ChE 2101:

Organic Chemistry
Group 3
Bayoneta, Sheree G.
Bonifacio, Kiara Beatriz A.
Garaygay, Mc Milklyn L.
Introduction to Thiols
Sulfur analogs of alcohols contain an SH group in place
of an OH group and are called thiols. The nomenclature
of thiols is similar to that of alcohols, but the suffix of the
name is “thiol” instead of “ol”

“e” is kepth before the suffix “thiol”

Introduction to Thiols
Sulfur analogs of alcohols contain an SH group in place
of an OH group and are called thiols. The nomenclature
of thiols is similar to that of alcohols, but the suffix of the
name is “thiol” instead of “ol”
“e” is kepth before the suffix “thiol”

3-methylbutanol 3-methylbutanethiol
Introduction to Thiols
However, when another functional group is present in the compound,
the SH group is named as a substituent and is called a mercapto group:
Introduction to Thiols
However, when another functional group is present in the compound,
the SH group is named as a substituent and is called a mercapto group:

3-mercapto-3-methylbutanol
Introduction to Thiols
Thiols were once called mercaptans, thus, the name “mercapto” is
derived from that fact. The term is derived from the Latin mercuirum
captans (capturing mercury) and is used to describe the ability of thiols
to form complexes with mercury as well as other metals.

Dimercaprol is used
to treat mercury and
lead poisoning.
Introduction to Thiols
Do Thiols smell good?
Thiols have pungent, unpleasant odors. Skunks use thiols as a defense
mechanism to ward off predators by spraying a mixture that delivers a
might stench. Methanethiol is added to natural gas so that gas leaks can
be easily detected.
Preparation of Thiols
Thiols can be prepared via an SN2 reaction between sodium
hydrosulfide(NaSH) and a suitable alkyl halide.

The reaction can occur even at secondary substrate without competing

E2 reactions, because HS- is an excellent nucleophile and a poor base.
Preparation of Thiols
When the nucleophile attacks a chirality center, inversion of
consiguration is observed.
Preparation of Thiols
Thiols easily undergo oxidation to produce disulfides.

The process begins with deprotontion of the thiol to generate a thiolate

ion. Hydroxide is a strong enough base that the equilibrium favors
formation of the thiolate ion. This thiolate ion is an excellent nucleophile
and can attack molecular bromine in an SN2 process. A second SN2
process then produces the disulfide.
Oxidation of Thiols
Oxidation of Thiols
There are many oxidizing agents that can be used to convert thiols into
disulfides. In fact, the reaction is accomplished with so much ease that
atmospheric oxygen can function as an oxidizing agent to produce
disulfides. Catalysts can be used to speed up the process. Disulfides are
also easily reduced back to thiols when treated with a reducing agent,
such as HCl in the presence of zinc.
Introduction to Amines

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Classification of Amines
Amines are derivatives of ammonia in which one or more of the protons
have been replaced with alkyl or aryl groups.

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Classification of Amines
Amines are abundant in nature. Naturally occurring amines isolated from
plants are called alkaloids.

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Classification of Amines
Many amines also play vital roles in neurochemistry (chemistry taking
place in the brain).

In fact, many pharmaceuticals are amines. 3

Reactivity of Amines
The nitrogen atom of an amine possesses a lone pair that represents a
region of high electron density. The presence of this lone pair is
responsible for most of the reactions exhibited by amines. Specifically,
the lone pair can function as a base or as a nucleophile

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Nomenclature of Amines
Nomenclature of Primary Amines
Nomenclature of Secondary and Tertiary Amines

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Primary Amines
A primary amine is a compound containing an NH2 group connected to
an alkyl group. IUPAC nomenclature allows two different ways to name
primary amines.
For Simple Alkyl Group:
The compound is named as an alkyl amine.
CH3-NH2 CH3CH2-NH2

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methylamine ethylamine
Primary Amines
For Complex Alkyl Groups:
The compound is named as an alkanamines.

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Primary Amines
For Complex Alkyl Groups:
The compound is named as an alkanamines.

(2R,4R)-4,6-Dimethyl-2-heptanol

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Primary Amines
For Complex Alkyl Groups:
The compound is named as an alkanamines.

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Primary Amines
For Complex Alkyl Groups:
The compound is named as an alkanamines.

