Ni-catalyzed Electrochemical Cross-Electrophile Coupling Paired with Oxygen Evolution Reaction

Ni-catalyzed Electrochemical Cross-Electrophile Coupling Paired with Oxygen Evolution Reaction | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Ni-catalyzed Electrochemical Cross-Electrophile Coupling Paired with Oxygen Evolution Reaction Renyi Shi, Donghao Huo, Wenjing Li, Rui Ma, Shentong Xie, Pengcheng Wang, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7763126/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Nickel-catalyzed cross-electrophile coupling (XEC) has emerged as an efficient and economical strategy for constructing C–C bonds, a pivotal transformation in diversifying molecular architectures. However, conventional XEC methodologies typically rely on stoichiometric metallic reductants, which present inherent challenges including safety risks, operational instability, and environmental concerns. Although electrochemical XEC in undivided cells circumvents the need for chemical reductants, it remains constrained by sustainability issues and chemo-selectivity limitations due to its dependence on sacrificial metal anodes or stoichiometric organic donors to supply electrons for cathodic reduction. Herein, we report a nickel-catalyzed electrochemical cross-electrophile coupling paired with the oxygen evolution reaction (OER). By utilizing water as an economical and sustainable sacrificial electron donor, this electrochemical platform facilitates the versatile construction of diverse C–C bonds, including Csp 2 –Csp 3 , Csp 3 –Csp 3 , and Csp–Csp 3 linkages, from readily accessible aryl, alkenyl, alkynyl, and alkyl halide electrophiles, affording products in yields up to 99%. The undivided cell configuration markedly reduces system complexity, lowers capital costs, and supports scalable electrochemical synthesis. Moreover, this electroreductive coupling strategy exhibits broad functional group tolerance and is amenable to the late-stage derivatization of complex drugs and natural products. This operationally simple, electricity-driven approach offers a sustainable and versatile platform for C–C bond formation. Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Green chemistry Figures Figure 1 Figure 2 Figure 3 Introduction Carbon–carbon (C–C) bonds constitute essential structural motifs in pharmaceuticals, agrochemicals, and functional materials, serving as central scaffolds in numerous bioactive molecules. [1,2] Conventional methodologies for constructing these bonds predominantly employ transition-metal-catalyzed cross-coupling reactions between organohalide electrophiles and preformed organometallic nucleophiles. [3–9] However, the reliance on such carbon nucleophiles—which themselves often necessitate pre-synthesis from organohalides—introduces synthetic inefficiencies and operational complexities. In response, cross-electrophile coupling (XEC) has emerged as an efficient alternative strategy, enabling the direct coupling of two electrophilic coupling partners. [7,10–21] The most prevalent XEC paradigm employs nickel catalysis paired with stoichiometric metallic reductants such as manganese or zinc powders (Fig. 1 a). Nevertheless, this approach suffers from several limitations that impede scalable implementation: inconsistent reactivity due to variations in metal particle morphology and surface passivation, practical difficulties in homogenizing high-density metal powders in batch reactors, and the generation of stoichiometric quantities of metal waste. These drawbacks have stimulated growing interest in electrochemical strategies as more sustainable and scalable avenues for XEC transformations. Electrochemical synthesis offers a promising platform for developing sustainable routes to industrial chemicals, presenting distinct advantages over traditional methods that often involve hazardous reagents or energy-intensive processes. [21–26] Anodic oxidation reactions, in particular, exhibit a favorable environmental profile, as they can frequently be conducted under reagent-free conditions with molecular hydrogen (H 2 ) generated as the sole byproduct at the counter electrode. [27,28] In contrast, reductive electrochemical cross-electrophile couplings conducted in undivided cells pose significant sustainability challenges due to their inherent demand for an external electron source to drive the cathodic transformation. At the laboratory scale, this electron requirement is typically supplied by sacrificial metal anodes or stoichiometric organic reductants. [29–44] While operationally simple for small-scale applications, such strategies become economically and environmentally prohibitive at scale due to the substantial consumption of sacrificial materials and concomitant generation of metal-containing waste or organic byproducts (Fig. 1 b). To address these issues, Stahl and co-workers reported a mediated H 2 anode that achieves indirect electrochemical oxidation of H 2 by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone. [39] This quinone-mediated H 2 anode is used to support nickel-catalysed electrochemical cross-electrophile couplings. In contrast to the electrochemical hydrogen oxidation reaction (HOR), which requires gaseous H 2 and specialized electrode architectures, the oxygen evolution reaction (OER)—involving the oxidation of water to molecular oxygen—represents a more sustainable and practically viable anodic process. [45,46] However, the implementation of OER in electrochemical cross-electrophile couplings faces two critical challenges: (i) the compatibility between aqueous OER and organic electrochemical reactions, and (ii) suppression of competitive substrate, product, or catalyst oxidation due to a more anodic the high operating potential required for OER (Fig. 1 c). The potential for OER in organic solvents can be described by the following expression: $$\:\text{E}\left(\text{O}\text{E}\text{R}\right)=\text{E}^\circ\:\left(\text{O}\text{E}\text{R}\right)+\:\frac{RT}{nF}ln\frac{\left[{\text{H}}^{+}\right]}{\left[{\text{H}}_{2}\text{O}\right]}+\eta\:$$ where E o (OER), R, T, n, F and η represent the thermodynamic standard potential of OER (about + 0.59 V vs. Fc/Fc⁺), gas constant, temperature, number of the