Computational study on the mechanism of CBT-Cys click reaction

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.