“On-water” photosensitization enables redox neutral acylation and alkylation of quinones

Domain: chemistry
Published: 2026-02-16
Editorial outcome: minor_revision

Abstract
Water-oil interfaces exhibit a high cohesive energy density and form a supra-molecular hydrogen-bonding network that supports organic reactions in various ways. Here, we introduce the redox-neutral photo-Friedel-Crafts acylation and alkylation of quinones at the aqueous-organic interface. Spectroscopic evidence and computational studies indicate extensive hydrogen bonding at the water surface, enabling the stabilization of the quinone’s photo-excited state and thus reducing its excited state energy, while increasing the excited state energy of the photosensitizer Eosin Y. This combined spectroscopic behavior allows photosensitization of quinone under visible light at the oil-water interface and facilitates the desired transformation. Mechanistic studies reveal that C‒C bond formation occurs via hydrogen atom transfer (HAT) from the aldehyde or alkyl reactant to the quinone, following an overall redox-neutral route, with concurrent radical recombination, efficiently producing 2-functionalized quinols. The versatility of the method is demonstrated with aromatic and aliphatic aldehydes, including natural and synthetic drug molecules, as well as ethers, thioethers, alkanes, silanes, and amines, which act as acylating or alkylating agents. The reactions have also been scaled up, and the acylated quinol products have been further functionalized to showcase their synthetic potential.

Introduction
Water is the most environmentally benign and biocompatible solvent, serving as the medium for biochemical reactions in living organisms1–3. The combined effect of hydrogen bonding, hydrophobic interactions, and high cohesive energy values (Fig. 1A. (i)) of water enhances the binding of substrates to enzymes, assists vesicle formation, and facilitates ligand or drug binding to receptors4–9. Therefore, in the field of organic synthesis, there is an increasing demand for the methods that use water as the reaction medium5,10–12. To demonstrate this, the preliminary research on Diels-Alder reactions by Breslow and later by Sharpless emphasized the unique reactivity at the water-organic interface13–15. The immiscible reactants stay agitated in the aqueous suspension, which enhances the reaction rate, a phenomenon known as the “on-water effect.” Further studies revealed that the reaction rates of classical [2+2] and [4+2] cycloaddition reactions could be significantly accelerated on the water surface (Fig. 1A. (ii))9,16,17. Additional research found that a heterogeneous micellar environment can increase the local concentrations of reactants, and the combined effect of hydrogen bonding (H-bonding) and trans-hydrogen bonding can increase the nucleophilicity and leaving ability of certain substrates (Fig. 1A. (iii)) to promote aromatic nucleophilic substitution reactions (S NAr)18–21.

In recent years, photoredox catalysis has become a promising tool in organic synthesis due to operational simplicity and precise reactivity10–12,18. Subsequently, the utilization of water as a solvent in photochemical reactions has received considerable interest among synthetic chemists13–15. In this realm, our group’s recent contribution, demonstrated that the oil-water interface facilitates the formation of an enforced electron donor-acceptor (EDA) complex in the ground state between an electron-rich and an electron-poor molecule through melting point depression16,17. Further photoexcitation of such an EDA complex afforded various cross-coupling reactions with accelerated reaction kinetics (Fig. 1A. (iv)). Nevertheless, photocatalytic reactions involving excited-state stabilization via supramolecular H-bonding on the water surface are still underexplored19–21. Fundamental studies on solvent polarization effect reveal that the photo-excited state of polar organic substances can be stabilized through H-bonding and dipole interaction, which may generate the corresponding relaxed excited state (Fig. 1A. (v))4–8,22,23. Therefore, sensitized photoexcitation of an organic fluorophore can be performed under visible light, facilitated by stabilization of its excited state and subsequent minimization of its singlet and triplet energies at the aqueous-organic interface23–26. We realized that substrates like quinones (or substrates with conjugated carbonyl groups) can participate in the dipole interaction with water to produce a stabilized excited state27–30, and this phenomenon could be further applied in hydrogen atom transfer (HAT) to form C‒C bonds31–33. We wanted to examine our hypothesis by exploring redox-neutral photo-Friedel-Crafts acylation and alkylation reactions of quinones. The quinone core represents a common structural motif of a wider range of bioactive natural products (Fig. 1B). 2-Acylated-1,4-naphthohydroquinones, such as Elutherin, Isoetherin, Saintophin, or Frenolicin, have shown cytotoxicity against cancer cells34–37. Among various synthetic strategies, the classical Friedel-Crafts acylation of quinols is a reliable method for accessing functionalized quinone scaffolds. However, it requires oxygen-labile substrates, acyl chlorides, and stoichiometric amounts of Lewis acids. The high reactivity of the starting materials and reagents, poor regioselectivity, and the formation of unwanted side products restrict the practical application38–40. To avoid these shortcomings, quinones have been utilized in photo-Friedel-Crafts acylation reactions, where aldehydes are directly used as the acylating agent to produce 2-acyl quinols41–46. It is worth mentioning that quinones absorb in the UV region and, after excitation, can engage in single electron transfer (SET), hydrogen atom transfer (HAT), or energy transfer (EnT) with suitable substrates29,30,47. However, the mentioned photo-Friedel-Crafts reactions were performed using high-power ultraviolet (UV) light sources or direct sunlight, often requiring prolonged reaction times and complex impractical reaction equipment. In addition, the desired quinol products have a higher UV extinction coefficient than the starting quinones, they experience decomposition upon irradiation and offer inferior yields48.

To address these shortcomings, in this report, we propose a sensitized photo-acylation and alkylation of quinones that uses visible light to initiate the reaction at the aqueous-organic interface. We observed that water’s hydrogen-bonding ability at the interface causes a significant bathochromic shift in the absorption and emission spectra of quinone. Additionally, the absorption and emission spectra of Eosin Y, the dye we employed as a sensitizer, shifted hypsochromically “on water”, providing a good match for photosensitization. The presented strategy resolves the recurring limitations stated in earlier reports and is generalized by demonstrating photo-Friedel-Crafts acylation and alkylation reactions with more than a hundred synthetic examples by applying an array of aromatic and aliphatic aldehydes, including several naturally occurring and drug candidates, ethers, thioethers, alkanes, silanes, and amines as the acylating or alkylating partner against quinone derivatives and maleimide.

