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

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Redox catalysis in organic electrosynthesis: basic principles and recent developments Robert Francke* and R. Daniel Little* Electroorganic synthesis has become an established, useful, and environmentally benign alternative to classic organic synthesis for the oxidation or the reduction of organic compounds. In this context, the use of redox mediators to achieve indirect processes is attaining increased significance, since it offers many advantages compared to a direct electrolysis. Kinetic inhibitions that are associated with the electron transfer at the electrode/electrolyte interface, for example, can be eliminated and higher or totally different selectivity can be achieved. In many cases, a mediated electron transfer can occur against a potential gradient, meaning that lower potentials are needed, reducing the probability of undesired sidereactions. In addition, the use of electron transfer mediators can help to avoid electrode passivation resulting from polymer film formation on the electrode surface. Although the principle of indirect electrolysis was established many years ago, new, exciting and useful developments continue to be made. In recent years, several new types of redox mediators have been designed and examined, a process that can be accomplished more efficiently and purposefully using modern computational tools. New protocols

Received 19th December 2013

including, the development of double mediatory systems in biphasic media, enantioselective mediation

DOI: 10.1039/c3cs60464k

and heterogeneous electrocatalysis using immobilized mediators have been established. Furthermore, the understanding of mediated electron transfer reaction mechanisms has advanced. This review describes

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progress in the field of electroorganic synthesis and summarizes recent advances.

1. Introduction Department of Chemistry and Biochemistry, University of California Santa Barbara, Santa Barbara, CA-93106, USA. E-mail: [email protected], [email protected]

Electroorganic synthesis is recognized as an environmentally friendly methodology for the oxidation and the reduction of

Robert Francke received his Diploma (equivalent to a MS degree) in chemistry from Bonn University (Germany) in 2008 while studying under the direction of Prof. S. R. Waldvogel. He then moved with Prof. Waldvogel to the University of Mainz (Germany), where he completed his PhD research on fluorinated electrolytes for electrochemical energy storage devices in 2012. With financial support by the Alexander von Humboldt Foundation (Feodor Lynen fellowship) he joined the group of Prof. R. D. Little at the University of California, Santa Barbara as a postdoctoral researcher. His current research focuses on the development and application of new redox catalysts for indirect electroorganic synthesis. R. Daniel Little (Dan) received his BS degree in chemistry and mathematics from the University of Wisconsin-Superior. Graduate Robert Francke (left) and R. Daniel Little (right) studies were carried out under the tutelage of Howard Zimmerman at the University of Wisconsin in Madison. Dan then moved to Yale University where he conducted postdoctoral research with Jerome Berson. Thereafter, he moved west to assume a faculty position at the University of California Santa Barbara. He has held visiting professorships at the University of British Columbia (Canada), the Beijing University of Technology (China), and the University of Regensburg (Germany). He is a member of a number of professional organizations including the American Chemical Society, the Electrochemical Society, the International Society of Electrochemistry, and is a Fellow of the American Association for the Advancement of Science.

This journal is © The Royal Society of Chemistry 2014

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organic compounds, since dangerous and toxic redox reagents are replaced by electric current, and the overall energy consumption is reduced.1,2 Although the electrochemical step is usually just one part of a multi-step sequence, it constitutes a key process for the generation of a variety of reactive intermediates.3,4 In addition, it provides a means whereby unstable or hazardous reagents can be produced in situ and allows reactions to be carried out under mild conditions.5,6 Therefore, organic electrochemistry often provides interesting and useful alternatives to conventional synthetic methods and constitutes a useful tool for the organic chemist. With numerous applications on the laboratory scale3,4,7–10 and several applications in industry,11,12 organic electrosynthesis can be regarded as a very versatile and mature field of organic synthesis. The indirect electrolysis represents a special case of electroorganic synthesis, where the electron transfer (ET) step is shifted from a heterogeneous process occurring at an electrode (a ‘‘direct electrolysis’’), to a homogeneous process that can afford an electrochemically generated reagent, or a substance that serves as a so-called ‘‘mediator’’.6 Ideally, the mediator engages in a reversible redox couple that is initiated at the electrode and followed by a reaction of interest. In this manner the catalytic employment of the electron transfer mediator is possible and reagent waste along with difficult separation procedures can be avoided. In addition, electron transfer mediators are useful in avoiding overoxidation/-reduction of the substrate and mitigating electrode passivation that may result by the formation of a polymer film on the electrode surface (see Section 2.2 and Scheme 3). Furthermore, the kinetic inhibition which is typically associated with the electron transfer from electrode to the substrate, can be eliminated.13,14 In addition, higher and/or totally different selectivity can be achieved (see Sections 2.1 and 2.2). As we will detail, the electron transfer can occur even against a potential gradient, if at least one of the subsequent steps is an irreversible chemical reaction. The last comprehensive reviews of the synthetic aspects of indirect electroorganic reactions date back to 1986 and 1987 when Eberhard Steckhan, one of the pioneers in this field, published two articles.13–15 Since then, many new intriguing applications have been found and new types of mediators tailored to meet specific applications have been developed. New and exciting concepts including for example, the use of double mediatory systems in biphasic media, enantioselective mediation and heterogeneous electrocatalysis using immobilized mediators, have been introduced. In addition, efforts have been made to more fully understand reaction mechanisms and to design new mediators using computational methods.16–21 The intent of this review is to present the fundamental aspects of mediator chemistry, and its scope is to highlight recent discoveries and synthetic applications since the publication of Steckhan’s reviews. It is important to emphasize the overlap and similarity of indirect electroorganic synthesis with other fields in chemistry. For instance, redox mediators play a crucial role in electroenzymatic reactions (co-factor regeneration) and electrochemical

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(bio)sensors. The indirect electrochemical reduction of CO2, a potentially useful reaction for the generation of fuels and synthetic building blocks, is also of interest. Since these fields are treated comprehensively in several books and reviews they are not discussed herein.22–27 Another electrochemical application of redox mediators lies in the field of battery research, where the mediator can serve as a redox shuttle for overcharge protection.28 Moreover, substances originally designed to be used in electron transfer catalysis are currently attracting attention outside of their electrochemical context. Given the similarities between photosensitized and electrochemically mediated transformations for example, it is reasonable to anticipate that catalysts originally designed to serve as a mediator will prove useful as excited state electron transfer agents in photoinitiated processes.29 Several of the commonly employed organic mediators currently attract attention in the field of optoelectronics, where they are used in active layers of dye sensitized solar cells or light emitting diodes.30–33 Given the close connections of each of these fields, the progress made in indirect electroorganic synthesis is of great interest to a broad audience.

2. Fundamental aspects 2.1

The principle of indirect electrolysis

Indirect electrochemical conversions are hybrids between direct electrochemical conversions and homogeneous redox reactions. The heterogeneous electron transfer between the electrode and substrate is replaced by a homogeneous redox reaction in solution, which occurs between an electrochemically activated species and the substrate. The electrochemical generation and regeneration of this activated species can either proceed in situ in the same electrochemical cell (in-cell process) or in a separate cell (ex-cell process). The in-cell approach allows one to employ the redox agent in catalytic amounts, since it can be regenerated continuously at the electrode during the reaction. Conditions are chosen so that only the mediator undergoes oxidation or reduction at the electrode, and the substrate, intermediate(s), and the product(s) do not interfere with the electrochemical regeneration of the catalyst. Using the in-cell method, the activated form of the electron transfer agent need only be stable enough to react with the substrate in situ, thereby allowing its conversion back to the inactive form. In contrast, the activated species must be sufficiently stable to be transferred to the second reaction vessel when it is generated ex-cell. Moreover, a catalytic process is not possible and this may result in a more difficult purification procedure. In some sense, the ex-cell process represents the simpler approach, since the two processes can be optimized independently. Nevertheless, the catalytic in-cell process as depicted in Scheme 1 (top) constitutes the more economically and ecologically desirable protocol. Mechanistically, two types of redox electron transfer processes can be distinguished (see Scheme 1, bottom). In the first case, a non-bonded or outer-sphere electron transfer occurs between the starting material (SM) and the mediator (Med).


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Scheme 1

General principle of redox mediation (top) and possible mechanisms for the homogeneous electron transfer (bottom).

In the second so-called inner sphere pathway, a homogeneous chemical reaction involving bond formation between the active form of the mediator and the substrate occurs and is followed by bond cleavage to regenerate Med along with the oxidized (reduced) form of the substrate. Alternatively, an inner sphere electron transfer may occur within a charge transfer complex. In the case of the outer-sphere mechanism, the mediator catalyzes the electron exchange between the substrate and the electrode. In indirect anodic oxidation reactions, the electron transfer equilibrium resides on the side of the substrate if the redox potential of the mediator is lower than the oxidation potential of the starting material (conversely for indirect cathodic reductions). However, the position of this equilibrium can be shifted toward the product when one or more of the subsequent steps consist of an irreversible chemical reaction. A typical example, in this case portraying a rapid and thermodynamically favorable follow-up reaction, is the deprotonation of a radical cation as depicted in Scheme 2. In this case, the electron transfer occurs against a potential gradient, meaning that the redox potential of the mediator is less than the potential of the substrate. This has a practical benefit in that the catalytic cycle can be set up using potentials lower than the redox potential of the starting material. Typical examples for this type of electron

Scheme 2

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Different mechanisms for mediated electron transfer.


transfer reaction include the reactions of the stabilized radical cations of para-substituted triarylamines for oxidations, and the radical anions of aromatic hydrocarbons to mediate reductions. Potential differences of up to 500 mV have reported for such redox mediated reactions.6,13,14,19 As described above, an inner-sphere electron transfer involves an initial chemical reaction between the substrate and mediator. A typical example might be the formation of an intermediate charge-transfer complex or a covalent bond prior to electron transfer. Other examples for inner-sphere processes include oxygen transfer from high valent metal ions to organic compounds, and hydrogen or hydride abstraction reactions involving DDQ and TEMPO (see Scheme 2). In these cases, large potential differences between the mediator and substrate can be overcome and electrolyses are known that proceed at electrode potentials of >1 V lower than the redox potential of the substrate. Moreover, the ensuing reactions are typically more selective than those involving outer-sphere ET, since the selectivity is not determined by the potential difference between mediator and substrate but by the chemical reactivity. To ensure a selective electron transfer from the electrode to the redox catalyst, the redox potential of the mediator must be below the potential of the substrate for indirect oxidations or above for indirect reductions. Thus in a controlled potential electrolysis, the electrode potential is adjusted to that of the mediator, not the substrate. Under galvanostatic conditions, the compounds present in the reaction medium are converted sequentially in the order of increasing redox potential. Consequently, the mediator will be selectively oxidized/reduced in the presence of starting material. One must exercise some caution, however, to ensure that the current density does not become too high. Should that occur, the mediator could be consumed at a rate that exceeds diffusion of fresh material to the electrode surface. Under galvanostatic conditions, the potential will then change in order to maintain the predetermined current level. The problem, of course, is that it could rise to a value that would match the substrate or the product rather than the mediator, thereby leading to side reactions.