electron transfer, Faraday constant and over potential respectively. This equation indicates that the OER potential in organic media is highly dependent on concentration of proton, concentration of water, and the electrocatalytic properties of the anode material, which determines the value of η. We hypothesized that these challenges could be mitigated through careful regulation of water content, screening of alkaline additives, and optimization of anode materials. Herein, we report a Ni-catalyzed electrochemical cross-electrophile coupling that facilitates C–C bond formation paired with oxygen evolution reaction (Fig. 1 d). This strategy circumvents the need for sacrificial metal anodes or stoichiometric organic reductants, offering a more sustainable and operationally simplified approach to reductive cross-coupling. Results and discussion To establish a general protocol for Ni-catalyzed electrochemical cross-electrophile coupling employing water as a sacrificial reductant, methyl 4-iodobenzoate (aryl halide, 1a ) and 4-iodotetrahydropyran (alkyl halide, 2a ) were selected as model substrates. The initial reaction conditions employed NiCl 2 ·dme (10 mol%) as the precatalyst, dtbpy (15 mol%) as the ligand, LiOTf (0.2 M) as the electrolyte, and DMA (6 mL) as the solvent, with a Pt anode, carbon felt cathode, and a constant current of 30 mA (Scheme 1a ). Water was identified as a critical sacrificial reductant for achieving high efficiency. Consequently, the effect of water equivalents was systematically evaluated. In the absence of added water, the reaction proceeded at room temperature for 4 hours to afford methyl 4-(tetrahydro-2H-pyran-4-yl)benzoate (3a) in 37% GC yield, presumably due to trace moisture present in the solvent. The low yield (3%) obtained when using anhydrous DMA as the solvent underscores the critical role of water as a sacrificial anode reagent in this reaction. The product yield increased significantly with higher water loading, reaching an optimum of 86% with 30 equivalents. A further increase to 1 mL of water resulted in a notable decrease in yield, likely attributable to compromised solubility of organic reactants. Subsequent efforts focused on reducing concentration of proton by the introduction of base to lower the potential of oxygen evolution reaction (OER) (Scheme 1b ). The addition of 20% sodium carbonate enhanced the yield of 3a to 99% (Entry 1). Alternative basic additives, including Cs 2 CO 3 and NaOH, were evaluated but proved detrimental to reactivity (Entries 2 and 3). Replacement of the Pt anode with an IrO 2 electrode—an efficient OER catalyst—yielded only trace product, likely owing to incompatibility with the organic medium (Entry 4). Other anode materials such as gold and carbon felt also exhibited inferior performance (Entries 5 and 6). Control experiments underscored the essential roles of the nickel catalyst, ligand, and electrochemical activation. No product formation was observed in the absence of NiCl 2 ·dme, dtbpy, or applied current (Entries 7–9). With the optimized reaction conditions in hand, we systematically evaluated the generality and functional group compatibility of the nickel-catalyzed electrochemical cross-electrophile coupling using water as a sacrificial reductant. Initially, the coupling between various aryl iodides and alkyl iodides was investigated (Scheme 2a ). Aryl iodides bearing electron-withdrawing groups like ester ( 3a – 3c ), trifluoromethyl ( 3d , 3e ), and cyano ( 3f ) were well tolerated. Substitutions at the meta -position of the phenyl ring significantly influenced the reaction yields ( 3c ), whereas ortho -substituents led to a slight decrease in yield ( 3b , 3e ), indicating notable steric effects. Notably, aryl iodides containing halogen substituents such as -F, -Cl, and even -Br proved to be suitable substrates, offering handles for further functionalization ( 3g – 3i ). Electron-rich aryl iodides also underwent smooth coupling, affording products in moderate yields ( 3j – 3p ). To our delight, substrates with unprotected amino groups were compatible, delivering 4-(tetrahydro-2H-pyran-4-yl)aniline in 81% yield ( 3q ). Substrate containing oxidation-sensitive functional groups like aldehyde could be successfully employed in the divided cell system, thereby delivering the desired products in moderate yields ( 3r ). The Bpin group was also tolerated under the standard conditions ( 3s ). Furthermore, complex aromatic systems including biphenyl ( 3t ), naphthalene ( 3u ), and dimethylfluorene ( 3v ) served as viable coupling partners. Indole, a privileged scaffold in bioactive molecules, was also compatible with this electrochemical system ( 3w ). As summarized in Scheme 2b , the reaction exhibited broad compatibility with diverse alkyl iodides. Secondary cyclic alkyl iodides including four-membered ( 3x ), five-membered ( 3y ), six-membered ( 3z ), and seven-membered rings ( 3aa ) underwent efficient coupling, demonstrating insensitivity to ring size and strain. 5-Iodo-2-phenyl-1,3-dioxane was also a suitable substrate, affording the product in moderate yield ( 3ab ). Primary alkyl iodides performed well, affording methyl 4-(3-(p-tolyl)propyl)benzoate in 97% yield ( 3ac ). The method further displayed excellent functional group tolerance on the alkyl partner, successfully accommodating chloride ( 3ad ), nitrile ( 3ae ), thioether ( 3af ), ether ( 3ag ), -CF₃ ( 3ah ), thiophene ( 3ai ), and furan ( 3aj ) functionalities. To further demonstrate the versatility of this electrochemical cross-coupling system, we expanded its scope to include alkyl-alkyl electrophilic couplings, encompassing both primary–secondary and primary–primary alkyl partners (Scheme 3a , 3 ak and 3al ). The protocol was also successfully applied to alkenyl bromides, affording the desired product in 61% yield ( 3am ). Additionally, the system proved effective for the construction of Csp–Csp 3 bonds, yielding disubstituted alkynes ( 3an ). Notably, the method was compatible with less reactive aryl bromides under the standard electrochemical conditions. A range of substituted aryl bromides including those bearing esters, fluorine, and chlorine underwent efficient coupling with both primary and