Results
Spectroscopic investigations
We initiated our investigation by examining the solvatochromic behavior of 1,4-naphthoquinone (A-1) in various dipolar aprotic solvents, including acetonitrile (MeCN), dimethylacetamide (DMA), dimethylsulfoxide (DMSO), tetrahydrofuran (THF), and acetone. The absorption maxima of A-1 were observed between 320 to 332 nm in the neat solvents (Fig. 2a). Upon addition of excess polar protic solvents, such as water or methanol (MeOH), the absorption spectra shifted to longer wavelengths with a notable example where the λmax of A-1 shifted from 330 nm to 355 nm in a water–acetone mixture (9:1). This finding was consistent for other water-organic solvent mixtures (9:1) as well. Furthermore, the emission maximum of A-1 was also shifted from 399 nm to 428 nm when the solvent system was altered from neat acetone to a 9:1 water-acetone mixture. The bathochromic shifts can be attributed to dipolar interactions between the fluorophore (A-1) and solvent molecules and are explained by the Franck-Condon principle49–51. In polar protic solvents, the absorption transition energy decreases due to the electronic interaction field induced by the excited-state dipole, resulting in a more stabilized, relaxed photo-excited state4,52–55. Normalized absorption-emission plots of A-1 reveal a bathochromic shift of the intersection from 357 nm in neat acetone to 386 nm in a water-acetone mixture (9:1), indicating a reduction in the excited-state energy of A-1 in the aqueous environment (Fig. 2b)56. Similar bathochromic shifts were observed for other quinone derivatives and maleimide (see SI Fig. S3). Furthermore, to elucidate the influence of H-bonding on the water surface for A-1, additional 1H and 13C NMR experiments were conducted in different solvent mixtures. It was observed that in the 1H NMR spectra, the alkene protons next to the carbonyl groups (Ha) exhibited a downfield shift from 7.05 ppm in neat acetone-d6 to 6.96 ppm in a 6:1 D2O/acetone-d6 solvent mixture (Fig. 2e, f). Moreover, Ha shifted to approximately 7.00 ppm when the solvent system was altered to either 5:2 H2O/acetone-d6 or 5:2 MeOH/acetone-d6. A similar trend of downfield shift was observed in the case of Hb as well, and it exhibited the δ values of 8.05 ppm, 7.90 ppm, 7.95 ppm and 8.02 ppm, respectively, in the solvent mixtures mentioned above (Fig. 2e). On the other hand, in the 13C NMR spectra, the carbonyl group of A-1 shifted from 185.7 ppm in neat acetone-d6 to 178.8, 181.2, and 183.9 ppm in 6:1 D2O/acetone-d6, 5:2 H2O/acetone-d6, and 5:2 MeOH/acetone-d6, respectively (Fig. 2f). These downfield shifts of the olefinic and aromatic protons (ortho to the carbonyl group of A-1) and carbonyl carbons are consistent with hydrogen-bonding interactions involving the naphthoquinone moiety, which further supports our working hypothesis17. To achieve visible-light sensitization of quinone A-1 in the aqueous reaction medium, we selected Eosin Y (EY) as a photosensitizer due to its large excitation window and water solubility. A hypsochromic shift in the absorption maxima and a significant increase in the extinction coefficient were observed in water-acetone (9:1) compared to the neat organic solvent. The increase in the extinction coefficient is explained in the literature by a possible aggregation of Eosin Y in the aqueous environment, while the negative solvatochromism implies destabilization in the excited state compared to the ground state, likely due to local (e.g., hydrogen bonding) and global polarity effects. The fluorescence emission band of EY exhibited a blue shift when the solvent was changed from pure acetone to a water-acetone (9:1) mixture57,58. Accordingly, a normalized absorption-emission plot for Eosin Y shows a noticeable hypsochromic shift of the intersection point from 548 nm in neat acetone to 538 nm in a water-acetone mixture (9:1), which suggests an increase in the excited-state energy of Eosin Y in the aqueous environment (Fig. 2c). In addition to that, the experimentally observed bathochromic shift of absorption and emission of A-1 in the presence of water was further confirmed by our computational studies, which suggest the stabilization of the photo-excited states (both the singlet and triplet) for A-1 under an aqueous environment (see SI Fig. S7 to S9 for detailed calculations). However, the effect of water on the electronic structure of Eosin Y is more complex, as it may affect tautomeric equilibria and their individual electronics, which go beyond the scope and the prime interest of this work59–62. The complementary bathochromic absorption shift of quinones and hypsochromic shift of the sensitizer Eosin Y at the aqueous-organic interface make them a perfect match to facilitate the sensitized HAT process under visible light. A luminescence quenching study of Eosin Y by A-1 was conducted in dry acetone and a water-acetone mixture (9:1). Stern-Volmer analysis (Fig. 2d) revealed pronounced quenching of the photosensitizer by A-1 in a water-acetone (9:1) solvent mixture.

Reaction development and optimization studies
To apply this interesting spectroscopic outcome, we explored the Friedel-Crafts (F-C) acylation by treating A-1 and B-1 in the presence of Eosin Y (EY) as the photosensitizer, using a water-acetone solvent mixture (9:1) under green LED (0.7 W, 525 nm) at 25 °C. To our delight, after 24 hours of irradiation under an inert atmosphere, C-1 was obtained in 80% isolated yield (Table 1, entry 1) [Please see the detailed optimization study in SI Tables 1 to 4]. The reaction ceased in the absence of light, even at elevated temperature (entry 2). The yield dropped when the reaction was performed under air (entry 3, 45%) or without Eosin Y (entry 4, 8%). The formation of C-1 decreased to 23% (entry 6) when the reaction was carried out in dry acetone, without changing any other parameters. Extending the reaction time to 18 h or 36 h had little effect on the reaction outcome (entry 7). Irradiation of the reaction mixture under 455 nm (0.7 W) improved the isolated yield of C-1 to 92%.

