Advances on the Merger of Electrochemistry and Transition Metal Catalysis for Organic Synthesis

Abstract

Synthetic organic electrosynthesis has grown in the past few decades by achieving many valuable transformations for synthetic chemists. Although electrocatalysis has been popular for improving selectivity and efficiency in a wide variety of energy-related applications, in the last two decades, there has been much interest in electrocatalysis to develop conceptually novel transformations, selective functionalization, and sustainable reactions. This review discusses recent advances in the combination of electrochemistry and homogeneous transition-metal catalysis for organic synthesis. The enabling transformations, synthetic applications, and mechanistic studies are presented alongside advantages as well as future directions to address the challenges of metal-catalyzed electrosynthesis.

Graphical Abstract

1. INTRODUCTION

Electroorganic synthesis has become an established and environmentally friendly alternative to classical organic synthesis for the functionalization of organic compounds because dangerous and toxic redox reagents are replaced by an electric current.^1–3 The electrochemical step constitutes a key process for the in situ generation of reactive intermediates, allowing reactions to be carried out in mild conditions. Moreover, electrosynthesis in the presence of redox mediators provides several advantages.⁴ For example, reactions can be performed under lower potentials that lead to fewer side reactions, novel, and sustainable transformations can be discovered, and reaction selectivities can be fine-tuned. Therefore, organic electrochemistry provides interesting and useful alternatives to conventional synthetic methods and constitutes a valuable tool for the organic chemist.

1.1. Electrosynthesis: Direct and Mediated Electrosynthesis

Electrosynthesis involves the electron transfer between an electrode and a molecule (substrate or mediator) followed by a chemical reaction to achieve the desired organic transformation. The reaction can be performed via direct or mediated (indirect) electrolysis. Direct electrolysis involves a heterogeneous electron-transfer between an electrode and a substrate of interest to generate a reactive intermediate. This is then followed by a chemical reaction with another molecule or functional group to obtain the desired product. Figure 1A is an example of a Shono oxidation of amines via direct electrolysis.^5,6 An amine (or amide) substrate is anodically oxidized to the iminium intermediate, which then undergoes nucleophilic addition with nucleophiles (e.g., alcohols) to generate the functionalized product.

Figure 1.

Direct (A) and indirect (mediated) (B) electrosynthesis in the context of anodic oxidation reactions.

In mediated (or indirect) electrosynthesis, a redox mediator (stoichiometric or catalytic) with a lower redox potential than the substrates undergo electron-transfer at the electrode to afford an electrochemically generated reagent that triggers the rection of interest (Figure 1B).⁴ During the last four decades, commonly employed organic redox mediators for anodic oxidations are triarylamines and nitroxyl radicals. Major advantages of redox-mediated electrolysis include: (a) to avoid problems associated with heterogeneous electron transfer, such as overpotentials, (b) electrolysis can be conducted at lower potentials than the redox potential of the substrate, (c) accelerate the reaction rate, and (d) achieve higher selectivities by circumventing potential side reactions.⁴ In most cases, when the mediator is a transition-metal (molecular electrocatalyst), they are used in catalytic amounts and many advances in this area have been developed in the last two decades. By definition, redox mediation implies a homogeneous outer-sphere electron transfer reactivity between the reduced or oxidized mediator and the substrate and this process is not covered in this review. Molecular electrocatalysis implies a metal-mediated electron transfer to a substrate, and in most cases, the molecular metal catalyst is involved in the bond-breaking and bond-forming steps to generate the desired product.

1.2. Transition Metal Electrocatalysis

Transition metal (TM) catalysis has been well established in achieving many selective organic transformations. Transition metals have a very rich reactivity, with many functional groups in organic molecules.⁷ In most cases, their reactivities are mechanistically understood and can be predicted. With the fast-growing advancements in catalyst and ligand design, many highly selective and challenging bond-breaking and bondforming steps can now be achieved. The utility of transition metals as catalytic mediators (TM-electrocatalysts) in electrosynthesis offers an important advantage in achieving high selectivity in substrate activation, functional group incorporation, bond-forming steps, and in achieving asymmetric reactions. In addition, electrochemistry offers additional advantages to this integration. For example, the presence of both cathodic reduction and anodic oxidation happening in an undivided cell, allows the access and control of the necessary oxidation states of the TM in each elementary step in a catalytic cycle.

Figure 2 shows the mechanism of the well-established Pd or Ni-catalyzed Buchwald–Hartwig amination^8,9 and a recently developed Ni-electrocatalyzed amination reaction of aryl halides.^10,11 In a Buchwald–Hartwig type amination, a Pd(0) or Ni(0) source (or chemically generated from stable M(II) precursors) undergoes oxidative addition to aryl halides to generate an aryl-M(II) intermediate. A base-mediated amine incorporation then generates the aryl-M(II)-amido complex. Reductive elimination, usually driven by the catalyst (bearing select phosphine ligands) or elevated temperature generates the aryl amine product and regeneration of M(0) active catalyst. In the Ni-catalyzed electrochemical amination, cathodic reduction of Ni(II) precatalyst to Ni(I) is followed by oxidative addition to aryl halides to generate aryl-Ni(III) intermediates. These intermediates are susceptible to another cathodic reduction to generate a more stable aryl-Ni(II) intermediate that can undergo a base-promoted incorporation of amine. An anodic oxidation of the aryl-Ni(II)-amine complex generates the reactive aryl-Ni(III)-amine intermediate that can readily undergo reductive elimination at room temperature. Recent mechanistic studies using voltammetric studies show the viability of a sequential two-electron reduction of Ni(II) to Ni(I) and Ni(0), thus, providing the possibility of aryl halide activation via oxidative addition of Ni(I) or Ni(0).¹²

Figure 2.

Pd (A) or Ni (B) catalyzed (nonelectrochemical and electrochemical) amination of aryl halides for the synthesis of aryl amines.

The ability of metal-catalyzed electrosynthesis in controlling redox states of the catalyst allows the transformation to preclude the use of highly air-sensitive M(0) catalysts and phosphine ligands as well as access to the desired Ni(III) intermediates. As such, the reactions can be performed at room temperature and in air. Importantly, the mechanistic implications can certainly be adopted in other challenging redox organic reactions.

1.3. Scope of This Review

Over the years, a variety of review articles have been published that summarize the impressive advances made in the field of organic electrochemistry. Pioneering reviews include those by Wawzonek and Weinberg in 1968.¹³ Anodic oxidation and/or cathodic reduction processes were reviewed by Shono⁶ and more recently by Boydston,¹⁴ Lei,¹⁵ Moeller,^3,16 Schafer,¹⁷ Wright,¹⁸ and Yoshida.¹⁹ Progress in mediated electrosynthesis was reviewed by Francke and Little,⁴ and more recently by Stahl²⁰ and Lin.²¹ The synthetic application in complex settings have been described recently by Baran.^1,22 Bioelectrosynthesis were reviewed by Freguia and Virdis,²³ and more recently by Zhu²⁴ and Minteer.^25,26 The utility of alternating current electrolysis in organic synthesis was described by Luo.²⁷ Electrosynthesis in flow chemistry was described by Atobe,²⁸ Noel,²⁹ and Pletcher.³⁰ More recently, functional group specific electrochemical transformations have also been reviewed, for instance, C–H functionalizations by Ackerman,³¹ Karkas,³² and Mei,³³ synthesis of heterocycles by Zeng³⁴ and Onomura,³⁵ fluorination of organic compounds by Fuchigami,³⁶ dehydrogenative biaryl synthesis by Waldvogel,³⁷ transformations involving N-centered radicals by Xu,³⁸ cationic intermediates by Yoshida,³⁹ carboxylic acids by Zhang⁴⁰ and Lam,⁴¹ and olefin and alkyne functionalization by Ahmed,^42,43 Sun and Han,⁴⁴ and Lin.^45,46

This review provides an overview of the recent developments on the integration of homogeneous transition-metal catalysis and electrochemistry for organic synthesis with an emphasis on reaction development and mechanistic insight. The use of electrochemical methods to elucidate elementary steps in organometallic compounds was reviewed by Jutand⁴⁷ in 2008 and are not covered in this review. The TM-electrocatalytic activation or reduction of small molecules (e.g., CO₂ reduction to CO, methane, light alkanes) are recently reviewed and were excluded in this overview as well, because they are focused on energy applications and not organic synthesis.⁴⁸

This review is organized based on the substrates being activated by the electrochemically generated TM electrocatalyst and their mechanistic feature. The majority of the reports in the past two decades focused on the functionalization of organohalides and pseudohalides, alkenes, carbon–hydrogen bonds, as well as functional group interconversions of alcohols (and deprotection of alcohols), organoboron, and organosilicon reagents. Within each topic, the review is organized based on the type of transformation (bond-forming step or product formed) or the metal catalyst involved. A set of graphical cell notations (Figure 3) were utilized to represent the electrochemical parameters of each reaction, including cell type (divided vs undivided), electrolytic conditions (constant current vs constant potential), and electrode compositions. This is meant to aid the reader to rapidly identify classes of reactions and setups without needing to refer to the text or the article. The aim of this review is to encourage researchers to explore and to adopt organic electrosynthesis, a technique with considerable potential, to the general synthetic organic toolbox.

Figure 3.

Cell notations used in this review. The following notations are used to easily differentiate the electrochemical conditions used (constant current vs constant potential electrolysis, the use of a divided vs undivided cell, and anodic oxidation vs cathodic reduction) in a given reaction scheme. A, constant current electrolysis; V, constant potential electrolysis; (+)X, anode material, (−)Y, cathode material.

2. ELECTROCATALYTIC REACTIONS OF ORGANOHALIDES

Organic halides are among the most sought substrates or electrophiles in metal-catalyzed reactions due to their commercial availability, stability, and low toxicity. Importantly, they have very rich and generally more understood reactivity with low valent transition metals.⁷ The activation of organohalides with chemically or electrochemically generated low valent metal catalysts typically undergoes via three major mechanistic pathways: (a) halogen abstraction to generate carbon-centered radical, (b) direct oxidative addition to generate organometallic intermediates, or via (c) two-step halogen abstraction and radical rebound mechanism. In all cases, organohalides are converted to reactive species, typically as organometallic intermediates that can undergo coupling reactions with various partners to achieve new functional groups.

2.1. Organohalide Activation, Protodehalogenations, and Dimerization

Among the earliest reports of metal-catalyzed electro-organic reactions (reported in 1970s) were protodehalogenation and dimerization of organohalides (Figure 4).^49–51 These reductive reactions are typically catalyzed by cobalt (e.g., vitamin B₁₂, cobalt-salen) to yield the reduced product or dimer. These early reports, however, were underutilized for organic synthesis, mainly due to the very poor selectivity in products (protodehalogenation vs dimerization and other byproducts). Nonetheless, they prompted the mechanistic studies done on organohalide activation with electrogenerated low-valent metals^52–54 that led to many electrochemical transformations of organohalides to generate various carbon–carbon and carbon–heteroatom bonds and are discussed throughout the rest of section 2. Protodehalogenation was found to be the major pathway when reactions were performed in ionic liquids, or when bidentate ligands such as bipyridines are used, or titanocene electrocatalysts were used. These strategies were utilized in several electrochemical reductive dehalogenations of halogenated pesticides.

