directly attached to an aromatic ring, commonly called aryl protons, show up about 6.5-8.0 PPM. This range is
typically called the aromatic region of an 1H NMR spectrum. Protons on carbons directly bonded to an aromatic ring,
called benzylic protons, show up about 2.0-3.0 PPM.

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 '

For the 1H NMR spectrum of p-bromotoluene, the absorption for the benzylic protons appears as a strong singlet at 2.28
ppm. Due to the molecule's symmetry, the aryl protons appear as two doublets at 6.96 & 7.29 ppm.

Characteristic 13C NMR Absorptions of Aromatic Compounds

Carbons in an aromatic ring absorb in the range of 120-150 ppm in a 13C NMR spectrum. This is virtually the same range
as nonaromatic alkenes (110-150 ppm) so peaks in this region are not definitive proof of a molecule's aromaticity.
Due to the decoupling in 13C NMR, the number of absorptions due to aromatic carbons can easily be observed. This can be
used to determine the relative positions (ortho, meta, or para) for di-substituted benzenes. Peak assignments can be
simplified by noting that 13C peaks tend to be larger if two carbons contribute to the absorption.

Symmetrical Di-substituted Benzenes

Benzenes substituted with two identical groups have a relatively high amount of symmetry. In all three configurations,
there is a plane of symmetry which reduces the number of distinct aryl carbon absorptions to less than six. The ortho
configuration has a plane of symmetry which mirrors each carbon in the benzene ring causing only three 13C aryl

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absorptions to occur. The meta configuration's plane of symmetry mirrors two carbons of the benzene ring allowing for
four aryl absorptions to occur. The para configuration actually has two planes of symmetry (one vertical and one
horizontal on the structure below) through the benzene ring, which only allows two distinct aryl absorptions to occur.

Asymmetrical Di-substituted Benzenes

The lack of a plane of symmetry in asymmetrical di-substituted benzenes makes each carbon in the ortho and meta
configuration unique. Consequently, their 13C NMR spectra show six arene absorptions. However, the para configuration
has a plane of symmetry drawn through the two substituents which mirrors two carbons of the benzene ring causing only 4
arene absorptions to appear.

Example 15.4.1

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Charateristic IR Absorption of Benzene Derivatives
Arenes have absorption bands in the 650-900 cm−1 region due to bending of the C–H bond out of the plane of the ring. The
exact placement of these absorptions can indicate the pattern of substitution on a benzene ring. However, this is beyond the
scope of introductory organic chemistry. Arenes also possess a characteristic absorption at about 3030-3100 cm−1 as a
result of the aromatic C–H stretch. It is somewhat higher than the alkyl C–H stretch (2850–2960 cm−1), but falls in the
same region as olefinic compounds. Two bands (1500 and 1660 cm−1) caused by C=C in plane vibrations are the most
useful for characterization as they are intense and are likely observed.
In aromatic compounds, each band in the spectrum can be assigned:
C–H stretch from 3100-3000 cm-1
overtones, weak, from 2000-1665 cm-1
C–C stretch (in-ring) from 1600-1585 cm-1
C–C stretch (in-ring) from 1500-1400 cm-1
C–H "oop" from 900-675 cm-1
Note that this is at slightly higher frequency than is the –C–H stretch in alkanes. This is a very useful tool for interpreting
IR spectra. Only alkenes and aromatics show a C–H stretch slightly higher than 3000 cm-1.

Figure 6. Infrared Spectrum of Toluene

Ultraviolet Spectroscopy
The presence of conjugated π bonds makes aromatic rings detectable in a UV/Vis spectrum. Benzene primarily absorbs
through a be a π-π* transition over the range from 160-208 nm with a λ max value of about 178 nm.

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Benzene shows a less intense absorption in 230-276 nm range. These absorptions are due to vibrational fine structure often
displayed by rigid molecules such as benzene and other aromatic compounds.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Layne Morsch (University of Illinois Springfield)

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15.5: Polycyclic Aromatic Hydrocarbons
 Objectives

After completing this section, you should be able to draw the resonance contributors for polycyclic aromatic
compounds, such as naphthalene, anthracene, etc.

 Key Terms

Make certain that you can define, and use in context, the key term below.
polycyclic aromatic compounds

 Study Notes

As their name indicates, polycyclic aromatic hydrocarbons are aromatic hydrocarbons which contain more than one
benzenoid (i.e., benzene-like) ring. This section deals only with those compounds in which the benzenoid rings are
fused together; in other words, compounds in which at least one carbon-carbon bond is common to two aromatic rings.
Another type of polycyclic aromatic hydrocarbon contains two or more benzenoid rings joined by a carbon-carbon
single bond. The simplest compound of this type is biphenyl, the compound from which PCBs (polychlorinated
biphenyls) are derived.

Figure 15.3: Structures of biphenyl and a typical PCB

Polycyclic Aromatic Compounds

Hückel's 4n +2 rule for aromaticity does not only apply to mono-cyclic compounds. Benzene rings may be joined together
(fused) to give larger polycyclic aromatic compounds. A few examples are drawn below, together with the approved
numbering scheme for substituted derivatives. The peripheral carbon atoms (numbered in all but the last three examples)
are all bonded to hydrogen atoms. Unlike benzene, all the C-C bond lengths in these fused ring aromatics are not the same,
and there is some localization of the pi-electrons. The six benzene rings in coronene are fused in a planar ring; whereas the
six rings in hexahelicene are not joined in a larger ring, but assume a helical turn, due to the crowding together of the
terminal ring atoms (in the structure below, note that the top right and center right rings are not attached to one another).
This helical configuration renders the hexahelicene molecule chiral, and it has been resolved into stable enantiomers.

Figure 2: Examples of Polycyclic Aromatic Hydrocarbons (PAHs).

Probably the most well know polycyclic aromatic compound which only contains carbon is naphthalene (C10H8).
Naphthalene shares many of the same characteristic as benzene. Naphthalene is cyclic and known to be flat. Each carbon

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in naphthalene is sp2 hybridized so it is completely conjugated. The true structure of naphthalene is a combination of three
resonance hybrids.

Naphthalene

Heat of hydrogenation experiments with naphthalene shows an unusual "aromatic" stabilization energy. Also, naphthalene
prefers to react with electrophiles to give substitution products rather than the typical double bond addition products.
Br

Br2
+ HBr
Fe Catalyst

Naphthalene 1-Bromonaphthalene
Substitution Product

Every carbon in naphthalene is sp2 hybridized so there is conjugated p orbital overlap over the entire ring system. The
electrostatic potential map shows that pi electrons in naphthalene are evenly distributed making each carbon equivalent.

Naphthalene
Aromatic
10 p electrons

Lastly, naphthalene has 10 pi electrons which fulfills Hückel's rule. The importance of the 4n + 2 rule can be seen when
considering the molecular orbital diagram of naphthalene. Naphthalene has 10 p orbitals which is 4 more than benzene. In
the molecular orbital diagram of naphthalene, the 4 additional p orbitals become 2 bonding orbitals and two anti-bonding
orbitals. The two additional bonding orbitals require 4 additional pi electrons to be filled so naphthalene needs 10 pi
electrons in total to fill all of the bonding molecular orbitals.

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Polycyclic Aromatic Heterocycles
There is a wide variety of polycyclic aromatic heterocycles, many of which contain nitrogen, oxygen, or sulfur. Some of
the biologically important structures, are the nitrogen containing polycyclic aromatic heterocycles indole, quinoline,
isoquinoline, and purine which are all polycyclic aromatic heterocycles commonly found in nature. Notice that these
compound all have 10 pi electrons.

Indole, quinoline, and isoquinoline all contain a hetrocyclic ring fused to benzene. Purine is made up to two heterocyclic
rings, imidazole and pyrimidine, fused together. Quinoline is found in the antimalarial drug quinine. Indole is found in the
neurotransmitter serotonin. The purine ring structure is found in adenine and guanine, two important parts of DNA and in
the stimulant caffeine.

Exercises
Exercise 15.5.1

1) The following molecule is an isomer of naphthalene. Is it aromatic? Draw a resonance structure for it.

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2) The following molecule is adenine. It has a purine core. Of the nitrogen in the core, how many electrons are donated
into the pi system?

Answer
1) It has 10 pi electrons which follows the 4n+2 rule making it aromatic.

2) There is only one nitrogen of the core that contributes a set of lone pair electrons as 2 pi electrons (in red). All
of the other nitrogens are sp2 hybrized and contribute 1 pi electron each. In total, the core is aromatic with 10
electrons in the pi-system.

 Exercise 15.5.2

This is an isomer of naphthalene. Is it aromatic? Draw a resonance structure for it.

Answer
Yes, it is aromatic. 4n+2 pi-electrons.

 Exercise 15.5.3
The following molecule is adenine. It has a purine core. Of the nitrogen in the core, how many electrons are donated
into the pi system?

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 NH2

N
N

N N
H

Answer
There is only one nitrogen of the core that contributes to the pi-system (in red). With this one lone pair the core is
aromatic with 10 electrons in the pi-system.
NH2

N
N

N N
H

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
James Kabrhel (University of Wisconsin - Green Bay, Sheboygan Campus)
If we extend the structure of corannulene by adding similar cycles of five benzene rings, the curvature of the resulting
molecule should increase, and eventually close into a sphere of carbon atoms. The archetypical compound of this kind
(C60) has been named buckminsterfullerene because of its resemblance to the geodesic structures created by Buckminster
Fuller. It is a member of a family of similar carbon structures that are called fullerenes. These materials represent a third
class of carbon allotropes. Alternating views of the C60 fullerene structure are shown on the right, together with a soccer
ball-like representation of the 12 five and 20 six-membered rings composing its surface. Precise measurement by Atomic
Force Microscopy (AFM) has shown that the C-C bond lengths of the six-membered rings are not all equal, and depend on
whether the ring is fused to a five or six-membered beighbor. By clicking on this graphic, a model of C60 will be displayed.
Although C60 is composed of fused benzene rings its chemical reactivity resembles that of the cycloalkenes more than
benzene. Indeed, exposure to light and oxygen slowly degrade fullerenes to cage opened products. Most of the reactions
thus far reported for C60 involve addition to, rather than substitution of, the core structure. These reactions include
hydrogenation, bromination and hydroxylation. Strain introduced by the curvature of the surface may be responsible for
the enhanced reactivity of C60.
. Larger fullerenes, such as C70, C76, C82 & C84have ellipsoidal or distorted spherical structures, and fullerene-like
assemblies up to C240 have been detected. A fascinating aspect of these structures is that the space within the carbon cage
may hold atoms, ions or small molecules. Such species are called endohedral fullerenes. The cavity of C60 is relatively
small, but encapsulated helium, lithium and atomic nitrogen compounds have been observed. Larger fullerenes are found
to encapsulate lanthanide metal atoms.
Interest in the fullerenes has led to the discovery of a related group of carbon structures referred to as nanotubes. As shown
in the following illustration, nanotubes may be viewed as rolled up segments of graphite. The chief structural components
are six-membered rings, but changes in tube diameter, branching into side tubes and the capping of tube ends is
accomplished by fusion with five and seven-membered rings. Many interesting applications of these unusual structures
have been proposed.

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15.6: Other Cyclic Polyenes: Huckel 's Rule
 Objectives

After completing this section, you should be able to

1. define aromaticity in terms of the Hückel 4n + 2 rule.
2. use the Hückel 4n + 2 rule to determine whether or not a given polyunsaturated cyclic hydrocarbon should exhibit
aromatic properties.
3. describe the difference in properties between an aromatic hydrocarbon, such as benzene, and a non-aromatic
polyunsaturated cyclic hydrocarbon, such as cyclobutadiene or cyclooctatetraene.
4. draw molecular orbital diagrams for aromatic species, such as benzene, the cyclopentadienyl anion and pyridine,
and compare these diagrams with those obtained for non-aromatic species, such as cyclobutadiene and the
cyclopentadienyl cation.

 Study Notes

The following mnemonic device will help you establish the approximate energy levels for the molecular orbitals of
various organic ring systems.
Whatever the size of the ring, place one point of the ring down to the bottom. The corners of the ring, where the
carbons are located, will roughly approximate the location and pattern of the molecular orbital energy levels. Cut the
ring exactly in half. The energy levels in the top half will be anti-bonding (Ψ*) orbitals and those in the bottom will be
bonding (Ψ) orbitals. If the carbons fall directly in the centre of the ring (e.g., four-membered rings) the energy levels
there are non-bonding.
cyclopropenyl ring (three-membered ring)

cyclobutadienyl ring (four-membered ring)

cyclopentadienyl ring (five-membered ring)

In 1931, German chemist and physicist Erich Hückel proposed a theory to help determine if a planar ring molecule would
have aromatic properties. His rule states that if a cyclic, planar molecule has 4n + 2 π electrons, it is considered aromatic.
This rule would come to be known as Hückel's Rule.

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Four Criteria for Aromaticity
When deciding if a compound is aromatic, go through the following checklist. If the compound does not meet all the
following criteria, it is likely not aromatic.
1. The molecule is cyclic (a ring of atoms)
2. The molecule is planar (all atoms in the molecule lie in the same plane)
3. The molecule is fully conjugated (p orbitals at every atom in the ring)
4. The molecule has 4n+2 π electrons (n=0 or any positive integer)

Counting π Electrons?
Perhaps the toughest part of Hückel's Rule is figuring out which electrons in the compound are actually π electrons. Once
this is figured out, the rule is quite straightforward. Pi electrons lie in the p orbitals and sp2 hybridized atoms have 1 of
these p orbitals each. When looking at a C=C double bond we know that there is one sigma bond and one pi bond. The pi
bond is formed by the overlap of 1 p orbital from each carbon in the double bond. Each p orbital contains one electron so
when the two p orbitals overlap the two electrons become a pi bond and are thus called pi electrons. Because aromaticity
deals directly with double bonds and conjugation it is simpler to just count the number pi electrons in a compound. Each
double bond (π bond) always contributes 2 π electrons. Benzene has 3 double bonds, so it has 6 π electrons.

Why 4n+2 π Electrons?

According to Hückel's Molecular Orbital Theory, a compound is particularly stable if all of its bonding molecular orbitals
are filled with paired electrons. This is true of aromatic compounds, meaning they are quite stable. With aromatic
compounds, 2 electrons fill the lowest energy molecular orbital, and 4 electrons fill each subsequent energy level (the
number of subsequent energy levels is denoted by n), leaving all bonding orbitals filled and no anti-bonding orbitals
occupied. This gives a total of 4n+2 π electrons. You can see how this works with the molecular orbital diagram for the
aromatic compound, benzene, below. Benzene has 6 π electrons. Its first 2 π electrons fill the lowest energy orbital, and it
has 4 π electrons remaining. These 4 fill in the orbitals of the succeeding energy level. Notice how all of its bonding
orbitals are filled, but none of the anti-bonding orbitals have any electrons.

To apply the 4n+2 rule, first count the number of π electrons in the molecule. Then, set this number equal to 4n+2 and
solve for n. If is 0 or any positive integer (1, 2, 3,...), the rule has been met. For example, benzene has six π electrons:

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 4n + 2 = 6 (15.6.1)

4n = 4 (15.6.2)

n =1 (15.6.3)

For benzene, we find that n = 1 , which is a positive integer, so the rule is met.
With Hückel's theory we can assume that if a molecule meets the other criteria for aromaticity and also has 2, 6, 10, 14, 18
ect. pi electrons it will most likely be aromatic.

Antiaromaticity
More than 100 years ago, chemists recognized the possible existence of other conjugated cyclic polyalkenes, which at least
superficially would be expected to have properties like benzene. The most interesting of these are cyclobutadiene, whose
shape and alignment of p orbitals suggested it should have substantial electron-delocalization energies.

Cyclobutadiene
However, cyclobutadiene was found to be an extremely unstable molecules. In fact, cyclobutadiene is even more reactive
than most alkenes. The synthesis of cyclobutadiene eluded chemists for almost 100 years. As more work was done, it
became increasingly clear that the molecule, when formed in reactions, was immediately converted to something else.
Finally, cyclobutadiene was captured in an essentially rigid matrix of argon at 8K. On warming to even 35K , it dimerizes
through a Diels Alder reaction to yield a tricyclicdiene.

Due to the square ring, cyclobutadiene was expected to have some degree of destabilization associated with ring strain.
However, estimations of the strain energies, though substantial, did not account for cyclobutadiene's high degree of
instability. Also, why was it not being stabilized through cyclic conjugation in the same way as benzene. The answer can
be seen in the molecular orbitals.
We considering the molecular orbitals diagram of the analogous 1,3-butadiene, the four 2p atomic orbitals combine to form
four pi molecular orbitals of increasing energy. Two bonding pi orbitals and two antibonding pi* orbitals. The 4 pi
electrons of 1,3-butadiene completely fill the bonding molecular orbitals giving is the additional stability associated with
conjugated double bonds.

However, when placed into a ring the molecular orbitals undergo a significant change. The four p orbitals of
cyclobutadiene combine to form the following 4 molecular orbitals:

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 a bonding molecular orbital which is lower in energy than the atomic orbitals
two degenerate non-bonding molecular orbitals which are of equivalent energy to the atomic orbitals
one antibonding molecular orbital which is higher in energy
The non-bonding orbitals represent that there is no direct interaction between adjacent atoms. When adding
cyclobutadiene's 4 pi electrons to the molecular orbital diagram, the bonding orbital is filled and both non-bonding orbitals
are singly occupied. If cyclobutadiene's double bonds were delocalized, all the pi electrons would be in low energy
bonding orbitals. However, only two of the pi electrons are in bonding orbitals; the other two are non-bonding. In addition,
the molecular orbital diagram shows that two of the electrons are unpaired, a situation called a triplet state, which usually
makes organic molecules very reactive. For cyclobutadiene cyclic conjugation has made the molecule less stable. This
unexpected instability in 4n π-electron cyclic conjugated compounds is termed antiaromaticity and the compounds are
called antiaromatic.

Antiaromaticity gives cyclobutadiene some interesting structural features. Cyclobutadiene's single and double bonds have
different bond lengths, 158 pm and 135 pm respectively which give it a rectangular shape. If the double bonds were
conjugated, there would only be one average bond length, like benzene, and shape would be square. In fact,
cyclobutadiene's double bonds are not conjugated but locked into position.
Just like 4n + 2 rule with aromaticity, compounds which are flat, cyclic, have a p orbital at every member of the ring, and
4n pi electrons should be antiaromatic. Another potentially antiaromatic molecule is 1,3,5,7-cyclooctatetraene.
Cyclooctatetraene was first synthesized in 1911 by a German chemist, R. Willstatter (Nobel Prize 1915), who reported an
extraordinary thirteen-step synthesis of cyclooctatetraene from a rare alkaloid called pseudopelletierine isolated from the
bark of pomegranate trees. However, during the Second World War, the German chemist W. Reppe found that
cyclooctatetraene can be made in reasonable yields by the tetramerization of ethyne under the influence of a nickel cyanide
catalyst:

If cyclooctatetraene was flat it would have all the requirements to be antiaromatic. It is cyclic, has a p orbital in every
member of the ring, and has 8 pi electrons. When looking at the molecular orbital diagram of cyclooctatetraene we see it
shares certain characteristics in common with cyclobutadiene. Two of the molecular orbitals are degenerate non-bonding
orbitals. When the molecular orbitals are fill with cyclooctatetraene's 8 pi electrons the last two electrons are unpaired in
the two nonbonding orbitals creating a triplet state. Based off the molecular orbital diagram cyclooctatetraene should be
antiaromatic.

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However, cyclooctatetraene is easily prepared and relatively stable. Also, it undergoes addition reactions typical of
alkenes. In reality, cyclooctatetraene is not flat but has a tub-like shape. By assuming this shape, the p orbtials between
double bond are out of alignment for overlap. Because the double bonds are not conjugated, cyclooctatetraene escapes the
destabilizing effects of antiaromaticity. This makes its its pi bonds react like 'normal' alkenes. Because cyclooctatetraene is
not flat nor conjugated it is properly defined as non-aromatic. In general, if an antiaromatic compound has the ability to
form a non-planar shape it will do so to avoid destabilization by becoming non-aromatic.

Determining if a Compound is Aromatic, Antiaromatic, or Nonaromatic

To make this determination it is important to first as if the compound has the possibility of cyclic conjugation. This
requires that the compound be cyclic and have a p orbital at every atom in the ring. If the compound does not have both of
these criteria it cannot be aromatic or antiaromatic and must therefore be nonaromatic. Next the number of pi electrons in
the ring is determined to see if it follows the count of aromaticity (4n + 2) or antiaromaticity (4n). Before making the final
determination, it is vital to know the actual geometry of the molecule. Despite the number of pi electrons, a compound
cannot be aromatic or antiaromatic if its geometry is not planar to allow for p orbital overlap.

 Example 15.6.1

Cyclopentadiene Pentalene (planar) Azulene (planar) Heptalene (planar)

(planar) 8 p Electrons 10 p Electrons 12 p Electrons
4 p Electrons Antiaromatic Aromatic Antiaromatic
Nonaromatic

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 A Common Misconception

A very common misconception is that hybridization can be used to predict the geometry, or that hybridization
somehow involves an energy cost associated with 'promoting' electrons into the hybrid orbitals. This is entirely
wrong. Hybridization is always determined by geometry. You can only assign hybridization states to an atom if you
already know its geometry, based on some experimental or theoretical evidence. The geometry of the oxygen in furan
is trigonal planar and therefore the hybridization must be sp2.
The specific rule is that if you have an sp2 conjugated system, the lone pair will be involved if it makes the system
more stable. In this case, conferring Hückel 4n+2 aromaticity. For furan with two lone pairs on the oxygen atom, if we
count electrons from the carbon atoms, we have 4 (one per carbon). So adding two electrons from one of the lone pairs
will give 6 = 4(1)+2, so Hückel rule is applicable and furan is aromatic.

 Exercise 15.6.1

Using the criteria for aromaticity, determine if the following molecules are aromatic:
H
S N
N

a) b) c) d) e)

H O
N N
S
NH

f) g) h) i) j)

Answer
a) Aromatic - only 1 of S's lone pairs counts as π electrons, so there are 6 π electrons, n=1
b) Not aromatic - not fully conjugated, top C is sp3 hybridized
c) Not aromatic - top C is sp2 hybridized, but there are 4 π electrons, n=1/2
d) Aromatic - N is using its 1 p orbital for the electrons in the double bond, so its lone pair of electrons are not π
electrons, there are 6 π electrons, n=1
e) Aromatic - there are 6 π electrons, n=1
f) Not aromatic - all atoms are sp2 hybridized, but only 1 of S's lone pairs counts as π electrons, so there 8 π
electrons, n=1.5
g) Not aromatic - there are 4 π electrons, n=1/2
h) Aromatic - only 1 of N's lone pairs counts as π electrons, so there are 6 π electrons, n=1
i) Not aromatic - not fully conjugated, top C is sp3 hybridized
j) Aromatic - O is using its 1 p orbital for the elections in the double bond, so its lone pair of electrons are not π
electrons, there are 6 π electrons, n=1

 Exercise 15.6.2

To be aromatic, a molecule must be planar conjugated, and obey the 4n+2 rule. The following is the following
molecule aromatic?

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 Answer
No, it is not. It does not obey the 4n+2 rule. Also it is not planar.

References
1. Vollhardt, Peter, and Neil E. Schore. Organic Chemistry: Structure and Function. 5th ed. New York: W. H. Freeman &
Company, 2007.
2. Berson, Jerome. Chemical Creativity: Ideas from the Work of Woodward, Hückel, Meerwein, and Others. New York:
Wiley-VCH, 1999.
3. Badger, G.M. Aromatic Character and Aromaticity. London, England: Cambridge University Press, 1969.
4. Lewis, David and David Peters. Facts and Theories of Aromaticity. London, England: Macmillan Press, 1975.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Layne Morsch (University of Illinois Springfield)
bon and Geoff Hutchison from Chemistry StackExchange
James Kabrhel (University of Wisconsin - Green Bay, Sheboygan)

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15.7: Huckel's Rule and Charged Molecules
Objectives
After completing this section, you should be able to
1. use the Hückel 4n + 2 rule to explain the stability of the cyclopentadienyl anion, the cycloheptatrienyl cation and
similar species.
2. use the Hückel 4n + 2 rule to determine whether or not a given unsaturated cyclic hydrocarbon anion or cation is
aromatic.
3. draw the resonance contributors for the cyclopentadienyl anion, cation and radical, and similar species.

Aromatic Ions
As previously, noted a ring must be fully conjugated to have the potential to be aromatic. This means that every atom in
the ring must have a p orbital which can overlap with adjacent p orbitals. Until now the atoms providing the p orbitals have
been neutral sp2 hybridized carbons, however it is also possible for sp2 hybridized carbons to have a charge. There are
several examples of cationic and anionic compounds with unexpected stabilities that suggest that they are aromatic. It is
important to understand how charged carbons in these compounds will affect the determination of aromaticity.
There are two main situations which need to be considered: The conjugation of a carbocation and the conjugation of a
carbanion. A carbocation carbon is surrounded by three electron groups giving it sp2 hybridization. The remaining
unhybridized p orbital holds the carbocation's positive charge and is vacant of pi electrons. Although a carbocation is
capable of extending conjugation it does not add to the compound's pi electron count.
A carbanion carbon is surrounded by four electron groups and would normally be sp3 hybridized. However, to obtain the
stabilizing effects of conjugation, carbanion carbons can becomes sp2 hybridized putting the set of lone pair electrons into
the unhybridized p orbital. Because the carbanion's p orbital contains two electrons in the form of a set of lone pair
electrons, it increases a compound's pi electron count by 2.

C C
C C C C

2 p Electrons Total 4 p Electrons Total

The carbocation adds The carbanion adds
0 p Electrons 2 p Electrons

Cyclopentadiene Ion
One of the most well know examples of an aromatic ion is the 1,3-cyclopentadiene ion. 1,3-Cyclopentadiene is
nonaromatic due to the presence of an intervening sp3 hybridized -CH2- carbon atom which prevents pi electrons from
delocalizing about the entire ring. Also, it only has 4 pi electrons which does not follow Hückel's 4n + 2 rule. However, if a
proton is removed form the CH2 group to form the cyclopentadienyl anion, the carbon atom becomes sp2 hybridized and
the two electrons of the resulting lone pair occupy the newly produced p orbital. This increases the number of pi electrons
in the cyclopentadienyl anion to 6 which follows the 4n +2 rule. Moreover, this new p orbital overlaps with the p orbitals
already present allowing for cyclic delocalization of pi electrons about the entire ring.

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The lone pair electrons and the negative charge are conjugated about the entire ring making each carbon in the
cyclopentadienyl anion equivalent with 1/5 the negative charge. The resonance hybrid can be shown by drawing a series of
five resonance form. Also, the electrostatic potential map of the cyclopentadienyl anion show the negative charge, seen in
red/yellow is distributed over the entire ring. The fact that the red/yellow color is held in the center of the ring indicates
that the extra electrons of the ion are involved in the aromatic p-electron system.

The reason why the 4n +2 rule still works for a 5 p orbital ring system can be seen by looking the molecular orbital
diagram of the cyclopentadienyl anion. As discussed in Section 15.3, the molecular orbital diagram of a 5 p orbital system
is made up of 3 bonding MO's and 2 antibonding MO's. The 6 pi electrons gained by forming an anion is enough to
completely fill the bonding MO's in the diagram giving the cyclopentadienyl anion aromaticity.

One of the effects of the aromaticity of the cyclopentadienyl anion is that the acidity of 1,3-cyclopentadiene is unusually
strong. As previously discussed, stabilizing the conjugate base increases the acidity of the corresponding acid. In this case,
the conjugate base of 1,3-cyclopentadiene, the cyclopentadienyl anion, is stabilized through aromaticity. This makes 1,3-
cyclopentadiene one of the most acidic hydrocarbons known with a pKa of 16. This is almost 1030 times more acidic than
cyclopentane. Because of its acidity, cyclopentadiene can be deprotonated by moderately strong bases such as NaOH.

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Tropylium ion
The molecule 1,3,5-cycloheptatriene has six pi electrons but is nonaromatic due the presence of an sp3 hybridized -CH2-
group which prevents cyclic delocalization. When 1,3,5-cycloheptatriene is reacted with a reagent that can remove a
hydride ion (H:-), the 1,3,5-cycloheptatrienyl cation, which is commonly known as the tropylium cation, is formed with
unexpected ease. Despite the presence of an electron deficient carbocation, the tropylium cation, is unusually stable and
can be isolated as a salt.
Removal of a hydride from the -CH2- group in 1,3,5-cycloheptatriene creates an sp2 hybridized carbocation with a vacant p
orbital. The new p orbital allows for cyclic conjugation to occur among the seven p orbitals in the tropylium cation. The
vacant p orbital does not change the pi electron count so the tropylium cation has 6 pi electrons which obeys the 4n + 2
rule for aromaticity.

The molecular orbital diagram for the 7 p orbitals in the tropylium cation has three bonding MO's and 4 antibonding MO's.
The tropylium cation's 6 pi electrons completely fill the bonding molecular orbitals which is consistent with the tropylium
cation being aromatic and therefore unusually stable.

As predicted with aromaticity, the positive charge is completely conjugated about the entire ring giving each carbon +1/7
charge. The true resonance hybrid can be depicted by drawing a series of seven resonance form. Also, the electrostatic
potential map of the tropylium cation shows the positive charge is evenly distributed over the entire ring. The equivalency
of the carbons in the seven membered ring is experimentally supported by an 1H NMR spectrum of the tropylium cation
which contains one peak showing that all seven protons are equivalent.

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Antiaromatic Ions
In a similar fashion, cyclically conjugated ions with 4n pi electrons can be predicted to be antiaromatic and therefore
highly unstable. An excellent example is the cyclopentadienyl cation. Above, the cyclopentadienyl anion was shown to be
aromatic, however, the formation of a carbocation produces a different result. Although the vacant p orbital provided by
the carbocation allows for cyclic conjugation to occur the compound only has 4 pi electrons.

After placing these 4 pi electrons into the molecular orbital for a cyclic 5 p orbital species the bonding molecular orbitals
remain unfilled. Two of the pi electrons are unpaired in degenerate molecular orbitals creating the highly unstable triplet
state. As predicted by Hückel's Rule, the cyclopentadienyl cation has 4n pi electrons and should be anitaromatic and very
unstable.

Although there is some discussion as to whether the cyclopentadienyl cation is truly antiaromatic, there is experimental
evidence which shows it is usually unstable. In particular, the compound 2,4-cyclopentadien-1-ol is usually resistant to SN1
reactions with acid halides. The carbocation intermediate created during the mechanism of this reaction would be expected
to easily form due to the resonance stabilization provided by the two double bonds. Because the carbocation intermediate
is antiaromatic it does not form so the reaction does not occur.

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 Exercise 15.7.1

1) Are all bonds equivalent cyclopentadienyl anion? How many lines (signals) would you expect to see in a H1 and
C13 NMR spectrum?
2) The following reaction occurs readily. Propose a reason why this occurs?

3) Is the cyclopropenium ion aromatic? Use the 4n + 2 rule and the MO diagram for a 3 p orbital ring system to
explain your answer.

Answer
1) Due to the cyclopentadienyl anion being fully conjugated a protons and carbons are equivalent. Both the 1H and
13C NMR spectrum would only have one signal.

2) The addition of two electrons gives the ring system 10 pi electrons which follows the 4n+2 rule making the
dianion aromatic. When looking at the MO diagram for an 8 p orbital ring system, 10 pi electrons completely fills
the three bonding MO's and the two nonbonding MO's allowing for aromaticity.
3) The cyclopropenium ion has 2 pi electrons which follows the 4n + 2 rule when n = 0. When considering the
molecular orbital diagram for a 3 p orbital ring system the is one bonding MO and two antibonding MO's. The two
pi electrons completely fill the bonding MO allowing for aromaticity.

Exercises

 Exercise 15.7.2
Draw the resonance structures for cycloheptatriene anion. Are all bonds equivalent? How many lines (signals) would
you see in a H1 NMR? C13 NMR?

Answer

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 All protons and carbons are the same, so therefore each spectrum will only have one signal each in the proton
NMR and carbon NMR.

 Exercise 15.7.3

The following reaction occurs readily. Propose a reason why this occurs?
2-

2Na+

Answer
The ring becomes aromatic with the addition of two electrons. Thereby obeying the 4n+2 rule.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
James Kabrhel (University of Wisconsins - Green Bay, Sheboygan Campus)
Layne Morsch (University of Illinois Springfield)

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15.8: Synthesis of Benzene Derivatives: Electrophilic Aromatic Substitution
☰
Bensene contains six pi electrons which are delocalized in six p orbitals above and below the plane of the benzene ring.
The six pi electrons obey Huckel's rule so benzene is especially stable. This means that the aromatic ring want to be
retained during reactions. Because of this benzene does not undergo addition like other unsaturated hydrocarbons.

Benzene can undergo electrophilic aromatic substitution because aromaticity is maintained.

Contributors
Prof. Steven Farmer (Sonoma State University)

The General Mechanism

Step 1 (Slow)

The e- in the pi bond attacks the electrophile

One carbon gets a positive charge the other forms a C-E bond
This forms the arenium ion.
The arenium ion is conjugated but not aromatic.
Step 2 (Fast)

The LPE on a base attacks the hydrogen.

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This causes the e- in the C-H bond to form a C-C double bond and aromaticity is reformed
☰
A Detailed discussion of the Mechanism for Electrophilic Substitution Reactions of Benzene

A two-step mechanism has been proposed for these electrophilic substitution reactions. In the first, slow or rate-
determining, step the electrophile forms a sigma-bond to the benzene ring, generating a positively charged benzenonium
intermediate. In the second, fast step, a proton is removed from this intermediate, yielding a substituted benzene ring. The
following four-part illustration shows this mechanism for the bromination reaction. Also, an animated diagram may be
viewed.

Preliminary step: Formation of the strongly electrophilic bromine cation

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☰

Step 1: The electrophile forms a sigma-bond to the benzene ring, generating a positively charged
benzenonium intermediate

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☰

Step 2: A proton is removed from this intermediate, yielding a substituted benzene ring
This mechanism for electrophilic aromatic substitution should be considered in context with other mechanisms involving
carbocation intermediates. These include SN1 and E1 reactions of alkyl halides, and Brønsted acid addition reactions of
alkenes.
To summarize, when carbocation intermediates are formed one can expect them to react further by one or more of
the following modes:
1. The cation may bond to a nucleophile to give a substitution or addition product.
2. The cation may transfer a proton to a base, giving a double bond product.
3. The cation may rearrange to a more stable carbocation, and then react by mode #1 or #2.
SN1 and E1 reactions are respective examples of the first two modes of reaction. The second step of alkene addition
reactions proceeds by the first mode, and any of these three reactions may exhibit molecular rearrangement if an initial
unstable carbocation is formed. The carbocation intermediate in electrophilic aromatic substitution (the benzenonium ion)
is stabilized by charge delocalization (resonance) so it is not subject to rearrangement. In principle it could react by either
mode 1 or 2, but the energetic advantage of reforming an aromatic ring leads to exclusive reaction by mode 2 (ie. proton
loss).

Other Examples of Electophilic Aromatic Substitution

Many other substitution reactions of benzene have been observed, the five most useful are listed below (chlorination and
bromination are the most common halogenation reactions). Since the reagents and conditions employed in these reactions

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are electrophilic, these reactions are commonly referred to as Electrophilic Aromatic Substitution. The catalysts and co-
☰
reagents serve to generate the strong electrophilic species needed to effect the initial step of the substitution. The specific
electrophile believed to function in each type of reaction is listed in the right hand column.
Reaction Type Typical Equation Electrophile E(+)

+ Cl2 & heat C6H5Cl + HCl

Halogenation: C6H6
FeCl3 catalyst
——> Chlorobenzene
Cl(+) or Br(+)

+ HNO3 & heat C6H5NO2 + H2O

Nitration: C6H6
H2SO4 catalyst
——> Nitrobenzene
NO2(+)

+ H2SO4 + SO3 C6H5SO3H + H2O

Sulfonation: C6H6
& heat
——> Benzenesulfonic acid
SO3H(+)

Alkylation: + R-Cl & heat C6H5-R + HCl

Friedel-Crafts
C6H6
AlCl3 catalyst
——> An Arene
R(+)

Acylation: + RCOCl & heat C6H5COR + HCl

Friedel-Crafts
C6H6
AlCl3 catalyst
——> An Aryl Ketone
RCO(+)

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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15.9: Halogenation of Benzene: The Need for a Catalyst
Halogenation is an example of electrophillic aromatic substitution. In electrophilic aromatic substitutions, a benzene is
attacked by an electrophile which results in substition of hydrogens. However, halogens are not electrophillic enough to
break the aromaticity of benzenes, which require a catalyst to activate.

Activation of Halogen
(where X= Br or Cl, we will discuss further in detail later why other members of the halogen family Flourine and Iodine
are not used in halogenation of benzenes)

Hence, Halogen needs the help and aid of Lewis Acidic Catalysts to activate it to become a very strong electrophile.
Examples of these activated halogens are Ferric Hallides (FeX3) Aluminum Halides (AlX3) where X= Br or Cl. In the
following examples, the halogen we will look at is Bromine.
In the example of bromine, in order to make bromine electrophillic enough to react with benzene, we use the aid of an
aluminum halide such as aluminum bromide.

With aluminum bromide as a Lewis acid, we can mix Br2 with AlBr3 to give us Br+. The presence of Br+ is a much better
electrophile than Br2 alone. Bromination is acheived with the help of AlBr3 (Lewis acid catalysts) as it polarizes the Br-Br
bond. The polarization causes polarization causes the bromine atoms within the Br-Br bond to become more electrophillic.
The presence of Br+ compared to Br2 alone is a much better electrophille that can then react with benzene.

As the bromine has now become more electrophillic after activation of a catalyst, an electrophillic attack by the benzene
occurs at the terminal bromine of Br-Br-AlBr3. This allows the other bromine atom to leave with the AlBr3 as a good
leaving group, AlBr4-.

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After the electrophilic attack of bromide to the benzene, the hydrogen on the same carbon as bromine substitutes the
carbocation in which resulted from the attack. Hence it being an electrophilic aromatic SUBSTITUTION. Since the by-
product aluminum tetrabromide is a strong nucleophile, it pulls of a proton from the Hydrogen on the same carbon as
bromine.

In the end, AlBr3was not consumed by the reaction and is regenerated. It serves as our catalyst in the halogenation of
benzenes.

Dissociation Energies of Halogens and its Effect on Halogenation of Benzenes

The electrophillic bromination of benzenes is an exothermic reaction. Considering the exothermic rates of aromatic
halogenation decreasing down the periodic table in the Halogen family, Flourination is the most exothermic and Iodination
would be the least. Being so exothermic, a reaction of flourine with benzene is explosive! For iodine, electrophillic
iodination is generally endothermic, hence a reaction is often not possible. Similar to bromide, chlorination would require
the aid of an activating presence such as Alumnium Chloride or Ferric Chloride. The mechanism of this reaction is the
same as with Bromination of benzene.

Outside links
http://www.chemguide.co.uk/mechanism...ogenation.html
http://en.wikipedia.org/wiki/Electro...c_halogenation

References
1. Vollhardt, Peter, and Neil Shore. Organic Chemistry: Structure and Function. 5th Edition. New York: W.H. Freeman
and Company, 2007.

Problems
1. What reagents would you need to get the given product?

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2. What product would result from the given reagents?

3. What is the major product given the reagents below?

4. Draw the formatin of Cl+ from AlCl3 and Cl2

5. Draw the mechanism of the reaction between Cl+ and a benzene.

Solutions
1. Cl2 and AlCl3 or Cl2 and FeCl3
2. No Reaction
3.

4.

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5.

Contributors
Catherine Nguyen

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15.10: Nitration and Sulfonation of Benzene
Nitration and sulfonation of benzene are two examples of electrophilic aromatic substitution. The nitronium ion (NO2+)
and sulfur trioxide (SO3) are the electrophiles and individually react with benzene to give nitrobenzene and
benzenesulfonic acid respectively.

Nitration of Benzene
The source of the nitronium ion is through the protonation of nitric acid by sulfuric acid, which causes the loss of a water
molecule and formation of a nitronium ion.

Sulfuric Acid Activation of Nitric Acid

The first step in the nitration of benzene is to activate HNO3with sulfuric acid to produce a stronger electrophile, the
nitronium ion.

Because the nitronium ion is a good electrophile, it is attacked by benzene to produce Nitrobenzene.

Mechanism

(Resonance forms of the intermediate can be seen in the generalized electrophilic aromatic substitution)

Sulfonation of Benzene
Sulfonation is a reversible reaction that produces benzenesulfonic acid by adding sulfur trioxide and fuming sulfuric acid.
The reaction is reversed by adding hot aqueous acid to benzenesulfonic acid to produce benzene.

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Mechanism
To produce benzenesulfonic acid from benzene, fuming sulfuric acid and sulfur trioxide are added. Fuming sulfuric acid,
also refered to as oleum, is a concentrated solution of dissolved sulfur trioxide in sulfuric acid. The sulfur in sulfur trioxide
is electrophilic because the oxygens pull electrons away from it because oxygen is very electronegative. The benzene
attacks the sulfur (and subsequent proton transfers occur) to produce benzenesulfonic acid.

Reverse Sulfonation
Sulfonation of benzene is a reversible reaction. Sulfur trioxide readily reacts with water to produce sulfuric acid and heat.
Therefore, by adding heat to benzenesulfonic acid in diluted aqueous sulfuric acid the reaction is reversed.

Further Applications of Nitration and Sulfonation

Nitration is used to add nitrogen to a benzene ring, which can be used further in substitution reactions. The nitro group acts
as a ring deactivator. Having nitrogen present in a ring is very useful because it can be used as a directing group as well as
a masked amino group. The products of aromatic nitrations are very important intermediates in industrial chemistry.
Because sulfonation is a reversible reaction, it can also be used in further substitution reactions in the form of a directing
blocking group because it can be easily removed. The sulfonic group blocks the carbon from being attacked by other
substituents and after the reaction is completed it can be removed by reverse sulfonation. Benzenesulfonic acids are also
used in the synthesis of detergents, dyes, and sulfa drugs. Bezenesulfonyl Chloride is a precursor to sulfonamides, which
are used in chemotherapy.

Outside Links
Aromatic Sulfonation
Wikipedia: http://en.wikipedia.org/wiki/Aromatic_sulfonation
Video: http://www.youtube.com/watch?v=s1qJ1...eature=related
Interactive 3D Reaction: http://www.chemtube3d.com/Electrophi...20benzene.html
Aromatic Nitration
Wikipedia: http://en.wikipedia.org/wiki/Nitration
Video: http://www.youtube.com/watch?v=i7ucl...eature=related
Interactive 3D Reaction: http://www.chemtube3d.com/Electrophi...20benzene.html

Problems
1. What is/are the required reagent(s)for the following reaction:

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2. What is the product of the following reaction:

3. Why is it important that the nitration of benzene by nitric acid occurs in sulfuric acid?
4. Write a detailed mechanism for the sulfonation of benzene, including all resonance forms.
5. Draw an energy diagram for the nitration of benzene. Draw the intermediates, starting materials, and products. Label the
transition states. (For questions 1 and 2 see Electrophilic Aromatic Substitution for hints)
For other problems involving Electrophilic Aromatic Substitution and similar reactions see:
Electrophilic Aromatic Substitution
Activating and Deactivating Benzene Rings
Electrophilic Attack on Disubstituted Benzenes

Solutions
1. SO3 and H2SO4 (fuming)
2.

3. Sulfuric acid is needed in order for a good electrophile to form. Sulfuric acid protonates nitric acid to form the nitronium
ion (water molecule is lost). The nitronium ion is a very good electrophile and is open to attack by benzene. Without
sulfuric acid the reaction would not occur.
4.

5.

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References
1. Laali, Kenneth K., and Volkar J. Gettwert. “Electrophilic Nitration of Aromatics in Ionic Liquid Solvents.” The Journal
of Organic Chemistry 66 (Dec. 2000): 35-40. American Chemical Society.
2. Malhotra, Ripudaman, Subhash C. Narang, and George A. Olah. Nitration: Methods and Mechanisms. New York: VCH
Publishers, Inc., 1989.
3. Sauls, Thomas W., Walter H. Rueggeberg, and Samuel L. Norwood. “On the Mechanism of Sulfonation of the
Aromatic Nucleus and Sulfone Formation.” The Journal of Organic Chemistry 66 (1955): 455-465. American
Chemical Society.
4. Vollhardt, Peter. Organic Chemistry : Structure and Function. 5th ed. Boston: W. H. Freeman & Company, 2007.

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15.11: Friedel-Crafts Alkylation
Friedel-Crafts Alkylation
Friedel-Crafts Alkylation was first discovered by French scientist Charles Friedel and his partner, American scientist
James Crafts, in 1877. This reaction allowed for the formation of alkyl benzenes from alkyl halides, but was plagued with
unwanted supplemental activity that reduced its efficiency.

The mechanism takes place as follows:

Step one:

The first step creates a cabocation that acts as the electrophile in the reaction. This step activates the haloalkane. Secondary
and teriary halides only form the free cabocation in the step.
Step two

The second step has an electrophilic attack on the benzene that results in multiple resonance forms. The halogen reactions
with the intermediate and picks up the hydrogen to eliminate the positive charge.
Finish

The final step shown above is the results of the end of step and shows the final products.
The reactivity of haloalkanes increases as you move up the periodic table and increase polarity. This means that an RF
haloalkane is most reactive followed by RCl then RBr and finally RI. This means that the Lewis acids used as catalysts in
Friedel-Crafts Alkylation reactions tend have similar halogen combinations such as BF3, SbCl5, AlCl3, SbCl5, and AlBr3,
all of which are commonly used in these reactions.

Some limitations of Friedel-Crafts Alkylation

There are possibilities of carbocation rearrangements when you are trying to add a carbon chain greater than two carbons.
The rearrangements occur due to hydride shifts and methyl shifts. For example, the product of a Friedel-Crafts Alkylation
will show an iso rearrangement when adding a three carbon chain as a substituent. Also, the reaction will only work if the
ring you are adding a substituent to is not deactivated. For a look at substituents that activating or deactivating Benzene
Rings.
The three key limitations of Friedel-Crafts alkylation are:

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 1. Carbocation Rearrangement - Only certain alkylbenzenes can be made due to the tendency of cations to rearrange.
2. Compound Limitations - Friedel-Crafts fails when used with compounds such as nitrobenzene and other strong
deactivating systems.
3. Polyalkylation - Products of Friedel-Crafts are even more reactive than starting material. Alkyl groups produced in
Friedel-Crafts Alkylation are electron-donating substituents meaning that the products are more susceptible to
electrophilic attack than what we began with. For synthetic purposes, this is a big dissapointment.
To remedy these limitations, a new and improved reaction was devised: The Friedel-Crafts Acylation. (also known as
Friedel-Crafts Alkanoylation).

Friedel-Crafts Acylation
The goal of the reaction is the following:

The very first step involves the formation of the acylium ion which will later react with benzene:

The second step involves the attack of the acylium ion on benzene as a new electrophile to form one complex:

The third step involves the departure of the proton in order for aromaticity to return to benzene:

During the third step, AlCl4 returns to remove a proton from the benzene ring, which enables the ring to return to
aromaticity. In doing so, the original AlCl3 is regenerated for use again, along with HCl. Most importantly, we have the
first part of the final product of the reaction, which is a ketone. Thie first part of the product is the complex with aluminum
chloride as shown:

The final step involves the addition of water to liberate the final product as the acylbenzene:

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Because the acylium ion (as was shown in step one) is stabilized by resonance, no rearrangement occurs (Limitation 1).
Also, because of of the deactivation of the product, it is no longer susceptible to electrophilic attack and hence, is no longer
susceptible to electrophilic attack and hence, no longer goes into further reactions (Limitation 3). However, as not all is
perfect, Limitation 2 still prevails where Friedel-Crafts Acylation fails with strong deactivating rings.

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15.12: Limitations of Friedel-Crafts Alkylations
Friedel-Crafts Alkylation
Friedel-Crafts Alkylation was first discovered by French scientist Charles Friedel and his partner, American scientist
James Crafts, in 1877. This reaction allowed for the formation of alkyl benzenes from alkyl halides, but was plagued with
unwanted supplemental activity that reduced its efficiency.

The mechanism takes place as follows:

Step one:

The first step creates a cabocation that acts as the electrophile in the reaction. This step activates the haloalkane. Secondary
and teriary halides only form the free cabocation in the step.
Step two

The second step has an electrophilic attack on the benzene that results in multiple resonance forms. The halogen reactions
with the intermediate and picks up the hydrogen to eliminate the positive charge.
Finish

The final step shown above is the results of the end of step and shows the final products.
The reactivity of haloalkanes increases as you move up the periodic table and increase polarity. This means that an RF
haloalkane is most reactive followed by RCl then RBr and finally RI. This means that the Lewis acids used as catalysts in
Friedel-Crafts Alkylation reactions tend have similar halogen combinations such as BF3, SbCl5, AlCl3, SbCl5, and AlBr3,
all of which are commonly used in these reactions.

Some limitations of Friedel-Crafts Alkylation

There are possibilities of carbocation rearrangements when you are trying to add a carbon chain greater than two carbons.
The rearrangements occur due to hydride shifts and methyl shifts. For example, the product of a Friedel-Crafts Alkylation
will show an iso rearrangement when adding a three carbon chain as a substituent. Also, the reaction will only work if the
ring you are adding a substituent to is not deactivated. For a look at substituents that activating or deactivating Benzene
Rings.
The three key limitations of Friedel-Crafts alkylation are:

15.12.1 10/31/2021 https://chem.libretexts.org/@go/page/32484

 1. Carbocation Rearrangement - Only certain alkylbenzenes can be made due to the tendency of cations to rearrange.
2. Compound Limitations - Friedel-Crafts fails when used with compounds such as nitrobenzene and other strong
deactivating systems.
3. Polyalkylation - Products of Friedel-Crafts are even more reactive than starting material. Alkyl groups produced in
Friedel-Crafts Alkylation are electron-donating substituents meaning that the products are more susceptible to
electrophilic attack than what we began with. For synthetic purposes, this is a big dissapointment.
To remedy these limitations, a new and improved reaction was devised: The Friedel-Crafts Acylation. (also known as
Friedel-Crafts Alkanoylation).

Friedel-Crafts Acylation
The goal of the reaction is the following:

The very first step involves the formation of the acylium ion which will later react with benzene:

The second step involves the attack of the acylium ion on benzene as a new electrophile to form one complex:

The third step involves the departure of the proton in order for aromaticity to return to benzene:

During the third step, AlCl4 returns to remove a proton from the benzene ring, which enables the ring to return to
aromaticity. In doing so, the original AlCl3 is regenerated for use again, along with HCl. Most importantly, we have the
first part of the final product of the reaction, which is a ketone. Thie first part of the product is the complex with aluminum
chloride as shown:

The final step involves the addition of water to liberate the final product as the acylbenzene:

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Because the acylium ion (as was shown in step one) is stabilized by resonance, no rearrangement occurs (Limitation 1).
Also, because of of the deactivation of the product, it is no longer susceptible to electrophilic attack and hence, is no longer
susceptible to electrophilic attack and hence, no longer goes into further reactions (Limitation 3). However, as not all is
perfect, Limitation 2 still prevails where Friedel-Crafts Acylation fails with strong deactivating rings.

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15.13: Friedel-Crafts Alkanoylation (Acylation)
☰
Friedel-Crafts Alkylation
Friedel-Crafts Alkylation was first discovered by French scientist Charles Friedel and his partner, American scientist
James Crafts, in 1877. This reaction allowed for the formation of alkyl benzenes from alkyl halides, but was plagued with
unwanted supplemental activity that reduced its efficiency.

The mechanism takes place as follows:

Step one:

The first step creates a cabocation that acts as the electrophile in the reaction. This step activates the haloalkane. Secondary
and teriary halides only form the free cabocation in the step.
Step two

The second step has an electrophilic attack on the benzene that results in multiple resonance forms. The halogen reactions
with the intermediate and picks up the hydrogen to eliminate the positive charge.
Finish

The final step shown above is the results of the end of step and shows the final products.
The reactivity of haloalkanes increases as you move up the periodic table and increase polarity. This means that an RF
haloalkane is most reactive followed by RCl then RBr and finally RI. This means that the Lewis acids used as catalysts in
Friedel-Crafts Alkylation reactions tend have similar halogen combinations such as BF3, SbCl5, AlCl3, SbCl5, and AlBr3,
all of which are commonly used in these reactions.

Some limitations of Friedel-Crafts Alkylation

There are possibilities of carbocation rearrangements when you are trying to add a carbon chain greater than two carbons.
The rearrangements occur due to hydride shifts and methyl shifts. For example, the product of a Friedel-Crafts Alkylation
will show an iso rearrangement when adding a three carbon chain as a substituent. Also, the reaction will only work if the
ring you are adding a substituent to is not deactivated. For a look at substituents that activating or deactivating Benzene
Rings.
The three key limitations of Friedel-Crafts alkylation are:

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 1. Carbocation Rearrangement - Only certain alkylbenzenes can be made due to the tendency of cations to rearrange.
☰2. Compound Limitations - Friedel-Crafts fails when used with compounds such as nitrobenzene and other strong
deactivating systems.
3. Polyalkylation - Products of Friedel-Crafts are even more reactive than starting material. Alkyl groups produced in
Friedel-Crafts Alkylation are electron-donating substituents meaning that the products are more susceptible to
electrophilic attack than what we began with. For synthetic purposes, this is a big dissapointment.
To remedy these limitations, a new and improved reaction was devised: The Friedel-Crafts Acylation. (also known as
Friedel-Crafts Alkanoylation).

Friedel-Crafts Acylation
The goal of the reaction is the following:

The very first step involves the formation of the acylium ion which will later react with benzene:

The second step involves the attack of the acylium ion on benzene as a new electrophile to form one complex:

The third step involves the departure of the proton in order for aromaticity to return to benzene:

During the third step, AlCl4 returns to remove a proton from the benzene ring, which enables the ring to return to
aromaticity. In doing so, the original AlCl3 is regenerated for use again, along with HCl. Most importantly, we have the
first part of the final product of the reaction, which is a ketone. Thie first part of the product is the complex with aluminum
chloride as shown:

The final step involves the addition of water to liberate the final product as the acylbenzene:

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☰

Because the acylium ion (as was shown in step one) is stabilized by resonance, no rearrangement occurs (Limitation 1).
Also, because of of the deactivation of the product, it is no longer susceptible to electrophilic attack and hence, is no longer
susceptible to electrophilic attack and hence, no longer goes into further reactions (Limitation 3). However, as not all is
perfect, Limitation 2 still prevails where Friedel-Crafts Acylation fails with strong deactivating rings.

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CHAPTER OVERVIEW
16: ELECTROPHILIC ATTACK ON DERIVATIVES OF BENZENE:
SUBSTITUENTS CONTROL REGIOSELECTIVITY
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

16.1: ACTIVATION OR DEACTIVATION BY SUBSTITUENTS ON A BENZENE RING

16.2: DIRECTING INDUCTIVE EFFECTS OF ALKYL GROUPS
16.3: DIRECTING EFFECTS OF SUBSTITUENTS IN CONJUGATION WITH THE BENZENE RING
16.4: ELECTROPHILIC ATTACK ON DISUBSTITUTED BENZENES
16.5: SYNTHETIC STRATEGIES TOWARD SUBSTITUTED BENZENES
16.6: REACTIVITY OF POLYCYCLIC BENZENOID HYDROCARBONS
16.7: POLYCYCLIC AROMATIC HYDROCARBONS AND CANCER

1 12/5/2021
16.1: Activation or Deactivation by Substituents on a Benzene Ring
 Objectives

After completing this section, you should be able to

1. describe the two ways in which a substituent influences the electrophilic substitution of a monosubstituted aromatic
compound.
2. classify each of the following substituents as being either activating or deactivating with respect to electrophilic
aromatic substitution: −NH , −OH, −NHR , −NR , −OR, −NHCOR, alkyl (R), phenyl, R N , −NO , −CN,
2 2 3
+
2

−COR, −CO H , −CO R , −CHO, halogens.

2 2

3. list a given series of substituents (selected from those given in Objective 2) in order of increasing or decreasing
ability to activate or deactivate an aromatic ring with respect to electrophilic substitution.
4. explain, in general terms, the factors that determine whether a given substituent will activate or deactivate an
aromatic ring with respect to electrophilic substitution.
5. list a given series of aromatic compounds in order of increasing or decreasing reactivity with respect to
electrophilic substitution.
6. explain the inductive effects displayed by substituents such as nitro, carboxyl, alkyl and the halogens during
electrophilic aromatic substitution reactions.
7. explain the resonance effects displayed by substituents such as nitro, carbonyl-containing, hydroxy, alkoxy and
amino groups during electrophilic aromatic substitution reactions.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
inductive effect
resonance effect

 Study Notes

On reading Objective 2 students may exclaim “How am I ever going to memorize all of this!”—or words to that effect.
The answer is that if you are trying to memorize such things, you are taking the wrong approach to organic chemistry.
What you should be doing is trying to understand the factors that determine whether a given substituent will activate or
deactivate a benzene ring with respect to electrophilic substitution.
You may wish to review earlier material on to the inductive effect. If so, refer to Sections 2.1, 7.9 (paying particular
attention to the “Study Notes”) and 14.5.
Note that one argument sometimes used to explain the ability of alkyl groups to donate electrons inductively to an
aromatic ring is that sp2‑hybridized carbon atoms are more electronegative than sp3‑hybridized carbon atoms. Thus, a
sigma bond between sp2- and sp3‑carbon is slightly polarized, as follows:

When substituted benzene compounds undergo electrophilic substitution reactions of the kind discussed above, two
related features must be considered:
I. The first is the relative reactivity of the compound compared with benzene itself. Experiments have shown that
substituents on a benzene ring can influence reactivity in a profound manner. For example, a hydroxy or methoxy
substituent increases the rate of electrophilic substitution about ten thousand fold, as illustrated by the case of anisole in the
virtual demonstration (above). In contrast, a nitro substituent decreases the ring's reactivity by roughly a million. This
activation or deactivation of the benzene ring toward electrophilic substitution may be correlated with the electron
donating or electron withdrawing influence of the substituents, as measured by molecular dipole moments. In the

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following diagram we see that electron donating substituents (blue dipoles) activate the benzene ring toward electrophilic
attack, and electron withdrawing substituents (red dipoles) deactivate the ring (make it less reactive to electrophilic attack).

The influence a substituent exerts on the reactivity of a benzene ring may be explained by the interaction of two effects:
The first is the inductive effect of the substituent. Most elements other than metals and carbon have a significantly greater
electronegativity than hydrogen. Consequently, substituents in which nitrogen, oxygen and halogen atoms form sigma-
bonds to the aromatic ring exert an inductive electron withdrawal, which deactivates the ring (left-hand diagram below).
The second effect is the result of conjugation of a substituent function with the aromatic ring. This conjugative
interaction facilitates electron pair donation or withdrawal, to or from the benzene ring, in a manner different from the
inductive shift. If the atom bonded to the ring has one or more non-bonding valence shell electron pairs, as do nitrogen,
oxygen and the halogens, electrons may flow into the aromatic ring by p-π conjugation (resonance), as in the middle
diagram. Finally, polar double and triple bonds conjugated with the benzene ring may withdraw electrons, as in the right-
hand diagram. Note that in the resonance examples all the contributors are not shown. In both cases the charge distribution
in the benzene ring is greatest at sites ortho and para to the substituent.
In the case of the nitrogen and oxygen activating groups displayed in the top row of the previous diagram, electron
donation by resonance dominates the inductive effect and these compounds show exceptional reactivity in electrophilic
substitution reactions. Although halogen atoms have non-bonding valence electron pairs that participate in p-π
conjugation, their strong inductive effect predominates, and compounds such as chlorobenzene are less reactive than
benzene. The three examples on the left of the bottom row (in the same diagram) are examples of electron withdrawal by
conjugation to polar double or triple bonds, and in these cases the inductive effect further enhances the deactivation of the
benzene ring. Alkyl substituents such as methyl increase the nucleophilicity of aromatic rings in the same fashion as they
act on double bonds.

Exercises

 Exercise 16.1.1
Draw the resonance structures for benzaldehyde to show the electron-withdrawing group.

Answer

O O O O

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 Exercise 16.1.2

Draw the resonance structures for methoxybenzene to show the electron-donating group.

Answer

O O O O

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
James Kabrhel (University of Wisconsin - Green Bay, Sheboygan Campus)

16.1.3 11/28/2021 https://chem.libretexts.org/@go/page/32486

16.2: Directing Inductive Effects of Alkyl Groups
Objectives
After completing this section, you should be able to
1. draw the resonance contributors for the carbocation intermediate formed during the reaction of a given
monosubstituted benzene derivative with any of the electrophiles discussed in this chapter.
2. classify each of the substituents listed in Objective 2 of Section 16.4 as being either meta or ortho/para directing.
3. classify each of the substituents listed in Objective 2 of Section 16.4 as being ortho/para directing activators,
ortho/para directing deactivators, or meta directing deactivators.
4. predict the product or products formed from the reaction of a given monosubstituted benzene derivative with each
of the electrophiles discussed in this chapter.
5. explain, by drawing the resonance contributors for the intermediate carbocation, why the electrophilic substitution
of an alkyl benzene results in a mixture of mainly ortho- and para- substituted products.
6. explain why the electrophilic substitution of phenols, amines and their derivatives proceeds more rapidly than the
electrophilic substitution of benzene itself.
7. explain, by drawing the resonance contributors for the intermediate carbocation, why meta substitution
predominates in electrophilic aromatic substitution reactions carried out on benzene derivatives containing one of
the substituents R3N+, NO2, CO2H, CN, CO2R, COR or CHO.
8. explain why electrophilic aromatic substitution of benzene derivatives containing one of the substituents listed in
Objective 7, above, proceeds more slowly than the electrophilic substitution of benzene itself.
9. explain, by drawing the resonance contributors for the intermediate carbocation, why the electrophilic aromatic
substitution of halobenzenes produces a mixture of mainly ortho- and para-substituted products.
10. explain why the electrophilic aromatic substitution of halobenzenes proceeds more slowly than does the
electrophilic substitution of benzene itself.
11. use the principles developed in this chapter to predict in which of the three categories listed in Objective 3, above, a
previously unencountered substituent should be placed.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
steric effect
steric hindrance

 Study Notes

As you saw in Section 16.4, a substituent on a benzene ring can be an activator or a deactivator. At the same time, a
substituent can also be a meta director or an ortho/para director. Of the four possible combinations, only three are
known—there are no meta directing activators.
If you look at the data for the nitration of toluene, you will see that the yield of o‑nitrotoluene is 63% and that of
p‑nitrotoluene is 34%. Statistically, we should expect to obtain twice as much ortho product as para product, because
the former is produced by attack at either of two carbon atoms whereas the latter is produced by attack at only one
carbon atom (see Figure below).

