Efficient Method for the Synthesis of 5-Methylfurfural from l-Rhamnose Using a Biphasic System

Abstract

In this work, the method of highly efficient conversion of l-rhamnose to 5-methylfurfural (MF) catalyzed by various catalysts in a biphasic system was developed. To enhance the MF yield, the effects of the catalyst species, reaction temperature (150–180 °C), extraction solvents and volume ratio of the extraction to the aqueous phase (0–5) on the conversion of l-rhamnose to MF were systematically investigated. Under optimal conditions, a high MF yield of 94% was achieved in the biphasic “diisopropyl ether (DIPE) + H₂O” system due to the fact that the extraction of MF to the DIPE phase significantly inhibits the condensation and degradation of MF in water. Finally, detailed reaction energetics and chemical structures of intermediates of the l-rhamnose dehydration to MF were investigated using the B3LYP level of theory and the SMD solvation model. It is evident that MF, which exhibits excellent chemical stability, harbors the potential to function as a bio-derived platform chemical within the domain of the green industry.

1. Introduction

The increasing consumption of fossil fuels and worry about their environmental impact are pushing people to the chemical production from the renewable biomass and chemistry [1,2]. Apart from fuel production, the production of various high-value chemical intermediates from renewable resources has also gained more significant attention, because these intermediates can be further transformed into solvents, polymers, and specialty chemicals [3,4]. However, only very few compounds of commercial interest are directly synthesized from biomass-derived carbohydrates by using non-enzymatic approaches currently.

5-Hydroxymethylfurfural (HMF) derived from biomass is a very important platform chemical and can be used to synthesize various chemicals [5]. HMF with a very reactive hydroxylmethyl is usually produced by the dehydration of fructose and glucose, during which the substrate (fructose or glucose), intermediates and HMF tend to condense into soluble polymers or insoluble humins, reducing the HMF yield [6]. Additionally, reactive HMF can further get involved into the hydrolysis reaction over acidic catalysts, resulting in levulinic acid that are significantly difficult to separate from HMF. Due to the good solubility of HMF in both water and organic solvents, extraction operation can hardly achieve a high yield of HMF [7,8]. Currently, the separation and purification of HMF is a highly energy-intensive process due to the chemically instability and low volatility, which also limits the industrial production of HMF, particularly in the context of the growing emphasis on green industrial concepts [9]. In this contribution, another significant furan derivative 5-methyl furfural (MF), the deoxygenated analog of HMF was reported. Compared with HMF, MF has better chemical stability and a lower boiling point, and an excellent solubility in organic solvents with the methyl group replacing the hydroxymethyl group [9,10,11]. MF derived from biomass is a commercial product and usually serves as a useful precursor for synthesizing pharmaceuticals, agricultural chemicals, perfumes, and other applications [12,13,14]. For instance, MF can be catalytic hydrogenated into biofuel 2,5-dimethylfuran, which can also be further transformed into high-quality C₁₁ and C₁₂ biodiesel via the C–C coupling reaction [15]. Additionally, our group has proved that MF can be used as the feedstock replacing the expensive and unstable HMF for producing the polymer monomer 2,5-furan dicarboxylic acid (FDCA) at high concentration with a high yield over industrial Co/Mn/Br catalysts [16,17]. MF is usually industrially prepared using the platform chemical furfural as the raw materials derived from the agricultural byproducts rich in polypentose, such as corncobs, cottonseed husk, rice bran, beet pulp, bagasse, and sawdust, all of which are incredibly cheap and abundantly available. but this method adopts significantly phosphorus oxychloride or phosgene as the reactant, which exerts an adverse impact on the environment (Route 1,

Table 1. Comparison of synthesis routes for MF.

