Abstract
Electrochemical organic synthesis is typically conducted in organic media. The solvent and related supporting electrolytes negatively affect the greenness of electrosynthesis. In this work, with 100% water used as the solvent, we realize aggregation-driven electrochemical radical cross coupling of unsaturated compounds driven by water tension. A key finding is that aggregation of the substrate at the electrode confined the radical intermediate and prevented side reactions, thus providing a way to regulate radical reactions in addition to their native properties. The reaction provides up to 90% yields with almost quantitative chemoselectivity. The pure water system readily yields the products via cold filtration, and the solvent is recycled repeatedly. In particular, the life span of the radical species generated in the reaction increase significantly because of the confined environment in the aggregation state. The greenness of this protocol is further enhanced with readily separation of product from media using cooling and filtration.
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Introduction
Aggregation-driven effects have been extensively studied for use in building optical materials and biomaterials1,2. Typically, in aqueous media, aggregation of hydrophobic compounds results in distinct photo-properties. In electrochemical organic syntheses, however, aggregation is not a useful phenomenon. Since mass transfer is frequently a key factor3,4, organic solvents are the most commonly applied media used to produce homogenous solutions5,6,7,8,9,10. Therefore, if water is used, an organic cosolvent11,12,13,14,15 or surfactant16,17 is typically necessary to prevent aggregation of the organic substrate. This micellar system in aqueous media has been established as an efficient protocol in electrochemical synthesis18,19,20. On the other hand, in the absence of phase transfer reagent, hydrophobic compounds aggregate due to their immiscibility, which creates a multiphase system and precludes efficient mass transfer. Therefore, fully aqueous electrochemical organic syntheses are limited21,22,23,24,25, and the aggregation-driven effect is overlooked in electro-organic synthesis.
On the other hand, multiphase systems could have multiple advantages in electrochemical syntheses, as reviewed by Marken and Wadhawan26 and Kobayashi27 We outlined a comparison of electrochemical reactions in organic solvents and aggregation of a substrate on an electrode driven by the water tension28. In a homogeneous solution, the concentration of the substrate localized at the electrode is limited and decreases as the reaction proceeds (Fig. 1a). In contrast, an electrode with a large surface/weight ratio, for example, graphite felt (ca. 0.2 m3/g)29, provides a lipophilic space for aggregation of organic substrates that would otherwise be suspended in water. Electron transfer between the electrode and the aggregated substrate is facilitated (Fig. 1b). If another water-soluble reactant forms a bond with the reduced substrate, the product will have better solubility and diffuse into the aqueous medium, leaving vacancy for substrate (vide infra). This reaction design uses pure water as the solvent with the on-water-catalysis strategy30,31 and has substantial advantages (Fig. 1c). First, aggregation provides a confined space for the radical intermediate32,33,34, regulating the reactivity of the radical beyond its intrinsic kinetics35,36. Second, the starting material remains concentrated at the electrode, which facilitates conversion. Third, a counterreaction, for example, the reduction or oxidation of water, occurs readily, which precludes the need external oxidants or reductants. All of these factors can ensure chemoselectivity, reduce the energy input, and achieve fast conversions. With this model, we report the formation of distinct electrochemical C‒C bonds between unsaturated compounds induced by aggregation in pure water.
a The distribution of substrate in homogenous solution around electrode. b The proposed distribution of substrate in aqueous media. c The advantages of aggregation-driven electrosynthesis.
Results
A reaction employing aldehyde 1a and acrylonitrile 2a was used to compare the outcomes obtained from water-driven aggregation and from a homogeneous solution in an organic solvent (Fig. 2). Water was found to be the optimum medium for achieving the desired conversion (Fig. 2a). The reaction furnished a 90% 1H NMR yield with almost quantitative chemoselectivity. The organic solvent resulted in oxidation of the aldehyde (MeOH) and a very messy mixture (DMF). In THF, the conversion rate was low, and the dimer of 1a was the major product. In MeCN, electrolysis led to dimerization of 1a to pinacol in 36% yield, dimerization of acrylonitrile to adiponitrile, and a 25% recovery of aldehyde 1a. Furthermore, the water was essential for high conversions and chemoselectivities (Fig. 2b). Even the use of 20% MeCN as the cosolvent decreased the yield of product 3a to 55%. A homogeneous solution of MeCN/water (4:1) afforded 3a in only 10% yield along with the other dimers. Surfactants are used for dispersing reactants in aqueous media. Sodium dodecyl benzene sulfonate (SDBS), a typical surfactant, was evaluated in the water medium (Fig. 2c). Even a half equivalent of SDBS decreased the conversion rate dramatically, and more equivalents of SDBS almost completely quenched the reaction. The cathode also substantially influenced the reaction (Fig. 2d). The graphite felt, which provided an adequate interface for aggregation, gave much better results than metals and carbon materials (see Supplementary Information, Section 2.2 for more details).