Evaluation of the scope for Friedel-Crafts acylation
After establishing the optimized reaction conditions, we explored the scope of the acylation reaction (Fig. 3). Mono-substituted aromatic aldehydes bearing electron neutral phenyl or alkyl groups (C-1 to C-4), electron rich -OMe, -SMe, -OiPr, -OCF3 groups (C-5 to C-8, C-17, and C-22), all types of halogens (C-9 to C-11 and C-18 to C-21) and electron withdrawing -CF3, -CN, -COOR (R=Me, Et, p-Tol) groups (C-12 to C-15 and C-23) at the para-, meta-, and ortho-positions were converted to the corresponding 2-acyl quinols in good to excellent yields (50% to 95%). However, a trace amount of expected product was formed in the case of C-23, which is probably due to a different steric and electronic factor that operates for 2-substituted aryl aldehydes bearing an electron-withdrawing group. Notably, aromatic rings containing a protected amine (-NHAc) and a free hydroxyl group were retained during the transformation and gave C-16 and C-24 in 76% and 54% yield, respectively. Di- and tri-substituted aromatic aldehydes also afforded the desired conversion to C-25 to C-32 in 58% to 73% isolated yields. The nitro group was also tolerated, and C-26 was obtained in 58% yield. The standard reaction conditions were applied to polyaromatic and heteroaromatic aldehydes (including NH-pyrrole), and the corresponding hydroacylated quinols (C-33 to C-40) were obtained in moderate to good yields (63% to 90%). Pleasingly, the reaction outcome was also uniform across a range of structurally diverse aliphatic aldehydes, including strained cyclopropane (C-49) and cyclobutene (C-50) scaffolds, and the transformations occurred smoothly to produce C-41 to C-53 in excellent yields of up to 97%. We further extended the scope of hydroacylation reactions of 1,4-naphthoquinone (A-1) and p-benzoquinone (A-2) by exploiting an array of naturally occurring aliphatic and aromatic aldehydes, which are important in the food and cosmetic industries (Fig. 4). In this regard, natural fragrance materials, such as cinnamaldehyde (C-54), cocoapentanal (C-55), lilac aldehyde (C-56), cocoahexanal (C-57), cyclamen aldehyde (C-58), perillaldehyde (C-59), safranal (C-60), myrtenal (C-61), vanillin (C-62), methoxymelonal (C-63), cuminaldehyde (C-64), eudesmicaldehyde (C-65), piperonal (C-66), acrylaldehyde (C-67), β-citronellal (C-68), melonal (C-69), jasminaldehyde (C-70), β-homocyclocitral (C-71) were converted to the desired products in commendable yields (57% to 94%).

Late-stage modifications
Next, we applied our Friedel-Crafts acylation strategy to a range of pharmaceutically relevant bioactive compounds (Fig. 5). Drugs containing the synthetic handle, such as a carboxylic acid or a hydroxyl group, were first attached to compatible benzaldehyde derivatives via traditional esterification reactions. The resultant aryl aldehydes were then subjected to optimized reaction conditions using A-1. Synthetically modified drug candidates and natural products such as ibuprofen (C-72), gemfibrozil (C-73), flurbiprofen (C-74), loxoprofen (C-75), naproxen (C-76), ketoprofen (C-77), febuxostat (C-78), fenofibric acid (C-79), oxaprozin (C-80), fenbufen (C-81), niacin (C-82), ciprofibrate (C-83), indomethacin (C-84), isoborneol (C-85), propofol (C-86), thymol (C-87), menthol (C-88), triclosan (C-89), myrtenol (C-90), and zingerone (C-91) were converted in 38% to 90% yield to the corresponding hydroacylated products.

Scope of quinone and other conjugated carbonyl moieties
We then examined the applicability of the method to various quinone scaffolds (Fig. 6). The hydroacylation reaction was successfully carried out when para-benzoquinone (A-2) was reacted with electronically distinct aromatic and aliphatic aldehydes, delivering C-92 to C-98 in decent yields (65% to 80%). Notably, an inseparable regio-isomeric mixture (C-99 and C-99’) was found in 76% of isolated yield in case of 2-methyl benzoquinone (A-3). Surprisingly, 2-acyl quinones (C-100, 67% and C-101, 65%) were obtained as the sole products when 2-chloro (A-4) and 2-bromonaphthoquinone (A-5) were reacted under standard conditions with benzaldehyde and 4-chlorobenzaldehyde. Naturally occurring quinones like menadione (A-6) and juglone (A-7) also reacted in the hydroacylation with both aromatic and aliphatic aldehydes to accomplish C-102 to C-104 in 25% to 66% yields. Polyaromatic quinone derivatives like anthracene-1,4-dione (A-8) and chrysene-1,4-dione (A-9) displayed a similar reactivity pattern to offer C-105 and C-106, respectively, in 22% and 73% isolated yields. Apart from quinones, we were interested in investigating other acceptors, such as N-arylmaleimide (A-10), which gave C-107 in 61% isolated yield. However, coumarin did not participate in the acylation reaction under the standard reaction conditions (remained unreacted), and neither of the anticipated products (C-108 or C-108’) was detected by GC-MS (Gas Chromatography-Mass Spectrometry).

