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

## TL;DR

This study uses simulations to show how solvent cages and transition states influence stereoselectivity in a specific type of chemical reaction.

## Contribution

The study reveals the solvent cage effect and SN2 character in the transition state of a stereoselective substitution reaction using explicit solvent dynamics.

## Key findings

- The nucleophilic attack transition state shows significant SN2 character with coupled bond formation and leaving group ejection.
- The solvent cage stabilizes the intimate ion pair intermediate, leading to high stereoselectivity.
- Without the solvent cage, a free carbocation forms, reducing stereoselectivity.

## 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 SN1 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 SN1 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 SN2 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.

The stereo-determining nucleophilic attack transition state from the intimate ion pair has significant SN2 character with dynamically coupled nitrogen–carbon bond formation and leaving group ejection.