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2.2

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Advantages of redox mediated electrolysis

Based on the considerations described above, homogeneous electron transfer processes exhibit several advantages over their heterogeneous counterpart, namely: (1) The kinetic inhibition of the heterogeneous electron transfer between electrode and substrate can be eliminated, which means that overpotentials can be avoided, and that reactions can be accelerated. This is particularly significant for large biomolecules that exhibit strong kinetic inhibition due to steric shielding of their redox centers.13 (2) Electron transfer mediators can exhibit higher or totally different selectivity. (3) When the direct electrochemical conversion causes passivation of the electrode, the employment of a mediator can be helpful, since direct interaction of the substrate with the electrode surface is avoided. (4) Since the electrolysis is conducted at potentials lower than the redox potential of the starting material, the reaction can be carried out under milder conditions and side reactions can be avoided. This can be particularly significant when sensitive functional groups, which are not intended to react, are present. Items (3) and (4) are illustrated by the example depicted in Scheme 3, where the desired outcome was to remove the p-methoxybenzyl ether (PMB) group from 4-phenyl-3-butenol by anodic oxidation.13 The substrate contains two electrophores whose potentials differ only by 100 mV. In contrast to direct electrolysis wherein electrode passivation occurs and a mixture of products are obtained, the indirect method proceeded efficiently to selectively deliver the deprotected product. More examples where severe passivation could be suppressed by using mediators are depicted in Schemes 7, 11 and 13. 2.3 Similarities between electrochemical mediation photoredox catalysis Like electrochemically-mediated catalysis, photocatalysis has a long and rich history. Its current popularity capitalizes upon the use of visible light to initiate a diverse array of useful transformations.29 There are many noteworthy similarities between the two fields. We note, for example, that both processes proceed indirectly. As previously described, electrochemically mediated processes are initiated either by a reduction or an oxidation of the mediator rather than the substrate (see Scheme 4, top). The resulting ion radical then intervenes to reduce or oxidize the substrate.

Scheme 4 Electrochemically mediated reactions (top) and photosensitized processes (bottom).

Similarly, photoredox processes begin by exciting the photosensitizer rather than the substrate (see Scheme 4, bottom). In many cases, the excited state of the sensitizer can serve either as a catalyst for the oxidation or the reduction of a substrate via a photoelectron transfer process. This concept is exemplified in Scheme 5, where the catalyst acts as an electron donor. In such cases, one also has to discriminate between inner-sphere and outersphere ET processes, as described in Section 2.1 for indirect electrochemical reactions.34 The resultant implications for the reaction kinetics are the same for both the photocatalytic and the electrochemically mediated process. Furthermore, catalysts which are frequently used as photoredox catalysts are useful mediators for electrochemical applications and vice versa. One prominent example is 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), which was applied as an electron acceptor in light initiated ET reactions as well as in indirect electrochemical oxidations.34–36 Whether the sensitizer/catalyst can act as a reducing agent (i.e., an electron donor, D) or an oxidizing agent (electron acceptor A) depends upon the redox potentials of the photoactivated catalyst and the substrate. The Rehm–Weller equation, noted below, is frequently used to calculate the free energy change DGoET of such an electron transfer event. It can be considered as a simple tool for determining whether electron transfer between an excited-state and ground-state molecule is spontaneous, based on the standard potentials E o of species A and D and the photoexcitation energy (0–0 transition) of the sensitizer E00 (F is the Faraday constant).29,37,38 o o DE00 þ wðDþ =A Þ wðD=AÞ DGoET ¼ F ED;D þ EA;A (1)

Scheme 3

Mediated selective deprotection of PMB ethers.

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Scheme 5

Principle of photoredox catalysis.


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Scheme 6

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Combination of photo- and electrochemical redox catalysis for the alkylation of Michael acceptors.

To use the expression one employs existing data from the literature, or measures the excitation energy and the potentials directly, being careful to use the same reference electrodes and experimental conditions for each measurement (see Section 4.2). In addition to the experimentally accessible parameters Eo and DE00, the electrostatic work terms w(D +/A ) and w(D/A) (see eqn (2) and (3)) should be considered. They account for the Coulombic interaction between products and between reactants, respectively. Since these terms depend on the nature of the species involved and the reaction medium, an exact determination is not always straightforward. However, in many cases the situation is much simpler when approximations are included. For instance, in polar solvents such as acetonitrile, the work term w(D +/A ) often becomes negligible. Also, when D and A are neutral species, the term w(D/A) can be omitted. While useful, the information obtained by using eqn (1) must be utilized cautiously since it does not account for the possible existence of one or more follow-up transformations that might kinetically drive an otherwise thermodynamically unfavorable process toward product. The similarity between this point and electrochemically mediated processes is unmistakable (compare Section 2.1, Scheme 2). It is an important concept that must be considered when assessing the feasibility of a transformation whether it is light or electrochemically initiated. Usually, in the case of photoredox catalysis, the catalyst is regenerated chemically by using a stoichiometric amount of co-oxidant or co-reductant.29 In order to avoid reagent waste and to simplify the purification process, the combination of photo- and electrochemical redox catalysis using one catalyst for both processes represents a very interesting alternative. However, this idea has been realized only a few times, as for instance in the photoelectrochemical alkylation of Michael acceptors (see Scheme 6).13 The starting Co(III)-complex, in this case vitamin B12, is cathodically reduced to the Co(I) species (0.9 V vs. SCE) which then reacts with an alkyl halide to form an alkylcobalt(III)-complex. The latter can be activated by visible light to undergo reductive elimination to afford an alkyl radical and finally, after cathodic reduction of the cobalt(II) intermediate, regenerate the Co(I)-complex. Natural products like sugars and pheromones were synthesized in good to excellent yields using


this approach.13 It should be noted that the reductive elimination can also be achieved in the dark when a much higher reduction potential of 1.5 V vs. SCE is applied. This case exemplifies how the use of visible light represents an elegant way to lower the redox potential in an indirect electrochemical process, thereby leading to reduced energy consumption and milder reaction conditions.

3. Advancements in mediator design As outlined in Section 2, the redox potentials of the electrocatalyst and substrate must generally be chosen with care. In this context, it is important to note that the potentials of several classes of redox catalysts can be tuned to afford a range of values. This is typically accomplished by varying one or more structural features of the mediator. For example, the redox potential of a metal complex can be adjusted by exchange of one metal for another, or modification of the ligand. For organic mediators consisting of extended p-systems (e.g., triarylamines), a variation of the substitution pattern usually leads to a broad range of accessible potentials. To avoid tedious trial-and-error synthesis in order to identify a mediator capable of attaining a particular potential, several empirical and semi-empirical methods can be employed.20,39–41 The general approach is to plot the experimentally measured redox potentials versus a theoretical parameter for a series of compounds that are similar to the compound of interest. A linear regression is then used to generate a calibration line that can be used to predict values for the related structure of interest. A traditional approach has been to plot a set of experimentally determined oxidation potentials Eox for a series of derivatives versus the sum of the Hammett constants (s). The s-values are related to the ability of an electron donating or withdrawing substituent to influence the potential39 while the slope of a linear correlation provides a measure of the influence of the substituents upon the observed potential and the intercept refers to the oxidation potential of the unsubstituted compound of the series. This treatment is exemplified for a set of differently substituted triarylamine mediators in Fig. 1.21,40 A linear fit reveals that the data is well correlated with a coefficient of determination (R2) of 0.96.

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In Fry’s approach, IP was obtained by subtracting the computed SCF energy of the cation radical from that of the neutral species according to eqn (2): þ


IP ¼ eNAr3 eNAr3

Fig. 1

Correlation between Eox and Ss of a set of triarylamine derivatives.

The use of computational methods can provide a more accurate guide to the design of new electrocatalysts. Here, the ionization potentials IP (or electron affinities EA) of a series of compounds are calculated and correlated with the experimental redox potentials. In the case of a good correlation, the redox potential of a compound yet to be synthesized can be predicted with very high accuracy.41 Fry and co-workers computed the IP’s of the same series of triarylamines as those that are depicted in Fig. 1. The results correlated nicely with the experimentally determined oxidation potentials. In fact, by using the B3LYP hybrid functional in combination with a 6-31G* basis set a much better correlation to Eox (R2 = 0.99) was obtained than by using Hammett constants (see Fig. 2).21

We note that the computed IP does not correspond to the vertical ionization potential, a quantity that is normally measured in the vapor phase. The computed value should simply be considered as a parameter that can be conveniently calculated and that correlates well with experimentally measured oxidation potentials. When a computational approach is utilized, it is possible to take into consideration the vastly differing time scales that are associated with voltammetry compared with vertical excitation. Due to the significantly longer voltammetry time-scale, the radical cation has sufficient time to relax to an energy minimum. Moreover, the solvation energies of both the neutral amine and cation radical in acetonitrile were included in the computations by applying the polarized continuum (PCM) method. Since cation radicals are strongly solvated by donor solvents, the calculated IP values allow a more realistic comparison with the experiment. Analogously, electron affinities (EA) can be obtained by subtraction of the SCF energy e of a negatively charged mediator species (Med ) from the energy of the neutral form as illustrated in eqn (3).41 EA = eMed eMed

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(3)

Fry et al. concluded that the reason for the poorer correlation with Hammett values is due to the fact that the experimental redox potential is related to the energy difference between the neutral species and its corresponding anion or cation radical, whereas the substituent constants are obtained by measurements involving the neutral species only. In other words, by using the computational approach the substituent effects on both species are incorporated into the final values, since the computation of either electron affinity or ionization potential involves calculation of the energy of both the neutral mediator and its charged counterpart. Experience has shown that in order to make full use of this advantage, the computation must be carried out at a sufficient level of theory to ensure good correlation. Whereas semi-empirical methods such as AM1 afford poor correlations, the density functional B3LYP/6-31G* level can suffice.41 This approach was also adopted by Little et al. for a series of triarylimidazoles; in these instances excellent correlations were obtained using the B3LYP hybrid functional in combination with the 6-31+G* basis set and a PCM solvent model.19 The polarized basis set is better suited to the needs presented by charged species, and ion radicals in particular. Still better correlations can be obtained when the absolute redox potential Eoabs is calculated instead of IP or EA. For a single electron redox process this quantity can be derived from the computed free energies of the oxidized and reduced species in solution (DGoox and DGored) and that of an electron in the gas phase (DG0e) according to eqn (4) (where F is the Faraday constant).20 E oabs = DGoox + DG0e DGored/F

Fig. 2 Correlation between Eox and the computed ionization potentials (IP) of a set of triarylamine derivatives.

(2)

(4)

Application of this method to a series of polycyclic aromatics that are of interest as potential anion radical mediators


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afforded exceptionally good correlations (R2 = 0.998) over a potential range of 4.4 V.

