Microwave-Assisted Production of 5-Hydroxymethylfurfural from Fructose Using Sulfamic Acid as a Green Catalyst

Abstract

The development of safe-by-design synthesis of valuable chemicals from biomass derivatives is a key step towards sustainable chemical transformations in both academia and industry. 5-Hydroxymethylfurfural (5-HMF) is a biomass derivative chemical of high commercial interest due to its wide range of chemical and biofuel applications. In this scenario, the present work contributes to a methodology for producing 5-hydroxymethylfurfural (5-HMF) through fructose dehydration reaction under microwave irradiation. The proposed protocol uses a simple sodium chloride–saturated aqueous-i-PrOH biphasic system and catalysis of sulfamic acid, a low-cost solid Brønsted–Lowry inorganic acid, which presents pivotal features of a sustainable catalyst. A 2³ full factorial design was applied to achieve the highest conversion and 5-HMF yield, allowing the identification of the main factors involved in the process. Under the optimized conditions, fructose at the concentration of 120 g L⁻¹ was converted with 91.15 ± 6.98% after 20 min at 180 °C, using 10 mol% of catalyst. 5-HMF was produced in 80.34 ± 8.41% yield and 73.20 ± 8.23% selectivity. Thus, the present contribution discloses a new optimized methodology for converting the biomass derivative fructose to 5-hydroxymethylfurfural (5-HMF).

1. Introduction

5-hydroxymethylfurfural (5-HMF) is an essential building block for the near future. Its unique structure allows a variety of transformations in search of alternative compounds for environmentally safer applications [1,2]. For example, the polymerization of reduced and oxidized 5-HMF products affords the monomers that are candidates to replace polyethylene terephthalate [3]. Moreover, 5-HMF has also gained increasing attention as a suitable biomass-derived platform to prepare valuable fine-chemical products and intermediates, which find their places in the production of plastics, resins, medicines, and diesel fuel additives, as examples [2].

The main approaches to produce 5-HMF typically involve the thermal or acid-catalyzed dehydration of C6-sugars, such as the biomass derivatives fructose and glucose. Among these sugars, fructose is particularly well-suited due to its predominant furanose form (5-member monosaccharide ring), which is easily dehydrated compared to the pyranose form (6-member monosaccharide ring) [4].

Generally, inorganic Brønsted–Lowry and Lewis acids are the most commonly investigated catalysts for converting fructose to 5-HMF [5]. Both homogeneous [6] and heterogeneous [7] catalysts are employed within aqueous monophasic or biphasic systems. Except for a few reported catalytic systems operating under lower temperatures [8,9,10], conversion of C6-sugars to 5-HMF requires high temperatures, commonly exceeding 120 °C, and relies predominantly on conventional heating methods.

Nevertheless, conventional heating has the inherent drawback of inefficient heat transfer, which leads to prolonged reaction times. One of the consequences of extended exposure of 5-HMF to high temperatures is the rehydration reaction, thus converting 5-HMF to levulinic and formic acids [11]. Moreover, prolonged reaction times and high temperatures contribute to the formation of humins, which are undesirable polymerization products [11,12].

Microwave-assisted dehydration of C6-sugars has been reported as a sustainable energy source alternative to conventional heating [13]. It provides fast and uniform volumetric heating, enhances reaction performance, and improves energy efficiency [14,15]. One of the first reports of MW-assisted catalytic dehydration of fructose to 5-HMF used the strong acid cationic ion-exchange resin Dowex 50wx8-100 as a catalyst [16]. The study found that the optimal fructose concentration for resin was 2 wt% when using an acetone–water mixture as the solvent. At a temperature of 150 °C and a reaction time of 15 min, the fructose conversion reached 95%, and a 73% yield of 5-HMF was obtained.

Microwave irradiation was applied as an alternative heating source to obtain 5-HMF from fructose in the presence of the Lewis acid catalyst AlCl₃ [17]. The study demonstrated that a 5-HMF yield of 69.4% can be achieved by performing the reaction at 140 °C for 5 min in the presence of 50 mol% of the catalyst and using dimethyl sulfoxide (DMSO) as the solvent. Furthermore, the same study also showed that a mixture of water and methyl isobutyl ketone (MIBK) is also a suitable reaction medium, furnishing the 5-HMF with 61% yield under similar reaction conditions.