Figure 16.2.1 : Proportions of o‑nitrotoluene and p‑nitrotoluene produced by the nitration of toluene

16.2.1 11/7/2021 https://chem.libretexts.org/@go/page/32487

 In this instance, the observed ortho/para ratio is almost 2:1, as we might expect. However, if we study the ortho/para
ratio found in the nitration of a number of other arenes, we see that this is not always the case. Note that the data for
the nitration of toluene given in the table below differ from those presented elsewhere. The variation may result from a
difference in temperature, reaction conditions or reagent, and emphasizes the point that it is the trends which are
important, not the numbers themselves.
Substrate % ortho % para ortho/para ratio

toluene 58 37 1.57:1
ethylbenzene 45 49 0.92:1
isopropylbenzene 30 62 0.48:1
tert-butylbenzene 16 73 0.22:1

[Source: These data were taken from the audiocassette Some Organic Reaction Pathways, by Peter Sykes. London:
Educational Techniques Subject Group, The Chemical Society, 1975.]
Table 16.2.1: Nitration of arenes
The table above shows us that as the size of the alkyl substituent already present in the ring increases, attack at the
ortho position becomes more difficult, and the percentage of ortho isomers in the mixture of products decreases. This
is an example of a steric effect—an effect caused by the size of the substituent—and we would say that as the size of
the alkyl group increases, attack at the ortho position becomes less favorable as a result of steric hindrance. Note that
the size of the electrophile can also be a factor in determining the ortho/para ratio: the larger the electrophile, the less
able it is to attack at the ortho position, particularly if the substituent already present in the ring is itself quite bulky.
When drawing the resonance contributors to the carbocation formed during an electrophilic aromatic substitution, bear
in mind that those of the type

are particularly important, because in such structures each atom possesses a complete octet of electrons.
Note that, as do the hydroxyl and amino groups, the halogens have an inductive electron-withdrawing effect and a
resonance electron-releasing effect on a benzene ring. The difference in behavior during electrophilic substitutions
arises because, with the hydroxyl and amino groups, the resonance effect is much greater than the inductive effect,
whereas with the halogens, there is a much finer balance. In the case of the latter, the inductive effect reduces the
overall reactivity, but the resonance effect means that this reduction is felt less at the ortho and para positions than at
the meta position.

Substituted rings are divided into two groups based on the type of the substituent that the ring carries:
Activated rings: the substituents on the ring are groups that donate electrons.
Deactivated rings: the substituents on the ring are groups that withdraw electrons.

Introduction
Examples of activating groups in the relative order from the most activating group to the least activating:
-NH2, -NR2 > -OH, -OR> -NHCOR> -CH3 and other alkyl groups
with R as alkyl groups (CnH2n+1)
Examples of deactivating groups in the relative order from the most deactivating to the least deactivating:
-NO2, -CF3> -COR, -CN, -CO2R, -SO3H > Halogens
with R as alkyl groups (CnH2n+1)

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The order of reactivity among Halogens from the more reactive (least deactivating substituent) to the least reactive (most
deactivating substituent) halogen is:
F> Cl > Br > I
The order of reactivity of the benzene rings toward the electrophilic substitution when it is substituted with a halogen
groups, follows the order of electronegativity. The ring that is substituted with the most electronegative halogen is the most
reactive ring (less deactivating substituent) and the ring that is substituted with the least electronegative halogen is the least
reactive ring (more deactivating substituent), when we compare rings with halogen substituents. Also the size of the
halogen effects the reactivity of the benzene ring that the halogen is attached to. As the size of the halogen increase, the
reactivity of the ring decreases.

The direction of the reaction

The activating group directs the reaction to the ortho or para position, which means the electrophile substitutes for the
hydrogen that is on carbon 2 or carbon 4. The deactivating group directs the reaction to the meta position, which means the
electrophile substitutes for the hydrogen that is on carbon 3 with the exception of the halogens which are deactivating
groups but direct the ortho or para substitution.

Substituents determine the reaction direction by resonance or inductive effect

Resonance effect is the conjugation between the ring and the substituent, which means the delocalizing of the π electrons
between the ring and the substituent. Inductive effect is the withdraw of the sigma ( the single bond ) electrons away from
the ring toward the substituent, due to the higher electronegativity of the substituent compared to the carbon of the ring.

Activating groups (ortho or para directors)

When substituents such as -OH have an unshared pair of electrons, the resonance effect is stronger than the inductive effect
which make these substituents stronger activators, since this resonance effect direct the electron toward the ring. In cases
where the subtituents is esters or amides, they are less activating because they form resonance structure that pull the
electron density away from the ring.

By looking at the mechanism above, we can see how electron donating groups direct electrophilic substitution to the ortho
and para positions. Since the extra electron density is localized on the ortho and para carbons, these carbons are more
likely to react with the electrophile.
Inductive effects of alkyl groups activate the direction of the ortho or para substitution, which is when s electrons gets
pushed toward the ring.

Deactivating group (meta directors)

The deactivating groups deactivate the ring by the inductive effect in the presence of an electronegative atom that
withdraws electron density away from the ring.

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The mechanism above shows that when electron density is withdrawn from the ring, that leaves the carbons at the ortho,
para positions with a parital positive charge which is unfavorable for the electrophile, so the electrophile attacks the carbon
at the meta positions.
Halogens are an exception of the deactivating group that directs to the ortho or para substitution. The halogens deactivate
the ring by inductive effect not by the resonance even though they have an unpaired pair of electrons. The unpaired pair of
electrons gets donated to the ring, but the inductive effect pulls away the s electrons from the ring by the electronegativity
of the halogens.

Substituents determine the reactivity of rings

The reaction of a substituted ring with an activating group is faster than the same reaction wtih benzene. On the other hand,
a substituted ring with a deactivated group reacts slower than benzene.
Activating groups speed up reaction with electrophiles due to increased electron density on the ring. This stabilizes the
intermediate carbocation, which decreases the activation energy for the reaction. On the other hand, deactivating groups
withdraw electron density away from the carbocation formed in the intermediate step, increasing the activation energy,
which slows down the reaction.

The CH3 Group is an ortho, para director

Alkyl groups are inductively donating, therefore are activators. This resulsts in o/p attack to form a tertiary arenium
carbocation which speeds up the reaction.

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The O-CH3 Group is an ortho, para director

The methoxy group is an example of groups that are ortho, para directors by having and oxygen or nitrogen adjacent to the
aromatic ring. This same activation is present with alcohols, amines, esters and amides (with the oxygen or nitrogen
attached to the ring, not the carbonyl).
Groups with an oxygen or nitrogen attached to the aromatic ring are ortho and para directors since the O or N can push
electrons into the ring, making the ortho and para positions more reactive and stabilizing the arenium ion that forms. This
causes the ortho and para products to form faster than meta. Generally, the para product is preferred because of steric
effects.

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Acyl groups are meta directors

Ketones are an example of groups that deactivate an aromatic ring through resonance. Similar deactivation also occurs
with ammonium ions, nitro groups, aldehydes, nitriles, sulfonic acids, and groups with a carbonyl attached to the ring
(amides, esters, carboxylic acids, and anhydrides).
Acyl groups are resonance deactivators. Ortho and para attack produces a resonance structure which places the arenium
cation next to an additional cation. This destabilizes the arenium cation and slows down ortho and para reaction. By default
the meta product forms faster because it lacks this destabilizing resonance structure.

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Halogens
Halogens are an interesting hybrid case. They are ortho, para directors, but deactivators. Overall, they remove electron
density from the ring, making it less reactive. However, due to their resonance donation to the ring, if it does react, it reacts
primarily at ortho and para positions.

References
1. Schore, N.E. and P.C. Vollhardt. 2007. Organic Chemistry, structure and function, 5th ed. New York,NY: W.H.
Freeman and Company.
2. Fryhle, C.B. and G. Solomons. 2008. Organic Chemistry, 9th ed.Danvers,MA: Wiley.

Outside Links
http://en.Wikipedia.org/wiki/Activating_group
http://en.Wikipedia.org/wiki/Deactivating_group
http://www.columbia.edu/itc/chemistry/c3045/client_edit/ppt/PDF/12_12_14.pdf

 Exercise 16.2.1

Predict the pattern of the electrophilic substitution on these rings:

Br

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Answer
The first substitution is going to be ortho and/or para substitution since we have a halogen subtituent. The second
substitution is going to be ortho and/or para substitution also since we have an alkyl substituent.

 Exercise 16.2.2

Which nitration product is going to form faster: nitration of aniline or nitration of nitrobenzene?

Answer
The nitration of aniline is going to be faster than the nitration of nitrobenzene, since the aniline is a ring with NH2
substituent and nitrobenzene is a ring with NO2 substituent. As described above NH2 is an activating group which
speeds up the reaction and NO2 is a deactivating group that slows down the reaction.

 Exercise 16.2.3

Predict the product of the following sulfonation reaction:

SO3
O
H2SO4
OH

Answer
SO3H

OH

 Exercise 16.2.4

Classify these two groups as activating or deactivating groups:

A. alcohol
B. ester

Answer
A. alcohol is an activating group.
B. Esters can be either. If the oxygen atom is next to the ring, esters are activating. However if the carbonyl is next
to the ring, the ester is a deactivating group.

 Exercise 16.2.5

Does a chloride substituent activate or deactivate an aromatic ring?

Answer
Chloride deactivate an aromatic ring due to the inductive effect.

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 Exercise 16.2.6
(Trichloromethyl)benzene has a strong concentration of electrons at the methyl substituent. Comparing this toluene,
which is more reactive toward electrophilic substitution?

Answer
The trichloromethyl group is an electron donor into the benzene ring, therefore making it more stable and therefore
more reactive compared to electrophilic substitution.

 Exercise 16.2.7

The following compound is less reactive towards electrophilic substitution than aniline? Explain.

N O

Answer
As seen in resonance the electron density is also localized off of the ring, thereby deactivating it compared to
aniline.

N O N O

 Exercise 16.2.8

Consider the intermediates of the following molecule during an electrophilic substitution. Draw resonance structures
for ortho, meta, and para attacks.
O

Answer

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 O

ortho

para
meta
O
O
H
X O

X H
H
X
O
O
H
X
O

X H
H
O X
H
O
X

X H
H
O
X
H
X O

X H

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Lana Alawwad (UCD)
Layne Morsch (University of Illinois Springfield)
James Kabrhel (Universtiy of Wisconsin - Green Bay, Sheboygan Campus)

16.2.10 11/7/2021 https://chem.libretexts.org/@go/page/32487

16.3: Directing Effects of Substituents in Conjugation with the Benzene Ring
Objectives
After completing this section, you should be able to
1. draw the resonance contributors for the carbocation intermediate formed during the reaction of a given
monosubstituted benzene derivative with any of the electrophiles discussed in this chapter.
2. classify each of the substituents listed in Objective 2 of Section 16.4 as being either meta or ortho/para directing.
3. classify each of the substituents listed in Objective 2 of Section 16.4 as being ortho/para directing activators,
ortho/para directing deactivators, or meta directing deactivators.
4. predict the product or products formed from the reaction of a given monosubstituted benzene derivative with each
of the electrophiles discussed in this chapter.
5. explain, by drawing the resonance contributors for the intermediate carbocation, why the electrophilic substitution
of an alkyl benzene results in a mixture of mainly ortho- and para- substituted products.
6. explain why the electrophilic substitution of phenols, amines and their derivatives proceeds more rapidly than the
electrophilic substitution of benzene itself.
7. explain, by drawing the resonance contributors for the intermediate carbocation, why meta substitution
predominates in electrophilic aromatic substitution reactions carried out on benzene derivatives containing one of
the substituents R3N+, NO2, CO2H, CN, CO2R, COR or CHO.
8. explain why electrophilic aromatic substitution of benzene derivatives containing one of the substituents listed in
Objective 7, above, proceeds more slowly than the electrophilic substitution of benzene itself.
9. explain, by drawing the resonance contributors for the intermediate carbocation, why the electrophilic aromatic
substitution of halobenzenes produces a mixture of mainly ortho- and para-substituted products.
10. explain why the electrophilic aromatic substitution of halobenzenes proceeds more slowly than does the
electrophilic substitution of benzene itself.
11. use the principles developed in this chapter to predict in which of the three categories listed in Objective 3, above, a
previously unencountered substituent should be placed.

 Key Terms

Make certain that you can define, and use in context, the key terms below.
steric effect
steric hindrance

 Study Notes

As you saw in Section 16.4, a substituent on a benzene ring can be an activator or a deactivator. At the same time, a
substituent can also be a meta director or an ortho/para director. Of the four possible combinations, only three are
known—there are no meta directing activators.
If you look at the data for the nitration of toluene, you will see that the yield of o‑nitrotoluene is 63% and that of
p‑nitrotoluene is 34%. Statistically, we should expect to obtain twice as much ortho product as para product, because
the former is produced by attack at either of two carbon atoms whereas the latter is produced by attack at only one
carbon atom (see Figure below).

Figure 16.3.1 : Proportions of o‑nitrotoluene and p‑nitrotoluene produced by the nitration of toluene

16.3.1 11/28/2021 https://chem.libretexts.org/@go/page/32488

 In this instance, the observed ortho/para ratio is almost 2:1, as we might expect. However, if we study the ortho/para
ratio found in the nitration of a number of other arenes, we see that this is not always the case. Note that the data for
the nitration of toluene given in the table below differ from those presented elsewhere. The variation may result from a
difference in temperature, reaction conditions or reagent, and emphasizes the point that it is the trends which are
important, not the numbers themselves.
Substrate % ortho % para ortho/para ratio

toluene 58 37 1.57:1
ethylbenzene 45 49 0.92:1
isopropylbenzene 30 62 0.48:1
tert-butylbenzene 16 73 0.22:1

[Source: These data were taken from the audiocassette Some Organic Reaction Pathways, by Peter Sykes. London:
Educational Techniques Subject Group, The Chemical Society, 1975.]
Table 16.3.1: Nitration of arenes
The table above shows us that as the size of the alkyl substituent already present in the ring increases, attack at the
ortho position becomes more difficult, and the percentage of ortho isomers in the mixture of products decreases. This
is an example of a steric effect—an effect caused by the size of the substituent—and we would say that as the size of
the alkyl group increases, attack at the ortho position becomes less favorable as a result of steric hindrance. Note that
the size of the electrophile can also be a factor in determining the ortho/para ratio: the larger the electrophile, the less
able it is to attack at the ortho position, particularly if the substituent already present in the ring is itself quite bulky.
When drawing the resonance contributors to the carbocation formed during an electrophilic aromatic substitution, bear
in mind that those of the type

are particularly important, because in such structures each atom possesses a complete octet of electrons.
Note that, as do the hydroxyl and amino groups, the halogens have an inductive electron-withdrawing effect and a
resonance electron-releasing effect on a benzene ring. The difference in behavior during electrophilic substitutions
arises because, with the hydroxyl and amino groups, the resonance effect is much greater than the inductive effect,
whereas with the halogens, there is a much finer balance. In the case of the latter, the inductive effect reduces the
overall reactivity, but the resonance effect means that this reduction is felt less at the ortho and para positions than at
the meta position.

Substituted rings are divided into two groups based on the type of the substituent that the ring carries:
Activated rings: the substituents on the ring are groups that donate electrons.
Deactivated rings: the substituents on the ring are groups that withdraw electrons.

Introduction
Examples of activating groups in the relative order from the most activating group to the least activating:
-NH2, -NR2 > -OH, -OR> -NHCOR> -CH3 and other alkyl groups
with R as alkyl groups (CnH2n+1)
Examples of deactivating groups in the relative order from the most deactivating to the least deactivating:
-NO2, -CF3> -COR, -CN, -CO2R, -SO3H > Halogens
with R as alkyl groups (CnH2n+1)

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The order of reactivity among Halogens from the more reactive (least deactivating substituent) to the least reactive (most
deactivating substituent) halogen is:
F> Cl > Br > I
The order of reactivity of the benzene rings toward the electrophilic substitution when it is substituted with a halogen
groups, follows the order of electronegativity. The ring that is substituted with the most electronegative halogen is the most
reactive ring (less deactivating substituent) and the ring that is substituted with the least electronegative halogen is the least
reactive ring (more deactivating substituent), when we compare rings with halogen substituents. Also the size of the
halogen effects the reactivity of the benzene ring that the halogen is attached to. As the size of the halogen increase, the
reactivity of the ring decreases.

The direction of the reaction

The activating group directs the reaction to the ortho or para position, which means the electrophile substitutes for the
hydrogen that is on carbon 2 or carbon 4. The deactivating group directs the reaction to the meta position, which means the
electrophile substitutes for the hydrogen that is on carbon 3 with the exception of the halogens which are deactivating
groups but direct the ortho or para substitution.

Substituents determine the reaction direction by resonance or inductive effect

Resonance effect is the conjugation between the ring and the substituent, which means the delocalizing of the π electrons
between the ring and the substituent. Inductive effect is the withdraw of the sigma ( the single bond ) electrons away from
the ring toward the substituent, due to the higher electronegativity of the substituent compared to the carbon of the ring.

Activating groups (ortho or para directors)

When substituents such as -OH have an unshared pair of electrons, the resonance effect is stronger than the inductive effect
which make these substituents stronger activators, since this resonance effect direct the electron toward the ring. In cases
where the subtituents is esters or amides, they are less activating because they form resonance structure that pull the
electron density away from the ring.

By looking at the mechanism above, we can see how electron donating groups direct electrophilic substitution to the ortho
and para positions. Since the extra electron density is localized on the ortho and para carbons, these carbons are more
likely to react with the electrophile.
Inductive effects of alkyl groups activate the direction of the ortho or para substitution, which is when s electrons gets
pushed toward the ring.

Deactivating group (meta directors)

The deactivating groups deactivate the ring by the inductive effect in the presence of an electronegative atom that
withdraws electron density away from the ring.

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The mechanism above shows that when electron density is withdrawn from the ring, that leaves the carbons at the ortho,
para positions with a parital positive charge which is unfavorable for the electrophile, so the electrophile attacks the carbon
at the meta positions.
Halogens are an exception of the deactivating group that directs to the ortho or para substitution. The halogens deactivate
the ring by inductive effect not by the resonance even though they have an unpaired pair of electrons. The unpaired pair of
electrons gets donated to the ring, but the inductive effect pulls away the s electrons from the ring by the electronegativity
of the halogens.

Substituents determine the reactivity of rings

The reaction of a substituted ring with an activating group is faster than the same reaction wtih benzene. On the other hand,
a substituted ring with a deactivated group reacts slower than benzene.
Activating groups speed up reaction with electrophiles due to increased electron density on the ring. This stabilizes the
intermediate carbocation, which decreases the activation energy for the reaction. On the other hand, deactivating groups
withdraw electron density away from the carbocation formed in the intermediate step, increasing the activation energy,
which slows down the reaction.

The CH3 Group is an ortho, para director

Alkyl groups are inductively donating, therefore are activators. This resulsts in o/p attack to form a tertiary arenium
carbocation which speeds up the reaction.

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The O-CH3 Group is an ortho, para director

The methoxy group is an example of groups that are ortho, para directors by having and oxygen or nitrogen adjacent to the
aromatic ring. This same activation is present with alcohols, amines, esters and amides (with the oxygen or nitrogen
attached to the ring, not the carbonyl).
Groups with an oxygen or nitrogen attached to the aromatic ring are ortho and para directors since the O or N can push
electrons into the ring, making the ortho and para positions more reactive and stabilizing the arenium ion that forms. This
causes the ortho and para products to form faster than meta. Generally, the para product is preferred because of steric
effects.

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Acyl groups are meta directors

Ketones are an example of groups that deactivate an aromatic ring through resonance. Similar deactivation also occurs
with ammonium ions, nitro groups, aldehydes, nitriles, sulfonic acids, and groups with a carbonyl attached to the ring
(amides, esters, carboxylic acids, and anhydrides).
Acyl groups are resonance deactivators. Ortho and para attack produces a resonance structure which places the arenium
cation next to an additional cation. This destabilizes the arenium cation and slows down ortho and para reaction. By default
the meta product forms faster because it lacks this destabilizing resonance structure.

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Halogens
Halogens are an interesting hybrid case. They are ortho, para directors, but deactivators. Overall, they remove electron
density from the ring, making it less reactive. However, due to their resonance donation to the ring, if it does react, it reacts
primarily at ortho and para positions.

References
1. Schore, N.E. and P.C. Vollhardt. 2007. Organic Chemistry, structure and function, 5th ed. New York,NY: W.H.
Freeman and Company.
2. Fryhle, C.B. and G. Solomons. 2008. Organic Chemistry, 9th ed.Danvers,MA: Wiley.

Outside Links
http://en.Wikipedia.org/wiki/Activating_group
http://en.Wikipedia.org/wiki/Deactivating_group
http://www.columbia.edu/itc/chemistry/c3045/client_edit/ppt/PDF/12_12_14.pdf

 Exercise 16.3.1

Predict the pattern of the electrophilic substitution on these rings:

Br

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Answer
The first substitution is going to be ortho and/or para substitution since we have a halogen subtituent. The second
substitution is going to be ortho and/or para substitution also since we have an alkyl substituent.

 Exercise 16.3.2

Which nitration product is going to form faster: nitration of aniline or nitration of nitrobenzene?

Answer
The nitration of aniline is going to be faster than the nitration of nitrobenzene, since the aniline is a ring with NH2
substituent and nitrobenzene is a ring with NO2 substituent. As described above NH2 is an activating group which
speeds up the reaction and NO2 is a deactivating group that slows down the reaction.

 Exercise 16.3.3

Predict the product of the following sulfonation reaction:

SO3
O
H2SO4
OH

Answer
SO3H

OH

 Exercise 16.3.4

Classify these two groups as activating or deactivating groups:

A. alcohol
B. ester

Answer
A. alcohol is an activating group.
B. Esters can be either. If the oxygen atom is next to the ring, esters are activating. However if the carbonyl is next
to the ring, the ester is a deactivating group.

 Exercise 16.3.5

Does a chloride substituent activate or deactivate an aromatic ring?

Answer
Chloride deactivate an aromatic ring due to the inductive effect.

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 Exercise 16.3.6
(Trichloromethyl)benzene has a strong concentration of electrons at the methyl substituent. Comparing this toluene,
which is more reactive toward electrophilic substitution?

Answer
The trichloromethyl group is an electron donor into the benzene ring, therefore making it more stable and therefore
more reactive compared to electrophilic substitution.

 Exercise 16.3.7

The following compound is less reactive towards electrophilic substitution than aniline? Explain.

N O

Answer
As seen in resonance the electron density is also localized off of the ring, thereby deactivating it compared to
aniline.

N O N O

 Exercise 16.3.8

Consider the intermediates of the following molecule during an electrophilic substitution. Draw resonance structures
for ortho, meta, and para attacks.
O

Answer

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 O

ortho

para
meta
O
O
H
X O

X H
H
X
O
O
H
X
O

X H
H
O X
H
O
X

X H
H
O
X
H
X O

X H

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Lana Alawwad (UCD)
Layne Morsch (University of Illinois Springfield)
James Kabrhel (Universtiy of Wisconsin - Green Bay, Sheboygan Campus)

16.3.10 11/28/2021 https://chem.libretexts.org/@go/page/32488

16.4: Electrophilic Attack on Disubstituted Benzenes
 Objectives

After completing this section, you should be able to

1. predict the position or positions at which electrophilic substitution will occur when a third substituent is introduced
into a disubstituted benzene ring.
2. explain the observed substitution pattern when a third substituent is introduced into a disubstituted benzene ring.

Orientational Interaction of Substituents

When a benzene ring has two substituent groups, each exerts an influence on subsequent substitution reactions. The
activation or deactivation of the ring can be predicted more or less by the sum of the individual effects of these
substituents. The site at which a new substituent is introduced depends on the orientation of the existing groups and their
individual directing effects. We can identify two general behavior categories, as shown in the following table. Thus, the
groups may be oriented in such a manner that their directing influences act in concert, reinforcing the outcome; or are
opposed (antagonistic) to each other. Note that the orientations in each category change depending on whether the groups
have similar or opposite individual directing effects.

Antagonistic or Non-Cooperative Reinforcing or Cooperative

D = Electron Donating Group (ortho/para-directing)

W = Electron Withdrawing Group (meta-directing)

Reinforcing or Cooperative Substitutions

The products from substitution reactions of compounds having a reinforcing orientation of substituents are easier to predict
than those having antagonistic substituents. For example, the six equations shown below are all examples of reinforcing or
cooperative directing effects operating in the expected manner. Symmetry, as in the first two cases, makes it easy to predict
the site at which substitution is likely to occur. Note that if two different sites are favored, substitution will usually occur at
the one that is least hindered by ortho groups.

The first three examples have two similar directing groups in a meta-relationship to each other. In examples 4 through 6,
oppositely directing groups have an ortho or para-relationship. The major products of electrophilic substitution, as shown,
are the sum of the individual group effects. The strongly activating hydroxyl (–OH) and amino (–NH2) substituents favor
dihalogenation in examples 5 and 6.

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Antagonistic or Non-Cooperative Substitutions
Substitution reactions of compounds having an antagonistic orientation of substituents require a more careful analysis. If
the substituents are identical, as in example 1 below, the symmetry of the molecule will again simplify the decision. When
one substituent has a pair of non-bonding electrons available for adjacent charge stabilization, it will normally exert the
product determining influence, examples 2, 4 & 5, even though it may be overall deactivating (case 2). Case 3 reflects a
combination of steric hindrance and the superior innate stabilizing ability of methyl groups relative to other alkyl
substituents. Example 6 is interesting in that it demonstrates the conversion of an activating ortho/para-directing group into
a deactivating meta-directing "onium" cation [–NH(CH3)2(+) ] in a strong acid environment.

Exercises

 Exercise 16.4.1

Predict the products of the following reactions:

CH3CH2Cl
Br
AlCl3

HNO3

H2SO4

CH3CH2Cl

O AlCl3

HNO3

H2SO4

Answer

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 Br

CH3CH2Cl
Br
AlCl3

HNO3 Br

H2SO4

NO2

CH3CH2Cl

O AlCl3

HNO3
O
H2SO4

NO2

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
James Kabrhel (University of Wisconsin - Green Bay, Sheboygan Campus)

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16.5: Synthetic Strategies Toward Substituted Benzenes
Objectives
After completing this section, you should be able to
1. design a multistep synthesis which may involve reactions in the alkyl side chain of an alkylbenzene and the
electrophilic substitution reactions discussed in this chapter. You should pay particular attention to
a. carrying out the reactions in the correct order.
b. using the most appropriate reagents and conditions.
c. the limitations of certain types of reactions.
2. analyse a proposed multistep synthesis involving aromatic substitution to determine its feasibility, point out any
errors in the proposal and identify possible problem areas.

 Study Notes

As you can see, designing a multistep synthesis requires an analytical mind and an ability to think logically, as well as
a knowledge of organic reactions. The best way to become an expert in designing such syntheses is to get lots of
practice by doing plenty of problems.

The ability to plan a successful multi step synthesis of complex molecules is one of the goals of organic chemists. It
requires a working knowledge of the uses and limitations of many organic reactions - not only which reactions to use, but
when. A few examples follow:

From benzene make m-bromoaniline

In this reaction three reactions are required.
1. A nitration
2. A conversion from the nitro group to an amine
3. A bromination
Because the end product is meta a meta directing group must be utilized. Of the nitro, bromine, and amine group, only the
nitro group is meta direction. This means that the first step need to be the nitration and not the bromination. Also, the
conversion of the nitro group to an amine must occur last because the amine group is ortho/para direction.

From benzene make p-nitropropylbenzene :

In this reaction three reactions are required.
1. A Friedel Crafts acylation
2. A conversion from the acyl group to an alkane
3. A nitration

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Because the propyl group has more than two carbons, it must be added in two steps. A Friedel Crafts acylation followed by
a Clemmensen Reduction. Remeber that Friedel Crafts reactions are hindered if the benzene ring is strongly deactivated.
This means that the acyl group must go on first. Because the end product is para a para directing group must be utilized. Of
the nitro, acyl, and alkane group, only the alkane group is meta direction. This means that the acyl group must be
converted to an alkane prior to the nitration step.

Exercises

 Exercise 16.5.1

How would make the following compounds from benzene?

A) m-bromonitrobenzene
B) m-bromoethylbenzene

Answer
Only one possible synthesis is shown for each compound. There are multiple possibilities.

NO2 NO2
HNO3 Br2
A)
H2SO4 FeBr3
Br

O
O O
Cl Br2
B)
FeBr3
AlCl3
Br

 Exercise 16.5.2
There is something wrong with the following reaction, what is it?

O H 1) HNO3, H2SO4
2) Br2, FeBr3 Br

3) H2, Pd/C
NO2

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 Answer
The bromine should be in the meta position. Right now it is in the ortho position, from perhaps having the ethyl
group present first and then the having it substituted there. BUT the ethyl group is last to form, and the aldehyde
and nitro groups would both encourage a meta substitution.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
James Kabrhel (University of Wisconsin - Green Bay, Sheboygan Campus)
Lauren Reutenauer (Amherst College)

Topic hierarchy

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16.6: Reactivity of Polycyclic Benzenoid Hydrocarbons

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16.7: Polycyclic Aromatic Hydrocarbons and Cancer
To Your Health: Polycyclic Aromatic Hydrocarbons and Cancer
The intense heating required for distilling coal tar results in the formation of PAHs. For many years, it has been known that
workers in coal-tar refineries are susceptible to a type of skin cancer known as tar cancer. Investigations have shown that a
number of PAHs are carcinogens. One of the most active carcinogenic compounds, benzopyrene, occurs in coal tar and has
also been isolated from cigarette smoke, automobile exhaust gases, and charcoal-broiled steaks. It is estimated that more
than 1,000 t of benzopyrene are emitted into the air over the United States each year. Only a few milligrams of
benzopyrene per kilogram of body weight are required to induce cancer in experimental animals.

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CHAPTER OVERVIEW
17: ALDEHYDES AND KETONES - THE CARBONYL GROUP
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

17.1: NAMING THE ALDEHYDES AND KETONES

17.2: STRUCTURE OF THE CARBONYL GROUP
17.3: SPECTROSCOPIC PROPERTIES OF ALDEHYDES AND KETONES
17.4: PREPARATION OF ALDEHYDES AND KETONES
17.5: REACTIVITY OF THE CARBONYL GROUP: MECHANISMS OF ADDITION
17.6: ADDITION OF WATER TO FORM HYDRATES
17.7: ADDITION OF ALCOHOLS TO FORM HEMIACETALS AND ACETALS
17.8: ACETALS AS PROTECTING GROUPS
17.9: NUCLEOPHILIC ADDITION OF AMMONIA AND ITS DERIVATIVES
17.10: DEOXYGENATION OF THE CARBONYL GROUP
17.11: ADDITION OF HYDROGEN CYANIDE TO GIVE CYANOHYDRINS
17.12: ADDITION OF PHOSPHORUS YLIDES: THE WITTIG REACTION
17.13: OXIDATION BY PEROXYCARBOXYLIC ACIDS: THE BAEYER- VILLIGER OXIDATION
17.14: OXIDATIVE CHEMICAL TESTS FOR ALDEHYDES

1 12/5/2021
17.1: Naming the Aldehydes and Ketones
Objectives
After completing this section, you should be able to
1. provide the IUPAC name of an aldehyde or ketone, given its Kekulé, condensed or shorthand structure.
2. draw the structure of an aldehyde or ketone, given its IUPAC name.
3. draw the structure of the following aldehydes and ketones, given their trivial names: formaldehyde, acetaldehyde,
benzaldehyde, acetone, acetophenone, benzophenone.

Study Notes
We only use those trivial names listed under Objective 3, above. We use systematic names in all other cases. For
example, the systematic name of the compound shown below is benzenecarbaldehyde, but it has the trivial name of
benzaldehyde.

When naming unsaturated aldehydes and ketones, you must give the carbonyl group “priority” over the double bond
when you are deciding which end of the carbon chain to begin numbering The carbonyl‑carbon of an aldehyde will
always be at the end of the carbon chain in an acyclic compound; and therefore numbering always starts at this carbon.
It is for this reason, too, that the number “1” is not required when naming a compound such as
2‑ethyl‑4‑methylpentanal.

The most potent and varied odors are aldehydes. Ketones are widely used as industrial solvents. Aldehydes and ketones
contain the carbonyl group. Aldehydes are considered the most important functional group. They are often called the
formyl or methanoyl group. Aldehydes derive their name from the dehydration of alcohols. Aldehydes contain the
carbonyl group bonded to at least one hydrogen atom. Ketones contain the carbonyl group bonded to two carbon atoms.

Introduction
Aldehydes and ketones are organic compounds which incorporate a carbonyl functional group, C=O. The carbon atom of
this group has two remaining bonds that may be occupied by hydrogen, alkyl or aryl substituents. If at least one of these
substituents is hydrogen, the compound is an aldehyde. If neither is hydrogen, the compound is a ketone.

Naming Aldehydes
The IUPAC system of nomenclature assigns a characteristic suffix -al to aldehydes. For example, H2C=O is methanal,
more commonly called formaldehyde. Since an aldehyde carbonyl group must always lie at the end of a carbon chain, it is
always is given the #1 location position in numbering and it is not necessary to include it in the name. There are several
simple carbonyl containing compounds which have common names which are retained by IUPAC.
Also, there is a common method for naming aldehydes and ketones. For aldehydes common parent chain names, similar to
those used for carboxylic acids, are used and the suffix –aldehyde is added to the end. In common names of aldehydes,
carbon atoms near the carbonyl group are often designated by Greek letters. The atom adjacent to the carbonyl function is
alpha, the next removed is beta and so on.

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If the aldehyde moiety (-CHO) is attached to a ring the suffix –carbaldehyde is added to the name of the ring. The
carbon attached to this moiety will get the #1 location number in naming the ring.

Summary of Aldehyde Nomenclature rules

1. Aldehydes take their name from their parent alkane chains. The -e is removed from the end and is replaced with -al.
2. The aldehyde funtional group is given the #1 numbering location and this number is not included in the name.
3. For the common name of aldehydes start with the common parent chain name and add the suffix -aldehyde. Substituent
positions are shown with Greek letters.
4. When the -CHO functional group is attached to a ring the suffix -carbaldehyde is added, and the carbon attached to that
group is C1.

Example 19.1.1
The IUPAC system names are given on top while the common name is given on the bottom in parentheses.

Naming Ketones
The IUPAC system of nomenclature assigns a characteristic suffix of -one to ketones. A ketone carbonyl function may be
located anywhere within a chain or ring, and its position is usually given by a location number. Chain numbering normally
starts from the end nearest the carbonyl group. Very simple ketones, such as propanone and phenylethanone do not require
a locator number, since there is only one possible site for a ketone carbonyl function
The common names for ketones are formed by naming both alkyl groups attached to the carbonyl then adding the suffix -
ketone. The attached alkyl groups are arranged in the name alphabetically.

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Summary of Ketone Nomenclature rules
1. Ketones take their name from their parent alkane chains. The ending -e is removed and replaced with -one.
2. The common name for ketones are simply the substituent groups listed alphabetically + ketone.
3. Some common ketones are known by their generic names. Such as the fact that propanone is commonly referred to as
acetone.

Example 19.1.2
The IUPAC system names are given on top while the common name is given on the bottom in parentheses.

Naming Aldehydes and Ketones in the Same Molecule

As with many molecules with two or more functional groups, one is given priority while the other is named as a
substituent. Because aldehydes have a higher priority than ketones, molecules which contain both functional groups are
named as aldehydes and the ketone is named as an "oxo" substituent. It is not necessary to give the aldehyde functional
group a location number, however, it is usually necessary to give a location number to the ketone.

Example 19.1.3

Naming Dialdehydes and Diketones

For dialdehydes the location numbers for both carbonyls are omitted because the aldehyde functional groups are expected
to occupy the ends of the parent chain. The ending –dial is added to the end of the parent chain name.

Example 19.1.4

For diketones both carbonyls require a location number. The ending -dione or -dial is added to the end of the parent chain.

Example 19.1.5

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Naming Cyclic Ketones and Diketones
In cyclic ketones the carbonyl group is assigned location position #1, and this number is not included in the name, unless
more than one carbonyl group is present. The rest of the ring is numbered to give substituents the lowest possible location
numbers. Remember the prefix cyclo is included before the parent chain name to indicate that it is in a ring. As with other
ketones the –e ending is replaced with the –one to indicate the presence of a ketone.
With cycloalkanes which contain two ketones both carbonyls need to be given a location numbers. Also, an –e is not
removed from the end but the suffix –dione is added.

Example 19.1.6

Naming Carbonyls and Hydroxyls in the Same

Molecule
When and aldehyde or ketone is present in a molecule which also contains an alcohol functional group the carbonyl is
given nomenclature priority by the IUPAC system. This means that the carbonyl is given the lowest possible location
number and the appropriate nomenclature suffix is included. In the case of alcohols the OH is named as a hydroxyl
substituent. However, the l in hydroxyl is generally removed.

Example 19.1.7

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Naming Carbonyls and Alkenes in the Same
Molecule
When and aldehyde or ketone is present in a molecule which also contains analkene functional group the carbonyl is given
nomenclature priority by the IUPAC system. This means that the carbonyl is given the lowest possible location number
and the appropriate nomenclature suffix is included.
When carbonyls are included with an alkene the following order is followed:
(Location number of the alkene)-(Prefix name for the longest carbon chain minus the -ane ending)-(an -en ending to
indicate the presence of an alkene)-(the location number of the carbonyl if a ketone is present)-(either an –one or and -anal
ending).
Remember that the carbonyl has priority so it should get the lowest possible location number. Also, remember that cis/tran
or E/Z nomenclature for the alkene needs to be included if necessary.

Example 19.1.8

Aldehydes and Ketones as Fragments

Alkanoyl is the common name of the fragment, though the older naming, acyl, is still widely used.
Formyl is the common name of the fragment.
Acety is the common name of the CH3-C=O- fragment.

Example 19.1.9

Additional Examples of Carbonyl Nomenclature

1) Please give the IUPAC name for each compound:

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Answers for Question 1
A. 3,4-dimethylhexanal
B. 5-bromo-2-pentanone
C. 2,4-hexanedione
D. cis-3-pentenal
E. 6-methyl-5-hepten-3-one
F. 3-hydroxy-2,4-pentanedione
G. 1,2-cyclobutanedione
H. 2-methyl-propanedial
I. 3-methyl-5-oxo-hexanal
J. cis-2,3-dihydroxycyclohexanone
K. 3-bromo-2-methylcyclopentanecarboaldehyde
L. 3-bromo-2-methylpropanal
2) Please give the structure corresponding to each name:
A) butanal
B) 2-hydroxycyclopentanone
C) 2,3-pentanedione
D) 1,3-cyclohexanedione
E) 3,4-dihydoxy-2-butanone
F) (E) 3-methyl-2-hepten-4-one
G) 3-oxobutanal

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H) cis-3-bromocyclohexanecarboaldehyde
I) butanedial
J) trans-2-methyl-3-hexenal
Answers to question 2:

References
1. Vollhardt, K. Peter C., and Neil E. Schore. Organic Chemistry. 5th ed. New York: W.H. Freeman, 2007.
2. Zumdahl, Steven S., and Susan A. Zumdahl. Chemistry. 6th ed. Boston: Houghton Mifflin College Division, 2002.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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17.2: Structure of the Carbonyl Group
A carbonyl group is a chemically organic functional group composed of a carbon atom double-bonded to an oxygen atom -
-> [C=O] The simplest carbonyl groups are aldehydes and ketones usually attached to another carbon compound. These
structures can be found in many aromatic compounds contributing to smell and taste.

The Carbonyl Group

C=O is prone to additions and nucleophillic attack because or carbon's positive charge and oxygen's negative charge. The
resonance of the carbon partial positive charge allows the negative charge on the nucleophile to attack the Carbonyl group
and become a part of the structure and a positive charge (usually a proton hydrogen) attacks the oxygen. Just a reminder,
the nucleophile is a good acid therefore "likes protons" so it will attack the side with a positive charge.
Before we consider in detail the reactivity of aldehydes and ketones, we need to look back and remind ourselves of what
the bonding picture looks like in a carbonyl. Carbonyl carbons are sp2 hybridized, with the three sp2 orbitals forming
soverlaps with orbitals on the oxygen and on the two carbon or hydrogen atoms. These three bonds adopt trigonal planar
geometry. The remaining unhybridized 2p orbital on the central carbonyl carbon is perpendicular to this plane, and forms a
‘side-by-side’ pbond with a 2p orbital on the oxygen.

The carbon-oxygen double bond is polar: oxygen is more electronegative than carbon, so electron density is higher on the
oxygen side of the bond and lower on the carbon side. Recall that bond polarity can be depicted with a dipole arrow, or by
showing the oxygen as holding a partial negative charge and the carbonyl carbon a partial positive charge.

A third way to illustrate the carbon-oxygen dipole is to consider the two main resonance contributors of a carbonyl group:
the major form, which is what you typically see drawn in Lewis structures, and a minor but very important contributor in
which both electrons in the pbond are localized on the oxygen, giving it a full negative charge. The latter depiction shows
the carbon with an empty 2p orbital and a full positive charge.

Some Carbonyl Compounds

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Prof. Steven Farmer (Sonoma State University)
This page explains what aldehydes and ketones are, and looks at the way their bonding affects their reactivity. It also
considers their simple physical properties such as solubility and boiling points. Aldehydes and ketones are simple
compounds which contain a carbonyl group - a carbon-oxygen double bond. They are simple in the sense that they don't
have other reactive groups like -OH or -Cl attached directly to the carbon atom in the carbonyl group - as you might find,
for example, in carboxylic acids containing -COOH.

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Aldehydes
In aldehydes, the carbonyl group has a hydrogen atom attached to it together with either a second hydrogen atom or, more
commonly, a hydrocarbon group which might be an alkyl group or one containing a benzene ring. For the purposes of this
section, we shall ignore those containing benzene rings.

Notice that these all have exactly the same end to the molecule. All that differs is the complexity of the other group
attached. When you are writing formulae for these, the aldehyde group (the carbonyl group with the hydrogen atom
attached) is always written as -CHO - never as COH. That could easily be confused with an alcohol. Ethanal, for example,
is written as CH3CHO; methanal as HCHO. The name counts the total number of carbon atoms in the longest chain -
including the one in the carbonyl group. If you have side groups attached to the chain, notice that you always count from
the carbon atom in the carbonyl group as being number 1.

Ketones
In ketones, the carbonyl group has two hydrocarbon groups attached. Again, these can be either alkyl groups or ones
containing benzene rings. Again, we'll concentrated on those containing alkyl groups just to keep things simple. Notice
that ketones never have a hydrogen atom attached to the carbonyl group.

Propanone is normally written CH3COCH3. Notice the need for numbering in the longer ketones. In pentanone, the
carbonyl group could be in the middle of the chain or next to the end - giving either pentan-3-one or pentan-2-one.

Bonding and reactivity

Oxygen is far more electronegative than carbon and so has a strong tendency to pull electrons in a carbon-oxygen bond
towards itself. One of the two pairs of electrons that make up a carbon-oxygen double bond is even more easily pulled
towards the oxygen. That makes the carbon-oxygen double bond very highly polar.

The slightly positive carbon atom in the carbonyl group can be attacked by nucleophiles. A nucleophile is a negatively
charged ion (for example, a cyanide ion, CN-), or a slightly negatively charged part of a molecule (for example, the lone
pair on a nitrogen atom in ammonia, NH3).
During the reaction, the carbon-oxygen double bond gets broken. The net effect of all this is that the carbonyl group
undergoes addition reactions, often followed by the loss of a water molecule. This gives a reaction known as addition-
elimination or condensation. You will find examples of simple addition reactions and addition-elimination if you explore
the aldehydes and ketones menu (link at the bottom of the page). Both aldehydes and ketones contain a carbonyl group.
That means that their reactions are very similar in this respect.
Where aldehydes and ketones differ
An aldehyde differs from a ketone by having a hydrogen atom attached to the carbonyl group. This makes the
aldehydes very easy to oxidise. For example, ethanal, CH3CHO, is very easily oxidised to either ethanoic acid,
CH3COOH, or ethanoate ions, CH3COO-.
Ketones don't have that hydrogen atom and are resistant to oxidation. They are only oxidised by powerful oxidising
agents which have the ability to break carbon-carbon bonds. You will find the oxidation of aldehydes and ketones

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 discussed if you follow a link from the aldehydes and ketones menu (see the bottom of this page).

Boiling Points
Methanal is a gas (boiling point -21°C), and ethanal has a boiling point of +21°C. That means that ethanal boils at close to
room temperature. The other aldehydes and the ketones are liquids, with boiling points rising as the molecules get bigger.
The size of the boiling point is governed by the strengths of the intermolecular forces.
Van der Waals dispersion forces: These attractions get stronger as the molecules get longer and have more electrons.
That increases the sizes of the temporary dipoles that are set up. This is why the boiling points increase as the number
of carbon atoms in the chains increases - irrespective of whether you are talking about aldehydes or ketones.
van der Waals dipole-dipole attractions: Both aldehydes and ketones are polar molecules because of the presence of
the carbon-oxygen double bond. As well as the dispersion forces, there will also be attractions between the permanent
dipoles on nearby molecules. That means that the boiling points will be higher than those of similarly sized
hydrocarbons - which only have dispersion forces. It is interesting to compare three similarly sized molecules. They
have similar lengths, and similar (although not identical) numbers of electrons.

molecule type boiling point (°C)

CH3CH2CH3 alkane -42

CH3CHO aldehyde +21
CH3CH2OH alcohol +78

Notice that the aldehyde (with dipole-dipole attractions as well as dispersion forces) has a boiling point higher than the
similarly sized alkane which only has dispersion forces. However, the aldehyde's boiling point isn't as high as the alcohol's.
In the alcohol, there is hydrogen bonding as well as the other two kinds of intermolecular attraction.

Although the aldehydes and ketones are highly polar molecules, they don't have
any hydrogen atoms attached directly to the oxygen, and so they can't hydrogen
bond with each other.
Solubility in water
The small aldehydes and ketones are freely soluble in water but solubility falls with chain length. For example, methanal,
ethanal and propanone - the common small aldehydes and ketones - are miscible with water in all proportions.The reason
for the solubility is that although aldehydes and ketones can't hydrogen bond with themselves, they can hydrogen bond
with water molecules. One of the slightly positive hydrogen atoms in a water molecule can be sufficiently attracted to one
of the lone pairs on the oxygen atom of an aldehyde or ketone for a hydrogen bond to be formed.

There will also, of course, be dispersion forces and dipole-dipole attractions between the aldehyde or ketone and the water
molecules. Forming these attractions releases energy which helps to supply the energy needed to separate the water
molecules and aldehyde or ketone molecules from each other before they can mix together.
As chain lengths increase, the hydrocarbon "tails" of the molecules (all the hydrocarbon bits apart from the carbonyl
group) start to get in the way. By forcing themselves between water molecules, they break the relatively strong hydrogen
bonds between water molecules without replacing them by anything as good. This makes the process energetically less
profitable, and so solubility decreases.

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Contributors
Jim Clark (Chemguide.co.uk)

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17.3: Spectroscopic Properties of Aldehydes and Ketones
☰
Objectives
After completing this section, you should be able to
1. identify the region of the infrared spectrum in which the carbonyl absorption of aldehydes and ketones is found.
2. identify the region of the infrared spectrum in which the two characteristic C−H absorptions of aldehydes are
found.
3. use a table of characteristic absorption frequencies to assist in the determination of the structure of an unknown
aldehyde or ketone, given its infrared spectrum and other spectral or experimental data.
4. identify the region of a proton NMR spectrum in which absorptions caused by the presence of aldehydic protons
and protons attached to the α‑carbon atoms of aldehydes and ketones occur.
5. identify two important fragmentations that occur when aliphatic aldehydes and ketones are subjected to analysis by
mass spectrometry.

Key Terms
Make certain that you can define, and use in context, the key term below.
McLafferty rearrangement

Study Notes

The appearance of a strong absorption at 1660–1770 cm−1 in the infrared spectrum of a compound is a clear indication
of the presence of a carbonyl group. Although you need not remember the detailed absorptions it is important that you
realize that the precise wavenumber of the infrared absorption can often provide some quite specific information about
the environment of the carbonyl group in a compound. Notice how conjugation between a carbonyl group and a double
bond (α, β‑unsaturated aldehyde or ketone or aromatic ring) lowers the absorption by about 25–30 cm−1.
You may wish to review the McLafferty rearrangement and the alpha cleavage in Section 12.3.

IR Spectra
The carbonyl stretching vibration band C=O of saturated aliphatic ketones appears:
C=O stretch
aliphatic ketones 1715 cm-1
alpha, beta-unsaturated ketones 1685-1666 cm-1
Figure 8. shows the spectrum of 2-butanone. This is a saturated ketone, and the C=O band appears at 1715.

Figure 8. Infrared Spectrum of 2-Butanone

If a compound is suspected to be an aldehyde, a peak always appears around 2720 cm-1 which often appears as a shoulder-
type peak just to the right of the alkyl C–H stretches.
H–C=O stretch 2830-2695 cm-1

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C=O stretch
☰
aliphatic aldehydes 1740-1720 cm-1
alpha, beta-unsaturated aldehydes 1710-1685 cm-1
Figure 9. shows the spectrum of butyraldehyde.

Figure 9. Infrared Spectrum of Butyraldehyde

NMR Spectra
Hydrogens attached to carbon adjacent to the sp2 hybridized carbon in aldehydes and ketones usually show up 2.0-2.5
ppm.

.
Aldehyde hydrogens are highly deshielded and appear far downfield as 9-10 ppm.
Chemical shift of each protons is predicted by 1H chemical shift ranges (Ha): chemical shift of methyl groups (1.1 ppm).
(Hb) The chemical shift of the -CH- group move downfield due to effect an adjacent aldehyde group: (2.4 ppm). The
chemical shift of aldehyde hydrogen is highly deshielded (9.6 ppm).

4) Splitting pattern is determined by (N+1) rule: Ha is split into two peaks by Hb(#of proton=1). Hb has the septet pattern
by Ha (#of proton=6). Hc has one peak.(Note that Hc has doublet pattern by Hb due to vicinal proton-proton coupling.)

Mass Spectra
16.4: Spectroscopic Properties

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
16.5: Typical Carbonyl-Addition Reactions

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17.4: Preparation of Aldehydes and Ketones
Objectives
After completing this section, you should be able to
1. describe in detail the methods for preparing aldehydes discussed in earlier units (i.e., the oxidation of primary
alcohols and the cleavage of alkenes).
2. write an equation to describe the reduction of an ester to an aldehyde.
a. identify the product formed when a given ester is reduced with diisobutylaluminum hydride.
b. identify the reagents and conditions used in the reduction of an ester to an aldehyde.
c. identify the disadvantages of using diisobutylaluminum hydride to reduce an ester to an aldehyde.
3. describe in detail the methods for preparing ketones discussed in earlier units (i.e., the oxidation of secondary
alcohols, the ozonolysis of alkenes, Friedel‑Crafts acylation, and the hydration of terminal alkynes).
a. write an equation to illustrate the formation of a ketone through the reaction of an acid chloride with a
dialkylcopper lithium reagent.
b. identify the ketone produced from the reaction of a given acid chloride with a specified dialkylcopper lithium
reagent.
c. identify the acid chloride, the dialkylcopper lithium reagent, or both, needed to prepare a specific ketone.

Study Notes

You may wish to review the sections in which we discuss the oxidation of alcohols (17.7) and the cleavage of alkenes
(8.8). A third method of preparing aldehydes is to reduce a carboxylic acid derivative; for example, to reduce an ester
with diisobutylaluminum hydride (DIBAL‑H).
There are essentially five methods of preparing ketones in the laboratory. Four of them have been discussed in earlier
sections:
1. the oxidation of a secondary alcohol—Section 17.7.
2. the ozonolysis of an alkene—Section 8.8.
3. Friedel‑Crafts acylation—Section 16.3.
4. the hydration of a terminal alkyne—Section 9.4.
The “new” method we introduce in this section involves the reaction of an acid chloride with a diorganocopper
reagent. The latter substances were discussed in Section 10.7, which you might now wish to review.

Aldehydes and ketones can be prepared using a wide variety of reactions. Although these reactions are discussed in greater
detail in other sections, they are listed here as a summary and to help with planning multistep synthetic pathways. Please
use the appropriate links to see more details about the reactions.

Oxidation of 1o alcohols with PCC to form aldehydes

Hydration of an alkyne to form aldehydes

Anti-Markovnikov addition of a hydroxyl group to an alkyne forms an aldehyde. The addition of a hydroxyl group to an
alkyne causes tautomerization which subsequently forms a carbonyl.

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Reduction of an ester, acid chloride or nitrile to form aldehydes

Oxidation of 2o alcohols to form ketones

Typically uses Jones reagent (CrO3 in H2SO4) but many other reagents can be used

Hydration of an alkyne to form ketones

The addition of a hydroxyl group to an alkyne causes tautomerization which subsequently forms a carbonyl. Markovnikov
addition of a hydroxyl group to an alkyne forms a ketone.

Friedel-Crafts acylation to form a ketone

Reaction of Grignard reagents with nitriles to form ketones

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Alkenes can be cleaved using ozone (O3) to form aldehydes and/or ketones

This is an example of a Ozonolysis reaction.

Organocuprate reagents convert acid chlorides to ketones

Example 1:

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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17.5: Reactivity of the Carbonyl Group: Mechanisms of Addition
Nucleophilic Addition to Aldehydes and Ketones
The result of carbonyl bond polarization, however it is depicted, is straightforward to predict. The carbon, because it is
electron-poor, is an electrophile: it is a great target for attack by an electron-rich nucleophilic group. Because the oxygen
end of the carbonyl double bond bears a partial negative charge, anything that can help to stabilize this charge by accepting
some of the electron density will increase the bond’s polarity and make the carbon more electrophilic. Very often a general
acid group serves this purpose, donating a proton to the carbonyl oxygen.

The same effect can also be achieved if a Lewis acid, such as a magnesium ion, is located near the carbonyl oxygen.
Unlike the situation in a nucleophilic substitution reaction, when a nucleophile attacks an aldehyde or ketone carbon there
is no leaving group – the incoming nucleophile simply ‘pushes’ the electrons in the pi bond up to the oxygen.

Alternatively, if you start with the minor resonance contributor, you can picture this as an attack by a nucleophile on a
carbocation.

After the carbonyl is attacked by the nucleophile, the negatively charged oxygen has the capacity to act as a nucleophile.
However, most commonly the oxygen acts instead as a base, abstracting a proton from a nearby acid group in the solvent
or enzyme active site.

This very common type of reaction is called a nucleophilic addition. In many biologically relevant examples of
nucleophilic addition to carbonyls, the nucleophile is an alcohol oxygen or an amine nitrogen, or occasionally a thiol
sulfur. In one very important reaction type known as an aldol reaction (which we will learn about in section 13.3) the
nucleophile attacking the carbonyl is a resonance-stabilized carbanion. In this chapter, we will concentrate on reactions
where the nucleophile is an oxygen or nitrogen.

Nucleophilic Substitution of RCOZ (Z = Leaving Group)

Carbonyl compounds with leaving groups have reactions similar to aldehydes and ketones. The main difference is the
presence of an electronegative substituent that can act as a leaving group during a nucleophile substitution reaction.

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Although there are many types of carboxylic acid derivatives known, this article focuses on four: acid halides, acid
anhydrides, esters, and amides.

General reaction

General mechanism
1) Nucleophilic attack on the carbonyl

2) Leaving group is removed

Although aldehydes and ketones also contain carbonyls, their chemistry is distinctly different because they do not contain
suitable leaving groups. Once a tetrahedral intermediate is formed, aldehydes and ketones cannot reform their carbonyls.
Because of this, aldehydes and ketones typically undergo nucleophilic additions and not substitutions.

The relative reactivity of carboxylic acid derivatives toward nucleophile substitutions is related to the electronegative
leaving group’s ability to activate the carbonyl. The more electronegative leaving groups withdraw electron density from
the carbonyl, thereby increasing its electrophilicity.

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Contributors
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Prof. Steven Farmer (Sonoma State University)

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17.6: Addition of Water to Form Hydrates
Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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17.7: Addition of Alcohols to Form Hemiacetals and Acetals
Objectives
After completing this section, you should be able to
1. write an equation to illustrate the formation of acetals.
2. identify the acetal formed from the reaction of a given aldehyde or ketone with a given alcohol.
3. identify the carbonyl compound, the alcohol, or both, needed to form a given acetal.
4. write a detailed mechanism for the reaction which occurs between an aldehyde or a ketone and an alcohol.
5. explain how an acid catalyst makes aldehydes and ketones more susceptible to attack by alcohols.
6. illustrate how the reversibility of the reaction between an aldehyde or a ketone and an alcohol can be used to
protect a carbonyl group during an organic synthesis.

Key Terms
Make certain that you can define, and use in context, the key terms below.
acetal
hemiacetal

Study Notes

This section presents a second example of the use of a protecting group. [The first was in the discussion of alcohols,
Section 17.8.] Because of the reactivity of hydroxy groups and carbonyl groups, we often need to protect such groups
during organic syntheses. When you are designing multi‑step syntheses as part of an assignment or examination
question, you must always keep in mind the possibility that you may need to protect such groups to carry out the
desired sequence of reactions successfully.

In this organic chemistry topic, we shall see how alcohols (R-OH) add to carbonyl groups. Carbonyl groups are
characterized by a carbon-oxygen double bond. The two main functional groups that consist of this carbon-oxygen double
bond are Aldehydes and Ketones.

Introduction
It has been demonstrated that water adds rapidly to the carbonyl function of aldehydes and ketones to form geminal-diol.
In a similar reaction alcohols add reversibly to aldehydes and ketones to form hemiacetals (hemi, Greek, half). This
reaction can continue by adding another alcohol to form an acetal. Hemiacetals and acetals are important functional groups
because they appear in sugars.
To achieve effective hemiacetal or acetal formation, two additional features must be implemented. First, an acid catalyst
must be used because alcohol is a weak nucleophile; and second, the water produced with the acetal must be removed from
the reaction by a process such as a molecular sieves or a Dean-Stark trap. The latter is important, since acetal formation
is reversible. Indeed, once pure hemiacetal or acetals are obtained they may be hydrolyzed back to their starting
components by treatment with aqueous acid and an excess of water.

Formation of Hemiacetals

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Example 19.10.1: Formation of Hemiacetals

Example 19.10.2: Hemiacetal Reversibility

Formation of Acetals
Acetals are geminal-diether derivatives of aldehydes or ketones, formed by reaction with two equivalents (or an excess
amount) of an alcohol and elimination of water. Ketone derivatives of this kind were once called ketals, but modern usage
has dropped that term. It is important to note that a hemiacetal is formed as an intermediate during the formation of an
acetal.

Example 19.10.3: Formation of Acetals

Example 19.10.4: Acetal Reversibility

Mechanism for Hemiacetal and Acetal Formation

The mechanism shown here applies to both acetal and hemiacetal formation
1) Protonation of the carbonyl

2) Nucleophilic attack by the alcohol

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3) Deprotonation to form a hemiacetal

4) Protonation of the alcohol

5) Removal of water

6) Nucleophilic attack by the alcohol

7) Deprotonation by water

Acetals as Protecting Groups

The importance of acetals as carbonyl derivatives lies chiefly in their stability and lack of reactivity in neutral to strongly
basic environments. As long as they are not treated by acids, especially aqueous acid, acetals exhibit all the lack of
reactivity associated with ethers in general. Among the most useful and characteristic reactions of aldehydes and ketones is
their reactivity toward strongly nucleophilic (and basic) metallo-hydride, alkyl and aryl reagents. If the carbonyl functional
group is converted to an acetal these powerful reagents have no effect; thus, acetals are excellent protective groups, when
these irreversible addition reactions must be prevented.
In the following example we would like a Grignard reagent to react with the ester and not the ketone. This cannot be done
without a protecting group because Grignard reagents react with esters and ketones.

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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17.8: Acetals as Protecting Groups
Acetals as Protecting Groups
The importance of acetals as carbonyl derivatives lies chiefly in their stability and lack of reactivity in neutral to strongly basic environments. As long as they are not treated by acids,
especially aqueous acid, acetals exhibit all the lack of reactivity associated with ethers in general. Among the most useful and characteristic reactions of aldehydes and ketones is their
reactivity toward strongly nucleophilic (and basic) metallo-hydride, alkyl and aryl reagents. If the carbonyl functional group is converted to an acetal these powerful reagents have no
effect; thus, acetals are excellent protective groups, when these irreversible addition reactions must be prevented.
In the following example we would like a Grignard reagent to react with the ester and not the ketone. This cannot be done without a protecting group because Grignard reagents react
with esters and ketones.

Contributors
Prof. Steven Farmer (Sonoma State University)
Compound 1.4.1.4A illustrates several important points in Protection / Deprotection protocol. Both the functional groups could react with a Grignard Reagent. Carboxylic acid group
would first react with one mole of the Grignard Reagent to give a carboxylate anion salt. This anion does not react any further with the reagent. When two moles of Grignard Reagent
are added to the reaction mixture, the second mole attacks the ketone to give a tertiary alcohol. On aqueous work-up, the acid group is regenerated. Thus, the first mole of the reagent
provides a selective transient protection for the –COOH group. Once the acid group is esterified, such selectivity towards this reagent is lost. The reagent attacks at both sites. If reaction
is desired only at the ester site, the keto- group should be selectively protected as an acetal. In the next step, the grignard reaction is carried out. Now the reagent has only one group
available for reaction. On treatment with acid, the ketal protection in the intermediate compound is also hydrolyzed to regenerated the keto- group.

Fig 1.4.1.4

Protection of Aldehydes and Ketones

Since alcohols, aldehydes and ketones are the most frequently manipulated functional groups in organic synthesis, a great deal of work has appeared in their protection / deprotection
strategies. In this discussion let us focus on the classes of protecting groups rather than an exhaustive treatment of all the protections.

Acetals
There are two general methods for the introduction of this protection. Transketalation is the method of choice when acetals (ketals) with methanol are desired. Acetone is the by-product,
which has to be removed to shift the equilibrium to the right hand side. This is achieved by refluxing with a large excess of the acetonide reagent. Acetone formed is constantly distilled.
In the case of cyclic diols, the water formed is continuously removed using a Dean-Stork condenser (Fig 1.4.1.6).
1.4.1.6...png

Fig 1.4.1.6
The rate of formation of ketals from ketones and 1,2-ethanediol (ethylene glycol), 1,3-propanediol and 2,2-dimethyl-1,3-propanediol are different. So is the deketalation reaction. This
has enabled chemists to selectively work at one center. The following examples from steroid chemistry illustrate these points (Fig 1.4.1.7).
1.4.1.7...png

Fig 1.4.1.7
The demand for Green Chemistry processes has prompted search for new green procedures. Some examples from recent literature are given here (Fig 1.4.1.8).
1.4.1.8...png

Fig 1.4.1.8

Thioketals
Compared with their oxygen analogues, thioketals markedly differ in their chemistry. The formation as well as deprotection is promoted by suitable Lewis acids. The thioacetals are
markedly stable under deketalation conditions, thus paving way for selective operations at two different centers. When conjugated ketones are involved, the ketal formation (as well as
deprotection) proceeds with double bond migration. On the other hand, thioketals are formed and deketalated without double bond migration (Fig 1.4.1.9).

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Fig 1.4.1.9

Silyl Ethers (R – OSiR3)

The oxygen – silicon sigma bond is stable to lithium and Grignard reagents, nucleophiles and hydride reagents but very unstable to water and mild aqueous acid and base conditions. A
silyl ether of secondary alcohol is less reactive than that of a primary alcohol. The O – trimethylsilyl (O – SiMe3) was first protection of this class. (Fig 1.4.1.24).

Fig 1.4.1.24
Replacement of methyl group with other alkyl and aryl groups gives a large variety of silyl ether with varying degrees of stability towards hydrolysis (Fig 1.4.1.25).

Fig 1.4.1.25
The following examples illustrate the selectivity in formation and hydrolysis of this group (Fig 1.4.1.26).

Fig 1.4.1.26

Contributors
Prof. R Balaji Rao (Department of Chemistry, Banaras Hindu University, Varanasi) as part of Information and Communication Technology

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17.9: Nucleophilic Addition of Ammonia and Its Derivatives
Objectives
After completing this section, you should be able to
1. write equations to describe the reactions that occur between aldehydes or ketones and primary or secondary
amines.
2. identify the product formed from the reaction of a given aldehyde or ketone with a given primary or secondary
amine.
3. identify the aldehyde or ketone, the amine, or both, required in the synthesis of a given imine or enamine.
4. write the detailed mechanism for the reaction of an aldehyde or ketone with a primary amine.
5. write the detailed mechanism for the reaction of an aldehyde or ketone with a secondary amine.
6. explain why the rate of a reaction between an aldehyde or ketone and a primary or secondary amine is dependent
on pH.

