Alkynes Electrooxidation to α,α-Dichloroketones in Seawater with Natural Chlorine Participation via Competitive Reaction Inhibition and Tip-Enhanced Reagent Concentration

The traditional synthesis of α,α-dichloroketones usually requires corrosive chlorine, harsh reaction conditions, or excessive electrolytes. Here, we report an electrooxidation strategy of ethynylbenzenes to α,α-dichloroketones by directly utilizing seawater as the chlorine source and electrolyte solution without an additional supporting electrolyte. High-curvature NiCo2O4 nanocones are designed to inhibit competitive O2 and Cl2 evolution reactions and concentrate Cl– and OH– ions, accelerating α,α-dichloroketone electrosynthesis. NiCo2O4 nanocones produce 81% yield, 61% Faradaic efficiency, and 44.2 mmol gcat.–1 h–1 yield rate of α,α-dichloroketones, outperforming NiCo2O4 nanosheets. A Cl• radical triggered Cl• and OH• radical addition mechanism is revealed by a variety of radical-trapping and control experiments. The feasibility of a solar-powered electrosynthesis system, methodological universality, and extended synthesis of α,α-dichloroketone–drug blocks confirm its practical potential. This work may provide a sustainable solution to the electrocatalytic synthesis of α,α-dichloroketones via the utilization of seawater resources.


■ INTRODUCTION
α,α-Dichloroketones are essential structural motifs in various pharmaceutical chemicals and natural products. 1,2−5 In these methods, excessive and corrosive chlorine (Cl 2 ) or expensive/toxic organochlorination reagents, such as N-chlorosuccinimide (NCS) and trichloroisocyanuric acid (TCCA), are used as chlorine sources.Additionally, excess strong oxidants and high reaction temperatures are usually needed, causing concerns about safety, cost, and sustainability.Therefore, it is highly desirable to develop an alternative strategy to achieve a sustainable, mild, and efficient synthesis of α,α-dichloroketones.
−16 An advance has been made in using trichloromethane (CHCl 3 ) as the chlorine source to realize the electrosynthesis of α,αdichloroketones from alkynes in organic electrolyte solution (Supplementary Figure 1c). 17In this process, tetrabutylammonium iodide (TBAI) was added to serve as a nucleophile; thus, Cl − was generated from CHCl 3 by nucleophilic substitution with I − .Then, Cl − was oxidized to chlorine radical (Cl • ) at the anode, triggering the oxydichlorination reaction.However, the reaction rate was severely restricted by the slow Cl − generation process.Additionally, carcinogenic CHCl 3 , toxic TBAI, and massive and expensive organic electrolytes are needed in the electrosynthesis process, causing sustainability and cost issues.Thus, it is highly significant to develop a sustainable electrolysis system for efficient α,α-dichloroketone electrocatalytic synthesis.
In the chlor-alkali process, using saturated NaCl as the electrolyte, Cl • radicals are first produced by Cl − ion electrooxidation and then self-coupled to form Cl 2 . 18,19nspired by this process, we speculate that the Cl • radicals generated in situ from Cl − ion oxidation can trigger the oxydichlorination reaction for α,α-dichloroketone electrosynthesis.−22 The dominant ions in seawater are Na + and Cl − , accounting for approximately 3.5 wt %.This encourages us to consider utilizing Na + and Cl − as the conducting ions, Cl − as the chlorine source, and H 2 O as the oxygen source; thus, the sustainable electrocatalytic synthesis of α,α-dichloroketones could be realized by directly using seawater as the electrolyte solution without an additional chlorine source and a supporting electrolyte.
Here, a strategy for the electrocatalytic synthesis of α,αdichloroketones without an additional chlorine source and a supporting electrolyte is demonstrated (Figure 1).A highcurvature NiCo 2 O 4 nanocone (NC) anode is proposed as a promising candidate to electrosynthesize α,α-dichloroketones from alkynes in seawater by analyzing the reaction process and possible competitive reactions.An 81% yield, 61% Faradaic efficiency (FE), and 44.2 mmol g cat.−1 h −1 yield rate of α,α-  The solar energy powered electrosynthesis system on a flow reactor demonstrates the potential of this strategy.Taking the electrosynthetic product as the building block, an adrenocortical carcinoma treatment drug, mitotane, was synthesized.This sustainable system is suitable for synthesizing other α,αdichloroketones with high yields.
