Nickel-electrocatalyzed enantioselective C–H activations for chemo-divergence

Nickel-electrocatalyzed enantioselective C–H activations for chemo-divergence | 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 Nickel-electrocatalyzed enantioselective C–H activations for chemo-divergence Lutz Ackermann, Tristan von Münchow, Neeraj Pandit, Suman Dana, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3760859/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Mar, 2025 Read the published version in Nature Catalysis → Version 1 posted You are reading this latest preprint version Abstract Enantioselective electrocatalysis bears unique potential for the sustainable assembly of enantiomerically enriched molecules 1–7 . This approach allows electro-oxidative C–H activation to be performed paired to the hydrogen evolution reaction 8,9 . While recent progress featured scarce transition metals with limited availability 10–17 , we, herein, reveal that the Earth-abundant 3d transition-metal nickel is characterized by unique performance, while having high natural abundance 18 and reduced toxicity 19 . Thereby, electrocatalytic C–H activation enabled enantioselective desymmetrizations with bicyclic alkenes, leading to three-dimensional molecular building blocks with multiple stereogenic elements 20 . Here, ligand optimization was guided by smart feature analysis for enantioselectivity enhancement. The detailed mechanistic investigation by experimental studies with organometallic intermediates in conjunction with computational studies identified key features of the ligand design including non-covalent interactions 21,22 to guarantee full selectivity control. Physical sciences/Chemistry/Electrochemistry/Electrocatalysis Physical sciences/Chemistry/Catalysis/Electrocatalysis Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Introduction In recent years, enantioselective electrochemical transition-metal catalysis has been recognized as a resource-economic tool for the synthesis of chiral organic architectures 1–7 . In this innovative strategy, catalytic transformations are enabled by the electrochemical redox manipulation of the transition-metal catalyst, avoiding the use of sacrificial redox agents. Especially, in electro-oxidative catalysis, the redox equivalents are provided by the formation of molecular hydrogen through the paired cathodic hydrogen evolution reaction (HER) 6 , offering a transformative platform to address the growing global demand for efficient and clean energy solutions 23–26 . Despite these beneficial features, enantioselective electro-oxidative C–H activation reactions are thus far severely limited to transition-metals with high risk of future supply shortages 27,28 , such as cobalt 10–14,29,30 as well as the precious 4d transition-metals palladium 15–17 and rhodium 31,32 . Hence, the exploration of transition-metals with high natural abundance 18 bears a major interest in this domain (Fig. 1 a). In this context, the cost-effective 33 and less-toxic 34 base metal nickel as catalyst is particularly attractive 35–39 , which, due to its flexibility in adopting various oxidation states, displays unique reactivity patterns for homogeneous catalysis 40,41 . However, the direct activation of inert C–H bonds under nickel catalysis often requires harsh reaction conditions, rendering the development of enantioselective methodologies very challenging 35,36 . The enantioselective catalyses described are limited to highly sensitive, low-valent nickel(0) precatalysts using chiral NHC 42 or HASPO 43 (pre)ligands and commonly rely on pyrophoric organoaluminium reagents 44,45 . Thus, enabling oxidative nickel-catalyzed C–H activation with chiral ligands for effective enantio-induction within an electro-oxidative high-valent nickel regime is a formidable challenge. Our previous work on C–(Het) bond formation without any enantiocontrol 46,47 has revealed that nickel-electrocatalysis also exhibits reaction patterns that feature unique activities compared to other transition-metals. Hence, we were particularly interested in unlocking this feature to unveil new synthetic opportunities, which can govern complementary reactivities in enantioselective electro-oxidative C–H activation. Here, we report on the enantioselective electrocatalytic desymmetrization with strained 7-oxabenzonorbornadienes through 3d transition-metal catalyzed C–H activation giving access to substituted chiral 7-oxabicyclo[2.2.1]heptanes - a skeleton encountered in various biologically active compounds 48,49 (Fig. 1 b). Intriguingly, the devised enantioselective C–H activation reveals an unprecedented chemo-divergence. While cobalt electrocatalysis furnishes the carboacylation product, the nickel electrocatalysis is selective for carboamination (Fig. 1 c). Results and Discussion Initially we intended to devise a model enantioselective desymmetrization reaction with 7-oxabenzonorbornadiene 50,51 using cobalta-electrocatalyzed C–H activation (Fig. 2 ). Conspicuously, the electrocatalytic enantioselective transformation of benzamide 1 and alkene 2 , proceeded with high effectivity in the presence of the chiral 2,4-di- tert -butyl-substituted salicyloxazoline 52 ligand L1 , giving the carboacylation product 3 in high levels of enantio- and diastereoselectivity (Fig. 2 a). Electricity was crucial for product formation (entry 4), whereas the electrochemically synthesized cyclometalated complex Co III -L1 could furnish the desired product with high selectivity in a stoichiometric fashion as well (entry 5). The enantioselective desymmetrization strategy encompassed a broad scope (Fig. 2 b), yielding the desired carboacylation products 5 – 16 in high yields and excellent enantiomeric control, including substrates bearing thioether ( 8 ), cyano ( 9 ), or carboxylic ester ( 10 , 11 , 14 ) groups, among others. With this initial insight in hand, we tackled the unprecedented enantioselective electro-oxidative nickel-catalyzed C–H activation, and, thus, we probed the viability of high-valent nickel-electrocatalysis for desymmetrizations with 7-oxabenzonorbornadiene ( 2 ) (Fig. 3 ). In contrast to the cobalt system, that gave primarily carbacylation product 3 , the oxidative nickel-electrocatalysis exclusively furnished carboamination product 4 . After the optimization of different reaction parameters, we identified conditions that allowed the nickel-catalyzed carboamination with promising enantiocontrol (Fig. 3 a). However, by pure empirical reaction optimization it was impossible to identify a ligand that would enhance the catalysis selectivity and performance. Thus, a data-driven approach 53,54 was pursued to assist in the ligand development. Following the workflow shown in Fig. 3 b with ligand screening data yet in hand, we commenced by optimizing the free ligand structures at the TPSS-D3(BJ)/def2-SVP, followed by the single-point calculations at the PW6B95-D4/def2-TZVPP + SMD(1,4-Dioxane) level of theory to acquire DFT derived descriptors (for further details see Supplementary Methods, Development of Nickel Catalysis). A wide range of descriptors 