Electrochemical oxidation enables aromatic C–H amination with dual mechanisms

Abstract

The selective amination of aromatic C–H bonds is a powerful strategy to access aryl amines, which offer functionalities used in many pharmaceuticals and agrochemicals. Despite advances in the field, a general platform for the direct, selective C–H amination of electronically diverse arenes, particularly electron-deficient (hetero)arenes, remains an unaddressed challenge. In addition, many (hetero)arenes are reluctant to undergo common selective prefunctionalization reactions, including halogenation, borylation and silylation. Here we report an electrochemical method for the selective C–H amination of a range of (hetero)arenes. Key to this strategy is mechanistic flexibility with convergent outcomes between anodic generation of electrophilic nitrogen radical dications from DABCOnium salts (DABCO = 1,4-diazabicyclo[2.2.2]octane) and arene radical cations from electron-rich arenes. Notably, oxidative conditions allow the electrocatalytic regeneration of DABCOnium salts that can participate in the functionalization of electron-deficient (hetero)arenes. This platform allows anodically generated N-radical cations to engage in aromatic C–H amination instead of well-reported hydrogen-atom transfer. This electrochemical DABCOylation reaction yields aryl DABCOnium salts that provide access to many complex drug-like aryl piperazines with high functionality tolerance, broad scope and site selectivity. Moreover, these salts can engage in catalytic functionalization reactions to form C–C, C–P and C–B bonds.

Aryl–nitrogen bonds are ubiquitous across material and medicinal chemistry^1–3. About a third of novel small-molecule drugs approved by the US Food and Drug Administration in 2023 include an aryl C–N bond⁴. Aromatic C–H bonds are 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 (Fig. 1a)^5–8. The first strategy relies on the production of arene radical cations, as pioneered by Yoshida and Nicewicz^9–11. In these systems, electron-rich arenes undergo one-electron oxidation and are then trapped by oxidatively stable sp² nitrogen nucleophiles to give aryl amines with moderate to high regioselectivity. The second strategy involves introducing radical C–H amination based on electrophilic nitrogen radicals, flipping the polarity of the reaction. Most successfully, these radicals have been generated by the reduction of compounds of the general form R₃N⁺–X (X = F, Cl, RCO₂, RSO₃) to form electrophilic N-radical (di)cations^12–27. The selectivity and reactivity of N-radical intermediates vary depending on the steric demand and electrophilicity of the radical species and the arene substrate^5,19,24. Despite exploring many N-radical scaffolds, these methods have failed to selectively functionalize electron-deficient (hetero)arenes (Fig. 1a). Past reports of oxidative electrophilic N-radical generation have struggled with arene scope due to limited radical electrophilicity^28–30.

Fig. 1 |. Aromatic C–H amination, challenges, and this work’s reaction design and discovery.

a, Two general approaches for radical arene C–H amination and challenge associated with electron-deficient arenes. b, Electron-deficient arenes do not react under reductive C–H DABCOylation reactions^19,25. c, Discovery and development of an oxidative arene C–H DABCOylation reaction as a general solution for a broad arene scope. d, Proposed synthetic and mechanistic strategy showcasing the dual-mechanistic features of this work. Electrochemical condition: 2.5 mA, 5–10 F mol⁻¹, LiPF₆, in MeCN. Yields based on ¹H NMR spectroscopic analysis of the reaction crude mixture. ^aElectrolysis run at 10 mA. [Ox], oxidation; [Red], reduction.

