hatu

HATU is a commonly used coupling reagent in organic synthesis, particularly for peptide bond formation. Its name stands for O-(benzotriazole-1-yl)tris(dimethylamino)phosphonium hexafluorophosphate. HATU activates carboxyl groups to form reactive esters that readily react with amines to give amide bonds, enabling efficient coupling under mild conditions.

In peptide synthesis, HATU is valued for high coupling efficiency, broad substrate scope, and relatively low racemization of chiral centers compared with some other uronium reagents. To further suppress racemization, HOAt (1-hydroxy-7-azabenzotriazole) is often used as an additive in conjunction with a base such as DIPEA or collidine. The typical procedure involves mixing the carboxylic acid, the amine, HATU, and the base in a polar aprotic solvent like DMF, DMSO, or NMP. Reactions usually proceed rapidly at or near room temperature, with workups yielding the amide product after standard purification. Byproducts include tetramethylurea derivatives and benzotriazole-containing species.

HATU is applicable to a wide range of substrates, including hindered amino acids and complex peptides, and is compatible with common protecting groups used in peptide synthesis. However, it is moisture-sensitive and can be corrosive to certain materials; handling is typically performed in an inert or dry atmosphere with appropriate protective equipment. It is one of several uronium-based coupling reagents, with HBTU and HCTU being related alternatives offering different reactivity profiles.