(2R,4R)-4,6-Dimethyl-2-heptanol
(2R,4R)-4,6-Dimethyl-2-heptanamine

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Primary Amines
Step 1. Identify the longest carbon chain bonded to the
amine nitrogen.
Step 2. Identify the substituents.
Step 3. Number the parent chain giving the amine the
lowest locant
Step 4. Put everything together having the substituents in
alphabetical order.
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Primary Amines
When another functional group is present in the compound, the amino
group is generally listed as a substituent. The other functional group (with
the exception of halogens) receives priority and its name becomes the
suffix.

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Primary Amines
When another functional group is present in the compound, the amino
group is generally listed as a substituent. The other functional group (with
the exception of halogens) receives priority and its name becomes the
suffix.

4-Aminobutanol

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Primary Amines
When another functional group is present in the compound, the amino
group is generally listed as a substituent. The other functional group (with
the exception of halogens) receives priority and its name becomes the
suffix.

4-Aminobutanol

para-Aminobenzoic acid 3
Primary Amines
Aromatic amines, also called aryl amines, are generally named as
derivatives of aniline.

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Secondary and Tertiary Amines

Secondary and tertiary amines can also be named as alkyl amines or as

alkanamines. The complexity of the alkyl groups typically determines
which system is chosen

If all alkyl groups are simple in structure:

The groups are listed in alphabetical order. The prefixes “di” and “tri” are
used if the same alkyl group appears more than once.

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Secondary and Tertiary Amines

If all alkyl groups are simple in structure:

Ethylmethylpropylamine Diethylamine Trimethylamine

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Secondary and Tertiary Amines

If there is a complex alkyl group:

The compound is typically named as an
alkanamine, with the most complex alkyl group
treated as the parent and the simpler alkyl
groups treated as substituents.
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Secondary and Tertiary Amines

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Secondary and Tertiary Amines

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Secondary and Tertiary Amines

(S)-2,2-dichloro-N-ethyl-N-methyl-3-hexanamine
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Secondary and Tertiary Amines

(S)-2,2-dichloro-N-ethyl-N-methyl-3-hexanamine
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Secondary and Tertiary Amines

(S)-2,2-dichloro-N-ethyl-N-methyl-3-hexanamine (R)-N-ethyl-6-methyl-3-heptanamine
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Recitation

Assign a name for each of the following compounds:

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Recitation

Assign a name for each of the following compounds:

cyclohexylmethylamine tricyclobutylamine 3,3-dimethylbutanamine

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Recitation

Assign a name for each of the following compounds:

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Recitation
Assign a name for each of the following compounds:

cyclopentanamine 4-bromo-N-methyl-1-hexanamine 3
Seatwork

Assign a name for each of the following compounds:

3
Seatwork

Assign a name for each of the following compounds:

(1R,2S)-2-methylcyclohexanamine (1S,3S)-3-aminocyclohexanol

diphenylamine

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N,N-diethylethanamine 1,4-butanediamine
Properties of Amines
Geometry

Amine Hybridization
Nitrogen in amines is typically sp3
hybridized, with a lone pair in an sp3-
hybridized orbital. Trimethylamine serves
as an example. Its nitrogen exhibits
trigonal pyramidal geometry with bond
angles of 108°.

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Properties of Amines
Geometry
Bond Lengths:
The C-N bond lengths in trimethylamine are 147 pm, shorter than C-C bonds in
alkanes (153 pm) and longer than C-O bonds in alcohols (143 pm).
Chirality in Amines:
Amines with three different alkyl groups are chiral due to the nitrogen atom having
four different groups (three alkyl groups and a lone pair).
Chirality and Optical Activity:
Amines with three different alkyl groups are generally not optically active at room
temperature due to rapid pyramidal inversion, leading to a racemic mixture of
enantiomers.
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Properties of Amines
Geometry
Pyramidal Inversion:
During pyramidal inversion, the nitrogen atom briefly transitions to sp2 hybridization,
with an energy barrier of about 25 kJ/mol (6 kcal/mol) higher than the sp3-hybridized
geometry. This barrier is easily surmounted at room temperature.

Resolution Challenge:
The small energy barrier makes it difficult to resolve amines with three different alkyl
groups at room temperature.

