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. 2025 Sep 25;5(6):492–497. doi: 10.1021/acsorginorgau.5c00091

Electrochemical Halogenation and Etherification of Alcohols Enabled by a Halide-Coupled Phosphine Oxidation

Emma A Hale 1, Vincent TC Ngo 1, Qilei Zhu 1,*
PMCID: PMC12679309  PMID: 41356455

Abstract

Phosphine-mediated nucleophilic substitution reactions of alcohol substrates, such as the Appel and Mitsunobu reactions, have found widespread applications in chemical synthesis. However, their reliance on stoichiometric chemical oxidants (e.g., carbon tetrachloride and azodicarboxylate reagents) often results in limited functional group tolerance, environmentally hazardous wastes, and unsatisfactory reaction economy. Herein, we describe a user-friendly electrochemical Appel reaction employing readily available tetrabutylammonium halide salts ( n Bu4N+X–, X = Cl, Br, and I) as the halogen source. A survey of alcohol substrates revealed broad functional group tolerance, including complex pharmaceutical and bioactive scaffolds. Electroanalytical voltammetry and control experiments support a halide-coupled phosphine oxidation pathway under mild anodic potentials, affording key alkoxyphosphonium intermediates prior to nucleophilic substitution. Notably, the electrochemical halogenation conditions can also facilitate intramolecular alcohol etherification with oxidation-sensitive phenols and weakly acidic alcohol nucleophiles.

Keywords: Electrosynthesis, Halogenation, Alcohol, Nucleophilic Substitution, Sustainability

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Despite the abundance of alcohol derivatives in feedstock chemicals and downstream products from biomass, direct and economical nucleophilic substitution of the hydroxyl group to access value-added products under mild conditions and with broad functional group tolerance remains a challenge. , Primary and secondary alcohols are typically activated stepwise by conversion into better leaving groups (e.g., sulfonate, phosphonate, and carboxylate esters) prior to nucleophilic substitution. Alternatively, Brønsted/Lewis acid additives can be employed to activate the hydroxyl group in situ. However, these methods often suffer from poor functional group compatibility and limited overall reaction economy. Over the past several decades, redox-condensation strategies, exemplified by the Appel and Mitsunobu reactions, , have emerged as widely used methods for converting alcohols into alkyl halides, esters, sulfonamides, and aryl ethers. These transformations proceed in the presence of stoichiometric chemical oxidants and phosphines via key alkoxyphosphonium (RO–PPh3 +) intermediates (Scheme A), which are more reactive toward nucleophilic substitution because the phosphine oxide (e.g., OPPh3) is a much better leaving group than the hydroxide anion (OH–). Nevertheless, the application of redox-condensation strategies, such as the Appel reaction, in large-scale synthesis is hindered by their reliance on stoichiometric carbon tetrahalides (CCl4 and CBr4), which exhibit poor atom economy and present significant environmental and biological hazards.

1. Appel Reactions Enabled by Chemical Oxidants and Electrochemical Oxidation.

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Recent advances in the Appel reaction have enabled the use of alternative oxidizing halogenation reagents, such as oxalyl chloride, hexachloroacetone, dialkyl bromomalonates, and N-halogen amides, thereby improving reaction practicality and expanding the synthetic scope. However, these methods still present notable drawbacks, including the need for tedious synthesis of the halogenating agents, high reagent loadings, and incompatibility with nucleophilic moieties or functional groups prone to oxidative decomposition. Furthermore, most of these halogenation reagents cannot be readily generalized across chlorination, bromination, and iodination reactions, due to both the synthetic challenges involved and the markedly different reactivities of analogous chlorine-, bromine-, and iodine-derived chemical oxidants.