Evaluation of the scope for Friedel-Crafts alkylation
Next, we attempted photo-Friedel-Crafts alkylation reactions of quinones, which was elusive in earlier attempts (Fig. 7). We reacted A-1 with a library of coupling partners that possess comparatively reactive C‒H bonds (BDE ~84 to 96 kcal/mol) and tend to undergo C‒H HAT to generate a carbon-centered radical. Satisfyingly, under the developed conditions, different ethers and thioethers participated in the hydroalkylation reaction yielding the desired products for tetrahydrofuran (C-109), phthalan (C-110), tetrahydropyran (C-111), isochroman (C-112), 1,4-dioxane (C-113), 1,3,5-trioxane (C-114), benzo[d][1,3]dioxole (C-115), protected benzyl alcohol (C-116), isopropoxybenzene (C-117), tetrahydrothiophene (C-118), and isopropyl(phenyl)sulfane (C-119) in 50% to 80% of isolated yields. Aryl and alkyl silanes show C‒Si bond forming63 reactions with A-1 to furnish C-120 to C-122 decent yields. The scope for Friedel-Crafts alkylation was further extended using partially saturated carbocycles, which include anthrone, fluorene, indan-1-one, celestolide (fragrance material), and phenylcyclopropane, which were transformed to the corresponding 2-alkyl quinols (C-124 to C-128) in moderate to good yields (56% to 85%). Additionally, acyclic aromatic hydrocarbon moieties such as diphenylmethane, cumylbenzene, sec-butylbenzene also delivered the expected products C-129 to C-133 in 53% to 92% isolated yield. However, the alkylation reaction was not successful for toluene derivative (C-123), as it was oxidized to the corresponding aldehyde and acylation occurred. Furthermore, the photosensitized HAT process transformed cyclic amines into C-134 and C-135 via the formation of α-amino radical intermediates (which may arise from photo-oxidation and proton elimination), affording yields of 66% and 54%, respectively. However, inferior productivity was observed for N-phenyl tetrahydropyrrole, and only a trace amount of C-136 was detected by GC-MS. This is probably due to the photochemical oxidation of the electron-rich amine center of N-phenyl tetrahydropyrrole, where SET is more likely facilitating than HAT to generate an iminium cation under the standard reaction conditions. The corresponding iminium cation underwent a nucleophilic water attack and a successive oxidation to release N-phenylpyrrolidone (detected by GC-MS)64–66.

Synthetic utilities
We performed several syntheses on a larger scale (Fig. 8A) under standard reaction conditions (7 mmol, 1.1 g). Pleasingly, the photocatalyzed hydroacylation on a gram scale yielded products C-1, C-41, and C-137 in 77%, 60%, and 72% isolated yields, respectively. Some of the products were further derivatized to illustrate applications.
Accordingly, C-1 was subjected to oxidation of the quinols structural motif using Ag2O to afford 2-benzoylquinone (D-1), exclusively (Fig. 8B(i))67. In contrast, reduction of C-1 using NaBH4 offered D-2 in 90% yield (Fig. 8B(ii))68. Next, compound C-1 was reacted with phenylacetyl chloride under basic conditions to give a substituted angular benzocoumarin scaffold (D-3) in 68% yield (Fig. 8B(iii))68. Interestingly, fluorinated product, C-137, underwent an intramolecular aromatic nucleophilic substitution reaction (S NAr) after treatment under basic conditions to yield a substituted angular xanthone derivative (D-4) in 84% yield (Fig. 8B(iv))68. Lastly, we successfully constructed the key intermediate (D-5b) for the natural product Balsaminone A by reacting C-41 sequentially with 2,3-dichloro-1,4-naphthoquinone followed by benzyl bromide (Fig. 8B(v))69.

Mechanistic studies and proposed reaction mechanism
To elucidate the reaction mechanism, we performed several control experiments (Fig. 9). Eosin Y photosensitization was confirmed by inhibiting the model reaction (Fig. 9A) in the presence of well-known triplet quenchers, such as trans-stilbene (ET = 49.3 kcal/mol) or azobenzene (ET = 35.4 kcal/mol)70,71. Under certain reaction conditions, Eosin Y may also act as a HAT agent72. To exclude this reaction pathway, the standard reaction was performed with other photosensitizers, such as [Ir] or [Ru] photocatalysts, which are known to exhibit sufficiently high triplet energies, yielding comparable yields of product C-1 (Fig. 9B)70,71. Next, we performed standard reactions in the presence of radical scavengers, such as TEMPO and 1,1-diphenyl ethylene, which significantly reduced the product yield. Intermediates, such as E-1 and E-2, were detected by HRMS. These experiments suggest the presence of an acyl radical intermediate in the photo-Friedel-Crafts acylation process (Fig. 9C). To determine the rate-determining step of the overall transformation, two parallel reactions were run under standard reaction conditions using normal benzaldehyde (B-1) and benzaldehyde-d6 (B-1’). After 12 hours, the crude reaction mixture was analyzed by 1H NMR using CH2Br2 as the internal standard. 63% of C-1 was formed, whereas C-1’ was produced only in 24% at 12 hours of reaction time, and a KIE of 2.63 was calculated (Fig. 9D). This experiment indicates that hydrogen atom abstraction from the C‒H bond of the coupling partner may be the rate-determining step of the overall reaction (See SI Fig. 2 for kinetic plots).
Finally, based on the spectroscopic findings and control experiments, we have proposed a plausible reaction mechanism for the Friedel-Crafts reaction of quinones (Fig. 9E). Upon photosensitization in the presence of Eosin Y, water H-bonded quinone is converted to its triplet state and abstracts a H-atom from the corresponding acyl or alkyl coupling partner (B) to produce the radical intermediate 2A and carbon-centered radical 1B. The hydroquinone radical, via its resonance structure 3A, combines with the acyl or alkyl radical 1B to give 4A. Lastly, a keto-enol tautomerism facilitates the aromatization to yield the hydro-functionalized quinols C.
In summary, we employed the concept of excited-state stabilization of a chromophore via H-bonding and dipole interaction “on-water” for the redox-neutral Friedel-Crafts acylation and alkylation of quinones. Comprehensive spectroscopic studies provided evidence of H-bonding at the aqueous-organic interface, which enables a simultaneous bathochromic shift for quinones (by excited-state stabilization) and a hypsochromic shift of the photosensitizer, Eosin Y, making them an appropriate pair for visible-light photosensitization. The practical viability of the photo-Friedel-Crafts reactions was demonstrated with aromatic and aliphatic aldehydes, ethers, thioethers, alkanes, silanes, and amines, including some naturally occurring substances and diversifications of biomolecules, as well as reactions on a gram scale. The proposed mechanism is experimentally supported by spectroscopic observations, computational studies, and control experiments. The aqueous-organic interface offers advantages for photo-Friedel-Crafts reactions that can be performed under visible light, thereby overcoming the practical limitations of product stability and versatility, as previously reported.