55 were explored to describe the variations in the ligand structures as well as their properties. For electronic features, frontier molecular orbital (FMO) energies, natural bond orbital (NBO) charges, and net dipole moments (µ net ) were derived from single-point DFT calculations. To assess the steric and geometric properties, Sterimol parameters 56 (B min , B max , and L) and dihedral angles were considered. In light of recent studies 57,58 demonstrating the use of vibrational features for integrated effects of steric behaviour and charge layout, vibrational modes of the ligand were also used. Based on the feature importance analysis employing a tree-based regression model (random forest regressor) on the obtained ligand screening data, steric parameter of C11 substituent (R1_L), asymmetric stretching mode 1 from phenyl ring (asym1_v), and NBO charge at C10 carbon (NBO_C10) emerged as the top three crucial ligand features, significantly affecting the enantioselectivity. In model screening, the GBR (Gradient Boosting) model proved to be the best model with the least test and validation mean absolute error (MAE test = 0.32 kcal mol − 1 , and MAE validation = 0.19 kcal mol − 1 ) on the training and validation dataset. Later, the permutation analysis on the trained GBR model likewise showed similar feature importance with NBO_C10 as the most significant feature after the R1_L. Based on the most relevant features, 5 ligands with variable substitution patterns were thereby newly designed, which were expected to be more prominent. The constructed model was used to predict the enantioselectivity (ΔΔG pred ) for the 5 devised ligands, followed by prediction evaluation with experimentally obtained ΔΔG exp . In agreement with the GBR model, ligand L8 was identified as the best-performing ligand within the group of newly designed ligands and overall dataset. Thus, with the help of feature analysis, the considered substitutional modifications to the ligand backbone resulted in a newly designed ligand variant L8 exhibiting effective enantio-induction for the challenging stereo-control in electro-oxidative nickel-catalyzed C–H activation (Fig. 3 b, for further details see Supplementary Methods, Development of Nickel Catalysis). To rationalize the high efficiency of the devised ligand L8 in controlling the stereoselectivity in the nickel electrocatalysis, a non-covalent interaction (NCI) 22 analysis of the transition state ( TS1 2 ) involved in the migratory insertion was carried out (Fig. 3 c, for the energy profile see Supplementary Methods, Computational Studies). Here, a significant secondary attractive π-π interaction between the arene at the oxazoline (C11) from the ligand L8 and the 8-quinolinyl of the benzamide was identified, along with a weak attractive CH-π interaction between the methyl at oxazoline (C10) and benzene plane of the benzamide. These findings highlight the ligand effect in the catalyst stabilization, facilitating the migratory insertion of the alkene. Interestingly these two ligand site feature roles (R1_L, and NBO_C10) were also indicated by the early feature analysis and post model development. In addition, the NCI plot unveiled a strong attractive polar interaction between oxygen of the 7-oxabenzonorbornadiene and carbonyl carbon centre from the benzamide, aligning with the experimentally observed excellent diastereo-selectivity. With a suitable ligand for enantioselectivity being identified by data science, we next improved the efficacy further (Fig. 4 a). Hence, we monitored the reaction progress during electrocatalysis and found that already in the initial stage the formation of product 4 only proceeded gradually, pointing at an inefficient anodic electron transfer. For this purpose, we probed ferrocene (Cp 2 Fe) as a redox mediator, which led to a considerable increase in the efficiency, while maintaining the excellent control of enantioselectivity (Fig. 4 a and 4 b). With the optimized conditions in hand, the versatility of the nickel electrocatalysis was examined (Fig. 4 c). The strategy thus allowed for the synthesis of a broad range of chiral bridged dihydroisoquinolinones in high enantiomeric excess ( 4 , 17 – 41 ) thereby tolerating various functional groups. The strategy showed high tolerance to oxidation-sensitive thioether groups ( 19 , 30 ) and electrophilic carbonyl motifs ( 20 – 22 , 32 ). Besides fluoro- ( 28 ), bromo- ( 18 ), and iodo-substituents ( 27 ), benzamides bearing acetamido motif ( 33 ) were found to be compatible. In addition, the electrocatalytic C–H activation on thiophene enabled the enantioselective synthesis of the desired carboamination products ( 35 , 36 ). Having identified Cp 2 Fe as a redox mediator, we were interested to explore whether ferrocenium ([Cp 2 Fe] + ) could serve as a redox agent in a stoichiometric reaction to form a putative cyclometalated nickel(III)-species bearing the optimized chiral ligand L8 . To this end, the cyclometalated complex Ni II -DMAP was synthesized and subjected to a reaction with 1 equivalent [Cp 2 Fe]PF 6 and the chiral ligand L8 . After 15 minutes of reaction time, a colour change from orange to dark red was observed and the cyclometalated complex Ni III -L8 could be isolated, whereby recovering the stoichiometrically generated Cp 2 Fe (Fig. 5 a). To determine the relevant oxidation states of the nickel catalyst involved in the C–H/N–H annulation process, the reactivity of the synthesized complex Ni III -L8 was next investigated in a stoichiometric reaction with alkene 2 (Fig. 5 b). Hence, Ni III -L8 furnished the desired carboamination product 4 with excellent enantioselectivity in the absence of oxidative conditions, pointing to a feasible reductive elimination from nickel(III). To gain further insights into the C–H/N–H activation pathway, the electrocatalytic reaction was monitored by high-resolution electrospray ionization mass spectrometry (HR ESI MS) under the standard conditions using a bromo substituted benzamide for clearly identifiable isotopic patterns. Here, a species corresponding to the nickel(III)-intermediate resulting from migratory insertion was detected by in-operando spectrometry (for details see Supplementary Methods, Monitoring the Nickel Catalysis by Mass Spectrometry). As the present experimental studies reveal that the nickel(II/III) redox event is crucial for the devised electrocatalysis, we further investigated the synthesized nickel complexes by cyclic voltammetry (CV) (Fig. 5 c). While the oxidation potential of Cp 2 Fe is below the oxidation potential of Ni II -DMAP in combination with ligand L8 with a potential difference of less than 200 mV, the cyclometalated complex Ni III -L8 shows no oxidation event in the relevant potential range. Furthermore, a catalytic current in the CV of Cp 2 Fe was observed when Ni II -DMAP together with L8 were added, indicated by a disappearance of the reduction wave and an enhancement of the oxidation wave (for further details see Supplementary Methods, Electroanalytical Investigations). These findings further support the hypothesis of Cp 2 Fe as a