Multimodal S(VI) Exchange Click Reactions Derived from SF₂ Moieties: Comparative Kinetics and Stereochemistry of...

The reaction mechanism of multimodal SuFEx and SuPhenEx click chemistries was investigated in detail for substitution of both the first and second fluoride or p-nitrophenolate leaving groups in ∼RN = SOF₂ and RN = SOF(p-NO₂-phenol) substrates by temperature-dependent kinetics and density functional theory (DFT) calculations. Both the DFT calculations and the experimentally derived ΔH^‡ indicate relatively small values for the activation enthalpies (4-15 kcal/mol), but almost constant and significant values of -TΔS₂₅^‡ (10-14 kcal/mol). This indicates that depending on the precise nucleophile and S(VI) core, the reaction is either controlled by a mixture of enthalpy and entropy or basically is dominated by entropy alone. Finally, we show using chiral HPLC and X-ray crystallography that the SuFEx reaction on chiral RN = SOF(p-substituted-phenol) substrates also proceeds enantiospecifically, opening up also multimodal click chemistry to chiral applications in chemical biology and materials science.