Parts-Per-Million-Level Organocatalysis Enabled by Harnessing π–π Stacking Interactions Beyond Active Sites

The direct use of π–π interactions as a key element in catalyst design to control activity and stereoselectivity remains largely unexplored, posing a significant challenge. In this work, we showcase that π–π interactions beyond active sites can serve as a powerful design tool to address major limitations in organocatalysis, including high catalyst loadings, self-aggregation of bifunctional catalysts, and catalyst recyclability issues. Incorporating a pyrene moiety into a squaramide organocatalyst enables a reduction in catalyst loading to parts-per-million (ppm)-levels for the enantioselective alcoholysis of meso-cyclic anhydrides. Intermolecular π–π stacking interactions between catalyst frameworks efficiently mitigate their inherent tendency toward hydrogen-bonded self-aggregation, thereby enabling ppm-level catalyst loadings while preserving high enantioselectivities. Furthermore, reversible immobilization of the pyrene-tagged catalyst onto reduced graphene oxides allows the reaction to proceed in the homogeneous tetrahydrofuran phase, with catalyst recovery achieved through precipitation in ethyl acetate. This approach effectively combines the benefits of both homogeneous and heterogeneous catalysis and accomplishes total turnover numbers surpassing 100,000, which was a previously deemed unattainable milestone for this reaction.