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. 2026 May 20;9:274. doi: 10.1038/s42004-026-02070-y

Electrochemical Direct Benzylic C–H Hydroxylation with H2O Enabled by an Unusual Dual Hydrogen-bonding Interaction

Shuaiyu Ji 1,2, Wing-Yiu Yu 1,✉, Peng Yu 2,✉
PMCID: PMC13458445  PMID: 42162199

Abstract

Minimizing side reactions is essential for achieving high yield and selectivity in organic synthesis, yet controlling overoxidation in direct benzylic C–H bond hydroxylation remains challenging. Here we show an electrochemical method for benzylic C–H hydroxylation using water as the oxygen source, in which overoxidation is suppressed by employing N-methyl-2-pyrrolidone as a co-solvent. The reaction proceeds without external oxidants, metal catalysts, or an inert atmosphere, using simple electrolytes. It is compatible with primary, secondary, and tertiary alkylarenes and exhibits good functional group tolerance. The method also enables isotope incorporation and is readily scalable, demonstrating practical synthetic utility. Mechanistic studies suggest that dual hydrogen-bonding interactions between the alcohol product and N-methyl-2-pyrrolidone may play a key role in suppressing overoxidation. Although the faradaic efficiency is moderate under the current conditions, this work provides a complementary strategy for selective benzylic C–H hydroxylation using water as a benign oxygen source.

Subject terms: Electrocatalysis, Synthetic chemistry methodology, Synthetic chemistry methodology

Overoxidation remains a selectivity challenge in direct benzylic C–H bond hydroxylation. Here, the authors present an electrochemical method using water as the hydroxyl source and N-methyl-2-pyrrolidone as a co-solvent, effectively suppressing overoxidation without external oxidants or metal catalysts.

Introduction

Benzyl alcohols play a crucial role in organic synthesis and pharmaceutical chemistry1–4. The presence of hydroxyl functionality at the benzylic position endows benzyl alcohols with unique reactivity, making them key intermediates in a wide range of organic transformations5–11. Thus, the development of effective methods for synthesizing benzyl alcohols has long been a significant pursuit in both the academic and industrial communities. Typical approaches for the synthesis of benzyl alcohols mainly include the reduction of corresponding carbonyl compounds, nucleophilic addition of organometallic reagents (e.g., Grignard reagents) to benzylic carbonyl compounds, and substitution reactions of benzylic electrophiles (e.g., benzylic halides)12,13. While these methods are well-established and widely used, they heavily rely on excess hazardous reagents and require prefunctionalized benzylic substrates, limiting their functional group compatibility and atom economy. In contrast, direct benzylic C−H bond hydroxylation offers a promising strategy to address these challenges, enabling a more practical and step-economical route to benzyl alcohols.

Various strategies for benzylic C−H bond hydroxylation have been developed, ranging from the use of enzymes or metals as catalysts to photocatalyzed approaches14–24. However, the reliance on stoichiometric hazardous oxidants or precious metal catalysts in many of these methods still limits their sustainability and broad synthetic applicability. To this end, an electrochemical approach offers an attractive alternative, as it eliminates the need for external oxidants or metal catalysts by harnessing electric current to drive the redox process25–31. This strategy allows for precise control over the oxidation potential, minimizes byproduct formation, and enhances both the efficiency and environmental compatibility of the transformation32–38. However, although photoelectrochemical strategies have demonstrated significant potential for achieving selective oxidation of benzylic hydrocarbons39,40, and selective oxidation of benzylic C−H bonds to benzyl alcohols via an electrocatalytic process41 or an imidazolium radical mediated electrochemical process42 have been reported recently, both focus on mechanistic study rather than method development, achieving electrochemical direct benzylic C−H bond hydroxylation remains particularly challenging and underdeveloped43. This is primarily due to the lower oxidation potentials of benzyl alcohols compared to their alkylarene precursors (Fig. 1a), which often leads to overoxidation, as well as the decreased bond dissociation energy (BDE) of the benzylic C−H bond in alcohols (Fig. 1a)41,44. As a result, many electrochemical benzylic C−H oxidation reactions reported to date predominantly yield overoxidized products, such as ketones and aldehydes, rather than alcohols45–50. To overcome the challenge of overoxidation, Stahl’s group and Xu’s group independently developed a two-step strategy for electrochemical benzylic C−H hydroxylation, wherein a protected benzyl alcohol is first produced, and subsequently converted to the free alcohol via either a photocatalytic process or hydrolysis (Fig. 1b)19,44. While this approach effectively addresses the overoxidation issue, it requires additional synthetic steps, which decrease overall atom economy and increase operational complexity. Therefore, the development of an electrochemical direct C−H bond hydroxylation remains highly desirable.

