amidation

Amidation is the chemical process by which an amide bond is formed from a carboxylic acid derivative and an amine, typically releasing a small molecule such as water or an alcohol as a leaving group. The canonical representation is R-COOH + R'NH2 → R-CONHR' + H2O, but direct condensation of carboxylic acids with amines is thermodynamically unfavorable. In practice, amidation is achieved by activating the carboxyl component or by using a reactive derivative.

Common activation strategies include conversion to acid chlorides (R-COCl), acid anhydrides (R-CO-O-CO-R'), or mixed anhydrides; formation of activated esters such as pentafluorophenyl or carbonyldiimidazole–mediated esters; or employing coupling reagents (carbodiimides like EDC, DCC; uronium or phosphonium reagents such as HATU, HBTU, COMU) that convert the carboxyl group into a reactive acylating species. In each case, the amine acts as a nucleophile, attacking the acyl center to give the amide after removal of the leaving group. Conditions are chosen to minimize racemization of chiral centers and to accommodate sensitive functionalities.

In biochemistry and biotechnology, amide bond formation is central to protein synthesis, where ribosomes catalyze peptide bond formation between amino acids, and nonribosomal peptide synthetases assemble diverse amide-containing peptides. Amide formation is also fundamental in polymer chemistry for making polyamides.

Applications span pharmaceuticals, agrochemicals, and materials science. Challenges include achieving high chemoselectivity and yield under mild conditions, especially for hindered substrates, and avoiding side reactions.