redox mediator via outer-sphere electron transfer 59 in the nickel(II/III) redox event. Subsequently, the nickel(II/III) interconversion was investigated by UV-vis absorption spectroelectrochemistry (UV-vis SEC) (Fig. 5 d-e). Intriguingly, for Ni II -DMAP , a change in the spectrum was already displayed when combined with L8 , being indicative of the formation of a nickel(II)-species coordinated by the bidentate ligand L8 (Fig. 5 d). In the analysis by UV-vis SEC, the change in absorbance in direct proximity to the working electrode was recorded as a function of time while applying defined potentials. Here, when + 1.5 V (vs Ag/Ag + ) were applied in a solution of Ni II -DMAP with L8 , a pattern in the absorbance change was revealed, being the mirror-image to the pattern observed for Ni III -L8 at − 0.5 V (vs Ag/Ag + ) (Fig. 5 e). This finding reflects the feasibility of the conversion of cyclometalated nickel(II) to nickel(III)-species induced by electron transfer (for further details see Supplementary Methods, Electroanalytical Investigations). As to the cathodic half reaction, the headspace of the electrochemical cell after catalysis was analysed by gas chromatography (GC) and molecular hydrogen was detected, supporting HER as the cathodic process (see Supplementary Methods, Detection of Hydrogen Gas for Nickel Catalysis). Subsequently, DFT calculations were performed to rationalize the observed chemo-divergence in electrocatalysis (Fig. 6 ) (for complete reaction profiles see Supplementary Methods, Computational Studies). For the nickel catalysis, in line with the experimental findings, the calculations pointed to the reductive elimination as product-determining step as the most favourable pathway with an energy barrier of 25.6 kcal mol − 1 ( TS2 2A ), while for the cobalt catalysis the nucleophilic addition resulting in carboacylation was kinetically more favourable with an energy barrier of 18.8 kcal mol − 1 ( TS2 5B ). Conclusions An unprecedented electro-oxidative high-valent nickel-catalyzed C–H activation was disclosed by data-science guided ligand optimization. The devised nickel electrocatalysis proceeded with high enantio- and diastereo-selectivity providing direct access to versatile chiral building blocks with multiple stereocenters with ample scope. The chemo-divergent cobalt-catalyzed carboacylation and nickel-catalyzed carboamination allowed enantioselective molecular catalysis enabled by the formation of molecular hydrogen through HER. Mechanistic investigations provided insights into the differences of the nickel and cobalt regime. Studies with isolated cyclometalated intermediates involving electroanalytical techniques shed light on the active nickel(III) species. The study presented herein showcases the unique potential of electrochemical C–H activation by nickel catalysis as an innovative and powerful tool for sustainable synthesis. Declarations Competing interests The authors declare no competing interests. Author contributions L.A. supervised the project. L.A. and T.V.M. conceived the work. T.V.M. designed the experimental studies. N.K.P. designed and conducted the computational studies. T.V.M., P.B., S.D., S.E.P., J.B., Y.R.L., A.S. conducted the experiments. T.V.M. and S.E.P. conducted the experimental mechanistic studies. L.A., T.V.M., and N.K.P. wrote the manuscript. L.A., T.V.M., N.K.P., and S.D. edited the manuscript. Acknowledgements The authors gratefully acknowledge support from the ERC Advanced Grant No. 101021358, the DFG (Gottfried Wilhelm Leibniz award and SPP 2363 to L. A.), and the FCI (Kekulé-Fellowship to T.V.M.). We thank C. Golz (University of Göttingen) for the assistance with the X-ray diffraction analysis. Data availability All data supporting the findings of this work are available within the paper and its Supplementary Information. References Siu, J. C., Fu, N. & Lin, S. 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Nature 507, 210–214, doi: 10.1038/nature13019 (2014). Niemeyer, Z. L., Milo, A., Hickey, D. P. & Sigman, M. S. Parameterization of phosphine ligands reveals mechanistic pathways and predicts reaction outcomes. Nat. Chem. 8, 610–617, doi: 10.1038/nchem.2501 (2016). Francke, R. & Little, R. D. Redox catalysis in organic electrosynthesis: basic principles and recent developments. Chem. Soc. Rev. 43, 2492–2521, doi: 10.1039/C3CS60464K (2014). Additional Declarations There is NO Competing Interest. Supplementary Files SupportingInformationNickel15dec.pdf Compound3cu2002CG0mfinalcif.cif Compound23cu2022CG0mfinalcif.cif Compound21cu2021CG0mfinalcif.cif Compound21checkcifcu2021CG0mfinalcif.pdf Compound11cu2001CG0mfinalcif.cif Compound13checkcifcu1998CG0mfinalcif.pdf Compound13cu1998CG0mfinalcif.cif ComplexNiL9mo2025CG0mfinalcif.cif Compound23checkcifcu2022CG0mfinalcif.pdf Compound3checkcifcu2002CG0mfinalcif.pdf ComplexNiL9checkcifmo2025CG0mfinalcif.pdf Compound11checkcifcu2001CG0mfinalcif.pdf Cite Share Download PDF Status: Published Journal Publication published 07 Mar, 2025 Read the published version in Nature Catalysis → 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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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3760859","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":267167597,"identity":"f1e6982e-08cf-4c47-a2b9-8cc5425e28e5","order_by":0,"name":"Lutz Ackermann","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-7034-8772","institution":"Georg-August-University Göttingen","correspondingAuthor":true,"prefix":"","firstName":"Lutz","middleName":"","lastName":"Ackermann","suffix":""},{"id":267167598,"identity":"a00b3b33-dfda-4947-912e-ca3a5048748c","order_by":1,"name":"Tristan von Münchow","email":"","orcid":"https://orcid.org/0000-0002-8911-6733","institution":"Georg-August-University Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Tristan","middleName":"","lastName":"von Münchow","suffix":""},{"id":267167599,"identity":"6559244a-327e-45b4-ab93-06607beeabdb","order_by":2,"name":"Neeraj Pandit","email":"","orcid":"","institution":"Georg-August-University Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Neeraj","middleName":"","lastName":"Pandit","suffix":""},{"id":267167600,"identity":"5528a560-e31b-46b0-9375-5a6069cbb1f4","order_by":3,"name":"Suman Dana","email":"","orcid":"","institution":"Georg-August-University Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Suman","middleName":"","lastName":"Dana","suffix":""},{"id":267167601,"identity":"325565f6-c034-4e01-98ee-664748fdfe33","order_by":4,"name":"Philipp Boos","email":"","orcid":"https://orcid.org/0009-0004-7864-1833","institution":"Georg-August-Universität Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Philipp","middleName":"","lastName":"Boos","suffix":""},{"id":267167602,"identity":"ec195ad5-0773-44d6-834b-aa1dfd678b88","order_by":5,"name":"Sven Peters","email":"","orcid":"","institution":"Georg-August-University Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Sven","middleName":"","lastName":"Peters","suffix":""},{"id":267167603,"identity":"f3e90a12-1ac6-4e8a-a9ac-510f8499911d","order_by":6,"name":"Josselin