Modern Electrochemical Aspects for the Synthesis of Value-Added Organic Products.

The use of electricity instead of stoichiometric amounts of oxidizers or reducing agents in synthesis is very appealing for economic and ecological reasons, and represents a major driving force for research efforts in this area. To use electron transfer at the electrode for a successful transformation in organic synthesis, the intermediate radical (cation/anion) has to be stabilized. Its combination with other approaches in organic chemistry or concepts of contemporary synthesis allows the establishment of powerful synthetic methods. The aim in the 21st Century will be to use as little fossil carbon as possible and, for this reason, the use of renewable sources is becoming increasingly important. The direct conversion of renewables, which have previously mainly been incinerated, is of increasing interest. This Review surveys many of the recent seminal important developments which will determine the future of this dynamic emerging field.

Introduction

The application of electrochemical methods to the synthesis of organic molepan class="Chemical">cules has undergone a revival during the last few decades.1 In terms of the eclass="Chemical">pan class="Chemical">cological footprint,2, 3, 4 the substitution of chemical redox reagents by electricity is an inevitable step towards green chemical processes.5 A variety of valuable synthetic pathways for electrochemical synthesis has been described in the previous review “Electrifying Organic Synthesis”.171 Besides the continuous development of new electrochemical reactions and the synthesis of complex organic molecules, significant progress has been made in the realization of electrochemical methods. These innovations include the merger of electrochemistry with conventional chemical ideas, such as organocatalysis and flow electrochemistry, as well as new procedures for controlling the selectivity of electrochemical transformations such as the “cation‐pool” method, the redox‐tag approach, and bio‐electrochemistry. In addition, the electrochemical conversion of renewables provides a sustainable alternative for the synthesis of valuable fine chemicals from current waste streams. All these innovative methods will help in the development of selective electrochemical transformations for value‐added organic products and help in the scale‐up for technical applications. A variety of these recent developments will be described in this Review.

All electrochemical methods are based on simple electron transfers from the electrode to the substrate or vice versa. In electroorganic syntheses, roughly three different scenarios for the electron transfer from the electrode to the substrate are feasible. The classical way is to use an inert electrode. In this case, the electropan class="Chemical">conversion occlass="Chemical">pan class="Chemical">curs at the electrode surface and selectivity can be achieved by adjusting the appropriate electrode potential (Figure 1 a).

Figure 1

Different operation modes of electrodes in electrosynthetic applications.

Since many molepan class="Chemical">cular moieties, such as class="Chemical">pan class="Chemical">alcohols or double bonds, cannot be selectivity addressed in complex molecules, an electrocatalytic approach is required. This can be achieved either by an active electrode or by using a mediator. An active electrode has electrocatalytically active species on the surface, which can be considered as immobilized redox‐active reagents (Figure 1 b). In the best case, a compact and electrically conductive coating is formed, which is electrochemically regenerated in situ.6 Such active electrodes usually provide a unique reactivity. In this particular case, the electroconversion becomes less dominated by the applied potential since the redox‐active layer serves as a redox filter. In addition, the immobilization of the electrocatalyst simplifies the experimental set‐up. Operation in undivided cells and at constant current is commonly the case. Since the redox‐active component stays on the surface because of its low solubility, such electrodes are not consumed and can even be easily operated in simple flow cells. Although this concept is well‐established for anodes, it is rarely applied for electroreductions. Typical examples are nickel‐based anodes for oxidation reactions in alkaline media or fluorinations (e.g. Scheme 20).

Scheme 20

Electrochemical degradation of lignosulfonate at nickel anodes.89

The third option describes electroactive species that are soluble in the electrolyte (Figure 1 c). Here, the redox‐active species are mediators and can be pan class="Chemical">considered as electrochemically regenerated reagents. Besides the unique reactivity, large over‐class="Chemical">potentials can usually be avoided. Therefore, the electroclass="Chemical">pan class="Chemical">conversion can be conducted at milder potentials compared to an electrolysis without a mediator.7 The disadvantage of this approach can be the generation of additional waste and costs.

In general, the application of novel organic synthesis pan class="Chemical">conceclass="Chemical">pts mostly relies on the use of inert electrodes, since the reactivity is not determined by a surface layer. Oclass="Chemical">peration at class="Chemical">pan class="Chemical">constant current has several advantages: Firstly, the electronic periphery is of low cost, since simple power supplies (DC‐type) can be employed. Secondly, no reference electrode is required. Thirdly, the reaction scale‐up is more straightforward in a two‐electrode arrangement. Although many novel electrode materials have been developed and established in electroorganic synthesis, the workhorse is still the carbon electrode. Such carbon systems range from various types of graphite to glassy carbon. Besides the compact electrode material, porous versions are also employed. For more extreme electrochemical potentials, doped‐diamond seems to be the material of choice.8 Since electrodes do not remain intact forever and corrosion or fouling might occur, carbon electrodes will be the only sustainable solution without using up critical metals or resources.

Organocatalysis in Electrosynthesis

Organocatalysis gained significant attention in the late 1990s and evolved into a popular research field of organic chemistry,9 although there were some reports of using organic molepan class="Chemical">cules as catalysts in the last century. The class="Chemical">potential for avoiding chemical waste, saving class="Chemical">pan class="Chemical">costs, and facilitating experimental procedures awakened the interest of many research groups. The combination of the advantages of organocatalysis with the sustainability of electroorganic reactions yielded a collection of effective synthetic strategies. Ogawa and Boydston recently reviewed this unification in detail.10

pan class="Chemical">Pyrrolidine derivatives are broadly used as catalysts in organocatalyzed reactions, in class="Chemical">particlass="Chemical">pan class="Chemical">cular for asymmetric synthesis.11 Jang and co‐workers developed a method for the anodic organocatalyzed α‐oxyamination of aldehydes under constant current conditions by using pyrrolidine as a catalyst.12 Earlier reported chemical oxidants such as ceric ammonium nitrate (CAN) or Cp2FeBF4 were not required; thus, the electrochemical variation is an elegant version to conduct this reaction (Scheme 1).13

Scheme 1

Electrochemical organocatalyzed α‐oxyamination of aldehydes.12

Electrochemical organocatalyzed α‐oxyamination of pan class="Chemical">aldehydes.12

The reaction of different pan class="Chemical">aldehydes with a variety of chiral seclass="Chemical">pan class="Chemical">condary amines was tested for the applicability of this method in asymmetric synthesis. Only pyrrolidine‐based chiral catalysts led to a successful conversion with moderate enantiomeric excess, with l‐proline methyl ester hydrochloride providing the best results. Cyclic voltammetry and control experiments enabled the mechanism to be elucidated. The in situ formed enamine derivatives exhibited a lower oxidation potential than the corresponding aldehydes, and the radical cations generated were intercepted by the 2,2,6,6‐tetramethylpiperidinyloxyl (TEMPO) radical present as the coupling partner. The formation of TEMPO+ species by anodic oxidation could be excluded.

This approach was expanded to the electrochemical α‐functionalization of pan class="Chemical">aldehydes.14 Different class="Chemical">pan class="Chemical">aliphatic aldehydes were coupled with xanthene (Scheme 2). The use of cycloheptatriene, instead of xanthene, as the coupling partner led to poor yields. Different organocatalysts were tested to improve the yield and stereoselectivity.

Scheme 2

Electrochemical organocatalyzed α‐alkylation of aldehydes.14 Bn=benzyl.

Electrochemical organocatalyzed α‐alkylation of pan class="Chemical">aldehydes.14 Bn=benzyl.

Two plpan class="Chemical">ausible mechanisms were class="Chemical">postulated: The first involved the formation of a class="Chemical">pan class="Chemical">xanthene cation and subsequent nucleophilic attack of the enamine. The other included the simultaneous oxidation of the enamine and xanthene, followed by a recombination of the radicals formed. The oxidation potentials of all the components were determined and control experiments were conducted. The addition of the radical inhibitor 2,6‐di‐tert‐butyl‐4‐methylphenol prevented the formation of product, thereby indicating the latter‐mentioned radical‐based mechanism was operative. The reported procedure was a more‐sustainable method for performing this reaction, as there was no need for photoredox catalysts or stoichiometric chemical oxidants, as used in previous studies.15

Another interesting pan class="Chemical">contribution to this toclass="Chemical">pic came from Jørgensen et al. Starting from class="Chemical">pan class="Chemical">aliphatic aldehydes and N‐tosylated 4‐aminophenols in the presence of a pyrrolidine‐based organocatalyst, electrochemical oxidation at a constant current led to meta‐substituted anilines in good yields and high enantiomeric excess (Scheme 3).16

Scheme 3

Electrochemical organocatalyzed synthesis of meta‐substituted anilines.16 TMS=trimethylsilyl, Ts=tosyl.

Electrochemical organocatalyzed synthesis of meta‐substituted anilines.16 TMS=pan class="Chemical">trimethylsilyl, Ts=tosyl.

The electrochemical oxidation of the 4‐aminophpan class="Chemical">enols at the anode induced an Umclass="Chemical">polung of the class="Chemical">pan class="Chemical">aromatic system. The catalytically formed enamine underwent a Michael addition, and a subsequent condensation formed the dihydrobenzofuran. Reduction of the dihydrobenzofuran enabled access to meta‐substituted anilines.

Even before the wide interest in organocatalysis, Chiba et al. reported the first organocatalyzed anodic oxidation in 1982. The oxidation of pan class="Chemical">aldehydes in class="Chemical">pan class="Chemical">methanol in the presence of sodium cyanide by using platinum electrodes and a constant current led to the corresponding methyl carboxylates, as shown in Scheme 4.17 Aromatic, non‐activated aldehydes were converted into methyl esters in good yields, whereas the oxidation of aliphatic substrates competed with side reactions such as aldol condensations.

