# Direct and TEMPO-Mediated Electro-Oxidation of 5-(Hydroxymethyl)furfural in Organic and Hydro-Organic Media

Nhat Tam Vo, Quentin Cacciuttolo, David Pasquier, Kim Larmier

► To cite this version:

Nhat Tam Vo, Quentin Cacciuttolo, David Pasquier, Kim Larmier. Direct and TEMPO-Mediated Electro-Oxidation of 5-(Hydroxymethyl)furfural in Organic and Hydro-Organic Media. ChemElectroChem, 2024, 11 (12), pp.e202400116. 10.1002/celc.202400116. hal-04694682

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# Direct and TEMPO-Mediated Electro-Oxidation of 5-(Hydroxymethyl)furfural in Organic and Hydro-Organic Media

Nhat Tam Vo,[a] Quentin Cacciuttolo,[a] David Pasquier,[a] and Kim Larmier*[a]

Biomass-derived 5-hydroxymethyl furfural (5-HMF) is a promising starting substrate for producing two high value-added products 2,5-diformylfuran (DFF) and 2,5-furandicarboxylic acid (FDCA). DFF, which is produced by selectively oxidizing the hydroxymethyl group of 5-HMF to an aldehyde group, has many applications in pharmaceuticals, macrocyclic ligands and fluorescent materials. Oxidizing both aldehyde and hydroxymethyl groups of 5-HMF leads to FDCA, which is an important monomer in the production of a bioplastic polyethylene furanoate polymer. Electrochemical conversion of 5-HMF is a potential route for sustainable chemical production of DFF and FDCA. In fact, using 2,2,6,6-tetramethyl- piperidine-1-oxyl (TEMPO) as a redox mediator leads to a highly efficient and

selective electro-oxidation of 5-HMF into FDCA in a basic buffer solution. In this report, the direct and TEMPO-mediated electro-oxidation of 5-HMF was investigated in various organic and hydro-organic media at room temperature. Direct electro-oxidation leads to a low selective conversion of 5-HMF to DFF (10% of yield) and the formation of unwanted products such as formic acid and protoanemonin (90% and 37% of yield respectively) in acetonitrile. Electrocatalytic 5-HMF conversion in the presence of TEMPO as a redox mediator achieved a near-quantitative yield of DFF in acetonitrile and γ-valerolactone. Importantly, we demonstrate the role of water in the conversion of aldehydes to carboxylic acids.

## Introduction

The production of products and platform chemicals from biomass-derived feedstocks is currently a major research challenge in the search of alternatives to oil-based chemistry.[1,2] Among the various potentially targetable platform chemicals, 5-HydroxyMethylFurfural (5-HMF) has been the focus of a large body of research in the last decade. It can be obtained by the dehydration of hexoses, in particular fructose, which are a major component of biomass, and may be transformed via catalytic processes into a variety of products for the chemical industry or as fuel additives.[3] Of particular interest are the products of its oxidation, 2,5-DiFormylFuran (DFF) and 2,5-FuranDiCarboxylic Acid (FDCA), which are each potentially valuable chemicals in the pharmaceutical industry and potential substitute monomers for p-terephthalic acid in the production of polyesters for the packaging industry.

The oxidation of 5-HMF into such products by chemo-catalytic, aerobic oxidation has triggered extensive research in the last two decades.[4-8] Reaction conditions are most often rather harsh and require the presence of a noble metal-based

catalyst. Electrocatalytic oxidation has also been examined by a number of research groups, although most of the time, the studies were carried out in water as a solvent.[9-17] However, although it is considered as a green solvent, water suffers from several major drawbacks when employed as a solvent for the (electro) oxidation of 5-HMF. Firstly, the oxidation products, in particular the carboxylic acids, have quite a low solubility in water, and so the products will tend to precipitate during the course of the reaction,[18] which compromises the applicability of a potential process. Secondly, it is well known that the synthesis of 5-HMF by the dehydration of sugars in water is suboptimal,[19,20] due to both slow kinetics and limited yields caused by the rehydration of 5-HMF into levulinic acid in acidic aqueous solutions; in contrast, syntheses carried out in polar aprotic solvents such as DiMethyl SulfOxide (DMSO)[21,22] or, as discovered more recently, γ-ValeroLactone (GVL),[23-25] are much more efficient and provide better yields.

In order to avoid costly separation steps, it would be desirable to develop a process which enabled 5-HMF to be oxidized in its organic solvent of synthesis. In this respect, aerobic chemocatalytic oxidation gives rise to significant safety issues due to the presence of oxygen and a heated organic solvent. In contrast, electrocatalytic oxidation does not suffer from this drawback.

