Amines

Chapter 24
Organic Chemistry, 8th Edition
John McMurry

1
 Introduction

Amines are stronger bases and better nucleophiles than other

neutral organic compounds.

2
 Nomenclature
1ry Amines are named using either systematic or common names.

methanamine cyclohexanamine 3-hexanamine

(methylamine) (cyclohexylamine)

Secondary and tertiary amines having identical alkyl groups are

named using the prefix di- or tri- with the name of the primary
amine.

Secondary and 3° amines having more than one kind of alkyl

group are named as N-substituted primary amines:

N-methyl-2-propanamine
3
 Nomenclature

Aromatic amines are named as derivatives of aniline.

There are many different nitrogen heterocycles, each with a

different name. The N atom is considered to be at position “1”.

4
 Structure and Bonding
An amine N atom is sp3 hybridized with trigonal pyramidal
geometry, with bond angles of approximately 109.5°.

In case an amine nitrogen has four different groups around it, it is

technically a stereogenic center.

5
 Structure and Bonding
However, the chirality of the amine nitrogen can be ignored
because the two enantiomers interconvert by passing through a
trigonal planar (achiral) transition state.

sp3 sp2 sp3

6
Inversion of Configuration in Amines
 Structure and Bonding
In contrast, the chirality of a quaternary ammonium salt with four
different groups cannot be ignored. Because there is no
nonbonded electron pair on the nitrogen atom, interconversion
cannot occur, and the N atom is just like a carbon atom with four
different groups around it.

8
 Physical Properties
• Amines exhibit dipole-dipole interactions because of the polar
C—N and N—H bonds.

• Primary and 2° amines are capable of intermolecular hydrogen

bonding because they contain N—H bonds.

9
Physical Properties

10
 Interesting and Useful Amines
• Many low molecular weight amines have foul odors.

• Trimethylamine [(CH3)3N], formed when enzymes break down

certain fish proteins, has the characteristic odor of rotting fish.

• Putrescine (NH2CH2CH2CH2CH2NH2) and cadaverine

(NH2CH2CH2CH2CH2CH2NH2) are both poisonous diamines with
putrid odors. They too are present in rotting fish, and are partly
responsible for the odors of semen, urine, and bad breath.

• Naturally occurring amines derived from plant sources are called

alkaloids.

11
Interesting and Useful Amines

12
Preparation of Amines—Direct Nucleophilic
Substitution

13
 Preparation of Amines—Direct Nucleophilic
Substitution
Although the process seems straightforward, polyalkylation of the
nitrogen nucleophile limits its usefulness.

43 % 42%)
1 : 2

3% 2%
Consequently, the reaction is most useful in preparing 1ry amines by
using a large excess of NH3, and for preparing quaternary ammonium
salts by alkylating any nitrogen nucleophile with one or more equivalents
of alkyl halide.

14
Preparation of Amines—Gabriel Synthesis of 1ry
Amines
The Gabriel synthesis is comprised of two steps and uses a
nucleophile derived from phthalimide to synthesize 1ry amines via
nucleophilic substitution.

15
 Preparation of Amines—Reduction of N-
Containing Functional Groups

Azides are reduced to 1° amines with LiAlH4

16
Preparation of Amines—Reduction of N-
Containing Functional Groups

17
Preparation of Amines—Reduction of N-
Containing Functional Groups

18
Preparation of Amines—Reductive Amination

Reductive amination is a two-step method that converts

aldehydes and ketones into 1ry, 2ry, and 3ry amines.

imine

19
 Preparation of Amines—Reductive Amination

With a 1ry or 2ry amine as starting material, reductive amination is

used to prepare 2ry and 3ry amines respectively.

20
Preparation of Amines—Reductive Amination

21
 Reactions of Amines—General Features
• The chemistry of amines is dominated by the lone pair of
electrons on nitrogen.

• Only three elements in the second row of the periodic table have
nonbonded electron pairs in neutral organic compounds:
nitrogen, oxygen and fluorine. Because basicity and
nucleophilicity decrease across a row, nitrogen is the most basic
and the most nucleophilic.