Scheme 4

Anodic oxidation of aldehydes in methanolic NaCN solution.17

Anodic oxidation of pan class="Chemical">aldehydes in class="Chemical">pan class="Chemical">methanolic NaCN solution.17

pan class="Chemical">Control exclass="Chemical">periments using different electrolytes highlighted the necessity of class="Chemical">pan class="Chemical">cyanide for the oxidation. The oxidation potential of benzaldehyde versus the saturated calomel electrode (SCE) in a lithium perchlorate/acetonitrile solution is about 2.3 V, whereas the oxidation in methanolic NaCN solution occurs at 1.7 V. Therefore, Chiba et al. assumed the electroactive intermediate was the formed cyanohydrin. The same mechanism was predicted in 1968 by Corey et al., who used an excess of manganese dioxide as the oxidant.18

N‐Heterocyclic pan class="Chemical">carbenes (class="Chemical">pan class="Gene">NHC) are also of significant interest for organocatalyzed reactions. Inspired by the oxidation of other electron‐rich alkenes, Boydston and co‐workers focused their studies on the oxidation of the Breslow intermediate formed by NHCs with aldehydes. The electrochemical oxidation of aldehydes in the presence of NHC and DBU led to esters.19 The low substrate concentrations necessitated the reaction being performed under potentiostatic control. The authors were able to convert a broad range of substrates, including aliphatic and aromatic aldehydes as well as sterically unhindered alcohols. The best results were obtained with a combination of graphite as the anode material and platinum as the cathode (Scheme 5, top). As previously mentioned, the effectiveness of the reaction was based on the lower oxidation potential of the intermediate species compared to the corresponding aldehyde. This principle is similar to the work of Chiba et al. with cyanohydrin intermediates. Besides esters, thioesters could also be successfully generated. It is noteworthy that the conversion did not work under the previously used conditions. The use of DBU as the base yielded about 58 % of the disulfide. Changing the base to DMAP and halving the base load to a 0.075 m concentration led to the ratio of thioester to disulfide being significantly improved. The method worked for aromatic and aliphatic aldehydes, and even bulky thiols could be used (Scheme 5, top).20 The predominant reason for these phenomena was the enhanced reactivity of thiols as nucleophiles.

Scheme 5

NHC‐mediated electrochemical oxidation of aldehydes to esters, thioesters, or amides.19, 20, 22 DIPP=2,6‐diisopropylphenyl, DMAP=4‐(dimethylamino)pyridine, DMF=N,N‐dimethylformamide, DBU=1,8‐diazabicyclo[5.4.0]undec‐7‐ene, Mes=mesityl, PVDF=polyvinylidene difluoride, TBAB=tetrabutylammonium fluoride, Tf=triflyl.

pan class="Gene">NHC‐mediated electrochemical oxidation of class="Chemical">pan class="Chemical">aldehydes to esters, thioesters, or amides.19, 20, 22 DIPP=2,6‐diisopropylphenyl, DMAP=4‐(dimethylamino)pyridine, DMF=N,N‐dimethylformamide, DBU=1,8‐diazabicyclo[5.4.0]undec‐7‐ene, Mes=mesityl, PVDF=polyvinylidene difluoride, TBAB=tetrabutylammonium fluoride, Tf=triflyl.

Recently, Brown and pan class="Chemical">co‐workers exclass="Chemical">panded the aclass="Chemical">pclass="Chemical">proach develoclass="Chemical">ped by Boydston and class="Chemical">pan class="Chemical">co‐workers by carrying out the electrochemical oxidation of the Breslow intermediate in a flow cell.21 Moreover, extension to amide formation was possible.22 Different aromatic aldehydes and aliphatic amines were tested. The method generally tolerated aromatic substitutions on the amidic alkyl chain. The application of a flow cell and the synthesis of amides underlined the versatility of the method and general applicability (Scheme 5, bottom).

As a pan class="Chemical">consequence of the crucial role of class="Chemical">pan class="Gene">NHCs such as thiamine pyrophosphate as enzymatic cofactors, their oxidation mechanism has been of interest to several research groups for many years.23 In 1990, Schlegel et al. used cyclic voltammetry and ESR spectroscopy to demonstrate a one‐electron oxidation via a thiazolium cation radical.24 The mechanistic studies were continued by Fukuzumi and co‐workers, who investigated the activated aldehydes of several substrates. For steric reasons, the radical intermediates resulting from single‐electron transfers were stable enough for detection by ESR spectroscopy.25 The first preparative electrochemical approach for the oxidation was reported by Diederich et al. in 1992. To investigate the biochemical process, they conducted the transformation with flavin as the mediator. They were able to produce methyl esters from aliphatic and aromatic aldehydes, whereby aromatic derivatives gave high yields and good faradaic efficiencies in methanol.26

The field of pan class="Gene">NHC‐catalyzed electrochemical transformations was exclass="Chemical">panded by Inesi and class="Chemical">pan class="Chemical">co‐workers, whose work was based on the electrochemical activation of an ionic liquid as an NHC catalyst. After electrolysis of the ionic liquid, the aldehyde was added. Catalyzed by the activated ionic liquid, the formation of the benzoin adduct of benzaldehyde was possible in good yields (Scheme 6, top).27 The substrate scope was later extended to enals, but instead of benzoin adducts, α,β‐saturated esters were formed in very good yields (Scheme 6, bottom).28 The major reason for this might be the electrolysis in the presence of the substrate. In this case, the mechanism proceeded analogously to the oxidation of the cyanohydrin or the Breslow intermediate. By implementation of an ionic liquid, Inesi and co‐workers added a further concept of sustainable chemistry.

Scheme 6

Electrochemical activation via the ionic liquid.27, 28

In pan class="Chemical">conclusion, the class="Chemical">pan class="Chemical">combination of organocatalysis and electrochemistry is highly valuable for the efficient oxidation of aldehydes to esters, amides, and thioesters; thus, this method could also be interesting for late‐stage functionalization of more complex molecules. Moreover, the large variety of examples for the carbon functionalization of enols proves that this method is broadly applicable and can be used in various fields of organic chemistry.

The “Cation‐Pool” Method

In 1999, Yoshida et al. presented the so‐called “cation‐pool” method.29 Since then, this method has evolved into a versatile and valuable tool. In electrochemistry and pan class="Chemical">conventional methods, the class="Chemical">pan class="Chemical">combination of a cation with a nucleophile is a challenging task, due to the exothermic nature of this conversion. Nucleophiles often do not tolerate the conditions which are necessary for generation of the cation. In electrochemistry, a nucleophile can also be unstable under anodic conditions.

For this reason, the cation‐pool pan class="Chemical">conceclass="Chemical">pt relies on the idea of seclass="Chemical">parating the cation generation and the nucleoclass="Chemical">phile addition sclass="Chemical">patially and in time (Scheme 7). Electrochemistry enables the mild and reagent‐free generation of cations without the necessity to remove any reagent waste afterwards. The key to this method is the enhanced lifetime and acclass="Chemical">pan class="Chemical">cumulation of the cations when the electrochemical oxidation is conducted at −78 °C. A nucleophile is subsequently added to afford the product.30

Scheme 7

General steps of the “cation‐pool” concept.29, 30

General steps of the “cation‐pool” pan class="Chemical">conceclass="Chemical">pt.29, 30

With this method, Yoshida and pan class="Chemical">co‐workers were able to generate a broad sclass="Chemical">pan class="Chemical">cope of cations such as N‐acyliminium,29, 31 alkoxycarbenium,32 diarylcarbenium,33 glycosyl,34 silyl,35 iodine,36 alkoxysulfonium,37, 38 benzylaminosulfonium,39 arene,40 and thioarenium cations,41 as well as thionium cations.42 Depending on the cation and the added nucleophile, various products were accessible with a high selectivity.43 It is noteworthy that radical cations were sometimes formed. Then, at least two equivalents of cations were required for the generation of the final product.44 Another possibility was the reduction of a cation pool to the corresponding radical, thereby leading to dimerization.45 The generation of the cations was also possible in a mediated fashion if aryl disulfides served as the mediators.46 This indirect “cation‐pool” method overcame the problem of the relative low efficiency of the reaction with regards to cation generation. Moreover, these mediators could also serve as reaction partners, which underwent addition to the substrate, and the concept of flow chemistry could also be applied.47 Although the cation‐pool method is valuable, the stabilization of the cationic intermediates sometimes demands expensive electrolyte systems.39, 40

Scheme 8 summarizes the major reaction types and cations which are accessible with the cation‐pool method. Some features of the reaction will be described in more detail. In the last few years, Yoshida and pan class="Chemical">co‐workers foclass="Chemical">pan class="Chemical">cussed on stabilization of the cation at elevated temperatures. The key for this was the incorporation of the mostly unstable cations in a stabilizing chemical structure. Alkoxysulfoniumions are important intermediates in chemical oxidations and represent a class of relatively stable cations. DMSO reacts with the initially formed oxidized species of, for example, halogens or diarylsulfides to generate alkoxysulfoniumions. Besides the accumulation of these ions and a subsequent quenching to generate ketones or alcohols, it could also be combined with halogenation (Scheme 9).37

Scheme 8

Potential reaction pathways and accumulated cations.

Scheme 9

Stabilized “cation‐pool” method for an integrated reaction sequence.37 DMSO=dimethyl sulfoxide.

pan class="Chemical">Potential reaction class="Chemical">pathways and acclass="Chemical">pan class="Chemical">cumulated cations.

Stabilized “cation‐pool” method for an integrated reaction sequence.37 pan class="Chemical">DMSO=class="Chemical">pan class="Chemical">dimethyl sulfoxide.

The stabilized “cation‐pool” method also allowed cross‐pan class="Chemical">couclass="Chemical">pling between class="Chemical">pan class="Chemical">aromatic and benzylic C−H groups. However, the use of another cation‐stabilizing agent, such as diphenylsulfilimine, is necessary (Scheme 10).39 Amination reactions are also possible using this reagent.48

Scheme 10

Stabilized “cation‐pool” for cross‐coupling between aromatic and benzylic groups.39

Stabilized “cation‐pool” for cross‐pan class="Chemical">couclass="Chemical">pling between class="Chemical">pan class="Chemical">aromatic and benzylic groups.39

Recently, Yoshida and pan class="Chemical">co‐workers acclass="Chemical">pan class="Chemical">cumulated a new type of cation by the indirect cation‐pool method. With aryldisulfides as mediators, thionium ions were generated and analyzed by NMR, UV/Vis, and IR spectroscopy. Several reaction pathways are possible, for example, cross‐coupling and homoallylation.42 Scheme 11 displays the conversion with a silyl ketenacetal as the nucleophile.

Scheme 11

Accumulation and conversion of thionium ions.42

Acpan class="Chemical">cumulation and class="Chemical">pan class="Chemical">conversion of thionium ions.42

The “cation‐pool” method is of great synthetic value, since the pan class="Chemical">conversion of relatively unstable intermediates is class="Chemical">possible with “green” methods such as electrochemistry. Nevertheless, much class="Chemical">preclass="Chemical">parative effort is necessary and scale‐uclass="Chemical">p is difficlass="Chemical">pan class="Chemical">cult. The generation of low temperatures is energy‐consuming and the electrochemical set‐ups are rather sophisticated.