Several potential electrocatalysts for the oxidation of alcohols have been proposed in the literature.[26,27] Various solid electrocatalysts have been employed, such as nickel or cobalt hydroxides,[10-13,28,29] but their use requires employing a basic aqueous medium and a relatively high electrochemical potential. Organic redox mediators such as nitroxide species have the advantage of being readily soluble in organic solvents and are

<footnote>[a] N. T. Vo, Q. Cacciuttolo, D. Pasquier, K. Larmier
IFP Energies nouvelles, Rond-point de l'échangeur de Solaize, BP 3, 69360
Solaize, France
E-mail: kim.larmier@ifpen.fr</footnote>

<footnote>Supporting information for this article is available on the WWW under
https://doi.org/10.1002/celc.202400116</footnote>

<footnote>© 2024 The Authors. ChemElectroChem published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.</footnote>
<figure><img src="image_3.png" /></figure>

oxidized at a lower electrochemical potential while concurrently being able to catalyze the oxidation of the substrate in solution.[30–37] Here, we examine the possibility of carrying out the electrocatalytic oxidation of 5-HMF in an organic solvent suitable for its synthesis, namely DMSO or GVL, using (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) as an electrocatalyst. We compare the results with the reaction carried out in acetonitrile as a reference polar aprotic solvent commonly used in electro-chemistry. We explore a series of reaction conditions and carry out qualitative cyclic voltammetry to assess the electrochemical behavior of the various systems and electrolyses in a flow cell in galvanostatic mode at current densities compatible with a potential industrial application in order to examine the feasibility of the oxidation, determine the yields and Faradic efficiency and quantify the product and by-product distribution.

# Experimental

## Chemicals and Materials

2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPO), 5-hydroxymethyl furfural (5-HMF), 2,5-diformylfuran (DFF), N-methylimidazole (NMI), 2,4,6-collidine, 1,8-diazabicyclo[5.4.0] undec-7-ene (DBU), sodium perchlorate, dry acetonitrile, dimethyl sulfoxide (DMSO), γ-valerolactone, maleic acid, glucose, boric acid and sodium hydroxide were purchased from Sigma Aldrich and used as received. Potassium perchlorate was purchased from TCI. The borate buffer solution was prepared from boric acid, sodium borate and Milli-Q water adjusted to pH 9.

## Electrochemical Measurements

All electrochemical measurements were carried out with an SP-300 Bio-Logic potentiostat monitored by the EC Lab software. All of the potentials in this study were referenced to a hand-made Ag⁺/Ag reference electrode made by using a silver wire immersed in a solution containing 0.1 M of silver perchlorate and 0.1 M of a supporting electrolyte such as sodium perchlorate, based on the same solvent as for the anolyte. Cyclic voltammetry (CV) was carried out in a standard three-electrode electrochemical cell. The counter-electrode was a platinum electrode. A 5 mm diameter glassy carbon disk electrode was used as the working electrode, which was polished with 0.05 µm diamond paste and cleaned with milli-Q

water in an ultrasonic bath before use. CV data were collected at a scan rate of 100 mV·s⁻¹. The electrolysis of 5-HMF was carried out in a divided flow electrolysis cell purchased from PinFlow Energy Storage (Figure 1). The anode and cathode chambers of the cell were separated with a cation-exchange Nafion 424 membrane (Sigma Aldrich). The treated carbon felt with dimensions of 5 cm by 4 cm, purchased from PinFlow Energy Storage, was used for both the working (anode) and counter (cathode) electrodes. A 40 mL basic aqueous solution (1 M NaOH) was used as the catholyte, while the anolyte consisted of 40 mL of a reactant solution containing 100 mM 5-HMF (4.0 mmol), corresponding to a percentage by weight of about 1% in acetonitrile. These two solutions were circulated in the cell through the carbon felts at a flow rate of 16 mL/min and degassed with N₂ for 30 min before running the experiment. The anolyte and catholyte were under a nitrogen atmosphere throughout the reaction. The Ag⁺/Ag reference electrode was immersed in the reactant solution using a T-connector on the line linking the working compartment and the tank and protected behind a salt bridge. The electrolysis of 5-HMF was carried out either in galvanostatic mode at 300 mA with potential limitation to 1.2 V vs Ag⁺/Ag, or in potentiostatic mode at 1.2 V vs Ag⁺/Ag.

All of the electrochemical experiments were carried out at room temperature.

## Product Analysis

Every 100 C passed between the anode (working) and cathode (counter) electrodes, 1 mL of reactant solution was collected from the anolyte reservoir. ¹H NMR, ¹³C NMR (Bruker Advance III spectrometer, 300 MHz) and HPLC were employed to analyze and quantify the 5-HMF oxidation products. Protoanemonin was identified and quantified by NMR (see Figure SI-1 and Table SI-2). Formic acid, 5-HMF and DFF were quantified by HPLC (Table SI-1). The product analysis and calculations for yield and Faradic efficiency are detailed in ESI. Water contents were determined by means of Karl-Fischer titration on a Titrando 835 apparatus from Metrohm. We report molar yields calculated on the basis of the fraction of carbon atoms from 5-HMF converted into a given reaction product.

<figure><img src="image_4.png" /></figure>

<figure><img src="image_5.png" /><figcaption>**Figure 1.** Divided flow electrolysis cell employed for the electrolysis of 5-HMF, photograph and scheme.</figcaption></figure>
<figure><img src="image_6.png" /></figure>

# Results and Discussion

## Direct Electro-Oxidation of 5-HMF

The direct electro-oxidation of 5-HMF was initially evaluated in the absence of catalyst by cyclic voltammetry (CV) in acetonitrile under a nitrogen atmosphere. A highly anodic peak in CV was observed when 100 mM of 5-HMF was added as the anolyte (Figure 2). That oxidative wave revealed that 5-HMF was directly electro-oxidized at the glassy carbon working electrode surface without redox mediator at 1.6 V.

