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

• Type of Material: Article
• Authors: Li-Ping Xu, Emory University; Shaoqun Qian, Scripps Research Institute; Zhe Zhuang, Scripps Research Institute; Jin-Quan Yu, Scripps Research Institute; Djamaladdin Musaev, Emory University
• Language: English
• Date: 2022-01-14
• Publisher: NATURE PORTFOLIO
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2022
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-022-27986-6
• Title of Journal or Parent Work: NATURE COMMUNICATIONS
• Volume: 13
• Issue: 1
• Start Page: 315
• End Page: 315
• Grant/Funding Information: This work was supported by the National Science Foundation under the CCI Center for Selective C–H Functionalization (CHE-1700982 for D.G.M.), the Natural Science Foundation of China (NSFC 21702126 for L.-P.X.), and the China Scholarship Council for support (for L.-P.X.)
• Keywords: FUNCTIONALIZATION; DERIVATIVES; FORMING REDUCTIVE ELIMINATION; ACTIVATION; LIGAND; Multidisciplinary Sciences; ARYLATION; OXIDATIVE ADDITION; Science & Technology - Other Topics; REACTIVITY; FEATURES; COMPLEXES; Science & Technology
• Research Categories: Chemistry, General

Abstract

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.