4. Setting up an electrocatalytic reaction 4.1

Choice of the appropriate mediator

Since the redox mediator represents the key-element in successfully implementing an indirect electroorganic synthesis, one must give some thought to its selection. For example, what is the intended use of the mediator? Is there reason to believe that an outer or an inner sphere electron transfer might be preferred? What are the redox properties of the mediator of interest and how do they compare with that of the substrate? In general, the mediator should fulfill the following basic criteria: (1) As discussed in Section 2, the redox potential of the mediator must be less than the potential of the substrate to allow it rather than the substrate to be oxidized/reduced. However, the potential difference may not be so large that reaction rates become impractically slow. As a rule of thumb, the potential difference can be up to 2 V when an inner-sphere mechanism is anticipated, and should not exceed 0.5 V for an outer-sphere electron transfer.6,13,14,19 (2) A fast and reversible electron transfer between the electrode and mediator as well as the mediator and substrate is clearly advantageous. Otherwise, slow reaction rates must be compensated for by using large surface area electrodes or by increasing the reaction temperature. (3) Both the reduced and the oxidized form of the mediator should be inert to all processes other than electron transfer, since irreversible side reactions reduce the catalytic activity dramatically. The stability of the activated form of the mediator does not need to be as high when the redox reaction between mediator and substrate exceeds the rate of the side reactions. In these instances, the performance of the catalyst can be maintained throughout the electrolysis and the side reactions will only become problematic after the desired reaction has been completed. (4) The solubility of both the oxidized and the reduced form of the mediator must be high enough to ensure homogeneity. If this is not the case, the use of a co-solvent or a biphasic electrolyte system may be considered. 4.2 Typical pitfalls in dealing with redox potentials from the literature In choosing a mediator from those reported in the literature, one should attempt to identify reaction parameters that are as close as possible to the electrolysis conditions of the planned reaction, since the use of different types of electrolytes and electrode materials may result in large potential differences. Particular care should be exercised when comparing redox potentials that have been measured using different reference electrodes, since the reference potentials which are commonly reported in the literature span a range of 630 mV (see Table 1, compare NHE with the ferrocene redox couple, Fc/Fc+).42 Thus, the comparison of redox potentials from one source of data


Review Article Table 1 Conversion of reference potentials; for a more detailed treatment see ref. 42

Fc/Fc+ Ag/0.1 M AgNO3a Ag/0.001 M AgNO3a SCE NHE a

Fc/Fc+

Ag/0.1 M AgNO3a

Ag/0.001 M AgNO3a

SCE

NHE

0 37 133 380 630

+37 0 97 343 593

+133 +97 0 246 496

+380 +343 +246 0 250

+630 +593 +496 +250 0

Silver wire immersed in 0.1 M Et4NClO4–CH3CN solution at 25 1C.

to another is usually not straightforward, and a conversion constant must be applied when different reference electrodes have been used. Half-cells based on silver salts dissolved in organic electrolytes are the most frequently used reference electrodes in electroorganic chemistry. These Ag/Ag+-type reference electrodes exhibit several advantages relative to the standard hydrogen electrode (SHE), the normal hydrogen electrode (NHE) and the saturated calomel electrode (SCE). For instance, water leakage into the cell can be avoided and the phase boundary liquid junction potential can be eliminated. However, the precise conversion of potentials measured with respect to these electrodes is not always clear, since they are frequently not standardized. Parameters such as the type and concentration of the silver salt may vary from author to author. Since a uniformly accepted convention for reporting the composition of reference electrodes has not been established, and many publications lack an exact description of the reference electrode employed, the comparison of redox potentials measured versus different reference electrodes represents a common source of confusion. For instance, a potential difference of 97 mV between the Ag/0.1 M AgNO3 and Ag/0.001 M AgNO3 electrodes (see Table 1) demonstrates the importance of specifying the silver salt concentration.42 In short, each of the parameters of the reference electrode have to be taken into account in order to accurately compare redox potentials, including the actual Ag+ concentration in the half-cell, the type of counter ion, the amount and nature of additional supporting electrolytes and the solvent. 4.3

Overview of common mediators

To guide the reader in the selection of a suitable mediator, we have summarized in Tables 2 and 3 a variety of oxidation and reduction reactions along with the mediator that was used to achieve them. We deliberately decided not to include the redox potentials of the mediators, since they were determined under a variety of different experimental conditions. As previously noted, the type of electrolyte, the nature of the electrode material and reference electrode, as well as the manner in which the redox potential is reported (E1/2, Eo, Ep) vary from author to author. Consequently, a conversion and the direct comparison is difficult or impossible and therefore, the inclusion of redox potentials in Table 2 and would be rather misleading. Instead, the typical reactivity and reaction types are highlighted in the tables. Readers interested in greater detail can, of course, refer to the original literature.

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A selection of common redox mediators for anodic oxidation including their typical reactivity and selected applications

Redox catalyst


Chem Soc Rev

Redox couple +

Typical reactivity

Reaction examples

Ref.

ET

Deprotection of thioacetals Anodic cleavage of C–S bonds and follow-up reactions Oxidative cleavage of benzylethers Oxidation of allylic and benzylic alcohol Functionalization of aromatic side chains a-Oxidation of aliphatic ethers Anodic fluorodesulfurization Formation of housane derived radical cations Oxidative cleavage of stilbenes

14 14 14 13 13 13 43–45 46–48 49

Triarylamines

Ar3N/Ar3N

TEMPO and other N-oxyl radicals

R2NO /R2NOH

Hydrogen abstraction

Oxidation of aliphatic, benzylic and allylic alcohols Oxidation of amines to nitrile and carbonyl compounds Conversion of propargyl acetates to a,a-dibromo ketone Conversion of tetrahydroisoquinolines to dihydro isoquinolinones

50 51 52 53

Halogenide salts

X/XO X/‘‘X+’’ X = Cl, Br, I

ET (outer sphere and inner sphere)

Oxidation of primary and secondary aliphatic alcohols Selective oxidation of 1,2-diols to a-hydroxy ketones Selective mono- and difluorination of dithioacetals Anodic methoxylation and acetoxylation of imines and imidates Conversions of olefins to epoxides 2,5-Disubstitution of furan Oxidative coupling of malonic acid esters and b-ketoesters Electrochemical synthesis of cyclopropane derivatives Electrochemical cyclodimerization of alkylidene–malonates into cyclobutanetetracarboxylates Selenations of olefins Formation of sulfenimines/sulfenimides from amines/amides and disulfides Conversion of amines to nitriles Dihydroxylation of olefins

54 55 56 57 13 13 13 58–64 65, 66 13 13 13 13

Iodobenzene derivatives

ArI/ArIX2

ET

Anodic fluorodesulfurization Electrochemical partial fluorination Synthesis of N-heterocyclic compounds

67–69 70 71

DDQ

H2DDQ/DDQ

Hydrogen abstraction

Selective side chain functionalization of substituted naphthalenes In situ formation of quinomethanes

36, 72 35

+

Triarylimidazoles

Ar3Im/Ar3Im

ET

Benzylic C–H activation

19, 73, 151

Nitrate salts

NO3/NO3

Hydrogen abstraction or ET

Oxidation of aromatic side chains Oxidation of aliphatic alcohols

13 13

Metal salts:

Cr(VI)/Cr(III) Fe(III)/Fe(II) V(IV)/V(III) Ce(IV)/Ce(III) Co(III)/Co(II) Ru(VIII)/Ru(IV) Os(VIII)/Os(VI) Mn(III)/Mn(II)

Oxygen transfer or ET

Oxidation of aromatic side chains Oxidation of alcohols and ethers Dihydroxylation of olefins Oxidation of arenes to quinones Generation of carboxymethyl and nitromethyl radicals Olefin oxidations

13, 14 13, 14 14 14 13 13

4.4

Analytical approach

Cyclic voltammetry is particularly useful for the initial evaluation of electrocatalytic processes, since the potential difference DEP between substrate and catalyst can be measured and the potential at which the catalytic step takes place can be determined. In addition, the efficiency of the catalytic process can be determined by measuring the voltammetric response in presence of mediator and substrate at the potential of the mediator. When the electron transfer and follow-up transformation are efficient, this leads to the appearance of the so-called catalytic current. The typical voltammetric response is

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exemplified in Fig. 3 for the case of a single electron transfer from a substrate (SH) to a mediator (Med) that is followed by deprotonation of the resulting radical cation (see eqn in Fig. 3). Compared to the voltammogram of the mediator in absence of substrate (solid line), the peak current increases when an excess amount of SH is added (dotted line). Since the active species Medox is consumed in this reaction, it is not available for cathodic reduction in the direction of the reverse scan and therefore, the voltammetric behavior becomes irreversible. Upon the addition of a base (B) the catalytic current is much more pronounced (dash-dotted line), since the rate of the following deprotonation step is dramatically increased.


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A selection of common redox mediators for cathodic reduction including their typical reactivity and selected applications

Redox catalyst


Review Article

Redox couple

Typical reactivity

Reaction examples

Ref.

ET

Reductive dehalogenation of alkylhalogenides Reductive cleavage of tosylamides and sulfonamides Reductive cleavage of aromatic sulfones Electrochemically induced opening of three-membered rings

14 14 14 74, 75

Aromatic hydrocarbons

Med/Med

Fullerenes and o-carboranes

Medn/Med(n+1)

ET

Cathodic reduction of vic-dihalides and perfluoroalkyl halides

76, 77

Ni- and Co-salen complexes

[M(II)salen]/[M(I)salen]

ET or ligand– substrate interaction

Intramolecular cyclization of a-bromo b-propargyloxy esters Synthesis of 4-methyl coumarin by intramolecular cyclization Electroreductive cyclization of a,b-unsaturated aldehydes and electrohydrocyclization of bisenoates Catalytic reduction of CFCs Carboxylation of alkyl-, allyl-, benzyl- and aryl halides

78 79 80

Alkylation of Michael acceptors Coupling of alkylhalogenides to olefins or acetylenes Homocoupling of aryl- and allylhalogenides Electroreductive carboxylation of aryl halides and allyl acetates with CO2 Electroreductive cleavage of allylic acetate Generation of NADH from NAD+ Reductive dehalogenations

14 13 13, 14 85

Generation of aminyl radicals and trapping with olefins or maleic acid Reductive coupling of allyl and benzyl halogenides Reductive dehalogenations Eliminations of b-substituted alkylhalogenides Pinacolization reactions

13, 14 13 13 13 14

Reduction of aromatic and aliphatic nitro compounds Reductive dehalogenation of alkylhalogenides

87 88

Other transition metal complexes

Ni(0)/Ni(II) Ni(I)/Ni(II) Co(I)/Co(III) Pd(0)/Pd(II)

Oxidative addition of R–X or ET

Rh(I)/Rh(III)

Low-valent metal salts

Ti(IV)/Ti(III)


Cr(III)/Cr(II)

Highly dispersed base metal particles

Zn(II)/Zn(0) Cu(II)Cu(0) Sn(II)/Sn(0) Fe(II)/Fe(0)


Fig. 3 The effect of mediator and base on the voltammetric profile of the electrooxidation process depicted in the reaction scheme (top).

Beyond the information that can be rapidly obtained using cyclic voltammetry, preparative-scale evaluation is crucial in order to establish the actual performance and efficiency of catalytic systems under synthetic conditions. In order to study the selectivity of the electrocatalytic reaction, a bulk-electrolysis


81–83 84

86 14 13

is indispensable. It allows one to determine Faradaic yields and to isolate and identify the products. When a potentiostatic electrolysis is used, the stability of the catalyst can be assessed by monitoring the current with time. A decrease might indicate that some unwanted process is consuming the mediator. Observation of the voltammetric response during the course of the electrolysis provides another means of evaluating the catalytic performance. Once the initial assessment has been completed, the optimization process begins. As usual, one can begin by focusing upon the choice of solvent and supporting electrolyte since their choice can greatly influence the product yield and selectivity. The nature of the working electrode is also important. In the case of a slow heterogeneous electron transfer, the use of a high surface area electrode material such as carbon felt or reticulated vitreous carbon (RVC) is recommended. When either the homogeneous electron transfer or the chemical follow-up reaction is slow, an increase of the electrolysis temperature might be considered. The need for and nature of additives is also of interest. If the chemical step involves protonation or deprotonation of intermediates, for example, then the addition of acids or non-nucleophilic bases should be considered in order to shift the electron transfer equilibrium to the product side and to accelerate the overall reaction course.

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5. Recent advances in indirect electroorganic synthesis


The following discourse highlights the development of indirect electroorganic synthesis since the publication of the Steckhan reviews in 1986 and 1987. 5.1

Scheme 7

Anodic fluorodesulfurization of b-phenylsulfenyl b-lactams.