The N-Me DABCOnium²⁺ radical (DABCO = 1,4-diazabicyclo[2.2.2] octane) represents one of the most sterically hindered and electrophilic N radicals utilized in synthetic methodology^5,19. Both Ritter¹⁹ and our group²⁵ have previously explored the reactivity of this N-radical dication, reductively generated from Selectfluor I/II, in radical arene C–H amination, showing it to be site selective across a range of electron-rich and electron-neutral arenes. Primary differences in the amination methods arise from the radical generation strategy; a dual-catalytic system driven by two transition metals¹⁹ or electroreduction²⁵. Despite the high electrophilicity of the N-Me DABCOnium²⁺ radical, both systems struggled to aminate electron-poor systems such as benzonitrile and nitrobenzene. With such arenes, we observed overreduction of Selectfluor II to N-Me DABCOnium, recovery of unreacted arenes and poor yield of aryl DABCOnium salts (Fig. 1b). We hypothesized that the interaction of the N-Me DABCOnium²⁺ radical with electron-deficient arenes is weak and is outcompeted by overreduction to form N-Me DABCOnium that could no longer participate in amination under reductive conditions. With its high electrophilicity and steric demand, the DABCOnium radical dication should be a promising candidate for selective amination of electron-poor arenes. We hypothesized that if the radical dication was instead sourced from N-Me DABCOnium (rather than Selectfluor) via anodic oxidation, electron-poor arenes could be aminated in satisfactory yields. With N-Me DABCOnium as the radical precursor, failure to form the aryl DABCOnium salt by N-Me DABCOnium²⁺ radical results in the reformation of N-Me DABCOnium, which can be reoxidized to the N-Me DABCOnium²⁺ radical. In this way, the low probability of C–N bond formation can be overcome with increased F mol⁻¹ passed during electrolysis. In this study, we report an oxidative arene C–H amination reaction that is effective across a broad electronic scope of (hetero)arenes. We demonstrate how two mechanisms synergistically participate in aromatic C–H amination, depending upon the oxidation potential of the arene substrate and leveraging the nature of N-alkyl DABCOnium salts as both precursors to electrophilic N-radical dications and as nucleophiles to trap arene radical cations.

Results and discussion

Reaction optimization

To discover and develop an arene C–H amination reaction via oxidatively generated N-radical cations (Fig. 1c), we pursued the mechanistic strategy summarized in Fig. 1d (mechanism A). First, N-radical dication 3 can be sourced oxidatively from DABCOnium 4 (E_p/2 ≈ 1.5 V versus Fc/Fc⁺). The bicyclic nature of N-alkyl DABCOniums appears to suppress unwanted Shono-type oxidations³¹. 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 to H₂ 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 (DABCO, quinuclidine) are known to undergo hydrogen-atom transfer (HAT) because they form strong N–H bonds upon accepting a hydrogen atom^32–34. However, density functional theory (DFT) calculations have shown that radical addition of 3 into an arene has a lower energy barrier than abstracting a benzylic hydrogen atom for electron-neutral arenes under typical amination conditions²⁵.

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 hexafluoroisopropanol (HFIP) provided much better yields. HFIP is probably superior to acetic acid for two reasons: generated acetate can compete with 4 for anodic oxidation (E_p = 1.45 V versus Fc/Fc⁺ in MeCN)³⁵ and HFIP is known to enhance cationic reactivities¹⁴. With 1:3 HFIP/MeCN as mixed solvent, LiPF₆ 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 (Supplementary Information, pages 16–18); however, the optimal conditions are shown in Fig. 1c. Initial screening of the arene scope showed that electron-rich arenes (for example anisole, biphenyl) also undergo efficient C–H DABCOylation under analogous reaction conditions (Fig. 1c). This prompted us to propose a reaction that can operate under dual mechanisms based on the oxidation potential of arene. Specifically, arenes with lower oxidation potentials than DABCOnium 4 probably operate via arene oxidation followed by nucleophilic trapping of DABCOnium 4 (Fig. 1d, mechanism B).