Bioelectrochemical Systems

The archetypal microbial bio‐electrochemical systems (BES) are microbial fuel cells (MFCs). In a microbially catalyzed process, organic or inorganic substances are oxidized and the produced electrons are transferred to the anode. Thus, the surplus of reducing equivalents in living systems is exploited. The chemical energy pan class="Chemical">contained in wasteclass="Chemical">pan class="Chemical">water streams is partly converted into electric energy by the catalytic (metabolic) activity of bacteria. If the cathodic process is the oxygen reduction reaction (ORR), the overall cell generates a surplus of energy. The cathodic process can be catalyzed microbially, enzymatically, or chemically (e.g. by the use of noble metals). However, the energy efficiency of such systems proved to be relatively low (e.g. 11 % for the bio‐electrochemical hydrogen production process reported by Kreysa et al.).49, 50, 51, 52, 53

This led to the development of microbial electrolysis cells (MECs), whereby the generated energy was directly used for the cathodic pan class="Chemical">hydrogen evolution reaction (HER). As the class="Chemical">potential delivered by the microbial anode was not sufficient for the HER, an additional voltage (0.2–0.7 V) had to be aclass="Chemical">pclass="Chemical">plied. However, this voltage is significantly lower than that required for the electrolysis of class="Chemical">pan class="Chemical">water (practically >1.6 V).49, 50, 51, 54 Furthermore, bio‐electrochemical systems were further developed by using the cathodic reaction for the synthesis of value‐added organic products through the reduction of CO2 or organic substrates (microbial electrosynthesis cell). This would be highly desirable, not only because of the production of valuable chemicals, but also because of the recycling of CO2. However, these processes are still at an early stage of development. Challenges arising on scale‐up, possible migration between the anodic and cathodic compartments, as well as the lifetime of the catalyst are just a few issues to mention.50, 51, 55, 56 Furthermore, reduction of CO2 leads to rather low‐value products such as methane, the biofuels ethanol and butanol, or carboxylates such as acetate or butyrate.51, 52, 55, 56, 57 Only a few examples of the production of high‐value compounds, such as 6‐bromo‐2‐tetralol (6‐bromo‐3,4‐dihydro‐2(1H)‐naphthol), have been reported. 6‐Bromo‐2‐tetralol, an intermediate in the synthesis of a potassium channel blocker, was obtained from 6‐bromo‐2‐tetralone in a biotransformation process by yeast cells of Trichosporon capitatum or its partially purified Br‐β‐tetralone reductase on a 10 mm scale.55, 58

Several redox‐enzymes require pan class="Chemical">cofactors for their oclass="Chemical">peration. These class="Chemical">pan class="Chemical">cofactors usually represent the reducing agents. The combination of high enantioselectivity with the sustainability of electroconversions is, thus, very appealing.59, 60, 61

The reduction of prochiral pan class="Chemical">ketones to oclass="Chemical">ptically enriched class="Chemical">pan class="Chemical">alcohols is of particular interest. For this, NAD+ has to be cathodically regenerated to NADH. As a consequence of the phosphorylated nature of this cofactor, a direct reduction at the cathode is hampered. The use of cationic rhodium mediators can solve this challenge (Scheme 12).61, 62, 63 However, even the mediators of the second generation provided a very limited total turnover of 113 h−1.62 Alternative mediators not based on precious metals and exhibiting a longer performance/durability are highly desired. Thus, much more research appears to be necessary to develop attractive bio‐electrochemical syntheses.

Scheme 12

Indirect electrochemical regeneration of the cofactor.62 bpy=2,2′‐bipyridine, Cp*=C5Me5.

Indirect electrochemical regeneration of the pan class="Chemical">cofactor.62 class="Chemical">pan class="Chemical">bpy=2,2′‐bipyridine, Cp*=C5Me5.

Redox Tags in Electrochemical Synthesis

Single electron transfer (SET) processes initiate a large variety of reactions in organic electrochemistry. Such reactions lead to open‐shell reactivity, often with pan class="Chemical">comclass="Chemical">plementary outclass="Chemical">pan class="Chemical">comes compared to traditional polarity‐driven reactions.64 Ashby has reported the universality of SET mechanisms and attempted to replace conventional polar mechanisms.65 Here, SN2 reactions are often discussed as polar processes, whereas Grignard reactions have been explained by SET mechanisms. Typically, these SETs take place between the electrode and the substrate or in an intermolecular manner. Nevertheless, intramolecular SET processes are key to mechanistic investigations, facilitate reaction pathways which would be forbidden, and offer important synthetic routes such as [2+2] cycloadditions66, 67 or Diels–Alder reactions.68 Intramolecular SET processes are rather elusive compared to intermolecular types, as these processes are net redox‐neutral and cannot be simply regarded as oxidations or reductions. These processes can be understood in combination with associated bond formations and bond cleavages. Such intramolecular SET processes can be regulated by so‐called “redox tags”. Electrochemical investigations on the synthetic application of this concept have been mainly conducted by Chiba and co‐workers. The main electrolyte used for the reported electrochemical reactions is lithium perchlorate in nitromethane. As a consequence of the unique Lewis acidity of lithium cations and weakly or noncoordinated counterions, this mixture is known to accelerate and promote a variety of chemical transformations, for example, Diels–Alder reactions.69

SET‐Triggered Formal [2+2] Cycloaddition versus Olefin Metathesis

Chiba and pan class="Chemical">co‐workers reclass="Chemical">ported the anodic treatment of class="Chemical">pan class="Chemical">enol ethers in MeNO2/LiClO4 in the presence of terminal olefins to yield cyclobutane derivatives by formal [2+2] cycloaddition reactions.67 The premise for a successful cycloaddition was the presence of an electron‐rich benzene ring in one of the reaction partners. The proposed mechanism is shown in Scheme 13.70 The enol ether is oxidized to the corresponding radical cation. This reactive intermediate can be trapped by the terminal olefin, which is present in large excess. Crucial for a successful cycloaddition is the subsequent intramolecular reduction of the cyclobutyl radical cation by a SET from the methoxyphenyl ring to form a relatively long‐lived aromatic radical cation. This species is then capable of oxidizing the starting enol ether to start the radical cation chain mechanism. The electrocatalytic nature of this reaction is also apparent because complete conversion is already achieved after 0.5 F (F=Faraday constant). For this type of reaction, the aromatic ring acts first as an electron donor and subsequently as an electron acceptor and, therefore, is a so‐called redox tag. This redox tag has the essential role of regulating the intramolecular SET process and, therefore, makes the cycloaddition reaction possible. Chiba and co‐workers investigated the limitations for the electron density of the aromatic ring and found that electron‐rich aromatic moieties such as either mono‐ or dimethoxy or mono‐, di‐, and trimethylbenzenes work as redox tags. Extremely electron‐rich benzene moieties with three methoxy groups or electron‐releasing nitrogen or sulfur moieties are not capable of working as redox tags, because they are too readily oxidized. The lower the oxidation potential of the redox tag, the more efficient is the cycloaddition reaction, but its oxidation potential has to be higher than the oxidation potential of the enol ether. This strictly limits the scope for synthetic applications, but gave an interesting insight for mechanistic investigations.

Scheme 13

Proposed mechanism for the [2+2] cycloaddition of enol ethers and terminal olefins. The oxidation potentials E Ox were measured versus the Ag/AgCl reference electrode.70

pan class="Chemical">Proclass="Chemical">posed mechanism for the [2+2] cycloaddition of class="Chemical">pan class="Chemical">enol ethers and terminal olefins. The oxidation potentials E Ox were measured versus the Ag/AgCl reference electrode.70

Carrying out the reaction with derivatives not pan class="Chemical">containing any substitution at the class="Chemical">phenyl ring also does not result in the desired [2+2] cycloaddition class="Chemical">product. In fact, this reaction oclass="Chemical">pened a new synthetic class="Chemical">pathway, since the unsubstituted class="Chemical">phenyl ring class="Chemical">pan class="Chemical">could not work as a redox tag. The reaction pathway is depicted in Scheme 14. First, oxidation takes places at the enol ether to form the radical cation. Trapping of this species by the olefin will result in the formation of the cyclobutyl radical cation. As a consequence of the ineffective intramolecular SET process, the final formation of the cyclobutane moiety cannot occur. Instead, the cyclobutyl radical cation is decomposed again. The decomposition can take place either to give the starting combination of the enol ether radical cation and the terminal olefin, or result in an olefin metathesis.71

Scheme 14

Proposed mechanism for olefin metathesis as a result of the ineffective redox tag.71

pan class="Chemical">Proclass="Chemical">posed mechanism for class="Chemical">pan class="Chemical">olefin metathesis as a result of the ineffective redox tag.71

The use of an pan class="Chemical">olefin with a cyclohexyl ring instead of the class="Chemical">phenyl ring enhanced the efficacy of the metathesis class="Chemical">pathway (Scheme 15). Thus, interestingly, the investigation of the limits of redox tags led to access to electrochemically initiated class="Chemical">pan class="Chemical">olefin metathesis reactions.72

Scheme 15

Comparison of olefins in electrocatalytic olefin metathesis.72

pan class="Chemical">Comclass="Chemical">parison of class="Chemical">pan class="Chemical">olefins in electrocatalytic olefin metathesis.72

Boydston and pan class="Chemical">co‐workers were able to use this class="Chemical">pan class="Chemical">concept to develop a metal‐free, photochemical ring‐opening metathesis polymerization.73 In general, electrochemical metathesis reactions provide a pathway to energy‐efficient, metal‐ and/or catalyst‐free metathesis reactions. Therefore, this route is a sustainable alternative to conventional metathesis reactions, when substrate combinations are suitable.

Anodic SET‐Triggered Diels–Alder Reactions

pan class="Chemical">Comclass="Chemical">pared to [2+2] cycloaddition reactions, SET‐triggered Diels–Alder reactions (or [4+2] cycloadditions between a class="Chemical">pan class="Chemical">diene and a dienophile) have a wider field of application in synthetic organic chemistry. SET processes are the most straightforward approaches to realize Umpolung and, therefore, achieve electronically mismatching Diels–Alder reactions. Chiba and co‐workers investigated electrochemical SET‐triggered Diels–Alder reactions.74 Comparison of this approach to [2+2] cycloadditions showed the mechanism is also based on a crucial intramolecular SET process. The first evidence for this is seen on comparing the reaction of trans‐anethole and 1‐propenylbenzene with isoprene (Scheme 16, top part). Whereas the SET‐triggered Diels–Alder reaction of trans‐anethole and isoprene gave excellent yields after application of just 0.1 F, no Diels–Alder reaction was observed with 1‐propenylbenzene.

