Organic Chemistry,

8th Edition
L. G. Wade, Jr.

Chapter 19
Lecture
Amines

Prof. Dr. Huriye Akdaş Kılıç

Yıldız Technical University
Davutpaşa-Istanbul
© 2013 Pearson Education, Inc.

© 2013 Pearson Education, Inc. Chapter 19 1

 Biologically Active Amines

 The alkaloids are an important group of biologically

active amines, mostly synthesized by plants to
protect them from being eaten by insects and other
animals.
 Many drugs of addiction are classified as alkaloids.

© 2013 Pearson Education, Inc. Chapter 19 2

 Biological Activity of Amines

© 2013 Pearson Education, Inc. Chapter 19 3

 Classes of Amines
 Primary (1): Has one alkyl group
bonded to the nitrogen (RNH2).
 Secondary (2): Has two alkyl groups
bonded to the nitrogen (R2NH).
 Tertiary (3): Has three alkyl groups
bonded to the nitrogen (R3N).
 Quaternary (4): Has four alkyl groups
bonded to the nitrogen and the nitrogen
+
bears a positive charge (R4N ).

© 2013 Pearson Education, Inc. Chapter 19 4

 Classification of Amines

© 2013 Pearson Education, Inc. Chapter 19 5

 Quaternary Ammonium Salts

 The nitrogen atom has four alkyl groups

attached.
 The nitrogen is positively charged.

© 2013 Pearson Education, Inc. Chapter 19 6

 Common Names

 Common names of amines are formed from

the names of the alkyl groups bonded to
nitrogen, followed by the suffix -amine.

© 2013 Pearson Education, Inc. Chapter 19 7

 Amine as Substituent

 On a molecule with a higher-priority functional

group, the amine is named as a substituent.

© 2013 Pearson Education, Inc. Chapter 19 8

 IUPAC Names
 Name is based on longest carbon chain.
 The -e of alkane is replaced with -amine.

© 2013 Pearson Education, Inc. Chapter 19 9

 Aromatic Amines

 In aromatic amines, the amino group is

bonded to a benzene ring.
 Parent compound is called aniline.

© 2013 Pearson Education, Inc. Chapter 19 10

 Heterocyclic Amines
When naming a cyclic amine, the nitrogen is
assigned position number 1.

© 2013 Pearson Education, Inc. Chapter 19 11

 Structure of Amines

 Nitrogen is sp3 hybridized with a lone pair of

electrons.
 The angle is less than 109.5º.

© 2013 Pearson Education, Inc. Chapter 19 12

 Interconversion of Chiral Amines

 Nitrogen may have three different groups and

a lone pair, but enantiomers cannot be
isolated due to inversion around N.

© 2013 Pearson Education, Inc. Chapter 19 13

 Chiral Amines

 Amines whose chirality stems from the

presence of chiral carbon atoms.
 Inversion of the nitrogen is not relevant
because it will not affect the chiral carbon.

© 2013 Pearson Education, Inc. Chapter 19 14

 Chiral Quaternary Ammonium
Salts

 Quaternary ammonium salts may have a chiral

nitrogen atom if the four substituents are different.
 Inversion of configuration is not possible because
there is no lone pair to undergo nitrogen inversion.

© 2013 Pearson Education, Inc. Chapter 19 15

 Chiral Cyclic Amines

 If the nitrogen atom is contained in a small ring, for

example, it is prevented from attaining the 120°
bond angle that facilitates inversion.
 Such a compound has a higher activation energy for
inversion, the inversion is slow, and the enantiomers
may be resolved.
© 2013 Pearson Education, Inc. Chapter 19 16
 Boiling Points

 N—H is less polar than O—H.

 Weaker hydrogen bonds, so amines will have a lower
boiling point than the corresponding alcohol.
 Tertiary amines cannot hydrogen-bond, so they have
lower boiling points than primary and secondary
amines.
© 2013 Pearson Education, Inc. Chapter 19 17
 Hydrogen Bonding and Boiling
Points

© 2013 Pearson Education, Inc. Chapter 19 18

 Solubility and Odor

 Small amines (< six Cs) are soluble in water.

 All amines accept hydrogen bonds from water
and alcohol.
 Branching increases solubility.
 Most amines smell like rotting fish.

© 2013 Pearson Education, Inc. Chapter 19 19

 Basicity of Amines
 Lone pair of electrons on nitrogen can accept a
proton from an acid.
 Aqueous solutions are basic to litmus.
 Ammonia pKb = 4.74.
 Alkyl amines are usually stronger bases than
ammonia.
 Increasing the number of alkyl groups decreases
solvation of ion, so 2 and 3 amines are similar
to 1 amines in basicity.