Deep eutectic solvents (NADES) were also successfully used as catalysts to promote fructose dehydration under microwave irradiation [18]. In this study, the authors employed the Design of Experiment (DoE) approach, specifically a 2² factorial design, to evaluate different betaine hydrochloride-based NADES. After optimization, it was determined that the NADES containing malic acid as the hydrogen bond donor exhibited the best performance, resulting in a remarkable 5-HMF yield of 94% after 11 min at 140 °C. Under similar conditions, sucrose yielded 5-HMF with a 73% yield at 160 °C and a reaction time of 11 min.

More recently, a study reported the scale-up synthesis of 5-HMF from fructose through a continuous flow MW-assisted process [19]. The authors also demonstrated that the limitations of MW-assisted production of 5-HMF can be overcome, as evidenced by other recent scale-up MW-assisted processes [20,21,22]. The authors achieved a productivity of 100 g h⁻¹ of 5-HMF from fructose using an aqueous hydrochloric acid (HCl) catalytic system.

Sulfamic acid (SA) is a zwitterionic inorganic acid with molecular formula NH₂SO₃H that has emerged as a suitable Brønsted–Lowry acid catalyst with the desired characteristics for the large-scale process. SA is a relatively strong acid, a non-hygroscopic crystalline solid, easy-to-handle, non-corrosive, non-volatile, odorless, and commercially available at low cost [23,24]. SA has been applied in the industry as an acid-cleaning agent and an environmentally friendly substitute for HCl and H₂SO₄ [25]. Moreover, it has been successfully utilized as a catalyst in numerous organic synthetic reactions [26,27,28].

SA was previously applied as a catalyst in converting bamboo fiber into 5-HMF under MW-assisted conditions [29]. The highest yield achieved in this study was 52.2% under microwave heating in an H₂O/THF biphasic medium after 40 min at 180 °C and in the presence of 40 mol% of SA.

SA (50% w/w) was also investigated as a bifunctional catalyst for the hydrolysis of holocellulose, which is composed of cellulose and hemicellulose, in a solvent medium comprising γ-verolactone and water (25:1 v/v) [30]. Under autoclave conditions (1 MPa) at 180 °C and in an inert N₂ atmosphere, 5-HMF and furan were obtained with 37.2% and 62.0% yields, respectively (HPLC yield), after 3 h. Comparative experiments revealed that Brønsted acids, such as H₂SO₄ and Amberlyst acid resins, furnished only traces of 5-HMF under the same reaction conditions. The authors suggested that SA could promote the three required steps: depolymerization of the cellulose to glucose, isomerization to fructose, and dehydration to 5-HMF. The first and third steps are allowed by the sulphonic group, while the basic amino group promotes the second step.

In this contribution, we investigated the SA catalytic properties, enhanced by microwave irradiation, to obtain 5-HMF from fructose in a suitable reaction medium. The effect of the reactional parameters, including temperature, reaction time, and catalyst loading, were investigated and optimized using the Design of Experiments (DoE) approach.

2. Materials and Methods

2.1. General Information

Unless otherwise indicated, all common reagents and solvents were used as received from commercial suppliers without further purification. Standard 5-HMF (purity > 99%, FG, Lot# STBF6986V) was purchased from Sigma-Aldrich. Analytical grade fructose was purchased from Synth (Brazil), and sulfamic acid (SA) from Cinética (Brazil) (purity of 99%). HPLC-grade i-PrOH was purchased from Merck. Milli-Q^® Type 1 ultrapure water was used in all experiments.

The microwave-assisted reactions were conducted in an Anton Paar Monowave^® 300 single-mode microwave reactor using a G30 sealed vial (20 mL maximum recommended capacity) and magnetically stirred at 600 rpm. The reaction temperature and pressure were continuously monitored via an integrated infrared and pressure sensor.

The NMR spectra were recorded on a Bruker Fourier 300 FT-NMR spectrometer (Bruker Biospin GmbH, Rheinstetten, Germany, 7.05 Tesla, 300 MHz for the ¹H nucleus, and 75.48 MHz for the ¹³C nucleus). The chemical shifts (δ) are expressed in parts per million (ppm), and the coupling constants are reported in hertz (Hz). The spectra were acquired at 293 K using 5 mm quartz tubes. The NMR data were acquired and processed using the TopSpin™ 3.2 software (Bruker, Germany).