Scheme 16

Anodic SET‐triggered Diels–Alder reaction with trans‐anethole and 1‐propenylbenzene as well as the proposed mechanism reaction involving an intramolecular SET process. The oxidation potentials E Ox were measured versus the Ag/AgCl reference electrode.74 Q=amount of charge.

Anodic SET‐triggered Diels–Alder reaction with trans‐anethole and 1‐propenylpan class="Chemical">benzene as well as the class="Chemical">proclass="Chemical">posed mechanism reaction involving an intramoleclass="Chemical">pan class="Chemical">cular SET process. The oxidation potentials E Ox were measured versus the Ag/AgCl reference electrode.74 Q=amount of charge.

The proposed mechanism is depicted in the lower part of Scheme 16. Based on the oxidation potentials, initial oxidation takes place on trans‐anethole to form a pan class="Chemical">radical cation. This intermediate is then traclass="Chemical">pclass="Chemical">ped by the class="Chemical">pan class="Chemical">diene to form the cyclohexenyl ring. To form the desired reaction product, this radical cation has to be immediately reduced through an intramolecular SET process by the methoxyphenyl redox tag. The resulting aromatic radical cation will again initiate the radical chain reaction. Although the oxidation potential of 1‐propenylbenzene (1.51 V versus Ag/AgCl) was suitable to generate the corresponding radical cation, similar to trans‐anethole, no desired product was obtained. This is explained by the inefficiency of the unsubstituted phenyl ring to act as a redox tag. Therefore, the intramolecular SET from the redox tag is a crucial part of a successful SET‐triggered Diels–Alder reaction.

Similar to the observations for the [2+2] cycloaddition, further substitution with methoxy groups at the redox tag decreased the yield of the Diels–Alder reaction product. This was rationalized by the reduced reactivity of the initially formed pan class="Chemical">radical cation by multiclass="Chemical">ple methoxy grouclass="Chemical">ps. Chiba et al. showed the versatility of this method by carrying out further investigations on anodic SET‐triggered Diels–Alder reactions and the reaction mechanism.

Electroconversion of Renewables

In the past 70 years, naphtha and natural gas have bepan class="Chemical">come the class="Chemical">primary feedstock for the industrial class="Chemical">production of organic chemicals.75, 76 Nowadays, the use of fossil raw materials is questionable due to the increasing environmental awclass="Chemical">pan class="Chemical">areness of society and the guiding principle of “sustainable development”, to which the chemical industry professes.77 Biomass seems to be a promising alternative as a renewable and sustainable source for fuels and chemicals.75 Moreover, organic electrosynthesis is a powerful and ecological method,4, 78 since the combination of organic electrosynthesis and the use of renewable biomass would be a sustainable and “green” approach for fuel and chemical production.

Carbon Dioxide as a Renewable Feedstock

A long‐standing challenge is closing the anthropogenic pan class="Chemical">carbon cycle by recycling class="Chemical">pan class="Chemical">CO2 from various sources into feedstock materials for fuels and chemical manufacturing. The direct electrochemical reduction of CO2 seems to be a powerful ecological method and, therefore, an appropriate intermediate step towards a carbon‐free future. The challenge in the electrochemical conversion of the greenhouse gas is the selectivity and faradaic efficiency. Here, the electrode plays a crucial role (Scheme 17).79, 80, 81

Scheme 17

Electrochemical reduction of carbon dioxide to various products.79, 80, 81

Electrochemical reduction of pan class="Chemical">carbon dioxide to various class="Chemical">products.79, 80, 81

During the past few decades, the electrocatalytic and electrochemical reduction of pan class="Chemical">CO2 at class="Chemical">pan class="Chemical">metal cathodes and related electrodes has been extensively investigated in aqueous and anhydrous (organic, ionic liquids or mixtures of them) media. The reduction products were found to depend strongly on the cathode material. Cu cathodes led to methane and ethylene as the major products, whereas Au, Ag, and Zn as the cathode led to the formation of CO. Formic acid was a major product in the reduction of CO2 at Pb and Hg cathodes.80, 82 It is noteworthy that only ethylene and, in particular, CO represent products of significantly added value. These products are in high demand and can be employed in conventional chemical plants for the generation of commodities.76

Recently, Koper and pan class="Chemical">co‐workers class="Chemical">published various methods for the direct electrochemical and electrocatalytical reduction of class="Chemical">pan class="Chemical">CO2. They used immobilized cobalt protoporphyrin on a pyrolytic graphite electrode and obtained CO as the major product of CO2 reduction. They enhanced the faradaic efficiency and the rate of CO formation significantly by designing a three‐dimensional porous hollow fiber Cu electrode. Besides Cu being used as an electrode material, it can also be used as an electrocatalyst. Thus, the electrocatalytic reduction of CO2 to methane and ethylene could be performed with a high turnover in aqueous media by using a Cu‐porphyrin complex. The use of PdPt100−/C nanoparticles as the electrocatalyst was reported for the selective production of formic acid with a high faradaic efficiency.83

Besides pan class="Chemical">metal‐based electrodes for the direct electrochemical reduction of class="Chemical">pan class="Chemical">CO2, various carbon electrodes, such as graphite, glassy carbon, BDD, and carbon nanotubes, were also used.81, 84 Compared to other electrode materials, BDD electrodes have a wide potential window and high electrochemical stability. As a consequence of the high over‐potential for cathodic hydrogen evolution, BDD is well‐suited for the cathodic reduction of CO2. Encouraging results for the reduction of carbon dioxide to formaldehyde is reported in Scheme 18. Here, Einaga and co‐workers showed the highly selective electrochemical production of formaldehyde from CO2 and seawater at BDD cathodes. The seawater served as the electrolyte and source of protons and electrons (Scheme 18).85

Scheme 18

Electrochemical reduction of carbon dioxide to formaldehyde at boron‐doped diamond anodes in seawater.85

Electrochemical reduction of pan class="Chemical">carbon dioxide to class="Chemical">pan class="Chemical">formaldehyde at boron‐doped diamond anodes in seawater.85

In addition, pan class="Chemical">carbon electrodes, in class="Chemical">particlass="Chemical">pan class="Chemical">cular BDD, are very attractive for carboxylation processes by electrosynthesis with CO2. A drawback of electrochemical carboxylations is that sacrificial electrodes are required. However, the use of BDD cathodes can reduce the required amount of sacrificial anodes. Thus, the electrochemical conversion of methional into 2‐hydroxy‐4‐methylsulfanylbutyric acid (MHA, an important technical product used as an additive for animal food), as well as 1‐hydroxy‐3‐methylsulfanylpropanol was achieved at BDD cathodes in the presence of Mg sacrificial anodes (Scheme 19).86

Scheme 19

Carboxylation of methional at BDD cathodes.86

Carboxylation of pan class="Chemical">methional at class="Chemical">pan class="Chemical">BDD cathodes.86

Degradation of Lignin to Valuable Fine Chemicals

Besides pan class="Chemical">cellulose and class="Chemical">pan class="Chemical">hemicellulose, lignin is one of the most abundant polymers in nature. It represents the major part of plant biomass. The polyphenolic structure of the biopolymer lignin qualified it as a potential sustainable and renewable feedstock for fuels and aromatic fine chemicals. Furthermore, about 50 million tons of lignin are produced every year as waste material by pulping industries. Kraft pulping is the predominant process used for the production of cellulose. As a consequence of the harsh reaction conditions, significant modifications in the native lignin take place. Technical Kraft lignin is characterized by inertness and degradation robustness, which complicates the selective degradation.87, 88

pan class="Chemical">Lignosulfonate is a waste stream from the almost reclass="Chemical">placed sulfite class="Chemical">pulclass="Chemical">ping class="Chemical">process. Utley and class="Chemical">pan class="Chemical">co‐workers carried out the electrooxidative cleavage of lignosulfate in alkaline media at Ni electrodes at 145 °C and 500 kPa. The major product was the aroma chemical vanillin in a yield of 5–7 wt % (Scheme 20). Moreover, a rationale for the mechanism was found on studying model lignin dimers. The system was also transferred to a flow reactor based on a filter press to allow continuous application.89, 90

Electrochemical degradation of pan class="Chemical">lignosulfonate at class="Chemical">pan class="Chemical">nickel anodes.89

As was mentioned before, Kraft pan class="Chemical">lignin is the major waste class="Chemical">product from the class="Chemical">pulclass="Chemical">ping industry. The electrochemical degradation of Kraft class="Chemical">pan class="Chemical">lignin to vanillin has been shown on Pt, Au, Ni, Cu, DSA‐O2 (DSA‐O2=dimensionally stable anode for oxygen evolution), and PbO2.91 The conversion and chemical yields depend mostly on the applied current density, while the nature of the electrode influences the reaction rate. The Waldvogel research group described the highly selective generation of the aroma chemical vanillin by anodic degradation of Kraft lignin at activated porous Ni/P‐foam electrodes under mild reaction conditions (Scheme 21). Furthermore, a combined electrochemical process with product isolation by adsorption on strong anionic exchange resins was established. This allowed isolation of vanillin without neutralization of the whole electrolyte or affecting the waste streams.92

Scheme 21

Highly selective electro‐depolymerization of Kraft lignin to vanillin on porous Ni/P‐foam electrodes.92

Highly selective electro‐depolymerization of Kraft pan class="Chemical">lignin to class="Chemical">pan class="Chemical">vanillin on porous Ni/P‐foam electrodes.92

Stiefel et al. reported a pan class="Chemical">controlled Kraft class="Chemical">pan class="Chemical">lignin depolymerization in an electrochemical reactor with an in situ nanoporous membrane.93 Another interesting method was reported by Tian et al. They described a novel approach which combined electrochemical and photochemical oxidation for the modification and degradation of Kraft lignin. In this approach, a Ta2O5‐IrO2 thin film was used as the electrocatalyst and TiO2 nanotubes arrays used as the photocatalyst.94 However, no yields for the degradation products were reported for either method.