Anodic oxidation

In the last two decades, the development of stable organic radicals and radical cations and the discovery of their effectiveness and versatility as redox catalysts has led to a shift away from the use of metal salts and metal complexes. Indirect anodic oxidations are carried out with increasing frequency using organic mediators such as triarylamines or TEMPO variants. The recent progress in electrosynthesis made with these mediators is truly impressive. For readers who are interested in oxidation reactions involving metal cations or inorganic anions as the mediating species, ref. 13 and 14 provide a comprehensive overview. 5.1.1 Advances in triarylamine mediator chemistry. Triarylamines constitute a versatile and well-established group of oxidative mediators and are among the most frequently employed for indirect electroorganic synthesis. Their radical cations, which represent the active species in the catalytic cycle, are only stable when a substituent in the para position is present to block dimerization or attack by nucleophiles.89 Bromo substituted compounds 1 and 2 (see Fig. 4) are the most frequently used. Although bromo and chloro substituted derivatives have proven to be particularly useful, their stability and hence their utility over the time course of a reaction, depends strongly upon the reaction medium. A broad selection of derivatives have been synthesized, with oxidation potentials ranging from +0.76 to +1.96 V vs. NHE, covering most of the oxidation potentials of common functional groups.14 Considering the fact that the redox potential of the mediator can be several hundred mV below the potential of the substrate when a favorable reaction follows the electron transfer, this range is even broader. Notably, such follow-up reactions typically involve C–H activation in allylic and benzylic frameworks, and when located alpha to heteroatoms, and in the irreversible cleavage of C–S bonds. In many cases high reaction rates were achieved despite the existence of potential gradients between the mediator and the substrate of up to 600 mV. A range of examples for triarylamine mediated reactions that exhibit a large potential gradient can be found in ref. 13 and 14 (a more recent example with DE = 0.52 V is depicted in Scheme 9). For these cases an inner sphere electron transfer

involving complex formation or bond formation is assumed. Numerous practical applications, such as the anodic deprotection of thioacetals, cleavage of anisylethers, oxidation of aromatic side chains and a-oxidation of aliphatic ethers have been described in Steckhan’s reviews.13,14 Therefore, we have chosen to focus on the recent developments in the ensuing presentation. An interesting application of triarylamine mediators was reported by Fuchigami et al. to achieve anodic fluorodesulfurizations using NEt3nHF (see example in Scheme 7; C.C.E. = constant current electrolysis).43,90 In this type of reaction, NEt3nHF ionic liquids serve both as the supporting electrolyte and as a mild fluoride source (the reactions can be carried out in normal glass vessels). The direct anodic conversion of organic compounds containing sulfur in low oxidation states generally leads to passivation of the electrode due to film formation. As a result, a complete conversion is therefore difficult to achieve.91 This problem also occurred when b-phenylsulfenyl b-lactams 3 were examined in acetonitrile containing NEt33HF in the absence of a mediator. Although the fluorinated structure 4 could be obtained, excessive amounts of charge were required in order to achieve low to moderate yields. The results improve when 10 mol% of mediator 2 was added to the reaction mixture (plausible reaction mechanism: see Scheme 8). In this fashion, the passivation was completely suppressed and yields of 71–100% could be obtained (Faradaic yields: 35–50%). In a similar manner, S-arylthiobenzoates can be desulfurized with mediator 2 to

Fig. 4 Commonly used triarylamine mediators.

Scheme 8

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Mechanism for the reaction depicted in Scheme 7.


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Fig. 5

Triarylamines bearing ionic tags.

afford benzoyl fluorides when conducted in the presence of fluoride donor, or to afford benzoic acid esters when conducted in the presence of methanol.44,45 A drawback to the use of halogenated triphenylamines such as 1 is their low solubility in protic media or ionic liquids. Since in many cases electrochemical partial fluorinations are preferably carried out solvent-free in NEt3nHF- or NEt4FnHFtype ionic liquids,92 triarylamine mediators bearing ionic tags (5 and 6, Fig. 5) have been developed by Fuchigami et al.93 They were successfully employed in electrocatalytic reactions including the deprotection and fluorodesulfurization of dithioacetals. Notably, it was demonstrated that electrolyte and mediator could be recycled after extraction of the product with hexane. Little and Park used an electrochemically mediated electron transfer to accomplish the key step of a total synthesis of a sesquiterpene called daucene (11).47 This natural product was synthesized in 15 steps from spirocyclic enone 7.47,48 In the key-step, the transformation of housane 9, which was readily available using a photochemically induced N2 extrusion from diazene precursor 8, was converted to the bicyclo[5.3.0] framework 10. The rearrangement was achieved in a 70% yield

Review Article

in an undivided cell using mediator 1. The process was carried out at a potential of 0.88 V vs. Ag/0.01 M AgNO3 in order to oxidize the mediator rather than the substrate (Eox B +1.4 V vs. Ag/0.01 M AgNO3). In the first step, radical cation 12 is formed upon reaction of 9 with the arylaminium cation radical. This initial electron transfer is thermodynamically unfavorable and the equilibrium reaction therefore represents the bottleneck. However, the subsequent irreversible Wagner Meerwein rearrangement, generating the seven-membered ring 13, serves to shift the equilibrium to the product side. Both of the putative intermediates 12 and 13 were examined using computational methods and it was found that 13 is of lower energy. Quantum calculations also confirmed that in the following step 13 is most likely reduced by 1 and not by housane 9, to form the [5.3.0] adduct 10. Interestingly, a chemically mediated electron transfer using the ( p-BrC6H4)3NSbCl6 salt as an electron transfer agent leads to a different chemoselectivity. Thus, instead of generating 10, a spirocyclic alkene was formed due to a Lewis acid promoted (SbCl5) ring opening of the strained framework found in the starting material. In the same manner as 9, methyl substituted housanes 14 can be converted to six-membered ring adducts 15 (see Scheme 9, bottom left).46,48 An oxidative cleavage of a series of symmetrical and unsymmetrical stilbenes bearing two or more electron-withdrawing groups was reported by Fry and co-workers (see Scheme 10; C.P.E. = controlled potential electrolysis).49 To achieve cleavage, triarylamine 16, a system with an unusually high oxidation potential of 1.32 V vs. Ag/0.1 M AgNO3, was synthesized using a room temperature nitration of commercially available tris-ptolylamine by Cu(NO3)2 in acetic anhydride. Amine 16 forms a stable cation radical, which in contrast to its brominated congeners, is soluble in many organic solvents. Most importantly, 16 has an oxidation potential 0.5 V higher than that of widely used amine, ( p-BrC6H4)3N (1). The cleavage reactions

Scheme 9 Housane rearrangement (center) as key step in the total synthesis of daucene (11) and application of the reaction conditions to other housane substrates 14 (bottom left).


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Scheme 12

Scheme 10

Oxidative cleavage of stilbenes.

were carried out under potentiostatic conditions in an aqueous acetonitrile solvent system. 5.1.2 Reactions with in situ electrogenerated hypervalent iodine species. Hypervalent iodobenzene difluorides have proven to be useful reagents in chemical fluorination reactions.94,95 However, such compounds are generally unstable and therefore difficult to isolate. In the past, their preparation required hazardous and costly fluorination reagents such as XeF2/HF. An elegant way to overcome these problems involves the electrochemical generation of iodo difluoride by an anodic conversion of iodobenzene derivatives in Et3NnHF electrolytes.67 Since anodic dimerization of iodobenzene occurs readily, the para position has to be blocked with a substituent that simultaneously serves to help tune the oxidation potential. Electrogenerated iodobenzene difluoride was successfully employed for the fluorodesulfurization of dithioketals, both in a stoichiometric and in a catalytic manner (see Scheme 11). Due to the low stability of the hypervalent iodine species, excess amounts of reagent were needed to achieve full conversion in the stoichiometric ex-cell method. The catalytic in-cell version using 5–20 mol% mediator at a potential of 1.9 V vs. SCE, is clearly advantageous, with yields reaching up to 98%. Notably, electrolysis of dithioketals under the same conditions in absence of the iodobenzene mediator does not give any of the desired product. In a further example, para-iodotoluene was used for the anodic fluorination of 1,3-dicarbonyl compounds in Et3N5HF (see Scheme 12).96

Scheme 11 Iodoaryl mediated anodic fluorodesulfurization.

Chem. Soc. Rev.

Fluorination of 1,3-dicarbonyl combounds.

To address the issues of separation of the mediator from the product mixture and its reusability in subsequent reaction batches, ionic iodoarene 17 was developed for electrochemical fluorination reactions.70 The introduction of the ionic tag provides solubility in a broad range of ionic liquids; in addition, the mediator is not extracted into organic solvents such as ether. Similar to ionic triarylamine mediators 5 and 6, the NEt3nHF electrolytes can be reused in subsequent reactions after extraction of the product mixture. These so-called task specific ionic liquids (TSILs) were successfully applied to the anodic fluorination of 2-pyrimidylsulfides in ionic liquid hydrogen fluoride salts (see Scheme 13). Since the mobility of mediator 17 in the viscous IL is significantly decreased compared to the unmodified iodoarene, the transport of the oxidized form to the cathode is slow enough to allow for operation in an undivided cell. Nishiyama and co-workers have utilized anodically generated hypervalent iodine species in key-transformations of the multistep syntheses of several natural products. For instance, they achieved oxidative cyclizations of biaryl 18 to carbazole 19 with in situ generated PhI(OCH2CF3)2, which was formed upon anodic oxidation of PhI in a reaction medium consisting of LiClO4 and 2,2,2-trifluoroethanol (see Scheme 14).97 This transformation served as the key-step in the synthesis of glycozoline 20 (Fig. 6), an antibacterial and antifungal agent. It was demonstrated by the authors that this in situ generated species is more effective for this cyclization reaction than the conventional PIFA reagent. In a similar fashion, 23 was converted to 24 (see Scheme 15) as a part of the total synthesis of two different tetrahydropyrroloiminoquinone alkaloids 21 and 22 (Fig. 6).71,98 5.1.3 Anodic oxidations of alcohols with N-oxyl radical mediators. In many cases, a direct anodic oxidation of alcohols is inefficient or not feasible, since high potentials have to be applied in order to achieve conversion. In addition, most

Scheme 13 Ionic tagging of a iodoarene mediator (bottom) and application to the fluorination of 2-pyrimidylsulfides (top).


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Scheme 14

Oxidative cyclization using anodically generated PhI(OCH2CF3)2.

Fig. 6 Natural products synthesized by Nishiyama et al. using electrochemically generated PhI(OCH2CF3)2 in the key-transformation.

Scheme 15 Oxidative cyclization using anodically generated PhI(OCH2CF3)2.

common functional groups are not compatible with the requisite conditions.99 Aliphatic alcohols are particularly unsuitable. In contrast, mediated electrooxidation of alcohols not only affords superior results in terms of selectivity and compatibility with other functional groups, but it can even facilitate reactions which are not feasible using direct oxidation methods.14 Some mediating systems elaborated for this purpose include alkali metal nitrates in acetonitrile or in biphasic solution,100,101 thioanisole in benzonitrile or 2,2,2-trifluoroethanol,102,103 and a double mediatory system consisting of RuO4/RuO2 and

Scheme 16

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Cl/Cl+ in a biphasic system.104 A further attractive and inexpensive method to transform simple primary and secondary alcohols to the corresponding carboxylic acids and ketones employs iodide salts. In this case, the electrolysis can be conducted galvanostatically and without addition of base.105 The most frequently studied class of mediators for the oxidation of alcohols are N-oxyl radicals, particularly, 2,2,6,6tetramethylpiperidinyl-N-oxyl (TEMPO) and several of its derivatives. In contrast to the conventional use of TEMPO, the mediated processes do not require the use of stoichiometric amounts of co-oxidant (e.g. NaClO). The indirect method allows for selective transformations of primary and secondary alcohols to carbonyl compounds at low potentials (typically around 0.4 V vs. Ag/0.1 M AgNO3).50,106 Over-oxidation to form carboxylic acids can be avoided under anhydrous conditions50 or by the use of a microfluidic electrolytic cell when the reaction is carried out in aqueous electrolytes.107 When the acid is desired, a constant current electrolysis using a conventional batch cell in combination with an aqueous basic electrolyte affords the carboxylic acid.106 Typically, primary alcohols react rapidly, which allows for a selective transformation in the presence of secondary hydroxy groups. A proposed reaction mechanism for the indirect oxidation is depicted in Scheme 16.106,108 Thus, anodic oxidation of the nitrosyl radical leads to the active oxoammonium ion 25 which then reacts with an alcohol to give the corresponding hydroxylamine and the carbonyl compound. Reasonable reaction rates are only achieved in the presence of a suitable base such as 2,6-lutidine or K2CO3/ KHCO3. Interestingly, the direct anodic regeneration of species 25 from the hydroxylamine requires a potential of 0.8 V vs. Ag/AgNO3.50 However, the catalytic cycle can be established at the oxidation potential of the N-oxyl radical, since it is regenerated from the hydroxylamine by a comproportionation reaction with the oxoammonium species. Since the interaction between 25 and alcohol is not an outer-sphere electron transfer but a process involving intermediate formation of a covalent bond (inner-sphere mechanism), the potential difference between mediator and substrate is not determining and can therefore be 1 V or more. Consequently, even aliphatic alcohols with an oxidation potential of >2 V vs. Ag/AgNO3 can be efficiently oxidized.50

Mechanism for electrochemical TEMPO oxidations of alcohols.