To address these challenges, we envisioned that a general alcohol halogenation protocol could benefit from decoupling the oxidizing reagent, which is responsible for generating the alkoxyphosphonium intermediate in the classic Appel reaction, from the source of the halide nucleophile. In this design, electrochemistry could serve as a tunable and traceless oxidant, replacing stoichiometric chemical oxidants, while readily available tetraalkylammonium halide salts ( n Bu4N+X–, X = Cl, Br, I) act as ideal halogen sources owing to their low costs, great stability, and operational simplicity. Inspired by both the stepwise and one-pot deoxygenative electrochemical strategies − for alcohol nucleophilic substitution reported by Ohmori , and others, , as well as our recent studies on alcohol amination and cyanation, we hypothesized that anodic oxidation of phosphine could be leveraged to generate the key alkoxyphosphonium cation, which would then undergo direct nucleophilic substitution by halide anions (Cl–, Br–, I–) from the tetraalkylammonium halides to afford the corresponding alkyl halides (Scheme B). Notably, while an electrochemical bromination step was previously proposed in the context of an alcohol cross-coupling reaction, the reaction efficiency and synthetic scope were not directly evaluated.

To test the feasibility of the electrochemical alcohol halogenation design, we initiated screening of electrolysis conditions with an alcohol chlorination reaction using n Bu4NCl as both the supporting electrolyte and Cl– source (Table ). Gratifyingly, electrolysis of 3-phenyl-1-propanol (1) with triphenylphosphine (PPh3) and n Bu4NCl under N2 atmosphere, employing a platinum mesh anode and a porous nickel foam cathode, afforded the desired chlorinated product 2 in 51% yield (entry 1). The addition of 1,8-diazabicyclo[5.4.0]­undec-7-ene (DBU, pK aH = 13.9 in DMSO as a Brønsted base increased the yield to 89% (entry 2), presumably by facilitating alcohol deprotonation and thereby enhancing trapping of the anodically generated PPh3 •+ to form the alkoxyphosphonium cation. In contrast, less basic 2,4,6-collidine (pK aH ≈ 4.0) , and oxidation-labile triethylamine (pK aH = 9.0, Ep/2 = 0.45 V vs Fc+/Fc) , bases led to diminished yields due to uncompetitive deprotonation of the alcohol and potential oxidation decomposition (entries 3–4). Solvent screening revealed that 1,2-dichloroethane gave a reduced yield of 34%, while more polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), and N-methylpyrrolidone (NMP) completely inhibited chlorination (see Supporting Information, Table S2.1). Control experiments conducted without PPh3 or electrolysis failed to produce any chlorinated product (entries 5–6), consistent with the electrochemical oxidation-enabled alcohol halogenation.

1. Survey of Reaction Conditions for Electrochemical Alcohol Chlorination, Bromination, and Iodination .

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Entry Supporting Electrolyte Base (2.0 equiv) Additive (8.0 equiv) Yield of 2 (%)
1 n Bu4N+Cl– no base – 51
2 n Bu4N+Cl– DBU – 89
3 n Bu4N+Cl– 1,3,5-collidine – 34
4 n Bu4N+Cl– NEt3 – 0
5 n Bu4N+Cl– DBU – 0
6 n Bu4N+Cl– DBU – 0
Entry Supporting Electrolyte Base (2.0 equiv) Additive (8.0 equiv) Yield of 3/4 (%)
7 n Bu4N+Br– DBU – 51
8 n Bu4N+Br– DBU HFIP 88
9 n Bu4N+Br– DBU HFIP 98
10 n Bu4N+Br– DBU CF3CH2OH 0
11 n Bu4N+Br– DBU MsOH 6
12 n Bu4N+Br– DBU (PhO)2POOH 0
13 n Bu4N+I– DBU HFIP 97
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a

No PPh3 is added.

b

No electrolysis.

c

Platinum mesh cathode.

d

All reactions were performed at room temperature on 0.2 mmol scale under a N2 atmosphere. Yields of product 2, 3 and 4were determined by gas chromatography.