© 2013 Pearson Education, Inc. Chapter 19 20

 Reactivity of Amines

© 2013 Pearson Education, Inc. Chapter 19 21

 Base-Dissociation Constant of
Amines

 Amines are strongly basic and as such they can

abstract a proton from water, giving an ammonium
ion and a hydroxide ion.
 The equilibrium constant for this reaction is called the
base-dissociation constant for the amine,
symbolized by Kb.
© 2013 Pearson Education, Inc. Chapter 19 22
 The pKa of RNH3+ is the pH at which
half of the molecules are
protonated. At lower (more acidic)
pH, the amine is mostly protonated
(RNH3+). At higher (more basic) pH,
the amine is mostly deprotonated
(RNH2).

© 2013 Pearson Education, Inc. Chapter 19 23

 Base Dissociation of an Amine

 Alkyl groups stabilize the ammonium ion,

making the amine a stronger base.

© 2013 Pearson Education, Inc. Chapter 19 24

 Alkyl Group Stabilization of
Amines

 Alkyl groups make the nitrogen a stronger base

than ammonia.
© 2013 Pearson Education, Inc. Chapter 19 25
 Resonance Effects

 Any delocalization of the electron pair weakens the

base.
© 2013 Pearson Education, Inc. Chapter 19 26
 Protonation of Pyrrole

 When the pyrrole nitrogen is protonated,

pyrrole loses its aromatic stabilization.
 Therefore, protonation on nitrogen is
unfavorable and pyrrole is a very weak base.

© 2013 Pearson Education, Inc. Chapter 19 27

 Hybridization Effects

 Pyridine is less basic than aliphatic amines,

but it is more basic than pyrrole because it
does not lose its aromaticity on protonation.

© 2013 Pearson Education, Inc. Chapter 19 28

 Aromatic amines are generally less
basic than aliphatic amines. This is
true both when the nitrogen atom is
part of the aromatic system (as in
pyridine, a hybridization effect) and
when the nitrogen atom is bonded to
the aromatic ring (as in aniline, a
resonance effect).
© 2013 Pearson Education, Inc. Chapter 19 29
 Ammonium Salts

 Ionic solids with high melting points.

 Soluble in water.
 No fishy odor.

© 2013 Pearson Education, Inc. Chapter 19 30

 Purifying an Amine

© 2013 Pearson Education, Inc. Chapter 19 31

 IR Spectroscopy

 N—H stretch between 3200 and 3500 cm-1.

 Two peaks for 1 amine, one for 2.

© 2013 Pearson Education, Inc. Chapter 19 32

 NMR Spectroscopy of Amines

 Nitrogen is not as electronegative as oxygen,

so the protons on the a carbon atoms of
amines are not as strongly deshielded.

© 2013 Pearson Education, Inc. Chapter 19 33

 NMR Spectrum

© 2013 Pearson Education, Inc. Chapter 19 34

 Carbon NMR Chemical Shifts

© 2013 Pearson Education, Inc. Chapter 19 35

 Mass Spectroscopy of Amines

 Nitrogen has an odd valence and an

even mass number.
 When a nitrogen atom is present in a
stable molecule, the molecular weight is
odd.
 Whenever an odd number of nitrogen
atoms are present in a molecule, the
molecular ion has an odd mass number.
© 2013 Pearson Education, Inc. Chapter 19 36
 Alpha Cleavage of Amines

 The most common fragmentation of amines is

a cleavage to give a resonance-stabilized
cation—an iminium ion.

© 2013 Pearson Education, Inc. Chapter 19 37

 MS of Butyl Propyl Amine

© 2013 Pearson Education, Inc. Chapter 19 38

 Fragmentation of Butyl Propyl
Amine

© 2013 Pearson Education, Inc. Chapter 19 39

 Reaction of Amines with Ketones
and Aldehydes

© 2013 Pearson Education, Inc. Chapter 19 40

 Aromatic Substitution of
Arylamines

 —NH2 is a strong activator and an

ortho-, para-director.
 Multiple substitution is a problem.
 Protonation of the amine under acidic
conditions converts the group into a
strong deactivator (—NH3+).