2.2. Experimental Design

A 2³ full factorial design with a central point was conducted as a screening method to investigate the effect of the following parameters: reaction time (10, 15, and 20 min), reaction temperature (150, 165, and 180 °C), and catalyst concentration (10, 15, and 20 mol%). The experiments (Run 1 to Run 8) were replicated twice, and the central point (Run 9) was carried out in triplicate, totaling 19 experiments. The responses were fructose conversion and 5-HMF yield.

The experiments indicated by the 2³ full factorial design were conducted as follows: fructose (30 mg, 0.17 mmol) was added to the microwave reaction vial, followed by 1.0 mL of an aqueous saturated sodium chloride solution, resulting in a 30 g/L of fructose solution. Next, SA (10, 15, or 20 mol%) and isopropanol (2.0 mL) were added to the vial. The vial was sealed and subjected to microwave heating at the established temperatures (150, 165, or 180 °C). Once the reaction temperature was reached, the reaction time was initialized and maintained for 10, 15, or 20 min.

2.3. Conversion, Yield, and Selectivity Measurement

For conversion and selectivity measurement, both layers were carefully separated and analyzed by High-Performance Liquid Chromatography (HPLC). The HPLC analyses were performed in a Shimadzu^® LC-20AD model equipped with a refractive index detector (RID-20A). The following chromatographic conditions were established: Aminex^® HPX-87H column (300 mm × 7.8 mm, 9 µm particle size, Bio-Rad, EUA) set up at 60 °C, mobile phase consisting of 0.05 mmol L⁻¹ sulfuric acid aqueous solution, a constant flow rate of 0.5 mL min⁻¹, and injection volume of 5 μL. The samples were quantified by comparing the respective peak areas with the analytical curve generated from solutions containing both standard fructose and 5-HMF at 0.5 to 20.0 g L⁻¹ (Table 1 and Supplementary Material Figures S1–S3). For the experiment analysis, after completing the reaction, the mixture was cooled to room temperature, and the organic upper layer was carefully separated from the bottom aqueous phase layer. Next, 200 µL of each phase was diluted with 800 µL of a 5 mmol L⁻¹ H₂SO₄ aqueous solution (HPLC analysis mobile phase) and filtered using 0.45 µm pore size nylon filters (Whatman Uniflo Syringe Filters, Merk, Germany), followed by HPLC analysis. The peak areas from the HPLC analysis were compared with the respective standard curves, and the obtained values in g L⁻¹ were converted to mols of fructose and 5-HMF. The conversion of fructose (Equation (1)), 5-HMF yield (Equation (1) to (3)), and 5-HMF selectivity were calculated as follows:

$$\mathrm{Fructose} \mathrm{conversion} (\%)=\frac{mols of consumed fructose}{mols of initial fructose}\times 100$$

(1)

$$5\text{-}\mathrm{HMF} \mathrm{yield} (\%)=\frac{mols of obtained 5-HMF}{mols of initial fructose}\times 100$$

(2)

$$5\text{-}\mathrm{HMF} \mathrm{selectivity} (\%)=\frac{mols of obtained 5-HMF}{mols of consumed fructose}\times 100$$

(3)

2.4. Production of 5-HMF under the Optimized Conditions

To a microwave reaction vial (Anton Paar G30 vial, maximum volume of 20 mL), 0.360 g of fructose (2.04 mmol) and 3 mL of an aqueous saturated sodium chloride solution were added, resulting in a 120 g L⁻¹ fructose solution. Next, 20 mg of SA (10 mol%; 0.2 mmol) and 6 mL of i-PrOH were added to the vial. The vial was sealed and subjected to microwave heating at 180 °C for 20 min. After the final cooling step, the organic phase containing mainly 5-HMF in i-PrOH was separated. The aqueous phase was extracted with ethyl acetate (3 × 3 mL) and combined with the i-PrOH phase, and the solvents were removed under reduced pressure. The crude product was resuspended in water (5 mL) to remove the water-insoluble humins by filtration, using a 0.45 µm pore size nylon filter (Whatman Uniflo Syringe Filters, Merk, Germany). Finally, 5-HMF was recovered from the aqueous solution by reduced pressure. 5-HMF was obtained as a pale brown semisolid in 79.7% yield (0.205 g; 1.63 mmol). ¹H and ¹³C NMR analyses confirmed the chemical structure and purity of the product (Supplementary material Figures S12 and S13).

