Electrochemical oxo-functionalization of cyclic alkanes and alkenes using nitrate and oxygen

Abstract

Direct functionalization of C(sp³)-H bonds allows rapid access to valuable products, starting from simple petrochemicals. However, the chemical transformation of non-activated methylene groups remains challenging for organic synthesis. Here, we report a general electrochemical method for the oxidation of C(sp³)-H and C(sp²)-H bonds, in which cyclic alkanes and (cyclic) olefins are converted into cycloaliphatic ketones as well as aliphatic (di)carboxylic acids. This resource-friendly method is based on nitrate salts in a dual role as anodic mediator and supporting electrolyte, which can be recovered and recycled. Reducing molecular oxygen as a cathodic counter reaction leads to efficient convergent use of both electrode reactions. By avoiding transition metals and chemical oxidizers, this protocol represents a sustainable oxo-functionalization method, leading to a valuable contribution for the sustainable conversion of petrochemical feedstocks into synthetically usable fine chemicals and commodities.

Fig. 1. Overview of known procedures and the subject of this work.

a Conventional synthesis protocols for converting cycloaliphatics to ketones and dicarboxylic acids. b Known electrochemical procedures for oxo-functionalizing C(sp³)–H and C=C bonds to ketones and dicarboxylic acids. Mediators labeled in red and supporting electrolytes are labeled in blue. c Subject of this work: application of one electrochemical method to valorize saturated and unsaturated cycloaliphatics. Oxygen as O₂ source and oxo-groups are labeled in red.

Fig. 2. Scope of ketones and (di)carboxylic acids, including batch and flow processes.

Unless separately indicated, all yields are isolated. Oxygen as O₂ source and oxo-groups are labeled in red. atm.: atmosphere. a Conditions: 100 mL round-bottom flask, acetonitrile (MeCN, 25 mL), substrate (0.2 mol L⁻¹), 400 rpm. ^a5 F. ^bIsobutyronitrile. ^c50 °C, air atmosphere. b Conditions: undivided 5 mL PFTE cell, acetonitrile (MeCN, 5 mL), substrate (0.05 mol L⁻¹), 350 rpm. ^aIsobutyronitrile. ^b5 °C. ^cCombined yield ratio determined via ¹H NMR. ^d25 °C. c Conditions: undivided 5 mL PFTE cell, isobutyronitrile (i-PrCN, 5 mL), NBu₄NO₃ (0.1 mol L⁻¹, 0.5 eq. toward combined mol of 1e and 5c), 350 rpm. ^a1e 0.02 mol L⁻¹, 5c 0.18 mol L⁻¹, 7,6 F. ^b1e 0.05 mol L⁻¹, 5c 0.15 mol L⁻¹, 7 F. ^c1e 0.1 mol L⁻¹, 5c 0.1 mol L⁻¹, 6 F. ^dYields are determined via GC calibration and refer to mol% of 1e. ^eIsolated yields refer to mol% of 5c. d Flow reactions were carried out using an IKA flow cell with a 2 × 6 cm² anode surface. ^aConditions: glassy carbon anode and cathode, isobutyronitrile (i-PrCN, 10 mL), substrate (0.05 mol L⁻¹), NBu₄NO₃ (0.5 eq.), 20 °C, O₂ atmosphere (100 vol%), electrolyte flow: 10 mL min⁻¹, gas flow: 10 mL min⁻¹, 4 F (ref. substrate), 5 mA cm⁻². ^bConditions: glassy carbon anode and cathode, dimethyl carbonate (DMC)/isopropanol (i-PrOH) 9:1 (9.12 mL), substrate (0.5 mol L⁻¹), NBu₄NO₃ (1 eq.), 50 °C, O₂ atmosphere (100 vol%), electrolyte flow: 18 mL min⁻¹, gas flow: 20 mL min⁻¹, 2 F (ref. substrate), 20 mA cm⁻². MFC: mass flow controller. e Conditions: undivided 5 mL PFTE cell, isobutyronitrile (i-PrCN, 5 mL), substrate (0.1 mol L⁻¹), 350 rpm. ^aYields determined via GC calibration. ^bIsolated yields.