Figure 4.

(A) Electrocatalytic protodehalogenation and dimerization of organohalides, and (B,C) generation of arylzinc reagents.

Recently, mechanistic studies by the groups of Minteer and Sigman, Toste and Chang, and Diao, using electrochemical methods and catalyst design has provided relevant mechanistic pathways and approaches to control selectivity in the activation of organohalides with cobalt catalysts.^{52,53,55–57} We expect that the fundamental mechanistic studies will soon be adapted in the context of selective electrocatalysis for organic synthesis.

2.2. Generation of Organozinc Reagents and Their Coupling Reactions

Gosmini and Perichon in 1990s to 2000s have reported highly efficient electrochemical generation of arylzinc reagents from aryl bromides and chlorides.^58–60 These reactions were realized using nickel and cobalt electrocatalysts with sacrificial Zn anode and a stoichiometric amount of zinc dihalides. Their preliminary reports using nickel/bipyridine as mediator required high excess of bipyridine ligands to stabilize the low valent nickel catalyst and restrict the formation of biaryls. Significant improvements in the reaction conditions were obtained using cobalt chloride and pyridine as the electrocatalyst. The scope and functional group tolerance of these reactions were comparable to those chemical methods of generating arylzinc reagents. Arylzinc reagents are very important carbon-based nucleophiles or coupling partners to obtain many functionalized aryl products. Gosmini and Perichon have reported the subsequent utility of the electrochemically generated arylzinc reagents in various functionalization and cross-coupling reactions to generate unsymmetrical biaryls, aryl iodides, and aryl ketones.

Notably, Huang recently reported a robust method for alkyl iodide allylation using electrocatalytic palladium in aqueous media (Figure 4C).⁶¹ Using Zn as a sacrificial anode, it was proposed that the reaction proceeds by the initial generation of organozinc reagents from allyl halides followed by Pd-catalyzed coupling. This report shows modest yields utilizing a ligand-free catalyst with a cocatalytic copper to chemoselectively synthesize an alkyl/allylic halide coupling product. This protocol is effective for coupling a large variety of alkyl halides, including activated and unactivated primary, secondary, and tertiary halides, without exclusion of air or moisture.

2.3. Addition of Organohalides to Alkenes and Alkynes

Foote and Imagawa reported electrocatalytic carbon–carbon bond-forming reactions by intramolecular coupling of primary alkyl bromides with enones via 1,4-addition (Figure 5A).⁶² Cobalt electrocatalysts (vitamin B₁₂ and derivatives) were utilized for the electroreductive coupling reaction to generate bicyclic ketones in good yields. This work prompted the development of various intermolecular conjugate addition reactions of organohalides.^63,64 Gosmini reported the Co/bypyridine conjugate addition of aryl bromides and iodides with terminal enones using iron as a sacrificial anode (Figure 5B).⁶⁵ Moderate yields of the addition products were obtained, and the reaction condition was compatible with various substituents on the aryl group. However, the present conditions was found challenging when aryl chloride was used the electrophile, with yields typically very low. Condon and Nedelec reported a Ni-catalyzed electrochemical arylation of enones (Figure 5C).⁶⁶ Moderate to good yields were obtained. The use of aryl chlorides as substrates was also found to be challenging, but improved yields were obtained when the reactions were performed at 100 °C instead of 70 °C. This method was also utilized toward arylation of acrolein diethyl acetals to access β-arylated aldehydes.

Figure 5.

Electrocatalytic addition of organohalides to (activated) alkenes and alkynes. Cyclic voltammograms in (D) is reproduced from ref 68. Copyright 2006 American Chemical Society.

The reductive intramolecular cyclization of organohalides with unactivated alkenes and alkynes was also reported. The coupling of aryl bromide with unactivated alkyne was reported by Peters and co-workers using Ni-electrocatalysis (Figure 5D).^67,68 Bulk electrolyses were performed at reticulated vitreous carbon cathodes using nickel(II)-salen as the electrocatalyst.⁶⁷ Good yields of cyclic alkenes were obtained, together with homocoupled byproducts. As shown in Figure 5D, cyclic voltammetry for the reduction of nickel(II)-salen in the presence of the substrate revealed that nickel(I)-salen catalytically reduces the organohalide at potentials more positive than those required for direct reduction.⁶⁸ During controlled-potential electrolysis of solutions containing nickelsalen and the substrate, catalytic reduction of the latter proceeds via one-electron cleavage of the carbon–halogen bond to form a radical intermediate that undergoes cyclization to afford the product. A tandem cyclization reaction of vinyl bromides with enones and unactivated alkenes was developed by Toyota and Ihara,⁶⁹ using nickel electrocatalysis to generate tricyclic ketones in good yields.

Budnikova reported electrochemical fluoroalkylation of alkenes utilizing platinum electrodes in the presence of pyridine-substituted nickel catalysts.⁷⁰ Modest yields were obtained for dimerization of alkenes and upon treatment with tributyltin hydride, a monomer product can be generated under the same conditions. Nedelec reported a Cu-catalyzed electrochemical coupling of activated olefins and α,α,α-trichloro or gem-dichloro compounds to form halogenated cyclopropanes.⁷¹ This reaction utilizes iron and nickel electrodes with copper bromide salt to generate a nucleophilic bimetallic copper–iron nucleophilic intermediate that can cyclize dichlorodiphenylmethane into an activated olefin. The reaction proceeds with low yields in direct electrolysis with an aluminum anode but with moderate yields through indirect electrolysis with an iron anode.

2.4. Addition of Organohalides to Carbonyls and Imines

The addition of organohalides to carbonyls or imines is a powerful reaction to forge new carbon–carbon bonds with the concomitant formation of alcohols or amines. Transition-metal electrocatalyzed methods for these transformations have been well reported. Hilt reported an In-electrocatalyzed allylation of aldehydes and ketones with allyl bromides to obtain alcohols (Figure 6A).⁷² This reaction was proposed to go through electrochemical reduction of In(III) to In(I) followed by activation of allyl bromide. A sacrificial anode such as aluminum was found to be critical for the reaction. The optimized conditions were also found applicable to the allylation of esters to generate bis-allylated alcohols as well as allylation of imines and aldimines to generate allylated amines (Figure 6B).⁷³ Electrochemical methods for allylation of carbonyls or imines mediated by Zn or Sn were also reported.^74,75 Electrochemical allylation of carbonyls using allyl acetates was reported by Durandetti using Fe(II)/bypridine as an electrocatalyst to obtain high yields of tertiary and secondary allyl alcohols (Figure 6C).⁷⁶ Electrochemical Reformatsky-type coupling of 2-halo-esters or nitriles to carbonyls were reported by Durandetti using Fe(II)/bipyridine as electrocatalysts (Figure 6D).⁷⁷ Ketones and aldehydes were also coupled with various alpha-halo esters and nitriles to generate β-hydroxy esters and nitriles in good yields.

Figure 6.

Electrocatalytic addition of organohalides to carbonyls and imines.

The Ni/Cr mediated addition of organohalides to carbonyls, also known as Nozaki–Hiyama–Kishi (NHK) coupling, is a highly interesting method for the construction of carbon–carbon bonds to form substituted alcohols. Nonelectrochemical approaches use a nickel catalyst and stoichiometric chromium salt as reductant. As shown in Figure 6F, the reaction is initiated by a chromium mediated reduction of Ni(II) to Ni(0) followed by oxidate addition to form organometallic Ni(II) intermediate. Transmetalation with Cr(III) generate the organometallic Cr(II) complex that reacts with aldehydes or ketones to for alcohol products. The incorporation of electrochemistry for NHK method will allow the anodic reduction of Cr(III) to regenerate the Cr(II) reductant.

The electrocatalytic Nozaki–Hiyama–Kishi (e-NHK) coupling using Ni(II)/bipyridine as an electrocatalyst and catalytic chromium to generate benzylic alcohols was reported by Durandetti (Figure 6E).^78,79 Under similar conditions, the addition of various organo(pseudo)halides (vinyl halides, allyl acetates, and 2-chloroesters) to aldehydes was also found effective. A highly general and practical electrocatalytic Nozaki–Hiyama–Kishi (e-NHK) coupling was recently reported through a collaborative effort from Baran, Blackmond, and Reisman groups (Figure 6F).⁸⁰ Inspired by early proof-of concept work by Grigg,⁸¹ Tanaka,⁸² and Durandetti,^78,79 a careful choice of ligand, Cr, and Ni sources and optimization of electrochemical parameters allows one to avoid the use of superstoichiometric metallic reducing agents and dramatically expand the scope of those original reports. Application to Kishi’s asymmetric variant as well as multiple realistic substrate classes is also demonstrated. The e-NHK can even enable noncanonical substrate classes, such as redox-active esters, to participate with low loadings of Cr when conventional chemical techniques fail. A combination of detailed kinetics, cyclic voltammetry, and in situ UV–vis spectroelectrochemistry of these processes illuminates the subtle features of this mechanistically intricate process. Specifically, electroanalytical studies illustrate the following: (1) the thermodynamic and kinetic redox properties of the Cr(III) are significantly different in the presence of Ni(II), (2) the e-NHK electron transfer processes likely proceed first by electrochemically reversible cathodic electron transfer to Cr(III) followed by electrochemically irreversible electron transfer from Cr(II) to the Ni(II) catalyst, (3) a Cr(III) species persists throughout the duration of the e-NHK, which could correspond to a putative resting state preceding rate-determining electron transfer observed under bulk electrolysis conditions, and (4) there does not appear to be an appreciable buildup of Cr(II) or low-valent Ni species by UV–vis spectroscopy during active electrocatalysis. The e-NHK can even enable noncanonical substrate classes, such as redox-active esters, to participate with low loadings of Cr when conventional chemical techniques fail.

2.5. Carboxylation of Organohalides with CO₂

The direct coupling of organohalides with CO₂ represents a powerful approach toward the synthesis of valuable carboxylic acid products. A large amount of work has been done on CO₂ utilization because of the ubiquity and high potential of CO₂ as C1 building block in organic synthesis. The majority of the work done on the carboxylation of organohalides goes through an initial generation of reactive organometallic intermediates such as organomagnesium and lithium reagents. More recently, Pd(0) and Ni(0) catalyzed carboxylation reactions were reported in high efficiencies.⁸³ Various types of organohalides and alcohol-based pseudohalides have been used as substrates in catalytic carboxylation reactions. As depicted in Figure 7A, a general mechanism using Ni catalysis showed several reduction processes were necessary in order to achieve organohalide activation, CO₂ insertion, and regeneration of the catalyst.⁸³ As such, the use of electrochemistry to facilitate carboxylation reactions provides new platforms to enable more selective transformations and enable the use of more sustainable transition metals.