Key Terms
Make certain that you can define, and use in context, the key terms below.
2,4‑dinitrophenylhydrozone
enamine
imine

Study Notes

An imine is a compound that contains the structural unit

An enamine is a compound that contains the structural unit

Both of these types of compound can be prepared through the reaction of an aldehyde or ketone with an amine.
You may have the opportunity to observe the reaction of an aldehyde and ketone with 2,4‑dinitrophenylhydrazine
(Brady’s reagent) to form a 2,4‑dinitrophenylhydrozone in the laboratory. This is a classical organic chemistry test to
confirm the presence of a carbonyl group. The reaction produces very colourful and bright precipitates of yellow,
orange and red.
If you can understand why the two reactions of imine and enamine formation are essentially identical, and can write a
detailed mechanism for each one, you are well on the way to mastering organic chemistry. If you understand how and
why these reactions occur, you can keep the amount of material that you need to memorize to a minimum.

Reaction with Primary Amines to form Imines

The reaction of aldehydes and ketones with ammonia or 1º-amines forms imine derivatives, also known as Schiff bases
(compounds having a C=N function). Water is eliminated in the reaction, which is acid-catalyzed and reversible in the
same sense as acetal formation. The pH for reactions which form imine compounds must be carefully controlled. The rate
at which these imine compounds are formed is generally greatest near a pH of 5, and drops at higher and lower pH's. At
high pH there will not be enough acid to protonate the OH in the intermediate to allow for removal as H2O. At low pH
most of the amine reactant will be tied up as its ammonium conjugate acid and will become non-nucleophilic.

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Converting reactants to products simply

Examples of imine forming reactions

Mechanism of imine formation

1) Nucleophilic attack

2) Proton transfer

3) Protonation of OH

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4) Removal of water

5) Deprotonation

Reversibility of imine forming reactions

Imines can be hydrolyzed back to the corresponding primary amine under acidic conditons.

Reactions involving other reagents of the type Y-NH2

Imines are sometimes difficult to isolate and purify due to their sensitivity to hydrolysis. Consequently, other reagents of
the type Y–NH2 have been studied, and found to give stable products (R2C=N–Y) useful in characterizing the aldehydes
and ketones from which they are prepared. Some of these reagents are listed in the following table, together with the
structures and names of their carbonyl reaction products. Hydrazones are used as part of the Wolff-Kishner reduction and
will be discussed in more detail in another module.

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With the exception of unsubstituted hydrazones, these derivatives are easily prepared and are often crystalline solids - even
when the parent aldehyde or ketone is a liquid. Since melting points can be determined more quickly and precisely than
boiling points, derivatives such as these are useful for comparison and identification of carbonyl compounds. It should be
noted that although semicarbazide has two amino groups (–NH2) only one of them is a reactive amine. The other is amide-
like and is deactivated by the adjacent carbonyl group.

Problems
1)Please draw the products of the following reactions.

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2) Please draw the structure of the reactant needed to produce the indicated product.

3) Please draw the products of the following reactions.

Answers
1)

2)

3)

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

Reaction with Secondary Amines to form Enamines

Most aldehydes and ketones react with 2º-amines to give products known as enamines. It should be noted that, like acetal
formation, these are acid-catalyzed reversible reactions in which water is lost. Consequently, enamines are easily converted
back to their carbonyl precursors by acid-catalyzed hydrolysis.

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Mechanism
1) Nuleophilic attack

2) Proton transfer

3) Protonation of OH

4) Removal of water

5) Deprotonation

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Reversibility of Enamines

Problems
1) Please draw the products for the following reactions.

2) Please give the structure of the reactant needed to product the following product

Answers
1)

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2)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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17.10: Deoxygenation of the Carbonyl Group
Objectives
After completing this section, you should be able to
1. write an equation to illustrate the Wolff‑Kishner reduction of an aldehyde or ketone.
2. identify the product formed from the Wolff‑Kishner reduction of a given aldehyde or ketone.

Key Terms
Make certain that you can define, and use in context, the key term below.
Wolff‑Kishner reduction

Study Notes

After studying this section, you can add yet another method of reducing organic compounds to your growing list of
reduction reactions.

Aldehydes and ketones can be converted to a hydrazine derivative by reaction with hydrazine. These "hydrazones" can be
further converted to the corresponding alkane by reaction with base and heat. These two steps can be combined into one
reaction called the Wolff-Kishner Reduction which represents a general method for converting aldehydes and ketones into
alkanes. Typically a high boiling point solvent, such as ethylene glycol, is used to provide the high temperatures needed for
this reaction to occur. Note! Nitrogen gas is produced as part of this reaction.

Reaction of Aldehydes or Ketones with Hydrazine Produces a Hydrazone

Reaction with a Base and Heat Converts a Hydrazone to an Alkane

Both Reactions Together Produces the Wolff-Kishner Reduction

Example

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Mechanism of the Wolff-Kishner Reduction
1) Deprotonation of Nitrogen

2) Protonation of the Carbon

3) Deprotonation of Nitrogen

4) Protonation of Carbon

Problems
1) Please draw the products of the following reactions.

Answers
1)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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17.11: Addition of Hydrogen Cyanide to Give Cyanohydrins
Objectives
After completing this section, you should be able to
1. write an equation to describe the formation of a cyanohydrin from an aldehyde or ketone.
2. identify the cyanohydrin formed from the reaction of a given aldehyde or ketone with hydrogen cyanide.
3. identify the aldehyde or ketone, the reagents, or both, needed to prepare a given cyanohydrin.
4. write the detailed mechanism for the addition of hydrogen cyanide to an aldehyde or ketone.

Key Terms
Make certain that you can define, and use in context, the key term below.
cyanohydrin

Study Notes

For successful cyanohydrin formation it is important to have free cyanide ions available to react with the ketone or
aldehyde. This can be achieved by using a salt (e.g. KCN or NaCN) or a silylated (e.g. Me3SiCN) form of cyanide
under acidic conditions or by using HCN with some base added to produce the needed CN− nucleophile.

Cyanohydrins have the structural formula of R2C(OH)CN. The “R” on the formula represents an alkyl, aryl, or hydrogen.
To form a cyanohydrin, a hydrogen cyanide adds reversibly to the carbonyl group of an organic compound thus forming a
hydroxyalkanenitrile adducts (commonly known and called as cyanohydrins).

Figure 19.6.1: General structure of a cyanohydrin

Hydrogen cyanide adds across the carbon-oxygen double bond in aldehydes and ketones to produce compounds known as
hydroxynitriles. For example, with ethanal (an aldehyde) you get 2-hydroxypropanenitrile:

With propanone (a ketone) you get 2-hydroxy-2-methylpropanenitrile:

The reaction isn't normally done using hydrogen cyanide itself, because this is an extremely poisonous gas. Instead, the
aldehyde or ketone is mixed with a solution of sodium or potassium cyanide in water to which a little sulphuric acid has
been added. The pH of the solution is adjusted to about 4 - 5, because this gives the fastest reaction. The solution will
contain hydrogen cyanide (from the reaction between the sodium or potassium cyanide and the sulphuric acid), but still
contains some free cyanide ions. This is important for the mechanism.

Mechanism of Cyanohydrin Formation

Acid-catalyzed hydrolysis of silylated cyanohydrins has recently been shown to give cyanohydrins instead of ketones; thus
an efficient synthesis of cyanohydrins has been found which works with even highly hindered ketones.

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Acetone Cyanohydrins
Acetone cyanohydrins (ACH) have the structural formula of (CH3)2C(OH)CN. It is an organic compound serves in the
production of methyl methacrylate (also known as acrylic).

Figure 19.6.2: Acetone cyanohydrins

It is classified as an extremely hazardous substance, since it rapidly decomposes when it's in contact with water. In ACH,
sulfuric acid is treated to give the sulfate ester of the methacrylamid. Preparations of other cyanohydrins are also used from
ACH: for HACN to Michael acceptors and for the formylation of arenas. The treatment with lithium hydride affords
anhydrous lithium cyanide.

Figure 19.6.3: Reduction of Acetone cyanohydrins

Other Cyanohydrins
Other cyanohydrins, excluding acetone cyanohydrins, are: mandelonitrile and glycolonitrile.

Figure 19.6.4: Structures of Madelonitrile (left) and glycolonitrile (right)

Mandelonitrile have a structural formula of C6H5CH(OH)CN and occur in pits of some fruits. Glycolonitrile is an organic
compound with the structural formula of HOCH2CN, which is the simplest cyanohydrin that is derived by formaldehydes.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Jim Clark (Chemguide.co.uk)

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17.12: Addition of Phosphorus Ylides: The Wittig Reaction
Objectives
After completing this section, you should be able to
1. write an equation to illustrate the formation of an ylide (phosphorane).
2. write an equation to illustrate the reaction that takes place between an ylide and an aldehyde or ketone.
3. identify the alkene which results from the reaction of a given ylide with a given aldehyde or ketone.
4. identify the aldehyde or ketone, the ylide, or both, needed to prepare a given alkene by a Wittig reaction.

Key Terms
Make certain that you can define, and use in context, the key terms below.
betaine
Wittig reaction
ylide (phosphorane)

Study Notes

The name triphenylphosphine is derived as follows: the compound PH3 is called phosphine; replacing the three
hydrogen atoms with phenyl groups therefore gives us triphenylphosphine.
Note the following series of IUPAC‑accepted trivial names:
NH3—ammonia
PH3—phosphine
AsH3—arsine

Organophosphorus ylides react with aldehydes or ketones to give substituted alkenes in a transformation called the Wittig
reaction. This reaction is named for George Wittig who was awarded the Nobel prize for this work in 1979. A principal
advantage of alkene synthesis by the Wittig reaction is that the location of the double bond is absolutely fixed, in contrast
to the mixtures often produced by alcohol dehydration.

Preparation of Phosphorus Ylides

It has been noted that dipolar phosphorus compounds are stabilized by p-d bonding. This bonding stabilization extends to
carbanions adjacent to phosphonium centers, and the zwitterionic conjugate bases derived from such cations are known as
ylides. An ylide is defined as a compound with opposite charges on adjacent atoms both of which have complete octets.
For the Wittig reaction discussed below an organophosphorus ylide, also called Wittig reagents, will be used. The ability of
phosphorus to hold more than eight valence electrons allows for a resonance structure to be drawn forming a double
bonded structure.

The stabilization of the carbanion provided by the phosphorus causes an increase in acidity (pKa ~35). Very strong bases,
such as butyl lithium, are required for complete formation of ylides.

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The ylides shown here are all strong bases. Like other strongly basic organic reagents, they are protonated by water and
alcohols, and are sensitive to oxygen. Water decomposes phosphorous ylides to hydrocarbons and phosphine oxides, as
shown.

Although many ylides are commercially available it is often necessary to create them synthetically. Ylides can be
synthesized from an alkyl halide and a trialkyl phosphine. Typically triphenyl phosphine is used to synthesize ylides.
Because a SN2 reaction is used in the ylide synthesis methyl and primary halides perform the best. Secondary halides can
also be used but the yields are generally lower. This should be considered when planning out a synthesis which involves a
synthesized Wittig reagent.

Mechanism of ylide formation

1) SN2 reaction

2) Deprotonation

Examples of ylide formation

The Wittig Reaction

The most important use of ylides in synthesis comes from their reactions with aldehydes and ketones, which are initiated in
every case by a covalent bonding of the nucleophilic alpha-carbon to the electrophilic carbonyl carbon. Ylides react to give
substituted alkenes in a transformation called the Wittig reaction. This reaction is named for George Wittig who was

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awarded the Nobel prize for this work in 1979. A principal advantage of alkene synthesis by the Wittig reaction is that the
location of the double bond is absolutely fixed, in contrast to the mixtures often produced by alcohol dehydration.

Going from reactants to products simplified

Examples of the Wittig reaction

Mechanism of the Wittig reaction

Following the initial carbon-carbon bond formation, two intermediates have been identified for the Wittig reaction, a
dipolar charge-separated species called a betaine and a four-membered heterocyclic structure referred to as an
oxaphosphatane. Cleavage of the oxaphosphatane to alkene and phosphine oxide products is exothermic and irreversible.
1) Nucleophillic attack on the carbonyl

2) Formation of a 4 membered ring

3) Formation of the alkene

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Limitation of the Wittig reaction
If possible both E and Z isomer of the double bond will be formed. This should be considered when planning a synthesis
involving a Wittig Reaction.

Problems
1) Please write the product of the following reactions.

2) Please indicate the starting material required to produce the product.

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3) Please draw the structure of the oxaphosphetane which is made during the mechanism of the reaction given that
produces product C.
4) Please draw the structure of the betaine which is made during the mechanism of the reaction given that produces
product D.
5) Please give a detailed mechanism and the final product of this reaction

6) It has been shown that reacting and epoxide with triphenylphosphine forms an alkene. Please propose a mechanism for
this reaction. Review the section on epoxide reactions if you need help.

Answers
1)

2)

3)

4)

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5)
Nucleophillic attack on the carbonyl

Formation of a 4 membered ring

Formation of the alkene

6) Nucleophillic attack on the epoxide

Formation of a 4 membered ring

Formation of the alkene

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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17.13: Oxidation by Peroxycarboxylic Acids: The Baeyer- Villiger Oxidation
Baeyer-Villiger oxidation is the oxidation of a ketone to a carboxylic acid ester using a peroxyacid as the oxidizing agent.
eg. 1:

eg. 2:

Mechanism

When the two ligands on the carbonyl carbon in the ketone are different, Baeyer-Villiger oxidation is regioselective. Of the
two alpha carbons in the ketone, the one that can stabilize a positive charge more effectively, which is the more highly
substituted one, migrates from carbon to oxygen preferentially.
eg. 1:

eg. 2:

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References
1. Baeyer-Villiger Oxidation of Ketones to Esters with Sodium Percarbonate/Trifluoroacetic Acid, G. A. Olah, Q. Wang,
N. J. Trivedi, G. K. S. Prakash, Synthesis, 1991, 739-740.
2. Baeyer, A.; Villiger, V. Ber. Dtsch. Chem. Ges. 1899, 32, 3625–3633.
3. P. A. S. Smith in Molecular Rearrangements Part 1, P. de Mayo, Ed. (Wiley- Interscience, New York, 1963) pp 577-
591; J. B. Lee, B. C. Uff, Quart. Rev. Chem. Soc. 21, 429-457 (1967);
4. C. H. Hassall, Org. React. 9,73 (1957); G. R. Krow,ibid. 43, 251-798 (1993);
5. C. H. Hassall,, Comp. Org. Syn. 7, 671-688 (1991).

Contributors
Gamini Gunawardena from the OChemPal site (Utah Valley University)

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17.14: Oxidative Chemical Tests for Aldehydes
Objectives
After completing this section, you should be able to
1. write an equation for the oxidation of an aldehyde using
a. CrO3/sulphuric acid.
b. Tollens reagent.
2. explain the difference in structure which makes aldehydes susceptible to oxidation and ketones difficult to oxidize.
3. identify the carboxylic acid produced when a given aldehyde is oxidized.
4. identify the aldehyde, the oxidizing agent, or both, needed to prepare a given carboxylic acid.

Key Terms
Make certain that you can define, and use in context, the key term below.
Tollens reagent

Study Notes
An important difference between aldehydes and ketones is the ease with which the latter can be oxidized. Tollen’s
reagent is a classical organic laboratory technique to test for the presence of an aldehyde. The reagent consists of
silver(I) ions dissolved in dilute ammonia. When the aldehyde is oxidized, the silver(I) ions are reduced to silver
metal. When the reaction is carried out in a test‑tube, the metallic silver is deposited on the walls of the tube, giving it
a mirrorlike appearance. This characteristic accounts for the term “silver mirror test” which is applied when this
reaction is used to distinguish between aldehydes and ketones—the latter, of course, do not react.

This page looks at ways of distinguishing between aldehydes and ketones using oxidizing agents such as acidified
potassium dichromate(VI) solution, Tollens' reagent, Fehling's solution and Benedict's solution.

Why do aldehydes and ketones behave differently?

You will remember that the difference between an aldehyde and a ketone is the presence of a hydrogen atom attached to
the carbon-oxygen double bond in the aldehyde. Ketones don't have that hydrogen.

Oxidation of Aldehydes
The presence of that hydrogen atom makes aldehydes very easy to oxidize. Or, put another way, they are strong reducing
agents. The most common reagent for this conversion is CrO3 in aqueous acid. This reaction generally gives good yields at
room temperature.

Unfortunately, the acid condition for the previous reaction can cause unwanted side reaction. If this problem occurs it can
be rectified by using a solution of sliver oxide, Ag2O, in aqueous ammonia, also called Tollens' reagent.

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Because ketones do not have that particular hydrogen atom, they are resistant to oxidation, and only very strong oxidizing
agents like potassium manganate(VII) solution (potassium permanganate solution) oxidize ketones. However, they do it in
a destructive way, breaking carbon-carbon bonds and forming two carboxylic acids.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Jim Clark (Chemguide.co.uk)

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CHAPTER OVERVIEW
18: ENOLS, ENOLATES, AND THE ALDOL CONDENSATION: A,B-
UNSATURATED ALDEHYDES AND KETONES
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

18.1: ACIDITY OF ALDEHYDES AND KETONES: ENOLATE IONS

18.2: KETO-ENOL EQUILIBRIA
18.3: HALOGENATION OF ALDEHYDES AND KETONES
18.4: ALKYLATION OF ALDEHYDES AND KETONES
18.5: ATTACK BY ENOLATES ON THE CARBONYL FUNCTION: ALDOL CONDENSATION
18.6: CROSSED ALDOL CONDENSATION
18.7: KEYS TO SUCCESS: COMPETITIVE RECTION PATHWAYS AND THE INTRAMOLECULAR ALDOL
CONDENSATION
18.8: PROPERTIES OF A,B-UNSATURATED ALDEHYDES AND KETONES
18.9: CONJUGATE ADDITIONS TO A,B-UNSATURATED ALDEHYDES AND KETONES
18.10: 1,2- AND 1,4-ADDITIONS OF ORGANOMETALLIC REAGENTS
18.11: CONJUGATE ADDITIONS OF ENOLATE IONS: MICHAEL ADDITION AND ROBINSON ANNULATION

1 12/5/2021
18.1: Acidity of Aldehydes and Ketones: Enolate Ions
☰
For alkylation reactions of enolate anions to be useful, these intermediates must be generated in high concentration in the
absence of other strong nucleophiles and bases. The aqueous base conditions used for the aldol condensation are not
suitable because the enolate anions of simple carbonyl compounds are formed in very low concentration, and hydroxide or
alkoxide bases induce competing SN2 and E2 reactions of alkyl halides. It is necessary, therefore, to achieve complete
conversion of aldehyde or ketone reactants to their enolate conjugate bases by treatment with a very strong base (pKa > 25)
in a non-hydroxylic solvent before any alkyl halides are added to the reaction system. Some bases that have been used for
enolate anion formation are: NaH (sodium hydride, pKa > 45), NaNH2 (sodium amide, pKa = 34), and LiN[CH(CH3)2]2
(lithium diisopropylamide, LDA, pKa 36). Ether solvents like tetrahydrofuran (THF) are commonly used for enolate anion
formation. With the exception of sodium hydride and sodium amide, most of these bases are soluble in THF. Certain other
strong bases, such as alkyl lithium and Grignard reagents, cannot be used to make enolate anions because they rapidly and
irreversibly add to carbonyl groups. Nevertheless, these very strong bases are useful in making soluble amide bases. In the
preparation of lithium diisopropylamide (LDA), for example, the only other product is the gaseous alkane butane.

Because of its solubility in THF, LDA is a widely used base for enolate anion formation. In this application, one equivalent
of diisopropylamine is produced along with the lithium enolate, but this normally does not interfere with the enolate
reactions and is easily removed from the products by washing with aqueous acid. Although the reaction of carbonyl
compounds with sodium hydride is heterogeneous and slow, sodium enolates are formed with the loss of hydrogen, and no
other organic compounds are produced.
The presence of these overlapping p orbitals gives α hydrogens (Hydrogens on carbons adjacent to carbonyls) special
properties. In particular, α hydrogens are weakly acidic because the conjugate base, called an enolate, is stabilized though
conjugation with the π orbitals of the carbonyl. The effect of the carbonyl is seen when comparing the pKa for the α
hydrogens of aldehydes (~16-18), ketones (~19-21), and esters (~23-25) to the pKa of an alkane (~50).

Of the two resonance structures of the enolate ion the one which places the negative charge on the oxygen is the most
stable. This is because the negative change will be better stabilized by the greater electronegativity of the oxygen.

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Acidity of α-Hydrogens in Some Activated Compounds
☰ Compound RCH2–NO2 RCH2–COR RCH2–C≡N RCH2–SO2R

pKa 9 20 25 25

Examples

If the formed enolate is stabilized by more than one carbonyl it is possible to use a weaker base such as sodium ethoxide.
NaOCH2CH3 = Na+ -OCH2CH3 = NaOEt

Because of the acidity of α hydrogens, carbonyls undergo keto-enol tautomerism. Tautomers are rapidly interconverted
constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom and a differently
located double bond. The equilibrium between tautomers is not only rapid under normal conditions, but it often strongly
favors one of the isomers (acetone, for example, is 99.999% keto tautomer). Even in such one-sided equilibria, evidence
for the presence of the minor tautomer comes from the chemical behavior of the compound. Tautomeric equilibria are
catalyzed by traces of acids or bases that are generally present in most chemical samples.

General Reaction of Enolates

The Ambident Character of Enolate Anions

Since the negative charge of an enolate anion is delocalized over the alpha-carbon and the oxygen, as shown earlier,
electrophiles may bond to either atom. Reactants having two or more reactive sites are called ambident, so this term is
properly applied to enolate anions. Modestly electrophilic reactants such as alkyl halides are not sufficiently reactive to
combine with neutral enol tautomers, but the increased nucleophilicity of the enolate anion conjugate base permits such
reactions to take place. Because alkylations are usually irreversible, their products should reflect the inherent (kinetic)
reactivity of the different nucleophilic sites.

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☰

If an alkyl halide undergoes an SN2 reaction at the carbon atom of an enolate anion the product is an alkylated aldehyde or
ketone. On the other hand, if the SN2 reaction occurs at oxygen the product is an ether derivative of the enol tautomer;
such compounds are stable in the absence of acid and may be isolated and characterized. These alkylations (shown above)
are irreversible under the conditions normally used for SN2 reactions, so the product composition should provide a
measure of the relative rates of substitution at carbon versus oxygen. It has been found that this competition is sensitive to
a number of factors, including negative charge density, solvation, cation coordination and product stability.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Steven Farmer (Sonoma State University)

Enolate of Unsymmetrical Carbonyl Compounds

Now let’s consider what happens when an unsymmetrical carbonyl is treated with a base. In the case displayed below there
are two possible enolates which can form. The removal of the 2o hydrogen forms the kinetic enolate and is formed faster
because it is less substituted and thereby less sterically hindered. The removal of the 3o hydrogen forms the
thermodynamic enolate which is more stable because it is more substituted.

Kinetic Enolates
Kinetic enolates are formed when a strong bulky base like LDA is used. The bulky base finds the 2o hydrogen less
sterically hindered and preferable removes it.
Low temperature are typically used when forming the kinetic enolate to prevent equilibration to the more stable
thermodynamic enolate. Typically a temperature of -78 oC is used.

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Thermodynamic Enolates
☰
The thermodynamic enolate is favored by conditions which allow for equilibration. The thermodynamic enolate is usually
formed by using a strong base at room temperature. At equilibrium the lower energy of the thermodynamic enolate is
preferred, so that the more stable, more stubstituted enolate is formed.

Contributors
Prof. Steven Farmer (Sonoma State University)

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18.2: Keto-Enol Equilibria
Acidity of Alpha Hydrogens
Functional groups, such as aldehydes, ketones and esters, contain a carbonyl group which is made up of a sp2 hybridized
carbon and oxygen. Because they are sp2 hybridized the carbon and oxygen both have unhybridized p orbitals which can
overlap to form the C=O π bond.

Keto-enol Tautomerism
Because of the acidity of α hydrogens carbonyls undergo keto-enol tautomerism. Tautomers are rapidly interconverted
constitutional isomers, usually distinguished by a different bonding location for a labile hydrogen atom and a differently
located double bond. The equilibrium between tautomers is not only rapid under normal conditions, but it often strongly
favors one of the isomers (acetone, for example, is 99.999% keto tautomer). Even in such one-sided equilibria, evidence
for the presence of the minor tautomer comes from the chemical behavior of the compound. Tautomeric equilibria are
catalyzed by traces of acids or bases that are generally present in most chemical samples.

Mechanism for Enol Formation

Acid conditions
1) Protonation of the Carbonyl

2) Enol formation

Basic conditions
1) Enolate formation

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2) Protonation

How Enols React

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Steven Farmer (Sonoma State University)
Due to the acidic nature of α hydrogens they can be exchanged with deuterium by reaction with D2O (heavy water). The
process is accelerated by the addition of an acid or base; an excess of D2O is required. The end result is the complete
exchange of all α hydrogens with deuterium.

General reaction

Example 1: Deuterium Exchange

Mechanism in basic conditions

1) Enolate Formation

2) Deuteration

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Problems
1) Please draw the product for the following reactions.

2) Answers

Contributors
Prof. Steven Farmer (Sonoma State University)

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18.3: Halogenation of Aldehydes and Ketones
A carbonyl containing compound with α hydrogens can undergo a substitution reaction with halogens. This reaction comes
about because of the tendency of carbonyl compounds to form enolates in basic condition and enols in acidic condition. In
these cases even weak bases, such as the hydroxide anion, is sufficient enough to cause the reaction to occur because it is
not necessary for a complete conversion to the enolate. For this reaction Cl2, Br2 or I2 can be used as the halogens.
General reaction

Example

Acid Catalyzed Mechanism

Under acidic conditions the reaction occurs thought the formation of an enol which then reacts with the halogen.
1) Protonation of the carbonyl

2) Enol formation

3) SN2 attack

4) Deprotonation

Base Catalyzed Mechanism

Under basic conditions the enolate forms and then reacts with the halogen. Note! This is base promoted and not base
catalyzed because an entire equivalent of base is required.
1) Enolate formation

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2) SN2 attack

Overreaction during base promoted α halogenation

The fact that an electronegative halogen is placed on an α carbon means that the product of a base promoted α
halogenation is actually more reactive than the starting material. The electron withdrawing effect of the halogen makes the
α carbon even more acidic and therefor promotes further reaction. Because of this multiple halogenations can occur. This
effect is exploited in the haloform reaction discussed later. If a monohalo product is required then acidic conditions are
usually used.

The Haloform Reaction

Methyl ketones typically undergo halogenation three times to give a trihalo ketone due to the increased reactivity of the
halogenated product as discussed above. This trihalomethyl group is an effective leaving group due to the three electron
withdrawing halogens and can be cleaved by a hydroxide anion to effect the haloform reaction. The product of this
reaction is a carboxylate and a haloform molecule (CHCl3, CHBr3, CHI3). Overall the haloform reaction represents an
effective method for the conversion of methyl ketones to carboxylic acids. Typically, this reaction is performed using
iodine because the subsequent iodoform (CHI3) is a bright yellow solid which is easily filtered off.
General reaction

Example: The Haloform Reaction

Mechanism
1) Formation of the trihalo species

2) Nulceophilic attack on the carbonyl carbon

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3) Removal of the leaving group

4) Deprotonation

Problems
1) Please draw the products of the following reactions

Answers
1)

Contributors
Prof. Steven Farmer (Sonoma State University)

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18.4: Alkylation of Aldehydes and Ketones
Enolates can act as a nucleophile in SN2 type reactions. Overall an α hydrogen is replaced with an alkyl group. This
reaction is one of the more important for enolates because a carbon-carbon bond is formed. These alkylations are affected
by the same limitations as SN2 reactions previously discussed. A good leaving group, Chloride, Bromide, Iodide, Tosylate,
should be used. Also, secondary and tertiary leaving groups should not be used because of poor reactivity and possible
competition with elimination reactions. Lastly, it is important to use a strong base, such as LDA or sodium amide, for this
reaction. Using a weaker base such as hydroxide or an alkoxide leaves the possibility of multiple alkylation’s occurring.

Example 1: Alpha Alkylation

Mechanism
1) Enolate formation

2) Sn2 attack

Alkylation of Unsymmetrical Ketones

Unsymmetrical ketones can be regioselctively alkylated to form one major product depending on the reagents.
Treatment with LDA in THF at -78oC tends to form the less substituted kinetic enolate.

Using sodium ethoxide in ethanol at room temperature forms the more substituted thermodynamic enolate.

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Problems
1) Please write the structure of the product for the following reactions.

Answers
1)

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Steven Farmer (Sonoma State University)

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18.5: Attack by Enolates on the Carbonyl Function: Aldol Condensation
A useful carbon-carbon bond-forming reaction known as the Aldol Reaction is yet another example of electrophilic
substitution at the alpha carbon in enolate anions. The fundamental transformation in this reaction is a dimerization of an
aldehyde (or ketone) to a beta-hydroxy aldehyde (or ketone) by alpha C–H addition of one reactant molecule to the
carbonyl group of a second reactant molecule. Due to the carbanion like nature of enolates they can add to carbonyls in a
similar manner as Grignard reagents. For this reaction to occur at least one of the reactants must have α hydrogens.

General Aldol reaction

Going from reactants to products simply

Example 1: Aldol Reactions

Aldol Reaction Mechanism

Step 1: Enolate formation

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Step 2: Nucleophilic attack by the enolate

Step 3: Protonation

Aldol Condensation: the dehydration of Aldol products to synthesize α, β unsaturated carbonyl

(enones)
The products of aldol reactions often undergo a subsequent elimination of water, made up of an alpha-hydrogen and the
beta-hydroxyl group. The product of this β-elimination reaction is an α,β-unsaturated aldehyde or ketone. Base-catalyzed
elimination occurs with heating. The additional stability provided by the conjugated carbonyl system of the product makes
some aldol reactions thermodynamically and mixtures of stereoisomers (E & Z) are obtained from some reactions.
Reactions in which a larger molecule is formed from smaller components, with the elimination of a very small by-product
such as water, are termed Condensations. Hence, the following examples are properly referred to as aldol condensations.
Overall the general reaction involves a dehydration of an aldol product to form an alkene:

Figure: General reaction for an aldol condensation

Going from reactants to products simply

Figure: The aldol condensatio example

Example 2: Aldol Condensation

Aldol Condensation Mechanism

1) Form enolate

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2) Form enone

When performing both reactions together always consider the aldol product first then convert to the enone. Note! The
double bond always forms in conjugation with the carbonyl.
Example

Contributors

Prof. Steven Farmer (Sonoma State University)

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18.6: Crossed Aldol Condensation
Mixed Aldol Reaction and Condensations
The previous examples of aldol reactions and condensations used a common reactant as both the enolic donor and the
electrophilic acceptor. The product in such cases is always a dimer of the reactant carbonyl compound. Aldol
condensations between different carbonyl reactants are called crossed or mixed reactions, and under certain conditions
such crossed aldol condensations can be effective.
Example 3: Mixed Aldol Reaction

The success of these mixed aldol reactions is due to two factors. First, aldehydes are more reactive acceptor electrophiles
than ketones, and formaldehyde is more reactive than other aldehydes. Second, aldehydes lacking alpha-hydrogens can
only function as acceptor reactants, and this reduces the number of possible products by half. Mixed aldols in which both
reactants can serve as donors and acceptors generally give complex mixtures of both dimeric (homo) aldols and crossed
aldols. Because of this most mixed aldol reactions are usually not performed unless one reactant has no alpha hydrogens.
The following abbreviated formulas illustrate the possible products in such a case, red letters representing the acceptor
component and blue the donor. If all the reactions occurred at the same rate, equal quantities of the four products would be
obtained. Separation and purification of the components of such a mixture would be difficult.
AACH2CHO + BCH2CHO + NaOH → A–A + B–B + A–B + B–A
The aldol condensation of ketones with aryl aldehydes to form α,β-unsaturated derivatives is called the Claisen-Schmidt
reaction.
Example 4: Claisen-Schmidt Reaction

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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18.7: Keys to Success: Competitive Rection Pathways and the Intramolecular
Aldol Condensation
Intramolecular aldol reaction
Molecules which contain two carbonyl functionalities have the possibility of forming a ring through an intramolecular
aldol reaction. In most cases two sets of α hydrogens need to be considered. As with most ring forming reaction five and
six membered rings are preferred.

As with other aldol reaction the addition of heat causes an aldol condensation to occur.

Contributors
Prof. Steven Farmer (Sonoma State University)

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18.8: Properties of a,b-Unsaturated Aldehydes and Ketones

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18.9: Conjugate Additions to a,b-Unsaturated Aldehydes and Ketones
One of the largest and most diverse classes of reactions is composed of nucleophilic additions to a carbonyl group.
Conjugation of a double bond to a carbonyl group transmits the electrophilic character of the carbonyl carbon to the beta-
carbon of the double bond. These conjugated carbonyl are called enones or α, β unsaturated carbonyls. A resonance
description of this transmission is shown below.

From this formula it should be clear that nucleophiles may attack either at the carbonyl carbon, as for any aldehyde, ketone
or carboxylic acid derivative, or at the beta-carbon. These two modes of reaction are referred to as 1,2-addition and 1,4-
addition respectively. A 1,4-addition is also called a conjugate addition.

Basic reaction of 1,2 addition

Here the nucleophile adds to the carbon which is in the one position. The hydrogen adds to the oxygen which is in the two
position.

Basic reaction of 1,4 addition

In 1,4 addition the Nucleophile is added to the carbon β to the carbonyl while the hydrogen is added to the carbon α to the
carbonyl.

Mechanism for 1,4 addition

1) Nucleophilic attack on the carbon β to the carbonyl

2) Proton Transfer

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Here we can see why this addition is called 1,4. The nucleophile bonds to the carbon in the one position and the hydrogen
adds to the oxygen in the four position.
3) Tautomerization

Going from reactant to products simplified

1,2 vs. 1,4 addition

Whether 1,2 or 1,4-addition occurs depends on multiple variables but mostly it is determined by the nature of the
nucleophile. During the addition of a nucleophile there is a competition between 1,2 and 1,4 addition products. If the
nucleophile is a strong base, such as Grignard reagents, both the 1,2 and 1,4 reactions are irreversible and therefor are
under kinetic control. Since 1,2-additions to the carbonyl group are fast, we would expect to find a predominance of 1,2-
products from these reactions.
If the nucleophile is a weak base, such as alcohols or amines, then the 1,2 addition is usually reversible. This means the
competition between 1,2 and 1,4 addition is under thermodynamic control. In this case 1,4-addition dominates because the
stable carbonyl group is retained.

Nucleophiles which add 1,4 to α, β unsaturated carbonyls

Water

Alcohols

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Thiols

1o Amines

2o Amines

HBr

Cyanides

Gilman Reagents
Another important reaction exhibited by organometallic reagents is metal exchange. Organolithium reagents react with
cuprous iodide to give a lithium dimethylcopper reagent, which is referred to as a Gilman reagent. Gilman reagents are a
source of carbanion like nucleophiles similar to Grignard and Organo lithium reagents. However, the reactivity of
organocuprate reagents is slightly different and this difference will be exploited in different situations. In the case of α, β
unsaturated carbonyls organocuprate reagents allow for an 1,4 addition of an alkyl group. As we will see later Grignard
and Organolithium reagents add alkyl groups 1,2 to α, β unsaturated carbonyls
Organocuprate reagents are made from the reaction of organolithium reagents and C uI
2RLi + C uI → R2 C uLi + LiI (18.9.1)

This acts as a source of R:-

2C H3 Li + C uI → (C H3 )2 C uLi + LiI (18.9.2)

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Example

Nucleophiles which add 1,2 to α, β unsaturated carbonyls

Metal Hydrides

Grignard Reagents

Organolithium Reagents

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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18.10: 1,2- and 1,4-Additions of Organometallic Reagents
One of the largest and most diverse classes of reactions is composed of nucleophilic additions to a carbonyl group.
Conjugation of a double bond to a carbonyl group transmits the electrophilic character of the carbonyl carbon to the beta-
carbon of the double bond. These conjugated carbonyl are called enones or α, β unsaturated carbonyls. A resonance
description of this transmission is shown below.

From this formula it should be clear that nucleophiles may attack either at the carbonyl carbon, as for any aldehyde, ketone
or carboxylic acid derivative, or at the beta-carbon. These two modes of reaction are referred to as 1,2-addition and 1,4-
addition respectively. A 1,4-addition is also called a conjugate addition.

Basic reaction of 1,2 addition

Here the nucleophile adds to the carbon which is in the one position. The hydrogen adds to the oxygen which is in the two
position.

Basic reaction of 1,4 addition

In 1,4 addition the Nucleophile is added to the carbon β to the carbonyl while the hydrogen is added to the carbon α to the
carbonyl.

Mechanism for 1,4 addition

1) Nucleophilic attack on the carbon β to the carbonyl

2) Proton Transfer

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Here we can see why this addition is called 1,4. The nucleophile bonds to the carbon in the one position and the hydrogen
adds to the oxygen in the four position.
3) Tautomerization

Going from reactant to products simplified

1,2 vs. 1,4 addition

Whether 1,2 or 1,4-addition occurs depends on multiple variables but mostly it is determined by the nature of the
nucleophile. During the addition of a nucleophile there is a competition between 1,2 and 1,4 addition products. If the
nucleophile is a strong base, such as Grignard reagents, both the 1,2 and 1,4 reactions are irreversible and therefor are
under kinetic control. Since 1,2-additions to the carbonyl group are fast, we would expect to find a predominance of 1,2-
products from these reactions.
If the nucleophile is a weak base, such as alcohols or amines, then the 1,2 addition is usually reversible. This means the
competition between 1,2 and 1,4 addition is under thermodynamic control. In this case 1,4-addition dominates because the
stable carbonyl group is retained.

Nucleophiles which add 1,4 to α, β unsaturated carbonyls

Water

Alcohols

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Thiols

1o Amines

2o Amines

HBr

Cyanides

Gilman Reagents
Another important reaction exhibited by organometallic reagents is metal exchange. Organolithium reagents react with
cuprous iodide to give a lithium dimethylcopper reagent, which is referred to as a Gilman reagent. Gilman reagents are a
source of carbanion like nucleophiles similar to Grignard and Organo lithium reagents. However, the reactivity of
organocuprate reagents is slightly different and this difference will be exploited in different situations. In the case of α, β
unsaturated carbonyls organocuprate reagents allow for an 1,4 addition of an alkyl group. As we will see later Grignard
and Organolithium reagents add alkyl groups 1,2 to α, β unsaturated carbonyls
Organocuprate reagents are made from the reaction of organolithium reagents and C uI
2RLi + C uI → R2 C uLi + LiI (18.10.1)

This acts as a source of R:-

2C H3 Li + C uI → (C H3 )2 C uLi + LiI (18.10.2)

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Example

Nucleophiles which add 1,2 to α, β unsaturated carbonyls

Metal Hydrides

Grignard Reagents

Organolithium Reagents

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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18.11: Conjugate Additions of Enolate Ions: Michael Addition and Robinson
Annulation
Basic reaction of 1,4 addition

In 1,4 addition the Nucleophile is added to the carbon β to the carbonyl while the hydrogen is added to the carbon α to the
carbonyl.

Mechanism for 1,4 addition

1) Nucleophilic attack on the carbon β to the carbonyl

2) Proton Transfer

Here we can see why this addition is called 1,4. The nucleophile bonds to the carbon in the one position and the hydrogen
adds to the oxygen in the four position.
3) Tautomerization

Enolates undergo 1,4 addition to α, β-unsaturated carbonyl compounds is a process called a Michael addition. The reaction
is named after American chemist Arthur Michael (1853-1942).

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Examples of Michael Additions

Contributors

Prof. Steven Farmer (Sonoma State University)

Many times the product of a Michael addition produces a dicarbonyl which can then undergo an intramolecular aldol
reaction. These two processes together in one reaction creates two new carbon-carbon bonds and also creates a ring. Ring-
forming reactions are called annulations after the Latin work for ring annulus. The reaction is named after English chemist
Sir Robert Robinson (1886-1975) who developed it. He received the Nobel prize in chemistry in 1947. Remember that
during annulations five and six membered rings are preferred.

Examples of Robinson Annulations

Contributors
Prof. Steven Farmer (Sonoma State University)

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CHAPTER OVERVIEW
19: CARBOXYLIC ACIDS
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

19.1: NAMING THE CARBOXYLIC ACIDS

19.2: STRUCTURAL AND PHYSICAL PROPERTIES OF CARBOXYLIC ACIDS
19.3: SPECTROSCOPY AND MASS SPECTROMETRY OF CARBOXYLIC ACIDS
19.4: ACIDIC AND BASIC CHARACTER OF CARBOXYLIC ACIDS
19.5: CARBOXYLIC ACID SYNTHESIS IN INDUSTRY
19.6: METHODS FOR INTRODUCING THE CARBOXY FUNCTIONAL GROUP
19.7: SUBSTITUTION AT THE CARBOXY CARBON: THE ADDITION-ELIMINATION MECHANISM
19.8: CARBOXYLIC ACID DERIVATIVES: ALKANOYL (ACYL) HALIDES AND ANHYDRIDES
19.9: CARBOXYLIC ACID DERIVATIVES: ESTERS
19.10: CARBOXYLIC ACID DERIVATIVES: AMIDES
19.11: REDUCTION OF CARBOXYLIC ACIDS BY LITHIUM ALUMINUM HYDRIDE
19.12: BROMINATION NEXT TO THE CARBOXY GROUP: THE HELL-VOLHARD-ZELINSKY REACTION
19.13: BIOLOGICAL ACTIVITY OF CARBOXYLIC ACIDS

1 12/5/2021
19.1: Naming the Carboxylic Acids
The IUPAC system of nomenclature assigns a characteristic suffix to these classes. The –e ending is removed from the
name of the parent chain and is replaced -anoic acid. Since a carboxylic acid group must always lie at the end of a carbon
chain, it is always is given the #1 location position in numbering and it is not necessary to include it in the name.
Many carboxylic acids are called by the common names. These names were chosen by chemists to usually describe a
source of where the compound is found. In common names of aldehydes, carbon atoms near the carboxyl group are often
designated by Greek letters. The atom adjacent to the carbonyl function is alpha, the next removed is beta and so on.

Formula Common Name Source IUPAC Name Melting Point Boiling Point

HCO2H formic acid ants (L. formica) methanoic acid 8.4 ºC 101 ºC

CH3CO2H acetic acid vinegar (L. acetum) ethanoic acid 16.6 ºC 118 ºC

milk (Gk. protus

CH3CH2CO2H propionic acid propanoic acid -20.8 ºC 141 ºC
prion)

CH3(CH2)2CO2H butyric acid butter (L. butyrum) butanoic acid -5.5 ºC 164 ºC

CH3(CH2)3CO2H valeric acid valerian root pentanoic acid -34.5 ºC 186 ºC

CH3(CH2)4CO2H caproic acid goats (L. caper) hexanoic acid -4.0 ºC 205 ºC

CH3(CH2)5CO2H enanthic acid vines (Gk. oenanthe) heptanoic acid -7.5 ºC 223 ºC

CH3(CH2)6CO2H caprylic acid goats (L. caper) octanoic acid 16.3 ºC 239 ºC

CH3(CH2)7CO2H pelargonic acid pelargonium (an herb) nonanoic acid 12.0 ºC 253 ºC

CH3(CH2)8CO2H capric acid goats (L. caper) decanoic acid 31.0 ºC 219 ºC

Example (Common Names Are in Red)

Naming carboxyl groups added to a ring

When a carboxyl group is added to a ring the suffix -carboxylic acid is added to the name of the cyclic compound. The
ring carbon attached to the carboxyl group is given the #1 location number.

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Naming carboxylates
Salts of carboxylic acids are named by writing the name of the cation followed by the name of the acid with the –ic acid
ending replaced by an –ate ending. This is true for both the IUPAC and Common nomenclature systems.

Naming carboxylic acids which contain other functional groups

Carboxylic acids are given the highest nomenclature priority by the IUPAC system. This means that the carboxyl group is
given the lowest possible location number and the appropriate nomenclature suffix is included. In the case of molecules
containing carboxylic acid and alcohol functional groups the OH is named as a hydroxyl substituent. However, the l in
hydroxyl is generally removed.

In the case of molecules containing a carboxylic acid and aldehydes and/or ketones functional groups the carbonyl is
named as a "Oxo" substituent.

In the case of molecules containing a carboxylic acid an amine functional group the amine is named as an "amino"
substituent.

When carboxylic acids are included with an alkene the following order is followed:
(Location number of the alkene)-(Prefix name for the longest carbon chain minus the -ane ending)-(an –enoic acid
ending to indicate the presence of an alkene and carboxylic acid)
Remember that the carboxylic acid has priority so it should get the lowest possible location number. Also, remember that
cis/tran or E/Z nomenclature for the alkene needs to be included if necessary.

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Naming dicarboxylic acids
For dicarboxylic acids the location numbers for both carboxyl groups are omitted because both functional groups are
expected to occupy the ends of the parent chain. The ending –dioic acid is added to the end of the parent chain.

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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19.2: Structural and Physical Properties of Carboxylic Acids
Structure of the carboxyl acid group
Carboxylic acids are organic compounds which incorporate a carboxyl functional group, CO2H. The name carboxyl comes
from the fact that a carbonyl and a hydroxyl group are attached to the same carbon.

The carbon and oxygen in the carbonyl are both sp2 hybridized which give a carbonyl group a basic trigonal shape. The
hydroxyl oxygen is also sp2 hybridized which allows one of its lone pair electrons to conjugate with the pi system of the
carbonyl group. This make the carboxyl group planar an can represented with the following resonance structure.

Carboxylic acids are named such because they can donate a hydrogen to produce a carboxylate ion. The factors which
affect the acidity of carboxylic acids will be discussed later.

Contributors
Prof. Steven Farmer (Sonoma State University)

Physical Properties of Some Carboxylic Acids

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The table at the beginning of this page gave the melting and boiling points for a homologous group of carboxylic acids
having from one to ten carbon atoms. The boiling points increased with size in a regular manner, but the melting points did
not. Unbranched acids made up of an even number of carbon atoms have melting points higher than the odd numbered
homologs having one more or one less carbon. This reflects differences in intermolecular attractive forces in the crystalline
state. In the table of fatty acids we see that the presence of a cis-double bond significantly lowers the melting point of a
compound. Thus, palmitoleic acid melts over 60º lower than palmitic acid, and similar decreases occur for the C18 and C20
compounds. Again, changes in crystal packing and intermolecular forces are responsible.
The factors that influence the relative boiling points and water solubilities of various types of compounds were discussed
earlier. In general, dipolar attractive forces between molecules act to increase the boiling point of a given compound, with
hydrogen bonds being an extreme example. Hydrogen bonding is also a major factor in the water solubility of covalent
compounds To refresh your understanding of these principles Click Here. The following table lists a few examples of these
properties for some similar sized polar compounds (the non-polar hydrocarbon hexane is provided for comparison).

Physical Properties of Some Organic Compounds

Formula IUPAC Name Molecular Weight Boiling Point Water Solubility

CH3(CH2)2CO2H butanoic acid 88 164 ºC very soluble

CH3(CH2)4OH 1-pentanol 88 138 ºC slightly soluble
CH3(CH2)3CHO pentanal 86 103 ºC slightly soluble
CH3CO2C2H5 ethyl ethanoate 88 77 ºC moderately soluble
CH3CH2CO2CH3 methyl propanoate 88 80 ºC slightly soluble
CH3(CH2)2CONH2 butanamide 87 216 ºC soluble
CH3CON(CH3)2 N,N-dimethylethanamide 87 165 ºC very soluble
CH3(CH2)4NH2 1-aminobutane 87 103 ºC very soluble
CH3(CH2)3CN pentanenitrile 83 140 ºC slightly soluble
CH3(CH2)4CH3 hexane 86 69 ºC insoluble

The first five entries all have oxygen functional groups, and the relatively high boiling points of the first two is clearly due
to hydrogen bonding. Carboxylic acids have exceptionally high boiling points, due in large part to dimeric associations
involving two hydrogen bonds. A structural formula for the dimer of acetic acid is shown here. When the mouse pointer
passes over the drawing, an electron cloud diagram will appear. The high boiling points of the amides and nitriles are due
in large part to strong dipole attractions, supplemented in some cases by hydrogen bonding.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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19.3: Spectroscopy and Mass Spectrometry of Carboxylic Acids
IR
The carboxyl group is associated with two characteristic infrared stretching absorptions which change markedly with
hydrogen bonding. The spectrum of a CCl4 solution of propionic acid (propanoic acid), shown below, is illustrative.
Carboxylic acids exist predominantly as hydrogen bonded dimers in condensed phases. The O-H stretching absorption for
such dimers is very strong and broad, extending from 2500 to 3300 cm-1. This absorption overlaps the sharper C-H
stretching peaks, which may be seen extending beyond the O-H envelope at 2990, 2950 and 2870 cm-1. The smaller peaks
protruding near 2655 and 2560 are characteristic of the dimer. In ether solvents a sharper hydrogen bonded monomer
absorption near 3500 cm-1 is observed, due to competition of the ether oxygen as a hydrogen bond acceptor. The carbonyl
stretching frequency of the dimer is found near 1710 cm-1, but is increased by 25 cm-1 or more in the monomeric state.
Other characteristic stretching and bending absorptions are marked in the spectrum.

NMR
The combination of anisotropy and electronegativity causes the O-H hydrogen in a carboxylic
acid to be very deshielded.

Hydrogen environments adjacent to a carboxylic acid are shifted to the region of 2.5-3.0
ppm.Deshielding occurs due to the fact that the sp2 hybridized carbon the the carboxylic acid is
more electronegative than a sp3 hybridized carbon.

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Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Steven Farmer (Sonoma State University)

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19.4: Acidic and Basic Character of Carboxylic Acids
Objectives
After completing this section, you should be able to
1. identify the form that carboxylic acids take within living cells.
2. use the Henderson‑Hasselbalch equation to calculate the percentages of dissociated and undissociated acids [A−]
and [HA] in a solution, given the pKa value of the acid and the pH of the solution.
3. explain why cellular carboxylic acids are always referred to by the name of their anion.

Key Terms
Make certain that you can define, and use in context, the key terms below.
Henderson‑Hasselbalch equation
physiological pH

Organic molecules in buffered solution: The Henderson-Hasselbalch equation

The environment inside a living cell, where most biochemical reactions take place, is an aqueous buffer with pH ~ 7 (or
sometimes referred to as the physiological pH). Recall from your General Chemistry course that a buffer is a solution of a
weak acid and its conjugate base. The key equation for working with buffers is the Henderson-Hasselbalch equation:

The Henderson-Hasselbalch equation:

The equation tells us that if our buffer is an equimolar solution of a weak acid and its conjugate base, the pH of the buffer
will equal the pKa of the acid (because the log of 1 is equal to zero). If there is more of the acid form than the base, then of
course the pH of the buffer is lower than the pKa of the acid.

Exercise 7.2.4

What is the pH of an aqueous buffer solution that is 30 mM in acetic acid and 40 mM in sodium acetate? The pKa of
acetic acid is 4.8.
Solution

The Henderson-Hasselbalch equation is particularly useful when we want to think about the protonation state of different
biomolecule functional groups in a pH 7 buffer. When we do this, we are always assuming that the concentration of the
biomolecule is small compared to the concentration of the buffer components. (The actual composition of physiological
buffer is complex, but it is primarily based on phosphoric and carbonic acids.).
Imagine an aspartic acid residue located on the surface of a protein in a human cell. Being on the surface, the side chain is
in full contact with the pH 7 buffer surrounding the protein. In what state is the side chain functional group: the protonated
state (a carboxylic acid) or the deprotonated state (a carboxylate ion)? Using the Henderson-Hasselbalch equation, we fill
in our values for the pH of the buffer and a rough pKa approximation of pKa = 5 for the carboxylic acid functional group.
Doing the math, we find that the ratio of carboxylate to carboxylic acid is about 100 to 1: the carboxylic acid is almost
completely ionized (in the deprotonated state) inside the cell. This result extends to all other carboxylic acid groups you
might find on natural biomolecules or drug molecules: in the physiological environment, carboxylic acids are almost
completely deprotonated. Indeed, often cellular carboxylic acids are often referred to by the name of their anion. So rather
than pyruvic acid, or acetic acid or lactic acid, it is pyruvate, acetate or lactate.
While we are most interested in the state of molecules at pH 7, the Henderson-Hasselbalch equation can of course be used
to determine the protonation state of functional groups in solutions buffered to other pH levels. The exercise below provide
some practice in this type of calculation.

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 Exercise 7.2.6
What is the ratio of acetate ion to neutral acetic acid when a small amount of acetic acid (pKa = 4.8) is dissolved in a
buffer of pH 2.8? pH 3.8? pH 4.8? pH 5.8? pH 6.8?
Solution

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
The resonance effect described here is undoubtedly the major contributor to the exceptional acidity of carboxylic acids.
However, inductive effects also play a role. For example, alcohols have pKa's of 16 or greater but their acidity is increased
by electron withdrawing substituents on the alkyl group. The following diagram illustrates this factor for several simple
inorganic and organic compounds (row #1), and shows how inductive electron withdrawal may also increase the acidity of
carboxylic acids (rows #2 & 3). The acidic hydrogen is colored red in all examples.

Water is less acidic than hydrogen peroxide because hydrogen is less electronegative than oxygen, and the covalent bond
joining these atoms is polarized in the manner shown. Alcohols are slightly less acidic than water, due to the poor
electronegativity of carbon, but chloral hydrate, Cl3CCH(OH)2, and 2,2,2,-trifluoroethanol are significantly more acidic
than water, due to inductive electron withdrawal by the electronegative halogens (and the second oxygen in chloral
hydrate). In the case of carboxylic acids, if the electrophilic character of the carbonyl carbon is decreased the acidity of the
carboxylic acid will also decrease. Similarly, an increase in its electrophilicity will increase the acidity of the acid. Acetic
acid is ten times weaker an acid than formic acid (first two entries in the second row), confirming the electron donating
character of an alkyl group relative to hydrogen, as noted earlier in a discussion of carbocation stability. Electronegative
substituents increase acidity by inductive electron withdrawal. As expected, the higher the electronegativity of the
substituent the greater the increase in acidity (F > Cl > Br > I), and the closer the substituent is to the carboxyl group the
greater is its effect (isomers in the 3rd row). Substituents also influence the acidity of benzoic acid derivatives, but
resonance effects compete with inductive effects. The methoxy group is electron donating and the nitro group is electron
withdrawing (last three entries in the table of pKa values).
For additional information about substituent effects on the acidity of carboxylic acids Click Here

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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19.5: Carboxylic Acid Synthesis in Industry

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19.6: Methods for Introducing the Carboxy Functional Group
Objectives
After completing this section, you should be able to
1. describe in detail the methods of preparing carboxylic acids discussed in previous chapters:
a. the oxidation of alkylbenzenes.
b. the oxidative cleavage of alkenes.
c. the oxidation of primary alcohols and aldehydes.
2. discuss, in detail, the hydrolysis of nitriles:
a. write an equation to illustrate the preparation of a carboxylic acid through nucleophilic attack by cyanide ion on
an alkyl halide and hydrolysis of the nitrile which results.
b. identify the carboxylic acid formed from the hydrolysis of a given nitrile, or from the reaction of a given alkyl
halide with cyanide ion followed by hydrolysis of the resulting nitrile.
c. identify the alkyl halide needed to prepare a given carboxylic acid by the formation and subsequent hydrolysis
of a nitrile.
d. identify the reagents needed to convert a given alkyl halide into a carboxylic acid containing one more carbon
atom.
3. discuss, in detail, the carboxylation of Grignard reagents:
a. write an equation describing the formation of a carboxylic acid from a Grignard reagent.
b. identify the carboxylic acid obtained through the treatment of a given Grignard reagent with carbon dioxide
followed by dilute acid.
c. identify the Grignard reagent (or the alkyl halide required to form the Grignard reagent) that must be used to
produce a given carboxylic acid by reaction with carbon dioxide.
d. write the detailed mechanism for the formation of a carboxylic acid using a Grignard reagent.

Study Notes
Review the methods of obtaining carboxylic acids presented in earlier sections:
1. oxidation of aromatic compounds—Section 16.9.
2. oxidative cleavage of alkenes—Section 8.8.
3. oxidation of primary alcohols and aldehydes—Sections 17.7 and 19.3.

The carbon atom of a carboxyl group has a high oxidation state. It is not surprising, therefore, that many of the chemical
reactions used for their preparation are oxidations. Such reactions have been discussed in previous sections of this text, and
the following diagram summarizes most of these. To review the previous discussion of any of these reaction classes simply
click on the number (1 to 4) or descriptive heading for the group.

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Two other useful procedures for preparing carboxylic acids involve hydrolysis of nitriles and carboxylation of
organometallic intermediates. As shown in the following diagram, both methods begin with an organic halogen compound
and the carboxyl group eventually replaces the halogen. Both methods require two steps, but are complementary in that the
nitrile intermediate in the first procedure is generated by a SN2 reaction, in which cyanide anion is a nucleophilic precursor
of the carboxyl group. The hydrolysis may be either acid or base-catalyzed, but the latter give a carboxylate salt as the
initial product.
In the second procedure the electrophilic halide is first transformed into a strongly nucleophilic metal derivative, and this
adds to carbon dioxide (an electrophile). The initial product is a salt of the carboxylic acid, which must then be released by
treatment with strong aqueous acid.

An existing carboxylic acid may be elongated by one methylene group, using a homologation procedure called the Arndt-
Eistert reaction. To learn about this useful method Click Here.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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19.7: Substitution at the Carboxy Carbon: The Addition-Elimination Mechanism
Objectives
After completing this section, you should be able to identify the four types of reaction which a carboxylic acid can
undergo.

Study Notes

You may wish to review Section 17.4 which discusses reduction of carbonyl compounds to form alcohols and Sections
20.2–20.4 which highlights the acidity of carboxylic acids, which is important to salt formation and substitution of the
hydroxyl hydrogen. Nucleophilic acyl substitution (Chapter 21) and alpha substitutions (Chapter 22) are discussed
later in more detail.

Four Categories of Carboxylic Acid Reactions

The scheme summarizes some of the general reactions that carboxylic acids undergo.

Four general reaction categories are represented here: (1) As carboxylic acid deprotonates quite readily, it is quite easy to
form a carboxylate salt or to substitute the hydroxyl hydrogen. (2) The category of nucleophilic acyl substitution represents
the substitution of the whole hydroxyl group, which we will see later in more detail leads to several carboxylic acid
derivatives (e.g. acid halides, esters, amides, thioesters, acid anhydrides etc.). (3) Like other carbonyl compounds,
carboxylic acids can be reduced by reagents like LiAlH4. (4) While the proton on the carbon alpha to the carbonyl group is
not as acidic as the hydroxyl hydrogen, it can be removed leading to substitution at the alpha site.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
1. Four Categories of Carboxylic Acid Reactions
2.
3. Contributors and Attributions
4. Introduction
5. General reaction
6. General mechanism

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7. Contributors

Introduction
Carboxylic acid derivatives are functional groups whose chemistry is closely related. The main difference is the presence
of an electronegative substituent that can act as a leaving group during a nucleophile substitution reaction. Although there
are many types of carboxylic acid derivatives known, this article focuses on four: acid halides, acid anhydrides, esters, and
amides.

General reaction

General mechanism
1) Nucleophilic attack on the carbonyl

2) Leaving group is removed

Although aldehydes and ketones also contain carbonyls, their chemistry is distinctly different because they do not contain
suitable leaving groups. Once a tetrahedral intermediate is formed, aldehydes and ketones cannot reform their carbonyls.
Because of this, aldehydes and ketones typically undergo nucleophilic additions and not substitutions.

The relative reactivity of carboxylic acid derivatives toward nucleophile substitutions is related to the electronegative
leaving group’s ability to activate the carbonyl. The more electronegative leaving groups withdraw electron density from
the carbonyl, thereby increasing its electrophilicity.

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Contributors
Prof. Steven Farmer (Sonoma State University)

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19.8: Carboxylic Acid Derivatives: Alkanoyl (Acyl) Halides and Anhydrides
Acid Chlorides react with carboxylic acids to form anhydrides

Carboxylic acids react with Thionyl Chloride (SOC l ) to form acid chlorides.
2

During the reaction the hydroxyl group of the carboxylic acid is converted to a chlorosulfite intermediate making it a better
leaving group. The chloride anion produced during the reaction acts a nucleophile.

Example

Mechanism
1) Nucleophilic attack on Thionyl Chloride

2) Removal of Cl leaving group

3) Nucleophilic attack on the carbonyl

4) Leaving group removal

5) Deprotonation

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Carboxylic acids can react with alcohols to form esters in a process called Fischer
esterification.
Usually the alcohol is used as the reaction solvent. An acid catalyst is required.

Basic Reaction

Going from reactants to products simplified

Example

Mechanism
1) Protonation of the carbonyl by the acid. The carbonyl is now activated toward nucleophilic attack.

2) Nucleophilic attack on the carbonyl

3) Proton transfer

4) Water leaves

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5) Deprotonation

Conversion of Carboxylic Acids to Amides

The direct reaction of a carboxylic acid with an amine would be expected to be difficult because the basic amine would
deprotonate the carboxylic acid to form a highly unreactive carboxylate. However when the ammonium carboxylate salt is
heated to a temperature above 100 oC water is driven off and an amide is formed.

General Reaction

Going from reactants to products simply

Conversion of Carboxylic acids to amide using DCC as an activating agent

The direct conversion of a carboxylic acid to an amide is difficult because amines are basic and tend to convert carboxylic
acids to their highly unreactive carboxylates. In this reaction the carboxylic acid adds to the DCC molecule to form a good
leaving group which can then be displaced by an amine during nucleophilic substitution. DCC induced coupling to form an
amide linkage is an important reaction in the synthesis of peptides.

Basic reaction

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Going from reactants to products simplified

Mechanism
1) Deprotonation

2) Nucleophilic attack by the carboxylate

3) Nucleophilic attack by the amine

4) Proton transfer

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5) Leaving group removal

Contributors
Prof. Steven Farmer (Sonoma State University)

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19.9: Carboxylic Acid Derivatives: Esters
Fischer esterification is the esterification of a Carboxylic acid by heating it with an alcohol in the presence of a strong acid
as the catalyst.

Going from reactants to products simplified

Example

Mechanism
The overall reaction is reversible; to drive the reaction to completion, it is necessary to exploit Le Châteliers principle,
which can be done either by continuously removing the water formed from the system or by using a large excess of the
alcohol.
1) Protonation of the carbonyl by the acid. The carbonyl is now activated toward nucleophilic attack.

2) Nucleophilic attack on the carbonyl

3) Proton transfer

4) Water leaves

5) Deprotonation

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Contributors
Prof. Steven Farmer (Sonoma State University)

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19.10: Carboxylic Acid Derivatives: Amides
☰
The direct reaction of a carboxylic acid with an amine would be expected to be difficult because the basic amine would
deprotonate the carboxylic acid to form a highly unreactive carboxylate. However when the ammonium carboxylate salt is
heated to a temperature above 100 oC water is driven off and an amide is formed.