In order to examine the products of the direct electro-oxidation and their yields, an electrolysis of 5-HMF was carried out in acetonitrile by applying a constant potential of 1.2 V vs Ag⁺/Ag and passing 1000 C (current density between 65 mA cm⁻² to approx. 1.7 mA cm⁻²) after 2 hours 20 min of electrolysis, representing the equivalent of 2.5 e⁻ per mole of HMF i. e. above the stoichiometry for the full oxidation of 5-HMF to DFF (2 e⁻) (Figure SI-2). Since the catholyte is an aqueous solution, water diffusion through the membrane occurred during electrolysis, so the concentration of water in the anolyte was not fully controllable and increased noticeably during the experiment. 10% by volume% of water was measured in the anolyte after 2 h 30 min of electrolysis. However, water and acetonitrile oxidation could not occur at the potential of 1.2 V,

and so the oxidation wave observed was essentially assigned to the oxidation of HMF. The conversion of 5-HMF and the yield of oxidation products were monitored during the electrolysis by analyzing the anolyte by HPLC. The Faradic efficiency and conversion of 5-HMF are represented in Figure 3. HMF was converted almost linearly with the charge passing through the cell, up to around 96% of conversion. At the end of the electrolysis, only about 14% of DFF yield was obtained, with no measurable quantities of HMFCA, FFCA or FDCA. This corresponds to only 10% of the Faradic efficiency for the electro-oxidation of 5-HMF into DFF.

To identify the by-products, the analyte solution was analyzed by NMR. The 2D NMR coupling between ¹H and ¹³C (HSQC) indicated that a hydrogen atom at 8.11 ppm is bonded to a carbon atom at 163 ppm assigned to a carbon atom in an acid, revealing that one of the unknown products is formic acid (Figure SI-1). The formation of formic acid was confirmed by HPLC. Another unwanted product was probably characterized by four singlet peaks with chemical shifts of 5.10, 5.27, 6.46, and 7.80 ppm in the ¹H NMR spectrum which are likely attributable to four distinct alkenyl hydrogen atoms (Figure SI-1). Moreover, the ¹H-¹³C HSQC spectrum indicated that these four hydrogen atoms are centered on three carbon atoms assigned to ¹³C peaks at 99.0, 121.1, and 145.0 ppm respectively, in the range for olefinic carbon atoms. Two hydrogen atoms at 5.1 and 5.27 ppm are bonded to a primary alkene carbon at 99.0 ppm (named H1 and H2, respectively), while two additional hydrogens at 6.46 and 7.8 ppm are bonded to two different secondary alkenes at 121.1 and 145.0 ppm respectively (H3 and H4, resp.). Importantly, the ¹H NMR spectrum exhibits a geminal coupling of 2.8 Hz between H1 and H2, a vicinal coupling of 5.6 Hz between H3 and H4, as well as long-range couplings between H1 and H4 (1.9 Hz) and H1 and H3 (0.7 Hz). On the basis of comparisons with reference spectra,[³⁸,³⁹] these NMR features revealed that the second unwanted product was 4-methylenebut-2-en-4-olide (protoanemonin), an ordinarily plant-derived antibiotic. To the best of our knowledge, no chemical or electrochemical oxidation of 5-HMF into protoanemonin has been reported in the literature. Our findings

<figure><img src="image_7.png" /><figcaption>**Figure 2.** CV in the absence (black) and presence (red) of 5-HMF (100 mM) in acetonitrile.</figcaption></figure>

<figure><img src="image_8.png" /><figcaption>**Figure 3.** (Right) Conversion of 5-HMF and yield of oxidation products during the electrochemical oxidation of HMF at 1.2 V for anolyte containing 100 mM 5-HMF in acetonitrile. (Left) Faradic efficiency (FE) for electro-oxidation of 5-HMF into DFF and protoanemonin.</figcaption></figure>

<figure><img src="image_9.png" /></figure>
<figure><img src="image_10.png" /></figure>

demonstrate for the first time that protoanemonin is a by-product of the electro-oxidation of 5-HMF.