Fig. 1. Background and our strategy to overcome the overoxidation in electrochemical benzylic C–H bond hydroxylation.

Fig. 1

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a Challenge analysis for electrochemical benzylic C–H bond hydroxylation. b Reported electrochemical benzylic C–H bond hydroxylation via an indirect strategy. c This work: electrochemical direct benzylic C–H bond hydroxylation with H2O enabled by a dual hydrogen-bonding interaction.

Herein, we report a practical electrochemical method for direct benzylic C–H bond hydroxylation using water (H2O) as the hydroxyl group source (Fig. 1c). This protocol exhibits high product selectivity and eliminates the need for any metal catalyst or chemical oxidant. It accommodates alkylarenes with diverse electronic properties and is compatible with primary, secondary, and tertiary benzylic C–H bonds. Remarkably, the reaction is readily scalable to a gram scale and applicable to the preparation of 18O-labeled benzylic alcohols, demonstrating its potential for broad synthetic applications. Mechanistic studies suggest that an unusual dual hydrogen bonding interaction between the alcohol product and the solvent (NMP) raises the oxidation potential of benzyl alcohol, thereby preventing overoxidation. It is worth noting that an elegant electrochemical direct benzylic C–H bond hydroxylation employing a similar strategy to avoid overoxidation was reported by Qiu and co-workers during the preparation of this manuscript51. In their study, however, hexafluoro-2-propanol (HFIP) served as both the solvent and hydrogen-bond donor, preventing the overoxidation through a mono-hydrogen-bonding interaction, which differs from our strategy, wherein NMP served as both the solvent and hydrogen-bond acceptor, enabling a distinct dual hydrogen-bonding interaction with the alcohol product. While the faradaic efficiency under the current conditions is moderate, this method demonstrates a practical, oxidant-free strategy for selective benzylic C–H hydroxylation using water as a benign oxygen source.

Results and discussion

Reaction development

We initially selected 4-butyl-1,1’-biphenyl (1S) as the model substrate for the electrochemical hydroxylation with H2O. After systematically investigating key parameters, including electrode materials, electrolytes, current, and solvents, the optimized conditions were established using reticulated vitreous carbon (RVC) as the anode, nickel foam as the cathode, tetra-n-butylammonium tetrafluoroborate (TBABF4) as the supporting electrolyte, and a combination of dimethyl sulfoxide (DMSO), N-methyl-2-pyrrolidone (NMP), and acetonitrile (MeCN) as the solvent (Table 1). Under these conditions, the desired alcohol product (1) was formed in an 81% yield after stirring for 17 hours at room temperature under ambient atmosphere, and notably, overoxidation was effectively suppressed, with the corresponding ketone detected in less than 10% yield (entry 1). Control experiments confirmed that both water and electricity are critical to the reaction, as no reactivity was observed when the reaction was performed in the absence of either current or water (entries 2 and 3). The current density and loading of water also proved to have notable effects on both the reactivity and selectivity (see Supplementary Information S5 and S7). Solvent investigation revealed that NMP plays a crucial role in achieving high selectivity for this reaction. Conducting the reaction in the absence of NMP resulted in the formation of the ketone rather than the desired alcohol, with a lower yield (entry 4). Similarly, replacing NMP with N,N-dimethylformamide (DMF), or decreasing its proportion in the mixed solvent also led to the corresponding ketone being the major product (entries 5 and 6), further highlighting the crucial role of NMP in enabling this selective hydroxylation52,53. In contrast, acetonitrile (MeCN) has a negligible impact on product selectivity; however, its presence can promote a competing Ritter-type pathway under certain conditions. Notably, this side reactivity is effectively suppressed upon incorporation of NMP and water into the reaction system54,55. Decreasing the amount of MeCN, or omitting it entirely, leads to a substantial decrease in the yield of the alcohol product (entries 7 and 8). While DMSO is not as critical as NMP or MeCN to the reaction performance, its absence resulted in a slightly decreased yield and selectivity (entry 9). Both anodic and cathodic electrodes were screened. Either replacing RVC with graphite felt (GF) or Ni foam with Pt led to diminished yields and selectivity (entries 10 and 11). Electrolytes were also examined in this selective hydroxylation. Using other electrolytes, such as TBAClO4, TBAPF6, or TBACl, rather than TBABF4, significantly diminished both reaction efficiency and product selectivity (entries 12–14). Notably, this approach does not require an inert atmosphere, as comparable results were obtained when the reaction was conducted under nitrogen (entry 15). This not only highlights the practicality of the transformation but also indicates that the oxygen atom in the alcohol product originates from H₂O rather than atmospheric O₂.

