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 that of
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 evidence of the covalent O-H and O-O bonds
rupture 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.