Electrochemical DABCOylation enables challenging aromatic C–H amination

Electrochemical DABCOylation enables challenging aromatic C–H amination | 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 Physical Sciences - Article Electrochemical DABCOylation enables challenging aromatic C–H amination Christian Malapit, Griffin Stewart, Eva Maria Alvarez, Chris Rapala, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5442169/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Oct, 2025 Read the published version in Nature Synthesis → Version 1 posted You are reading this latest preprint version Abstract The selective amination of aromatic C–H bonds is a powerful strategy to access aryl amines, functionalities found in many pharmaceuticals and agrochemicals. Despite advances in the field, a platform for the direct, selective C–H amination of electronically diverse (hetero)arenes, particularly electron-deficient (hetero)arenes, remains an unaddressed fundamental challenge. 1-10 In addition, many (hetero)arenes present difficulty in common selective pre-functionalization reactions, such as halogenation 11 , or metal-catalyzed borylation 12 and silylation 13 . Here, we report a general solution to these limitations that enables selective C–H amination across a comprehensive scope of (hetero)arenes. Key to this strategy’s success is the oxidative generation of highly electrophilic N -radical dications from bicyclic tertiary amines (DABCO) that reacts across a wide range of arenes with high selectivity. Notably, this platform constitutes the first anodically generated N -radical cations that engage in aromatic C–H amination over well-reported hydrogen atom transfer (HAT) with weak C­–H bonds. 14-16 This C–­H amination reaction that allows selective functionalization of both electron-rich and deficient arenes, as well as pyridines, is a rarity in the general area of non-directed aromatic C–H functionalization. 1-4 This sustainable electrochemical DABCOylation reaction provides access to many complex drug-like aryl- and pyridinylpiperazines with high functionality tolerance, chemoselectivity, and site-selectivity. 17 Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Aryl nitrogen bonds are ubiquitous across material and medicinal chemistry. 18,19 About a third of novel small molecule drugs approved by the US Food & Drug Administration in 2023 include an aryl C–N bond. 20 Aromatic C–H bonds are the ideal substrates for aromatic amination due to their abundance, yet selectivity and substrate scope remain ongoing challenges. Radical redox chemistry has come to fill the void of selective arene C–H amination with two main approaches (Figure 1a). 1-4 The first such methodology relies on the production of arene radical cations, as pioneered by Yoshida and Nicewicz. 21-23 In these systems, electron-rich arenes undergo one-electron oxidation, and are then trapped by oxidatively stable sp 2 – N nucleophiles to give aryl amines with moderate to high regioselectivity. Second, radical C–H amination based on electrophilic nitrogen radicals was developed, flipping the polarity of the reaction. Most successfully, these radicals have been generated by the reduction of compounds of the general form R 3 N + –X (X = F, Cl, RCO 2 , RSO 3 ) to form electrophilic N -radical (di)cations. 6-10, 24-32 Selectivity and reactivity for N -radical intermediates vary depending on the steric demand and electrophilicity of the radical species and the arene substrate. 1,26 Despite exploring many N -radical scaffolds, these methods have failed to selectively functionalize electron deficient (hetero)arenes (Figure 1a). Past reports of oxidative electrophilic N -radical generation have struggled with arene scope due to limited radical electrophilicity. 33-35 Our group recently published a reductive electrochemical DABCOylation of (hetero)arenes ( 1 ) utilizing Selectfluor II as the aminating reagent (Figure 1b) to form aryl DABCOnium salts ( 2 ). 32 Despite the high electrophilicity of the N -Me-DABCOnium radical dication ( 3a ), this system struggled to aminate electron-poor systems such as benzonitrile and nitrobenzene. With such arenes, we observed over-reduction of Selectfluor II to N -Me-DABCOnium ( 4a ) and full recovery of the unreacted arenes (Figure 1b). We hypothesized that the interaction of 3a with electron-deficient arenes is weak and outcompeted by over-reduction to form 4a that could no longer participate in amination under reductive conditions. With its high electrophilicity and steric demand, the DABCOnium radical dication ( 3a ) should be a promising candidate for selective amination of electron-poor arenes. We hypothesized that if the radical dication 3 was instead sourced from 4a (rather than Selectfluor) via anodic oxidation, electron-poor reactivity would be unlocked. We therefore envisioned an anodic aromatic C–H amination using a DABCOnium framework to take advantage of the greater reactivity and selectivity of the N -radical dication intermediates and the diversification of their products, while also benefitting from the lack of added chemical oxidants with potential substrate incompatibilities. Results And Discussion To discover and develop an arene C–H amination reaction via oxidatively generated N -radical cations (Figure 1c), we pursued the mechanistic strategy summarized in Figure 1d. First, N -radical cation 3 can be sourced oxidatively from DABCOnium 4 ( E p/2 ~ 1.5 V vs Fc/Fc + ). The bicyclic nature of N -alkyl DABCOniums appears to suppress unwanted Shono-type oxidations. 36 Second, a sacrificial oxidant that undergoes cathodic reduction is needed, which would allow for an operationally convenient undivided electrochemical cell. We hypothesized that proton reduction would meet this requirement. And third, a base that will deprotonate intermediate III to form aryl DABCOnium salt 2 is needed. Anodically generated N –radical cations from tertiary bicyclic amines are known to undergo hydrogen atom transfer (HAT), as they form strong N–H bonds upon accepting a hydrogen atom. 14-16 However, DFT calculations have shown that radical addition of 3 into an arene has a lower energy barrier than extracting a benzylic hydrogen atom for electron-neutral arenes under typical amination conditions. 32 Our initial studies provided promising results using fluorobenzene as the arene and acetic acid as both the sacrificial oxidant and base (as acetate), furnishing the desired product 2a in 9% yield. Upon further study, we found that HFIP provided much better yields. HFIP is likely superior for two reasons: generated acetate can compete with 4 for anodic oxidation ( E p = 1.45 V vs Fc/Fc + in MeCN) 37 and HFIP is known to enhance cationic reactivities. 8 With 1:3 HFIP/MeCN as mixed solvent, LiPF 6 as supporting electrolyte, and graphite/platinum (anode/cathode) as electrodes, the amination of fluorobenzene to form 2a was obtained in quantitative yield with high regioselectivity towards the para -product (32:1.3:1 p / o / m ). Other parameters were also investigated (see SI for details); however, the optimal conditions are shown in Figure 1c. Free N -radical arene C–H amination has previously struggled to selectively aminate electron-poor arenes. Recently, Lei and coworkers published a selective para -amination of nitroarenes utilizing proton coupled oxidation of amines. However, this transformation, by design, works only with nitroarenes. 5 Utilizing our anodic DABCOylation method, a variety of electron-deficient arenes including cyano- ( 5b ) and nitro- ( 5c ) benzene, triphenyl phosphine oxide ( 5d ), trifluorotoluene ( 5e ), methyl-2-bromo benzoate ( 5f ), and 1,2-dichlorobenzene ( 5g ) undergo amination in moderate to quantitative yields with high to singular selectivity. Moreover, the observed selectivity is in agreement with the Fukui index value and thus can be predicted. 32 Our method has unusually high selectivity for such compounds in free-radical arene C–H functionalization, where functionalization of electron-poor arenes is usually unselective. 6-10,38,39 To our knowledge, this anodic amination represents the only selective C–H functionalization of benzonitrile with significant diversification potential, as electrophilic halogenation and transition metal-catalyzed borylation/silylation methods are ineffective or unselective on this substrate. 11-13 Moreover, aryl DABCOnium salts 2 can be isolated as crude solids or can be readily converted to their corresponding aryl piperazines 5 , using an iterative S N 2/E2 process with potassium cyanide or through use of the aqueous reductant sodium thiosulfate. 26,32 An X-ray crystal structure of aryl DABCOnium salt 2a was obtained revealing a comparable aryl C–N bond length (1.49 Å) to related aryl trimethyl ammonium salts (1.52 Å). 40 This could explain why the reactivity profile of aryl DABCOnium salts is comparable to aryl trimethyl ammonium salts when engaged with transition-metal catalysts. 41 Pyridines are a privileged class of heterocyclic compounds, and their direct and selective functionalization remains an active goal for reaction development. 42-44 A variety of halo- and alkyl-pyridine derivatives are amenable to anodic DABCOylation ( 5h-l ). Interestingly, the C–H amination takes place selectively at the α-position, even when the substituent does not normally direct for the α-position ( 2l ), delivering direct access to 2-pyridinylpiperazine derivatives 5h-l , a framework commonly found in neurological and antiretroviral drugs, from simple pyridines. Importantly, α-C–H amination of pyridines is a challenging transformation, traditionally accessible only through the Chichibabin reaction. 45 Hartwig and Fier have modernized pyridine α-C–H amination, leveraging a tandem AgF 2 -mediated fluorination/S N Ar type reactivity or Chichibabin type amination through pyridine activation. 