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

Domain: chemistry
Published: 2026-02-21
Editorial outcome: major_revision

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.

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.

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 effort 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 (E*red > +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
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.

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.

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.

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.

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.

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 glovebox, 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 glovebox, 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.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "Oku, Miura and coworkers describe a new Cu(II) catalyst that is a good photooxidant and promotes anti-Markovnikov alkene hydration reactions. The authors first prepared and characterized a bathophenanthroline-ligated Cu complex that showed promising photoproperties (such as long excited lifetime and strong oxidizing power). This complex could be used to promote styrene hydration under purple LED, and the authors subsequently showed that most likely the activate catalyst also has two thiolates binding to the Cu complex. A full hydration scope is shown using 1,1-diarylethylenes and alpha/beta-substituted styrenes. Several additional oxidative alkene transformations are also shown to illustrate the generality of this catalyst.\nI am supportive of publication in Nat. Commun. The manuscript is well written and concise, with a useful introduction describing the background of this catalyst design. This work is useful because it describes a rare example of a Cu(II) photocatalyst that is capable of oxidizing high oxidation potential substrates. The catalyst is easy to prepare, inexpensive and more modular than precious metal or organic-based photocatalysts. The use of this catalyst for anti-Markovnikov hydration is a good decision because this represents a highly useful/desirable catalytic alternative to traditional hydroboration/oxidation sequences. The performance of the catalyst is generally good, although it is not entirely clear how much better it is than existing catalysts for this same transformation. Thus, prior to publication, the authors should detail how this substrate scope/yields/rates compare to Lei’s report and any other photocatalytic hydration methods (only a brief statement on rate is included in the current version, whereas I believe scope comparisons should be made so that readers understand if this catalyst has expanded the range of alkenes that can be functionalized). As part of this revision, the authors should also acknowledge other photocatalytic anti-Markovnikov studies, especially that of Nicewicz which these methods are largely based off.", "reviewer_2": "In this manuscript, Oku and Miura report an anti-Markovnikov hydration of alkenes to alcohols using photooxidative copper(II) catalysis. The key catalyst is an in situ generated copper(II) complex bearing bathophenanthroline and 3,4-dimethoxybenzenethiolate ligands. Although its exact structure is only proposed and not definitively established, this complex is excited under visible light and exhibits sufficient oxidative power to convert styrene derivatives—and other alkenes—into the corresponding radical cations. These intermediates are subsequently intercepted by water to afford the corresponding alcohols in fair to good yields.\nMechanistic studies were undertaken to shed light on the nature of the photoactive copper species responsible for alkene oxidation. However, the precise identity of the active catalyst remains unresolved, as the proposed Cu(II)(phen)(SAr)₂ complex could not be isolated or fully characterized. The authors are encouraged to comment on whether alternative thiol ligands were investigated to: (1) evaluate their efficiency in promoting alkene photooxidation, and (2) assess whether they can yield a stable, isolable copper(II) complex amenable to full characterization.\nRegarding the scope, the reaction demonstrates reasonable breadth across styrene and diarylethylene substrates. The authors note that electron-rich alkenes are incompatible, likely due to the instability of the products under the reaction conditions. It would be helpful if the authors could discuss any side products formed in these cases to better clarify the limitations of the method.\nNotably, the methodology is extended to one aliphatic alkene example. While promising, the inclusion of additional examples would strengthen the case for generality in non-aromatic systems and enhance the overall impact of the work.