Webinar: Unraveling organic reactions with the Amsterdam Modeling Suite – Catalysis and regioselectivity in Lewis acid-catalyzed cycloaddition reactions

In this final webinar of the AMS 2024 webinar series, Dr. Trevor A. Hamlin, Assistant Professor at the Vrije Universiteit Amsterdam, challenges our textbook views on organic reaction mechanisms with deep insights obtained from quantum chemical calculations and bonding analysis with AMS.

Abstract

In this talk, we showcase how the Amsterdam Modeling Suite (AMS) can be used to unravel the mechanism and driving forces behind organic reactions. We do a deep dive into the origin of catalysis and regioselectivity in Lewis-acid-catalyzed cycloaddition reactions using density functional theory calculations. We start with understanding how Lewis acids (LA) catalyze archetypal Diels-Alder reactions.^[1] Then we focus on two general methods to tempt the unreactive tropone to react in cycloadditions. First, we study the uncatalyzed and LA-catalyzed cycloaddition reactions between tropone and 1,1-dimethoxyethene.^[2] Our findings reveal that LA catalysts, namely BF₃, B(C₆H₅)₃, and B(C₆F₅)₃, significantly enhance reaction rates and lower reaction barriers by up to 12 kcal mol–1 through LUMO-lowering catalysis.^[3] Furthermore, we explain how the judicious choice of the LA catalyst can effectively impart regiocontrol of the cycloaddition: B(C₆H₅)₃ furnishes the [8+2] adduct while B(C₆F₅)₃ yields the [4+2] adduct. Second, we explore how reversing the polarity of the carbonyl group (umpolung), e.g., by converting tropone into its hydrazone analog, catalyzes the Diels-Alder reaction with maleimide.^[4] We challenge the established explanation attributed to antiaromaticity-induced HOMO raising. Instead, we propose that the increased reactivity arises from enhanced asynchronicity, resulting in reduced strain and diminished destabilizing Pauli repulsion.^[5] Our findings provide a deep understanding of the mechanism behind tropone activation.

Webinar Details:
Date: Tuesday 28.11.2024
Time: 15.00 (CET) / 9.00 (ET)

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References
[1] P. Vermeeren, T. A. Hamlin, I. Fernandez, F. M. Bickelhaupt, Angew. Chem. Int. Ed. 2020, 59, 6201.
[2] P. Li and H. Yamamoto, J. Am. Chem. Soc. 2009, 131, 16628.
[3] E. Tiekink, P. Vermeeren, T. A. Hamlin, Chem. Eur. J. 2023, 29, e202301223.
[4] L. J. Karas, A. T. Campbell, I. V. Alabugin, J. I. Wu, Org. Lett. 2020, 22, 7083.
[5] E. Tiekink, P. Vermeeren, T. A. Hamlin, Chem. Commun. 2023, 59, 3703.