42-44 Meanwhile, modern transition metal-catalyzed borylation 12 or silylation 13 of pyridines are selective at the C-3 or C-4 positions. This anodic DABCOylation represents the first electrophilic method for accessing such α-aminated pyridines, with potential for downstream diversification due to the tolerance of halogen substituents. Aside from aryl halides many useful and sensitive functionalities were tolerated, such as unprotected alcohols ( 5v, 5x ), allylic and benzylic C–H bonds ( 5q, 2r, 2t, 5u) , epoxides ( 2r ), benzyl chlorides ( 2t ), imines ( 5u ), enol ethers ( 5w ), and many common N -heterocycles, such as pyridines ( 5h – 5m ), pyrroles ( 5s ), triazoles ( 5v ), and tetrazoles ( 5u ). Additionally, to our knowledge, this is the first demonstration of an electrophilic N -radical reacting selectively with an arene over an olefin or alkyne, as seen in 5q , 5y , and 5z (Figure 3a). 35,46 Some free radical arene C–H functionalization methods that are efficacious on electron-poor arenes struggle with electron-rich arenes, due to tendency of the highly electrophilic radicals to participate in SET over π-system addition. 47 However, this anodic DABCOylation method remains tolerant of electron-rich arenes (Figure 2b) such as anisole (see SI), pyrrole derivatives ( 5s ), and biphenyl derivatives ( 2t, 5u ). Another key advantage of this chemistry is its ability to quickly build complexity towards drug-like piperazine compounds. A diverse set of functionalized DABCOnium salts can be used as amine source compared to previous work that is limited to Selectfluor I & II. 26,32 Using simple S N 2 alkylation reactions, with no chromatography or crystallization, DABCO was converted to N -alkyl DABCOnium salts 4x – 4ac containing a diverse set of functional groups. 48 Subjecting these N -alkyl DABCOnium salts to the electrochemical amination reaction, followed by bridge removal, provided easy access to designer aryl piperazines bearing important functional groups such as free alcohols ( 5x ), olefins ( 5y ), alkynes ( 5z ), CF 3 groups ( 5ab ) and other arenes ( 5ac ). Tolerance of an alkyne is noteworthy, as they can be used in bio-orthogonal chemistry for in vivo applications. In addition, aryl-DABCOnium salts can be utilized in photoredox and transition metal catalyzed diversifications. This includes methylation, 41 arylation, 32 phosphorylation ( 6 ), and borylation ( 7 ), showing the potential of the aryl DABCOnium as an intermediate for C–C, C–P, and C–B bond formation. To gain insight into the mechanism of this reaction, we performed several experiments including cyclic voltammetry (CV), competition trials, kinetic isotope effect (KIE) experiments, and electrochemical UV–vis spectroscopy (spectroelectrochemistry). CV analysis (Figure 4a) of the reaction components reveal that N -alkyl DABCOnium salts 4 undergo accessible oxidation ( E p /2 ~ 1.5 V vs Fc/Fc + ) in 3:1 MeCN/HFIP. Moreover, HFIP undergoes proton reduction ( E red = –1.0 V). while the aryl DABCOnium salt product reduces at more negative potentials ( E red = –1.8 V). CV studies (Figure 4b) also revealed that upon addition of benzene (Figure 4b) or toluene (see SI) to a solution of 4 , the oxidation profile increases in current and shifts cathodically (44 mV cathodic shift from 1-4 mM benzene). This change is an indication of rapid trapping of the arene, perhaps via an N -radical-cation–pi interaction I , 32 leading to faster diffusion away from the working electrode. 49 In addition, spectroelectrochemical studies provide evidence of the rapid trapping of electrochemically generated dicationic N -radical 3 in the presence of benzonitrile, suppressing features associated with oxidation of 4 (Figure 4b). This observation provides evidence for the proposed charge transfer or rapid turnover into radical addition intermediate II . The slope of cathodic shift reduces as arene concentration increases, possibly indicating that the arene is saturating almost all generated 3 . Seeking further clarification of the mechanism, we performed a series of competition experiments. Intermolecular competition between different monosubstituted arenes (Figure 4c) 50 show that more electron-rich arenes were able to outcompete their electron-poor counterparts. In addition, an intermolecular KIE between benzene and benzene- d 6 revealed a k H / k D of 0.93 (Figure 4d). Overall, these experiments rule out C–H bond cleavage as the rate-limiting step and narrows the rate-limiting step to the radical cation–arene interaction or the C–N bond formation. Previously reported N -radical C–H amination reactions have proposed C–N bond formation to be rate-limiting by computation. 5 Overall, we propose a dual mechanistic regime that depends upon the oxidation potential of the arene substrate. The mechanism that enables the selective DABCOylation of electron-deficient arenes and is operational for most shown substrates is summarized is Figure 1c. DABCOnium salt 4 is oxidized on the anode to radical intermediate 3 , which then undergoes trapping by the arene substrate, leading to radical addition intermediate II , perhaps through charge transfer complex I . Subsequent anodic oxidation to Wheland-type intermediate III followed by deprotonation leads to the aryl-DABCOnium salt 2 . Meanwhile, on the cathode, HFIP is reduced to its anion and hydrogen gas via the hydrogen evolution reaction, furnishing the base required for the deprotonation of intermediate III . The high site selectivity for most substrates is likely due to the high electrophilicity of the N -radical dication and its steric demand. 1,26 It is also notable that amine 3 is recyclable. When C­–N bond formation is challenging, cathodic reduction of 3 can occur, thus regenerating the amine source 4 . That effect, along with the HFIP as co-solvent, likely explains this method’s success with electron-poor arenes where reductive methods have failed. 26,32 While the above mechanism is probable for electron-poor and -neutral arenes, arenes that oxidize easier than 4 proceed through a direct arene oxidation mechanism. Evidence of this competing mechanism can be seen in the product obtained from irbesartan (Figure 2b, 5u ), which underwent intramolecular amination with its tetrazole moiety (enabled by the oxidation of its biphenyl core) during DABCOylation electrolysis. Other electron-rich arene substrates such as 1s and anisole (see SI) most likely undergo amination via arene oxidation. This is supported by the spectroelectrochemical data (see SI). In a sample containing anisole and 4 , the oxidation of anisole dominates the spectral features, even at potentials that oxidize 4 . This is unlike similar experiments with more electron-poor benzene and benzonitrile, which show the oxidation of 4 instead. This methodology is particularly advantageous in its mechanistic flexibility, producing a wide range of desired C–H amination products by either the oxidation of 4 or by the direct oxidation of arenes. Since both mechanisms are broadly selective for the most electron-rich site in the molecule, results of arene oxidation in our system are not appreciably different from reductive systems which are always going through N -radical mechanisms. 41 This allows for improved arene scope compared to existing systems. Conclusion In summary, we have developed a general and selective non-directed aromatic C–H amination, effectively addressing a longstanding challenge in late-stage C–H functionalization. In this method, (hetero)arenes that are typically challenging towards C–H amination, classical halogenation, or metal-catalyzed borylation/silylation reactions can effectively undergo C–H DABCOylation with high selectivity. Key to the success of this methodology is the development of an oxidative electrochemical approach to generate highly electrophilic bicyclic N -radical dications that rapidly reacts across a wide range of arenes. The electrochemical conditions used bias the generated N -radical dications toward aryl reactivity, representing the first oxidatively generated N -radical cation that undergoes aryl C–H amination over known reactivity via HAT or olefin addition. The synthetic value of this functionalization strategy is showcased in the rapid construction of many complex drug-like aryl- and pyridinylpiperazines that contain sensitive functionalities such as free alcohols, terminal alkynes, olefins, aryl and alkyl halides, and many common heterocycles. We anticipate that this system can serve as a model for advancing other C–H functionalization reactions that is general and selective for both electron-rich and deficient arenes and amenable to late-stage functionalization. Declarations Data Availability All experimental data, copies of spectra, and CIF data are available in the supplementary information. Acknowledgements This work was supported by Northwestern University with a start-up grant for C.A.M. We thank the support from the National Institute of General Medical Sciences of the National Institute of Health under award number R00GM140249 for C.A.M. We thank the National Science Foundation Graduate Research Fellowship for G.S. We thank the Air Force Office of Scientific Research for funding support under the award number FA9550-22-1-0421 for J.H.S. and J.A.K. The facilities at IMSERC at Northwestern University were used with funding support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633). Author Contributions G.S., E.M.A., and C.A.M. conceived the work and designed the experiments. G.S. performed the electrochemical experiments and mechanistic studies. E.M.A. performed the photocatalytic reactions. C.R. and G.S. synthesized the DABCOnium salts. J.H.S. performed the spectroelectrochemical experiments. G.S. and C.A.M. wrote the manuscript and all authors provided revisions. All authors have given approval to the final version of the manuscript. Competing Interests The authors do not claim any competing interests. Author Information Correspondence should be addressed to [email protected] References Ruffoni, A., Mykura, R. C., Bietti, M. & Leonori, D. The interplay of polar effects in controlling the selectivity of radical reactions. Nat. Synth. 