Boucat","email":"","orcid":"","institution":"Georg-August-University Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Josselin","middleName":"","lastName":"Boucat","suffix":""},{"id":267167604,"identity":"7a4eb523-cec9-4d43-ab4e-082543103dc3","order_by":7,"name":"Yi-Ru Liu","email":"","orcid":"","institution":"Georg-August-University Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Yi-Ru","middleName":"","lastName":"Liu","suffix":""},{"id":267167605,"identity":"91a8220c-e552-49b9-8c4a-c29e853f2fea","order_by":8,"name":"Alexej Scheremetjew","email":"","orcid":"","institution":"Georg-August-University Göttingen","correspondingAuthor":false,"prefix":"","firstName":"Alexej","middleName":"","lastName":"Scheremetjew","suffix":""}],"badges":[],"createdAt":"2023-12-15 22:30:10","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3760859/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3760859/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41929-025-01306-9","type":"published","date":"2025-03-07T05:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":49656520,"identity":"b38c54b1-d149-44d6-95ec-4951890955ed","added_by":"auto","created_at":"2024-01-16 03:57:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":45644,"visible":true,"origin":"","legend":"\u003cp\u003eEnantioselective electrochemical C–H activation for full selectivity control. a. Sustainability aspects of nickel in comparison. b. Selected chiral biologically active compounds containing an oxabicyclo[2.2.1]heptane skeleton. c. Chemo-divergent desymmetrizations enabled by electrocatalytic C–H activation (this work). Ar = arene.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3760859/v1/f522ed8c86d8cd100bc3a25c.png"},{"id":49657004,"identity":"f3c41df3-bab1-4c51-bcc4-85d8724fe089","added_by":"auto","created_at":"2024-01-16 04:05:01","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":73439,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEnantioselective carboacylation by cobalta-electrocatalyzed C–H activation.\u003c/strong\u003e a. Reaction development. Reaction conditions for catalytic reactions: 1 (0.2 mmol), 2 (0.3 mmol), Co(OAc)\u003csub\u003e2\u003c/sub\u003e•4H\u003csub\u003e2\u003c/sub\u003eO (0.04 mmol), L1 (0.06 mmol), NaOPiv (0.6 mmol), AcOH (5 mL), undivided cell, graphite felt anode (GF), platinum plate cathode (Pt), 600 rpm stirring rate, constant current electrolysis (CCE) at 1.0 mA, 100 °C, 24 h reaction time. During optimization carboamination product 4 was obtained in up to 15% yield. Experimental details for stoichiometric reaction with cyclometalated complex Co\u003csup\u003eIII\u003c/sup\u003e-L1 are provided in Supplementary Methods. MP, 4-methoxypyridine. Q = 8-quinolinyl. e.r. = enantiomeric ratio. b. Versatility of enantioselective cobalt-catalyzed C–H activation under optimized conditions. Isolated yields.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3760859/v1/52ab02b48028d4ac6eaf9f95.png"},{"id":49656522,"identity":"2794ca7d-df0c-41db-a67e-0b6eafe08737","added_by":"auto","created_at":"2024-01-16 03:57:01","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":188977,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eData-driven optimization of the chiral ligand.\u003c/strong\u003e a. Initial experimental ligand screening. Reaction conditions: 1 (0.2 mmol), 2 (0.3 mmol), Ni(OAc)\u003csub\u003e2\u003c/sub\u003e•4H\u003csub\u003e2\u003c/sub\u003eO (0.04 mmol), ligand (0.06 mmol), BmimPF\u003csub\u003e6\u003c/sub\u003e (0.05 M), 1,4-dioxane/DMA (4:1, v/v, 5 mL). Undivided cell. Graphite felt anode (GF). Platinum plate cathode (Pt). 600 rpm stirring rate. Constant current electrolysis (CCE) at 2.0 mA. 100 °C, 18 h reaction time. e.r. = enantiomeric ratio. Q = 8-quinolinyl. Bmim = 1-Butyl-3-methylimidazolium. b. General workflow for data-driven ligand optimization. c. Respective visualization of the non-covalent interactions (π-π, CH-π, and polar) calculated with the help of the NCIPLOT program.\u0026nbsp;Red represents strong repulsive interactions in the plotted surfaces, whereas green and blue represent weak and strong attractive interactions, respectively.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-3760859/v1/22def8eb87246e88e98b7951.png"},{"id":49657492,"identity":"a887e682-821e-4b1b-9ce2-0b60b8de50f0","added_by":"auto","created_at":"2024-01-16 04:13:01","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":85870,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDevelopment and scope of nickel-catalyzed enantioselective electrochemical C–H activation.\u003c/strong\u003e a. Reaction optimization: 1 (0.2 mmol), 2 (0.3 mmol), Ni(OAc)\u003csub\u003e2\u003c/sub\u003e•4H\u003csub\u003e2\u003c/sub\u003eO (0.04 mmol), L8 (0.04 mmol), Cp\u003csub\u003e2\u003c/sub\u003eFe (0.06 mmol), BmimPF\u003csub\u003e6\u003c/sub\u003e (0.05 M), 1,4-dioxane/DMA (9:1, v/v, 5 mL). Undivided cell. Graphite felt anode (GF). Nickel foam cathode (Ni). 600 rpm stirring rate. Constant current electrolysis (CCE) at 1.5 mA. 100 °C, 15 h reaction time. e.r. = enantiomeric ratio. Q = 8-quinolinyl. Bmim = 1-Butyl-3-methylimidazolium. b. Monitoring of the reaction progress with and without the addition of Cp\u003csub\u003e2\u003c/sub\u003eFe (30 mol %) by NMR spectroscopy using 4,4'-dimethylbenzophenone as standard. Experimental details are provided in the supplementary methods. c. Versatility of nickel-catalyzed enantioselective electrochemical C–H activation under optimized conditions. Isolated yields.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-3760859/v1/7af9545695f8db7bbea8b3ee.png"},{"id":49656531,"identity":"1e97b217-9f6c-47d9-95ff-d14fd738c9a3","added_by":"auto","created_at":"2024-01-16 03:57:01","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":72291,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMechanistic insights.\u003c/strong\u003e a. Synthesis of the cyclometalated complex Ni\u003csup\u003eIII\u003c/sup\u003e-L8 with [Cp\u003csub\u003e2\u003c/sub\u003eFe]PF\u003csub\u003e6\u003c/sub\u003e as redox reagent. The structure of Ni\u003csup\u003eIII\u003c/sup\u003e-L8 is derived from the X-ray structure obtained for complex Ni\u003csup\u003eIII\u003c/sup\u003e-L9 (CCDC 2278180). b. Stoichiometric reaction of complex Ni\u003csup\u003eIII\u003c/sup\u003e-L8 with alkene 2 without electricity. c. Cyclic voltammograms (CV) to probe Cp\u003csub\u003e2\u003c/sub\u003eFe as redox mediator. CVs measured at 50 mVs\u003csup\u003e-1\u003c/sup\u003e using dioxane/DMA (4:1) and \u003cem\u003en\u003c/em\u003e-Bu\u003csub\u003e4\u003c/sub\u003eNPF\u003csub\u003e6\u003c/sub\u003e (0.1 M) as the electrolyte. d. UV-vis spectra of Ni\u003csup\u003eII\u003c/sup\u003e-DMAP (0.5 mM), Ni\u003csup\u003eII\u003c/sup\u003e-DMAP (0.5 mM) with L8 (0.5 mM), and Ni\u003csup\u003eIII\u003c/sup\u003e-L8 (0.5 mM) in dioxane/DMA (4:1) at 20 °C. e. Spectroelectrochemical (SEC) analysis of complex Ni\u003csup\u003eII\u003c/sup\u003e-DMAP and Ni\u003csup\u003eIII\u003c/sup\u003e-L8 with dioxane/DMA (4:1) and \u003cem\u003en\u003c/em\u003e-Bu\u003csub\u003e4\u003c/sub\u003eNPF\u003csub\u003e6\u003c/sub\u003e (0.1 M) as the electrolyte.