Next, we investigated whether the optimized chlorination conditions could be extended to alcohol bromination and iodination. Simply replacing n Bu4NCl supporting electrolyte with n Bu4NBr under the standard conditions afforded desired (3-bromopropyl)­benzene (3) product in 51% yield, accompanied by 42% of the chlorinated byproduct 2 (entry 7). We attributed this byproduct formation to competitive trapping of the alkoxyphosphonium intermediate by chloride anion generated in situ from cathodic reduction of the CH2Cl2 solvent. We hypothesized that suppressing CH2Cl2 reduction would improve bromination efficiency. To this end, we introduced a proton donor additive to promote the proton reduction/hydrogen evolution reaction (HER) over CH2Cl2 reduction. Indeed, addition of acidic 1,1,1,3,3,3-hexafluoroisopropanol (HFIP, pK a = 17.9) , increased the yield of 3 to 88% with only 9% of 2 formed (entry 8). The bromination yield was further improved to 98% by using a platinum mesh cathode, which can catalyze HER more efficiently than nickel (entry 9). In contrast, use of less acidic and more nucleophilic 2,2,2-trifluoroethanol (TFE, pK a = 23.5) completely suppressed bromination (entry 10), likely due to competitive trapping of PPh3 •+ by TFE rather than the alcohol substrate 1. More acidic additives, such as methanesulfonic acid (MsOH, pK a = 1.56) and diphenylphosphoric acid (pK a = 3.8), also diminished the electrochemical bromination efficiency (entries 11–12), presumably by protonating and deactivating the DBU base, thereby impeding anodic generation of the alkoxyphosphonium intermediate. Notably, the optimized bromination conditions (entry 9) were also effective for iodination, as replacement of n Bu4NBr with n Bu4NI in CH2Cl2 furnished the iodoalkane product 4 in 97% yield (entry 13). The conventional approach in electrosynthesis to suppress undesired side reactions due to redox events on the counter-electrodes is the use of divided cells, which physically separate the two electrochemical half-reactions. However, this setup can be practically challenging for electrolysis under inert atmosphere and often leads to high cell resistance. In this work, the addition of HFIP effectively inhibited deleterious CH2Cl2 solvent reduction at the cathode by promoting proton reduction and hydrogen evolution, thereby drastically enhancing the efficiency of electrochemical bromination and iodination.

In our previous report on electrochemical alcohol cyanation, we proposed an iodide-coupled phosphine oxidation mechanism in which anodic oxidation of iodide generates an iodophosphonium cation (I–PPh3 +) intermediate, which subsequently undergoes alcohol substitution to yield the alkoxyphosphonium cation under mild anodic potentials. To determine whether analogous chloride- or bromide-coupled phosphine oxidation pathways operate under the present electrochemical halogenation conditions, we performed cyclic voltammetry (CV) experiments. On a platinum (Pt) working electrode in CH2Cl2, n Bu4NCl exhibited an irreversible anodic oxidation peak at Ep = 0.66 V vs Fc+/Fc, while n Bu4NBr displayed two oxidation peaks at Ep1 = 0.31 V and Ep2 = 0.54 V (Scheme A). These results indicate that both n Bu4NCl and n Bu4NBr are redox-active, with anodic oxidation thermodynamically more favorable than phosphine oxidation on Pt. To further characterize halide oxidation, we performed linear sweep voltammetry (LSV) on a Pt rotating disk electrode (RDE) and determined the electron-transfer stoichiometry from Koutecký–Levich analysis. Comparing the LSV results of n Bu4NCl with that of a Fc+/Fc redox couple revealed that Cl– oxidation proceeds via a single-electron transfer, consistent with the Cl2/Cl– redox couple (Scheme B; also see Supporting Information, Section S5.2). In contrast, Br– oxidation displayed cumulative electron-transfer stoichiometries of 0.72 at E = 0.47 V and 1.00 at E = 0.82 V (see Supporting Information Section S5.4), indicating a stepwise oxidation pathway involving a tribromide (Br3 –) intermediate. This assignment is in agreement with prior studies of Et4NBr in acetonitrile and nitrobenzene, , in which the first oxidation corresponds to the Br3 –/Br– couple and the second to the Br2/Br3 – couple.

2. Mechanism of the Electrochemical Appel Reactions.

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a Cyclic voltammograms were collected on a Pt working electrode with 1 mM n Bu4NCl, n Bu4NBr, and PPh3.

b Determined from linear sweep voltammetry on a Pt rotating disc electrode.

c The carboxylation reaction was heated to 100 °C.