Substrate scope

Radical arene amination has previously struggled to selectively aminate electron-poor arenes. Recently, Lei and co-workers published a selective para-amination of nitroarenes utilizing proton-coupled oxidation of amines. However, this transformation, by design, works only with nitroarenes³⁶. 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 moderate to singular site selectivity (Fig. 2a). This anodic amination appears to represent the only selective C–H functionalization of benzonitrile with notable diversification potential because electrophilic halogenation and transition metal-catalysed borylation/silylation methods are ineffective or unselective on this substrate^37–39. Moreover, aryl DABCOnium salts 2 can be isolated as crude solids or readily converted to their corresponding aryl piperazines 5, using an iterative S_N2/E2 process with potassium cyanide or through use of the aqueous reductant sodium thiosulfate^19,25. 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 profiles of aryl DABCOnium salts are comparable to those of aryl trimethyl ammonium salts when engaged with transition metal catalysts⁴¹.

Fig. 2 |. Arene scope and selectivity of electrochemical aromatic C–H DABCOylation.

a, Scope of arene C–H amination reaction and observed regioselectivity. b, Observed regioselectivity (arrows) compared to Fukui nucleophilicity indices (greatest value for each compound highlighted in red) calculated by semi-empirical methods (Supplementary Information, pages 85–89). Electron-withdrawing and redox-sensitive functional groups in the scope are highlighted with a coloured circle background. General reaction conditions: 4a (0.30 mmol, 1.0 equiv.), LiPF₆ (1.3 equiv.), arene (1.5–3 equiv.), 1:3 HFIP/MeCN (0.075 M), graphite anode, platinum cathode, 3-mA constant-current electrolysis, 6 F mol⁻¹. Yields are isolated yields, values in parentheses are NMR spectroscopic yields of the aromatic C–H amination step. *Denotes the site of C–N bond formation for minor isomers, if detected, with the prevalence of that isomer given alongside the total yield. Compounds 2a, 2q were not characterized as solids. For 2i, 2x: 2X⁻ = ⁻OMs, PF₆⁻. For 2l, 2v: 2X⁻ = 2⁻OMs. ^aProducts contain >5% inseparable impurity after purification. For detailed reaction conditions, see Supplementary Information entry for the compound of interest. OMs, mesylate (CH₃SO₃⁻); [Hal], halogen (for example, Cl, Br, I). For crystal of 2a, white = H, grey = C, blue = N, green = F.

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 aromatic C–H amination takes place selectively at the α-position, 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 reaction⁴⁵. Hartwig and Fier have modernized pyridine α-C–H amination, leveraging a tandem AgF₂-mediated fluorination/S_NAr-type reactivity or Chichibabin-type amination through pyridine activation^42–44. Meanwhile, modern transition metal-catalysed borylation³⁸ or silylation³⁹ of pyridines are selective for the β or γ positions. This anodic DABCOylation represents an intriguing electrophilic example of accessing such α-aminated pyridines, in contrast to the known nucleophilic methods, 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 (5z, 5ab), allylic and benzylic C–H bonds (5t, 5u, 2v, 2x, 5y), epoxides (2v), benzyl chlorides (2x), imines (5y), enol ethers (5z) and many common N heterocycles, such as pyridines (5h–m), pyrroles (5w), triazoles (5z) and tetrazoles (5y). Additionally, the electrophilic N radical 3 reacts selectively with an arene over an olefin or alkyne, as seen in 5u, 5ac and 5ad (Fig. 3a), contrasting other reports of free N-radical amination^30,46. Previous reports have shown tolerance for olefins and alkynes when the radical is intercepted by a transition metal²⁷.

Fig. 3 |. Synthetic utility of arene C–H DABCOylation reaction.

a, Scope of arene diversification with designer DABCOnium salts. b, Functionalization and demonstration of synthetic utility of aryl DABCOnium salts to generate aryl piperazines, and aryl C–C, C–P and C–B bonds. Yields are isolated yields, values in parentheses are ¹H NMR yields. ^aProducts contain >5% inseparable impurity after purification. ^bObtained from aryl DABCOnium salt resulting from 4ae. Sensitive functional groups in the scope are highlighted with a coloured circle background. For detailed reaction conditions, see Supplementary Information entry for the compound of interest. OMs, CH₃SO₃⁻; OTf, CF₃SO₃⁻; Cy, cyclohexyl; ppy, 2-phenylpyridinyl; B₂pin₂, bis(pinacolato)diboron.

