Carbodiimide

Carbodiimide refers to a class of compounds that contain the functional group R-N=C=N-R', where two substituents are attached to the nitrogens. They are versatile dehydration reagents in organic synthesis, most notably used to activate carboxylic acids for amide formation. The best-known members include dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). DCC and DIC are typically used in non-aqueous solvents, while EDC is water-soluble and commonly employed in peptide coupling in aqueous or mixed media.

In typical coupling reactions, the carboxyl group reacts with a carbodiimide to form an O-acylisourea intermediate. This activates the carboxyl group toward nucleophilic attack by an amine, leading to amide bond formation and yielding a urea byproduct (for example dicyclohexylurea in the case of DCC). Side reactions can include rearrangement of the activated intermediate to N-acylurea, which is less reactive toward amines and reduces yield. The efficiency and selectivity of carbodiimide-mediated couplings are enhanced by additives such as N-hydroxysuccinimide (NHS) or O-(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium (BOP) in various protocols.

Applications are widespread, with peptide synthesis being the historical and most prominent use. Carbodiimide reagents enable formation of amide bonds in small-molecule synthesis, polymer conjugation, and bioconjugation under relatively mild conditions. Safety concerns include irritant and sensitization potential for several reagents; the byproducts, particularly DCU, can be difficult to remove in nonpolar solvents.