Intriguingly, addition of PPh3 to solutions of n Bu4NCl and n Bu4NBr resulted in new, cathodically shifted, irreversible oxidation peaks in the cyclic voltammograms at Ep = 0.57 and 0.28 V, respectively, accompanied by increased peak currents (Scheme A). Koutecký–Levich analysis indicated that both oxidation events correspond to two-electron processes (see Supporting Information, Section S5), consistent with previously reported iodide-mediated PPh3 oxidation. These results support that Cl– and Br– anions can also mediate PPh3 oxidation to form the corresponding Cl– PPh3 + and Br–PPh3 + species at lower potentials than direct PPh3 oxidation. Furthermore, density functional theory (DFT) thermodynamic calculations revealed that the halogen–phosphorus (X–P) covalent interactions in Cl–PPh3 • and Br–PPh3 • radicals are stronger than the halogen–halogen (X–X) bonds in Cl2 •– and Br2 •– radical anions (see Supporting Information, Section S6). Such X•–PPh3 interactions likely contribute to stabilizing the X• radicals generated from anodic halide oxidation, thereby accounting for the cathodic shift in oxidation potentials observed in the presence of PPh3.

Additionally, control experiments in which PPh3 and n Bu4NCl or n Bu4NBr were replaced with Ph3PCl2 or Ph3PBr2, respectively, without electrolysis, yielded no chlorinated or brominated products (2 or 3) from alcohol 1. This result suggests that Ph3PCl2 or Ph3PBr2 is unlikely to be an intermediate under the electrochemical halogenation conditions. Taken together, these findings support the proposed mechanism for the electrochemical Appel reaction shown in Scheme C. The process begins with halide-coupled anodic oxidation of PPh3 to form the X–PPh3 + cation intermediate. Subsequent alcohol substitution and deprotonation generate the alkoxyphosphonium intermediate, which then undergoes nucleophilic substitution by the halide anion to afford the halogenated product. The cathodic half-reaction likely involves CH2Cl2 reduction under chlorination conditions or hydrogen evolution from HFIP under bromination and iodination conditions, thereby completing the electrochemical circuit. Moreover, chlorination and bromination of a chiral secondary alcohol selectively afforded the stereochemically inverted chiral alkyl chloride and bromide products (Scheme D; also see Supporting Information, Section S7), consistent with the stereochemical outcome of the classic Appel reaction. In contrast, the electrochemical iodination resulted in significant racemization, likely due to a Finkelstein-type nucleophilic self-exchange process.

Halogenation of diverse alcohol substrates was performed under the optimized electrochemical halogenation reaction conditions (Table ). Consistent with the reaction optimization experiments, isolated yields for chlorination, bromination, and iodination of alcohol 1 were 86%, 96%, and 91%, respectively. Secondary alcohols (5–7) were also smoothly converted to the corresponding alkyl halides. Unsaturated alcohols bearing terminal or internal alkenes and alkynes (8–21) furnished the desired halogenated products in good to excellent yields. Notably, electrophilic phosphine radical cations have previously been shown to undergo radical addition to alkenes , and alkyne to give tetrasubstituted phosphonium cations; however, no alkene/alkyne phosphonation products were detected here, indicating that nucleophilic trapping of PPh3 •+ by the hydroxyl group is favored over addition to unsaturated C–C bonds. Gratifyingly, a wide range of functional groups was tolerated under the electrochemical halogenation conditions, including sulfonamides (22–24), carbamates (25), amides (26), electron-rich arenes (27–29), and epoxides (30–31), with no detectable nucleophilic epoxide ring-opening byproducts. In addition, 64% yield of the bromination product 28 was also obtained from electrolysis using standardized IKA ElectraSyn under the same conditions (see Supporting Information, section VIII), indicating the compatibility of the electrochemical Appel reaction conditions with different electrolysis setups. Heterocyclic alcohols, including pyridine (32–37) and thiazole (38–40) derivatives, also underwent chlorination, bromination, and iodination in moderate to high yields. Furthermore, Simvastatin, a drug used to treat hypercholesterolemia, was successfully halogenated to yield the chloro-, bromo-, and iodo-derivatives (41–43) in 61%, 81%, and 71% isolated yields, respectively. Gram-scale electrolysis of Simvastatin in a batch reactor also delivered 41–43 in 68%, 64%, and 66% yields. Excitingly, primary and secondary alcohols in cholesterol steroid (44–46) and nucleotide building blocks, such as uridine (47–49), were efficiently halogenated, demonstrating the potential of this method for the late-stage functionalization of complex drug molecules and bioactive compounds. In addition, the alcohol halogenation could be combined in a cascade sequence with in situ etherification to furnish aromatic ether 50 in 97% yield. Although phenols and phenoxides can be anodically oxidized at potentials lower than the PPh3 •+/PPh3 redox couple, no phenol oxidation products were detected, highlighting the mild electrochemical potentials of the halogenation conditions. Moreover, cyclic ethers 51 and 52 were obtained in 68% and 55% yields, respectively, from the corresponding diol substrates. This reactivity underscores the advantage of replacing azodicarboxylate oxidants in the classical Mitsunobu reaction with anodic oxidation, by enabling the use of weakly acidic nucleophiles, such as alcohols that are ineffective in traditional Mitsunobu chemistry, to react with the alkoxyphosphonium intermediates. Intriguingly, intermolecular etherification byproducts were not observed during the optimized bromination and iodination reactions (Table , entries 9 and 13), likely due to the kinetically more favorable nucleophilic trapping of the alkoxyphosphonium cation by the Br– and I– counteranions.

