Emerging applications and mechanistic insights of copper mediated electrocatalysts in organic transformations

	Fig. 2 Schematic representation showing the typical experimental variables/parameters during (A) constant potential electrolysis and (B) constant current electrolysis.

For constant potential experiments, knowing the electrochemical profile of the solution is necessary. When carrying out a constant potential electrolysis, minimizing ohmic (E_iR) drop is desirable as this represents the difference between the applied potential (E_app) and the actual electrochemical potential of the working electrode. Making the membrane that separates the anode and cathode cell compartments in a divided cell more porous, enhancing the solution conductivity (e.g., adding more inert electrolyte), or using an internal software (iR compensation mode) are different ways to overcome this problem. During the bulk electrolysis experiment, current is measured over time (known as amperometry) and integrated with time to give the overall charge (coulometry) according to Faraday's law of electrolysis. In constant potential electrolysis experiments, the current is directly proportional to the concentration of redox-active molecules under a specific applied potential (Fig. 2A). As the substrates are consumed, the current gradually decreases. Consequently, the reaction typically stops when the current reaches a level of <5%.^54,55 If the current efficiency is 100% (all electrons participate in the redox process), the charge passed (in Coulombs) is Q = nFN where n is the electron stoichiometry (typically n = 2), F is the Faraday constant (96485 C mol⁻¹) and N is number of moles of product.^56,57

In the early stages of an electrochemical experiment, the target (most electroactive) substrate is electrolysed at a working electrode potential adjusted by the instrument to sustain the set current. Once the substrate has been consumed, the potential of the working electrode changes and drives other electrochemical reactions to sustain the constant current. This can lead to unwanted side reactions, such as overoxidation/overreduction of different components (product, inert electrolyte, solvent, etc.) so the finish time of a constant current experiment (proportional to the overall charge) must be calculated to ensure selective electrolysis of the desired starting material.⁵⁴

	Fig. 3 Electrosynthesis pathway via (A) direct and (B) indirect (mediated) electrochemical method for substrate oxidation (cathodic reactions not shown).

Redox active catalysts overcome many of the issues of high overpotentials and poor selectivity. In indirect electrolysis (Fig. 3B), a redox-active mediator acts as a catalyst to facilitate the reaction, thereby reducing energy consumption and enabling the production of more chemoselective processes.⁶⁰ This method of electrolysis is typically conducted at a lower overpotential and doesn’t require heterogeneous electron transfer of the substrate at the electrode. This results in milder conditions, helping to prevent side reactions. Mediators such as 2,2,6,6-tetramethylpiperidinyl-1-oxyl (TEMPO) derivatives, hypervalent iodine reagents, and ferrocene/ferrocenium have been used for anodic (oxidation) reactions.^60–63 These mediators are regenerated electrochemically in situ to initiate further homogeneous electron transfer reactions with the starting material. Leach et al. presented the oxidation of benzyl alcohol to benzaldehyde using TEMPO at high pH.⁹

The Bernhardt group utilized cyclic voltammetry analysis combined with spectroscopy and electrochemical simulations to determine the rate constants for radical activation and deactivation in Cu(II)-catalyzed atom transfer radical polymerization (ATRP).^83–87 ATRP is a major technological advancement within the family of reversible-activation/deactivation radical polymerizations.^88–94

As a further development, the group has recently established an electrochemical methodology for forming C–C bonds via atom transfer radical addition using electrochemically generated organocopper(II) complex [Cu^IILR]⁺ (L is a tetradentate N-donor ligand). This methodology employs [Cu^II(L)(NCMe)]²⁺ species as a pre-catalyst, which is air-stable and converts to the active Cu(I) species in situ at the electrode under an argon atmosphere (Fig. 4).⁹⁵

	Fig. 4 Cu-catalysed atom transfer radical addition (ATRA) with various possible side products.

The first study of electrochemical-mediated atom transfer radical addition (eATRA) reactions were conducted in an H-cell with Pt working and counter electrodes, and a non-aqueous Ag^+/0 reference electrode and (Et₄N)(ClO₄) electrolytes in MeCN at room temperature, aiming to synthesise γ-halonitriles from various functionalized alkenes (see Scheme 4).⁹⁵ In this study, [Cu^II(L¹)(NCMe)]²⁺ (L¹ = Me₆TREN) served as a precatalyst, under electrochemical conditions the addition of XCH₂CN (X = Cl or Br) to [Cu^I(L¹)]⁺ achieves radical activation and formation of [Cu^II(L¹)(X)]⁺ and ˙CH₂CN radicals via homolytic C–X cleavage. This subsequently generates the organocopper(II) complex [Cu^II(L¹)(CH₂CN)]⁺in situ, which can act as a controlled radical source for atom transfer radical addition reactions (eATRA) and suppressing undesirable radical homocoupling reactions that typically plague this chemistry.

	Scheme 4 (A) Scope of the eATRA reaction utilizing functionalized alkenes in the formation of γ-halonitriles. (B) eATRA catalytic cycle involving [CuIIL1(CH2CN)]+. Note that the electrolysis starts with single-electron reduction of [CuIIL1(NCCH3)]2+ (not shown) to [CuIL1]+, as followed by reduction of [CuIIL1X]+. The ligand L1 = Me6TREN (see Fig. 4, bottom left).