The direct electro-oxidation converted 96% of 5-HMF into DFF (14% of yield), protoanemonin (31% of yield) and formic acid (15% of yield). While the formation of DFF is known to be based on the oxidation of an alcohol group to an aldehyde group, the formation of formic acid and protoanemonin should be investigated. It is well known that 5-HMF can undergo hydration to form formic acid and levulinic acid in acidic media.[40] However, formic acid was also obtained at the first 200 C, and the electrolysis was not carried out in acid media. Besides, no trace of levulinic acid was detected by NMR spectra and HPLC analyses. Therefore, the formic acid does not derive from this degradation reaction under our reaction conditions. The formation of both formic acid and protoanemonin suggests that 5-HMF is electro-oxidized by an oxidative scission of a carbon-carbon bond.[41,42] We propose that the C–C bond between the furan ring and the aldehyde group, –CHO, is cleaved by a 2-electron oxidation at the working electrode surface (Scheme 1). The cleavage is followed by a rearrangement assisted by hydroxyl ions and loss of a water molecule to form protoanemonin and formic acid. The hydroxyl ion in the proposed mechanism may come from water molecules, which can diffuse through the Nafion® membrane from the cathode compartment to the anode compartment. Based on the proposed mechanism, the yield of formic acid should be equal to that of protoanemonin. However, while the formic acid-to-protoanemonin molar ratio was indeed about 1 beyond 200 °C (1.2), it then increased up to about 3 as more charge passed through the system (Figure S1-3). It is known that protoanemonin can be electro-oxidized and dimerized into anemonin, which would indeed lead to an increase in the formic acid-to-protoanemonin molar ratio.[43] We could not detect such species by our analyses, however we emphasize that this latter product may be further hydrolyzed to other products that may undergo further side reactions.

<figure><img src="image_11.png" /><figcaption>**Scheme 1.** Proposed mechanism for the direct electrochemical oxidative scission of 5-HMF into protoanemonin and formic acid.</figcaption></figure>

## TEMPO-Mediated Electro-Oxidation of 5-HMF in Organic Media

Our study on the electrochemical reactivity of TEMPO for 5-HMF oxidation was carried out in three different organic solvents: acetonitrile, γ-valerolactone (GVL) and dimethyl sulfoxide (DMSO). Acetonitrile was the first organic solvent used in our study as it is widely used in electrochemistry because it has a broader electrochemical stability window. An efficient and selective electrocatalytic activity of TEMPO in the oxidation of benzyl alcohol has been reported in acetonitrile in the presence of NMI as a base.[44]

Firstly, the electrochemical behavior of TEMPO was studied by cyclic voltammetric techniques in acetonitrile, GVL and DMSO. CVs of TEMPO in acetonitrile and GVL under a nitrogen atmosphere showed a reversible anodic wave at 0.25 V and 0.07 V vs Ag⁺/Ag respectively (Figure 4). The anodic peak indicates that TEMPO is electro-oxidized to oxoammonium TEMPO⁺ which is relatively stable in such solvents and can be electro-reduced to TEMPO as revealed by the cathodic peak. TEMPO⁺ is identified as an active species which can oxidize 5-HMF into FDCA in a basic aqueous solution.[45] Unlike its behavior in acetonitrile and GVL, the TEMPO oxidative wave at 0.34 V is not reversible in DMSO. The absence of a cathodic peak suggests a chemical decomposition of TEMPO⁺ in DMSO. It should be noted that TEMPO is more easily oxidized in GVL than in acetonitrile or DMSO. This behavior could be due to the donor-acceptor interaction between TEMPO and the various solvents characterized by a different polarity, dielectric constant and Gutmann acceptor and donor number (Table 1).[46,47] The change in current densities obtained in these three solvents could be related to the ion conductivity of the electrolyte. The current density is higher in acetonitrile compared with GVL. It could be related to the higher ion conductivity in acetonitrile than in GVL, as determined by impedance spectroscopy (Table 1). On the other hand, the diffusion coefficient of TEMPO in each solvent could also affect the current density.[48]

We first examined the electro-oxidation of 5-HMF in acetonitrile as a reference solvent. We evaluated the reactivity

<figure><img src="image_12.png" /><figcaption>**Figure 4.** CVs of TEMPO (1 mM) in acetonitrile (green), GVL (blue) and DMSO (red).</figcaption></figure>
<figure><img src="image_13.png" /></figure>

<table><caption>**Table 1.** Physical properties of the solvents of interest in this study.</caption><thead><tr><th>Solvent</th><th>Relative dielectric constant</th><th>Dipole moment (D)</th><th>Donor Number</th><th>Acceptor Number</th><th>Conductivity* (mS m<sup>-1</sup>)</th></tr></thead><tbody><tr><td>DMSO</td><td>46.5</td><td>4.06</td><td>29.8</td><td>19.3</td><td>2.7</td></tr><tr><td>ACN</td><td>35.9</td><td>3.53</td><td>14.1</td><td>18.9</td><td>2.5</td></tr><tr><td>GVL</td><td>32.9</td><td>4.3</td><td>23.4</td><td>13.8</td><td>13.4</td></tr></tbody></table>