secondary alkyl iodides to deliver the corresponding products in moderate yields ( 3a , 3g , 3h , 3u , 3ao , 3y ). The synthetic utility of this methodology was further highlighted through the late-stage functionalization of complex bioactive molecules and natural product derivatives (Scheme 3b ). Successful couplings were achieved with substrates derived from Gemfibrozil ( 3ap ), Clofibrate ( 3aq , 3ar ) and Ibuprofen ( 3as ). These transformations proceeded efficiently, underscoring the potential of this electrochemical strategy for the modular functionalization of pharmacologically relevant compounds. To assess the scalability of the electrochemical cross-coupling, a gram-scale reaction was performed at 10 mmol scale under slightly modified conditions (constant current: 100 mA). The desired coupled product was isolated in 58% yield (1.36 g), demonstrating the practical utility of this method for larger-scale synthesis (Scheme 4 , Eq. 1). This approach offers a direct route to alkyl–aryl linkages from carboxylic acid derivatives, eliminating the need for preformed alkyl halides (Scheme 4 , Eq. 2). To probe the reaction mechanism, a series of control experiments were conducted. Analysis of the headspace gas via GC during the standard reaction confirmed the evolution of oxygen (0.18 mmol), supporting the occurrence of the oxygen evolution reaction (OER) under the electrochemical conditions (Scheme 4 , Eq. 3). The addition of stoichiometric TEMPO completely inhibited product formation, suggesting the involvement of radical intermediates (Scheme 4 , Eq. 4). This hypothesis was further corroborated by the reaction of methyl 4-iodobenzoate ( 1a ) with (iodomethyl)cyclopropane, which yielded the ring-opened product 3at , consistent with the generation of a primary alkyl radical that undergoes rapid ring fragmentation (Scheme 4 , Eq. 5). Further mechanistic insight was gained through cyclic voltammetry (CV) studies (Fig. 2 ). In the presence of ligand, the Ni complex exhibited two reduction peaks at -1.19 V and − 1.88 V (vs. Ag/AgCl), attributed to the Ni II /Ni I and Ni I /Ni 0 redox couples, respectively (Fig. 2 a). The reduction potentials of iodobenzene and 4-iodotetrahydropyran were observed at -2.22 V and − 2.16 V (vs. Ag/AgCl), respectively, indicating that reduction of the NiCl 2 ·dme/dtbpy complex occurs more readily than that of the organic iodides. Upon addition of iodobenzene, a catalytic current increase was observed for the Ni I /Ni 0 couple, while the Ni II /Ni I couple remained largely unaffected, suggesting that oxidative addition of aryl iodide preferentially occurs at Ni 0 (Fig. 2 b). In contrast, introduction of 4-iodotetrahydropyran led to an increase in catalytic current for both the Ni II /Ni I and Ni I /Ni 0 redox events, indicating that alkyl iodides are more likely to react with Ni I species (Fig. 2 c). Based on the results described above, a plausible mechanism is proposed as shown in Fig. 3 . Cathodic reduction of catalyst precursor generates an active Ni 0 species ( A ), which undergoes oxidative addition with aryl iodide (Ar-I) to form an aryl-Ni II -I intermediate ( B ). Subsequent electrochemical reduction yields an aryl-Ni I -I complex ( C ), which participates in single-electron transfer (SET) with alkyl iodide (R-I) to generate an alkyl radical (R•) and regenerate aryl-Ni II -I ( D ). Radical capture affords a high-valent Ar-Ni III -R species ( E ), and reductive elimination delivers the coupled product while regenerating a Ni I intermediate ( F ). The Ni I species is reduced at the cathode to Ni o , regenerating the catalyst. Conclusions In summary, we have developed a novel nickel-catalyzed electroreductive cross-coupling method for C–C bond formation, using H 2 O as an economical and sustainable sacrificial reductant. This electrochemical platform enables the versatile construction of diverse C–C bonds including Csp 2 –Csp 3 , Csp 3 –Csp 3 , and Csp–Csp 3 linkages, from readily accessible aryl, alkenyl, alkynyl, and alkyl halide electrophiles, delivering products in yields of up to 99%. The approach eliminates the need for sacrificial metal anodes or stoichiometric organic reductants, offering a more sustainable and operationally straightforward alternative for cross-electrophile coupling. Furthermore, this electroreductive coupling strategy displays excellent functional group tolerance and is suitable for the late-stage derivatization of complex drugs and natural products. This operationally simple, electricity-driven method provides a sustainable and versatile platform for C–C bond formation. We anticipate that this strategy will find broad utility in synthetic and medicinal chemistry. Declarations Competing interests The authors declare no competing interests. Author contributions R.S. directed the project. A.L. and R.S. conceived the idea, designed the experiments and wrote the manuscript. D.H., W.L. and R.M. performed the synthetic experiments. All the authors participated in the discussion and preparation of the manuscript. Acknowledgements This work is supported by the “Young Talent Support Plan” of Xi’an Jiaotong University and the Natural Science Foundation of Shaanxi Province (2023-JC-QN-0102). 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Supplementary Files supportinginformation.pdf supporting information GA.png SC1.png Scheme 1 Screening of the reaction conditions. [a] Reaction conditions: 1a (0.5 mmol), 2a (0.6 mmol), NiCl₂·dme (10 mol%), dtbpy (15 mol%), LiOTf (0.2 M), DMA (6 mL), Pt anode, Carbon felt cathode, undivided cell, I = 30 mA, rt, 4 h. Yields were determined by GC using naphthalene as an internal standard. [b] 1a (0.5 mmol), 2a (0.6 mmol), NiCl₂·dme (10 mol%), dtbpy (15 mol%), 20 mol% Na2CO3, 30 eq. H₂O, LiOTf (0.2 M), DMA (6 mL), Pt anode, carbon felt cathode, undivided cell, I = 30 mA, rt, 4 h. Yields were determined by GC using naphthalene as an internal standard. SC2.png Scheme 2. Electrochemical cross-electrophile coupling between aryl iodides and alkyl iodidies. Reaction conditions: 0.5 mmol aryl idodies 1, 0.6 mmol alkyl iodides 2, 10 mol% NiCl2·dme, 15 mol% dtbpy, 6 mL DMA, 30 eq. H2O, 0.2 M LiOTf, 20 mol% Na2CO3, Pt anode, carbon felt cathode, undivided cell, rt, 30 mA, 4 h, isolated yields. [a] Deviation: Divided cell. SC3.png Scheme 3. Csp/sp2/sp3-Csp3 electrochemical cross-electrophile coupling and late-stage modification of biorelevant compounds. Reaction conditions: 0.5 mmol 1, 0.6 mmol 2, 10 mol% NiCl2·dme, 15 mol% dtbpy, 6 mL DMA, 30 eq. H2O, 0.2 M LiOTf, 20 mol% Na2CO3, Pt anode, carbon felt cathode, undivided cell, rt, 30 mA, 4 h, isolated yields. [a] Deviation: 3 eq. 1, 0.5 mmol 2, divided cell. [b] Deviation: 2 eq. 1, 0.5 mmol 2. [c] Deviation: 0.5 mmol 1, 2 eq. 2, divided cell. SC4.png Scheme 4. Scale-up experiment and control experiments. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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06:38:26","extension":"html","order_by":21,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":119434,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/6775e11a0f62da40887d99f0.html"},{"id":93994286,"identity":"28098320-6619-4dd0-b79d-5218fa112d47","added_by":"auto","created_at":"2025-10-21 06:38:25","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":222666,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Cross-electrophile coupling (XEC). (b) Electrochemical cross-electrophile coupling. (c) The integration of electrochemical cross-electrophile coupling with the oxygen evolution reaction (OER). (d) Our reaction.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/b25d0dee3134fbba153a8002.png"},{"id":93993927,"identity":"41ed971d-447b-4e97-89a0-a5a15b451948","added_by":"auto","created_at":"2025-10-21 06:30:25","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":212785,"visible":true,"origin":"","legend":"\u003cp\u003eCyclic voltammetry experiments.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/ad5cd4de64e12bae2a700847.png"},{"id":93993930,"identity":"d405229a-be13-458d-9519-e5d0dfe5efd5","added_by":"auto","created_at":"2025-10-21 06:30:25","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":38849,"visible":true,"origin":"","legend":"\u003cp\u003eProposed mechanism\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/f3901eea0cbb8d6945bbe138.png"},{"id":96362805,"identity":"96eefa2b-fb48-485d-88a7-2508af10f4fc","added_by":"auto","created_at":"2025-11-20 09:54:23","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1318699,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/9deb203e-edba-455d-a313-e36dd89cbcf6.pdf"},{"id":93993932,"identity":"048ac07e-e7d1-4f4b-84e1-3e2d12cdfa9a","added_by":"auto","created_at":"2025-10-21 06:30:26","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":6995081,"visible":true,"origin":"","legend":"supporting information","description":"","filename":"supportinginformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/ac0c0603590c2520e3998728.pdf"},{"id":93994287,"identity":"4be72864-2d88-4b0e-a750-da0f2b828ac7","added_by":"auto","created_at":"2025-10-21 06:38:25","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":88883,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"GA.png","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/3ca9689a382a6429c9593e70.png"},{"id":93994289,"identity":"bcfdd849-ec96-4490-8123-acee0258800e","added_by":"auto","created_at":"2025-10-21 06:38:26","extension":"png","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":163085,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 1\u003c/strong\u003e Screening of the reaction conditions. [a] Reaction conditions: \u003cstrong\u003e1a\u003c/strong\u003e (0.5 mmol), \u003cstrong\u003e2a\u003c/strong\u003e (0.6 mmol), NiCl₂·dme (10 mol%), dtbpy (15 mol%), LiOTf (0.2 M), DMA (6 mL), Pt anode, Carbon felt cathode, undivided cell, I = 30 mA, rt, 4 h. Yields were determined by GC using naphthalene as an internal standard. [b] \u003cstrong\u003e1a\u003c/strong\u003e (0.5 mmol), \u003cstrong\u003e2a\u003c/strong\u003e (0.6 mmol), NiCl₂·dme (10 mol%), dtbpy (15 mol%), 20 mol% Na2CO3, 30 eq. H₂O, LiOTf (0.2 M), DMA (6 mL), Pt anode, carbon felt cathode, undivided cell, I = 30 mA, rt, 4 h. Yields were determined by GC using naphthalene as an internal standard.\u003c/p\u003e","description":"","filename":"SC1.png","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/24dba8c3212b09fd1cabb183.png"},{"id":93993937,"identity":"21199484-805f-41ff-90ac-82396b3201a6","added_by":"auto","created_at":"2025-10-21 06:30:26","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":281239,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 2. \u003c/strong\u003eElectrochemical cross-electrophile coupling between aryl iodides and alkyl iodidies. Reaction conditions: 0.5 mmol aryl idodies \u003cstrong\u003e1\u003c/strong\u003e, 0.6 mmol alkyl iodides \u003cstrong\u003e2\u003c/strong\u003e, 10 mol% NiCl2·dme, 15 mol% dtbpy, 6 mL DMA, 30 eq. H2O, 0.2 M LiOTf, 20 mol% Na2CO3, Pt anode, carbon felt cathode, undivided cell, rt, 30 mA, 4 h, isolated yields. [a] Deviation: Divided cell.\u003c/p\u003e","description":"","filename":"SC2.png","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/05f92a45ba66cd2e59203b53.png"},{"id":93993935,"identity":"9ddd7df8-092a-49b3-ad3b-09d7cf9b5bc8","added_by":"auto","created_at":"2025-10-21 06:30:26","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":279593,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 3. \u003c/strong\u003eCsp/sp2/sp3-Csp3 electrochemical cross-electrophile coupling and late-stage modification of biorelevant compounds. Reaction conditions: 0.5 mmol \u003cstrong\u003e1\u003c/strong\u003e, 0.6 mmol \u003cstrong\u003e2\u003c/strong\u003e, 10 mol% NiCl2·dme, 15 mol% dtbpy, 6 mL DMA, 30 eq. H2O, 0.2 M LiOTf, 20 mol% Na2CO3, Pt anode, carbon felt cathode, undivided cell, rt, 30 mA, 4 h, isolated yields. [a] Deviation: 3 eq. \u003cstrong\u003e1\u003c/strong\u003e, 0.5 mmol \u003cstrong\u003e2\u003c/strong\u003e, divided cell. [b] Deviation: 2 eq. \u003cstrong\u003e1\u003c/strong\u003e, 0.5 mmol \u003cstrong\u003e2\u003c/strong\u003e. [c] Deviation: 0.5 mmol \u003cstrong\u003e1\u003c/strong\u003e, 2 eq. \u003cstrong\u003e2\u003c/strong\u003e, divided cell.