Ligand-switchable modular γ-C−H functionalization of unbiased aliphatic acids

Selective functionalization of C(sp³)−H bonds in free carboxylic acids remains a cornerstone objective in synthetic chemistry, offering opportunities for late-stage diversification and streamlined retrosynthetic strategies. While α- and β-C−H functionalizations have seen broad success, the functionalization of remote γ-C(sp³)−H bonds, particularly in unbiased, acyclic aliphatic acids, has proven exceptionally challenging due to entropic and geometric constraints. Existing approaches often require rigid substrates or α-substitution to preorganize the metal center for distal activation, limiting their generality and synthetic utility. Here, we report a ligand-controlled catalytic strategy that overcomes these limitations, enabling -functionalization of free aliphatic carboxylic acids with high site-selectivity and divergent reactivity. Two structurally and electronically distinct ligands enable orthogonal transformations from the same class of aliphatic carboxylic acid substrates. In both cases, the reactions proceed through a cascade sequence involving, β,γ-dehydrogenation followed by arylation. However, one of the ligands uniquely promotes an additional intramolecular cyclization step, resulting in lactonization. This divergence in reactivity highlights the critical role of ligand design in steering the reaction pathway and enabling distinct outcomes from a common intermediate. Both linear and cyclic acids are amenable to this method, with broad tolerance for functional groups and complex molecular frameworks. Aryl bromides which is more abundant but relatively less explored for aliphatic domain were also compatible with the developed protocol. Mechanistic investigations, including control experiments and kinetic studies, reveal that ligand identity dictates not only the site of C−H activation but also the overall reaction trajectory, offering a blueprint for programmable C−H functionalization. This work establishes a powerful platform for remote molecular editing, showcasing how tailored ligand environments can unlock both reactivity and selectivity in otherwise unreactive aliphatic systems