22
 Amines as Bases
Amines react with a variety of organic and inorganic acids.

pKb 3-4

23
 Structural Effects on Amine Basicity
1. Inductive Effects

1°, 2°, and 3° alkylamines are more basic than NH3 because of
the electron-donating inductive effect of the R groups.

pKa 9.3 10.8 11.1 11.0

(conjugate
acid)

24
 Amines as Bases
Arylamines are less basic than alkylamines because the electron pair on N
is delocalized.

25
Substituted Anilines

26
 Amides, Imines, Nitriles
Amides are much less basic than amines because the election pair
on N is delocalised

Imines and nitriles are less basic than amines because the electron pair on
N is in an sp2 and sp orbital, respectively.

basicity

sp3 orbitals are farther from the nucleus and therefore more available; sp
orbitals are nearer to the nucleus and therefore less available. 27
 Heterocyclic Amines
1. Hybridization

more basic less basic

28
 Heterocyclic Amines
2. Aromaticity

29
Amines as Bases

30
Amines as Bases

31
 Amines as Nucleophiles
alkylation (any amine):

acylation:

X = Cl, OCOR, NH3, 1ry, 2ry 1ry, 2ry, 3ry

OR’, OH

condensation with aldehydes and ketones:

NH3, 1ry 2ry

immina enammina
32
 meccanismo con ammine primarie

addizione del nucleofilo prototropia eliminazione di acqua

al carbonio carbonilico

immina
meccanismo con ammine secondarie

enammina
Amines as Nucleophiles. Acylation

35
Amines as Nucleophiles. Reaction with
Aldehydes and Ketones

36
 SEAr of Aromatic Amines

The amino group is the strongest neutral activating group

1. It is impossible to stop the

reaction at the monobromination
step

The amino group reacts with electrophiles

2. Aniline does not react under

acid (Broensted or Lewis)
conditions

strongly
37
deactivated
 SEAr of Aromatic Amines. Protection
• The conversion of amines to amides is useful in the synthesis of
substituted anilines.

less basic
less nucleophilic
sufficientlyactivating

sulfanilamide 38
 Amine as Leaving Group

NH2- is not a good

leaving group

Hoffman
better better
elimination: leaving group leaving group

- N(CH3)3
- H2O

very bulky L.G.

E2 mechanism:

less hindered
more hindered

39
Reaction of Amines with Nitrous Acid

40
Reaction of Amines with Nitrous Acid

1. generation of the electrophile

nitrosonium ion
2. nitrosation

N-nitrosamine

3. acid-catalysed elimination

diazonium ion

41
Substitution Reactions of Aryl Diazonium Salts

• Aryl diazonium salts react with a variety of reagents to form

products in which a nucleophile Z replaces N2, a very good
leaving group.

• The mechanism of these reactions varies with the identity of Z.

42
Substitution Reactions of Aryl Diazonium Salts

Reactions often take place in the presence of Cu(I) salts

(Sandmayer reaction)

43
Substitution Reactions of Aryl Diazonium Salts

A diazonium salt reacts with hypophosphorus acid to form

benzene. This reaction is useful in synthesizing compounds
that have substitution patterns that are not available by other
means.

Cu2O

44
Substitution Reactions of Aryl Diazonium Salts

This is called the Sandmeyer reaction. It provides an

alternative to direct chlorination and bromination of the
aromatic ring using Cl2 or Br2 and a Lewis acid catalyst.

Since the cyano group can be converted into a variety of other

functional groups, this reaction provides easy access to a wide
variety of benzene derivatives. 45
Substitution Reactions of Aryl Diazonium Salts

This is a useful reaction because aryl fluorides cannot be

produced by direct fluorination with F2 and a Lewis acid
catalyst.

This is a useful reaction because aryl iodides cannot be

produced by direct iodination with I2 and a Lewis acid catalyst.
46
Substitution Reactions of Aryl Diazonium Salts

• Diazonium salts provide easy access to many different benzene

derivatives. Keep in mind the following four-step sequence,
because it will be used to synthesize many substituted
benzenes.

47
Substitution Reactions of Aryl Diazonium Salts

48
Coupling Reactions of Aryl Diazonium Salts

When a diazonium salt is treated with an aromatic compound

activated by a strong electron-donor group, a substitution
reaction takes place giving an azo compound.

Mechanism:

The para position is preferred for steric reasons

49
 Azo Dyes
Azo compounds are highly conjugated, rendering them colored.
Many of these compounds are synthetic dyes. Butter yellow was
once used to color margarine.

50
 Azo Dyes
Azo compounds are highly conjugated, rendering them colored.
Many of these compounds are synthetic dyes. Butter yellow was
once used to color margarine.

Allura Red Chrysoine Resorcinol Janus Green B

51
Direct Blue 1
 Natural and Synthetic Dyes
• Wool and silk contain charged functional groups, such as NH3+ and
COO¯. Thus, they bind to ionic dyes by electrostatic interactions.

• Positively charged NH3+ groups bonded to the protein backbone are

electrostatically attracted to anionic groups in a dye like methyl orange.

52
 Indicators
Alizarine yellow

pKa 11

Methyl red

pKa 5.3

53