Table 1.

Reaction optimization.a

graphic file with name 42004_2026_2070_Taba_HTML.gif
Entry Change in standard conditions Yield of 1 (%)b Yield of 1′ (%)b
1 None 81 8
2 w/o electricity n.d. –
3 w/o H2O n.d. n.d.
4 w/o NMP trace 56
5 DMF instead of NMP 4 45
6 NMP: MeCN = 1:3 10 56
7 NMP: MeCN = 3:1 70 6
8 w/o MeCN 15 trace
9 w/o DMSO 73 16
10 GF instead of RVC 22 7
11 Pt instead of Ni foam 72[c] 19
12 TBAClO4 instead of TBABF4 36 43
13 TBAPF6 instead of TBABF4 56 23
14 TBACl instead of TBABF4 trace n.d.
15 N2 instead of air 83 8
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aReaction conditions: 1s (0.1 mmol), TBABF4 (0.42 mmol), H2O (230.0 μL), DMSO (260.0 μL), MeCN (3.0 mL), NMP (3.0 mL), under air, undivided cell, at room temperature, 17 h, constant current = 11.0 mA. bYield of NMR using dibromomethane as an internal standard. cYield of the isolated product.

Substrate scope

With the optimized conditions in hand, we next explored the substrate scope of this direct electrochemical benzylic C–H hydroxylation with H2O. As shown in Fig. 2a, a range of alkylarenes were oxidized to the corresponding benzyl alcohols in moderate to high yields, with overoxidation effectively suppressed. In addition to secondary alkylarenes, primary and tertiary benzylic C–H bonds also proved to be suitable substrates under the optimized conditions, delivering the desired alcohols with high efficiency and excellent product selectivities in the case of primary substrates (2–2c, 3). Linear alkyl chains with varying carbon length were well tolerated, yielding the corresponding alcohol in high yields and with high selectivities (1, 4, 5). Likewise, carbocyclic alkylarenes also underwent efficient hydroxylation, affording the desired alcohols with high selectivities, and in most cases, high yields (7, 8, 10–12). In the case of 9, the diminished yield of product is attributed to the formation of a benzofuran side product (see page S32 of the Supplementary Information for experimental details). The successful transformation of these diverse frameworks under standard conditions highlights the robustness and broad applicability of this electrochemical protocol for selective direct benzylic C–H hydroxylation. However, at the current stage, the method is primarily effective for biaryl substrates, and extension to more general substrate classes remains a subject for further investigation.

Fig. 2. Substrate scope of electrochemical C–H bond hydroxylation.

Fig. 2

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a Reaction scope of electrochemical C–H bond hydroxylation. b Synthesis of isotope-labeled benzylic alcohol. c Scale-up reaction. Reaction conditions: Undivided cell, RVC anode (4.0 mm × 4.0 mm × 12 mm), Ni foam cathode (0.3 mm × 50.0 mm × 10.0 mm) folded in half, reaction scale (0.1 mmol), TBABF4 (0.42 mmol), H2O (230.0 μL), DMSO (260.0 μL), MeCN (3.0 mL), NMP (3.0 mL) under air at room temperature for 17 h, constant current = 11.0 mA. Isolated yields. The ratio of desired product to overoxidized product in the parentheses was determined based on isolated yields. r.r. = regioselectivity ratio. The prime symbol indicates the overoxidized product. aReaction time was prolonged to 20 h.

We further examined the functional group tolerance of this electrochemical hydroxylation and found that a broad range of functional groups, whether electron-drawing, electron-donating, or electron-neutral, were well tolerated under the optimized conditions. Notably, aromatic halides remained untouched during electrolysis, leading to the production of halogenated benzyl alcohols with high efficiency and selectivity (11, 14, 15). These halide-containing products are valuable synthetic intermediates in organic synthesis, particularly for downstream functionalization via cross-coupling reactions56. In addition, aromatic boronates, which are also important and widely used synthetic building blocks57, were also effectively tolerated under the reaction conditions (12). Other groups, including a cyano group (6), a ketone group (7), a trifluoromethyl group (17, 24), an ester group (18), an ether group (21, 22), and a naphthyl group (25), were also well tolerated, with no detected side reactions occurring on them. Aromatic heterocycles are prevalent structural motifs in pharmaceuticals58, making their compatibility a critical benchmark for evaluating synthetic methodologies. In this approach, gratifyingly, heterocycles such as pyridines and thiophenes were compatible with the electrochemical conditions (26, 27), demonstrating the potential of this methodology for applications in medicinal chemistry and drug development.