The bulk electrochemical reactions were conducted at an applied potential (E_app = −860 mV vs. Fc^+/0 with a Cu(II) catalyst loading of 10 mol%) within a window low enough to reduce [Cu^IIL¹X]⁺ yet high enough to avoid reduction of [Cu^II(L¹)(CH₂CN)]⁺ (E⁰_[CuLR] < E < E⁰_[CuLX]), (Fig. 5). Where [Cu^II(L¹)(X)]⁺ (X = Cl or Br) underwent reduction to [Cu^I(L¹)]⁺ and ˙CH₂CN radicals forming the organometallic complex [Cu^II(L¹)(CH₂CN)]²⁺. This subsequently reacts with the alkene to give the radical adduct intermediate, which then reacted with a second equivalent of [Cu^II(L¹)(X)]⁺ to yield the desired γ-halonitrile products in good to excellent yield (see Scheme 4, eATRA catalytic cycle).

	Fig. 5 The cyclic voltammetry of [CuII(L1)(NCMe)]2+ (2 mM, L1 = Me6TREN)) before and after the addition of 20 mM of XCH2CN (X = Cl or Br) at a scan rate of 100 mV s−1 in glassy carbon: note highlighted in red the potential window for forming [Cu(L1)(CH2CN)]+. Reprinted with permission.95 Copyright 2022, Royal Society of Chemistry.

In contrast, when ATRA reactions were performed using the Schlenk line technique under an inert atmosphere with electro-generated [Cu^II(L¹)(CH₂CN)]⁺ as a catalyst but without continued electrolysis, the yields were lower, despite optimization of temperature and catalyst loading.⁹⁵ This result underscores the importance of the electrochemical method in achieving higher yields for these reactions. A variety of organic halide initiators (RX) containing both mono and poly halogenated functionality, and including nitrile, keto and ester functional groups have also been studied in the presence of two different catalysts, [Cu^IIL¹(NCMe)]²⁺ (L¹ = Me₆TREN) and [Cu^IIL²(NCMe)]²⁺ (L² = a bispidine derivative, Fig. 4). In most cases, syntheses are carried out at room temperature and consume very little current once the organocopper(II) intermediate is established in solution as the reaction is catalytic. This eATRA chemistry has also been expanded to include the addition of halomalonic esters to various styrenes which then undergo cyclisation to give a family of cyclopropane derivatives.⁹⁶

The Bernhardt group also investigated a series of N4 macrocyclic Cu(II) complexes (Me₃pyclen, Me₂pyclen, Me₄cyclen, and Me₄cyclam) for eATRA reactions (Fig. 6).^97,98 The Cu^II/I redox potential is an important indicator of radical activation efficiency in eATRA studies. The macrocyclic complex [Cu^II(Me₃pyclen)(NCCH₃)]²⁺ in MeCN showed a quasi-reversible peak for Cu^II/I with a redox potential of −0.42 V vs. Fc^+/0. The Cu(II) complex demonstrated the ability to cleave the C–Br bond of BrCH₂CN, releasing the ˙CH₂CN radical and forming the in situ organometallic complex, [Cu^I(Me₃pyclen)(CH₂CN)]. Under electrochemical conditions, this complex exhibited three orders of magnitude greater ATRA activity compared to its parent compound [Cu^I(Me₃pyclen)]⁺, which was further confirmed by electrochemical simulation. This complex was further investigated in the bulk electrochemical synthesis of γ-halonitriles in MeCN using the same substrates (para-substituted styrene) and initiator (BrCH₂CN). In this case, the applied potential was held (in the range of −0.9 to −1.0 V vs. Fc^+/0) in the vicinity of the [Cu^II(Me₃pyclen)(CH₂CN)]^+/0 couple (Fig. 6) to obtain the γ-halonitrile products in isolated yields ranging from 25% to 50%. The lower yields compared to the [Cu^II(Me₆tren)(CH₂CN)]⁺ copper catalyst was attributed to the activity of the γ-halonitrile products as initiators, leading to further reactions and the formation of byproducts during prolonged electrolysis.

	Fig. 6 (A) Tetradentate macrocyclic N4 ligands relevant to Cu-catalyzed atom transfer radical chemistry and (B) the cyclic voltammetry of the corresponding Cu(II) complexes in the presence of BrCH2CN. Reprinted with permission.97,98 Copyright 2023, 2024, American Chemical Society.

Following the above studies other macrocyclic complexes, including [Cu^II(Me₂py₂clen)(NCMe)₂]²⁺ and [Cu^II(Me₄cyclen)(NCMe)]²⁺ were evaluated (Fig. 6A). The cyclam complex [Cu^II(Me₂py₂clen)(NCMe)₂]²⁺ exhibited a low Cu²⁺/Cu⁺ redox potential (−0.50 V vs. Fc^+/0) in MeCN and demonstrated high radical activation in its Cu^I state, followed by the rapid radical capture leading to in situ formation of the organocopper complex [Cu^II(Me₂py₂clen)(CH₂CN)Br]. However, it was not an effective catalyst for eATRA because the rate of radical activation exceeded that of radical deactivation, resulting in the self-termination of the cyanomethyl radical (˙CH₂CN) rather than the formation of eATRA products, as confirmed by bulk electrochemical synthesis.