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Scheme 18

Kinetic resolution of racemic sec-alcohols.

A significant improvement of the method described above employs a double mediatory system in a biphasic medium consisting of an organic solvent and an aqueous electrolyte containing a halide salt (see Scheme 17), wherein the active bromine species that is generated anodically reacts with the N-oxyl radical to form the oxoammonium species.108 The conversion of alcohols to carbonyl compounds then proceeds in the organic phase. The advantage of this method is its simplicity. In contrast to the single mediatory system, it is possible to use an undivided cell under galvanostatic conditions within a wide range of current densities. A broad range of primary and secondary alcohols (both aliphatic and benzylic) have been oxidized efficiently in this manner.108 Numerous modifications of TEMPO mediators have been designed in order to tailor the system to meet specific purposes (see Fig. 7). From the environmental point of view, the employment of ion-tagged water soluble TEMPO derivatives 26a and 26b (WS-TEMPOs) is attractive, since they allow for the use of aqueous electrolytes.109,110 With this type of mediator, the scope is not simply limited to water soluble alcohols, as nanoemulsions are formed upon ultrasonic irradiation of a solution of WS-TEMPO and lipophilic alcohol in an aqueous electrolyte. After electrolysis, the resulting aldehyde can easily be isolated by extraction with

an organic solvent. The aqueous electrolyte can be reused for several cycles since the concentration of the mediator remains almost unaffected. It has also been demonstrated that amphiphilic alcohols such as diethylene glycol monomethylether can be oxidized efficiently in an aqueous solution even without using WS-TEMPO, since the substrate itself is able to form stable nanoemulsions.111,112 When an optically active N-oxyl species is used for oxidation of racemic sec-alcohols, a kinetic resolution can be achieved (see Scheme 18). In this case the product mixture contains ketone and enantiomerically enriched alcohol. This concept was originally developed for the conventional (non-electrochemical) oxidation method and later transferred to the electrocatalytic reaction using 27 as an optically active mediator.113–115 The employment of a double-mediatory system such as sodium bromide combined with 28 in biphasic solution (compare Scheme 17) again proved to be beneficial, allowing for operation in an undivided cell under galvanostatic conditions.116 Similar results can be obtained in an organic solvent-free method using an aqueous silica gel supported system.117 The slower reaction of secondary compared to primary alcohols is typical for TEMPO-based mediators. This feature can be utilized to discriminate between hydroxyl groups located at different ¨fer et al. for positions of a molecule, as demonstrated by Scha the indirect anodic oxidation of carbohydrates.106,118,119 However, the reduced rate turns into a drawback when the oxidation of sterically hindered secondary alcohols such as ()-menthol is intended (see Scheme 19).120 When a substrate contains sterically demanding groups adjacent to the secondary hydroxy functionality, azabicyclo-N-oxyls 29 exhibit superior catalytic performance compared to TEMPO. In analogy with the chemistry shown in Scheme 18, optically active versions of 29 have been successfully employed for the kinetic resolution of racemic sec-alcohols.121 The scope of substrates that can be oxidized using anodically generated N-oxoammonium species is not limited to alcohols. For instance, TEMPO proved to be efficient in the mediated conversion of propargyl acetate 30 to a,a-dibromo ketone 31 in a

Fig. 7 Modifications of TEMPO for different mediator applications.

Scheme 19

Scheme 17

Double mediatory system (Br/TEMPO) in biphasic electrolyte.

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Oxidation of sterically hindered sec-alcohols.


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Scheme 20

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TEMPO mediated oxidation of propargyl acetate 30.

two-phase mixture of CH2Cl2 and aqueous 25% NaBr solution buffered with NaCO3/NaHCO3 (see Scheme 20).52 The oxidation was carried out in an undivided cell under galvanostatic conditions using platinum electrodes, and with an isolated yield of 88%. The scope was extended to other propargyl acetates leading to similarly high yields. For the case shown in Scheme 20, the product was converted in 2 steps into furaneol, a flavoring ingredient in food industry. In a recent example by Zeng et al. it was demonstrated that the TEMPO/NaBr dual redox system depicted in Scheme 17 can be employed for anodic C–H functionalization in benzylic positions.53 In a biphasic mixture of CH2Cl2 and aqueous buffer solution, tetrahydroisoquinolines were converted to the corresponding dihydroisoquinolinones (see Scheme 21). Analogously to the reactions involving the TEMPO/NaBr double-mediatory system that were described previously (Scheme 17 and 20), the use of an undivided cell under galvanostatic conditions is feasible. The scope of this transformation was extended to the oxidation of isochroman and xanthene to isochromanone and xanthenone, respectively. 5.1.4 Employment of DDQ in indirect electrosynthesis. Due to its utility as an oxidation and hydride transfer reagent, 2,3-dichloro5,6-dicyano-1,4-benzoquinone (DDQ) is widely used in synthetic organic chemistry. Among the numerous applications, we note oxidative coupling122,123 and the oxidative cleavage of benzyl ethers.124,125 Although it was established early that the corresponding dihydroquinone (H2DDQ) can be electrochemically regenerated after completion of the reaction,126,127 the application of DDQ as a mediator in organic electrosynthesis has not yet been fully explored. Voltammetric studies reveal that the redox couple DDQ/H2DDQ is chemically reversible in aqueous acetic acid (with Eo = 0.44 V vs. SCE), whereas irreversibility is observed in aprotic electrolytes, an outcome that is consistent with the mechanism depicted in Scheme 22.72 Utley et al. reported the anodic conversion of a series of 2-methyl and 2-benzylnaphthalenes (32) in presence and absence

Scheme 21 Mediated oxidation of tetrahydroisoquinolines using the Br/ TEMPO dual redox system.


Scheme 22

Stepwise oxidation/deprotonation of H2DDQ to DDQ.

Scheme 23

Benzylic oxidation using DDQ as mediator.

of catalytic amounts of DDQ.36,72 Whereas in nucleophilic media and in absence of the mediator dimerization reactions are predominant, the addition of catalytic amounts of DDQ allows for an efficient side-chain functionalization. The latter is consistent with hydride transfer, which proceeds via sequential electron–proton–electron transfer from substrate to DDQ. In aqueous acetic acid, the 2-methyl and 2-benzyl groups are oxidized to the corresponding aldehydes and ketones 33 (see Scheme 23). In contrast, the formation of adducts of 32 and DDQ is observed in dry aprotic solvent and a sufficiently acidic electrolyte is therefore crucial to achieving product selectivity. Since the reaction between substrates 32 and the mediator is slow at room temperature, the electrolysis was carried out at elevated temperatures. Along with the desired product 33, the acetoxy-substituted adduct 34 was isolated. It represents an intermediate in the oxidation process formed upon nucleophilic attack of an acetate ion on the oxidized form of 32. The oxidation potentials of naphthalenes 32 were measured to be between 1.41 and 1.50 V vs. SCE, that is, nearly 1 V more positive than Eo(DDQ). The fact that the reaction can still proceed, points towards a strong molecular interaction between substrate and mediator prior to electron transfer. For oxidations of aromatic compounds using DDQ the formation of a charge transfer complex (Ar +DDQ ) prior to the initial electron transfer has been proposed.128,129 Chiba and co-workers found an interesting indirect anodic oxidation method involving DDQ as a redox catalyst and applied

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Scheme 24

Chem Soc Rev

Synthesis of euglobal model compounds 37–39 via electrochemically induced Diels–Alder reaction.

it to natural product synthesis. It was successfully employed in catalytic amounts in the key-step of the synthesis of structures 37–39, models for euglobals, natural products which are extracted from Eucalyptus.35 These frameworks are composed of a terpene moiety and a phloroglucinol structural element and exhibit antiviral activity. They can be generated in an indirect electrochemical conversion of 35 with a terpene as illustrated in Scheme 24. In the proposed mechanism, the unstable quinomethane 36, which is formed in situ upon reaction of 35 with electrogenerated DDQ, reacts with a-phellandrene in a Diels–Alder cycloaddition to form euglobal analogue 37. Analogously, 36 can be trapped with a- and b-pinene to afford compounds 38 and 39. When the reaction is carried out in an undivided cell at a potential of 0.45 V vs. SCE (close to the oxidation potential of the mediator) with a nitromethane-based electrolyte, the desired compounds can be isolated in good yields. A PTFE-fiber coated platinum plate was used as the working electrode. The reaction sequence proceeds within this hydrophobic coating on the electrode surface which is presumed to protect the highly reactive intermediate and to facilitate the reaction with the hydrophobic dienophile. It should be noted that the chemical alternative to the transformation to 38 and 39 is not practical since it requires excess amounts of DDQ. Moreover, under those conditions 37 is not formed due to cycloaddition of DDQ to a-phellandrene.130 The employment of DDQ in catalytic amounts therefore seems to be crucial. 5.1.5 Progress with halide mediated electrooxidations. Halide salts are among the most versatile and cost-efficient mediators. Typically, the active species (molecular halogen, hypohalite ions, or halonium ions) is generated anodically from the halide salt, which is also used as the supporting electrolyte. The redox reaction of these mediators is often combined with a chemical reaction (inner sphere mechanism) and therefore, very high potential differences between substrate and redox catalyst of up to 2 V can be overcome. Halide salt mediators have been known for many years and a summary of the progress until 1987 can be found in Steckhan’s reviews.13,14 Despite many past successes, remarkable developments in this field continue to emerge. Nikishin and Elinson et al. have developed a variety of indirect electrochemical transformations of C–H-acidic compounds using

Chem. Soc. Rev.

halide salt mediators. Usually, these reactions are carried out in alcoholic solutions and are initiated with the cathodic formation of alcoholate base which deprotonates the C–H acid 40. Simultaneously, elemental halogen is formed on the anode which reacts with anion 41 to give intermediate 42. Subsequently, activated species 43 can be formed by deprotonation of 42. Since the reaction mixture contains two reactive intermediates (41 and 43) which can participate in multiple reaction pathways, it is crucial to carefully control the conditions, viz., temperature, concentrations, type of halide salt, and substitution patterns of the substrates, in order to drive the reaction to the desired outcome. Furthermore, a variety of products becomes accessible upon addition of electrophile trapping agents. Since base and oxidant act catalytically and since both are generated in situ in a paired process, this can be considered as a particularly mild and efficient protocol. One application of the chemistry depicted in Scheme 25 is the electrolysis of phenylacetonitriles in methanol in an

Scheme 25 Principle of the indirect paired process developed by Nikishin and Elinson.


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Scheme 26 stilbenes.