1 , 682–695 (2022). Holmberg-Douglas, N. & Nicewicz, D. A. Photoredox-Catalyzed C–H Functionalization Reactions. Chem. Rev. 122 , 1925–2016 (2022). Zhang, L. & Ritter, T. A Perspective on Late-Stage Aromatic C–H Bond Functionalization. J. Am. Chem. Soc. 144 , 2399–2414 (2022). Stewart, G., Rapala, C., & Malapit, A. Electrochemical Non-Directed Arene C–H Amination. ChemCatChem (2024). e202400867. Zhang, Z. et al. Para-selective nitrobenzene amination lead by C(sp 2 )-H/N-H oxidative cross-coupling through aminyl radical. Nat. Commun. 15 , 4186 (2024). Rössler, S. L. et al. Pyridyl Radical Cation for C−H Amination of Arenes. Angew. Chem. Int. Ed. 58 , 526–531 (2019). Ham, W. S., Hillenbrand, J., Jacq, J., Genicot, C., & Ritter, T. Divergent Late-Stage (Hetero)aryl C–H Amination by the Pyridinium Radical Cation. Angew. Chem. Int. Ed. 58 , 532-536 (2019). D’Amato, E. M., Börgel, J. & Ritter, T. Aromatic C–H amination in hexafluoroisopropanol. Chem. Sci. 10 , 2424–2428 (2019). Hillenbrand, J., Ham, W. S. & Ritter, T. C–H Pyridonation of (Hetero-)Arenes by Pyridinium Radical Cations. Org. Lett. 21 , 5363–5367 (2019). Allen, L. J., Cabrera, P. J., Lee, M. & Sanford, M. S. N -Acyloxyphthalimides as Nitrogen Radical Precursors in the Visible Light Photocatalyzed Room Temperature C–H Amination of Arenes and Heteroarenes. J. Am. Chem. Soc. 136 , 5607–5610 (2014). Wang, W. et al. Catalytic Electrophilic Halogenation of Arenes with Electron-Withdrawing Substituents. J. Am. Chem. Soc. 144 , 13415–13425 (2022). Roque, J. B. et al. Kinetic and thermodynamic control of C(sp 2 )–H activation enables site-selective borylation. Science 382 , 1165–1170 (2023). Cheng, C. & Hartwig, J. F. Rhodium-Catalyzed Intermolecular C–H Silylation of Arenes with High Steric Regiocontrol. Science 343 , 853–857 (2014). Kawamata, Y. et al. Scalable, Electrochemical Oxidation of Unactivated C–H Bonds. J. Am. Chem. Soc. 139 , 7448–7451 (2017). Holt, E. et al. An Electrochemical Approach to Directed Fluorination. J. Org. Chem. 88 , 2557–2560 (2023). Zhang, S. & Findlater, M. Electrochemically Driven Hydrogen Atom Transfer Catalysis: A Tool for C(sp 3 )/Si–H Functionalization and Hydrofunctionalization of Alkenes. ACS Catal. 13 , 8731–8751 (2023). Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals: Miniperspective. J. Med. Chem. 57 , 10257–10274 (2014). Brown, D. G. & Boström, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?: Miniperspective. J. Med. Chem. 59 , 4443–4458 (2016). Ertl, P., Altmann, E. & McKenna, J. M. The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time. J. Med. Chem. 63 , 8408–8418 (2020). Novel Drug Approvals for 2023. Food and Drug Administration. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023. (accessed 8-9-2024). Morofuji, T., Shimizu, A. & Yoshida, J. Electrochemical C–H Amination: Synthesis of Aromatic Primary Amines via N -Arylpyridinium Ions. J. Am. Chem. Soc. 135 , 5000–5003 (2013). Romero, N. A., Margrey, K. A., Tay, N. E. & Nicewicz, D. A. Site-selective arene C-H amination via photoredox catalysis. Science 349 , 1326–1330 (2015). Wang, J.-H. et al. Regioselective Ortho Amination of an Aromatic C–H Bond by Trifluoroacetic Acid via Electrochemistry. Org. Lett. 21 , 5581–5585 (2019). Foo, K., Sella, E., Thomé, I., Eastgate, M. D. & Baran, P. S. A Mild, Ferrocene-Catalyzed C–H Imidation of (Hetero)Arenes. J. Am. Chem. Soc. 136 , 5279–5282 (2014). Legnani, L., Prina Cerai, G. & Morandi, B. Direct and Practical Synthesis of Primary Anilines through Iron-Catalyzed C–H Bond Amination. ACS Catal. 6 , 8162–8165 (2016). Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T. Charge-transfer-directed radical substitution enables para-selective C–H functionalization. Nat. Chem. 8 , 810–815 (2016). Svejstrup, T. D., Ruffoni, A., Juliá, F., Aubert, V. M. & Leonori, D. Synthesis of Arylamines via Aminium Radicals. Angew. Chem. Int. Ed. 56 , 14948–14952 (2017). Ruffoni, A. et al. Practical and regioselective amination of arenes using alkyl amines. Nat. Chem. 11 , 426–433 (2019). See, Y. Y. & Sanford, M. S. C–H Amination of Arenes with Hydroxylamine. Org. Lett. 22 , 2931–2934 (2020). Gillespie, J. E., Morrill, C. & Phipps, R. J. Regioselective Radical Arene Amination for the Concise Synthesis of ortho -Phenylenediamines. J. Am. Chem. Soc. 143 , 9355–9360 (2021). Behnke, N. E., Kwon, Y.-D., Davenport, M. T., Ess, D. H. & Kürti, L. Directing-Group-Free Arene C(sp 2 )–H Amination Using Bulky Aminium Radicals and DFT Analysis of Regioselectivity. J. Org. Chem. 88 , 11847–11854 (2023). Alvarez, E. M., Stewart, G., Ullah, M., Lalisse, R., Gutierrez, O. & Malapit, C. A. Site-Selective Electrochemical Arene C–H Amination. J. Am. Chem. Soc. 146 , 3591–3597 (2024). Margrey, K. A., Levens, A. & Nicewicz, D. A. Direct Aryl C−H Amination with Primary Amines Using Organic Photoredox Catalysis. Angew. Chem. Int. Ed. 56 , 15644–15648 (2017). Liu, K. et al. Electrooxidative para-selective C–H/N–H cross-coupling with hydrogen evolution to synthesize triarylamine derivatives. Nat. Commun. 10 , 639 (2019). Hu, X., Zhang, G., Nie, L., Kong, T. & Lei, A. Electrochemical oxidation induced intermolecular aromatic C-H imidation. Nat. Commun. 10 , 5467 (2019). Shono, T., Matsumura, Y. & Tsubata, K. Electroorganic chemistry. 46. A new carbon-carbon bond forming reaction at the alpha-position of amines utilizing anodic oxidation as a key step. J. Am. Chem. Soc. 103 , 1172–1176 (1981). Klein, M. & Waldvogel, S. R. Anodic Dehydrogenative Cyanamidation of Thioethers: Simple and Sustainable Synthesis of N ‐Cyanosulfilimines. Angew. Chem. Int. Ed. 60 , 23197–23201 (2021). Jelier, B., Tripet, P., Pietrasiak, E., Franzoni, I., Jeschke, G & Togni, A. Radical Trifluoromethoxylation of Arenes Triggered by a Visible-Light-Mediated N–O Bond Redox Fragmentation. Angew. Chem. Int. Ed. 57 , 13784-13789 (2018). Börgel, J., Tanwar, L., Berger, F. & Ritter, T. Late-Stage Aromatic C–H Oxygenation. J. Am. Chem. Soc. 140 , 16026–16031 (2018). Loehr, H. G. et al. Three-dimensional linkage by electron donor-acceptor interactions: complexes of organic ammonium halides with triiodomethane. J. Org. Chem. 49 , 1621-1627 (1984). Serpier, F., Pan, F., Ham, W.S., Jacq, J., Genicot, C. & Ritter, R. Selective Methylation of Arenes: A Radical C—H Functionalization/Cross-Coupling Sequence. Angew. Chem. Int. Ed. 57 , 10697-10701 (2018). Fier, P. S. & Hartwig, J. F. Selective C-H Fluorination of Pyridines and Diazines Inspired by a Classic Amination Reaction. Science 342 , 956–960 (2013). Fier, P. S. & Hartwig, J. F. Synthesis and Late-Stage Functionalization of Complex Molecules through C–H Fluorination and Nucleophilic Aromatic Substitution. J. Am. Chem. Soc. 136 , 10139–10147 (2014). Fier, P. S., Kim, S. & Cohen, R. D. A Multifunctional Reagent Designed for the Site-Selective Amination of Pyridines. J. Am. Chem. Soc. 142 , 8614–8618 (2020). Chichibabin, A. E.; Zeide, O. A. New Reaction for Compounds Containing the Pyridine Nucleus J. Russ. Phys. Chem. Soc. 46 , 1216–36 (1914). Legnani, L., Prina-Cerai, G., Delcaillau, T., Willems, S. & Morandi, B. Efficient access to unprotected primary amines by iron-catalyzed aminochlorination of alkenes. Science 362 , 434–439 (2018). Fernandes, A. J., Giri, R., Houk, K. N. & Katayev, D. Review and Theoretical Analysis of Fluorinated Radicals in Direct C Ar −H Functionalization of (Hetero)arenes. Angew. Chem. Int. Ed. 63 , e202318377 (2024). Maraš, N., Polanc, S. & Kočevar, M. Ring-opening reactions of 1,4-diazabicyclo[2.2.2]octane (DABCO) derived quaternary ammonium salts with phenols and related nucleophiles. Org. Biomol. Chem. 10 , 1300 (2012). Rafiee, M. et al. Cyclic voltammetry and chronoamperometry: mechanistic tools for organic electrosynthesis. Chem. Soc. Rev. 53 , 566–585 (2024). Hansch, Corwin., Leo, A. & Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. Chem. Rev. 91 , 165–195 (1991). Additional Declarations There is NO Competing Interest. Supplementary Files 01XRayDataPhFDABCOsaltCIF.txt Supplementary information - X-ray Data 01OxidativeCHAminationSIFinal.pdf Supplementary Information Cite Share Download PDF Status: Published Journal Publication published 16 Oct, 2025 Read the published version in Nature Synthesis → 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-5442169","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Physical Sciences - Article","associatedPublications":[],"authors":[{"id":391373865,"identity":"7e73ec7a-cf22-43ca-b9b2-404837b2af4a","order_by":0,"name":"Christian Malapit","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-8471-4208","institution":"Northwestern University","correspondingAuthor":true,"prefix":"","firstName":"Christian","middleName":"","lastName":"Malapit","suffix":""},{"id":391373867,"identity":"67deddcf-bd58-421d-8394-7d08026ed957","order_by":1,"name":"Griffin Stewart","email":"","orcid":"","institution":"Northwestern University","correspondingAuthor":false,"prefix":"","firstName":"Griffin","middleName":"","lastName":"Stewart","suffix":""},{"id":391373868,"identity":"91e0768e-44a3-45f5-a17e-18793297018a","order_by":2,"name":"Eva Maria Alvarez","email":"","orcid":"","institution":"Northwestern University","correspondingAuthor":false,"prefix":"","firstName":"Eva","middleName":"Maria","lastName":"Alvarez","suffix":""},{"id":391373869,"identity":"ea73fe09-ce59-4fe5-b37e-a9599e08cc69","order_by":3,"name":"Chris