■ RESULTS AND DISCUSSION Calculation-Assisted Electrocatalyst Screening and Design.The first consideration in selecting a catalyst is its stability under electrooxidation conditions in the presence of seawater.It was learned from the electrolytic seawater oxidation reaction that cobalt-based oxides with spinel structures are good electrocatalytic oxidation catalysts with high stability 23−27 and thus are considered candidates for alkyne oxydichlorination to synthesize α,α-dichloroketones.For a high reaction rate and FE α,α-dichloroketone electrosynthesis, three fundamental factors should be considered for a suitable electrocatalyst:  2a), which is favorable for producing *OH to synthesize α,αdichloroketones but inhibits the competitive OER.Moreover, the adsorption energy (E ads ) of Cl on Ni is much higher than that on Co, while OH shows the opposite trend (Figure 2b and Supplementary Figures 2−4).Thus, Cl preferentially adsorbs on Ni sites, and OH tends to adsorb on Co sites.This nonadjacent adsorption site can suppress the self-coupling of Cl • to form Cl 2 . 11o verify the above analysis, we synthesized four cobaltbased spinel oxides and tested their α,α-dichloroketone electrosynthesis performances (Supplementary Figures 5−8).Natural seawater collected in the Bohai Sea was used as the electrolyte solution with a Cl − ion concentration of ∼18 g L −1 (determined by ion chromatography; Figure 2c).1-Chloro-2ethynylbenzene was selected as the model substrate.After electrolysis for 10 min at 1.30 V vs Ag/AgCl, NiCo 2 O 4 NSs show the highest α,α-dichloroketone yield rate (16 mmol g cat.−1 h −1 ) and FE (42%), corresponding to the theoretical prediction (Figure 2d).The target product of α,α-dichloroketone was confirmed by 1 H nuclear magnetic resonance ( 1 H NMR) and gas chromatography−mass spectrometry (GC− MS) (Figure 2e,f).These results indicate that the electrosynthesis of α,α-dichloroketone using seawater as the electrolyte is workable and that NiCo 2 O 4 is a good anode candidate.
High-curvature nanostructures can enhance the local electric field to enrich reactant ions near the electrode surface, thus accelerating the reaction rate. 34,35In our proposed reaction process, Cl − and OH − ions are needed for α,α-dichloroketone electrosynthesis.Thus, it is supposed that enhancing the local electric field of the anode can concentrate Cl − and OH − ions from the seawater electrolyte solution and thus promote α,αdichloroketone electrosynthesis.This speculation was confirmed by the finite element method simulation.The electric field intensity was obviously enhanced as the radius decreased from 12 to 5 nm due to the migration of free electrons to the regions of the sharpest curvature on a charged metallic electrode (Figure 2g and Supplementary Figure 9). 36As a result, the concentration of Cl − and OH − ions in the Helmholtz layer of the electrical double layer increased by 60-fold at the nanocone tips compared with that of the bulk electrolyte solution (Figure 2h,i).Thus, a high-curvature nanostructure is expected to promote α,α-dichloroketone electrosynthesis.