Some radical arene C–H functionalization methods that are successful on electron-poor arenes struggle with electron-rich arenes due to tendency of the highly electrophilic radicals to participate in single-electron transfer over π-system addition⁴⁷. However, this anodic DABCOylation method remains tolerant of electron-rich arenes (Fig. 2a) such as anisole derivatives (2q, 5r, 6), pyrrole derivatives (5w), o-xylene (5t), biphenyl derivatives (5s, 2x, 5y), and thiophene (Supplementary Information, page 66). Electron-rich arene substrates that are easier to oxidize than DABCOnium 4 go through an arene oxidation mechanism rather than an electrophilic N-radical mechanism (Fig. 1d). Although electron-poor arenes saw greatly increased yields from our previous work (5a, 5b, 5g, 5m), many arenes saw comparable yields to our previous work (for example, 2a, 5o, 2q, 5t) and some saw notable decreases (5n, 5p)²⁵. We attribute this difference to the sensitivity of each substrate to electrolysis conditions, in contrast to our previous work.

This work and previous reports of DABCOylation show arene selectivity that corresponds to their Fukui nucleophilicity indices^19,25. However, we observed counterintuitive selectivity with some electron-deficient substrates (Fig. 2b), notably arenes with π-withdrawing groups (5b–d) and pyridine derivatives (5h, 2i, 5j, 5k, 2l). To explain this, the selectivity-determining intermediate of the mechanism must be identified. Reasonable candidates could be the radical addition intermediate (II) and the Wheland intermediate (III). The step by which II is converted to III is a single-electron oxidation. In our undivided electrochemical cell, this is most probably an anodic and irreversible process⁴⁸. Thus, for regioselectivity, the stability of II should be primarily considered. For a π-withdrawing arene, para (or ortho) addition allows for the radical in II to be delocalized into the substituent, while meta addition confines the radical to the ring¹⁹. This explains why stronger π-withdrawing substituents yield greater para selectivity, irrespective of whether the major isomer follows the Fukui index (as in 5b, 5d) or defies it (as in 5c, Supplementary Information, page 61). However, this effect can be overcome with a group that causes large electronic biases (as in 5f). For pyridine derivatives, the β position is the most nucleophilic, but the stability of II must still be considered. Addition at the β position furnishes an entirely C-centred radical, while α (or γ) addition, results in a partly N-centred radical, which can enhance the stability of II⁴⁹. We hypothesize that stabilization via hyperconjugation of the N radical with the proximate sp³ C–H bond in II provides additional stability that furnishes α selectivity over γ selectivity (Supplementary Information, page 62)⁵⁰. Arenes with σ-donating or σ-withdrawing groups, or π-donating groups aminate according to their nucleophilicity because delocalization effects in II will be minimal. σ-Donating and σ-withdrawing groups provide only modest electronic biases and result in only modest selectivity (as in 5e, 5u, 2v), whereas π-donating groups provide more significant electronic biases and selectivity (as in 2a, 5n–p, 2q, 5r–s, 2x). Substrates that undergo arene oxidation will also aminate according to the most nucleophilic position in the neutral molecule because those positions will have the largest coefficients in the lowest unoccupied molecular orbital of the aryl radical cation⁹.