Additionally, the complex [Cu^II(Me₄cyclen)(NCMe)]²⁺ showed a quasi-reversible Cu^II/I peak with a redox potential of −0.67 V vs. Fc^+/0 in MeCN (see Fig. 6B). However, no significant radical activity was observed upon reduction to its Cu^I form in the presence of the initiators, likely due to slow radical activation via electrochemical methods. The 14-membered analog [Cu^II(Me₄cyclam)(NCMe)]²⁺, with a lower redox potential of −0.71 V vs. Fc^+/0, also exhibited very low activity upon the addition of BrCH₂CN (Fig. 6), which halted further study of these complexes for bulk electrochemical reactions. From these studies it was concluded that achieving eATRA products via electrochemical methods requires fine-tuning of the Cu^II catalyst.

In 2015, Gennaro et al. conducted a study on electrochemically promoted atom transfer radical cyclization (eATRC) of N-allyl-α,α-dichloro-amides to dichlorinated γ-lactams.¹⁰² This investigation introduced two different catalysts, [Cu^IIL]²⁺ [whereby L represents tris-(2-pyridylmethyl)amine (TPMA), and N,N,N′,N′′,N′′-pentamethyldiethylenetriamine (PMDETA)], with TPMA demonstrating better catalytic activity over PMDETA (Scheme 5).⁸ The overall catalytic efficiency is significantly influenced by the choice of polyamine ligands coordinating the Cu(II) catalysts and the corresponding redox potential of the Cu^II/I couple. The [Cu^II(TPMA)]^2+/+ redox potential is −0.019 V vs. SCE, which is more negative than that of [Cu^II(PMDETA)]²⁺ (0.063 V vs. SCE), indicating a greater catalytic activity of the TPMA complex. Upon the addition of the N-allyl-α,α-dichloroamide, the reversible cyclic voltammetric response of [Cu^II(TPMA)]²⁺ becomes irreversible, accompanied by the appearance of a new cathodic peak at a lower potential (−0.358 V), corresponding to the formation of the [Cu^II(TPMA)(Cl)]⁺ complex. Consequently, the applied electrolysis potential (E_app) was selected at a region after the reduction of [Cu^II(TPMA)(Cl)]⁺ to [Cu^I(TPMA)(Cl)] (Scheme 5A).

	Scheme 5 (A) Molecular structures of reagents, products and amine ligands used for electrochemical ATRC. (B) Proposed mechanism of copper-catalyzed ATRC under electrochemical (re)generation of the activator. Part of (A) was reprinted with permission.102 Copyright 2015, John Wiley and Sons.

Notably, after a few hours of electrolysis in presence of a 1% loading of Cu(II) complex with tris(2-pyridylmethyl)amine (TPMA) at constant potential (−0.68 V vs. SCE) using a Pt working and counter electrode in MeCN with (Et₄N)(BF₄) as electrolyte, resulted in γ-lactams in yields ranging from 60–80% with reasonable cis-selectivity [(cis/trans) = 59/41–83/17]. The progress of the reaction was monitored by HPLC, tracking the disappearance of the N-allyl-α,α-dichloroamides as the reaction proceeded to completion.

The proposed reaction mechanism involves an initial electrochemical reduction of [Cu^IIL]²⁺ to [Cu^IL]⁺ at the electrode surface. The generated [Cu^IL]⁺ subsequently activates N-allyl-α,α-dichloroamide, forming the intermediate [Cu^IILCl]⁺ and the N-allyl-α-chloroamide radical, which undergoes intramolecular cyclization to yield the final product (see Scheme 5B) after reaction with [Cu^IILCl]⁺. Furthermore, the study revealed that the activation rate constant (k_act) measured from the reaction of RCl with [Cu^I(TPMA)]⁺ or [Cu^II(PMDETA)]⁺ showed the Cu-TPMA complex activity to be 3 orders of magnitude higher than that of Cu-PMDETA, with an average ratio of . These findings underscored the significance of both the redox potential and the molecular structures of the complex in determining catalytic activity, shedding light on essential factors governing this electrochemical process.

	Scheme 6 Electrochemical copper(I)acetylides synthesis.

This protocol employs an H-cell with a metallic Cu working electrode, a Pt wire counter-electrode, and a Ag wire quasi-reference electrode. The reaction employs 0.1 M (Bu₄N)(PF₆) as the supporting electrolyte and is carried out at 0.5 V vs. the Ag wire for 5 hours anaerobically in the presence of 0.1 M (Bu₄N)(PF₆) in MeCN. The organic base 1,4-diazabicyclo[2.2.2]octane (DABCO) was used, which afforded the copper acetylides in good to excellent yields (64–92%) (Scheme 6).¹⁰³

Following their previous work, the same group explored a different strategy to generate organocopper(I) complexes. In this approach, they performed the reaction in an undivided cell, which incorporated the reduction of the [Bu₄N]⁺ electrolyte salt to produce Bu₃N in situ, thereby eliminating the need for an additional base in the experimental protocol (Scheme 7).¹⁰⁴ In this case, the same electrolyte/solvent system and electrode set-up was used to electro-generate the active organocopper(I) species. The optimized protocol consisted of using phenylacetylene and an electrolyte salt in MeCN, which gave a yield of 97% after 4 h of electrolysis at 0.5 V vs. the Ag quasi-reference electrode. Multiple electrogenerated organocopper(I) species were prepared from various alkynes under the optimized conditions, giving yields from 21–99% (Scheme 7). Inferior results were obtained when reagent-grade MeCN was used instead of anhydrous MeCN. With the isolated organocopper(I) species, Wilden et al. performed click reactions, yielding 72% compared to 75% when the pure organocopper(I) was produced by traditional methods. The ‘click’ reaction was also performed as a ‘one-pot’ reaction, starting from the alkyne, affording yields of 49–79%, depending on the electrolyte salt used.¹⁰⁴ Interestingly, a side product, tentatively a Cu(II) species, was reported, exhibiting lower activity in the click reaction.