¹H NMR (300 MHz, CDCl₃) δ 9.55 (s, 1H), 7.24 (d, ³J = 3.6 Hz, 2H), 6.52 (d, 3J = 3.6 Hz, 1H), 4.70 (s, 2H), 3.46 (bs, 1H). ¹³C NMR (75 MHz, CDCl₃) δ 177.9, 161.1, 152.1, 123.6, 110.1, 57.3.

2.5. Statistical Analysis

The statistical evaluation of the results was performed using Analysis of Variance (ANOVA). TIBCO Statistica^® software v.13.5 (TIBCO Software Inc., Palo Alto, CA, USA) was employed for all statistical, plotting, and mathematical calculations. The results were expressed as mean ± standard deviation. ANOVA followed by Tukey’s test (5% of significance) was calculated to verify the statistical differences between each experiment.

3. Results and Discussion

Conversion of Fructose into 5-HMF

The first attempt to certify SA as a suitable catalyst for the dehydration of carbohydrates into 5-HMF was carried out under conventional heating. Fructose was used as the C6-carbohydrate model, and the amount of SA was first established as 10% (w/w), related to the mass of fructose. The transformation was carried out in a sealed stainless steel PTFE-lined reactor at 120 °C in the biphasic system formed by saturated aqueous sodium chloride and isopropanol (1:2) for 2 h. Under these conditions, fructose was totally consumed (99% conversion). However, 5-HMF was obtained with only a 38% yield, as represented in Figure 1. The low selectivity to 5-HMF was accompanied by a considerable amount of humins. The formation of humins is one of the main drawbacks of 5-HMF production. High temperature and long reaction times are conditions that promoted the polymerization of the in situ formed 5-HMF into humins [31]. Decreasing the reaction time to 30 min reveals that fructose conversion and 5-HMF yield were reduced to 38% and 21%, respectively.

Thus, we evaluated the effect of microwave irradiation in promoting the rapid temperature increase of the reaction medium, consequently aiming to decrease 5-HMF polymerization into humins. After a brief temperature and reaction time screening, we found that at 180 °C, the fructose conversion and the 5-HMF yield were measured as 96% and 76%, respectively, after only 20 min, as illustrated in Figure 1. Also, it was noticed that usual coproducts, such as formic acid and levulinic acid, were not observed in the HPLC analysis (Supplementary Material Figures S4 and S5).

Next, we took advantage of the Design of Experiments (DoE) approach to find the optimized condition under microwave irradiation. As shown in Table 1, a 2³ full factorial design with a central point was used as a screening method to evaluate the following parameters: reaction times of 10 min (−1, low level), 15 min (0, center point), and 20 min (+1, high level); reaction temperatures at 150 °C (−1, low level), 165 °C (0, center point), and 180 °C (+1, high level); and finally, catalyst concentration in 10 mol% (−1, low level), 15 mol% (0, center point), and 20 mol% (+1, high level).

Table 1. Coded (−1, 0, and 1) and real parameters of the 2³ full factorial design and experimental results for the responses conversion and yield.

Run	Temperature (°C)	Time (min)	Catalyst (mol%)	Conversion (%) (mean ± SD)	Yield (%) (mean ± SD)
1	150 (−1)	10 (−1)	10 (−1)	42.04 ± 3.54 e	37.22 ± 3.28 c
2	150 (−1)	10 (−1)	20 (+1)	54.58 ± 3.45 b	45.96 ± 4.29 cd
3	150 (−1)	20 (+1)	10 (−1)	68.54 ± 2.45 cd	64.61 ± 5.29 ab
4	150 (−1)	20 (+1)	20 (+1)	60.04 ± 6.38 bc	58.20 ± 6.46 bd
5	180 (+1)	10 (−1)	10 (−1)	89.32 ± 4.16 a	71.33 ± 2.16 ab
6	180 (+1)	10 (−1)	20 (+1)	96.47 ± 0.83 a	76.59 ± 6.52 a
7	180 (+1)	20 (+1)	10 (−1)	96.75 ± 1.06 a	75.81 ± 4.99 a
8	180 (+1)	20 (+1)	20 (+1)	96.84 ± 2.31 a	74.94 ± 3.49 a
9	165 (0)	15 (0)	15 (0)	73.74 ± 0.57 d	62.61 ± 1.04 ab

