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DOI: 10.1055/a-1511-8869
Chemoselective Electrochemical Oxidation of Secondary Alcohols Using a Recyclable Chloride-Based Mediator
The CCFLOW Project (Austrian Research Promotion Agency FFG No. 862766) is funded through the Austrian COMET Program by the Austrian Federal Ministry of Transport, Innovation and Technology (BMVIT), the Austrian Federal Ministry of Science, Research and Economy (BMWFW), and the State of Styria (Styrian Funding Agency SFG).
Abstract
Selective anodic oxidation of alcohols in the presence of other functional groups can be accomplished by using nitroxyl radical mediators. However, the electrochemical chemoselective oxidation of secondary alcohols in the presence of primary alcohols is an unsolved issue. Herein, we report an electrochemical procedure for the selective oxidation of secondary alcohols by using an inexpensive chloride salt that acts as a redox mediator and supporting electrolyte. The method is based on the controlled anodic generation of active chlorine species, which selectively oxidize secondary alcohols to the corresponding ketones when primary hydroxy groups are present. The method has been demonstrated for a variety of substrates. The corresponding ketones were obtained in good to excellent yields. Moreover, the chloride salt can be easily recovered by a simple extraction procedure for reuse, rendering the method highly sustainable.
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Key words
electroorganic synthesis - alcohols - oxidation - redox mediators - anodic oxidation - sustainabilityOxidations of alcohols to aldehydes, ketones, or carboxylic acids are chemical transformations that are commonly used on large scale in the pharmaceutical industry.[1] Classical metal-based reagents to accomplish selective alcohol oxidation, such as CrO3 or pyridinium chlorochromate (PCC), are highly problematic for industrial applications, due to the toxicity of chromium salts and the undesirable waste generated.[2] During the past few decades, alternative metal-free oxidation procedures have been used extensively for the synthesis of pharmaceuticals, including, for example, the Moffatt process, involving activation of DMSO, and its modifications (e.g., Swern oxidation)[3] and TEMPO-mediated transformations (Scheme [1a]).[4]
In parallel to the development of TEMPO-mediated alcohol oxidations with stoichiometric amounts of oxidants, anodic oxidation has emerged as a practical and greener strategy.[5] Indeed, since its conception by Semmelhack et al. in the 1980s,[6] anodic oxidation of alcohols mediated by TEMPO or other nitroxyl radicals has been considered as an archetypal example of an electrochemical transformation that cannot be accomplished through direct electrolysis.[7] TEMPO enables the facile and selective electrochemical oxidation of hydroxy groups to aldehydes or ketones in the presence of other functional groups.[5] [7] In addition to nitroxyl radicals, other mediators for the electrochemical oxidation of alcohols have been reported. Examples include bromides,[8] iodides,[9] nitrates,[10] nickel peroxide species generated in situ,[11] and dual halide–TEMPO mediatory systems.[12] Despite this progress, little attention has been devoted to the chemoselectivity of the electrochemical reaction when both primary and secondary alcohol groups are present in a molecule. Indeed, TEMPO-like mediators typically favor the oxidation of primary alcohols over secondary ones (Scheme [1b]; top) due to steric effects, as the mechanism involves the coupling of a nitroxonium cation intermediate with the hydroxy group.[5] [6] [7]
We questioned whether a different mediator system might realize selective oxidation of secondary alcohols in the presence of primary alcohols, which would significantly expand the scope of electrochemical alcohol oxidations. Among the many conventional strategies for the selective oxidation of secondary alcohols using chemical oxidants,[13] the chlorine–pyridine (Cl2–py) complex drew our attention. In this complex, the reactivity of Cl2 is diminished.[14] Indeed, the complex has been described as a mild chlorine reagent that can selectively oxidize secondary alcohols in the presence of primary alcohols.[15] We envisaged that electrochemical generation of active chlorine, in which the amount of the reactive species is controlled by the cell current, would have a similar effect on the chemoselectivity of the reaction (Scheme [1b]; bottom).
