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. 2026 Feb 21;17:3003. doi: 10.1038/s41467-026-69807-0

Photooxidative Copper(II) Catalysis for Promoting anti-Markovnikov Hydration of Alkenes

Naoki Oku 1,✉, Keito Fuke 1, Rikako Masui 1, Ken Yamazaki 1, Yasunori Matsui 2,3, Hiroshi Ikeda 2,3, Tomoya Miura 1,✉
PMCID: PMC13036079  PMID: 41723144

Abstract

Photoredox catalysis enables the generation of radical intermediates under mild conditions, yet photoredox catalysts have heavily relied on precious transition metal complexes. Therefore, the development of photocatalysts based on earth-abundant metals is increasingly demanded. Here, we report a highly photooxidative capability of a heteroleptic copper(II) complex for promoting anti-Markovnikov hydration of alkenes. The copper(II) complex containing bathophenanthroline and 3,4-dimethoxybenzenethiolate ligands is generated in situ from copper(II) chloride dihydrate. Upon visible-light irradiation, the copper(II) complex is photoexcited and exhibits an excited-state lifetime sufficiently long to oxidize various alkenes, including aliphatic substrates. Consequently, anti-Markovnikov hydration can be achieved under mild conditions, and the late-stage functionalization of natural products and pharmaceutical derivatives is also feasible. The developed catalytic system can be extended for photooxidative reactions of alkenes, such as intramolecular cyclization reactions and anti-Markovnikov addition of nucleophiles other than water.

Subject terms: Photocatalysis, Synthetic chemistry methodology, Photocatalysis

Alkene hydration provides an atom-economical and redox-neutral route to aliphatic alcohols yet controlling regioselectivity remains challenging. Here, the authors reveal that a photooxidative heteroleptic copper(II) complex enables efficient anti-Markovnikov hydration of alkenes.

Introduction

Photoredox catalysis has emerged as a powerful tool in modern organic synthesis, enabling the generation of radical intermediates from organic molecules under mild conditions via visible-light-induced single-electron transfer (SET) (Fig. 1a)1–3. In particular, polypyridyl complexes of precious transition metals such as ruthenium(II) and iridium(III) have dominated the field due to their remarkable properties: (i) strong absorption in the visible region, (ii) long-lived excited states on the microsecond timescale, and (iii) tunable redox potentials in both ground and excited states4–6. However, the use of ruthenium(II) or iridium(III) complexes presents several disadvantages with respect to cost, toxicity, and limited availability.

Fig. 1. anti-Markovnikov hydration of alkenes by copper(II) photocatalysis.

Fig. 1

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a Radical generation via single-electron transfer by photoredox catalysis. PC = photocatalysts, Sub = substrates. b Overview of copper-based photoredox catalysis. c anti-Markovnikov hydration by photoredox catalysis. SCE = saturated calomel electrode.

Organic photoredox catalysts have garnered increasing attention as attractive transition metal-free alternatives due to their affordability and low toxicity7,8. Some organic catalysts exhibit unique reactivity that is inaccessible to transition metal-based photoredox catalysts, such as the strong oxidation power of acridinium salts and triphenyl amines9,10. Nevertheless, they tend to suffer from photoinstability and the cumbersome separation of catalysts from products. Furthermore, tuning their redox behavior often requires laborious multistep syntheses of individual derivatives, whereas the photocatalytic behavior of transition-metal complexes can be easily modulated through ligand exchange. Therefore, there is a pressing need to develop a new class of photoredox catalysts that can reconcile high reactivity with facile accessibility.