\nFinally, the demonstration that nucleophiles other than water can be employed is a valuable extension, further highlighting the synthetic utility of the transformation.\nIn summary, this is a well-executed study that makes a meaningful contribution to the field of copper-based photoredox catalysis and broadens its application to oxidative transformations. With due consideration of the points raised above, the manuscript would be suitable for publication in Nature Communications.", "reviewer_3": "Oku, Miura and co-workers have reported an interesting photooxidative copper(II) catalysis for promoting anti-Markovnikov hydration of alkenes. Copper(II) photoredox catalysis has been widely used in the photo-induced organic transformations, but generally speaking, the copper(II) complex typically undergo ligand-to-metal charge transfer (LMCT), the SET process is indeed interesting. The scope of the reaction with respect to the Alkenes and is broad, however, the method seems to be mainly limited to styrenes. In addition, visible-light-mediated anti-Markovnikov hydration of olefins has been reported by Lei and Ritter. In summary, although this is an interesting study, I am unable to recommend publication of this manuscript in Nature communication due to a lack of novelty and a relatively limited scope.\nSome more minor points:\n1. The author mentioned an example of an aliphatic alkene in Fig 4. However, the redox potential of the catalyst and the alkene did not match. The author should provide a detailed explanation for this.\n2. EPR spectrum for the expected trapped radical should be presented.\n3. When studying the reduction potential of Cu(bphen)(SAr)2, why is the ratio of Cu(bphen)Cl2 to ArSH not 1:1? The excess thiol may affect the test results.", "reviewer_4": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts."}, "author_response": "Response: We wish to deeply thank you for the opportunity to address the points raised by the reviewers. To fully address their concerns and strengthen our manuscript, we carefully revisited all comments provided. In particular, we expanded the substrate scope, as you also pointed out. After a vigorous investigation, we found that the anti-Markovnikov hydration reaction proceeds with a wide range of substrates, including aliphatic alkenes, natural products, and pharmaceutical derivatives (Fig. I, please see the next page). We added these results to the revised manuscript.\nAromatic alkenes, such as exocyclic alkenes and β,β-dimethyl styrenes, underwent the anti-Markovnikov hydration reaction to provide the primary and tertiary alcohols, respectively. It should be noteworthy that aliphatic alkenes with diverse substitution patterns were also converted into the corresponding alcohols. gem- and vic-Disubstituted aliphatic alkenes reacted well with water to give the corresponding primary and secondary alcohols in a regioselective manner. Trisubstituted aliphatic alkenes afforded the desired alcohols in good yields, albeit with poor regioselectivity. The observed regioisomeric ratios were dependent 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 trisubstituted aliphatic alkene moieties were transformed into the corresponding alcohols in high yields. The hydration of (+)-nootkatone proceeded selectively at the gem-disubstituted aliphatic alkene moiety, while no reaction was observed at the electron-deficient alkene moiety. Loxoprofen (NSAID) and fenofibrate (lipid-regulating) derivatives also gave the anti-Markovnikov hydration products.\nIn summary, we reinvestigated the substrate scope and included additional twenty substrates including aliphatic alkenes and complex molecules. We believe that these results will address the concerns about the substrate scope raised by the editor and the reviewers. Please see the detailed revision below (Response to Reviewers #1~#3).\nReviewer #1\nComments: Oku, Miura and coworkers describe a new Cu(II) catalyst that is a good photooxidant and promotes anti-Markovnikov alkene hydration reactions. The authors first prepared and characterized a bathophenanthroline-ligated Cu complex that showed promising photoproperties (such as long excited lifetime and strong oxidizing power). This complex could be used to promote styrene hydration under purple LED, and the authors subsequently showed that most likely the activate catalyst also has two thiolates binding to the Cu complex. A full hydration scope is shown using 1,1-diarylethylenes and alpha/beta-substituted styrenes. Several additional oxidative alkene transformations are also shown to illustrate the generality of this catalyst.