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Properties of Amines
Colligative Properties
Solubility Trends:
Amines with fewer than five carbon atoms per amino group are generally water-soluble; those with
more than five carbon atoms are sparingly soluble.
Example: Ethylamine is soluble in water, while octylamine is not.
Hydrogen Bonding:
Primary and secondary amines can form intermolecular hydrogen bonds, leading to higher boiling
points than analogous alkanes but lower than analogous alcohols.

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Properties of Amines
Colligative Properties
Boiling Point Trends:
Boiling points of amines increase with their capacity to form hydrogen bonds.
Primary amines generally have higher boiling points, while tertiary amines have
lower boiling points.

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Properties of Amines
Other Distinctive Features of Amines
1. Fishlike Odor: Amines with low molecular weights, like trimethylamine, often exhibit a
fishlike odor.
2. Fish Odor Source: The fish odor is caused by amines produced when enzymes
break down certain fish proteins.
3. Putrescine and Cadaverine: These compounds, found in rotting fish, contribute to
the characteristic odor of decaying fish.
4. Presence in Urine: Putrescine and cadaverine are also present in urine, contributing
to its characteristic odor.

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Properties of Amines
Basicity of Amines
One of the most important properties of amines is their basicity. Amines are generally
stronger bases than alcohols or ethers, and they can be effectively protonated even by
weak acids.

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Properties of Amines

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Properties of Amines
Delocalization Effects
pKa Values of Ammonium Ions:
Alkyl amines typically have a pKa value between 10 and 11. Aryl amines are more acidic
(lower pKa) than alkyl amines, making them less basic.

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Properties of Amines
Delocalization Effects
pKa Values of Ammonium Ions:
Alkyl amines typically have a pKa value between 10 and 11. Aryl amines are more acidic
(lower pKa) than alkyl amines, making them less basic.

Effect of Substituents on Aryl Amines:

Electron-donating groups (e.g., methoxy) slightly increase basicity.
Electron-withdrawing groups (e.g., nitro) significantly decrease basicity.

Amides and Lone-Pair Delocalization:

Amides exhibit extensive lone-pair delocalization through resonance.
Amides do not function as bases and are poor nucleophiles due to low electron
3
density.
Properties of Amines
Amines at Physiological pH
Henderson-Hasselbalch equation to show that a carboxylic acid group (COOH)
exists primarily as a carboxylate ion at physiological pH. A similar argument can be
used to show that an amine group also exists primarily as a charged ammonium ion
at physiological pH:

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PREPARATION OF AMINES: A REVIEW

Preparing an Amine from an Alkyl Halide

Amines can be prepared from alkyl halides in a two-step process in
which the alkyl halide is converted to a nitrile, which is then reduced.
PREPARATION OF AMINES: A REVIEW

Preparing an Amine from Carboxylic Acid

Amines can be prepared from carboxylic acids using the following
approach:
PREPARATION OF AMINES: A REVIEW

Preparing Aniline and Its Derivatives from Benzene

Aryl amines, such as aniline, can be prepared from benzene using the
following approach:.
PREPARATION OF AMINES: A REVIEW

For example, a nitro group can be selectively reduced in the

presence of a carbonyl group:
 PREPARATION OF AMINES via SUBSTITUTION
REACTIONS
Alkylation of Ammonia
Ammonia is a very good nucleophile and will readily undergo alkylation
when treated with an alkyl halide.

This reaction proceeds via an SN2 process followed by deprotonation

to give a primary amine.
PREPARATION OF AMINES via SUBSTITUTION
REACTIONS
As the primary amine is
formed, it can undergo
further alkylation to produce
a secondary amine, which
undergoes further alkylation
to produce a tertiary amine.
Finally, the tertiary amine
undergoes alkylation one
more time to produce a
quaternary ammonium salt.
 PREPARATION OF AMINES via SUBSTITUTION
REACTIONS
The Azide Synthesis
The azide synthesis is a better method for preparing primary amines than alkylation of
ammonia because it avoids the formation of secondary and tertiary amines. This method
involves treating an alkyl halide with sodium azide followed by reduction.
 PREPARATION OF AMINES via SUBSTITUTION
REACTIONS

Mechanism of the Azide Synthesis

 PREPARATION OF AMINES via SUBSTITUTION
REACTIONS

The Gabriel Synthesis

The Gabriel synthesis is another method for preparing primary amines while
avoiding formation of secondary and tertiary amines. The key reagent is potassium
phthalimide, which is prepared by treating phthalimide with potassium hydroxide
PREPARATION OF AMINES via SUBSTITUTION
REACTIONS

This reaction proceeds via an

SN2 process, so it works best with
primary alkyl halides. It can be
performed with secondary alkyl
halides in many cases, but
tertiary alkyl halides cannot be
used.