To test our hypothesis, we began our investigation with two preliminary experiments, aimed at assessing whether electrochemically generated active chlorine inverts the chemoselectivity of primary versus secondary alcohol oxidation when compared with TEMPO under analogous conditions (Scheme [2]). For this purpose, 2-ethylhexane-1,3-diol (1a) was used as a model substrate. Tetramethylammonium chloride (Me4NCl) was selected as the supporting electrolyte and the source of the chloride mediator, giving it a dual role in the reaction. This chloride source was chosen due to its low price, relatively good solubility in polar aprotic solvents containing small amounts of water, and the ease with which it can be separated from organic mixtures, for example, by extraction. Electrolysis experiments were carried out in standard 5 mL IKA ElectraSyn 2.0 vials with graphite as the anode material and stainless steel as the cathode. A MeCN–H2O mixture was used as the solvent in both cases, with a concentration of 1a of 0.1 M. For the TEMPO-mediated oxidation, the aqueous phase contained 0.1 M of a phosphate buffer of pH 9.2,[5] [16] which also acted as the supporting electrolyte. As expected, when TEMPO was used as the mediator, aldehyde 3a was observed as the major oxidation product (Scheme [2]). After 2 F/mol of charge had been passed at 10 mA (6.7 mA/cm2), 85% of the starting material had been oxidized, with 80% selectivity toward aldehyde 3a. Gratifyingly, with Me4NCl as the supporting electrolyte and mediator, ketone 2a was almost exclusively formed, although with a modest conversion of 12% (based on GC/FID analysis).
The electrolysis conditions for the chemoselective oxidation of secondary alcohols were then optimized with the aim of increasing the reaction conversion while maintaining the high selectivity (Table [1]). The nature of the active chlorine species present in solution is highly dependent on the acidity of the reaction medium. Therefore, the effects of the presence of an acid (5 equiv AcOH) or a basic pH in the aqueous component of the solvent mixture were evaluated (Table [1], entries 1–3). As in the previous experiments, electrolysis was carried out at a constant current of 10 mA (~6.7 mA/cm2). Notably, both these variations from neutral pH had a positive effect on the reaction outcome, most probably due to the presence of hypochlorite (in the basic medium) or hypochlorous acid (with AcOH) in solution. When reticulated vitreous carbon (RVC) was used as the anode material (entry 4), a lower selectivity was observed. This might be ascribed to more-efficient chloride oxidation by the graphite material compared with RVC. The best results were obtained with five equivalents of AcOH, corresponding to a ~40:1:1 MeCN–H2O–AcOH solvent mixture. Consequently, all subsequent experiments were carried out in the presence of the acid.
a Reaction conditions: 5 mL IKA ElectraSyn 2.0 vial, solvent (3 mL), 1a [0.3 mmol (entries 1–7) or 0.6 mmol (entries 8–11)], Me4NCl [0.1 M (entries 1–7) or 0.5 M (entries 8–11)]. (+): anode. (–): cathode; Cgr: graphite; RVC: reticulated vitreous carbon; Fe: stainless steel.
b Determined by GC/FIC analysis.
c Determined by GC/FID analysis as the peak area percentage of 2a with respect to all other peaks except the starting material.
The use of a different anode (RVC; Table [1], entry 4) or cathode material (Ni; entry 5) did not improve the results. Indeed, RVC provided a significantly reduced selectivity toward the target ketone 2a, and the solution turned orange upon electrolysis. As expected, the current density had a significant effect on both the reaction conversion (current efficiency) and the oxidation chemoselectivity (entries 6 and 7). Thus, when the electrolysis was performed at 20 mA (~13 mA/cm2), a lower conversion and a lower selectivity were obtained with respect to those at 10 mA (entry 3 versus entry 6). Decreasing the current to 5 mA (3.3 mA/cm2) improved the conversion to 53% and resulted in an excellent selectivity to 2a of 97%. Increasing the concentration of the reaction components (entry 8) followed by a gradual increase in the amount of charge (entries 8–10) led to excellent conversion (96%) and selectivity (96%) after 4.5 F/mol had been passed (entry 10). A further increase of the charge to 5 F/mol increased the amounts of overoxidation byproducts (95% selectivity; entry 11). Because the solvent proportion had been kept constant, experiments with 0.2 M 1a used 2.5 equivalents of AcOH. As expected, when the reaction mixture was stirred without electrolysis, no conversion of the starting material was observed (entry 12). Additional optimization results are reported in Table S1 of the Supporting Information (SI). Under these conditions, the method can be regarded as an electrochemical version of Stevens’s alcohol oxidation procedure using NaOCl in acetic acid.[17] Notably, anodic generation of the active chlorine species avoids the use of the corrosive reagent and requires only a small excess of AcOH to proceed.