Rapala","email":"","orcid":"","institution":"Northwestern University","correspondingAuthor":false,"prefix":"","firstName":"Chris","middleName":"","lastName":"Rapala","suffix":""},{"id":391373870,"identity":"688612d7-13a4-40e2-8f62-ab5533e0289a","order_by":4,"name":"Jonathan Sklar","email":"","orcid":"","institution":"Northwestern University","correspondingAuthor":false,"prefix":"","firstName":"Jonathan","middleName":"","lastName":"Sklar","suffix":""},{"id":391373871,"identity":"f5512d44-387f-493c-9ef7-edf5fc2e3757","order_by":5,"name":"Julia Kalow","email":"","orcid":"https://orcid.org/0000-0002-4449-9566","institution":"Northwestern University","correspondingAuthor":false,"prefix":"","firstName":"Julia","middleName":"","lastName":"Kalow","suffix":""}],"badges":[],"createdAt":"2024-11-12 21:00:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-5442169/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-5442169/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s44160-025-00890-9","type":"published","date":"2025-10-16T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":73176583,"identity":"d7d70791-3013-4c41-9fb8-0e8665478e38","added_by":"auto","created_at":"2025-01-07 12:10:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":118152,"visible":true,"origin":"","legend":"\u003cp\u003e(a) Selective arene C­­–H amination reactions and challenge associated with electron-deficient arenes. (b) Electron-deficient arenes do not react under reductive C–H DABCOylation reaction.\u003csup\u003e32\u003c/sup\u003e (c) Discovery and development of an oxidative arene C–H DABCOylation reaction as a general solution to electron-deficient arenes and (d) proposed synthetic and mechanistic strategy.\u003c/p\u003e","description":"","filename":"image1.png","url":"https://assets-eu.researchsquare.com/files/rs-5442169/v1/8735a59404aa94128b3073ad.png"},{"id":73175013,"identity":"1f34985d-b23b-4e5c-b443-f043ea9b1196","added_by":"auto","created_at":"2025-01-07 12:02:02","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":134833,"visible":true,"origin":"","legend":"\u003cp\u003eScope of arene C–H amination reaction. General reaction conditions: \u003cstrong\u003e4a\u003c/strong\u003e (0.30 mmol, 1.0 equiv.), LiPF\u003csub\u003e6\u003c/sub\u003e (1.3 equiv.), arene (1.5-3 equiv.), 1:3 HFIP/MeCN (0.075M), graphite anode, platinum cathode, 3 mA constant current electrolysis, 6 F/mol. Yields are isolated yields, values in parentheses are NMR yields of the C–H amination step; for detailed reaction conditions, see SI.\u003c/p\u003e","description":"","filename":"image2.png","url":"https://assets-eu.researchsquare.com/files/rs-5442169/v1/80cb39a762521c2806e4cb7b.png"},{"id":73175009,"identity":"042c25b2-1266-4e38-993f-c007cea6f077","added_by":"auto","created_at":"2025-01-07 12:02:02","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":83701,"visible":true,"origin":"","legend":"\u003cp\u003eScope of arene diversification with designer DABCOnium salts (a) and photoredox functionalization of aryl DABCOnium salts (b). Yields are isolated yields, values in parentheses are \u003csup\u003e1\u003c/sup\u003eH NMR yields, for detailed reaction conditions, see SI. \u003csup\u003ea\u003c/sup\u003eObtained from aryl DABCOnium salt resulting from \u003cstrong\u003e4aa\u003c/strong\u003e; \u003csup\u003eb\u003c/sup\u003e10 mA, 5 F/mol was used; TMP, 2,2,6,6-tetramethylpiperidine.\u0026nbsp;\u003c/p\u003e","description":"","filename":"image3.png","url":"https://assets-eu.researchsquare.com/files/rs-5442169/v1/fbd386f25d7b9452e692da9a.png"},{"id":73175012,"identity":"51dc9dfb-846b-4d83-9c6b-853ed2e308c7","added_by":"auto","created_at":"2025-01-07 12:02:02","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":159488,"visible":true,"origin":"","legend":"\u003cp\u003eMechanistic studies. (a) Redox potentials of various reaction components. (b) CV of electrochemically generated dicationic \u003cem\u003eN\u003c/em\u003e-radical \u003cstrong\u003e3\u003c/strong\u003e (\u003cem\u003evia\u003c/em\u003e oxidation of \u003cstrong\u003e4\u003c/strong\u003e) with benzene and spectroelectrochemical analysis with benzonitrile. The spectroelectrochemical analysis is reported \u003cem\u003evs\u003c/em\u003e Ag/AgCl pseudo-reference electrode. (c, d) Competition and KIE studies. See the SI for more details.\u003c/p\u003e","description":"","filename":"image4.png","url":"https://assets-eu.researchsquare.com/files/rs-5442169/v1/6997cfc68f9f41ea239ed3cd.png"},{"id":93748411,"identity":"773feb0e-40dc-42e5-8fa9-69152f2954f6","added_by":"auto","created_at":"2025-10-17 07:14:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1172956,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5442169/v1/5b7ca40e-fd49-40c6-b13c-657283597975.pdf"},{"id":73176584,"identity":"4b3e647a-b751-4dea-97cd-f74036fdc078","added_by":"auto","created_at":"2025-01-07 12:10:02","extension":"txt","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1263015,"visible":true,"origin":"","legend":"Supplementary information - X-ray Data","description":"","filename":"01XRayDataPhFDABCOsaltCIF.txt","url":"https://assets-eu.researchsquare.com/files/rs-5442169/v1/b8e3b0c970fdc1717d93db53.txt"},{"id":73175014,"identity":"1b33039e-299d-4ed5-a650-3e7ddbe2e54e","added_by":"auto","created_at":"2025-01-07 12:02:02","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13251836,"visible":true,"origin":"","legend":"Supplementary Information","description":"","filename":"01OxidativeCHAminationSIFinal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5442169/v1/070cdd5c0ef2f61a8d394eea.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Electrochemical DABCOylation enables challenging aromatic C–H amination","fulltext":[{"header":"Introduction","content":"\u003cp\u003eAryl nitrogen bonds are ubiquitous across material and medicinal chemistry.\u003csup\u003e18,19\u003c/sup\u003e About a third of novel small molecule drugs approved by the US Food \u0026amp; Drug Administration in 2023 include an aryl C\u0026ndash;N bond.\u003csup\u003e20\u003c/sup\u003e Aromatic C\u0026ndash;H bonds are the ideal substrates for aromatic amination due to their abundance, yet selectivity and substrate scope remain ongoing challenges. Radical redox chemistry has come to fill the void of selective arene C\u0026ndash;H amination with two main approaches (Figure 1a).\u003csup\u003e1-4\u003c/sup\u003e The first such methodology relies on the production of arene radical cations, as pioneered by Yoshida and Nicewicz.\u003csup\u003e21-23\u003c/sup\u003e In these systems, electron-rich arenes undergo one-electron oxidation, and are then trapped by oxidatively stable sp\u003csup\u003e2\u003c/sup\u003e\u0026ndash;\u003cem\u003eN\u003c/em\u003e nucleophiles to give aryl amines with moderate to high regioselectivity. Second, radical C\u0026ndash;H amination based on electrophilic nitrogen radicals was developed, flipping the polarity of the reaction. Most successfully, these radicals have been generated by the reduction of compounds of the general form R\u003csub\u003e3\u003c/sub\u003eN\u003csup\u003e+\u003c/sup\u003e\u0026ndash;X (X = F, Cl, RCO\u003csub\u003e2\u003c/sub\u003e, RSO\u003csub\u003e3\u003c/sub\u003e) to form electrophilic \u003cem\u003eN\u003c/em\u003e-radical (di)cations.\u003csup\u003e6-10, 24-32\u003c/sup\u003e Selectivity and reactivity for \u003cem\u003eN\u003c/em\u003e-radical intermediates vary depending on the steric demand and electrophilicity of the radical species and the arene substrate.\u003csup\u003e1,26\u003c/sup\u003e Despite exploring many \u003cem\u003eN\u003c/em\u003e-radical scaffolds, these methods have failed to selectively functionalize electron deficient (hetero)arenes (Figure 1a). Past reports of oxidative electrophilic \u003cem\u003eN\u003c/em\u003e-radical generation have struggled with arene scope due to limited radical electrophilicity.\u003csup\u003e33-35\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eOur group recently published a reductive electrochemical DABCOylation of (hetero)arenes (\u003cstrong\u003e1\u003c/strong\u003e) utilizing Selectfluor II as the aminating reagent (Figure 1b) to form aryl DABCOnium salts (\u003cstrong\u003e2\u003c/strong\u003e).\u003csup\u003e32\u003c/sup\u003e Despite the high electrophilicity of the \u003cem\u003eN\u003c/em\u003e-Me-DABCOnium radical dication (\u003cstrong\u003e3a\u003c/strong\u003e), this system struggled to aminate electron-poor systems such as benzonitrile and nitrobenzene. With such arenes, we observed over-reduction of Selectfluor II to \u003cem\u003eN\u003c/em\u003e-Me-DABCOnium (\u003cstrong\u003e4a\u003c/strong\u003e) and full recovery of the unreacted arenes (Figure 1b). We hypothesized that the interaction of \u003cstrong\u003e3a\u003c/strong\u003e with electron-deficient arenes is weak and outcompeted by over-reduction to form \u003cstrong\u003e4a\u003c/strong\u003e that could no longer participate in amination under reductive conditions. With its high electrophilicity and steric demand, the DABCOnium radical dication (\u003cstrong\u003e3a\u003c/strong\u003e) should be a promising candidate for selective amination of electron-poor arenes. We hypothesized that if the radical dication \u003cstrong\u003e3\u003c/strong\u003e was instead sourced from \u003cstrong\u003e4a\u0026nbsp;\u003c/strong\u003e(rather than Selectfluor) via anodic oxidation, electron-poor reactivity would be unlocked. We therefore envisioned an anodic aromatic C\u0026ndash;H amination using a DABCOnium framework to take advantage of the greater reactivity and selectivity of the \u003cem\u003eN\u003c/em\u003e-radical dication intermediates and the diversification of their products, while also benefitting from the lack of added chemical oxidants with potential substrate incompatibilities.