Enhancing Substrate–Metal Catalyst Affinity via Hydrogen Bonding: Pd(II)-Catalyzed β-C(sp<sup>3</sup>)–H Bromination of Free Carboxylic Acids
Liang Hu, Guangrong Meng, Xiangyang Chen, Joseph S Yoon, Jing‐Ran Shan, Nikita Chekshin, Daniel A. Strassfeld, Tao Sheng, Zhe Zhuang, Rodolphe Jazzar, Guy Bertrand, K. N. Houk, Jin‐Quan Yu
Abstract
The achievement of sufficient substrate–metal catalyst affinity is a fundamental challenge for the development of synthetically useful C–H activation reactions of weakly coordinating native substrates. While hydrogen bonding has been harnessed to bias site selectivity in existing C(sp 2 )–H activation reactions, the potential for designing catalysts with hydrogen bond donors (HBDs) to enhance catalyst–substrate affinity and, thereby, facilitate otherwise unreactive C(sp 3 )–H activation remains to be demonstrated. Herein, we report the discovery of a ligand scaffold containing a remote amide motif that can form a favorable meta -macrocyclic hydrogen bonding interaction with the aliphatic acid substrate. The utility of this ligand scaffold is demonstrated through the development of an unprecedented C(sp 3 )–H bromination of α-tertiary and α-quaternary free carboxylic acids, which proceeds in exceedingly high mono -selectivity. The geometric relationship between the NHAc hydrogen bond donor and the coordinating quinoline ligand is crucial for forming the meta -macrocyclophane-like hydrogen bonding interaction, which provides a guideline for the future design of catalysts employing secondary interactions.