The alkylation mechanism of zinc-bound thiolates depends upon the zinc ligands

Alkylation of zinc-bound thiolates occurs in both catalytic and structural zinc sites of enzymes. Recent biomimetic studies have led to a controversy as to which mechanism is operative in thiolate alkylation. Building on one of these biomimetic complexes, we have devised a series of models that allow for an appraisal of the roles of charge, ligand nature, and hydrogen bonding to sulfur on reactivity. The reactions of these complexes with methyl iodide, leading to thioethers and zinc iodide complexes, have been examined by density functional theory calculations, in the gas phase as well as in an aqueous solution. In all cases, a S_N2 reaction is favored over σ-bond metathesis. Both the net electronic charge and the hydrogen bond play a significant role in the nucleophilicity of the thiolate. We find that the mechanistic diversity observed experimentally can be explained by the difference in the net charge of the complexes. A dianionic complex follows a dissociative pathway, whereas an associative one is preferred for a neutral system.