Figure 7.

(A) General scheme and proposed mechanism for the metal-catalyzed carboxylation of organohalides with CO₂. (B–D) Examples of electrocatalytic carboxylation of organohalides to generate carboxylic acids.

The electrochemical and metal-catalyzed carboxylation of organohalides have also been reported using cobalt and nickel electrocatalysts.⁸⁴ The direct reduction of CO₂ occurs at rather very negative potentials (more negative than −2.0 V vs SCE in most solvents). Depending on the experimental conditions, reduction of CO₂ results in the formation of a mixture of products, including oxalate, formate, carbon monoxide, and others. As such, the search for electrocatalysts able to decrease the relatively high overpotential and to increase the selectivity of the reductive process has become an important challenge. Initial reports of metal-catalyzed electrochemical carboxylation of aryl halides were disclosed by Perichon, Jutand, Amatore, and co-workers in the 1980s using Ni, Pd, and Co catalysts.^85,86 Amatore and Jutand reported a detailed study on Ni(II)(dppe)Cl₂ electrocatalyzed carboxylation of bromobenzene in 1991 (Figure 7B). This reductive potentiostatic carboxylation at −2.0 V (vs SCE) resulted in a high yield of benzoic acid and a trace amount of biphenyl byproduct. Mechanistic studies implicate initial cathodic reduction of Ni(II) to Ni(0) followed by two-electron oxidative addition to bromobenzene to generate PhNi(II)(dppe)Br intermediate. It was also proposed that CO₂ insertion happens after one-electron reduction of the organometallic intermediate to PhNi(II) species. While this is an important early report in this area, its synthetic utility is limited by the use of mercury pool working electrode and HMPA as a cosolvent.

Asymmetric carboxylation of 2-chloroethylbenzene was reported by Wang and Lu using chiral cobalt-salen electrocatalysts (Figure 7C).⁸⁷ Enantioselectivities up to 83% were obtained; however, the reaction gave rather low yields and required high catalyst loading (38% yield using 30% catalyst loading). The major product in this reaction was found to be the dimerized benzyl chloride and was found as a major challenge in earlier reports on cobalt-catalyzed carboxylation of benzyl halides. The development of electrocatalysts capable of selective and asymmetric carboxylation of organohalides remains to be a challenge in this area, as well as in general metal-catalyzed carboxylation of organohalides. Electrocatalytic carboxylations of organo pseudohalides were also reported. Dunach reported a Ni-catalyzed electrochemical carboxylation of allylic acetates.⁸⁸ Fujihara and Tsuji reported a Ni or Co electrocatalyzed carboxylation of aryl/alkenyl triflates and propargyl acetates in good yields.^89,90

The groups of Mei⁹¹ and Ackerman⁹² have developed electrocatalytic carboxylation reactions of allylic esters and halides using Pd and Co electrocatalysts, respectively. Using cobalt and phosphine ligands, Ackerman showed the conversion of allylic chlorides to linear and branched allylic carboxylic acids in good yield under atmospheric CO₂ (Figure 7D). This reaction was performed under constant current electrolysis and required the use of Mg as a sacrificial anode.

2.6. Cross-electrophile Couplings of Organohalides

Cross-electrophile coupling of two different organohalides (or pseudohalides) is an interesting strategy to obtain various sp²–sp² and sp²–sp³ carbon–carbon bonds from readily available materials.^93,94 Two central challenges of cross-electrophile couplings include the carefully chosen scope of electrophiles and cross-selectivity. Recent nonelectrochemical synthetic advances and mechanistic studies have shed light on possible methods for overcoming this challenge: (1) employing an excess of one reagent, (2) electronic differentiation of starting materials, and (3) catalyst–substrate steric matching.⁹⁴ As depicted in Figure 8A, the reaction mechanism and selectivity in electrophile activation rely on the oxidation number of transition metal to obtain reactivity and selectivity on substrate activation and product formation.^95,96 Importantly, the required reduction steps can be controlled using an appropriate oxidant. Electrocatalysis provides a unique opportunity to access the necessary oxidation states and reactivity and selectivity of the catalyst in cross-electrophile coupling. As such, electrocatalysis has been well adapted to provide selectivity and broaden the scope of cross-electrophile coupling.

Figure 8.

(A) Cross-electrophile coupling reaction of two organo(pseudo)halides and comparison of selectivity control and reduction approach using electrochemical and nonelectrochemical approaches. (B–D) Nickel and cobalt catalyzed electrochemical cross-electrophile couplings. Cyclic voltammograms in (B) are reproduced from ref 101. Copyright 2013 American Chemical Society.

Gosmini reported the cross-electrophile coupling of 2-halopyridine, 2-chloropyrimidine, 2-chloropyrazine, and 4-chloroquinolines with various functionalized aryl halides by using nickel/bipyridine to generate nitrogen-containing biaryls.^97–99 These reactions use nickel/bipyridine or cobalt electrocatalysts as well as sacrificial anodes (Mg, Zn, or Fe) to generate products in high yields and selectivities. Leonel and co-workers reported a nickel-catalyzed electrochemical arylation of 3-amino-6-chloropyridazines and chloropyrimidines with aryl halides using an iron/nickel as the sacrificial anode (Figure 8B).^100,101 Voltammetric studies show that an electrochemically generated Ni(I) complex activates the chloropyridazine substrate via an EC’-type mechanism.

Unsymmetrical biaryls via the coupling of two non-heteroatom-containing aryl halides (aryl bromide and aryl iodide) were also realized using cobalt catalysis under cathodic reduction (Figure 8C). This reaction is highly promising in the context of biaryl synthesis; however, achieving high product selectivity remains a great challenge due to the high propensity of homocoupling of the aryl iodide. With the proper selection of coupling partners and conditions, the formation of unsymmetrical biaryls can be obtained in good yields. Vinylation of aryl halides using vinyl acetates was also reported by Gosmini using cobalt electrocatalysis to generate functionalized styrenes.¹⁰²

Early reports on the electrochemical cross-electrophile coupling to generate sp²–sp³ carbon–carbon bonds were limited to activated alkyl halides. Sibille, Durandetti, and coworkers reported the coupling of aryl halides with various activated organohalides such as α-chloro esters and nitriles, as well as benzylic and allylic halides under nickel electrocatalysis.^103,104 An initial electrochemical reduction for Ni(II) to Ni(0) was proposed, followed by oxidative addition to the activated organohalide. These reactions necessitate the use of sacrificial anodes such as Fe, Zn, or Al. In some cases, the yields are improved by the slow addition of the more reactive organohalide.

Gosmini reported a cobalt-electrocatalyzed coupling of aryl halides with allylic acetates and carbonates to generate allylated arenes in good yields (Figure 8D).¹⁰² The use of pyridine as cosolvent was found to be critical to prevent catalyst decomposition.

Enantioselective electrocatalytic cross-electrophile couplings are highly desirable transformations in organic synthesis as they deliver chiral products from two abundant and stable organohalide starting materials. DeLano and Reisman reported one of the earliest examples of an enantioselective cross-electrophile coupling under electrocatalysis in 2019 (Figure 9A).¹⁰⁵ Alkenyl bromides were coupled with benzylic chlorides to generate chiral Csp²–Csp³ bonds in high yields and excellent enantioselectivities. Electrocatalysis was performed using RVC working electrodes and Zn as sacrificial anodes under constant current conditions. High enantioselectivities were obtained using the combination of catalytic NiCl₂ and chiral bis(oxazoline) ligand A as electrocatalysts. Various functionalities, including aryl methyl ethers, pyridines, free alcohols, and alkyl chlorides, were tolerated. More recently, Mei and co-workers described an electrocatalytic enantioselective homocoupling of aryl bromides to generate biaryl atropisomers (Figure 9B).¹⁰⁶ Chiral biaryls were generated in good yields and enantioselectivities using catalytic NiCl₂ and chiral pyrox ligand B under constant current electrolysis in an undivided cell. Reactions can be performed on gram scale to generate enantioenriched axially chiral biaryls. Moreover, the use of common metal reductants such as Mn or Zn powder resulted in significantly lower yields in the absence of electric current under otherwise identical conditions, underscoring the enhanced reactivity provided by the combination of transition metal catalysis and electrochemistry.

Figure 9.

Enantioselective electrocatalytic cross-electrophile couplings of organohalides.

The electrochemical cross-electrophile coupling of aryl halides with unactivated alkyl halides was found to be very challenging. This is mainly due to competing protodehalogenation of the aryl halides caused by the decomposition of arylmetal organometallic species from overpotential. The groups of Hansen and Weix developed a multiligand system for the nickel catalyzed electrochemical coupling of aryl bromides and alkyl bromides to generate sp³–sp² carbon–carbon bonds with great selectivity (Figure 10A).¹⁰⁷ This electrocatalytic process in an undivided cell provided products in moderate to good yields and was showcased via scale-up.

Figure 10.

Nickel catalyzed electrochemical cross-electrophile coupling of aryl and alkyl halides. (B,C) Use of shuttle molecules for overcharge protection in nickel catalyzed electrochemical cross-electrophile sp²–sp³ couplings. (A) Reproduced from ref 108. Copyright 2020 American Chemical Society.

Sevov recently reported an efficient nickel-catalyzed electrochemical coupling of aryl halides with various primary and secondary unactivated alkyl halides to generate sp³–sp² carbon–carbon bonds (Figure 10B).¹⁰⁸ The protodehalogenation of aryl halides was circumvented by the use of shuttle molecular electrocatalysts as overcharge protectors. This enabling strategy is inspired by the use of overcharge protection molecules in the energy storage industry. Various organic and metal complexes utilized in nonaqueous flow batteries were investigated because of their reversible reduction potentials and high persistence in all redox states. Furthermore, these shuttles were deliberately selected because their potentials bracket the key redox events of the coupling catalyst (red and blue markers). By using shuttle S4 (Figure 10C), high yields and selectivity of the desired product were observed.

2.7. Cross-coupling with Carbon-based Nucleophiles

The Heck reaction has been a well-utilized method for the coupling of organohalides with olefins to generate carbon– carbon bonds.¹⁰⁹ Figure 11A summarizes a general Heck coupling reaction and the proposed mechanism. While traditional Heck reactions utilize chemical reductants to generate the active M(0) catalyst, the use of electrochemistry provides electric charge as a benign reductant and could potentially broaden the reaction’s scope and functional group tolerance.

Figure 11.

(A) General metal-catalyzed Heck reactions and proposed mechanism. (B–D) Pd and Ni catalyzed electrochemical Heck and Suzuki cross-coupling reactions. Figures in (C) are reproduced from ref 112. Copyright 2010 American Chemical Society.