Methods
“On-water” Eosin Y catalyzed redox-neutral Friedel-Crafts acylation of quinones
A 5mL crimp top vial was charged with 1,4-quinone derivative (A, 0.30 mmol, 1.0 equiv), aromatic or aliphatic aldehyde (B, 0.45 mmol, 1.5 equiv), and Eosin Y (6 mg, 0.009 mmol, 0.03 equiv). Then the vial was crimped. The vial was degassed and refilled with nitrogen using the Schlenk line technique (3 times). A pre-degassed (15 min) mixture of water/acetone (9:1, 3 mL) was added to the reaction vial and stirred at room temperature for 24 h under the irradiation of a single blue LED (λmax = 455 ± 15 nm). Upon completion, the reaction mixture was diluted with EtOAc (20 mL), washed with saturated Na2CO3 solution (15 mL, twice), followed by brine (15 mL, once), and extracted with EtOAc. The combined organic layer was dried over Na2SO4, concentrated under vacuum, and the residue was purified by silica gel (100–200 mesh) column chromatography using a mixture of PE/EtOAc as the eluent, yielding pure products.

“On-water” Eosin Y catalyzed redox-neutral Friedel-Crafts alkylation of quinones
A 5mL crimp top vial was charged with 1,4-quinone derivative (A, 0.30 mmol, 1.0 equiv), alkyl coupling partner (B-98 to B-123), 0.9 mmol, 3.0 equiv), and Eosin Y (6 mg, 0.009 mmol, 0.03 equiv). Then the vial was crimped. The vial was degassed and refilled with nitrogen using the Schlenk line technique (3 times). A pre-degassed (15 min) mixture of water/acetone (9:1, 3 mL) was added to the reaction vial and stirred at room temperature for 24 h under the irradiation of a single blue LED (λmax = 455 ± 15 nm). Upon completion, the reaction mixture was diluted with EtOAc (20 mL), washed with saturated Na2CO3 solution (15 mL, twice), followed by brine (15 mL, once), and extracted with EtOAc. The combined organic layer was dried over Na2SO4, concentrated under vacuum, and the residue was purified by silica gel (100-200 mesh) column chromatography using a mixture of PE/EtOAc as the eluent, yielding pure products.

