Conspectus Electrochemical organic oxidation reactions are highly appealing because protons are often effective terminal electron acceptors, thereby avoiding undesirable stoichiometric oxidants. These reactions are often plagued by high overpotentials, however, that greatly limit their utility. Single-electron transfer (SET) from organic molecules generates high-energy radical-cations. Formation of such intermediates often requires electrode potentials far above the thermodynamic potentials of the reaction and frequently causes decomposition and/or side reactions of ancillary functional groups. In this Account, we show how electrocatalytic electron–proton transfer mediators (EPTMs) address this challenge. EPTMs bypass the formation of radical-cation intermediates by supporting mechanisms that operate at electrode potentials much lower (≥1 V) than those of analogous direct electrolysis reactions. The stable aminoxyl radical TEMPO (2,2,6,6-tetramethylpiperidine N-oxyl) is an effective mediator for electrochemical alcohol oxidation, and we have employed such processes for applications ranging from pharmaceutical synthesis to biomass conversion. A complementary electrochemical alcohol oxidation method employs a cooperative Cu/TEMPO mediator system that operates at 0.5 V lower electrode potential than the TEMPO-only mediated process. This difference, which arises from a different catalytic mechanism, rationalizes the broad functional group tolerance of Cu/TEMPO-based aerobic alcohol oxidation catalysts. Aminoxyl mediators address long-standing challenges in the “Shono oxidation,” an important method for α-C–H oxidation of tertiary amides and carbamates. Shono oxidations are initiated by a high-potential SET step that limits their utility. Aminoxyl-mediated Shono-type oxidations have been developed that operate at much lower potentials and tolerate diverse functional groups. Analogous reactivity underlies α-C–H cyanation of secondary cyclic amines, a new method that enables efficient diversification of piperidine-based pharmaceutical building blocks and preparation of non-natural amino acids. Electrochemical oxidations of benzylic C–H bonds are commonly initiated by SET to generate arene radical cations, but such methods are again plagued by large overpotentials. Mediated electrolysis methods that promote hydrogen-atom-transfer (HAT) from benzylic C–H bonds to Fe-oxo species and phthalimide N-oxyl (PINO) support C–H oxygenation, iodination, and oxidative-coupling reactions. A complementary method merges photochemistry with electrochemistry to achieve amidation of C­(sp3)–H bonds. This unique process operates at much lower overpotentials compatible with diverse functional groups. These results have broad implications for organic electrochemistry, highlighting the importance of “overpotential” considerations and the prospects for expanding synthetic utility by using mediators to bypass high-energy outer-sphere electron-transfer mechanisms. Principles demonstrated here for oxidation are equally relevant to electrochemical...

The direct transformation of C-H bonds into diverse functional groups represents one of the most atom- and step-economical strategies for organic synthesis and has received substantial attention over the last few decades. Despite recent advances, asymmetric C-H bond functionalizations are less developed, especially asymmetric oxidations of sp C-H bonds. Inspired by enzyme (e.g., P450) catalysis, chemists have made great efforts to develop non-enzymatic systems for enantioselective oxidations of sp C-H bonds. However, the involvement of highly reactive radical intermediates makes enantioselective transformations extremely challenging. In this Account, we present our recent studies on the enantioselective induction of prochiral benzylic radicals using a chiral bisoxazoline (Box)/Cu catalytic system. This reaction system was developed on the basis of our extensive studies of copper-catalyzed intermolecular alkene difunctionalizations, such as azidotrifluoromethylations, trifluoromethylcyanations, and trifluoromethylarylations. In these reactions, the proposed catalytic cycle starts from the oxidation of the Cu(I) species by the activated Togni-I reagent (via a Lewis acid/base interaction with a silyl reagent or arylboronic acid) through a single electron transfer process. The generated CF radical can efficiently add to the alkene, and the resultant carbon-centered radical is subsequently trapped by an active Cu(II) species bearing a nucleophile (e.g., an N, CN, or Ar moiety) to form a new C-heteroatom or C-C bond and regenerate the Cu(I) catalyst. Kinetic studies of the trifluoromethylarylation of alkenes support a Cu(I/II/III) catalytic cycle in which the carbon radical reacts with the Cu(II) species to form a highly reactive Cu(III) intermediate and its reductive elimination contributes to the final bond formation. This assumption inspired us to explore asymmetric radical transformations by introducing chiral ligands. Enantioselective cyanations and arylations of benzylic radicals have been demonstrated in the presence of chiral Box/Cu(I) catalysts, and a series of asymmetric difunctionalizations of styrenes have been successfully achieved. In addition, by means of the same benzylic radical trapping process, enantioselective decarboxylative cyanations have been demonstrated using a cooperative photocatalysis and copper catalysis system. Compared with radical addition and decarboxylative processes, hydrogen atom abstraction (HAA) provides direct and facile access to benzylic radicals. By using bisbenzenesulfonimidyl radical for HAA, our group has developed an enantioselective cyanation of benzylic C-H bonds via a copper-catalyzed radical relay, and excellent reactivity and enantioselectivity were achieved in the presence of chiral Box/Cu(I) catalysts. In addition, a regioselective benzylic C-H bond arylation proceeding through a similar process was also developed, providing simple access to 1,1-diarylalkanes. Notably, alkyl arenes were used as the limiting reagent in these reactions, which allowed the late-stage fu...

Direct amination of C(sp3)−H bonds is of broad interest in the realm of C−H functionalization because of the prevalence of nitrogen heterocycles and amines in pharmaceuticals and natural products. Reported here is a combined electrochemical/photochemical method for dehydrogenative C(sp3)−H/N−H coupling that exhibits good reactivity with both sp2 and sp3 N−H bonds. The results show how use of iodide as an electrochemical mediator, in combination with light‐induced cleavage of intermediate N−I bonds, enables the electrochemical process to proceed at low electrode potentials. This approach significantly improves the functional‐group compatibility of electrochemical C−H amination, for example, tolerating electron‐rich aromatic groups that undergo deleterious side reactions in the presence of high electrode potentials.

A novel copper-catalyzed intermolecular trifluoromethylazidation of alkenes has been developed under mild reaction conditions. A variety of CF3 -containing organoazides were directly synthesized from a wide range of olefins, including activated and unactivated alkenes, and the resulting products can be easily transformed into the corresponding CF3 -containing amine derivatives.