Moeller and co-workers developed Pd-catalyzed electrochemical Heck coupling reactions between aryl iodides and activated alkenes (Figure 11B).¹¹⁰ Their discovery resulted from their initial efforts in developing electrode chip-based Heck reactions. The developed methodology allows Heck reactions to occur at room temperatures and in the absence of ligand. Various aryl iodides were coupled with various activated terminal olefins to give substituted styrenes in good yields. This electrochemical transformation was further utilized in size-selective Pd-catalyzed reactions such as Suzuki and allylation reactions to functionalize a microelectrode array (Figure 11C).^111,112 Microelectrode arrays hold great promise, as analytical platforms for detecting ligand–receptor interactions in real-time. Suzuki reactions are faster than the Heck reactions and thus require more careful control of the reactions in order to maintain confinement.

Recently, Sevov developed a Heck coupling reaction of aryl halides and a broad range of alkenes that utilizes electrochemistry as a means to promote Ni-catalyzed coupling under mild conditions (Figure 11D).¹¹³ Stoichiometric studies implicate low-valent Ni complexes as key intermediates in route to rapid reactions with even unactivated alkenes. Cyclohexenone was found to be an unreactive substrate but a crucial additive that promotes facile electroreduction of the Ni catalyst and functionalization of other alkenes in high yields.

2.8. Cross-coupling with Heteroatoms (C–N, C–O, C–S, C–P)

More recently, the development of metal-catalyzed electrochemical cross-coupling of arylhalides to generate aryl amines, thiols, and phosphonates was reported. Baran, Minteer, and Neurock reported a nickel-catalyzed electrochemical amination of aryl halides to generate aryl amines (Figure 12A).^10,11 Mechanistic information from voltammetric studies and DFT calculations informed the development of a highly efficient amination protocol. This reaction proceeds at room temperature using a weak organic base and applicable to a broad range of aryl halides and amine nucleophiles, including: complex examples of oligopeptides, heterocycles, sugars, and natural products. The methodology was also demonstrated in batch and flow scale-ups (up to 100 g scale). The optimized condition was also tested for C–O coupling using alcohols and water as nucleophiles. Aryl ethers and phenol were obtained, however, in low yields.

Figure 12.

Electrocatalytic cross-coupling reactions of aryl halides to generate carbon–heteroatom bonds.

Very recently, Baran reported an electrochemical approach for the coupling of aryl halides with alkyl alcohols to generate aryl alkyl ethers in good yields (Figure 12B).¹¹⁴ This scalable process uses a nickel/bipyridine electrocatalyst and has been shown to give exceptionally broad substrate scope and functional group tolerance. To date, the use of phenolic coupling partners in electrochemical etherification to obtain diaryl ethers has been found to be challenging.^11,114

The groups of Buchwald and Jensen showed a nickel catalyzed electrochemical coupling of aryl bromides and carboxylic acids to form esters.¹¹⁵ The catalytic C–O bond forming reaction was performed via a microfluidic redox neutral electrochemistry platform where both reactive intermediates of the coupling partners are generated from the cathode and anode and a rapid molecular diffusion across a microfluidic channel outpaces the decomposition of the intermediates.

Mei reported the first examples of nickel-catalyzed electrochemical thiolation of aryl bromides and chlorides in the absence of an external base at room temperature using undivided electrochemical cells (Figure 12C).¹¹⁶ Conventional transition-metal-catalyzed thiolation of aryl bromides and chlorides typically requires the use of a strong base under elevated reaction temperature. The proposed mechanism involves the oxidative addition of electrochemically generated low-valent Ni to aryl halides followed by the coordination of thiolates generated from cathodic reduction.

Leonel and co-workers disclosed a nickel catalyzed electrochemical phosphonation from the coupling of aryl halides and dimethylphosphonite (Figure 12D).¹¹⁷ Very mild and simple conditions are employed as the cross-coupling is carried out in galvanostatic mode, in an undivided cell at room temperature, using NiBr₂bpy as the easily available precatalyst. Various aryl bromides and iodides as well as vinyl bromides were converted to aryl or vinylphosphonates in good yield.

3. ELECTROCATALYTIC FUNCTIONALIZATIONS OF ALKENES AND ALKYNES

Alkenes and alkynes provide an opportunity for multicomponent cross-coupling reactions. Electrocatalytic functionalization methods provide an additional reaction development platform enabling cleaner reaction conditions and/or access to additional reactivity.

3.1. Annulation Reactions of Alkenes

Lei and co-workers reported the Co-catalyzed [4 + 2] annulation with alkenes/alkynes and acrylamide/benzamide derivatives (Figure 13A) using quinoline as directing group.¹¹⁸ Co catalysts have been used in C–H functionalizations for a number of years,^119–121 but these methods required stoichiometric oxidants such as Ag and Mn salts to regenerate the active Co catalyst.^122–124 The authors found that the use of a carbon anode could facilitate the catalyst to turnover. Additionally, the utilization of a Ni cathode (to effect hydrogen reduction) afforded the product in greater yield than other counter-electrodes. The addition of NaOPiv aided in the C–H/N–H functionalization, and the reaction occurred optimally at a constant current. The functional group tolerance included aryl halides, a thiophene derivative, and yields were similar between both alkenes and alkynes.

Figure 13.

Electrocatalytic annulation reactions of alkenes and allenes and Wacker oxidations of alkenes.

The same year, Ackerman and co-workers reported the same transformation with allenes, albeit with pyridine N-oxide (PyO) as the directing group instead of quinoline (Figure 13B).¹²⁵ The authors found similar conditions for this transformation as those utilized by Lei and co-workers above, including the Co(OAc)₂ catalyst, NaOPiv base, and methanol solvent. The functional group tolerance was similar, with the requirement of R¹ being an electron-withdrawing group.

3.2. Wacker Oxidations of Alkenes

In 2018, Hu and co-workers reported the Cu-catalyzed electrochemical Aza-Wacker cyclization (Figure 13C).¹²⁶ Nonelectrochemically mediated Aza-Wacker reactions typically use stoichiometric oxidants such as benzoquinone and metal salts to regenerate the active catalyst.^127,128 The byproducts of these oxidants generate significant amounts of waste and can be difficult to remove in some cases. The authors found the use of NaOPiv as an additive to be beneficial to the reaction, with LiClO₄ serving as the electrolyte in a DCM/MeOH (1:1) solvent. Constant current electrolysis afforded oxazolidinone derivative products from aryl amide substrates.

Pericàs and co-workers reported a Cu/Mn-catalyzed Wacker–Tsuji type oxidation of styrene derivatives to obtain acetophenone derivatives (Figure 13D).¹²⁹ In general, electron-rich arenes were not well tolerated, but electron-withdrawing groups were common in the reported scope. Endocyclic and acyclic alkenes performed similarly in the reaction. The authors found that an applied voltage of +2.8 V afforded the products in the greatest yields, with a carbon anode and platinum cathode. Furthermore, Pericàs and coworkers proposed a mechanism requiring two separate one-electron oxidations, the first one being mediated by Mn, and the second one mediated by either Cu or the acetonitrile (MeCN) solvent (Figure 13E). The addition of water to the carbocation and an elimination affords the product.

3.3. Difunctionalization of Alkenes

Lin and co-workers have found that manganese can convert alkenes and sodium azide to vicinal diazides with a single step and high selectivity, which can be seen in Figure 14A.¹³⁰ The resulting vicinal diazide products can easily be converted to vicinal diamines via a single step. The substrate and sodium azide were dissolved acetic acid/acetonitrile with graphite as the anodic working electrode and the counter electrode as platinum at an applied potential of 2.3 V. The graphite was used as the working electrode because of the high surface area, easy fabrication, and low cost. Platinum was used as the counter-electrode because of its low overpotential for the reduction of protons, only producing hydrogen gas. The acetic acid provided protons to be reduced on the platinum electrode. Sodium azide was utilized as the azide source due to its low toxicity and its high availability. The electrolyte, lithium perchlorate, can be replaced with tetrabutylammonium salts, as its role is simply conducting charge. In general, the scope of the alkene is general, including styrene derivatives, stilbenes, enynes, and tri- and tetrasubstituted alkenes.

Figure 14.

Electrocatalytic difunctionalization and heterodifunctionalization of alkenes.

It was found that without the redox-active manganese complex, a radical is formed that undergoes many transformations: dimerization, polymerization, oxidation, and reduction because of its reactivity. Thus, the occurrence of many competing reactions resulted in a low yield of the diazide. The redox-active catalyst is to improve selectivity through kinetic control by complexing the azide ion, N₃⁻, forming a metal azidyl complex, M–N₃, which can then undergo direct transfer of the azidyl radical. A second M–N₃ can then intercept the resulting carbon-centered radical to afford the diazide product. The proposed mechanism can be seen in Figure 14A. The reaction is irreversible, as the azide ion decomposes on the electrode. Under constant current electrolysis, the reactions proceed with a similar yield with a slight increase in voltage, showing that the manganese operates at the potential close to where the azide oxidation occurs at 0.71 V. The faradaic efficiencies were found to be about 70%, suggesting that most of the potential was toward the reaction with a small amount going toward azidyl dimerization. Upon removing the Mn catalyst, and adding TEMPO, an azidooxygenated product was formed. This aided in the elucidation of the proposed mechanism.

Inspired by the above diazidation, the reaction shows the possibility of performing other types of alkene difunctionalization.¹³¹ Simply, the addition of other anions to the same reaction platform that has been developed could afford a wide array of products. Lin and co-workers have applied this same reaction to halogens, specifically chloride, for alkene dichlorination (Figure 14B). A number of chloride sources were examined. The chlorine salts were chosen as they are readily available. Sodium and calcium chloride were tested as possible reagents but were unsuccessful due to their solubility. Magnesium chloride performed better than LiCl as the chloride source. The reaction operates at a slightly higher temperature because the reaction proceeds at a slower rate with chloride. The reaction is a similar setup as the azide, with the change being a chlorine salt instead of an azide as the nucleophilic source that is being dissolved in the electrolyte solution. This process was able to achieve both chemo- and stereoselectivity from the dichlorination via oxidation of the chlorine radical.

Under the optimal conditions, dichlorination was found to be successful for a range of substrates, especially with cyclic alkenes and β-alkylsytrenes, as they displayed interesting diastereochemistry. The reaction also worked with aliphatic alkenes with a range of substitution patterns. Mono-, di-, and tri- substituted alkene show reactivity toward the product of interest. Tetrasubstituted alkenes would react, but the products were not isolated in significant yields, likely due to product instability and the propensity to form a stabilized chloronium ion. Although they were reactive to tetrasubstituted alkenes, they were hard to isolate. This electrochemical technique has shown wider access to a variety of dichlorinated compounds from alkenes. The catalytic mechanism of the alkene dichlorination is similar to the diazidation, with the exception of the reagent used for the difunctionalization.

3.4. Heterodifunctionalization of Alkenes

Lin and co-workers developed a heterodifunctionalization of alkenes, installing both a chloride and trifluoromethyl group vicinal to one another (Figure 14C).¹³² This reaction utilized the Langlois reagent (CF₃SO₂Na) as a trifluoromethyl source¹³³ and MgCl₂ as the chloride source utilized previously. A variety of alkenes were compatible with this reaction, with various functional groups, such as amines and aryl chlorides, being well-tolerated. Endocyclic, exocyclic, and acyclic alkenes are reactive under these conditions. A tetrasubstituted alkene also reacts under these conditions, albeit with reduced yield due to the slow reactivity of tetrasubstituted alkenes. Furthermore, the use of a radical clock afforded a ring-opened product, and the use of an enyne generated the cyclized product.

