Beyond Kolbe and Hofer–Moest: Electrochemical Synthesis of Carboxylic Anhydrides from Carboxylic Acids

Abstract Herein we report a conceptually new non‐decarboxylative electrolysis of carboxylic acids to obtain their corresponding anhydrides as highly valuable reagents in organic synthesis. All carbon atoms of the starting material are preserved in the product in an overall redox‐neutral reaction. In a broad substrate scope of carboxylic acids the anhydrides are generated with high selectivity, which demonstrates the versatility of the developed method. Beneficially, no dehydrating reagents are required in comparison to conventional methods and the synthesis is based on uncritical starting materials using graphite and stainless steel as very inexpensive and eco‐friendly electrode materials.


Chemicals
All carboxylic acids, supporting electrolytes, solvents, and additives were used as received from commercial suppliers. For all experiments under ambient conditions, HPLC grade acetonitrile was used. For electrolysis under inert conditions, anhydrous acetonitrile was prepared by refluxing 500 mL acetonitrile with 1 g phosphorous pentoxide for 30 min, distilling it off under a nitrogen atmosphere, and storing it over activated 3 Å molecular sieves in the dark.

High Resolution Mass Spectrometry (ESI-MS/APCI-MS)
High resolution m/z were measured on a G6545A Q-ToF mass spectrometer (Agilent, Germany) with electrospray ionization (ESI) or chemical ionization at atmospheric pressure (APCI). The sample was introduced via a 1260 Infinity II HPLC system (Agilent, Germany) equipped with a G7111B 1260 Quaternary Pump, a G7129A 1260 Vialsampler, and a G7116A 1260 Multicolumn Thermostat. The mass calibration was performed on the day of the measurement using an external standard. The mass accuracy of the measurement is better than 5 ppm.

IR Spectroscopy
IR spectra were recorded on an Alpha spectrometer (Bruker, Germany) using ATR.

Electrolysis Setup
Experiments up to 5 mL electrolyte volume were carried out under ambient atmosphere in undivided beaker-type cells made from Teflon ® developed by the Waldvogel lab. [1] Dimensions of the electrodes are 7 cm × 1 cm × 0.3 cm.
The electrodes were cleaned with water and acetone after each use and sanded in case of strongly adhesive residues. The immersion depth into 5 mL electrolyte is 1.7 cm and 0.9 cm into 3 mL electrolyte volume. The current density is given in mA/cm². The current set at the galvanostat is calculated as I [mA] = j [mA/cm²] × A [cm²]. The system including a magnetic stirrer, the electrolysis cells, and the galvanostat is commercially available from IKA ® -Werke GmbH & CO. KG, Germany. For larger volume experiments, undivided beaker-type glass cells developed by the Waldvogel lab were used.

Optimization
Optimization of carboxylic anhydride yield was performed with isobutyric acid (1h, 99.0%). The yield was determined via 1 H NMR (general procedure A, see experimental data) using 1,3,5-trimethoxybenzene (98.0%) as absolute internal standard, or via GC (general procedure B) using dibutyl fumarate (4% in DMF) as relative internal standard.
Both methods have the same error of measurement.   Mechanistic Studies
The electrolyte was degassed for 10 min by purging it with a stream of dry N2. The headspace of the electrolysis chamber was purged with a slow stream of dry N2 throughout the experiment. The mixture was electrolyzed at 80 mA/cm² and 288 K. The exhaust gas from the electrolysis cell was carried through two bubble counters in series ( Figure S8), which were empty at the beginning of the electrolysis. After start of the electrolysis, the bubble counters were purged with the exhaust gas for 10 min. Each bubble counter was then filled under countercurrent from the electrolysis cell with 10 mL of a solution of pyrogallol (2.5 mg/mL) in aqueous 1 M NaOH, which was prepared under inert conditions. Until the end of the electrolysis after 1.1 F, no staining was visible in the bubble counters. Shortly after the end of the electrolysis, the N2-stream was stopped. The solution in the right bubble counter ( Figure S8) immediately started turning brown due to diffusion of air into the solution. 8 min after stopping the N2-stream, the tubing from the electrolysis cell to the left bubble counter was removed. The solution in the left bubble counter immediately started turning brown ( Figure S8, bottom right). We conclude that no O2 is formed in the electrolysis cell. Figure S8: Analysis of gaseous by-products formed during electrolysis of valeric acid (1d).