Another key advantage of this chemistry is its ability to quickly build complexity towards drug-like piperazine compounds (Fig. 3a). A diverse set of functionalized DABCOnium salts can be used as amine source compared with previous work, which was limited to Selectfluor I and II^19,25. Using simple S_N2 alkylation reactions, with no chromatography or crystallization, DABCO was converted to N-alkyl DABCOnium salts 4ab–4ag containing a diverse set of functional groups⁵¹. Subjecting these N-alkyl DABCOnium salts to the electrochemical amination reaction, followed by dealkylative reduction (with KCN or Na₂S₂O₃), provided easy access to designer aryl piperazines bearing important functional groups such as free alcohols (5ab), olefins (5ac), alkynes (5ad), CF₃ groups (5af) and other arenes (5ag). Tolerance of an alkyne is noteworthy because they can be used in bio-orthogonal chemistry for in vivo applications. Finally, we showcase the already diverse reactivity of these aryl DABCOnium salts (Fig. 3b) including comparable reactivities found in well-studied synthetic linchpins such as aryl halides, aryl boronic acids, aryl silanes and aryl thianthrenium salts⁷. In addition to the direct access of diverse aryl piperazines, aryl DABCOnium salts can be utilized in photoredox and transition metal-catalysed diversifications. This includes arylation²⁵, phosphorylation (6), borylation (7) and methylation⁴¹, showing the potential of the aryl DABCOnium as a synthetic intermediate for the net conversion of C–H bonds to C–C, C–P and C–B bonds in a highly selective manner.

Mechanistic studies

To gain insight into the mechanism of this reaction, we performed several experiments (Fig. 4) including cyclic voltammetry (CV), competition trials, kinetic isotope effect (KIE) experiments and electrochemical ultraviolet–visible spectroscopy (spectroelectrochemistry). CV analysis (Fig. 4a) of the reaction components reveals that N-alkyl DABCOnium salts 4 undergo accessible oxidation (E_p/2 ≈ 1.5 V versus Fc/Fc⁺) in 1:3 HFIP/MeCN. 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 (Fig. 4b) also revealed that upon addition of benzene (Fig. 4b) or toluene (Supplementary Information, page 77) 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–π interaction I²⁵, leading to faster diffusion away from the working electrode⁵². The slope of cathodic shift reduces as arene concentration increases, possibly indicating that the arene is saturating almost all generated 3. 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 (Fig. 4b). This observation is consistent with the proposed charge transfer or rapid turnover into radical addition intermediate II.

Fig. 4 |. Mechanistic studies for electrochemical C–H DABCOylation.

a, Redox potentials of various reaction components determined by CV. b, CV of electrochemically generated dicationic N radical 3 (via oxidation of 4) with benzene and normalized spectroelectrochemical traces for a blank solution (black), a solution of amine 4 (red), a solution of benzonitrile (blue) and a solution of amine 4 and benzonitrile (green). For more details on spectroelectrochemical studies, see Supplementary Figs. 30–40. The spectroelectrochemical analysis is reported versus a Ag/AgCl pseudo-reference electrode. c, Competition studies on reactivity of different arenes. d, KIE studies. I, current (mA); V, voltage (V, measured against a reference electrode); Fc/Fc⁺, ferrocene/ferrocenium redox couple; σ_p, Hammett para-substituent coefficient, k_H/k_D, rate constant ratio for arene and deuterated arene.

Seeking further clarification of the mechanism, we performed a series of competition experiments. Intermolecular competition between different monosubstituted arenes (Fig. 4c)⁵³ show that more electron-rich arenes were able to outcompete their electron-poor counterparts. In addition, an intermolecular KIE between benzene and benzene-d₆ revealed a k_H/k_D of 0.93 (Fig. 4d). Overall, these experiments rule out C–H bond cleavage as the rate-limiting step and narrow 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 computational studies³⁶.

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 in Fig. 1d as mechanism A. 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, possibly 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. Direct HAT of II to 2 utilizing 3 cannot be categorically ruled out; however, we view it as less likely than stepwise oxidation deprotonation due to presumed charge repulsion between 3 and II⁵⁴. The high site selectivity for most substrates is probably due to the high electrophilicity of the N-radical dication and its steric demand^5,19. It is also notable that amine 4 is recyclable. When C–N bond formation is challenging, reduction of 3 can occur, thus regenerating the amine source 4. That effect, along with the HFIP as co-solvent, probably explains this method’s success with electron-poor arenes where reductive methods have failed^19,25.