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-3760859/v1/8155dfcce22c58455b1b8c88.png"},{"id":49657005,"identity":"690a82c0-27cf-4312-96c2-6652121ba492","added_by":"auto","created_at":"2024-01-16 04:05:01","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":162107,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEnergy profiles for product-determining step.\u003c/strong\u003e Free energy diagrams of cobalt and nickel catalyzed carboamination (A —) and carboacylation (B ---) step. Computed relative Gibbs free energies (ΔG\u003csub\u003e373.15\u003c/sub\u003e) in kcal mol\u003csup\u003e-1\u003c/sup\u003e. The located energy values are in reference with Int0, see Supplementary information for complete energy profile. Calculations were performed at the PW6B95-D4/def2-TZVPP+SMD(1,4-Dioxane\u003csup\u003eNi\u003c/sup\u003e/Aceticacid\u003csup\u003eCo\u003c/sup\u003e)//TPSS-D3(BJ)/def2-SVP level of theory. Superscripted numbers (1/3/5, and 2/4/6) in each stationary point labels represents the spin multiplicity. Non-relevant hydrogens in the transition state structures were omitted for clarity.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-3760859/v1/40a5ffc047b86f7ac16825d0.png"},{"id":78033682,"identity":"60c90ea7-0ce5-441a-bff1-5999fc5f248f","added_by":"auto","created_at":"2025-03-08 08:08:50","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1316959,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3760859/v1/fc7f2a30-f45d-4784-a068-76e1dffd685f.pdf"},{"id":49656539,"identity":"34a08497-9fbe-4b67-8316-dbbf731d6142","added_by":"auto","created_at":"2024-01-16 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03:57:01","extension":"pdf","order_by":13,"title":"","display":"","copyAsset":false,"role":"supplement","size":73084,"visible":true,"origin":"","legend":"","description":"","filename":"Compound11checkcifcu2001CG0mfinalcif.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3760859/v1/354bb11e251bbe83562d2753.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Nickel-electrocatalyzed enantioselective C–H activations for chemo-divergence","fulltext":[{"header":"Introduction","content":"\u003cp\u003eIn recent years, enantioselective electrochemical transition-metal catalysis has been recognized as a resource-economic tool for the synthesis of chiral organic architectures\u003csup\u003e1\u0026ndash;7\u003c/sup\u003e. In this innovative strategy, catalytic transformations are enabled by the electrochemical redox manipulation of the transition-metal catalyst, avoiding the use of sacrificial redox agents. Especially, in electro-oxidative catalysis, the redox equivalents are provided by the formation of molecular hydrogen through the paired cathodic hydrogen evolution reaction (HER)\u003csup\u003e6\u003c/sup\u003e, offering a transformative platform to address the growing global demand for efficient and clean energy solutions\u003csup\u003e23\u0026ndash;26\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eDespite these beneficial features, enantioselective electro-oxidative C\u0026ndash;H activation reactions are thus far severely limited to transition-metals with high risk of future supply shortages\u003csup\u003e27,28\u003c/sup\u003e, such as cobalt\u003csup\u003e10\u0026ndash;14,29,30\u003c/sup\u003e as well as the precious 4d transition-metals palladium\u003csup\u003e15\u0026ndash;17\u003c/sup\u003e and rhodium\u003csup\u003e31,32\u003c/sup\u003e. Hence, the exploration of transition-metals with high natural abundance\u003csup\u003e18\u003c/sup\u003e bears a major interest in this domain (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ea). In this context, the cost-effective\u003csup\u003e33\u003c/sup\u003e and less-toxic\u003csup\u003e34\u003c/sup\u003e base metal nickel as catalyst is particularly attractive\u003csup\u003e35\u0026ndash;39\u003c/sup\u003e, which, due to its flexibility in adopting various oxidation states, displays unique reactivity patterns for homogeneous catalysis\u003csup\u003e40,41\u003c/sup\u003e. However, the direct activation of inert C\u0026ndash;H bonds under nickel catalysis often requires harsh reaction conditions, rendering the development of enantioselective methodologies very challenging\u003csup\u003e35,36\u003c/sup\u003e. The enantioselective catalyses described are limited to highly sensitive, low-valent nickel(0) precatalysts using chiral NHC\u003csup\u003e42\u003c/sup\u003e or HASPO\u003csup\u003e43\u003c/sup\u003e (pre)ligands and commonly rely on pyrophoric organoaluminium reagents\u003csup\u003e44,45\u003c/sup\u003e. Thus, enabling oxidative nickel-catalyzed C\u0026ndash;H activation with chiral ligands for effective enantio-induction within an electro-oxidative high-valent nickel regime is a formidable challenge.\u003c/p\u003e \u003cp\u003eOur previous work on C\u0026ndash;(Het) bond formation without any enantiocontrol\u003csup\u003e46,47\u003c/sup\u003e has revealed that nickel-electrocatalysis also exhibits reaction patterns that feature unique activities compared to other transition-metals. Hence, we were particularly interested in unlocking this feature to unveil new synthetic opportunities, which can govern complementary reactivities in enantioselective electro-oxidative C\u0026ndash;H activation.\u003c/p\u003e \u003cp\u003eHere, we report on the enantioselective electrocatalytic desymmetrization with strained 7-oxabenzonorbornadienes through 3d transition-metal catalyzed C\u0026ndash;H activation giving access to substituted chiral 7-oxabicyclo[2.2.1]heptanes - a skeleton encountered in various biologically active compounds\u003csup\u003e48,49\u003c/sup\u003e (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb). Intriguingly, the devised enantioselective C\u0026ndash;H activation reveals an unprecedented chemo-divergence. While cobalt electrocatalysis furnishes the carboacylation product, the nickel electrocatalysis is selective for carboamination (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003ec).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Results and Discussion","content":"\u003cp\u003eInitially we intended to devise a model enantioselective desymmetrization reaction with 7-oxabenzonorbornadiene\u003csup\u003e50,51\u003c/sup\u003e using cobalta-electrocatalyzed C\u0026ndash;H activation (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Conspicuously, the electrocatalytic enantioselective transformation of benzamide \u003cstrong\u003e1\u003c/strong\u003e and alkene \u003cstrong\u003e2\u003c/strong\u003e, proceeded with high effectivity in the presence of the chiral 2,4-di-\u003cem\u003etert\u003c/em\u003e-butyl-substituted salicyloxazoline\u003csup\u003e52\u003c/sup\u003e ligand \u003cstrong\u003eL1\u003c/strong\u003e, giving the carboacylation product \u003cstrong\u003e3\u003c/strong\u003e in high levels of enantio- and diastereoselectivity (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea). Electricity was crucial for product formation (entry 4), whereas the electrochemically synthesized cyclometalated complex \u003cstrong\u003eCo\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eIII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-L1\u003c/strong\u003e could furnish the desired product with high selectivity in a stoichiometric fashion as well (entry 5). The enantioselective desymmetrization strategy encompassed a broad scope (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb), yielding the desired carboacylation products \u003cstrong\u003e5\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e16\u003c/strong\u003e in high yields and excellent enantiomeric control, including substrates bearing thioether (\u003cspan class=\"CitationRef\"\u003e8\u003c/span\u003e), cyano (\u003cspan class=\"CitationRef\"\u003e9\u003c/span\u003e), or carboxylic ester (\u003cspan class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e14\u003c/span\u003e) groups, among others.