To overcome the individual limitations of both noble transition metal and organic photoredox catalysts, increasing efforts have been directed toward the development of photocatalysts based on earth-abundant 3d transition metal complexes11–15. Among 3d transition metals, copper complexes have attracted particular interest in recent years, owing to their high abundance in the Earth’s crust and unique photocatalytic behavior stemming from multiple accessible oxidation states16–21. Recent developments have demonstrated that copper(I) complexes, especially homoleptic bis-diimine and heteroleptic diamine-diphosphine species, can function as strongly reducing photoredox catalysts with excited-state lifetimes in the nanosecond range (Fig. 1b, up). These copper(I) catalysts typically operate via oxidative quenching cycles, facilitating various photoredox reactions by single-electron reduction of substrates. In contrast to their reductive characters, copper(I) complexes are seldom employed in photoredox reactions via reductive quenching cycles22–26. Although it is well known that copper(II) species are widely used as oxidants in the ground states, to the best of our knowledge, there have been no reports describing the SET mechanism of photoexcited copper(II) complexes. Instead, photoexcited copper(II) complexes typically undergo ligand-to-metal charge transfer (LMCT), rather than the SET process (Fig. 1b, bottom)27–34. This LMCT pathway induces homolytic cleavage of a copper–ligand bond, yielding a copper(I) species and a radical intermediate. While this reactivity highlights the intrinsic oxidative character of copper(II) species, it also hinders their application in intermolecular SET-based photoredox catalysis. We hypothesized that extending the excited-state lifetime of copper(II) complexes could shift the photochemical pathway from LMCT to intermolecular SET, thereby enabling their use as potent oxidative photoredox catalysts.

Highly oxidative photoredox catalysts are particularly desirable for challenging transformations such as anti-Markovnikov hydration of alkenes. The direct addition of water to alkenes, namely alkene hydration, provides an atom-economical and redox-neutral route to produce aliphatic alcohols. Conventional acid-catalyzed hydration, which is well-established and widely employed in industrial processes, yields secondary or tertiary alcohols because the reaction proceeds via the formation of a carbocation intermediate in accordance with Markovnikov’s rule35,36. In contrast, anti-Markovnikov-type hydration would yield primary alcohols from terminal alkenes. Despite extensive efforts to develop anti-Markovnikov hydration, the realization remains a longstanding synthetic challenge37–40. In confronting this challenge, photocatalytic anti-Markovnikov functionalization of alkenes, primarily developed by the Nicewicz group, presented an attractive strategy41–43. In 2017, Lei reported a notable breakthrough for anti-Markovnikov hydration of styrenes using an organic photoredox catalyst ([Acr+–Mes][ClO4−]: Fukuzumi’s catalyst) (Fig. 1c, top)44,45. Single-electron oxidation of styrenes generates a radical cation intermediate, which undergoes regioselective addition of water in an anti-Markovnikov manner. Despite this progress, reliance on organic photocatalysts limits the reaction's general applicability. Thus, developing a transition-metal-based system capable of achieving similarly strong oxidative power remains an important challenge, and we sought to explore whether a copper(II) photoredox system could serve not only as a viable alternative to organic photoredox catalysts but also offer complementary advantages, such as modularity, robustness, and scalability.

Herein, we report that a heteroleptic copper(II) complex containing bathophenanthroline and 3,4-dimethoxybenzothiolate ligands exhibits a remarkably high oxidative capability (Ered* > +2.3 V vs SCE) (Fig. 1c, bottom). The copper(II) complex acts as a photoredox catalyst to promote anti-Markovnikov hydration of various alkenes, including di- and trisubstituted aliphatic substrates. Notably, whether based on ruthenium(II) or iridium(III), very few transition-metal complexes attain such a high redox potential in their photoexcited states, underscoring the exceptional nature of the developed copper(II) photoredox catalyst. Mild reaction conditions allow late-stage functionalization of natural products and pharmaceutical derivatives. Moreover, our catalytic system is applicable to other anti-Markovnikov functionalizations of alkenes, such as intramolecular cyclization reactions and nucleophilic additions of alcohols and azoles.