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Indirect electrochemical synthesis of trans-a,b-dicyano-

undivided cell in the presence of sodium halides leading to the formation of trans-a,b-dicyanostilbenes (see Scheme 26).131 The generation of intermediate 44 is conceivable in two ways: either by nucleophilic attack of 43 on 42 or by reaction of 41 with 42 and subsequent deprotonation/halogenation. The reaction of 44 to afford the olefin proceeds with trans-selectivity. When aldehydes are electrolyzed in the presence of two equivalents of malononitrile in an EtOH/NaBr electrolyte in an undivided cell, 3-substituted-1,1,2,2-tetracyanocyclopropanes are obtained in good to excellent yields (Scheme 27).62,64 This one-pot reaction is initiated by deprotonation of malononitrile using ethoxide, an electrogenerated base (EGB) and subsequent reaction with the aldehyde to give alkylidene malononitrile, which then reacts with 43a to give the cyclopropane compound 45. Similarly, malonates can be used as C–H active component for this type of transformation.60 Since ketones react at a significantly slower rate, they must be employed in large excess.62 Another possibility to obtain 3,3-disubstituted cyclopropanes is to subject the dialkylidene precursors, prepared ex situ from ketone and malononitrile, to the aforementioned electrolysis conditions.62 In this way a variety of (E)-3-substituted 2-cyano-1,1,2-tricarboxylates were synthesized stereoselectively.61,63 It was also discovered that under the typical electrolysis conditions the cyano substituted cyclopropyl electrolysis products can undergo further cyclization triggered by nucleophilic attack of alcoholate on the nitrile group.62 This reactivity can be utilized to form azabicyclo[3.1.0]hexanes in a one-pot procedure from malononitrile or malonates and alkylidene precursors.132,133 For instance, electrolysis of arylidene- or alkylidenemalononitriles and malonate

Scheme 27 Cyclopropane synthesis using the process depicted in Scheme 25.


Scheme 28

One-pot reaction to form azabicyclo[3.1.0]hexanes 46.

Scheme 29

Cyclodimerization of alkylidenes.

leads to the stereoselective formation of azabicyclo[3.1.0]hexane 46 in moderate to good yield (Scheme 28).132 The second cyclization is a result of the successive addition of two MeOH molecules to the intermediate cyclopropane, which is triggered by cathodically formed methanolate. Since methoxide is regenerated in the last step, only small amounts of charge are consumed. Another facet of this chemistry is depicted in Scheme 29 which shows the course of the reaction when alkylidene compounds are electrolyzed in absence of an aldehyde or ketone; here, cyclodimerization to the corresponding cyclobutane derivatives 47 occurs.65,66 More recently, Nikishin, Elinson and co-workers were able to apply their indirect electrochemical approach to the construction of a series of pharmacologically relevant frameworks.58,59,134 In one example, the indirect electrochemical oxidation of 48 under the usual conditions (viz., NaBr/MeOH electrolyte, undivided cell) resulted in the formation of the corresponding bis(spiro)cyclopropanes (49) in 85–96% yield (Scheme 30). The reaction occurred diastereoselectively via intermediate 50.59 Halide mediators have also been used for the selective conversion of vicinal diols to a-ketoalcohols, in this case by Onomura and co-workers. This transformation represents a challenging task, since common oxidizing reagents such as Pb(OAc)4, IO4, direct electrolysis or the use of Swern reagents lead to the oxidative cleavage of vicinal diols or oxidation to the diketone, respectively. The transformation can be accomplished by converting the 1,2-diol into the corresponding stannylene acetal (51) followed by subjection to brominolysis (see Scheme 31, left).135 However, this non-electrochemical method suffers from the

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Scheme 33

Scheme 30

Electrochemical bis(spiro)cyclopropane synthesis.

Scheme 31 Selective conversion of vicinal diols to a-ketoalcohols.

employment of excess Bu2SnO and bromine. In this context, a more elegant electrochemical version of this reaction was developed, where the active bromine species was generated anodically from the supporting electrolyte and Bu2SnO was employed catalytically (see Scheme 31, right side).136 In a plausible mechanism (Scheme 32) the diol substrate reacts with (MeO)2SnBu2 to form stannylene acetal 51 or the related zwitterion 52. After reaction with the anodically activated bromine species and reaction with cathodically formed MeO the hydroxyketone is obtained and the organotin catalyst is regenerated. The oxidation state of the tin catalyst remains

Scheme 32 Proposed mechanism for the selective conversion of vicinal diols to a-ketoalcohols.

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Synthesis of 2-substituted benzoxazoles from Schiff bases.

unchanged throughout the catalysis cycle and the bromide mediator serves solely in the oxidation of the hydroxyl group. Therefore, this reaction can be considered as a combination of a single-mediatory system (Br/Br2) and a conventional catalytic cycle involving the stannane species rather than as a doublemediatory process. This electrochemical method was successfully applied to a broad range of 1,2-glycol derivatives and guidelines for achieving regioselectivity were developed.55 Since terminal hydroxyl groups cannot be oxidized using this method, secondary alcohols are transformed selectively when they occur in the presence of primary alcohols. In the case of two secondary hydroxy groups, the sterically less hindered unit is oxidized predominantly. In the presence of a third hydroxy group as for example in glycerol, a high selectivity for the formation of 1,2-diols is observed. Zeng, Little and co-workers recently identified a method for the synthesis of 2-substituted benzoxazoles from Schiff bases 53 using sodium iodide as the mediator. As illustrated in Scheme 33, the electrolysis is carried out in an undivided cell under galvanostatic conditions. Sodium iodide (20 mol%) was used as the mediator in a two-phase electrolyte system consisting of a sodium carbonate buffer solution and dichloromethane.137 5.1.6 Combination of redox mediation with catalytic Pd(0)/ Pd(II) cycles. The electrochemical regeneration of transition metal catalysts in order to avoid using stoichiometric quantities of redox agents, is well established; the subject was treated comprehensively in Steckhan’s reviews.13,14 Recent progress can be found in the literature that describes the anodic regeneration of Pd(II) species in oxidative processes, which is best achieved in combination with a redox mediator. A very interesting example for this concept is the combination of TEMPO-mediation with Pd(0)/Pd(II) chemistry in order to achieve a Wacker type oxidation of olefins to carbonyl compounds (Scheme 34b).138 Traditionally, copper salts have been used as co-catalysts under an oxygen atmosphere in order to reoxidize Pd(0) to Pd(II). However, reactions carried out in this way are often not completely homogeneous and therefore, relatively large amounts of Cu and Pd catalysts have to be employed. Moreover, when copper(II) chloride is used, chlorination of the carbonyl containing adducts can occur and in the case of volatile olefin substrates, explosive mixtures of gases can be formed with oxygen.139 The indirect anodic regeneration of Pd(II) using organic mediators provides a safe and useful alternative. This approach was first realized by Tsuji et al. using 2–5 mol% Pd(OAc)2 and 20–30 mol% benzoquinone as mediator


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Scheme 37

Scheme 34 Anodically formed [Pd(CH3CN)4]X2 (top) in the Wacker-type oxidation of olefines (bottom).

Scheme 35

Cyclization reaction using a Pd(II)/Tempo catalyst system.

in CH3CN/H2O (7 : 1), leading to the formation of a variety of carbonyl compounds in good yields from their olefinic precursors.140 This method was later adopted by others using ( p-BrPh)3N (1) or TEMPO as the mediator under similar conditions. In this manner the scope of usable olefinic substrates was significantly expanded.138,141 The electrolysis when carried out in the absence of substrate and mediator affords [Pd(CH3CN)4]X2 (with X = ClO4, BF4, PF6, depending on the supporting electrolyte), which suggests that [Pd(CH3CN)4]2+ which is probably formed in a Kolbe-type reaction (see Scheme 34a), represents the active species in this process.138 Another interesting version of TEMPO mediated Wacker-type oxidation is illustrated by the cyclization of 54 (see Scheme 35).142 The TEMPO/Pd(OAc)2 system was also applied to the homocoupling of aryl boronic acids and aryl boronates (see Scheme 36).143,144 The reactions were carried out in a divided cell under galvanostatic conditions using a CH3CN–H2O solvent mixture. In the presence of a catalytic amount of Pd(OAc)2, 30 mol% TEMPO and 2 equivalents of Na2CO3, this electrooxidation process gives the corresponding biaryls in moderate to excellent yields. Both electron withdrawing and electron

Scheme 36 Electrochemical homo-coupling of boronic acids and boronates using Pd(OAc)2 and TEMPO.


Heck-type reaction using a Pd(II)/p-quinone catalyst system.

donating substituents on the arene rings were found to be compatible with the reaction conditions. Simultaneously with the reports of Tanaka et al., similar results for the homo-coupling of boronic acids and boronates with Pd(OAc)2 were published by Amatore, Jutand et al.145 In their approach, the Pd(II) species is regenerated by a p-quinone/p-hydroquinone redox mediator system and the reaction is carried out in DMF and/or water. Amatore and Jutand et al. also reported a Pd(OAc)2 catalyzed Heck-type reaction with the same Pd(II)/p-quinone catalyst system (see Scheme 37).146 It is noteworthy that this reaction does not proceed via the usual oxidative addition of aryl halogenides to the Pd(0) species but via C–H activation by Pd(II). While the transformation represents a particularly useful and environmentally benign process, it is restricted to substrates containing a substituent that can coordinate and direct Pd, as for example the amide functionality found in structure 56, to achieve the C–H activation. The reaction can be carried out in acetic acid at room temperature using a carbon felt anode. The electrolysis must be conducted in a divided cell since the active form of the mediator can easily be transformed cathodically into the inactive p-dihydrobenzoquinone. 5.1.7 Other types of mediators. Several other types of redox catalysts that cannot be assigned to one of the mediator groups described in Sections 5.1.1–5.1.6 have been used sporadically in the past. Quinones other than DDQ are worth mentioning in this context, since they were successfully applied in Pd-catalyzed transformations (see Section 5.1.6).140,146 A further, more ‘‘exotic’’ mediating system that is based on the ArS(ArSSAr)+ species (an equivalent of ArS+), was introduced by Yoshida, Suga and co-workers. This cationic species can be generated by low-temperature electrochemical oxidation of ArSSAr and serves as a reagent for the generation of organic cations (indirect cation-pool method).147–149 When a thioaryl group is present in the substrate, ‘‘ArS+’’ is continuously regenerated and therefore, ArSSAr can be employed catalytically. This idea was realized by Yoshida, Suga and co-workers for the intramolecular bond formation between thioacetal and olefin units in substrates of type 58 (see Scheme 38).150 After reaction with ArS+ alkoxycarbenium ion 59 is formed, which after cyclization reacts with regenerated ArSSAr to give 60. Substrates 58 can either be converted in-cell using catalytic amounts of ArSSAr/charge, or ex-cell by generation of catalytic amounts of ArS(ArSSAr)+. Recently, a promising new class of mediators based on the triarylimidazole framework 61a was developed by Little, Zeng et al.19,73 A series of structures 61a was synthesized in a simple one-step procedure and subsequently characterized electrochemically.

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Scheme 39

Scheme 38

Cyclization of 58 using anodically generated ‘‘ArS+’’.