Acid catalyzed or base-catalyzed hydrolysis is then performed to

release the amine. Acidic conditions are more common than basic
conditions.
 PREPARATION OF AMINES via SUBSTITUTION
REACTIONS
Under acidic conditions, an ammonium ion is generated, which must be treated with a base to
release the uncharged amine. The mechanism of hydrolysis is directly analogous to the
hydrolysis of amides. The hydrolysis step is slow, and many alternative approaches have been
developed. One such alternative employs hydrazine to release the amine and involves two
successive nucleophilic acyl substitution reactions.
 PREPARATION OF AMINES via REDUCTIVE
ANIMATION
Recall that ketones or aldehydes can be converted into imines when treated with ammonia in
acidic conditions. If the reaction is carried out in the presence of a reducing agent, such as H2,
then the imine is reduced as soon as it is formed, giving an amine.
This process, called reductive
amination, can be accomplished
in one reaction flask by
hydrogenating a solution
containing the ketone, ammonia,
and a proton source. With this
approach, the imine is reduced
under the conditions of its
formation.
 PREPARATION OF AMINES via REDUCTIVE
ANIMATION

Many other reducing agents are also frequently employed instead of hydrogenation. The
most common reducing agent for this purpose is sodium cyanoborohydride (NaBH3CN), which
is similar in structure to sodium borohydride (NaBH4), but a cyano group has replaced one of
the hydrogen atoms.
 PREPARATION OF AMINES via REDUCTIVE
ANIMATION

Recall that a cyano group is electron withdrawing, and its presence stabilizes the negative
charge on the boron atom. As a result, NaBH3CN is a more selective hydride-reducing agent
than NaBH4. This selectivity can be exploited to achieve the reductive amination of a ketone
or aldehyde:
PREPARATION OF AMINES via REDUCTIVE
ANIMATION
This process cannot be achieved with
NaBH4, which would simply reduce the
ketone before it is converted into an
imine. In contrast, NaBH3CN does not
react with ketones but will reduce an
iminium ion (a protonated imine). This
process enables the conversion of a
ketone or aldehyde into an amine in one
reaction flask. The identity of the
nucleophile (NH3) can be changed,
enabling the preparation of primary,
secondary, or tertiary amines.
 SYNTHESIS STRATEGIES

In the previous sections, we explored a variety of methods for preparing primary amines.
Each of these methods utilizes a different source of nitrogen atoms.
 SYNTHESIS STRATEGIES
Secondary amines are readily prepared from primary amines via reductive amination.
Similarly, tertiary amines are readily prepared from secondary amines via reductive.
amination.

Direct alkylation of the primary amine is not efficient because

polyalkylation is generally unavoidable. Therefore, it is more efficient to
use reductive amination as an indirect method for alkylating the nitrogen
atom of an amine.
 SYNTHESIS STRATEGIES

Tertiary amines can be converted into quaternary ammonium salts via alkylation. This
process is efficient because polyalkylation is not possible with tertiary amines.
SYNTHESIS STRATEGIES

Summary
of
Synthesis
Strategies
 ACYLATION OF AMINES

The reaction takes place via a nucleophilic acyl substitution process, and HCl is a by-product
of the reaction. As HCl is produced, the starting amine is protonated to form an ammonium
ion, which will not attack the acyl halide. Therefore, two equivalents of the amine are
required. Polyacylation does not occur, because the resulting amide is not nucleophilic.
 ACYLATION OF AMINES

Acylation of an amino group is an extremely useful technique when performing electrophilic

aromatic substitution reactions, because it enables transformations that are otherwise
difficult to achieve. For example, consider what happens when aniline is treated with
bromine.