of TEMPO by CV with and without 5-HMF. When 100 mM of 5-HMF was added to 1 mM of TEMPO solution in acetonitrile, the anodic and cathodic current of the TEMPO oxidation peak were unchanged in the CV (Figure SI-4), indicating that TEMPO taken alone is not capable of catalyzing the 5-HMF oxidation in acetonitrile. Because TEMPO exhibits a high electrocatalytic reactivity for alcohol oxidation in acetonitrile in the presence of NMI as a base and for 5-HMF oxidation to FDCA in basic pH 9 aqueous solution,[10,44,49] NMI was used to promote the reactivity of TEMPO. Figure 5 (Left) presents the CV of TEMPO with and without NMI and 5-HMF. In the absence of 5-HMF but in the presence of NMI, the anodic wave of TEMPO was less reversible, revealing that TEMPO⁺ becomes more reactive in basic media. In the presence of NMI, TEMPO and 5-HMF, a catalytic current through an increase in the anodic current with a concomitant decrease in the cathodic current was observed at the activated potential of TEMPO (0.25 V), revealing that TEMPO is capable of efficiently electro-oxidizing 5-HMF in the presence of NMI as a base in acetonitrile. The catalytic current increased with NMI concentration and achieved saturation at 400 mM NMI, corresponding to 400 eq. with respect to TEMPO (Figure SI-4). Thus, a concentration of 450 mM was chosen for all of our subsequent studies. Similarly, the catalytic current also increases with 5-HMF concentration, reaching a saturation at 80 mM (Figure SI-5). The chosen concentration of 5-HMF for the study was fixed at 100 mM.

The electrolysis of 5-HMF at anode compartment of a flow cell in the presence of TEMPO as a redox mediator and 450 mM

of NMI as a base was carried out with a controlled current of 300 mA (15 mA cm⁻²). During the electrolysis, the potential was limited to 1.0 vs. Ag⁺/Ag because 5-HMF is electro-oxidized directly at 1.2 V vs. Ag⁺/Ag to unwanted products such as protoanemonin, as we showed above. Indeed, in this series of experiments, no protoanemonin was detected, while only minor amounts of formic acid could be detected by ¹H NMR, prompting to a secondary source for its production even at lower voltage, such as that proposed elsewhere.[50] Figure 5 (right) reports the 5-HMF conversion, the yield of DFF and the Faradic efficiency. The measurements of potential and charge during the electrolysis are collected in Figure SI-6. At the beginning of the electrolysis, the potential was held at 0.2 V vs. Ag⁺/Ag, where TEMPO catalytically electro-oxidizing 5-HMF was observed in the CV. 95% of 5-HMF was converted into DFF within 40 min with 600 C of charge passed. The Faraday efficiency for generating DFF was 100% at this time). After this time, the potential slowly began to rise to the limited applied potential of 1.0 V vs. Ag⁺/Ag due to the decreasing 5-HMF concentration. The electrolysis was continued at 1.0 V potential until the current reached zero after an additional 600 C of charge had been passed. Therefore, electro-oxidation of a compound occurred during this time. The amount of DFF did not decrease, and the products such as FFCA, FDCA from the oxidation of DFF were not found at the end of the electrolysis, revealing that no oxidation of 5-HMF and DFF occurred. Moreover, no oxidation of water to dioxygen gas was observed. Although the direct electro-oxidation of NMI on a glassy carbon

<figure><img src="image_14.png" /><figcaption>**Figure 5.** (Left) CVs of 1 mM TEMPO (black) in the presence of 450 mM NMI (red) with 100 mM 5-HMF (blue) and CV of 100 mM 5-HMF alone (green) in acetonitrile. (Right) Conversion of 5-HMF, yield of DFF (orange) and Faradic efficiency for the generated DFF (green) during electrolysis at 300 mA and a limit of potential at 1.0 V.</figcaption></figure>

<figure><img src="image_15.png" /></figure>

<footnote>* Measured with 0.1 M of NaClO₄ as in all experiments reported herein.</footnote>
<figure><img src="image_16.png" /></figure>

<figure><img src="image_17.png" /><figcaption>**Figure 6.** (Left) CVs of 1 mM TEMPO (black) in the presence of 450 mM NMI (red) with 100 mM 5-HMF (blue) and CV of 100 mM 5-HMF alone (green) in GVL. (Right) Conversion of 5-HMF, yield of DFF and Faradic efficiency for generating DFF (green) during electrolysis at 300 mA and a limit of potential at 1.0 V.</figcaption></figure>

<figure><img src="image_18.png" /></figure>

electrode was observed at 1.4 V by a CV of NMI recorded in acetonitrile (Figure SI-7), NMI was probably electro-oxidized at 1.0 V in the presence of TEMPO as a redox mediator. The NMI oxidation product could not be identified in these experiments.

Figure 6 shows the CVs measured in GVL as a solvent for the various combinations of interest in this study (Left) and the conversion of 5-HMF into DFF and Faradic efficiency during 300 mA electrolysis (Right). Figure SI-8 represents the potential and the charge measured during this electrolysis. They show that, contrary to acetonitrile, where the oxidation of 5-HMF without TEMPO is well defined, in GVL only a small wave is observed at 1.7 V vs. Ag/Ag⁺. However, TEMPO exhibits a similar redox behavior and a high reactivity towards 5-HMF electro-oxidation in the presence of NMI in the GVL. The electrolysis experiment at 300 mA with a potential limitation at 1.0 V revealed that 85% of 5-HMF was electro-oxidized to DFF with 80% of the Faradic efficiency after 700 C. In the first period up to 500 C, the Faradic efficiency was 100% for the oxidation of 75% 5-HMF into DFF at a very low potential around 0.1 V. The potential then rose because the concentration of the 5-HMF around 0.1 V decreased, leading to slower kinetics and a higher overpotential to maintain the current density. 5-HMF was not the only compound oxidized at the second level potential around 0.7 V, which led to a decrease in the Faradic efficiency for the oxidation of 5-HMF into DFF. It should be noted that reducing the potential limit to 0.3–0.4 V would have led to better selectivity towards DFF and 5-HMF final conversion, but such electrolysis conditions would increase the electrolysis time. After an additional charge of 800 C had passed, only traces of FFCA were found, suggesting that a little DFF was oxidized at the second level potential around 0.8 V. The main reaction that occurred in the later period was probably the oxidation of NMI or the oxidation of the open GVL form into levulinic acid. The open GVL form can be obtained by reverse esterification in the presence of a base. However, after the electrolysis, no levulinic acid was found by either NMR or HPLC. Therefore, NMI was probably oxidized to unknown products, as was observed with acetonitrile.