\nI am supportive of publication in Nat. Commun. The manuscript is well written and concise, with a useful introduction describing the background of this catalyst design. This work is useful because it describes a rare example of a Cu(II) photocatalyst that is capable of oxidizing high oxidation potential substrates. The catalyst is easy to prepare, inexpensive and more modular than precious metal or organic-based photocatalysts. The use of this catalyst for anti-Markovnikov hydration is a good decision because this represents a highly useful/desirable catalytic alternative to traditional hydroboration/oxidation sequences. The performance of the catalyst is generally good, although it is not entirely clear how much better it is than existing catalysts for this same transformation. Thus, prior to publication, the authors should detail how this substrate scope/yields/rates compare to Lei’s report and any other photocatalytic hydration methods (only a brief statement on rate is included in the current version, whereas I believe scope comparisons should be made so that readers understand if this catalyst has expanded the range of alkenes that can be functionalized). As part of this revision, the authors should also acknowledge other photocatalytic anti-Markovnikov studies, especially that of Nicewicz which these methods are largely based off.\nResponse: We wish to thank you for the positive comments and meaningful suggestions on our manuscript. As requested, the following revisions have been made.\n1. The performance of the catalyst is generally good, although it is not entirely clear how much better it is than existing catalysts for this same transformation. Thus, prior to publication, the authors should detail how this substrate scope/yields/rates compare to Lei’s report and any other photocatalytic hydration methods (only a brief statement on rate is included in the current version, whereas I believe scope comparisons should be made so that readers understand if this catalyst has expanded the range of alkenes that can be functionalized).\nResponse: We made comparative studies of product yields, redox potentials of photocatalysts, and accessibility to the photocatalysts for anti-Markovnikov hydration (Fig. II, please see next page). We added these comparisons in the Supplementary Information.\nFirst, we compared our catalytic system with that reported by Lei and co-workers (ACS Catal. 7, 1432–1437 (2017)). Stern-Volmer quenching experiments revealed that our catalytic system exhibits a higher redox potential than Lei’s system. Then, we reinvestigated substrate scope and found that a wide range of aliphatic alkenes are compatible with our reaction conditions. On the other hand, Lei and co-workers reported only two examples of the hydration of aliphatic alkenes. In the case of aromatic alkenes, the yields in our catalytic system are slightly lower than those in Lei’s system. We attribute this difference to our catalyst's high redox potential; however, this characteristic also underpins the broader substrate compatibility observed in our system and does not detract from the overall utility and value of the method. Regarding the reaction rates, Lei and co-workers stated that the protonation of thiolates was the rate-determining step. Thus, when comparing the acidity of various thiol catalysts, our system using a more electron-rich thiol catalyst exhibits a faster reaction rate. Furthermore, since the single-electron oxidation is considered to be the rate-determining step for substrates with high redox potentials, the reaction with such alkenes proceeds more rapidly in our catalytic system, as demonstrated in the revised Supplementary Information.\nRecently, Ritter et al. reported an anti-Markovnikov hydration of alkenes using N-protonated acridinium photocatalyst (J. Am. Chem. Soc. 147, 4736–4742 (2025)). Their catalytic system exhibits a higher redox potential than that of Lei’s system and is applicable to a wide range of aliphatic alkenes. While our substrate scope is comparable to that demonstrated in their report with reaction yields slightly higher in some cases, it is noteworthy that their reactions were conducted under acidic conditions (in the presence of 10 mol % of HBF ), and a multistep synthesis of the photocatalyst was required. In contrast, our reaction system operates under neutral conditions, and the photocatalyst exhibits a high degree of modularity. Therefore, enhanced functional group tolerance can be expected, and the catalyst screening for other photooxidative reactions can be performed in a simple and efficient manner.\nIn summary, our catalytic system enables the photooxidation of a wide range of aliphatic alkenes under the mild and neutral conditions by utilizing a readily accessible and modular photocatalyst that possesses high redox potential. Although the yields are modest in certain cases, these characteristics underscore the complementary nature of our approach and highlight its potential for broader application in other photooxidative transformations.\n2. As part of this revision, the authors should also acknowledge other photocatalytic anti-Markovnikov studies, especially that of Nicewicz which these methods are largely based off.