Automated Microsolvation for Minimum Energy Path Construction in Solution

TL;DR

This paper introduces an automated, stepwise microsolvation method for constructing minimum energy paths in solution, combining quantum-classical models with continuum solvation and active solvent molecule identification.

Contribution

It presents a novel automated protocol for microsolvation that efficiently identifies active solvent molecules and integrates them into free-energy calculations for reaction pathways in solution.

Findings

Successfully applied to methanediol formation from formaldehyde.

Demonstrated versatility with solvent mixture in CO2 hydration.

Validated approach for chlorination of phenol with hypochlorous acid.

Abstract

Describing chemical reactions in solution on a molecular level is a challenging task due to the high mobility of weakly interacting solvent molecules which requires configurational sampling. For instance, polar and protic solvents can interact strongly with solutes and may interfere in reactions. However, to define and identify representative arrangements of solvent molecules modulating a transition state is a non-trivial task. Here, we propose to monitor their active participation in the decaying normal mode at a transition state, which defines active solvent molecules. Moreover, it is desirable to prepare a low-dimensional microsolvation model in a well-defined, fully automated, high-throughput, and easy-to-deploy fashion, which we propose to derive in a stepwise protocol. First, transition state structures are optimized in a sufficiently solvated quantum-classical hybrid model, which are then subjected to a re-definition of a then reduced quantum region. From the reduced model, minimally microsolvated structures are extracted that contain only active solvent molecules. Modeling the remaining solvation effects is deferred to a continuum model. To establish an easy-to-use free-energy model, we combine the standard thermochemical gas-phase model with a correction for the cavity entropy in solution. We assess our microsolvation and free-energy models for methanediol formation from formaldehyde, for the hydration of carbon dioxide (which we consider in a solvent mixture to demonstrate the versatility of our approach), and, finally, for the chlorination of phenol with hypochlorous acid.