General Reaction

Going from reactants to products simply

Contributors
Prof. Steven Farmer (Sonoma State University)

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19.11: Reduction of Carboxylic Acids by Lithium Aluminum Hydride
Carboxylic acids can be converted to 1o alcohols using Lithium aluminum hydride (LiAlH4). Note that NaBH4 is not
strong enough to convert carboxylic acids or esters to alcohols. An aldehyde is produced as an intermediate during this
reaction, but it cannot be isolated because it is more reactive than the original carboxylic acid.

General reaction

Example

Possible Mechanism
1) Deprotonation

2) Nucleopilic attack by the hydride anion

3) Leaving group removal

4) Nucleopilic attack by the hydride anion

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5) The alkoxide is protonated

Contributors
Prof. Steven Farmer (Sonoma State University)

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19.12: Bromination Next to the Carboxy Group: The Hell-Volhard-Zelinsky
Reaction
Although the alpha bromination of some carbonyl compounds, such as aldehydes and ketones, can be accomplished with
Br2 under acidic conditions, the reaction will generally not occur with acids, esters, and amides. This is because only
aldehydes and ketones enolize to a sufficient extent to allow the reaction to occur. However, carboxylic acids, can be
brominated in the alpha position with a mixture of Br2 and PBr3 in a reaction called the Hell-Volhard-Zelinskii reaction.

The mechanism of this reaction involves an acid bromide enol instead of the expected carboxylic acid enol. The reaction
stats with the reaction of the carboxylic acid with PBr3 to form the acid bromide and HBr. The HBr then catalyzes the
formation of the acid bromide enol which subsequently reacts with Br2 to give alpha bromination. Lastly, the acid bromide
reacts with water to reform the carboxylic acid.

Contributors
Prof. Steven Farmer (Sonoma State University)

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19.13: Biological Activity of Carboxylic Acids
Glutamine synthetase
You have already learned that the carboxylate functional group is a very unreactive substrate for an enzyme-catalyzed acyl
substitution reactions. How, then, does a living system accomplish an ‘uphill’ reaction such as the one shown below, where
glutamate (a carboxylate) is converted to glutamine (an amide)?

It turns out that this conversion is not carried out directly. Rather, the first conversion is from a carboxylate (the least
reactive acyl transfer substrate) to an acyl phosphate (the most reactive acyl transfer substrate). This transformation
requires a reaction that we are familiar with from chapter 10: phosphorylation of a carboxylate oxygen with ATP as the
phosphate donor.

Note that this is just one of the many ways that ATP is used as a energy storage unit: in order to make a high energy acyl
phosphate molecule from a low energy carboxylate, the cell must ‘spend’ the energy of one ATP molecule.
The acyl phosphate version of glutamate is now ready to be converted directly to an amide (glutamine) via a nucleophilic
acyl substitution reaction, as an ammonia molecule attacks the carbonyl and the phosphate is expelled.

Overall, this reaction can be written as:

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Asparagine synthetase
Another common form of activated carboxylate group is an acyl adenosine phosphate. Consider another amino acid
reaction, the conversion of aspartate to asparagine. In the first step, the carboxylate group of aspartate must be activated:

Once again, ATP provides the energy for driving the uphill reaction. This time, however, the activated carboxylate takes
the form of an acyl adenosine (mono)phosphate. All that has happened is that the carboxylate oxygen has attacked the a-
phosphate of ATP rather than the g-phosphate.
The reactive acyl-AMP version of aspartate is now ready to be converted to an amide (asparagine) via nucleophilic attack
by ammonia. In the case of glutamine synthase, the source of ammonia was free ammonium ion in solution. In the case of
asparagine synthase, the NH3 is derived from the hydrolysis of glutamine (this is simply another acyl substitution
reaction):

The hydrolysis reaction is happening in the same enzyme active site – as the NH3 is expelled in the hydrolysis of
glutamine, it immediately turns around and acts as the nucleophile in the conversion of aspartyl-AMP to asparagine:

Keep in mind that the same enzyme is also binding ATP and using it to activate aspartate – this is a busy construction
zone!
Overall, this reaction can be written in condensed form as:

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The use of glutamine as a ‘carrier’ for ammonia is a fairly common strategy in metabolic pathways. This strategy makes
sense, as it allows cells to maintain a constant source of NH3 for reactions that require it, without the need for high solution
concentrations of free ammonia.

Glycinamide ribonucleotide synthetase

One of the early steps in the construction of purine bases (the adenine and guanine bases in DNA and RNA) involves an
acyl substitution reaction with an acyl phosphate intermediate. In this case, the attacking nucleophile is not ammonia but a
primary amine. The strategy, however, is similar to that of glutamine synthase. The carboxylate group on glycine is
converted to an acyl phosphate, at the cost of one ATP molecule. The acyl group is then transferred to 5-
phosphoribosylamine, resulting in an amide product.

Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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CHAPTER OVERVIEW
20: CARBOXYLIC ACID DERIVATIVES
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

20.1: RELATIVE REACTIVITIES, STRUCTURES, AND SPECTRA OF CARBOXYLIC ACID DERIVATIVES

20.2: CHEMISTRY OF ALKANOYL HALIDES
20.3: CHEMISTRY OF CARBOXYLIC ANHYDRIDES
20.4: CHEMISTRY OF ESTERS
20.5: ESTERS IN NATURE: WAXES, FATS, OILS, AND LIPIDS
20.6: AMIDES: THE LEAST REACTIVE CARBOXYLIC ACID DERIVATIVES
20.7: AMIDATES AND THEIR HALOGENATION: THE HOFMANN REARRANGEMENT
20.8: ALKANENITRILES: A SPECIAL CLASS OF CARBOXYLIC

1 12/5/2021
20.1: Relative Reactivities, Structures, and Spectra of Carboxylic Acid
Derivatives
Objectives

After completing this section, you should be able to

1. compare the reactions of carboxylic acid derivatives with nucleophiles to the reactions of aldehydes and ketones
with nucleophiles.
2. arrange a given list of carboxylic acid derivatives in order of increasing or decreasing reactivity towards
nucleophiles.
3. explain the difference in reactivity towards nucleophiles of two or more given carboxylic acid derivatives.
4. explain why esters and amides are commonly found in nature, but acid halides and acid anhydrides are not.

Study Notes
The general nucleophilic acyl substitution reaction, and its mechanism, were discussed earlier in “III. General
Reactions of Carbonyl Compounds.” Review if necessary.
The reading describes the relative reactivities of “biologically relevant acyl groups.” Both acid anhydrides and acid
halides readily react with water and cannot exist for any length of time in living organisms. The following scheme
illustrates the relative reactivities of most carboxylic acid derivatives that you will encounter.

Carboxylic acid derivatives and acyl groups

The functional groups that undergo nucleophilic acyl substitutions are called carboxylic acid derivatives: these include
carboxylic acids themselves, carboxylates (deprotonated carboxylic acids), amides, esters, thioesters, and acyl phosphates.
Two more examples of carboxylic acid derivatives which are less biologically relevant but important in laboratory
synthesis are carboxylic acid anyhydrides and acid chlorides.

The carboxylic acid derivatives can be distinguished from aldehydes and ketones by the presence of a group containing an
electronegative heteroatom - usually oxygen, nitrogen, or sulfur – bonded directly to the carbonyl carbon. You can think of
a carboxylic acid derivative as having two sides. One side is the carbonyl group and the attached alkyl group: this is called
an acyl group (in the specific case where R is a methyl group, the term acetyl group is used). One the other side is the
heteroatom-containing group: in this text, we will sometimes refer to this component as the ‘acyl X' group (this, however,
is not a standard term in organic chemistry).

Notice that the acyl X groups are simply deprotonated forms of other functional groups: in an amide, for example, the acyl
X group is an amine, while in an ester the acyl X group is an alcohol.

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Example 21.2.1
What is the ‘acyl X’ group in:

a. an acid anhydride?
b. a thioester?
c. a carboxylic acid?
Solution

The nucleophilic acyl substitution reaction

The fact that the atom adjacent to the carbonyl carbon in carboxylic acid derivatives is an electronegative heteroatom –
rather than a carbon like in ketones or a hydrogen like in aldehydes - is critical to understanding the reactivity of these
functional groups. Just like in aldehydes and ketones, carboxylic acid derivatives are attacked from one side of their
trigonal planar carbonyl carbon by a nucleophile, converting this carbon to tetrahedral (sp3) geometry. In carboxylic acid
derivatives, the acyl X group is a potential leaving group. What this means is that the tetrahedral product formed from
attack of the nucleophile on the carbonyl carbon is not the product: it is a reactive intermediate. The tetrahedral
intermediate rapidly collapses: the carbon-oxygen double bond re-forms, and the acyl X group is expelled.

Notice that in the product, the nucleophile becomes the new acyl X group. This is why this reaction type is called a
nucleophilic acyl substitution: one acyl X group is substituted for another. For example, in the reaction below, one alcohol
X group (3-methyl-1-butanol) is replaced by another alcohol X group (methanol), as one ester is converted to another.

Another way of looking at this reaction is to picture the acyl group being transferred from one acyl X group to another: in
the example above, the acetyl group is being transferred from 3-methyl-1-butanol to methanol. For this reason,
nucleophilic acyl substitutions are also commonly referred to as acyl transfer reactions.
When the incoming nucleophile in an acyl substitution is a water molecule, the reaction is also referred to as an acyl
hydrolysis. For example, the following reaction can be described as the hydrolysis of an ester (to form a carboxylic acid
and an alcohol).

We could also describe this reaction as the transfer of an acyl group from an alcohol to a water molecule.
In a similar vein, the hydrolysis of an amide to form a carboxylic acid could be described as the transfer of an acyl group
from ammonia (NH3) to water.

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As we will see in later sections of this chapter the hydrolysis of esters and amides are particularly important reaction types
in biochemical pathways. When your body digests the fat in a hamburger, for example, enzymes in your pancreas called
lipases first catalyze ester hydrolysis reactions to free the fatty acids (we'll look more closely at this reaction in section
12.4D).

The relative reactivity of carboxylic acid derivatives

The relative reactivity of the carboxylic acid derivatives is an important concept to understand before entering into a
detailed examination of nucleophilic acyl substitutions. As a general rule, the carbonyl carbon in an acyl group is less
electrophilic than that in an aldehyde or ketone. This is because in carboxylic acid derivatives, the partial positive charge
on the carbon is stabilized somewhat by resonance effects from the adjacent heteroatom.

Among the carboxylic acid derivatives, carboxylate groups are the least reactive towards nucleophilic acyl substitution,
followed by amides, then esters and (protonated) carboxylic acids, thioesters, and finally acyl phosphates, which are the
most reactive among the biologically relevant acyl groups.

The different reactivities of the functional groups can be understood by evaluating the basicity of the leaving group in each
case - remember from section 8.5 that weaker bases are better leaving groups! A thioester is more reactive than an ester,
for example, because a thiolate (RS-) is a weaker base than an alkoxide (RO-). In general, if the incoming nucleophile is a
weaker base than the ‘acyl X’ group that is already there, the first nucleophilic step will simply reverse itself and we’ll get
the starting materials back:

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This is why it is not possible to directly convert an ester, for example, into a thioester by an acyl substitution reaction – this
would be an uphill reaction.
Here’s another way to think about the relative reactivites of the different carboxylic acid derivatives: consider the relative
electrophilicity, or degree of partial positive charge, on the carbonyl carbon in each species. This depends on how much
electron density the neighboring heteroatom on the acyl X group is able to donate: greater electron donation by the
heteroatom implies lower partial positive charge on the carbonyl carbon, which in turn implies lower electrophilicity.
The negatively charged oxygen on the carboxylate group has lots of electron density to donate, thus the carbonyl carbon is
not very electrophilic. In amides, the nitrogen atom is a powerful electron donating group by resonance - recall that the
carbon-nitrogen bond in peptides has substantial double-bond character - thus amides are relatively unreactive. Amides do
undergo acyl substitution reactions in biochemical pathways, but these reactions are inherently slow and the enzymes
catalyzing them have evolved efficient strategies to lower the activation energy barrier.
Carboxylic acids and esters are in the middle range of reactivity, while thioesters are somewhat more reactive. The most
reactive of the carboxylic acid derivatives frequently found in biomolecules are the acyl phosphates. These are most often
present in two forms: the simple acyl monophosphate, and the acyl-adenosine monophosphate.

Both are highly reactive to acyl substitution reactions, and are often referred to as ‘activated acyl groups’ or ‘activated
carboxylic acids’. The high reactivity of acyl phosphates is due mainly to the ability to form complexes with magnesium
ions.

The magnesium ion acts as a Lewis acid to accept electron density from the oxygen end of the acyl carbonyl bond, thus
greatly increasing the degree of partial positive charge - and thus the electrophilicity - of the carbonyl carbon. The
magnesium ion also balances negative charge on the phosphate, making it an excellent leaving group.
In our examination of acyl substitution reactions, we will start with the formation and reactions of the highly reactive acyl
phosphates. We will then discuss how thioesters play a key role in the acyl substitution reactions of lipid metabolism.
Finally, we will take a look at some important acyl substitution reactions involving esters, as well as the formation and
cleavage of the amide linkages in the peptide bonds of proteins.

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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20.2: Chemistry of Alkanoyl Halides
Objectives
After completing this section, you should be able to
1. identify the reagent normally used to convert a carboxylic acid to an acid bromide.
2. write equations to show how an acid halide may be converted into each of the following: a carboxylic acid, an
ester, an amide.
3. write a detailed mechanisms for the reaction of an acid halide with each of the following: water, an alcohol,
ammonia, a primary or secondary amine.
4. identify the product formed when a given acid halide reacts with any of the following reagents: water, an alcohol, a
primary or secondary amine.
5. identify the acid halide, the reagents, or both, needed to prepare a given carboxylic acid, ester or amide.
6. identify the product formed when a given acid halide reacts with water, a given alcohol, ammonia, or a given
primary or secondary amine.
7. identify lithium aluminum hydride as a reagent for reducing acid halides to primary alcohols, and explain the
limited practical value of this reaction.
8. identify the partial reduction of an acid halide using lithium tri‑tert‑butoxyaluminum to form an aldehyde.
9. write an equation to describe the formation of a tertiary alcohol by the reaction of an acid halide with a Grignard
reagent.
10. write a detailed mechanism for the reaction of an acid halide with a Grignard reagent.
11. identify the product formed from the reaction of a given acid halide with a given Grignard reagent.
12. identify the acid halide, the Grignard reagent, or both, needed to prepare a given tertiary alcohol.
13. write an equation to illustrate the reaction of an acid halide with a lithium diorganocopper reagent.
14. identify the product formed from the reaction of a given acid halide with a given lithium diorganocopper reagent.
15. identify the acid halide, the lithium diorganocopper reagent, or both, that must be used to prepare a given ketone.

Study Notes
This figure provides a convenient general summary of a few of the reactions described in Section 21.4.
Note that LiAlH4 is a common reagent for hydride [H−] reduction of and acid chloride to an alcohol.

Formation of Acid Halides

Carboxylic acids react with thionyl chloride (SOC l ) to form acid chlorides. During the reaction the hydroxyl group of the
2

carboxylic acid is converted to a chlorosulfite intermediate making it a better leaving group. The chloride anion produced

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during the reaction acts a nucleophile.

Earlier (Section 10.5) we saw that primary and secondary alcohols react with PBr3 to afford the corresponding alkyl
bromide. In a similar fashion acid bromides can be formed from the carboxylic acid.

Nucleophilic Acyl Substitution Mechanism

If you understand the mechanism of a typical nucleophilic acyl substitution, the reaction of an acyl halide with water, an
alcohol or ammonia should not present you with any difficulty.

X = Cl, Br :Nu = H2O, ROH, NH2R, NHR2 etc.

Acid chlorides react with water to form carboxylic acids.

General reaction

Example 21.4.1

Mechanism
1) Nucleophilic attack by water

2) Leaving group is removed

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3) Deprotonation

Acid chlorides react with carboxylic acids to form anhydrides

Acid chlorides react with alcohols to form esters

Example 21.4.2

Acid chlorides react with ammonia, 1o amines and 2o amines to form amides.

Example 21.4.3

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Acid Chlorides can be Reduced to form 1o Alcohols

Grignard reagents convert acid chloride to 3o alcohols

Organocuprate reagents convert acid chlorides to ketones.

Example 21.4.4

Exercises
Questions
Q21.4.1
Draw the mechanism for the following reaction

Q21.4.2
Propose a synthesis of the following molecules from an acid chloride and an amide.

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(a)

(b)

(c)
Solutions
S21.4.1

S21.4.2
a. Acetyl chloride and dimethylamine
b. Benzoyl chloride and ethylamine
c. Acetyl chloride and ammonia

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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20.3: Chemistry of Carboxylic Anhydrides
☰
Objectives
After completing this section, you should be able to
1. write an equation to illustrate the preparation of an acid anhydride from an acid halide and the sodium salt of a
carboxylic acid.
2. identify the product formed from the reaction of a given acid halide with the sodium salt of a given carboxylic acid.
3. identify the acid halide, carboxylate salt, or both, required to prepare a given acid anhydride.
4. write an equation to describe the reaction of an acid anhydride with each of the following: water, alcohol,
ammonia, a primary or secondary amine, lithium aluminum hydride.
5. identify the product formed when a given acid anhydride is reacted with any of the reagents listed in Objective 4,
above.
6. write a detailed mechanism for the reaction of an acid anhydride with any of the reagents listed in Objective 4,
above.
7. identify the acid anhydride, the nucleophilic reagent, or both, needed to prepare a specified carboxylic acid, ester,
amide, or primary alcohol.

Study Notes
The reactions described in this section are, in principle, identical to those discussed in Section 21.4. Once you have
understood the mechanism of nucleophilic acyl substitution, these reactions should not present you with any great
difficulty, and memorization can be kept to a minimum.
This figure provides a convenient general summary of a few of the reactions described in Section 21.5. Note that from
a synthetic perspective the ester‑ and amide‑forming reactions are the most common, so they are the focus of this
section.

Preparation of Acid Anhydrides

Acid Chlorides react with carboxylic acids to form anhydrides

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Acid Anhydrides react with alcohols to form esters
☰
Reactions of anhydrides use Pyridine as a solvent

Example 21.5.1

Mechanism
1) Nucleophilic Attack by the Alcohol

2) Deprotonation by pyridine

3) Leaving group removal

4) Protonation of the carboxylate

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☰

Acid Anhydrides react with amines to form amides

Example 21.5.2

Mechanism
1) Nucleophilic Attack by the Amine

2) Deprotonation by the amine

3) Leaving group removal

Exercises
Questions
Q21.5.1
Draw out the mechanism for the following reaction.

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☰

Q21.5.2
Draw the product of the reaction between these two molecules.

Solutions
S21.5.1

S21.5.1

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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20.4: Chemistry of Esters
Objectives
After completing this section, you should be able to
1. discuss the wide occurrence of esters in nature, and their important commercial uses, giving one example of an
ester linkage in nature, and one example of a commercially important ester.
2. write an equation to describe the hydrolysis of an ester under acidic or basic conditions.
3. identify the products formed from the hydrolysis of an given ester.
4. identify the reagents that can be used to bring about ester hydrolysis.
5. identify the structure of an unknown ester, given the products of its hydrolysis.
6. write the mechanism of alkaline ester hydrolysis.
7. write the mechanism of acidic ester hydrolysis.
8. write an equation to describe the reduction of an ester with lithium aluminum hydride.
9. identify the product formed from the reduction of a given ester (or lactone) with lithium aluminum hydride.
10. identify the ester, the reagents, or both, that should be used to prepare a given primary alcohol.
11. write a detailed mechanism for the reduction of an ester by lithium aluminum hydride.
12. identify diisobutylaluminum hydride as a reagent for reducing an ester to an aldehyde, and write an equation for
such a reaction.
13. write an equation to describe the reaction of an ester with a Grignard reagent.
14. identify the product formed from the reaction of a given ester with a given Grignard reagent.
15. identify the ester, the Grignard reagent, or both, needed to prepare a given tertiary alcohol.
16. write a detailed mechanism for the reaction of an ester with a Grignard reagent.

Key Terms
Make certain that you can define, and use in context, the key terms below.
lactone
saponification

Study Notes

Many esters have characteristic aromas and flavours. Some examples are listed below.
Basic structure:

Table 21.1 Structures and characteristic odours of selected esters

IUPAC name R R′ Aroma

octyl ethanoate CH3 CH3(CH2)6CH2 orange

propyl ethanoate CH3 CH3CH2 CH2 pear

2‑methylpropyl propanoate CH3CH2 (CH3)2CHCH2 rum
methyl butanoate CH3CH2CH2 CH3 apple
ethyl butanoate CH3CH2CH2 CH3CH2 pineapple

A “lactone” is a cyclic ester and has the general structure

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 By recognizing that the steps in the acidic hydrolysis of an ester are exactly the same as those in a Fischer
esterification (but in the reverse order!), you can again minimize the amount of memorization that you must undertake.
The details of both mechanisms can be deduced from the knowledge that both reactions are acid‑catalyzed
nucleophilic acyl substitutions.

Introduction
Esters are readily synthesized and naturally abundant contributing to the flavors and aromas in many fruits and flowers.

They also make up the bulk of animal fats and vegetable oils—glycerides (fatty acid esters of glycerol). Soap is produced
by a saponification (basic hydrolysis) reaction of a fat or oil.

Esters are also present in a number of important biological molecules and have several
commercial and synthetic application. For example, polyester molecules make excellent fibers and are used in
many fabrics. A knitted polyester tube, which is biologically inert, can be used in surgery to repair or replace diseased
sections of blood vessels. PET is used to make bottles for soda pop and other beverages. It is also formed into films called
Mylar. When magnetically coated, Mylar tape is used in audio- and videocassettes. Synthetic arteries can be made from
PET, polytetrafluoroethylene, and other polymers.
The most important polyester, polyethylene terephthalate (PET), is made from terephthalic acid and ethylene glycol
monomers:

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Preparation of Esters
Carboxylic acids can react with alcohols to form esters

Acid chlorides react with alcohols to form esters

Acid Anhydrides react with alcohols to form esters

Conversion of Ester into Carboxylic acids: Hydrolysis

Esters can be cleaved back into a carboxylic acid and an alcohol by reaction with water and a catalytic amount of acid.

Example 21.6.1

Mechanism
1) Protonation of the Carbonyl

2) Nucleophilic attack by water

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3) Proton transfer

4) Leaving group removal

Esters can be cleaved back into a carboxylic acid and an alcohol by reaction with water and a base. The reaction is called a
saponification from the Latin sapo which means soap. The name comes from the fact that soap used to me made by the
ester hydrolysis of fats. Due to the basic conditions a carboxylate ion is made rather than a carboxylic acid.

Example 21.6.2

Mechanism
1) Nucleophilic attack by hydroxide

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2) Leaving group removal

3) Deprotonation

Conversion of Esters into Amides: Aminolysis

Esters reaction with ammonia and alkyl amines to yield amides.

Conversion of Ester into Alcohols: Reduction

Esters can be converted to 1o alcohols using LiAlH4, while sodium borohydride (N aBH ) is not a strong enough reducing
4

agent to perform this reaction.

Example 21.6.3

Mechanism
1) Nucleophilic attack by the hydride

2) Leaving group removal

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3) Nucleopilic attack by the hydride anion

4) The alkoxide is protonated

Esters can be converted to aldehydes using diisobutylaluminum hydride (DIBAH)

The reaction is usually carried out at -78 oC to prevent reaction with the aldehyde product.

Example 21.6.4

Addition of Grignard reagents convert esters to 3o alcohols.

In effect the Grignard reagent adds twice.

Example 21.6.5

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Mechanism
1) Nucleophilic attack

2) Leaving group removal

3) Nucleophilic attack

4) Protonation

Exercises
Questions
Q21.6.1
Why is the alkaline hydrolysis of an ester not a reversible process? Why doesn't the reaction with a hydroxide ion and a
carboxylic acid produce an ester?
Q21.6.2
Draw the product of the reaction between the following molecule and LiAlH4, and the product of the reaction between the
following molecule and DIBAL.

Q21.6.3
How might you Prepare the following molecules from esters and Grignards?

(a)

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(b)

(c)
Solutions
S21.6.1
The reaction between a carboxylic acid and a hydroxide ion is an acid base reaction, which produces water and a
carboxylate anion.
S21.6.2

S21.6.3

(a)

(b)

(c)
.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook

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20.5: Esters in Nature: Waxes, Fats, Oils, and Lipids

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20.6: Amides: The Least Reactive Carboxylic Acid Derivatives
Objectives
After completing this section, you should be able to
1. write an equation to describe the preparation of an amide from an acid chloride.
2. identify the amide linkage as the basic unit from which all proteins are made, and hence recognize the importance
of the amide linkage to biologists and biochemists.
3. write detailed mechanisms for the acidic and basic hydrolysis of amides.
4. write an equation to describe the reduction of an amide to an amine.
5. write a detailed mechanism for the reduction of an amide to an amine.
6. identify the product formed when a given amide is reduced with lithium aluminum hydride.
7. identify the amide, the reagents, or both, necessary to prepare a given amine by direct reduction.
8. identify lactams as being cyclic amides which undergo hydrolysis and reduction in a manner analogous to that of
their acyclic counterparts.

Key Terms
Make certain that you can define, and use in context, the key term below.
lactam

Study Notes

As the chapter which deals with amino acids and proteins is optional, it is possible for you to complete this course
without studying these compounds in detail. However, because of their importance in biological systems, it is essential
for all students completing this course to have some knowledge of their structure and properties.
When we talk about amino acids, we are generally referring to α‑amino acids; that is, compounds in which an amino
(NH2) group and a carboxyl group are attached to the same carbon atom:

Notice that such compounds contain a chiral carbon atom (unless R = H). Proteins can be considered to consist of
amino acid residues joined by amide (or peptide) links. These peptide links consist of exactly the same structural units
that we find in secondary amides

Note: Although the terms secondary amide and tertiary amide have been used here, this usage is not in agreement with
IUPAC recommendations. According to IUPAC, the secondary amide shown above should be referred to as an

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 N‑substituted primary amide, and the tertiary amide should be referred to as a N, N‑disubstituted primary amide.
IUPAC reserves the term secondary amide for compounds of the type

Because of the presence of the amide link in proteins,

we can expect the properties of these compounds to resemble those of secondary amides.
A lactam is a cyclic amide, in the same way that a lactone is a cyclic ester:

Among the most important molecules that contain lactam rings are the penicillins:

Preparation of Amides
Nitriles can be converted to amides. This reaction can be acid or base catalyzed

Carboxylic acid can be converted to amides by using DCC as an activating agent

Direct conversion of a carboxylic acid to an amide by reaction with an amine.

Acid chlorides react with ammonia, 1o amines and 2o amines to form amides

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Acid Anhydrides react with ammonia, 1o amines and 2o amines to form amides

Conversion of Amides into Carboxylic Acids: Hydrolysis

This page describes the hydrolysis of amides under both acidic and alkaline conditions. It also describes the
use of alkaline hydrolysis in testing for amides.

What is hydrolysis?
Technically, hydrolysis is a reaction with water. That is exactly what happens when amides are hydrolyzed in
the presence of dilute acids such as dilute hydrochloric acid. The acid acts as a catalyst for the reaction
between the amide and water. The alkaline hydrolysis of amides actually involves reaction with hydroxide ions,
but the result is similar enough that it is still classed as hydrolysis.

Hydrolysis under acidic conditions

Taking ethanamide as a typical amide. If ethanamide is heated with a dilute acid (such as dilute hydrochloric
acid), ethanoic acid is formed together with ammonium ions. So, if you were using hydrochloric acid, the final
solution would contain ammonium chloride and ethanoic acid.

Hydrolysis under alkaline conditions

Also, if ethanamide is heated with sodium hydroxide solution, ammonia gas is given off and you are left with a
solution containing sodium ethanoate.

Conversion of Amides into Amines: Reduction

Amides can be converted to 1°, 2° or 3° amines using LiAlH4.

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Example 21.7.1: Amide Reductions

Alkyl groups attached to the nitrogen do not affect the reaction.

Mechanism
1) Nucleophilic attach by the hydride

2) Leaving group removal

3) Nucleophilic attach by the hydride

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Exercises
Questions

Q21.7.1
How would you prepare the following compounds from N-Propypl benzamide?

(a)

(b)

(c)
Q21.7.2
Propose a synthesis for the following.

Solutions
S21.7.1
a. NaOH, H2O
b. NaOH, H2O, then LAH
c. LAH
S21.7.2

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Jim Clark (Chemguide.co.uk)

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20.7: Amidates and Their Halogenation: The Hofmann Rearrangement
Hofmann rearrangement, also known as Hofmann degradation and not to be confused with Hofmann elimination, is the
reaction of a primary amide with a halogen (chlorine or bromine) in strongly basic (sodium or potassium hydroxide)
aqueous medium, which converts the amide to a primary amine. For example:

Mechanism:

Contributors
Gamini Gunawardena from the OChemPal site (Utah Valley University)

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20.8: Alkanenitriles: A Special Class of Carboxylic
Name the parent alkane (include the carbon atom of the nitrile as part of the parent) followed with the word -nitrile. The
carbon in the nitrile is given the #1 location position. It is not necessary to include the location number in the name
because it is assumed that the functional group will be on the end of the parent chain.

Cycloalkanes are followed by the word -carbonitrile. The substituent name is cyano.

1-butanenitrile or 1-cyanopropane
Try to name the following compounds using these conventions�

J
Try to draw structures for the following compounds�
butanedinitrile J
2-methycyclohexanecarbonitrile J
Some common names that you should know are...

acetonitrile

benzonitrile
Try to draw a structure for the following compound�
2-methoxybenzonitrile J

Contributors
Prof. Steven Farmer (Sonoma State University)
Richard Banks (Boise State University)
The electronic structure of nitriles is very similar to that of an alkyne with the main difference being the presence of a set
of lone pair electrons on the nitrogen. Both the carbon and the nitrogen are sp hydridized which leaves them both with two
p orbitals which overlap to form the two π bond in the triple bond. The R-C-N bond angle in and nitrile is 180° which give
a nitrile functional group a linear shape.

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The lone pair electrons on the nitrogen are contained in a sp hybrid orbital which makes them much less basic and an
amine. The 50% character of an sp hybrid orbital close to the nucleus and therefore less basic compared to other nitrogen
containing compounds such as amines.

The presence of an electronegative nitrogen causes nitriles to be very polar molecules. Consequently, nitriles tend to have
higher boiling points than molecules with a similar size.

Contributors
Prof. Steven Farmer (Sonoma State University)
Nitriles can be converted to carboxylic acid with heating in sulfuric acid. During the reaction an amide intermediate is
formed.

General Reaction

Example

Contributors
Prof. Steven Farmer (Sonoma State University)
Grignard reagents can attack the electophillic carbon in a nitrile to form an imine salt. This salt can then be hydrolyzed to
become a ketone.

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General Reaction

Example

Mechanism
1) Nucleophilic Attack by the Grignard Reagent

2) Protonation

3) Protonation

4) Nucleophilic attack by water

5) Proton Transfer

6) Leaving group removal

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7) Deprotonation

Contributors
Prof. Steven Farmer (Sonoma State University)
Nitriles can be converted to 1° amines by reaction with LiAlH4. During this reaction the hydride nucleophile attacks the
electrophilic carbon in the nitrile to form an imine anion. Once stabilized by a Lewis acid-base complexation the imine salt
can accept a second hydride to form a dianion. The dianion can then be converted to an amine by addition of water.

General Reaction

Going from reactants to products simplified

Example

Mechanism
1) Nucleophilic Attack by the Hydride

2) Second nucleophilic attack by the hydride.

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3) Protonation by addition of water to give an amine

Contributors
Prof. Steven Farmer (Sonoma State University)

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CHAPTER OVERVIEW
21: AMINES AND THEIR DERIVATIVES
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

21.1: NAMING THE AMINES

21.2: STRUCTURAL AND PHYSICAL PROPERTIES OF AMINES
21.3: SPECTROSCOPY OF THE AMINE GROUP
21.4: ACIDITY AND BASICITY OF AMINES
21.5: SYNTHESIS OF AMINES BY ALKYLATION
21.6: SYNTHESIS OF AMINES BY REDUCTIVE AMINATION
21.7: SYNTHESIS OF AMINES FROM CARBOXYLIC AMIDES
21.8: QUATERNARY AMMONIUM SALTS: HOFMANN ELIMINATION
21.9: MANNICH REACTION: ALKYLATION OF ENOLS BY IMINIUM IONS
21.10: NITROSATION OF AMINES

1 12/5/2021
21.1: Naming the Amines
Objectives
After completing this section, you should be able to
1. classify a given amine as being primary, secondary or tertiary.
2. explain, briefly, the difference in meaning of the terms primary, secondary and tertiary when they are applied to the
structures of amines and alcohols.
3. determine whether a given structure represents a quaternary ammonium cation.
4. provide an acceptable IUPAC name for an amine, given its Kekulé, condensed or shorthand structure.
5. draw the structure of an amine, given its IUPAC name.
6. give the name and structure of one typical heterocyclic amine (e.g., pyridine).

Key Terms
Make certain that you can define, and use in context, the key terms below.
amine
primary amine
secondary amine
quaternary ammonium cation
tertiary amine

Study Notes

You should recognize that heterocyclic amines—compounds in which the nitrogen atom occurs as part of a ring—are
very common in organic chemistry. Be prepared to meet such compounds throughout this, and subsequent chapters,
but do not try to memorize all of the names and structures givenin the reading. You should, however, commit the
structures of pyridine and pyrrole to memory.

Amines are derivatives of ammonia in which one or more of the hydrogens has been replaced by an alkyl or aryl group.
The nomenclature of amines is complicated by the fact that several different nomenclature systems exist, and there is no
clear preference for one over the others. Furthermore, the terms primary (1º), secondary (2º) & tertiary (3º) are used to
classify amines in a completely different manner than they were used for alcohols or alkyl halides. When applied to
amines these terms refer to the number of alkyl (or aryl) substituents bonded to the nitrogen atom, whereas in other
cases they refer to the nature of an alkyl group. The four compounds shown in the top row of the following diagram are all
C4H11N isomers. The first two are classified as 1º-amines, since only one alkyl group is bonded to the nitrogen; however,
the alkyl group is primary in the first example and tertiary in the second. The third and fourth compounds in the row are 2º
and 3º-amines respectively. A nitrogen bonded to four alkyl groups will necessarily be positively charged, and is called a
quaternary (4º)-ammonium cation. For example, (CH3)4N(+) Br(–) is tetramethylammonium bromide.

The IUPAC names are listed first and colored blue. This system names amine functions as substituents on the largest
alkyl group. The simple -NH substituent found in 1º-amines is called an amino group. For 2º and 3º-amines a
compound prefix (e.g. dimethylamino in the fourth example) includes the names of all but the root alkyl group.

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 The Chemical Abstract Service has adopted a nomenclature system in which the suffix -amine is attached to the root
alkyl name. For 1º-amines such as butanamine (first example) this is analogous to IUPAC alcohol nomenclature (-ol
suffix). The additional nitrogen substituents in 2º and 3º-amines are designated by the prefix N- before the group name.
These CA names are colored magenta in the diagram.
Finally, a common system for simple amines names each alkyl substituent on nitrogen in alphabetical order, followed
by the suffix -amine. These are the names given in the last row (colored black).
Many aromatic and heterocyclic amines are known by unique common names, the origins of which are often unknown to
the chemists that use them frequently. Since these names are not based on a rational system, it is necessary to memorize
them. There is a systematic nomenclature of heterocyclic compounds, but it will not be discussed here.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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21.2: Structural and Physical Properties of Amines
Objectives
After completing this section, you should be able to
1. describe the geometry and bonding of simple amines.
2. explain why most chiral amines cannot be resolved into their two enantiomers.

Key Terms
Make certain that you can define, and use in context, the key term below.
pyramidal inversion

Study Notes

Molecular models may help you to understand pyramidal inversion.

Amines typically have three bonds and one pair of lone pair electrons. This makes the nitrogen sp3 hybridized, trigonal
pyramidal, with a bond angle of roughly 109.5o.

Stereogenic Nitrogen
Single-bonded nitrogen is pyramidal in shape, with the non-bonding electron pair pointing to the unoccupied corner of a
tetrahedral region. Since the nitrogen in these compounds is bonded to three different groups, its configuration is chiral.
The non-identical mirror-image configurations are illustrated in the following diagram (the remainder of the molecule is
represented by R, and the electron pair is colored yellow). If these configurations were stable, there would be four
additional stereoisomers of ephedrine and pseudoephedrine. However, pyramidal nitrogen is normally not
configurationally stable. It rapidly inverts its configuration (equilibrium arrows) by passing through a planar, sp2-
hybridized transition state, leading to a mixture of interconverting R and S configurations. If the nitrogen atom were the
only chiral center in the molecule, a 50:50 (racemic) mixture of R and S configurations would exist at equilibrium. If other
chiral centers are present, as in the ephedrin isomers, a mixture of diastereomers will result. The take-home message is that
nitrogen does not contribute to isolable stereoisomers.

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Boiling Point and Water Solubility
It is instructive to compare the boiling points and water solubility of amines with those of corresponding alcohols and
ethers. The dominant factor here is hydrogen bonding, and the first table below documents the powerful intermolecular
attraction that results from -O-H---O- hydrogen bonding in alcohols (light blue columns). Corresponding -N-H---N-
hydrogen bonding is weaker, as the lower boiling points of similarly sized amines (light green columns) demonstrate.
Alkanes provide reference compounds in which hydrogen bonding is not possible, and the increase in boiling point for
equivalent 1º-amines is roughly half the increase observed for equivalent alcohols.

Compound CH3CH3 CH3OH CH3NH2 CH3CH2CH3 CH3CH2OH CH3CH2NH2

Mol.Wt. 30 32 31 44 46 45

Boiling
-88.6º 65º -6.0º -42º 78.5º 16.6º
Point ºC

The second table illustrates differences associated with isomeric 1º, 2º & 3º-amines, as well as the influence of chain
branching. Since 1º-amines have two hydrogens available for hydrogen bonding, we expect them to have higher boiling
points than isomeric 2º-amines, which in turn should boil higher than isomeric 3º-amines (no hydrogen bonding). Indeed,
3º-amines have boiling points similar to equivalent sized ethers; and in all but the smallest compounds, corresponding
ethers, 3º-amines and alkanes have similar boiling points. In the examples shown here, it is further demonstrated that chain
branching reduces boiling points by 10 to 15 ºC.
Compound CH3(CH2)2CH3 CH3(CH2)2OH CH3(CH2)2NH2CH3CH2NHCH(CH
3 3)3CH (CH3)2CHOH (CH3)2CHNH2 (CH3)3N

Mol.Wt. 58 60 59 59 58 60 59 59

Boiling
-0.5º 97º 48º 37º -12º 82º 34º 3º
Point ºC

The water solubility of 1º and 2º-amines is similar to that of comparable alcohols. As expected, the water solubility of 3º-
amines and ethers is also similar. These comparisons, however, are valid only for pure compounds in neutral water. The
basicity of amines (next section) allows them to be dissolved in dilute mineral acid solutions, and this property facilitates
their separation from neutral compounds such as alcohols and hydrocarbons by partitioning between the phases of non-
miscible solvents.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

21.2.2 11/28/2021 https://chem.libretexts.org/@go/page/32543

21.3: Spectroscopy of the Amine Group
Objectives
After completing this section, you should be able to
1. identify the region of the infrared spectrum that shows absorptions resulting from the N−H bonds of primary and
secondary amines.
2. describe a characteristic change that occurs in the infrared spectrum of an amine when a small amount of mineral acid
is added to the sample.
3. use 1H NMR spectra in determining the structure of an unknown amine.
4. use the “nitrogen rule” of mass spectrometry to determine whether a compound has an odd or even number of nitrogen
atoms in its structure.
5. predict the prominent peaks in the mass spectrum of a given amine.
6. use the mass spectrum of an unknown amine in determining its structure.

Key Terms
Make certain that you can define, and use in context, the key term below.
nitrogen rule

Study Notes

You should note the spectroscopic similarities between amines and alcohols: both have infrared absorptions in the 3300–
3360 cm−1 region, and in both cases, the proton that is attached to the heteroatom gives rise to an often indistinct signal in
the 1H NMR spectrum.

NMR
The hydrogens attached to an amine show up ~ 0.5-5.0 ppm. The location is dependent on the amount of hydrogen bonding
and the sample's concentration.
The hydrogens on carbons directly bonded to an amine typically appear ~2.3-3.0 ppm.
Addition of D2O will normally cause all hydrogens on non-carbon atoms to exchange with deuteriums, thus making these
resonances "disappear." Addition of a few drops of D2O causing a signal to vanish can help confirm the presence of -NH.

IR
The infrared spectrum of aniline is shown beneath the following table. Some of the characteristic absorptions for C-H
stretching and aromatic ring substitution are also marked, but not colored.

Bending
Amine Class Stretching Vibrations Vibration
s

Primary (1°) The N-H stretching absorption is less sensitive to hydrogen bonding than are O-H absorptions. In Strong
the gas phase and in dilute CCl4 solution free N-H absorption is observed in the 3400 to 3500 cm-1 in-plane
region. Primary aliphatic amines display two well-defined peaks due to asymmetric (higher NH2
frequency) and symmetric N-H stretching, separated by 80 to 100 cm-1. In aromatic amines these scissorin
absorptions are usually 40 to 70 cm-1 higher in frequency. A smaller absorption near 3200 cm-1 g
(shaded orange in the spectra) is considered to be the result of interaction between an overtone of the absorptio
1600 cm-1 band with the symmetric N-H stretching band. ns at
1550 to

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 C-N stretching absorptions are found at 1200 to 1350 cm-1 for aromatic amines, and at 1000 to 1250 1650 cm-
cm-1 for aliphatic amines. 1, and
out-of-
plane
wagging
at 650 to
900 cm-1
(usually
broad)
are
character
istic of
1°-
amines.
A weak
N-H
bending
absorptio
n is
sometim
es visible
at 1500
-1 to 1600
Secondary amines exhibit only one absorption near 3420 cm . Hydrogen bonding in concentrated
-1 cm-1. A
liquids shifts these absorptions to lower frequencies by about 100 cm . Again, this absorption
broad
Secondary (2°) appears at slightly higher frequency when the nitrogen atom is bonded to an aromatic ring.
wagging
The C-N absorptions are found in the same range, 1200 to 1350 cm-1(aromatic) and 1000 to 1250
-1 absorptio
cm (aliphatic) as for 1°-amines.
n at 650
to 900
cm-1
may be
discerne
d in
liquid
film
samples.
Aside
from the
C-N
stretch
noted on
the left,
these
compoun
No N-H absorptions. The C-N absorptions are found in the same range, 1200 to 1350 cm-1
Tertiary (3°) ds have
(aromatic) and 1000 to 1250 cm-1 (aliphatic) as for 1°-amines.
spectra
character
istic of
their
alkyl and
aryl
substitue
nts.

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Nitrogen Rule
The nitrogen rule states that a molecule that has no or even number of nitrogen atoms has an even nominal mass, whereas a
molecule that has an odd number of nitrogen atoms has an odd nominal mass.
eg. 1:

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eg. 2:

eg. 3:

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Gamini Gunawardena from the OChemPal site (Utah Valley University)

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21.4: Acidity and Basicity of Amines
Objectives

After completing this section, you should be able to

1. account for the basicity and nucleophilicity of amines.
2. explain why amines are more basic than amides, and better nucleophiles.
3. describe how an amine can be extracted from a mixture that also contains neutral compounds illustrating the reactions which
take place with appropriate equations.
4. explain why primary and secondary (but not tertiary) amines may be regarded as very weak acids, and illustrate the synthetic
usefulness of the strong bases that can be formed from these weak acids.

Key Terms
Make certain that you can define, and use in context, the key term below.
amide

Study Notes

The lone pair of electrons on the nitrogen atom of amines makes these compounds not only basic, but also good nucleophiles.
Indeed, we have seen in past chapters that amines react with electrophiles in several polar reactions (see for example the
nucleophilic addition of amines in the formation of imines and enamines in Section 19.8).
The ammonium ions of most simple aliphatic amines have a pKa of about 10 or 11. However, these simple amines are all more
basic (i.e., have a higher pKa) than ammonia. Why? Remember that, relative to hydrogen, alkyl groups are electron releasing,
and that the presence of an electron‑releasing group stabilizes ions carrying a positive charge. Thus, the free energy difference
between an alkylamine and an alkylammonium ion is less than the free energy difference between ammonia and an ammonium
ion; consequently, an alkylamine is more easily protonated than ammonia, and therefore the former has a higher pKa than the
latter.

Basicity of nitrogen groups

In this section we consider the relative basicity of amines. When evaluating the basicity of a nitrogen-containing organic functional
group, the central question we need to ask ourselves is: how reactive (and thus how basic and nucleophilic) is the lone pair on the
nitrogen? In other words, how much does that lone pair want to break away from the nitrogen nucleus and form a new bond with a
hydrogen. The lone pair electrons makes the nitrogen in amines electron dense, which is represents by a red color in the electrostatic
potential map present below left. Amine are basic and easily react with the hydrogen of acids which are electron poor as seen below.

Amines are one of the only neutral functional groups which are considered basis which is a consequence of the presence of the lone
pair electrons on the nitrogen. During an acid/base reaction the lone pair electrons attack an acidic hydrogen to form a N-H bond.
This gives the nitrogen in the resulting ammonium salt four single bonds and a positive charge.

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Amines react with water to establish an equilibrium where a proton is transferred to the amine to produce an ammonium salt and the
hydroxide ion, as shown in the following general equation:
+ −
RN H 2(aq) + H2 O(l) ⇌ RN H 3 + OH (21.4.1)
(aq) (aq)

The equilibrium constant for this reaction is the base ionization constant (Kb), also called the base dissociation constant:
+ −
[RN H 3 ][OH ]
Kb = (21.4.2)
[N H 2]

pKb = -log Kb
Just as the acid strength of a carboxylic acid can be measured by defining an acidity constant Ka (Section 2-8), the base strength of
an amine can be measured by defining an analogous basicity constant Kb. The larger the value of Kb and the smaller the value of
pKb, the more favorable the proton-transfer equilibrium and the stronger the base.
However, Kb values are often not used to discuss relative basicity of amines. It is common to compare basicity's of amines by using
the Ka's of their conjugate acids, which is the corresponding ammonium ion. Fortunately, the Ka and Kb values for amines are
directly related.
Consider the reactions for a conjugate acid-base pair, RNH3+ − RNH2:
[ RNH ][ H O]
+ + 2 3
RNH (aq) + H O(l) ⇌ RNH (aq) + H O (aq) Ka = (21.4.3)
3 2 2 3 +
[ RNH ]
3

+
[ RNH ][OH−]
+ − 3
RNH (aq) + H O(l) ⇌ RNH (aq) + OH (aq) Kb = (21.4.4)
2 2 3
[ RNH ]
2

Adding these two chemical equations together yields the equation for the autoionization for water:
+ + − +
RNH (aq) + H O(l) + RNH (aq) + H O(l) ⇌ H O (aq) + RNH (aq) + OH (aq) + RNH (aq) (21.4.5)
3 2 2 2 3 2 3

+ −
2 H O(l) ⇌ H O (aq) + OH (aq) (21.4.6)
2 3

Given that the K expression for a chemical equation formed from adding two or more other equations is the mathematical product of
the input equations’ K constants.
Ka X Kb = {2 H2O} / (H3O+}{OH-} = Kw
Kw
Ka = (21.4.7)
Kb

pKa + pKb =14

Thus if the Ka for an ammonium ion is know the Kb for the corresponding amine can be calculated using the equation Kb = Kw / Ka.
This relationship shows that as an ammonium ion becomes more acidic (Ka increases / pKa decreases) the correspond base becomes
weaker (Kb decreases / pKb increases)
Weaker Base = Larger Ka and Smaller pKa of the Ammonium ion
Stronger Base = Smaller Ka and Larger pKa of the Ammonium ion
Like ammonia, most amines are Brønsted-Lowry and Lewis bases, but their base strength can be changed enormously by
substituents. Most simple alkyl amines have pKa's in the range 9.5 to 11.0, and their aqueous solutions are basic (have a pH of 11 to
12, depending on concentration).
Aromatic herterocyclic amines (such as pyrimidine, pyridine, imidazole, pyrrole) are significantly weaker bases as a consequence of
three factors. The first of these is the hybridization of the nitrogen. In each case the heterocyclic nitrogen is sp2 hybridized. The
increasing s-character brings it closer to the nitrogen nucleus, reducing its tendency to bond to a proton compared to sp3 hybridized
nitrogens. The very low basicity of pyrrole reflects the exceptional delocalization of the nitrogen electron pair associated with its
incorporation in an aromatic ring. Imidazole (pKa = 6.95) is over a million times more basic than pyrrole because the sp2 nitrogen
that is part of one double bond is structurally similar to pyridine, and has a comparable basicity.

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 Basicity of common amines (pKa of the conjugate ammonium ions)

Inductive Effects in Nitrogen Basicity

Alkyl groups donate electrons to the more electronegative nitrogen. The inductive effect makes the electron density on the
alkylamine's nitrogen greater than the nitrogen of ammonia. The small amount of extra negative charge built up on the nitrogen
atom makes the lone pair even more attractive towards hydrogen ions. Correspondingly, primary, secondary, and tertiary alkyl
amines are more basic than ammonia.

Compound pKa

NH3 9.3

CH3NH2 10.66

(CH3)2NH 10.74

(CH3)3N 9.81

Comparing the Basicity of Alkylamines to Amides

The nitrogen atom is strongly basic when it is in an amine, but not significantly basic when it is part of an amide group. While the
electron lone pair of an amine nitrogen is localized in one place, the lone pair on an amide nitrogen is delocalized by resonance. The
electron density – in the form of a lone pair – is stabilized by resonance delocalization, even though there is not a negative charge
involved. Here’s another way to think about it: the lone pair on an amide nitrogen is not as available for bonding with a proton –
these two electrons are too stable being part of the delocalized pi-bonding system. The electrostatic potential map shows the effect
of resonance on the basicity of an amide. The map shows that the electron density, shown in red, is almost completely shifted
towards the oxygen. This greatly decreases the basicity of the lone pair electrons on the nitrogen in an amide.

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Amine Extraction in the Laboratory
Extraction is often employed in organic chemistry to purify compounds. Liquid-liquid extractions take advantage of the difference
in solubility of a substance in two immiscible liquids (e.g. ether and water). The two immiscible liquids used in an extraction
process are (1) the solvent in which the solids are dissolved, and (2) the extracting solvent. The two immiscible liquids are then
easily separated using a separatory funnel. For amines one can take advantage of their basicity by forming the protonated salt
(RNH2+Cl−), which is soluble in water. The salt will extract into the aqueous phase leaving behind neutral compounds in the non-
aqueous phase. The aqueous layer is then treated with a base (NaOH) to regenerate the amine and NaCl. A second extraction-
separation is then done to isolate the amine in the non-aqueous layer and leave behind NaCl in the aqueous layer.

Important Reagent Bases

The significance of all these acid-base relationships to practical organic chemistry lies in the need for organic bases of varying
strength, as reagents tailored to the requirements of specific reactions. The common base sodium hydroxide is not soluble in many
organic solvents, and is therefore not widely used as a reagent in organic reactions. Most base reagents are alkoxide salts, amines or
amide salts. Since alcohols are much stronger acids than amines, their conjugate bases are weaker than amine bases, and fill the gap
in base strength between amines and amide salts.
Triethyl Barton's Potassium
Base Name Pyridine Hünig's Base Sodium HMDS LDA
Amine Base t-Butoxide

Formula (C2H5)3N (CH3)3CO(–) K(+)[(CH3)3Si]2N(–) Na (+) ) CH] N(–)

[(CH 3 2 2

pKa of conjugate
5.3 10.7 11.4 14 19 26 35.7
acid

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 Basicity of common amines (pKa of the conjugate ammonium ions)
Pyridine is commonly used as an acid scavenger in reactions that produce mineral acid co-products. Its basicity and nucleophilicity
may be modified by steric hindrance, as in the case of 2,6-dimethylpyridine (pKa=6.7), or resonance stabilization, as in the case of
4-dimethylaminopyridine (pKa=9.7). Hünig's base is relatively non-nucleophilic (due to steric hindrance), and is often used as the
base in E2 elimination reactions conducted in non-polar solvents. Barton's base is a strong, poorly-nucleophilic, neutral base that
serves in cases where electrophilic substitution of other amine bases is a problem. The alkoxides are stronger bases that are often
used in the corresponding alcohol as solvent, or for greater reactivity in DMSO. Finally, the two amide bases see widespread use in
generating enolate bases from carbonyl compounds and other weak carbon acids.
In addition to acting as a base, 1o and 2o amines can act as very weak acids. Their N-H proton can be removed if they are reacted
with a strong enough base. An example is the formation of lithium diisopropylamide (LDA, LiN[CH(CH3)2]2) by reacting n-
butyllithium with diisopropylamine (pKa 36) (Section 22-5). LDA is a very strong base and is commonly used to create enolate ions
by deprotonating an alpha-hydrogen from carbonyl compounds (Section 22-7).

Exercises
Questions
Q24.3.1
Select the more basic amine from each of the following pairs of compounds.

(a)

(b)

(c)
Q24.3.2
The 4-methylbenzylammonium ion has a pKa of 9.51, and the butylammonium ion has a pKa of 10.59. Which is more basic?
What's the pKb for each compound?
Solutions
S24.3.1

(a)

(b)

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(c)
S24.3.2
The butylammonium is more basic. The pKb for butylammonium is 3.41, the pKb for 4-methylbenzylammonium is 4.49.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

Objectives
After completing this section, you should be able to
1. use the concept of resonance to explain why arylamines are less basic than their aliphatic counterparts.
2. arrange a given series of arylamines in order of increasing or decreasing basicity.
3. discuss, in terms of inductive and resonance effects, why a given arylamine is more or less basic than aniline.

Study Notes
With reference to the discussion of base strength, the traditional explanation for the base‑strengthening effect of
electron‑releasing (I) substituents is that such substituents help to stabilize the positive charge on an arylammonium ion more
than they stabilize the unprotonated compound, thereby lowering ΔG°.
The electron‑withdrawing (i.e., deactivating) substituents decrease the stability of a positively charged arylammonium ion.
Note that the arylammonium ion derived from aniline, PhNH3+, is commonly referred to as the anilinium ion.

Basicity of Aniline
Aniline is substantially less basic than methylamine, as is evident by looking at the pKa values for their respective ammonium
conjugate acids (remember that the lower the pKa of the conjugate acid, the weaker the base).

This difference is basicity can be explained by the observation that, in aniline, the lone pair of electrons on the nitrogen are
delocalized by the aromatic p system, making it less available for bonding to H+ and thus less basic. The lone pair electrons of
aniline are involved in four resonance forms making them more stable and therefore less reactive relative to alkylamines.

The effect of delocalization can be seen when viewing the electrostatic potential maps of aniline an methyl amine. The nitrogen of
methyl amine has a significant amount of electron density on its nitrogen, shown as a red color, which accounts for it basicity
compared to aniline. While the electron density of aniline's nitrogen is delocalized in the aromatic ring making it less basic.

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Basicity of Substituted Arylamines
The addition of substituents onto the aromatic ring can can make arylamines more or less basic. Substituents which are electron-
withdrawing (-Cl, -CF3, -CN, -NO2) decrease the electron density in the aromatic ring and on the amine making the arylamine less
basic. In particular, the nitro group of para-nitroaniline allows for an additional resonance form to be drawn, which further stabilizes
the lone pair electrons from the nitrogen, making the substituted arylamine less basic than aniline. This effect is analogous to the one
discussed for the acidity of substituted phenols in Section 17.2.

Substituents which are electron-donating (-CH3, -OCH3, -NH2) increase the electron density in the aromatic ring and on the amine
making the arylamine more basic. In the case of para-methoxyaniline, the lone pair on the methoxy group donates electron density
to the aromatic system, and a resonance contributor can be drawn in which a negative charge is placed on the carbon adjacent to the
nitrogen, which makes the substituted arylamine more basic than aniline.

Increased Basicity of para-Methoxyaniline due to Electron-Donation

The shifting electron density of aniline, p-nitroaniline, and p-methoxyaniline are seen in their relative electrostatic potential maps.
For p-Nitroaniline virtually all of the electron density, shown as a red/yellow color. is pulled toward the electron-withdrawing nitro
group. In p-methoxyaninline the electron donating methoxy group donates electron density into the ring. The amine in p-
methoxyaniline is shown to have more electron density, shown as a yellow color, when compared to the amine in aniline.

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Exercise s21.4.1

1) Using the knowledge of the electron donating or withdrawing effects of subsituents gained in Section 16.6, rank the
following compound in order of decreasing basicity.
a) p-Nitroaniline, methyl p-aminobenzoate, p-chloroaniline
b) p-Bromoaniline, p-Aminobenzonitrile, p-ethylaniline
c) p-(Trifluoromethyl)aniline, p-methoxyaniline, p-methylaniline

Answers
1)
a) p-Chloroaniline, methyl p-aminobenzoate, p-nitroaniline
b) p-Ethylaniline, p-Bromoaniline, p-aminobenzonitrile
c) p-Methoxyaniline, p-methylaniline, p-(trifluoromethyl)aniline

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

Acidity of Amines

We normally think of amines as bases, but it must be remembered that 1º and 2º-amines are also very weak acids (ammonia has a
pKa = 34). In this respect it should be noted that pKa is being used as a measure of the acidity of the amine itself rather than its
conjugate acid, as in the previous section. For ammonia this is expressed by the following hypothetical equation:
NH3 + H2O ____> NH2(–) + H2O-H(+)
The same factors that decreased the basicity of amines increase their acidity. This is illustrated by the following examples, which are
shown in order of increasing acidity. It should be noted that the first four examples have the same order and degree of increased
acidity as they exhibited decreased basicity in the previous table. The first compound is a typical 2º-amine, and the three next to it
are characterized by varying degrees of nitrogen electron pair delocalization. The last two compounds (shaded blue) show the
influence of adjacent sulfonyl and carbonyl groups on N-H acidity. From previous discussion it should be clear that the basicity of
these nitrogens is correspondingly reduced.

Compound C6H5SO2NH2

pKa 33 27 19 15 10 9.6

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The acids shown here may be converted to their conjugate bases by reaction with bases derived from weaker acids (stronger bases).
Three examples of such reactions are shown below, with the acidic hydrogen colored red in each case. For complete conversion to
the conjugate base, as shown, a reagent base roughly a million times stronger is required.

C6H5SO2NH2 + KOH C6H5SO2NH(–) K(+) + H2O a sulfonamide base

(CH3)3COH + NaH (CH3)3CO(–) Na(+) + H2 an alkoxide base

(C2H5)2NH + C4H9Li (C2H5)2N(–) Li(+) + C4H10 an amide base

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21.5: Synthesis of Amines by Alkylation
This page summarises the reactions of amines as nucleophiles. This includes their reactions with halogenoalkanes
(haloalkanes or alkyl halides), with acyl chlorides (acid chlorides) and with acid anhydrides.

Amines by direct nucleophilic substitution

A nucleophile is something which is attracted to, and then attacks, a positive or slightly positive part of another
molecule or ion. All amines contain an active lone pair of electrons on the very electronegative nitrogen atom. It is
these electrons which are attracted to positive parts of other molecules or ions.

The reactions of primary amines with halogenoalkanes

You get a complicated series of reactions on heating to give a mixture of products - probably one of the most confusing
sets of reactions you will meet at this level. The products of the reactions include secondary and tertiary amines and
their salts, and quaternary ammonium salts.

Making secondary amines and their salts

In the first stage of the reaction, you get the salt of a secondary amine formed. For example if you started with
ethylamine and bromoethane, you would get diethylammonium bromide

In the presence of excess ethylamine in the mixture, there is the possibility of a reversible reaction. The ethylamine
removes a hydrogen from the diethylammonium ion to give free diethylamine - a secondary amine.

Making tertiary amines and their salts

But it doesn't stop here! The diethylamine also reacts with bromoethane - in the same two stages as before. This is
where the reaction would start if you reacted a secondary amine with a halogenoalkane.
In the first stage, you get triethylammonium bromide.

There is again the possibility of a reversible reaction between this salt and excess ethylamine in the mixture.

The ethylamine removes a hydrogen ion from the triethylammonium ion to leave a tertiary amine - triethylamine.

Making a quaternary ammonium salt

The final stage! The triethylamine reacts with bromoethane to give tetraethylammonium bromide - a quaternary
ammonium salt (one in which all four hydrogens have been replaced by alkyl groups).

This time there isn't any hydrogen left on the nitrogen to be removed. The reaction stops here.

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Preparation of Primary Amines
Although direct alkylation of ammonia by alkyl halides leads to 1º-amines, alternative procedures are preferred in many
cases. These methods require two steps, but they provide pure product, usually in good yield. The general strategy is to
first form a carbon-nitrogen bond by reacting a nitrogen nucleophile with a carbon electrophile. The following table lists
several general examples of this strategy in the rough order of decreasing nucleophilicity of the nitrogen reagent. In the
second step, extraneous nitrogen substituents that may have facilitated this bonding are removed to give the amine product.

Nitrogen Carbon 1st Reaction 2nd Reaction 2nd Reaction

Initial Product Final Product
Reactant Reactant Type Conditions Type

RCH2-X or RCH2-N3 or LiAlH4 or RCH2-NH2 or

N3(–) SN2 Hydrogenolysis
R2CH-X R2CH-N3 4 H2 & Pd R2CH-NH2
RCH2-X or RCH2-NHSO2C6H5 or RCH2-NH2 or
C6H5SO2NH(–) SN2 Na in NH3 (liq) Hydrogenolysis
R2CH-X R2CH-NHSO2C6H5 R2CH-NH2
RCH2-X or RCH2-CN or RCH2-CH2NH2 or
CN(–) SN2 LiAlH4 Reduction
R2CH-X R2CH-CN R2CH-CH2NH2
RCH=O or Addition / RCH=NH or H2 & Ni RCH2-NH2 or
NH3 Reduction
R2C=O Elimination R2C=NH or NaBH3CN R2CH-NH2
Addition /
NH3 RCOX RCO-NH2 LiAlH4 Reduction RCH2-NH2
Elimination
NH2CONH2
R3C(+) SN1 R3C-NHCONH2 NaOH soln. Hydrolysis R3C-NH2
(urea)

A specific example of each general class is provided in the diagram below. In the first two, an anionic nitrogen species
undergoes an SN2 reaction with a modestly electrophilic alkyl halide reactant. For example #2 an acidic phthalimide
derivative of ammonia has been substituted for the sulfonamide analog listed in the table. The principle is the same for the
two cases, as will be noted later. Example #3 is similar in nature, but extends the carbon system by a methylene group
(CH2). In all three of these methods 3º-alkyl halides cannot be used because the major reaction path is an E2 elimination.

The methods illustrated by examples #4 and #5 proceed by attack of ammonia, or equivalent nitrogen nucleophiles, at the
electrophilic carbon of a carbonyl group. A full discussion of carbonyl chemistry is presented later, but for present
purposes it is sufficient to recognize that the C=O double bond is polarized so that the carbon atom is electrophilic.
Nucleophile addition to aldehydes and ketones is often catalyzed by acids. Acid halides and anhydrides are even more
electrophilic, and do not normally require catalysts to react with nucleophiles. The reaction of ammonia with aldehydes or
ketones occurs by a reversible addition-elimination pathway to give imines (compounds having a C=N function). These

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intermediates are not usually isolated, but are reduced as they are formed (i.e. in situ). Acid chlorides react with ammonia
to give amides, also by an addition-elimination path, and these are reduced to amines by LiAlH4.
The 6th example is a specialized procedure for bonding an amino group to a 3º-alkyl group (none of the previous methods
accomplishes this). Since a carbocation is the electrophilic species, rather poorly nucleophilic nitrogen reactants can be
used. Urea, the diamide of carbonic acid, fits this requirement nicely. The resulting 3º-alkyl-substituted urea is then
hydrolyzed to give the amine.
One important method of preparing 1º-amines, especially aryl amines, uses a reverse strategy. Here a strongly electrophilic
nitrogen species (NO2(+)) bonds to a nucleophilic carbon compound. This nitration reaction gives a nitro group that can be
reduced to a 1º-amine by any of several reduction procedures.
The Hofmann rearrangement of 1º-amides provides an additional synthesis of 1º-amines. To learn about this useful
procedure Click Here.