Results and discussion

Reaction development

We began our investigation with the preparation of copper(II) chloride bathophenanthroline complex: Cu(bphen)Cl2 (Fig. 2a). The complex was synthesized by a simple addition of copper(II) chloride and bathophenanthroline (bphen) in CH2Cl2 at room temperature. The synthesis from copper(II) chloride dihydrate instead of the anhydrous form was also available. The structure of Cu(bphen)Cl2 was elucidated by a single-crystal X-ray diffraction. The complex exhibited planar geometry, and two molecules weakly interacted to form a µ-Cl-bridged dimer in the crystalline state. Next, to disclose the photophysical properties of Cu(bphen)Cl2, we performed the UV-vis absorption, excitation/emission spectroscopy, and fluorescence decay measurements. A solution of Cu(bphen)Cl2 in MeCN/acetone/H2O (5:5:1) displayed an absorption tailing to 450 nm and a broad absorption from the visible region to the near-infrared region, characteristic of copper(II) complexes. Upon excitation at 445 nm, an emission centered at 512 nm was observed. Notably, although 3d transition metal complexes typically exhibit short-lived excited states, the emission lifetime of Cu(bphen)Cl2 was 18.3 ns, sufficiently long to allow intermolecular quenching. Based on the result of the cyclic voltammetry (CV) and E0-0 value, the excited-state redox potential of Cu(bphen)Cl2 was estimated as +2.51 V vs SCE. A quenching experiment with styrene (Eox = +1.97 V vs SCE) showed linear quenching with increasing quencher concentration, supporting the photoinduced single-electron oxidation of styrene by photoexcited Cu(bphen)Cl2. Encouraged by these findings, we next turned to optimizing the reaction conditions for photoinduced copper(II)-catalyzed anti-Markovnikov hydration of alkenes.

Fig. 2. Optimization of reaction conditions for anti-Markovnikov hydration.

Fig. 2

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a Preparation and physical properties of Cu(bphen)Cl2. Potentials are vs SCE. b Development of anti-Markovnikov hydration of alkenes. aReactions performed on a 0.30 mmol scale. bYields determined by 1H NMR analysis using 1,1,2,2-tetrabromoethane as an internal standard. cIsolated yield after preparative thin-layer chromatographic purification. n.d. = not detected.

4-tert-Butylstyrene was selected as an archetypal substrate, and the optimization results are shown in Fig. 2b. A mixture of 4-tert-butylstyrene (0.30 mmol, 1.0 equiv), H2O (0.45 mL), CuCl2·2H2O (2.5 mol %), bphen (2.5 mol %), and 3,4-dimethoxybenzenethiol (20 mol %) in MeCN/acetone (1:1, 4.5 mL) was irradiated with purple LEDs (λmax = 390 nm, 23 W) at room temperature. After 5 h, the primary alcohol 1 was obtained in 60% NMR yield, with no formation of the Markovnikov-type product. Purification by preparative thin-layer chromatography afforded 1 in an isolated yield of 54% (entry 1). Although pre-isolated Cu(bphen)Cl₂ improved the reaction rate, we adopted the in situ complexation procedure for operational simplicity. The reaction did not proceed at all in the absence of CuCl2·2H2O (entry 2). Other copper(II) salts such as CuBr2 and Cu(OTf)2 gave comparable yields (entries 3 and 4). The bphen ligand was indispensable for the reaction (entry 5). Only 6% of the primary alcohol 1 was formed when 1,10-phenanthroline (phen) was used instead of bphen (entry 6). The reaction also needed the thiol catalyst (entry 7). No product formation was observed in the absence of photoirradiation, even at elevated temperatures (entries 8 and 9), confirming the photoinduced nature of the reaction.