Xu and co-workers reported a ferrocene-mediated, intramolecular hydroamination of alkenes (Figure 14D).¹³⁴ Other methods to generate nitrogen-centered radicals include chemical oxidants,^135,136 such as 2-iodoxybenzoic acid (IBX) or direct electrolysis.^137,138 These methods suffer from reduced selectivity or electrode passivation.¹³⁹ The authors found that ferrocene could oxidize the anion of an amide in MeOH/THF but not the amide in basic MeOH. 1,4-Cyclohexadiene was used as a hydrogen source to quench the radical and generate the product, and Na₂CO₃ as the base to deprotonate the amide. Both carbamates and ureas were tolerated, as well as endocyclic, acyclic, and trisubstituted alkenes. The reaction generally proceeded with high diastereoselectivity.

3.5. Carboxylation and Carbonylation Reactions of Alkynes

In 1988, Perichon and co-workers reported the Ni-catalyzed carboxylation of terminal alkynes with CO₂ to afford the 1,1-disubstituted alkene products and internal alkenes as a mixture of isomers (Figure 15A).¹⁴⁰ This stemmed from their previous carboxylation of alkenes.¹⁴¹ The authors used a carbon fiber anode and a Mg cathode at a constant current. One limitation of this work was the product selectivity, as substantial amounts of both carboxylated products would be formed. A number of functional groups were tolerated, albeit in reduced selectivity. Following these results, Perichon and co-workers reported the carboxylation of internal alkynes in 1989 to generate carboxylated products using the same conditions as above.¹⁴² Symmetrical alkynes provided the monocarboxylated product in moderate yields, with low amounts of the dicarboxylated products being obtained. Unsymmetrical internal alkynes suffered from either low yields or poor regioselectivity.

Figure 15.

Electrocatalytic carboxylation and carbonylation reactions of alkynes.

In 2002, Carelli and co-workers published the Pd-catalyzed carboxylation with terminal alkynes and carbon monoxide to afford methyl alkynoates (Figure 15B).¹⁴³ The presence of the constant voltage ensures that Pd(0) is oxidized to Pd(II), which is required for the reaction to proceed. Terminal alkynes with aryl and alkyl substituents were well-tolerated and provided the products in moderate yields. The authors found that using triethylamine instead of sodium acetate afforded the product in higher yield.

3.6. Annulation Reactions of Alkynes

Pan and co-workers reported an intermolecular annulation between acetophenone derivatives and alkynes to obtain 1-naphthalenol derivatives (Figure 16A).¹⁴⁴ Using an undivided cell, with RVC cathode, Pt anode, and ferrocene as a mediator to facilitate oxidation of the putative enolate intermediate formed in the reaction. An aryl bromide, thiophene, and a cyclopropyl group were all well tolerated to furnish the products.

Figure 16.

Electrocatalytic annulations of alkynes.

In 2017, Xu and co-workers reported the intramolecular annulation of alkynes and arenes to obtain polycyclic aromatic hydrocarbon products (Figure 16B).¹⁴⁵ The authors employed ferrocene as a mediator to facilitate oxidation of the substrate and generate a radical intermediate that could then undergo the reaction to form the products. This reaction tolerated aryl halides and an alkyl group for the substituent, albeit in reduced yield. The authors found that an increase in applied current density caused reduced yield, possibly due to oxidation of the products. Cyclic voltammetric studies showed that the starting material had an oxidation potential of +1.43 V vs SCE, while the product exhibited an oxidation potential of only +0.89 V vs SCE. However, upon deprotonation of the amide, the oxidation potential of the starting material is only +0.53 V vs SCE, much closer to that of ferrocene, 0.49 V vs SCE. In 2016, Xu and co-workers reported the ferrocene-mediated, electrochemical synthesis of indoles via an oxidative process.¹⁴⁶ This work represents an expansion of their previous work with alkenes to include alkynes. Electron-rich and poor arenes were well tolerated, as well as a cyclohexene moiety.

In 2018, Xu and co-workers reported the difluoromethylation of aryl alkynes to form dibenzazipenes (Figure 16C,D).¹⁴⁷ The authors used the precedence by Baran and Blackmond to electrochemically form the difluoromethyl radical from the sulfonamide reagent in the solution.¹⁴⁸ This radical then reacts with the alkyne in an undivided cell, leading to product formation. With respect to the arenes, the scope was rather broad, including benzothiophene and pyridine, among others (not shown). This reaction was ferrocene-mediated, with an RVC cathode and Pt anode under constant current electrolysis. It is important to note that the difluoromethyl radical reacted preferentially with the alkene over the alkyne. This afforded the formation of polycyclic aromatic hydrocarbons bearing a difluoromethyl group.

Ackerman and co-workers reported the generation of polycyclic aromatic hydrocarbons with boronic acids and internal alkynes in a [2 + 2 + 2] cycloaddition (Figure 16E).¹⁴⁹ This was accomplished under constant current conditions of 4 mA with an RVC anode and Pt cathode to generate oxidative conditions. Rhodium facilitated the reaction, but its exact role was not elucidated. The model substrate afforded product 3d in 73% yield, and changes to either the boronic acid or alkyne generally resulted in reduced yield, but functional group tolerance was fairly broad, including electron-donating and-withdrawing groups. Protic solvents performed the best, with a mixture of t-AmOH/H₂O (3:1) providing the best yield, with KOAc as the additive.

Finn and co-workers reported the electrochemical, Cu(I)-catalyzed azide/alkyne [4 + 2] cycloaddition in 2008 (Figure 17A).³¹ The authors used an RVC anode and a Pt cathode to apply a constant voltage of −0.2 V vs Ag/AgCl. This transformation furnished the triazole product in excellent yield. Steckhan and co-workers reported the oxidative functionalization of alkenes and alkynes with α-nitroketones to afford functionalized isoxazole N-oxide products.³² They demonstrated this method with superstoichiometric Mn(III) and electrochemically generated Mn(III). Figure 17B displays the nonelectrochemical method. The yields of the products are similar between the two developed methods, with the electrochemical method consuming less Mn catalyst. The authors proposed that the role of Mn(III) is to oxidize the α-nitroketone enolate to generate an α-radical that reacts with the alkene/alkyne.³²

Figure 17.

Electrocatalytic cycloaddition reactions of alkynes with azides and α-nitroketones.

4. ELECTROCATALYTIC C–H FUNCTIONALIZATION REACTIONS

Selective C–H functionalization reactions on arene cores are crucial to building complexity on aromatic molecules.^150,151 Expanding this class of reactions equips synthetic chemists with more reliable routes to develop new scaffolds that appeal to the pharmaceutical and technological sectors.

4.1. Electrocatalytic Palladium C–H Functionalizations

The catalytic C–H functionalization using Pd catalyst has proven to be highly effective under nonelectrochemical conditions. Employing electrochemistry to access necessary oxidation states of Pd intermediate for C–H activation and bond-forming steps will provide reaction selectivity as well as the incorporation of a desired functional group. Traditionally, installing C–C bonds on aromatic molecules relies on the prefunctionalization of the arene core. For instance, in the Heck reaction, coupling arenes with alkenes using palladium requires an aryl halide, crucial for the initial oxidative addition step.¹⁰⁹ Fujiwara–Moritani type reactions represent a more sustainable alternative because no prefunctionalization of the arene partner is required and the functionalization of the aromatic C–H moiety renders a C–C bond.^152,153 In this case, the main challenge relies on the recovery of Pd(II), which is the active intermediate, from Pd(0) that is produced after the reductive elimination step. Traditionally, Heck-type reactions employ stoichiometric amounts of oxidants, including: Ag(I), Cu(II), t-BuOOH, and PhCO₃Bu.^109,154 Benzoquinone has been used in catalytic amounts for recovering Pd(II) in C–H functionalization reactions, but again it requires toxic cooxidants.¹⁵⁵ The use of electrochemistry to propel palladium/benzoquinone systems has been established before by Backwall in the oxidation of dienes.¹⁵⁶ Taking this work into account, Amatore and Jutand developed a Fujiwara–Moritani type C–H alkynylation reaction using a catalytic Pd(II/0) manifold and cocatalytic quantities of 1,4-benzoquinone (Figure 18).¹⁵⁷ In this system, the oxidation of [Pd⁰] does not take place directly at the electrode, rather, the 1,4-benzoquinone plays a shuttle role in transferring the electrons to the anode. This work shows the compatibility of palladium C–H functionalization catalysis with electrosynthesis as well as the significance of merging these two fields in the future evolution of chemical synthesis.

Figure 18.

Palladium electrocatalytic Fujiwara–Moritani transformation.

The proposed mechanism is outlined in Figure 18. Initial coordination of Pd(OAc)₂ with substrate followed by a based-assisted C–H activation process¹⁵⁸ renders the palladacycle intermediate. This dimeric complex undergoes a carbopalladation process, with alkene leading to the formation of the appropriate intermediate that can undergo β-elimination to give the functionalized product and [Pd⁰]. Oxidation of the [Pd⁰] intermediate is mediated by 1,4-benzoquinone resulting in hydroquinone and the catalytically active Pd(II), which continues with the C–H functionalization cycle. Hydroquinone undergoes an oxidation process at the carbon anode recovering 1,4-benzoquione, while reduction of protons to produce molecular hydrogen takes place at the nickel cathode.

In 2009, Kakiuchi reported an electrocatalytic halogenation process of phenylpyridine substrates (Figure 19A).¹⁵⁹ This transformation is normally performed using chemical oxidant reagents that are normally in excess and also produce toxic byproducts after the reaction is completed, making the purification step rather cumbersome.^160–168 In this example, however, the authors developed an environmentally friendly and selective electrochemical reaction in which the substrate is subjected to constant current electrolysis conditions to produce the halogenating agent required to yield the product in excellent efficiencies. The proposed mechanism of this transformation is illustrated in Figure 19A. Coordination of pyridine substrate to PdCl₂ gives an intermediate that undergoes a proximity-driven C–H activation process to form the palladacycle. Reaction of the cyclopalladated intermediate with the anodically generated halonium ion results in the formation of C–X bond at the ortho position. Ligand exchange at the produced cationic intermediate delivers the final halogenated product. Given the importance of iodoarenes in cross-coupling reactions,^169–172 the same research team developed an electrocatalytic palladium halogenation procedure to produce iodo-containing arenes using elemental iodine as iodonium precursor (Figure 19B).¹⁷³ This transformation proved to be efficient rendering the iodine-containing products in good yields.

Figure 19.

Palladium electrocatalytic C–H functionalization of phenylpyridines and benzamides.

