Electroorganic synthesis has become an established, useful, and environmentally benign alternative to classic organic synthesis for the oxidation or the reduction of organic compounds. In this context, the use of redox mediators to achieve indirect processes is attaining increased significance, since it offers many advantages compared to a direct electrolysis. Kinetic inhibitions that are associated with the electron transfer at the electrode/electrolyte interface, for example, can be eliminated and higher or totally different selectivity can be achieved. In many cases, a mediated electron transfer can occur against a potential gradient, meaning that lower potentials are needed, reducing the probability of undesired side-reactions. In addition, the use of electron transfer mediators can help to avoid electrode passivation resulting from polymer film formation on the electrode surface. Although the principle of indirect electrolysis was established many years ago, new, exciting and useful developments continue to be made. In recent years, several new types of redox mediators have been designed and examined, a process that can be accomplished more efficiently and purposefully using modern computational tools. New protocols including, the development of double mediatory systems in biphasic media, enantioselective mediation and heterogeneous electrocatalysis using immobilized mediators have been established. Furthermore, the understanding of mediated electron transfer reaction mechanisms has advanced. This review describes progress in the field of electroorganic synthesis and summarizes recent advances.

Redox catalysis in organic electrosynthesis: basic principles and recent developments.

While preparative electrolysis of organic molecules has been an active area of research over the past century, modern synthetic chemists have generally been reluctant to adopt this technology. In fact, electrochemical methods possess many benefits over traditional reagent-based transformations, such as high functional group tolerance, mild conditions, and innate scalability and sustainability. In this Outlook we highlight illustrative examples of electrochemical reactions in the context of the synthesis of complex molecules, showcasing the intrinsic benefits of electrochemical reactions versus traditional reagent-based approaches. Our hope is that this field will soon see widespread adoption in the synthetic community.

https://pubsdc3.acs.org/doi/pdf/10.1021/acscentsci.6b00091

Synthetic Organic Electrochemistry: An Enabling and Innately Sustainable Method

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-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.

While organic electrochemistry can look quite different to a chemist not familiar with the technique, the reactions are at their core organic reactions. As such, they are developed and optimized using the same physical organic chemistry principles employed during the development of any other organic reaction. Certainly, the electron transfer that triggers the reactions can require a consideration of new “wrinkles” to those principles, but those considerations are typically minimal relative to the more traditional approaches needed to manipulate the pathways available to the reactive intermediates formed downstream of that electron transfer. In this review, three very different synthetic challenges—the generation and trapping of radical cations, the development of site-selective reactions on microelectrode arrays, and the optimization of current in a paired electrolysis—are used to illustrate this point.

Using Physical Organic Chemistry To Shape the Course of Electrochemical Reactions.

1,3-Migration of acetoxy group, a new type of rearrangement of acetoxyalkyl radicals

A New Method for Synthesis of N‐(3‐Acyloxypropyl)‐Substituted Six‐ to Thirteen‐Membered Alkan‐n‐olides.

1.

The reaction of lead tetraacetate with dicarboxylic acids of general formula RCH2CH(COOH)(CH2)n-COOH (R=Alk, n=1, 2, 3 or 10) in the presence of pyridine led to their selective oxidation decarboxylation and the generation of carboxyalkyl radicals RCH2ĊH(CH2)COOH. In a similar manner, the 1-(carbomethoxymethyl)nonyl and 2-carbomethoxycyclohexyl radicals were obtained from the monomethyl esters of the 2-octylsuccinic and cyclohexane-1,2-dicarboxylic acids.




2.

The main products when the radicals are oxidized with the Pb(IV) and Cu(II) carboxylates are alkenoic acids and their esters, γ- and δ-laetones (in the oxidation of the carboxylalkyl radicals with n = 2 and 3), and esters of acetoxy-substituted monocarboxylic acids (when oxidation is with Pb(IV) carboxylates).




3.

The carboxy and carbomethoxy groups in the 2- and 3-carboxy- and 2-carbomethoxyalkyl radicals direct the oxidativeΒ-deprotonation of these radicals under the influence of copper ions predominantly toward the formation of alkenoic acids or of their esters, where the double bond is further away from the functional group.

Oxidative decarboxylation of dicarboxylrc acids by lead tetraacetate and oxidation of generated carboxyalkyl radicals by Pb(IV) and Cu(II) carboxylates

Conversion of Ω-cyanoalkyl radicals to cycloalkanones by a new type of homolytic cyclization

1.

The methyl and ethyl esters of maleic acid form 1∶1 and 2∶1 adducts with the methyl and ethyl esters of malonic and succinic acids in a reaction initiated by tert-butyl peroxide with high conversion (from 85 to 100%) and yield (from 75 to 100%).




2.

Ethyl malonate and the alkyl succinates form two types of adducts with the alkyl maleates as a result of addition at the α-carbon atoms of the acid and alcohol segments of the ester. The addition of methyl malonate to alkyl maleates occurs only at the methylene group.




3.

The alkyl malonates and methyl succinate predominantly add two molecules of alkyl maleate.

Yu. N. Ogibin

Papers

1,3-Migration of acetoxy group, a new type of rearrangement of acetoxyalkyl radicals

A New Method for Synthesis of N‐(3‐Acyloxypropyl)‐Substituted Six‐ to Thirteen‐Membered Alkan‐n‐olides.

Oxidative decarboxylation of dicarboxylrc acids by lead tetraacetate and oxidation of generated carboxyalkyl radicals by Pb(IV) and Cu(II) carboxylates

Conversion of Ω-cyanoalkyl radicals to cycloalkanones by a new type of homolytic cyclization

Homolytic addition of malonic and succinic acid esters to alkyl maleates