The catalytic cycle of a new derivative of ebselen, 1, was elucidated via three steps by the density functional theory and solvent-assisted proton exchange procedure involving indirect proton exchange through a hydrogen-bonded transfer network. Different behaviors of the aromatic and aliphatic thiols were investigated in the reduction of selenoxide (step 2→3) and selenurane (step 3→1) based on their nucleophilicity. The reduction of selenoxide in the presence of thiophenol (ΔG≠=15.9 kcal.mol-1) is faster than methanethiol (ΔG≠=29.3 kcal.mol-1), and methanethiol makes the reduction of selenoxide unspontaneous and kinetically unfavorable (ΔG=2.8 kcal.mol-1). The nucleophilic attack may be enhanced by using the thiophenol backbone at the selenium center to lower the energy barrier of the selenoxide reduction (ΔG≠=15.9 kcal.mol-1). On the basis of the turnover frequency calculations, during the catalytic cycle, the rate of the reaction was analyzed and discussed. Low values of the electron density and Laplacian at the transition states are the evidences of the covalent O-H and O-O bonds rupture the in the presence of methanethiol and thiophenol. The nature of the critical bond points was characterized, using the quantum theory of atoms in molecules, based on the electron location function and localized orbital locator values. Finally, the charge transfer process at the rate-determining step was investigated based on the natural bond orbital analysis.

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