Selenium Nucleophilicity and Electrophilicity in the Intra‐ and Intermolecular SN2 Reactions of Selenenyl Sulfide Probes

Chalcogenide exchange reactions are an important class of bimolecular nucleophilic substitution reactions (SN2) involving sulfur and selenium species as nucleophile, central atom, and/or leaving group, which are fundamental throughout redox biology and metabolism. While thiol‐disulfide exchange reactions have been deeply investigated, those involving selenium are less understood, especially with regards to the polarised selenenyl sulfides RSe–SR' even though the directed reactivity of selenenyl sulfides is biologically crucial for selenoenzymes such as thioredoxin reductase (TrxR) and glutathione peroxidase (GPx). Synthetic methods to create asymmetric selenenyl sulfides with high regiochemical purity only emerged over the last five years; this functional group has already demonstrated powerful applications to cell biology, through probes for molecular imaging (e.g. the TrxR probe "RX1") or reagents for thiol‐mediated uptake (e.g. remote ammonium thiaselenanes). Here, we investigate the SN2@S and SN2@Se reactions of selenenyl sulfides in silico to provide the first comprehensive overview of their kinetic and thermodynamic trends, referencing against symmetrical disulfides and diselenides. We quantify the role of alternative exchange reactions in the double‐exchange chemistry of RX1. This analysis rationalises the origins of RX1's TrxR‐specificity even within thiol‐rich cellular environments and can support the design and applications of a range of selenenyl sulfide‐based bioactive probes.