a Reaction in different solvents (5 mL) with a graphite felt anode and cathode. b Reaction in cosolvent H2O/MeCN (5 mL) with a graphite felt anode and cathode. c Surfactant was used in 5 mL of water with a graphite felt anode and cathode. d Water (5 mL), graphite felt anode and other electrode as the cathode.
These results showed the substantial effect of aggregation, which led us to conduct additional investigations. First, the aggregated state of substrate 1a on the cathode is shown in Fig. 3b for electrolysis for 10 s. Condensation of the substrate locally at the surface of the cathode was observed with aqueous media, but was not observed with MeCN as the solvent (Fig. 3c), which is similar to original material (Fig. 3a). This enrichment was confirmed by analyzing the mass distributions of the electrode and solution (Fig. 3d). For the water/GF electrode combination, approximately 90% of 1a was aggregated at the electrode interface; in comparison, with organic solvents, the adsorption of 1a on the surface of the electrode did not generate a significant imbalance (DMF 8%, MeCN 17%). Subsequently, the mass distributions of reactants 1a and 2a and product 3a were measured in aqueous media (Fig. 3e). In contrast to aldehyde 1a, acrylonitrile 2a was soluble in water, which resulted in an average population. In addition, product 3a showed better solubility than 1a in water and did not aggregate significantly at the interface with the electrode. These differences led to a locally high concentration of 1a, possibly due to the combined effects of the water tension and the lipophilicity of the electrode. We also measured the distribution of 1a at graphite felt anode (Ti as cathode) and graphite felt cathode (Ti as anode) respectively in the absence of 2a when the electrolysis was conducted for 10 min (Fig. 3f). It was found the graphite felt anode could adsorb 91% of 1a and 9% of 1a dispensed in aqueous media. In comparison, the 1a was almost completely adsorbed on graphite felt cathode along with 23% of benzyl alcohol as the reduced product aggregated, and was almost not detected in aqueous media (<1%). Therefore, the aggregation was also influenced by the electric field effects significantly. This synergy effect brought the aggregated substrate closer to the interface with the electrode than it was in the organic solvent. To verify this hypothesis, we used cyclic voltammetry to study 1a in aqueous media and in MeCN (Fig. 3g). Two clear differences were observed: (1) In aqueous media, the reduction of 1a took place more readily, which supported the push-pull effect. (2) The peak current for 1a in the aqueous medium was lower than that in MeCN, possibly because of confined mass transfer in the aggregated environment. This confined mass transfer prevented dimerization of the radical intermediates observed in organic solvents. In comparison, water-soluble acrylonitrile exhibited a high current (Fig. 3h). This reduction potential and current profile implied that either a single reduction of 1a or dual reduction of 1a and 2a might be possible. Therefore, a reaction was conducted with a controlled cathodic potential, and the dual reduction profile predominated (Fig. 3i). This dual reduction model was verified with radical trapping (Fig. 3j), which showed that both radicals were trapped by DMPO from the aggregated layer at the initial stage of the reaction using both HRMS and ERP analyses (5–15 min). Next, to determine whether the radical from 1a was generated from the aggregated substrate or from the trace amount dissolved in water, a reaction employing a saturated solution of 1a in water was carried out. Due to the poor solubility, no current or product was observed with identical electrochemical parameters (Fig. 3k). Alternatively, we used 1,4-benzenedialdehyde 1b as a substrate and obtained product 3b as the only cross-coupled product (Fig. 3l). This suggested that the aggregated aldehyde underwent the reaction, and product 3b, which had higher solubility, diffused into the solution, and did not undergo electron transfer. Several kinetic features of this reaction were also evaluated (Fig. 3m). The yield of 3a remained steady when the formal concentration of 1a was changed from an experimental level (0.1 M based on the ratio of 1a/water, but not a solution) to a productive level (1.0 M). Next, the influence of the current density on the conversion of 1a was investigated (Fig. 3n). An increase in the current density did not lead to a significant increase in the conversion of 1a. This observation prompted us to examine the influence of 2a on the reaction (Fig. 3o). Unexpectedly, an increase in 2a resulted in the consumption of only 2a. In contrast, the conversion rate of 1a decreased from 57% to 33%, suggesting that dimerization of 2a was a major side reaction at high concentrations of 2a. By tracking the conversion of substrate 1a and the corresponding yield under standard conditions (Fig. 2), it was found that the chemoselectivity of the reaction continued to increase from the beginning and was almost complete in the aqueous medium (Fig. 3p). In contrast, with MeCN/water as a cosolvent, the chemoselectivity decreased, especially at high conversions (More details in Supplementary Information, Sections 2.4–2.7).