	Scheme 7 (A) Reaction scope and (B) the mechanism of electrochemical Cu(I) and base generation/catalytic regeneration (bottom).

Another example of catalytic azide–alkyne cycloaddition (electro-click chemistry) was reported by Praveen et al. and involved an electrochemically generated copper(I) species from a copper(II) pre-catalyst. 1,2,3-Triazoles were successfully generated from terminal aromatic or aliphatic alkynes and terminal aromatic azides, and yields were generally good at 60–85% and reaction times between 2–3 hours (Scheme 8).¹⁰⁵ The working conditions involved an undivided cell using a graphite rod as a working electrode and Pt as a counter electrode. The reaction mixture consisted of (Bu₄N)(BF₄), Cu(NO₃)₂·3H₂O, alkyne, azide and 2,2′-bipyridine in DMSO. A potential of −0.25 V vs. Ag/AgCl (sat’d) was applied to reduce the Cu(II) species, and the reaction was carried out at room temperature.

	Scheme 8 Electrochemically generated Cu(I)-catalyzed click synthesis and the proposed mechanism for the e-click chemistry.

The speculated mechanism involves a carbophilic interaction between the electro-generated copper(I)-bipyridine complex species and the alkyne, followed by a σ,π-dicopper acetylide. The C–N bond formation would take place between the terminal nitrogen of the azide and the β-carbon of the cupric acetylide to form a dinuclear copper intermediate (which has also been proposed in the past).¹⁰⁶ Ring closure (leading to decupration) and proto-decupration are the final steps, which afford the triazolyl product and Cu(I), closing the cycle.¹⁰⁷

	Scheme 10 Enantioselective Cu-catalyzed cyanophosphinylation by rational optimisation of chiral bisoxazoline (BOX), bisphosphine ligand.

The optimized reaction conditions employed an undivided electrochemical cell with a carbon felt anode (working electrode) and a Pt cathode. A constant current of 3 mA was applied, resulting in an anodic potential between 165–185 mV versus the ferrocene/ferrocenium (Fc^0/+) reference. The reaction mixture contained (TBA)(BF₄), trifluoroethanol as a proton source, Cu(OTf)₂ (3 mol%), TMSCN, alkene and phosphine oxide in DMF. Under these conditions, the highest yields achieved were 51% with an 84% enantiomeric excess (ee). Notably, using trifluoroethanol instead of acetic acid as the proton source improved selectivity towards the desired product and reduced side-product formation. Post-electrolysis, the Pt cathode was visibly coated with metallic copper. Stahl and Liu¹¹⁰ reported a mechanistic study on the C–CN bond formation catalyzed by Cu and reported that a Cu(III) intermediate is crucial in the enantioselectivity-determining step; this intermediate has a pentacoordinate structure with two CN⁻ ligands in addition to a C-centered radical (from the cyanide). Several other articles report these penta-coordinated Cu(III) intermediates.^111–114 Following this, the same group functionalized a BOX ligand scaffold with an ancillary ligand (ester group) in anticipation of stabilizing the putative pentacoordinated Cu(III) complex prior to reductive elimination. These ligands produced 95% yields under optimized conditions; other alkene substrates were evaluated, giving moderate to high yields (46–86%) and high enantioselectivities in the range of 82–96%.

The proposed electro-catalytic mechanism was derived from CV data of the oxidation of Cu^I(BOX)(OTf) at 0.35 V. Upon adding TMSCN, a new oxidation peak formed at 0.15 V, when the phosphine oxide was added, in addition to TMSCN, the catalytic current was amplified (Fig. 7). They argued that two anodic events are taking place: firstly, the Cu(I) species is coordinating the CN⁻ ligand, which would be oxidized at the electrode and react with the phosphine oxide to generate a P-centered radical. This radical would react with the alkene via radical addition. Then, another anodic event would take place where the P-centered radical, captures ˙CN and then re-generates the Cu(I) complex. This then reacts with the transient radical intermediate with the newly formed C–P bond, generating the final product (Fig. 7). However, the stereoinduction induced by the complex is still not well understood.¹⁰⁹

	Fig. 7 (A) Cyclic voltammetry data and (B) proposed electrocatalytic cycle. (A) was adapted with permission.109 Copyright 2019, American Chemical Society.

Xu et al. recently reported an electro-catalytic method towards diazidation of alkenes (Scheme 11).¹¹⁵ This methodology is quite important given the prevalence of 1,2-diamines as valuable fine chemicals. Electron-deficient alkenes and alkenes with many functional groups are particularly difficult to functionalize in this manner. In the article, they employed very low loadings of simple copper complexes, copper(II) acetylacetonate (0.02 mol%) and reported that their method is compatible with many functional groups and proceeds with a variety of unactivated alkenes. The working conditions consisted of an undivided cell protected from air with a two-electrode configuration (constant current electrolysis). The optimized conditions consisted of constant electrolysis in MeCN/H₂O (1:2) at −10 °C in the presence of Cu(acac)₂ (0.02 mol%) as the electro-catalyst, 0.4 mmol for alkene, using TMSN₃ (6 equiv.) as the azido donor, and K₃PO₄ (0.8 equiv.) as the base. An RVC anode and a Pt cathode were used, and the inert electrolyte was (Bu₄)(BF₄) (Scheme 11). The optimized yield was 69% in these conditions. When evaluating the scope, the yields were moderate (43–81%), and the methodology tolerated many reactive functional groups, such as coordinating heteroarenes, electrophilic tosylates, alkyl bromides, Boc-protected amines, etc.