\nResponse: We thank you for pointing out the important research background. We added the following sentence and references in the revised manuscript.\n“In confronting this challenge, photocatalytic anti-Markovnikov functionalization of alkenes, primarily developed by the Nicewicz group, presented an attractive strategy.41–43”\nRef. 41: Nicewicz, D. A., Hamilton, D. S. Organic Photoredox Catalysis as a General Strategy for Anti-Markovnikov Alkene Hydrofunctionalization. Synlett 25, 1191–1196 (2014).\nRef. 42: Romero, N. A., Nicewicz, D. A. Mechanistic Insight into the Photoredox Catalysis of Anti-Markovnikov Alkene Hydrofunctionalization Reactions. J. Am. Chem. Soc. 136, 17024–17035 (2014).\nRef. 43: Margrey, K. A., Nicewicz, D. A. A General Approach to Catalytic Alkene Anti-Markovnikov Hydrofunctionalization Reactions via Acridinium Photoredox Catalysis. Acc. Chem. Res. 49, 1997–2006 (2016).\nReviewer #2\nComments: In this manuscript, Oku and Miura report an anti-Markovnikov hydration of alkenes to alcohols using photooxidative copper(II) catalysis. The key catalyst is an in situ generated copper(II) complex bearing bathophenanthroline and 3,4-dimethoxybenzenethiolate ligands. Although its exact structure is only proposed and not definitively established, this complex is excited under visible light and exhibits sufficient oxidative power to convert styrene derivatives—and other alkenes—into the corresponding radical cations. These intermediates are subsequently intercepted by water to afford the corresponding alcohols in fair to good yields.\nMechanistic studies were undertaken to shed light on the nature of the photoactive copper species responsible for alkene oxidation. However, the precise identity of the active catalyst remains unresolved, as the proposed Cu(II)(phen)(SAr)₂ complex could not be isolated or fully characterized. The authors are encouraged to comment on whether alternative thiol ligands were investigated to: (1) evaluate their efficiency in promoting alkene photooxidation, and (2) assess whether they can yield a stable, isolable copper(II) complex amenable to full characterization.\nRegarding the scope, the reaction demonstrates reasonable breadth across styrene and diarylethylene substrates. The authors note that electron-rich alkenes are incompatible, likely due to the instability of the products under the reaction conditions. It would be helpful if the authors could discuss any side products formed in these cases to better clarify the limitations of the method.\nNotably, the methodology is extended to one aliphatic alkene example. While promising, the inclusion of additional examples would strengthen the case for generality in non-aromatic systems and enhance the overall impact of the work. Finally, the demonstration that nucleophiles other than water can be employed is a valuable extension, further highlighting the synthetic utility of the transformation.\nIn summary, this is a well-executed study that makes a meaningful contribution to the field of copper-based photoredox catalysis and broadens its application to oxidative transformations. With due consideration of the points raised above, the manuscript would be suitable for publication in Nature Communications.\nResponse: We wish to thank you for the positive comments and meaningful suggestions on our manuscript. As requested, the following revisions have been made.\n1. The authors are encouraged to comment on whether alternative thiol ligands were investigated to: (1) evaluate their efficiency in promoting alkene photooxidation,\nResponse: We conducted the screening of thiol/disulfide catalysts, and the selected results are described below (Fig. III). These results were added to the Supplementary Information. While the desired product was obtained with aromatic thiols and disulfides, only a trace amount of the product was detected in the case of aliphatic thiols.\nWe next carried out the quenching experiments with selected thiols (Fig. IV). These results were added to the Supplementary Information. The most efficient quenching of Cu(bphen)(SR) was observed with 3,4-dimethoxybenzenethiol. On the other hand, quenching of photoexcited copper(II) species did not occur in the presence of 4-trifluoromethylbenzenethiol or (4-chlorophenyl)methanethiol. Therefore, we considered that the oxidation ability of the photoactive species derived from 4-trifluorobenzenethiol is sufficient to oxidize styrenes but does not reach the redox potentials required for aliphatic alkenes. In addition, we found that the photoactive species from the alkyl thiol was unable to oxidize even styrenes. These results were consistent with their reactivities in anti-Markovnikov hydration.\n2. and (2) assess whether they can yield a stable, isolable copper(II) complex amenable to full characterization.