Electrocatalyst Synthesis and Characterizations.Selfsupported NiCo 2 O 4 NCs and NiCo 2 O 4 NSs were successfully synthesized via a hydrothermal method followed by calcination in air. 37,38Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images show NiCo 2 O 4 NCs and NiCo 2 O 4 nanosheets (NSs) grown on the substrate uniformly with the nanocone and nanosheet morphologies (Figure 2j and Supplementary Figures 10 and 11).The lattice fringes with interplanar distances of 0.468 nm for NiCo 2 O 4 NCs and 0.467 nm for NiCo 2 O 4 NSs in the high-resolution TEM (HRTEM) images are both ascribed to the (111) plane of NiCo 2 O 4 (Supplementary Figure 12). 37The energy dispersive X-ray (EDX) mapping images reveal uniformly dispersed Ni, Co, and O elements throughout the entire nanocones or nanosheets (Supplementary Figure 13).All the diffraction peaks in the X-ray diffraction (XRD) patterns of the NiCo 2 O 4 NCs and NiCo 2 O 4 NSs are indexed to the standard NiCo 2 O 4 (JCPDS No. 20-0781) (Supplementary Figure 14). 37,38X-ray photoelectron spectroscopy (XPS) spectra for Ni 2p, Co 2p, and O 1s of the two materials show similar results.In Ni 2p, two spin−orbit doublets at 874.0 and 872.3 eV correspond to the characteristic Ni 2+ , while two shake-up satellites at 856.3 and 854.5 eV are ascribed to Ni 3+ (Supplementary Figure 15). 37,38In Co 2p, the peaks at 797.1 and 795.0 eV are assigned to Co 2+ and 781.7 and 779.9 eV correspond to Co 3+ (Supplementary Figure 15). 37,38The peaks at 529.6 and 531.2 eV in O 1s are distributed to the metal− oxygen bonds and the oxygen defect sites (Supplementary Figure 15). 37,38These results indicate the successful synthesis of NiCo 2 O 4 NCs and NSs.
α,α-Dichloroketone Electrosynthesis Performance.−22 The α,α-dichloroketone electrosynthesis performance over NiCo 2 O 4 NCs and NSs was tested in a divided three-electrode system.1-Chloro-2-ethynylbenzene (1a) was chosen as the model substrate.Acetonitrile was added as a cosolvent to increase the solubility of the substrate.All potentials refer to Ag/AgCl unless otherwise noted.Linear sweep voltammetry (LSV) curves show a remarkable increase in current density for NiCo 2 O 4 NCs compared with NSs (Supplementary Figure 16).Potential-dependent tests indicate that NiCo 2 O 4 NCs present a superior performance compared to NiCo 2 O 4 NSs in the potential range 1.15−1.35V (Figure 3a and Supplementary Figure 17).NiCo 2 O 4 NCs exhibit the optimum performance of 84% yield, 64% FE, and 57.2 mmol g cat.−1 h −1 yield rate at a potential of 1.30 V.The yield rate of NiCo 2 O 4 NCs is nearly 3 times that of NiCo 2 O 4 NSs at 1.30 V, indicating the promoting effect of the high-curvature structure for this electrocatalytic reaction (Figure 3b).Time-dependent experiments show that 0.1 mmol of 1a could be consumed totally, and an 84% 2a yield was obtained within 20 min (Figure 3c), which is far faster than the I − -mediated electrosynthesis method in organic electrolyte solution (0.3 mmol of substrate was consumed within 6 h). 17Furthermore, no performance degeneration is observed during eight cycles of electrocatalytic tests, and the morphology and composition can be maintained as before, suggesting that NiCo 2 O 4 NCs are a promising candidate for α,α-dichloroketone electrosynthesis with high intrinsic activity and durability (Figure 3d and Supplementary Figures 18−20).In addition, the performances of NiCo 2 O 4 NCs and NiCo 2 O 4 NSs were tested in seawater.The performance of NiCo 2 O 4 NCs reaches 81% yield, 61% FE, and 44.2 mmol g cat.−1 h −1 yield rate, which far exceeds that of NiCo 2 O 4 NSs (Supplementary Figure 21).This further confirms the promotional effect of the high-curvature structure for this electrocatalytic reaction.
Further experiments were conducted to understand the promotion origin of the high-curvature structure in α,αdichloroketone electrosynthesis.First, the electrochemical surface areas (ECSAs) of NiCo 2 O 4 NCs and NSs were evaluated by double layer capacitance (C dl ) measurements.The C dl of NiCo 2 O 4 NCs is 18.05 mF cm −2 , slightly higher than that of NiCo 2 O 4 NSs (16.52 mF cm −2 ) (Supplementary Figure 22).However, the difference in the ECSA (EC-SA NCs :ECSA NSs = 1.1) of the two catalysts is much smaller than that of the yield rate (Y, Y NCs :Y NSs = 3.1), indicating that the performance improvement is mainly from the intrinsic activity of the catalyst rather than the ECSA increase.Furthermore, it is supposed that the enhanced positive electric field around the tips of NiCo Control experiments and radical-trapping experiments were performed to identify the pathway for α,α-dichloroketone electrosynthesis.First, LSV curves were tested in 0.5 M Na 2 SO 4 (Figure 4a).A higher current density and lower initial potential were observed after introducing 0.1 mmol of NaCl.