Electrolysis with Addition of Water
The electrolysis of valeric acid (1d) was performed with addition of water to gain insight on the reaction mechanism (Table S1). Analogous to general procedure C, valeric acid (1d, 0.9 M) and KSCN (0.35 M) were dissolved in MeCN, and a defined amount of water was added. The mixture was electrolyzed, and the yield of valeric anhydride (2d) was determined via GC. As expected, the yield of 2d is lower in the presence of water. Importantly, water does not Exposed to air N 2 >10 miñ2 min Air suppress the anhydride formation but only slows it down. If the amount of charge is increased, the anhydride yield increases too. The reaction can be considered self-drying since any water present at the beginning will react with the anhydride and form the acid again. We conclude that anhydrous conditions are not necessary, but the reaction can be run under ambient conditions. H NMR spectra were recorded within 1 h after the aliquot was taken from the electrolyte. 13 C NMR spectra were recorded within 12 h after end of the electrolysis. No stoichiometric by-product is visible in any of the recorded spectra ( Figure S9, Figure S10).

Electrolysis in a Divided Cell
Divided cells made from Teflon ® with a ceramic frit as separator [1] were used to study the anodic reaction separately  Figure S14). In the anodic compartment, an orange solid was formed ( Figure S15), which covered the anode completely. The anolyte was analyzed analogously general procedure A ( Figure S12). No valeric anhydride (2d) was detected (ISTD: 27.9 mg ethylene carbonate (99%)). The conversion of 1d was 1%.
The orange solid was filtered off and washed with H2O and MeOH. The IR absorptions of the dried sample match those of (SCN)x ( Figure S15). [2] The experimental data suggest that the formation of the anhydride is a convergent paired electrolysis. No or only little anhydride is formed in a divided cell. Instead, the oxidation of SCNto (SCN)x becomes the main reaction in the anodic compartment. The small amount of anhydride formed with tetramethylammonium valerate can be explained by imperfect separation of the two half cells. The experiment did not reveal the electroactive species on the anode.

Experimental Procedures General Procedure A
The supporting electrolyte and the starting material 1 were dissolved in MeCN in an undivided Teflon cell with a magnetic stirrer. A graphite anode and stainless steel cathode were immersed into the solution, and the mixture was electrolyzed without temperature control. An internal standard (ISTD) was added and the mixture was stirred for 5 min. An aliquot of 0.5-0.6 mL of the mixture was evaporated, and the residue was suspended in 0.5-0.6 mL CDCl3. The suspension was filtered through a cotton plug into an NMR tube. The yield was determined via 1 H NMR with the following formula: Ca. 30 mg of the mixture were dissolved in 0.5-0.6 mL CDCl3. The yield was determined via 1 H NMR with the following formula: The supporting electrolyte and isobutyric acid (1h, 99%) were dissolved in 5.0 mL MeCN in an undivided Teflon cell with a magnetic stirrer. The electrodes were immersed into the solution, and the mixture was electrolyzed without temperature control. 0.50 mL Dibutyl fumarate (4% in DMF) were added as internal standard (ISTD), and the mixture was stirred for 5 min. The mixture was added to 10 mL saturated aqueous NaHCO3, and the mixture was shaken for 10 s. 0.8-1.0 mL of the organic phase were filtered through a plug of silica. 0.2 mL of the filtrate were diluted with 1 mL MeCN, and the yield was determined via GC-FID with the following formula: The calibration curve was created as a power function Ianhydride/IISTD = a × manhydride b from five calibration points. The error of measurement was calculated as the mean deviation of six control points. For the calibration and control points, a defined amount of isobutyric anhydride (2h, 97%) was dissolved in 5.0 mL MeCN. 0.50 mL Dibutyl fumarate (4% in DMF) were added as internal standard, and the mixture was stirred for 5 min. 0.2 mL of the solution were diluted with 1 mL MeCN and measured three times (calibration points) or once (control points). The analytic data is in agreement with previously reported data. [3]  The analytic data is in agreement with previously reported data. [3] 2a, 37% Figure S18: 1 H NMR of the crude mixture from electrolysis of propionic acid (1b); 400 MHz, 296 K. The analytic data is in agreement with previously reported data. [4] Figure S20: 1 H NMR of the crude mixture from electrolysis of butyric acid (1c); 400 MHz, 296 K. The analytic data is in agreement with previously reported data. [5] 2c, 46% Figure S22: 1 H NMR of the crude mixture from electrolysis of valeric acid (1d); 400 MHz, 296 K.  The analytic data is in agreement with previously reported data. [6] Figure S26: 1 H NMR of the crude mixture from electrolysis of caproic acid (1e); 400 MHz, 296 K. The analytic data is in agreement with previously reported data. [7] 2e, 60% Figure S28: 1 H NMR of the crude mixture from electrolysis of caprylic acid (1f); 400 MHz, 296 K.  The analytic data is in agreement with previously reported data. [3] Figure S33: 1 H NMR of the crude mixture from electrolysis of isobutyric acid (1h); 400 MHz, 296 K. The analytic data is in agreement with previously reported data. [9,10] 2h, 58% Figure S35: 1 H NMR of the crude mixture from electrolysis of pivalic acid (1i); 400 MHz, 296 K. Figure S36: 13 C NMR of the crude mixture from electrolysis of pivalic acid (1i); 101 MHz, 296 K; ISTD: 1,3,5-trimethoxybenzene.