With the optimized conditions in hand, we applied the electrochemical procedure to several compounds containing both a secondary and a primary alcohol in their structures (Scheme [3a]). The high purity with which the model product 2a was obtained permitted a simple workup procedure involving only evaporation of the solvent under reduced pressure, dilution of the residue with aqueous NaHCO3, and extraction with CH2Cl2.[18] By using this procedure, 2a was obtained in near-quantitative yield (95%) and ketone 2b was obtained in 78% yield by oxidation of hexadecane-1,2-diol (78%). More complex substrates containing aromatic rings produced higher amounts of byproducts, mainly due to overoxidation (up to 20%). In these cases, purification by column chromatography was necessary. Indeed, separation by chromatography proved difficult to achieve, and some of the products could be isolated in moderate yields only, or with small amounts of impurities (for details, see the SI).
However, the method proved compatible with several aromatic diols containing halo (2d and 2e), nitro (2f), or cyano groups (2g). Compounds 2f and 2g were obtained in relatively low yields. In both cases, only an 80% conversion was achieved and byproduct formation was observed. Several additional alcohols 3 containing either a primary or a secondary hydroxy group (Scheme [3b]) were also subjected to the reaction conditions. Thus, borneol and cyclohexanol produced the corresponding ketones 4a and 4b in good yields. Benzylic alcohols were transformed into benzaldehydes (4c and 4d) or aryl ketones (4e and 4f) in good yields, proving that this chloride-mediated electrochemical method is highly versatile.
An additional advantage of using Me4NCl as the supporting electrolyte and redox mediator is that it has a very low solubility in nonpolar solvents and can therefore be readily separated from the reaction mixture for recycling. To demonstrate this feature, the model reaction 1a → 2a was carried out under the standard conditions. Once the electrolysis was finished, the reaction mixture was evaporated under reduced pressure. Treatment of the residue with CH2Cl2 (5 mL) resulted in precipitation of Me4NCl. Then, 75 μL of H2O were added to the mixture and the vessel was thoroughly shaken until all the solid had dissolved. The aqueous phase was carefully retrieved with a syringe and added to a fresh solution of 1a in 40:1 MeCN–AcOH (see Figure S1 in the SI). Gratifyingly, electrolysis of the resulting mixture under standard conditions resulted in identical results to those of the initial oxidation. Facile electrolyte recovery through this recycling strategy was repeated several times without any decrease in the reaction conversion.
Under the mild acidic conditions in which the electrochemical reaction is carried out, two-electron anodic oxidation of chloride most probably forms hypochlorous acid (HClO; pK a = 7.5) (Scheme [4]). Hypochlorous acid is a known oxidizing agent for primary and secondary alcohols, as suggested for NaOCl–AcOH oxidizing mixtures.[19] The alcohol oxidation probably follows the known HClO oxidation pathway, in which an alkyl hypochlorite 5 is formed (Scheme [4]). In this case, when the chloride anion is released upon formation of the carbonyl compound 4, the electrocatalytic cycle is restarted. At the cathodic side, the two protons released during the anodic oxidation are reduced to H2, thus maintaining a constant acidity of the reaction medium. Electrochemical generation of active chlorine as ClO– would also explain the observed high selectivity toward secondary alcohols in the presence of primary alcohols, as a similar selectivity has been observed for the NaOCl–AcOH system.[17] [20]
In summary, we have developed an electrochemical procedure for the chemoselective oxidation of secondary alcohols in the presence of primary ones, based on the anodic generation of active chlorine in acidic media. Me4NCl was used as a convenient and inexpensive chloride source and acted as both a redox mediator and a supporting electrolyte. Very good selectivity was obtained for a variety of alcohols, with good to excellent yields in all cases. Moreover, a simple extraction procedure for the easy recovery and reuse of the chloride salt was developed. By using this strategy the chloride salt could be reused several times without any apparent loss of efficiency, which significantly improves the sustainability of this method.
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Conflict of Interest
The authors declare no conflict of interest.
Supporting Information
- Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1511-8869.