When 5-HMF is dissolved in DMSO, an no oxidation wave is observed. This could be explain because the oxidation of DMSO take place at lower potential than the expected oxidation of 5-HMF alone. The small oxidation peak observed at –0.1 V vs. Ag/Ag⁺ is directly correlated with the reduction peak at lower potential. Furthermore, unlike acetonitrile and GVL, the CVs presented in Figure 7 revealed that TEMPO exhibits a small catalytic current once 5-HMF and NMI were added into the TEMPO solution in DMSO. That poor catalytic reactivity was probably due to the instability of the TEMPO⁺ oxoammonium species in DMSO. The electrolysis in DMSO carried out at a constant current of 300 mA and a potential limit of 1.0 V confirmed that DMSO is not a good solvent for the electro-oxidation of 5-HMF using TEMPO as a redox mediator. The potential and charge measured during this electrolysis are represented in Figure SI-9. Due to the low catalytic current at 0.2 V, the potential immediately rose to 1.0 V at the beginning

<figure><img src="image_19.png" /><figcaption>**Figure 7.** CVs of 1 mM TEMPO (black) in the presence of 450 mM NMI (red) with 100 mM 5-HMF (blue) and CV of 100 mM 5-HMF alone (green) in DMSO.</figcaption></figure>
<figure><img src="image_20.png" /></figure>

of the electrolysis and stayed at this potential for 2 hours with a total charge of 700 C passed. This rapid potential increase is a sign of a greater resistance, probably related to poorer kinetics of TEMPO-mediated 5-HMF electro-oxidation in DMSO compared to that in acetonitrile, and the lower catalytic reactivity of TEMPO. In fact, the amount of 5-HMF did not decrease, and no products such as DFF, HFMCA, FFCA, FDCA were found. This shows that 5-HMF was not electro-oxidized in DMSO with TEMPO as a redox mediator. The charge passed is then dedicated to the oxidation of other species such as DMSO and NMI. The oxidation of DMSO to DMSO₂ was found, with only 6% Faradic efficiency when 700 C had been passed. The main reaction in this electrolysis was probably the oxidation of NMI.

As we have shown above, the presence of a base is required in order to promote the catalytic activity of TEMPO. We employed NMI as a base, as suggested in the literature, but we also demonstrated above that NMI itself undergoes significant oxidation which prevents full oxidation of 5-HMF to DFF or further oxidation of DFF to FFCA or FDCA. We therefore explored various bases to examine the effect of the Brønsted base on TEMPO's reactivity towards the oxidation of 5-HMF in GVL. A series of CVs revealed that significant catalytic features were observed with several bases (Figure SI-10). We screened a series of nitrogenated bases (pyridine, methyl-benzimidazole, 2,6-lutidine, imidazole, 2,4,6-collidine, DBU, NH₄OH) as well as NaOH, with various pKa in water (see ESI). The concentration of the bases used in the TEMPO's reactivity study was 450 mM within the concentration-independent regime range, except for NaOH and DBU. Because of its low solubility in an organic aprotic solvent, the NaOH concentration was limited to 50 mM. DBU is a strong base which caused the degradation of 5-HMF if a high concentration of DBU was used. The DBU concentration was therefore also limited to 50 mM.

In principle, the oxidation of the alcohol group to the aldehyde group catalyzed by TEMPO is more efficient when the alcohol is deprotonated by a base.⁵¹ However, none of the other bases we used showed reactivity towards the oxidation of 5-HMF in the presence of TEMPO which was comparable to that of NMI. It seems that the catalytic reactivity of TEMPO is not just related to the basicity (referring to the pKa in water). For instance, when comparing NMI and 2,4,6-collidine, although their basicities (pKa of 7.4 and 7.5 respectively) and oxidation potentials (ca. 1.4 V) are similar, NMI led to the highest reactivity of TEMPO while that of 2,4,6 collidine was very low. What is more, the strongest bases in this study (DBU, pKa = 13.5 and NaOH, pKa = 14) did not lead to a catalytic activity as large as that of NMI. The influence of the Brønsted base on the electrocatalytic reactivity of TEMPO towards the oxidation of 5-HMF was also examined in acetonitrile. Similarly, 2,4,6-collidine (450 mM) showed a low efficiency reactivity towards the oxidation of 5-HMF compared with NMI (450 mM) (see Figure SI-11). Conversely, DBU led to an interesting catalytic current when TEMPO and 5-HMF were present (see Figure SI-11). However, two catalytic waves were observed at 0.2 V and 0.4 V vs. Ag⁺/Ag, suggesting many catalytic reactions at different potentials. The lower peak current obtained with DBU (0.9 mA cm⁻² at 0.4 V) compared to that with NMI (1.8 mA cm⁻²)