Reaction conditions: fructose (30.0 mg, 0.17 mmol), saturated NaCl aqueous solution (1.0 mL), i-PrOH (2.0 mL), SA (1.65 mg for 10 mol%, 2.47 mg for 15 mol%, or 3.30 mg for 20 mol%), MW heating at 180 °C, for 10 min. All reactions were performed in duplicate except Run 9, which was performed in triplicate. All the measurements were determined by HPLC analysis. For all experiments, Tukey’s test (5%) was applied between the experiments (Runs 1 to 9). Different letters in the same column indicate statistical differences. SD: Standard deviation.

Table 1. Coded (−1, 0, and 1) and real parameters of the 2³ full factorial design and experimental results for the responses conversion and yield.

Run	Temperature (°C)	Time (min)	Catalyst (mol%)	Conversion (%) (mean ± SD)	Yield (%) (mean ± SD)
1	150 (−1)	10 (−1)	10 (−1)	42.04 ± 3.54 e	37.22 ± 3.28 c
2	150 (−1)	10 (−1)	20 (+1)	54.58 ± 3.45 b	45.96 ± 4.29 cd
3	150 (−1)	20 (+1)	10 (−1)	68.54 ± 2.45 cd	64.61 ± 5.29 ab
4	150 (−1)	20 (+1)	20 (+1)	60.04 ± 6.38 bc	58.20 ± 6.46 bd
5	180 (+1)	10 (−1)	10 (−1)	89.32 ± 4.16 a	71.33 ± 2.16 ab
6	180 (+1)	10 (−1)	20 (+1)	96.47 ± 0.83 a	76.59 ± 6.52 a
7	180 (+1)	20 (+1)	10 (−1)	96.75 ± 1.06 a	75.81 ± 4.99 a
8	180 (+1)	20 (+1)	20 (+1)	96.84 ± 2.31 a	74.94 ± 3.49 a
9	165 (0)	15 (0)	15 (0)	73.74 ± 0.57 d	62.61 ± 1.04 ab

Reaction conditions: fructose (30.0 mg, 0.17 mmol), saturated NaCl aqueous solution (1.0 mL), i-PrOH (2.0 mL), SA (1.65 mg for 10 mol%, 2.47 mg for 15 mol%, or 3.30 mg for 20 mol%), MW heating at 180 °C, for 10 min. All reactions were performed in duplicate except Run 9, which was performed in triplicate. All the measurements were determined by HPLC analysis. For all experiments, Tukey’s test (5%) was applied between the experiments (Runs 1 to 9). Different letters in the same column indicate statistical differences. SD: Standard deviation.

We maintained the biphasic system formed by saturated NaCl aqueous solution and isopropanol (i-PrOH) in all planned experiments. Using a biphasic reaction medium consisting of an organic solvent and aqueous solutions containing a salting-out agent is well-documented for the 5-HMF production [17,32]. NaCl is the common salting-out agent of choice due to its inertness, low cost, nontoxicity, and easy workup. The salting out agent decreases the mutual solubility of the solvents, forcing the less polar components, which is the case of the 5-HMF, to be extracted by the organic phase, thus avoiding the interaction of the product with the catalyst. It prevents the subsequent dehydration reaction of 5-HMF to levulinic acid (LA) and formic acid (FA). Besides the beneficial salting-out effect, another positive effect of NaCl is the strong intermolecular interaction between the chloride anion and fructose, which inhibits the formation of soluble humins [31]. Dimethylsulfoxide (DMSO) has also shown an effective effect on reducing side reactions [32]. Nevertheless, in the present study, i-PrOH was the organic solvent of choice. In addition to the appropriated biphasic system formation, i-PrOH is relatively non-toxic and has a lower boiling point than DMSO, making the 5-HMF recovery and purification process easy.

