Question

Explain the high rate of eletrophilic aromatic substitution observed in arylamines and state the synthetic strategy which must be taken to make the substitution successful.

Answer 1

Arylamines are potentially very reactive towards electrophilic aromatic substitution. This is because -NH2, -NHR2 and -NR2 are very strong activators and are ortho, para-directing.

However the basicity of the amino group means it is unsuitable for reactions with acids (e.g. H2SO4 or AlCl3) such as nitration, sulfonation and Friedel-Crafts alkylation or acylation. Polysubstitution can also be a problem. For example, bromination is very rapid, even in the absence of a catalyst, leading to bromination in all available ortho- and para- positions. To avoid these problems, it is customary to "protect" aryl amines by converting them to their N-acyl derivatives i.e. amides. The protecting group (an amide) can later be removed by either acid or base hydrolysis.

The amide is a less powerful activating group than the simple amino group, -NH2 since resonance within the N-acetyl group of the amide (see below) competes with delocalisation of the N lone pair into the ring.

In conclusion, the sequence should be protect the arylamines, substitute it and then deprotect it.