While a N-radical mechanism is probable for electron-poor and electron-neutral arenes, arenes that oxidize easier than 4 proceed through a direct arene oxidation mechanism (Fig. 1d, mechanism B)^9–11. Evidence of this competing mechanism can be seen in the product obtained from irbesartan (Fig. 2b, 5y), 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 1q, 1r, 1s and 1x most probably undergo amination via arene oxidation. This is supported by the spectroelectrochemical data with anisole (Supplementary Information, 83). In a sample containing anisole and 4, the oxidation of anisole dominates the spectral features, even at potentials that oxidize 4. It is worth noting that our system provides the potential for C–O bond formation (by trapping with HFIP or its anion) in competition with C–N bond formation⁵⁵. However, this side product is not detected for any compound in the scope. 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. Because 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^19,25,41. This allows for improved arene scope compared with existing systems.

Conclusions

We have developed a general and selective non-directed aromatic C–H amination, effectively addressing a long-standing challenge in late-stage C–H functionalization. In this method, (hetero)arenes for which C–H amination, classical halogenation or metal-catalysed borylation/silylation reactions are typically challenging can effectively undergo C–H DABCOylation with high selectivity. This method has successfully utilized both roles of the DABCOnium amine as an electrophile in electrophilic N-radical C–H functionalization and as a nucleophile in arene oxidation C–H functionalization, harmonizing the two major free-radical C–H amination strategies. The electrochemical conditions used resulted in electrophilic N-radical reactivity that is preferential to arenes, contrasting previous reports that show preferential reactivity towards olefins or HAT. 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 aromatic C–H functionalization reactions that are general and selective for both electron-rich and electron-deficient arenes and amenable to late-stage functionalization.

Methods

General method for the electrochemical aromatic C–H DABCOylation

Under ambient conditions, to a 5-ml ElectraSyn vial equipped with a magnetic stir bar were added arene (if solid, 1.5–3.0 equiv.), LiPF₆ (68 mg, 0.45 mmol, 1.5 equiv.) and N-Me DABCOnium mesylate salt (67 mg, 0.30 mmol, 1.0 equiv.), in sequence. Quickly, 3 ml MeCN (c = 0.075 M) was added followed by arene (if liquid, 1.5–3.0 equiv.) and 1 mL HFIP. The ElectraSyn vial was equipped with two electrodes (graphite and platinum wire electrode with mesh) and sealed with an ElectraSyn septum-cap. The reaction mixture was electrolysed under high stirring (1,500 r.p.m.), using electrolysis parameters 10 mA, 5 F mol⁻¹ (j₍₊₎ = 1.6 mA cm⁻²). The crude reaction mixture was dried under reduced pressure and washed with THF (3×5 ml) to remove unreacted organics. Excess THF was removed with a nitrogen stream. MeCN (8 ml) and KCN (59 mg, 0.84 mmol, 3.0 equiv.) were added to the crude mixture, which was then stirred at 40 °C for 48 h. MeCN was removed with reduced pressure. The product was purified with silica gel chromatography (DCM >100–5–0.5 (DCM, methanol, 28% aq. NH₄OH, v/v/v)). The eluent solvent was dried off to afford the piperazine product.

Supplementary Material

Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s44160-025-00890-9.

Data availability

The data supporting the findings of the present study are available within the Article and its Supplementary Information and source data files (experimental detail, characterization data, NMR spectra, CIF data, raw numerical data for cyclic voltammograms and spectroelectrochemical studies). Crystallographic data for the structures reported in this Article have been deposited at the Cambridge Crystallographic Data Centre, under deposition number CCDC 2384712 (2a). Copies of the data can be obtained free of charge via https://www.ccdc.cam.ac.uk/structures/.