\u003c/p\u003e","description":"","filename":"SC3.png","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/c096019e11fceb6a4965d993.png"},{"id":93994916,"identity":"428bec31-71b6-4163-bfc0-33bfa7e0cbfb","added_by":"auto","created_at":"2025-10-21 06:46:26","extension":"png","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":101964,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eScheme 4. \u003c/strong\u003eScale-up experiment and control experiments.\u003c/p\u003e","description":"","filename":"SC4.png","url":"https://assets-eu.researchsquare.com/files/rs-7763126/v1/417e72c56fad48a393852af3.png"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Ni-catalyzed Electrochemical Cross-Electrophile Coupling Paired with Oxygen Evolution Reaction","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCarbon\u0026ndash;carbon (C\u0026ndash;C) bonds constitute essential structural motifs in pharmaceuticals, agrochemicals, and functional materials, serving as central scaffolds in numerous bioactive molecules.\u003csup\u003e[1,2]\u003c/sup\u003e Conventional methodologies for constructing these bonds predominantly employ transition-metal-catalyzed cross-coupling reactions between organohalide electrophiles and preformed organometallic nucleophiles.\u003csup\u003e[3\u0026ndash;9]\u003c/sup\u003e However, the reliance on such carbon nucleophiles\u0026mdash;which themselves often necessitate pre-synthesis from organohalides\u0026mdash;introduces synthetic inefficiencies and operational complexities. In response, cross-electrophile coupling (XEC) has emerged as an efficient alternative strategy, enabling the direct coupling of two electrophilic coupling partners.\u003csup\u003e[7,10\u0026ndash;21]\u003c/sup\u003e The most prevalent XEC paradigm employs nickel catalysis paired with stoichiometric metallic reductants such as manganese or zinc powders (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). Nevertheless, this approach suffers from several limitations that impede scalable implementation: inconsistent reactivity due to variations in metal particle morphology and surface passivation, practical difficulties in homogenizing high-density metal powders in batch reactors, and the generation of stoichiometric quantities of metal waste. These drawbacks have stimulated growing interest in electrochemical strategies as more sustainable and scalable avenues for XEC transformations.\u003c/p\u003e\u003cp\u003eElectrochemical synthesis offers a promising platform for developing sustainable routes to industrial chemicals, presenting distinct advantages over traditional methods that often involve hazardous reagents or energy-intensive processes.\u003csup\u003e[21\u0026ndash;26]\u003c/sup\u003e Anodic oxidation reactions, in particular, exhibit a favorable environmental profile, as they can frequently be conducted under reagent-free conditions with molecular hydrogen (H\u003csub\u003e2\u003c/sub\u003e) generated as the sole byproduct at the counter electrode.\u003csup\u003e[27,28]\u003c/sup\u003e In contrast, reductive electrochemical cross-electrophile couplings conducted in undivided cells pose significant sustainability challenges due to their inherent demand for an external electron source to drive the cathodic transformation. At the laboratory scale, this electron requirement is typically supplied by sacrificial metal anodes or stoichiometric organic reductants.\u003csup\u003e[29\u0026ndash;44]\u003c/sup\u003e While operationally simple for small-scale applications, such strategies become economically and environmentally prohibitive at scale due to the substantial consumption of sacrificial materials and concomitant generation of metal-containing waste or organic byproducts (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). To address these issues, Stahl and co-workers reported a mediated H\u003csub\u003e2\u003c/sub\u003e anode that achieves indirect electrochemical oxidation of H\u003csub\u003e2\u003c/sub\u003e by pairing thermal catalytic hydrogenation of an anthraquinone mediator with electrochemical oxidation of the anthrahydroquinone.\u003csup\u003e[39]\u003c/sup\u003e This quinone-mediated H\u003csub\u003e2\u003c/sub\u003e anode is used to support nickel-catalysed electrochemical cross-electrophile couplings.\u003c/p\u003e\u003cp\u003eIn contrast to the electrochemical hydrogen oxidation reaction (HOR), which requires gaseous H\u003csub\u003e2\u003c/sub\u003e and specialized electrode architectures, the oxygen evolution reaction (OER)\u0026mdash;involving the oxidation of water to molecular oxygen\u0026mdash;represents a more sustainable and practically viable anodic process.\u003csup\u003e[45,46]\u003c/sup\u003e However, the implementation of OER in electrochemical cross-electrophile couplings faces two critical challenges: (i) the compatibility between aqueous OER and organic electrochemical reactions, and (ii) suppression of competitive substrate, product, or catalyst oxidation due to a more anodic the high operating potential required for OER (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec). The potential for OER in organic solvents can be described by the following expression:\u003cdiv id=\"Equa\" class=\"Equation\"\u003e\u003cdiv format=\"TEX\" class=\"mathdisplay\" id=\"FileID_Equa\" name=\"EquationSource\"\u003e\n$$\\:\\text{E}\\left(\\text{O}\\text{E}\\text{R}\\right)=\\text{E}^\\circ\\:\\left(\\text{O}\\text{E}\\text{R}\\right)+\\:\\frac{RT}{nF}ln\\frac{\\left[{\\text{H}}^{+}\\right]}{\\left[{\\text{H}}_{2}\\text{O}\\right]}+\\eta\\:$$\u003c/div\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003ewhere E\u003csup\u003eo\u003c/sup\u003e(OER), R, T, n, F and η represent the thermodynamic standard potential of OER (about\u0026thinsp;+\u0026thinsp;0.59 V vs. Fc/Fc⁺), gas constant, temperature, number of the electron transfer, Faraday constant and over potential respectively. This equation indicates that the OER potential in organic media is highly dependent on concentration of proton, concentration of water, and the electrocatalytic properties of the anode material, which determines the value of η. We hypothesized that these challenges could be mitigated through careful regulation of water content, screening of alkaline additives, and optimization of anode materials. Herein, we report a Ni-catalyzed electrochemical cross-electrophile coupling that facilitates C\u0026ndash;C bond formation paired with oxygen evolution reaction (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ed). This strategy circumvents the need for sacrificial metal anodes or stoichiometric organic reductants, offering a more sustainable and operationally simplified approach to reductive cross-coupling.