Reduction of Other Functional Groups that Contain Nitrogen

Reduction of Nitro Groups

Several methods for reducing nitro groups to amines are known. These include catalytic hydrogenation (H2 + catalyst),
zinc or tin in dilute mineral acid, and sodium sulfide in ammonium hydroxide solution. The procedures described above
are sufficient for most case

Nitriles can be converted to 1° amines by reaction with LiAlH4

During this reaction the hydride nucleophile attacks the electrophilic carbon in the nitrile to form an imine anion. Once
stabilized by a Lewis acid-base complexation the imine salt can accept a second hydride to form a dianion. The dianion
can then be converted to an amine by addition of water.

Amides can be converted to 1°, 2° or 3° amines using LiAlH4

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Reductive amination
Aldehydes and ketones can be converted into 1o, 2o and 3o amines using reductive amination. The reaction takes place in
two parts. The first step is the nucleophiic addition of the carbonyl group to form an imine. The second step is the
reduction of the imine to an amine using an reducing agent. A reducing agent commonly used for this reaction is sodium
cyanoborohydride (NaBH3CN).

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Contributors
Jim Clark (Chemguide.co.uk)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Steven Farmer (Sonoma State University)

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21.6: Synthesis of Amines by Reductive Amination
Reductive Amination

Aldehydes and ketones can be converted into 1o, 2o and 3o amines using reductive amination. The reaction takes place in
two parts. The first step is the nucleophiic addition of the carbonyl group to form an imine. The second step is the
reduction of the imine to an amine using an reducing agent. A reducing agent commonly used for this reaction is sodium
cyanoborohydride (NaBH3CN).

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21.7: Synthesis of Amines from Carboxylic Amides
Objectives
After completing this section, you should be able to
1. write equations to illustrate the synthesis of amines by
a. reduction of nitriles or amides and nitro compounds.
b. reactions involving alkyl groups:
i. SN2 reactions of alkyl halides, ammonia and other amines.
ii. nucleophilic attack by an azide ion on an alkyl halide, followed by reduction of the azide so formed.
iii. alkylation of potassium phthalimide, followed by hydrolysis of the N‑alkyl phthalimide so formed (i.e., the
Gabriel synthesis).
c. reductive amination of aldehydes or ketones.
d. Hofmann or Curtius rearrangements.
2. write detailed mechanisms for each of the steps involved in the synthetic routes outlined in Objective 1.
3. identify the product or products formed when
a. a given nitrile or amide is reduced using lithium aluminum hydride.
b. a given alkyl halide is reacted with ammonia or an alkylamine.
c. a given alkyl halide is reacted with azide ion and the resulting product is reduced.
d. a given alkyl halide is reacted with potassium phthalimide and the resulting product is hydrolyzed.
e. a given aldehyde or ketone is reacted with ammonia or an amine in the presence of nickel catalyst.
f. a given amide is treated with halogen and base.
g. a given acyl azide is heated and then hydrolyzed.
4. identify the starting material, the other reagents, or both, needed to synthesize a given amine by any of the routes
listed in Objective 1.
5. write a general equation to illustrate the preparation of an arylamine by the reduction of a nitro compound, and
balance such an equation.
6. identify the product formed from the reduction of a given aromatic nitro compound.
7. identify the organic compound, the inorganic reagents, or both, needed to prepare a given arylamine.

Key Terms
Make certain that you can define, and use in context, the key terms below.
azide synthesis
Curtius rearrangement
Hofmann rearrangement
Gabriel synthesis
imide
reductive amination

Study Notes
You may wish to review the mechanism of SN2 reactions which is discussed in some detail in Sections 11.2 and 11.3.
Azide synthesis is the first method on the table of synthesis of primary amines. The Lewis structure of the azide ion,
N3−, is as shown below.

An “imide” is a compound in which an N−H group is attached to two carbonyl groups; that is,

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 You should note the commonly used trivial names of the following compounds.

The phthalimide alkylation mentioned in the reading is also known as the Gabriel synthesis.
If necessary, review the reduction of nitriles (Section 20.7) and the reduction of amides (Section 21.7).
Before you read the section on reductive amination you may wish to remind yourself of the structure of an imine (see
Section 19.8).
The Hofmann rearrangement is usually called the Hofmann degradation. In a true rearrangement reaction, no atoms are
lost or gained; however, in this particular reaction one atom of carbon and one atom of oxygen are lost from the amide
starting material, thus the term “rearrangement” is not really appropriate. There is a rearrangement step in the overall
degradation process, however: this is the step in which the alkyl group of the acyl nitrene migrates from carbon to
nitrogen to produce an isocyanate.

You get a complicated series of reactions on heating primary amines with halogenoalkanes
to give a mixture of products - probably one of the most confusing sets of reactions you
will meet at this level. The products of the reactions include secondary and tertiary
amines and their salts, and quaternary ammonium salts.
Making secondary amines and their salts
In the first stage of the reaction, you get the salt of a secondary amine formed. For
example if you started with ethylamine and bromoethane, you would get
diethylammonium bromide

In the presence of excess ethylamine in the mixture, there is the possibility of a reversible
reaction. The ethylamine removes a hydrogen from the diethylammonium ion to give free
diethylamine - a secondary amine.

Making tertiary amines and their salts

But it doesn't stop here! The diethylamine also reacts with bromoethane - in the same
two stages as before. This is where the reaction would start if you reacted a secondary
amine with a halogenoalkane.
In the first stage, you get triethylammonium bromide.

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There is again the possibility of a reversible reaction between this salt and excess
ethylamine in the mixture.

The ethylamine removes a hydrogen ion from the triethylammonium ion to leave a
tertiary amine - triethylamine.

Making a quaternary ammonium salt

The final stage! The triethylamine reacts with bromoethane to give tetraethylammonium
bromide - a quaternary ammonium salt (one in which all four hydrogens have been
replaced by alkyl groups).

This time there isn't any hydrogen left on the nitrogen to be removed. The reaction stops
here.
Preparation of Primary Amines
Although direct alkylation of ammonia by alkyl halides leads to 1º-amines, alternative procedures are preferred in many
cases. These methods require two steps, but they provide pure product, usually in good yield. The general strategy is to
first form a carbon-nitrogen bond by reacting a nitrogen nucleophile with a carbon electrophile. The following table lists
several general examples of this strategy in the rough order of decreasing nucleophilicity of the nitrogen reagent. In the
second step, extraneous nitrogen substituents that may have facilitated this bonding are removed to give the amine product.
Nitrogen Carbon 1st Reaction 2nd Reaction 2nd Reaction
Initial Product Final Product
Reactant Reactant Type Conditions Type

RCH2-X or RCH2-N3 or LiAlH4 or RCH2-NH2 or

N3(–) SN2 Hydrogenolysis
R2CH-X R2CH-N3 4 H2 & Pd R2CH-NH2
RCH2-X or RCH2-NHSO2C6H5 or RCH2-NH2 or
C6H5SO2NH(–) SN2 Na in NH3 (liq) Hydrogenolysis
R2CH-X R2CH-NHSO2C6H5 R2CH-NH2
RCH2-X or RCH2-CN or RCH2-CH2NH2 or
CN(–) SN2 LiAlH4 Reduction
R2CH-X R2CH-CN R2CH-CH2NH2
RCH=O or Addition / RCH=NH or H2 & Ni RCH2-NH2 or
NH3 Reduction
R2C=O Elimination R2C=NH or NaBH3CN R2CH-NH2
Addition /
NH3 RCOX RCO-NH2 LiAlH4 Reduction RCH2-NH2
Elimination
NH2CONH2
R3C(+) SN1 R3C-NHCONH2 NaOH soln. Hydrolysis R3C-NH2
(urea)

A specific example of each general class is provided in the diagram below. In the first two, an anionic nitrogen species
undergoes an SN2 reaction with a modestly electrophilic alkyl halide reactant. For example #2 an acidic phthalimide
derivative of ammonia has been substituted for the sulfonamide analog listed in the table. The principle is the same for the

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two cases, as will be noted later. Example #3 is similar in nature, but extends the carbon system by a methylene group
(CH2). In all three of these methods 3º-alkyl halides cannot be used because the major reaction path is an E2 elimination.

The methods illustrated by examples #4 and #5 proceed by attack of ammonia, or equivalent nitrogen nucleophiles, at the
electrophilic carbon of a carbonyl group. A full discussion of carbonyl chemistry is presented later, but for present
purposes it is sufficient to recognize that the C=O double bond is polarized so that the carbon atom is electrophilic.
Nucleophile addition to aldehydes and ketones is often catalyzed by acids. Acid halides and anhydrides are even more
electrophilic, and do not normally require catalysts to react with nucleophiles. The reaction of ammonia with aldehydes or
ketones occurs by a reversible addition-elimination pathway to give imines (compounds having a C=N function). These
intermediates are not usually isolated, but are reduced as they are formed (i.e. in situ). Acid chlorides react with ammonia
to give amides, also by an addition-elimination path, and these are reduced to amines by LiAlH4.
The 6th example is a specialized procedure for bonding an amino group to a 3º-alkyl group (none of the previous methods
accomplishes this). Since a carbocation is the electrophilic species, rather poorly nucleophilic nitrogen reactants can be
used. Urea, the diamide of carbonic acid, fits this requirement nicely. The resulting 3º-alkyl-substituted urea is then
hydrolyzed to give the amine. One important method of preparing 1º-amines, especially aryl amines, uses a reverse
strategy. Here a strongly electrophilic nitrogen species (NO2(+)) bonds to a nucleophilic carbon compound. This nitration
reaction gives a nitro group that can be reduced to a 1º-amine by any of several reduction procedures.
The Hofmann rearrangement of 1º-amides provides an additional synthesis of 1º-amines.

Reduction of Other Functional Groups that Contain Nitrogen

Reduction of Nitro Groups

Several methods for reducing nitro groups to amines are known. These include catalytic hydrogenation (H2 + catalyst),
zinc or tin in dilute mineral acid, and sodium sulfide in ammonium hydroxide solution. The procedures described above
are sufficient for most case

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Nitriles can be converted to 1° amines by reaction with LiAlH4
During this reaction the hydride nucleophile attacks the electrophilic carbon in the nitrile to form an imine anion. Once
stabilized by a Lewis acid-base complexation the imine salt can accept a second hydride to form a dianion. The dianion
can then be converted to an amine by addition of water.

Amides can be converted to 1°, 2° or 3° amines using LiAlH4

Reductive Amination
Aldehydes and ketones can be converted into 1o, 2o and 3o amines using reductive amination. The reaction takes place in
two parts. The first step is the nucleophiic addition of the carbonyl group to form an imine. The second step is the
reduction of the imine to an amine using an reducing agent. A reducing agent commonly used for this reaction is sodium
cyanoborohydride (NaBH3CN).

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Hofmann rearrangement
Hofmann rearrangement, also known as Hofmann degradation and not to be confused with Hofmann elimination, is the
reaction of a primary amide with a halogen (chlorine or bromine) in strongly basic (sodium or potassium hydroxide)
aqueous medium, which converts the amide to a primary amine. For example:

Mechanism:

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Curtius Rearrangement
The Curtius rearrangement involves an acyl azide.

The mechanism of the Curtius rearrangement involves the migration of an -R group form the carbonyl carbon to the the
neighboring nitrogen.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Jim Clark (Chemguide.co.uk)
Gamini Gunawardena from the OChemPal site (Utah Valley University)

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21.8: Quaternary Ammonium Salts: Hofmann Elimination
Amine functions seldom serve as leaving groups in nucleophilic substitution or base-catalyzed elimination reactions.
Indeed, they are even less effective in this role than are hydroxyl and alkoxyl groups. In the case of alcohols and ethers, a
useful technique for enhancing the reactivity of the oxygen function was to modify the leaving group (OH(–) or OR(–)) to
improve its stability as an anion (or equivalent). This stability is conveniently estimated from the strength of the
corresponding conjugate acids.
As noted earlier, 1º and 2º-amines are much weaker acids than alcohols, so it is not surprising that it is difficult to force the
nitrogen function to assume the role of a nucleophilic leaving group. For example, heating an amine with HBr or HI does
not normally convert it to the corresponding alkyl halide, as in the case of alcohols and ethers. In this context we note that
the acidity of the putative ammonium leaving group is at least ten powers of ten less than that of an analogous oxonium
species. The loss of nitrogen from diazonium intermediates is a notable exception in this comparison, due to the extreme
stability of this leaving group (the conjugate acid of N2 would be an extraordinarily strong acid).
One group of amine derivatives that have proven useful in SN2 and E2 reactions is that composed of the tetraalkyl (4º-)
ammonium salts. Most applications involving this class of compounds are eliminations, but a few examples of SN2
substitution have been reported.

acetone & heat

C6H5–N(CH3)3(+) Br(–) + R-S(–) Na(+) R-S-CH3 + C6H5–N(CH3)2 + NaBr

heat
(CH3)4N(+) OH(–) CH3–OH + (CH3)3N

Hofmann Elimination
Elimination reactions of 4º-ammonium salts are termed Hofmann eliminations. Since the counter anion in most 4º-
ammonium salts is halide, this is often replaced by the more basic hydroxide ion through reaction with silver hydroxide (or
silver oxide). The resulting hydroxide salt must then be heated (100 - 200 ºC) to effect the E2-like elimination of a 3º-
amine. Example #1 below shows a typical Hofmann elimination. Obviously, for an elimination to occur one of the alkyl
substituents on nitrogen must have one or more beta-hydrogens, as noted earlier in examining elimination reactions of
alkyl halides.

In example #2 above, two of the alkyl substituents on nitrogen have beta-hydrogens, all of which are on methyl groups
(colored orange & magenta). The chief product from the elimination is the alkene having the more highly substituted
double bond, reflecting not only the 3:1 numerical advantage of those beta-hydrogens, but also the greater stability of the
double bond.

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Example #3 illustrates two important features of the Hofmann elimination:
1. Simple amines are easily converted to the necessary 4º-ammonium salts by exhaustive alkylation, usually with methyl
iodide (methyl has no beta-hydrogens and cannot compete in the elimination reaction). Exhaustive methylation is
shown again in example #4.
2. When a given alkyl group has two different sets of beta-hydrogens available to the elimination process (colored orange
& magenta here), the major product is often the alkene isomer having the less substituted double bond.
The tendency of Hofmann eliminations to give the less-substituted double bond isomer is commonly referred to as the
Hofmann Rule, and contrasts strikingly with the Zaitsev Rule formulated for dehydrohalogenations and dehydrations. In
cases where other activating groups, such as phenyl or carbonyl, are present, the Hofmann Rule may not apply. Thus, if 2-
amino-1-phenylpropane is treated in the manner of example #3, the product consists largely of 1-phenylpropene (E & Z-
isomers).
To understand why the base-induced elimination of 4º-ammonium salts behaves differently from that of alkyl halides it is
necessary to reexamine the nature of the E2 transition state, first described for dehydrohalogenation. The energy diagram
shown earlier for a single-step bimolecular E2 mechanism is repeated below.

The E2 transition state is less well defined than is that of SN2 reactions. More bonds are being broken and formed, with the
possibility of a continuum of states in which the extent of C–H and C–X bond-breaking and C=C bond-making varies. For
example, if the bond to the leaving group (X) is substantially broken relative to the other bond changes, the transition state
approaches that for an E1 reaction (initial ionization followed by a fast second step). At the other extreme, if the acidity of
the beta-hydrogens is enhanced, then substantial breaking of C–H may occur before the other bonds begin to be affected.
For most simple alkyl halides it was proper to envision a balanced transition state, in which there was a synchronous
change in all the bonds. Such a model was consistent with the Zaitsev Rule.
When the leaving group X carries a positive charge, as do the 4º-ammonium compounds discussed here, the inductive
influence of this charge will increase the acidity of both the alpha and the beta-hydrogens. Furthermore, the 4º-ammonium
substituent is much larger than a halide or hydroxyl group and may perturb the conformations available to substituted beta-
carbons. It seems that a combination of these factors acts to favor base attack at the least substituted (least hindered and
most acidic) set of beta-hydrogens. The favored anti orientation of the leaving group and beta-hydrogen, noted for
dehydrohalogenation, is found for many Hofmann eliminations; but syn-elimination is also common, possibly because the
attraction of opposite charges orients the hydroxide base near the 4º-ammonium leaving group.
Three additional examples of the Hofmann elimination are shown in the following diagram. Example #1 is interesting in
two respects. First, it generates a 4º-ammonium halide salt in a manner different from exhaustive methylation. Second, this
salt is not converted to its hydroxide analog prior to elimination. A concentrated aqueous solution of the halide salt is
simply dropped into a refluxing sodium hydroxide solution, and the volatile hydrocarbon product is isolated by distillation.

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Example #2 illustrates an important aspect of the Hofmann elimination. If the nitrogen atom is part of a ring, then a single
application of this elimination procedure does not remove the nitrogen as a separate 3º-amine product. In order to sever the
nitrogen function from the molecule, a second Hofmann elimination must be carried out. Indeed, if the nitrogen atom was
a member of two rings (fused or spiro), then three repetitions of the Hofmann elimination would be required to sever the
nitrogen from the remaining molecular framework.
Example #3 is noteworthy because the less stable trans-cyclooctene is the chief product, accompanied by the cis-isomer.
An anti-E2-transition state would necessarily give the cis-cycloalkene, so the trans-isomer must be generated by a syn-
elimination. The cis-cyclooctene produced in this reaction could also be formed by a syn-elimination. Cyclooctane is a
conformationally complex structure. Several puckered conformations that avoid angle strain are possible, and one of the
most stable of these is shown on the right. Some eclipsed bonds occur in all these conformers, and transannular hydrogen
crowding is unavoidable. Since the trimethylammonium substituent is large (about the size of tert-butyl) it will probably
assume an equatorial-like orientation to avoid steric crowding. An anti-E2 transition state is likely to require an axial-like
orientation of this bulky group, making this an unfavorable path.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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21.9: Mannich Reaction: Alkylation of Enols by Iminium Ions
The acid-catalyzed reaction of an enolizable aldehyde or an enolizable ketone with an imminium ion, usually generated in
situ by the reaction of formaldehyde with a secondary amine, followed by a base to give a β-aminoaldehyde of a β-
aminoketone, respectively, is known as the Mannich reaction. The product of the Mannich reaction is called the Mannich
base.

Gamini Gunawardena from the OChemPal site (Utah Valley University)

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21.10: Nitrosation of Amines
Nitrous acid (H N O or H ON O ) reacts with aliphatic amines in a fashion that provides a useful test for distinguishing primary, secondary and tertiary amines.
2

1°-Amines + HONO (cold acidic solution) → Nitrogen Gas Evolution from a Clear Solution
2°-Amines + HONO (cold acidic solution) → An Insoluble Oil (N-Nitrosamine)
3°-Amines + HONO (cold acidic solution) → A Clear Solution (Ammonium Salt Formation)
Nitrous acid is a Brønsted acid of moderate strength (pKa = 3.3). Because it is unstable, it is prepared immediately before use in the following manner:

Under the acidic conditions of this reaction, all amines undergo reversible salt formation:

This happens with 3º-amines, and the salts are usually soluble in water. The reactions of nitrous acid with 1°- and 2°- aliphatic amines may be explained by considering their behavior with
the nitrosonium cation, NO(+), an electrophilic species present in acidic nitrous acid solutions.

Primary Amines

Secondary Amines

The distinct behavior of 1º, 2º & 3º-aliphatic amines is an instructive challenge to our understanding of their chemistry, but is of little importance as a synthetic tool. The SN1 product
mixtures from 1º-amines are difficult to control, and rearrangement is common when branched primary alkyl groups are involved. The N-nitrosamines formed from 2º-amines are
carcinogenic, and are not generally useful as intermediates for subsequent reactions.

Aryl Amines

Aqueous solutions of these diazonium ions have sufficient stability at 0º to 10 ºC that they may be used as intermediates in a variety of nucleophilic substitution reactions. For example, if
water is the only nucleophile available for reaction, phenols are formed in good yield.

2º-Aryl Amines:
2º-Aryl amines give N-nitrosamine derivatives on reaction with nitrous acid, and thus behave identically to their aliphatic counterparts.

3º-Aryl Amines:
Depending on ring substitution, 3º-Aryl amines may undergo aromatic ring nitrosation at sites ortho or para to the amine substituent. The nitrosonium cation is not sufficiently electrophilic
to react with benzene itself, or even toluene, but highly activated aromatic rings such as amines and phenols are capable of substitution. Of course, the rate of reaction of NO(+) directly at
nitrogen is greater than that of ring substitution, as shown in the previous example. Once nitrosated, the activating character of the amine nitrogen is greatly diminished; and N-
nitrosoaniline derivatives, or indeed any amide derivatives, do not undergo ring nitrosation.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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CHAPTER OVERVIEW
22: CHEMISTRY OF THE BENZENE SUBSTITUENTS: ALKYLBENZENES,
PHENOLS, AND BENZENAMINES
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

Thumbnail: Ball-and-stick model of a phenol molecule. (Public Domain; Benjah-bmm27).

22.1: REACTIVITY AT THE PHENYLMETHYL (BENZYL) CARBON: BENZYLIC RESONANCE STABILIZATION

22.2: BENZYLIC OXIDATIONS AND REDUCTIONS
22.3: NAMES AND PROPERTIES OF PHENOLS
22.4: PREPARATION OF PHENOLS: NUCLEOPHILIC AROMATIC SUBSTITUTION
22.5: ALCOHOL CHEMISTRY OF PHENOLS
22.6: ELECTROPHILIC SUBSTITUTION OF PHENOLS
22.7: AN ELECTROCYCLIC REACTION OF THE BENZENE RING: THE CLAISEN REARRANGEMENT
22.8: OXIDATION OF PHENOLS: BENZOQUINONES
22.9: OXIDATION-REDUCTION PROCESSES IN NATURE
22.10: ARENEDIAZONIUM SALTS
22.11: ELECTROPHILIC SUBSTITUTION WITH ARENEDIAZONIUM SALTS: DIAZO COUPLING

1 12/5/2021
22.1: Reactivity at the Phenylmethyl (Benzyl) Carbon: Benzylic Resonance
Stabilization

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22.2: Benzylic Oxidations and Reductions
Oxidation of Alkyl Side-Chains

The benzylic hydrogens of alkyl substituents on a benzene ring are activated toward free radical attack, as noted earlier.
Furthermore, , and E1 reactions ofbenzylic halides, show enhanced reactivity, due to the adjacent aromatic ring.
The possibility that these observations reflect a general benzylic activation is supported by the susceptibility of alkyl side-
chains to oxidative degradation, as shown in the following examples (the oxidized side chain is colored). Such oxidations
are normally effected by hot acidic pemanganate solutions, but for large scale industrial operations catalyzed air-oxidations
are preferred. Interestingly, if the benzylic position is completely substituted this oxidative degradation does not occur
(second equation, the substituted benzylic carbon is colored blue).

C6H5–CH2CH2CH2CH3 + KMnO4 + H3O(+) & heat C6H5–CO2H + CO2

p-(CH3)3C–C6H4–CH3 + KMnO4 + H3O(+) & heat p-(CH3)3C–C6H4–CO2H

These equations are not balanced. The permanganate oxidant is reduced, usually to Mn(IV) or Mn(II). Two other examples
of this reaction are given below, and illustrate its usefulness in preparing substituted benzoic acids.

Reduction of Nitro Groups and Aryl Ketones

Electrophilic nitration and Friedel-Crafts acylation reactions introduce deactivating, meta-directing substituents on an
aromatic ring. The attached atoms are in a high oxidation state, and their reduction converts these electron withdrawing
functions into electron donating amino and alkyl groups. Reduction is easily achieved either by catalytic hydrogenation
(H2 + catalyst), or with reducing metals in acid. Examples of these reductions are shown here, equation 6 demonstrating
the simultaneous reduction of both functions. Note that the butylbenzene product in equation 4 cannot be generated by
direct Friedel-Crafts alkylation due to carbocation rearrangement. The zinc used in ketone reductions, such as 5, is usually
activated by alloying with mercury (a process known as amalgamation).

Several alternative methods for reducing nitro groups to amines are known. These include zinc or tin in dilute mineral acid,
and sodium sulfide in ammonium hydroxide solution. The procedures described above are sufficient for most cases.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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22.3: Names and Properties of Phenols
Naming phenols
Phenols are named using the rules for aromatic compounds discussed in seciton 15.1 Note! that -phenol is used rather than
-benzene.

Compounds like alcohols and phenol which contain an -OH group attached to a hydrocarbon are very weak acids.
Alcohols are so weakly acidic that, for normal lab purposes, their acidity can be virtually ignored. However, phenol is
sufficiently acidic for it to have recognizably acidic properties - even if it is still a very weak acid. A hydrogen ion can
break away from the -OH group and transfer to a base.

Why is phenol acidic?

Compounds like alcohols and phenol which contain an -OH group attached to a hydrocarbon are very weak acids.
Alcohols are so weakly acidic that, for normal lab purposes, their acidity can be virtually ignored. However, phenol is
sufficiently acidic for it to have recognizably acidic properties - even if it is still a very weak acid. A hydrogen ion can
break away from the -OH group and transfer to a base. For example, in solution in water:

Phenol is a very weak acid and the position of equilibrium lies well to the left. Phenol can lose a hydrogen ion because the
phenoxide ion formed is stabilised to some extent. The negative charge on the oxygen atom is delocalised around the ring.
The more stable the ion is, the more likely it is to form. One of the lone pairs on the oxygen atom overlaps with the
delocalised electrons on the benzene ring.

This overlap leads to a delocalization which extends from the ring out over the oxygen atom. As a result, the negative
charge is no longer entirely localized on the oxygen, but is spread out around the whole ion.

Spreading the charge around makes the ion more stable than it would be if all the charge remained on the oxygen.
However, oxygen is the most electronegative element in the ion and the delocalized electrons will be drawn towards it.

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That means that there will still be a lot of charge around the oxygen which will tend to attract the hydrogen ion back again.
That is why phenol is only a very weak acid.
Why is phenol a much stronger acid than cyclohexanol? To answer this question we must evaluate the manner in which an
oxygen substituent interacts with the benzene ring. As noted in our earlier treatment of electrophilic aromatic substitution
reactions, an oxygen substituent enhances the reactivity of the ring and favors electrophile attack at ortho and para sites. It
was proposed that resonance delocalization of an oxygen non-bonded electron pair into the pi-electron system of the
aromatic ring was responsible for this substituent effect. A similar set of resonance structures for the phenolate anion
conjugate base appears below the phenol structures.
The resonance stabilization in these two cases is very different. An important principle of resonance is that charge
separation diminishes the importance of canonical contributors to the resonance hybrid and reduces the overall
stabilization. The contributing structures to the phenol hybrid all suffer charge separation, resulting in very modest
stabilization of this compound. On the other hand, the phenolate anion is already charged, and the canonical contributors
act to disperse the charge, resulting in a substantial stabilization of this species. The conjugate bases of simple alcohols are
not stabilized by charge delocalization, so the acidity of these compounds is similar to that of water. An energy diagram
showing the effect of resonance on cyclohexanol and phenol acidities is shown on the right. Since the resonance
stabilization of the phenolate conjugate base is much greater than the stabilization of phenol itself, the acidity of phenol
relative to cyclohexanol is increased. Supporting evidence that the phenolate negative charge is delocalized on the ortho
and para carbons of the benzene ring comes from the influence of electron-withdrawing substituents at those sites.

Properties of phenol as an acid

With indicators
The pH of a typical dilute solution of phenol in water is likely to be around 5 - 6 (depending on its concentration). That
means that a very dilute solution isn't really acidic enough to turn litmus paper fully red. Litmus paper is blue at pH 8 and
red at pH 5. Anything in between is going to show as some shade of "neutral". Phenol reacts with sodium hydroxide
solution to give a colourless solution containing sodium phenoxide.

In this reaction, the hydrogen ion has been removed by the strongly basic hydroxide ion in the sodium hydroxide solution.

With sodium carbonate or sodium hydrogencarbonate

Phenol isn't acidic enough to react with either of these. Or, looked at another way, the carbonate and hydrogencarbonate
ions aren't strong enough bases to take a hydrogen ion from the phenol. Unlike the majority of acids, phenol does not give
carbon dioxide when you mix it with one of these. This lack of reaction is actually useful. You can recognise phenol
because:
It is fairly insoluble in water.
It reacts with sodium hydroxide solution to give a colourless solution (and therefore must be acidic).
It does not react with sodium carbonate or hydrogencarbonate solutions (and so must be only very weakly acidic).

With metallic sodium

Acids react with the more reactive metals to give hydrogen gas. Phenol is no exception - the only difference is the slow
reaction because phenol is such a weak acid. Phenol is warmed in a dry tube until it is molten, and a small piece of sodium
added. There is some fizzing as hydrogen gas is given off. The mixture left in the tube will contain sodium phenoxide.

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Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Jim Clark (Chemguide.co.uk)
Substitution of the hydroxyl hydrogen atom is even more facile with phenols, which are roughly a million times more
acidic than equivalent alcohols. This phenolic acidity is further enhanced by electron-withdrawing substituents ortho and
para to the hydroxyl group, as displayed in the following diagram. The alcohol cyclohexanol is shown for reference at the
top left. It is noteworthy that the influence of a nitro substituent is over ten times stronger in the para-location than it is
meta, despite the fact that the latter position is closer to the hydroxyl group. Furthermore additional nitro groups have an
additive influence if they are positioned in ortho or para locations. The trinitro compound shown at the lower right is a
very strong acid called picric acid.

Why is phenol a much stronger acid than cyclohexanol? To answer this question we must evaluate the manner in which an
oxygen substituent interacts with the benzene ring. As noted in our earlier treatment of electrophilic aromatic substitution
reactions, an oxygen substituent enhances the reactivity of the ring and favors electrophile attack at ortho and para sites. It
was proposed that resonance delocalization of an oxygen non-bonded electron pair into the pi-electron system of the
aromatic ring was responsible for this substituent effect. Formulas illustrating this electron delocalization will be displayed
when the "Resonance Structures" button beneath the previous diagram is clicked. A similar set of resonance structures for
the phenolate anion conjugate base appears below the phenol structures.

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The resonance stabilization in these two cases is very different. An important principle of resonance is that charge
separation diminishes the importance of canonical contributors to the resonance hybrid and reduces the overall
stabilization. The contributing structures to the phenol hybrid all suffer charge separation, resulting in very modest
stabilization of this compound. On the other hand, the phenolate anion is already charged, and the canonical contributors
act to disperse the charge, resulting in a substantial stabilization of this species. The conjugate bases of simple alcohols are
not stabilized by charge delocalization, so the acidity of these compounds is similar to that of water. An energy diagram
showing the effect of resonance on cyclohexanol and phenol acidities is shown on the right. Since the resonance
stabilization of the phenolate conjugate base is much greater than the stabilization of phenol itself, the acidity of phenol
relative to cyclohexanol is increased. Supporting evidence that the phenolate negative charge is delocalized on the ortho
and para carbons of the benzene ring comes from the influence of electron-withdrawing substituents at those sites.

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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22.4: Preparation of Phenols: Nucleophilic Aromatic Substitution
Objectives
After completing this section, you should be able to
1. identify the reagents and conditions required to produce phenol from chlorobenzene on an industrial scale.
2. write the mechanism for the conversion of an alkyl halide to a phenol through a benzyne intermediate.
3. discuss the experimental evidence which supports the existence of benzyne intermediates.
4. discuss the bonding in benzyne, and hence account for its high reactivity.

Key Terms
Make certain that you can define, and use in context, the key terms below.
benzyne
elimination-addition mechanism

Study Notes

An elimination-addition mechanism involves the elimination of the elements of a small molecule from a substrate to
produce a highly reactive intermediate, which then undergoes an addition reaction.

The elimination-addition mechanism of nucleophilic aromatic substitution involves the remarkable intermediate called
benzyne or arynes.

14-6C Elimination-Addition Mechanism of Nucleophilic Aromatic Substitution. Arynes

The reactivities of aryl halides, such as the halobenzenes, are exceedingly low toward nucleophilic reagents that normally
effect displacements with alkyl halides and activated aryl halides. Substitutions do occur under forcing conditions of either
high temperatures or very strong bases. For example, chlorobenzene reacts with sodium hydroxide solution at temperatures
around 340 and this reaction was once an important commercial process for the production of benzenol (phenol):
o

In addition, aryl chlorides, bromides, and iodides can be converted to areneamines ArNH by the conjugate bases of
2

amines. In fact, the reaction of potassium amide with bromobenzene is extremely rapid, even at temperatures as low as
−33 with liquid ammonia as solvent:
o

However, displacement reactions of this type differ from the previously discussed displacements of activated aryl halides
in that rearrangement often occurs. That is, the entering group does not always occupy the same position on the ring as
that vacated by the halogen substituent. For example, the hydrolysis of 4-chloromethylbenzene at 340 gives an equimolar
o

mixture of 3- and 4-methylbenzenols:

Even more striking is the exclusive formation of 3-methoxybenzenamine in the amination of 2-chloromethoxybenzene.
Notice that this result is a violation of the principle of least structural change (Section 1-1H):

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The mechanism of this type of reaction has been studied extensively, and much evidence has accumulated in support of a
stepwise process, which proceeds first by base-catalyzed elimination of hydrogen halide (HX) from the aryl halide - as
illustrated below for the amination of bromobenzene:
Elimination

The product of the elimination reaction is a highly reactive intermediate 9 called benzyne, or dehydrobenzene, which
differs from benzene in having two less hydrogen and an extra bond between two ortho carbons. Benzyne reacts rapidly
with any available nucleophile, in this case the solvent, ammonia, to give an addition product:
Addition

The rearrangements in these reactions result from the attack of the nucleophile at one or the other of the carbons of the
extra bond in the intermediate. With benzyne the symmetry is such that no rearrangement would be detected. With
substituted benzynes isomeric products may result. Thus 4-methylbenzyne, 10, from the reaction of hydroxide ion with 4-
chloro-1-methylbenzene gives both 3- and 4-methylbenzenols:

In the foregoing benzyne reactions the base that produces the benzyne in the elimination step is derived from the
nucleophile that adds in the addition step. This need not always be so, depending on the reaction conditions. In fact, the
synthetic utility of aryne reactions depends in large part of the success with which the aryne can be generated by one
reagent but captured by another. One such method will be discussed in Section 14-10C and involves organometallic
compounds derived from aryl halides. Another method is to generate the aryne by thermal decomposition of a 1,2-
disubstituted arene compound such as 11, in which both substituents are leaving groups - one leaving with an electron pair,
the other leaving without:

When 11 decomposes in the presence of an added nucleophile, the benzyne intermediate is trapped by the nucleophile as it
is formed. Or, if a conjugated diene is present, benzyne will react with it by a [4 + 2] cycloaddition. In the absence of other
compounds with which it can react, benzyne will undergo [2 + 2] cycloaddition to itself:

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Exercises
Questions
Q16.8.1
When p-chlorotoluene is reacted with NaOH, two products are seen. While when m-chlorotoluene is reacted with NaOH,
three products are seen. Explain this.
Solutions
S16.8.1
You need to look at the benzyne intermediates. The para substituted only allows for two products, while the para produces
two different alkynes which give three different products.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
John D. Robert and Marjorie C. Caserio (1977) Basic Principles of Organic Chemistry, second edition. W. A. Benjamin,
Inc. , Menlo Park, CA. ISBN 0-8053-8329-8. This content is copyrighted under the following conditions, "You are granted
permission for individual, educational, research and non-commercial reproduction, distribution, display and performance
of this work in any format."

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22.5: Alcohol Chemistry of Phenols
As with the alcohols, the phenolic hydroxyl hydrogen is rather easily replaced by other substituents. For example, phenol
reacts easily with acetic anhydride to give phenyl acetate. Likewise, the phenolate anion is an effective nucleophile in SN2
reactions, as in the second example below.
Examples:

Contributors
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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22.6: Electrophilic Substitution of Phenols
Over reaction of Aniline and Phenol

The strongest activating and ortho/para-directing substituents are the amino (-NH2) and hydroxyl (-OH) groups. Direct
nitration of phenol (hydroxybenzene) by dilute nitric acid gives modest yields of nitrated phenols and considerable
oxidative decomposition to tarry materials; aniline (aminobenzene) is largely destroyed. Bromination of both phenol and
aniline is difficult to control, with di- and tri-bromo products forming readily. Because of their high nucleophilic reactivity,
aniline and phenol undergo substitution reactions with iodine, a halogen that is normally unreactive with benzene
derivatives. The mixed halogen iodine chloride (ICl) provides a more electrophilic iodine moiety, and is effective in
iodinating aromatic rings having less powerful activating substituents.

p-I–C6H4–NH2 + NaI + CO2 +

C6H5–NH2 + I2 + NaHCO3
H2O

By acetylating the heteroatom substituent on phenol and aniline, its activating influence can be substantially attenuated.
For example, acetylation of aniline gives acetanilide (first step in the following equation), which undergoes nitration at low
temperature, yielding the para-nitro product in high yield. The modifying acetyl group can then be removed by acid-
catalyzed hydrolysis (last step), to yield para-nitroaniline. Although the activating influence of the amino group has been
reduced by this procedure, the acetyl derivative remains an ortho/para-directing and activating substituent.

pyridine (a base) HNO3 , 5 ºC H3O(+) & heat

C6H5–NH2 + (CH3CO)2O C6H5–NHCOCH3 p-O2N–C6H4–NHCOCH3 p-O2N–C6H4–NH

The following diagram illustrates how the acetyl group acts to attenuate the overall electron donating character of oxygen
and nitrogen. The non-bonding valence electron pairs that are responsible for the high reactivity of these compounds (blue
arrows) are diverted to the adjacent carbonyl group (green arrows). However, the overall influence of the modified
substituent is still activating and ortho/para-directing.

Objectives
After completing this section, you should be able to
1. explain why phenols and phenoxide ions are very reactive towards electrophilic aromatic substitution (see Section
16.4 of the textbook).

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 2. write an equation to illustrate the oxidation of a phenol or an arylamine to a quinone, and identify the reagents used
to oxidize phenols.
3. write an equation to illustrate the reduction of a quinone to a hydroquinone, and identify the reagents used to
reduce quinones.
4. describe, briefly, the biological importance of the redox properties of quinones.

Key Terms
Make certain that you can define, and use in context, the key terms below.
hydroquinone
quinone
ubiquinone

Study Notes
“Quinone” is a term used to describe cyclohexadiendiones in general, and p‑benzoquinone in particular. In addition to
benzene, other aromatic systems also give rise to quinones; for example, 1,4‑naphthoquinone

“Hydroquinones” are produced by the reduction of quinones according to the following half‑reaction:

“Ubiquinones” are naturally occurring quinones whose role is to transfer a pair of electrons from one substance to
another in enzyme‑catalyzed reactions. Ubiquinones are also called coenzymes Q.

Electrophilic Aromatic Substitution Reactions

The facility with which the aromatic ring of phenols and phenol ethers undergoes electrophilic substitution has been noted.
Two examples are shown in the following diagram. The first shows the Friedel-Crafts synthesis of the food preservative
BHT from para-cresol. The second reaction is interesting in that it further demonstrates the delocalization of charge that
occurs in the phenolate anion. Carbon dioxide is a weak electrophile and normally does not react with aromatic
compounds; however, the negative charge concentration on the phenolate ring enables the carboxylation reaction shown in
the second step. The sodium salt of salicylic acid is the major product, and the preference for ortho substitution may reflect
the influence of the sodium cation. This is called the Kolbe-Schmidt reaction, and it has served in the preparation of
aspirin, as the last step illustrates.

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Oxidation of Phenols: Quinones
Phenols are rather easily oxidized despite the absence of a hydrogen atom on the hydroxyl bearing carbon. Among the
colored products from the oxidation of phenol by chromic acid is the dicarbonyl compound para-benzoquinone (also
known as 1,4-benzoquinone or simply quinone); an ortho isomer is also known. These compounds are easily reduced to
their dihydroxybenzene analogs, and it is from these compounds that quinones are best prepared. Note that meta-quinones
having similar structures do not exist. The redox equilibria between the dihydroxybenzenes hydroquinone and catechol and
their quinone oxidation states are so facile that milder oxidants than chromate (Jones reagent) are generally preferred.
One such oxidant is Fremy's salt, shown on the right. Reducing agents other than stannous chloride (e.g. NaBH4) may be
used for the reverse reaction. The position of the quinone-hydroquinone redox equilibrium is proportional to the square of
the hydrogen ion concentration, as shown by the following half-reactions (electrons are colored blue). The electrode
potential for this interconversion may therefore be used to measure the pH of solutions.
2e(–)
Quinone + 2H(+)
Hydroquinone
–2e(–)

Exercises
Questions
Q17.10.1
Predict the major product if the following reagents/reagents were used. No reaction is also a possible answer.

(a) 1 equivalent of PBr3 (b) 1 equivalent of SOCl2 (c) Dess–Martin periodinane (d) 3 equivalents of acetyl chloride and
AlCl3 as a catalyst
(e) Heat and H2SO4 (assume the phenol does not act as a nucleophile in this case)

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Q17.10.2
Predict the major product if the following reagents/conditions were used. No reaction is also a possible answer.

(a) 2 equivalents of RMgBr and H3O+ work-up (b) LiAlH4 and H3O+ work-up (c) NaBH4 and H3O+ work-up
Solutions
S17.10.1

(a) (b) (c) (d) (e)

S17.10.2

(a) (b) (c) No reaction. NaBH4 is milder oxidant than LiAlH4. It typically only
reduces ketones and aldehydes.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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22.7: An Electrocyclic Reaction of the Benzene Ring: The Claisen
Rearrangement
Objectives

After completing this section, you should be able to

1. write an equation to represent the Claisen rearrangement of allyl phenyl ester.
2. account for the formation of a specific product from a Claisen rearrangement, without giving mechanistic details.

 Key Terms

Make certain that you can define, and use in context, the key term below.
Claisen rearrangement

Cope and Claisen rearrangements

The [3,3] sigmatropic rearrangement of 1,5-dienes or allyl vinyl ethers, known respectively as the Cope and Claisen
rearrangements, are among the most commonly used sigmatropic reactions. Three examples of the Cope rearrangement are
shown in the following diagram. Reactions 1 and 2 (top row) demonstrate the stereospecificity of this reaction. The light
blue σ-bond joins two allyl groups, oriented so their ends are near each other. Since each allyl segment is the locus of a
[1,3] shift, the overall reaction is classified as a [3,3] rearrangement. The three pink colored curved arrows describe the
redistribution of three bonding electron pairs in the course of this reversible rearrangement. The diene reactant in the third
reaction is drawn in an extended conformation. This molecule must assume a coiled conformation (as above) before the
[3,3] rearrangement can take place. The product of this rearrangement is an enol which immediately tautomerizes to its
keto form. Such variants are termed the oxy-Cope rearrangement, and are useful because the reverse rearrangement is
blocked by rapid ketonization. If the hydroxyl substituent is converted to an alkoxide salt, the activation energy of the
rearrangement is lowered significantly.
The degenerate or self-replicating Cope rearrangement has been a fascinating subject of research. For examples .

Two examples of the Claisen Rearrangement may be seen. Reaction 4 is the classic rearrangement of an allyl phenyl ether
to an ortho-allyl phenol. The methyl substituent on the allyl moiety serves to demonstrate the bonding shift at that site. The
initial cyclohexadienone product immediately tautomerizes to a phenol, regaining the stability of the aromatic ring.
Reaction 5 is an aliphatic analog in which a vinyl group replaces the aromatic ring. In both cases three pairs of bonding
electrons undergo a reorganization.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)

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William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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22.8: Oxidation of Phenols: Benzoquinones
Phenols are rather easily oxidized despite the absence of a hydrogen atom on the hydroxyl bearing carbon. Among the
colored products from the oxidation of phenol by chromic acid is the dicarbonyl compound para-benzoquinone (also
known as 1,4-benzoquinone or simply quinone); an ortho isomer is also known. These compounds are easily reduced to
their dihydroxybenzene analogs, and it is from these compounds that quinones are best prepared. Note that meta-quinones
having similar structures do not exist. The redox equilibria between the dihydroxybenzenes hydroquinone and catechol and
their quinone oxidation states are so facile that milder oxidants than chromate (Jones reagent) are generally preferred. One
such oxidant is Fremy's salt, shown on the right. Reducing agents other than stannous chloride (e.g. NaBH4) may be used
for the reverse reaction.
The position of the quinone-hydroquinone redox equilibrium is proportional to the square of the hydrogen ion
concentration, as shown by the following half-reactions (electrons are colored blue). The electrode potential for this
interconversion may therefore be used to measure the pH of solutions.

2e(–)

Quinone + 2H(+) Hydroquinone

–2e(–)

Further Reading

Chemgapedia
Oxidation of Phenols
Carey 5th Ed Online
Phenol Oxidation

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22.9: Oxidation-Reduction Processes in Nature

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22.10: Arenediazonium Salts
Objectives
After completing this section, you should be able to
1. a. identify the product formed when a given arylamine is reacted with aqueous bromine.
b. give an appropriate example to illustrate the high reactivity of arylamines in electrophilic aromatic substitution
reactions.
c. explain why arylamines cannot be used in Friedel‑Crafts reactions.
2. a. show how the problems associated with carrying out electrophilic aromatic substitution reactions on arylamines
can be circumvented by first converting the amine to an amide, and illustrate this process with an appropriate
example.
b. outline a possible synthetic route for the preparation of a given sulfa drug.
c. identify the starting material, the necessary organic reagents, inorganic reagents, or both, and the intermediate
compounds formed during the synthesis of a given sulfa drug.
d. design a multi‑step synthesis for a given compound in which it is necessary to protect the amino group by
acetylation.
3. a. write a general equation to describe the formation of an arenediazonium salt.
b. identify the product formed when a given arenediazonium salt is reacted with any of the following compounds:
copper(I) chloride, copper(I) bromide, sodium iodide, copper(I) cyanide, hot aqueous acid, hypophosphorous
acid.
c. identify the arenediazonium salt, the inorganic reagents, or both, needed to produce a given compound by a
diazonium replacement reaction.
4. a. illustrate, with appropriate examples, the importance to the synthetic chemist of the overall reaction sequence A
nitration, B reduction, C diazotization, and D replacement.
b. show how the removal of an amino (or nitro) group from an aromatic ring through the reaction of an
arenediazonium salt with hypophosphorous acid (H3PO2) can sometimes be of use in organic synthesis.
5. a. write a general equation to represent a diazonium coupling reaction.
b. write the detailed mechanism for the coupling reaction which takes place between arenediazonium salts and the
electon‑rich aromatic rings of phenols and arylamines.
c. identify the product formed from the reaction of a given arenediazonium salt with a given arylamine or phenol.
d. identify the arenediazonium salt and the arylamine or phenol needed to prepare a given azo compound.

Key Terms
Make certain that you can define, and use in context, the key terms below.
arenediazonium salt
azo compound
Sandmeyer reaction
sulfa drug

Study Notes
This section contains a considerable amount of new information. To absorb all of it, you should use the three
subsections indicated in the reading: electrophilic aromatic substitution and overreaction of aniline (Objectives 1 and
2), the preparation of diazonium salts and the Sandmeyer reaction (Objectives 3 and 4), and diazonium coupling
reactions (Objective 5).
The general process in which an aromatic amine is reacted with acetic anhydride, substituted, and then hydrolyzed is
known as “protecting the amino group.”
Sulfa drugs have the general formula

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Typical examples are sulfathiazole

and sulfapyridine

The reagent used to bring about the chlorosulfonation of acetanilide is chlorosulfuric acid

Sulfanilamide itself is toxic to humans, but derivatives of this compound, such as sulfathiazole, are less harmful to
humans and are effective in killing many types of bacteria. The drugs work by “deceiving” the bacteria in the
following way. To survive, many micro‑organisms use p‑aminobenzoic acid to synthesize folic acid, a coenzyme in a
number of biochemical processes. These micro‑organisms cannot distinguish between sulfa drugs and p‑aminobenzoic
acid; so, when the drug is administered, the bacteria use it to produce a compound which has a structure similar to that
of folic acid, but which is unable to act as a coenzyme in essential biochemical processes. The result is that many of
the bacteria’s amino acids and nucleotides cannot be made, and the bacteria die. Amino acids are discussed in Chapter
26; nucleotides are discussed in Section 28.1.

An “arenediazonium salt” is formed by the reaction of an aromatic amine with nitrous acid at 0–5°C, and has the
structure shown below.

Alkanediazonium salts are very unstable; therefore, arenediazonium salts are often simply referred to as diazonium
salts.
As is mentioned in the textbook, arenediazonium salts are very useful intermediates from which a wide variety of
aromatic compounds can be prepared. You should be thoroughly familiar with the use of diazonium salts to prepare
each of the classes of compounds. In addition, you should be aware that fluoroarenes can also be prepared from
diazonium salts, as follows:

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 In this case the diazonium salt is prepared using fluoroboric acid, HBF4, and sodium nitrite. The thermal
decomposition of the salt, called the Schiemann reaction, can be quite hazardous.
Note that the IUPAC‑preferred name for cuprous chloride is copper(I) chloride; similarly, cuprous cyanide is called
copper(I) cyanide.
Hypophosphorous acid has the structure shown below:

The presence of the letters “azo” in a compound’s name usually implies that a nitrogen‑nitrogen double bond is present
in its structure. Azo compounds t in which two aryl groups are joined by an −N=N− linkage are usually very
colourful.

Overreaction of Aniline
Arylamines are very reactive towards electrophilic aromomatic substitution. The strongest activating and ortho/para-
directing substituents are the amino (-NH2) and hydroxyl (-OH) groups. Direct nitration of phenol (hydroxybenzene) by
dilute nitric acid gives modest yields of nitrated phenols and considerable oxidative decomposition to tarry materials;
aniline (aminobenzene) is largely destroyed. Monobromination of both phenol and aniline is difficult to control, with di-
and tri-bromo products forming readily.

Because of their high nucleophilic reactivity, aniline and phenol undergo substitution reactions with iodine, a halogen that
is normally unreactive with benzene derivatives. The mixed halogen iodine chloride (ICl) provides a more electrophilic
iodine moiety, and is effective in iodinating aromatic rings having less powerful activating substituents.

p-I–C6H4–NH2 + NaI + CO2 +

C6H5–NH2 + I2 + NaHCO3
H2O

In addition to overreactivity, we have previously seen (Section 16.3) that Friedel-Crafts reactions employing AlCl3 catalyst
does not work with aniline. A salt complex forms and prevents electrophilic aromatic substitution.

Both this problem and the aniline overreactivity can be circumvented by first going through the corresponding amide.

Modifying the Influence of Strong Activating Groups

By acetylating the heteroatom substituent on aniline, its activating influence can be substantially attenuated. For example,
acetylation of aniline gives acetanilide (first step in the following equation), which undergoes nitration at low temperature,
yielding the para-nitro product in high yield. The modifying acetyl group can then be removed by acid-catalyzed
hydrolysis (last step), to yield para-nitroaniline. Although the activating influence of the amino group has been reduced by
this procedure, the acetyl derivative remains an ortho/para-directing and activating substituent.

pyridine (a base) HNO3 , 5 ºC H3O(+) & heat

C6H5–NH2 + (CH3CO)2O C6H5–NHCOCH3 p-O2N–C6H4–NHCOCH3 p-O2N–C6H4–NH

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The following diagram illustrates how the acetyl group acts to attenuate the overall electron donating character of oxygen
and nitrogen. The non-bonding valence electron pairs that are responsible for the high reactivity of these compounds (blue
arrows) are diverted to the adjacent carbonyl group (green arrows). However, the overall influence of the modified
substituent is still activating and ortho/para-directing.

Sulfa Drug Synthesis

Sulfa drugs are an important group of synthetic antimicrobial agents (pharmaceuticals) that contain the sulfonamide group.
The synthesis of sulfanilamide (a sulfa drug) illustrates how the reactivity of aniline can be modified to make possible an
electrophilic aromatic substitution. The corresponding acetanilide undergoes chlorosulfonation. The resulting 4-
acetamidobenzenesulfanyl chloride is treated with ammonia to replace the chlorine with an amino group and affords 4-
acetamidobenzenesulfonamide. The subsequent hydrolysis of the sulfonamide produces the sulfanilamide.

Diazonium Salts: The Sandmeyer Reaction

Aryl diazonium salts are important intermediates. They are prepared in cold (0 º to 10 ºC) aqueous solution, and generally
react with nucleophiles with loss of nitrogen. Some of the more commonly used substitution reactions are shown in the
following diagram. Since the leaving group (N2) is thermodynamically very stable, these reactions are energetically
favored. Those substitution reactions that are catalyzed by cuprous salts are known as Sandmeyer reactions. Fluoride
substitution occurs on treatment with BF4(–), a reaction known as the Schiemann reaction. Stable diazonium
tetrafluoroborate salts may be isolated, and on heating these lose nitrogen to give an arylfluoride product. The top reaction
with hypophosphorus acid, H3PO2, is noteworthy because it achieves the reductive removal of an amino (or nitro) group.
Unlike the nucleophilic substitution reactions, this reduction probably proceeds by a radical mechanism.

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These aryl diazonium substitution reactions significantly expand the tactics available for the synthesis of polysubstituted
benzene derivatives. Consider the following options:
I. The usual precursor to an aryl amine is the corresponding nitro compound. A nitro substituent deactivates an aromatic
ring and directs electrophilic substitution to meta locations.
II. Reduction of a nitro group to an amine may be achieved in several ways. The resulting amine substituent strongly
activates an aromatic ring and directs electrophilic substitution to ortho & para locations.
III. The activating character of an amine substituent may be attenuated by formation of an amide derivative (reversible), or
even changed to deactivating and meta-directing by formation of a quaternary-ammonium salt (irreversible).
IV. Conversion of an aryl amine to a diazonium ion intermediate allows it to be replaced by a variety of different groups
(including hydrogen), which may in turn be used in subsequent reactions.
The following examples illustrate some combined applications of these options to specific cases. You should try to
conceive a plausible reaction sequence for each. Once you have done so, you may check suggested answers below.

Answer 1:
It should be clear that the methyl substituent will eventually be oxidized to a carboxylic acid function. The timing is
important, since a methyl substituent is ortho/para-directing and the carboxyl substituent is meta-directing. The cyano
group will be introduced by a diazonium intermediate, so a nitration followed by reduction to an amine must precede
this step.

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Answer 2:
The hydroxyl group is a strong activating substituent and would direct aromatic ring chlorination to locations ortho &
para to itself, leading to the wrong product. As an alternative, the nitro group is not only meta-directing, it can be
converted to a hydroxyl group by way of a diazonium intermediate. The resulting strategy is self evident.

Answer 3:
Selective introduction of a fluorine is best achieved by treating a diazonium intermediate with boron tetrafluoride
anion. To get the necessary intermediate we need to make p-nitroaniline. Since the nitro substituent on the starting
material would direct a new substituent to a meta-location, we must first reduce it to an ortho/para-directing amino
group. Amino groups are powerful activating substituents, so we deactivate it by acetylation before nitration. The
acetyl substituent also protects the initial amine function from reaction with nitrous acid later on. It is removed in the
last step.

Answer 4:
Polybromination of benzene would lead to ortho/para substitution. In order to achieve the mutual meta-relationship of
three bromines, it is necessary to introduce a powerful ortho/para-directing prior to bromination, and then remove it
following the tribromination. An amino group is ideal for this purpose. Reductive removal of the diazonium group may
be accomplished in several ways (three are shown).

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Answer 5:
The propyl substituent is best introduced by Friedel-Crafts acylation followed by reduction, and this cannot be carried
out in the presence of a nitro substituent. Since an acyl substituent is a meta-director, it is logical to use this property to
locate the nitro and chloro groups before reducing the carbonyl moiety. The same reduction method can be used to
reduce both the nitro group (to an amine) and the carbonyl group to propyl. We have already seen the use of diazonium
intermediates as precursors to phenols.

Answer 6:
Aromatic iodination can only be accomplished directly on highly activated benzene compounds, such as aniline, or
indirectly by way of a diazonium intermediate. Once again, a deactivated amino group is the precursor of p-nitroaniline
(prb.#3). This aniline derivative requires the more electrophilic iodine chloride (ICl) for ortho-iodination because of the
presence of a deactivating nitro substituent. Finally, the third iodine is introduced by the diazonium ion procedure.

Diazonium Coupling Reactions

A resonance description of diazonium ions shows that the positive charge is delocalized over the two nitrogen atoms. It is
not possible for nucleophiles to bond to the inner nitrogen, but bonding (or coupling) of negative nucleophiles to the
terminal nitrogen gives neutral azo compounds. As shown in the following equation, this coupling to the terminal nitrogen
should be relatively fast and reversible. The azo products may exist as E / Z stereoisomers. In practice it is found that the
E-isomer predominates at equilibrium.

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Unless these azo products are trapped or stabilized in some manner, reversal to the diazonium ion and slow nucleophilic
substitution at carbon (with irreversible nitrogen loss) will be the ultimate course of reaction, as described in the previous
section. For example, if phenyldiazonium bisufate is added rapidly to a cold solution of sodium hydroxide a relatively
stable solution of sodium phenyldiazoate (the conjugate base of the initially formed diazoic acid) is obtained. Lowering the
pH of this solution regenerates phenyldiazoic acid (pKa ca. 7), which disassociates back to the diazonium ion and
eventually undergoes substitution, generating phenol.

C6H5N2(+) HSO4(–) + NaOH (cold solution) C6H5N2–OH + NaOH (cold) C6H5N2–O(–) Na(+)

phenyldiazonium bisulfate phenyldiazoic acid sodium phenyldiazoate

Aryl diazonium salts may be reduced to the corresponding hydrazines by mild reducing agents such as sodium bisulfite,
stannous chloride or zinc dust. The bisulfite reduction may proceed by an initial sulfur-nitrogen coupling, as shown in the
following equation.

NaHSO3 NaHSO3 H2O

Ar-N2(+) X(–) Ar-N=N-SO3H Ar-NH-NH-SO3H Ar-NH-NH2 + H2SO4

The most important application of diazo coupling reactions is electrophilic aromatic substitution of activated benzene
derivatives by diazonium electrophiles. The products of such reactions are highly colored aromatic azo compounds that
find use as synthetic dyestuffs, commonly referred to as azo dyes. Azobenzene (Y=Z=H) is light orange; however, the
color of other azo compounds may range from red to deep blue depending on the nature of the aromatic rings and the
substituents they carry. Azo compounds may exist as cis/trans isomer pairs, but most of the well-characterized and stable
compounds are trans.

Some examples of azo coupling reactions are shown below. A few simple rules are helpful in predicting the course of such
reactions:
I. At acid pH (< 6) an amino group is a stronger activating substituent than a hydroxyl group (i.e. a phenol). At alkaline
pH (> 7.5) phenolic functions are stronger activators, due to increased phenoxide base concentration.
II. Coupling to an activated benzene ring occurs preferentially para to the activating group if that location is free.
Otherwise ortho-coupling will occur.
III. Naphthalene normally undergoes electrophilic substitution at an alpha-location more rapidly than at beta-sites;
however, ortho-coupling is preferred. See the diagram for examples of α / β notation in naphthalenes.
You should try to conceive a plausible product structure for each of the following couplings.

Exercises

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Questions
Q24.8.1
Propose a synthesis for the following compound via benzene and any amine you may require.

Q24.8.2
Proposes synthesis for each of the following compounds via benzene.
(a) N,N-Diethylaniline
(b) p-Bromoaniline
(c) m-Bromoaniline
(d) 2,4-Diethylaniline
Q24.8.3
Propose a synthesis for each of the following molecules from benzene via the diazonium ion.
(a) p-Chlorobenzoic acid
(b) m-Chlorobenzoic acid
(c) m-Dichlorobenzene
(d) p-Ethylbenzoic acid
(e) 1,2,4-Trichlorobenzene
Solutions
S24.8.1

S24.8.2
(a) 1. HNO3, H2SO4; 2. Zn(Hg), HCl; 3. EtBr
(b) 1. HNO3, H2SO4; 2. Zn(Hg), HCl; 3. (CH3CO)O2; 4. Br2, FeBr3; 5. H2O, NaOH
(c) 1. HNO3, H2SO4; 2. Br2, FeBr3; 3. Zn(Hg), HCl
(d) 1. HNO3, H2SO4; 2. Zn(Hg), HCl; 3. (CH3CO)O2; 4. EtCl, AlCl3; 5. H2O, NaOH

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S24.8.3
(a) 1. CH3CH2Cl, AlCl3; 2. HNO3, H2SO4; 3. SnCl2; 4. NaNO2, H2SO4; 5. CuBr; 6. KMnO4, H2O
(b) 1. HNO3, H2SO4; 2. Cl2, FeCl3; 3. SnCl2, H3O+; 4. NaNO2, H2SO4; 5. CuCN; 6. H3O+
(c) 1. HNO3, H2SO4; 2. Cl2, FeCl3; 3. SnCl2; 4. NaNO2, H2SO4; 5. CuCl
(d) 1. CH3CH2Cl, AlCl3: 2. HNO3, H2SO4; 3. SnCl2; 4. NaNO2, H2SO4; 5. CuCN; 6. H3O+
(e) 1. HNO3, H2SO4; 2. H2/PtO2; 3. (CH3CO)2O; 4. 2 Cl2; 5. H2O, NaOH; 6. NaNO2, H2SO4; 7. CuCl

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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22.11: Electrophilic Substitution with Arenediazonium Salts: Diazo Coupling
Objectives
After completing this section, you should be able to
1. a. identify the product formed when a given arylamine is reacted with aqueous bromine.
b. give an appropriate example to illustrate the high reactivity of arylamines in electrophilic aromatic substitution
reactions.
c. explain why arylamines cannot be used in Friedel‑Crafts reactions.
2. a. show how the problems associated with carrying out electrophilic aromatic substitution reactions on arylamines
can be circumvented by first converting the amine to an amide, and illustrate this process with an appropriate
example.
b. outline a possible synthetic route for the preparation of a given sulfa drug.
c. identify the starting material, the necessary organic reagents, inorganic reagents, or both, and the intermediate
compounds formed during the synthesis of a given sulfa drug.
d. design a multi‑step synthesis for a given compound in which it is necessary to protect the amino group by
acetylation.
3. a. write a general equation to describe the formation of an arenediazonium salt.
b. identify the product formed when a given arenediazonium salt is reacted with any of the following compounds:
copper(I) chloride, copper(I) bromide, sodium iodide, copper(I) cyanide, hot aqueous acid, hypophosphorous
acid.
c. identify the arenediazonium salt, the inorganic reagents, or both, needed to produce a given compound by a
diazonium replacement reaction.
4. a. illustrate, with appropriate examples, the importance to the synthetic chemist of the overall reaction sequence A
nitration, B reduction, C diazotization, and D replacement.
b. show how the removal of an amino (or nitro) group from an aromatic ring through the reaction of an
arenediazonium salt with hypophosphorous acid (H3PO2) can sometimes be of use in organic synthesis.
5. a. write a general equation to represent a diazonium coupling reaction.
b. write the detailed mechanism for the coupling reaction which takes place between arenediazonium salts and the
electon‑rich aromatic rings of phenols and arylamines.
c. identify the product formed from the reaction of a given arenediazonium salt with a given arylamine or phenol.
d. identify the arenediazonium salt and the arylamine or phenol needed to prepare a given azo compound.