\u003c/p\u003e"},{"header":"Results And Discussion","content":"\u003cp\u003eTo discover and develop an arene C\u0026ndash;H amination reaction via oxidatively generated \u003cem\u003eN\u003c/em\u003e-radical cations (Figure 1c), we pursued the mechanistic strategy summarized in Figure 1d. First, \u003cem\u003eN\u003c/em\u003e-radical cation \u003cstrong\u003e3\u003c/strong\u003e can be sourced oxidatively from DABCOnium \u003cstrong\u003e4\u003c/strong\u003e (\u003cem\u003eE\u003c/em\u003e\u003csub\u003ep/2\u0026nbsp;\u003c/sub\u003e~ 1.5 V \u003cem\u003evs\u003c/em\u003e Fc/Fc\u003csup\u003e+\u003c/sup\u003e). The bicyclic nature of \u003cem\u003eN\u003c/em\u003e-alkyl DABCOniums appears to suppress unwanted Shono-type oxidations.\u003csup\u003e36\u003c/sup\u003e Second, a sacrificial oxidant that undergoes cathodic reduction is needed, which would allow for an operationally convenient undivided electrochemical cell. We hypothesized that proton reduction would meet this requirement. And third, a base that will deprotonate intermediate \u003cstrong\u003eIII\u003c/strong\u003e to form aryl DABCOnium salt \u003cstrong\u003e2\u0026nbsp;\u003c/strong\u003eis needed. Anodically generated \u003cem\u003eN\u003c/em\u003e\u0026ndash;radical cations from tertiary bicyclic amines are known to undergo hydrogen atom transfer (HAT), as they form strong N\u0026ndash;H bonds upon accepting a hydrogen atom.\u003csup\u003e14-16\u003c/sup\u003e However, DFT calculations have shown that radical addition of \u003cstrong\u003e3\u003c/strong\u003e into an arene has a lower energy barrier than extracting a benzylic hydrogen atom for electron-neutral arenes under typical amination conditions.\u003csup\u003e32\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eOur initial studies provided promising results using fluorobenzene as the arene and acetic acid as both the sacrificial oxidant and base (as acetate), furnishing the desired product \u003cstrong\u003e2a\u003c/strong\u003e in 9% yield. Upon further study, we found that HFIP provided much better yields. HFIP is likely superior for two reasons: generated acetate can compete with \u003cstrong\u003e4\u003c/strong\u003e for anodic oxidation (\u003cem\u003eE\u003c/em\u003e\u003csub\u003ep\u0026nbsp;\u003c/sub\u003e= 1.45 V \u003cem\u003evs\u003c/em\u003e Fc/Fc\u003csup\u003e+\u003c/sup\u003e in MeCN)\u003csup\u003e37\u003c/sup\u003e and HFIP is known to enhance cationic reactivities.\u003csup\u003e8\u003c/sup\u003e With 1:3 HFIP/MeCN as mixed solvent, LiPF\u003csub\u003e6\u003c/sub\u003e as supporting electrolyte, and graphite/platinum (anode/cathode) as electrodes, the amination of fluorobenzene to form \u003cstrong\u003e2a\u003c/strong\u003e was obtained in quantitative yield with high regioselectivity towards the \u003cem\u003epara\u003c/em\u003e-product (32:1.3:1 \u003cem\u003ep\u003c/em\u003e/\u003cem\u003eo\u003c/em\u003e/\u003cem\u003em\u003c/em\u003e). Other parameters were also investigated (see SI for details); however, the optimal conditions are shown in Figure 1c.\u003c/p\u003e\n\u003cp\u003eFree \u003cem\u003eN\u003c/em\u003e-radical arene C\u0026ndash;H amination has previously struggled to selectively aminate electron-poor arenes. Recently, Lei and coworkers published a selective \u003cem\u003epara\u003c/em\u003e-amination of nitroarenes utilizing proton coupled oxidation of amines. However, this transformation, by design, works only with nitroarenes.\u003csup\u003e5\u003c/sup\u003e Utilizing our anodic DABCOylation method, a variety of electron-deficient arenes including cyano- (\u003cstrong\u003e5b\u003c/strong\u003e) and nitro- (\u003cstrong\u003e5c\u003c/strong\u003e) benzene, triphenyl phosphine oxide (\u003cstrong\u003e5d\u003c/strong\u003e), trifluorotoluene (\u003cstrong\u003e5e\u003c/strong\u003e), methyl-2-bromo benzoate (\u003cstrong\u003e5f\u003c/strong\u003e), and 1,2-dichlorobenzene (\u003cstrong\u003e5g\u003c/strong\u003e) undergo amination in moderate to quantitative yields with high to singular selectivity. Moreover, the observed selectivity is in agreement with the Fukui index value and thus can be predicted.\u003csup\u003e32\u003c/sup\u003e Our method has unusually high selectivity for such compounds in free-radical arene C\u0026ndash;H functionalization, where functionalization of electron-poor arenes is usually unselective.\u003csup\u003e6-10,38,39\u003c/sup\u003e To our knowledge, this anodic amination represents the only selective C\u0026ndash;H functionalization of benzonitrile with significant diversification potential, as electrophilic halogenation and transition metal-catalyzed borylation/silylation methods are ineffective or unselective on this substrate.\u003csup\u003e11-13\u003c/sup\u003e Moreover, aryl DABCOnium salts \u003cstrong\u003e2\u003c/strong\u003e can be isolated as crude solids or can be readily converted to their corresponding aryl piperazines \u003cstrong\u003e5\u003c/strong\u003e, using an iterative S\u003csub\u003eN\u003c/sub\u003e2/E2 process with potassium cyanide or through use of the aqueous reductant sodium thiosulfate.\u003csup\u003e26,32\u003c/sup\u003e An X-ray crystal structure of aryl DABCOnium salt \u003cstrong\u003e2a\u003c/strong\u003e was obtained revealing a comparable aryl C\u0026ndash;N bond length (1.49 \u0026Aring;) to related aryl trimethyl ammonium salts (1.52 \u0026Aring;).\u003csup\u003e40\u003c/sup\u003e This could explain why the reactivity profile of aryl DABCOnium salts is comparable to aryl trimethyl ammonium salts\u003csup\u003e\u0026nbsp;\u003c/sup\u003ewhen\u003csup\u003e\u0026nbsp;\u003c/sup\u003eengaged with transition-metal catalysts.\u003csup\u003e41\u003c/sup\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePyridines are a privileged class of heterocyclic compounds, and their direct and selective functionalization remains an active goal for reaction development.\u003csup\u003e42-44\u003c/sup\u003e A variety of halo- and alkyl-pyridine derivatives are amenable to anodic DABCOylation (\u003cstrong\u003e5h-l\u003c/strong\u003e). Interestingly, the C\u0026ndash;H amination takes place selectively at the \u0026alpha;-position, even when the substituent does not normally direct for the \u0026alpha;-position (\u003cstrong\u003e2l\u003c/strong\u003e), delivering direct access to 2-pyridinylpiperazine derivatives \u003cstrong\u003e5h-l\u003c/strong\u003e, a framework commonly found in neurological and antiretroviral drugs, from simple pyridines. Importantly, \u0026alpha;-C\u0026ndash;H amination of pyridines is a challenging transformation, traditionally accessible only through the Chichibabin reaction.\u003csup\u003e45\u003c/sup\u003e Hartwig and Fier have modernized pyridine \u0026alpha;-C\u0026ndash;H amination, leveraging a tandem AgF\u003csub\u003e2\u003c/sub\u003e-mediated fluorination/S\u003csub\u003eN\u003c/sub\u003eAr type reactivity or Chichibabin type amination through pyridine activation.\u003csup\u003e42-44\u0026nbsp;\u003c/sup\u003eMeanwhile, modern transition metal-catalyzed borylation\u003csup\u003e12\u003c/sup\u003e or silylation\u003csup\u003e13\u003c/sup\u003e of pyridines are selective at the C-3 or C-4 positions. This anodic DABCOylation represents the first electrophilic method for accessing such \u0026alpha;-aminated pyridines, with potential for downstream diversification due to the tolerance of halogen substituents.\u003c/p\u003e\n\u003cp\u003eAside from aryl halides many useful and sensitive functionalities were tolerated, such as unprotected alcohols (\u003cstrong\u003e5v, 5x\u003c/strong\u003e), allylic and benzylic C\u0026ndash;H bonds (\u003cstrong\u003e5q, 2r, 2t, 5u)\u003c/strong\u003e, epoxides (\u003cstrong\u003e2r\u003c/strong\u003e), benzyl chlorides (\u003cstrong\u003e2t\u003c/strong\u003e), imines (\u003cstrong\u003e5u\u003c/strong\u003e), enol ethers (\u003cstrong\u003e5w\u003c/strong\u003e), and many common \u003cem\u003eN\u003c/em\u003e-heterocycles, such as pyridines (\u003cstrong\u003e5h\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e5m\u003c/strong\u003e), pyrroles (\u003cstrong\u003e5s\u003c/strong\u003e), triazoles (\u003cstrong\u003e5v\u003c/strong\u003e), and tetrazoles (\u003cstrong\u003e5u\u003c/strong\u003e). Additionally, to our knowledge, this is the first demonstration of an electrophilic \u003cem\u003eN\u003c/em\u003e-radical reacting selectively with an arene over an olefin or alkyne, as seen in \u003cstrong\u003e5q\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;5y\u003c/strong\u003e, and \u003cstrong\u003e5z\u0026nbsp;\u003c/strong\u003e(Figure 3a).\u003csup\u003e35,46\u003c/sup\u003e Some free radical arene C\u0026ndash;H functionalization methods that are efficacious on electron-poor arenes struggle with electron-rich arenes, due to tendency of the highly electrophilic radicals to participate in SET over \u0026pi;-system addition.\u003csup\u003e47\u003c/sup\u003e However, this anodic DABCOylation method remains tolerant of electron-rich arenes (Figure 2b) such as anisole (see SI), pyrrole derivatives (\u003cstrong\u003e5s\u003c/strong\u003e), and biphenyl derivatives (\u003cstrong\u003e2t, 5u\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAnother key advantage of this chemistry is its ability to quickly build complexity towards drug-like piperazine compounds. A diverse set of functionalized DABCOnium salts can be used as amine source compared to previous work that is limited to Selectfluor I \u0026amp; II.\u003csup\u003e26,32\u003c/sup\u003e Using simple S\u003csub\u003eN\u003c/sub\u003e2 alkylation reactions, with no chromatography or crystallization, DABCO was converted to \u003cem\u003eN\u003c/em\u003e-alkyl DABCOnium salts \u003cstrong\u003e4x\u003c/strong\u003e\u0026ndash;\u003cstrong\u003e4ac\u003c/strong\u003e containing a diverse set of functional groups.