According to the data shown in Table 1, the conversions of fructose to 5-HMF range between 42.04 ± 3.54% and 96.84 ± 2.31%. The highest conversion was achieved in experiment Run 8, which is associated with the following reaction conditions: temperature of 180 °C (+1), reaction time of 20 min (+1), and 20 mol% (+1) of the catalyst. However, no statistical difference was found when comparing the result from Run 8 with experiments Run 5 (89.32 ± 4.16%), Run 6 (96.47 ± 0.83%), and Run 7 (96.75 ± 1.06%). Thus, the data suggest that it is possible to achieve high conversion rates at the higher temperature of 180 °C but using low levels (−1) of reaction time (10 min) and catalyst (10 mol%), as indicated by Run 5, saving time and reagent consumption.

The lowest conversion was noticed from Run 1 (42.04 ± 3.54%), in which the lowest parameter levels were employed. However, when the reaction temperature was set to 180 °C (Run 5), the conversion value increased to 89.32 ± 4.16%. This response suggests that the low temperature and catalyst concentration are not enough to promote the dehydration process of fructose, and the reaction temperature is a key parameter for conversion.

Focusing on 5-HMF yield response, values from 37.22 ± 3.28% to 76.59 ± 6.52% were observed. The experiment from Run 6 suggests that when the reaction parameters were set as 10 min (−1), 180 °C (+1), and 20 mol% (+1) of SA, the highest 5-HMF yield can be obtained (76.59 ± 6.52%). Nevertheless, it was possible to observe from the statistical analysis that the yield response from Runs 3, 5, 7, 8, and 9 do not indicate statistical differences compared to Run 6. Thus, the reaction temperature of 150 °C and the lowest amount of catalyst (10 mol%) can be applied without significantly decreasing the yield response. Runs 1 and 2 were statistically equivalent and produced the lowest 5-HMF yields of 37.22 ± 3.28% and 45.96 ± 4.29%, respectively. These findings suggest that increasing the amount of the catalyst did not impact the yield response.

After conducting all runs, the results were analyzed by ANOVA to determine the significance of the parameters on the responses. The planned DoE included center points to check the curvature effect and, thus, evaluate whether the factorial model should be appropriate. In this case, the curvature effect was not significant for both conversion and yield responses and the linear regression model can be considered accurate enough to predict the main effects. In addition, two-way interaction terms were considered to lead to the best-fitted model.

From the results reported in

Table 2. Initial fructose concentration effect on the conversion, 5-HMF yield, and selectivity.

Entry	Fructose Concentration (g L−1)	Conversion (%) (Mean ± SD)	Yield (%) (Mean ± SD)	Selectivity (%) (Mean ± SD)
1	30	98.13 ± 0.39 a	78.98 ± 0.17 a	77.50 ± 0.34 a
2	60	96.84 ± 7.08 a	76.52 ± 6.86 a	74.41 ± 7.01 a
3	120	91.15 ± 6.98 a	80.34 ± 8.41 a	73.20 ± 8.23 a
4	150	94.03 ± 0.25 a	60.79 ± 1.18 b	57.16 ± 1.78 b

Reaction conditions: fructose (0.17 mmol for 30 g L⁻¹, 0.34 mmol for 60 g L⁻¹, 0.68 mmol for 120 g L⁻¹, and 0.85 mmol for 150 g L⁻¹), saturated NaCl aqueous solution (1.0 mL), i-PrOH (2.0 mL), sulfamic acid (10 mol%), MW heating at 180 °C, for 20 min. All reactions were performed in triplicate. All the measurements were determined by HPLC analysis. For all experiments, Tukey’s test (5%) was applied between the experiments. Different letters in the same column indicate statistical differences. SD: Standard deviation.

, the analysis of the estimated effects reveals that temperature is the most significant parameter, followed by the reaction time in affecting both conversion and yield responses (p-value < 0.05). In contrast, the parameter catalyst was not considered significant as a model term (p-value > 0.05). Nevertheless, it is worth mentioning that no conversion was detected when the reaction was carried out in the absence of the catalyst. Moreover, to achieve the best fit significant model, the interaction term between temperature and catalyst was neglected in the conversion response model due to its lack of statistical significance (p-value > 0.6).