	Scheme 11 (A) Cyclic voltammograms obtained at a scan rate of 100 mV s−1 and (B) proposed mechanism. (A) was adapted with permission.115 Copyright 2022, American Chemical Society.

To investigate the mechanism, the cyclic voltammograms of the Cu(acac)₂ catalyst were investigated in the presence of TMSN₃ and K₃PO₄. When TMSN₃ was added, no apparent oxidation peak was observed, but in the presence of K₃PO₄, two irreversible waves with amplification of the current were observed, the first one of which was tentatively attributed to a Cu^II/III oxidation event. In the presence of alkene, no difference was observed for this oxidation peak, suggesting that a tentative Cu(III) would not react with the alkene fast enough on the timescale of the CV scan. As such, the proposed mechanism involves an electro-generated Cu(III)–N₃ species at the anode, followed by homolytic release of an azide radical, which reacts with an alkene. This generates a radical intermediate with a newly formed C–N₃ bond, which can react with a Cu(II)–N₃ species to leave behind a Cu(I) species and the final organic diazide product.

	Scheme 12 Electrocarboxylation of 1,4-diarylbuta-1,3-diynes with CO2 in the presence of a CuI catalyst and the proposed mechanism.

Similarly, the use of different metal salts, such as CuBr, CuCl, CuCl₂, FeCl₂, and FeCl₃ also afforded satisfactory yields of the lactone product while the use of Pd(OAc)₂ gave lower yields. Without current no product formation was observed, even in the presence of the CuI catalyst, confirming the essential role of electricity in the electrocarboxylation process. Regarding the mechanism, the authors argued that the role of the Cu(I) species is to facilitate the intramolecular cyclization of the carboxylate anion.

Huang and coworkers studied the formation of phenols and anilines under electrochemical conditions from aromatic boronic acids with electron-deficient or electron-rich groups (Scheme 13). Hydroxylation and amination of arylboronic acids were accomplished under constant potential conditions using metallic copper foil as anode and cathode, Ag/AgCl electrode as the reference electrode. The reaction was carried out in a saturated KNO₃ aqueous solution of NH₃ in an undivided cell (Scheme 13).¹²³

	Scheme 13 Electrochemical synthesis of phenols and aniline from arylboronic acid using dual copper anode/cathode system.

The dominant product formation was optimized by varying both the concentration of NH₃(aq) and the applied potential. At an applied potential of 0.6 V vs. Ag/AgCl with 0.13 M NH₃(aq), phenol was obtained as the major product (92%) with only 4% aniline. In contrast, selective formation of aniline (86% yield) was achieved by carefully lowering the applied potential to 0.2 V and increasing the NH₃(aq) concentration to 2.61 M. This result highlights the crucial role of NH₃(aq) concentration and applied potential in controlling the chemoselectivity of the transformation.

Inspired by the work of Huang et al., Gale-Day and co-workers explored an electrochemical version of the Chan–Evans–Lam cross-coupling reaction (Scheme 14). The methodology, employing a dual copper electrode system in combination with inexpensive Cu(OAc)₂, was particularly effective even for challenging couplings involving electron-deficient boronic acids. The optimized reaction conditions, with up to 98% yields, required the presence of both 2,6-lutidine and triethylamine (TEA), highlighting the critical role of an organic base in facilitating Chan–Evans–Lam coupling. This additive pair was proposed to enhance the formation of the active catalyst complex and accelerate the Cu^I/Cu^II oxidation process. Interestingly, cyclic voltammetry experiments did not exhibit an oxidative Cu^III/II peak, suggesting that Cu(III) species were not generated directly at the electrode surface. Instead, the authors proposed that Cu(II) species underwent disproportionation in solution to form Cu(III) intermediates, which subsequently underwent reductive elimination to yield the final product (Scheme 14).¹²⁴

	Scheme 14 Proposed catalytic cycle of the electrochemical Chan–Evans–Lam cross-coupling by Gale-Day et al.

Sevov et al. further advanced electrochemical Chan–Evans–Lam coupling by utilizing redox mediators, such as ferrocene (Fc), under anaerobic conditions (Scheme 15).¹²⁵ Their study demonstrated the multifaceted role of redox mediators, including (i) oxidation of low-valent copper intermediates, (ii) facilitating copper stripping from the anode to regenerate the catalyst and expose the active Pt surface for proton reduction, and (iii) providing moderate anodic potentials to prevent substrate over-oxidation. The mediator ferrocenium (Fc⁺) was employed due to its ability to readily oxidize Cu^I and Cu⁰ (E_1/2 = −0.8 V vs. Fc/Fc⁺), while being too mild to oxidize the amine substrate (E_1/2 = +0.5 V vs. Fc/Fc⁺). However, the use of ferrocene alone resulted in incomplete conversion, prompting the use of the pre-oxidized mediator ferrocenium hexafluorophosphate [Fc][PF₆] instead. This methodology was applied to a broad range of aryl-, heteroaryl-, and alkylamines with arylboronic acids, delivering coupled products in higher yields without the need for chemical oxidants. The reactions were conducted in an N₂-filled glovebox using an undivided cell, with aniline and phenylboronic acid as model substrates, triethylamine as a base, Cu(OAc) as a catalyst, NaOAc, [Fc][PF₆] as the mediator, and KPF₆ in MeCN as the supporting electrolyte (Scheme 15).