\u003csup\u003e48\u003c/sup\u003e Subjecting these \u003cem\u003eN\u003c/em\u003e-alkyl DABCOnium salts to the electrochemical amination reaction, followed by bridge removal, provided easy access to designer aryl piperazines bearing important functional groups such as free alcohols (\u003cstrong\u003e5x\u003c/strong\u003e), olefins (\u003cstrong\u003e5y\u003c/strong\u003e), alkynes (\u003cstrong\u003e5z\u003c/strong\u003e), CF\u003csub\u003e3\u003c/sub\u003e groups (\u003cstrong\u003e5ab\u003c/strong\u003e) and other arenes (\u003cstrong\u003e5ac\u003c/strong\u003e). Tolerance of an alkyne is noteworthy, as they can be used in bio-orthogonal chemistry for \u003cem\u003ein vivo\u003c/em\u003e applications. In addition, aryl-DABCOnium salts can be utilized in photoredox and transition metal catalyzed diversifications. This includes methylation,\u003csup\u003e41\u003c/sup\u003e arylation,\u003csup\u003e32\u003c/sup\u003e phosphorylation (\u003cstrong\u003e6\u003c/strong\u003e), and borylation (\u003cstrong\u003e7\u003c/strong\u003e), showing the potential of the aryl DABCOnium as an intermediate for C\u0026ndash;C, C\u0026ndash;P, and C\u0026ndash;B bond formation.\u003c/p\u003e\n\u003cp\u003eTo gain insight into the mechanism of this reaction, we performed several experiments including cyclic voltammetry (CV), competition trials, kinetic isotope effect (KIE) experiments, and electrochemical UV\u0026ndash;vis spectroscopy (spectroelectrochemistry). CV analysis (Figure 4a) of the reaction components reveal that \u003cem\u003eN\u003c/em\u003e-alkyl DABCOnium salts \u003cstrong\u003e4\u003c/strong\u003e undergo accessible oxidation (\u003cem\u003eE\u003csub\u003ep\u003c/sub\u003e\u003c/em\u003e\u003csub\u003e/2\u0026nbsp;\u003c/sub\u003e~ 1.5 V \u003cem\u003evs\u0026nbsp;\u003c/em\u003eFc/Fc\u003csup\u003e+\u003c/sup\u003e) in 3:1 MeCN/HFIP. Moreover, HFIP undergoes proton reduction (\u003cem\u003eE\u003c/em\u003e\u003csub\u003ered\u003c/sub\u003e = \u0026ndash;1.0 V). while the aryl DABCOnium salt product reduces at more negative potentials (\u003cem\u003eE\u003c/em\u003e\u003csub\u003ered\u003c/sub\u003e = \u0026ndash;1.8 V). CV studies (Figure 4b) also revealed that upon addition of benzene (Figure 4b) or toluene (see SI) to a solution of \u003cstrong\u003e4\u003c/strong\u003e, the oxidation profile increases in current and shifts cathodically (44 mV cathodic shift from 1-4 mM benzene). This change is an indication of rapid trapping of the arene, perhaps via an \u003cem\u003eN\u003c/em\u003e-radical-cation\u0026ndash;pi interaction \u003cstrong\u003eI\u003c/strong\u003e,\u003csup\u003e32\u003c/sup\u003e leading to faster diffusion away from the working electrode.\u003csup\u003e49\u003c/sup\u003e In addition, spectroelectrochemical studies provide evidence of the rapid trapping of electrochemically generated dicationic \u003cem\u003eN\u003c/em\u003e-radical \u003cstrong\u003e3\u003c/strong\u003e in the presence of benzonitrile, suppressing features associated with oxidation of \u003cstrong\u003e4\u003c/strong\u003e (Figure 4b). This observation provides evidence for the proposed charge transfer or rapid turnover into radical addition intermediate \u003cstrong\u003eII\u003c/strong\u003e. The slope of cathodic shift reduces as arene concentration increases, possibly indicating that the arene is saturating almost all generated \u003cstrong\u003e3\u003c/strong\u003e.\u003c/p\u003e\n\u003cp\u003eSeeking further clarification of the mechanism, we performed a series of competition experiments. Intermolecular competition between different monosubstituted arenes (Figure 4c)\u003csup\u003e50\u003c/sup\u003e show that more electron-rich arenes were able to outcompete their electron-poor counterparts. In addition, an intermolecular KIE between benzene and benzene-\u003cem\u003ed\u003csub\u003e6\u003c/sub\u003e\u003c/em\u003e revealed a \u003cem\u003ek\u003c/em\u003e\u003csub\u003eH\u003c/sub\u003e/\u003cem\u003ek\u003c/em\u003e\u003csub\u003eD\u003c/sub\u003e of 0.93 (Figure 4d). Overall, these experiments rule out C\u0026ndash;H bond cleavage as the rate-limiting step and narrows the rate-limiting step to the radical cation\u0026ndash;arene interaction or the C\u0026ndash;N bond formation. Previously reported \u003cem\u003eN\u003c/em\u003e-radical C\u0026ndash;H amination reactions have proposed C\u0026ndash;N bond formation to be rate-limiting by computation.\u003csup\u003e5\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eOverall, we propose a dual mechanistic regime that depends upon the oxidation potential of the arene substrate. \u0026nbsp;The mechanism that enables the selective DABCOylation of electron-deficient arenes and is operational for most shown substrates is summarized is Figure 1c. DABCOnium salt \u003cstrong\u003e4\u003c/strong\u003e is oxidized on the anode to radical intermediate \u003cstrong\u003e3\u003c/strong\u003e, which then undergoes trapping by the arene substrate, leading to radical addition intermediate \u003cstrong\u003eII\u003c/strong\u003e, perhaps through charge transfer complex \u003cstrong\u003eI\u003c/strong\u003e. Subsequent anodic oxidation to Wheland-type intermediate \u003cstrong\u003eIII\u003c/strong\u003e followed by deprotonation leads to the aryl-DABCOnium salt \u003cstrong\u003e2\u003c/strong\u003e. Meanwhile, on the cathode, HFIP is reduced to its anion and hydrogen gas via the hydrogen evolution reaction, furnishing the base required for the deprotonation of intermediate \u003cstrong\u003eIII\u003c/strong\u003e. The high site selectivity for most substrates is likely due to the high electrophilicity of the \u003cem\u003eN\u003c/em\u003e-radical dication and its steric demand.\u003csup\u003e1,26\u003c/sup\u003e It is also notable that amine \u003cstrong\u003e3\u003c/strong\u003e is recyclable. When C\u0026shy;\u0026ndash;N bond formation is challenging, cathodic reduction of \u003cstrong\u003e3\u003c/strong\u003e can occur, thus regenerating the amine source \u003cstrong\u003e4\u003c/strong\u003e. That effect, along with the HFIP as co-solvent, likely explains this method\u0026rsquo;s success with electron-poor arenes where reductive methods have failed.\u003csup\u003e26,32\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eWhile the above mechanism is probable for electron-poor and -neutral arenes, arenes that oxidize easier than \u003cstrong\u003e4\u0026nbsp;\u003c/strong\u003eproceed through a direct arene oxidation mechanism. Evidence of this competing mechanism can be seen in the product obtained from irbesartan (Figure 2b, \u003cstrong\u003e5u\u003c/strong\u003e), which underwent intramolecular amination with its tetrazole moiety (enabled by the oxidation of its biphenyl core) during DABCOylation electrolysis. Other electron-rich arene substrates such as \u003cstrong\u003e1s\u003c/strong\u003e and anisole (see SI) most likely undergo amination via arene oxidation. This is supported by the spectroelectrochemical data (see SI). In a sample containing anisole and \u003cstrong\u003e4\u003c/strong\u003e,\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003ethe oxidation of anisole dominates the spectral features, even at potentials that oxidize \u003cstrong\u003e4\u003c/strong\u003e. This is unlike similar experiments with more electron-poor benzene and benzonitrile, which show the oxidation of \u003cstrong\u003e4\u0026nbsp;\u003c/strong\u003einstead. This methodology is particularly advantageous in its mechanistic flexibility, producing a wide range of desired C\u0026ndash;H amination products by either the oxidation of \u003cstrong\u003e4\u003c/strong\u003e or by the direct oxidation of arenes. Since both mechanisms are broadly selective for the most electron-rich site in the molecule, results of arene oxidation in our system are not appreciably different from reductive systems which are always going through \u003cem\u003eN\u003c/em\u003e-radical mechanisms.\u003csup\u003e41\u003c/sup\u003e This allows for improved arene scope compared to existing systems.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn summary, we have developed a general and selective non-directed aromatic C\u0026ndash;H amination, effectively addressing a longstanding challenge in late-stage C\u0026ndash;H functionalization. In this method, (hetero)arenes that are typically challenging towards C\u0026ndash;H amination, classical halogenation, or metal-catalyzed borylation/silylation reactions can effectively undergo C\u0026ndash;H DABCOylation with high selectivity. Key to the success of this methodology is the development of an oxidative electrochemical approach to generate highly electrophilic bicyclic \u003cem\u003eN\u003c/em\u003e-radical dications that rapidly reacts across a wide range of arenes. The electrochemical conditions used bias the generated \u003cem\u003eN\u003c/em\u003e-radical dications toward aryl reactivity, representing the first oxidatively generated \u003cem\u003eN\u003c/em\u003e-radical cation that undergoes aryl C\u0026ndash;H amination over known reactivity via HAT or olefin addition. The synthetic value of this functionalization strategy is showcased in the rapid construction of many complex drug-like aryl- and pyridinylpiperazines that contain sensitive functionalities such as free alcohols, terminal alkynes, olefins, aryl and alkyl halides, and many common heterocycles. We anticipate that this system can serve as a model for advancing other C\u0026ndash;H functionalization reactions that is general and selective for both electron-rich and deficient arenes and amenable to late-stage functionalization.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData Availability\u0026nbsp;\u003c/strong\u003eAll experimental data, copies of spectra, and CIF data are available in the supplementary information.