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003eTo establish a general protocol for Ni-catalyzed electrochemical cross-electrophile coupling employing water as a sacrificial reductant, methyl 4-iodobenzoate (aryl halide, \u003cb\u003e1a\u003c/b\u003e) and 4-iodotetrahydropyran (alkyl halide, \u003cb\u003e2a\u003c/b\u003e) were selected as model substrates. The initial reaction conditions employed NiCl\u003csub\u003e2\u003c/sub\u003e\u0026middot;dme (10 mol%) as the precatalyst, dtbpy (15 mol%) as the ligand, LiOTf (0.2 M) as the electrolyte, and DMA (6 mL) as the solvent, with a Pt anode, carbon felt cathode, and a constant current of 30 mA (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1a\u003c/span\u003e). Water was identified as a critical sacrificial reductant for achieving high efficiency. Consequently, the effect of water equivalents was systematically evaluated. In the absence of added water, the reaction proceeded at room temperature for 4 hours to afford methyl 4-(tetrahydro-2H-pyran-4-yl)benzoate (3a) in 37% GC yield, presumably due to trace moisture present in the solvent. The low yield (3%) obtained when using anhydrous DMA as the solvent underscores the critical role of water as a sacrificial anode reagent in this reaction. The product yield increased significantly with higher water loading, reaching an optimum of 86% with 30 equivalents. A further increase to 1 mL of water resulted in a notable decrease in yield, likely attributable to compromised solubility of organic reactants. Subsequent efforts focused on reducing concentration of proton by the introduction of base to lower the potential of oxygen evolution reaction (OER) (Scheme \u003cspan refid=\"Sch1\" class=\"InternalRef\"\u003e1b\u003c/span\u003e). The addition of 20% sodium carbonate enhanced the yield of \u003cb\u003e3a\u003c/b\u003e to 99% (Entry 1). Alternative basic additives, including Cs\u003csub\u003e2\u003c/sub\u003eCO\u003csub\u003e3\u003c/sub\u003e and NaOH, were evaluated but proved detrimental to reactivity (Entries 2 and 3). Replacement of the Pt anode with an IrO\u003csub\u003e2\u003c/sub\u003e electrode\u0026mdash;an efficient OER catalyst\u0026mdash;yielded only trace product, likely owing to incompatibility with the organic medium (Entry 4). Other anode materials such as gold and carbon felt also exhibited inferior performance (Entries 5 and 6). Control experiments underscored the essential roles of the nickel catalyst, ligand, and electrochemical activation. No product formation was observed in the absence of NiCl\u003csub\u003e2\u003c/sub\u003e\u0026middot;dme, dtbpy, or applied current (Entries 7\u0026ndash;9).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eWith the optimized reaction conditions in hand, we systematically evaluated the generality and functional group compatibility of the nickel-catalyzed electrochemical cross-electrophile coupling using water as a sacrificial reductant. Initially, the coupling between various aryl iodides and alkyl iodides was investigated (Scheme \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2a\u003c/span\u003e). Aryl iodides bearing electron-withdrawing groups like ester (\u003cb\u003e3a\u003c/b\u003e\u0026ndash;\u003cb\u003e3c\u003c/b\u003e), trifluoromethyl (\u003cb\u003e3d\u003c/b\u003e, \u003cb\u003e3e\u003c/b\u003e), and cyano (\u003cb\u003e3f\u003c/b\u003e) were well tolerated. Substitutions at the \u003cem\u003emeta\u003c/em\u003e-position of the phenyl ring significantly influenced the reaction yields (\u003cb\u003e3c\u003c/b\u003e), whereas \u003cem\u003eortho\u003c/em\u003e-substituents led to a slight decrease in yield (\u003cb\u003e3b\u003c/b\u003e, \u003cb\u003e3e\u003c/b\u003e), indicating notable steric effects. Notably, aryl iodides containing halogen substituents such as -F, -Cl, and even -Br proved to be suitable substrates, offering handles for further functionalization (\u003cb\u003e3g\u003c/b\u003e\u0026ndash;\u003cb\u003e3i\u003c/b\u003e). Electron-rich aryl iodides also underwent smooth coupling, affording products in moderate yields (\u003cb\u003e3j\u003c/b\u003e\u0026ndash;\u003cb\u003e3p\u003c/b\u003e). To our delight, substrates with unprotected amino groups were compatible, delivering 4-(tetrahydro-2H-pyran-4-yl)aniline in 81% yield (\u003cb\u003e3q\u003c/b\u003e). Substrate containing oxidation-sensitive functional groups like aldehyde could be successfully employed in the divided cell system, thereby delivering the desired products in moderate yields (\u003cb\u003e3r\u003c/b\u003e). The Bpin group was also tolerated under the standard conditions (\u003cb\u003e3s\u003c/b\u003e). Furthermore, complex aromatic systems including biphenyl (\u003cb\u003e3t\u003c/b\u003e), naphthalene (\u003cb\u003e3u\u003c/b\u003e), and dimethylfluorene (\u003cb\u003e3v\u003c/b\u003e) served as viable coupling partners. Indole, a privileged scaffold in bioactive molecules, was also compatible with this electrochemical system (\u003cb\u003e3w\u003c/b\u003e).\u003c/p\u003e\u003cp\u003eAs summarized in Scheme \u003cspan refid=\"Sch2\" class=\"InternalRef\"\u003e2b\u003c/span\u003e, the reaction exhibited broad compatibility with diverse alkyl iodides. Secondary cyclic alkyl iodides including four-membered (\u003cb\u003e3x\u003c/b\u003e), five-membered (\u003cb\u003e3y\u003c/b\u003e), six-membered (\u003cb\u003e3z\u003c/b\u003e), and seven-membered rings (\u003cb\u003e3aa\u003c/b\u003e) underwent efficient coupling, demonstrating insensitivity to ring size and strain. 5-Iodo-2-phenyl-1,3-dioxane was also a suitable substrate, affording the product in moderate yield (\u003cb\u003e3ab\u003c/b\u003e). Primary alkyl iodides performed well, affording methyl 4-(3-(p-tolyl)propyl)benzoate in 97% yield (\u003cb\u003e3ac\u003c/b\u003e). The method further displayed excellent functional group tolerance on the alkyl partner, successfully accommodating chloride (\u003cb\u003e3ad\u003c/b\u003e), nitrile (\u003cb\u003e3ae\u003c/b\u003e), thioether (\u003cb\u003e3af\u003c/b\u003e), ether (\u003cb\u003e3ag\u003c/b\u003e), -CF₃ (\u003cb\u003e3ah\u003c/b\u003e), thiophene (\u003cb\u003e3ai\u003c/b\u003e), and furan (\u003cb\u003e3aj\u003c/b\u003e) functionalities.