Conventional methods for carrying out carbon–hydrogen functionalization and carbon–nitrogen bond formation are typically conducted at elevated temperatures, and rely on expensive catalysts as well as the use of stoichiometric, and perhaps toxic, oxidants. In this regard, electrochemical synthesis has recently been recognized as a sustainable and scalable strategy for the construction of challenging carbon–carbon and carbon–heteroatom bonds. Here, electrosynthesis has proven to be an environmentally benign, highly effective and versatile platform for achieving a wide range of nonclassical bond disconnections via generation of radical intermediates under mild reaction conditions. This review provides an overview on the use of anodic electrochemical methods for expediting the development of carbon–hydrogen functionalization and carbon–nitrogen bond formation strategies. Emphasis is placed on methodology development and mechanistic insight and aims to provide inspiration for future synthetic applications in the field of electrosynthesis.

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Electrochemical strategies for C-H functionalization and C-N bond formation.

N-centered radicals are versatile reaction intermediates that can react with various π systems to construct C-N bonds. Current methods for generating N-centered radicals usually involve the cleavage of an N-heteroatom bond; however, similar strategies that are applicable to N-H bonds prove to be more challenging to develop and therefore are attracting increasing attention. In this Account, we summarize our recent efforts in the development of electrochemical methods for the generation and synthetic utilization of N-centered radicals. In our studies, N-aryl amidyl radical, amidinyl radical and iminyl radical cation intermediates are generated from N-H precursors through direct electrolysis or indirect electrolysis assisted by a redox catalyst. In addition, an electrocatalytic method that converts oximes to iminoxyl radicals has also been developed. The electrophilic amidyl radical intermediates can participate in 5-exo or 6-exo cyclization with alkenes and alkynes to afford C-centered radicals, which can then undergo various transformations such as H atom abstraction, single-electron transfer oxidation to a carbocation, cyclization, or aromatic substitution, leading to a diverse range of N-heterocyclic products. Furthermore, amidinyl radicals, iminyl radical cations, and iminoxyl radicals can undergo intramolecular aromatic substitution to afford various N-heteroaromatic compounds. Importantly, the electrochemical reaction can be channeled toward a specific product despite the presence of other competing pathways. For a successful electrosynthesis, it is important to take into consideration of both the electron transfer steps associated with the electrode and the nonelectrode related processes. A unique feature of electrochemistry is the simultaneous occurrence of anodic oxidation and cathodic reduction, which, as this Account demonstrates, allows the dehydrogenative transformations to proceed through H2 evolution without the need for chemical oxidants. In addition, cathodic solvent reduction can continuously generate a low concentration of base, which facilitates anodic substrate oxidation. Such a mechanistic paradigm obviates the need for stoichiometric strong bases and avoids base-promoted decomposition of sensitive substrates or products. Furthermore, electrode materials can also be adjusted to control the reaction outcome, as demonstrated by the synthesis of N-heteroaromatics and the corresponding N-oxides from biaryl ketoximes.

Chemistry with Electrochemically Generated N-Centered Radicals

Given its many distinct characteristics, electrochemistry represents an attractive approach to meet the prevailing trends in organic synthesis. In particular, electrocatalysis—a process that integrates electrochemistry and small-molecule catalysis—has the potential to substantially improve the scope of synthetic electrochemistry and provide a wide range of useful transformations. Recently, we have demonstrated new catalytic approaches that combine electrochemistry and redox-metal catalysis for the oxidative difunctionalization of alkenes to access a diverse array of vicinally functionalized structures. This Perspective details our design principles underpinning the development of electrochemical diazidation, dichlorination, and halotrifluoromethylation of alkenes, which were built on foundational work by others in the areas of synthetic electrochemistry, radical chemistry, and transition-metal catalysis. The introduction of redox-active Mn catalysts allows the generation of radical intermediates from read...