The derivatives prepared thus far exhibit an accessible potential range of >700 mV and form stable radical cations upon anodic oxidation. Their oxidation potentials exhibit a good linear correlation with the ionization potentials calculated using DFT methods, allowing one to make predictions for derivatives yet to be synthesized.19 Their utility as redox mediators was demonstrated on a preparative scale. They proved to be efficient mediators for the activation of benzylic C–H bonds under mild conditions. In practice, a broad range of benzylic alcohols and benzyl ethers was successfully converted into the corresponding aryl aldehydes and benzyl esters using 61a as the redox catalyst.73 A significant improvement of the triarylimidazole redox catalysts was achieved by linkage of the ortho-carbons of the aromatics positioned at C-4 and C-5 (see Fig. 8).151 The resulting fused framework 61b exhibits an enhanced influence of the substituents on the oxidation potential, which was demonstrated with a Hammett treatment of a set of derivatives. Moreover, this modification leads to improved stability of the corresponding radical cation. As was the case for 61a, a linear correlation of the computed ionization potentials with the experimental oxidation potentials was observed for the phenanthroimidazoles 61b. Moreover, high catalytic activity was found

for the electrooxidative conversion of benzyl alcohols and benzyl ethers. An indirect electrochemical method for the cross-coupling of phenols with arenes has been reported by Waldvogel and co-workers (see Scheme 39).152,153 It was shown that a variety of unsymmetrical biaryls AB could be constructed when a phenolic substrate A is subjected to electrolysis in the presence of excess arene B and water or methanol (typically 9–18% by volume), using a boron-doped diamond electrode (BDD). A solution of methyl triethylammonium methylsulfate (MTES) in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) served as electrolyte. The product ratio AB : BB can be adjusted by variation of the ratio between starting material A and B as well as by varying the amount of added methanol or H2O. Under optimal conditions, selectivities of >100 : 1 can be obtained with good yields. Electrolytes based on fluorinated alcohols such as HFIP turned out to be crucial to attaining selectivity in the cross-coupling. Since neither metal catalysts nor leaving groups are required and since the fluorinated solvent and excess amounts of starting material can be recovered by simple short-path distillation, this C,C-coupling method is particularly eco-friendly. Moreover, the reactions can be carried out under simple galvanostatic conditions in an undivided cell. A mechanism that explains the observations was proposed (see Scheme 40). Thus, in the presence of anodically generated oxyl radicals, RO , the phenolic substrates undergo H-radical abstraction. The resulting phenoxyl radicals are trapped by electron-rich arenes B and the resulting tautomers undergo further oxidation to give the final cross-coupling product. Fluorinated alcohols, which are known to have a stabilizing effect on radical species, are necessary to prolong the lifetime of the oxyl radicals and to avoid undesired side reactions. Notably substrate A and B exhibit very similar oxidation potentials and therefore, electrolysis in absence of methanol or water renders the expected statistical product mixture. 5.2

Fig. 8 The triarylimidazole (left) and the phenanthroimidazole (right) frameworks as redox mediators developed by Little et al.

Chem. Soc. Rev.

Indirect electrochemical cross-coupling of phenols and arenes.

Cathodic reduction

In contrast to mediated electrooxidation reactions, the progress in the field of indirect reductions have slowed during the last two decades. Apart from the rapidly growing number of studies on indirect CO2 reduction (see reviews 24–27), recent progress in indirect electroreductive chemistry appears to be restricted to the use of transition metal salen complexes, fullerenes and carboranes (see paragraphs 5.2.1 and 5.2.2). However, in the older literature numerous indirect reductions using other transition


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Fig. 9

Scheme 40 Proposed mechanism for the phenol arene cross-coupling reaction depicted in Scheme 39.

metal complexes, low-valent metal salts and aromatic hydrocarbons are reported (see Table 3). Interested readers are referred once again to Steckhan’s reviews (ref. 13 and 14). 5.2.1 New applications involving Ni- and Co-salen mediators. Transition metal complexes have long been known to be suitable redox catalysts for electroreductions. One significant attribute is that one can tune their redox potentials and selectivity by altering the ligand, the metal, or both. Most frequently, Ni(0)-, Ni(I)-, Co(I)-, Rh(I)-, Pd(0)-, Sn(0)-complexes have been used as cathodically generated active forms in reductive dehalogenations of organic compounds. Typically, the active forms of such complexes undergo an initial oxidative addition with alkylating reagents followed by a cathodically induced reductive elimination of the thus formed alkyl complex. Synthetically useful applications of this reactivity include the coupling of alkylhalogenides to olefins and alkynes, homocoupling of aryl- and allylhalogenides and the alkylation of Michael acceptors. A good overview of the older literature is provided in Steckhan’s reviews.13,14 In the last two decades, much effort has been devoted to understanding the mechanisms of reactions involving electrogenerated Ni(I)- and Co(I)-salen or -tetramethylcyclam (tmc) species (see Fig. 9) and to develop new synthetically useful applications.79,154–157 In this context, the electrochemical reduction of environmentally detrimental CFC’s (chlorofluorocarbons) is worth mentioning, since degradation can potentially yield less


Ni and Co catalysts for electroreductive applications.

deleterious or even commercially viable products. Peters et al. studied the electroreductive conversion in the presence of Ni(I)salen complexes and found that partial dehalogenation can take place under very mild conditions.81,82 Moreover, Co(II)salen was found to be a suitable redox catalyst for the reductive degradation of highly chlorinated pesticides such as hexachlorobenzene and DDT.83,158 The electroreductive (ERC) and electrohydrocyclization (EHC) reactions have received considerable attention by both the mechanistic and synthetic communities.159,160 In the absence of a mediator, each transformation begins with the reduction of an electron deficient alkene. In the case of the ERC reaction, intramolecular cyclization occurs onto a pendant carbonyl unit, while the EHC reaction features closure onto a pendant electron deficient alkene (see Scheme 41). With an appropriate choice of mediator, both transformations can be carried out indirectly, as depicted in Scheme 42 for ERC substrate 62 and EHC substrate 63.80 It was found by Little and co-workers that nickel, but not cobalt salen is effective in catalyzing both processes. The reason for the differing behavior is easy to understand when one compares the reduction potentials Ered for the substrate 62 (2.7 V vs. Ag/0.01 M AgNO3) with that of nickel salen (2.1 V) and cobalt salen (1.6 V). For this chemistry, the >1 V potential difference between the substrate and cobalt salen is simply too large for an efficient electron transfer equilibrium to be established, and the starting material is recovered unchanged. The reactions are carried out in presence of a mild acid such as dimethyl malonate to ensure protonation of the intermediates.

Scheme 41 Principle of the electroreductive (ERC) and the electrohydrocyclization (EHC) reaction.

Scheme 42

Indirect ERC and EHC reaction using a Ni(II)salen catalyst.

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Scheme 43 Inner sphere ET step between substrate and Ni catalyst for the reaction depicted in Scheme 42.

Mechanistic studies revealed that electron transfer occurs via an inner sphere mechanism involving an initial ligandcentered Michael addition of the salen radical anion onto the substrate leading to intermediate adduct 64 (see Scheme 43). Subsequent release leads to the substrate radical anion and regenerates the mediator. In accord with this mechanistic hypothesis, a modified Ni(salen) species equipped with a methyl group on each imino C-atom (65, see Fig. 10) did not lead to the cyclization of structures 62 and 63. Instead, the sterically hindered radical anion behaved as a base rather than a nucleophile. Peters et al. used this observation to their advantage for the reductive dehalogenation of alkyl halides. Thus, the catalytic performance of mediator 65 was significantly enhanced relative to nickel(salen) itself.161,162 This stems from the fact that alkylation of the salen ligand at the imino position is a typical side reaction of such transformations, a process that can be efficiently suppressed with sterically demanding moieties. Radical cyclization of unsaturated alkylhalogenides constitutes one of the key-methodologies for the preparation of natural products containing heterocyclic rings. Traditionally they are accomplished with toxic tri-n-butyltin hydride in the presence of a radical initiator such as azobisisobutyronitrile (AIBN). An interesting alternative uses electrogenerated nickel(I) complexes as mediators. Peters and co-workers, successfully applied this idea to the reaction of bromo propargyloxy ester 66 using [Ni(tmc)]Br2 as catalyst, leading to cyclization products 67 and 68 (Scheme 44).78 The product distribution strongly depends upon the acidity of the medium. Under aprotic conditions, the formation of 67 is favored, whereas in presence of HFIP (1,1,1,3,3,3-hexafluoroisopropanol) as a proton donor, adduct 68 is formed quantitatively. Based on the product distribution, the Faradaic yields and cyclic voltammetry data a mechanism was proposed (see Scheme 45) wherein cathodically generated [Ni(tmc)]+ transfers an electron to 66, leading to a cleavage of the C–Br bond in the

Fig. 10 Modified Ni(salen) catalyst for the reductive dehalogenation of alkyl halides.

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Scheme 44 Ni(II)tmc.

Radical cyclization of unsaturated alkylhalogenides using

Scheme 45 Proposed Scheme 44.

mechanism

for

the

reaction

depicted

in

rate-determining step. The resulting radical undergoes rapid intramolecular cyclization, followed by hydrogen atom abstraction from the solvent DMF to afford 67 which ultimately equilibrates to form the more stable a,b-unsaturated product 68. 5.2.2 Fullerenes and carboranes as redox catalysts. The C60 fullerene has been studied as a redox mediator by Fuchigami and co-workers.77 In an electrolyte consisting of PhCN and Bu4NClO4 it exhibits three reversible reduction waves between 0 and 2 V vs. SCE, which correspond to the C60/C60, C60/C602 and C602/C603 redox couples. With redox potentials (Eo) of about 0.5, 0.9 and 1.4 V vs. SCE, a range of nearly one volt can be covered with a single compound. Therefore, C60 represents a versatile mediating system since the reducing power can be controlled without any modification of the parent structure. This property is impressively illustrated by the chemistry depicted in Scheme 46.77 Since the vic-dibromides 69 are reduced at different potentials depending upon the nature of R1 and R2, it is possible to choose amongst the fullerene redox couples the one that matches the requirements of the substrate. Thus, 69b and 69c can be reduced by the C60/C602


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In the presence of 1,2-dibromo-1,2-diphenylethane, a significant catalytic current can be observed at the more negative reduction peak. The preparative scale reduction of the dibromide 69a was conducted under potentiostatic conditions in a divided cell (note Scheme 46). Remarkably, trans-stilbene was obtained in 95% yield using only 1 mol% of mediator 71a. The product can be separated from the electrolyte by simple extraction with hexane. Since mediator 71a is extracted with the product, 71b was developed (see Fig. 11, right) in order to immobilize the mediator in the polar layer. The electrolyte containing 71b could therefore be reused several times without significant deterioration of the product yield. 5.3

Scheme 46 Reductive dehalogenation of vic-dibromides using C60 fullerene as mediator.

couple at a potential between 0.8 and 0.9 V vs. SCE, while the C602/C603 couple can be used to convert 69a to the trans disubstituted product 70 (electrolysis potential: 1.3 V). Similar to C60, icosahedral o-carborane (C2B10H12) derivatives are also useful redox mediators. Their electron transfer behavior was studied using cyclic voltammetry and macro-scale electrolysis.76 Between 0 and 2 V vs. SCE, 1,2-diphenyl-o-carborane (71a, see Fig. 11, left) exhibits two reversible reduction waves centered near 1.1 and 1.3 V (measured in 0.1 M Bu4NClO4/ DMF electrolyte). These two redox couples correspond to Med/ Med and Med /Med2. Although the reduction potential range is smaller for o-carboranes than C60, their voltammetric behavior means that the reducing power can be adjusted without changing the structure. Using DFT calculations it was demonstrated that the LUMO of the neutral form of 71 is located on the aryl moieties, whereas the SOMO of the anion and the HOMO of the dianion are mainly located within the icosahedral unit. This suggests that the electron is transferred to the aryl rings and that after reduction of the aryl moiety the negative charge is stabilized in the boron cluster.

Fig. 11 o-Carborane mediators developed by Fuchigami et al.


