How Lewis acids catalyze ring-openings of cyclohexene oxide

Hansen, T.; Vermeeren, P.; Yoshisada, R.; Filippov, D.V.; Marel, G.A. van der; Codee, J.D.C.; Hamlin, T.A.

doi:doi:10.1021/acs.joc.0c02955

We have quantum chemically studied the Lewis acid-catalyzed epoxide ring-opening reaction of cyclohexene epoxide by MeZH (Z = O, S, and NH) using relativistic dispersion-corrected density functional theory. We found that the reaction barrier of the Lewis acid-catalyzed epoxide ring-opening reactions decreases upon ascending in group 1 along the series Cs+ > Rb+ > K+ > Na+ > Li+ > H+. Our activation strain and Kohn-Sham molecular orbital analyses reveal that the enhanced reactivity of the Lewis acid-catalyzed ring-opening reaction is caused by the reduced steric (Pauli) repulsion between the filled orbitals of the epoxide and the nucleophile, as the Lewis acid polarizes the filled orbitals of the epoxide more efficiently away from the incoming nucleophile. Furthermore, we established that the regioselectivity of these ring-opening reactions is, aside from the "classical" strain control, also dictated by a hitherto unknown mechanism, namely, the steric (Pauli) repulsion between the...Show moreWe have quantum chemically studied the Lewis acid-catalyzed epoxide ring-opening reaction of cyclohexene epoxide by MeZH (Z = O, S, and NH) using relativistic dispersion-corrected density functional theory. We found that the reaction barrier of the Lewis acid-catalyzed epoxide ring-opening reactions decreases upon ascending in group 1 along the series Cs+ > Rb+ > K+ > Na+ > Li+ > H+. Our activation strain and Kohn-Sham molecular orbital analyses reveal that the enhanced reactivity of the Lewis acid-catalyzed ring-opening reaction is caused by the reduced steric (Pauli) repulsion between the filled orbitals of the epoxide and the nucleophile, as the Lewis acid polarizes the filled orbitals of the epoxide more efficiently away from the incoming nucleophile. Furthermore, we established that the regioselectivity of these ring-opening reactions is, aside from the "classical" strain control, also dictated by a hitherto unknown mechanism, namely, the steric (Pauli) repulsion between the nucleophile and the substrate, which could be traced back to the asymmetric orbital density on the epoxide. In all, this work again demonstrates that the concept of Pauli-lowering catalysis is a general phenomenon.Show less

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How Lewis acids catalyze ring-openings of cyclohexene oxide