During the development of the electrochemical iodination procedure, the authors were able to isolate a byproduct that corresponded to the dimer of the phenylpyridine substrates.^173,174 The formation of this dimeric species can be rationalized as depicted in Figure 19C. Coordination of phenylpyridine substrates to Pd(OAc)₂ gives a complex intermediate after a C–H activation process. Then the intermediate undergoes a second C–H activation event with a free phenylpyridine substrate to afford the bis-(phenylpyridine) palladium complex. Exposure of this intermediate to the anodically generated iodonium species renders the dimer.^175–179 Kakiuchi and co-workers explored further these results, seeking to develop efficient catalytic conditions for a C–C bond-forming reaction while suppressing the iodination pathway.¹⁷⁴ Thus, the authors observed that increasing the concentration of the phenylpyridine substrate would lead to high amounts of the palladium complex, which is key to favor the dimerization route. Catalytic conditions were developed to afford dimeric products bearing different functional groups in moderate yields. This transformation showed high levels of regioselectivity, which is remarkable because traditional arene homocoupling reactions sometimes give a mixture of products.^{169,180–184} Additionally, the Sanford group previously investigated palladium-catalyzed oxidative coupling of arenes using oxone as an oxidant.¹⁸⁵

Direct C–H oxygenation transformations^186,187 are also important targets for electrocatalytically driven transition metal C–H functionalization. Budnikova and co-workers were able to achieve a palladium-catalyzed electrochemical perfluorocarboxylation reaction¹⁸⁸ on phenylpyridine substrates, giving the desired products (Figure 19D).¹⁸⁹ The electrocatalytic procedure works efficiently for long-chain perfluoro carboxylic acids. Increasing the current resulted in the formation of perfluoroalkylation compound, which is an interesting observation, albeit in low yield. Only traces of trifluoroacetylation product was observed. The same group led by Budnikova reported a catalytic phosphonation reaction by means of electrochemistry coupled with palladium catalysis (Figure 19E).^190–192 The resulting phosphonate-containing pyridines are particularly relevant for their bidentate ability to coordinate metals and potentially used in ligand development.^193–198 Electrolysis of a mixture of phenylpyridines, phosphonate, and in the presence of catalytic amounts of Pd(OAc)₂ renders product in an excellent yield. This reaction is thought to occur via the acetate-bridged palladium complex that breaks in the presence of the phosphonate to form the binuclear phosphonate palladium(II) complex. Electrooxidation of the Pd(II) complex generates a putative Pd(IV) intermediate in the solution that renders the desired product after reductive elimination.

The ability of bidentate coordination to direct C–H activation reactions has been broadly explored in transition metal catalysis.^199–202 In particular, the 8-aminoquinoline directing group (8-AQ) has facilitated a range of palladium-catalyzed C–H functionalization processes.^203–211 Kakiuchi and co-workers engineered an 8-AQ derivative to efficiently guide a selective ortho-chlorination reaction (Figure 19F).²¹² Substrates bearing different functional groups were tolerated in good efficiencies. An important achievement that demonstrates the practicality of this electrochemical methodology was mirrored by the synthesis of vismodegib, an FDA-approved drug for the treatment of cell carcinoma.^213,214

While the majority of the Pd-catalyzed electrochemical approaches have been focused on C(sp²)-H transformations, efforts activating C(sp³)-H bonds remain elusive.^215–217 In 2017, electrochemistry appeared in this field in an elegant piece of work led by Mei and co-workers.²¹⁸ The authors developed a palladium-based electrocatalytic C–H acetoxylation strategy that allowed aliphatic oxime substrates to give the desired products (Figure 20A). The same group published two electrochemical palladium-catalyzed C–H functionalization reactions by means of methylation and benzoylation of oxime substrates (Figure 20B).²¹⁹ Starting from aryl oximes, optimized electrochemical conditions using CH₃BF₃K and catalytic amounts of Pd(OAc)₂, ortho-methylated products can be obtained. Mechanistically, this reaction is believed to begin with the interaction between Pd(OAc)₂ and the substrate to form a complex that undergoes a C–H activation process to give a palladacycle intermediate. It is important to note that intermediate was isolated and its structure confirmed by X-ray crystallography. This provided mechanistic evidence on the relevance of high-valent Pd in the C–H functionalization reaction. High valent palladium species ArPd(III)CH₃ or ArPd(IV)CH₃ are generated under anodic conditions by either a transmetalation process of CH₃BF₃K or the attack of a radical generated from the same reagent to the palladacycle. Desired methylated products are obtained via a reductive elimination process. Moreover, oxime substrates can also undergo a benzoylation reaction using 2-oxo-2-phenylacetic acid as a reaction partner under palladium catalyzed electrochemical conditions. Different benzoylation products can be synthesized in moderate to good yields.

Figure 20.

Palladium electrocatalytic C–H functionalization of oximes, quinolines, and other directing groups.

Mei and co-workers also expanded their electrocatalytic acetoxylation strategy to ketoximes²²⁰ (Figure 20C). Subjection of the ketoxime to palladium-catalyzed electrocatalytic conditions rendered the desired acetoxylated scaffolds. The Sanford group also reported an acetoxylation strategy enabled by palladium catalysis merged with electrochemical oxidation (Figure 20D).²²¹ Different quinoline substrates and derivatives were subjected to electrocatalytic conditions to produce acetoxylated molecules in high yields. Pyridine and pyrazole analogues were also efficient substrates under the optimized electrocatalytic conditions.

Pyrido[1,2-a]benzimidazole are important motifs present in biologically relevant molecules, including: antimalarial,²²² anticancer,²²³ and antiviral agents.²²⁴ Several efforts have been published describing methods to access to this privileged class of heterocycles. These approaches rely on an oxidative annulation process, using Cu salts, I₂, or hypervalent iodine reagents.^225–228 Recently, Lei reported an electrocatalytic approach for the synthesis of pyrido[1,2-a]benzimidazole²²⁹ (Figure 20E). The authors developed electrochemical conditions to transform pyridine-2-amines into the desired scaffolds. Substituents including methyl, methoxy, and halogens were compatible with the optimized electrochemical conditions and gave the heterocycle products in good efficiencies.

Despite the efforts on electrocatalytic palladium C–H activation reactions, examples displaying high levels of enantioselectivity have been poorly explored. In fact, to date, there is only one report by the Ackermann group in which they show an enantioselective electrocatalytic palladium C–H activation reaction (Figure 21).²³⁰ This transformation was achieved with the aid of a transient directing group, a strategy widely used in the C–H functionalization field.

Figure 21.

Enantioselective electrocatalytic palladium C–H functionalization by a transient directing group.

Axially chiral biaryls moieties are privileged scaffolds because they have been successfully used as ligands^231–233 in catalysis and are present in biologically privileged natural products.^234,235 A number of efforts have reported atroposelective synthesis of axially chiral biaryls.^236–241 The group led by Ackermann unraveled the first electrocatalytic enantioselective synthesis of axially chiral biaryls using a transient group strategy. As shown in Figure 21, starting materials are subjected to electrochemical conditions in the presence of electron-withdrawing alkenes using l-tert-leucine as a transient directing group and catalytic Pd(OAc)₂ to render the olefinated product. Different substituents on the arene moiety are compatible with the electrochemical conditions, affording the desired products in good yields and excellent enantioselectivities. Acrylates, perfluoroalkenes, vinyl phosphantes, vinyl sulfone, and even a cholesterol derivative worked well under optimized conditions, showing the versatility and robustness of this methodology. This reaction proceeds via the formation of the palladacycle that, in the presence of an electron-withdrawing alkene, undergoes coordination and insertion followed by a reductive elimination event to give the final product. The resulting Pd(0) is oxidized in the anode, restoring the catalytically active Pd(II).

The field of electrocatalytic C–H functionalization using Pd catalyst has proven to be effective in electrochemically generating active Pd species necessary for C–H^• activation step. Moreover, the field has advanced to functionalize sp² and sp³ C–H bonds and generate carbon–carbon and carbon– heteroatom bonds. Their application toward asymmetric synthesis of biaryls was also demonstrated. With the rich chemistry being developed in Pd C–H functionalization, we expect this area to soon expand in selective nondirected C–H activation strategies.

4.2. Electrocatalytic Rhodium C–H Functionalizations

Rhodium(III) catalysis has proven to be contributory in the development of C–H functionalization processes,^242,243 with an emphasis on oxidative C–H reactions. While unassailable progress has been made,^244–249 rhodium(III) catalyzed oxidative C–H transformations require stoichiometric amounts of harmful and/or costly copper(II) or silver(I) salts. The integration of electrochemistry in this area is expected to not only provide selective formation of active Rh catalysts toward C–H activation but also in eliminating the necessity of using stoichiometric metal salts as oxidants or reductants.

The group led by Ackermann has reported a seminal work in which rhodium(III) catalyzes a cross-dehydrogenative alkenylation of arenes using carboxylic acid as weak coordinating directing group and electricity as sole oxidant²⁵⁰ (Figure 22A). The versatility of this transformation is given by the number of substrates that produced the desired products in synthetically useful yields. The proposed working mechanism of this electrochemical rhodium-catalyzed alkenylation reaction is shown in Figure 22. The catalytically active rhodium complex 22-I, which is formed in the reaction mixture, undergoes coordination followed by a C–H activation step with the substrate rendering the rhodacycle 22-II. Coordination of alkene followed by migratory insertion process provides the seven-membered ring species 22-III. The rhodium complex 22-III undergoes a β-hydride elimination followed by a reductive elimination and anodic oxidation gives the final product and the catalytically active rhodium species 22-I.

Figure 22.

Electrocatalytic rhodium cross-dehydrogenative alkenylation and alkenylation reaction.

Selective C–H alkenylation of arene cores, enabled by chelation assistance, is a powerful strategy to form C–C bonds.^158,251,252 Despite the significant efforts on merging electrochemistry with transition metal C–H functionalization during recent years, there is only one example of a metal-catalyzed C–H olefination reaction propelled by electricity. This example, reported by Jutand and Amatore in 2007, shows few examples of a catalytic Fujiwara–Moritani type reaction, using a palladium–benzoquinone system.¹⁵⁷ Given the importance of developing electrooxidative C–H olefination reactions, the Ackermann group has recently unraveled a novel rhodium-catalyzed C–H alkenylation transformation using electricity as oxidant (Figure 22B).²⁵³ Different styrene substrates displaying a range of substituents were compatible with the electrooxidative rhodium C–H alkenylation reaction.

