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.

The oxidation of cyanohydrins by the S2O82−-Ag+ system begins with the reaction of the OH group of the cyanohydrin with silver ions, which results in the formation of 1-cyanoalkoxyl radicals. The sulfate ion-radicals practically do not take part in the direct oxidation of cyanohydrins.




2.

The initiation of the oxidation of cyanohydrins by peroxydisulfate in the absence of Ag+ ion proceeds via the cleavage of H atoms from the hydrocarbon groupings of the cyanohydrin by the sulfate ion-radicals. The 4(5)-hydroxy-4(5)-cyanoalkyl radicals, formed as a result of the 1, 4- and 1, 5-migration of the cyano group and subsequent oxidation, are converted to 5- and 6-cyanoalkanones. The oxidative rearrangement of alkanone cyanohydrins to 6-cyanoalkanones was observed for the first time.

Oxidative rearrangement of cyanohydrins with migration of cyano group: Mechanism of initiation by S2O8 2−-Ag+ system

1.

A study was made of the addition reaction, initiated by peroxides, of diethyl malonate, dimethyl succinate and ethyl monochloroacetate to the polyhaloolefins — to hexafluoropropylene, trichloroethylene and tetrachloroethylene.




2.

The reaction proceeds by an anomalous direction: the α-carbon atom of the alcohol portion of the ester molecule takes part either exclusively or predominantly in the formation of the new carbon — carbon bond of the adducts.




3.

The reaction of esters with trichloro- and tetrachloroethylene is accompanied by the elimination of hydrogen chloride and leads to the respective formation of either the 1-(dichlorovinyl) or 1-(trichlorovinyl) derivatives of alkyl esters of carboxylic acids.

Unusual direction of the radical reaction of esters with ethylenic compounds

A one-step general synthesis has been developed for the synthesis of-γ-and δ-cyano-ketones and cyanoacids, based on the remote oxidative cyanation of carbonyl compounds by the sodium peroxydisulfate-sodium cyanide system.

One-step remote oxidative cyanation of ketones and aldehydes

One-pot electrochemical method of synthesis of ketones, diketones, and esters of monoketo- and diketoalkanoic acids is elaborated. This method is based on the diaphragmless galvanostatic electrolysis of Na salts of secondary nitro compounds—derivatives of nitrohydrocarbons, nitroketones, and esters of nitrated alkanoic acids—in methanol.

Electrolysis of nitro compound salts: Application in ketone synthesis

1.

The oxidative decarboxylation of acids with carboxyl groups at secondary and tertiary C atoms under the action of the S2O82−- Ag+ and S2O82−-Ag+- Cu2+ systems is at least an order of magnitude faster than that of acids with COOH groups at a primary C atom, as a result of which 3- and 4-carboxyalkyl radicals with the general formula R'RĊ(CH2)nCOOH (R is alkyl or phenyl, R′ is H or alkyl, n=2 or 3) are generated with > 90% selectivity from 2-substituted glutaric and adipic acids.




2.

The 3- and 4-carboxyalkyl radicals are completely or partially converted under their generation conditions into lactones. The selectivity of the oxidative lactonization increases from 0.30 to 0.97 along the series of radicals C2H5ĊH(CH2)3COOH, C2H5ĊH(CH2)2COOH, ĊH2(CH2)3COOH, ĊH2(CH2)2COOH, (CH3)2Ċ(CH2)2-COOH, and C2H5ĊH(CH2)2COOH in the case of the S2O82−-Ag+ system and from 0.72 to 1 along this series in the case of the S2O82−- Ag+- Cu2+ system.

Yu. N. Ogibin

Papers

Oxidative rearrangement of cyanohydrins with migration of cyano group: Mechanism of initiation by S2O8 2−-Ag+ system

Unusual direction of the radical reaction of esters with ethylenic compounds

One-step remote oxidative cyanation of ketones and aldehydes

Electrolysis of nitro compound salts: Application in ketone synthesis

Selectivity of the generation of 3- and 4-carboxyalkyl radicals from substituted glutaric and adipic acids and their oxidative lactonization