2. Substrate Scope Survey of Electrochemical Chlorination, Bromination, and Iodination of Alcohols.

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a

0.1 M n Bu4NI supporting electrolyte.

b

With 1.0 eq. DBU base.

c

With 1.0 eq 2,6-ditertbutylpyridine base.

d

All reactions were performed at room temperature on 1.0 mmol scale under a N2 atmosphere.

In conclusion, we have developed an electrochemical alcohol halogenation reaction that operates under mild anodic potentials to generate alkoxyphosphonium intermediates for the chlorination, bromination, and iodination of alcohols. The method employs readily available and inexpensive tetraalkylammonium chloride, bromide, and iodide salts as halogen sources. By replacing the oxidizing halogenation reagents used in the classic Appel reaction, these electrochemical conditions exhibit broad functional group tolerance and are compatible with structurally complex substrates. This work highlights the potential of electrochemistry to improve the practicality and cost-effectiveness of Appel- and Mitsunobu-type alcohol functionalizations, while simultaneously expanding their synthetic scope beyond the limitations of stoichiometric chemical oxidants.

Supplementary Material

gg5c00091_si_001.pdf (9.4MB, pdf)

Acknowledgments

V. Ngo thanks the undergraduate researcher fellowship from the Wilkes Center for Climate Science & Policy, University of Utah and the Undergraduate Research Opportunity Program (UROP) from the University of Utah. E. A. Hale thanks the Graduate Research Fellowship from the University of Utah.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsorginorgau.5c00091.

  • Materials and methods, data analysis, control and optimization experiments, product isolation and characterization data. Electrochemical mechanistic studies (PDF)

†.

E.A.H. and V.T.C.N. contributed equally to this work. E. A. Hale, V. Ngo, and Q. Zhu conceived and designed the project. E. A. Hale, V. Ngo carried out the synthesis and electrolysis experiments. The manuscript was written through contributions of all authors and all authors have given approval to the final version of the manuscript. CRediT: Emma A. Hale data curation, formal analysis, investigation, methodology, writing - review & editing; Vincent TC Ngo data curation, formal analysis, investigation, methodology, validation.

This work was supported by the startup fund given by the University of Utah. Acknowledgment is also made to the donors of the American Chemical Society Petroleum Research Fund, for partial support of this research (PRF# 67421-DNI1).

The authors declare no competing financial interest.

Published as part of ACS Organic & Inorganic Au special issue “2025 Rising Stars in Organic and Inorganic Chemistry”.

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Associated Data

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Supplementary Materials

gg5c00091_si_001.pdf (9.4MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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