© 2013 Pearson Education, Inc. Chapter 19 41

 Multiple Substitutions

© 2013 Pearson Education, Inc. Chapter 19 42

 Ortho and Para Substitution of
Aniline

© 2013 Pearson Education, Inc. Chapter 19 43

 Protonation of Aniline in
Substitution Reactions

 Strongly acidic reagents protonate the amino group,

producing an ammonium salt.
 The —NH3+ group is strongly deactivating (and meta-
allowing).
 Therefore, strongly acidic reagents are unsuitable for
substitution of anilines.
© 2013 Pearson Education, Inc. Chapter 19 44
 Aromatic Substitution of Pyridine

 Strongly deactivated toward electrophilic attack by the

electronegative nitrogen atom.
 Substitutes in the 3-position in a manner analogous to
the meta substitution.
 Electrons on N may react with the electrophile.
© 2013 Pearson Education, Inc. Chapter 19 45
 Electrophilic Aromatic Substitution
of Pyridine

© 2013 Pearson Education, Inc. Chapter 19 46

 Attack on 2-Position

 Attack at the 2-position would have an

unfavorable resonance structure in which the
positive charge is localized on the nitrogen.
 Substitution at the 2-position is not observed.
© 2013 Pearson Education, Inc. Chapter 19 47
 Nucleophilic Substitution of Pyridine

 Activated toward nucleophilic aromatic substitution.

 Nucleophile will replace a good leaving group in the
2- or 4-position.

© 2013 Pearson Education, Inc. Chapter 19 48

 Nucleophilic Attack on 3-Position

 Attack at the 3-position does not place the

negative charge on the nitrogen.
 Substitution at the 3-position is not observed.

© 2013 Pearson Education, Inc. Chapter 19 49

 Alkylation of Amines by Alkyl
Halides

 Proceeds by the SN2 mechanism.

 Secondary alkyl halides will give elimination products.
 Multiple alkylations is a major problem. Complex
mixtures are obtained.
© 2013 Pearson Education, Inc. Chapter 19 50
 Exhaustive Alkylation

 Exhaustive alkylation forms the

tetraalkylammonium salt.
 Mild basic conditions (NaHCO3) are used to
deprotonate the intermediates and neutralize
the acid formed.

© 2013 Pearson Education, Inc. Chapter 19 51

 Alkylations with Excess Ammonia

 Reaction with large excess of NH3 to

form the primary amine in good yields.
 Excess ammonia is allowed to
evaporate after reaction.
© 2013 Pearson Education, Inc. Chapter 19 52
 Acylation of Amines

 Primary and secondary amines react with

acid halides to form amides.
 This reaction is a nucleophilic acyl
substitution.

© 2013 Pearson Education, Inc. Chapter 19 53

 Mechanism of Acyl
Substitution
Step 1: Nucleophile attacks the carbonyl carbon, forming the tetrahedral
intermediate.

Step 2: Expulsion of the chloride ion. Step 3: Loss of a proton gives the
amide

© 2013 Pearson Education, Inc. Chapter 19 54

 Acylation of Aromatic Amines

 The resulting amide is still activating and ortho, para-

directing.
 The acyl group can be removed later by acidic or
basic hydrolysis.

© 2013 Pearson Education, Inc. Chapter 19 55

 Solved Problem 1
Show how you would accomplish the following synthetic conversion in good yield.

Solution
An attempted Friedel–Crafts acylation on aniline would likely meet with disaster. The free amino
group would attack both the acid chloride and the Lewis acid catalyst.

© 2013 Pearson Education, Inc. Chapter 19 56

 Solved Problem 1 (Continued)
Solution (Continued)
We can control the nucleophilicity of aniline’s amino group by converting it to an amide, which is still
activating and ortho, para-directing for the Friedel–Crafts reaction. Acylation, followed by hydrolysis
of the amide, gives the desired product.

© 2013 Pearson Education, Inc. Chapter 19 57

 Formation of Sulfonamides

 Primary or secondary amines react with sulfonyl

chloride to produce an amide.
 Amides of sulfonic acid are called sulfonamides.

© 2013 Pearson Education, Inc. Chapter 19 58

 Synthesis of Sulfanilamide

 The sulfa drugs are a class of sulfonamides

used as antibacterial agents.
 In 1936, sulfanilamide was found to be
effective against streptococcal infections.
© 2013 Pearson Education, Inc. Chapter 19 59
 Biological Activity of Sulfanilamide

 Sulfanilamide is an analogue of p-aminobenzoic acid.

 Streptococci use p-aminobenzoic acid to synthesize
folic acid, an essential compound for growth and
reproduction. Sulfanilamide cannot be used to make
folic acid.
 Bacteria cannot distinguish between sulfanilamide
and p-aminobenzoic acid, so it will inhibit their growth
and reproduction.
© 2013 Pearson Education, Inc. Chapter 19 60
 Amines as Leaving Groups
 Amines can undergo elimination
reactions to form alkenes.
– –
 The NH2 or NHR groups are not good
leaving groups because they are very
strong bases.
 Exhaustive methylation can convert the
amino group into a quaternary
ammonium salt, which can leave as the
neutral amine.
© 2013 Pearson Education, Inc. Chapter 19 61
 Hofmann Elimination

 A quaternary ammonium salt has a good

leaving group—a neutral amine.
 Heating the hydroxide salt produces the least
substituted alkene.