However, when 0.1 mmol of 1a was added, no current density increase was observed.These results indicate that Cl − ion electrooxidation occurs more easily than the OER, while 1a electrooxidation may have difficulty taking place in the tested potential range.This was further confirmed by the electrolysis experiment at 1.30 V in 0.5 M Na 2 SO 4 containing 0.1 mmol of 1a.No 1a oxidative product was detected after the reaction (Supplementary Figure 24a).Moreover, a radical scavenger of 1,1-diphenylethylene was added during the reaction, and the hydroxyl radical (OH • ) was trapped, while no carbon radical (C • ) was captured (Supplementary Figure 24b).These results prove that H 2 O can be oxidized to OH • , but 1a cannot be electrooxidized under the tested potential.Thus, path 1 can be excluded.
To see whether the reaction occurs through path 2, 1a was added to 0.5 M NaCl containing 0.5 M ClO − , and no oxydichlorination product was probed without bias (Supplementary Figure 25).Therefore, path 2 is not the possible path.
Further experiments were performed to explore whether α,α-dichloroketone electrosynthesis occurs via path 3. When 1,1-diphenylethylene was added as a radical scavenger during the reaction process, the yield of 2a decreased by 59% with Cl • and OH • radicals trapped, indicating the radical-mediated pathway for 2a electrosynthesis (Figure 4b and Supplementary Figure 26).This result is further confirmed by electron  4f,g).These results prove that the electrosynthesis undergoes a radical mechanism triggered by Cl • , as proposed in path 3. Furthermore, the oxygen source for 2a electrosynthesis is from H 2 O, as confirmed by the 18 O isotope labeling experiment (Figure 4h).
On the basis of the above discussion, a possible reaction mechanism is proposed (Figure 4i).Cl • radicals are initially produced by the electrooxidation of Cl − ions at the anode, which trigger the oxydichlorination reaction by attacking the alkynyl of 1a to form vinyl radical I.The resulting radical intermediate I was then subjected to nucleophilic attack by OH • , generated from H 2 O splitting, to produce enol II.The reason for intermediate I integrating with OH • rather than the more concentrated Cl • is that OH • has a lower binding energy to I, as suggested in the theoretical calculation (Supplementary Figure 27 and Supplementary Note 1).Finally, enol III rapidly combines with the chlorine radical and is then further oxidized, affording the final oxydichlorination product 2a, as well as a proton.
Utility and Universality Studies.A solar-powered electrosynthesis system was designed and assembled (Figure 5a,b).A solar panel was used to provide constant bias, a homemade flow cell with NiCo 2 O 4 NCs was employed as the anode, and seawater was directly utilized as the electrolyte and chlorine and oxygen source.The solar-powered electrosynthesis system successfully achieved the gram-scale electrosynthesis of α,α-dichloroketone under AM 4.5G illumination (300 mW cm −2 ) (Figure 5c).This demonstrates the potential of the electrosynthesis strategy for the sustainable production of organochlorides from seawater.Moreover, taking the electrosynthetic product as the building block, mitotane, the only FDA-approved drug for adrenocortical carcinoma treatment, was successfully synthesized with a 66% overall isolated yield (Figure 5d).This highlights the application potential of our electrosynthesis method in drug synthesis.Furthermore, the universality of this electrosynthesis strategy for α,α-dichloroketones was examined (Figure 5e).A series of alkynes bearing electron-donating and electron-withdrawing groups on the phenyl ring were all efficiently transformed to the corresponding α,α-dichloroketone products.Moreover, internal alkynes were also applicable for the oxydichlorination with good yield.These results highlight the applicability of electrosynthesis system without additional chlorine sources and electrolytes for electrocatalytic oxydichlorination.

