Preparation of Amines

Preparation of Amines
 Three types of reactions are commonly used to
prepare an amine:

[1] Nucleophilic substitution using nitrogen nucleophiles.

[2] Reduction of other nitrogen-containing functional
groups.
[3] Reductive amination of aldehydes and ketones .
Nucleophilic Substitution
 Nucleophilic Substitution
 Nucleophilic substitution is the key step in two different
methods for synthesizing amines: direct nucleophilic
substitution and the Gabriel synthesis of 1° amines.
A) Direct Nucleophilic Substitution:
 Depends on SN2 reaction of an alkyl halide with NH3 or an
amine.
 The method requires two steps:
[1] Nucleophilic attack of the nitrogen nucleophile forms an
ammonium salt.
[2] Removal of a proton on N forms the amine.
 The identity of the nitrogen nucleophile determines the type of
amine or ammonium salt formed as product.
 Because the reaction follows an SN2 mechanism, the alkyl halide
must be unhindered
Nucleophilic Substitution
 Nucleophilic Substitution
(Poly-alkylation problem)
 Any amine formed by nucleophilic substitution still has a
nonbonded electron pair, making it a nucleophile as well.
 It will react with remaining alkyl halide to form a more
substituted amine giving mixture of 1°, 2°, and 3° amines .
 Polyalkylation in nucleophilic substitution limits its usefulness,
except for the quaternary ammonium salts.
 Alkylation of Azide Ion and Reduction

 A better method for preparing primary amines is to use azide ion,

N3, as the nucleophile rather than ammonia for SN2 reaction with a
primary or secondary alkyl halide.
 The product is an alkyl azide, which is not nucleophilic, so
overalkylation can’t occur.
 Subsequent reduction of the alkyl azide with LiAlH4 then leads to
the desired primary amine.
 Problem (1)
 Draw the product of each reaction.
 Problem (2)
 Draw a stepwise, detailed mechanism for the following
reaction.
 Problem (3)
 Nicotine can be made when the following ammonium salt
is treated with Na2CO3. Draw a stepwise mechanism for
this reaction.
The Gabriel Synthesis of 1°
Amines
 The Gabriel Synthesis of 1° Amines
 The Gabriel synthesis consists of two steps and uses a resonance-
stabilized nitrogen nucleophile to synthesize 1° amines via
nucleophilic substitution.
 The Gabriel synthesis begins with phthalimide, one of a group of
compounds called imides.
 The N – H bond of an imide is especially acidic because the
resulting anion is resonance stabilized by the two flanking carbonyl
groups.
The Gabriel Synthesis of 1° Amines
Example
 Problem (1)
 What alkyl halide is needed to prepare each 1° amine
by a Gabriel synthesis?
 Problem (2)
 Which amines cannot be prepared by a Gabriel synthesis?
Explain your choices.
Reduction methods
Reduction of Nitro & Nitriles Compounds

 Amines can be prepared by reduction of nitro compounds,

nitriles, and amides.
 [1] From nitro compounds: Nitro groups are reduced to 1°
amines using a variety of reducing agents.

 [2] From Nitriles: are reduced to 1° amines with LiAlH4.

 Reduction of Nitriles Compounds
 Because a cyano group is readily introduced by S N2
substitution of alkyl halides with –CN, this provides a
two-step method to convert an alkyl halide to a 1° amine
with one more carbon atom.
 The conversion of CH3Br to CH3CH2NH2 illustrates this
two-step sequence.
 Reduction of amides Compounds
 [3] From amides: 1°, 2°, and 3° amides are reduced to
1°, 2°, and 3° amines, respectively, by using LiAlH4.
 Reduction of Nitro Compounds

 The most widely used method for preparing aromatic

amines involves nitration of the ring and subsequent
reduction of the nitro group to an amino group:
 Reduction of Nitro Compounds
 The most frequently used methods employ catalytic
hydrogenation, or treatment of the nitro compound with
acid and iron.
 Problem (1)
 What nitro compound, nitrile, and amide are reduced
to each compound?
 Problem (2)
 What amine is formed by reduction of each amide?
 Problem (3)
 Which amines cannot be prepared by reduction of an
amide?
Reductive Amination of
Aldehydes and Ketones
 Reductive Amination of Aldehydes
and Ketones
 Reductive amination: is a two-step method that
converts aldehydes and ketones into 1°, 2°, and 3°
amines.

 There are two distinct parts in reductive amination:

[1] Nucleophilic attack of NH3 on the carbonyl group
forms an imine, which is not isolated; then,
[2] Reduction of the imine forms an amine.
Reductive Amination of Aldehydes
and Ketones
 Reductive Amination of Aldehydes
and Ketones
 The most effective reducing agent for this reaction is
sodium cyanoborohydride (NaBH3CN).
 This hydride reagent is a derivative of sodium
borohydride (NaBH4), formed by replacing one H atom
by CN.
Reductive Amination of Aldehydes
and Ketones
 Reductive Amination of Aldehydes
and Ketones
 With a 1° or 2° amine as starting material, reductive
amination is used to prepare 2° and 3° amines, respectively.
 Synthesis of methamphetamine
 In reductive amination, one of the H atoms bonded to N is
replaced by an alkyl group.
 As a result, a 1° amine is converted to a 2° amine and a 2° amine
is converted to a 3° amine.

 CH3NH2 (a 1° amine) is converted to methamphetamine (a 2°

amine).
 Reductive Amination of Aldehydes
and Ketones
 To use reductive amination in synthesis, you must be able to
determine what aldehyde or ketone and nitrogen compound are
needed to prepare a given amine—that is, you must work
backwards in the retrosynthetic direction.
 Keep in mind the following two points:
 One alkyl group on N comes from the carbonyl compound.
 The remainder of the molecule comes from NH3 or an amine.
Retrosynthetic analysis for preparing 2-
phenylethylamine
 Sample Problem

 What aldehyde or ketone and nitrogen component are

needed to synthesize N-ethylcyclohexanamine by a
reductive amination reaction?
 Solution

 Because N-ethylcyclohexanamine has two different alkyl

groups bonded to the N atom, either R group can come

from the carbonyl component and there are two different

ways to form a C–N bond by reductive amination.

Solution
 Problem (1)
 Draw the product of each reaction.
 Problem (2)
 What starting materials are needed to prepare each drug
using reductive amination? Give all possible pairs of
compounds when more than one route is possible.