Solvophobic Effect-Driven C4-Selective Oxidation of Alkyl Substrates by a Macrocyclic Supramolecular Catalyst

The selective oxidation of inert aliphatic C–H bonds remains a formidable challenge in organic synthesis, particularly at medial positions in substrates lacking directing groups. We report a novel macrocyclic supramolecular manganese catalyst that achieves site-selective C–H oxidation by harnessing the solvophobic effect for substrate binding. Compared to our previous system with limited scope and modest C5 selectivity, the macrocyclic design enhances preorganization and enables robust C4-selective oxidation across a broad substrate range. Under optimized conditions in fluorinated alcohol solvents, the catalyst delivers high C4 selectivity (60–70%), reaching up to 90% for n-octane. It is effective on both linear alkanes and complex molecules containing functional groups such as chlorides, nitriles, esters, and protected amines, underscoring its potential for late-stage functionalization. Notably, the catalyst also provides moderate enantioselectivity (39% ee), a rare feat for unfunctionalized alkanes. This macrocyclic platform offers a blueprint for the rational design of next-generation supramolecular catalysts with tunable site-selectivity for C–H functionalization.