a The image of net cathode. b The image of aggregated state of substrate 1a on graphite felt cathode in aqueous media under standard conditions. c The image of graphite cathode in reaction of 1a under standard conditions in MeCN. d Mass distribution of 1a between solvent and aggregation on electrode in different solvents. e Mass distribution of compounds between water and aggregation on electrode. f Mass distribution of 1a between water and aggregation on graphite felt anode and cathode in reaction with water as solvent g CV analyses of 1a in different solvents. (Pt(+)|Glassy carbon(-)|Hg/HgO ref, 50 mV/s, solute 0.04 mol/L in 0.1 M NaOH or MeCN). h CV analyses of 1a and 2a in water (Pt(+)|Glassy carbon(−)|Hg/HgO ref, 50 mV/s, solute 0.04 mol/L in 0.1 M NaOH). i Reaction of 1a and 2a under controlled cathodic potential. j Trapping radicals in the reaction mixture. k Result from highly diluted homogenous aqueous solution of 1a. l reaction of substrate 1b involving double reactive sites. m The influence of 1a on the yield of 3a. n The influence of current density on the conversion of 1a. o The influence of 2a on the conversions of 1a and 2a. p The conversion and chemoselectivity in varied solvents.
With these results, two plausible cathodic pathways were proposed (Fig. 4). For pathway 1 (Fig. 4a), two electrons were transferred to the aggregated aldehyde 1a and acrylonitrile along with protonation by water, giving the two radicals adjacent to A. Subsequently, cross-coupling gives rise to product 3a, which diffuses to aqueous media due to the difference in solubility between substrate 1a and product 3a. In pathway 2 (Fig. 4b), one electron transfer with protonation occurs to give radical species B. A second radical transfer with protonation furnishes product 3a. This product diffused into the solution and left the surface of the electrode open for substrate aggregation. At the anode, the oxygen evolution reaction occurred under basic conditions and provided a mass balance with oxygen as the only side product and a theoretical atom economy >82% (Fig. 4c). In such an aggregation state, the local electric field could have a more persistent effect on the aggregated species than under homogenous conditions and would be important to help with cross-coupling. Especially, due to the acid/base equilibrium, the existence of 3a/3a−/H2O/HO− could facilitate the diffusion of product, and more possibly its’ anion to bulky phase.
a Two-electron-reduction pathway takes place at cathode. b One-electron-reduction pathway takes place twice at cathode. c The oxygen evolution at anode.
This aggregation-driven radical cross coupling was exhibited with additional substances (Fig. 5). Various aromatic aldehydes underwent cross-coupling to the desired g-hydroxyl-nitriles 3a-3al in decent to good yields. Furan, pyridine, and ferrocenyl groups were well tolerated. These ketones were also suitable for this reaction protocol. The g-tertiary alcohol nitriles 3s-3am were synthesized in good yields. In particular, for product 3ad, the radical cross-coupling reaction was faster than ring opening of the cyclopropyl group. The 3an product from progesterone was obtained from a modified protocol with Cp2TiCl2 used as a catalyst. As an extension, the reactions of 1a with a-methylacrylonitrile and t-butyl acrylate gave the corresponding products 3ao and 3ap, respectively, under standard conditions. In contrast to the readily hydrolysis in wet organic solvent, an imine substrate gave 3aq as major product in 51% isolated yield under this condition. With the same manner, product from 3ar ketimine was obtained in comparable yield. A tetrahydroquinoline 3as was prepared from quinoline and 2a in 32% yield. 4-CN-pyridine converted to compound 3at in 70% yield.
a Reaction conditions: 1 (0.4 mmol), 2 (0.8 mmol), NaOH (0.4 mmol), H2O (5 mL), graphite felt anode and cathode; Ucell = 4.5-6.5 V under air for 4-11 h, isolated yields.
