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 C-S bond formation followed by amino nitrogen attack pathway is the most favorable mechanism. This mechanism includes C-S bond formation, C-N bond formation, C-N bond cleavage, and several facile proton transfer steps. The rate-determining step is the C-N bond cleavage step. Except for the C-S 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.