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo further demonstrate the versatility of this electrochemical cross-coupling system, we expanded its scope to include alkyl-alkyl electrophilic couplings, encompassing both primary\u0026ndash;secondary and primary\u0026ndash;primary alkyl partners (Scheme \u003cspan refid=\"Sch3\" class=\"InternalRef\"\u003e3a\u003c/span\u003e, 3\u003cb\u003eak\u003c/b\u003e and \u003cb\u003e3al\u003c/b\u003e). The protocol was also successfully applied to alkenyl bromides, affording the desired product in 61% yield (\u003cb\u003e3am\u003c/b\u003e). Additionally, the system proved effective for the construction of Csp\u0026ndash;Csp\u003csup\u003e3\u003c/sup\u003e bonds, yielding disubstituted alkynes (\u003cb\u003e3an\u003c/b\u003e). Notably, the method was compatible with less reactive aryl bromides under the standard electrochemical conditions. A range of substituted aryl bromides including those bearing esters, fluorine, and chlorine underwent efficient coupling with both primary and secondary alkyl iodides to deliver the corresponding products in moderate yields (\u003cb\u003e3a\u003c/b\u003e, \u003cb\u003e3g\u003c/b\u003e, \u003cb\u003e3h\u003c/b\u003e, \u003cb\u003e3u\u003c/b\u003e, \u003cb\u003e3ao\u003c/b\u003e, \u003cb\u003e3y\u003c/b\u003e). The synthetic utility of this methodology was further highlighted through the late-stage functionalization of complex bioactive molecules and natural product derivatives (Scheme \u003cspan refid=\"Sch3\" class=\"InternalRef\"\u003e3b\u003c/span\u003e). Successful couplings were achieved with substrates derived from Gemfibrozil (\u003cb\u003e3ap\u003c/b\u003e), Clofibrate (\u003cb\u003e3aq\u003c/b\u003e, \u003cb\u003e3ar\u003c/b\u003e) and Ibuprofen (\u003cb\u003e3as\u003c/b\u003e). These transformations proceeded efficiently, underscoring the potential of this electrochemical strategy for the modular functionalization of pharmacologically relevant compounds.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eTo assess the scalability of the electrochemical cross-coupling, a gram-scale reaction was performed at 10 mmol scale under slightly modified conditions (constant current: 100 mA). The desired coupled product was isolated in 58% yield (1.36 g), demonstrating the practical utility of this method for larger-scale synthesis (Scheme \u003cspan refid=\"Sch4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Eq.\u0026nbsp;1). This approach offers a direct route to alkyl\u0026ndash;aryl linkages from carboxylic acid derivatives, eliminating the need for preformed alkyl halides (Scheme \u003cspan refid=\"Sch4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Eq.\u0026nbsp;2). To probe the reaction mechanism, a series of control experiments were conducted. Analysis of the headspace gas via GC during the standard reaction confirmed the evolution of oxygen (0.18 mmol), supporting the occurrence of the oxygen evolution reaction (OER) under the electrochemical conditions (Scheme \u003cspan refid=\"Sch4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Eq.\u0026nbsp;3). The addition of stoichiometric TEMPO completely inhibited product formation, suggesting the involvement of radical intermediates (Scheme \u003cspan refid=\"Sch4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Eq.\u0026nbsp;4). This hypothesis was further corroborated by the reaction of methyl 4-iodobenzoate (\u003cb\u003e1a\u003c/b\u003e) with (iodomethyl)cyclopropane, which yielded the ring-opened product \u003cb\u003e3at\u003c/b\u003e, consistent with the generation of a primary alkyl radical that undergoes rapid ring fragmentation (Scheme \u003cspan refid=\"Sch4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Eq.\u0026nbsp;5).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eFurther mechanistic insight was gained through cyclic voltammetry (CV) studies (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In the presence of ligand, the Ni complex exhibited two reduction peaks at -1.19 V and \u0026minus;\u0026thinsp;1.88 V (vs. Ag/AgCl), attributed to the Ni\u003csup\u003eII\u003c/sup\u003e/Ni\u003csup\u003eI\u003c/sup\u003e and Ni\u003csup\u003eI\u003c/sup\u003e/Ni\u003csup\u003e0\u003c/sup\u003e redox couples, respectively (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The reduction potentials of iodobenzene and 4-iodotetrahydropyran were observed at -2.22 V and \u0026minus;\u0026thinsp;2.16 V (vs. Ag/AgCl), respectively, indicating that reduction of the NiCl\u003csub\u003e2\u003c/sub\u003e\u0026middot;dme/dtbpy complex occurs more readily than that of the organic iodides. Upon addition of iodobenzene, a catalytic current increase was observed for the Ni\u003csup\u003eI\u003c/sup\u003e/Ni\u003csup\u003e0\u003c/sup\u003e couple, while the Ni\u003csup\u003eII\u003c/sup\u003e/Ni\u003csup\u003eI\u003c/sup\u003e couple remained largely unaffected, suggesting that oxidative addition of aryl iodide preferentially occurs at Ni\u003csup\u003e0\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). In contrast, introduction of 4-iodotetrahydropyran led to an increase in catalytic current for both the Ni\u003csup\u003eII\u003c/sup\u003e/Ni\u003csup\u003eI\u003c/sup\u003e and Ni\u003csup\u003eI\u003c/sup\u003e/Ni\u003csup\u003e0\u003c/sup\u003e redox events, indicating that alkyl iodides are more likely to react with Ni\u003csup\u003eI\u003c/sup\u003e species (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cp\u003eBased on the results described above, a plausible mechanism is proposed as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. Cathodic reduction of catalyst precursor generates an active Ni\u003csup\u003e0\u003c/sup\u003e species (\u003cb\u003eA\u003c/b\u003e), which undergoes oxidative addition with aryl iodide (Ar-I) to form an aryl-Ni\u003csup\u003eII\u003c/sup\u003e-I intermediate (\u003cb\u003eB\u003c/b\u003e). Subsequent electrochemical reduction yields an aryl-Ni\u003csup\u003eI\u003c/sup\u003e-I complex (\u003cb\u003eC\u003c/b\u003e), which participates in single-electron transfer (SET) with alkyl iodide (R-I) to generate an alkyl radical (R\u0026bull;) and regenerate aryl-Ni\u003csup\u003eII\u003c/sup\u003e-I (\u003cb\u003eD\u003c/b\u003e). Radical capture affords a high-valent Ar-Ni\u003csup\u003eIII\u003c/sup\u003e-R species (\u003cb\u003eE\u003c/b\u003e), and reductive elimination delivers the coupled product while regenerating a Ni\u003csup\u003eI\u003c/sup\u003e intermediate (\u003cb\u003eF\u003c/b\u003e). The Ni\u003csup\u003eI\u003c/sup\u003e species is reduced at the cathode to Ni\u003csup\u003eo\u003c/sup\u003e, regenerating the catalyst.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn summary, we have developed a novel nickel-catalyzed electroreductive cross-coupling method for C\u0026ndash;C bond formation, using H\u003csub\u003e2\u003c/sub\u003eO as an economical and sustainable sacrificial reductant. This electrochemical platform enables the versatile construction of diverse C\u0026ndash;C bonds including Csp\u003csup\u003e2\u003c/sup\u003e\u0026ndash;Csp\u003csup\u003e3\u003c/sup\u003e, Csp\u003csup\u003e3\u003c/sup\u003e\u0026ndash;Csp\u003csup\u003e3\u003c/sup\u003e, and Csp\u0026ndash;Csp\u003csup\u003e3\u003c/sup\u003e linkages, from readily accessible aryl, alkenyl, alkynyl, and alkyl halide electrophiles, delivering products in yields of up to 99%. The approach eliminates the need for sacrificial metal anodes or stoichiometric organic reductants, offering a more sustainable and operationally straightforward alternative for cross-electrophile coupling. Furthermore, this electroreductive coupling strategy displays excellent functional group tolerance and is suitable for the late-stage derivatization of complex drugs and natural products. This operationally simple, electricity-driven method provides a sustainable and versatile platform for C\u0026ndash;C bond formation. We anticipate that this strategy will find broad utility in synthetic and medicinal chemistry.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting interests\u003c/h2\u003e\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e\u003cp\u003eR.S. directed the project. A.L. and R.S. conceived the idea, designed the experiments and wrote the manuscript. D.H., W.L. and R.M. performed the synthetic experiments. All the authors participated in the discussion and preparation of the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e\u003cp\u003eThis work is supported by the \u0026ldquo;Young Talent Support Plan\u0026rdquo; of Xi\u0026rsquo;an Jiaotong University and the Natural Science Foundation of Shaanxi Province (2023-JC-QN-0102).\u003c/p\u003e\n\u003ch3\u003eData availability\u003c/h3\u003e\n\u003cp\u003eThe authors declare that the data supporting the findings of this study are available within the article and Supplementary Information files or from the corresponding author upon request. The experimental procedures and characterization of all new compounds are provided in the Supplementary Information.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLovering, F.; Bikker, J.; Humblet, C. 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Rev.\u003c/em\u003e \u003cstrong\u003e2008\u003c/strong\u003e, \u003cem\u003e37\u003c/em\u003e, 1603\u0026ndash;1618.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Schemes","content":"\u003cp\u003eSchemes 1 and 4 are available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-7763126/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7763126/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eNickel-catalyzed cross-electrophile coupling (XEC) has emerged as an efficient and economical strategy for constructing C\u0026ndash;C bonds, a pivotal transformation in diversifying molecular architectures. However, conventional XEC methodologies typically rely on stoichiometric metallic reductants, which present inherent challenges including safety risks, operational instability, and environmental concerns. Although electrochemical XEC in undivided cells circumvents the need for chemical reductants, it remains constrained by sustainability issues and chemo-selectivity limitations due to its dependence on sacrificial metal anodes or stoichiometric organic donors to supply electrons for cathodic reduction. Herein, we report a nickel-catalyzed electrochemical cross-electrophile coupling paired with the oxygen evolution reaction (OER). By utilizing water as an economical and sustainable sacrificial electron donor, this electrochemical platform facilitates the versatile construction of diverse C\u0026ndash;C bonds, including Csp\u003csup\u003e2\u003c/sup\u003e\u0026ndash;Csp\u003csup\u003e3\u003c/sup\u003e, Csp\u003csup\u003e3\u003c/sup\u003e\u0026ndash;Csp\u003csup\u003e3\u003c/sup\u003e, and Csp\u0026ndash;Csp\u003csup\u003e3\u003c/sup\u003e linkages, from readily accessible aryl, alkenyl, alkynyl, and alkyl halide electrophiles, affording products in yields up to 99%. The undivided cell configuration markedly reduces system complexity, lowers capital costs, and supports scalable electrochemical synthesis. Moreover, this electroreductive coupling strategy exhibits broad functional group tolerance and is amenable to the late-stage derivatization of complex drugs and natural products. This operationally simple, electricity-driven approach offers a sustainable and versatile platform for C\u0026ndash;C bond formation.\u003c/p\u003e\u003cp\u003e\u003c/p\u003e","manuscriptTitle":"Ni-catalyzed Electrochemical Cross-Electrophile Coupling Paired with Oxygen Evolution Reaction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 06:30:21","doi":"10.21203/rs.3.rs-7763126/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"169535c8-bd1f-490f-9d3c-f6d6bd83ee18","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":56568519,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"},{"id":56568520,"name":"Physical sciences/Chemistry/Green chemistry"}],"tags":[],"updatedAt":"2025-11-14T08:46:48+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 06:30:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7763126","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7763126","identity":"rs-7763126","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}