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e This work was supported by Northwestern University with a start-up grant for C.A.M. We thank the support from the National Institute of General Medical Sciences of the National Institute of Health under award number R00GM140249 for C.A.M. We thank the National Science Foundation Graduate Research Fellowship for G.S. We thank the Air Force Office of Scientific Research for funding support under the award number FA9550-22-1-0421 for J.H.S. and J.A.K. The facilities at IMSERC at Northwestern University were used with funding support from the Soft and Hybrid Nanotechnology Experimental (SHyNE) Resource (NSF ECCS-2025633).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e G.S., E.M.A., and C.A.M. conceived the work and designed the experiments. G.S. performed the electrochemical experiments and mechanistic studies. E.M.A. performed the photocatalytic reactions. C.R. and G.S. synthesized the DABCOnium salts. J.H.S. performed the spectroelectrochemical experiments. G.S. and C.A.M. wrote the manuscript and all authors provided revisions. All authors have given approval to the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e The authors do not claim any competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Information\u003c/strong\u003e Correspondence should be addressed to [email protected]\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRuffoni, A., Mykura, R. C., Bietti, M. \u0026amp; Leonori, D. The interplay of polar effects in controlling the selectivity of radical reactions. \u003cem\u003eNat. Synth.\u003c/em\u003e\u003cstrong\u003e1\u003c/strong\u003e, 682\u0026ndash;695 (2022).\u003c/li\u003e\n\u003cli\u003eHolmberg-Douglas, N. \u0026amp; Nicewicz, D. A. Photoredox-Catalyzed C\u0026ndash;H Functionalization Reactions. \u003cem\u003eChem. Rev.\u003c/em\u003e\u003cstrong\u003e122\u003c/strong\u003e, 1925\u0026ndash;2016 (2022).\u003c/li\u003e\n\u003cli\u003eZhang, L. \u0026amp; Ritter, T. A Perspective on Late-Stage Aromatic C\u0026ndash;H Bond Functionalization. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e144\u003c/strong\u003e, 2399\u0026ndash;2414 (2022).\u003c/li\u003e\n\u003cli\u003eStewart, G., Rapala, C., \u0026amp; Malapit, A. Electrochemical Non-Directed Arene C\u0026ndash;H Amination. \u003cem\u003eChemCatChem\u003c/em\u003e (2024). e202400867.\u003c/li\u003e\n\u003cli\u003eZhang, Z. \u003cem\u003eet al.\u003c/em\u003e Para-selective nitrobenzene amination lead by C(sp\u003csup\u003e2\u003c/sup\u003e)-H/N-H oxidative cross-coupling through aminyl radical. \u003cem\u003eNat. Commun.\u003c/em\u003e\u003cstrong\u003e15\u003c/strong\u003e, 4186 (2024). \u003c/li\u003e\n\u003cli\u003eR\u0026ouml;ssler, S. L. \u003cem\u003eet al.\u003c/em\u003e Pyridyl Radical Cation for C\u0026minus;H Amination of Arenes. \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e\u003cstrong\u003e58\u003c/strong\u003e, 526\u0026ndash;531 (2019).\u003c/li\u003e\n\u003cli\u003eHam, W. S., Hillenbrand, J., Jacq, J., Genicot, C., \u0026amp; Ritter, T. Divergent Late-Stage (Hetero)aryl C\u0026ndash;H Amination by the Pyridinium Radical Cation. \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e\u003cstrong\u003e58\u003c/strong\u003e, 532-536 (2019).\u003c/li\u003e\n\u003cli\u003eD\u0026rsquo;Amato, E. M., B\u0026ouml;rgel, J. \u0026amp; Ritter, T. Aromatic C\u0026ndash;H amination in hexafluoroisopropanol. \u003cem\u003eChem. Sci.\u003c/em\u003e\u003cstrong\u003e10\u003c/strong\u003e, 2424\u0026ndash;2428 (2019).\u003c/li\u003e\n\u003cli\u003eHillenbrand, J., Ham, W. S. \u0026amp; Ritter, T. C\u0026ndash;H Pyridonation of (Hetero-)Arenes by Pyridinium Radical Cations. \u003cem\u003eOrg. Lett.\u003c/em\u003e\u003cstrong\u003e21\u003c/strong\u003e, 5363\u0026ndash;5367 (2019).\u003c/li\u003e\n\u003cli\u003eAllen, L. J., Cabrera, P. J., Lee, M. \u0026amp; Sanford, M. S. \u003cem\u003eN\u003c/em\u003e -Acyloxyphthalimides as Nitrogen Radical Precursors in the Visible Light Photocatalyzed Room Temperature C\u0026ndash;H Amination of Arenes and Heteroarenes. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e136\u003c/strong\u003e, 5607\u0026ndash;5610 (2014).\u003c/li\u003e\n\u003cli\u003eWang, W. \u003cem\u003eet al.\u003c/em\u003e Catalytic Electrophilic Halogenation of Arenes with Electron-Withdrawing Substituents. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e144\u003c/strong\u003e, 13415\u0026ndash;13425 (2022).\u003c/li\u003e\n\u003cli\u003eRoque, J. B. \u003cem\u003eet al.\u003c/em\u003e Kinetic and thermodynamic control of C(sp\u003csup\u003e2\u003c/sup\u003e)\u0026ndash;H activation enables site-selective borylation. \u003cem\u003eScience\u003c/em\u003e\u003cstrong\u003e382\u003c/strong\u003e, 1165\u0026ndash;1170 (2023).\u003c/li\u003e\n\u003cli\u003eCheng, C. \u0026amp; Hartwig, J. F. Rhodium-Catalyzed Intermolecular C\u0026ndash;H Silylation of Arenes with High Steric Regiocontrol. \u003cem\u003eScience\u003c/em\u003e\u003cstrong\u003e343\u003c/strong\u003e, 853\u0026ndash;857 (2014).\u003c/li\u003e\n\u003cli\u003eKawamata, Y. \u003cem\u003eet al.\u003c/em\u003e Scalable, Electrochemical Oxidation of Unactivated C\u0026ndash;H Bonds. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e139\u003c/strong\u003e, 7448\u0026ndash;7451 (2017).\u003c/li\u003e\n\u003cli\u003eHolt, E. \u003cem\u003eet al.\u003c/em\u003e An Electrochemical Approach to Directed Fluorination. \u003cem\u003eJ. Org. Chem.\u003c/em\u003e\u003cstrong\u003e88\u003c/strong\u003e, 2557\u0026ndash;2560 (2023).\u003c/li\u003e\n\u003cli\u003eZhang, S. \u0026amp; Findlater, M. Electrochemically Driven Hydrogen Atom Transfer Catalysis: A Tool for C(sp\u003csup\u003e3\u003c/sup\u003e)/Si\u0026ndash;H Functionalization and Hydrofunctionalization of Alkenes. \u003cem\u003eACS Catal.\u003c/em\u003e\u003cstrong\u003e13\u003c/strong\u003e, 8731\u0026ndash;8751 (2023).\u003c/li\u003e\n\u003cli\u003eVitaku, E., Smith, D. T. \u0026amp; Njardarson, J. T. Analysis of the Structural Diversity, Substitution Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA Approved Pharmaceuticals: Miniperspective. \u003cem\u003eJ. Med. Chem.\u003c/em\u003e\u003cstrong\u003e57\u003c/strong\u003e, 10257\u0026ndash;10274 (2014).\u003c/li\u003e\n\u003cli\u003eBrown, D. G. \u0026amp; Bostr\u0026ouml;m, J. Analysis of Past and Present Synthetic Methodologies on Medicinal Chemistry: Where Have All the New Reactions Gone?: Miniperspective. \u003cem\u003eJ. Med. Chem.\u003c/em\u003e\u003cstrong\u003e59\u003c/strong\u003e, 4443\u0026ndash;4458 (2016).\u003c/li\u003e\n\u003cli\u003eErtl, P., Altmann, E. \u0026amp; McKenna, J. M. The Most Common Functional Groups in Bioactive Molecules and How Their Popularity Has Evolved over Time. \u003cem\u003eJ. Med. Chem.\u003c/em\u003e\u003cstrong\u003e63\u003c/strong\u003e, 8408\u0026ndash;8418 (2020).\u003c/li\u003e\n\u003cli\u003eNovel Drug Approvals for 2023. Food and Drug Administration. https://www.fda.gov/drugs/new-drugs-fda-cders-new-molecular-entities-and-new-therapeutic-biological-products/novel-drug-approvals-2023. (accessed 8-9-2024). \u003c/li\u003e\n\u003cli\u003eMorofuji, T., Shimizu, A. \u0026amp; Yoshida, J. Electrochemical C\u0026ndash;H Amination: Synthesis of Aromatic Primary Amines via \u003cem\u003eN\u003c/em\u003e -Arylpyridinium Ions. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e135\u003c/strong\u003e, 5000\u0026ndash;5003 (2013).\u003c/li\u003e\n\u003cli\u003eRomero, N. A., Margrey, K. A., Tay, N. E. \u0026amp; Nicewicz, D. A. Site-selective arene C-H amination via photoredox catalysis. \u003cem\u003eScience\u003c/em\u003e\u003cstrong\u003e349\u003c/strong\u003e, 1326\u0026ndash;1330 (2015).\u003c/li\u003e\n\u003cli\u003eWang, J.-H. \u003cem\u003eet al.\u003c/em\u003e Regioselective \u003cem\u003eOrtho\u003c/em\u003e Amination of an Aromatic C\u0026ndash;H Bond by Trifluoroacetic Acid via Electrochemistry. \u003cem\u003eOrg. Lett.\u003c/em\u003e\u003cstrong\u003e21\u003c/strong\u003e, 5581\u0026ndash;5585 (2019).\u003c/li\u003e\n\u003cli\u003eFoo, K., Sella, E., Thom\u0026eacute;, I., Eastgate, M. D. \u0026amp; Baran, P. S. A Mild, Ferrocene-Catalyzed C\u0026ndash;H Imidation of (Hetero)Arenes. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e136\u003c/strong\u003e, 5279\u0026ndash;5282 (2014).\u003c/li\u003e\n\u003cli\u003eLegnani, L., Prina Cerai, G. \u0026amp; Morandi, B. Direct and Practical Synthesis of Primary Anilines through Iron-Catalyzed C\u0026ndash;H Bond Amination. \u003cem\u003eACS Catal.\u003c/em\u003e\u003cstrong\u003e6\u003c/strong\u003e, 8162\u0026ndash;8165 (2016).\u003c/li\u003e\n\u003cli\u003eBoursalian, G. B., Ham, W. S., Mazzotti, A. R. \u0026amp; Ritter, T. Charge-transfer-directed radical substitution enables para-selective C\u0026ndash;H functionalization. \u003cem\u003eNat. Chem.\u003c/em\u003e\u003cstrong\u003e8\u003c/strong\u003e, 810\u0026ndash;815 (2016).\u003c/li\u003e\n\u003cli\u003eSvejstrup, T. D., Ruffoni, A., Juli\u0026aacute;, F., Aubert, V. M. \u0026amp; Leonori, D. Synthesis of Arylamines via Aminium Radicals. \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e\u003cstrong\u003e56\u003c/strong\u003e, 14948\u0026ndash;14952 (2017).\u003c/li\u003e\n\u003cli\u003eRuffoni, A. \u003cem\u003eet al.\u003c/em\u003e Practical and regioselective amination of arenes using alkyl amines. \u003cem\u003eNat. Chem.\u003c/em\u003e\u003cstrong\u003e11\u003c/strong\u003e, 426\u0026ndash;433 (2019).\u003c/li\u003e\n\u003cli\u003eSee, Y. Y. \u0026amp; Sanford, M. S. C\u0026ndash;H Amination of Arenes with Hydroxylamine. \u003cem\u003eOrg. Lett.\u003c/em\u003e\u003cstrong\u003e22\u003c/strong\u003e, 2931\u0026ndash;2934 (2020).\u003c/li\u003e\n\u003cli\u003eGillespie, J. E., Morrill, C. \u0026amp; Phipps, R. J. Regioselective Radical Arene Amination for the Concise Synthesis of \u003cem\u003eortho\u003c/em\u003e -Phenylenediamines. