Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence.

Moritz Weiß,Martin Brehm

doi:10.3390/molecules25245861

Moritz Weiß, Martin Brehm

Open Access

https://doi.org/10.3390/molecules25245861

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Abstract

We present a computational study on the enantioselectivity of organocatalytic proline-catalyzed aldol reactions between aldehydes in dimethylformamide (DMF). To explore the free energy surface of the reaction, we apply two-dimensional metadynamics on top of ab initio molecular dynamics (AIMD) simulations with explicit solvent description on the DFT level of theory. We avoid unwanted side reactions by utilizing our newly developed hybrid AIMD (HyAIMD) simulation scheme, which adds a simple force field to the AIMD simulation to prevent unwanted bond breaking and formation. Our condensed phase simulation results are able to nicely reproduce the experimental findings, including the main stereoisomer that is formed, and give a correct qualitative prediction of the change in syn:anti product ratio with different substituents. Furthermore, we give a microscopic explanation for the selectivity. We show that both the explicit description of the solvent and the inclusion of entropic effects are vital to a good outcome—metadynamics simulations in vacuum and static nudged elastic band (NEB) calculations yield significantly worse predictions when compared to the experiment. The approach described here can be applied to a plethora of other enantioselective or organocatalytic reactions, enabling us to tune the catalyst or determine the solvent with the highest stereoselectivity.

Highlights

One of the most important tasks in organic chemistry is the controlled formation of new C–C bonds in order to build up complicated molecules from simpler educts
After a description and validation of our newly developed hybrid ab initio molecular dynamics (AIMD) simulation approach, we present and discuss the results from static nudged elastic band (NEB) calculations, metadynamics simulations in vacuum, and metadynamics simulations in explicit solvent, respectively
When performing metadynamics with ab initio molecular dynamics (AIMD) simulations in order to study free energy profiles of chemical reactions, the forced bond-breaking leads to all kinds of unwanted side reactions in the simulations: the transition states of reactions often feature highly reactive sites, which readily react with the closest solvent molecule to form adducts

Summary

Introduction

One of the most important tasks in organic chemistry is the controlled formation of new C–C bonds in order to build up complicated molecules from simpler educts. One of the most efficient ways to introduce defined chirality into a molecule is to use a catalytic amount of a chiral controller to induce the stereoselective transformation. Those controllers often were organometallic compounds earlier, but with the emergence of the concepts of green chemistry [2,3,4,5,6,7,8,9], metal-free organic molecules were found to serve this purpose, and the way to the field of Molecules 2020, 25, 5861; doi:10.3390/molecules25245861 www.mdpi.com/journal/molecules

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