Fig. 3. Mechanistic studies and proposal.

atm.: atmosphere, electr.: electrolysis. Oxygen as O₂ source and oxo-groups are labeled in red. a Schematic, mechanistic proposal for cycloalkane oxidation. b Schematic, mechanistic proposal for alkene double bond cleavage. c Schematic, mechanistic proposal for further oxidation of aldehyde species to carboxylic acids. d Cyclic voltammetry of nitrate anion oxidation compared with PF₆⁻. Electrolyte: acetonitrile (5 mL), NBu₄NO₃ (0.1 mol L⁻¹), or NBu₄PF₆ (0.1 mol L⁻¹). Conditions: glassy carbon disk (working electrode, 3 mm diameter), glassy carbon rod (counter electrode), Ag/AgCl in saturated LiCl/EtOH (reference electrode), Ferrocene/Ferrocenium (FcH/FcH⁺) as internal reference (E_1/2 = 0.55–0.57 V), 50 mV s⁻¹. e Cyclic voltammetry of nitrate anion oxidation compared with PF₆⁻ in the presence of cyclooctene 5b. Electrolyte: see Fig. 3d, 5b (0.2 mol L⁻¹). Conditions: see Fig. 3d, (E_1/2(FcH/FcH⁺) = 0.55–0.58 V). f Quenching experiment in an undivided 5 mL PTFE and schematic mechanism proposal for the formation of nitrated species. MeCN: acetonitrile. For further information, see Supplementary Note 3.2.6. g Anion chromatography of the aqueous layer after extractive workup. For preparative information, see Methods: Workup procedure for cyclic ketones and benzaldehydes. h Griess test for nitrite detection is negative if the reaction solution is exposed to an O₂ atmosphere (100 vol%) and positive under argon. See Supplementary Note 3.2.1 for detailed protocol. i Cyclic voltammetry of oxygen reduction in argon (blue line), air (orange line), and oxygen (gray line) atmosphere above the electrolyte solution. Electrolyte: acetonitrile (5 mL), NBu₄NO₃ (0.1 mol L⁻¹). Conditions: see Fig. 3d, (E_1/2(FcH/FcH⁺) = 0.55 V). j Peroxide test with titanyl sulfate. See Supplementary Note 3.2.4 for detailed protocol. k Karl Fischer titration after electrolysis of the reaction solution. See Supplementary Note 3.2.5 for detailed protocol.

Fig. 4. Benzylic oxidation as a further application of the method.

a Oxidation of toluene substrates to either semicarbazones 13 (semicarbazide moiety in blue) via benzaldehydes or to benzoic acids 14 (carboxyl group in red). Yields are isolated. Condition a: undivided 25 mL beaker-type cell, glassy carbon anode, and cathode, acetonitrile (25 mL), NBu₄NO₃ (1 eq.), substrate (0.02 mol L⁻¹), 33 °C, O₂ atmosphere (100 vol%), 400 rpm, 5 F, 10 mA cm⁻². Condition b: undivided 25 mL beaker-type cell, glassy carbon anode, and cathode, acetonitrile (25 mL), NBu₄NO₃ (0.5 eq.), substrate (0.1 mol L⁻¹), 27 °C, O₂ atmosphere (100 vol%), 500 rpm, 12 F, 30 mA cm⁻². ^a7 F. b Reaction monitoring via a 60 MHz NMR benchtop spectrometer. The ¹H integral intensity was normalized to one proton for better comparison. Recorded tracks of the corresponding protons are assigned by colors (green dots: aromatic protons of 12a, orange dots: aldehydic proton of 13’a, blue dots: aromatic protons in the ortho position of 14a).