An Electrocatalytic Approach to the Radical Difunctionalization of Alkenes

Electrochemistry has been used as a tool to drive chemical reactions for over two centuries. With the help of an electrode and a power source, chemists are bestowed with an imaginary reagent whose potential can be precisely dialed in. The theoretically infinite redox range renders electrochemistry capable of oxidizing or reducing some of the most tenacious compounds (e.g., F- to F2 and Li+ to Li0). Meanwhile, a granular level of control over the electrode potential allows for the chemoselective differentiation of functional groups with minute differences in potential. These features make electrochemistry an attractive technique for the discovery of new modes of reactivity and transformations that are not readily accessible with chemical reagents alone. Furthermore, the use of an electrical current in place of chemical redox agents improves the cost-efficiency of chemical processes and reduces byproduct generation. Therefore, electrochemistry represents an attractive approach to meet the prevailing trends in organic synthesis and has seen increasingly broad use in the synthetic community over the past several years.While electrochemical oxidation or reduction can provide access to reactive intermediates, redox-active molecular catalysts (i.e., electrocatalysts) can also enable the generation of these intermediates at reduced potentials with improved chemoselectivity. Moreover, electrocatalysts can impart control over the chemo-, regio-, and stereoselectivities of the chemical processes that take place after electron transfer at electrode surfaces. Thus, electrocatalysis has the potential to significantly broaden the scope of organic electrochemistry and enable a wide range of new transformations. Our initial foray into electrocatalytic synthesis led to the development of two generations of alkene diazidation reactions, using transition-metal and organic catalysis, respectively. In these reactions, the electrocatalysts play two critical roles; they promote the single-electron oxidation of N3- at a reduced potential and complex with the resultant transient N3• to form persistent reactive intermediates. The catalysts facilitate the sequential addition of 2 equiv of azide across the alkene substrates, leading to a diverse array of synthetically useful vicinally diaminated products.We further applied this electrocatalytic radical mechanism to the heterodifunctionalization of alkenes. Anodically coupled electrolysis enables the simultaneous anodic generation of two distinct radical intermediates, and the appropriate choice of catalyst allowed the subsequent alkene addition to occur in a chemo- and regioselective fashion. Using this strategy, a variety of difunctionalization reactions, including halotrifluoromethylation, haloalkylation, and azidophosphinoylation, were successfully developed. Importantly, we also demonstrated enantioselective electrocatalysis in the context of Cu-promoted cyanofunctionalization reactions by employing a chiral bisoxazoline ligand. Finally, by introducing a second electrocatalyst that mediates oxidatively induced hydrogen atom transfer, we expanded scope of electrocatalysis to hydrofunctionalization reactions, achieving hydrocyanation of conjugated alkenes in high enantioselectivity. These developments showcase the generality of our electrocatalytic strategy in the context of alkene functionalization reactions. We anticipate that electrocatalysis will play an increasingly important role in the ongoing renaissance of synthetic organic electrochemistry.

Catalyzing Electrosynthesis: A Homogeneous Electrocatalytic Approach to Reaction Discovery

ConspectusTo improve the efficacy of molecular syntheses, researchers wish to capitalize upon the selective modification of otherwise inert C–H bonds. The past two decades have witnessed considerab...

Metalla-electrocatalyzed C-H Activation by Earth-Abundant 3d Metals and Beyond.

N-Oxyl compounds represent a diverse group of reagents that find widespread use as catalysts for the selective oxidation of organic molecules in both laboratory and industrial applications. While turnover of N-oxyl catalysts in oxidation reactions may be accomplished with a variety of stoichiometric oxidants, N-oxyl reagents have also been extensively used as catalysts under electrochemical conditions in the absence of chemical oxidants. Several classes of N-oxyl compounds undergo facile redox reactions at electrode surfaces, enabling them to mediate a wide range of electrosynthetic reactions. Electrochemical studies also provide insights into the structural properties and mechanisms of chemical and electrochemical catalysis by N-oxyl compounds. This review provides a comprehensive survey of the electrochemical properties and electrocatalytic applications of aminoxyls, imidoxyls, and related reagents, of which the two prototypical and widely used examples are 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) a...

