Methylmercury (CH₃Hg⁺) binding to thiol- and selenol- based enzymes is a key-element to explain its high toxicity. CH₃Hg⁺ is not found in its free form in biological environment, but is present as a chalcogenolate complex. Thus, chalcogen-mercury bond reactivity is implicated in the distribution of this toxicant in the human body. Particularly, Hg – S and Hg – Se bond formation and disruption is responsible for glutathione depletion and CH₃Hg⁺ delivery to target enzymes. We have investigated systematically, in silico, trends and mechanisms of nine ligand-exchange model reactions between a methylchalcogenolate and a methylmercury methylchalcogenolate complex in order to understand the role of the chalcogen (S, Se, Te) and of the environment (gas phase vs solvent).¹ We discuss trends in activation and reaction energies, highlighting a change in mechanism (from a single-well to a unimodal/double-well potential energy surface) when moving from gas to condensed phase, in analogy with S_N2 reactions. Further similarities with S_N2 reactions are quantified by means of activation strain analysis. Reactions involving S and Se display very similar energetics and (low) activation energies. Therefore, the reasons behind the biochemically challenging detoxification of CH₃Hg⁺ inhibited (seleno)proteins clearly emerge also from our minimal model, which paves the route to future mechanistic investigations.

1. A. Madabeni, M. Dalla Tiezza, O. B. Folorunsho, P. A. Nogara, M. Bortoli, J. B. Rocha, L. Orian, J. Comput. Chem. 2020, 41, 2045-2059