Mechanistic studies

Interestingly, comparable results were obtained regardless of the kind of copper(II) precursors (Fig. 2b, entries 3 and 4). Then, we hypothesized that the same catalytically active species was generated in situ by the ligand exchange between the copper(II) complexes and the thiol catalyst. Indeed, the emission/excitation spectra of Cu(bphen)Cl2 disappeared in the presence of 3,4-dimethoxybenzenethiol, and new spectra indicating the formation of another copper species were observed. The in situ-generated copper(II) complex exhibited a broad absorption in the visible region, and excitation at 361 nm yielded an emission spectrum with a maximum at 442 nm. Identical spectra were observed when Cu(bphen)Br2 or Cu(bphen)(OTf)2 was employed instead of Cu(bphen)Cl2, which strongly supported the formation of the same photoactive species by ligand exchange. Furthermore, Cu(bphen)(SAr)2 (Ar: 3,4-dimethoxyphenyl) was detected by high-resolution mass spectrometry (HRMS), indicating the ligand exchange of Cu(bphen)Cl2 (Fig. 3a). However, isolation of Cu(bphen)(SAr)2 was unsuccessful due to its instability46, and thus, the exact redox potential of Cu(bphen)(SAr)2 could not be determined. Instead, quenching experiments were conducted using Cu(bphen)Cl2 in the presence of 3,4-dimethoxybenzenethiol. A linear quenching of photoexcited Cu(bphen)(SAr)2 was observed with prenyl benzoate as a quencher, and thus the redox potential of Cu(bphen)(SAr)2 was estimated as exceeding +2.33 V vs SCE (Fig. 3b)13. This result suggested that Cu(bphen)(SAr)2 would be the true active species in the anti-Markovnikov hydration of alkenes.

Fig. 3. Mechanistic studies.

Fig. 3

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a In situ formation of Cu(bphen)(SAr)2. HRMS = high-resolution mass spectrometry. b Stern-Volmer quenching experiment of Cu(bphen)(SAr)2. [Q] = concentration of the quencher. kq = kinetic rate constant of electron transfer. c Ligand effect on the photochemical properties of various CuL(SAr)2 complexes. L = 1,10-phenanthroline-type ligands. d Radical-clock experiment. e Light on-off experiment. f Proposed reaction mechanism. SET = single-electron transfer, HAT = hydrogen atom transfer.

To clarify the importance of the bphen ligand, we evaluated the photophysical properties of copper(II) complexes bearing various 1,10-phenanthroline-type ligands in the presence of the thiol catalyst (Fig. 3c). The 3d transition metal complexes generally suffer from a rapid deactivation of their photoexcited states before intermolecular SET events. Therefore, to achieve intermolecular SET of copper(II) complexes, an appropriate ligand design to extend the excited-state lifetimes is essential47–52. While UV-vis absorption spectra of the in situ formed complex were similar to each other across ligands, the intensity and lifetime of the emission were significantly influenced by the substituents at the 4,7-positions on the 1,10-phenanthroline core. As a result, Cu(bphen)(SAr)2 exhibited the most intense and long-lived fluorescence among the examined complexes. We assumed that bulky ligands suppressed the deactivation of the excited state of copper(II) complexes by increasing structural rigidity, promoting efficient photocatalysis for the anti-Markovnikov hydration53–56.

Control experiments provided further mechanistic insight. A radical-clock experiment gave the ring-opening product 2 in 23% yield, suggesting the presence of the benzylic radical intermediate (Fig. 3d). A light on-off experiment using indene as a substrate revealed that the reaction proceeded only under photoirradiation (Fig. 3e). Thus, we considered that continuous photoirradiation was necessary to sustain a catalytic cycle, and a radical-chain process was unlikely to occur.

A proposed reaction mechanism is depicted in Fig. 3f. Initially, Cu(bphen)(SAr)2 is formed in situ by ligand exchange. The copper(II) complex is photoexcited under purple LEDs irradiation. Then, a SET process takes place between the excited copper(II) complex and an alkene, leading to the formation of a copper(I) complex and a radical cation species. Nucleophilic addition of water to the radical cation and subsequent deprotonation furnish an alkyl radical intermediate, which was converted into the desired product by a hydrogen atom transfer from the thiol catalyst. The copper(I) complex is oxidized by the thiyl radical, regenerating the copper(II) complex. The resulting thiolate is immediately protonated back to the thiol.

