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

Autor: Li-Ping Xu, Shaoqun Qian, Zhe Zhuang, Jin-Quan Yu, Djamaladdin G. Musaev
Rok vydání: 2021
Předmět:
Zdroj: Nature Communications
Nature Communications, Vol 13, Iss 1, Pp 1-8 (2022)
ISSN: 2041-1723
Popis: 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 SN2 nucleophilic substitution mechanism with the rate-limiting C–O bond formation step for the Pd(II)-catalyzed C(sp3)–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 O2 oxidant) intermediates is unfavorable. Critical factors controlling the outcome of this reaction are the presence of the η3-(π-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 η3-(π-benzylic)–Pd and η2-(π-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(sp3)–H bond lactonization in the presence of C(sp2)–H.
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.
Databáze: OpenAIRE
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