- Supporting Information
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References and Notes
- 1 Caron S, Dugger RW, Ruggeri SG, Ragan JA, Brown Ripin DH. Chem. Rev. 2006; 106: 2943
- 2a Cohen MD, Kargacin B, Klein CB, Costa M. Crit. Rev. Toxicol. 1993; 23: 255
- 2b Shekhawat K, Chatterjee S, Joshi B. Int. J. Adv. Res. 2015; 3: 167
- 3 Tidwell TT. Synthesis 1990; 857
- 4a Beejapur HA, Zhang Q, Hu K, Zhu L, Wang J, Ye Z. ACS Catal. 2019; 9: 2777
- 4b de Nooy AE. J, Besemer AC, van Bekkum H. Synthesis 1996; 1153
- 4c Ciriminna R, Pagliaro M. Org. Process Res. Dev. 2010; 14: 245
- 5a Nutting JE, Rafiee M, Stahl SS. Chem. Rev. 2018; 118: 4834
- 5b Ciriminna R, Ghahremani M, Karimi B, Pagliaro M. ChemistryOpen 2017; 6: 5
- 6 Semmelhack MF, Chou CS, Cortes DA. J. Am. Chem. Soc. 1983; 105: 4492
- 7 Francke R, Little RD. Chem. Soc. Rev. 2014; 43: 2492
- 8 Yoshida J.-i, Nakai R, Kawabata N. J. Org. Chem. 1980; 45: 5269
- 9 Shono T, Matsumura Y, Hayashi J, Mizoguchi M. Tetrahedron Lett. 1979; 20: 165
- 10 Leonard JE, Scholl PC, Steckel TP, Lentsch SE, Van De Mark MR. Tetrahedron Lett. 1980; 21: 4695
- 11 Bender MT, Lam YC, Hammes-Schiffer S, Choi K.-S. J. Am. Chem. Soc. 2020; 142: 21538
- 12a Demizu Y, Shiigi H, Oda T, Matsumura Y, Onomura O. Tetrahedron Lett. 2008; 49: 48
- 12b Kuroboshi M, Yoshihisa H, Cortona MN, Kawakami Y, Gao Z, Tanaka H. Tetrahedron Lett. 2000; 41: 8131
- 13 Tojo G, Fernández M. Oxidation of Alcohols to Aldehydes and Ketones: A Guide to Current Common Practice. Springer Science; New York: 2006
- 14 Goehring RR. In Encyclopedia of Reagents for Organic Synthesis . Wiley; Chichester: 2001.
- 15 Wicha J, Zarecki A. Tetrahedron Lett. 1974; 3059
- 16a Hill-Cousins JT, Kuleshova J, Green RA, Birkin PR, Pletcher D, Underwood TJ, Leach SG, Brown RC. D. ChemSusChem 2012; 5: 326
- 16b Sommer F, Kappe CO, Cantillo D. Chem. Eur. J. 2021; 27: 6044
- 17 Stevens RV, Chapman KT, Stubbs CA, Tam WW, Albizati KF. Tetrahedron Lett. 1982; 23: 4647
- 18 3-(Hydroxymethyl)heptan-4-one (2a); Typical Procedure A 5 mL IKA ElectraSyn 2.0 vial (undivided cell) equipped with a stirrer bar was charged with Me4NCl (164 mg, 1.5 mmol) and MeCN (3 mL). Diol 1a (0.6 mmol), H2O (75 μL), and AcOH (86 μL) were added, and the vial was capped with a cell head equipped with a standard IKA ElectraSyn graphite anode and a stainless-steel cathode. The mixture was stirred until all the supporting electrolyte was dissolved and then a constant current of 5 mA was applied, with stirring at 1000 rpm. After 4.5 F/mol of charge had been passed, the mixture was evaporated under reduced pressure. The residue was treated with aq NaHCO3 and extracted with CH2Cl2. The organic phase was dried (Na2SO4) and concentrated under reduced pressure to give a pale-yellow oil; yield: 82 mg (95%).
- 19 H NMR (300 MHz, CDCl3): δ = 3.82 (dd, J = 11.1, 7.3 Hz, 1 H), 3.72 (dd, J = 11.1, 4.0 Hz, 1 H), 2.69–2.61 (m, 1 H), 2.49 (t, J = 14.6 Hz, 2 H), 1.76–1.36 (m, 4 H), 0.98–0.92 (m, 6 H). MS (EI): m/z (%) = 55 (100), 56 (60), 57 (11), 71 (73), 73 (10), 83 (27), 89 (60), 97 (8), 114 (5).