Substrate scope

We next investigated the substrate scope of aromatic alkenes (Fig. 4). An electronically diverse array of para-substituted styrene derivatives reacted well to give the corresponding primary alcohols 3–7. However, electron-rich substrates, such as 4-methoxy and 4-siloxystyrenes, were not suitable for the reaction because undesired side reactions occurred instead of anti-Markovnikov hydration (see Fig. S20). 1,1-Diarylethylenes were also applicable to the hydration reaction (8–15). α-Substituted styrenes, including exocyclic alkenes, underwent the reaction to form the desired primary alcohols 16–22. β-Methylstyrenes provided the corresponding secondary alcohols 23–30 regardless of the geometry of the C–C double bond. On the other hand, β-arylstyrenes such as stilbene failed to participate in the reaction. Cyclic alkenes were also converted into the desired products 31 and 32. Interestingly, when 2,3-benzofuran was used as a substrate, 2-hydroxy-2,3-dihydrobenzofuran 33 was formed as a mixture with a hydrolyzed product 34. Trisubstituted alkenes, including β,β-dimethylstyrenes, were also converted into the secondary and tertiary alcohols 35–37.

Fig. 4. Substrate scope of aromatic alkenes.

Fig. 4

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Reactions performed on a 0.30 mmol scale in H2O (0.45 mL) and MeCN/acetone = 1:1 (4.5 mL). Isolated yields after chromatographic purification. The C–C bond derived from the alkene C = C bond is highlighted in blue. aThe reaction time was 7 h. bThe reaction time was 15 h. cCuCl2·2H2O (10 mol %) and bphen (10 mol %) were used. dThe reaction time was 30 h. eThe reaction time was 8 h. fCuCl2·2H2O (5.0 mol %) and bphen (5.0 mol %) were used.

Aliphatic alkenes and complex molecules were also subjected to the anti-Markovnikov hydration (Fig. 5). Aliphatic alkenes with diverse substitution patterns were transformed into the corresponding alcohols. gem-Disubstituted aliphatic alkenes gave the primary alcohols 38 and 39 in a regioselective manner, and vic-disubstituted aliphatic alkenes also reacted smoothly to give 40 and 41. Trisubstituted aliphatic alkenes afforded the desired alcohols 42–45 in good yields, albeit with diminished regioselectivity. The regioisomeric ratio appeared to depend on the substrate structure. Moreover, our system was applicable to the late-stage functionalization of natural products and pharmaceutical derivatives. (−)-β-Citronellol, osthole, dehydroepiandrosterone, and pregnenolone, possessing a trisubstituted aliphatic alkene moiety, were smoothly transformed into the corresponding anti-Markovnikov hydration products 46–49 in high yields. The hydration of (+)-nootkatone proceeded selectively at the gem-disubstituted aliphatic alkene moiety, with no reaction observed at the electron-deficient alkene moiety (50). Estrone and L-phenylalanine derivatives provided the corresponding alcohols 51 and 52, respectively. Pharmaceutical derivatives, such as loxoprofen [non-steroidal anti-inflammatory drug (NSAID)] and fenofibrate (lipid-regulating), were also converted into the desired alcohols 53 and 54.

Fig. 5. Substrate scope of aliphatic alkenes and complex molecules.

Fig. 5

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Reactions performed on a 0.30 mmol scale in H2O (0.45 mL) and MeCN/acetone = 1:1 (4.5 mL). Isolated yields after chromatographic purification. The C–C bond derived from the alkene C = C bond is highlighted in blue. rr = regioisomeric ratio. aThe reaction time was 72 h. b1H NMR yield using 1,1,2,2-tetrabromoethane as an internal standard. cCuCl2·2H2O (20 mol %) and bphen (20 mol %) were used. dThe reaction time was 15 h. eCuCl2·2H2O (2.5 mol %) and bphen (2.5 mol %) were used. The reaction time was 8 h.

Further applications

Beyond the hydration, our catalytic system was applicable to various photooxidative alkene transformations. Intramolecular cyclization reactions of aliphatic alkenes provided tetrahydrofuran and pyrrolidine derivatives 55 and 56, respectively (Fig. 6a)57,58. Furthermore, other nucleophiles were examined instead of water (Fig. 6b). When methanol and tert-amyl alcohol were used as nucleophiles, anti-Markovnikov hydroetherification proceeded to afford methyl and sterically hindered ethers 57 and 58, respectively59. anti-Markovnikov hydroazolation with 1H-pyrazole also occurred to provide the desired product 5960.

Fig. 6. Applications for other oxidative alkene functionalization.

Fig. 6

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Copper(II)-photocatalyzed anti-Markovnikov a Intramolecular cyclizations. b Hydrofunctionalizations with other nucleophiles. Isolated yields after chromatographic purification.

In summary, we have developed highly oxidative copper(II) photoredox catalysis for anti-Markovnikov hydration of alkenes. A wide range of alkenes participated in the reaction to give the corresponding alcohols under mild conditions. The catalyst system was demonstrated to be applicable to other oxidative functionalizations of alkenes. These findings indicate the potential of copper(II) photoredox catalysis in synthetic chemistry and provide a promising foundation for the development of 3d transition-metal-based photoredox catalysts, expanding the landscape of sustainable, high-redox-potential photocatalysts.

Methods

Typical procedure for anti-Markovnikov hydration of alkenes by copper(II) photoredox catalysis

CuCl2·2H2O and bathophenanthroline (bphen) were added to a 25 mL test tube equipped with a stirrer bar. Alkene (0.30 mmol, 1.0 equiv) and 3,4-dimethoxybenzenethiol (20 mol %) were added to a 4 mL vial. In the glove box, the mixture in the vial was transferred to the test tube using MeCN (2.25 mL) and acetone (2.25 mL). The test tube was taken outside the glove box, and H2O (0.45 mL; degassed with argon gas for 30 min) was added via syringe. The mixture was stirred vigorously under purple LEDs (390 nm, 23 W) irradiation with a fan. After the reaction was complete, the mixture was passed through a pad of Florisil® with AcOEt. The filtrate was concentrated under reduced pressure. The crude mixture was purified by preparative thin-layer chromatography or flash silica gel column chromatography to give the product.

Supplementary information

Supplementary Information (21.7MB, pdf)
Transparent Peer Review file (1.8MB, pdf)

Acknowledgements

The authors are deeply grateful to Emeritus Professor Masahiro Murakami (Kyoto University) and Professor Naoki Ishida (Kyoto University) for helpful discussion and encouragement during this work. The authors also thank Associate Professor Koichi Mitsudo (Okayama University) for his assistance with CV analysis and Ms. Karin Nishimura (Kyoto University) for her assistance with HRMS analysis. This work was supported in part by JSPS KAKENHI [22H05368, 24H01083, 22K19032, 25K01769 (T.M.), 22H05377, 24H01092 (H.I.), 24H01861, 24K17682 (K.Y.)], JSPS Program for Forming Japan’s Peak Research Universities [J-PEAKS: JPJS00420230010 (T.M.)], Mayekawa Houonkai Foundation [A3-24006 (Y.M.)], the Iwatani Naoji Foundation (T.M.), and Takahashi Industrial and Economic Research Foundation (T.M.). N.O. thanks the JST for the establishment of university fellowships towards the creation of science, technology, and innovation (JPMJFS2123).

Author contributions

N.O. and T.M. conceived and directed the project. K.Y. provided general advice. N.O., K.F., and R.M. conducted all the experimental work and analyzed the data. Photophysical analysis was conducted under the direction of Y.M. and H.I. The manuscript was written by N.O. and T.M., with contributions and proofreading from all authors.

Peer review

Peer review information

Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Data availability

The data supporting this article have been included as part of the Supplementary Information. General information, experimental procedure, product characterization data, and NMR spectra are available. All data are available from the corresponding authors upon request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2475193. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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

Naoki Oku, Email: noku@okayama-u.ac.jp.

Tomoya Miura, Email: tmiura@okayama-u.ac.jp.

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-026-69807-0.

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Supplementary Materials

Supplementary Information (21.7MB, pdf)
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Data Availability Statement

The data supporting this article have been included as part of the Supplementary Information. General information, experimental procedure, product characterization data, and NMR spectra are available. All data are available from the corresponding authors upon request. The X-ray crystallographic coordinates for structures reported in this study have been deposited at the Cambridge Crystallographic Data Centre (CCDC), under deposition numbers 2475193. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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