This hydroxylation reaction can also be applied to isotope incorporation. As shown in Fig. 2b, an 18O-labeled benzyl alcohol was successfully synthesized in high yields and selectivity (28), demonstrating the utility of this method for tracer studies and mechanistic investigations59,60. Furthermore, a scale-up experiment was carried out under standard conditions, affording the desired alcohol product with comparable efficiency and selectivity (73%, 1.7 g, 1:1′ = 8.5:1), highlighting the practical potential and synthetic utility of this electrochemical hydroxylation (Fig. 2c).

Mechanistic investigations

The mechanistic investigation of this electrochemical direct hydroxylation centered on elucidating the underlying factors responsible for the effective suppression of oxidation of the alcohol product to the corresponding ketone, which is crucial to the success of this transformation. First, we carried out cyclic voltammetry (CV) studies, aiming to investigate the solvent effect on the oxidation potential of alkylarenes and their corresponding alcohol products. The CV data showed that in acetonitrile, 4-butyl-1,1′-biphenyl (Ep/2 = 1.84 V vs. Ag/AgCl) was more difficult to oxidize than the corresponding alcohol (Ep/2 = 1.77 V vs. Ag/AgCl), which is consistent with the experimental result that only the ketone product was produced under the conditions using MeCN as a solvent (Fig. 3a, left). In contrast, when NMP was added to the system, a slightly lower oxidation potential was observed for 4-butyl-1,1′-bipheny (Ep/2 = 1.78 V vs. Ag/AgCl) than the corresponding alcohol (Ep/2 = 1.87 V vs. Ag/AgCl), indicating a more difficult oxidation of the alcohol than its starting material (Fig. 3a, right). These CV results suggest that the unique redox environment provided by NMP plays a crucial role in modulating the oxidation pathways, enabling selective benzylic C–H hydroxylation while minimizing overoxidation.

Fig. 3. Mechanistic investigation and proposed reaction pathway.

Fig. 3

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a CV studies. b Control experiments using various solvents. c NMR studies to investigate the interaction between product and NMP. d DFT calculations. e The proposed mechanism.

In addition, control experiments using the alcohol product (1) as the starting material were performed in various solvents (Fig. 3b). The results showed that the alcohol was completely converted to the corresponding ketone in MeCN after 2 h. In contrast, the oxidation was significantly suppressed when the reaction was conducted in the mixture of MeCN and NMP in a ratio of 1:1. Notably, when NMP was used as the sole solvent, the oxidation was nearly fully suppressed. These results further support the crucial role of NMP in effectively suppressing overoxidation. To further elucidate the mechanism by which NMP influences the oxidation process under the reaction conditions, we investigated the potential interaction between the benzyl alcohol and NMP using NMR spectroscopy. As shown in Fig. 3c, the NMR analysis showed a downfield shift of the hydroxyl proton signal from 2.32 ppm to 4.46 ppm in a 1:1 mixture of benzyl alcohol and NMP, indicating a decreased electron density at the hydroxyl group. This observation supports a hydrogen bonding interaction between the benzyl alcohol and NMP, with the carbonyl oxygen of NMP serving as the hydrogen-bond acceptor61–64. Moreover, the benzylic proton signal also shifted to downfield (from 4.70 ppm to 4.99 ppm) when mixing the benzyl alcohol and NMP. This result, together with the fact that no obvious changes were observed in the chemical shifts of this benzylic proton upon mixing product 1 with isopropanol, ethyl acetate, or MeOH (see Supplementary Information S16 and S17), implies a possible involvement of this proton in the hydrogen-bonding interaction. Thus, we proposed an unusual dual hydrogen-bonding interaction mode between NMP and the alcohol product wherein the nitrogen and carbonyl oxygen of NMP serve as hydrogen-bond acceptors, and the benzyl alcohol proton and the benzylic proton serve as donors. Further investigations of this proposed dual hydrogen-bonding interaction model by DFT calculations indicate that this dual interaction favors the formation of hydrogen bonds between the carbonyl oxygen of NMP and the hydroxyl proton of the alcohol product, as well as between the nitrogen of NMP and the benzylic proton of the alcohol product. This model exhibits a higher binding energy (ΔEbind = –12 kcal/mol) than the other evaluated models, including the typical single hydrogen-bonding model (ΔEbind = −11.8 kcal/mol). Although an alternative dual interaction model involving a hydrogen bond between the α proton and the NMP carbonyl group and the alcohol oxygen shows a comparable binding energy, this interaction is less consistent with the experimentally observed NMR chemical shift changes and the general hydrogen-bond donor ability of C–H bonds. Additionally, an NMR titration experiment of the benzyl alcohol supports the involvement of a single NMP molecule in the proposed hydrogen-bonding interaction65 (see details in Supplementary Information S17 and S18).