- 20 Sakai A, Hendrickson DG, Hendrickson WH. Tetrahedron Lett. 2000; 41: 2759
Basic pH values favor TEMPO-mediated alcohol oxidations; see:
Corresponding Author
Publication History
Received: 30 March 2021
Accepted after revision: 19 May 2021
Accepted Manuscript online:
19 May 2021
Article published online:
02 June 2021
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References and Notes
- 1 Caron S, Dugger RW, Ruggeri SG, Ragan JA, Brown Ripin DH. Chem. Rev. 2006; 106: 2943
- 2a Cohen MD, Kargacin B, Klein CB, Costa M. Crit. Rev. Toxicol. 1993; 23: 255
- 2b Shekhawat K, Chatterjee S, Joshi B. Int. J. Adv. Res. 2015; 3: 167
- 3 Tidwell TT. Synthesis 1990; 857
- 4a Beejapur HA, Zhang Q, Hu K, Zhu L, Wang J, Ye Z. ACS Catal. 2019; 9: 2777
- 4b de Nooy AE. J, Besemer AC, van Bekkum H. Synthesis 1996; 1153
- 4c Ciriminna R, Pagliaro M. Org. Process Res. Dev. 2010; 14: 245
- 5a Nutting JE, Rafiee M, Stahl SS. Chem. Rev. 2018; 118: 4834
- 5b Ciriminna R, Ghahremani M, Karimi B, Pagliaro M. ChemistryOpen 2017; 6: 5
- 6 Semmelhack MF, Chou CS, Cortes DA. J. Am. Chem. Soc. 1983; 105: 4492
- 7 Francke R, Little RD. Chem. Soc. Rev. 2014; 43: 2492
- 8 Yoshida J.-i, Nakai R, Kawabata N. J. Org. Chem. 1980; 45: 5269
- 9 Shono T, Matsumura Y, Hayashi J, Mizoguchi M. Tetrahedron Lett. 1979; 20: 165
- 10 Leonard JE, Scholl PC, Steckel TP, Lentsch SE, Van De Mark MR. Tetrahedron Lett. 1980; 21: 4695
- 11 Bender MT, Lam YC, Hammes-Schiffer S, Choi K.-S. J. Am. Chem. Soc. 2020; 142: 21538
- 12a Demizu Y, Shiigi H, Oda T, Matsumura Y, Onomura O. Tetrahedron Lett. 2008; 49: 48
- 12b Kuroboshi M, Yoshihisa H, Cortona MN, Kawakami Y, Gao Z, Tanaka H. Tetrahedron Lett. 2000; 41: 8131
- 13 Tojo G, Fernández M. Oxidation of Alcohols to Aldehydes and Ketones: A Guide to Current Common Practice. Springer Science; New York: 2006
- 14 Goehring RR. In Encyclopedia of Reagents for Organic Synthesis . Wiley; Chichester: 2001.
- 15 Wicha J, Zarecki A. Tetrahedron Lett. 1974; 3059
- 16a Hill-Cousins JT, Kuleshova J, Green RA, Birkin PR, Pletcher D, Underwood TJ, Leach SG, Brown RC. D. ChemSusChem 2012; 5: 326
- 16b Sommer F, Kappe CO, Cantillo D. Chem. Eur. J. 2021; 27: 6044
- 17 Stevens RV, Chapman KT, Stubbs CA, Tam WW, Albizati KF. Tetrahedron Lett. 1982; 23: 4647
- 18 3-(Hydroxymethyl)heptan-4-one (2a); Typical Procedure A 5 mL IKA ElectraSyn 2.0 vial (undivided cell) equipped with a stirrer bar was charged with Me4NCl (164 mg, 1.5 mmol) and MeCN (3 mL). Diol 1a (0.6 mmol), H2O (75 μL), and AcOH (86 μL) were added, and the vial was capped with a cell head equipped with a standard IKA ElectraSyn graphite anode and a stainless-steel cathode. The mixture was stirred until all the supporting electrolyte was dissolved and then a constant current of 5 mA was applied, with stirring at 1000 rpm. After 4.5 F/mol of charge had been passed, the mixture was evaporated under reduced pressure. The residue was treated with aq NaHCO3 and extracted with CH2Cl2. The organic phase was dried (Na2SO4) and concentrated under reduced pressure to give a pale-yellow oil; yield: 82 mg (95%).
- 19 H NMR (300 MHz, CDCl3): δ = 3.82 (dd, J = 11.1, 7.3 Hz, 1 H), 3.72 (dd, J = 11.1, 4.0 Hz, 1 H), 2.69–2.61 (m, 1 H), 2.49 (t, J = 14.6 Hz, 2 H), 1.76–1.36 (m, 4 H), 0.98–0.92 (m, 6 H). MS (EI): m/z (%) = 55 (100), 56 (60), 57 (11), 71 (73), 73 (10), 83 (27), 89 (60), 97 (8), 114 (5).
- 20 Sakai A, Hendrickson DG, Hendrickson WH. Tetrahedron Lett. 2000; 41: 2759
Basic pH values favor TEMPO-mediated alcohol oxidations; see:
