The Pauli Repulsion-Lowering Concept in Catalysis.

Organic chemistry has undoubtedly had a profound impact on humanity. Day in and day out, we find ourselves constantly surrounded by organic compounds. Pharmaceuticals, plastics, fuels, cosmetics, detergents, and agrochemicals, to name a few, are all synthesized by organic reactions. Very often, these reactions require a catalyst in order to proceed in a timely and selective manner. Lewis acids and organocatalysts are commonly employed to catalyze organic reactions and are considered to enhance the frontier molecular orbital (FMO) interactions. A vast number of textbooks and primary literature sources suggest that the binding of a Lewis acid or an iminium catalyst to a reactant (R1) stabilizes its LUMO and leads to a smaller HOMO(R2)-LUMO(R1) energy gap with the other reactant (R2), thus resulting in a faster reaction. This forms the basis for the so-called LUMO-lowering catalysis concept. Despite the simplicity and popularity of FMO theory, a number of deficiencies have emerged over the years, as a consequence of these FMOs not being the operative factor in the catalysis. LUMO-lowering catalysis is ultimately incomplete and is not always operative in catalyzed organic reactions. Our groups have recently undertaken a concerted effort to generate a unified framework to rationalize and predict chemical reactivity using a causal model that is rooted in quantum mechanics. In this Account, we propose the concept of Pauli repulsion-lowering catalysis to understand the catalysis in fundamental processes in organic chemistry. Our findings emerge from state-of-the-art computational methods, namely, the activation strain model (ASM) of reactivity in conjunction with quantitative Kohn-Sham molecular orbital theory (KS-MO) and a matching energy decomposition analysis (EDA). The binding of the catalyst to the substrate not only leads to a stabilization of its LUMO but also induces a significant reduction of the two-orbital, four-electron Pauli repulsion involving the key molecular orbitals of both reactants. This repulsion-lowering originates, for the textbook Lewis acid-catalyzed Diels-Alder reaction, from the catalyst polarizing the occupied π orbital of the dienophile away from the carbon atoms that form new bonds with the diene. This polarization of the occupied dienophile π orbital reduces the occupied orbital overlap with the diene and constitutes the ultimate physical factor responsible for the acceleration of the catalyzed process as compared to the analogous uncatalyzed reaction. We show that this physical mechanism is generally applicable regardless of the type of reaction (Diels-Alder and Michael addition reactions) and the way the catalyst is bonded to the reactants (i.e., from pure covalent or dative bonds to weaker hydrogen or halogen bonds). We envisage that the insights emerging from our analysis will guide future experimental developments toward the design of more efficient catalytic transformations.