50. Radicals as Exceptional Electron-Withdrawing Groups: Nucleophilic Aromatic Substitution of Halophenols Via Homolysis-Enabled Electronic Activation

Nick Y. Shin, Elaine Tsui, Adam Reinhold, Gregory D. Scholes, Matthew J. Bird, Robert R. Knowles

J. Am. Chem. Soc. 2022144, 21783–21790. DOI: 10.1021/jacs.2c10296


ABSTRACT: While heteroatom-centered radicals are understood to be highly electrophilic, their ability to serve as transient electron-withdrawing groups and facilitate polar reactions at distal sites has not been extensively developed. Here, we report a new strategy for the electronic activation of halophenols, wherein generation of a phenoxyl radical via formal homolysis of the aryl O–H bond enables direct nucleophilic aromatic substitution of the halide with carboxylate nucleophiles under mild conditions. Pulse radiolysis and transient absorption studies reveal that the neutral oxygen radical (O) is indeed an extraordinarily strong electron-withdrawing group [σp(O) = 2.79 vs σp(NO2) = 1.27]. Additional mechanistic and computational studies indicate that the key phenoxyl intermediate serves as an open-shell electron-withdrawing group in these reactions, lowering the barrier for nucleophilic substitution by more than 20 kcal/mol relative to the closed-shell phenol form of the substrate. By using radicals as transient activating groups, this homolysis-enabled electronic activation strategy provides a powerful platform to expand the scope of nucleophile–electrophile couplings and enable previously challenging transformations.