Solvent–Temperature Coupled Hydride Transfer Controls Product Selectivity in the HSiR₃/KOtBu Catalytic System

Abstract

The HSiR₃/KO^tBu catalytic system affords a notable regioselective C-H silylation reaction using alkaline earth metals, yet its mechanistic origins and the temperature-dependent selectivity inversion remain unresolved. Here, we combine active learning neural network potentials with long-timescale ab initio quality molecular dynamics and enhanced sampling to simulate the HSiEt₃/KO^tBu catalyzed deprotonation reaction of N-methylindole in a complete operando solution environment. We found that KO^tBu can rapidly aggregate in organic solution to form catalyst cluster, which are able to activate and stabilize hydride derived from silane hydride, and this operando generated hydride is the catalytically active species. The hydride is able to deprotonate C2 and C3 protons on N-methylindole, and this reaction site selectivity is affected by the stability of cluster controlled by solvent and temperature coupling, which gives rise to nonlinear activation entropy of the C3 pathway in the neat silane environment. Unlike tetrahydrofuran solutions, the weak polarity of neat silanes makes it difficult to support deprotonation reactions at the less acidic C3 position at high temperature, thus affecting temperature-dependent selectivity. These results provide a microscopic predictive framework for tuning the selectivity in base-promoted hydrosilane chemistry and illustrate how explicit operational solvation and cluster formation can reshape mechanistic conclusions drawn from static models.