Calcium Bistriflimide-Mediated Sulfur(VI)-Fluoride Exchange (SuFEx): Mechanistic Insights toward Instigating Catalysis

We report a mechanistic investigation of calcium bistriflimide-mediated sulfur(VI)-fluoride exchange (SuFEx) between sulfonyl fluorides and amines. We determine the likely pre-activation resting state-a calcium bistriflimide complex with ligated amines-thus allowing for corroborated calculation of the SuFEx activation barrier at similar to 21 kcal/mol, compared to 21.5 +/- 0.14 kcal/mol derived via kinetics experiments. Transition state analysis revealed: (1) a two-point calcium-substrate contact that activates the sulfur(VI) center and stabilizes the leaving fluoride and (2) a 1,4-diazabicydo[2.2.2]octane additive that provides Bronsted-base activation of the nucleophilic amine. Stable Ca-F complexes upon sulfonamide formation are likely contributors to inhibited catalytic turnover, and a proof-of-principle redesign provided evidence that sulfonamide formation is feasible with 10 mol % calcium bistriflimide.

Automated summary

In this study, we investigated the mechanistic aspects of the sulfur(VI)-fluoride exchange (SuFEx) between sulfonyl fluorides and amines mediated by calcium bistriflimide. We determined the likely pre-activation resting state and calculated the SuFEx activation barrier. Transition state analysis revealed the effects of calcium-substrate contact and additive on the reaction. Stable Ca-F complexes inhibited catalytic turnover, but a proof-of-principle redesign showed that sulfonamide formation is still feasible.