12-Mar-21

Amines (cont.)
Chemical properties (cont.).
• Acidity of amines.
• The Hofmann elimination.
• The Mannich reaction
• Nitrosation of amines
Diazonium salts. Azo, Hydrazo and
Diazo-compounds.

Acidity of amines

Amine acting as an acid:

Amines are very weak acids. The deprotonation of amines requires

extremely strong bases as alkyllithium reagents.
For example, lithium diisopropylamide (a sterically hindered strong base)
is made in laboratory by treatment of diisopropylamine with butyllithium.

1
 12-Mar-21

The Hofmann elimination

Much like the protonation of alcohols, turns the –OH into a good leaving group
–OH2+, the transformation of amines into tetraalkylammonium salts makes
them good leaving groups, which allows the Hofmann elimination.

Bimolecular Elimination of Quaternary Ammonium Ions

Alkylation of amines leads to the corresponding quaternary alkylammonium

salts. These species are unstable in the presence of strong base, because of a
bimolecular elimination reaction that furnishes alkenes. The base attacks the
hydrogen in the b-position with respect to the nitrogen, and a trialkylamine
departs as a neutral leaving group.

The Hofmann elimination

The amine is first completely methylated with excess iodomethane and then
treated with wet silver oxide (a source of HO-) to produce the ammonium
hydroxide. Heating degrades this salt to the alkene.

2
 12-Mar-21

The Hofmann elimination

The most useful aspect of the Hofmann elimination is its regioselectivity.

Elimination in alkyltrimethylammonium hydroxides proceeds in the direction
opposite to that of the Zaitsev rule and favors formation of the less substituted
alkene.

The Mannich reaction

It is a three component reaction between carbonyl compound possessing a-

CH acidity formaldehyde and primary or secondary amine.
Enol is acting as nucleophile attacking imine function (formed between
formaldehyde and a primary amine) or iminium ion (formed between
formaldehyde and a secondary amine).

3
 12-Mar-21

The Mannich reaction

The mechanism of this process starts with iminium ion formation between the
formaldehyde and the amine, on the one hand, and enolization of the ketone, on
the other. As soon as the enol is formed, it undergoes nucleophilic attack on the
electrophilic iminium carbon, and the resulting species converts to the Mannich
salt by proton transfer from the carbonyl oxygen to the amino group. The free
amine (b-aminocarbonyl) product is obtained upon treatment with base.

Nitrosation of amines
Amines react with nitrous acid, through nucleophilic attack on the nitrosyl cation,
NO+. The product depends very much on whether the reactant is an alkanamine
or a benzenamine (aniline) and on whether it is primary, secondary, or tertiary.

To generate NO+, we must first prepare the unstable nitrous acid by the
treatment of sodium nitrite with aqueous HCl. In such an acid solution, an
equilibrium is established with the nitrosyl cation.

The nitrosyl cation is electrophilic and is attacked by amines to form an N-

nitrosammonium salt.

4
 12-Mar-21

Nitrosation of amines
Tertiary N-nitrosammonium salts are stable only at low temperatures and
decompose upon heating to give a mixture of compounds.
Secondary N-nitrosammonium salts are formed simply by deprotonation of
secondary amines to furnish the relatively stable N-nitrosamines as the major
products.

N-Nitrosodialkanamines are notoriously potent carcinogens.

Nitrosation of amines
Similar treatment of primary amines initially gives the analogous monoalkyl-N-
nitrosamines. However, these products are unstable because of the remaining proton on
the nitrogen. By a series of hydrogen shifts, they first rearrange to the corresponding
diazohydroxides. Then protonation, followed by loss of water, gives highly reactive
diazonium ions.

Alkyl diazonium ions are not very stable, decomposing rapidly to form a carbocation and
molecular nitrogen. The result is formation of product mixtures.

5
 12-Mar-21

Nitrosation of Arylamines
Primary arylamines, like primary alkylamines, form diazonium ion salts on
nitrosation.

Aryl diazonium salts are considerably more stable and can be stored in
aqueous solution at 0–5°C for a reasonable time. They undergo a variety of
reactions that make them versatile intermediates for preparing a host of ring-
substituted aromatic compounds.

Nitrosation of Arylamines

6
 12-Mar-21

Nitrosation of Arylamines
(examples)

Azo Coupling
Aryl diazonium ions are relatively weak electrophiles but have sufficient
reactivity to attack strongly activated aromatic rings (phenols or arylamines).
The reaction is known as azo coupling; two aryl groups are joined together by
an azo (—N=N—) function.

Soon after azo coupling was discovered in the mid-nineteenth century, the
reaction received major attention as a method for preparing dyes.

7
 12-Mar-21

Azo compounds

Preparation: • Azo coupling.

• Oxidation of hydrazo compounds.

Azo compounds
Chemical properties
Mild reduction to hydrazo compounds

Reduction to amines

Photoisomerisation

8
 12-Mar-21

Hydrazo compounds

Hydrazo compounds
The Benzidine Rearrangement

9
 12-Mar-21

Diazo Compounds

Preparation: Diazomethane is prepared by hydrolysis of an ethereal solution of

an N-methyl nitrosamides with aqueous base.

In the pure form at room temperature, diazomethane is an extremely sensitive

explosive yellow gas; thus, it is almost universally used as a solution in diethyl
ether. The compound is a popular methylating agent in the laboratory, but it is
extremely hazardous and carcinogenic.

Diazo Compounds

Mild methylation with diazomethane:

10