pan class="Chemical">Lignin class="Chemical">preclass="Chemical">pared from different organic‐solvent‐based class="Chemical">procedures are known as class="Chemical">pan class="Chemical">organosolv lignins. The anodic oxidation of organosolv lignin from spruce was reported in alkaline media at high temperatures. Lower temperatures could be used by adding nitrobenzene or 1,3‐dinitrobenzene as a co‐catalyst. The major degradation products were vanillic acid, 4‐hydroxybenzaldehyde, and vanillin, but no absolute yields were given.95 Crude enzymatically derived lignin was depolymerized by Zhu et al. The degradation was achieved through a combination of direct anodic oxidation at a RuO2/Ti mesh and oxidation by cathodic generated H2O2 at a graphite felt. The depolymerization was unselective and a broad spectrum of monomers and dimers were obtained.96 Aspen lignin was depolymerized at Pb/PbO2 electrodes in an alkaline electrolyte. This lignin was degraded by hydroxyl radicals and hydrogenated by alkaline water electrolysis to afford 4‐methylanisol and other products.97 Pb/PbO2 anodes were also used for the degradation of bamboo lignin in alkali solution. The main products consisted of vanillin, syringaldehyde, and p‐coumaric acid (Scheme 22).98 The Stephenson research group developed a selective one‐pot method for the oxidative β‐O‐ether bond cleavage of lignin‐type dimers and native‐like lignin. The method was a combination of electrocatalytic oxidation and photocatalytic fragmentation at ambient temperature.99

Scheme 22

Products from the electrochemical depolymerization of bamboo lignin: vanillin (left), syringaldehyde (center), and p‐coumaric acid (right).98

pan class="Chemical">Products from the electrochemical declass="Chemical">polymerization of bamboo class="Chemical">pan class="Chemical">lignin: vanillin (left), syringaldehyde (center), and p‐coumaric acid (right).98

Several anodic degradations of different pan class="Chemical">lignin tyclass="Chemical">pes have been reclass="Chemical">ported, usually aiming to generate class="Chemical">pan class="Chemical">vanillin and related compounds (Schemes 20–22). Besides the mostly anodic cleavage of lignin, there are a few cathodic degradation methods. They are usually based on the electrocatalyzed reduction of lignin. Most of the methods were reviewed by Weckhuysen and co‐workers.88 However, electrochemistry can be used to obtain aromatic lignin degradation or extraction products. Here, the Moeller research group is notable. They reported the temperature‐ and pressure‐controlled solvolysis of sawdust to generate cinnamyl ether and/or aryl aldehyde products. Those electron‐rich aromatic compounds were used to synthesize a variety of more‐complex platform chemicals. Here, electrochemistry has been identified as a sustainable method to accomplish these transformations.100

Electrochemical Conversion of Sugars

pan class="Chemical">Carbohydrates, such as C5 and C6 class="Chemical">pan class="Chemical">sugars, are extremely abundant in nature and can be used as renewable feedstock for fuels and chemicals. The selective oxidation of carbohydrates, in particular to uronic acids, has been intensively studied in the last few decades and continues to be an area of current interest. Schäfer et al. established a selective method for the direct anodic oxidation of carbohydrates to their corresponding uronic acids in moderate to excellent yields. The key step was the use of TEMPO as a redox mediator. In this way, methyl‐β‐d‐glucopyranoside was converted into the corresponding acid derivative.101 Besides the glycoside, various monosaccharides were anodically oxidized under these TEMPO‐mediated conditions. Furthermore, di‐, oligo‐, and polysaccharides were electrochemically converted into their corresponding uronic acid derivatives. In this way, unprotected d‐maltose was oxidized at the anomeric center to the corresponding triacid, without significant oxidation of the five secondary alcohol groups (Scheme 23).101, 102

Scheme 23

Selective anodic TEMPO‐mediated oxidation of the primary hydroxy group of a glycoside (left), methyl‐l‐sorbopyranose (middle), and d‐maltose (right).

Selective anodic pan class="Chemical">TEMPO‐mediated oxidation of the class="Chemical">primary hydroxy grouclass="Chemical">p of a class="Chemical">pan class="Chemical">glycoside (left), methyl‐l‐sorbopyranose (middle), and d‐maltose (right).

The direct anodic oxidation of pan class="Chemical">saccharides at class="Chemical">pan class="Chemical">Cu or Au anodes continues to be of significant interest and was reviewed by Torto.103 Matsumoto et al. investigated the electrooxidation of glucose on Hg adatom‐modified Au eletrodes, while Park and co‐workers studied the same reaction on electrodes modified with Ag nanoparticles. Both groups used cyclic voltammetry as an electrochemical tool.104

Schröder and pan class="Chemical">co‐workers reclass="Chemical">ported the first one‐class="Chemical">pot electrochemical declass="Chemical">pan class="Chemical">oxygenation of xylolactone to δ‐valerolactone. The process was realized by the partially separated selective oxidation with electrogenerated chlorine and cathodic reduction (Scheme 24).105

Scheme 24

Simplified pathway of the electrochemical deoxygenation of xylolactone to δ‐valerolactone.105 DSA=dimensionally stable anode.

Simplified pathway of the electrochemical depan class="Chemical">oxygenation of class="Chemical">pan class="Chemical">xylolactone to δ‐valerolactone.105 DSA=dimensionally stable anode.

The most important electrochemical reduction of pan class="Chemical">sugars is the class="Chemical">pan class="Chemical">conversion of glucose into sorbitol. The polyol sorbitol is used in foodstuffs as well as in cosmetic, medical, and industrial applications. For example, sorbitol is used as a feedstock for the synthesis of vitamin C. The electroreduction of glucose can be performed directly at a Pb cathode or indirectly by electrocatalytic hydrogenation at a Raney‐Ni cathode (Scheme 25).106 Other pentoses, such as ribose and xylose can also be electrochemically reduced at amalgamated Pb cathodes under galvanostatic conditions.107

Scheme 25

Electrochemical reduction of glucose to sorbitol.106

Electrochemical reduction of pan class="Chemical">glucose to class="Chemical">pan class="Chemical">sorbitol.106

Tessonnier and pan class="Chemical">co‐workers reclass="Chemical">ported recently an interesting route that class="Chemical">pan class="Chemical">combines biotechnology with electrochemical transformation to convert glucose into bio‐based unsaturated nylon‐6,6. In this approach, the monosaccharide was converted into muconic acid by fermentation. This resulting diene diacid was further electrochemically hydrogenated, without prior isolation, to 3‐hexenedioic acid in 94 % yield. The cathodic electrosynthesis promotes the generation of isolated double bonds. It is noteworthy that the fermentation broth is directly subjected to electroconversion. The cathodic hydrogenation was carried out under ambient conditions at a lead rod cathode at a constant potential of −1.5 V versus Ag/AgCl. Afterwards the unsaturated nylon was finally obtained by a polycondensation reaction of the 3‐hexenedioic acid with hexamethylenediamine (Scheme 26).108 The obtained polyamide can undergo subsequent modifications, such as cross‐linking.

Scheme 26

Combined method of bio‐ and electrochemical transformation for the conversion of glucose into bio‐based nylon‐6,6.108

pan class="Chemical">Combined method of bio‐ and electrochemical transformation for the class="Chemical">pan class="Chemical">conversion of glucose into bio‐based nylon‐6,6.108

Biologically produced pan class="Chemical">muconic acid has emerged as a class="Chemical">platform chemical for the synthesis of a wide range of bio‐based monomers. The class="Chemical">pan class="Chemical">conversion, selectivity, and current efficiency can be tuned by varying the nature of the metal cathode and the applied potential.109

Glypan class="Chemical">cosylations are essential class="Chemical">processes in the chemical synthesis of class="Chemical">pan class="Chemical">oligosaccharides. Electrochemical oxidation is a powerful method to activate glycosyl donors. For example, Nokami et al. developed a highly efficient electrochemical glycosylation reaction with Bu4NOTf as a supporting electrolyte. They also combined the electroglycosylation with a subsequent one‐pot cleavage of a fluorenylmethoxycarbonyl (Fmoc) protecting group. This one‐pot reaction can be used as a highly practical method for the synthesis of oligosaccharides (Scheme 27).110 A complete overview of electrochemical glycosylation was reported by Nokami et al.111

Scheme 27

Electrochemical glycosylation and sequential one‐pot cleavage of the fluorenylmethoxycarbonyl (Fmoc) group.110 Bz=benzoyl.

Electrochemical glypan class="Chemical">cosylation and sequential one‐class="Chemical">pot cleavage of the fluorenylmethoxyclass="Chemical">pan class="Chemical">carbonyl (Fmoc) group.110 Bz=benzoyl.

The generation of pan class="Chemical">furan derivatives from class="Chemical">pan class="Chemical">sugars is a classical conversion in chemistry. Furfural and 5‐hydroxymethylfurfural can be generated by the acid‐catalyzed dehydration of pentoses (C5) and hexoses (C6), respectively. The possibility of oxidation, dehydration, and hydrogenation of these furanic compounds makes them potential alternative commodity chemicals to fossil‐fuel‐based platform chemicals. Direct electrochemical or electrocatalytic conversion has emerged as a useful technology for both oxidation and hydrogenation processes. The electrochemically reduced products, such as methylfuran and dimethylfuran, can be used as biofuels, whereas electrooxidation leads to 2‐furancarboxylic acid and 2,5‐difurandicarboxylic acid, which are bulk chemicals for renewable biopolymers. The dicarboxylic acid has potential as a biogenic substitute for terephthalic acid (Scheme 28).112

Scheme 28

Electrochemical conversion of furanic compounds.112

Electrochemical pan class="Chemical">conversion of class="Chemical">pan class="Chemical">furanic compounds.112

An important technical process is the electrochemical dialkoxylation of pan class="Chemical">furans.113 Breinbclass="Chemical">pan class="Chemical">auer and co‐workers reported the indirect eletroorganic synthesis of 2,5‐dimethoxylated furanic compounds on a solid support. Here, Br2 was used as a mediator and the chemical transformation had a broad product scope.114 The anodic methoxylation of furans can be used for the synthesis of pyridoxine derivatives such as a vitamin B6 precursor (Scheme 29).115

Scheme 29

Electrochemical dialkoxylation of a furan derivative and synthesis of a pyridoxine derivative.115

Electrochemical dialkoxylation of a pan class="Chemical">furan derivative and synthesis of a class="Chemical">pan class="Chemical">pyridoxine derivative.115

Conversion and Modification of Fatty Acids

pan class="Chemical">Oil and fat are high‐energy storage materials of biological organisms, which makes their usage very attractive as fuels and for chemical synthesis.116 Electrochemistry is a sustainable and class="Chemical">powerful tool for the modification and class="Chemical">pan class="Chemical">conversion of fatty acids. The electroactive sites of fatty acids are the carboxy group, C−C double bonds, and activated C−H bonds. Carboxy groups can be decarboxylated at the anode to form radicals; this reaction is better known as Kolbe electrolysis. High current densities and hydrogen atoms in the α‐position facilitate the formation of radicals. Thus, the Kolbe electrolysis is a preferred method for the conversion of fatty acids.117, 118 The homocoupling of two identical fatty acids affords a symmetric dimer. For example, the dimerization of the ricinoleic acid derivative shown in Scheme 30.119