	Scheme 15 Ligandless copper electrocatalysis in Chan–Evans–Lam coupling facilitated by redox mediator.

The working electrode consisted of Ni foam, and a Pt electrode was used as the counter electrode; the reaction was carried out at 40 °C open to the atmosphere and a constant current (3 mA, 4 F mol⁻¹ where a Faraday = 96495 C). The reaction could be successfully scaled up to multigram synthesis with a yield of 72%. This mediator-based strategy once again highlighted higher yields can be obtained, methods can be scaled, and reduced reaction times achieved over the classical counterpart of this reaction in milder conditions.¹²⁵

Hu et al. introduced an electrochemical approach utilizing copper catalysis for the conversion of alkyl radicals into alkenes, enabling an aza-Wacker-type cyclization of internal alkenes to form a diverse range of five-membered N-heterocycles (Scheme 16).¹²⁹ This method facilitated the transformation of both secondary and primary alkyl radical intermediates, offering a broader scope compared to the traditional aza-Wacker cyclization. The reaction was optimized for both electron-donating and electron-withdrawing substituents by varying the base and applying a constant current. Notably, the reaction scarcely proceeded in the absence of a base, highlighting its crucial role. This approach allows the reaction to be conducted at room temperature, yielding the desired products efficiently.

	Scheme 16 The electrochemical Cu-mediated aza-Wacker cyclization (top) and the proposed mechanism (below).

The optimised reaction protocol involves a divided cell using MeOH and DCM (1:1) as the solvent system, a carbon fibre working electrode, Pt foil as the anode, Bu₄NOTs as the electrolyte, Cu(OAc)₂ as the catalyst, NaOPiv as the base under constant current mode (1.5 mA, j = 0.1 mA cm⁻²), and, yielding 33% of the product after passing 2.2 F at room temperature. Without copper, yields decreased substantially, and a H-abstraction byproduct was observed for some substrates. Tertiary alkyl radicals showed no difference in reactivity with or without Cu, possibly due to their rapid oxidation at the electrode. To understand the active species in the catalytic cycle, CV experiments were carried out, which suggested that a Cu(II)-catalyzed process is unlikely for cyclization. Instead, the group argued that its role may be to capture the electro-generated radical, forming a Cu(III) alkyl intermediate by reaction with the Cu(II) species, followed by base-assisted elimination to furnish the alkene product and Cu(I), which is reoxidized at the anode to Cu(II) (Scheme 16).

	Scheme 17 Oxidant free-copper(II) catalyzed electrooxidative C–H/N–H coupling and proposed mechanism.

Another strategy towards C–H amination of arenes with secondary amines was presented by Mei and co-workers (Scheme 18).¹³¹ Prior to their study, the group acknowledged several challenges that may be involved in this copper-catalyzed C–H amination, such as (1) overoxidation in light of the amine having a lower redox potential than the arene substrate, (2) functional group tolerance given the high redox potentials required to reach a Cu^III/II oxidation process, and (3) possible catalyst deactivation since alkyl amines and the amination products could compete for coordination e.g., undergo ligand exchange with the active Cu(II) species.

	Scheme 18 (A) Cu-catalyzed electrooxidative C–H amination (B) indirect electrolysis using a redox mediator.

To circumvent these challenges, a redox mediator was used, (Bu₄N)I, to carry out the reaction at a lower potential. Arenes with a variety of electron withdrawing and electron donating substituted functional groups were examined under the optimized conditions. The electrolysis was performed at a constant current for 24 h in an undivided cell and at room temperature, employing 10 mol% of Cu and 50 mol% of the redox mediator, using Pt electrodes as working and counter electrodes, KOPiv as the base, and MeCN as the solvent. The cyclic voltammetry experiment revealed different aspects that were used as arguments for a mechanistic proposal. In the presence of an arene substrate, the oxidation wave was assigned to a Cu(II) species which was shifted significantly to lower potentials (from 2.42 to 1.75 V vs. Ag/AgI). Furthermore, when a morpholine unit was added, the potential decreased to 1.51 V, which is also attributed to metal coordination. When (Bu₄N)I was added, a catalytic current appeared, assigned to Cu^II/III oxidation by an iodine radical. The reactions were tested at high potentials (1.4 V, 2.0 V vs. Ag/AgI) by substituting the salt with (Bu₄N)I, which gave yields of product in the order of 20% and 53%. In contrast, when the reaction was carried out at 0.8 V, higher currents were observed, and the product was obtained in a much higher yield of 78%.

Mechanistic studies showed that faster rates were observed for substrates bearing electron-donating groups, and the Hammett plot revealed a negative slope consistent with an expected single electron transfer (SET) mechanism, which favours electron-rich substrates. Kinetic isotope effect (KIE) studies yielded a value of 1.0, indicating that the putative C–H cleavage is not involved in the rate-determining step. Instead, the rate-determining step is the electron transfer between the iodine radical and the copper complex. Radical trapping experiments with TEMPO completely inhibited the reaction. The mechanism proposed involved coordination to the arene substrate and amine, followed by oxidation of I⁻ to I˙ at the anode, generating Cu(III), which undergoes a single-electron transfer (SET) to give a Cu(II) intermediate, and another SET to give a Cu(I) species and de-coordination of the product. The Cu(II) species in solution would likely be regenerated by I˙ (Scheme 19).