© 2013 Pearson Education, Inc. Chapter 19 62

 Exhaustive Methylation of Amines

 Methyl iodide is usually used as methylating

agent.
 The leaving group is the neutral amine.

© 2013 Pearson Education, Inc. Chapter 19 63

 Conversion to the Hydroxide Salt

 The iodide salt is converted to the hydroxide

salt by treatment with silver oxide and water.
 The hydroxide will serve as the base in the
elimination step.

© 2013 Pearson Education, Inc. Chapter 19 64

 Mechanism of the Hofmann
Elimination

 The Hofmann elimination is a one-step,

concerted E2 reaction in which the amine is
the leaving group.

© 2013 Pearson Education, Inc. Chapter 19 65

 Regioselectivity of the Hofmann
Elimination

 The least substituted product is the major

product of the reaction (Hofmann product).
© 2013 Pearson Education, Inc. Chapter 19 66
 E2 Mechanism

© 2013 Pearson Education, Inc. Chapter 19 67

 The key to solving Hofmann
elimination problems is to find all
possible ways the compound can
eliminate. Then, the one that gives
the least substituted alkene is
probably favored.

© 2013 Pearson Education, Inc. Chapter 19 68

 Solved Problem 2
Predict the major product(s) formed when the following amine is treated with excess iodomethane,
followed by heating with silver oxide.

Solution
Solving this type of problem requires finding every possible elimination of the methylated salt. In this
case, the salt has the following structure:

© 2013 Pearson Education, Inc. Chapter 19 69

 Solved Problem 2 (Continued)
Solution (Continued)
The green, blue, and red arrows show the three possible elimination routes. The corresponding
products are

The first (green) alkene has a disubstituted double bond. The second (blue) alkene is monosubstituted,
and the red alkene (ethylene) has an unsubstituted double bond. We predict that the red products will
be favored.

© 2013 Pearson Education, Inc. Chapter 19 70

 Oxidation of Amines

 Amines are easily oxidized, even in air.

 Common oxidizing agents: H2O2 , MCPBA.
 2 amines oxidize to hydroxylamine (—NOH).
 3 amines oxidize to amine oxide (R3N+—O-).

© 2013 Pearson Education, Inc. Chapter 19 71

 Preparation of Amine Oxides

 Tertiary amines are oxidized to amine oxides, often in

good yields.
 Either H2O2 or peroxyacid may be used for this
oxidation.
 The N-oxide can undergo elimination to form alkenes
in a reaction analogous to the Hofmann elimination.
© 2013 Pearson Education, Inc. Chapter 19 72
 Cope Rearrangement

 E2 mechanism.
 The amine oxide acts as its own base through a
cyclic transition state, so a strong base is not needed.

© 2013 Pearson Education, Inc. Chapter 19 73

 Solved Problem 3
Predict the products expected when the following compound is treated with H 2O2 and heated.

Solution
Oxidation converts the tertiary amine to an amine oxide. Cope elimination can give either of two
alkenes. We expect the less hindered elimination to be favored, giving the Hofmann product.

© 2013 Pearson Education, Inc. Chapter 19 74

 Formation of Diazonium Salts

R NH2 + NaNO2 + 2 HCl R N N Cl- + 2 H2O + NaCl

R N N R + N N

 Primary amines react with nitrous acid

(HNO2) to form dialkyldiazonium salts.
 The diazonium salts are unstable and
decompose into carbocations and nitrogen.

© 2013 Pearson Education, Inc. Chapter 19 75

 Diazotization of an Amine
Step 1: The amine attacks the nitrosonium ion and forms N-
nitrosoamine.

Step 2: A proton transfer (a tautomerism) from nitrogen to

oxygen forms a hydroxyl group and a second N-N bond.

© 2013 Pearson Education, Inc. Chapter 19 76

 Diazotization of an Amine
(Continued)
Step 3: Protonation of the hydroxyl group, followed by the loss
of water, gives the diazonium ion.

© 2013 Pearson Education, Inc. Chapter 19 77

 Arenediazonium Salts

 By forming and diazotizing an amine, an

activated aromatic position can be converted
into a wide variety of functional groups.

