We present here a review of the photochemical and electrochemical applications of multi-site proton-coupled electron transfer (MS-PCET) in organic synthesis. MS-PCETs are redox mechanisms in which both an electron and a proton are exchanged together, often in a concerted elementary step. As such, MS-PCET can function as a non-classical mechanism for homolytic bond activation, providing opportunities to generate synthetically useful free radical intermediates directly from a wide variety of common organic functional groups. We present an introduction to MS-PCET and a practitioner’s guide to reaction design, with an emphasis on the unique energetic and selectivity features that are characteristic of this reaction class. We then present chapters on oxidative N–H, O–H, S–H, and C–H bond homolysis methods, for the generation of the corresponding neutral radical species. Then, chapters for reductive PCET activations involving carbonyl, imine, other X=Y π-systems, and heteroarenes, where neutral ketyl, α-amino, and heteroarene-derived radicals can be generated. Finally, we present chapters on the applications of MS-PCET in asymmetric catalysis and in materials and device applications. Within each chapter, we subdivide by the functional group undergoing homolysis, and thereafter by the type of transformation being promoted. Methods published prior to the end of December 2020 are presented.

Deracemization is an attractive strategy for asymmetric synthesis, but intrinsic energetic challenges have limited its development. Here, we report a deracemization method in which amine derivatives undergo spontaneous optical enrichment upon exposure to visible light in the presence of three distinct molecular catalysts. Initiated by an excited-state iridium chromophore, this reaction proceeds through a sequence of favorable electron, proton, and hydrogen-atom transfer steps that serve to break and reform a stereogenic C–H bond. The enantioselectivity in these reactions is jointly determined by two independent stereoselective steps that occur in sequence within the catalytic cycle, giving rise to a composite selectivity that is higher than that of either step individually. These reactions represent a distinct approach to creating out-of-equilibrium product distributions between substrate enantiomers using excited-state redox events.

A new strategy for catalytic deracemization is presented, wherein amine derivatives undergo spontaneous optical enrichment upon exposure to visible light in the presence of three distinct molecular catalysts. Initiated by an excited-state iridium chromophore, this reaction proceeds <i>via </i>a sequence of favorable electron, proton, and hydrogen atom transfer steps that serve to break and reform a stereogenic C–H bond. The enantioselectivity in these reactions is jointly determined by two independent stereoselective steps that occur in sequence within the catalytic cycle, giving rise to a composite selectivity that is higher than that of either step individually. These reactions represent a distinct and potentially general approach to creating out-of-equilibrium product distributions between substrate enantiomers using excited-state redox events.

We report evidence of excited-state ion pair reorganisation in a cationic iridium (III) photoredox catalyst in 1,4-dioxane. Microwave-frequency dielectric-loss measurements combined with accurate calculations of dipolar relaxation time allow us to assign both ground and excited-state molecular dipole moments in solution and determine the polarizability volume in the excitedstate. These measurements show significant changes in ground-state dipole moment between [Ir[dF(CF 3 )ppy] 2 (dtbpy)]PF 6 (10.74 Debye) and [Ir[dF(CF 3 )ppy] 2 (dtbpy)]BAr F 4 (4.86 Debye). Photoexcitation of each complex results in population of highly mixed ligand centered and metal-to-ligand charge transfer states with enormous polarizability. Relaxation to the lowest lying excited-state leads to a negative change in the dipole moment for [Ir[dF(CF 3 )ppy] 2 (dtbpy)]PF 6 , and a positive change in dipole moment for [Ir[dF(CF 3 )ppy] 2 (dtbpy)]BAr F 4 . These observations are consistent with a sub-nanosecond reorganization with the PF − 6 counter-ion, which cancels the dipole moment of the lowest lying excited-state, a process which is absent for the BAr F− 4 counter-ion. Taken together, these observations suggest contact-ion pair formation between the cationic metal complex and the PF − 6 anion and, at most, solvent-separated pairing with BAr F− 4 . The dynamic ion pair reorganisation we observe with the PF − 6 counter-ion may substantially modify both the thermodynamic potential available for electron transfer and kinetically inhibit oxidative catalysis, as the anion moves to cover the positively charged end of the molecule, providing a possible mechanistic explanation for recently observed trends in the catalytic activity of these complexes as a function of anion identity in low-polarity solvents. These tunable ion-pair dynamics could prove to be a valuable tool for tailoring the reactivity of both new and extant photocatalysts.

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.