couplingreagenser

Coupling reagents are organic compounds used to promote the formation of covalent bonds between two substrates in chemical synthesis, most prominently for forming amide and ester linkages. In peptide synthesis they enable the coupling of amino groups to carboxyl groups to extend the peptide chain. The term encompasses several families, including carbodiimide-based reagents and uronium or phosphonium-based reagents.

Carbodiimides such as dicyclohexylcarbodiimide (DCC) and water-soluble 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) activate carboxyls to form reactive intermediates that react with amines; often used with additives like hydroxybenzotriazole (HOBt) or hydroxyazodibutazide (HOAt) to suppress side reactions and racemization. Uronium/phosphonium reagents such as HATU, HBTU, PyBOP and related salts generate more reactive esters, often providing higher coupling efficiency and lower racemization.

Mechanistically, these reagents convert a carboxylic acid into an activated intermediate (O-acylisourea, or an active ester) that is attacked by an amine to form the amide; byproducts include ureas or phosphine oxides that can be removed by filtration or chromatography. Racemization can occur with some carbodiimide systems, particularly at hindered or chiral centers; additives or alternative reagents are used to minimize it.

Applications include peptide synthesis, oligonucleotide conjugation, and general amide or ester bond formation in medicinal chemistry. Safety considerations involve handling of moisture-sensitive reagents, potential sensitization or irritation, and in the case of some additives, hazardous or explosive materials.