The amino group strongly

activates the ring, and
tribromination occurs readily.
 ACYLATION OF AMINES
Monobromination of aniline is extremely difficult to achieve. Even when one equivalent of
bromine is used, a mixture of products is obtained. This problem can be circumvented by first
acylating the amino group. The resulting amide group is less activating than an amino group,
and monobromination becomes possible. After the bromination step, the amide group can be
removed by hydrolysis. This three-step route provides a method for the monobromination of
aniline, which would otherwise be difficult to achieve.
 ACYLATION OF AMINES
As another example, consider what happens if we try to perform a Friedel-Crafts reaction
(alkylation or acylation) using aniline as a starting material.

The amino group attacks the Lewis acid to form an acid-base complex in
which the aromatic ring is now strongly deactivated. Recall that strongly
deactivated rings are unreactive toward Friedel-Crafts reactions. As a
result, it is not possible to achieve a Friedel-Crafts reaction with aniline
as a starting material.
 ACYLATION OF AMINES

Once again, this problem can be circumvented by first acylating the amino group. The
nitrogen atom of the resulting amide is not nucleophilic. Under these conditions, a Friedel-
Crafts reaction can be performed, and the amide group can then be removed via hydrolysis.
This three-step route provides a method for alkylating aniline, something that cannot be
accomplished directly.
Hofmann Elimination
Amines, like alcohols, can serve as precursors in the
preparation of alkenes
 Hofmann Elimination
All alcohols can only undergo an E2 process if the OH group is first converted into a
better leaving group (such as a tosylate). Similarly, amines can also undergo an E2
reaction if the amino group is first converted into a better leaving group. This can be
accomplished by treating the amine with excess methyl iodide.
 Hofmann Elimination
Amines will undergo exhaustive alkylation in the presence of excess methyl iodide,
producing a quaternary ammonium salt.

This process is called a Hofmann elimination. The function of silver oxide is to convert one
ammonium salt into another ammonium salt by exchanging the iodide ion for a hydroxide ion
Hofmann Elimination
The newly formed hydroxide ion then serves as the base that triggers the
E2 process:
Hofmann Elimination
Gauche interaction
Hofmann Elimination
Gauche interaction
Hofmann Elimination
Draw the major product obtained when 3-methyl-3-hexanamine is treated with
excess methyl iodide followed by aqueous silver oxide and heat
Hofmann Elimination
Reactions of Amines with Nitrous Acid

Amines are treated with nitrous acid

Formation of Nitrous Acid and Nitrosonium Ions

Reactions of Amines with Nitrous Acid
Secondary Amines and Nitrous Acid
Reactions of Amines with Nitrous Acid
The amine functions as a nucleophile and attacks a nitrosonium ion that was generated in situ from
sodium nitrite and HCl. The resulting ammonium ion is then deprotonated to give the product.
Nitrosamines are known to be potent carcinogens. Several examples are shown below:
Reactions of Amines with Nitrous Acid
Primary Amines and Nitrous Acid
Reactions of Amines with Nitrous Acid
When the R group of the primary amine is an alkyl group as opposed to an aryl group, then the resulting
diazonium salt is highly unstable and is too reactive to be isolated. It can spontaneously liberate nitrogen
gas to form a carbocation, which then reacts in a variety of ways
 Reactions of Aryldiazonium Ions

Aryl amines can be converted into aryldiazonium salts upon treatment with nitrous acid
 Reactions of Aryldiazonium Ions
Sandmeyer Reactions
The Sandmeyer reactions utilize copper salts (CuX) and enable the installation
of a halogen or a cyano group on an aromatic ring:
 Reactions of Aryldiazonium Ions
Fluorination
When treated with fluoroboric acid (HBF4), an aryl diazonium salt is converted into a fluorobenzene.
This reaction, called the Schiemann reaction, is useful for installing fluorine on an aromatic ring, which
is not easy to accomplish with other methods.
 Reactions of Aryldiazonium Ions
Other Substitution Reactions of Aryl Diazonium Salts
When an aryl diazonium salt is heated in the presence of water, the diazo group is replaced
with a hydroxyl group.
 Reactions of Aryldiazonium Ions
Azo Coupling -aryldiazonium salts are also known to react with activated aromatic rings.

