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Decoding the impact of solvents in altering the conversion rates and stereoselectivity in proline-catalyzed asymmetric aldol reaction

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Abstract

The choice of solvent plays a crucial role in aldol reactions, often affecting both the conversion rate and stereoselectivity. In this study, we investigated the influence of solvents (water, methanol and hydroalcoholic) on the proline-catalyzed aldol reactions. We focused on elucidating the solute–solvent interactions at the rate-determining step and the stereoselective step. Our theoretical finding suggests, hydroalcoholic-mediated reaction exhibits a higher conversion rate as compared to pure water and pure methanol-mediated system with the generation of most stable transition state structure. This can be attributed to the existence of strong hydrogen bonding and the formation of stable six-membered transition state structures in hydroalcoholic-mediated system. In addition to this, our research demonstrates that the choice of solvent plays a crucial role in determining the percentage of enantiomeric excess in the reaction. Theoretical finding suggest that the anti-product is preferentially formed in the presence of water and hydroalcoholic media as solvents. Pure water and hydroalcoholic solvents surprisingly showed a higher enantiomeric excess for the anti-product due to formation of strong hydrogen bonding between reaction moiety and solvents. In contrast, methanol-assisted reactions resulted in a racemic mixture, consistent with experimental observations. Results reported in the present study contribute to the broader understanding of solvent effects in organic reactions and offer valuable insights for the design of organic reactions.

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Acknowledgements

The author Arati S. Gavali acknowledge Mahatma Jyotiba Phule Research & Training Institute (MAHAJYOTI), Nagpur, India, for providing financial support.

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  1. Department of Chemistry, University of Mumbai, Vidyanagari, Kalina, Santacruz, Mumbai, 400098, India

    Arati S. Gavali, Parimal J. Maliekal, Vaishnavi A. Naik & Purav M. Badani

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Dr. PB: Conceptualization, Visualization, Supervision, Writing- Review and Editing. AG: Resources, Theoretical (computational) analysis, Data curation, Investigation, Writing original draft. PJ and VN: NCI plots and reviewed manuscript.

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Correspondence to Purav M. Badani.

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Gavali, A.S., Maliekal, P.J., Naik, V.A. et al. Decoding the impact of solvents in altering the conversion rates and stereoselectivity in proline-catalyzed asymmetric aldol reaction. Theor Chem Acc 143, 14 (2024). https://doi.org/10.1007/s00214-023-03088-4

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