Mechanism and Origins of Selectivity for [Ga4L6]12- -Catalyzed SN2 Reaction with Benzylic Ether and Methanol: A Computational Mechanistic Study

Supramolecular catalysis often considered as the mimic of enzymatic catalysis, exhibits the properties of high reactivity and selectivity with various transformations. Bergman demonstrated that the reaction of chiral benzylic ester and methanol with Brønsted acid catalyst in bulk solution proceeded through an S _N 2 mechanism and generate chirality-inversed product, while when the reaction occurred with the supramolecular [Ga ₄ L ₆ ] ^12- catalyst it formed the chirality-retained product. The detailed reaction mechanism as well as the origins of selectivity remains unclear. Therefore, in this work we have performed a comprehensive theoretical study on the nucleophilic substitution reaction catalyzed by both Brønsted acid and [Ga ₄ L ₆ ] ^12- catalyst. Our calculations are in agreement with experiment. Detailed analyses indicate that compared to that of a classical S _N 2 reaction in bulk solution, after the encapsulation of the reactants in [Ga ₄ L ₆ ] ^12- , the same-side nucleophilic attack of the methanol with the leaving group is more favorable than the back-side attack, which is due to more favorable hydrogen bonding interactions and π-π stacking interaction between the reactants and the supramolecular cage. Understanding the mechanism and origins of the stereochemical outcome in the nucleophilic substitution reaction with the supramolecular host-guest catalysis would lead to the development of more efficient and selective transformations.