Full experimental procedures are provided in the supplemental information.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "König et al. disclose a redox-neutral photo-Friedel–Craft acylation/alkylation of quinones that proceeds at the aqueous–\norganic interface through H-bonding and dipole interactions. The protocol tolerates a broad substrate scope and has been\nvalidated on gram scale; downstream derivatizations underscore its synthetic utility. Spectroscopic studies were provided to\nrationalize the enhancement of reactivity, yet the mechanistic rationale remains incomplete.\nOverall, I support the publication of this work in after minor revisions.\n1. Apart from spectral analysis, more evidences are suggested to be provided to support the proposed H-bonding and dipole\ninteraction, such as NMR.\n2. For the coumarin acylation, the product depicted is the α-acylated isomer (C108). Please clarify why the β-acylated\nregioisomer—expected on the basis of the mechanistic argument—is not observed.\n3. N-Phenyltetrahydropyrrole affords only trace amounts of C-136. Discuss whether this outcome arises from steric shielding,\ndiminished H-bonding ability, or competing side reactions.\n4. Diaryl ketones are common triplet photosensitizers. When aryl aldehydes are used, the corresponding ketone products\ncould conceivably act as internal sensitizers. Report Stern–Volmer quenching data, triplet-energy calculations, or sensitizer-\nfree control reactions to exclude product-sensitized pathways.", "reviewer_2": "The submitted manuscript by Konig and co-workers presents another application of on-water photochemistry in organic\nsynthesis and follows up the original paper from the group in Science. The authors present the concept of influencing\nexcited states by the water environment based on hydrogen bonds. This effect is manifested both on the substrate\n(benzoquinone and other quinones) and on the catalyst (EOSIN Y), and allows the activation of the substrate by energy\ntransfer. Subsequently, acylation/alkylation of the substrate can occur, which is based on the abstraction of hydrogen from\nthe aldehyde or precursor of stable radicals. The authors document the effect of water on the absorption/fluorescence\nproperties. Subsequently, they use an optimized methodology to prepare a series of acylated/alkylated quinones with\nvarious aldehydes or alkylating agents. Small-scale experiments are supplemented by experiments on a gram scale. The\nreactions tolerate various substrates and functional groups, with the exception of alkylating agents producing unstable\nradicals. Overall, I conclude that the work is clearly and comprehensibly written, most (see below for other comments)\nconclusions are clearly supported by measured data. Since this is a new and rapidly developing topic and the article, even\nin its current state, provides a guarantee (after minor edits) of an important message of interest to a wide range of readers, I\nrecommend accepting the article for publication in Nature Communication after minor revision.\nOther comments:\n1/ Authors claim (see abstract) that water surface reduces triplet state energy of quinone substrate and increases triplet state\nenergy of Eosin Y. On my own, it can be hardly concluded from data reported. Authors measured effect of water on\nabsorption and fluorescence emission spectra but it can show only effect on singlet excited state. Of course, also triplet state\nenergy might be changed but there is no direct evidence.\n2/ Regarding substrate scope of alkylation (Table 6), ethylbenzene derivative is missing. Only toluene and then trisubstituted\nderivatives were proven. It would be interesting to see whether switch to secondary derivative giving secondary radical is\nenough to provide the reaction.\n3/ Blue point is missing in legend in Figure 2D. Note, description A…D is not shown.\n4/ Only traces of product are given in Table 2 for C23. But it is not commented accordingly in the text.\n5/ Naphthaquinone should be naphthoquinone on page 7 down.\n6/ Figure 3a is missing in the main text.\n7/ I suggest catalytic role of EY should be better shown in Figure 3. By excitation and ISC, triplet excited state is formed\nwhich likely provides EnT.", "reviewer_3": "This manuscript describes a photo-induced, redox-neutral Friedel-Craft acylation and alkylation of quinones under water-oil\ninterfaces in the presence of Eosin Y as photosensitizer. The method operates under transition-metal-free conditions, shows\nhigh substrate adaptability, and gives access to functionalized quinone products of potential synthetic value. The reaction\ndesign is conceptually appealing, and the operational simplicity makes it attractive. I recommend acceptance of this work for\npublication, upon addressing the following minor issues:\n1. In Table 2, the reason for lower yields for substrates like C-23, C-53 was not discussed. Did the author observe\nbyproducts?\n2. The authors should note that C-134 and C-135/C-136 are not the same class of compounds. I support the statement that\nC-134 can generate an α-amino radical via light-mediated HAT. However, applying the same description to C-135 and C-\n136 — that they also generate an α-amino radical via light-mediated HAT — may not be appropriate. For C-135 and C-136,\na single-electron transfer (SET) pathway is likely more favorable than HAT.\nIn addition, for C-136, no obvious product was observed. What might be the possible reasons for this outcome? Is it\nnecessary to further examine the reactivity of the N-phenylpiperidine substrate? For this type of substrate, the authors may\nneed to discuss the mechanism of α-amino radical generation separately.\n3. The scope of the reaction may be further illuminated by two key references (Angew. Chem. Int. Ed. 2016, 55, 4040; Chem.\nSci. 2016, 7, 7002).\n4. Please verify that all citations and labels in Scheme 1 correspond accurately to their sources in the text and reference list."}, "author_response": "Our manuscript was reviewed by three expert referees, and we are pleased to receive their positive\ncomments. Based on their feedback, we have revised the manuscript to address the reviewers' concerns.\nWe conducted a new set of experiments and accordingly modified the SI. We found the reviewers’\ncomments very helpful, and they assisted us in improving our manuscript. A point-by-point response to\nthe reviewers’ comments is enclosed. Additionally, we have uploaded a separate revised manuscript\nfile with the major changes highlighted in yellow to track the modifications from the original version.\nPoint by point reply:\nReviewer #1 (Remarks to the Author):\nKönig et al. disclose a redox-neutral photo-Friedel–Craft acylation/alkylation of quinones that proceeds\nat the aqueous–organic interface through H-bonding and dipole interactions. The protocol tolerates a\nbroad substrate scope and has been validated on gram scale; downstream derivatizations underscore its\nsynthetic utility. Spectroscopic studies were provided to rationalize the enhancement of reactivity, yet\nthe mechanistic rationale remains incomplete.\nOverall, I support the publication of this work in after minor revisions.\nComment:\n1. Apart from spectral analysis, more evidences are suggested to be provided to support the proposed\nH-bonding and dipole interaction, such as NMR.\nOur response: We thank the reviewer for this suggestion. We performed 1H and 13C NMR studies using\n1,4-naphthoquinone (A-1) individually in neat acetone-d , 6:1 mixture of D O/ acetone-d , 5:2 mixture\n6 2 6\nof H O/ acetone-d and 5:2 mixture of MeOH/ acetone-d , respectively, to support the H-bonding\n2 6 6\ninteraction of quinone in water/acetone mixture. The following observation is now added to the revised\nmanuscript (Figure 2e and 2f).