Nucleophile Exchange Mechanistic Paths in Chalcogenolate‐Dichalcogenide Systems: Insight From Computational Chemistry

Organochalcogen compounds play an essential role in redox biology, such as in the reduction of hydroperoxides by thiol‐based proteins. In vivo, this function is notably mediated by sulfur‐ and selenium‐based enzymes like glutathione peroxidases (GPxs). However, low molecular weight GPx‐mimics are frequently unable to achieve optimal catalytic efficiency, an issue prompting for extensive investigation into chalcogen‐centered reaction pathways. In this work, we present a theoretical investigation of nucleophilic exchange reactions between methylchalcogenolates and dimethyldichalcogenides, conducted using density functional theory at the (COSMO)‐ZORA‐OLYP/TZ2P level. The energy trends are interpreted within the activation strain analysis framework, assessing the effect of the nucleophile, the dichalcogenide substrate, and continuum solvation. The biological implications of model reactions mimicking the reductive steps of the GPx catalytic cycle are discussed in detail. The mechanistic insight provided aims to support the rational design of improved biomimetic chalcogen‐based catalysts.