\nResponse: We proposed the behavior of the copper species in the presence of the thiol (Fig. V). Ligand exchange between Cu(bphen)Cl and the thiol furnishes the photoactive copper(II) species. In the presence of a small amount of thiol, the ligand exchange proceeds slowly. On the other hand, although the use of an excess amount of thiol accelerates the generation of the photoactive copper(II) species, the resulting photoactive species is in equilibrium with inactive copper(I) species. The disulfide is formed through the redox process. These equilibria complicate the isolation of the photoactive species.\nWe expected that binaphthyl dithiol ligands would form a stable and isolable photoactive copper(II) complex by stabilizing the active species through strong bidentate coordination and suppressing the formation of the disulfide through steric hindrance. First, we confirmed that the hydration reaction of 4-t-Bu-styrene proceeded with binaphthyl dithiol (Fig. VI_A). The desired alcohol was obtained in 61% yield. Then, we tried to isolate the copper(II) thiolate complex. However, we failed to isolate the desired copper(II) complex, and the formation of binaphthyl disulfide was observed (Fig. VI_B).\nIt is important to emphasize that these results do not imply that only a trace amount of photoactive copper(II) species is present under the reaction conditions. A homolytic cleavage of the disulfide S–S bond occurs under visible light irradiation, and the resulting thiyl radicals oxidize copper(I) species (Fig. VII_A). This is expected to maintain a high concentration of photoreactive copper(II) species, allowing the reaction to proceed efficiently. The comparison of emission spectra before and after photoirradiation supported this proposal. Stronger emission of photoactive copper(II) species was observed after purple LEDs irradiation for 1 h (Fig. VII_B).\n3. The authors note that electron-rich alkenes are incompatible, likely due to the instability of the products under the reaction conditions. It would be helpful if the authors could discuss any side products formed in these cases to better clarify the limitations of the method.\nResponse: When 4-methoxystyrene was used as a substrate, the desired product was not detected (Fig. VIII_A). Instead, the dimerization products were obtained along with the thiol-ene product. This result indicated that electron-rich aromatic alkenes could act as better nucleophiles than water. Next, we investigated the stability of 2-arylethanols, which were the desired products from styrene derivatives by anti-Markovnikov hydration (Fig. VIII_B). Neither electron-rich nor electron-poor 2-arylethanols are decomposed under the reaction conditions. Based on these results, we concluded that the reason why electron-rich alkenes were unsuitable for photooxidative anti-Markovnikov hydration was not the instability of the products but the unexpected side reactions. Therefore, we corrected the manuscript and added the figure in the Supplementary Information.\nBefore: “However, electron-rich substrates, such as 4-methoxy and 4-siloxystyrenes, were not suitable for the reaction because the corresponding products were still reactive under the reaction conditions.”\nAfter: “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 the Supplementary Information).”\n4. While promising, the inclusion of additional examples would strengthen the case for generality in non-aromatic systems and enhance the overall impact of the work.\nResponse: We reinvestigated the substrate scope of aliphatic alkenes in this reaction. We have added fifteen aliphatic alkenes to the substrate scope, including natural products and pharmaceutical derivatives (see Fig. I). We believe that this result strongly supports the strength of our study. These results were added to the revised manuscript. We also updated the table of unsuccessful substrates in the Supplementary Information (Fig. IX).\nReviewer #3\nComments: Oku, Miura and co-workers have reported an interesting photooxidative copper(II) catalysis for promoting anti-Markovnikov hydration of alkenes. Copper(II) photoredox catalysis has been widely used in the photo-induced organic transformations, but generally speaking, the copper(II) complex typically undergo ligand-to-metal charge transfer (LMCT), the SET process is indeed interesting. The scope of the reaction with respect to the Alkenes and is broad, however, the method seems to be mainly limited to styrenes. In addition, visible-light-mediated anti-Markovnikov hydration of olefins has been reported by Lei and Ritter. In summary, although this is an interesting study, I am unable to recommend publication of this manuscript in Nature communication due to a lack of novelty and a relatively limited scope. Some more minor points:\n1. The author mentioned an example of an aliphatic alkene in Fig 4. However, the redox potential of the catalyst and the alkene did not match. The author should provide a detailed explanation for this.