\u003c/p\u003e\n\u003cp\u003eWith this initial insight in hand, we tackled the unprecedented enantioselective electro-oxidative nickel-catalyzed C\u0026ndash;H activation, and, thus, we probed the viability of high-valent nickel-electrocatalysis for desymmetrizations with 7-oxabenzonorbornadiene (\u003cspan class=\"CitationRef\"\u003e2\u003c/span\u003e) (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eIn contrast to the cobalt system, that gave primarily carbacylation product \u003cstrong\u003e3\u003c/strong\u003e, the oxidative nickel-electrocatalysis exclusively furnished carboamination product \u003cstrong\u003e4\u003c/strong\u003e. After the optimization of different reaction parameters, we identified conditions that allowed the nickel-catalyzed carboamination with promising enantiocontrol (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ea). However, by pure empirical reaction optimization it was impossible to identify a ligand that would enhance the catalysis selectivity and performance. Thus, a data-driven approach\u003csup\u003e53,54\u003c/sup\u003e was pursued to assist in the ligand development. Following the workflow shown in Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb with ligand screening data yet in hand, we commenced by optimizing the free ligand structures at the TPSS-D3(BJ)/def2-SVP, followed by the single-point calculations at the PW6B95-D4/def2-TZVPP\u0026thinsp;+\u0026thinsp;SMD(1,4-Dioxane) level of theory to acquire DFT derived descriptors (for further details see Supplementary Methods, Development of Nickel Catalysis). A wide range of descriptors\u003csup\u003e55\u003c/sup\u003e were explored to describe the variations in the ligand structures as well as their properties. For electronic features, frontier molecular orbital (FMO) energies, natural bond orbital (NBO) charges, and net dipole moments (\u0026micro;\u003csub\u003enet\u003c/sub\u003e) were derived from single-point DFT calculations. To assess the steric and geometric properties, Sterimol parameters\u003csup\u003e56\u003c/sup\u003e (B\u003csub\u003emin\u003c/sub\u003e, B\u003csub\u003emax\u003c/sub\u003e, and L) and dihedral angles were considered. In light of recent studies\u003csup\u003e57,58\u003c/sup\u003e demonstrating the use of vibrational features for integrated effects of steric behaviour and charge layout, vibrational modes of the ligand were also used.\u003c/p\u003e\n\u003cp\u003eBased on the feature importance analysis employing a tree-based regression model (random forest regressor) on the obtained ligand screening data, steric parameter of C11 substituent (R1_L), asymmetric stretching mode 1 from phenyl ring (asym1_v), and NBO charge at C10 carbon (NBO_C10) emerged as the top three crucial ligand features, significantly affecting the enantioselectivity. In model screening, the GBR (Gradient Boosting) model proved to be the best model with the least test and validation mean absolute error (MAE\u003csub\u003etest\u003c/sub\u003e = 0.32 kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e, and MAE\u003csub\u003evalidation\u003c/sub\u003e = 0.19 kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e) on the training and validation dataset. Later, the permutation analysis on the trained GBR model likewise showed similar feature importance with NBO_C10 as the most significant feature after the R1_L. Based on the most relevant features, 5 ligands with variable substitution patterns were thereby newly designed, which were expected to be more prominent. The constructed model was used to predict the enantioselectivity (\u0026Delta;\u0026Delta;G\u003csub\u003epred\u003c/sub\u003e) for the 5 devised ligands, followed by prediction evaluation with experimentally obtained \u0026Delta;\u0026Delta;G\u003csub\u003eexp\u003c/sub\u003e. In agreement with the GBR model, ligand \u003cstrong\u003eL8\u003c/strong\u003e was identified as the best-performing ligand within the group of newly designed ligands and overall dataset. Thus, with the help of feature analysis, the considered substitutional modifications to the ligand backbone resulted in a newly designed ligand variant \u003cstrong\u003eL8\u003c/strong\u003e exhibiting effective enantio-induction for the challenging stereo-control in electro-oxidative nickel-catalyzed C\u0026ndash;H activation (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003eb, for further details see Supplementary Methods, Development of Nickel Catalysis).\u003c/p\u003e\n\u003cp\u003eTo rationalize the high efficiency of the devised ligand \u003cstrong\u003eL8\u003c/strong\u003e in controlling the stereoselectivity in the nickel electrocatalysis, a non-covalent interaction (NCI)\u003csup\u003e22\u003c/sup\u003e analysis of the transition state (\u003cstrong\u003eTS1\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e2\u003c/strong\u003e\u003c/sup\u003e) involved in the migratory insertion was carried out (Fig. \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003ec, for the energy profile see Supplementary Methods, Computational Studies). Here, a significant secondary attractive \u0026pi;-\u0026pi; interaction between the arene at the oxazoline (C11) from the ligand \u003cstrong\u003eL8\u003c/strong\u003e and the 8-quinolinyl of the benzamide was identified, along with a weak attractive CH-\u0026pi; interaction between the methyl at oxazoline (C10) and benzene plane of the benzamide. These findings highlight the ligand effect in the catalyst stabilization, facilitating the migratory insertion of the alkene. Interestingly these two ligand site feature roles (R1_L, and NBO_C10) were also indicated by the early feature analysis and post model development. In addition, the NCI plot unveiled a strong attractive polar interaction between oxygen of the 7-oxabenzonorbornadiene and carbonyl carbon centre from the benzamide, aligning with the experimentally observed excellent diastereo-selectivity.