Scheme 30

Homocoupling of a ricinoleic acid derivative by Kolbe electrolysis.119

Homopan class="Chemical">couclass="Chemical">pling of a class="Chemical">pan class="Chemical">ricinoleic acid derivative by Kolbe electrolysis.119

Two different pan class="Chemical">fatty acids with class="Chemical">pK a values in the same range can be unsymmetrical cross‐class="Chemical">pan class="Chemical">coupled by co‐electrolyzation, with the intermediate radicals coupling statistically. For an increased formation of the cross‐coupling product, the less expensive acid is used in excess. The radicals generated from the electrochemical decarboxylation (Kolbe reaction) can react with double bonds (Scheme 31, top).117 Dimethyl pentadecandioate was electrogenerated from monomethyl dodecanedioate and monomethyl glutarate. The obtained diester can be further converted into rac‐muscone (Scheme 31, bottom).117, 119

Scheme 31

Top: Anodic addition of a Kolbe radical from monomethyladipate to ethylene. Bottom: Unsymmetrical electrochemical coupling of two fatty acids to the precursor to generate a muscone precursor.117, 119

Top: Anodic addition of a pan class="Chemical">Kolbe radical from class="Chemical">pan class="Chemical">monomethyladipate to ethylene. Bottom: Unsymmetrical electrochemical coupling of two fatty acids to the precursor to generate a muscone precursor.117, 119

Double bonds can also be directly oxidized at very positive potentials. For example, double bonds in pan class="Chemical">vicinal class="Chemical">pan class="Chemical">dialkyl olefins are oxidized at potentials above +1.8 V versus SCE. A radical cation is probably formed that can react with a nucleophile or deprotonates to form an allylic radical. For example, methyl oleate can be oxidized in acetic acid at a Pt anode. Two isomeric diacetates were formed as major products after consumption of 4 F (Scheme 32).120

Scheme 32

Anodic diacetoxylation of methyl oleate.120

Anodic diacetoxylation of pan class="Chemical">methyl oleate.120

The oxidation potential of pan class="Chemical">conjugated class="Chemical">pan class="Chemical">dienes is lower than the oxidation potential of the isolated olefin system. For example, the anodic oxidation of the conjugated fatty diene shown in Scheme 33, which can be prepared from linoleic acid ester, takes places at 1.4 V versus SCE in AcOH/AcONa. The electrochemical conversion provides in good yields the 1,4‐diacetate, which has applications as a plasticizer.101

Scheme 33

Electrochemical diacetoxylation of a doubly unsaturated fatty acid derived from linoleic acid ester.101

Electrochemical diacetoxylation of a doubly pan class="Chemical">unsaturated fatty acid derived from class="Chemical">pan class="Chemical">linoleic acid ester.101

Activated allylic pan class="Chemical">hydrogen bonds can be oxidized to the class="Chemical">pan class="Chemical">corresponding ketone by using substoichiometric amounts of TEMPO as a mediator. The use of the mediator enables a significantly lower potential to be applied. This TEMPO‐mediated anodic oxidation allows the trienone to be generated from methyl linolenoate (Scheme 34).121

Scheme 34

TEMPO‐mediated anodic oxidation of methyl linolenoate.121

pan class="Chemical">TEMPO‐mediated anodic oxidation of class="Chemical">pan class="Chemical">methyl linolenoate.121

Furthermore, electroorganic synthesis can be used for the production of biofuels from pan class="Chemical">fatty acids. With class="Chemical">pan class="Disease">good coulomb efficiencies, the electrochemical decarboxylation of fatty acids in methanolic and ethanolic solution leads to the formation of diesel‐like olefin/ether mixtures (Scheme 35). In addition, the electrochemical conversion of levulinic acid into octane has been reported.122

Scheme 35

Anodic decarboxylation of oleic acid to diesel‐like compounds.122

Anodic decarboxylation of pan class="Chemical">oleic acid to diesel‐like class="Chemical">pan class="Chemical">compounds.122

The cathodic reduction of pan class="Chemical">enones derived from class="Chemical">pan class="Chemical">fatty acids in DMF afforded the corresponding hydrodimers (Scheme 36).123

Scheme 36

Hydrodimerization by cathodic reduction of a fatty acid enone.123

Hydrodimerization by cathodic reduction of a pan class="Chemical">fatty acid enone.123

Amino Acids as Feed Stock for Nitrogen‐Containing Chemicals

The Baizer process is probably one of the best‐known electrochemical procedures and provides access to the important bulk chemical pan class="Chemical">adiponitrile. This class="Chemical">pan class="Chemical">dinitrile is used for the production of the popular polymer nylon‐6.6.124 Remarkably, all the industrial routes for the synthesis of adiponitrile, including the Baizer process, are based on petrochemicals and require external nitrogen sources (i.e. NH3, NaCN, or HCN). Amino acids represent a renewable biomass, which could be used as a sustainable nitrogen source. The electrochemical synthesis of adiponitrile from glutamic acid has been reported. Glutamic acid, the most abundant non‐essential amino acid in plant proteins, was conventionally converted into the mono ester methylglutamate.125 After that, the anodic decarboxylation of the monomethyl glutamate to 3‐cyanopropanoic acid methyl ester was performed with NaBr as the supporting electrolyte and mediator. Adiponitrile was obtained from the 3‐cyanopropanoic acid methyl ester in a final one‐pot reaction with electrochemical substeps (Scheme 37).126

Scheme 37

Sequential electrochemical synthesis of adiponitrile from glutamic acid.126

Sequential electrochemical synthesis of pan class="Chemical">adiponitrile from class="Chemical">pan class="Chemical">glutamic acid.126

Another electrochemical pan class="Chemical">conversion of an amino acid was demonstrated by De Vos and class="Chemical">pan class="Chemical">co‐workers. They efficiently decarboxylated lysine electrochemically and with bromide assistance. In this manner, the selectivity of the carboxylation could be tuned, depending on the cathode material used, to obtain nitrile, amine, or amide groups (Scheme 38).127

Scheme 38

Electrochemical decarboxylation of lysine to the corresponding nitrile, amine, or amide.127

Electrochemical decarboxylation of pan class="Chemical">lysine to the class="Chemical">pan class="Chemical">corresponding nitrile, amine, or amide.127

Onomura and pan class="Chemical">co‐workers class="Chemical">published an electrochemical method for the direct α‐cyanation of N‐class="Chemical">protected cyclic class="Chemical">pan class="Chemical">amines on graphite electrodes. For example, the direct cyanation of a proline derivative at position 5 was reported (Scheme 39).128

Scheme 39

Electrochemical α‐cyanation of an N‐protected proline derivative.128 Tr=trityl.

Electrochemical α‐cyanation of an N‐protected pan class="Chemical">proline derivative.128 Tr=trityl.

Electrochemical Reactions in Flow Cells

The development and evolution of electrochemical processes under pan class="Chemical">continuous flow class="Chemical">pan class="Chemical">conditions has occurred in the last two decades. Usually, electrosynthesis in flow cells is associated with large‐scale operations, since scale‐up is viable by simply increasing the number of electrolyzing devices. On the one hand, the use of flow cells for electroconversion requires significantly more electrical equipment, such as pumps. On the other hand, continuous synthesis under well‐defined conditions can be achieved. In comparison with classical flask chemistry, flow chemistry offers the possibility to reduce the amounts of solvents and substrates as well as making process optimization much easier. The generation of a homogeneous electric field represents a big advantage. In this regard, a variety of electrooxidations and electroreductions, as well as a combination of them, have been developed over the years.

Electrooxidations in Flow Cells

One of the very first examples of electrooxidation was carried out by Yoshida and pan class="Chemical">co‐workers. They reclass="Chemical">ported a direct electrooxidative C−C bond formation using a low‐temclass="Chemical">perature electrochemical microflow system to class="Chemical">pan class="Chemical">combine carbamates with allylsilanes by exploiting the “cation‐pool” method described in Section 3. Different carbamates as well as allylsilanes proved to be suitable for the reaction (Scheme 40).47 A few examples involving vinyl ethers were also described.129

Scheme 40

Continuous electrochemical α‐allylation of carbamates using allylsilanes as electrophiles.47

pan class="Chemical">Continuous electrochemical α‐allylation of class="Chemical">pan class="Chemical">carbamates using allylsilanes as electrophiles.47

pan class="Chemical">Common electroclass="Chemical">pan class="Chemical">conversions were used to demonstrate the power of electrosynthetic methods and devices under continuous flow conditions. Most of these transformations exhibit a technical significance. One such anodic conversion is the dimethoxylation of toluene derivatives. These ketals are important intermediates for condensation reactions. The first experiments on this transformation were described by Löwe and Ehrfeld.130 Yoshida and co‐workers developed an electrochemical oxidation of p‐methoxytoluene to afford the corresponding ketal under flow conditions, without using a supporting electrolyte (Scheme 41, top). Several other examples of the electrochemical methoxylation of organic compounds were also reported.131 This reaction was also tested in the development of new microreactors and flow cells.132 A similar process was described by the Roth research group. In this case, they were able to expand the scope of substituents appended to the arene moiety, as well as synthesize not only ketals and subsequent aldehydes, but also methyl esters of certain substrates by using a polyvinylidene fluoride (PVDF) anode (Scheme 41, bottom).133

Scheme 41

Electrochemical oxidation of different para‐substituted toluene derivatives in flow cells.131, 133

Electrochemical oxidation of different para‐substituted pan class="Chemical">toluene derivatives in flow cells.131, 133

The installation of two methoxy groups at the α‐positions of a pan class="Chemical">furan ring was demonstrated by Atobe and class="Chemical">pan class="Chemical">co‐workers.134 They used a thin‐layer flow cell and just a single pass of the furan solution (Scheme 42). A supporting electrolyte was not needed, since the methoxide anions generated provided sufficient conductivity.

