Synthetic toolbox: Amidation

Condensation

Amide bond formation between an acid and an amine are formally condensations. The related esterification reactions are governed by equilibrium however, the mixing of an amine with a carboxylic acid or an acid base reaction forms a stable salt. This means that amide bond formation between these reactants is thermodynamically disfavoured as the equilibrium lies on the side of hydrolysis rather than bond formation, Scheme 1.

Scheme 1: Amide bond formation by reaction of an amine with a carboxylic acid is thermodynamically disfavoured

The subsequent condensation of the salt to give the amide bond can be achieved at high reaction temperatures ~160-180 °C, which is not only energy demanding but can be incompatible in the presence of other functionalities. These forcing reaction conditions have been circumvented by activating the carboxylic acid by using a good leaving group bound to the acyl group of the acid, allowing the necessary attack by the amine group, Scheme 2.

Scheme 2: Amide bond formation through activating of the acyl carbon