Computational study on the mechanism of CBT-Cys click reaction

Abstract

Mechanism of CBT-Cys click reaction was studied by density functional theory calculations. Calculations show that the CS bond formation followed by amino nitrogen attack pathway is the most favorable mechanism. This mechanism includes CS bond formation, CN bond formation, CN bond cleavage, and several facile proton transfer steps. The rate-determining step is the CN bond cleavage step. Except for the CS bond formation step, all the steps occur with the assistance of phosphoric acid. The promotion of phosphoric acid on the reaction results from its strong proton-donating ability, low ring strain of the cluster structural transition states, and stabilizing effect of the hydrogen bonds in the transition states. The calculated results of the reactivities of β-mercaptoethanol, N-terminal homocysteine residues and N-terminal serine residues towards 2-cyanobenzothiazole are all consistent with the experimental observations.