Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence
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 <i>ab initio</i> molecular dyn...
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| Format: | Article |
| Language: | English |
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MDPI AG
2020-12-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/25/24/5861 |
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| author | Moritz Weiß Martin Brehm |
| author_facet | Moritz Weiß Martin Brehm |
| author_sort | Moritz Weiß |
| collection | DOAJ |
| description | 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 <i>ab initio</i> 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 <i>syn:anti</i> 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. |
| first_indexed | 2024-03-10T14:09:09Z |
| format | Article |
| id | doaj.art-c136571a7b364902a572df3c28ee0963 |
| institution | Directory Open Access Journal |
| issn | 1420-3049 |
| language | English |
| last_indexed | 2024-03-10T14:09:09Z |
| publishDate | 2020-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj.art-c136571a7b364902a572df3c28ee09632023-11-21T00:23:10ZengMDPI AGMolecules1420-30492020-12-012524586110.3390/molecules25245861Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent InfluenceMoritz Weiß0Martin Brehm1Institut für Chemie, Martin-Luther-Universität Halle-Wittenberg, von-Danckelmann-Platz 4, D-06120 Halle (Saale), GermanyInstitut für Chemie, Martin-Luther-Universität Halle-Wittenberg, von-Danckelmann-Platz 4, D-06120 Halle (Saale), GermanyWe 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 <i>ab initio</i> 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 <i>syn:anti</i> 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.https://www.mdpi.com/1420-3049/25/24/5861aldol reactionorganocatalysisenantioselectivityfree energy profilemetadynamicsmolecular dynamics |
| spellingShingle | Moritz Weiß Martin Brehm Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence Molecules aldol reaction organocatalysis enantioselectivity free energy profile metadynamics molecular dynamics |
| title | Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence |
| title_full | Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence |
| title_fullStr | Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence |
| title_full_unstemmed | Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence |
| title_short | Exploring Free Energy Profiles of Enantioselective Organocatalytic Aldol Reactions under Full Solvent Influence |
| title_sort | exploring free energy profiles of enantioselective organocatalytic aldol reactions under full solvent influence |
| topic | aldol reaction organocatalysis enantioselectivity free energy profile metadynamics molecular dynamics |
| url | https://www.mdpi.com/1420-3049/25/24/5861 |
| work_keys_str_mv | AT moritzweiß exploringfreeenergyprofilesofenantioselectiveorganocatalyticaldolreactionsunderfullsolventinfluence AT martinbrehm exploringfreeenergyprofilesofenantioselectiveorganocatalyticaldolreactionsunderfullsolventinfluence |