is probably due to the higher NMI concentration (450 mM). Besides, DBU is electro-oxidized at 0.8 V vs. Ag⁺/Ag, which can hinder the electro-oxidation of 5-HMF catalyzed by TEMPO.

Thus, NMI exhibits a particular feature affecting the reactivity of TEMPO towards the oxidation of 5-HMF in organic solvents, and we thus show that the choice of the base is non-innocent, and that N-methylimidazole performs much better than other bases. This result is in sharp contrast with previous literature,[³⁵] where 2,6-lutidine is considered as the most efficient base. Our result shows on the opposite a suboptimal behavior of this compound (see Figure SI-7), which nuances the conclusions brought by previous studies, and opens new questions regarding the exact role of the base. Possible explanations include direct participation of NMI in the reaction mechanism, or a potential catalytic effect of oxidized NMI (which would still require the presence of TEMPO as without it, no catalytic activity would be observed). Explaining this feature is certainly of interest, but falls outside the scope of the present contribution and is left for future work.

The electrochemical syntheses presented in the present manuscript have been performed under conditions that are in the author's opinion representative of a potential electrochemical process. We indeed employed a flow cell featuring two divided chambers and operating at current densities suitable for an industrial application (about 15 mA/cm²). We thus demonstrate the feasibility of the electrocatalytic oxidation using such a catalytic system.

## TEMPO-Mediated Electro-Oxidation of 5-HMF in Hydro-Organic Media

So far, the catalytic systems provided a good yield and efficiency of electro-oxidation of the hydroxyl function of 5-HMF into DFF in acetonitrile and GVL, but little or no oxidation of the carbonyl functions was observed under our conditions. Note that under the conditions mentioned above, the absence of observation of the production of carboxylic acids also rules out the occurrence of Cannizzaro reaction despite the alkaline character of the solutions employed. In order to target FDCA, the intermediacy of geminal diols in the presence of water may be required in order to oxidize the carbonyl functions. In fact, the literature shows that TEMPO exhibits a high reactivity and efficiency for the electro-oxidation of 5-HMF into FDCA in pH 9 buffer solution. Consequently, we attempted to oxidize 5-HMF into FDCA by using mixtures of an organic solvent and water with a significant amount of water. A pH 9 buffer solution was therefore also examined in order to provide an environment that was basic, but not too strong to avoid degradation reactions of 5-HMF.

In a first series of experiments, we examined the electrochemical behavior of TEMPO in a hydro-organic medium by cyclic voltammetry (Figure 8). In an acetonitrile/water mixture (Figure 8a), a catalytic current was observed in the CVs when 5-HMF was added to the TEMPO and NMI solution in an acetonitrile/water mixture (v/v = 1/1), although the catalytic current observed was lower in magnitude compared with that
<figure><img src="image_21.png" /></figure>

<figure><img src="image_22.png" /><figcaption>**Figure 8.** CVs of 1 mM TEMPO (black) in the presence of a base (red) with 100 mM HMF (blue) or 20 mM DFF (green) in different solvent/water/base mixtures (a) Acetonitrile/water (v/v = 1/1), 450 mM NMI (b) Acetonitrile/water (v/v = 1/1), 100 mM pH 9 borate buffer, (c) GVL/water (v/v = 1/1), 450 mM NMI (d) GVL/water (v/v = 1/1), 100 mM pH 9 borate buffer, (e) DMSO/water (v/v = 1/1), 450 mM NMI (f) DMSO/water (v/v = 1/1), 100 mM pH 9 borate buffer.</figcaption></figure>

in pure acetonitrile. By using DFF as a substrate, the CV shows a catalytic current, which shows that it is possible to oxidize DFF in an ACN/water medium into carboxylic moieties using a TEMPO/NMI system. When testing a pH 9 buffer (Figure 8b) instead of NMI, the reactivity of TEMPO towards the oxidation of 5-HMF increased markedly (by about 3 times) The same observation was made with the DFF oxidation. This confirms the efficiency of using a borate buffer in the presence of water. In a GVL/water medium (Figure 8c and 8d), despite the efficiency of the catalytic system in pure GVL, unlike acetonitrile/water mixtures, no catalytic current for the oxidation of 5-HMF was observed. In addition, whatever the base (NMI or buffer) used, the electrochemical behavior of TEMPO was not symmetrical in oxidation and reduction. Thus, we cannot expect to produce FDCA using this strategy with GVL as the organic solvent.