The considered model showed a coefficient of determination R² calculated as 0.977 and 0.937 for conversion and yield, respectively, indicating that 97.7% and 93.7% of the variability of the responses conversion and yield, respectively, can be explained by the model. In addition, the adjusted R² values of 0.968 and 0.912 for conversion and yield, respectively, represent that respective models are suitable to explain 96.8% and 91.2% of the variability of the models. The goodness of fit for both models was validated with the insignificant lack of fit values. The lack of fit F-value of 2.077 (p-value 0.166) for the conversion response model also implies that the lack of fit is not significant relative to the pure error. The same was stated for the lack of fit F-value of 0.395 (p-value 0.759) for the yield response model. The following polynomial Equations 4 and 5 represent the linear models that represent the estimated conversion and yield responses:

$$\begin{gathered} Conversion \left(\%\right)=-287.13+\left(1.89\times Temperature\right)+\left(9.75\times Time\right)+\left(2.39\times Catalyst\right) \\ -\left(0.04\times Temperature\times Time\right)-\left(0.14\times Time\times Catalyst\right) \end{gathered}$$

(4)

$$\begin{gathered} Yield \left(\%\right)=-258.61+\left(1.69\times Temperature\right)+\left(12.78\times Time\right)+\left(1.76\times Catalyst\right) \\ -\left(0.06\times Temperature\times Time\right)-\left(0.11\times Time\times Catalyst\right) \end{gathered}$$

(5)

The Pareto chart of the standardized effects, shown in Figure 2a and Figure 3a, illustrates better the significance of the main effects and the interaction between the evaluated parameters for responses: fructose conversion and 5-HMF yield. The temperature is the most significant parameter considering the conversion, in which the conversion response increased by increasing the temperature from 150 °C to 180 °C. The reaction time parameter also shows a positive effect, although considerably lower than the reaction temperature. Therefore, by increasing the reaction time from 10 min to 20 min, the conversion will be slightly increased. However, the catalyst amount was not significant, indicating that using low levels of SA (i.e., 10 mol%) is enough to promote fructose conversion. According to the model, the interactions temperature–reaction time and temperature–catalyst promote a noticeable negative significant effect on fructose conversion. This indicates that these interactions (between the variables at the higher levels) did not contribute to increasing the conversion value. The 3D response surface graph generated from the model (Figure 2b) shows how the conversion strongly depends on the temperature. Furthermore, it demonstrates the slight, however positive, impact of the reaction time.

Considering the 5-HMF yield response, the Pareto chart for the estimated effects (Figure 3a) indicates that both temperature and time at their higher levels presented a significant positive effect. Similarly, as observed in the conversion, the temperature parameter was the most significant variable, followed by the reaction time. In addition, the interaction between temperature and time suggests a significant negative effect, indicating that the interaction between these variables at their high levels did not increase the yield. As noted for the response conversion, the catalyst parameter did not show statistical significance. The predicted response surface for 5-HMF yield (Figure 3b) reveals the impact of the temperature and time parameters, which is in accordance with the data shown in the Pareto chart (Figure 3a).

Based on the statistical analysis of the experimental data, the best reaction condition was stipulated through the desirability tool (Supplementary Material Figure S9). From the profiles of the predicted values, the same experimental conditions established for Run 7 (Table 1), with higher levels of temperature (180 °C) and reaction time (20 min) and a lower level of catalyst (10 mol%), should provide an estimated fructose conversion and 5-HMF yield values of 98.5% and 81.2%, respectively. The results from Run 7 were 96.75 ± 1.06% and 75.81 ± 4.99%, respectively. In addition, in a second set of experiments, the Run 7 experimental conditions were replicated (Table 2, entry 1), affording a fructose conversion and 5-HMF yield in 98.13 ± 0.39% and 78.98 ± 0.17%, respectively, which were in good agreement with predicted values.

For comparison, under the optimized condition but with conventional heating, the reaction achieved a fructose conversion of 38% and a 5-HMF yield of only 20.3%. Due to the short reaction time of 20 min, it may not be possible to reach the target temperature of 180 °C using conventional heating. In contrast, microwave heating ensures that the desired temperature of the reaction medium is reached quickly and uniformly.

With the optimized conditions established, we explored the effect of the fructose concentration in the aqueous phase to evaluate the process scalability. Therefore, in a second set of experiments, fructose concentrations of 60 g L⁻¹, 120 g L⁻¹, and 150 g L⁻¹ were evaluated and compared against the optimized fructose concentration of 30 g L⁻¹. All reactions were run in triplicate, and the selectivity was also measured for this set of experiments.