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e143\u003c/strong\u003e, 9355\u0026ndash;9360 (2021).\u003c/li\u003e\n\u003cli\u003eBehnke, N. E., Kwon, Y.-D., Davenport, M. T., Ess, D. H. \u0026amp; K\u0026uuml;rti, L. Directing-Group-Free Arene C(sp\u003csup\u003e2\u003c/sup\u003e)\u0026ndash;H Amination Using Bulky Aminium Radicals and DFT Analysis of Regioselectivity. \u003cem\u003eJ. Org. Chem.\u003c/em\u003e\u003cstrong\u003e88\u003c/strong\u003e, 11847\u0026ndash;11854 (2023).\u003c/li\u003e\n\u003cli\u003eAlvarez, E. M., Stewart, G., Ullah, M., Lalisse, R., Gutierrez, O. \u0026amp; Malapit, C. A. Site-Selective Electrochemical Arene C\u0026ndash;H Amination. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e146\u003c/strong\u003e, 3591\u0026ndash;3597 (2024).\u003c/li\u003e\n\u003cli\u003eMargrey, K. A., Levens, A. \u0026amp; Nicewicz, D. A. Direct Aryl C\u0026minus;H Amination with Primary Amines Using Organic Photoredox Catalysis. \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e\u003cstrong\u003e56\u003c/strong\u003e, 15644\u0026ndash;15648 (2017).\u003c/li\u003e\n\u003cli\u003eLiu, K. \u003cem\u003eet al.\u003c/em\u003e Electrooxidative para-selective C\u0026ndash;H/N\u0026ndash;H cross-coupling with hydrogen evolution to synthesize triarylamine derivatives. \u003cem\u003eNat. Commun.\u003c/em\u003e\u003cstrong\u003e10\u003c/strong\u003e, 639 (2019).\u003c/li\u003e\n\u003cli\u003eHu, X., Zhang, G., Nie, L., Kong, T. \u0026amp; Lei, A. Electrochemical oxidation induced intermolecular aromatic C-H imidation. \u003cem\u003eNat. Commun.\u003c/em\u003e\u003cstrong\u003e10\u003c/strong\u003e, 5467 (2019).\u003c/li\u003e\n\u003cli\u003eShono, T., Matsumura, Y. \u0026amp; Tsubata, K. Electroorganic chemistry. 46. A new carbon-carbon bond forming reaction at the alpha-position of amines utilizing anodic oxidation as a key step. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e103\u003c/strong\u003e, 1172\u0026ndash;1176 (1981).\u003c/li\u003e\n\u003cli\u003eKlein, M. \u0026amp; Waldvogel, S. R. Anodic Dehydrogenative Cyanamidation of Thioethers: Simple and Sustainable Synthesis of \u003cem\u003eN\u003c/em\u003e ‐Cyanosulfilimines. \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e\u003cstrong\u003e60\u003c/strong\u003e, 23197\u0026ndash;23201 (2021).\u003c/li\u003e\n\u003cli\u003eJelier, B., Tripet, P., Pietrasiak, E., Franzoni, I., Jeschke, G \u0026amp; Togni, A. Radical Trifluoromethoxylation of Arenes Triggered by a Visible-Light-Mediated N\u0026ndash;O Bond Redox Fragmentation. \u003cem\u003eAngew. Chem. Int. Ed. \u003c/em\u003e\u003cstrong\u003e57\u003c/strong\u003e, 13784-13789 (2018). \u003c/li\u003e\n\u003cli\u003eB\u0026ouml;rgel, J., Tanwar, L., Berger, F. \u0026amp; Ritter, T. Late-Stage Aromatic C\u0026ndash;H Oxygenation. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e140\u003c/strong\u003e, 16026\u0026ndash;16031 (2018).\u003c/li\u003e\n\u003cli\u003eLoehr, H. G. \u003cem\u003eet al.\u003c/em\u003e Three-dimensional linkage by electron donor-acceptor interactions: complexes of organic ammonium halides with triiodomethane. \u003cem\u003eJ. Org. Chem. \u003c/em\u003e\u003cstrong\u003e49\u003c/strong\u003e, 1621-1627 (1984).\u003c/li\u003e\n\u003cli\u003eSerpier, F., Pan, F., Ham, W.S., Jacq, J., Genicot, C. \u0026amp; Ritter, R. Selective Methylation of Arenes: A Radical C\u0026mdash;H Functionalization/Cross-Coupling Sequence. \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e\u003cstrong\u003e57\u003c/strong\u003e, 10697-10701 (2018).\u003c/li\u003e\n\u003cli\u003eFier, P. S. \u0026amp; Hartwig, J. F. Selective C-H Fluorination of Pyridines and Diazines Inspired by a Classic Amination Reaction. \u003cem\u003eScience\u003c/em\u003e\u003cstrong\u003e342\u003c/strong\u003e, 956\u0026ndash;960 (2013).\u003c/li\u003e\n\u003cli\u003eFier, P. S. \u0026amp; Hartwig, J. F. Synthesis and Late-Stage Functionalization of Complex Molecules through C\u0026ndash;H Fluorination and Nucleophilic Aromatic Substitution. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e136\u003c/strong\u003e, 10139\u0026ndash;10147 (2014).\u003c/li\u003e\n\u003cli\u003eFier, P. S., Kim, S. \u0026amp; Cohen, R. D. A Multifunctional Reagent Designed for the Site-Selective Amination of Pyridines. \u003cem\u003eJ. Am. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e142\u003c/strong\u003e, 8614\u0026ndash;8618 (2020).\u003c/li\u003e\n\u003cli\u003eChichibabin, A. E.; Zeide, O. A. New Reaction for Compounds Containing the Pyridine Nucleus \u003cem\u003eJ. Russ. Phys. Chem. Soc.\u003c/em\u003e\u003cstrong\u003e46\u003c/strong\u003e, 1216\u0026ndash;36 (1914).\u003c/li\u003e\n\u003cli\u003eLegnani, L., Prina-Cerai, G., Delcaillau, T., Willems, S. \u0026amp; Morandi, B. Efficient access to unprotected primary amines by iron-catalyzed aminochlorination of alkenes. \u003cem\u003eScience\u003c/em\u003e\u003cstrong\u003e362\u003c/strong\u003e, 434\u0026ndash;439 (2018). \u003c/li\u003e\n\u003cli\u003eFernandes, A. J., Giri, R., Houk, K. N. \u0026amp; Katayev, D. Review and Theoretical Analysis of Fluorinated Radicals in Direct C\u003csub\u003eAr\u003c/sub\u003e\u0026minus;H Functionalization of (Hetero)arenes. \u003cem\u003eAngew. Chem. Int. Ed.\u003c/em\u003e\u003cstrong\u003e63\u003c/strong\u003e, e202318377 (2024). \u003c/li\u003e\n\u003cli\u003eMara\u0026scaron;, N., Polanc, S. \u0026amp; Kočevar, M. Ring-opening reactions of 1,4-diazabicyclo[2.2.2]octane (DABCO) derived quaternary ammonium salts with phenols and related nucleophiles. \u003cem\u003eOrg. Biomol. Chem.\u003c/em\u003e\u003cstrong\u003e10\u003c/strong\u003e, 1300 (2012).\u003c/li\u003e\n\u003cli\u003eRafiee, M. \u003cem\u003eet al.\u003c/em\u003e Cyclic voltammetry and chronoamperometry: mechanistic tools for organic electrosynthesis. \u003cem\u003eChem. Soc. Rev.\u003c/em\u003e\u003cstrong\u003e53\u003c/strong\u003e, 566\u0026ndash;585 (2024).\u003c/li\u003e\n\u003cli\u003eHansch, Corwin., Leo, A. \u0026amp; Taft, R. W. A survey of Hammett substituent constants and resonance and field parameters. \u003cem\u003eChem. Rev.\u003c/em\u003e\u003cstrong\u003e91\u003c/strong\u003e, 165\u0026ndash;195 (1991).\u003c/li\u003e\n\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-5442169/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5442169/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe selective amination of aromatic C–H bonds is a powerful strategy to access aryl amines, functionalities found in many pharmaceuticals and agrochemicals. Despite advances in the field, a platform for the direct, selective C–H amination of electronically diverse (hetero)arenes, particularly electron-deficient (hetero)arenes, remains an unaddressed fundamental challenge.\u003csup\u003e1-10\u003c/sup\u003e In addition, many (hetero)arenes present difficulty in common selective pre-functionalization reactions, such as halogenation\u003csup\u003e11\u003c/sup\u003e, or metal-catalyzed borylation\u003csup\u003e12\u003c/sup\u003e and silylation\u003csup\u003e13\u003c/sup\u003e. Here, we report a general solution to these limitations that enables selective C–H amination across a comprehensive scope of (hetero)arenes. Key to this strategy’s success is the oxidative generation of highly electrophilic \u003cem\u003eN\u003c/em\u003e-radical dications from bicyclic tertiary amines (DABCO) that reacts across a wide range of arenes with high selectivity. Notably, this platform constitutes the first anodically generated \u003cem\u003eN\u003c/em\u003e-radical cations that engage in aromatic C–H amination over well-reported hydrogen atom transfer (HAT) with weak C­–H bonds.\u003csup\u003e14-16\u003c/sup\u003e This C–­H amination reaction that allows selective functionalization of both electron-rich and deficient arenes, as well as pyridines, is a rarity in the general area of non-directed aromatic C–H functionalization.\u003csup\u003e1-4\u003c/sup\u003e This sustainable electrochemical DABCOylation reaction provides access to many complex drug-like aryl- and pyridinylpiperazines with high functionality tolerance, chemoselectivity, and site-selectivity.\u003csup\u003e17\u003c/sup\u003e\u003c/p\u003e","manuscriptTitle":"Electrochemical DABCOylation enables challenging aromatic C–H amination","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-01-07 12:01:57","doi":"10.21203/rs.3.rs-5442169/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-synthesis","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natsynth","sideBox":"Learn more about [Nature Synthesis](https://www.nature.com/natsynth/)","snPcode":"","submissionUrl":"https://mts-natsynth.nature.com/cgi-bin/main.plex","title":"Nature Synthesis","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e29eec0a-03eb-4dd4-834d-d239e441df65","owner":[],"postedDate":"January 7th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":41713084,"name":"Physical sciences/Chemistry/Organic chemistry/Synthetic chemistry methodology"},{"id":41713085,"name":"Physical sciences/Chemistry/Chemical synthesis/Synthetic chemistry methodology"}],"tags":[],"updatedAt":"2025-10-17T07:14:34+00:00","versionOfRecord":{"articleIdentity":"rs-5442169","link":"https://doi.org/10.1038/s44160-025-00890-9","journal":{"identity":"nature-synthesis","isVorOnly":false,"title":"Nature Synthesis"},"publishedOn":"2025-10-16 04:00:00","publishedOnDateReadable":"October 16th, 2025"},"versionCreatedAt":"2025-01-07 12:01:57","video":"","vorDoi":"10.1038/s44160-025-00890-9","vorDoiUrl":"https://doi.org/10.1038/s44160-025-00890-9","workflowStages":[]},"version":"v1","identity":"rs-5442169","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5442169","identity":"rs-5442169","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}