\n2. EPR spectrum for the expected trapped radical should be presented.\n3. When studying the reduction potential of Cu(bphen)(SAr)2, why is the ratio of Cu(bphen)Cl2 to ArSH not 1:1? The excess thiol may affect the test results.\nResponse: We wish to thank you for the valuable feedback on our manuscript. We have revised the manuscript based on the reviewers’ comments and would appreciate your reconsideration.\n1. The scope of the reaction with respect to the Alkenes and is broad, however, the method seems to be mainly limited to styrenes.\nResponse: We reinvestigated the substrate scope of aliphatic alkenes in this reaction. We added fifteen aliphatic alkenes to the substrate scope, including natural products and pharmaceutical derivatives (see Fig. I). We believe that this result strongly supports the strength of our study. These results were added to the revised manuscript. Furthermore, we also updated the table of unsuccessful substrates in the Supplementary Information (Fig. IX).\n2. In addition, visible-light-mediated anti-Markovnikov hydration of olefins has been reported by Lei and Ritter.\nResponse: We fully acknowledge the previous reports by the Lei and the Ritter groups, which represent important milestones in the development of anti-Markovnikov hydration reactions. However, the central and most fundamental aspect of our study is that the copper(II) species function as a genuine photoredox catalyst with sufficiently high oxidative power that enables single-electron oxidation of substrates including aliphatic alkenes.\nFirst, we would like to emphasize that intermolecular quenching of photoexcited copper(II) species has not been reported to date. As described in the manuscript, replacing conventional photoredox catalysts with inexpensive and earth-abundant metals is of great significance in synthetic chemistry, yet the use of first-row transition metals as photocatalysts remains highly challenging. In the case of copper(II) complexes, the previous studies have been limited to radical generation via ligand-to-metal charge transfer (LMCT) processes. In contrast, our work uncovers a fundamentally new photoredox reactivity of copper(II), thereby demonstrating the untapped potential of this inexpensive and sustainable metal and contributing to the development of environmentally benign synthetic methodologies.\nThe exceptionally high oxidative power of our catalytic system is another key feature of this study. Transition metal-based photocatalysts capable of oxidizing styrenes (E = +1.97 V vs SCE) are rare, and acridinium photocatalysts have been essentially the only class of catalysts widely employed for oxidizing styrenes. Remarkably, our copper-based system is capable of promoting single-electron oxidation not only of styrenes but also of aliphatic alkenes, highlighting its outstanding oxidative ability. When photocatalytic reactions are developed based on the oxidative character of the photocatalyst, our catalytic system provides an alternative to acridinium catalysts, which significantly contribute to the advancement of synthetic chemistry.\nTherefore, although the chemical transformation itself has precedent, our study combines novelty in catalyst design with interesting reactivity. We believe that the performance and conceptual novelty of the catalyst developed in this study will make a substantial contribution to organic synthetic chemistry and, importantly, provide new design principles for photocatalyst development based on first-row transition metals.\n3. In summary, although this is an interesting study, I am unable to recommend publication of this manuscript in Nature communication due to a lack of novelty and a relatively limited scope.\nResponse: We believe that Responses 1 and 2 mentioned above address your concerns regarding novelty and substrate scope. The single-electron oxidation of alkenes mediated by highly oxidizing copper(II) species represents an intriguing advance in the development of photocatalysis, and thus, we consider that our study possesses sufficient novelty. Moreover, upon reinvestigation of the substrate scope, we demonstrated that our reaction system can be applicable to a wide range of aliphatic alkenes, including natural products and pharmaceutical derivatives. We would be grateful if you could kindly reconsider whether our study is suitable for publication in Nature Communications.\n4. The author mentioned an example of an aliphatic alkene in Fig 4. However, the redox potential of the catalyst and the alkene did not match. The author should provide a detailed explanation for this.