As demonstrated in Table 2 (entry 2), by doubling the initial fructose concentration, it was possible to maintain the conversion, yield, and selectivity values statistically comparable to results obtained from experiments with 30 g L⁻¹ of fructose (entry 1). It was also demonstrated that the efficiency of the process was maintained when increasing the amount of fructose four times (entry 3). With an initial concentration of 120 g L⁻¹, a slight decrease in fructose conversion was observed. Nevertheless, 5-HMF yield and selectivity were maintained. These findings agree with the DoE results, demonstrating that the catalyst did not show statistical significance.

Furthermore, when the fructose amount was increased to 150 g L⁻¹, a high conversion of 94.03 ± 0.025% was achieved (Table 2, entry 4). However, this increase in the fructose concentration resulted in a decrease in 5-HMF yield and, as a result, a decrease in selectivity. Under these conditions, the formation of insoluble humins was clearly observed.

Finally, we assessed the scalability of the reaction while maintaining a fructose concentration of 120 g L⁻¹. One limitation associated with benchtop laboratory microwave reactors is the scalability of the reaction. The microwave reactor used in this study uses sealed vials in which reaction temperature, pressure, and energy consumption are monitored during the reaction. However, for safety reasons, the reaction scale was limited to three times the initial volume, resulting in a 12-fold increase in the original amount of fructose used in the optimization studies. Remarkably, the isolated yield of 5-HMF from this scaled-up experiment was found to be 79.7% (Figure 4), which was consistent with the 5-HMF yield obtained through HPLC analysis (Table 2, entry 3).

Also, after the standard procedure to recover 5-HMF from the reaction medium, ¹H and ¹³C NMR analyses revealed that the product was isolated in high purity (Supplementary Material Figures S12 and S13). No by-products, such as isopropyl ether derivatives, formed by the etherification reaction with the solvent i-PrOH were detected [33]. Additionally, under the optimized reaction conditions, the measured pH of the aqueous phase was determined to be 2.0. This benign acidic condition may also play a role in avoiding the formation of the 5-HMF rehydrated by-products LA and FA, as previously observed [14].

In addition, the total energy delivered by the microwave reactor during the reaction was determined to be 63.48 kJ. This value includes the initial energy boost provided by the microwave reactor in the first seconds of heating and the energy delivered throughout the entire reaction time (Supplementary Material Figures S14 and S15).

Even though the scalability of the reaction was limited by the microwave reactor applied in this study, this challenge can be overcome by microwave reactors that allow reactions on a kilogram scale [34] or even microwave apparatus operating in a continuous flow regime [35]. A continuous-flow microwave reactor was recently developed to produce 5-HMF from fructose with a 55% yield and a productivity of 0.1 kg/h, using a homogeneous HCl aqueous system [19]. Hence, there is an interesting opportunity to adopt these conditions due to the short reaction time, small amount of catalyst, and beneficial green solvent characteristics.

4. Conclusions

In conclusion, the proposed method for producing 5-HMF by microwave-assisted sulfamic acid-catalyzed fructose dehydration provides an additional approach for developing 5-HMF production technologies. The significance of the main factors, including temperature, reaction time, and catalyst loading, as well as their interaction, were evaluated using 2³ full factorial designs.

Among these factors, it was found that the reaction temperature had the most significant impact on achieving high conversion and 5-HMF yield. The optimized reaction conditions yielded excellent values of conversion (91.15 ± 6.98%), yield (80.34 ± 8.41%), and selectivity (73.20 ± 8.23%). The fast heating rate promoted by microwave irradiation provided the short reaction time required for complete conversion and, consequently, reduced energy consumption and by-product formation. The combination of a saturated NaCl aqueous solution and i-PrOH contributes to the sustainability of the process. Moreover, SA proved to be a suitable catalyst for this transformation, demonstrating its potential for sustainable large-scale industrial applications. While large-scale microwave reaction methodologies are still in development, the results obtained in this study significantly contribute to the understanding of fructose dehydration to 5-HMF under microwave conditions. Finally, the proposed method deserves further investigation on converting other carbohydrates into 5-HMF, such as glucose and sucrose.