Catalysis by neutral, organic, small molecules capable of binding and activating substrates solely via noncovalent interactions-particularly H-bonding-has emerged as an important approach in organocatalysis. The mechanisms by which such small molecule catalysts induce high enantioselectivity may be quite different from those used by catalysts that rely on covalent interactions with substrates. Attractive noncovalent interactions are weaker, less distance dependent, less directional, and more affected by entropy than covalent interactions. However, the conformational constraint required for high stereoinduction may be achieved, in principle, if multiple noncovalent attractive interactions are operating in concert. This perspective will outline some recent efforts to elucidate the cooperative mechanisms responsible for stereoinduction in highly enantioselective reactions promoted by noncovalent catalysts.enantioselectivity | H bonding | organocatalysis | transition state stabilization

Conspectus Redox events in which an electron and proton are exchanged in a concerted elementary step are commonly referred to as proton-coupled electron transfers (PCETs). PCETs are known to operate in numerous important biological redox processes, as well as recent inorganic technologies for small molecule activation. These studies suggest that PCET catalysis might also function as a general mode of substrate activation in organic synthesis. Over the past three years, our group has worked to advance this hypothesis and to demonstrate the synthetic utility of PCET through the development of novel catalytic radical chemistries. The central aim of these efforts has been to demonstrate the ability of PCET to homolytically activate a wide variety of common organic functional groups that are energetically inaccessible using known molecular H-atom transfer catalysts. To do so, we made use of a simple formalism first introduced by Mayer and coworkers that allowed us to predict the thermodynamic capacity of any oxidant/base or reductant/acid pair to formally add or remove H• from a given substrate. With this insight, we were able to rationally select catalyst combinations thermodynamically competent to homolyze the extraordinarily strong E-H σ-bonds found in many common protic functional groups (BDFEs >100 kcal/mol) or to form unusually weak bonds to hydrogen via the reductive action of common organic π-systems (BDFEs <35 kcal/mol). These ideas were reduced to practice through the development of new catalyst systems for reductive PCET activations of ketones and oxidative PCET activation of amide N-H bonds to directly furnish reactive ketyl and amidyl radicals, respectively. In both systems the reaction outcomes were found to be successfully predicted using the effective bond strength formalism, suggesting that these simple thermochemical considerations can provide useful and actionable insights into PCET reaction design. The ability of PCET catalysis to control enantioselectivity in free radical processes has also been established. Specifically, multisite PCET requires the formation of a pre-equilibrium hydrogen-bond between the substrate and a proton donor/acceptor prior to charge transfer. We recognized that these H-bond interfaces persist following the PCET event, resulting in the formation of non-covalent complexes of the nascent radical intermediates. When chiral proton donors/acceptors are employed, this association can provide a basis for asymmetric induction in subsequent bond-forming steps. We discuss our efforts to capitalize on this understanding via the development of a catalytic protocol for enantioselective aza-pinacol cyclizations. Lastly, we highlight an alternative PCET mechanism that exploits the ability of redox-active metals to homolytically weaken the bonds in coordinated ligands, enabling nominally strong bonds (BDFEs ~100 kcal) to be abstracted by weak H-atom acceptors with concomitant oxidation of the metal center. This ‘soft homolysis’ mechanism enables the generation of metallated intermediates...

Despite significant advances in hydrogen atom transfer (HAT) catalysis,1–5 there are currently no molecular HAT catalysts capable of homolyzing the strong N-H bonds of N-alkyl amides (Figure 1a). The motivation to develop amide homolysis protocols stems from the synthetic utility of the resulting amidyl radicals, which engage in a variety of synthetically useful transformations, including olefin amination6–11 and directed C-H bond functionalization.12–16 The latter process, a subset of the well-known Hofmann-Löffler-Freytag (HLF) reaction, relies on a favorable bond strength differential to enable amidyls to abstract H• from unactivated aliphatic C-H bonds (Figure 1b).17–21 While powerful, these transforms typically require oxidative N-prefunctionalization of the amide starting materials to achieve efficient amidyl generation. Moreover, as these N-activating groups are often incorporated into the final products, these methods are generally not amenable to the direct construction of C-C bonds. Here we report a new approach that overcomes these limitations by homolyzing the N-H bonds of N-alkyl amides through a proton-coupled electron transfer (PCET) event. In this protocol, an excited state iridium photocatalyst and a weak phosphate base cooperatively serve to remove both a proton and an electron from an amide substrate in a concerted elementary step. The resulting amidyl radical intermediates are shown to be competent to promote subsequent C-H abstraction and radical alkylation steps (Figure 1c). As such, this C-H alkylation represents a novel catalytic variant of the HLF reaction that makes use of simple, unfunctionalized amides to direct the formation of new C-C bonds. Given the prevalence of amides in pharmaceuticals and natural products, we anticipate that this method will simplify the synthesis and structural elaboration of amine-containing targets. Moreover, these studies further demonstrate that concerted PCET can enable homolytic activation of common organic functional groups that are energetically inaccessible using traditional HAT-based approaches.

The first highly enantioselective catalytic protocol for the reductive coupling of ketones and hydrazones is reported. These reactions proceed through neutral ketyl radical intermediates generated via a concerted proton-coupled electron transfer (PCET) event jointly mediated by a chiral phosphoric acid catalyst and the photoredox catalyst Ir(ppy)2(dtbpy)PF6. Remarkably, these neutral ketyl radicals appear to remain H-bonded to the chiral conjugate base of the Brønsted acid during the course of a subsequent C-C bond-forming step, furnishing syn 1,2-amino alcohol derivatives with excellent levels of diastereo- and enantioselectivity. This work provides the first demonstration of the feasibility and potential benefits of concerted PCET activation in asymmetric catalysis.

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.