Key Terms
Make certain that you can define, and use in context, the key terms below.
arenediazonium salt
azo compound
Sandmeyer reaction
sulfa drug

Study Notes
This section contains a considerable amount of new information. To absorb all of it, you should use the three
subsections indicated in the reading: electrophilic aromatic substitution and overreaction of aniline (Objectives 1 and
2), the preparation of diazonium salts and the Sandmeyer reaction (Objectives 3 and 4), and diazonium coupling
reactions (Objective 5).
The general process in which an aromatic amine is reacted with acetic anhydride, substituted, and then hydrolyzed is
known as “protecting the amino group.”
Sulfa drugs have the general formula

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Typical examples are sulfathiazole

and sulfapyridine

The reagent used to bring about the chlorosulfonation of acetanilide is chlorosulfuric acid

Sulfanilamide itself is toxic to humans, but derivatives of this compound, such as sulfathiazole, are less harmful to
humans and are effective in killing many types of bacteria. The drugs work by “deceiving” the bacteria in the
following way. To survive, many micro‑organisms use p‑aminobenzoic acid to synthesize folic acid, a coenzyme in a
number of biochemical processes. These micro‑organisms cannot distinguish between sulfa drugs and p‑aminobenzoic
acid; so, when the drug is administered, the bacteria use it to produce a compound which has a structure similar to that
of folic acid, but which is unable to act as a coenzyme in essential biochemical processes. The result is that many of
the bacteria’s amino acids and nucleotides cannot be made, and the bacteria die. Amino acids are discussed in Chapter
26; nucleotides are discussed in Section 28.1.

An “arenediazonium salt” is formed by the reaction of an aromatic amine with nitrous acid at 0–5°C, and has the
structure shown below.

Alkanediazonium salts are very unstable; therefore, arenediazonium salts are often simply referred to as diazonium
salts.
As is mentioned in the textbook, arenediazonium salts are very useful intermediates from which a wide variety of
aromatic compounds can be prepared. You should be thoroughly familiar with the use of diazonium salts to prepare
each of the classes of compounds. In addition, you should be aware that fluoroarenes can also be prepared from
diazonium salts, as follows:

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 In this case the diazonium salt is prepared using fluoroboric acid, HBF4, and sodium nitrite. The thermal
decomposition of the salt, called the Schiemann reaction, can be quite hazardous.
Note that the IUPAC‑preferred name for cuprous chloride is copper(I) chloride; similarly, cuprous cyanide is called
copper(I) cyanide.
Hypophosphorous acid has the structure shown below:

The presence of the letters “azo” in a compound’s name usually implies that a nitrogen‑nitrogen double bond is present
in its structure. Azo compounds t in which two aryl groups are joined by an −N=N− linkage are usually very
colourful.

Overreaction of Aniline
Arylamines are very reactive towards electrophilic aromomatic substitution. The strongest activating and ortho/para-
directing substituents are the amino (-NH2) and hydroxyl (-OH) groups. Direct nitration of phenol (hydroxybenzene) by
dilute nitric acid gives modest yields of nitrated phenols and considerable oxidative decomposition to tarry materials;
aniline (aminobenzene) is largely destroyed. Monobromination of both phenol and aniline is difficult to control, with di-
and tri-bromo products forming readily.

Because of their high nucleophilic reactivity, aniline and phenol undergo substitution reactions with iodine, a halogen that
is normally unreactive with benzene derivatives. The mixed halogen iodine chloride (ICl) provides a more electrophilic
iodine moiety, and is effective in iodinating aromatic rings having less powerful activating substituents.

p-I–C6H4–NH2 + NaI + CO2 +

C6H5–NH2 + I2 + NaHCO3
H2O

In addition to overreactivity, we have previously seen (Section 16.3) that Friedel-Crafts reactions employing AlCl3 catalyst
does not work with aniline. A salt complex forms and prevents electrophilic aromatic substitution.

Both this problem and the aniline overreactivity can be circumvented by first going through the corresponding amide.

Modifying the Influence of Strong Activating Groups

By acetylating the heteroatom substituent on aniline, its activating influence can be substantially attenuated. For example,
acetylation of aniline gives acetanilide (first step in the following equation), which undergoes nitration at low temperature,
yielding the para-nitro product in high yield. The modifying acetyl group can then be removed by acid-catalyzed
hydrolysis (last step), to yield para-nitroaniline. Although the activating influence of the amino group has been reduced by
this procedure, the acetyl derivative remains an ortho/para-directing and activating substituent.

pyridine (a base) HNO3 , 5 ºC H3O(+) & heat

C6H5–NH2 + (CH3CO)2O C6H5–NHCOCH3 p-O2N–C6H4–NHCOCH3 p-O2N–C6H4–NH

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The following diagram illustrates how the acetyl group acts to attenuate the overall electron donating character of oxygen
and nitrogen. The non-bonding valence electron pairs that are responsible for the high reactivity of these compounds (blue
arrows) are diverted to the adjacent carbonyl group (green arrows). However, the overall influence of the modified
substituent is still activating and ortho/para-directing.

Sulfa Drug Synthesis

Sulfa drugs are an important group of synthetic antimicrobial agents (pharmaceuticals) that contain the sulfonamide group.
The synthesis of sulfanilamide (a sulfa drug) illustrates how the reactivity of aniline can be modified to make possible an
electrophilic aromatic substitution. The corresponding acetanilide undergoes chlorosulfonation. The resulting 4-
acetamidobenzenesulfanyl chloride is treated with ammonia to replace the chlorine with an amino group and affords 4-
acetamidobenzenesulfonamide. The subsequent hydrolysis of the sulfonamide produces the sulfanilamide.

Diazonium Salts: The Sandmeyer Reaction

Aryl diazonium salts are important intermediates. They are prepared in cold (0 º to 10 ºC) aqueous solution, and generally
react with nucleophiles with loss of nitrogen. Some of the more commonly used substitution reactions are shown in the
following diagram. Since the leaving group (N2) is thermodynamically very stable, these reactions are energetically
favored. Those substitution reactions that are catalyzed by cuprous salts are known as Sandmeyer reactions. Fluoride
substitution occurs on treatment with BF4(–), a reaction known as the Schiemann reaction. Stable diazonium
tetrafluoroborate salts may be isolated, and on heating these lose nitrogen to give an arylfluoride product. The top reaction
with hypophosphorus acid, H3PO2, is noteworthy because it achieves the reductive removal of an amino (or nitro) group.
Unlike the nucleophilic substitution reactions, this reduction probably proceeds by a radical mechanism.

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These aryl diazonium substitution reactions significantly expand the tactics available for the synthesis of polysubstituted
benzene derivatives. Consider the following options:
I. The usual precursor to an aryl amine is the corresponding nitro compound. A nitro substituent deactivates an aromatic
ring and directs electrophilic substitution to meta locations.
II. Reduction of a nitro group to an amine may be achieved in several ways. The resulting amine substituent strongly
activates an aromatic ring and directs electrophilic substitution to ortho & para locations.
III. The activating character of an amine substituent may be attenuated by formation of an amide derivative (reversible), or
even changed to deactivating and meta-directing by formation of a quaternary-ammonium salt (irreversible).
IV. Conversion of an aryl amine to a diazonium ion intermediate allows it to be replaced by a variety of different groups
(including hydrogen), which may in turn be used in subsequent reactions.
The following examples illustrate some combined applications of these options to specific cases. You should try to
conceive a plausible reaction sequence for each. Once you have done so, you may check suggested answers below.

Answer 1:
It should be clear that the methyl substituent will eventually be oxidized to a carboxylic acid function. The timing is
important, since a methyl substituent is ortho/para-directing and the carboxyl substituent is meta-directing. The cyano
group will be introduced by a diazonium intermediate, so a nitration followed by reduction to an amine must precede
this step.

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Answer 2:
The hydroxyl group is a strong activating substituent and would direct aromatic ring chlorination to locations ortho &
para to itself, leading to the wrong product. As an alternative, the nitro group is not only meta-directing, it can be
converted to a hydroxyl group by way of a diazonium intermediate. The resulting strategy is self evident.

Answer 3:
Selective introduction of a fluorine is best achieved by treating a diazonium intermediate with boron tetrafluoride
anion. To get the necessary intermediate we need to make p-nitroaniline. Since the nitro substituent on the starting
material would direct a new substituent to a meta-location, we must first reduce it to an ortho/para-directing amino
group. Amino groups are powerful activating substituents, so we deactivate it by acetylation before nitration. The
acetyl substituent also protects the initial amine function from reaction with nitrous acid later on. It is removed in the
last step.

Answer 4:
Polybromination of benzene would lead to ortho/para substitution. In order to achieve the mutual meta-relationship of
three bromines, it is necessary to introduce a powerful ortho/para-directing prior to bromination, and then remove it
following the tribromination. An amino group is ideal for this purpose. Reductive removal of the diazonium group may
be accomplished in several ways (three are shown).

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Answer 5:
The propyl substituent is best introduced by Friedel-Crafts acylation followed by reduction, and this cannot be carried
out in the presence of a nitro substituent. Since an acyl substituent is a meta-director, it is logical to use this property to
locate the nitro and chloro groups before reducing the carbonyl moiety. The same reduction method can be used to
reduce both the nitro group (to an amine) and the carbonyl group to propyl. We have already seen the use of diazonium
intermediates as precursors to phenols.

Answer 6:
Aromatic iodination can only be accomplished directly on highly activated benzene compounds, such as aniline, or
indirectly by way of a diazonium intermediate. Once again, a deactivated amino group is the precursor of p-nitroaniline
(prb.#3). This aniline derivative requires the more electrophilic iodine chloride (ICl) for ortho-iodination because of the
presence of a deactivating nitro substituent. Finally, the third iodine is introduced by the diazonium ion procedure.

Diazonium Coupling Reactions

A resonance description of diazonium ions shows that the positive charge is delocalized over the two nitrogen atoms. It is
not possible for nucleophiles to bond to the inner nitrogen, but bonding (or coupling) of negative nucleophiles to the
terminal nitrogen gives neutral azo compounds. As shown in the following equation, this coupling to the terminal nitrogen
should be relatively fast and reversible. The azo products may exist as E / Z stereoisomers. In practice it is found that the
E-isomer predominates at equilibrium.

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Unless these azo products are trapped or stabilized in some manner, reversal to the diazonium ion and slow nucleophilic
substitution at carbon (with irreversible nitrogen loss) will be the ultimate course of reaction, as described in the previous
section. For example, if phenyldiazonium bisufate is added rapidly to a cold solution of sodium hydroxide a relatively
stable solution of sodium phenyldiazoate (the conjugate base of the initially formed diazoic acid) is obtained. Lowering the
pH of this solution regenerates phenyldiazoic acid (pKa ca. 7), which disassociates back to the diazonium ion and
eventually undergoes substitution, generating phenol.

C6H5N2(+) HSO4(–) + NaOH (cold solution) C6H5N2–OH + NaOH (cold) C6H5N2–O(–) Na(+)

phenyldiazonium bisulfate phenyldiazoic acid sodium phenyldiazoate

Aryl diazonium salts may be reduced to the corresponding hydrazines by mild reducing agents such as sodium bisulfite,
stannous chloride or zinc dust. The bisulfite reduction may proceed by an initial sulfur-nitrogen coupling, as shown in the
following equation.

NaHSO3 NaHSO3 H2O

Ar-N2(+) X(–) Ar-N=N-SO3H Ar-NH-NH-SO3H Ar-NH-NH2 + H2SO4

The most important application of diazo coupling reactions is electrophilic aromatic substitution of activated benzene
derivatives by diazonium electrophiles. The products of such reactions are highly colored aromatic azo compounds that
find use as synthetic dyestuffs, commonly referred to as azo dyes. Azobenzene (Y=Z=H) is light orange; however, the
color of other azo compounds may range from red to deep blue depending on the nature of the aromatic rings and the
substituents they carry. Azo compounds may exist as cis/trans isomer pairs, but most of the well-characterized and stable
compounds are trans.

Some examples of azo coupling reactions are shown below. A few simple rules are helpful in predicting the course of such
reactions:
I. At acid pH (< 6) an amino group is a stronger activating substituent than a hydroxyl group (i.e. a phenol). At alkaline
pH (> 7.5) phenolic functions are stronger activators, due to increased phenoxide base concentration.
II. Coupling to an activated benzene ring occurs preferentially para to the activating group if that location is free.
Otherwise ortho-coupling will occur.
III. Naphthalene normally undergoes electrophilic substitution at an alpha-location more rapidly than at beta-sites;
however, ortho-coupling is preferred. See the diagram for examples of α / β notation in naphthalenes.
You should try to conceive a plausible product structure for each of the following couplings.

Exercises

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Questions
Q24.8.1
Propose a synthesis for the following compound via benzene and any amine you may require.

Q24.8.2
Proposes synthesis for each of the following compounds via benzene.
(a) N,N-Diethylaniline
(b) p-Bromoaniline
(c) m-Bromoaniline
(d) 2,4-Diethylaniline
Q24.8.3
Propose a synthesis for each of the following molecules from benzene via the diazonium ion.
(a) p-Chlorobenzoic acid
(b) m-Chlorobenzoic acid
(c) m-Dichlorobenzene
(d) p-Ethylbenzoic acid
(e) 1,2,4-Trichlorobenzene
Solutions
S24.8.1

S24.8.2
(a) 1. HNO3, H2SO4; 2. Zn(Hg), HCl; 3. EtBr
(b) 1. HNO3, H2SO4; 2. Zn(Hg), HCl; 3. (CH3CO)O2; 4. Br2, FeBr3; 5. H2O, NaOH
(c) 1. HNO3, H2SO4; 2. Br2, FeBr3; 3. Zn(Hg), HCl
(d) 1. HNO3, H2SO4; 2. Zn(Hg), HCl; 3. (CH3CO)O2; 4. EtCl, AlCl3; 5. H2O, NaOH

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S24.8.3
(a) 1. CH3CH2Cl, AlCl3; 2. HNO3, H2SO4; 3. SnCl2; 4. NaNO2, H2SO4; 5. CuBr; 6. KMnO4, H2O
(b) 1. HNO3, H2SO4; 2. Cl2, FeCl3; 3. SnCl2, H3O+; 4. NaNO2, H2SO4; 5. CuCN; 6. H3O+
(c) 1. HNO3, H2SO4; 2. Cl2, FeCl3; 3. SnCl2; 4. NaNO2, H2SO4; 5. CuCl
(d) 1. CH3CH2Cl, AlCl3: 2. HNO3, H2SO4; 3. SnCl2; 4. NaNO2, H2SO4; 5. CuCN; 6. H3O+
(e) 1. HNO3, H2SO4; 2. H2/PtO2; 3. (CH3CO)2O; 4. 2 Cl2; 5. H2O, NaOH; 6. NaNO2, H2SO4; 7. CuCl

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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CHAPTER OVERVIEW
23: ESTER ENOLATES AND THE CLAISEN CONDENSATION
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

Ester Enolates and the Claisen Condensation: Synthesis of β-Dicarbonyl Compounds; Acyl Anion Equivalents

23.1: B-DICARBONYL COMPOUNDS: CLAISEN CONDENSATIONS

23.2: B-DICARBONYL COMPOUNDS AS SYNTHETIC INTERMEDIATES
23.3: B-DICARBONYL ANION CHEMISTRY: MICHAEL ADDITIONS
23.4: ALKANOYL (ACYL) ANION EQUIVALENTS: PREPARATION OF A-HYDROXYKETONES

1 12/5/2021
23.1: B-Dicarbonyl Compounds: Claisen Condensations
Because esters can contain α hydrogens they can undergo a condensation reaction similar to the aldol reaction called a
Claisen Condensation. In a fashion similar to the aldol, one ester acts as a nucleophile while a second ester acts as the
electrophile. During the reaction a new carbon-carbon bond is formed. The product is a β-keto ester. A major difference
with the aldol reaction is the fact that hydroxide cannot be used as a base because it could possibly react with the ester.
Instead, an alkoxide version of the alcohol used to synthesize the ester is used to prevent transesterification side products.

Claisen Condensation
Basic reaction

Going from reactants to products simply

Example 1: Claisen Condensation

Claisen Condensation Mechanism

1) Enolate formation

2) Nucleophilic attack

3) Removal of leaving group

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Contributor
Prof. Steven Farmer (Sonoma State University)

Crossed Claisen Condensation

Claisen condensations between different ester reactants are called Crossed Claisen reactions. Crossed Claisen reactions in
which both reactants can serve as donors and acceptors generally give complex mixtures. Because of this most Crossed
Claisen reactions are usually not performed unless one reactant has no alpha hydrogens.
Example 3: Crossed Claisen Condensation

Contributors
Prof. Steven Farmer (Sonoma State University)

Dieckmann Condensation
A diester can undergo an intramolecular reaction called a Dieckmann condensation.
Example 2: Dieckman Condensation

Contributors
Prof. Steven Farmer (Sonoma State University)

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23.2: B-Dicarbonyl Compounds as Synthetic Intermediates
Enolates can act as a nucleophile in SN2 type reactions. Overall an α hydrogen is replaced with an alkyl group. This
reaction is one of the more important for enolates because a carbon-carbon bond is formed. These alkylations are affected
by the same limitations as SN2 reactions previously discussed. A good leaving group, Chloride, Bromide, Iodide, Tosylate,
should be used. Also, secondary and tertiary leaving groups should not be used because of poor reactivity and possible
competition with elimination reactions. Lastly, it is important to use a strong base, such as LDA or sodium amide, for this
reaction. Using a weaker base such as hydroxide or an alkoxide leaves the possibility of multiple alkylation’s occurring.

Example 1: Alpha Alkylation

Mechanism
1) Enolate formation

2) Sn2 attack

Alkylation of Unsymmetrical Ketones

Unsymmetrical ketones can be regioselctively alkylated to form one major product depending on the reagents.
Treatment with LDA in THF at -78oC tends to form the less substituted kinetic enolate.

Using sodium ethoxide in ethanol at room temperature forms the more substituted thermodynamic enolate.

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Problems
1) Please write the structure of the product for the following reactions.

Answers
1)

Contributors
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Steven Farmer (Sonoma State University)
Malonic ester is a reagent specifically used in a reaction which converts alkyl halides to carboxylic acids called the
Malonic Ester Synthesis. Malonic ester synthesis is a synthetic procedure used to convert a compound that has the general
structural formula 1 into a carboxylic acid that has the general structural formula 2.

R1 = alkyl group
L = leaving group
The group —CH2CO2H in 2 is contributed by a malonic ester, hence the term malonic ester synthesis.

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 R2 = alkyl, aryl

Mechanism
Malonic ester synthesis consists of four consecutive reactions that can be carried out in the same pot.
reaction 1: acid-base reaction
reaction 2: nucleophilic substitution
reaction 3: ester hydrolysis (using saponification)
reaction 4: decarboxylation
eg:

reaction 1:

reaction 2:

reaction 3:

reaction 4:

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A more direct method to convert 3 into 4 is the reaction of 3 with the enolate ion (5) of ethyl acetate followed by
hydrolysis of the resultant ester.

However, the generation of 5 from ethyl acetate quantitatively in high yield is not an easy task because the reaction
requires a very strong base, such as LDA, and must be carried out at very low temperature under strictly anhydrous
conditions.

Malonic ester synthesis provides a more convenient alternative to convert 3 to 4.

Malonic ester synthesis can be adapted to synthesize compounds that have the general structural formula 6.

R3, R4 = identical or different alkyl groups

eg:

reaction 1:

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reaction 2:

reaction 1 (repeat):

reaction 2 (repeat):

reaction 3:

reaction 4:

Malonic Ester Synthesis

Due to the fact that Malonic ester’s α hydrogens are adjacent to two carbonyls, they can be deprotonated by sodium
ethoxide (NaOEt) to form Sodio Malonic Ester.

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Because Sodio Malonic Ester is an enolate, it can then be alkylated with alkyl halides.

After alkylation the product can be converted to a dicarboxylic acid through saponification and subsequently one of the
carboxylic acids can be removed through a decarboxylation step.

Mechanism
1) Saponification

2) Decarboxylation

3) Tautomerization

All of the steps together form the Malonic ester synthesis.

RX → RC H 2 C O2 H (23.2.1)

Example

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 Bernard E. Hoogenboom , Phillip J. Ihrig , Arne N. Langsjoen , Carol J. Linn and Stephen D. Mulder, The malonic
ester synthesis in the undergraduate laboratory, J. Chem. Educ., 1991, 68 (8), p 689

Contributors
Prof. Steven Farmer (Sonoma State University)
Gamini Gunawardena from the OChemPal site (Utah Valley University)
The acetoacetic ester synthesis allows for the conversion of ethyl acetoacetate into a methyl ketone with one or two alkyl
groups on the alpha carbon.

Steps
1) Deprotonation with ethoxide

2) Alkylation via and SN2 Reaction

3) Hydrolysis and decarboxylation

Addition of a second alky group

After the first step and additional alkyl group can be added prior to the decarboxylation step. Overall this allows for the
addition of two different alkyl groups.

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Contributors
Prof. Steven Farmer (Sonoma State University)

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23.3: B-Dicarbonyl Anion Chemistry: Michael Additions
☰
Basic reaction of 1,4 addition

In 1,4 addition the Nucleophile is added to the carbon β to the carbonyl while the hydrogen is added to the carbon α to the
carbonyl.

Mechanism for 1,4 addition

1) Nucleophilic attack on the carbon β to the carbonyl

2) Proton Transfer

Here we can see why this addition is called 1,4. The nucleophile bonds to the carbon in the one position and the hydrogen
adds to the oxygen in the four position.
3) Tautomerization

Enolates undergo 1,4 addition to α, β-unsaturated carbonyl compounds is a process called a Michael addition. The reaction
is named after American chemist Arthur Michael (1853-1942).

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Examples of Michael Additions
☰

Contributors

Prof. Steven Farmer (Sonoma State University)

Many times the product of a Michael addition produces a dicarbonyl which can then undergo an intramolecular aldol
reaction. These two processes together in one reaction creates two new carbon-carbon bonds and also creates a ring. Ring-
forming reactions are called annulations after the Latin work for ring annulus. The reaction is named after English chemist
Sir Robert Robinson (1886-1975) who developed it. He received the Nobel prize in chemistry in 1947. Remember that
during annulations five and six membered rings are preferred.

Examples of Robinson Annulations

Contributors
Prof. Steven Farmer (Sonoma State University)

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23.4: Alkanoyl (Acyl) Anion Equivalents: Preparation of a-Hydroxyketones
Solutions to exercises
Thiamine diphosphate (TPP) is another very important coenzyme which, like PLP, acts as an electron sink to stabilize key
carbanion intermediates. The important part of the TPP molecule from a catalytic standpoint is its thiazole ring.

14.5A: The benzoin condensation reaction

In a very simple experiment that can performed in an undergraduate organic chemistry lab, benzaldehyde (a liquid compound
at room temperature that is used as an artificial cherry flavoring) self-condenses to form benzoin (a crystalline solid) when
stirred in ethanol with a catalytic amount of sodium hydroxide and thiamine.

The laboratory synthesis of benzoin is interesting because it mimics the mechanism of TPP-dependant enzymatic reactions in
biological systems. This reaction is not catalyzed by an enzyme – rather, the thiamine molecule acts on its own, playing a
similar catalytic role to that played by its diphosphate ester cousin (TPP) in enzymatic reactions.
Look carefully at the connectivity of the starting compounds and product in the benzoin condensation. Essentially what has
happened is that the carbonyl carbon of one benzaldehyde molecule has somehow been turned into a nucleophile, and has
attacked a second benzaldehyde molecule in a nucleophilic carbonyl addition reaction.

This probably seems quite strange - we know that carbonyl carbons are good electrophiles, but how can they be nucleophilic?
For the aldehyde carbon to be a nucleophile, it would have to be deprotonated, and become a carbonyl anion. But aldehyde
protons are not at all acidic!

The thiamine catalyst is the key: it allows the formation of what is essentially the equivalent of a nucleophilic benzaldehyde
carbanion. Let's follow the benzoin condensation reaction mechanism through step-by-step, and see how thiamine
accomplishes this task.
The important part of the thiamine molecule is the thiazole ring (look again at the structure of thiamine diphosphate on the
previous page), thus we will draw thiamine (and later, thiamine diphosphate) using R groups to depict the unreactive parts of
the molecule. The first step of the benzoin condensation is deprotonation of thiamine by hydroxide.

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It may surprise you to learn that this proton is acidic. The reason for its acidity lies partly in the ability of the neighboring
sulfur atom to accept, in its open d orbitals, some of the excess electron density of the conjugate base. Another reason is that
the positive charge on the nitrogen helps to stabilize the negative charge on the conjugate base. The deprotonated thiazole is
called an ylide, which is a species with adjacent positively and negatively charged atoms.
The negatively charged carbon on the thiazole ylide next attacks the carbonyl of the first benzaldehyde molecule in a
nucleophilic carbonyl addition (from here on out, thiamine will be colored green in order to help you to focus on the chemistry
going on with the substrate).

In the resulting molecule, what used to be the aldehyde hydrogen is now acidic - this is so because, when the proton is
abstracted by hydroxide, the negative charge on the conjugate base is stabilized by resonance with the positively-charged
thiazole ring of thiamine. This is the function of thiamine: it acts as an electron sink, accepting electron density so as to allow
for the formation of what amounts to a carbonyl anion.
Now the first benzaldehyde molecule, assisted by thiamine, can finally act as a nucleophile, attacking the carbonyl of a second
benzaldehyde (step 3).

Once this is accomplished, the thiamine ylide can be kicked off as the original carbonyl on the first benzaldehyde re-forms
(step 4). The thiamine ylide is now free to catalyze another reaction.

14.5B: The transketolase reaction

Now let's look at a biochemical reaction carried out by an enzyme called transketolase, with the assistance of thiamine
diphosphate. Transketolase is one of a series of enzymes (along with ribulose-5-phosphate-3-epimerase, which we considered
in section 13.2B) in the 'Calvin cycle' of carbon fixation in plants. Animals and bacteria also use transketolase in sugar
metabolism. In the transketolase reaction, a 2-carbon unit (in the smaller, red box) is transferred between two sugar molecules:

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First, let's consider how this reaction might hypothetically proceed without the assistance of the TPP cofactor. The breaking off
of the 2-carbon unit from fructose-6-phosphate might be depicted as a kind of retro-aldol event:

This would lead to glyceraldehyde-3-phosphate, the first product, plus an intermediate in the form of a carbonyl anion.
Continuing to think hypothetically, this strange 2-carbon ionic intermediate could attack the glyceraldehyde-3-phosphate
carbonyl, resulting in sedoheptulose-7-phosphate, the second product.

Everything in this hypothetical scenario is fine, chemically speaking, with one major exception: the carbonyl anion
intermediate. It would be an extremely high energy, unlikely species. But we have seen something like this before, haven't we,
in the non-enzymatic benzoin condensation reaction above! This is exactly the kind of carbanion that thiamine (this time in its
diphosphate form, TPP) makes possible. The carbonyl anion is generated in different ways in the two reactions: in the benzoin
condensation it is the result of the deprotonation of benzaldehyde, while in the transketolase it results from a retro-aldol-like
cleavage. But that doesn't really matter - what does matter is that in each case, a thiazole ring is present to modify the starting
carbonyl group and act as an electron sink, allowing it to take on a negative charge. Here, then, is the real (as opposed to
hypothetical) transketolase reaction, with the role of TPP revealed.

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Make sure that you can follow the electron movement throughout the mechanism, that you can see how TPP acts as an
electron sink cofactor, and that you clearly recognize the mechanistic parallels to the benzoin condensation.

14.5C: Pyruvate decarboxylase

The thiamine diphosphate coenzyme also assists in the decarboxylation of an acyl group, such as in this reaction catalyzed by
pyruvate decarboxylase (this is a key reaction in the fermentation of glucose to ethanol by yeast):

In this example, the TPP-stabilized carbonyl carbanion simply acts as a base rather than as a nucleophile, abstracting a proton
from an enzymatic acid to form acetaldehyde.
Example 14.7
Propose a mechanism for the reaction catalyzed by pyruvate decarboxylase.

14.5D: Synthetic parallel - carbonyl nucleophiles via dithiane anions

Nature uses thiamine to generate the equivalent of a nucleophilic carbonyl anion, but with the specific exception of the
benzoin condensation, a chemist working in an organic synthesis laboratory before the mid-1970's had no equivalent
procedure. In 1975, E. J. Corey and Dieter Seebach reported that they had developed a method to accomplish reactions such as
the following, in which aldehyde carbons act as nucleophiles in SN2 and carbonyl addition reactions (J. Org. Chem. 1975, 40,
231).

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In this technique, the aldehyde is first converted to a cyclic thioketal using 1,3-propanedithiol and acid catalyst - this is the
same as the method used to 'protect' aldehydes as cyclic acetals, discussed in section 11.4B, except that a dithiol is used
instead of a diol.

The original aldehyde proton is now somewhat acidic, because the empty d orbitals on the two adjacent sulfur atoms are able
to delocalize excess electron density of the conjugate base. A strong base, such as an organolithium compound (section 13.6B)
will deprotonate the cyclic thioacetal, which can then act as a nucleophile, attacking an alkyl halide or a carbonyl electrophile
(the latter case is illustrated below):

The thioacetal can then be hydrolyzed back to an aldehyde group, a process that is facilitated by the use of methyl iodide.
Example 14.8
Show a mechanism for the hydrolysis of a cyclic thioacetal, in the presence of catalytic acid and methyl iodide. Propose a
role for methyl iodide in this reaction.
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

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CHAPTER OVERVIEW
24: CARBOHYDRATES: POLYFUNCTIONAL COMPOUNDS IN NATURE
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

24.1: NAMES AND STRUCTURES OF CARBOHYDRATES

24.2: CONFORMATIONS AND CYCLIC FORMS OF SUGARS
24.3: ANOMERS OF SIMPLE SUGARS - MUTAROTATION OF GLUCOSE
24.4: POLYFUNCTIONAL CHEMISTRY OF SUGARS: OXIDATION TO CARBOXYLIC ACIDS
24.5: OXIDATIVE CLEAVAGE OF SUGARS
24.6: REDUCTION OF MONOSACCHARIDES TO ALDITOLS
24.7: CARBONYL CONDENSATIONS WITH AMINE DERIVATIVES
24.8: ESTER AND ETHER FORMATION: GLYCOSIDES
24.9: STEP-BY-STEP BUILDUP AND DEGRADATION OF SUGARS
24.10: RELATIVE CONFIGURATIONS OF THE ALDOSES: AN EXERCISE IN STRUCTURE DETERMINATION
24.11: COMPLEX SUGARS IN NATURE: DISACCHARIDES
24.12: POLYSACCHARIDES AND OTHER SUGARS IN NATURE

1 12/5/2021
24.1: Names and Structures of Carbohydrates
Objectives
After completing this section, you should be able to
1. classify a specific carbohydrate as being a monosaccharide, disaccharide, trisaccharide, etc., given the structure of the
carbohydrate or sufficient information about its structure.
2. classify a monosaccharide according to the number of carbon atoms present and whether it contains an aldehyde or ketone
group.

Key Terms
Make certain that you can define, and use in context, the key terms below.
aldose
disaccharide
ketose
monosaccharide (simple sugar)
polysaccharide

Carbohydrates are the most abundant class of organic compounds found in living organisms. They originate as products of
photosynthesis, an endothermic reductive condensation of carbon dioxide requiring light energy and the pigment chlorophyll.

nC O2 + nH2 O + Energy → Cn H2n On + nO2 (24.1.1)

As noted here, the formulas of many carbohydrates can be written as carbon hydrates, C (H O) , hence their name. The
n 2 n

carbohydrates are a major source of metabolic energy, both for plants and for animals that depend on plants for food. Aside from
the sugars and starches that meet this vital nutritional role, carbohydrates also serve as a structural material (cellulose), a component
of the energy transport compound ATP/ADP, recognition sites on cell surfaces, and one of three essential components of DNA and
RNA.
Carbohydrates are called saccharides or, if they are relatively small, sugars. Several classifications of carbohydrates have proven
useful, and are outlined in the following table.

Complex Carbohydrates
Simple Carbohydrates
Complexity disaccharides, oligosaccharides
monosaccharides
& polysaccharides

Tetrose Pentose Hexose Heptose

Size etc.
C4 sugars C5 sugars C6 sugars C7 sugars

Aldose
sugars having an aldehyde function or an acetal equivalent.
C=O Function
Ketose
sugars having a ketone function or an acetal equivalent.

Reducing
sugars oxidized by Tollens' reagent (or Benedict's or Fehling's reagents).
Reactivity
Non-reducing
sugars not oxidized by Tollens' or other reagents.

Exercises
Questions
Q25.1.1
Classify each of the following sugars.

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(a)

(b)

(c)

(d)
Solutions
S25.1.1
(a) Aldoterose
(b) Ketopentose
(c) Ketohexose
(d) Aldopentose

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

Objectives
After completing this section, you should be able to
1. draw the Fischer projection of a monosaccharide, given its wedge‑and‑broken‑line structure or a molecular model.
2. draw the wedge‑and‑broken‑line structure of a monosaccharide, given its Fischer projection or a molecular model.
3. construct a molecular model of a monosaccharide, given its Fischer projection or wedge‑and‑broken‑line structure.

Key Terms

Make certain that you can define, and use in context, the key term below.
Fischer projection

Study Notes
When studying this section, use your molecular model set to assist you in visualizing the structures of the compounds that are
discussed. It is important that you be able to determine whether two apparently different Fischer projections represent two

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 different structures or one single structure. Often the simplest way to check is to construct a molecular model corresponding to
each projection formula, and then compare the two models.

The problem of drawing three-dimensional configurations on a two-dimensional surface, such as a piece of paper, has been a long-
standing concern of chemists. The wedge and hatched line notations we have been using are effective, but can be troublesome when
applied to compounds having many chiral centers. As part of his Nobel Prize-winning research on carbohydrates, the great German
chemist Emil Fischer, devised a simple notation that is still widely used. In a Fischer projection drawing, the four bonds to a chiral
carbon make a cross with the carbon atom at the intersection of the horizontal and vertical lines. The two horizontal bonds are
directed toward the viewer (forward of the stereogenic carbon). The two vertical bonds are directed behind the central carbon (away
from the viewer). Since this is not the usual way in which we have viewed such structures, the following diagram shows how a
stereogenic carbon positioned in the common two-bonds-in-a-plane orientation ( x–C–y define the reference plane ) is rotated into
the Fischer projection orientation (the far right formula). When writing Fischer projection formulas it is important to remember
these conventions. Since the vertical bonds extend away from the viewer and the horizontal bonds toward the viewer, a Fischer
structure may only be turned by 180º within the plane, thus maintaining this relationship. The structure must not be flipped over
or rotated by 90º.

In the above diagram, if x = CO2H, y = CH3, a = H & b = OH, the resulting formula describes (R)-(–)-lactic acid. The mirror-image
formula, where x = CO2H, y = CH3, a = OH & b = H, would, of course, represent (S)-(+)-lactic acid.
The Fischer Projection consists of both horizontal and vertical lines, where the horizontal lines represent the atoms that are pointed
toward the viewer while the vertical line represents atoms that are pointed away from the viewer. The point of intersection between
the horizontal and vertical lines represents the central carbon.

Using the Fischer projection notation, the stereoisomers of 2-methylamino-1-phenylpropanol are drawn in the following manner.
Note that it is customary to set the longest carbon chain as the vertical bond assembly.

The usefulness of this notation to Fischer, in his carbohydrate studies, is evident in the following diagram. There are eight
stereoisomers of 2,3,4,5-tetrahydroxypentanal, a group of compounds referred to as the aldopentoses. Since there are three chiral
centers in this constitution, we should expect a maximum of 23 stereoisomers. These eight stereoisomers consist of four sets of
enantiomers. If the configuration at C-4 is kept constant (R in the examples shown here), the four stereoisomers that result will be
diastereomers. Fischer formulas for these isomers, which Fischer designated as the "D"-family, are shown in the diagram. Each of
these compounds has an enantiomer, which is a member of the "L"-family so, as expected, there are eight stereoisomers in all.
Determining whether a chiral carbon is R or S may seem difficult when using Fischer projections, but it is actually quite simple. If
the lowest priority group (often a hydrogen) is on a vertical bond, the configuration is given directly from the relative positions of
the three higher-ranked substituents. If the lowest priority group is on a horizontal bond, the positions of the remaining groups give
the wrong answer (you are in looking at the configuration from the wrong side), so you simply reverse it.

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The aldopentose structures drawn above are all diastereomers. A more selective term, epimer, is used to designate diastereomers
that differ in configuration at only one chiral center. Thus, ribose and arabinose are epimers at C-2, and arabinose and lyxose are
epimers at C-3. However, arabinose and xylose are not epimers, since their configurations differ at both C-2 and C-3.

How to make Fischer Projections

To make a Fischer Projection, it is easier to show through examples than through words. Lets start with the first example, turning a
3D structure of ethane into a 2D Fischer Projection.

Example 25.2.1
Start by mentally converting a 3D structure into a Dashed-Wedged Line Structure. Remember, the atoms that are pointed
toward the viewer would be designated with a wedged lines and the ones pointed away from the viewer are designated with
dashed lines.

Figure A Figure B
Notice the red balls (atoms) in Figure A above are pointed away from the screen. These atoms will be designated with dashed
lines like those in Figure B by number 2 and 6. The green balls (atoms) are pointed toward the screen. These atoms will be
designated with wedged lines like those in Figure B by number 3 and 5. The blue atoms are in the plane of the screen so they
are designated with straight lines.
Now that we have our Dashed- Wedged Line Structure, we can convert it to a Fischer Projection. However, before we can
convert this Dashed-Wedged Line Structure into a Fischer Projection, we must first convert it to a “flat” Dashed-Wedged Line
Structure. Then from there we can draw our Fischer Projection. Lets start with a more simpler example. Instead of using the
ethane shown in Figure A and B, we will start with a methane. The reason being is that it allows us to only focus on one central
carbon, which make things a little bit easier.

Figure C Figure D
Lets start with this 3D image and work our way to a dashed-wedged image. Start by imagining yourself looking directly at the
central carbon from the left side as shown in Figure C. It should look something like Figure D. Now take this Figure D and
flatten it out on the surface of the paper and you should get an image of a cross.

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 As a reminder, the horizontal line represents atoms that are coming out of the paper and the vertical line represents atoms that
are going into the paper. The cross image to the right of the arrow is a Fischer projection.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

Objectives

After completing this section, you should be able to

1. identify a specific enantioner of a monosaccharide as being D or L, given its Fischer projection.
2. identify the limitations of the D, L system of nomenclature for carbohydrates.
3. assign an R or S configuration to each of the chiral carbon atoms present in a monosaccharide, given its Fischer projection.
4. draw the Fischer projection formula for a monosaccharide, given its systematic name, complete with the configuration of
each chiral carbon atom.
5. construct a molecular model of a monosaccharide, given its systematic name, complete with the configuration of each chiral
carbon atom.

Key Terms
Make certain that you can define, and use in context, the key terms below.
D sugar
L sugar

Study Notes
If you find that you have forgotten the meanings of terms such as dextrorotatory and polarimeter, refer back to Section 5.3 in
which the fundamentals of optical activity were introduced.
How would you set about the task of deciding whether each chiral carbon has an R or an S configuration? True, you could use
molecular models, but suppose that a model set had not been available—what would you have done then?
One approach is to focus on the carbon atom of interest and sketch a three-dimensional representation of the configuration
around that atom, remembering the convention used in Fischer projections: vertical lines represent bonds going into the page,
and horizontal lines represent bonds coming out of the page. Thus, the configuration around carbon atom 2 in structure a can be
represented as follows:

In your mind, you should be able to imagine how this molecule would look if it was rotated so that the bonds that are shown as
coming out of the page are now in the plane of the page. [One possible way of doing this is to try and imagine how the
molecule would look if it was viewed from a point at the bottom of the page.] What you should see in your mind is a
representation similar to the one drawn below.

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 To determine whether the configuration about the central carbon atom is R or S, we must rotate the molecule so that the group
with the lowest priority (H), is directed away from the viewer. This effect can be achieved by keeping the hydroxyl group in its
present position and moving each of the other three groups one position clockwise.

The Cahn-Ingold-Prelog order of priority for the three remaining groups is OH > CHO > CH(OH)CH2OH; thus, we see that we
could trace out a counterclockwise path going from the highest-priority group to the second- and third-highest, and we
conclude that the central carbon atom has an S configuration.

The Configuration of Glucose

The four chiral centers in glucose indicate there may be as many as sixteen (24) stereoisomers having this constitution. These would
exist as eight diastereomeric pairs of enantiomers, and the initial challenge was to determine which of the eight corresponded to
glucose. This challenge was accepted and met in 1891 by the German chemist Emil Fischer. His successful negotiation of the
stereochemical maze presented by the aldohexoses was a logical tour de force, and it is fitting that he received the 1902 Nobel Prize
for chemistry for this accomplishment. One of the first tasks faced by Fischer was to devise a method of representing the
configuration of each chiral center in an unambiguous manner. To this end, he invented a simple technique for drawing chains of
chiral centers, that we now call the Fischer projection formula. Click on this link for a review.
At the time Fischer undertook the glucose project it was not possible to establish the absolute configuration of an enantiomer.
Consequently, Fischer made an arbitrary choice for (+)-glucose and established a network of related aldose configurations that he
called the D-family. The mirror images of these configurations were then designated the L-family of aldoses. To illustrate using
present day knowledge, Fischer projection formulas and names for the D-aldose family (three to six-carbon atoms) are shown
below, with the asymmetric carbon atoms (chiral centers) colored red. The last chiral center in an aldose chain (farthest from the
aldehyde group) was chosen by Fischer as the D / L designator site. If the hydroxyl group in the projection formula pointed to the
right, it was defined as a member of the D-family. A left directed hydroxyl group (the mirror image) then represented the L-family.
Fischer's initial assignment of the D-configuration had a 50:50 chance of being right, but all his subsequent conclusions concerning
the relative configurations of various aldoses were soundly based. In 1951 x-ray fluorescence studies of (+)-tartaric acid, carried out
in the Netherlands by Johannes Martin Bijvoet, proved that Fischer's choice was correct.
It is important to recognize that the sign of a compound's specific rotation (an experimental number) does not correlate with its
configuration (D or L). It is a simple matter to measure an optical rotation with a polarimeter. Determining an absolute
configuration usually requires chemical interconversion with known compounds by stereospecific reaction paths.

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Exercises
Questions
Q25.3.1
Assign R and S for each chiral center and determine whether each sugar is a D or L sugar.
(a)

(b)

(c)

Solutions
S25.3.1
(a) From top to bottom, 2R, 3R, and it is a D sugar.
(b) From top to bottom, 2S, 3R, 4S, and it is an L sugar.
(c) From to to bottom, 3R, 4S, and it is an L sugar.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

Objectives
After completing this section, you should be able to
1. draw the structures of all possible aldotetroses, aldopentoses, and aldohexoses, without necessarily being able to assign
names to the individual compounds.
2. draw the Fischer projection of D‑glyceraldehyde, D‑ribose and D‑glucose from memory.

The four chiral centers in glucose indicate there may be as many as sixteen (24) stereoisomers having this constitution. These would
exist as eight diastereomeric pairs of enantiomers, and the initial challenge was to determine which of the eight corresponded to
glucose. This challenge was accepted and met in 1891 by the German chemist Emil Fischer. His successful negotiation of the
stereochemical maze presented by the aldohexoses was a logical tour de force, and it is fitting that he received the 1902 Nobel Prize
for chemistry for this accomplishment. One of the first tasks faced by Fischer was to devise a method of representing the
configuration of each chiral center in an unambiguous manner. To this end, he invented a simple technique for drawing chains of
chiral centers, that we now call the Fischer projection formula.

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At the time Fischer undertook the glucose project it was not possible to establish the absolute configuration of an enantiomer.
Consequently, Fischer made an arbitrary choice for (+)-glucose and established a network of related aldose configurations that he
called the D-family. The mirror images of these configurations were then designated the L-family of aldoses. To illustrate using
present day knowledge, Fischer projection formulas and names for the D-aldose family (three to six-carbon atoms) are shown
below, with the asymmetric carbon atoms (chiral centers) colored red.

The last chiral center in an aldose chain (farthest from the aldehyde group) was chosen by Fischer as the D / L designator site. If the
hydroxyl group in the projection formula pointed to the right, it was defined as a member of the D-family. A left directed hydroxyl
group (the mirror image) then represented the L-family. Fischer's initial assignment of the D-configuration had a 50:50 chance of
being right, but all his subsequent conclusions concerning the relative configurations of various aldoses were soundly based. In
1951 x-ray fluorescence studies of (+)-tartaric acid, carried out in the Netherlands by Johannes Martin Bijvoet (pronounced "buy
foot"), proved that Fischer's choice was correct.
It is important to recognize that the sign of a compound's specific rotation (an experimental number) does not correlate with its
configuration (D or L). It is a simple matter to measure an optical rotation with a polarimeter. Determining an absolute
configuration usually requires chemical interconversion with known compounds by stereospecific reaction paths.

Exercises
Questions
Q25.4.1
Draw the following sugars.
(a) D-Xylose
(b) D-Galactose
(c) D-Allose
Solutions
S25.4.1
(a)
O H

H OH
HO H
H OH
CH2OH

(b)

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(c)

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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24.2: Conformations and Cyclic Forms of Sugars
Objectives
After completing this section, you should be able to
1. determine whether a given monosaccharide will exist as a pyranose or furanose.
2. draw the cyclic pyranose form of a monosaccharide, given its Fischer projection.
3. draw the Fischer projection of a monosaccharide, given its cyclic pyranose form.
4. draw, from memory, the cyclic pyranose form of D‑glucose.
5. determine whether a given cyclic pyranose form represents the D or L form of the monosaccharide concerned.
6. describe the phenomenon known as mutarotation.
7. explain, through the use of chemical equations, exactly what happens at the molecular level during the mutarotation
process.

Key Terms
Make certain that you can define, and use in context, the key terms below.
alpha anomer
anomer
anomeric centre
beta anomer
furanose
mutarotation
pyranose

Study Notes

If necessary, before you attempt to study this section, review the formation of hemiacetals discussed in Section 19.10.

As noted above, the preferred structural form of many monosaccharides may be that of a cyclic hemiacetal. Five and six-
membered rings are favored over other ring sizes because of their low angle and eclipsing strain. Cyclic structures of this
kind are termed furanose (five-membered) or pyranose (six-membered), reflecting the ring size relationship to the common
heterocyclic compounds furan and pyran shown on the right. Ribose, an important aldopentose, commonly adopts a
furanose structure, as shown in the following illustration. By convention for the D-family, the five-membered furanose ring
is drawn in an edgewise projection with the ring oxygen positioned away from the viewer. The anomeric carbon atom
(colored red here) is placed on the right. The upper bond to this carbon is defined as beta, the lower bond then is alpha.

The cyclic pyranose forms of various monosaccharides are often drawn in a flat projection known as a Haworth formula,
after the British chemist, Norman Haworth. As with the furanose ring, the anomeric carbon is placed on the right with the
ring oxygen to the back of the edgewise view. In the D-family, the alpha and beta bonds have the same orientation defined
for the furanose ring (beta is up & alpha is down). These Haworth formulas are convenient for displaying stereochemical
relationships, but do not represent the true shape of the molecules. We know that these molecules are actually puckered in
a fashion we call a chair conformation. Examples of four typical pyranose structures are shown below, both as Haworth
projections and as the more representative chair conformers. The anomeric carbons are colored red.

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The size of the cyclic hemiacetal ring adopted by a given sugar is not constant, but may vary with substituents and other
structural features. Aldolhexoses usually form pyranose rings and their pentose homologs tend to prefer the furanose form,
but there are many counter examples. The formation of acetal derivatives illustrates how subtle changes may alter this
selectivity. A pyranose structure for D-glucose is drawn in the rose-shaded box on the left. Acetal derivatives have been
prepared by acid-catalyzed reactions with benzaldehyde and acetone. As a rule, benzaldehyde forms six-membered cyclic
acetals, whereas acetone prefers to form five-membered acetals. The top equation shows the formation and some reactions
of the 4,6-O-benzylidene acetal, a commonly employed protective group. A methyl glycoside derivative of this compound
(see below) leaves the C-2 and C-3 hydroxyl groups exposed to reactions such as the periodic acid cleavage, shown as the
last step. The formation of an isopropylidene acetal at C-1 and C-2, center structure, leaves the C-3 hydroxyl as the only
unprotected function. Selective oxidation to a ketone is then possible. Finally, direct di-O-isopropylidene derivatization of
glucose by reaction with excess acetone results in a change to a furanose structure in which the C-3 hydroxyl is again
unprotected. However, the same reaction with D-galactose, shown in the blue-shaded box, produces a pyranose product in
which the C-6 hydroxyl is unprotected. Both derivatives do not react with Tollens' reagent. This difference in behavior is
attributed to the cis-orientation of the C-3 and C-4 hydroxyl groups in galactose, which permits formation of a less strained
five-membered cyclic acetal, compared with the trans-C-3 and C-4 hydroxyl groups in glucose. Derivatizations of this kind
permit selective reactions to be conducted at different locations in these highly functionalized molecules.

Anomers of Simple Sugars: Mutarotation of Glucose

Figure 1: Cyclization of D-Glucose. D-Glucose can be represented with a Fischer projection (a) or three dimensionally
(b). By reacting the OH group on the fifth carbon atom with the aldehyde group, the cyclic monosaccharide (c) is
produced.

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When a straight-chain monosaccharide, such as any of the structures shown in Figure 1, forms a cyclic structure, the
carbonyl oxygen atom may be pushed either up or down, giving rise to two stereoisomers, as shown in Figure 2. The
structure shown on the left side of Figure 2, with the OH group on the first carbon atom projected downward, represent
what is called the alpha (α) form. The structures on the right side, with the OH group on the first carbon atom pointed
upward, is the beta (β) form. These two stereoisomers of a cyclic monosaccharide are known as anomers; they differ in
structure around the anomeric carbon—that is, the carbon atom that was the carbonyl carbon atom in the straight-chain
form.

Figure 2: Monosaccharides. In an aqueous solution, monosaccharides exist as an equilibrium mixture of three forms. The
interconversion between the forms is known as mutarotation, which is shown for D-glucose (a) and D-fructose (b).
It is possible to obtain a sample of crystalline glucose in which all the molecules have the α structure or all have the β
structure. The α form melts at 146°C and has a specific rotation of +112°, while the β form melts at 150°C and has a
specific rotation of +18.7°. When the sample is dissolved in water, however, a mixture is soon produced containing both
anomers as well as the straight-chain form, in dynamic equilibrium (part (a) of Figure 2). You can start with a pure
crystalline sample of glucose consisting entirely of either anomer, but as soon as the molecules dissolve in water, they open
to form the carbonyl group and then reclose to form either the α or the β anomer. The opening and closing repeats
continuously in an ongoing interconversion between anomeric forms and is referred to as mutarotation (Latin mutare,
meaning “to change”). At equilibrium, the mixture consists of about 36% α-D-glucose, 64% β-D-glucose, and less than
0.02% of the open-chain aldehyde form. The observed rotation of this solution is +52.7°.
Even though only a small percentage of the molecules are in the open-chain aldehyde form at any time, the solution will
nevertheless exhibit the characteristic reactions of an aldehyde. As the small amount of free aldehyde is used up in a
reaction, there is a shift in the equilibrium to yield more aldehyde. Thus, all the molecules may eventually react, even
though very little free aldehyde is present at a time.
Commonly, (e.g., in Figures 1 and 2) the cyclic forms of sugars are depicted using a convention first suggested by Walter
N. Haworth, an English chemist. The molecules are drawn as planar hexagons with a darkened edge representing the side
facing toward the viewer. The structure is simplified to show only the functional groups attached to the carbon atoms. Any
group written to the right in a Fischer projection appears below the plane of the ring in a Haworth projection, and any
group written to the left in a Fischer projection appears above the plane in a Haworth projection.
The difference between the α and the β forms of sugars may seem trivial, but such structural differences are often crucial in
biochemical reactions. This explains why we can get energy from the starch in potatoes and other plants but not from
cellulose, even though both starch and cellulose are polysaccharides composed of glucose molecules linked together.

Summary
Monosaccharides that contain five or more carbons atoms form cyclic structures in aqueous solution. Two cyclic
stereoisomers can form from each straight-chain monosaccharide; these are known as anomers. In an aqueous solution, an

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equilibrium mixture forms between the two anomers and the straight-chain structure of a monosaccharide in a process
known as mutarotation.

Exercises
1. Draw the cyclic structure for β-D-glucose. Identify the anomeric carbon.
2. Given that the aldohexose D-mannose differs from D-glucose only in the configuration at the second carbon atom,
draw the cyclic structure for α-D-mannose.

Answers

1.

2.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
The Basics of General, Organic, and Biological Chemistry by David W. Ball, John W. Hill, and Rhonda J. Scott.

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24.3: Anomers of Simple Sugars - Mutarotation of Glucose
Learning Objectives
Define what is meant by anomers and describe how they are formed.
Explain what is meant by mutarotation.

So far we have represented monosaccharides as linear molecules, but many of them also adopt cyclic structures. This
conversion occurs because of the ability of aldehydes and ketones to react with alcohols:

You might wonder why the aldehyde reacts with the OH group on the fifth carbon atom rather than the OH group on the
second carbon atom next to it. Recall that cyclic alkanes containing five or six carbon atoms in the ring are the most stable.
The same is true for monosaccharides that form cyclic structures: rings consisting of five or six carbon atoms are the most
stable.

Figure 24.3.1 : Cyclization of D-Glucose. D-Glucose can be represented with a Fischer projection (a) or three
dimensionally (b). By reacting the OH group on the fifth carbon atom with the aldehyde group, the cyclic monosaccharide
(c) is produced.
When a straight-chain monosaccharide, such as any of the structures shown in Figure 24.3.1, forms a cyclic structure, the
carbonyl oxygen atom may be pushed either up or down, giving rise to two stereoisomers, as shown in Figure 24.3.2. The
structure shown on the left side of Figure 24.3.2, with the OH group on the first carbon atom projected downward,
represent what is called the alpha (α) form. The structures on the right side, with the OH group on the first carbon atom
pointed upward, is the beta (β) form. These two stereoisomers of a cyclic monosaccharide are known as anomers; they
differ in structure around the anomeric carbon—that is, the carbon atom that was the carbonyl carbon atom in the straight-
chain form.
It is possible to obtain a sample of crystalline glucose in which all the molecules have the α structure or all have the β
structure. The α form melts at 146°C and has a specific rotation of +112°, while the β form melts at 150°C and has a
specific rotation of +18.7°. When the sample is dissolved in water, however, a mixture is soon produced containing both
anomers as well as the straight-chain form, in dynamic equilibrium (part (a) of Figure 24.3.2). You can start with a pure
crystalline sample of glucose consisting entirely of either anomer, but as soon as the molecules dissolve in water, they open
to form the carbonyl group and then reclose to form either the α or the β anomer. The opening and closing repeats
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continuously in an ongoing interconversion between anomeric forms and is referred to as mutarotation (Latin mutare,
meaning “to change”). At equilibrium, the mixture consists of about 36% α-D-glucose, 64% β-D-glucose, and less than
0.02% of the open-chain aldehyde form. The observed rotation of this solution is +52.7°.

Figure 24.3.2 : Monosaccharides. In an aqueous solution, monosaccharides exist as an equilibrium mixture of three forms.
The interconversion between the forms is known as mutarotation, which is shown for D-glucose (a) and D-fructose (b).
Even though only a small percentage of the molecules are in the open-chain aldehyde form at any time, the solution will
nevertheless exhibit the characteristic reactions of an aldehyde. As the small amount of free aldehyde is used up in a
reaction, there is a shift in the equilibrium to yield more aldehyde. Thus, all the molecules may eventually react, even
though very little free aldehyde is present at a time.
Commonly, (e.g., in Figures 24.3.1 and 24.3.2) the cyclic forms of sugars are depicted using a convention first suggested
by Walter N. Haworth, an English chemist. The molecules are drawn as planar hexagons with a darkened edge
representing the side facing toward the viewer. The structure is simplified to show only the functional groups attached to
the carbon atoms. Any group written to the right in a Fischer projection appears below the plane of the ring in a Haworth
projection, and any group written to the left in a Fischer projection appears above the plane in a Haworth projection.
The difference between the α and the β forms of sugars may seem trivial, but such structural differences are often crucial in
biochemical reactions. This explains why we can get energy from the starch in potatoes and other plants but not from
cellulose, even though both starch and cellulose are polysaccharides composed of glucose molecules linked together.

Summary
Monosaccharides that contain five or more carbons atoms form cyclic structures in aqueous solution. Two cyclic
stereoisomers can form from each straight-chain monosaccharide; these are known as anomers. In an aqueous solution, an
equilibrium mixture forms between the two anomers and the straight-chain structure of a monosaccharide in a process
known as mutarotation.

Concept Review Exercises

1. Define each term.
a. mutarotation
b. anomer
c. anomeric carbon
2. How can you prove that a solution of α-D-glucose exhibits mutarotation?

Answers
1. a. the ongoing interconversion between anomers of a particular carbohydrate to form an equilibrium mixture
b. a stereoisomer that differs in structure around what was the carbonyl carbon atom in the straight-chain form of a
monosaccharide
c. the carbon atom that was the carbonyl carbon atom in the straight-chain form of a monosaccharide

24.3.2 11/28/2021 https://chem.libretexts.org/@go/page/32569

2. Place a sample of pure α-D-glucose in a polarimeter and measure its observed rotation. This value will change as
mutarotation occurs.

Exercises
1. Draw the cyclic structure for β-D-glucose. Identify the anomeric carbon.
2. Draw the cyclic structure for α-D-fructose. Identify the anomeric carbon.
3. Given that the aldohexose D-mannose differs from D-glucose only in the configuration at the second carbon atom,
draw the cyclic structure for α-D-mannose.
4. Given that the aldohexose D-allose differs from D-glucose only in the configuration at the third carbon atom, draw the
cyclic structure for β-D-allose.

Answers

1.

3.

24.3.3 11/28/2021 https://chem.libretexts.org/@go/page/32569

24.4: Polyfunctional Chemistry of Sugars: Oxidation to Carboxylic Acids
Objectives
After completing this section, you should be able to
1. a. write equations to illustrate that the hydroxyl groups of carbohydrates can react to form esters and ethers.
b. identify the product formed when a given monosaccharide is reacted with acetic anhydride or with silver oxide
and an alkyl halide.
c. identify the reagents required to convert a given monosaccharide to its ester or ether.
2. a. write an equation to show how a monosaccharide can be converted to a glycoside using an alcohol and an acid
catalyst.
b. identify the product formed when a given monosaccharide is treated with an alcohol and an acid catalyst.
c. write a detailed mechanism for the formation of a glycoside by the reaction of the cyclic form of a
monosaccharide with an alcohol and an acid catalyst.
3. identify the ester formed by phosphorylation in biologically important compounds.
4. a. identify the product formed when a given monosaccharide is reduced with sodium borohydride.
b. identify the monosaccharide which should be reduced in order to form a given polyalcohol (alditol).
5. a. explain that a sugar with an aldehyde or hemiacetal can be oxidized to the corresponding carboxylic acid (also
known as aldonic acid). Note: The sugar is able to reduce an oxidizing agent, and is thus called a reducing
sugar. Tests for reducing sugars include the use of Tollens’ reagent, Fehling’s reagent and Benedict’s reagent.
b. explain why certain ketoses, such as fructose, behave as reducing sugars even though they do not contain an
aldehyde group.
c. identify warm HNO3 as the reagent needed to form dicarboxylic acid (an aldaric acid).
6. a. describe the chain‑lengthening effect of the Kiliani‑Fischer synthesis.
b. predict the product that would be produced by the Kiliani‑Fischer synthesis of a given aldose.
c. identify the aldose that would yield a given product following Kiliani‑Fischer synthesis.
7. a. describe the chain‑shortening effect of the Wohl degradation.
b. predict the product that would be produced by the Wohl degradation of a given aldose.
c. identify the aldose or aldoses that would yield a given product following Wohl degradation.

Key Terms
Make certain that you can define, and use in context, the key terms below.
aldaric acid
aldonic acid
alditol
aldonic acid
glycoside
Kiliani-Fischer synthesis
neighbouring group effect
reducing sugar
Wohl degradation

Study Notes

While several reactions are covered in this section, keep in mind that you have encountered them in previous sections.
The active functional groups on monosaccharides are essentially carbonyls and hydroxyls. Although they now are a
part of much larger molecules, their chemistry should be familiar.
The formation of esters and ethers is quite straightforward and should not require further clarification.

24.4.1 12/5/2021 https://chem.libretexts.org/@go/page/32570

 Note that glycosides are in fact acetals, and that glycoside formation is therefore analogous to acetal formation. To
refresh your memory about the chemistry of acetals, quickly review Section 19.10

Ester and Ether Formation

The -OH groups on a monosaccharide can be readily converted to esters and ethers. Esterfication can be done with an acid
chloride (Section 21.4) or acid anhydride (Section 21.5), while treatment with an alkyl halide by a Williamson ether
synthesis (Section 18.2) leads to the ether.

Glycoside Formation
Acetal derivatives formed when a monosaccharide reacts with an alcohol in the presence of an acid catalyst are called
glycosides. This reaction is illustrated for glucose and methanol in the diagram below. In naming of glycosides, the "ose"
suffix of the sugar name is replaced by "oside", and the alcohol group name is placed first. As is generally true for most
acetals, glycoside formation involves the loss of an equivalent of water. The diether product is stable to base and alkaline
oxidants such as Tollen's reagent. Since acid-catalyzed aldolization is reversible, glycosides may be hydrolyzed back to
their alcohol and sugar components by aqueous acid.
The anomeric methyl glucosides are formed in an equilibrium ratio of 66% alpha to 34% beta. From the structures in the
previous diagram, we see that pyranose rings prefer chair conformations in which the largest number of substituents are
equatorial. In the case of glucose, the substituents on the beta-anomer are all equatorial, whereas the C-1 substituent in the
alpha-anomer changes to axial. Since substituents on cyclohexane rings prefer an equatorial location over axial
(methoxycyclohexane is 75% equatorial), the preference for alpha-glycopyranoside formation is unexpected, and is
referred to as the anomeric effect.

Glycosides abound in biological systems. By attaching a sugar moiety to a lipid or benzenoid structure, the solubility and
other properties of the compound may be changed substantially. Because of the important modifying influence of such
derivatization, numerous enzyme systems, known as glycosidases, have evolved for the attachment and removal of sugars
from alcohols, phenols and amines. Chemists refer to the sugar component of natural glycosides as the glycon and the
alcohol component as the aglycon.
Two examples of naturally occurring glycosides and one example of an amino derivative are displayed above. Salicin, one
of the oldest herbal remedies known, was the model for the synthetic analgesic aspirin. A large class of hydroxylated,

24.4.2 12/5/2021 https://chem.libretexts.org/@go/page/32570

aromatic oxonium cations called anthocyanins provide the red, purple and blue colors of many flowers, fruits and some
vegetables. Peonin is one example of this class of natural pigments, which exhibit a pronounced pH color dependence. The
oxonium moiety is only stable in acidic environments, and the color changes or disappears when base is added. The
complex changes that occur when wine is fermented and stored are in part associated with glycosides of anthocyanins.
Finally, amino derivatives of ribose, such as cytidine play important roles in biological phosphorylating agents, coenzymes
and information transport and storage materials.