This process, called azo coupling, is believed to occur via an electrophilic aromatic
substitution reaction.
 Nitrogen Heterocycles
A heterocycle is a ring that contains atoms of more than one element. Common organic
heterocycles are comprised of carbon and either nitrogen, oxygen, or sulfur. Consider, for
example, the structures of Viagra and Nexium. Both of these compounds contain nitrogen
heterocycles, highlighted in red. Many different kinds of heterocycles are commonly found in
the structures of biological molecules and pharmaceuticals. We will discuss just a few simple
heterocycles in this section
 Nitrogen Heterocycles
Pyrrole and Imidazole
Pyrrole, a five-membered aromatic ring containing one nitrogen atom, is numbered
starting with the nitrogen atom.

Pyrrole undergoes reactions that are expected for an aromatic system, such as electrophilic aromatic
substitution. In fact, pyrrole is even more reactive than benzene, and low temperatures are often
required to control the reaction.
 Nitrogen Heterocycles
Pyrrole and Imidazole
Electrophilic aromatic substitution occurs primarily at C2, because the intermediate
formed during attack at C2 is stabilized by resonance.

When an attack takes place at C2, the intermediate has three resonance structures. In contrast,
when an attack takes place at C3, the intermediate has only two resonance structures. An
imidazole ring is like pyrrole but has one extra nitrogen atom at the 3 position. Histamine is an
example of an important biological compound that contains an imidazole ring.
 Nitrogen Heterocycles
Pyridine and Pyrimidine
Pyridine is a six-membered aromatic ring containing one
nitrogen atom and is numbered starting with the nitrogen
atom:
Pyridine undergoes electrophilic aromatic substitution reactions;
however, the yields are generally quite low, because the
inductive effect of the nitrogen atom renders the ring electron
poor. High temperatures are required:

Pyrimidine is similar in structure to pyridine but contains

one extra nitrogen atom at the 3 position. Pyrimidine rings
are very common in biological molecules. Pyrimidine is less
basic than pyridine due to the inductive effect of the
second nitrogen atom:
 Spectroscopy of Amines
IR Spectroscopy
In their IR spectra, primary and secondary amines exhibit signals between 3350 and 3500
cm^-1. These signals correspond with N-H stretching and are typically less intense than
O-H signals. Primary amines give two peaks (symmetric and asymmetric stretching),
while secondary amines give only one peak.

Tertiary amines lack an N-H bond and do not exhibit a signal in the region between 3350
and 3500 cm^-1 . Tertiary amines can be detected with IR spectroscopy by treatment with
HCl. The resulting N-H bond exhibits a characteristic signal between 2200 and 3000
cm^-1
 Spectroscopy of Amines
NMR Spectroscopy
In the 1 H NMR spectrum of an amine, any proton attached directly to the nitrogen atom (for primary and
secondary amines) will typically appear as a broad signal somewhere between 0.5 and 5.0 ppm. The
precise location is sensitive to many factors, including the solvent, concentration, and temperature.
Splitting is generally not observed for these protons, because they are labile and are exchanged at a rate
that is faster than the timescale of the NMR spectrometer. The broad signal for these protons can
generally be removed from the spectrum by dissolving the amine in D2O, which results in a proton
exchange that replaces these protons for deuterons.
 Spectroscopy of Amines
NMR Spectroscopy
Protons connected to the a position typically appear between 2 and 3
ppm because of the deshielding effect of the nitrogen atom. As an
example, consider the chemical shifts for the protons in
propylamine:

Notice that the deshielding effect of the nitrogen atom is greatest for
the a protons (2.7 ppm) and tapers off with distance. The b protons
are affected to a lesser extent (1.5 ppm), and the g protons are not
measurably affected (0.9 ppm). In the 13C NMR spectrum of an
amine, the a carbon atoms typically appear between 30 and 50 ppm.
That is, they are shifted about 20 ppm downfield due to the
deshielding effect of the nitrogen atom
 Spectroscopy of Amines
Mass Spectroscopy
The mass spectrum of an amine is characterized by the presence of a parent ion with an odd
molecular weight. This follows the nitrogen rule, which states that a compound with an odd
number of nitrogen atoms will produce a parent ion with an odd molecular weight. In addition,
amines generally exhibit a characteristic fragmentation pattern. They undergo a cleavage to
generate a radical and a resonance-stabilized cation.