amideformation

Amide formation refers to reactions that create amide bonds, the linkage R-CO-NR'R''. In most cases this involves a nucleophilic acyl substitution in which an amine attacks a carbonyl compound and a leaving group is expelled, yielding the amide and a benign byproduct. Direct amidation of carboxylic acids with amines is thermodynamically disfavored without removing water or activating the carbonyl.

Common methods rely on carboxyl activation. Activated derivatives such as acid chlorides, anhydrides, or activated esters (for example NHS esters) react more readily with amines to form amides. Coupling reagents are widely used to convert carboxylic acids and amines into amides in one pot. Reagents such as DCC, DIC, or EDC form reactive intermediates (e.g., uronium or ubiquitin-like species or stable active esters) in the presence of additives like HOBt, HOAt, or Oxyma, which improve reactivity and reduce side reactions. These approaches are standard in peptide synthesis, where careful control of racemization is important.

In polymer chemistry, amide formation under condensation conditions leads to polyamides (for example nylons) via reaction of diacids with diamines, typically at elevated temperatures with water removal.

Applications and scope extend across pharmaceuticals, natural product synthesis, and materials science. Industrial and laboratory conditions vary widely: solvent choice (often polar aprotic or chlorinated solvents), base or acid scavengers, temperature, and the nature of the leaving group determine yield, rate, and selectivity. Amide bonds are relatively stable to hydrolysis and oxidation, contributing to the ubiquity and significance of amide formation in chemistry.