Dynamics-based transition states reveal solvent cage effect and SN2 transition state motion in Lewis acid catalyzed stereoselective tertiary alcohol nucleophilic substitution reactions

Abstract

It has been known for a very long time that optically active tertiary sp³ carbons with a leaving group can undergo substitution with some selectivity for configuration inversion. The Weinstein model proposes that this stereoselectivity is governed by a S_N1 mechanism involving an intimate ion pair, but transition states for this type of reaction pathway have not yet been examined with explicit solvent. Here we have used quantum mechanics/molecular mechanics (QM/MM) based direct dynamics trajectories in explicit solvent to identify and characterize the S_N1 reaction mechanism for a model tertiary alcohol conversion to an isonitrile with Sc(OTf)₃ in TMSCN solvent that was experimentally reported have high configuration inversion. Using dynamics trajectories, we located both the leaving group loss and nucleophilic attack transition states along with the intimate ion pair intermediate. The stereo-determining nucleophilic attack transition state from the intimate ion pair has significant S_N2 character with dynamically coupled nitrogen–carbon bond formation and leaving group ejection. Comparison with continuum solvent trajectories revealed that the intimate ion pair intermediate is the result of the solvent cage and that without the cage a free carbocation intermediate would be formed leading either little or no stereoselectivity.