Unconventional mechanism and selectivity of the Pd-catalyzed C-H bond lactonization in aromatic carboxylic acid

Methods to functionalize inert C-H bonds are a critical focus of synthetic organic chemistry. In this work the authors use computations and experiments to uncover the mechanisms of palladium-catalysed C-H lactonizations in aromatic carboxylic acids, and explain the origin of an observed preference for functionalization of a C(sp3)-H bond over a C(sp2)-H bond in a recent report. The search for more effective and highly selective C-H bond oxidation of accessible hydrocarbons and biomolecules is a greatly attractive research mission. The elucidating of mechanism and controlling factors will, undoubtedly, help to broaden scope of these synthetic protocols, and enable discovery of more efficient, environmentally benign, and highly practical new C-H oxidation reactions. Here, we reveal the stepwise intramolecular S(N)2 nucleophilic substitution mechanism with the rate-limiting C-O bond formation step for the Pd(II)-catalyzed C(sp(3))-H lactonization in aromatic 2,6-dimethylbenzoic acid. We show that for this reaction, the direct C-O reductive elimination from both Pd(II) and Pd(IV) (oxidized by O-2 oxidant) intermediates is unfavorable. Critical factors controlling the outcome of this reaction are the presence of the eta(3)-(pi-benzylic)-Pd and K+-O(carboxylic) interactions. The controlling factors of the benzylic vs ortho site-selectivity of this reaction are the: (a) difference in the strains of the generated lactone rings; (b) difference in the strengths of the eta(3)-(pi-benzylic)-Pd and eta(2)-(pi-phenyl)-Pd interactions, and (c) more pronounced electrostatic interaction between the nucleophilic oxygen and K+ cation in the ortho-C-H activation transition state. The presented data indicate the utmost importance of base, substrate, and ligand in the selective C(sp(3))-H bond lactonization in the presence of C(sp(2))-H.

Automated summary

This study investigates the mechanisms of palladium-catalyzed C-H lactonizations in aromatic carboxylic acids and explains the preference for functionalization of a C(sp3)-H bond. Understanding these mechanisms is important for expanding synthetic protocols and discovering more efficient and practical new C-H oxidation reactions.