\nResponse: The exact redox potential of the catalyst could not be determined because the Cu(bphen)(SAr) complex could not be isolated. Therefore, we estimated its approximate redox potential using quenching experiments. We carried out the quenching experiment using the prenyl benzoate (+2.33 V vs SCE) as a quencher and confirmed the linear quenching depending on the concentration of the alkene (Fig. X). This result was added to the revised manuscript.\n5. EPR spectrum for the expected trapped radical should be presented.\nResponse: We deeply appreciate your constructive idea for the radical trapping experiment. We tried radical trapping experiments using TEMPO. However, the reaction was completely inhibited in the presence of only a catalytic amount of TEMPO, and no radical adducts were detected. This result suggested that the paramagnetic copper catalyst was quenched by TEMPO. EPR spectrum analysis is difficult for the same reason. In the reaction system, various spin-active species are generated under photoirradiation, but the EPR analysis is difficult in the presence of paramagnetic copper(II) species.\nInstead, transient absorption measurements were carried out (Fig. XI). Almost the same absorption spectra of triphenyl amine radical cation were observed in the presence of a strong acceptor 9,10-dicyanoanthcene (DCA) and our copper(II) complex. Therefore, single-electron oxidation reactions were confirmed in both cases. This result was added to the Supplementary Information.\n6. When studying the reduction potential of Cu(bphen)(SAr)2, why is the ratio of Cu(bphen)Cl2 to ArSH not 1:1? The excess thiol may affect the test results.\nResponse: We carried out the hydration reaction of styrenes using 2.5 mol % of the copper catalyst and 20 mol % of the thiol catalyst as the standard conditions. Therefore, we performed the photochemical analysis using a solution of Cu(bphen)Cl and 3,4-dimethoxybenzenethiol in a 1:8 ratio. However, as the reviewer pointed out, an excess amount of the thiol might be affecting the result. Then, we compared the emission efficiency of in situ generated photoactive copper(II) species in the presence of variable amounts of the thiol (Fig. XII). The intensity of the emission diminished with the decrease in the amount of the thiol. This is probably because the ligand exchange between Cu(bphen)Cl and the thiol is slow in the presence of a small amount of thiol. These results were added to the Supplementary Information."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have substantially revised their manuscript to address all of my initial comments. This work has now been carefully compared to existing photocatalytic methods for alkene hydration. The authors have also properly acknowledged the background of this methodology. The scope has been extensively enhanced and in particular now shows this method is applicable to alkyl-substituted alkenes, not just styrenes. I recommend acceptance. This method is inspired by Nicewicz (mostly intramolecular reactions) and Lei (intermolecular) hydration protocols; therefore, the reaction and its mechanism is not novel. However, anti-Markovnikov hydration is a very important transformation and this work describes a new and simple Cu catalyst as opposed to organic photocatalysts.", "reviewer_2": "The authors have done a tremendous amount of work to address the reviewers' comments.\nThe manuscript is now fully suitable for publication in Nature Communications.", "reviewer_3": "The author has made detailed revisions based on the reviewers' suggestions. I suggest accepting the paper in its current form.", "reviewer_4": "I co-reviewed this manuscript with one of the reviewers who provided the listed reports. This is part of the Nature Communications initiative to facilitate training in peer review and to provide appropriate recognition for Early Career Researchers who co-review manuscripts."}, "author_response": ""}]

Decision letter
Decision on Nature Communications manuscript NCOMMS-25-63084:
Thank you again for submitting your manuscript "Photooxidative Copper(II) Catalysis for Promoting anti-Markovnikov Hydration of Alkenes" to Nature Communications. We have now received reports from 4 reviewers and, after careful consideration, we have decided to invite a major revision of the manuscript.
As you will see from the reports copied below, the reviewers raise important concerns. We find that these concerns limit the strength of the study, and therefore we ask you to address them with additional work. Without substantial revisions, we will be unlikely to send the paper back to review. In particular, we require expansion of the substrate scope, per the comments of multiple referees.
If you feel that you are able to comprehensively address the reviewers’ concerns, please provide a point-by-point response to these comments along with your revision. Please show all changes in the manuscript text file with track changes or colour highlighting. If you are unable to address specific reviewer requests or find any points invalid, please explain why in the point-by-point response.