\n“Furthermore, to elucidate the influence of H-bonding on water surface for A-1, additional 1H and 13C\nNMR experiments were conducted in different solvent mixture. It was observed that in the 1H NMR\nspectra, the alkene protons next to the carbonyl groups (H ) exhibited a downfield shift from 7.05 ppm\na\nin neat acetone-d to 6.96 ppm in a 6:1 D₂O/acetone-d solvent mixture (See NMR spectra in SI for\n6 6\ndetails). Moreover, H shifted approximately to 7.00 ppm when the solvent system was altered to either\na\n5:2 H₂O/acetone-d or 5:2 MeOH/acetone-d . A similar trend of downfield shift was observed in case\n6 6\nof H as well and it exhibited the  values of 8.05 ppm, 7.90 ppm, 7.95 ppm and 8.02 ppm, respectively\nb\nin the solvent mixtures mentioned above (Figure 2e). On the other hand, in the 13C NMR spectra, the\ncarbonyl group of A-1 shifted from 185.7 ppm in neat acetone-d6 to 178.8, 181.2, and 183.9 ppm in 6:1\nD₂O/acetone-d , 5:2 H₂O/acetone-d , and 5:2 MeOH/acetone-d , respectively (Figure 2f). These\n6 6 6\ndownfield shifts of the olefinic and aromatic protons (ortho to the carbonyl group of A-1) and carbonyl\ncarbons are consistent with hydrogen‐bonding interactions involving the naphthoquinone moiety, which\nfurther supports our working hypothesis.5b”\n13CNMR\n1H NMR\nIn MeOH/acetone-d6 (5:2)\nIn MeOH/acetone-d6 (5:2)\nIn H2O/acetone-d6 (5:2)\nIn H2O/acetone-d6 (5:2)\nIn D2O/acetone-d6 (6:1)\nIn D2O/acetone-d6 (6:1)\nIn neat acetone-d6\nIn neat acetone-d6\nComment:\n2. For the coumarin acylation, the product depicted is the α-acylated isomer (C108). Please clarify why\nthe β-acylated regioisomer—expected on the basis of the mechanistic argument—is not observed.\nOur response: We thank the reviewer for this question. The crude reaction mixture was analyzed in\nGC-MS. Neither of the α-acylated or β-acylated product was detected because coumarin failed to\nparticipate in the C‒H HAT process under the standard conditions to generate the corresponding acyl\nradical for further reaction. The following outcome is now mentioned in the revised manuscript and\nhighlighted in yellow.\n“However, coumarin did not participate in the acylation reaction under the standard reaction\nconditions (remained unreacted), and neither of the anticipated products (C-108 or C-108’) was\ndetected in GC-MS.”\nComment:\n3. N-Phenyltetrahydropyrrole affords only trace amounts of C-136. Discuss whether this outcome arises\nfrom steric shielding, diminished H-bonding ability, or competing side reactions.\nOur response: We thank the reviewer for asking this insightful question. The lower yield was observed,\npossibly due to the side reaction. In this particular case, the electron-rich amine center of N-\nphenyltetrahydropyrrole underwent photochemical oxidation (by SET) in the presence of Eosin Y and\n1,4-naphthoquinone to deliver the corresponding iminium cation species, which experienced water\nattack and successive oxidation to deliver N-phenyl pyrrolidone as the major product (ChemSusChem,\n2019, 12, 2898 – 2910). Therefore, we have added the following line to the manuscript:\n“This is probably due to the photochemical oxidation of the electron-rich amine center of N-\nphenyltetrahydropyrrole, where SET is more favorable over HAT to generate an iminium cation under\nthe standard reaction conditions. The corresponding iminium cation underwent a nucleophilic water\nattack and a successive oxidation to release N-phenylpryrrolidone (detected in GC-MS).22”\nComment:\n4. Diaryl ketones are common triplet photosensitizers. When aryl aldehydes are used, the corresponding\nketone products could conceivably act as internal sensitizers. Report Stern–Volmer quenching data,\ntriplet-energy calculations, or sensitizer-free control reactions to exclude product-sensitized pathways.\nOur response: We thank the reviewer for the valuable suggestion. We agree that diaryl ketones (formed\nupon quinone acylation) may act as photosensitizers. To negate the possibility of product-catalyzed\nreactions, we performed the standard reaction between 1,4-naphthoquinone (A-1) and benzaldehyde\n(B-1) in the absence of the photosensitizer Eosin Y but in the presence of C-1 (5 mol%). We observed\na trace amount of product formation in this case, and most of the starting materials remained unreacted,\nconfirming that the reaction is not product-catalysed (analyzed by GC-MS). Furthermore, it is important\nto note that we obtain a dihydroxy diarylketone after the acylation reaction, which is highly susceptible\nto further oxidation and shows an absorption maximum at 404 nm for C-1 (see SI, Fig. S3). We\nattempted to perform a Stern-Volmer quenching experiment for C-1 and excited the molecule at 455\nnm, but we did not observe any significant emission peak for the product. Afterwards, we tried to excite\nC-1 at 400 nm, which provides an emission band. Next, for the quenching experiment we added 1,4-\nnaphthoquinone (A-1) as the quencher. Unfortunately, we observed a messy emission band that\ncontained many small peaks. This probably occurred because the product (C-1) is highly reactive, and\nphotoexcitation of C-1 at 400 nm in the presence of 1,4-naphthoquinone (A-1) led to its decomposition.\nThese two experiments confirmed that the product-catalyzed reaction is unlikely under standard\nreaction conditions.\nReviewer #2 (Remarks to the Author):\nThe submitted manuscript by Konig and co-workers presents another application of on-water\nphotochemistry in organic synthesis and follows up the original paper from the group in Science. The\nauthors present the concept of influencing excited states by the water environment based on hydrogen\nbonds. This effect is manifested both on the substrate (benzoquinone and other quinones) and on the\ncatalyst (EOSIN Y), and allows the activation of the substrate by energy transfer. Subsequently,\nacylation/alkylation of the substrate can occur, which is based on the abstraction of hydrogen from the\naldehyde or precursor of stable radicals. The authors document the effect of water on the\nabsorption/fluorescence properties. Subsequently, they use an optimized methodology to prepare a\nseries of acylated/alkylated quinones with various aldehydes or alkylating agents. Small-scale\nexperiments are supplemented by experiments on a gram scale. The reactions tolerate various substrates\nand functional groups, with the exception of alkylating agents producing unstable radicals. Overall, I\nconclude that the work is clearly and comprehensibly written, most (see below for other comments)\nconclusions are clearly supported by measured data. Since this is a new and rapidly developing topic\nand the article, even in its current state, provides a guarantee (after minor edits) of an important message\nof interest to a wide range of readers, I recommend accepting the article for publication in Nature\nCommunication after minor revision.\nComments:\n1. Authors claim (see abstract) that water surface reduces triplet state energy of quinone substrate and\nincreases triplet state energy of Eosin Y. On my own, it can be hardly concluded from data reported.\nAuthors measured effect of water on absorption and fluorescence emission spectra but it can show only\neffect on singlet excited state. Of course, also triplet state energy might be changed but there is no direct\nevidence.