Mediator-modified electrodes

A promising approach to improving the efficiency of indirect electrolysis is to modify an electrode surface by attaching catalytically active species to it. The main advantage of this method is that the mediator does not have to be separated from the reaction mixture after the desired conversion has been completed. Several criteria must be fulfilled in order to render this approach useful. On the one hand, the mediator redox couple must be highly reversible in order to allow for the multiple use of the electrode. The attachment of organic mediators might be problematic in this context. Additionally, the catalyst turnover number must be high since the amount of material that can be attached to the electrode surface is limited. Therefore, electrode materials with high surface area are usually employed. Moreover, one must be cognizant of the fact that the surface bound catalysts might behave differently than the same mediator in solution. In fact, even totally different selectivity can be obtained. A TEMPO-modified graphite felt electrode was developed by Osa and co-workers (see Fig. 12).163 The modification begins when a carbon felt is dipped into a methanolic poly(acrylic acid) (PAA) solution and dried. The PAA coating is then allowed to react with 4-amino-TEMPO using N,N 0 -dicyclohexylcarbodiimide

Fig. 12

TEMPO-modified graphite felt electrode.

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(DCC). Cross-linking is then achieved via amide formation using a,o-diamines in the presence of DCC. The remaining carboxylic acid groups are capped using diazomethane or dialkyl sulfates since the presence of free acid would catalyze the degradation of TEMPO. By varying the length of the alkyl connector chains, the lipophilicity of the electrode surface can be adapted to meet the needs of the substrate. Multiple electrocatalytic conversions using this TEMPOmodified electrode were conducted, including the oxidation of alcohols, and the oxidative coupling of monothiols to disulfides.163–166 The electrode was reported to be reusable, although a slow irreversible degradation was observed over time, presumably due to partial reduction of the N-oxyl unit to the amine during the reaction. Nevertheless, the functionality can be fully restored by immersion of the deactivated electrode in a solution containing MCPBA. A prominent and well-established example of a useful surface modification is found in the chemistry of the Ni(OH)2 electrode.167,168 Among other uses, it has been successfully ¨fer and co-workers for the preparativeemployed by Scha scale oxidation of alcohols in aqueous alkaline media (see Scheme 47).169–172 To prepare the Ni(OH)2 electrode, a Ni plate is activated by electrodeposition of a thin Ni(OH)2 film from an aqueous basic Ni(II) salt solution. A black layer of Ni(III)oxide hydroxide is continuously electrogenerated on this film during the electrolysis (see Scheme 48).167,168 In the presence of an alcohol substrate, this catalytically active film induces hydrogen atom abstraction, which represents the rate determining step in the oxidation process. The resulting a-hydroxyl radical is then readily oxidized to the corresponding carboxylic acid in the case of aldehydes or to the ketone in the case of secondary alcohols.172 Since the formation of the NiOOH film occurs at 0.6 V vs. SCE and the reaction follows an inner-sphere mechanism, the electrolysis can be conducted at the potential of the film formation. Functional groups such as ester, alkyne and some more easily oxidized electron-rich aromatic rings (i.e. furans) are tolerated under these conditions. The scope of this method includes the oxidation of primary and secondary aliphatic and benzylic alcohols, chemoselective

Scheme 47

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oxidation of hydroxysteroids and partially protected carbohydrates as well as oxidative cleavage of vicinal diols.169–172 5.4

Solid supported redox catalysts

The use of solid supported mediators provides an interesting and useful alternative to surface-modified electrodes. Usually, the redox catalyst is attached to particles of the supporting material and then dispersed in the electrolyte solution. The obvious advantage of this approach is the easy separation process that can be achieved after the conversion has been completed, since the mediator can be simply filtered off, washed and reused multiple times. A system based on cross-linked poly-4-vinylpyridine was developed by Yoshida, Kawabata, and co-workers. After activation in aqueous hydrobromic acid, the polymer can be employed in a galvanostatic electrolysis for mediation of the oxidation of alcohols to ketones (Scheme 49).173 Anodically generated hypobromite serves as the active species in the process. Notably, the electrolysis can be conducted in a mixture of water and acetonitrile without the addition of a supporting electrolyte. This method was also applied to the electrochemical epoxidation of alkenes, the anodic conversion of sulfides to sulfoxides, and the side-chain oxidation of alkylarenes.174–176 Tanaka et al. prepared an easily recyclable redox catalyst based on N-oxyl immobilized silica by the conversion of 4amino substituted TEMPO with isocyanate 72 to urea compound 73 and subsequent addition of silica gel (Scheme 50).177 The resulting catalyst 74 proved to be useful for the oxidation of various benzylic and aliphatic alcohols as well as for the oxidative cleavage of vicinal diols. To achieve oxidation, the alcohol is first adsorbed on the modified silica (74) and the solid is then dispersed in an aqueous NaOCl solution. Notably, the reaction proceeds in the absence of any bromide salts, base or co-solvent. After filtration and washing the solid phase with acetone, the product is obtained and the solid supported catalyst can be reused at least ten times without any significant deterioration of the product yield. In a similar fashion, the conversion was realized

Anodic oxidation of alcohols using the Ni(OH)2 electrode.

Scheme 48 Mechanism for alcohol oxidations using the Ni(OH)2 electrode.

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Scheme 49 catalyst.

Cross-linked poly-4-vinylpyridine as a solid supported redox


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Scheme 52 Anomeric glycoside fluorination using polystyrene-supported iodobenzene (PSIB).

Scheme 50

Synthesis of silica supported TEMPO mediator 74.

Scheme 51 Using TEMPO immobilized silica gel in a flow system.

with a flow system as depicted in Scheme 51. The in situ regeneration of catalytically employed NaOCl has not been reported in this context; therefore this example has to be considered as an ex-cell process. However, more recently it was demonstrated that in a buffer solution containing bromide salt, a dispersion of the catalyst 74 can be employed for the in-cell electrooxidation of alcohols.178 Moreover, several polymers were modified with TEMPO units, including poly(ethylene-co-acrylic acid), poly( p-phenylene benzobisthiazole) and polyethylene, which was functionalized with fuming HNO3 prior to N-oxyl immobilization.178–180 Similar to the modified silica gel, the N-oxylimmobilized polymer particles have been successfully used to achieve the indirect electrochemical oxidation of alcohols using dispersed systems in aqueous NaBr/NaHCO3. Another way to facilitate product separation and to improve reusability of the mediator utilizes polystyrene-supported iodobenzene (PSIB).68 PSIB can be prepared in one step by treatment of polystyrene with iodine and diiodo pentoxide in nitrobenzene/carbon tetrachloride/H2SO4. As was the case for the iodobenzene mediators described in Section 5.1.2, it can be employed in indirect anodic fluorinations using NEt3nHF


Scheme 53

Fluorination of ethylene carbonate mediated by PSIB.

ionic liquids. However, since the two-phase electron transfer between anode and the suspended PSIB is inhibited, the addition of a co-mediator is necessary in order to facilitate the fluorination reaction. In this context, the use of Et4NCl proved to be beneficial; in situ generated ‘‘Cl+’’ serves as the co-oxidant. Whereas in absence of either PSIB mediator or Et4NCl only very low product yields can be obtained, the presence of both species leads to satisfactory results. Presumably, [(chloro)(fluoro)iodo]benzene moieties represent the active species in the catalytic cycle. Previous studies suggest that this species serves merely to oxidize the substrate and that the NEt3nHF ionic liquid is the actual fluoride source.69 The double-mediatory approach could successfully be applied to the gem-difluorination of dithioacetals (analogously to Scheme 11), the anomeric fluorination of glycosides (see Scheme 52) and the fluorination of ethylene carbonate (Scheme 53). After completion of the electrolysis, the polymer can be filtered off, washed and reused – after 10 cycles, no significant deterioration of the catalytic performance was found. An even more intriguing approach combines the mediator and supporting electrolyte into a redox active polyelectrolyte system. Steckhan et al. realized this idea by copolymerization of trifluoromethylvinyl modified triarylamines with 4-vinylpyridine to give 75, followed by quaternization of the pyridine subunits with methyl iodide to form 76 and subsequent anion exchange by hexafluorophosphate (Scheme 54).181 The process leads to polymer backbone 77 with methylated pyridinium cations and hexafluorophosphate counterions; it exhibits good solubility in water and in many organic solvents, such as dichloromethane and acetonitrile. Cyclic voltammetry demonstrated a reversible redox process suggesting an efficient electron-hopping mechanism. The conductivity was reported to be high enough to allow for electrolysis in absence of additional supporting electrolyte. After electrolysis the polymer could be recovered by ultrafiltration using a polyamide membrane. These polyelectrolyte mediators were successfully applied to the preparative scale indirect oxidation of benzylic alcohols; good to excellent yields of the corresponding benzaldehydes

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Scheme 54

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Synthesis of the redox active polyelectrolyte system 77.

were obtained. However, the performance of polyelectrolyte 77 deteriorated after several runs, since the triarylamine subunits can be cleaved from the polymer backbone in the course of electrolysis. The authors concluded that the electron-withdrawing trifluoromethyl group was responsible for this instability and speculated that replacement by a methyl group might help to stabilize the triarylamine subunits in order to improve reusability.

6. Concluding remarks The steadily increasing number of examples of redox catalysis demonstrates that the principle finds wide application in organic electrosynthesis and related fields. This is mainly due to the fact that mediated processes frequently afford higher and/or different selectivity than a direct process. In addition, electrode reactions are accelerated and the overall energy consumption reduced, while reagent waste and difficult separation procedures can be avoided. Redox catalysis provides a useful alternative when electrode passivation or over-reaction poses a problem in reaction control. Many of the redox catalysts described in this manuscript are increasingly finding application in other fields such as in battery research, optoelectronics, and photoelectron transfer processes.28–33 Much progress has been made since Steckhan’s reviews appeared in 1986 and 1987. Although organic ions or radical ions were originally considered to be too unstable to establish efficient catalytic cycles, metal-free mediators like triarylamines and TEMPO have in fact become the most frequently used redox catalysts. Their evolution has led to new applications including the total synthesis of natural products. New concepts like solid supported mediators, ion-tagging and biphasic electrolytes have been developed in order to improve the efficiency of indirect processes and simplify product isolation. Computational methods can now be routinely used to assist in tailoring the properties of redox catalysts to meet specific purposes. While many new catalysts and applications have been developed in the field of anodic oxidation, the progress in indirect electroreduction has slowed. This means, of course that there are many unexplored territories and opportunities in the field of reductive mediation. The design of new metal-free reductive

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redox catalysts and the discovery of creative and useful applications remain a challenge. A further very promising approach is the combination of photoredox chemistry with indirect electrolysis. The idea of integrating an electrochemical step into a photocatalytic cycle has been realized only a few times and the potential of this powerful combination is therefore far from being exhausted. Moreover, stereoselective mediation as depicted in Scheme 18 is another area that has rarely been explored and that deserves more attention. Clearly, the field of mediated electron transfer constitutes a fertile arena in which to conduct research. We have no doubt that many important and exciting developments will be forthcoming in the future.

List of abbreviations ET C.C.E. C.P.E. NHE SCE Eox, Ered Eo E1/2 Eoabs IP EA R2 TEMPO PIFA DDQ PTFE AIBN PSIB

Electron transfer Constant current electrolysis Controlled potential electrolysis Normal hydrogen electrode Saturated calomel electrode Peak potentials for oxidation and reduction Standard potential Half-wave potential Absolute standard potential Ionization potential Electron affinity Coefficient of determination 2,2,6,6-Tetramethylpiperidine-1-oxyl Phenyliodine bis(trifluoroacetate) 2,3-Dichloro-5,6-dicyano-1,4-benzoquinone Poly(tetrafluoroethylene) Azobisisobutyronitrile Polymer-supported iodobenzene

Acknowledgements R. F. is particularly grateful to the Alexander von Humboldt Foundation for granting a Feodor Lynen Fellowship. The authors acknowledge partial support of their research efforts from the Center for the Sustainable Use of Renewable


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Feedstocks (CenSURF), an NSF Center for Chemical Innovation (CHE-1240194).


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