■ CONCLUSIONS
In summary, we demonstrate the efficient electrosynthesis of α,α-dichloroketones by directly using seawater as the chlorine source and electrolyte solution.A NiCo 2 O 4 NC anode was designed by analyzing the reaction process, which can inhibit the competitive O 2 and Cl 2 evolution reactions and concentrate Cl − and OH − ions, accelerating α,α-dichloroketone electrosynthesis.NiCo 2 O 4 NCs yield α,α-dichloroketone with 81% yield, 61% FE, and 44.2 mmol g cat.−1 h −1 yield rate at the optimum potential of 1.30 V, which is superior to the performance of NiCo 2 O 4 NSs.A mechanistic study revealed that this reaction is triggered by the attack of Cl • radicals on alkynes, followed by OH • and another Cl • radical addition.The key Cl • , OH • , and carbon radical species were identified by EPR and HR−MS.Additionally, a solar-powered electrosynthesis system was designed and achieved gram-scale α,αdichloroketone electrosynthesis.Moreover, an adrenocortical carcinoma treatment drug, mitotane, was synthesized with the use of the obtained α,α-dichloroketones as building blocks.Furthermore, 14 other examples of functionalized alkynes were oxydichlorinated in our electrosynthesis system, highlighting the universality of our strategy.This work not only opens up a sustainable strategy to synthesize organochlorides but also provides a new avenue for the direct utilization of abundant seawater.
■ METHODS Synthesis of NiCo 2 O 4 Nanocones (NCs) and NiCo 2 O 4 Nanosheets (NSs). 37,38In situ growth of NiCo 2 O 4 nanocones on as-treated carbon paper (CP) was carried out by a general hydrothermal method followed by subsequent calcination.Specifically, 2 mmol of Co(NO 3 ) 2 •6H 2 O along with 1 mmol of Ni(NO 3 ) 2 •6H 2 O were dissolved in 40 mL of DI water, followed by the addition of 3 mmol of NH 4 F and 6 mmol of urea into the solution with continuous stirring.After transfer of the solution into a 50 mL Teflon-lined autoclave and immersion of a piece of as-treated CP (2 × 3 cm 2 ) into the solution, the autoclave was properly sealed and treated at 100 °C for 12 h.After cooling to room temperature, the sample was washed with DI water and ethanol several times and then dried in a vacuum drying oven at 60 °C overnight.Finally, the dried sample was annealed in a tube furnace at 350 °C for 2 h under an air atmosphere.The loading mass of NiCo 2 O 4 NCs was 4.4 mg cm −2 .NiCo 2 O 4 nanosheets were synthesized by a similar method, except 12 mmol of hexamethylene-tetramine was used to replace urea.The loading mass of NiCo 2 O 4 NSs was 4.9 mg cm −2 .Electrochemical Measurements.Electrochemical tests were carried out using a CS350MA (CorrTest, Wuhan) electrochemical workstation in a two-chamber electrochemical cell consisting of a working electrode, a Pt plate counter electrode, and a Ag/AgCl reference electrode.All the potentials in this work were referenced to Ag/AgCl without iR correction unless otherwise stated.The cathode cell (8 mL) and anode cell (8 mL) contained seawater/0.5 M NaCl (8.0 mL) and a mixed solution of 0.5 M NaCl (6.0 mL) and acetonitrile (2.0 mL) with 0.1 mmol of 1a was dissolved.Then, chronoamperometry or chronopotentiometry was carried out under magnetic stirring (800 rpm).After the reactions were finished, dodecane was added to the reaction system as an internal standard.Then, the solution at the anode cell was extracted with dichloromethane (DCM) and tested using GC to calculate the product yield.The double layer capacitance (C dl ) was calculated from the slope of the linear fit of plots of current density versus scan rate.The cyclic voltammograms (CVs) were recorded in the non-Faradaic region, where charging of the double layer is responsible for the current density.
Additional characterizations, performance measurements, theoretical models, and 1 H and 13

Figure 2 .
