What is the Role of Acid-Acid Interactions in Asymmetric Phosphoric Acid Organocatalysis? A Detailed Mechanistic Study using Interlocked and Non-Interlocked Catalysts

Organocatalysis has revolutionized asymmetric synthesis. However, the supramolecular interactions of organocatalysts in solution are often neglected, although the formation of catalyst aggregates can have a strong impact on the catalytic reaction. For phosphoric acid based organocatalysts, we have now established that catalyst-catalyst interactions can be suppressed by using macrocyclic catalysts, which react predominantly in a monomeric fashion, while they can be favored by integration into a bifunctional catenane, which react mainly as phosphoric acid dimers. For acyclic phosphoric acids, we found a strongly concentration dependent behavior, involving both monomeric and dimeric catalytic pathways. Based on a detailed experimental analysis, DFT-calculations and a direct NMR-based observation of the catalyst aggregates, we could demonstrate that intermolecular acid-acid interactions have a drastic influence on the reaction rate and stereoselectivity of the asymmetric transfer-hydrogenation catalyzed by chiral phosphoric acids