Light-Driven C(sp3)-C(sp3) Bond Functionalizations Enabled by the PCET Activation of Alcohol O-H Bonds

Abstract

ConspectusMethods that enable the selective functionalization of C-C bonds offer unique opportunities for the skeletal diversification of complex molecules and provide access to unique structures without the need for de novo synthesis. While considerable advances have been made in transition-metal-based approaches, much recent work has focused on alternative strategies for C-C bond cleavage enabled by transient free radicals. In particular, alkoxy radicals derived from simple alcohols are known to significantly destabilize adjacent C-C bonds, enabling spontaneous cleavage to eject a carbon-centered radical and afford carbonyl products via β-fragmentation. While this reactivity has long been recognized, its applications in synthesis have been limited, in part, by the challenges associated with generating the key alkoxy radical intermediates. The high bond dissociation free energies (BDFEs) of aliphatic alcohol O-H bonds (∼105 kcal/mol) preclude direct homolytic activation by hydrogen atom transfer, and most established strategies rely instead on stoichiometric prefunctionalization of the O-H bond. These approaches often further limit the scope of amenable chemistries that can be applied for postcleavage alkyl radical functionalization. Methods that could overcome these constraints have considerable synthetic potential, enabling straightforward access to reconfigured carbon frameworks from an abundant class of starting materials, as well as modular opportunities for radical functionalization. In this Account, we present our efforts toward the development of proton-coupled electron transfer (PCET) as a general mechanism for alkoxy radical generation from simple alcohols. In turn, this advance enabled us to develop a suite of novel methods for editing complex carbon frameworks via the cleavage and functionalization of C(sp³)-C(sp³) bonds. We first discuss the development of catalytic ring-opening isomerization reactions of cyclic benzylic carbinols to access linear aryl ketone products through a redox-relay approach. In these reactions, single electron oxidation of the substrate arene by an excited-state Ir(III) photocatalyst generates an arene radical cation that serves as an internal oxidant for an intramolecular PCET event, furnishing the alkoxy radical intermediate. This intermediate then undergoes C-C β-scission to provide the isomerized linear ketone products. We next present the discovery of an improved catalytic system for the direct activation of simple aliphatic alcohols. We then apply these chemistries for the light-driven depolymerization of lignin biopolymers, commercial phenoxy resins, hydroxylated polymers, and thiol epoxy thermosets. Notably, many of these redox isomerization reactions are thermodynamically unfavorable, providing isomerization products that are thermodynamically less stable than their corresponding starting materials. We then discuss the application of O-H PCET for the reconfiguration of saturated carbocyclic frameworks to provide expanded and contracted carbocyclic products. Applications of this reconfiguration strategy toward the 1,3-alkyl rearrangement of linear alcohols are also presented. Lastly, we discuss a method for the peripheral-to-core transposition of amine groups of saturated cyclic amino alcohols to access nitrogen-containing heterocyclic products. Taken together, these examples highlight how excited-state PCET can be leveraged for the catalytic generation of high energy O-centered radicals for regioselective C-C bond cleavage and enables the direct reconfiguration of complex carbon frameworks.