HBTU
HBTU is a coupling reagent used in solid phase peptide synthesis. It was introduced in 1978 and shows resistance against racemization. It is used because of its mild activating properties.
HBTU is prepared by reaction of hydroxybenzotriazole with TCFH under basic conditions and was assigned to a uronium type structure, presumably by analogy with the corresponding phosphonium salts, which bear a positive carbon atom instead of the phosphonium residue. Later, it was shown by X-ray analysis that salts crystallize as guanidinium rather than the corresponding uronium salts.
Mechanism
HBTU activates carboxylic acids by forming a stabilized HOBt leaving group. The activated intermediate species attacked by the amine during aminolysis is the HOBt ester.To create the HOBt ester, the carboxyl group of the acid attacks the imide carbonyl carbon of HBTU. Subsequently, the displaced anionic benzotriazole N-oxide attacks of the acid carbonyl, giving the tetramethyl urea byproduct and the activated ester. Aminolysis displaces the benzotriazole N-oxide to form the desired amide.