Scheme 42

Electrodimethoxylation of furan without a supporting electrolyte in a flow cell.134

Electrodimethoxylation of pan class="Chemical">furan without a suclass="Chemical">pclass="Chemical">porting electrolyte in a flow cell.134

Another example of an anodic methoxylation was developed by the Brown research group. In a Shono‐type reaction, N‐formylpan class="Chemical">pyrrolidine was methoxylated at the α‐class="Chemical">position (Scheme 43).135 The class="Chemical">process was oclass="Chemical">ptimized later136 and exclass="Chemical">panded to other electroclass="Chemical">pan class="Chemical">conversions, including the formation of quinone ketals, fluorinations, generation of CeIV, and synthesis of esters and amides from aldehydes.137

Scheme 43

α‐Methoxylation of N‐formylpyrrolidine in a flow cell.135

α‐Methoxylation of N‐formylpan class="Chemical">pyrrolidine in a flow cell.135

The Atobe research group have made significant pan class="Chemical">contributions to the field of electrooxidation class="Chemical">processes. The electrogeneration of o‐class="Chemical">pan class="Chemical">benzoquinone from catechol, and a subsequent Michael‐type addition of benzenethiols led to the formation of diaryl thioethers (Scheme 44).138 It is noteworthy that the yields under flow cell conditions proved to be much higher than the yields achieved for the same process in a batch‐type cell. This finding could be explained by the fact that benzoquinone could be generated effectively without interference of thiol oxidation. In addition, the generated benzoquinone could be used directly without decomposition. The Atobe research group also performed aromatic C−C cross‐coupling between naphthalene and differently substituted methylbenzene derivatives (Scheme 45).139

Scheme 44

Formation of aryl thioethers by electrooxidation of catechol.138

Scheme 45

Continuous C−C cross‐coupling reaction between naphthalenes and methylbenzenes.139

Formation of pan class="Chemical">aryl thioethers by electrooxidation of class="Chemical">pan class="Chemical">catechol.138

pan class="Chemical">Continuous C−C cross‐class="Chemical">pan class="Chemical">coupling reaction between naphthalenes and methylbenzenes.139

However, not only simple and direct oxidation processes have been described using electrochemistry in flow cells. Very recently, some more elaborate examples of electrooxidations in flow cells have also been reported. Wirth and pan class="Chemical">co‐workers described the electrosynthesis of a broad variety of class="Chemical">pan class="Chemical">diaryliodonium salts in flow by using a microreactor (Scheme 46),140 as well as the installation of CF3 and CF2H groups on electron‐deficient alkenes such as acrylates and acrylamides.141 In this second case, the radicals were produced by Kolbe electrolysis of di‐ and trifluoroacetic acid at the platinum anode and subsequently reacted with the alkene to afford the final products (Scheme 47).

Scheme 46

Electrosynthesis of diaryliodonium salts in flow cells.140

Scheme 47

Continuous electrochemical introduction of CF3 and CF2H groups in electron‐deficient alkenes.141 EWG=electron‐withdrawing group.

Electrosynthesis of pan class="Chemical">diaryliodonium salts in flow cells.140

pan class="Chemical">Continuous electrochemical introduction of CF3 and CF2H grouclass="Chemical">ps in electron‐deficient class="Chemical">pan class="Chemical">alkenes.141 EWG=electron‐withdrawing group.

The Atobe group, in pan class="Chemical">collaboration with the Waldvogel grouclass="Chemical">p, develoclass="Chemical">ped an electrochemical flow class="Chemical">process for an aryl‐class="Chemical">phclass="Chemical">pan class="Chemical">enol cross‐coupling (Scheme 48).142 Depending on the additive and on the solvent, a mixture of the desired phenolic product and the undesired homocoupling product was obtained, but the selectivity for the production of the cross‐coupling product could be easily controlled and tuned.

Scheme 48

Electrochemical anodic aryl‐phenol cross‐coupling in a flow cell.142

Electrochemical anodic aryl‐phpan class="Chemical">enol cross‐class="Chemical">pan class="Chemical">coupling in a flow cell.142

The Brown research group described a catalytic pan class="Chemical">TEMPO‐mediated electrooxidation of class="Chemical">primary and seclass="Chemical">pan class="Chemical">condary alcohols in a microfluidic electrolytic cell.143 The TEMPO radical was oxidized at the PVDF anode, and the resulting oxoammonium cation subsequently oxidized the alcohol to yield the corresponding aldehyde or ketone (Scheme 49).

Scheme 49

Oxidation of alcohols by electrogeneration of an oxammonium cation in a flow cell.143

Oxidation of pan class="Chemical">alcohols by electrogeneration of an class="Chemical">pan class="Chemical">oxammonium cation in a flow cell.143

Electrosynthesis in flow cells by oxidation reactions has also been used to synthesize natural products and different metabolites. Nishiyama and pan class="Chemical">co‐workers were able to transform class="Chemical">pan class="Chemical">isoeugenol into licarin A in just one reaction step (Scheme 50).144 The very low yield of the reaction mainly results from the reaction between MeOH and the formed radical.

Scheme 50

Electrosynthesis of licarin A from isoeugenol.144

Electrosynthesis of licarin A from pan class="Chemical">isoeugenol.144

A representative example was described by Stalder and Roth. They performed different electrochemical transformations of five pan class="Chemical">commercial drugs in flow cells.145 The aim of this study was to investigate the versatility of class="Chemical">pan class="Chemical">continuous flow electrosynthesis for the generation, isolation, and full characterization of drug metabolites on a preparatory scale (Scheme 51).

Scheme 51

Electrosynthetic generation of metabolites from different commercial drugs in flow cells.145

Electrosynthetic generation of metabolites from different pan class="Chemical">commercial drugs in flow cells.145

Electroreductions in Flow Cells

In addition to oxidations, several electroreduction processes in flow cells have been reported, most of them developed by Atobe and pan class="Chemical">co‐workers. In a recent examclass="Chemical">ple, they class="Chemical">performed the electrochemically assisted reduction of class="Chemical">pan class="Chemical">toluene to the corresponding methylcyclohexane by using hydrogen as a reducing agent.146 The formation of anions prior to electroreduction has also been utilized as a useful method in the development of some processes. In this regard, there are two similar examples. In the first one, a process was designed for the α‐alkylation of methyl phenylacetate,147 in which 2‐pyrrolidone was electroreduced in flow, with the formed anion acting as a base. The base could abstract the α‐proton of methyl phenylacetate, thereby forming a carbanion which reacted subsequently with iodomethane to afford the methylated product (Scheme 52, top). In the second example, the pyrrolidone anion was used to deprotonate chloroform to form a trichloromethyl anion, which could easily attack benzaldehyde to yield 2,2,2‐trichloro‐1‐phenylethanol (Scheme 52, bottom).148

Scheme 52

Continuous formation of a 2‐pyrrolidone anion by electroreduction and subsequent reactions.147, 148

pan class="Chemical">Continuous formation of a 2‐class="Chemical">pan class="Chemical">pyrrolidone anion by electroreduction and subsequent reactions.147, 148

The same idea of forming anions from pan class="Chemical">allyl149 or class="Chemical">pan class="Chemical">benzyl halides150 and using them as nucleophiles in two different reactions has been described. In the first case, an aryl aldehyde was utilized to trap the anion and form the corresponding alcohol (Scheme 53, top). However, the use of hexamethylphosphoric triamide (HMPA) as solvent is less beneficial. In the second case, CO2 was used, which allowed the electrosynthesis of different benzyl carboxylic acids in a flow cell (Scheme 53, bottom).

Scheme 53

Anions as nucleophiles in the synthesis of alcohols or carboxylic acids in flow cells.149, 150 HMPA=hexamethylphosphoric triamide.

Anions as nucleophiles in the synthesis of pan class="Chemical">alcohols or class="Chemical">pan class="Chemical">carboxylic acids in flow cells.149, 150 HMPA=hexamethylphosphoric triamide.

Haswell and pan class="Chemical">co‐workers reclass="Chemical">ported a cathodic dimerization of 4‐nitrobenzyl class="Chemical">pan class="Chemical">bromide in a flow cell by using benzyl bromides.151 This process opened the possibility to functionalize this compound and some derivatives with other molecules. They were able to couple different benzyl bromides with acetic anhydride,152 as well as with different activated olefins.153 These reactions are depicted in Scheme 54.

Scheme 54

Cathodic coupling of benzyl bromides with acetic anhydride and activated olefins in a flow cell.151, 152, 153

Cathodic pan class="Chemical">couclass="Chemical">pling of class="Chemical">pan class="Chemical">benzyl bromides with acetic anhydride and activated olefins in a flow cell.151, 152, 153

A different electroreductive process in a flow cell was developed by Waldvogel and pan class="Chemical">co‐workers. They were able to carry out a double dehalogenation in flow for the synthesis of a key intermediate for NS5A inhibitors (Scheme 55).154

Scheme 55

Electrochemical double dehalogenation of a cyclopropane derivative in a flow cell.154 Boc=tert‐butoxycarbonyl.

Electrochemical double dehalogenation of a pan class="Chemical">cyclopropane derivative in a flow cell.154 Boc=tert‐butoxyclass="Chemical">pan class="Chemical">carbonyl.

Electrooxidation and Electroreduction Sequences in Flow Cells

Finally, there are two flow processes in the literature in which both an electrooxidation and an electroreduction were involved at the same time. The first one was developed by Willians and pan class="Chemical">co‐workers and class="Chemical">pan class="Chemical">consisted of the formation of copper‐NHC complexes.155 Different imidazolium cations were reduced to form carbenes, while Cu0 from a sacrificial anode was oxidized to CuI (Scheme 56). The effectiveness of the formed complexes was demonstrated, since they were used directly from the electrochemical flow cell in a hydrosilylation reaction.

Scheme 56

Electrosynthesis of copper‐NHC complexes in a flow cell.155

Electrosynthesis of pan class="Chemical">copper‐class="Chemical">pan class="Gene">NHC complexes in a flow cell.155

The other example, reported by Waldvogel and pan class="Chemical">co‐workers, class="Chemical">pan class="Chemical">consisted of the oxidation of an ortho,ortho‐disubtituted aryl oxime to form the corresponding nitrile oxide, which was later reduced to afford a nitrile.156 In this example, the absence of a supporting electrolyte had a strong influence on the selectivity (Scheme 57).