© 2013 Pearson Education, Inc. Chapter 19 78

 Reactions of Arenediazonium
Salts

© 2013 Pearson Education, Inc. Chapter 19 79

 The Sandmeyer Reaction

© 2013 Pearson Education, Inc. Chapter 19 80

 Reductive Amination: 1º Amines

 Primary amines result from the condensation of

hydroxylamine (zero alkyl groups) with a ketone or an
aldehyde, followed by reduction of the oxime.
 LiAlH4 or NaBH3CN can be used to reduce the oxime.

© 2013 Pearson Education, Inc. Chapter 19 81

 Reductive Amination: 2º Amines

 Condensation of a ketone or an aldehyde with a

primary amine forms an N-substituted imine (a Schiff
base).
 Reduction of the N-substituted imine gives a
secondary amine.

© 2013 Pearson Education, Inc. Chapter 19 82

 Reductive Amination: 3º Amines

 Condensation of a ketone or an aldehyde with a

secondary amine gives an iminium salt.
 Iminium salts are frequently unstable, so they are
rarely isolated.
 A reducing agent in the solution reduces the iminium
salt to a tertiary amine.
© 2013 Pearson Education, Inc. Chapter 19 83
 Solved Problem 3
Show how to synthesize the following amines from the indicated starting materials.
(a) N-cyclopentylaniline from aniline (b) N-ethylpyrrolidine from pyrrolidine

Solution
(a) This synthesis requires adding a cyclopentyl group to aniline (primary) to make a secondary
amine. Cyclopentanone is the carbonyl compound.

(b) This synthesis requires adding an ethyl group to a secondary amine to make a tertiary amine. The
carbonyl compound is acetaldehyde. Formation of a tertiary amine by Na(AcO)3BH reductive
amination involves an iminium intermediate, which is reduced by sodium triacetoxyborohydride.

© 2013 Pearson Education, Inc. Chapter 19 84

 Synthesis of 1º Amines by
Acylation–Reduction

 Acylation of the starting amine by an acid chloride

gives an amide with no tendency toward
overacylation.
 Reduction of the amide by LiAlH4 gives the
corresponding amine.

© 2013 Pearson Education, Inc. Chapter 19 85

 Synthesis of 2º Amines by
Acylation–Reduction

 Acylation–reduction converts a primary amine

to a secondary amine.
 LiAlH4, followed by hydrolysis, can easily
reduce the intermediate amide to the amine.

© 2013 Pearson Education, Inc. Chapter 19 86

 Synthesis of 3º Amines by
Acylation–Reduction

 Acylation–reduction converts a secondary

amine to a tertiary amine.
 Reduction of the intermediate amide is
accomplished with LiAlH4.

© 2013 Pearson Education, Inc. Chapter 19 87

 Solved Problem 4
Show how to synthesize N-ethylpyrrolidine from pyrrolidine using acylation–reduction.

Solution
This synthesis requires adding an ethyl group to pyrrolidine to make a tertiary amine. The acid chloride
needed will be acetyl chloride (ethanoyl chloride). Reduction of the amide gives N-ethylpyrrolidine.

Compare this synthesis with Solved Problem 19-5(b) to show how reductive amination and acylation–
reduction can accomplish the same result.

© 2013 Pearson Education, Inc. Chapter 19 88

 The Gabriel Synthesis

 The phthalimide ion is a strong nucleophile, displacing

the halide or tosylate ion from the alkyl halide (SN2).
 Heating the N-alkyl phthalimide with hydrazine
displaces the primary amine and the very stable
hydrazide of phthalimide.

© 2013 Pearson Education, Inc. Chapter 19 89

 Reduction of Azides

 Azide ion, –N3, is a good nucleophile.

 React azide with unhindered 1 or 2 halide or
tosylate (SN2).
 Alkyl azides are explosive, so reduction is carried out
without purifying the azide.
© 2013 Pearson Education, Inc. Chapter 19 90
 Reduction of Nitriles

 Nitrile (CN) is a good SN2 nucleophile.

 Reduction with H2 or LiAlH4 converts the
nitrile into a primary amine.

© 2013 Pearson Education, Inc. Chapter 19 91

 To convert an alkyl halide (or alcohol, via
the tosylate) to an amine, form the azide
and reduce. To convert it to an amine
with an additional carbon atom, form the
nitrile and reduce. In either case, the alkyl
group must be suitable for displacement.

© 2013 Pearson Education, Inc. Chapter 19 92

 Reduction of Nitro Compounds

 The nitro group can be reduced to the amine

by catalytic hydrogenation or by an active
metal and H+.
 Commonly used to synthesize anilines.

© 2013 Pearson Education, Inc. Chapter 19 93