Biological Ester Formation: Phosphorylation

Recall that almost all biomolecules are charged species, which 1) keeps them water soluble, and 2) prevents them from
diffusing across lipid bilayer membranes. Although many biomolecules are ionized by virtue of negatively charged
carboxylate and positively charged amino groups, the most common ionic group in biologically important organic
compounds is phosphate - thus the phosphorylation of alcohol groups is a critical metabolic step. In alcohol
phosphorylations, ATP is almost always the phosphate donor, and the mechanism is very consistent: the alcohol oxygen
acts as a nucleophile, attacking the gamma-phosphorus of ATP and expelling ADP (look again, for example, at the glucose
kinase reaction that we first saw in section 10.1D).

Oxidation Edit section

As noted above, sugars may be classified as reducing or non-reducing based on their reactivity with Tollens', Benedict's
or Fehling's reagents. If a sugar is oxidized by these reagents it is called reducing, since the oxidant (Ag(+) or Cu(+2)) is
reduced in the reaction, as evidenced by formation of a silver mirror or precipitation of cuprous oxide. The Tollens' test is
commonly used to detect aldehyde functions; and because of the facile interconversion of ketoses and aldoses under the
basic conditions of this test, ketoses such as fructose also react and are classified as reducing sugars.
When the aldehyde function of an aldose is oxidized to a carboxylic acid the product is called an aldonic acid. Because of
the 2º hydroxyl functions that are also present in these compounds, a mild oxidizing agent such as hypobromite must be
used for this conversion (equation 1). If both ends of an aldose chain are oxidized to carboxylic acids the product is called
an aldaric acid. By converting an aldose to its corresponding aldaric acid derivative, the ends of the chain become identical
(this could also be accomplished by reducing the aldehyde to CH2OH, as noted below). Such an operation will disclose
any latent symmetry in the remaining molecule. Thus, ribose, xylose, allose and galactose yield achiral aldaric acids which
are, of course, not optically active. The ribose oxidation is shown in equation 2 below.

1.
2.

24.4.3 12/5/2021 https://chem.libretexts.org/@go/page/32570

3.

Other aldose sugars may give identical chiral aldaric acid products, implying a unique configurational relationship. The
examples of arabinose and lyxose shown in equation 3 above illustrate this result. Remember, a Fischer projection formula
may be rotated by 180º in the plane of projection without changing its configuration.

Reduction
Sodium borohydride reduction of an aldose makes the ends of the resulting alditol chain identical,
HOCH2(CHOH)nCH2OH, thereby accomplishing the same configurational change produced by oxidation to an aldaric
acid. Thus, allitol and galactitol from reduction of allose and galactose are achiral, and altrose and talose are reduced to the
same chiral alditol. A summary of these redox reactions, and derivative nomenclature is given in the following table.
Table: Derivatives of H OC H 2 (C H OH )n C H O

HOC H2 (CHOH )n C O2 H
HOBr Oxidation ⟶
an Aldonic Acid
H2 OC(CHOH )n C O2 H
HN O3 Oxidation ⟶
an Aldaric Acid
HOC H2 (CHOH )n C H2 OH
N aBH4 Reduction ⟶
an Alditol

Chain Shortening and Lengthening

1. Ruff
Degradatio
n

2.
Kiliani-
Fischer
Synthes
is

These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The
importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural
connections are given by the dashed blue lines. Thus Ruff degradation of the pentose arabinose gives the tetrose erythrose.

24.4.4 12/5/2021 https://chem.libretexts.org/@go/page/32570

Working in the opposite direction, a Kiliani-Fischer synthesis applied to arabinose gives a mixture of glucose and
mannose. An alternative chain shortening procedure known as the Wohl degradation is essentially the reverse of the
Kiliani-Fischer synthesis.
Note that in the Kiliani-Fischer synthesis the first step is to generate a cyanohydrin intermediate, which is then has its
nitrile group hydrolyzed to the carboxylic acid. From there the cyclic ester (lactone) is formed and reduced to the final
products (epimers).

Wohl Degradation
The ability to shorten (degrade) an aldose chain by one carbon was an important tool in the structure elucidation of
carbohydrates. This was commonly accomplished by the Ruff procedure. An interesting alternative technique, known as
the Wohl degradation has also been used. The following equation illustrates the application of this procedure to the
aldopentose, arabinose. Based on your knowledge of carbonyl chemistry, and considering that the Wohl degradation is in
essence the reverse of the Kiliani-Fischer synthesis.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

24.4.5 12/5/2021 https://chem.libretexts.org/@go/page/32570

24.5: Oxidative Cleavage of Sugars

24.5.1 12/5/2021 https://chem.libretexts.org/@go/page/32571

24.6: Reduction of Monosaccharides to Alditols
Objectives
After completing this section, you should be able to
1. a. write equations to illustrate that the hydroxyl groups of carbohydrates can react to form esters and ethers.
b. identify the product formed when a given monosaccharide is reacted with acetic anhydride or with silver oxide
and an alkyl halide.
c. identify the reagents required to convert a given monosaccharide to its ester or ether.
2. a. write an equation to show how a monosaccharide can be converted to a glycoside using an alcohol and an acid
catalyst.
b. identify the product formed when a given monosaccharide is treated with an alcohol and an acid catalyst.
c. write a detailed mechanism for the formation of a glycoside by the reaction of the cyclic form of a
monosaccharide with an alcohol and an acid catalyst.
3. identify the ester formed by phosphorylation in biologically important compounds.
4. a. identify the product formed when a given monosaccharide is reduced with sodium borohydride.
b. identify the monosaccharide which should be reduced in order to form a given polyalcohol (alditol).
5. a. explain that a sugar with an aldehyde or hemiacetal can be oxidized to the corresponding carboxylic acid (also
known as aldonic acid). Note: The sugar is able to reduce an oxidizing agent, and is thus called a reducing
sugar. Tests for reducing sugars include the use of Tollens’ reagent, Fehling’s reagent and Benedict’s reagent.
b. explain why certain ketoses, such as fructose, behave as reducing sugars even though they do not contain an
aldehyde group.
c. identify warm HNO3 as the reagent needed to form dicarboxylic acid (an aldaric acid).
6. a. describe the chain‑lengthening effect of the Kiliani‑Fischer synthesis.
b. predict the product that would be produced by the Kiliani‑Fischer synthesis of a given aldose.
c. identify the aldose that would yield a given product following Kiliani‑Fischer synthesis.
7. a. describe the chain‑shortening effect of the Wohl degradation.
b. predict the product that would be produced by the Wohl degradation of a given aldose.
c. identify the aldose or aldoses that would yield a given product following Wohl degradation.

Key Terms
Make certain that you can define, and use in context, the key terms below.
aldaric acid
aldonic acid
alditol
aldonic acid
glycoside
Kiliani-Fischer synthesis
neighbouring group effect
reducing sugar
Wohl degradation

Study Notes

While several reactions are covered in this section, keep in mind that you have encountered them in previous sections.
The active functional groups on monosaccharides are essentially carbonyls and hydroxyls. Although they now are a
part of much larger molecules, their chemistry should be familiar.
The formation of esters and ethers is quite straightforward and should not require further clarification.

24.6.1 11/28/2021 https://chem.libretexts.org/@go/page/32572

 Note that glycosides are in fact acetals, and that glycoside formation is therefore analogous to acetal formation. To
refresh your memory about the chemistry of acetals, quickly review Section 19.10

Ester and Ether Formation

The -OH groups on a monosaccharide can be readily converted to esters and ethers. Esterfication can be done with an acid
chloride (Section 21.4) or acid anhydride (Section 21.5), while treatment with an alkyl halide by a Williamson ether
synthesis (Section 18.2) leads to the ether.

Glycoside Formation
Acetal derivatives formed when a monosaccharide reacts with an alcohol in the presence of an acid catalyst are called
glycosides. This reaction is illustrated for glucose and methanol in the diagram below. In naming of glycosides, the "ose"
suffix of the sugar name is replaced by "oside", and the alcohol group name is placed first. As is generally true for most
acetals, glycoside formation involves the loss of an equivalent of water. The diether product is stable to base and alkaline
oxidants such as Tollen's reagent. Since acid-catalyzed aldolization is reversible, glycosides may be hydrolyzed back to
their alcohol and sugar components by aqueous acid.
The anomeric methyl glucosides are formed in an equilibrium ratio of 66% alpha to 34% beta. From the structures in the
previous diagram, we see that pyranose rings prefer chair conformations in which the largest number of substituents are
equatorial. In the case of glucose, the substituents on the beta-anomer are all equatorial, whereas the C-1 substituent in the
alpha-anomer changes to axial. Since substituents on cyclohexane rings prefer an equatorial location over axial
(methoxycyclohexane is 75% equatorial), the preference for alpha-glycopyranoside formation is unexpected, and is
referred to as the anomeric effect.

Glycosides abound in biological systems. By attaching a sugar moiety to a lipid or benzenoid structure, the solubility and
other properties of the compound may be changed substantially. Because of the important modifying influence of such
derivatization, numerous enzyme systems, known as glycosidases, have evolved for the attachment and removal of sugars
from alcohols, phenols and amines. Chemists refer to the sugar component of natural glycosides as the glycon and the
alcohol component as the aglycon.
Two examples of naturally occurring glycosides and one example of an amino derivative are displayed above. Salicin, one
of the oldest herbal remedies known, was the model for the synthetic analgesic aspirin. A large class of hydroxylated,

24.6.2 11/28/2021 https://chem.libretexts.org/@go/page/32572

aromatic oxonium cations called anthocyanins provide the red, purple and blue colors of many flowers, fruits and some
vegetables. Peonin is one example of this class of natural pigments, which exhibit a pronounced pH color dependence. The
oxonium moiety is only stable in acidic environments, and the color changes or disappears when base is added. The
complex changes that occur when wine is fermented and stored are in part associated with glycosides of anthocyanins.
Finally, amino derivatives of ribose, such as cytidine play important roles in biological phosphorylating agents, coenzymes
and information transport and storage materials.

Biological Ester Formation: Phosphorylation

Recall that almost all biomolecules are charged species, which 1) keeps them water soluble, and 2) prevents them from
diffusing across lipid bilayer membranes. Although many biomolecules are ionized by virtue of negatively charged
carboxylate and positively charged amino groups, the most common ionic group in biologically important organic
compounds is phosphate - thus the phosphorylation of alcohol groups is a critical metabolic step. In alcohol
phosphorylations, ATP is almost always the phosphate donor, and the mechanism is very consistent: the alcohol oxygen
acts as a nucleophile, attacking the gamma-phosphorus of ATP and expelling ADP (look again, for example, at the glucose
kinase reaction that we first saw in section 10.1D).

Oxidation Edit section

As noted above, sugars may be classified as reducing or non-reducing based on their reactivity with Tollens', Benedict's
or Fehling's reagents. If a sugar is oxidized by these reagents it is called reducing, since the oxidant (Ag(+) or Cu(+2)) is
reduced in the reaction, as evidenced by formation of a silver mirror or precipitation of cuprous oxide. The Tollens' test is
commonly used to detect aldehyde functions; and because of the facile interconversion of ketoses and aldoses under the
basic conditions of this test, ketoses such as fructose also react and are classified as reducing sugars.
When the aldehyde function of an aldose is oxidized to a carboxylic acid the product is called an aldonic acid. Because of
the 2º hydroxyl functions that are also present in these compounds, a mild oxidizing agent such as hypobromite must be
used for this conversion (equation 1). If both ends of an aldose chain are oxidized to carboxylic acids the product is called
an aldaric acid. By converting an aldose to its corresponding aldaric acid derivative, the ends of the chain become identical
(this could also be accomplished by reducing the aldehyde to CH2OH, as noted below). Such an operation will disclose
any latent symmetry in the remaining molecule. Thus, ribose, xylose, allose and galactose yield achiral aldaric acids which
are, of course, not optically active. The ribose oxidation is shown in equation 2 below.

1.
2.

24.6.3 11/28/2021 https://chem.libretexts.org/@go/page/32572

3.

Other aldose sugars may give identical chiral aldaric acid products, implying a unique configurational relationship. The
examples of arabinose and lyxose shown in equation 3 above illustrate this result. Remember, a Fischer projection formula
may be rotated by 180º in the plane of projection without changing its configuration.

Reduction
Sodium borohydride reduction of an aldose makes the ends of the resulting alditol chain identical,
HOCH2(CHOH)nCH2OH, thereby accomplishing the same configurational change produced by oxidation to an aldaric
acid. Thus, allitol and galactitol from reduction of allose and galactose are achiral, and altrose and talose are reduced to the
same chiral alditol. A summary of these redox reactions, and derivative nomenclature is given in the following table.
Table: Derivatives of H OC H 2 (C H OH )n C H O

HOC H2 (CHOH )n C O2 H
HOBr Oxidation ⟶
an Aldonic Acid
H2 OC(CHOH )n C O2 H
HN O3 Oxidation ⟶
an Aldaric Acid
HOC H2 (CHOH )n C H2 OH
N aBH4 Reduction ⟶
an Alditol

Chain Shortening and Lengthening

1. Ruff
Degradatio
n

2.
Kiliani-
Fischer
Synthes
is

These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The
importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural
connections are given by the dashed blue lines. Thus Ruff degradation of the pentose arabinose gives the tetrose erythrose.

24.6.4 11/28/2021 https://chem.libretexts.org/@go/page/32572

Working in the opposite direction, a Kiliani-Fischer synthesis applied to arabinose gives a mixture of glucose and
mannose. An alternative chain shortening procedure known as the Wohl degradation is essentially the reverse of the
Kiliani-Fischer synthesis.
Note that in the Kiliani-Fischer synthesis the first step is to generate a cyanohydrin intermediate, which is then has its
nitrile group hydrolyzed to the carboxylic acid. From there the cyclic ester (lactone) is formed and reduced to the final
products (epimers).

Wohl Degradation
The ability to shorten (degrade) an aldose chain by one carbon was an important tool in the structure elucidation of
carbohydrates. This was commonly accomplished by the Ruff procedure. An interesting alternative technique, known as
the Wohl degradation has also been used. The following equation illustrates the application of this procedure to the
aldopentose, arabinose. Based on your knowledge of carbonyl chemistry, and considering that the Wohl degradation is in
essence the reverse of the Kiliani-Fischer synthesis.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

24.6.5 11/28/2021 https://chem.libretexts.org/@go/page/32572

24.7: Carbonyl Condensations with Amine Derivatives
Objectives
After completing this section, you should be able to
1. a. write equations to illustrate that the hydroxyl groups of carbohydrates can react to form esters and ethers.
b. identify the product formed when a given monosaccharide is reacted with acetic anhydride or with silver oxide
and an alkyl halide.
c. identify the reagents required to convert a given monosaccharide to its ester or ether.
2. a. write an equation to show how a monosaccharide can be converted to a glycoside using an alcohol and an acid
catalyst.
b. identify the product formed when a given monosaccharide is treated with an alcohol and an acid catalyst.
c. write a detailed mechanism for the formation of a glycoside by the reaction of the cyclic form of a
monosaccharide with an alcohol and an acid catalyst.
3. identify the ester formed by phosphorylation in biologically important compounds.
4. a. identify the product formed when a given monosaccharide is reduced with sodium borohydride.
b. identify the monosaccharide which should be reduced in order to form a given polyalcohol (alditol).
5. a. explain that a sugar with an aldehyde or hemiacetal can be oxidized to the corresponding carboxylic acid (also
known as aldonic acid). Note: The sugar is able to reduce an oxidizing agent, and is thus called a reducing
sugar. Tests for reducing sugars include the use of Tollens’ reagent, Fehling’s reagent and Benedict’s reagent.
b. explain why certain ketoses, such as fructose, behave as reducing sugars even though they do not contain an
aldehyde group.
c. identify warm HNO3 as the reagent needed to form dicarboxylic acid (an aldaric acid).
6. a. describe the chain‑lengthening effect of the Kiliani‑Fischer synthesis.
b. predict the product that would be produced by the Kiliani‑Fischer synthesis of a given aldose.
c. identify the aldose that would yield a given product following Kiliani‑Fischer synthesis.
7. a. describe the chain‑shortening effect of the Wohl degradation.
b. predict the product that would be produced by the Wohl degradation of a given aldose.
c. identify the aldose or aldoses that would yield a given product following Wohl degradation.

Key Terms
Make certain that you can define, and use in context, the key terms below.
aldaric acid
aldonic acid
alditol
aldonic acid
glycoside
Kiliani-Fischer synthesis
neighbouring group effect
reducing sugar
Wohl degradation

Study Notes

While several reactions are covered in this section, keep in mind that you have encountered them in previous sections.
The active functional groups on monosaccharides are essentially carbonyls and hydroxyls. Although they now are a
part of much larger molecules, their chemistry should be familiar.
The formation of esters and ethers is quite straightforward and should not require further clarification.

24.7.1 11/14/2021 https://chem.libretexts.org/@go/page/32573

 Note that glycosides are in fact acetals, and that glycoside formation is therefore analogous to acetal formation. To
refresh your memory about the chemistry of acetals, quickly review Section 19.10

Ester and Ether Formation

The -OH groups on a monosaccharide can be readily converted to esters and ethers. Esterfication can be done with an acid
chloride (Section 21.4) or acid anhydride (Section 21.5), while treatment with an alkyl halide by a Williamson ether
synthesis (Section 18.2) leads to the ether.

Glycoside Formation
Acetal derivatives formed when a monosaccharide reacts with an alcohol in the presence of an acid catalyst are called
glycosides. This reaction is illustrated for glucose and methanol in the diagram below. In naming of glycosides, the "ose"
suffix of the sugar name is replaced by "oside", and the alcohol group name is placed first. As is generally true for most
acetals, glycoside formation involves the loss of an equivalent of water. The diether product is stable to base and alkaline
oxidants such as Tollen's reagent. Since acid-catalyzed aldolization is reversible, glycosides may be hydrolyzed back to
their alcohol and sugar components by aqueous acid.
The anomeric methyl glucosides are formed in an equilibrium ratio of 66% alpha to 34% beta. From the structures in the
previous diagram, we see that pyranose rings prefer chair conformations in which the largest number of substituents are
equatorial. In the case of glucose, the substituents on the beta-anomer are all equatorial, whereas the C-1 substituent in the
alpha-anomer changes to axial. Since substituents on cyclohexane rings prefer an equatorial location over axial
(methoxycyclohexane is 75% equatorial), the preference for alpha-glycopyranoside formation is unexpected, and is
referred to as the anomeric effect.

Glycosides abound in biological systems. By attaching a sugar moiety to a lipid or benzenoid structure, the solubility and
other properties of the compound may be changed substantially. Because of the important modifying influence of such
derivatization, numerous enzyme systems, known as glycosidases, have evolved for the attachment and removal of sugars
from alcohols, phenols and amines. Chemists refer to the sugar component of natural glycosides as the glycon and the
alcohol component as the aglycon.
Two examples of naturally occurring glycosides and one example of an amino derivative are displayed above. Salicin, one
of the oldest herbal remedies known, was the model for the synthetic analgesic aspirin. A large class of hydroxylated,

24.7.2 11/14/2021 https://chem.libretexts.org/@go/page/32573

aromatic oxonium cations called anthocyanins provide the red, purple and blue colors of many flowers, fruits and some
vegetables. Peonin is one example of this class of natural pigments, which exhibit a pronounced pH color dependence. The
oxonium moiety is only stable in acidic environments, and the color changes or disappears when base is added. The
complex changes that occur when wine is fermented and stored are in part associated with glycosides of anthocyanins.
Finally, amino derivatives of ribose, such as cytidine play important roles in biological phosphorylating agents, coenzymes
and information transport and storage materials.

Biological Ester Formation: Phosphorylation

Recall that almost all biomolecules are charged species, which 1) keeps them water soluble, and 2) prevents them from
diffusing across lipid bilayer membranes. Although many biomolecules are ionized by virtue of negatively charged
carboxylate and positively charged amino groups, the most common ionic group in biologically important organic
compounds is phosphate - thus the phosphorylation of alcohol groups is a critical metabolic step. In alcohol
phosphorylations, ATP is almost always the phosphate donor, and the mechanism is very consistent: the alcohol oxygen
acts as a nucleophile, attacking the gamma-phosphorus of ATP and expelling ADP (look again, for example, at the glucose
kinase reaction that we first saw in section 10.1D).

Oxidation Edit section

As noted above, sugars may be classified as reducing or non-reducing based on their reactivity with Tollens', Benedict's
or Fehling's reagents. If a sugar is oxidized by these reagents it is called reducing, since the oxidant (Ag(+) or Cu(+2)) is
reduced in the reaction, as evidenced by formation of a silver mirror or precipitation of cuprous oxide. The Tollens' test is
commonly used to detect aldehyde functions; and because of the facile interconversion of ketoses and aldoses under the
basic conditions of this test, ketoses such as fructose also react and are classified as reducing sugars.
When the aldehyde function of an aldose is oxidized to a carboxylic acid the product is called an aldonic acid. Because of
the 2º hydroxyl functions that are also present in these compounds, a mild oxidizing agent such as hypobromite must be
used for this conversion (equation 1). If both ends of an aldose chain are oxidized to carboxylic acids the product is called
an aldaric acid. By converting an aldose to its corresponding aldaric acid derivative, the ends of the chain become identical
(this could also be accomplished by reducing the aldehyde to CH2OH, as noted below). Such an operation will disclose
any latent symmetry in the remaining molecule. Thus, ribose, xylose, allose and galactose yield achiral aldaric acids which
are, of course, not optically active. The ribose oxidation is shown in equation 2 below.

1.
2.

24.7.3 11/14/2021 https://chem.libretexts.org/@go/page/32573

3.

Other aldose sugars may give identical chiral aldaric acid products, implying a unique configurational relationship. The
examples of arabinose and lyxose shown in equation 3 above illustrate this result. Remember, a Fischer projection formula
may be rotated by 180º in the plane of projection without changing its configuration.

Reduction
Sodium borohydride reduction of an aldose makes the ends of the resulting alditol chain identical,
HOCH2(CHOH)nCH2OH, thereby accomplishing the same configurational change produced by oxidation to an aldaric
acid. Thus, allitol and galactitol from reduction of allose and galactose are achiral, and altrose and talose are reduced to the
same chiral alditol. A summary of these redox reactions, and derivative nomenclature is given in the following table.
Table: Derivatives of H OC H 2 (C H OH )n C H O

HOC H2 (CHOH )n C O2 H
HOBr Oxidation ⟶
an Aldonic Acid
H2 OC(CHOH )n C O2 H
HN O3 Oxidation ⟶
an Aldaric Acid
HOC H2 (CHOH )n C H2 OH
N aBH4 Reduction ⟶
an Alditol

Chain Shortening and Lengthening

1. Ruff
Degradatio
n

2.
Kiliani-
Fischer
Synthes
is

These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The
importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural
connections are given by the dashed blue lines. Thus Ruff degradation of the pentose arabinose gives the tetrose erythrose.

24.7.4 11/14/2021 https://chem.libretexts.org/@go/page/32573

Working in the opposite direction, a Kiliani-Fischer synthesis applied to arabinose gives a mixture of glucose and
mannose. An alternative chain shortening procedure known as the Wohl degradation is essentially the reverse of the
Kiliani-Fischer synthesis.
Note that in the Kiliani-Fischer synthesis the first step is to generate a cyanohydrin intermediate, which is then has its
nitrile group hydrolyzed to the carboxylic acid. From there the cyclic ester (lactone) is formed and reduced to the final
products (epimers).

Wohl Degradation
The ability to shorten (degrade) an aldose chain by one carbon was an important tool in the structure elucidation of
carbohydrates. This was commonly accomplished by the Ruff procedure. An interesting alternative technique, known as
the Wohl degradation has also been used. The following equation illustrates the application of this procedure to the
aldopentose, arabinose. Based on your knowledge of carbonyl chemistry, and considering that the Wohl degradation is in
essence the reverse of the Kiliani-Fischer synthesis.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

24.7.5 11/14/2021 https://chem.libretexts.org/@go/page/32573

24.8: Ester and Ether Formation: Glycosides
Objectives
After completing this section, you should be able to
1. a. write equations to illustrate that the hydroxyl groups of carbohydrates can react to form esters and ethers.
b. identify the product formed when a given monosaccharide is reacted with acetic anhydride or with silver oxide
and an alkyl halide.
c. identify the reagents required to convert a given monosaccharide to its ester or ether.
2. a. write an equation to show how a monosaccharide can be converted to a glycoside using an alcohol and an acid
catalyst.
b. identify the product formed when a given monosaccharide is treated with an alcohol and an acid catalyst.
c. write a detailed mechanism for the formation of a glycoside by the reaction of the cyclic form of a
monosaccharide with an alcohol and an acid catalyst.
3. identify the ester formed by phosphorylation in biologically important compounds.
4. a. identify the product formed when a given monosaccharide is reduced with sodium borohydride.
b. identify the monosaccharide which should be reduced in order to form a given polyalcohol (alditol).
5. a. explain that a sugar with an aldehyde or hemiacetal can be oxidized to the corresponding carboxylic acid (also
known as aldonic acid). Note: The sugar is able to reduce an oxidizing agent, and is thus called a reducing
sugar. Tests for reducing sugars include the use of Tollens’ reagent, Fehling’s reagent and Benedict’s reagent.
b. explain why certain ketoses, such as fructose, behave as reducing sugars even though they do not contain an
aldehyde group.
c. identify warm HNO3 as the reagent needed to form dicarboxylic acid (an aldaric acid).
6. a. describe the chain‑lengthening effect of the Kiliani‑Fischer synthesis.
b. predict the product that would be produced by the Kiliani‑Fischer synthesis of a given aldose.
c. identify the aldose that would yield a given product following Kiliani‑Fischer synthesis.
7. a. describe the chain‑shortening effect of the Wohl degradation.
b. predict the product that would be produced by the Wohl degradation of a given aldose.
c. identify the aldose or aldoses that would yield a given product following Wohl degradation.

Key Terms
Make certain that you can define, and use in context, the key terms below.
aldaric acid
aldonic acid
alditol
aldonic acid
glycoside
Kiliani-Fischer synthesis
neighbouring group effect
reducing sugar
Wohl degradation

Study Notes

While several reactions are covered in this section, keep in mind that you have encountered them in previous sections.
The active functional groups on monosaccharides are essentially carbonyls and hydroxyls. Although they now are a
part of much larger molecules, their chemistry should be familiar.
The formation of esters and ethers is quite straightforward and should not require further clarification.

24.8.1 12/5/2021 https://chem.libretexts.org/@go/page/32574

 Note that glycosides are in fact acetals, and that glycoside formation is therefore analogous to acetal formation. To
refresh your memory about the chemistry of acetals, quickly review Section 19.10

Ester and Ether Formation

The -OH groups on a monosaccharide can be readily converted to esters and ethers. Esterfication can be done with an acid
chloride (Section 21.4) or acid anhydride (Section 21.5), while treatment with an alkyl halide by a Williamson ether
synthesis (Section 18.2) leads to the ether.

Glycoside Formation
Acetal derivatives formed when a monosaccharide reacts with an alcohol in the presence of an acid catalyst are called
glycosides. This reaction is illustrated for glucose and methanol in the diagram below. In naming of glycosides, the "ose"
suffix of the sugar name is replaced by "oside", and the alcohol group name is placed first. As is generally true for most
acetals, glycoside formation involves the loss of an equivalent of water. The diether product is stable to base and alkaline
oxidants such as Tollen's reagent. Since acid-catalyzed aldolization is reversible, glycosides may be hydrolyzed back to
their alcohol and sugar components by aqueous acid.
The anomeric methyl glucosides are formed in an equilibrium ratio of 66% alpha to 34% beta. From the structures in the
previous diagram, we see that pyranose rings prefer chair conformations in which the largest number of substituents are
equatorial. In the case of glucose, the substituents on the beta-anomer are all equatorial, whereas the C-1 substituent in the
alpha-anomer changes to axial. Since substituents on cyclohexane rings prefer an equatorial location over axial
(methoxycyclohexane is 75% equatorial), the preference for alpha-glycopyranoside formation is unexpected, and is
referred to as the anomeric effect.

Glycosides abound in biological systems. By attaching a sugar moiety to a lipid or benzenoid structure, the solubility and
other properties of the compound may be changed substantially. Because of the important modifying influence of such
derivatization, numerous enzyme systems, known as glycosidases, have evolved for the attachment and removal of sugars
from alcohols, phenols and amines. Chemists refer to the sugar component of natural glycosides as the glycon and the
alcohol component as the aglycon.
Two examples of naturally occurring glycosides and one example of an amino derivative are displayed above. Salicin, one
of the oldest herbal remedies known, was the model for the synthetic analgesic aspirin. A large class of hydroxylated,

24.8.2 12/5/2021 https://chem.libretexts.org/@go/page/32574

aromatic oxonium cations called anthocyanins provide the red, purple and blue colors of many flowers, fruits and some
vegetables. Peonin is one example of this class of natural pigments, which exhibit a pronounced pH color dependence. The
oxonium moiety is only stable in acidic environments, and the color changes or disappears when base is added. The
complex changes that occur when wine is fermented and stored are in part associated with glycosides of anthocyanins.
Finally, amino derivatives of ribose, such as cytidine play important roles in biological phosphorylating agents, coenzymes
and information transport and storage materials.

Biological Ester Formation: Phosphorylation

Recall that almost all biomolecules are charged species, which 1) keeps them water soluble, and 2) prevents them from
diffusing across lipid bilayer membranes. Although many biomolecules are ionized by virtue of negatively charged
carboxylate and positively charged amino groups, the most common ionic group in biologically important organic
compounds is phosphate - thus the phosphorylation of alcohol groups is a critical metabolic step. In alcohol
phosphorylations, ATP is almost always the phosphate donor, and the mechanism is very consistent: the alcohol oxygen
acts as a nucleophile, attacking the gamma-phosphorus of ATP and expelling ADP (look again, for example, at the glucose
kinase reaction that we first saw in section 10.1D).

Oxidation Edit section

As noted above, sugars may be classified as reducing or non-reducing based on their reactivity with Tollens', Benedict's
or Fehling's reagents. If a sugar is oxidized by these reagents it is called reducing, since the oxidant (Ag(+) or Cu(+2)) is
reduced in the reaction, as evidenced by formation of a silver mirror or precipitation of cuprous oxide. The Tollens' test is
commonly used to detect aldehyde functions; and because of the facile interconversion of ketoses and aldoses under the
basic conditions of this test, ketoses such as fructose also react and are classified as reducing sugars.
When the aldehyde function of an aldose is oxidized to a carboxylic acid the product is called an aldonic acid. Because of
the 2º hydroxyl functions that are also present in these compounds, a mild oxidizing agent such as hypobromite must be
used for this conversion (equation 1). If both ends of an aldose chain are oxidized to carboxylic acids the product is called
an aldaric acid. By converting an aldose to its corresponding aldaric acid derivative, the ends of the chain become identical
(this could also be accomplished by reducing the aldehyde to CH2OH, as noted below). Such an operation will disclose
any latent symmetry in the remaining molecule. Thus, ribose, xylose, allose and galactose yield achiral aldaric acids which
are, of course, not optically active. The ribose oxidation is shown in equation 2 below.

1.
2.

24.8.3 12/5/2021 https://chem.libretexts.org/@go/page/32574

3.

Other aldose sugars may give identical chiral aldaric acid products, implying a unique configurational relationship. The
examples of arabinose and lyxose shown in equation 3 above illustrate this result. Remember, a Fischer projection formula
may be rotated by 180º in the plane of projection without changing its configuration.

Reduction
Sodium borohydride reduction of an aldose makes the ends of the resulting alditol chain identical,
HOCH2(CHOH)nCH2OH, thereby accomplishing the same configurational change produced by oxidation to an aldaric
acid. Thus, allitol and galactitol from reduction of allose and galactose are achiral, and altrose and talose are reduced to the
same chiral alditol. A summary of these redox reactions, and derivative nomenclature is given in the following table.
Table: Derivatives of H OC H 2 (C H OH )n C H O

HOC H2 (CHOH )n C O2 H
HOBr Oxidation ⟶
an Aldonic Acid
H2 OC(CHOH )n C O2 H
HN O3 Oxidation ⟶
an Aldaric Acid
HOC H2 (CHOH )n C H2 OH
N aBH4 Reduction ⟶
an Alditol

Chain Shortening and Lengthening

1. Ruff
Degradatio
n

2.
Kiliani-
Fischer
Synthes
is

These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The
importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural
connections are given by the dashed blue lines. Thus Ruff degradation of the pentose arabinose gives the tetrose erythrose.

24.8.4 12/5/2021 https://chem.libretexts.org/@go/page/32574

Working in the opposite direction, a Kiliani-Fischer synthesis applied to arabinose gives a mixture of glucose and
mannose. An alternative chain shortening procedure known as the Wohl degradation is essentially the reverse of the
Kiliani-Fischer synthesis.
Note that in the Kiliani-Fischer synthesis the first step is to generate a cyanohydrin intermediate, which is then has its
nitrile group hydrolyzed to the carboxylic acid. From there the cyclic ester (lactone) is formed and reduced to the final
products (epimers).

Wohl Degradation
The ability to shorten (degrade) an aldose chain by one carbon was an important tool in the structure elucidation of
carbohydrates. This was commonly accomplished by the Ruff procedure. An interesting alternative technique, known as
the Wohl degradation has also been used. The following equation illustrates the application of this procedure to the
aldopentose, arabinose. Based on your knowledge of carbonyl chemistry, and considering that the Wohl degradation is in
essence the reverse of the Kiliani-Fischer synthesis.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

24.8.5 12/5/2021 https://chem.libretexts.org/@go/page/32574

24.9: Step-by-Step Buildup and Degradation of Sugars
Objectives
After completing this section, you should be able to
1. a. write equations to illustrate that the hydroxyl groups of carbohydrates can react to form esters and ethers.
b. identify the product formed when a given monosaccharide is reacted with acetic anhydride or with silver oxide
and an alkyl halide.
c. identify the reagents required to convert a given monosaccharide to its ester or ether.
2. a. write an equation to show how a monosaccharide can be converted to a glycoside using an alcohol and an acid
catalyst.
b. identify the product formed when a given monosaccharide is treated with an alcohol and an acid catalyst.
c. write a detailed mechanism for the formation of a glycoside by the reaction of the cyclic form of a
monosaccharide with an alcohol and an acid catalyst.
3. identify the ester formed by phosphorylation in biologically important compounds.
4. a. identify the product formed when a given monosaccharide is reduced with sodium borohydride.
b. identify the monosaccharide which should be reduced in order to form a given polyalcohol (alditol).
5. a. explain that a sugar with an aldehyde or hemiacetal can be oxidized to the corresponding carboxylic acid (also
known as aldonic acid). Note: The sugar is able to reduce an oxidizing agent, and is thus called a reducing
sugar. Tests for reducing sugars include the use of Tollens’ reagent, Fehling’s reagent and Benedict’s reagent.
b. explain why certain ketoses, such as fructose, behave as reducing sugars even though they do not contain an
aldehyde group.
c. identify warm HNO3 as the reagent needed to form dicarboxylic acid (an aldaric acid).
6. a. describe the chain‑lengthening effect of the Kiliani‑Fischer synthesis.
b. predict the product that would be produced by the Kiliani‑Fischer synthesis of a given aldose.
c. identify the aldose that would yield a given product following Kiliani‑Fischer synthesis.
7. a. describe the chain‑shortening effect of the Wohl degradation.
b. predict the product that would be produced by the Wohl degradation of a given aldose.
c. identify the aldose or aldoses that would yield a given product following Wohl degradation.

Key Terms
Make certain that you can define, and use in context, the key terms below.
aldaric acid
aldonic acid
alditol
aldonic acid
glycoside
Kiliani-Fischer synthesis
neighbouring group effect
reducing sugar
Wohl degradation

Study Notes

While several reactions are covered in this section, keep in mind that you have encountered them in previous sections.
The active functional groups on monosaccharides are essentially carbonyls and hydroxyls. Although they now are a
part of much larger molecules, their chemistry should be familiar.
The formation of esters and ethers is quite straightforward and should not require further clarification.

24.9.1 10/31/2021 https://chem.libretexts.org/@go/page/32575

 Note that glycosides are in fact acetals, and that glycoside formation is therefore analogous to acetal formation. To
refresh your memory about the chemistry of acetals, quickly review Section 19.10

Ester and Ether Formation

The -OH groups on a monosaccharide can be readily converted to esters and ethers. Esterfication can be done with an acid
chloride (Section 21.4) or acid anhydride (Section 21.5), while treatment with an alkyl halide by a Williamson ether
synthesis (Section 18.2) leads to the ether.

Glycoside Formation
Acetal derivatives formed when a monosaccharide reacts with an alcohol in the presence of an acid catalyst are called
glycosides. This reaction is illustrated for glucose and methanol in the diagram below. In naming of glycosides, the "ose"
suffix of the sugar name is replaced by "oside", and the alcohol group name is placed first. As is generally true for most
acetals, glycoside formation involves the loss of an equivalent of water. The diether product is stable to base and alkaline
oxidants such as Tollen's reagent. Since acid-catalyzed aldolization is reversible, glycosides may be hydrolyzed back to
their alcohol and sugar components by aqueous acid.
The anomeric methyl glucosides are formed in an equilibrium ratio of 66% alpha to 34% beta. From the structures in the
previous diagram, we see that pyranose rings prefer chair conformations in which the largest number of substituents are
equatorial. In the case of glucose, the substituents on the beta-anomer are all equatorial, whereas the C-1 substituent in the
alpha-anomer changes to axial. Since substituents on cyclohexane rings prefer an equatorial location over axial
(methoxycyclohexane is 75% equatorial), the preference for alpha-glycopyranoside formation is unexpected, and is
referred to as the anomeric effect.

Glycosides abound in biological systems. By attaching a sugar moiety to a lipid or benzenoid structure, the solubility and
other properties of the compound may be changed substantially. Because of the important modifying influence of such
derivatization, numerous enzyme systems, known as glycosidases, have evolved for the attachment and removal of sugars
from alcohols, phenols and amines. Chemists refer to the sugar component of natural glycosides as the glycon and the
alcohol component as the aglycon.
Two examples of naturally occurring glycosides and one example of an amino derivative are displayed above. Salicin, one
of the oldest herbal remedies known, was the model for the synthetic analgesic aspirin. A large class of hydroxylated,

24.9.2 10/31/2021 https://chem.libretexts.org/@go/page/32575

aromatic oxonium cations called anthocyanins provide the red, purple and blue colors of many flowers, fruits and some
vegetables. Peonin is one example of this class of natural pigments, which exhibit a pronounced pH color dependence. The
oxonium moiety is only stable in acidic environments, and the color changes or disappears when base is added. The
complex changes that occur when wine is fermented and stored are in part associated with glycosides of anthocyanins.
Finally, amino derivatives of ribose, such as cytidine play important roles in biological phosphorylating agents, coenzymes
and information transport and storage materials.

Biological Ester Formation: Phosphorylation

Recall that almost all biomolecules are charged species, which 1) keeps them water soluble, and 2) prevents them from
diffusing across lipid bilayer membranes. Although many biomolecules are ionized by virtue of negatively charged
carboxylate and positively charged amino groups, the most common ionic group in biologically important organic
compounds is phosphate - thus the phosphorylation of alcohol groups is a critical metabolic step. In alcohol
phosphorylations, ATP is almost always the phosphate donor, and the mechanism is very consistent: the alcohol oxygen
acts as a nucleophile, attacking the gamma-phosphorus of ATP and expelling ADP (look again, for example, at the glucose
kinase reaction that we first saw in section 10.1D).

Oxidation Edit section

As noted above, sugars may be classified as reducing or non-reducing based on their reactivity with Tollens', Benedict's
or Fehling's reagents. If a sugar is oxidized by these reagents it is called reducing, since the oxidant (Ag(+) or Cu(+2)) is
reduced in the reaction, as evidenced by formation of a silver mirror or precipitation of cuprous oxide. The Tollens' test is
commonly used to detect aldehyde functions; and because of the facile interconversion of ketoses and aldoses under the
basic conditions of this test, ketoses such as fructose also react and are classified as reducing sugars.
When the aldehyde function of an aldose is oxidized to a carboxylic acid the product is called an aldonic acid. Because of
the 2º hydroxyl functions that are also present in these compounds, a mild oxidizing agent such as hypobromite must be
used for this conversion (equation 1). If both ends of an aldose chain are oxidized to carboxylic acids the product is called
an aldaric acid. By converting an aldose to its corresponding aldaric acid derivative, the ends of the chain become identical
(this could also be accomplished by reducing the aldehyde to CH2OH, as noted below). Such an operation will disclose
any latent symmetry in the remaining molecule. Thus, ribose, xylose, allose and galactose yield achiral aldaric acids which
are, of course, not optically active. The ribose oxidation is shown in equation 2 below.

1.
2.

24.9.3 10/31/2021 https://chem.libretexts.org/@go/page/32575

3.

Other aldose sugars may give identical chiral aldaric acid products, implying a unique configurational relationship. The
examples of arabinose and lyxose shown in equation 3 above illustrate this result. Remember, a Fischer projection formula
may be rotated by 180º in the plane of projection without changing its configuration.

Reduction
Sodium borohydride reduction of an aldose makes the ends of the resulting alditol chain identical,
HOCH2(CHOH)nCH2OH, thereby accomplishing the same configurational change produced by oxidation to an aldaric
acid. Thus, allitol and galactitol from reduction of allose and galactose are achiral, and altrose and talose are reduced to the
same chiral alditol. A summary of these redox reactions, and derivative nomenclature is given in the following table.
Table: Derivatives of H OC H 2 (C H OH )n C H O

HOC H2 (CHOH )n C O2 H
HOBr Oxidation ⟶
an Aldonic Acid
H2 OC(CHOH )n C O2 H
HN O3 Oxidation ⟶
an Aldaric Acid
HOC H2 (CHOH )n C H2 OH
N aBH4 Reduction ⟶
an Alditol

Chain Shortening and Lengthening

1. Ruff
Degradatio
n

2.
Kiliani-
Fischer
Synthes
is

These two procedures permit an aldose of a given size to be related to homologous smaller and larger aldoses. The
importance of these relationships may be seen in the array of aldose structures presented earlier, where the structural
connections are given by the dashed blue lines. Thus Ruff degradation of the pentose arabinose gives the tetrose erythrose.

24.9.4 10/31/2021 https://chem.libretexts.org/@go/page/32575

Working in the opposite direction, a Kiliani-Fischer synthesis applied to arabinose gives a mixture of glucose and
mannose. An alternative chain shortening procedure known as the Wohl degradation is essentially the reverse of the
Kiliani-Fischer synthesis.
Note that in the Kiliani-Fischer synthesis the first step is to generate a cyanohydrin intermediate, which is then has its
nitrile group hydrolyzed to the carboxylic acid. From there the cyclic ester (lactone) is formed and reduced to the final
products (epimers).

Wohl Degradation
The ability to shorten (degrade) an aldose chain by one carbon was an important tool in the structure elucidation of
carbohydrates. This was commonly accomplished by the Ruff procedure. An interesting alternative technique, known as
the Wohl degradation has also been used. The following equation illustrates the application of this procedure to the
aldopentose, arabinose. Based on your knowledge of carbonyl chemistry, and considering that the Wohl degradation is in
essence the reverse of the Kiliani-Fischer synthesis.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

24.9.5 10/31/2021 https://chem.libretexts.org/@go/page/32575

24.10: Relative Configurations of the Aldoses: An Exercise in Structure
Determination
Objectives

After completing this section, you should be able to

1. identify disaccharides as compounds consisting of two monosaccharide units joined by a glycoside link between
the C1 of one sugar and one of the hydroxyl groups of a second sugar.
2. identify the two monosaccharide units in a given disaccharide.
3. identify the type of glycoside link (e.g., 1,4′‑β) present in a given disaccharide structure.
4. draw the structure of a specific disaccharide, given the structure of the monosaccharide units and the type of
glycoside link involved.
Note: If α‑ or β‑D‑glucose were one of the monosaccharide units, its structure would not be provided.
5. identify the structural feature that determines whether or not a given disaccharide behaves as a reducing sugar and
undergoes mutarotation, and write equations to illustrate these phenomena.
6. identify the products formed from the hydrolysis of a given disaccharide.

Key Terms
Make certain that you can define, and use in context, the key terms below.
1,4′ link
disaccharide (see Section 25.1)
invert sugar

Study Notes
Notice that most of the disaccharides discussed in this section contain one unit of D-glucose. You are not expected to
remember the detailed structures of maltose, lactose and sucrose. Similarly, we do not expect you to remember the
systematic names of these substances.

Previously, you learned that monosaccharides can form cyclic structures by the reaction of the carbonyl group with an OH
group. These cyclic molecules can in turn react with another alcohol. Disaccharides (C12H22O11) are sugars composed of
two monosaccharide units that are joined by a carbon–oxygen-carbon linkage known as a glycosidic linkage. This linkage
is formed from the reaction of the anomeric carbon of one cyclic monosaccharide with the OH group of a second
monosaccharide.

24.10.1 11/28/2021 https://chem.libretexts.org/@go/page/32576

The disaccharides differ from one another in their monosaccharide constituents and in the specific type of glycosidic
linkage connecting them. There are three common disaccharides: maltose, lactose, and sucrose. All three are white
crystalline solids at room temperature and are soluble in water. We’ll consider each sugar in more detail.

Maltose
Maltose occurs to a limited extent in sprouting grain. It is formed most often by the partial hydrolysis of starch and
glycogen. In the manufacture of beer, maltose is liberated by the action of malt (germinating barley) on starch; for this
reason, it is often referred to as malt sugar. Maltose is about 30% as sweet as sucrose. The human body is unable to
metabolize maltose or any other disaccharide directly from the diet because the molecules are too large to pass through the
cell membranes of the intestinal wall. Therefore, an ingested disaccharide must first be broken down by hydrolysis into its
two constituent monosaccharide units. In the body, such hydrolysis reactions are catalyzed by enzymes such as maltase.
The same reactions can be carried out in the laboratory with dilute acid as a catalyst, although in that case the rate is much
slower, and high temperatures are required. Whether it occurs in the body or a glass beaker, the hydrolysis of maltose
produces two molecules of D-glucose.
+
H or maltase

maltose −−−−−−−−→ 2 D-glucose (24.10.1)

Maltose is a reducing sugar. Thus, its two glucose molecules must be linked in such a way as to leave one anomeric carbon
that can open to form an aldehyde group. The glucose units in maltose are joined in a head-to-tail fashion through an α-
linkage from the first carbon atom of one glucose molecule to the fourth carbon atom of the second glucose molecule (that
is, an α-1,4-glycosidic linkage; see Figure 1). The bond from the anomeric carbon of the first monosaccharide unit is
directed downward, which is why this is known as an α-glycosidic linkage. The OH group on the anomeric carbon of the
second glucose can be in either the α or the β position, as shown in Figure 1.

Figure 1 An Equilibrium Mixture of Maltose Isomers

Lactose
Lactose is known as milk sugar because it occurs in the milk of humans, cows, and other mammals. In fact, the natural
synthesis of lactose occurs only in mammary tissue, whereas most other carbohydrates are plant products. Human milk
contains about 7.5% lactose, and cow’s milk contains about 4.5%. This sugar is one of the lowest ranking in terms of
sweetness, being about one-sixth as sweet as sucrose. Lactose is produced commercially from whey, a by-product in the
manufacture of cheese. It is important as an infant food and in the production of penicillin.
Lactose is a reducing sugar composed of one molecule of D-galactose and one molecule of D-glucose joined by a β-1,4-
glycosidic bond (the bond from the anomeric carbon of the first monosaccharide unit being directed upward). The two
monosaccharides are obtained from lactose by acid hydrolysis or the catalytic action of the enzyme lactase:

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Many adults and some children suffer from a deficiency of lactase. These individuals are said to be lactose intolerant
because they cannot digest the lactose found in milk. A more serious problem is the genetic disease galactosemia, which
results from the absence of an enzyme needed to convert galactose to glucose. Certain bacteria can metabolize lactose,
forming lactic acid as one of the products. This reaction is responsible for the “souring” of milk.

Example 1

For this trisaccharide, indicate whether each glycosidic linkage is α or β.

Solution
The glycosidic linkage between sugars 1 and 2 is β because the bond is directed up from the anomeric carbon. The
glycosidic linkage between sugars 2 and 3 is α because the bond is directed down from the anomeric carbon.

To Your Health: Lactose Intolerance and Galactosemia

Lactose makes up about 40% of an infant’s diet during the first year of life. Infants and small children have one form
of the enzyme lactase in their small intestines and can digest the sugar easily; however, adults usually have a less
active form of the enzyme, and about 70% of the world’s adult population has some deficiency in its production. As a
result, many adults experience a reduction in the ability to hydrolyze lactose to galactose and glucose in their small
intestine. For some people the inability to synthesize sufficient enzyme increases with age. Up to 20% of the US
population suffers some degree of lactose intolerance.
In people with lactose intolerance, some of the unhydrolyzed lactose passes into the colon, where it tends to draw
water from the interstitial fluid into the intestinal lumen by osmosis. At the same time, intestinal bacteria may act on
the lactose to produce organic acids and gases. The buildup of water and bacterial decay products leads to abdominal
distention, cramps, and diarrhea, which are symptoms of the condition.
The symptoms disappear if milk or other sources of lactose are excluded from the diet or consumed only sparingly.
Alternatively, many food stores now carry special brands of milk that have been pretreated with lactase to hydrolyze
the lactose. Cooking or fermenting milk causes at least partial hydrolysis of the lactose, so some people with lactose
intolerance are still able to enjoy cheese, yogurt, or cooked foods containing milk. The most common treatment for
lactose intolerance, however, is the use of lactase preparations (e.g., Lactaid), which are available in liquid and tablet

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 form at drugstores and grocery stores. These are taken orally with dairy foods—or may be added to them directly—to
assist in their digestion.
Galactosemia is a condition in which one of the enzymes needed to convert galactose to glucose is missing.
Consequently, the blood galactose level is markedly elevated, and galactose is found in the urine. An infant with
galactosemia experiences a lack of appetite, weight loss, diarrhea, and jaundice. The disease may result in impaired
liver function, cataracts, mental retardation, and even death. If galactosemia is recognized in early infancy, its effects
can be prevented by the exclusion of milk and all other sources of galactose from the diet. As a child with
galactosemia grows older, he or she usually develops an alternate pathway for metabolizing galactose, so the need to
restrict milk is not permanent. The incidence of galactosemia in the United States is 1 in every 65,000 newborn babies.

Sucrose
Sucrose, probably the largest-selling pure organic compound in the world, is known as beet sugar, cane sugar, table sugar,
or simply sugar. Most of the sucrose sold commercially is obtained from sugar cane and sugar beets (whose juices are
14%–20% sucrose) by evaporation of the water and recrystallization. The dark brown liquid that remains after the
recrystallization of sugar is sold as molasses.
The sucrose molecule is unique among the common disaccharides in having an α-1,β-2-glycosidic (head-to-head) linkage.
Because this glycosidic linkage is formed by the OH group on the anomeric carbon of α-D-glucose and the OH group on
the anomeric carbon of β-D-fructose, it ties up the anomeric carbons of both glucose and fructose.

This linkage gives sucrose certain properties that are quite different from those of maltose and lactose. As long as the
sucrose molecule remains intact, neither monosaccharide “uncyclizes” to form an open-chain structure. Thus, sucrose is
incapable of mutarotation and exists in only one form both in the solid state and in solution. In addition, sucrose does not
undergo reactions that are typical of aldehydes and ketones. Therefore, sucrose is a nonreducing sugar.
The hydrolysis of sucrose in dilute acid or through the action of the enzyme sucrase (also known as invertase) gives an
equimolar mixture of glucose and fructose. This 1:1 mixture is referred to as invert sugar because it rotates plane-polarized
light in the opposite direction than sucrose. The hydrolysis reaction has several practical applications. Sucrose readily
recrystallizes from a solution, but invert sugar has a much greater tendency to remain in solution. In the manufacture of
jelly and candy and in the canning of fruit, the recrystallization of sugar is undesirable. Therefore, conditions leading to the
hydrolysis of sucrose are employed in these processes. Moreover, because fructose is sweeter than sucrose, the hydrolysis
adds to the sweetening effect. Bees carry out this reaction when they make honey.
The average American consumes more than 100 lb of sucrose every year. About two-thirds of this amount is ingested in
soft drinks, presweetened cereals, and other highly processed foods. The widespread use of sucrose is a contributing factor
to obesity and tooth decay. Carbohydrates such as sucrose, are converted to fat when the caloric intake exceeds the body’s
requirements, and sucrose causes tooth decay by promoting the formation of plaque that sticks to teeth.

Summary
Maltose is composed of two molecules of glucose joined by an α-1,4-glycosidic linkage. It is a reducing sugar that is found
in sprouting grain. Lactose is composed of a molecule of galactose joined to a molecule of glucose by a β-1,4-glycosidic
linkage. It is a reducing sugar that is found in milk. Sucrose is composed of a molecule of glucose joined to a molecule of
fructose by an α-1,β-2-glycosidic linkage. It is a nonreducing sugar that is found in sugar cane and sugar beets.

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Concept Review Exercise
1. What monosaccharides are obtained by the hydrolysis of each disaccharide?
a. sucrose
b. maltose
c. lactose

Answer
1. a. D-glucose and D-fructose
b. two molecules of D-glucose
c. D-glucose and D-galactose

Exercises
1. Identify each sugar by its common chemical name.
a. milk sugar
b. table sugar
2. For each disaccharide, indicate whether the glycosidic linkage is α or β.

a.

b.
3. Identify each disaccharide in Exercise 2 as a reducing or nonreducing sugar. If it is a reducing sugar, draw its structure
and circle the anomeric carbon. State if the OH group at the anomeric carbon is in the α or the β position
4. Melibiose is a disaccharide that occurs in some plant juices. Its structure is as follows:

a. What monosaccharide units are incorporated into melibiose?

b. What type of linkage (α or β) joins the two monosaccharide units of melibiose?
c. Melibiose has a free anomeric carbon and is thus a reducing sugar. Circle the anomeric carbon and indicate whether
the OH group is α or β

Answers
1. a. lactose
b. sucrose

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 2. a.

2. b.
3. a. nonreducing
3. b. reducing

4. a. galactose and glucose

4. b.α-glycosidic linkage

4. c.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
The Basics of General, Organic, and Biological Chemistry by David W. Ball, John W. Hill, and Rhonda J. Scott.

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24.11: Complex Sugars in Nature: Disaccharides
Objectives
After completing this section, you should be able to
1. identify the structural difference between cellulose and the cold‑water‑insoluble fraction of starch (amylose), and
identify both of these substances as containing many glucose molecules joined by 1,4′‑glycoside links.
2. identify the cold‑water‑soluble fraction of starch (amylopectin) as having a more complex structure than amylose
because of the existence of 1,6′‑glycoside links in addition to the 1,4′‑links.
3. compare and contrast the structures and uses of starch, glycogen and cellulose.

Key Terms
Make certain that you can define, and use in context, the key terms below.
amylopectin
amylose
polysaccharide

Learning Objectives
To compare and contrast the structures and uses of starch, glycogen, and cellulose.

The polysaccharides are the most abundant carbohydrates in nature and serve a variety of functions, such as energy storage
or as components of plant cell walls. Polysaccharides are very large polymers composed of tens to thousands of
monosaccharides joined together by glycosidic linkages. The three most abundant polysaccharides are starch, glycogen,
and cellulose. These three are referred to as homopolymers because each yields only one type of monosaccharide (glucose)
after complete hydrolysis. Heteropolymers may contain sugar acids, amino sugars, or noncarbohydrate substances in
addition to monosaccharides. Heteropolymers are common in nature (gums, pectins, and other substances) but will not be
discussed further in this textbook. The polysaccharides are nonreducing carbohydrates, are not sweet tasting, and do not
undergo mutarotation.

Starch
Starch is the most important source of carbohydrates in the human diet and accounts for more than 50% of our
carbohydrate intake. It occurs in plants in the form of granules, and these are particularly abundant in seeds (especially the
cereal grains) and tubers, where they serve as a storage form of carbohydrates. The breakdown of starch to glucose
nourishes the plant during periods of reduced photosynthetic activity. We often think of potatoes as a “starchy” food, yet
other plants contain a much greater percentage of starch (potatoes 15%, wheat 55%, corn 65%, and rice 75%). Commercial
starch is a white powder.
Starch is a mixture of two polymers: amylose and amylopectin. Natural starches consist of about 10%–30% amylose and
70%–90% amylopectin. Amylose is a linear polysaccharide composed entirely of D-glucose units joined by the α-1,4-
glycosidic linkages we saw in maltose (part (a) of Figure 24.11.1). Experimental evidence indicates that amylose is not a
straight chain of glucose units but instead is coiled like a spring, with six glucose monomers per turn (part (b) of Figure
24.11.1). When coiled in this fashion, amylose has just enough room in its core to accommodate an iodine molecule. The

characteristic blue-violet color that appears when starch is treated with iodine is due to the formation of the amylose-iodine
complex. This color test is sensitive enough to detect even minute amounts of starch in solution.

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 Figure 24.11.1: Amylose. (a) Amylose is a linear chain of α-D-glucose units joined together by α-1,4-glycosidic bonds. (b)
Because of hydrogen bonding, amylose acquires a spiral structure that contains six glucose units per turn.
Amylopectin is a branched-chain polysaccharide composed of glucose units linked primarily by α-1,4-glycosidic bonds but
with occasional α-1,6-glycosidic bonds, which are responsible for the branching. A molecule of amylopectin may contain
many thousands of glucose units with branch points occurring about every 25–30 units (Figure 24.11.2). The helical
structure of amylopectin is disrupted by the branching of the chain, so instead of the deep blue-violet color amylose gives
with iodine, amylopectin produces a less intense reddish brown.

Figure 24.11.2: Representation of the Branching in Amylopectin and Glycogen. Both amylopectin and glycogen contain
branch points that are linked through α-1,6-linkages. These branch points occur more often in glycogen.
Dextrins are glucose polysaccharides of intermediate size. The shine and stiffness imparted to clothing by starch are due to
the presence of dextrins formed when clothing is ironed. Because of their characteristic stickiness with wetting, dextrins
are used as adhesives on stamps, envelopes, and labels; as binders to hold pills and tablets together; and as pastes. Dextrins
are more easily digested than starch and are therefore used extensively in the commercial preparation of infant foods.
The complete hydrolysis of starch yields, in successive stages, glucose:
starch → dextrins → maltose → glucose
In the human body, several enzymes known collectively as amylases degrade starch sequentially into usable glucose units.

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Glycogen
Glycogen is the energy reserve carbohydrate of animals. Practically all mammalian cells contain some stored
carbohydrates in the form of glycogen, but it is especially abundant in the liver (4%–8% by weight of tissue) and in
skeletal muscle cells (0.5%–1.0%). Like starch in plants, glycogen is found as granules in liver and muscle cells. When
fasting, animals draw on these glycogen reserves during the first day without food to obtain the glucose needed to
maintain metabolic balance.
Glycogen is structurally quite similar to amylopectin, although glycogen is more highly branched (8–12 glucose units
between branches) and the branches are shorter. When treated with iodine, glycogen gives a reddish brown color.
Glycogen can be broken down into its D-glucose subunits by acid hydrolysis or by the same enzymes that catalyze the
breakdown of starch. In animals, the enzyme phosphorylase catalyzes the breakdown of glycogen to phosphate esters
of glucose.

About 70% of the total glycogen in the body is stored in muscle cells. Although
the percentage of glycogen (by weight) is higher in the liver, the much greater
mass of skeletal muscle stores a greater total amount of glycogen.

Cellulose
Cellulose, a fibrous carbohydrate found in all plants, is the structural component of plant cell walls. Because the earth
is covered with vegetation, cellulose is the most abundant of all carbohydrates, accounting for over 50% of all the
carbon found in the vegetable kingdom. Cotton fibrils and filter paper are almost entirely cellulose (about 95%), wood
is about 50% cellulose, and the dry weight of leaves is about 10%–20% cellulose. The largest use of cellulose is in the
manufacture of paper and paper products. Although the use of noncellulose synthetic fibers is increasing, rayon (made
from cellulose) and cotton still account for over 70% of textile production.
Like amylose, cellulose is a linear polymer of glucose. It differs, however, in that the glucose units are joined by β-1,4-
glycosidic linkages, producing a more extended structure than amylose (part (a) of Figure 24.11.3). This extreme
linearity allows a great deal of hydrogen bonding between OH groups on adjacent chains, causing them to pack closely
into fibers (part (b) of Figure 24.11.3). As a result, cellulose exhibits little interaction with water or any other solvent.
Cotton and wood, for example, are completely insoluble in water and have considerable mechanical strength. Because
cellulose does not have a helical structure, it does not bind to iodine to form a colored product.

Figure 24.11.3: Cellulose. (a) There is extensive hydrogen bonding in the structure of cellulose. (b) In this electron
micrograph of the cell wall of an alga, the wall consists of successive layers of cellulose fibers in parallel arrangement.

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Cellulose yields D-glucose after complete acid hydrolysis, yet humans are unable to metabolize cellulose as a source of
glucose. Our digestive juices lack enzymes that can hydrolyze the β-glycosidic linkages found in cellulose, so although
we can eat potatoes, we cannot eat grass. However, certain microorganisms can digest cellulose because they make the
enzyme cellulase, which catalyzes the hydrolysis of cellulose. The presence of these microorganisms in the digestive
tracts of herbivorous animals (such as cows, horses, and sheep) allows these animals to degrade the cellulose from
plant material into glucose for energy. Termites also contain cellulase-secreting microorganisms and thus can subsist on
a wood diet. This example once again demonstrates the extreme stereospecificity of biochemical processes.

Career Focus: Certified Diabetes Educator

Certified diabetes educators come from a variety of health professions, such as nursing and dietetics, and specialize
in the education and treatment of patients with diabetes. A diabetes educator will work with patients to manage
their diabetes. This involves teaching the patient to monitor blood sugar levels, make good food choices, develop
and maintain an exercise program, and take medication, if required.

A certified diabetes educator at Naval Medical Center Portsmouth (left) and a registered dietician at the medical
center (center), provide nutritional information to a diabetes patient and her mother at the Diabetes Boot Camp.
Diabetes educators also work with hospital or nursing home staff to improve the care of diabetic patients.
Educators must be willing to spend time attending meetings and reading the current literature to maintain their
knowledge of diabetes medications, nutrition, and blood monitoring devices so that they can pass this information
to their patients.

Summary
Starch is a storage form of energy in plants. It contains two polymers composed of glucose units: amylose (linear) and
amylopectin (branched). Glycogen is a storage form of energy in animals. It is a branched polymer composed of
glucose units. It is more highly branched than amylopectin. Cellulose is a structural polymer of glucose units found in
plants. It is a linear polymer with the glucose units linked through β-1,4-glycosidic bonds.

Concept Review Exercises

Answers

Exercises

Answers

1. What purposes do starch and cellulose serve in plants?

2. What purpose does glycogen serve in animals?
3. Starch is the storage form of glucose (energy) in plants, while cellulose is a structural component of the plant cell
wall.
4. Glycogen is the storage form of glucose (energy) in animals.

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 5. What monosaccharide is obtained from the hydrolysis of each carbohydrate?
a. starch
b. cellulose
c. glycogen
6. For each carbohydrate listed in Exercise 1, indicate whether it is found in plants or mammals.
7. Describe the similarities and differences between amylose and cellulose.
8. Describe the similarities and differences between amylopectin and glycogen.
9. a. glucose
b. glucose
c. glucose
10. Amylose and cellulose are both linear polymers of glucose units, but the glycosidic linkages between the glucose
units differ. The linkages in amylose are α-1,4-glycosidic linkages, while the linkages in cellulose they are β-1,4-
glycosidic linkages.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
Anonymous by request
The Basics of General, Organic, and Biological Chemistry by David W. Ball, John W. Hill, and Rhonda J. Scott.