	Scheme 19 Proposed catalytic cycle for copper-catalyzed electrooxidative C–H amination using (Bu4N)I as a redox mediator.

Budnikova and co-workers also studied the single-step (2e⁻ oxidation) C–H amidation of benzene derivatives to form N-arylamides achieving desired products in moderate to high yields (42–78%) (Scheme 20).¹³² Classically, these reactions have involved harsh conditions (i.e. strong oxidants and high temperatures) leading to by-product formation, and require stoichiometric amounts of reagents, making them less practical and sustainable. The Budnikova et al. experimental set-up consisted of a divided cell with a Pt cylinder and rod as the working and counter electrodes. The reaction mixture consisted of the benzene derivative substrate, Cu(OAc)₂, and MeCN or PhCN as the solvent; the reaction was carried out at room temperature under constant current (2–4 F) for 2–4 hours (Scheme 20). In the case of naphthalene, 2,6-dimethylnaphthalene, 2-phenylpyridine, p-bromoanisole and anisole the electrooxidation afforded C–C bond formation rather than C–N bond formation.

	Scheme 20 Different C–H transformations depend on the nature of the substrate and oxidation potentials.

For substrates where the reaction could proceed at the benzylic C(sp³)–H bond or aromatic C(sp²)–H bond, it seems that the oxidation potential of the benzene derivative determines the outcome. In the case of amidation of the aromatic ring, this takes place for substrates that are harder to oxidize, as determined by cyclic voltammetry. The case for copper mediation (or catalysis) here is argued to be the involvement of an organocopper(III) complex, followed by a series of ligand attacks (Scheme 21).

	Scheme 21 Proposed mechanism for the amidation of substituted benzenes.

The Kakiuchi group reported the electrolytic chlorination of various 1,3-dicarbonyls using HCl as an accessible chlorine source and catalytic amounts of Cu(OTf)₂ (Scheme 23).¹³⁷ When investigating substrates with different allylic and alkyl symmetric and asymmetric functional groups (e.g., –NMe₂, –Ph, 2-furyl, –Me, etc.), they observed moderate to good yields (53–82%), with dichlorination also being detected. Additionally, copper(II) triflate was explored as a catalyst, yielding similar results, whereas copper(II) chloride led to a lower yield.

	Scheme 23 Copper-catalyzed electrochemical α-chlorination of 1,3-dicarbonyls.

The reaction was carried out in an H-cell equipped with an anion-exchange membrane, using Pt electrodes as both working and counter electrodes. The anodic chamber contained the 1,3-dicarbonyl substrate (0.25 mmol), Cu(OTf)₂ in MeCN, while the cathodic chamber was filled with an aqueous solution of hydrochloric acid (2.0 M). A constant current density of 0.42 mA cm⁻² (2.5 mA current) was applied at room temperature, and the anodic chamber containing the working electrode was stirred for 6 h.

Kakiuchi et al. argued that the β-ketoester, methyl 3-oxo-3-phenylpropanoate, forms a complex with Cu(OTf)₂, involving two deprotonated ligands, as evidenced by ESI-MS analysis. However, the addition of two equivalents of triflic acid (HOTf) to this copper complex resulted in a 77% yield of the desired product, comparable to the 70% yield obtained with Cu(OTf)₂. The exact mechanism remains ambiguous, but it is suggested that the copper enolate reacts with a chlorinating agent, possibly Cl⁺, generated through anodic oxidation of chloride ions that migrate from the cathodic chamber through the anion-exchange membrane.

Fang and co-workers reported electrochemical C–H activation of 8-aminoquinoline amides to give C–Br bond formation at C5 by employing methodology that utilized Cu(OAc)₂ in catalytic amounts and NH₄Br as the brominating agent (Scheme 24).¹³⁸ CuI and Cu(OTf)₂ were also tested as catalysts but yielded lower results compared to Cu(OAc)₂. The optimized conditions were achieved by adjusting the temperature and selecting an appropriate brominating agent. The general electrochemical set-up consisted of an undivided cell with Pt as the working and counter electrodes, and DMF as the solvent. The electrolysis was performed under a constant current of 3 mA cm⁻² at 60 °C, and the reaction was monitored by TLC until completion (30–40 h). Excellent yields of 89–98% were obtained with different aromatic and aliphatic functional groups.

	Scheme 24 Electrochemical Cu-catalyzed bromination of 8-aminoquinoline amide and the proposed mechanism.

Based on the results of the scope study and cyclic voltammetry analysis, the proposed reaction mechanism (Scheme 24) was suggested to involve initial coordination of the substrate to Cu(OAc)₂via both the secondary amido and quinoline N-donors, forming complex (i). The Cu(I) species (ii) is then generated through a single-electron transfer (SET) process, initiated by the attack of a bromine atom arising from anodic oxidation of Br⁻ in solution, forming either Br₃⁻ or Br₂. The Cu(I) intermediate (ii) is then re-oxidized at the anode, yielding intermediate (iii), which tautomerises to form complex (iv) and dissociates to complete the cycle. Kinetic isotope effect (KIE) studies indicate that the C–H bond activation step was not the rate-determining step of the reaction.¹³⁸

