Selenium Nucleophilicity and Electrophilicity in the Intra- and Intermolecular S_N2 Reactions of Selenenyl Sulfide...

Chalcogenide exchange reactions are an important class of bimolecular nucleophilic substitution reactions (S_N2) 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'. This functional group, which is fundamental in the biochemistry of glutathione peroxidase and thioredoxin reductase enzymes, was recently incorporated in the molecular scaffold of a TrxR1 specific probe, "RX1". Here, we investigate the S_N2@S and S_N2@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. Then, the role of S_N2@S and S_N2@Se reactions in RX1 chemistry is explored, and a mechanistic picture of its biological chemistry is provided. Additionally, 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. Particularly, we observe that the intramolecular S_N2@Se reaction which restores RX1 ground state is an effective protective mechanism against unspecific activation by thiols, explaining its capacity to work in high-thiol concentration.