Performing electrosynthesis in a flow^254,255 fashion renders a number of benefits, including improvements on electrode surface area/volume ratio as well as mass and heat transfer. The scaling-up process is also facilitated, and the electrolyte footprint can be reduced.^28,30 Despite all these advantages, the use of flow systems in electrochemical-assisted metal C–H functionalization has been scarcely studied. A recent report released by the Ackermann group shows the implementation of a flow system for the development of an electrocatalyzed alkyne annulation via a rhodium C–H functionalization (Figure 23A).²⁵⁶ Electrochemical conditions were optimized to enable the intermolecular annulation of imidate substrates and unsymmetrical alkynes, affording the corresponding isoquinoline products. Different substituents were tolerated, including methoxy, bromo, and thiophene groups, yielding the final products in good yields. Moreover, an intramolecular version was also implemented, as depicted in Figure 23B. Starting from the appropriate substrate containing the reacting alkyne and imidate functionalities, a range of azo-tetracycles were also synthesized. Mechanistically, this reaction is believed to proceed via a chelation-assisted C–H activation between the catalytically active rhodium complex 23-I and the substrate to afford the rhodacycle 23-II. Coordination of the alkyne to the 23-II complex gives rise to the intermediate 23-III. Anodic oxidation and a subsequent migratory insertion event produce the high valent rhodium(IV) species 23-IV. Reductive elimination followed by anodic oxidation provides the desired product and regeneration of the active catalyst.

Figure 23.

Electrochemical Rh catalyzed C–H annulations.

Polycyclic aromatic hydrocarbons (PAHs) are a class of molecules with a wide range of applications, including: catalysis, optoelectronics, and bioimaging.^257–261 The physicochemical behavior of PAHs can be tuned by manipulating variables such as edge topology, shape, and π-extension. Thus, the development of a synthetic tool to ensemble PAHs at atom-level precision has gained attention in the chemistry community. Chemical methods to access PAHs have relied on cross-couplings, Diels–Alder cycloadditions, and cyclotrimerization strategies.^262–265 Metal catalyzed C–H functionalization approaches, which heavily rely on stoichiometric amounts of oxidants, have also been developed for the synthesis of these aromatic materials.^266–278 However, the Ackermann group has designed an electrocatalytic platform to access PAHs by combining two distinct processes (Figure 23C): (1) unprecedented annulative [2 + 2 + 2] cycloaddition via a rhodium electrocatalyzed C–H activation process, using boronic acid as starting materials, and (2) electrocatalytic dehydrogenation reaction, using DDQ (2,3-dichloro-5,6-dicyanobenzoquinone) as redox mediator, to allow the formation of the final PAHs.¹⁴⁹

The optimized rhodium-catalyzed electrochemical conditions enabled the C–H annulation process between boronic acids and alkynes, yielding the desired products in high efficiencies. Different substrates were also tested in the alkyne reaction partner giving the annulated product in reasonable yields. The role of electrochemistry in this reaction is thought to restore the catalytically active rhodium(III) species by anodic oxidation. The incorporation of heteroatoms into PAHs scaffolds can considerably alter the physicochemical properties of these relevant materials.^279–284 Thus, aza-PAHs are important targets for the synthetic community and existing strategies to access these scaffolds remain difficult, relying on laborious multistep procedures.^{262–264,285,286} Recently, however, the same group has developed a rhoda-electrocatalyzed alkyne annulation protocol to access aza-PAHs.²⁸⁷

Organophosphorus compounds play a central role in catalysis, material science, and chemical biology.^288–293 The use of metal-catalyzed approaches to synthesize these types of compounds can be difficult due to the intrinsic coordinating ability of phosphorus reacting partners, potentially leading to catalyst poisoning.^294–296 However, the Xu group has developed an electrochemical rhodium-catalyzed platform to access aryl phosphine oxides (Figure 24).²⁹⁷ Different phosphine structures displaying a range of electronically as well as sterically different substituents were evaluated, resulting in the desired products in high efficiencies. The proposed mechanism involves rhodium(III) complex to undergo an ortho C–H activation event with the substrate producing a rhodacycle intermediate. Ligand exchange with phosphine oxide gives rise to an intermediate that goes through anodic oxidation to form high valent rhodium species. This facilitates the reductive elimination process, releasing the final product as well as the catalytically relevant rhodium(III) complex.

Figure 24.

Electrocatalytic rhodium C–H phosphorylation.

The past decade has shown the effective utility of electrochemistry in Rh-catalyzed directed C–H functionalization to generate carbon–carbon and carbon–heteroatom bonds. More importantly, they have been found useful in annulation reactions involving arene C–H bonds with saturated systems. These reactions provide useful nitrogen and oxygen-containing heterocycles as products, and we expect their utility in to provide a general construction of heterocycles as well as bicyclic compounds.

4.3. Electrocatalytic Ruthenium C–H Functionalizations

Ruthenium catalysis has proven to be instrumental in the development of a myriad of chemoselective C–H activation processes.^298–312 Initial efforts merging electrochemistry with ruthenium-catalyzed C–H activation processes have been reported by Xu and co-workers. In this case, the authors showed an electrochemical annulation process driven by ruthenium catalysis (Figure 25A).³¹³ Subjecting aniline and alkyne substrates under electrochemical ruthenium-catalyzed conditions delivered indole scaffolds. While this reaction has been previously reported using chemical oxidants,³¹⁴ the work developed by Xu has proven to be efficient with a broad scope using electricity as sole oxidant. Different aniline substrates bearing electron-donating and withdrawing substituents were tolerated in high yields. The authors believe this reaction proceeds via an initial C–H activation process promoted via the in situ generated Ru(II) catalyst and substrate to give a ruthenacycle. Coordination to alkyne substrate and migratory insertion event delivers the desired product and Ru(0), after reductive elimination. Anodic oxidation recovers the catalytically active Ru(II) intermediate.

Figure 25.

Electrochemical ruthenium catalyzed annulation arene C–H annulation with alkynes.

Almost simultaneously, the Ackermann group released an electrochemical annulation process driven by ruthenium catalysis to produce isocoumarins, as shown in Figure 25B.³¹⁵ Benzoic acids and alkynes were subjected to electrochemical conditions and catalytic amounts of ruthenium salts, delivering the desired heterocycles products.

The group led by He also reported the use of electrochemical conditions to promote a [4 + 2] annulation process between arylglyoxylic acids and alkynes, producing substituted isocoumarines (Figure 25C).³¹⁶ Symmetrical alkynes bearing fluoroarene groups as well as unsymmetrical substrates containing a cyclopropyl moiety were well tolerated. Isocoumarines substituted with the biologically relevant estrone unit were also synthesized by this methodology. The same research team also reported an electrocatalytic annulation process between benzylic alcohols and alkynes to produce isocoumarine products.³¹⁷

The Ackermann group disclosed another electrocatalytic annulation process involving alkynes, but in this case, with aryl carbamates as reaction partners to afford pyridine derivatives (Figure 25E).³¹⁸ Different symmetrical alkynes substrates containing arene and alkyl substituents worked well under the electrochemical conditions. A range of functionalities installed on the aryl carbamate reaction partner was also explored, producing the desired pyridine derivatives in high yields. This transformation also proceeds with the in situ formation of the catalytically active Ru(II) complex.

Electrocatalytic ruthenium annulation strategies to produce isoquinoline derivatives from amides and alkynes have also been reported.³¹⁹ Ackermann also reported that alkenyl imidazoles are also effective to undergo an electrocatalytic annulation process with alkynes to produce N-fused bicyclic heteroarenes.³²⁰

A novel electrocatalyzed oxygenation transformation enabled by weak coordination has recently been reported by Ackermann and co-workers (Figure 26A,B).³²¹ Catalytic amounts of iodoarenes together with catalytic amounts of ruthenium(II) complexes facilitate this reaction to occur broadly and efficiently. Different amides were subjected to this dual electrocatalytic setup and rendered synthetically useful hydroxylated Weinreb analogues in high yields and selectivity. Ketones were also successful substrates for this transformation, not only tolerating variations on the carbonyl group but also on the arene scaffold. The working mechanism of this reaction is depicted in Figure 26C. Ligand exchange of complex Ru-A with TFA generates the highly electrophilic ruthenium intermediate 26-I, which undergoes a C–H activation process with carbonyl substrates, producing a ruthenacycle intermediate 26-II. This intermediate is then oxidized by a hypervalent iodine reagent, giving rise to the Ru(IV) complex 26-III. Reductive elimination of this intermediate releases the product that readily hydrolyses to give the final phenolic product.

Figure 26.

Electrochemical ruthenium catalyzed arene C–H oxidation aryl amides and ketones.

4.4. Electrocatalytic Cobalt C–H Functionalizations

While outstanding developments in the field of C–H activation have been achieved by precious 4d and 5d transition metals, cost-effective earth-abundant base metals represent a more sustainable alternative to the field.^{121,130,131,199,200,322–335} Recently, efforts showing the efficacy of electrochemical protocols to achieve C−H activation processes using cobalt catalysis is a growing area. In 2017, the Ackermann group reported the first electrocatalytic cobalt C–H activation process (Figure 27A).³³⁶ After screening different directing groups, the authors found pyridine N-oxides to be the most efficient scaffolds for the C–H activation process of benzamide substrates in the presence of alcohols. Electrocatalytic cobalt conditions delivered the desired oxygenated products in good efficiencies. The same group explored this reactivity further by developing a C–H/N–H activation process using the same class of substrates.³³⁷ Subjection of benzamides in the presence of alkynes under cobalt catalyzed electrochemical conditions delivered the final annulated products (Figure 27B). The Lei group also explored this chemistry by developing [4 + 2] annulation reactions using the N-(quinoline-8-yl)benzamides and ethylene or ethyne (Figure 27B).¹¹⁸

Figure 27.

Electrochemical cobalt catalyzed arene C–H oxygenation and annulation.

Ackermann developed an electrocatalytic cobalt C–H activation process on aromatic C–H bonds using hydrazides as directing groups (Figure 27B).³³⁸ Hydrazides react with alkynes under electrocatalytic cobalt conditions to give the annulated products. Symmetrical and unsymmetrical alkynes were tolerated in this transformation, affording the desired products in decent efficiencies. Substituents on the aromatic core were also investigated, producing the annulated outcomes in good yields. The same reactivity was explored with other reaction partners, including diynes and allenes, giving products in excellent yields (Figure 27C).

Amination reactions can also be achieved by this reactivity mode.³³⁹ Figure 28A shows the electrochemical conditions by which benzamides react with free amines to form aniline derivatives. A range of piperidines proved to be efficient substrates for this transformation, and scope studies on the benzamide core also revealed a good set of working substrates. Lei explored further this electrosynthetic methodology and developed conditions for an amination process based on benzamide substrates.³⁴⁰ Different arene and heteroarenes were tolerated in the benzamide core. Carbonylation reactions can also be achieved on benzamides by electrochemical cobalt catalysis (Figure 28B).³⁴¹ Intramolecular carbonylation products were obtained in excellent yields on different substrates. Moreover, intermolecular carbonylation in the presence of an external amine was also possible.

Figure 28.

Electrochemical cobalt catalyzed arene C–H functionalization.

Ackermann and co-workers have also implemented a C–H allylation method using benzamides and unactivated alkenes as reaction partners (Figure 28C).³⁴² Substitutions on the benzamide core were compatible with the electrochemical conditions delivering the desired products in good efficiencies. Also, different chemicals anchored to the alkenes were tolerated. The mechanism of the reaction is depicted in Figure 28D. Selective C–H activation after substrate coordination and an anodic oxidation process affords the Co(III) metallacycle 28-I. This reacts with the incoming alkene to render the seven-membered ring intermediate 28-II. β-Hydride elimination generates the desired product and Co(I) species, which undergoes an anodic oxidation to regenerate the active catalyst.