Tetramethylpiperidine N-Oxyl (TEMPO), Phthalimide N-Oxyl (PINO), and Related N-Oxyl Species: Electrochemical Properties and Their Use in Electrocatalytic Reactions.

The generation and intermolecular functionalisation of carbon-centred radicals has broad potential synthetic utility. Herein, we show that benzylic radicals may be generated electrochemically from benzylboronate derivatives at low electrode potentials (ca. −0.3 V vs. Cp2Fe0/+) via single electron oxidation. Use of a catalytic quantity of a ferrocene-based electron-transfer mediator is crucial to achieve successful radical functionalisation and avoid undesirable side reactions arising from direct electrochemical oxidation or from the use of stoichiometric ferrocenium-based oxidants.

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Selective electrochemical generation of benzylic radicals enabled by ferrocene-based electron-transfer mediators

High-valent iron-oxo complexes are key intermediates in C–H functionalization reactions. Herein, we report the generation of a (TAML)Fe-oxo species (TAML = tetraamido macrocyclic ligand) via electrochemical proton-coupled oxidation of the corresponding (TAML)FeIII–OH2 complex. Cyclic voltammetry (CV) and spectroelectrochemical studies are used to elucidate the relevant (TAML)Fe redox processes and determine the predominant (TAML)Fe species present in solution during bulk electrolysis. Evidence for iron(IV) and iron(V) species is presented, and these species are used in the electrochemical oxygenation of benzylic C–H bonds and dehydrogenation of alcohols to ketones.

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Electrochemical C–H oxygenation and alcohol dehydrogenation involving Fe-oxo species using water as the oxygen source

Redox reactions are ubiquitous in organic synthesis and intrinsic to organic electrosynthesis. The language and concepts used to describe reactions in these domains are sufficiently different to create barriers that hinder broader adoption and understanding of electrochemical methods. To bridge these gaps, this Synopsis compares chemical and electrochemical redox reactions, including concepts of free energy, voltage, kinetic barriers, and overpotential. This discussion is intended to increase the accessibility of electrochemistry for organic chemists lacking formal training in this area.

"How Should I Think about Voltage? What Is Overpotential?": Establishing an Organic Chemistry Intuition for Electrochemistry.

Aerobic alcohol oxidations catalyzed by transition metal salts and aminoxyls are prominent examples of cooperative catalysis. Cu/aminoxyl catalysts have been studied previously and feature "integrated cooperativity", in which CuII and the aminoxyl participate together to mediate alcohol oxidation. Here we investigate a complementary Fe/aminoxyl catalyst system and provide evidence for "serial cooperativity", involving a redox cascade wherein the alcohol is oxidized by an in situ-generated oxoammonium species, which is directly detected in the catalytic reaction mixture by cyclic step chronoamperometry. The mechanistic difference between the Cu- and Fe-based catalysts arises from the use iron(III) nitrate, which initiates a NOx-based redox cycle for oxidation of aminoxyl/hydroxylamine to oxoammonium. The different mechanisms for the Cu- and Fe-based catalyst systems are manifested in different alcohol oxidation chemoselectivity and functional group compatibility.

Jordan E. Nutting

Papers

Tetramethylpiperidine N-Oxyl (TEMPO), Phthalimide N-Oxyl (PINO), and Related N-Oxyl Species: Electrochemical Properties and Their Use in Electrocatalytic Reactions.

Selective electrochemical generation of benzylic radicals enabled by ferrocene-based electron-transfer mediators

Electrochemical C–H oxygenation and alcohol dehydrogenation involving Fe-oxo species using water as the oxygen source

"How Should I Think about Voltage? What Is Overpotential?": Establishing an Organic Chemistry Intuition for Electrochemistry.

Iron(III) Nitrate/TEMPO-Catalyzed Aerobic Alcohol Oxidation: Distinguishing between Serial versus Integrated Redox Cooperativity.