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Article

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

Institut für Chemie, Martin-Luther-Universität Halle-Wittenberg, von-Danckelmann-Platz 4, D-06120 Halle (Saale), Germany
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Academic Editor: Benedito José Costa
Molecules 2020, 25(24), 5861; https://doi.org/10.3390/molecules25245861
Received: 13 October 2020 / Revised: 5 December 2020 / Accepted: 8 December 2020 / Published: 11 December 2020
(This article belongs to the Special Issue Describing Bulk Phase Effects with Ab Initio Methods)
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. View Full-Text
Keywords: aldol reaction; organocatalysis; enantioselectivity; free energy profile; metadynamics; molecular dynamics; ab initio molecular dynamics; nudged elastic band; energy barrier; solvent influence aldol reaction; organocatalysis; enantioselectivity; free energy profile; metadynamics; molecular dynamics; ab initio molecular dynamics; nudged elastic band; energy barrier; solvent influence
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MDPI and ACS Style

Weiß, M.; Brehm, M. Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence. Molecules 2020, 25, 5861. https://doi.org/10.3390/molecules25245861

AMA Style

Weiß M, Brehm M. Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence. Molecules. 2020; 25(24):5861. https://doi.org/10.3390/molecules25245861

Chicago/Turabian Style

Weiß, Moritz, and Martin Brehm. 2020. "Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence" Molecules 25, no. 24: 5861. https://doi.org/10.3390/molecules25245861

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