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.

Here we report a catalytic method for the intermolecular anti-Markovnikov hydroamination of unactivated alkenes using primary and secondary sulfonamides. These reactions occur at room temperature under visible light irradiation and are jointly catalyzed by an iridium(III) photocatalyst, a dialkyl phosphate base, and a thiol hydrogen atom donor. Reaction outcomes are consistent with the intermediacy of an N-centered sulfonamidyl radical generated via proton-coupled electron transfer activation of the sulfonamide N-H bond. Studies outlining the synthetic scope (>60 examples) and mechanistic features of the reaction are presented.

We describe a new catalytic method for accessing carbocation intermediates via the mesolytic cleavage of alkoxyamine radical cations. In this process, electron transfer between an excited state oxidant and a TEMPO-derived alkoxyamine substrate gives rise to a radical cation with a remarkably weak C-O bond. Spontaneous scission results in the formation of the stable nitroxyl radical TEMPO• as well as a reactive carbocation intermediate that can be intercepted by a wide range of nucleophiles. Notably, this process occurs under neutral conditions and at comparatively mild potentials, enabling catalytic cation generation in the presence of both acid sensitive and easily oxidized nucleophilic partners.

The direct, site-selective alkylation of unactivated C­(sp3)–H bonds in organic substrates is a long-standing goal in synthetic chemistry. General approaches to the activation of strong C–H bonds include radical-mediated processes involving highly reactive intermediates, such as heteroatom-centered radicals. Herein, we describe a catalytic, intermolecular C–H alkylation that circumvents such reactive species via a new elementary step for C–H cleavage involving multisite-proton-coupled electron transfer (multisite-PCET). Mechanistic studies indicate that the reaction is catalyzed by a noncovalent complex formed between an iridium­(III) photocatalyst and a monobasic phosphate base. The C–H alkylation proceeds efficiently using diverse hydrocarbons and complex molecules as the limiting reagent and represents a new approach to the catalytic functionalization of unactivated C­(sp3)–H bonds.

Chlorine radicals readily activate C–H bonds, but the high reactivity of these intermediates precludes their use in regioselective C–H functionalization reactions. We demonstrate that the secondary coordination sphere of a metal complex can confine photoeliminated chlorine radicals and afford steric control over their reactivity. Specifically, a series of iron­(III) chloride pyridinediimine complexes exhibit activity for photochemical C­(sp3)–H chlorination and bromination with selectivity for primary and secondary C–H bonds, overriding thermodynamic preference for weaker tertiary C–H bonds. Transient absorption spectroscopy reveals that Cl· remains confined through formation of a Cl·|arene complex with aromatic groups on the pyridinediimine ligand. Furthermore, photocrystallography confirms that this selectivity arises from the generation of Cl· within the steric environment defined by the iron secondary coordination sphere.