In contrast, while the oxidation wave of TEMPO was not reversible in pure DMSO, we found that it was reversible in DMSO/water mixtures (v/v = 1), and we observed a catalytic current for the oxidation of 5-HMF in the presence of NMI (Figure 8e) and buffer (Figure 8f). The oxidative wave of TEMPO is known to be reversible in water, suggesting that the active species generated from TEMPO, the oxoammonium species, is relatively stable in water. Thus, water modulates the redox behavior of TEMPO in DMSO, and thereby its reactivity.

When the amount of water in the solvent mixture was decreased, we observed a decrease in the reactivity of TEMPO towards the oxidation of 5-HMF according to the CVs (Figure S1-12). In fact, no reactivity was observed in the CVs with 30 volume% of pH 9 borate buffer; it seems that TEMPO is capable of electro-oxidizing 5-HMF with a minimum of 40 volume% of pH 9 borate buffer.
<figure><img src="image_23.png" /></figure>

<figure><img src="image_24.png" /><figcaption>**Figure 9.** (Left) Conversion of 5-HMF, yield of DFF and HMFCA. (Right) Faradic efficiency for generating DFF, HMFCA and DMSO₂ during the electrolysis in DMSO/pH 9 buffer (v/v = 6/4).</figcaption></figure>

This intriguing behavior led us to carry out a prolonged electrolysis in a DMSO/water mixture.

The electrolysis of 5-HMF with TEMPO in DMSO/50 mM pH 9 borate buffer (v/v = 6/4) was carried out by applying a constant current of 300 mA with a potential limit of 1.0 V. The potential represented in Figure SI-13 immediately rose to 1.0 V, in agreement with the low reactivity of TEMPO at 0.2 V observed in the CVs. 94% of 5-HMF was electro-oxidized within 5.5 h after 1400 C had been passed. The conversion of 5-HMF and Faradic efficiency are collected in Figure 9. Interestingly, in that case both DFF and HMFCA, two distinct, parallel products of the primary oxidation of 5-HMF, were obtained after the electrolysis. While 13% DFF conversion was obtained after 1400 C, the maximum conversion of HMFCA (21%) was attained when only 400 C had been passed inside 1.5 h of the electrolysis. Undoubtedly, water facilitated the oxidation of the aldehyde function, demonstrating the principle of the strategy. However, FFCA and FDCA were not produced, indicating that TEMPO was not capable of catalytically electro-oxidizing DFF and HMFCA with 40% by volume of water in the solvent mixture. The durability of TEMPO should be questioned in this study. Formic acid and protoanemonin were also produced up to about a 12% yield after 1400 C of charge had been passed. However, under such conditions, DMSO was oxidized to DMSO₂ with 30% Faradic efficiency over the electrolysis. Although water can improve the electro-oxidation of 5-HMF in the presence of TEMPO as a redox mediator, its selectivity and efficiency were still not impressive. The instability of TEMPO with DMSO could still occur, despite the presence of significant amounts of water.

## Conclusions

In this contribution, we have demonstrated the highly efficient and selective electro-oxidation of 5-HMF into DFF in acetonitrile and GVL using TEMPO as a redox mediator and NMI as a Brønsted base. This allows the formation of unwanted products such as formic acid and protoanemonin by the oxidative scission of the C–C bond observed during the direct electro-oxidation of 5-HMF to be avoided. Importantly, using TEMPO

significantly reduced the amount of overpotential necessary for the oxidation of 5-HMF, and dramatically increased the current density that can be achieved. We additionally show that NMI employed as a base affords much better activity compared to other organic or inorganic bases. The exact role of this base is quite puzzling, though this does not seem related to the pKa, and deciphering its exact role is left for future work. Overall, we demonstrate the feasibility of using such catalytic system under conditions representative of a potential electrochemical process. Unlike acetonitrile and GVL, no reactivity was observed in DMSO using TEMPO as a redox mediator.

However, in pure organic solvents, DFF was the main product, with very slow oxidation of aldehyde functions to carboxylic acids. We therefore turned to hydro-organic media to improve this part. TEMPO exhibited a moderate reactivity in DMSO/water mixture towards the oxidation of 5-HMF into DFF and HMFCA. Water probably facilitates the oxidation of the aldehyde function to a carboxylic acid, though so far limitations were reached that prevent the formation of FDCA under the conditions under study. Thus, TEMPO is still a promising redox mediator for the oxidation of 5-HMF into FDCA in the presence of water. Though the issues associated to the use of a relatively expensive redox mediator (TEMPO) and its potential recycling needs to be addressed, for instance by using immobilized species[52–54] or considering the extraction of the product (DFF for instance) from the reactive medium,[55] our result paves the way for the development of this strategy to further improve the oxidation of aldehyde moieties and reduce the amount of base required.

## Supporting Information

2D-NMR spectra, Additional cyclic voltammetry results, Additional chronopotentiometry results.
<figure><img src="image_25.png" /></figure>

## Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

## Conflict of Interests

The authors declare no conflict of interest.

## Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

**Keywords:** Electrocatalysis · TEMPO · 5-Hydroxymethylfurfural · Biomass

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Manuscript received: February 5, 2024

Revised manuscript received: March 27, 2024

Version of record online: May 8, 2024