Organic Electrochemistry: Molecular Syntheses with Potential.

Efficient and selective molecular syntheses are paramount to inter alia biomolecular chemistry and material sciences as well as for practitioners in chemical, agrochemical, and pharmaceutical industries. Organic electrosynthesis has undergone a considerable renaissance and has thus in recent years emerged as an increasingly viable platform for the sustainable molecular assembly. In stark contrast to early strategies by innate reactivity, electrochemistry was recently merged with modern concepts of organic synthesis, such as transition-metal-catalyzed transformations for inter alia C-H functionalization and asymmetric catalysis. Herein, we highlight the unique potential of organic electrosynthesis for sustainable synthesis and catalysis, showcasing key aspects of exceptional selectivities, the synergism with photocatalysis, or dual electrocatalysis, and novel mechanisms in metallaelectrocatalysis until February of 2021.

3d metallaelectrocatalysis for resource economical syntheses.

Resource economy constitutes one of the key challenges for researchers and practitioners in academia and industries, in terms of rising demand for sustainable and green synthetic methodology. To achieve ideal levels of resource economy in molecular syntheses, novel avenues are required, which include, but are not limited to the use of naturally abundant, renewable feedstocks, solvents, metal catalysts, energy, and redox reagents. In this context, electrosyntheses create the unique possibility to replace stoichiometric amounts of oxidizing or reducing reagents as well as electron transfer events by electric current. Particularly, the merger of Earth-abundant 3d metal catalysis and electrooxidation has recently been recognized as an increasingly viable strategy to forge challenging C-C and C-heteroatom bonds for complex organic molecules in a sustainable fashion under mild reaction conditions. In this review, we highlight the key developments in 3d metallaelectrocatalysis in the context of resource economy in molecular syntheses until February 2020.

Cobaltaelectro-catalyzed C-H activation for resource-economical molecular syntheses.

The direct cleavage of otherwise inert C-H bonds has emerged as a sustainable approach for organic synthesis; in contrast to other approaches, these reactions result in the formation of fewer undesired by-products and do not require pre-functionalization steps. In recent years, oxidative C-H/N-H alkyne annulations and C-H oxygenations were realized by 3d metals. Unfortunately, most of these reactions require stoichiometric amounts of often toxic chemical oxidants. This protocol provides a general method for cobaltaelectro-catalyzed C-H activations of benzamides. Here, anodic oxidation obviates the need for a chemical oxidant and uses 10-20% of a more environmentally benign, inexpensive catalyst. We outline a detailed and precise description of the designed electrolytic cell for metallaelectrocatalysis, including readily available electrode materials and electrode holders. The custom-made device is further compared with the commercially available and standardized ElectraSyn 2.0 electrochemistry kit. As example applications of this approach, we describe cobaltaelectro-catalyzed C-H activation protocols for the direct C-H oxygenation of benzamides and resource-economical synthesis of isoquinolones. The cobaltaelectrocatalysis setup and reaction take about 17 h, while an additional 5 h have to be anticipated for workup and chromatographic purification. The methods described herein feature broad functional group tolerance, operational simplicity, low waste-product formation and an overall exceptional level of resource economy.

Insights into Cobalta(III/IV/II)-Electrocatalysis: Oxidation-Induced Reductive Elimination for Twofold C-H Activation.

The merger of cobalt-catalyzed C-H activation and electrosynthesis provides new avenues for resource-economical molecular syntheses, unfortunately their reaction mechanisms remain poorly understood. Herein, we report the identification and full characterization of electrochemically generated high-valent cobalt(III/IV) complexes as crucial intermediates in electrochemical cobalt-catalyzed C-H oxygenations. Detailed mechanistic studies provided support for an oxidatively-induced reductive elimination via highly-reactive cobalt(IV) intermediates. These key insights set the stage for unprecedented cobaltaelectro two-fold C-H/C-H activation.

Cobalta-Electrocatalyzed C-H Activation in Biomass-Derived Glycerol: Powered by Renewable Wind and Solar Energy.

Aqueous glycerol was identified as a renewable reaction medium for metalla-electrocatalyzed C-H activation powered by sustainable energy sources. The renewable solvent was employed for cobalt-catalyzed C-H/N-H functionalizations under mild conditions. The cobalta-electrocatalysis manifold occurred with high levels of chemo- and positional selectivity and allowed for electrochemical C-H activations with broad substrate scope. The resource economy of this strategy was considerably substantiated by the direct use of renewable solar and wind energy.

Carboxylate breaks the arene C-H bond via a hydrogen-atom-transfer mechanism in electrochemical cobalt catalysis.

Combined computational and experimental studies elucidated the distinctive mechanistic features of electrochemical cobalt-catalyzed C-H oxygenation. A sequential electrochemical-chemical (EC) process was identified for the formation of an amidylcobalt(iii) intermediate. The synthesis, characterization, cyclic voltammetry studies, and stoichiometric reactions of the related amidylcobalt(iii) intermediate suggested that a second on-cycle electro-oxidation occurs on the amidylcobalt(iii) species, which leads to a formal Co(iv) intermediate. This amidylcobalt(iv) intermediate is essentially a cobalt(iii) complex with one additional single electron distributed on the coordinating heteroatoms. The radical nature of the coordinating pivalate allows the formal Co(iv) intermediate to undergo a novel carboxylate-assisted HAT mechanism to cleave the arene C-H bond, and a CMD mechanism could be excluded for a Co(iii/i) catalytic scenario. The mechanistic understanding of electrochemical cobalt-catalyzed C-H bond activation highlights the multi-tasking electro-oxidation and the underexplored reaction channels in electrochemical transition metal catalysis.

Renewable resources for sustainable metallaelectro-catalysed C-H activation.