Next, we demonstrated additional applications of this aggregation-driven chemistry (Supplementary Information, Sections 2.3, 2.8). A decigram scale reaction gave 3a in 70% isolated yield (Fig. 6a). Recycling of the aqueous medium was evaluated by chilling the reaction mixture and using filtration to separate the organic product from water. The water was reused as a solvent, and the product was obtained with a comparable 1H NMR yield of 88% (Fig. 6b). After three recycles of water media, the yield of 3a remained high with adequate purity in crude NMR, and extraction with an organic solvent was not involved. The reaction of formal concentration of 1 M was conducted in 5 h, giving products 3c in 71% yield (Fig. 6c). Next, the product 3au, an intermediate for ticagrelor requiring a three-step route previously37, was generated in 66% yield in single step (Fig. 6d). Similarly, the endothelin antagonist 438 was synthesized with compound 3ao as a building block with an overall 52% yield (Fig. 6e). The aqueous medium provided another advantage, as shown in Fig. 6f. 4-Methylanisole was oxidized in an acidic aqueous solution. In turn, by regulating the pH with added NaOH, product 3d was obtained in a tandem process without workup and isolation.
a A standard reaction at dec-gram scale. b The recycle of water without any organic workup. c The reaction of 5 mmol 1c in 5 mL water. d The synthesis of ticagrelor’s intermediate 3au. e The synthesis of endothelin antagonist 4. f A tandem reaction in aqueous media.
Discussion
In summary, we demonstrated an aggregation effect during electrosynthesis. The tension of the water and the surface of the graphite felt constituted a push-pull combination. In this reaction, the substrate and, in turn, the poorly soluble radical intermediate was confined via aggregation, providing an opportunity for cross coupling of radicals with good solubility. Another significant advantage of aggregation is the high chemoselectivities seen at high conversions, as the local high concentration at the electrode was maintained. This reaction reveals a model for electrochemical organic syntheses, including mass transfer, chemoselectivity, and reaction design.
Methods
General procedure for the synthesis of 3
To a 10 mL reaction flask was added 4-fluorobenzaldehyde 1a (0.4 mmol,0.0496 g, 43 μL), and acrylonitrile 2a (0.8 mmol, 2.0 equiv, 54 μL). NaOH (0.4 mmol, 0.016 g) in 5.0 mL H2O was added as the reaction solvent. The reaction mixture was subject to electrolysis under 6.0 V constant voltage for 4 h with graphite felt as both anode and cathode. The color of reaction turned from colorless brown. Thin-layer chromatography analysis of reaction mixture showed the complete conversion was achieved. The reaction mixture was extracted with methylene chloride twice. The combined organic layer was dried (Na2SO4), filtered and concentrated. The residue was purified by silica chromatography with EA/PE = 1:5 (v/v) to offer 3a as colorless oil.
Data availability
The authors declare that the experimental data generated in this study are provided in the Supplementary Information, and also are available from the corresponding author upon request.
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Acknowledgements
This work is supported by the National Science Foundation of China: 22471125, 22031008 and 22071105 to C.X. This work is supported by the Elite Student Development Program for Fundamental Disciplines 2.0: 20221021 to C.X.
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L.M.F. conducted the experiments for reaction optimization, mechanism elucidation, and wrote the Supplementary Information. C.X. gave the reaction design and concept, and wrote the manuscript. L.M.F. and C.X. worked on the revision together.
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Li, M., Cheng, X. Aggregation-induced C–C bond formation on an electrode driven by the surface tension of water. Nat Commun 15, 7540 (2024). https://doi.org/10.1038/s41467-024-52042-w
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DOI: https://doi.org/10.1038/s41467-024-52042-w