Substituent Effects on Sulfur Phenolate Exchange Reactions: Reactivity and Bonding Analysis

The Sulfur Phenolate Exchange reaction (SuPhenEx) provides a fluorine-free alternative S(VI) exchange chemistry by substituting nitrophenolate as the leaving group instead of fluoride (as in SuFEx reactions), offering a synthetically appealing and environmentally friendly approach in click chemistry. Despite its significance, the reaction mechanism and the underlying electronic interactions in the course of the reaction have yet to be thoroughly explored at the molecular level. Here, we elucidate the electronic interactions of a series of SuPhenEx model reactions between various para-substituted phenolates (p-R-Ph-O^–) as nucleophiles and PhSO₂-OPh–p-NO₂ as an electrophile, in both gas and solvent (acetonitrile) phases. As tools, we apply the Activation Strain Model based on density functional theory. We identified the HOMO–LUMO interaction as the key determinant of reactivity in the gas phase, which shifts to include (HOMO-1)–(LUMO + 1) contributions in the solvent phase, and showed how these interactions can be tuned through the choice of the substituent in the para-substituted phenolate nucleophiles. The resulting insights, consistent across both phases, facilitate steering future experiments in these and related S(VI) substitution reactions.