Zhang et al. recently studied the copper-catalyzed electrochemical fluorination of C–H bonds (Scheme 25).¹⁴² They previously detected a [Cu^IIILF] species (L = pyridine bis-carboxaldehyde) with a low redox potential (0.47 vs. Ag⁺/Ag) that could perform C–H fluorination reactions, albeit under stoichiometric quantities. Following this, the researchers developed a catalytic process utilizing an isolable Cu(III) fluoride complex with a stoichiometric approach for C–H fluorination. The group claimed that the method overcomes the limitations associated with expensive fluoride salts by employing a simple salt as the fluoride source. The optimized reaction conditions consisted of [Cu^II(L)(MeCN)] (L = pyridine bis-carboxaldehyde) as the catalyst, CsF as the fluoride source, and (Bu₄N)(ClO₄) as the supporting electrolyte in tetrahydrofuran (THF) as the C–H source. Reactions were carried out in an undivided electrochemical cell at a constant voltage of 3.3 V in MeCN and propylene carbonate (PC). This setup enabled precise control over the potential and oxidation rates, ensuring efficient fluorination under electrochemical conditions.

	Scheme 25 Copper-catalyzed electrochemical C–H fluorination.

Yield optimization and stability of the electro-generated Cu(III) complex were explored, and it was observed that aprotic polar solvents such as MeCN and propylene carbonate gave the highest yields. Fluorination selectivity of the C–H substrates was reportedly driven by an oxidative asynchronous proton-coupled electron transfer (PCET) at the electrophilic Cu^III–F complex. This mechanism was selective for strongly hydridic C–H bonds over weaker C–H bonds that are less acidic.

	Fig. 8 (A) Spectrophotometric evidence for (bpy)Cu(II)-mediated oxidation of TEMPOH (and benzyl alcohol) under anaerobic conditions. (B) The proposed mechanism of (bpy)Cu/TEMPO-mediated alcohol oxidation. Fig. 8A was adapted with permission.143 Copyright 2016, Nature.

The cyclic voltammograms were also examined, the best Brønsted bases (NMI, Et₃N, etc.) were screened by addition to a mixture of [Cu((II)(bpy)/(nitroxyl)] in 0.1 M (Bu₄N)(ClO₄) in MeCN, which showed significant catalytic features, with triethylamine (Et₃N) being particularly effective. A catalytic sigmoidal shaped curve was observed in the presence of these bases, allowing quantification of their effectiveness. Other optimization protocols (e.g. concentration of alcohol), and mechanistic information (kinetic isotope effect) could also be elucidated by cyclic voltammetry. A synthetic-scale experiment was not conducted; however, electrolysis was performed to monitor UV-Vis spectral changes over a 20-minute reaction period. The experiment was carried out using a glassy carbon working electrode in MeCN, with (Bu₄N)(ClO₄) as the supporting electrolyte. Cu(II)(OTf)₂ and 2,2′-bipyridine (bpy) were employed as catalytic components. TEMPO and 2,6-lutidine were included, with the latter serving as a Brønsted base (proton acceptor). Additionally, PhCH₂OH was introduced as a reagent (Fig. 8). The mechanism using the [Cu(II)(bpy)(nitroxyl)] catalysts was proposed to involve the (bpy)Cu(II)/(bpy)Cu(I) redox couple. In this process, the nitroxyl species facilitates a combined one-proton/two-electron oxidation of the Cu(II)-coordinated alkoxide ligand, a crucial step for catalytic activity. This process resembles β-hydride elimination, whereby the proton and two electrons are distributed between Cu(II) and the nitroxyl species, ultimately generating Cu(I)[(bpy)] and hydroxylamine (e.g., TEMPOH). Overall, Cu(II) functions as a one-electron oxidant, while the nitroxyl species acts as an electron-proton acceptor, enabling efficient catalytic turnover (Fig. 8).

	Scheme 26 Proposed reaction mechanism for the copper-catalyzed electrochemical selective B–H oxygenation of o-carboranes. Adapted with permission.144 Copyright 2020, American Chemical Society.

The study focused on the reaction of carbonyl amides with lithium tert-butoxide (LiO^tBu) to selectively form the B(4)-monooxygenated product. Using Cu(OTf)₂ as a catalyst, the electrochemical reaction was conducted in a divided cell with an RVC anode and a Pt cathode at room temperature for 12 hours, yielding a moderate 60% yield in THF. Notably, replacing the AMI-7001 cell membrane with a P4 sintered glass membrane significantly enhanced the yields to 83–96%.

Control experiments confirmed the necessity of both the copper catalyst and the applied electric current for the reaction. The electrolysis was performed at a constant current of 4 mA for 12 hours. The low yields obtained in the absence of an oxidative current, along with increased yields when using O₂ as the oxidant, suggested the involvement of a high-valent Cu(III) species, likely generated either by oxidation in the presence of O₂ or by disproportionation of the Cu(II) salt. A radical pathway was ruled out, as the addition of radical scavengers did not affect the reaction outcome. The proposed mechanism involves bidentate chelation of the carboranyl amide with Cu(OTf)₂, followed by anodic oxidation to generate a Cu(III) species. This species then undergoes an electrophilic attack at the B(4)–H bond, followed by reductive elimination and protonation, ultimately yielding the B(4,5)-dioxygenated products (Scheme 26).¹⁴⁴ Ackermann et al. reported analogous Cu-electrocatalysed, C–H chalcogenation reactions of o-carboranes with various thiols and selenols in good yields.¹⁴⁸