Scheme 57

Domino oxidation‐reduction sequence of an oxime to the corresponding nitrile in a flow cell.156

Domino oxidation‐reduction sequence of an pan class="Chemical">oxime to the class="Chemical">pan class="Chemical">corresponding nitrile in a flow cell.156

Technical Significance

For a long time, the use of electricity in synthesis was fopan class="Chemical">cused on inorganic class="Chemical">pan class="Chemical">commodities such as the chloralkali process or aluminum production. The electrochemical synthesis of organic compounds represents rather niche applications because of their scale. However, some processes can generate up to several thousand tons per year.157 On this scale, only a few industrial organizations are interested (such as: BASF, Otsuka, Lanxess, and Clariant).158 The electrochemical production process has to be competitive with conventional transformations. On the one hand, the attractiveness of this technology is based on the avoidance of reagent waste and the use of electricity from regenerative resources. On the other hand, the electrochemical production technology is usually not carried out in a multipurpose plant and, therefore, rather specific know‐how is required. For the applicability of such processes, the current density should be in the range of 10–30 mA cm−2.159 This guarantees that the electrolysis cell will not be too large and the space‐time yield will be acceptable. However, for higher value‐added compounds, these numbers are less strict. The successful electrochemical conversion is the key step when establishing a technical process. Other crucial points are valid work‐up strategies and the recovery or recycling of electrolyte components. Since only partial conversion is often achieved by flow electrolyzers, a good separation of the desired compound from the electrolyte, intermediates, and starting materials is necessary. In addition, certain constraints exist for supporting electrolytes:160 They have be compatible with wastewater treatment facilities, and potentially explosive precipitates need to be avoided. Therefore, common supporting electrolytes, for example, perchlorates are not acceptable in industry. For a long time, the largest process was Monsanto's Baizer process. The cathodic reduction of acrylonitrile to adipontrile provides access to a central commodity for making polyamides such as nylon‐6.6. The beauty of the process consists of the use of water as the hydrogen source and molecular oxygen as the by‐product. At the end of the 1970s, this process reached 100 000 tons per year and the worldwide total capacity tripled some years later.161 However, the seminal scientific discovery happened almost 20 years earlier and was described as an inferior electroconversion in a divided cell.162 This impressively demonstrates the power of chemical engineering and process development. The Baizer process was initially conducted at cadmium cathodes, which created a significant environmental issue. After the technology came to BASF, the process was ameliorated and the cadmium cathodes were substituted by less‐hazardous copper‐lead alloys. By the end of the century, fossil energy was much less expensive than electricity and the uncertain cost of propylene led to a shutdown of most facilities. However, if large amounts of electricity have to be employed for the synthesis of valuable compounds, this process will be among the first candidates to be resumed (Scheme 58).

Scheme 58

Examples of currently used technical electrochemical processes.

Examples of pan class="Chemical">currently used technical electrochemical class="Chemical">processes.

A major industrial user of electroorganic synthesis is BASF. pan class="Chemical">Currently, the largest organic electroclass="Chemical">pan class="Chemical">conversion is the dimethoxylation of 4‐tert‐butyltoluene to afford the protected benzaldehyde. This intermediate is used for a condensation reaction with propanal and subsequent hydrogenation to form lysmeral, which is a fragrance with the smell of lily of the valleys. By condensation, the methanol is recovered and the hydrogen formed during electrolysis could be used in the hydrogenation process. This electrochemical formation of benzaldehyde is conducted on several 10 000 tons per year. Another product of this process is anisaldehyde, which is used as a chemical intermediate and to cover strong odors. Another anodic conversion provides a methylketal of 2‐hydroxycyclohexanone, which is a common chemical intermediate. Starting from cyclohexanone in an iodide‐mediated process, this compound is selectively formed in very good yield on a ton scale. Another important fragrance is made by the Japanese company Otsuka: Starting from 2‐hydroxyethylfuran, which is readily accessible from furfural, an anodic dimethoxylation is carried out. Rearrangement of this intermediate provides maltol in about 150 tons per year.

These are only a few examples, but since several pan class="Chemical">comclass="Chemical">panies are now beclass="Chemical">pan class="Chemical">coming interested in electrosynthesis there will undoubtedly be many more reported electroconversions on a ton scale in the near future.

Future Perspectives

The adoption of novel pan class="Chemical">conceclass="Chemical">pts and strategies from other fields has oclass="Chemical">pened uclass="Chemical">p new class="Chemical">possibilities for electrosynthesis. The use of electricity for chemical class="Chemical">pan class="Chemical">conversions instead of using stoichiometric amounts of reagents provides an enormous potential for process development. In the future, tremendous advances will occur and subsequently push the field into broad applications:

Innovative electrolyte and electrode systems have to be elaborated to enable novel transformations. Thus, actual limits resulting from pan class="Chemical">current electrode materials will be circlass="Chemical">pan class="Chemical">cumvented. Future electrode materials should avoid heavy metals such as lead or mercury. Synthetic carbon allotropes with tailor‐made surfaces seem to be a very promising option, as they provide larger over‐potentials for undesired side reactions, for example, hydrogen evolution. Moreover, such electrode systems should be highly resistant to fouling or corrosion processes and, therefore, be almost maintenance‐free. Initial steps in this direction have been made with boron‐doped diamond electrodes.163 In the electrolyte research, the solvent will not only be investigated as a reaction media, but also with regard to specific solvent effects that may tune the selectivity and enable novel electrosynthetic pathways. The supporting electrolytes are often considered as a significant drawback in electrochemical synthesis, since they cause significant costs and are mostly not compatible with modern wastewater treatments. The use of narrow gap cells in combination with the residual conductivity of the solvent may completely abolish the use of such supporting electrolytes.156, 164 In particular, protic solvents are splendid candidates and make such electrosynthetic approaches even more attractive.

In addition, very robust electrosyntheses are highly desired. Electrosynthetic pan class="Chemical">conversions are class="Chemical">pan class="Chemical">commonly successful in a narrow current density range. If the required electrochemical conditions are not fulfilled because either the data reported are not precise enough or the geometry of the electrolysis cell is altered, problems with reproducibility will occur. On the one hand, the procedure should definitely be described in detail. This applies, in particular, to the electrode mounting and arrangement. On the other hand, the electrosyntheses should be developed as robust transformations, wherein the product is not prone to severe over‐conversion or the desired product is protected by solvent effects, for example.165 This will, in particular, be beneficial for newcomers in electrosynthesis, since small variations to the original procedures will not lead to dramatically inferior results or complete failure. In addition, this will open the opportunity to all‐rounder electrolysis cells, which can be employed as a standard setup in the laboratory.

Furthermore, the design and innovative pan class="Chemical">conceclass="Chemical">pts of electrolysis cells will allow the aclass="Chemical">pclass="Chemical">plicability of this technique to be exclass="Chemical">panded. When, for examclass="Chemical">ple, over‐reaction at the electrode turns out to be challenge, mass transclass="Chemical">port from the electrode regime into the bulk usually beclass="Chemical">pan class="Chemical">comes an issue. Some approaches from the electrochemical generation of inorganic commodities might be adopted, for example zero‐gap flow cells166 or spinning‐disk electrodes.167 Great hope also lies in the combination of physical effects, such as ultrasonication168 or magneto‐electrochemistry,169 with the electrolysis. Indeed, the study of the influence of magnetic fields on chiral electrolytic events has just begun.170 However, the current research is still at a level far from being applicable in practical synthesis.

In pan class="Chemical">conclusion, electroorganic synthesis will transform from a niche technology to a class="Chemical">pan class="Chemical">common synthetic method. Therefore, electrosynthesis also has to find its place in teaching and student training. The sustainability of this particular approach will make the use of this method inevitable at an academic and a technical level.

Conflict of interest

The pan class="Chemical">authors declare no class="Chemical">pan class="Chemical">conflict of interest.

Biographical Information

Sabine Möhle obtained her pan class="Gene">BSc in chemistry from the University of Regensburg in 2013. After an internshiclass="Chemical">p at the University of California, Santa Barbara (class="Chemical">pan class="Chemical">Prof. R. D. Little) in 2014, she finished her MSc in chemistry in the group of Prof. Dr. O. Reiser at the University of Regensburg in 2014. She is currently a PhD student under the supervision of Prof. S. R. Waldvogel, working on the electrochemical amination of arenes. Her PhD studies are supported by a Kekulé Fellowship of the Funds of the Chemical Industry.

Michael Zirbes obtained his pan class="Gene">BSc in chemistry in 2014 from the Johannes Gutenberg University Mainz. After working there as an undergraduate research assistant in 2015, he obtained his MSc in organic chemistry in 2017 from the same university. class="Chemical">pan class="Chemical">Currently, he is a PhD student under the supervision of Prof. S. R. Waldvogel, working on the electrochemical conversion of renewable raw materials.

Eduardo Rodrigo obtained his pan class="Gene">BSc in chemistry in 2009 and his MSc in organic chemistry in 2011 from the University class="Chemical">pan class="Chemical">Autónoma of Madrid. In 2014, he was a visitor at the University of Jyväskylä, Finland (Prof. P. M. Pihko). He finished his PhD in 2016 at the University Autónoma of Madrid in the field of organocatalysis under the supervision of Dr. M. B. Cid. Currently, he is as a postdoctoral researcher at the Johannes Gutenberg University Mainz in the group of Prof. S. R. Waldvogel, working on organic electrosynthesis.

Tile Gieshoff obtained his Diploma in chemistry from the Johannes Gutenberg University Mainz in 2014, after pan class="Chemical">conducting the Diclass="Chemical">ploma work at Sanofi‐Aventis Deutschland GmbH. He is class="Chemical">pan class="Chemical">currently a PhD student under the supervision of Prof. S. R. Waldvogel and member of the MAINZ graduate school, working on the electroorganic synthesis of heterocycles. In 2016, he was a visiting researcher at the Washington University in St. Louis (Prof. K. D. Moeller).

Anton Wiebe obtained his Diploma in chemistry from the Johannes Gutenberg University Mainz in 2014 in the group of pan class="Chemical">Prof. S. R. Waldvogel, with a research internshiclass="Chemical">p at the University of Otago, New Zealand (class="Chemical">pan class="Chemical">Prof. Sally Brooker). He is currently a PhD student under the supervision of Prof. S. R. Waldvogel and member of the Max Planck Graduate Center, working on electrochemical oxidative coupling reactions of aromatic molecules.

Siegfried R. Waldvogel studied chemistry in Konstanz and repan class="Chemical">ceived his class="Chemical">pan class="Chemical">PhD in 1996 from the University of Bochum/Max‐Planck‐Institute for Coal Research with Prof. M. T. Reetz. After postdoctoral research at the Scripps Research Institute in La Jolla, California (Prof. J. Rebek, Jr.), he completed his habilitation in 1998 at the University of Münster. In 2004, he became professor for organic chemistry at the university of Bonn, and in 2010, full professor at the Johannes Gutenberg University Mainz. His main research interests are organic electrochemistry, oxidative coupling with Mo reagents, and supramolecular sensing.

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