Figure 2. Electrocatalyst screen, design, and characterization.(a) ΔG(* + OH − − e − → *OH) and ΔG(*OH + OH − − e − → *O + H 2 O) over different anode materials.(b) Comparison of E ads values for OH and Cl on Ni and Co sites.(c) Concentrations of the main anions in the natural seawater collected from the Bohai Sea, Tianjin, China.(d) Comparison of electrosynthesis performances at 1.30 V. (e) 1 H NMR and (f) GC−MS detection of the products.(g) Electric field on the surface of NiCo 2 O 4 samples with different tip radii of 5 (top) and 12 nm (bottom).(h) Surface Cl − and (i) OH − concentration distributions adjacent to the surface of NiCo 2 O 4 NCs.(j) SEM image of NiCo 2 O 4 NCs.Error bars correspond to the standard deviation (SD) of three independent measurements.

Figure 3 .
Figure 3. Eectrosynthesis performance.(a) Potential-dependent FEs and yields and (b) yield rates toward 2a.(c) Time-dependent yields over NiCo 2 O 4 NCs.(d) Cycle-dependent FEs and yields of 2a electrosynthesis over NiCo 2 O 4 NCs.(e) Cl 2p XPS spectra of NiCo 2 O 4 NCs and NSs.(f) Field-induced Cl − loss in the electrolytes caused by NiCo 2 O 4 NCs and NSs.(g) Nyquist plots at 1.30 V vs Ag/AgCl of NiCo 2 O 4 NCs and NSs.Error bars correspond to the SD of three independent measurements.

2 O 4
NCs can concentrate electronegative OH − and Cl − ions.It was verified by experiments.A constant voltage of 1.30 V was applied to the NiCo 2 O 4 NCs and NiCo 2 O 4 NSs for 20 min, and then the two electrodes were washed with deionized water and dried under vacuum for characterization.XPS measurements (Figure 3e) show that the NiCo 2 O 4 NCs exhibit two typical Cl 2p XPS peaks at 198.1 eV (Cl 2p 3/2 ) and 199.8 eV (Cl 2p 1/2 ), 9 while the NiCo 2 O 4 NSs exhibit much weaker Cl 2p peaks at the same position.Meanwhile, the adsorption of Cl − ions was quantified by measuring the Cl − ion concentration variation of the electrolyte solution.A larger Cl − ion concentration difference value was observed before and after electrolysis when NiCo 2 O 4 NCs was used as the electrode, demonstrating that NiCo 2 O 4 NCs adsorb more Cl − ions than NiCo 2 O 4 NSs (Figure 3f).Moreover, after electrolysis for 20 min at 1.30 V, the electrolyte solution pH values decreased to 1.73 and 1.97 for NiCo 2 O 4 NCs and NiCo 2 O 4 NSs, respectively.The lower pH indicates that more OH − ions are consumed, caused by the ion enrichment effect of NiCo 2 O 4 NCs.These results experimentally prove that the high-curvature nanostructure can concentrate Cl − and OH − ions, as predicted by theoretical calculations.Additionally, NiCo 2 O 4 NCs show a much smaller charge transfer resistance (R ct ) in electrochemical impedance spectra, reflecting an acceleration of the charge transfer process at electrode/solution interfaces over NiCo 2 O 4 NCs (Figure 3g).Therefore, the concentrated reactant ions and accelerated charge transfer around the tips of NiCo 2 O 4 NCs conjointly promote the α,α-dichloroketone electrosynthesis performance.Mechanistic Study.Three possible pathways are considered to trigger the oxydichlorination of alkynes (Supplementary Figure 23): (1) The alkynyls on alkynes are first electrooxidized to form carbocations and then react with Cl − to form vinyl radicals.(2) Cl − ions are first oxidized to Cl 2 and dissolved in water to form ClO − , which acts as an oxidation and chlorination agent to react with alkynes.(3) Cl − ions are initially electrooxidized to Cl • radicals, which attack the αcarbon of alkynes to form vinyl radicals for the following transformation.

Figure 4 .
Figure 4. Mechanistic studies.(a) LSV curves measured in 0.5 M Na 2 SO 4 solution.(b) Comparison of 2a yields with and without 1,1diphenylethylene in 0.5 M NaCl solution.(c) EPR trapping for radicals during the electrosynthesis process over NiCo 2 O 4 NCs.HR−MS analysis of the spin-trapping experiment of (d, e) carbon radicals, (f) chlorine radicals, (g) hydroxyl radicals, and (h) 18 O-labeled product.(i) A proposed possible reaction mechanism.