The use of nonprecious metals for C–H functionalization reactions has been an active research area in this field. The integration of electrochemistry to access reactive intermediates such as low and high valent cobalt species will help advance this field. We expect the development of various electrocatalytic cobalt C–H functionalization reactions using various directing groups and coupling partners.

5. ELECTROCATALYTIC OXIDATION OF ALCOHOLS

The electrochemical oxidation of alcohols is one of the key fundamental chemical transformations and often requires complexes of noble metal catalysts.^343–347 Accordingly, the past decade has seen considerable efforts in developing electrocatalytic alcohol oxidations employing nonprecious metals as catalysts. Attempts in this regard include the application of homogeneous nickel diphosphine complexes^348,349 and organic N-oxyls.³⁵⁰ For example, Weiss et al. reported that the incorporation of pendant amines to the phosphine ligand could facilitate the oxidation of primary and secondary alcohols to the corresponding aldehydes and ketones. While this method is effective, the reactivity was poor, especially toward methanol and ethanol.³⁴⁸ In contrast, organic nitroxyls often exhibit good reactivity with a turnover rate of 1–2 s⁻¹. Particularly, TEMPO (2,2,6,6-tetramethyl-1-piperidine N-oxyl) has been extensively studied for electrocatalytic alcohol oxidation.^350,351 Typically, TEMPO is electrochemically oxidized to generate the oxidant oxoammonium species (TEMPO⁺), followed by the formation of TEMPO⁺/alkoxide adduct, which yields aldehyde or ketone products via intramolecular hydrogen transfer (Figure 28A). This electrochemical generation of TEMPO⁺ by one-electron oxidation of TEMPO is simple and clean as compared to chemical oxidation. Nevertheless, the high electrode potentials required for the TEMPO/TEMPO⁺ are not desirable for energy transformations.

To resolve this dilemma, Stahl reported a (bpy)Cu/TEMPO cocatalyst system (where bpy is 2,2’-bipyridine) for electrochemical alcohol oxidation.³⁵² Using this system, the reaction rate for benzyl alcohol as substrate (k_obs) was improved to 11.6 s⁻¹, while the TEMPO-only system only showed a rate of 2.3 s⁻¹. Additionally, this fast turnover rate was achieved at an applied potential of −0.14 V, a half-volt lower than that used in the TEMPO-only regime (0.36 V). To gain more insights into the Cu/TEMPO system, kinetic isotope effects and Hammett studies were performed. Very interestingly, the Hammett plot showed the opposite electronic trends in comparison to the TEMPO-only process: electron-deficient alcohols are instead oxidized more easily than electron-rich alcohols. These differences indicated that the rate-limiting step for the Cu/TEMPO system is the Cu(II)/alkoxide formation, while in the TEMPO-only system, it is the hydrogen transfer from the alcohol to TEMPO⁺ within the TEMPO⁺/alkoxide adduct. As a result, the Cu/TEMPO system affords a unique catalytic path: Cu(II) acts as a one-electron oxidant, while TEMPO only serves as an electron–proton acceptor (Figure 29). This observation is nontrivial, as it implies the synergy effect of cooperating electron–proton-transfer mediators with transition metals to increase the reactivity for proton-coupled two-electron reactions. As two-electron redox reactions are widely present, developing cooperative electrocatalysts are poised to play a critical role in energy conversions.

Figure 29.

Copper/TEMPO electrocatalyzed oxidation of alcohols.

6. ELECTROCATALYTIC TRANSFORMATIONS OF ORGANOBORON REAGENTS

Organoboron reagents are highly attractive starting materials in organic synthesis due to their abundance, stability, and ease of preparation. Electrochemical methods for their coupling with organohalides via Suzuki-type reactions have been reported (see section 2.7).¹¹² The direct functionalization of organoboron reagents to generate phenols, anilines, and other functional groups has been realized more recently. Huang reported an electrochemical conversion of aryl boronic acids to anilines and phenols using copper as both the cathode and anode materials using aqueous ammonia under undivided cell electrolysis (Figure 30A).³⁵³ By simply changing the concentration of aqueous ammonia and the anode potential, good yields of phenols and anilines can be obtained chemoselectively with high reaction rates. It is believed that the reaction is mediated by copper species generated during the electrolysis. Recently, Gale-Day and co-workers reported an electrocatalytic coupling of arylboronic acids with anilines using a copper catalyst and a dual copper electrode system (Figure 30B).³⁵⁴ In their work, they enabled the coupling of anilines that are found challenging under the conditions previously reported by Huang. The coupling reaction was enabled by the use of base additives such as 2,6-lutidine and triethyl amine under constant potential electrolysis and aerobic conditions to give desired aniline products in good to high yields.

Figure 30.

Electrocatalytic functionalization and cross-coupling of organoboron reagents.

Despite the success of electrochemical amination of boronic acids, electrooxidative reactions with ligandless copper catalysts are known to be plagued by slow electron-transfer kinetics, irreversible copper plating, and competitive substrate oxidation. Sevov reported an electrochemical Chan–Lam coupling of aryl-, heteroaryl-, and alkylamines with arylboronic acids with higher yields and shorter reaction times than conventional reactions in air and provided complementary substrate reactivity (Figure 30C).³⁵⁵ This was enabled by the implementation of substoichiometric quantities of redox mediators to address limitations to Cu-catalyzed electrosynthesis. Mechanistic studies reveal that mediators serve multiple roles by (i) rapidly oxidizing low-valent Cu intermediates, (ii) stripping Cu metal from the cathode to regenerate the catalyst and reveal the active Pt surface for proton reduction, and (iii) providing anodic overcharge protection to prevent substrate oxidation. Under similar conditions, when phenol was used as the coupling partner, diaryl ether was obtained, albeit in lower yield.

7. CONCLUSIONS AND FUTURE DIRECTIONS

In the past two decades, there have been significant advancements made toward the development of molecular transition metal electrocatalysis for organic synthesis. These advancements were made possible by the increased recognition of electrochemistry as a highly effective benign reagent in electron transfer processes to generate highly reactive intermediates. In addition, the rapidly growing developments in transition metal catalysis and ligand design as potential electrocatalysts to mediate electron transfer and facilitate bond-forming and bond-breaking events led to the development of new, highly efficient, and selective electrochemical transformations. This review demonstrates that electrocatalysis, through the merger of homogeneous transition metal catalyst and electrochemistry, has greatly expanded the scope and improved the selectivity and reaction conditions in many important and challenging transformations, including cross-coupling of organohalides, to form various carbon–carbon and carbon–heteroatom bonds, functionalization of alkene and alkynes, and C–H functionalizations.

We expect that transition metal electrocatalysis will continue to expand toward reaction discovery and address challenges in organic synthesis, especially in the context of sustainable, selective, and efficient transformations. In the coming years, we anticipate several emerging research directions of synthetic organic electrocatalysis, such as

1. Development of new chemical spaces, especially those that involve challenging bond-breaking and bond-forming reactions to enable the utility of abundant reagents toward organic synthesis.

2. Enabling abundant and nontoxic transition metals in place of precious and rare transition metals as electrocatalysts for sustainable organic synthesis.

3. Development of highly selective transformations including stereo- and regioselectivity.

4. Applications toward synthesis and functionalization of complex molecules that will allow electrosynthesis to be part of a medicinal chemist’s toolbox through late-stage functionalization and diversification.

5. Integration of synthetic organic electrochemistry with well-developed and advancing technologies including: flow chemistry for scale-up processes, material science for heterogeneous catalysis and electrode design, high-throughput screening for rapid reaction development, photocatalysis and biocatalysis toward efficiency and sustainability, and the upgrading of chemical feedstock.

6. Adoption of electrochemical and analytical techniques together with organometallic chemistry, physical organic chemistry, and data science to understand reaction mechanisms and predict reactivity. This will streamline the tedious process of reaction discovery and development and aid in the discovery of new chemical spaces.

Overall, we anticipate that transition metal electrocatalysis will drive the discovery of new reactivities and help solve key challenges in contemporary organic synthesis. The advancement of transition metal catalysis and ligand design and the innovative application of fundamental and applied electrochemistry will catalyze future developments in organic synthesis. Moreover, the integration of transition metal electrocatalysis with multidisciplinary fields such as material science, data science, and medicinal chemistry through academic and industry collaborations will provide a strong foundation for the utility and advancement of electrosynthesis in modern synthesis.

Biographies

Biographies

Christian A. Malapit received his Ph.D. in Organic Chemistry at the University of Connecticut in 2016. He then pursued his postdoctoral studies in organometallic catalysis at the University of Michigan. Christian is currently an NIH Pathway to Independence investigator at the University of Utah. His research interests include electrosynthesis and organometallic catalysis and will start as an Assistant Professor of Chemistry at Northwestern University in January 2022.

Matthew B. Prater received his Ph.D. from the University of Utah in 2020. He is currently working under Prof. Shelley Minteer as a postdoctoral researcher, developing electrocatalytic methods. His primary interests are transition metal catalyzed reactions and electrocatalysis.

Jaime R. Cabrera-Pardo obtained his Bachelor’s degree in Biochemistry from the University of Concepcion, Chile. He then moved to the USA to earn his Ph.D. in Chemistry as a Fulbright Fellow at The University of Chicago. Then, Jaime pursued his postdoctoral research at The University of Cambridge (UK), where he was a Marie Curie Fellow. Currently, Jaime works at the University of Utah as an assistant research professor.

Min Li is currently a postdoctoral researcher in the Minteer group at the University of Utah. She earned her Ph.D. in Chemistry for the work on coupling dielectrophoresis with bipolar electrodes for the marker-free selection and detection of single circulating tumor cells at the Iowa State University (2018). Her current research centers on electrosynthesis and organic redox-flow batteries.

Tammy D. Pham received her B.S. in Chemistry at San Diego State University. She obtained her M.S. in Chemistry at the University of Utah under the supervision of Prof. Shelley Minteer in 2020. Her research interests include electrocatalysis and proton-coupled electron tranfer.

Timothy Patrick McFadden received his B.A. in Marketing from Loyola University Chicago in 2011. He is currently pursuing his Ph.D. in Chemistry at the University of Utah. His current research focuses on organic electrosynthesis.

Skylar Blank received his B.S. at the University of Utah in 2020. He is currently working towards his Ph.D. under Prof. Shelley Minteer. His current research interests focus on organic electrochemical methodologies.

Shelley D. Minteer received her Ph.D. at the University of Iowa in 2000, focusing on electrochemistry. She is currently the Center Director for the National Science Foundation Center for Synthetic Organic Electrochemistry at the University of Utah. Her research interests include electrosynthesis, electrocatalysis, and catalytic cascades.