Taken together, a proposed mechanism for the electrochemical direct benzylic C–H hydroxylation reaction is depicted in Fig. 3e. Anodic oxidation of the alkylarene generates a radical cation, which undergoes a deprotonation and a second oxidation to produce the corresponding benzylic cation. This cation is then trapped by water, followed by a proton transfer to yield the benzyl alcohol product. The key to the success of this proposed mechanism lies in the formation of a dual hydrogen-bonding interaction between the produced alcohol and NMP, which enables the effective suppression of the further oxidation of alcohol products to the corresponding carbonyl compounds.

Summary

In conclusion, we have successfully developed a straightforward and efficient electrochemical approach for direct hydroxylation of benzylic C–H bonds without the need for any metal catalyst or external oxidant, and with overoxidation effectively being suppressed. The method proceeds under ambient air and is compatible with a range of substrates bearing various functional groups. Moreover, the approach applies to primary, secondary, and tertiary benzylic C–H bonds and is amenable to the preparation of ¹⁸O-labeled compounds and gram-scale synthesis. Mechanistic studies suggest that dual hydrogen-bonding interaction may contribute to suppressing overoxidation during the hydroxylation process. We anticipate that these findings, particularly the dual hydrogen-bonding interaction between an alcohol and NMP, will not only advance the development of C(sp3)–H bond oxidation but also provide valuable insight into minimizing the undesired side reactivity.

Methods

Representative procedure for the electrochemical direct benzylic C–H hydroxylation with H2O

To a 10 mL three-necked flask containing a magnetic stir bar, which was equipped with RVC (0.5 cm×0.5 cm×0.6 cm, supported by a ⌀ = 3.0 mm and sharpened graphite rod) and Ni foam (5.0 cm × 1.0 cm × 0.01 cm) folded in half as anode and cathode, was added start materials (0.1 mmol), H2O (230.0 μL), TBABF4 (0.42 mmol), DMSO (260.0 μL), NMP (3.0 mL), and MeCN (3.0 mL) in the air. The mixture was stirred using a constant current of 11.0 mA at room temperature under air. The progress of the reaction was monitored by TLC. After the reaction was complete, the reaction mixture was allowed to be diluted with distilled water (20.0 mL) and extracted with dichloromethane (DCM, 3 × 10.0 mL). The organic layer was washed with saturated brine (3 × 10.0 mL), dried over anhydrous MgSO₄, concentrated under reduced pressure, and purified by column chromatography on silica gel to afford the benzylic alcohol product.

Supplementary information

Supplemental Material (6.5MB, pdf)

Acknowledgements

We are grateful for the financial support provided by the Eastern Institute of Technology, Ningbo, the Hong Kong Research Grants Council (PolyU153061/24 P, PolyU153037/23 P, PolyU153041/21 P), and the State Key Laboratory for Chemical Biology and Drug Discovery.

Author contributions

S. Ji designed and performed the experiments, mechanistic studies, and analyzed the data. W.-Y. Yu and P. Yu supervised the project. S. Ji and P. Yu wrote the paper.

Peer review

Peer review information

Communications Chemistry thanks the anonymous reviewers for their contribution to the peer review of this work.

Funding

P. Yu discloses support for the research and publication of this work from the Eastern Institute of Technology, Ningbo. W.-Y. Yu discloses support for the research of this work from the Hong Kong Research Grants Council (PolyU153061/24 P, PolyU153037/23 P, PolyU153041/21 P) and the State Key Laboratory for Chemical Biology and Drug Discovery. S. Ji declares no relevant funding.

Data availability

The data that support the findings of this study are available in the Supplementary Information of this article.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Wing-Yiu Yu, Email: wing-yiu.yu@polyu.edu.hk.

Peng Yu, Email: pyu@eitech.edu.cn.

Supplementary information

The online version contains supplementary material available at 10.1038/s42004-026-02070-y.

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