Objectives

You may omit Section 25.11.

Carbohydrates are covalently attached to many different biomolecules, including lipids, to form glycolipids, and proteins,
to form glycoproteins. Glycoproteins and glycolipids are often found in biological membranes, to which they are anchored
by through nonpolar interactions. A special kind of glycoprotein, a proteoglycan, actually has more carbohydrate mass
than protein. What is the function of these carbohydrates? Two are apparent. First, glycosylation of proteins helps protect
the protein from degradation by enzyme catalysts within the body. However, there main functions arises from the fact that
covalently attached carbohydrates that "decorate" the surface of glycoproteins or glycolipids provide new binding site
interactions that allow interactions with other biomolecules. Hence glycosylation allows for cell:cell, cell:protein, or
protein:protein interactions. Unfortunately, bacteria and viruses often recognize glycosylated molecules on cell
membranes, allowing for their import into the cell.
Here are some "cartoon" examples of carbohydrates covalently linked to the amino acid asparagine (Asn) on a
glycoprotein.

Here are some examples of biomolecular interactions promoted by IMFs involving carbohydrates.
Influenza Virus binding to Cell Surface Glycoproteins with Neu5Ac - A protein on the surface of influenza virus,
hemagluttinin, bind to sialic acid (Sia), which is covalently attached to many cell membrane glycoproteins on host cells.
The sialic acid is usually connected through an alpha (2,3) or alpha (2,6) link to galactose on N-linked glycoproteins. The
subtypes found in avian (and equine) influenza isolates bind preferentially to Sia (alpha 2,3) Gal which predominates in
avian GI tract where viruses replicate. Human virus of H1, H2, and H3 subtype (cause of the 1918, 1957, and 1968
pandemics) recognize Sia (alpha 2,6) Gal, the major form in human respiratory tract. The swine influenza HA bind to Sia
(alpha 2,6) Gal and some Sia (alpha 2,3)both of which found in swine.

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 Jmol model of viral hemagluttinin bound to antiviral drugs and sialic (neuraminic acid) from Proteopedia
Leukocyte: Cell Wall binding - During inflammation, circulating leukocytes (a type of white blood cell) tether and roll on
the walls of blood vessels where they become active. E-, L- and P-selectin proteins are the primary proteins responsible for
the tethering and rolling of these leukocytes. P-selectin binds, in part, to a tetrasaccharide, sialyl-Lewisx (SLEX) on the
cell surface.. The interaction between P-selectin and the cell mediates the initial binding/rolling of the leukocyte on the
vessel wall.
Jmol model of P-selectin binding to tetrasaccharide

Contributors and Attributions

Prof. Steven Farmer (Sonoma State University)
Chris P Schaller, Ph.D., (College of Saint Benedict / Saint John's University)

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24.12: Polysaccharides and Other Sugars in Nature

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CHAPTER OVERVIEW
25: HETEROCYCLES: HETEROATOMS IN CYCLIC ORGANIC COMPOUNDS
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

Thumbnail: Ball-and-stick model of the tetrahydrofuran molecule. (Public Domain; Ben Mills).

25.1: NAMING THE HETEROCYCLES

25.2: NONAROMATIC HETEROCYCLES
25.3: STRUCTURE AND PROPERTIES OF AROMATIC HETEROCYCLOPENTADIENES
25.4: REACTIONS OF THE AROMATIC HETEROCYCLOPENTADIENES
25.5: STRUCTURE AND PREPARATION OF PYRIDINE: AN AZABENZENE
25.6: REACTIONS OF PYRIDINE
25.7: QUINOLINE AND ISOQUINOLINE: THE BENZOPYRIDINES
25.8: ALKALOIDS: PHYSIOLOGICALLY POTENT NITROGEN HETEROCYCLES IN NATURE

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25.1: Naming the Heterocycles

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25.2: Nonaromatic Heterocycles

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25.3: Structure and Properties of Aromatic Heterocyclopentadienes

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25.4: Reactions of the Aromatic Heterocyclopentadienes
☰

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25.5: Structure and Preparation of Pyridine: An Azabenzene
☰

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25.6: Reactions of Pyridine
☰

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25.7: Quinoline and Isoquinoline: The Benzopyridines

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25.8: Alkaloids: Physiologically Potent Nitrogen Heterocycles in Nature

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CHAPTER OVERVIEW
26: AMINO ACIDS, PEPTIDES, PROTEINS, AND NUCLEIC ACIDS: NITROGEN-
CONTAINING POLYMERS IN NATURE
An organic chemistry Textmap organized around the textbook
Organic Chemistry
by Peter Vollhardt and Neil Schore

26.1: STRUCTURE AND PROPERTIES OF AMINO ACIDS

26.2: SYNTHESIS OF AMINO ACIDS: A COMBINATION OF AMINE AND CARBOXYLIC ACID CHEMISTRY
26.3: SYNTHESIS OF ENANTIOMERICALLY PURE AMINO ACIDS
26.4: PEPTIDES AND PROTEINS: AMINO ACID OLIGOMERS AND POLYMERS
26.5: DETERMINATION OF PRIMARY STRUCTURE: AMINO ACID SEQUENCING
26.6: SYNTHESIS OF POLYPEPTIDES: A CHALLENGE IN THE APPLICATION OF PROTECTING GROUPS
26.7: MERRIFIELD SOLID-PHASE PEPTIDE SYNTHESIS
26.8: POLYPEPTIDES IN NATURE: OXYGEN TRANSPORT BY THE PROTEINS MYOGLOBIN AND HEMOGLOBIN
26.9: BIOSYNTHESIS OF PROTEINS: NUCLEIC ACIDS
26.10: PROTEIN SYNTHESIS THROUGH RNA
26.11: DNA SEQUENCING AND SYNTHESIS: CORNERSTONES OF GENE TECHNOLOGY

1 12/5/2021
26.1: Structure and Properties of Amino Acids
Objectives
After completing this section, you should be able to
1. identify the structural features present in the 20 amino acids commonly found in proteins.
Note: You are not expected to remember the detailed structures of all these amino acids, but you should be
prepared to draw the structures of the two simplest members, glycine and alanine.
2. draw the Fischer projection formula of a specified enantiomer of a given amino acid.
Note: To do so, you must remember that in the S enantiomer, the carboxyl group appears at the top of the
projection formula and the amino group is on the left.
3. classify an amino acid as being acidic, basic or neutral, given its Kekulé, condensed or shorthand structure.
4. draw the zwitterion form of a given amino acid.
5. account for some of the typical properties of amino acids (e.g., high melting points, solubility in water) in terms of
zwitterion formation.
6. write appropriate equations to illustrate the amphoteric nature of amino acids.

Key Terms

Make certain that you can define, and use in context, the key terms below.
α‑amino acids
amphoteric
essential amino acids
zwitterion

Study Notes
This is a good point at which to review some of the principles of stereochemistry presented in Chapter 5. Be sure to
make full use of molecular models when any stereochemical issues arise.
You should recognize that a three‑letter shorthand code is often used to represent individual amino acids. You need not
memorize this code.
The distinction between essential and nonessential amino acids is not as clear‑cut as one might suppose. For example,
arginine is often regarded as being nonessential.

Introduction to Amino Acids

Amino acids form polymers through a nucleophilic attack by the amino group of an amino acid at the electrophilic
carbonyl carbon of the carboxyl group of another amino acid. The carboxyl group of the amino acid must first be activated
to provide a better leaving group than OH-. (We will discuss this activation by ATP later in the course.) The resulting link
between the amino acids is an amide link which biochemists call a peptide bond. In this reaction, water is released. In a
reverse reaction, the peptide bond can be cleaved by water (hydrolysis).
Structure and Property of the Naturally-Occurring Amino Acids (Too large to include in text: print separately)
When two amino acids link together to form an amide link, the resulting structure is called a dipeptide. Likewise, we can
have tripeptides, tetrapeptides, and other polypeptides. At some point, when the structure is long enough, it is called a
protein. There are many different ways to represent the structure of a polypeptide or protein, each showing differing
amounts of information.
Figure: Different Representations of a Polypeptide (Heptapeptide)

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 Figure: Amino Acids React to Form Proteins

(Note: above picture represents the amino acid in an unlikely protonation state with the weak acid protonated and the weak
base deprotonated for simplicity in showing removal of water on peptide bond formation and the hydrolysis reaction.)
Proteins are polymers of twenty naturally occurring amino acids. In contrast, nucleic acids are polymers of just 4 different
monomeric nucleotides. Both the sequence of a protein and its total length differentiate one protein from another. Just for
an octapeptide, there are over 25 billion different possible arrangements of amino acids. Compare this to just 65536
different oligonucleotides of 8 monomeric units (8mer). Hence the diversity of possible proteins is enormous.

Stereochemistry
The amino acids are all chiral, with the exception of glycine, whose side chain is H. As with lipids, biochemists use the L
and D nomenclature. All naturally occuring proteins from all living organisms consist of L amino acids. The absolute
stereochemistry is related to L-glyceraldehyde, as was the case for triacylglycerides and phospholipids. Most naturally
occurring chiral amino acids are S, with the exception of cysteine. As the diagram below shows, the absolute configuration
of the amino acids can be shown with the H pointed to the rear, the COOH groups pointing out to the left, the R group to
the right, and the NH3 group upwards. You can remember this with the anagram CORN.
Figure: Stereochemistry of Amino Acids.

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Why do biochemists still use D and L for sugars and amino acids? This explanation (taken from the link below) seems
reasonable.
"In addition, however, chemists often need to define a configuration unambiguously in the absence of any reference
compound, and for this purpose the alternative (R,S) system is ideal, as it uses priority rules to specify configurations.
These rules sometimes lead to absurd results when they are applied to biochemical molecules. For example, as we have
seen, all of the common amino acids are L, because they all have exactly the same structure, including the position of the R
group if we just write the R group as R. However, they do not all have the same configuration in the (R,S) system: L-
cysteine is also (R)-cysteine, but all the other L-amino acids are (S), but this just reflects the human decision to give a
sulphur atom higher priority than a carbon atom, and does not reflect a real difference in configuration. Worse problems
can sometimes arise in substitution reactions: sometimes inversion of configuration can result in no change in the (R) or
(S) prefix; and sometimes retention of configuration can result in a change of prefix.
It follows that it is not just conservatism or failure to understand the (R,S) system that causes biochemists to continue with
D and L: it is just that the DL system fulfils their needs much better. As mentioned, chemists also use D and L when they
are appropriate to their needs. The explanation given above of why the (R,S) system is little used in biochemistry is thus
almost the exact opposite of reality. This system is actually the only practical way of unambiguously representing the
stereochemistry of complicated molecules with several asymmetric centres, but it is inconvenient with regular series of
molecules like amino acids and simple sugars. "

Natural α-Amino Acids

Hydrolysis of proteins by boiling aqueous acid or base yields an assortment of small molecules identified as α-
aminocarboxylic acids. More than twenty such components have been isolated, and the most common of these are listed in
the following table. Those amino acids having green colored names are essential diet components, since they are not
synthesized by human metabolic processes. The best food source of these nutrients is protein, but it is important to
recognize that not all proteins have equal nutritional value. For example, peanuts have a higher weight content of protein
than fish or eggs, but the proportion of essential amino acids in peanut protein is only a third of that from the two other
sources. For reasons that will become evident when discussing the structures of proteins and peptides, each amino acid is
assigned a one or three letter abbreviation.

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Natural α-Amino Acids

Some common features of these amino acids should be noted. With the exception of proline, they are all 1º-
amines; and with the exception of glycine, they are all chiral. The configurations of the chiral amino acids are
the same when written as a Fischer projection formula, as in the drawing on the right, and this was defined as
the L-configuration by Fischer. The R-substituent in this structure is the remaining structural component that varies from
one amino acid to another, and in proline R is a three-carbon chain that joins the nitrogen to the alpha-carbon in a five-
membered ring. Applying the Cahn-Ingold-Prelog notation, all these natural chiral amino acids, with the exception of
cysteine, have an S-configuration. For the first seven compounds in the left column the R-substituent is a hydrocarbon. The
last three entries in the left column have hydroxyl functional groups, and the first two amino acids in the right column
incorporate thiol and sulfide groups respectively. Lysine and arginine have basic amine functions in their side-chains;
histidine and tryptophan have less basic nitrogen heterocyclic rings as substituents. Finally, carboxylic acid side-chains are
substituents on aspartic and glutamic acid, and the last two compounds in the right column are their corresponding amides.
The formulas for the amino acids written above are simple covalent bond representations based upon previous
understanding of mono-functional analogs. The formulas are in fact incorrect. This is evident from a comparison of the
physical properties listed in the following table. All four compounds in the table are roughly the same size, and all have
moderate to excellent water solubility. The first two are simple carboxylic acids, and the third is an amino alcohol. All
three compounds are soluble in organic solvents (e.g. ether) and have relatively low melting points. The carboxylic acids
have pKa's near 4.5, and the conjugate acid of the amine has a pKa of 10. The simple amino acid alanine is the last entry.
By contrast, it is very high melting (with decomposition), insoluble in organic solvents, and a million times weaker as an
acid than ordinary carboxylic acids.

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Physical Properties of Selected Acids and Amines
Solubility in
Compound Formula Mol.Wt. Solubility in Ether Melting Point pKa
Water

isobutyric acid (CH3)2CHCO2H 88 20g/100mL complete -47 ºC 5.0

CH3CH(OH)CO2
lactic acid 90 complete complete 53 ºC 3.9
H
3-amino-2- CH3CH(NH2)CH(
89 complete complete 9 ºC 10.0
butanol OH)CH3
CH3CH(NH2)CO2
alanine 89 18g/100mL insoluble ca. 300 ºC 9.8
H

Zwitterion
These differences above all point to internal salt formation by a proton transfer from the acidic carboxyl function to the
basic amino group. The resulting ammonium carboxylate structure, commonly referred to as a zwitterion, is also
supported by the spectroscopic characteristics of alanine.

CH3CH(NH2)CO2H CH3CH(NH3)(+)CO2(–)

As expected from its ionic character, the alanine zwitterion is high melting, insoluble in nonpolar solvents and has the acid
strength of a 1º-ammonium ion. Examples of a few specific amino acids may also be viewed in their favored neutral
zwitterionic form. Note that in lysine the amine function farthest from the carboxyl group is more basic than the alpha-
amine. Consequently, the positively charged ammonium moiety formed at the chain terminus is attracted to the negative
carboxylate, resulting in a coiled conformation.
The structure of an amino acid allows it to act as both an acid and a base. An amino acid has this ability because at a
certain pH value (different for each amino acid) nearly all the amino acid molecules exist as zwitterions. If acid is added to
a solution containing the zwitterion, the carboxylate group captures a hydrogen (H+) ion, and the amino acid becomes
positively charged. If base is added, ion removal of the H+ ion from the amino group of the zwitterion produces a
negatively charged amino acid. In both circumstances, the amino acid acts to maintain the pH of the system—that is, to
remove the added acid (H+) or base (OH−) from solution.

Example 26.1
a. Draw the structure for the anion formed when glycine (at neutral pH) reacts with a base.
b. Draw the structure for the cation formed when glycine (at neutral pH) reacts with an acid.
Solution
a. The base removes H+ from the protonated amine group.

b. The acid adds H+ to the carboxylate group.

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Other Natural Amino Acids
The twenty alpha-amino acids listed above are the primary components of proteins, their incorporation being governed by
the genetic code. Many other naturally occurring amino acids exist, and the structures of a few of these are displayed
below. Some, such as hydroxylysine and hydroxyproline, are simply functionalized derivatives of a previously described
compound. These two amino acids are found only in collagen, a common structural protein. Homoserine and homocysteine
are higher homologs of their namesakes. The amino group in beta-alanine has moved to the end of the three-carbon chain.
It is a component of pantothenic acid, HOCH2C(CH3)2CH(OH)CONHCH2CH2CO2H, a member of the vitamin B complex
and an essential nutrient. Acetyl coenzyme A is a pyrophosphorylated derivative of a pantothenic acid amide. The gamma-
amino homolog GABA is a neurotransmitter inhibitor and antihypertensive agent.

Many unusual amino acids, including D-enantiomers of some common acids, are produced by microorganisms. These
include ornithine, which is a component of the antibiotic bacitracin A, and statin, found as part of a pentapeptide that
inhibits the action of the digestive enzyme pepsin.

Exercises
Questions
Q26.1.1
Why is cysteine the only L amino acid with an R configuration at the alpha carbon?
Q26.1.2
Isoleucine has two stereogenic centers.
(a) Draw a Fischer projection of isoleucine.
(b) Draw a Fischer projection of an isoleucine diastereomer, and label each stereocenter as R or S.
Solutions
S26.1.1
The sulfur atom in the side chain causes the side chain to have higher priority than the other substituents.
S26.1.2
(a)

(b)

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Contributors and Attributions
Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Prof. Henry Jakubowski (College of St. Benedict/St. John's University)

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26.2: Synthesis of Amino Acids: A Combination of Amine and Carboxylic Acid
Chemistry
Objectives

After completing this section, you should be able to

1. outline, by means of equations, how a racemic mixture of given amino acid can be prepared from a carboxylic acid
using reactions you studied earlier in the course.
2. a. outline, by means of equations, the preparation of a given amino acid by the amidomalonate synthesis.
b. identify the amino acid formed from using a given alkyl halide in an amidomalonate synthesis.
c. identify the alkyl halide needed to produce a given amino acid by the amidomalonate synthesis.
3. describe, by means of equations, how an α‑keto acid can be transformed to an amino acid by reductive amination.
4. a. describe a general method for resolving a racemic mixture of a given amino acid.
b. provide a brief example of how a biological method may be employed to resolve a racemic mixture of a given
amino acid.
c. show the enantioselective preparation of an amino acid from the corresponding Z enamido acid.

Key Terms

Make certain that you can define, and use in context, the key terms below.
amidomalonate synthesis
enantioselective synthesis
racemic mixture

Study Notes
Do not be alarmed by the number of methods to synthesize amino acids described in this section.You have seen many
of these reactions in previous sections and should already be familiar with the approaches discussed here.
To fulfill the requirements of Objective 1, review the Hell‑Volhard‑Zelinskii reaction (Section 22.4) and the Gabriel
phthalimide synthesis (Section 24.6).
The amidomalonate synthesis is a simple variation of the malonic ester synthesis (Section 22.7). A base abstracts a
proton from the alpha carbon, which is then alkylated with an alkyl halide. Then both the hydrolysis of the esters and
the amide protecting group under aqueous acidic conditions generates the α‑amino acid.

Another method of getting to the α‑amino acid is by reductive amination of the α‑keto acid which you have also
previously encountered (Section 24.6).

Synthesis of α-Amino Acids Edit section

1) Amination of alpha-bromocarboxylic acids, illustrated by the following equation, provides a straightforward method for
preparing alpha-aminocarboxylic acids. The bromoacids, in turn, are conveniently prepared from carboxylic acids by
reaction with Br2 + PCl3. Although this direct approach gave mediocre results when used to prepare simple amines from

26.2.1 12/5/2021 https://chem.libretexts.org/@go/page/32588

alkyl halides, it is more effective for making amino acids, thanks to the reduced nucleophilicity of the nitrogen atom in the
product. Nevertheless, more complex procedures that give good yields of pure compounds are often chosen for amino acid
synthesis.

2) By modifying the nitrogen as a phthalimide salt, the propensity of amines to undergo multiple substitutions is removed,
and a single clean substitution reaction of 1º- and many 2º-alkylhalides takes place. This procedure, known as the Gabriel
synthesis, can be used to advantage in aminating bromomalonic esters, as shown in the upper equation of the following
scheme. Since the phthalimide substituted malonic ester has an acidic hydrogen (colored orange), activated by the two
ester groups, this intermediate may be converted to an ambident anion and alkylated. Finally, base catalyzed hydrolysis of
the phthalimide moiety and the esters, followed by acidification and thermal decarboxylation, produces an amino acid and
phthalic acid (not shown).

3) An elegant procedure, known as the Strecker synthesis, assembles an alpha-amino acid from ammonia (the amine
precursor), cyanide (the carboxyl precursor), and an aldehyde. This reaction (shown below) is essentially an imino analog
of cyanohydrin formation. The alpha-amino nitrile formed in this way can then be hydrolyzed to an amino acid by either
acid or base catalysis.

4) Resolution The three synthetic procedures described above, and many others that can be conceived, give racemic amino
acid products. If pure L or D enantiomers are desired, it is necessary to resolve these racemic mixtures. A common method
of resolving racemates is by diastereomeric salt formation with a pure chiral acid or base. This is illustrated for a generic
amino acid in the following diagram. Be careful to distinguish charge symbols, shown in colored circles, from optical
rotation signs, shown in parenthesis.
In the initial display, the carboxylic acid function contributes to diastereomeric salt formation. The racemic amino acid is
first converted to a benzamide derivative to remove the basic character of the amino group. Next, an ammonium salt is
formed by combining the carboxylic acid with an optically pure amine, such as brucine (a relative of strychnine). The
structure of this amine is not shown, because it is not a critical factor in the logical progression of steps. Since the amino
acid moiety is racemic and the base is a single enantiomer (levorotatory in this example), an equimolar mixture of
diastereomeric salts is formed (drawn in the green shaded box). Diastereomers may be separated by crystallization,
chromatography or other physical manipulation, and in this way one of the isomers may be isolated for further treatment,
in this illustration it is the (+):(-) diastereomer. Finally the salt is broken by acid treatment, giving the resolved (+)-amino
acid derivative together with the recovered resolving agent (the optically active amine). Of course, the same procedure
could be used to obtain the (-)-enantiomer of the amino acid.

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Since amino acids are amphoteric, resolution could also be achieved by using the basic character of the amine function.
For this approach we would need an enantiomerically pure chiral acid such as tartaric acid to use as the resolving agent.
This alternative resolution strategy will be illustrated. Note that the carboxylic acid function is first esterified, so that it will
not compete with the resolving acid.
Resolution of aminoacid derivatives may also be achieved by enzymatic discrimination in the hydrolysis of amides. For
example, an aminoacylase enzyme from pig kidneys cleaves an amide derivative of a natural L-amino acid much faster
than it does the D-enantiomer. If the racemic mixture of amides shown in the green shaded box above is treated with this
enzyme, the L-enantiomer (whatever its rotation) will be rapidly converted to its free zwitterionic form, whereas the D-
enantiomer will remain largely unchanged. Here, the diastereomeric species are transition states rather than isolable
intermediates. This separation of enantiomers, based on very different rates of reaction, is called kinetic resolution.

Enantioselective Synthesis
Till now all of the synthetic routes to α-amino acids we have discussed yield a racemic mixture. Once produced one could
resolve the mixture to obtain pure L or D enantiomers. However, enantioselective synthetic methods to produce pure
compounds directly are being developed. For instance, several catalysts are now available for reduction of C=C to expose
enantiopure amino acids. A good example is the industrial synthesis of L-DOPA, a drug used in the treatment of
Parkinson’s disease. W.S. Knowles shared the 2001 Nobel Price with R. Noyori and K.B. Sharpless for their contributions
in the area of asymmetric catalytic reductions. Knowles developed several chiral phosphine–metal catalysts for asymmetric
reductions. The rhodium(I) catalyst shown, which is complexed by large organic ligands, facilitates production of almost
pure L-DOPA.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

26.2.3 12/5/2021 https://chem.libretexts.org/@go/page/32588

26.3: Synthesis of Enantiomerically Pure Amino Acids
Objectives
After completing this section, you should be able to
1. outline, by means of equations, how a racemic mixture of given amino acid can be prepared from a carboxylic acid
using reactions you studied earlier in the course.
2. a. outline, by means of equations, the preparation of a given amino acid by the amidomalonate synthesis.
b. identify the amino acid formed from using a given alkyl halide in an amidomalonate synthesis.
c. identify the alkyl halide needed to produce a given amino acid by the amidomalonate synthesis.
3. describe, by means of equations, how an α‑keto acid can be transformed to an amino acid by reductive amination.
4. a. describe a general method for resolving a racemic mixture of a given amino acid.
b. provide a brief example of how a biological method may be employed to resolve a racemic mixture of a given
amino acid.
c. show the enantioselective preparation of an amino acid from the corresponding Z enamido acid.

Key Terms

Make certain that you can define, and use in context, the key terms below.
amidomalonate synthesis
enantioselective synthesis
racemic mixture

Study Notes
Do not be alarmed by the number of methods to synthesize amino acids described in this section.You have seen many
of these reactions in previous sections and should already be familiar with the approaches discussed here.
To fulfill the requirements of Objective 1, review the Hell‑Volhard‑Zelinskii reaction (Section 22.4) and the Gabriel
phthalimide synthesis (Section 24.6).
The amidomalonate synthesis is a simple variation of the malonic ester synthesis (Section 22.7). A base abstracts a
proton from the alpha carbon, which is then alkylated with an alkyl halide. Then both the hydrolysis of the esters and
the amide protecting group under aqueous acidic conditions generates the α‑amino acid.

Another method of getting to the α‑amino acid is by reductive amination of the α‑keto acid which you have also
previously encountered (Section 24.6).

Synthesis of α-Amino Acids Edit section

1) Amination of alpha-bromocarboxylic acids, illustrated by the following equation, provides a straightforward method for
preparing alpha-aminocarboxylic acids. The bromoacids, in turn, are conveniently prepared from carboxylic acids by
reaction with Br2 + PCl3. Although this direct approach gave mediocre results when used to prepare simple amines from
alkyl halides, it is more effective for making amino acids, thanks to the reduced nucleophilicity of the nitrogen atom in the

26.3.1 12/5/2021 https://chem.libretexts.org/@go/page/32589

product. Nevertheless, more complex procedures that give good yields of pure compounds are often chosen for amino acid
synthesis.

2) By modifying the nitrogen as a phthalimide salt, the propensity of amines to undergo multiple substitutions is removed,
and a single clean substitution reaction of 1º- and many 2º-alkylhalides takes place. This procedure, known as the Gabriel
synthesis, can be used to advantage in aminating bromomalonic esters, as shown in the upper equation of the following
scheme. Since the phthalimide substituted malonic ester has an acidic hydrogen (colored orange), activated by the two
ester groups, this intermediate may be converted to an ambident anion and alkylated. Finally, base catalyzed hydrolysis of
the phthalimide moiety and the esters, followed by acidification and thermal decarboxylation, produces an amino acid and
phthalic acid (not shown).

3) An elegant procedure, known as the Strecker synthesis, assembles an alpha-amino acid from ammonia (the amine
precursor), cyanide (the carboxyl precursor), and an aldehyde. This reaction (shown below) is essentially an imino analog
of cyanohydrin formation. The alpha-amino nitrile formed in this way can then be hydrolyzed to an amino acid by either
acid or base catalysis.

4) Resolution The three synthetic procedures described above, and many others that can be conceived, give racemic amino
acid products. If pure L or D enantiomers are desired, it is necessary to resolve these racemic mixtures. A common method
of resolving racemates is by diastereomeric salt formation with a pure chiral acid or base. This is illustrated for a generic
amino acid in the following diagram. Be careful to distinguish charge symbols, shown in colored circles, from optical
rotation signs, shown in parenthesis.
In the initial display, the carboxylic acid function contributes to diastereomeric salt formation. The racemic amino acid is
first converted to a benzamide derivative to remove the basic character of the amino group. Next, an ammonium salt is
formed by combining the carboxylic acid with an optically pure amine, such as brucine (a relative of strychnine). The
structure of this amine is not shown, because it is not a critical factor in the logical progression of steps. Since the amino
acid moiety is racemic and the base is a single enantiomer (levorotatory in this example), an equimolar mixture of
diastereomeric salts is formed (drawn in the green shaded box). Diastereomers may be separated by crystallization,
chromatography or other physical manipulation, and in this way one of the isomers may be isolated for further treatment,
in this illustration it is the (+):(-) diastereomer. Finally the salt is broken by acid treatment, giving the resolved (+)-amino
acid derivative together with the recovered resolving agent (the optically active amine). Of course, the same procedure
could be used to obtain the (-)-enantiomer of the amino acid.

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Since amino acids are amphoteric, resolution could also be achieved by using the basic character of the amine function.
For this approach we would need an enantiomerically pure chiral acid such as tartaric acid to use as the resolving agent.
This alternative resolution strategy will be illustrated. Note that the carboxylic acid function is first esterified, so that it will
not compete with the resolving acid.
Resolution of aminoacid derivatives may also be achieved by enzymatic discrimination in the hydrolysis of amides. For
example, an aminoacylase enzyme from pig kidneys cleaves an amide derivative of a natural L-amino acid much faster
than it does the D-enantiomer. If the racemic mixture of amides shown in the green shaded box above is treated with this
enzyme, the L-enantiomer (whatever its rotation) will be rapidly converted to its free zwitterionic form, whereas the D-
enantiomer will remain largely unchanged. Here, the diastereomeric species are transition states rather than isolable
intermediates. This separation of enantiomers, based on very different rates of reaction, is called kinetic resolution.

Enantioselective Synthesis
Till now all of the synthetic routes to α-amino acids we have discussed yield a racemic mixture. Once produced one could
resolve the mixture to obtain pure L or D enantiomers. However, enantioselective synthetic methods to produce pure
compounds directly are being developed. For instance, several catalysts are now available for reduction of C=C to expose
enantiopure amino acids. A good example is the industrial synthesis of L-DOPA, a drug used in the treatment of
Parkinson’s disease. W.S. Knowles shared the 2001 Nobel Price with R. Noyori and K.B. Sharpless for their contributions
in the area of asymmetric catalytic reductions. Knowles developed several chiral phosphine–metal catalysts for asymmetric
reductions. The rhodium(I) catalyst shown, which is complexed by large organic ligands, facilitates production of almost
pure L-DOPA.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

26.3.3 12/5/2021 https://chem.libretexts.org/@go/page/32589

26.4: Peptides and Proteins: Amino Acid Oligomers and Polymers
Objectives
After completing this section, you should be able to
1. a. show, by means of a diagram, how two different amino acid residues can be combined to give two different
dipeptides.
b. draw the structure of a relatively simple peptide, given its full or abbreviated name and the structures of the
appropriate amino acids.
c. draw, or name, the six possible isomeric tripeptides that can be formed by combining three different amino acid
residues (amino acid units) of given structure.
2. account for the fact that there is restricted rotation about the C−N bonds in peptides.
3. illustrate the formation of a disulfide linkage between two cysteine residues, and show how such bonds can link
together two separate peptide chains or can provide a bridge between two cysteine residues present in a single
peptide molecule.

Key Terms
Make certain that you can define, and use in context, the key terms below.
C‑terminal amino acid
N‑terminal amino acid
peptides
residues

Study Notes

If necessary, review the discussion of the delocalization of the nitrogen lone‑pair electrons in amides that was
presented in Section 24.3. Similarly, you may wish to refer back to Section 18.8 to review the interconversion of thiols
and disulfides.

Peptide Bond Formation or Amide Synthesis

The formation of peptides is nothing more than the application of the amide synthesis reaction. By convention, the amide
bond in the peptides should be made in the order that the amino acids are written. The amine end (N terminal) of an amino
acid is always on the left, while the acid end (C terminal) is on the right. The reaction of glycine with alanine to form the
dipeptide glyclalanine is written as shown in the graphic on the left. Oxygen (red) from the acid and hydrogens (red) on the
amine form a water molecule. The carboxyl oxygen (green) and the amine nitrogen (green) join to form the amide bond.

If the order of listing the amino acids is reversed, a different dipeptide is formed such as alaninylglycine.

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 Exercise 26.4.1

Write the reactions for:

a. ala + gly ---> Answer graphic
b. phe + ser ----> Answer graphic

Resonance contributors for the peptide bonds

A consideration of resonance contributors is crucial to any discussion of the amide functional group. One of the most
important examples of amide groups in nature is the ‘peptide bond’ that links amino acids to form polypeptides and
proteins.

Critical to the structure of proteins is the fact that, although it is conventionally drawn as a single bond, the C-N bond in a
peptide linkage has a significant barrier to rotation, almost as if it were a double bond.

This, along with the observation that the bonding around the peptide nitrogen has trigonal planar geometry, strongly
suggests that the nitrogen is sp2-hybridized. An important resonance contributor has a C=N double bond and a C-O single
bond, with a separation of charge between the oxygen and the nitrogen.

Although B is a minor contributor due to the separation of charges, it is still very relevant in terms of peptide and protein
structure – our proteins would simply not fold up properly if there was free rotation about the peptide C-N bond.

Backbone Peptide or Protein Structure

The structure of a peptide can be written fairly easily without showing the complete amide synthesis reaction by learning
the structure of the "backbone" for peptides and proteins.
The peptide backbone consists of repeating units of "N-H 2, CH, C double bond O; N-H 2, CH, C double bond O; etc. See
the graphic on the left .
After the backbone is written, go back and write the specific structure for the side chains as represented by the "R" as gly-
ala-leu for this example. The amine end (N terminal) of an amino acid is always on the left (gly), while the acid end (C
terminal) is on the right (leu).

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Exercise 26.4.2

Write the tripeptide structure for val-ser-cys. First write the "backbone" and then add the specific side chains.
Solution
Answer graphic

QUES. Write the structure for the tripeptide:

2 a ) glu-cys-gly ---> Answer graphic
2 b) phe-tyr-asn ---> Answer graphic

Disulfide Bridges and Oxidation-Reduction

The amino acid cysteine undergoes oxidation and reduction reactions involving the -SH (sulfhydryl group). The oxidation
of two sulfhydryl groups results in the formation of a disulfide bond by the removal of two hydrogens. The oxidation of
two cysteine amino acids is shown in the graphic. An unspecified oxidizing agent (O) provides an oxygen which reacts
with the hydrogen (red) on the -SH group to form water. The sulfurs (yellow) join to make the disulfide bridge. This is an
important bond to recognize in protein tertiary structure. The reduction of a disulfide bond is the opposite reaction which
again leads to two separate cysteine molecules. Remember that reduction is the addition of hydrogen.

Cysteine residues in the the peptide chain can form a loop buy forming the disulfide bond (—S—S—), while cysteine
residues in different peptide chains can actually link what were otherwise separate chains. Insulin was the first protein
whose amino acid sequence was determined. This pioneering work, completed in 1953 after some 10 years of effort,
earned a Nobel Prize for British biochemist Frederick Sanger (born 1918). He found the primary structure to comprise of
two chains linked by two cysteine disulfide bridges. Also note the first peptide chain possesses an internal loop.

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 Insulin

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Charles Ophardt (Professor Emeritus, Elmhurst College); Virtual Chembook
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)

Objectives
After completing this section, you should be able to
1. discuss, with reference to a suitable example (either given or of your own choice), the structure of proteins, paying
particular attention to distinguishing between the primary, secondary, tertiary and quaternary structure.
2. describe the α‑helical secondary structure displayed by many proteins.
3. describe the β‑pleated‑sheet structure displayed by many proteins.

Key Terms

Make certain that you can define, and use in context, the key terms below.
α helix
β pleated sheet
primary structure
quaternary structure
secondary structure
tertiary structure

Study Notes
Note that in a diagram of the α‑helical structure of a protein, the C‑terminal of the protein is at the bottom of the
diagram and the N‑terminal is at the top. In an α helix, such as the one shown in Figure 26.9.1, the bulky R groups are
all found on the outside of the helix, where they have the most room.

The four levels of protein structure Edit section

Protein structure can be discussed at four distinct levels. A protein’s primary structure is two-dimensional - simply the
sequence of amino acids in the peptide chain. Below is a Lewis structure of a short segment of a protein with the sequence
CHEM (cysteine - histidine - glutamate - methionine)

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Secondary structure is three-dimensional, but is a local phenomenon, confined to a relatively short stretch of amino acids.
For the most part, there are three important elements of secondary structure: helices, beta-sheets, and loops. In a helix, the
main chain of the protein adopts the shape of a clockwise spiral staircase, and the side chains point out laterally.

In a beta-sheet (or beta-strand) structure, two sections of protein chain are aligned side-by-side in an extended
conformation. The figure below shows two different views of the same beta-sheet: in the left-side view, the two regions of
protein chain are differentiated by color.

Loops are relatively disordered segments of protein chain, but often assume a very ordered structure when in contact with
a second protein or a smaller organic compound.
Both helix and the beta-sheet structures are held together by very specific hydrogen-bonding interactions between the
amide nitrogen on one amino acid and the carbonyl oxygen on another. The hydrogen bonding pattern in a section of a
beta-strand is shown below.

Secondary structure refers to the shape of a folding protein due exclusively to hydrogen bonding between its backbone
amide and carbonyl groups. Secondary structure does not include bonding between the R-groups of amino acids,
hydrophobic interactions, or other interactions associated with tertiary structure. The two most commonly encountered
secondary structures of a polypeptide chain are α-helices and beta-pleated sheets. These structures are the first major steps
in the folding of a polypeptide chain, and they establish important topological motifs that dictate subsequent tertiary
structure and the ultimate function of the protein.

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α-Helices

Figure 26.9.1 Ball-and-stick model of the α helix. Hydrogen bonds are shown as dotted bonds. Note that R groups extend
almost perpendicular from the axis.
An α-helix is a right-handed coil of amino-acid residues on a polypeptide chain, typically ranging between 4 and 40
residues. This coil is held together by hydrogen bonds between the oxygen of C=O on top coil and the hydrogen of N-H on
the bottom coil. Such a hydrogen bond is formed exactly every 4 amino acid residues, and every complete turn of the helix
is only 3.6 amino acid residues. This regular pattern gives the α-helix very definite features with regards to the thickness of
the coil and the length of each complete turn along the helix axis.
The structural integrity of an α-helix is in part dependent on correct steric configuration. Amino acids whose R-groups are
too large (tryptophan, tyrosine) or too small (glycine) destabilize α-helices. Proline also destabilizes α-helices because of
its irregular geometry; its R-group bonds back to the nitrogen of the amide group, which causes steric hindrance. In
addition, the lack of a hydrogen on Proline's nitrogen prevents it from participating in hydrogen bonding.
Another factor affecting α-helix stability is the total dipole moment of the entire helix due to individual dipoles of the C=O
groups involved in hydrogen bonding. Stable α-helices typically end with a charged amino acid to neutralize the dipole
moment.

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BETA-PLEATED SHEETS Edit section

This structure occurs when two (or more, e.g. ψ-loop) segments of a polypeptide chain overlap one another and form a row
of hydrogen bonds with each other. This can happen in a parallel arrangement:

Or in anti-parallel arrangement:

Parallel and anti-parallel arrangement is the direct consequence of the directionality of the polypeptide chain. In anti-
parallel arrangement, the C-terminus end of one segment is on the same side as the N-terminus end of the other segment.
In parallel arrangement, the C-terminus end and the N-terminus end are on the same sides for both segments. The "pleat"
occurs because of the alternating planes of the peptide bonds between amino acids; the aligned amino and carbonyl group
of each opposite segment alternate their orientation from facing towards each other to facing opposite directions.
The parallel arrangement is less stable because the geometry of the individual amino acid molecules forces the hydrogen
bonds to occur at an angle, making them longer and thus weaker. Contrarily, in the anti-parallel arrangement the hydrogen
bonds are aligned directly opposite each other, making for stronger and more stable bonds.
Commonly, an anti-parallel beta-pleated sheet forms when a polypeptide chain sharply reverses direction. This can occur
in the presence of two consecutive proline residues, which create an angled kink in the polypeptide chain and bend it back
upon itself. This is not necessary for distant segments of a polypeptide chain to form beta-pleated sheets, but for proximal
segments it is a definite requirement. For short distances, the two segments of a beta-pleated sheet are separated by 4+2n
amino acid residues, with 4 being the minimum number of residues.

α-PLEATED SHEETS Edit section

A similar structure to the beta-pleated sheet is the α-pleated sheet. This structure is energetically less favorable than the
beta-pleated sheet, and is fairly uncommon in proteins. An α-pleated sheet is characterized by the alignment of its carbonyl
and amino groups; the carbonyl groups are all aligned in one direction, while all the N-H groups are aligned in the opposite
direction. The polarization of the amino and carbonyl groups results in a net dipole moment on the α-pleated sheet. The
carbonyl side acquires a net negative charge, and the amino side acquires a net positive charge.

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A protein’s tertiary structure is the shape in which the entire protein chain folds together in three-dimensional space, and
it is this level of structure that provides protein scientists with the most information about a protein’s specific function.

While a protein's secondary and tertiary structure is defined by how the protein chain folds together, quaternary structure
is defined by how two or more folded protein chains come together to form a 'superstructure'. Many proteins consist of
only one protein chain, or subunit, and thus have no quaternary structure. Many other proteins consist of two identical
subunits (these are called homodimers) or two non-identical subunits (these are called heterodimers).

Quaternary structures can be quite elaborate: below we see a protein whose quaternary structure is defined by ten identical
subunits arranged in two five-membered rings, forming what can be visualized as a 'double donut' shape (this is fructose
1,6-bisphosphate aldolase):

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The molecular forces that hold proteins together Edit section

The question of exactly how a protein ‘finds’ its specific folded structure out of the vast number of possible folding
patterns is still an active area of research. What is known, however, is that the forces that cause a protein to fold properly
and to remain folded are the same basic noncovalent forces that we talked about in chapter 2: ion-ion, ion-dipole, dipole-
dipole, hydrogen bonding, and hydrophobic (van der Waals) interactions. One interesting type of hydrophobic interaction
is called ‘aromatic stacking’, and occurs when two or more planar aromatic rings on the side chains of phenylalanine,
tryptophan, or tyrosine stack together like plates, thus maximizing surface area contact.

Hydrogen bonding networks are extensive within proteins, with both side chain and main chain atoms participating. Ionic
interactions often play a role in protein structure, especially on the protein surface, as negatively charged residues such as
aspartate interact with positively-charged groups on lysine or arginine.
One of the most important ideas to understand regarding tertiary structure is that a protein, when properly folded, is polar
on the surface and nonpolar in the interior. It is the protein's surface that is in contact with water, and therefore the surface
must be hydrophilic in order for the whole structure to be soluble. If you examine a three dimensional protein structure you
will see many charged side chains (e.g. lysine, arginine, aspartate, glutamate) and hydrogen-bonding side chains (e.g.
serine, threonine, glutamine, asparagine) exposed on the surface, in direct contact with water. Inside the protein, out of
contact with the surrounding water, there tend to be many more hydrophobic residues such as alanine, valine,
phenylalanine, etc. If a protein chain is caused to come unfolded (through exposure to heat, for example, or extremes of
pH), it will usually lose its solubility and form solid precipitates, as the hydrophobic residues from the interior come into
contact with water. You can see this phenomenon for yourself if you pour a little bit of vinegar (acetic acid) into milk. The
solid clumps that form in the milk are proteins that have come unfolded due to the sudden acidification, and precipitated
out of solution.
In recent years, scientists have become increasing interested in the proteins of so-called ‘thermophilic’ (heat-loving)
microorganisms that thrive in hot water environments such as geothermal hot springs. While the proteins in most
organisms (including humans) will rapidly unfold and precipitate out of solution when put in hot water, the proteins of
thermophilic microbes remain completely stable, sometimes even in water that is just below the boiling point. In fact, these
proteins typically only gain full biological activity when in appropriately hot water - at room-temperature they act is if they
are ‘frozen’. Is the chemical structure of these thermostable proteins somehow unique and exotic? As it turns out, the
answer to this question is ‘no’: the overall three-dimensional structures of thermostable proteins look very much like those
of ‘normal’ proteins. The critical difference seems to be simply that thermostable proteins have more extensive networks
of noncovalent interactions, particularly ion-ion interactions on their surface, that provides them with a greater stability to
heat. Interestingly, the proteins of ‘psychrophilic’ (cold-loving) microbes isolated from pockets of water in arctic ice show
the opposite characteristic: they have far fewer ion-ion interactions, which gives them greater flexibility in cold
temperatures but leads to their rapid unfolding in room temperature water.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry
Organic Chemistry With a Biological Emphasis by Tim Soderberg (University of Minnesota, Morris)
Ed Vitz (Kutztown University), John W. Moore (UW-Madison), Justin Shorb (Hope College), Xavier Prat-Resina
(University of Minnesota Rochester), Tim Wendorff, and Adam Hahn.

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26.5: Determination of Primary Structure: Amino Acid Sequencing
☰
Objectives
After completing this section, you should be able to
1. describe how an Edman degradation is used to determine the sequence of the amino acid residues in peptides
containing up to 20 such residues.
2. describe, briefly, how the procedure is modified to deal with peptides and proteins containing more than 20 amino
acid residues.
3. write a detailed mechanism for the Edman degradation.
4. determine the structure of a peptide, given a list of the fragments that are produced by a partial acid hydrolysis.
5. determine the structure of a peptide, given a list of the fragments that are produced when the peptide is cleaved by a
specific enzyme and the details of the types of bonds cleaved by that enzyme.
6. predict the fragments that would be produced when a peptide of known structure is cleaved by a specific enzyme,
given sufficient information about the types of bonds that are cleaved by the enzyme in question.

Key Terms
Make certain that you can define, and use in context, the key term below.
Edman degradation

Study Notes

The reagent used in the Edman degradation is phenyl isothiocyanate. You may find it helpful to review the relationship
between cyanates, isocyanates, thiocyanates and isothiocyanates.

You need not memorize the specific peptide bonds that are broken by the enzymes trypsin and chymotrypsin.

Edman degradation is the process of purifying protein by sequentially removing one residue at a time from the amino end
of a peptide. To solve the problem of damaging the protein by hydrolyzing conditions, Pehr Edman created a new way of
labeling and cleaving the peptide. Edman thought of a way of removing only one residue at a time, which did not damage
the overall sequencing. This was done by adding Phenyl isothiocyanate, which creates a phenylthiocarbamoyl derivative
with the N-terminal. The N-terminal is then cleaved under less harsh acidic conditions, creating a cyclic compound of
phenylthiohydantoin PTH-amino acid. This does not damage the protein and leaves two constituents of the peptide. This
method can be repeated for the rest of the residues, separating one residue at a time.

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☰

Edman degradation is very useful because it does not damage the protein. This allows sequencing of the protein to be done
in less time. Edman sequencing is done best if the composition of the amino acid is known. As we saw in Section 26.5, to
determine the composition of the amino acid, the peptide must be hydrolyzed. This can be done by denaturing the protein
and heating it and adding HCl for a long time. This causes the individual amino acids to be separated, and they can be
separated by ion exchange chromatography. They are then dyed with ninhydrin and the amount of amino acid can be
determined by the amount of optical absorbance. This way, the composition but not the sequence can be determined

Sequencing Larger Proteins

Larger proteins cannot be sequenced by the Edman sequencing because of the less than perfect efficiency of the method. A
strategy called divide and conquer successfully cleaves the larger protein into smaller, practical amino acids. This is done
by using a certain chemical or enzyme which can cleave the protein at specific amino acid residues. The separated peptides
can be isolated by chromatography. Then they can be sequenced using the Edman method, because of their smaller size.
In order to put together all the sequences of the different peptides, a method of overlapping peptides is used. The strategy
of divide and conquer followed by Edman sequencing is used again a second time, but using a different enzyme or
chemical to cleave it into different residues. This allows two different sets of amino acid sequences of the same protein, but
at different points. By comparing these two sequences and examining for any overlap between the two, the sequence can
be known for the original protein.
For example, trypsin can be used on the initial peptide to cleave it at the carboxyl side of arginine and lysine residues.
Using trypsin to cleave the protein and sequencing them individually with Edman degradation will yield many different
individual results. Although the sequence of each individual cleaved amino acid segment is known, the order is scrambled.
Chymotrypsin, which cleaves on the carboxyl side of aromatic and other bulky nonpolar residues, can be used. The
sequence of these segments overlap with those of the trypsin. They can be overlapped to find the original sequence of the
initial protein. However, this method is limited in analyzing larger sized proteins (more than 100 amino acids) because of
secondary hydrogen bond interference. Other weak intermolecular bonding such as hydrophobic interactions cannot be
properly predicted. Only the linear sequence of a protein can be properly predicted assuming the sequence is small enough.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Wikibooks (Structural Biopchemistry). The content on this page is licensed under a CC-SA-BY 3.0 license.

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26.6: Synthesis of Polypeptides: A Challenge in the Application of Protecting
Groups
Objectives

After completing this section, you should be able to

1. describe why it is necessary to protect certain amino and carboxyl groups during the synthesis of a peptide.
2. describe, using appropriate equations, how carboxyl groups are protected by ester formation and amino groups are
protected by the formation of their tert‑butoxycarbonyl amide derivatives.
3. write a detailed mechanism for the formation of a peptide link between an amino acid with a protected amino group
and an amino acid with a protected carboxyl group using dicyclohexylcarbodiimide.
4. outline the five steps required in order to form a dipeptide from two given amino acids.

In order to synthesize a peptide from its component amino acids, two obstacles must be overcome. The first of these is
statistical in nature, and is illustrated by considering the dipeptide Ala-Gly as a proposed target. If we ignore the chemistry
involved, a mixture of equal molar amounts of alanine and glycine would generate four different dipeptides. These are:
Ala-Ala, Gly-Gly, Ala-Gly & Gly-Ala. In the case of tripeptides, the number of possible products from these two amino
acids rises to eight. Clearly, some kind of selectivity must be exercised if complex mixtures are to be avoided.
The second difficulty arises from the fact that carboxylic acids and 1º or 2º-amines do not form amide bonds on mixing,
but will generally react by proton transfer to give salts (the intermolecular equivalent of zwitterion formation).
From the perspective of an organic chemist, peptide synthesis requires selective acylation of a free amine. To accomplish
the desired amide bond formation, we must first deactivate all extraneous amine functions so they do not compete for the
acylation reagent. Then we must selectively activate the designated carboxyl function so that it will acylate the one
remaining free amine. Fortunately, chemical reactions that permit us to accomplish these selections are well known.
First, the basicity and nucleophilicity of amines are substantially reduced by amide formation. Consequently, the acylation
of amino acids by treatment with acyl chlorides or anhydrides at pH > 10, as described earlier, serves to protect their amino
groups from further reaction.
Second, acyl halide or anhydride-like activation of a specific carboxyl reactant must occur as a prelude to peptide (amide)
bond formation. This is possible, provided competing reactions involving other carboxyl functions that might be present
are precluded by preliminary ester formation. Remember, esters are weaker acylating reagents than either anhydrides or
acyl halides, as noted earlier.
Finally, dicyclohexylcarbodiimide (DCC) effects the dehydration of a carboxylic acid and amine mixture to the
corresponding amide under relatively mild conditions. The structure of this reagent and the mechanism of its action have
been described. Its application to peptide synthesis will become apparent in the following discussion.
The strategy for peptide synthesis, as outlined here, should now be apparent. The following example shows a selective
synthesis of the dipeptide Ala-Gly.

An important issue remains to be addressed. Since the N-protective group is an amide, removal of this function might
require conditions that would also cleave the just formed peptide bond. Furthermore, the harsh conditions often required
for amide hydrolysis might cause extensive racemization of the amino acids in the resulting peptide. This problem strikes
at the heart of our strategy, so it is important to give careful thought to the design of specific N-protective groups. In
particular, three qualities are desired:

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1. The protective amide should be easy to attach to amino acids.
2. The protected amino group should not react under peptide forming conditions.
3. The protective amide group should be easy to remove under mild conditions.
A number of protective groups that satisfy these conditions have been devised; and two of the most widely used,
carbobenzoxy (Cbz) and t-butoxycarbonyl (BOC or t-BOC), are described here.

The reagents for introducing these N-protective groups are the acyl chlorides or anhydrides shown in the left portion of the
above diagram. Reaction with a free amine function of an amino acid occurs rapidly to give the "protected" amino acid
derivative shown in the center. This can then be used to form a peptide (amide) bond to a second amino acid. Once the
desired peptide bond is created the protective group can be removed under relatively mild non-hydrolytic conditions.
Equations showing the protective group removal will be displayed above by are shown above. Cleavage of the reactive
benzyl or tert-butyl groups generates a common carbamic acid intermediate (HOCO-NHR) which spontaneously loses
carbon dioxide, giving the corresponding amine. If the methyl ester at the C-terminus is left in place, this sequence of
reactions may be repeated, using a different N-protected amino acid as the acylating reagent. Removal of the protective
groups would then yield a specific tripeptide, determined by the nature of the reactants and order of the reactions.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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26.7: Merrifield Solid-Phase Peptide Synthesis
Objectives
After completing this section, you should be able to describe, briefly, the Merrifield solid‑phase technique for the
synthesis of polypeptides.

Key Terms

Make certain that you can define, and use in context, the key term below.
solid‑phase method (solid‑phase synthesis)

Study Notes
The solid‑phase used in this method is a polymer support. You will not be examined on the details of the Merrifield
solid‑phase method; however, you should be prepared to write a couple of paragraphs describing this important
process.
For his work on the synthesis of peptides, Bruce Merrifield was awarded the 1984 Nobel Prize in chemistry.

The synthesis of a peptide of significant length (e.g. ten residues) by this approach requires many steps, and the product
must be carefully purified after each step to prevent unwanted cross-reactions. To facilitate the tedious and time consuming
purifications, and reduce the material losses that occur in handling, a clever modification of this strategy has been
developed. This procedure, known as the Merrifield Synthesis after its inventor R. Bruce Merrifield, involves attaching
the C-terminus of the peptide chain to a polymeric solid, usually having the form of very small beads. Separation and
purification is simply accomplished by filtering and washing the beads with appropriate solvents. The reagents for the next
peptide bond addition are then added, and the purification steps repeated. The entire process can be automated, and peptide
synthesis machines based on the Merrifield approach are commercially available. A series of equations illustrating the
Merrifield synthesis may be viewed below. The final step, in which the completed peptide is released from the polymer
support, is a simple benzyl ester cleavage. This is not shown in the display.

The Merrifield Peptide Synthesis

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Two or more moderately sized peptides can be joined together by selective peptide bond formation, provided side-chain
functions are protected and do not interfere. In this manner good sized peptides and small proteins may be synthesized in
the laboratory. However, even if chemists assemble the primary structure of a natural protein in this or any other fashion, it
may not immediately adopt its native secondary, tertiary and quaternary structure. Many factors, such as pH, temperature
and inorganic ion concentration influence the conformational coiling of peptide chains. Indeed, scientists are still trying to
understand how and why these higher structures are established in living organisms.

Contributors and Attributions

Dr. Dietmar Kennepohl FCIC (Professor of Chemistry, Athabasca University)
Prof. Steven Farmer (Sonoma State University)
William Reusch, Professor Emeritus (Michigan State U.), Virtual Textbook of Organic Chemistry

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26.8: Polypeptides in Nature: Oxygen Transport by the Proteins Myoglobin and
Hemoglobin
Oxygen Transport
Many microorganisms and most animals obtain energy by respiration, the oxidation of organic or inorganic molecules by
O2. At 25°C, however, the concentration of dissolved oxygen in water in contact with air is only about 0.25 mM. Because
of their high surface area-to-volume ratio, aerobic microorganisms can obtain enough oxygen for respiration by passive
diffusion of O2 through the cell membrane. As the size of an organism increases, however, its volume increases much more
rapidly than its surface area, and the need for oxygen depends on its volume. Consequently, as a multicellular organism
grows larger, its need for O2 rapidly outstrips the supply available through diffusion. Unless a transport system is available
to provide an adequate supply of oxygen for the interior cells, organisms that contain more than a few cells cannot exist. In
addition, O2 is such a powerful oxidant that the oxidation reactions used to obtain metabolic energy must be carefully
controlled to avoid releasing so much heat that the water in the cell boils. Consequently, in higher-level organisms, the
respiratory apparatus is located in internal compartments called mitochondria, which are the power plants of a cell. Oxygen
must therefore be transported not only to a cell but also to the proper compartment within a cell.
Three different chemical solutions to the problem of oxygen transport have developed independently in the course of
evolution, as indicated in Table 26.8.13. Mammals, birds, reptiles, fish, and some insects use a heme protein called
hemoglobin to transport oxygen from the lungs to the cells, and they use a related protein called myoglobin to temporarily
store oxygen in the tissues. Several classes of invertebrates, including marine worms, use an iron-containing protein called
hemerythrin to transport oxygen, whereas other classes of invertebrates (arthropods and mollusks) use a copper-containing
protein called hemocyanin. Despite the presence of the hem- prefix, hemerythrin and hemocyanin do not contain a metal–
porphyrin complex.
Table 26.8.13 Some Properties of the Three Classes of Oxygen-Transport Proteins

Protein Source M per Subunit M per O2 Bound Color (deoxy form) Color (oxy form)

mammals, birds, fish,

hemoglobin 1 Fe 1 Fe red-purple red
reptiles, some insects
hemerythrin marine worms 2 Fe 2 Fe colorless red
mollusks,
hemocyanin 2 Cu 2 Cu colorless blue
crustaceans, spiders

Myoglobin and Hemoglobin

Myoglobin is a relatively small protein that contains 150 amino acids. The functional unit of myoglobin is an iron–
porphyrin complex that is embedded in the protein (Figure 26.8.1). In myoglobin, the heme iron is five-coordinate, with
only a single histidine imidazole ligand from the protein (called the proximal histidine because it is near the iron) in
addition to the four nitrogen atoms of the porphyrin. A second histidine imidazole (the distal histidine because it is more
distant from the iron) is located on the other side of the heme group, too far from the iron to be bonded to it. Consequently,
the iron atom has a vacant coordination site, which is where O2 binds.

Figure 26.8.1: The Structure of Deoxymyoglobin, Showing the Heme Group. The iron in deoxymyoglobin is five-
coordinate, with one histidine imidazole ligand from the protein. Oxygen binds at the vacant site on iron.

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In the ferrous form (deoxymyoglobin), the iron is five-coordinate and high spin. Because high-spin Fe2+ is too large to fit
into the “hole” in the center of the porphyrin, it is about 60 pm above the plane of the porphyrin. When O2 binds to
deoxymyoglobin to form oxymyoglobin, the iron is converted from five-coordinate (high spin) to six-coordinate (low spin;
Figure 26.8.2). Because low-spin Fe2+ and Fe3+ are smaller than high-spin Fe2+, the iron atom moves into the plane of the
porphyrin ring to form an octahedral complex. The O2 pressure at which half of the molecules in a solution of myoglobin
are bound to O2 (P1/2) is about 1 mm Hg (1.3 × 10−3 atm).

affinity unchanged, which is important because carbon monoxide is produced continuously in the body
by degradation of the porphyrin ligand (even in nonsmokers). Under normal conditions, CO occupies
approximately 1% of the heme sites in hemoglobin and myoglobin. If the affinity of hemoglobin and
myoglobin for CO were 100 times greater (due to the absence of the distal histidine), essentially 100%
of the heme sites would be occupied by CO, and no oxygen could be transported to the tissues. Severe
carbon-monoxide poisoning, which is frequently fatal, has exactly the same effect. Thus the primary
function of the distal histidine appears to be to decrease the CO affinity of hemoglobin and myoglobin to
avoid self-poisoning by CO.

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26.9: Biosynthesis of Proteins: Nucleic Acids

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26.10: Protein Synthesis Through RNA
28.05 Translation of RNA: Protein Biosynthesis

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26.11: DNA Sequencing and Synthesis: Cornerstones of Gene Technology
 Objectives

You may omit Section 28.6. You will not be examined on this material.

We will discuss one method of reading the sequence of DNA. This method, developed by Sanger won him a second Nobel
prize. To sequence a single stranded piece of DNA, the complementary strand is synthesized. Four different reaction
mixtures are set up. Each contain all 4 radioactive deoxynucleotides (dATP, dCTP, dGTP, dTTP) required for the reaction
and DNA polymerase. In addition, dideoxyATP (ddATP) is added to one reaction tube The dATP and ddATP attach
randomly to the growing 3' end of the complementary stranded. If ddATP is added no further nucleotides can be added
after since its 3' end has an H and not a OH. That's why they call it dideoxy. The new chain is terminated.. If dATP is
added, the chain will continue to grow until another A needs to be added. Hence a whole series of discreet fragments of
DNA chains will be made, all terminated when ddATP was added. The same scenario occurs for the other 3 tubes, which
contain dCTP and ddCTP, dTTP and ddTTP, and dGTP and ddGTP respectively. All the fragments made in each tube will
be placed in separate lanes for electrophoresis, where the fragments will separate by size.

Didexoynucleotides

Figure: Didexoynucleotides

 Example 28.6.1
You will pretend to sequence a single stranded piece of DNA as shown below. The new nucleotides are added by the
enzyme DNA polymerase to the primer, GACT, in the 5' to 3' direction. You will set up 4 reaction tubes, Each tube
contains all the dXTP's. In addition, add ddATP to tube 1, ddTTP to tube 2, ddCTP to tube 3, and ddGTP to tube 4. For
each separate reaction mixture, determine all the possible sequences made by writing the possible sequences on one of
the unfinished complementary sequences below. Cut the completed sequences from the page, determine the size of the

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 polynucleotide sequences made, and place them as they would migrate (based on size) in the appropriate lane of a
imaginary gel which you have drawn on a piece of paper. Lane 1 will contain the nucleotides made in tube 1, etc. Then
draw lines under the positions of the cutout nucleotides to represent DNA bands in the gel. Read the sequence of the
complementary DNA synthesized. Then write the sequence of the ssDNA that was to be sequenced.
5' T C A A C G A T C T G A 3' (STAND TO SEQUENCE)
3' G A C T 5' (primer)
3' G A C T 5' (primer)
3' G A C T 5' (primer)
3' G A C T 5' (primer)
3' G A C T 5' (primer)
3' G A C T 5' (primer)
3' G A C T 5' (primer)
3' G A C T 5' (primer)
Since the DNA fragments have no detectable color, they can not be directly visualized in the gel. Alternative methods
are used. In the one described above, radiolabeled ddXTP's where used. Once the sequencing gel is run, it can be dried
and the bands visualized by radioautography (also called autoradiography). A place of x-ray film is placed over the
dried gel in a dark environment. The radiolabeled bands will emit radiation which will expose the x-ray film directly
over the bands. The film can be developed to detect the bands. In a newer technique, the primer can be labeled with a
flourescent dye. If a different dye is used for each reaction mixture, all the reaction mixtures can be run in one lane of a
gel. (Actually only one reaction mix containing all the ddXTP's together need be performed.) The gel can then be
scanned by a laser, which detects fluorescence from the dyes, each at a different wavelength.

Figure: DNA sequencing using different fluorescent primers for each ddXTP reaction
One recent advance in sequencing allows for real-time determination of a sequence. The four deoxynucleotides are each
labeled with a different fluorphore on the 5' phosphate (not the base as above). A tethered DNA polymerase elongates the
DNA on a template, releasing the fluorophore into solution (i.e. the fluorophore is not incorporated into the DNA chain).
The reaction takes place in a visualization chamber called a zero mode waveguide which is a cylindrical metallic chamber
with a width of 70 nm and a volume of 20 zeptoliters (20 x 10-21 L). It sits on a glass support through which laser
illumination of the sample is achieved. Given the small volume, non-incorporated fluorescently tagged deoxynucleotides
diffuse in and out in the microsecond timescale. When a deoxynucleotide is incorporated into the DNA, its residence time
is in the millisecond time scale. This allows for prolonged detection of fluorescence which give a high signal to noise ratio.
This method might bring the cost of sequencing the human genome down from the initial billion dollar range to $100.

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Front Matter

TitlePage

InfoPage

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Index
C L P
Coulombic force Lewis structures pheromones
1.4: Electron-Dot Model of Bonding - Lewis 12.17: Alkenes in Nature - Insect Pheromones
1.2: Coulomb Forces - A Simplified View of
Structures
Bonding
S
O solvolysis
octet rule 7.1: Solvolysis of Tertiary and Secondary
1.3: Ionic and Covalent Bonds - The Octet Rule Haloalkanes
Glossary

Sample Word 1 | Sample Definition 1

Back Matter

Index

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