\nOur response: We thank the reviewer for this insightful feedback. We agree that the fluorescence\nemission spectra of any substance provide information only about the singlet state. The experimentally\nobserved bathochromic shifts in the absorption and emission of A-1 in the presence of water were\nconfirmed by our computational studies, which suggest stabilization of the photoexcited states (both\nthe singlet and triplet) in the aqueous environment (see SI, Fig S7-S9 for detailed calculations).\nHowever, the effect of water on the electronic structure of Eosin Y is more complex, as it may affect\ntautomeric equilibria and their individual electronics. Therefore, the following lines were added to the\nmanuscript.\n“The experimentally observed bathochromic shift of absorption and emission of A-1 in the presence of\nwater was confirmed by the computational studies, which suggest the stabilization of the photo-excited\nstates (both the singlet and triplet) for A-1 in the aqueous environment (see SI, Fig S7-S9 for detailed\ncalculations). However, the effect of water on the electronic structure of Eosin Y is more complex, as it\nmay affect tautomeric equilibria and their individual electronics. A detailed evaluation goes beyond the\nscope of this work.20”.\nAdditionally, the manuscript was modified accordingly and highlighted in yellow in the revised version.\nComments:\n2. Regarding substrate scope of alkylation (Table 6), ethylbenzene derivative is missing. Only toluene\nand then trisubstituted derivatives were proven. It would be interesting to see whether switch to\nsecondary derivative giving secondary radical is enough to provide the reaction.\nOur response: We thank the reviewer for this interesting suggestion. Other than toluene, we performed\nthe alkylation reaction in the presence of some secondary derivatives (C-124 to C-127), which shows\nthat secondary carbon-centered radicals can participate in the reaction. However, for a substrate like\nethylbenzene, we observed a different product. Further studies to investigate this different reactivity are\ncurrently ongoing in our lab; results on this will be reported in a future publication.\nComments:\n3. Blue point is missing in legend in Figure 2D. Note, description A…D is not shown.\nOur response: We thank the reviewer for pointing out these missing points. Figure 2D is now revised,\nand the description for 2A to 2D is now mentioned more elaborately and highlighted in yellow in the\nrevised manuscript.\nComments:\n4. Only traces of product are given in Table 2 for C23. But it is not commented accordingly in the text.\nOur response: The outcome for C-23 is now mentioned in the revised manuscript and highlighted in\nyellow.\nComments:\n5. Naphthaquinone should be naphthoquinone on page 7 down.\nOur response: We apologise for the mistake. The typo is corrected in the revised manuscript and\nhighlighted in yellow.\nComments:\n6. Figure 3a is missing in the main text.\nOur response: Figure 3 is now cited in the revised manuscript and highlighted in yellow.\nComments:\n7. I suggest catalytic role of EY should be better shown in Figure 3. By excitation and ISC, triplet\nexcited state is formed which likely provides EnT.\nOur response: We thank this reviewer for the suggestion. The mechanism has been modified to more\nclearly highlight the role of Eosin Y.\nReviewer #3 (Remarks to the Author):\nThis manuscript describes a photo-induced, redox-neutral Friedel-Craft acylation and alkylation of\nquinones under water-oil interfaces in the presence of Eosin Y as photosensitizer. The method operates\nunder transition-metal-free conditions, shows high substrate adaptability, and gives access to\nfunctionalized quinone products of potential synthetic value. The reaction design is conceptually\nappealing, and the operational simplicity makes it attractive. I recommend acceptance of this work for\npublication, upon addressing the following minor issues:\nComments:\n1. In Table 2, the reason for lower yields for substrates like C-23, C-53 was not discussed. Did the author\nobserve byproducts?\nOur response: The lower yield for C-23 is now discussed in the revised manuscript and highlighted in\nyellow. The reason could be a different stereo-electronic factor operating in ortho-substituted aryl\naldehydes bearing an electron-withdrawing group. However, for C-53, we observed an isolated yield of\n76%, with the remaining starting materials unreacted.\nComments:\n2. The authors should note that C-134 and C-135/C-136 are not the same class of compounds. I support\nthe statement that C-134 can generate an α-amino radical via light-mediated HAT. However, applying\nthe same description to C-135 and C-136 — that they also generate an α-amino radical via light-\nmediated HAT — may not be appropriate. For C-135 and C-136, a single-electron transfer (SET)\npathway is likely more favorable than HAT.\nIn addition, for C-136, no obvious product was observed. What might be the possible reasons for this\noutcome? Is it necessary to further examine the reactivity of the N-phenylpiperidine substrate? For this\ntype of substrate, the authors may need to discuss the mechanism of α-amino radical generation\nseparately.\nOur response: We thank the reviewer for the insightful feedback. We agree on the argument that for\nsubstrates like N-phenyltetrahydropyrrole, photochemical oxidation of the amine center by SET is more\nlikely than C‒H activation under the standard reaction conditions. The photo-oxidation of the electron-\nrich nitrogen center produced an iminium cation under the standard reaction conditions. The\ncorresponding iminium cation underwent a nucleophilic attack by water, followed by oxidation, to\nrelease N-phenylpryrrolidone (detected by GC-MS) as the major product. The outcome is mentioned in\nthe revised manuscript and highlighted in yellow. Surprisingly, for the substrate like N-phenyl\nmorpholine (C-135), we could not detect any oxidation product, and the excess starting materials\nremained unreacted. However, the alternative mechanistic route for this kind of reaction is now\nmentioned in the revised manuscript and highlighted in yellow.\n“This is probably due to the photochemical oxidation of the electron-rich amine center of N-\nphenyltetrahydropyrrole, where SET is more favorable over HAT to generate an iminium cation under\nthe standard reaction conditions. The corresponding iminium cation underwent a nucleophilic water\nattack and a successive oxidation to release N-phenylpryrrolidone (detected in GC-MS).22”\nComments:\n3. The scope of the reaction may be further illuminated by two key references (Angew. Chem. Int. Ed.\n2016, 55, 4040; Chem. Sci. 2016, 7, 7002).\nOur response: We thank the reviewer for the suggestion. The mentioned references are now cited in\nthe revised manuscript and highlighted in yellow.\nComments:\n4. Please verify that all citations and labels in Scheme 1 correspond accurately to their sources in the\ntext and reference list.\nOur response: We apologise for the mistake. All the citations in Scheme 1 are now labelled properly\nand highlighted in yellow in the revised manuscript."}, {"round": 2, "reviewer_comments": {"reviewer_1": "The authors have addressed all the issues raised. The revised manuscript is recommended for acceptance.", "reviewer_2": "The manuscript represents a significant contribution to a highly appealing topic in the field of photoredox catalysis. During\nrevision, the authors carefully corrected and supplemented the original manuscript according to the comments of the\nreviewers. I can now happily recommend the manuscript as suitable for publication in Nature Communication.", "reviewer_3": "The author has addressed most of my concerns, and the manuscript can be published in its current form in Nature\nCommunications."}, "author_response": ""}]

Decision letter