The necessity for more sustainable industrial chemical processes has internationally been agreed upon. During the last decade, the scientific community has responded to this urgent need by developing novel sustainable methodologies targeted at molecular transformations that not only produce reduced amounts of byproducts, but also by the use of cleaner and renewable energy sources. A prime example is the electrochemical functionalization of organic molecules, by which toxic and costly chemicals can be replaced by renewable electricity. Unrivalled levels of resource economy can thereby be achieved via the merger of metal-catalyzed C-H activation with electrosynthesis. This perspective aims at highlighting the most relevant advances in metallaelectro-catalysed C-H activations, with a particular focus on the use of green solvents and sustainable wind power and solar energy until June 2020.

Mangana(iii/iv)electro-catalyzed C(sp3)-H azidation.

Manganaelectro-catalyzed azidation of otherwise inert C(sp3)-H bonds was accomplished using most user-friendly sodium azide as the nitrogen-source. The operationally simple, resource-economic C-H azidation strategy was characterized by mild reaction conditions, no directing group, traceless electrons as the sole redox-reagent, Earth-abundant manganese as the catalyst, high functional-group compatibility and high chemoselectivity, setting the stage for late-stage azidation of bioactive compounds. Detailed mechanistic studies by experiment, spectrophotometry and cyclic voltammetry provided strong support for metal-catalyzed aliphatic radical formation, along with subsequent azidyl radical transfer within a manganese(iii/iv) manifold.

C-H Oxygenation Reactions Enabled by Dual Catalysis with Electrogenerated Hypervalent Iodine Species and Ruthenium Complexes.

The catalytic generation of hypervalent iodine(III) reagents by anodic electrooxidation was orchestrated towards an unprecedented electrocatalytic C-H oxygenation of weakly coordinating aromatic amides and ketones. Thus, catalytic quantities of iodoarenes in concert with catalytic amounts of ruthenium(II) complexes set the stage for versatile C-H activations with ample scope and high functional group tolerance. Detailed mechanistic studies by experiment and computation substantiate the role of the iodoarene as the electrochemically relevant species towards C-H oxygenations with electricity as a sustainable oxidant and molecular hydrogen as the sole by-product. para-Selective C-H oxygenations likewise proved viable in the absence of directing groups.

Iridium-Catalyzed Electrooxidative C-H Activation by Chemoselective Redox-Catalyst Cooperation.

Iridium-catalyzed electrochemical C-H activation was accomplished within a cooperative catalysis manifold, setting the stage for electrooxidative C-H alkenylations through weak O-coordination. The iridium-electrocatalyzed C-H activation featured high functional-group tolerance through assistance of a metal-free redox mediator through indirect electrolysis. Detailed mechanistic insights provided strong support for an organometallic C-H cleavage and a synergistic iridium(III/I)/redox catalyst regime, enabling the use of sustainable electricity as the terminal oxidant with improved selectivity features.

Catalyst- and Reagent-Free Electrochemical Azole C-H Amination.

Catalyst- and chemical oxidant-free electrochemical azole C-H aminations were accomplished via cross-dehydrogenative C-H/N-H functionalization. The catalyst-free electrochemical C-H amination proved feasible on azoles with high levels of efficacy and selectivity, avoiding the use of stoichiometric oxidants under ambient conditions. Likewise, the C(sp3 )-H nitrogenation proved viable under otherwise identical conditions. The dehydrogenative C-H amination featured ample scope, including cyclic and acyclic aliphatic amines as well as anilines, and employed sustainable electricity as the sole oxidant.

Electrochemical Cobalt-Catalyzed C-H Activation.

Carbon-heteroatom bonds represent omnipresent structural motifs of the vast majority of functionalized materials and bioactive compounds. C-H activation has emerged as arguably the most efficient strategy to construct C-Het bonds. Despite of major advances, these C-H transformations were largely dominated by precious transition metal catalysts, in combination with stoichiometric, toxic metal oxidants. Herein, we discuss the recent evolution of cobalt-catalyzed C-H activations that enable C-Het formations with electricity as the sole sustainable oxidant until May 2018.

Electrochemical C-H/N-H Activation by Water-Tolerant Cobalt Catalysis at Room Temperature.

Electrochemistry enabled C-H/N-H functionalizations at room temperature by external oxidant-free cobalt catalysis. Thus, the sustainable cobalt electrocatalysis manifold proceeds with excellent levels of chemoselectivity and positional selectivity, and with ample scope, thus allowing electrochemical C-H activation under exceedingly mild reaction conditions at room temperature in water.

Electrochemical Cobalt-Catalyzed C-H Oxygenation at Room Temperature.

Electrochemical cobalt-catalyzed C-H functionalizations were achieved in terms of C-H oxygenation under mild conditions at 23 °C. The robust electrochemical C-H functionalization was characterized by ample substrate scope, whereas mechanistic studies provided support for a facile C-H cleavage. The electrochemical cobalt-catalyzed C-H oxygenation proved viable on arenes and alkenes with excellent levels of positional and diastereo-selectivity, avoiding the use of stoichiometric silver(I) oxidants under ambient conditions.

Manganese(I)-Catalyzed Dispersion-Enabled C-H/C-C Activation.

C-H/C-C Functionalizations were achieved with the aid of a versatile manganese(I) catalyst. Thus, an organometallic manganese-catalyzed C-H activation set the stage for silver-free C-H/C-C transformations with ample substrate scope and excellent levels of chemo-, site-, and diastereo-selectivities. The robust nature of the manganese(I) catalysis regime was reflected by the first C-H/C-C functionalization on amino acids under racemization-free reaction conditions. Detailed experimental and computational mechanistic studies provided strong evidence for a facile C-H activation and a rate-determining C-C cleavage, with considerable contribution from London dispersion interactions.