\u003c/p\u003e\n\u003cp\u003eWith a suitable ligand for enantioselectivity being identified by data science, we next improved the efficacy further (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea). Hence, we monitored the reaction progress during electrocatalysis and found that already in the initial stage the formation of product \u003cstrong\u003e4\u003c/strong\u003e only proceeded gradually, pointing at an inefficient anodic electron transfer. For this purpose, we probed ferrocene (Cp\u003csub\u003e2\u003c/sub\u003eFe) as a redox mediator, which led to a considerable increase in the efficiency, while maintaining the excellent control of enantioselectivity (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ea and \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003eb).\u003c/p\u003e\n\u003cp\u003eWith the optimized conditions in hand, the versatility of the nickel electrocatalysis was examined (Fig. \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003ec). The strategy thus allowed for the synthesis of a broad range of chiral bridged dihydroisoquinolinones in high enantiomeric excess (\u003cspan class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e41\u003c/span\u003e) thereby tolerating various functional groups. The strategy showed high tolerance to oxidation-sensitive thioether groups (\u003cspan class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e30\u003c/span\u003e) and electrophilic carbonyl motifs (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e32\u003c/span\u003e). Besides fluoro- (\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e), bromo- (\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e), and iodo-substituents (\u003cspan class=\"CitationRef\"\u003e27\u003c/span\u003e), benzamides bearing acetamido motif (\u003cspan class=\"CitationRef\"\u003e33\u003c/span\u003e) were found to be compatible. In addition, the electrocatalytic C\u0026ndash;H activation on thiophene enabled the enantioselective synthesis of the desired carboamination products (\u003cspan class=\"CitationRef\"\u003e35\u003c/span\u003e, \u003cspan class=\"CitationRef\"\u003e36\u003c/span\u003e).\u003c/p\u003e\n\u003cp\u003eHaving identified Cp\u003csub\u003e2\u003c/sub\u003eFe as a redox mediator, we were interested to explore whether ferrocenium ([Cp\u003csub\u003e2\u003c/sub\u003eFe]\u003csup\u003e+\u003c/sup\u003e) could serve as a redox agent in a stoichiometric reaction to form a putative cyclometalated nickel(III)-species bearing the optimized chiral ligand \u003cstrong\u003eL8\u003c/strong\u003e. To this end, the cyclometalated complex \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-DMAP\u003c/strong\u003e was synthesized and subjected to a reaction with 1 equivalent [Cp\u003csub\u003e2\u003c/sub\u003eFe]PF\u003csub\u003e6\u003c/sub\u003e and the chiral ligand \u003cstrong\u003eL8\u003c/strong\u003e. After 15 minutes of reaction time, a colour change from orange to dark red was observed and the cyclometalated complex \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eIII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-L8\u003c/strong\u003e could be isolated, whereby recovering the stoichiometrically generated Cp\u003csub\u003e2\u003c/sub\u003eFe (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ea). To determine the relevant oxidation states of the nickel catalyst involved in the C\u0026ndash;H/N\u0026ndash;H annulation process, the reactivity of the synthesized complex \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eIII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-L8\u003c/strong\u003e was next investigated in a stoichiometric reaction with alkene \u003cstrong\u003e2\u003c/strong\u003e (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003eb). Hence, \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eIII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-L8\u003c/strong\u003e furnished the desired carboamination product \u003cstrong\u003e4\u003c/strong\u003e with excellent enantioselectivity in the absence of oxidative conditions, pointing to a feasible reductive elimination from nickel(III). To gain further insights into the C\u0026ndash;H/N\u0026ndash;H activation pathway, the electrocatalytic reaction was monitored by high-resolution electrospray ionization mass spectrometry (HR ESI MS) under the standard conditions using a bromo substituted benzamide for clearly identifiable isotopic patterns. Here, a species corresponding to the nickel(III)-intermediate resulting from migratory insertion was detected by in-operando spectrometry (for details see Supplementary Methods, Monitoring the Nickel Catalysis by Mass Spectrometry). As the present experimental studies reveal that the nickel(II/III) redox event is crucial for the devised electrocatalysis, we further investigated the synthesized nickel complexes by cyclic voltammetry (CV) (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ec). While the oxidation potential of Cp\u003csub\u003e2\u003c/sub\u003eFe is below the oxidation potential of \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-DMAP\u003c/strong\u003e in combination with ligand \u003cstrong\u003eL8\u003c/strong\u003e with a potential difference of less than 200 mV, the cyclometalated complex \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eIII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-L8\u003c/strong\u003e shows no oxidation event in the relevant potential range. Furthermore, a catalytic current in the CV of Cp\u003csub\u003e2\u003c/sub\u003eFe was observed when \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-DMAP\u003c/strong\u003e together with \u003cstrong\u003eL8\u003c/strong\u003e were added, indicated by a disappearance of the reduction wave and an enhancement of the oxidation wave (for further details see Supplementary Methods, Electroanalytical Investigations). These findings further support the hypothesis of Cp\u003csub\u003e2\u003c/sub\u003eFe as a redox mediator via outer-sphere electron transfer\u003csup\u003e59\u003c/sup\u003e in the nickel(II/III) redox event. Subsequently, the nickel(II/III) interconversion was investigated by UV-vis absorption spectroelectrochemistry (UV-vis SEC) (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ed-e). Intriguingly, for \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-DMAP\u003c/strong\u003e, a change in the spectrum was already displayed when combined with \u003cstrong\u003eL8\u003c/strong\u003e, being indicative of the formation of a nickel(II)-species coordinated by the bidentate ligand \u003cstrong\u003eL8\u003c/strong\u003e (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ed). In the analysis by UV-vis SEC, the change in absorbance in direct proximity to the working electrode was recorded as a function of time while applying defined potentials. Here, when +\u0026thinsp;1.5 V (vs Ag/Ag\u003csup\u003e+\u003c/sup\u003e) were applied in a solution of \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-DMAP\u003c/strong\u003e with \u003cstrong\u003eL8\u003c/strong\u003e, a pattern in the absorbance change was revealed, being the mirror-image to the pattern observed for \u003cstrong\u003eNi\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003eIII\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e-L8\u003c/strong\u003e at \u0026minus;\u0026thinsp;0.5 V (vs Ag/Ag\u003csup\u003e+\u003c/sup\u003e) (Fig. \u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003ee). This finding reflects the feasibility of the conversion of cyclometalated nickel(II) to nickel(III)-species induced by electron transfer (for further details see Supplementary Methods, Electroanalytical Investigations). As to the cathodic half reaction, the headspace of the electrochemical cell after catalysis was analysed by gas chromatography (GC) and molecular hydrogen was detected, supporting HER as the cathodic process (see Supplementary Methods, Detection of Hydrogen Gas for Nickel Catalysis).