1-Methylcyclohexanecarboxylic Anhydride (2q)
Following general procedure A, electrolysis of 1-methylcyclohexanecarboxylic acid (1q, 99%, 718 mg, 5.00 mmol, For analytic purposes, the residual electrolyte was filtered through a mixture of silica (ca. 4 g) and K2CO3 (ca. 1 g) on a p4 frit. The silica layer was rinsed with 60 mL cyclohexane, and the filtrate was washed with cold aqueous K2CO3 (0.1 M, 20 mL). The organic phase was dried with MgSO4 and the solvent was evaporated to give 262 mg of a mixture of 1-methylcyclohexanecarboxylic anhydride (2q, 87%) and 1,3,5-trimethoxybenzene (13%). The isolated amount of 1-methylcyclohexanecarboxylic anhydride (2q) corresponds to 34% yield. No spectroscopic data for this compound has been reported before.    The analytic data is in agreement with previously reported data. [9] Figure S55: 1 H NMR of the crude mixture from electrolysis of adamantane-1-carboxylic acid (1r); 400 MHz, 296 K. The analytic data is in agreement with previously reported data. [17] 2r, 28% Figure S57: 1 H NMR of the crude mixture from electrolysis of levulinic acid (1s); 400 MHz, 296 K.  No spectroscopic data for this compound has been reported before. No spectroscopic data for this compound has been reported before.    The analytic data is in agreement with previously reported data. [18] 2u, 17% Figure S66: 1 H NMR of the crude mixture from electrolysis of 2-(4-(trifluoromethyl)phenyl)acetic acid (1v); 400 MHz, 296 K.  No spectroscopic data for this compound has been reported before.   in 15% yield and 51% selectivity (30% conversion) after 1.3 F (ISTD: 26.2 mg 1,3,5-trimethoxybenzene (98.0%)). For analytic purposes, the residual electrolyte of two different experiments was combined and filtered through a mixture of silica (ca. 4 g) and K2CO3 (ca. 1 g) on a p4 frit. The silica layer was rinsed with 60 mL cyclohexane, and the filtrate was washed with cold aqueous K2CO3 (0.1 M, 20 mL). The organic phase was dried with MgSO4 and the solvent was evaporated to give a mixture of linoleic anhydride (2x), traces of linoleic acid (1x), and 1,3,5-trimethoxybenzene. The analytic data is in agreement with previously reported data. [19]