HBTU (Hexafluorophosphate Benzotriazole Tetramethyl Uronium) is a couplingreagent used in solid phase peptide synthesis. It was introduced in 1978 and shows resistance against racemization.[1][2] It is used because of its mild activating properties.[3]
The product obtained by reaction of HOBt with tetramethyl chloro uronium salt (TMUCl) 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 aminium rather than the corresponding uronium salts.[4][5]
Mechanism
Файл:Mechanism tiff.tifThis scheme depicts the general mechanistic steps of HBTU creating an activated ester out of the carboxylate anion of the acid substrate. The deprotination of the carboxylic acid and the aminolysis of the activated ester are not shown.
HBTU activates carboxylic acids by forming a stabilized HOBt (Hydroxybenzotriazole) 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.[6]