\u003c/p\u003e\n\u003cp\u003eSubsequently, DFT calculations were performed to rationalize the observed chemo-divergence in electrocatalysis (Fig. \u003cspan class=\"InternalRef\"\u003e6\u003c/span\u003e) (for complete reaction profiles see Supplementary Methods, Computational Studies). For the nickel catalysis, in line with the experimental findings, the calculations pointed to the reductive elimination as product-determining step as the most favourable pathway with an energy barrier of 25.6 kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (\u003cstrong\u003eTS2\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e2A\u003c/strong\u003e\u003c/sup\u003e), while for the cobalt catalysis the nucleophilic addition resulting in carboacylation was kinetically more favourable with an energy barrier of 18.8 kcal mol\u003csup\u003e\u0026minus;\u0026thinsp;1\u003c/sup\u003e (\u003cstrong\u003eTS2\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e5B\u003c/strong\u003e\u003c/sup\u003e).\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAn unprecedented electro-oxidative high-valent nickel-catalyzed C\u0026ndash;H activation was disclosed by data-science guided ligand optimization. The devised nickel electrocatalysis proceeded with high enantio- and diastereo-selectivity providing direct access to versatile chiral building blocks with multiple stereocenters with ample scope. The chemo-divergent cobalt-catalyzed carboacylation and nickel-catalyzed carboamination allowed enantioselective molecular catalysis enabled by the formation of molecular hydrogen through HER. Mechanistic investigations provided insights into the differences of the nickel and cobalt regime. Studies with isolated cyclometalated intermediates involving electroanalytical techniques shed light on the active nickel(III) species. The study presented herein showcases the unique potential of electrochemical C\u0026ndash;H activation by nickel catalysis as an innovative and powerful tool for sustainable synthesis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eCompeting interests\u003c/h2\u003e \u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\u003ch2\u003eAuthor contributions\u003c/h2\u003e \u003cp\u003eL.A. supervised the project. L.A. and T.V.M. conceived the work. T.V.M. designed the experimental studies. N.K.P. designed and conducted the computational studies. T.V.M., P.B., S.D., S.E.P., J.B., Y.R.L., A.S. conducted the experiments. T.V.M. and S.E.P. conducted the experimental mechanistic studies. L.A., T.V.M., and N.K.P. wrote the manuscript. L.A., T.V.M., N.K.P., and S.D. edited the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors gratefully acknowledge support from the ERC Advanced Grant No. 101021358, the DFG (Gottfried Wilhelm Leibniz award and SPP 2363 to L. A.), and the FCI (Kekul\u0026eacute;-Fellowship to T.V.M.). We thank C. Golz (University of G\u0026ouml;ttingen) for the assistance with the X-ray diffraction analysis.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eAll data supporting the findings of this work are available within the paper and its Supplementary Information.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSiu, J. C., Fu, N. \u0026amp; Lin, S. Catalyzing Electrosynthesis: A Homogeneous Electrocatalytic Approach to Reaction Discovery. Acc. Chem. 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Rev. 43, 2492\u0026ndash;2521, doi:\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1039/C3CS60464K\u003c/span\u003e\u003cspan address=\"10.1039/C3CS60464K\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e (2014).\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-3760859/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3760859/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eEnantioselective electrocatalysis bears unique potential for the sustainable assembly of enantiomerically enriched molecules\u003csup\u003e1\u0026ndash;7\u003c/sup\u003e. This approach allows electro-oxidative C\u0026ndash;H activation to be performed paired to the hydrogen evolution reaction\u003csup\u003e8,9\u003c/sup\u003e. While recent progress featured scarce transition metals with limited availability\u003csup\u003e10\u0026ndash;17\u003c/sup\u003e, we, herein, reveal that the Earth-abundant 3d transition-metal nickel is characterized by unique performance, while having high natural abundance\u003csup\u003e18\u003c/sup\u003e and reduced toxicity\u003csup\u003e19\u003c/sup\u003e. Thereby, electrocatalytic C\u0026ndash;H activation enabled enantioselective desymmetrizations with bicyclic alkenes, leading to three-dimensional molecular building blocks with multiple stereogenic elements\u003csup\u003e20\u003c/sup\u003e. Here, ligand optimization was guided by smart feature analysis for enantioselectivity enhancement. The detailed mechanistic investigation by experimental studies with organometallic intermediates in conjunction with computational studies identified key features of the ligand design including non-covalent interactions\u003csup\u003e21,22\u003c/sup\u003e to guarantee full selectivity control.\u003c/p\u003e","manuscriptTitle":"Nickel-electrocatalyzed enantioselective C–H activations for chemo-divergence","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-16 03:56:56","doi":"10.21203/rs.3.rs-3760859/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-catalysis","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natcatal","sideBox":"Learn more about [Nature Catalysis](http://www.nature.com/natcatal/)","snPcode":"","submissionUrl":"","title":"Nature Catalysis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"54840360-dc41-4433-a803-e839490a19be","owner":[],"postedDate":"January 16th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":28143468,"name":"Physical sciences/Chemistry/Electrochemistry/Electrocatalysis"},{"id":28143469,"name":"Physical sciences/Chemistry/Catalysis/Electrocatalysis"}],"tags":[],"updatedAt":"2025-03-08T08:08:42+00:00","versionOfRecord":{"articleIdentity":"rs-3760859","link":"https://doi.org/10.1038/s41929-025-01306-9","journal":{"identity":"nature-catalysis","isVorOnly":false,"title":"Nature Catalysis"},"publishedOn":"2025-03-07 05:00:00","publishedOnDateReadable":"March 7th, 2025"},"versionCreatedAt":"2024-01-16 03:56:56","video":"","vorDoi":"10.1038/s41929-025-01306-9","vorDoiUrl":"https://doi.org/10.1038/s41929-025-01306-9","workflowStages":[]},"version":"v1","identity":"rs-3760859","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3760859","identity":"rs-3760859","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}