Routes	Raw Materials	Catalysts	Reaction Conditions	MF Yield (%)	Drawbacks	References
1	2-Methylfuran	COCl2	60 °C, 12 h	96	Highly toxic reactant	[18,19]
2	Glucose, Fructose	H2, HI, RuCl3, or Pd/C	90 °C, 0.5–1 h	68	Highly deleterious and corrosive	[20]
3	Glucose, Sucrose, Cellulose	(1) aq. HCl/(ClCH2)2; (2) H2, Pd/C	(1) 100 °C, 3 h; (2) 40 °C, 5 h	(1) CMF yield 90%; (2) MF yield 95%	Two steps, long time, large amount of organic solvent	[21,22]
4	HMF	HCOOH, PVP/Pd	THF, 200–220 °C, 7.5 h	80	High temperature, corrosive solvent, long time	[23]
5	l-Rhamnose	[BMIM]Cl/CrCl2	110 °C, 2 h	61	Expensive ionic liquid, low yield	[11]
6	l-Rhamnose	NaCl-H2O/AlCl3	155 °C, 0.5 h	97	Large amount of organic solvent	[24]

) [18,19].

Some researchers developed the method of converting carbohydrates directly to MF in a biphasic system composed of water and an organic solvent, and a viable MF yield of 68% was given. However, the water phase used is the highly concentrated HI (57 wt %) aqueous solution, which is highly deleterious and corrosive for the equipment (Route 2, Table 1) [20]. Another developed method was that MF was synthesized from carbohydrates, including glucose, sucrose, and cellulose via a two-step process. Saccharides as the feedstock were first converted into 5-(chloromethyl)furfural (CMF) in a highly concentrated HCl with 1,2-dichloroethane as the extraction solvent [21]. Then, CMF was reduced by hydrogen into MF in the presence of a palladium catalyst [22]. However, MF synthesis from carbohydrates requires two steps, a long reaction time of at least 8 h, and a huge amount of organic solvent, increasing operation cost (Route 3, Table 1). Some researchers also suggested that MF was converted from HMF with PVP-assisted palladium nanoparticles with formic acid as the hydrogen-donating agent (Route 4, Table 1) [23]. But a high reaction temperature (200–220 °C), corrosive solvent (HCOOH), and a long reaction time (7.5 h) are required in the production process. P. Ananikov proposed a method of producing MF from renewable l-rhamnose over Lewis acids in a biphasic system. But highly expensive ionic liquid 1-butyl-3-methylimidazolium chloride ([Bmim]Cl) was used as the reaction solvent and only 61% MF yield was given, making the process commercially unattractive (Route 5, Table 1) [11]. Zeng et al. reported that l-rhamnose was used as the raw material to generate MF in a biphasic system, and MF yield of 97% was obtained over AlCl₃ catalysts within 30 min (Route 6, Table 1) [24]. However, the dehydration process takes a great amount of organic solvent with a large volume ratio of organic phase to water (4/1) and detailed reaction energetics and pathways were overlooked.

As mentioned above, the existing methods using sugars, 2-methylfuran and HMF as the feedstocks are worth further improvement. There are only a few studies on the MF synthesis from the catalytic dehydration of commercially available l-rhamnose (6-deoxy-L-mannopyranose), which is abundant in plants and can also be artificially produced [25,26]. In this work, due to the extremely low solubility of MF in water, a biphasic system consisting of water and an organic extraction was adopted to prevent the condensation reactions of MF with intermediates and l-rhamnose by continuously extracting MF from the aqueous phase to the organic solvent [10]. Different Brønsted or Lewis acid catalysts have been evaluated for the dehydration process. The effects of the extraction solvents such as toluene, carbon tetrachloride, cyclohexane, diisopropyl ether (DIPE), and methyl isobutyl ketone (MIBK) and other operation variables on the MF yield were estimated systematically. Finally, quantum chemical studies were carried out to study the detailed free energy landscapes of the l-rhamnose conversion to MF using the high-level B3LYP/6-31G (2df, p) method.

2. Results and Discussion

2.1. Influence of Catalyst Species on l-Rhamnose Conversion to MF

The conversion of l-rhamnose to MF was investigated with a variety of metal salts and acids in a biphasic toluene-H₂O system. As shown in Figure 1, only 21% l-rhamnose was converted and the MF yield was only 5% in the absence of the catalyst, while MF yields of 13%, 27%, 46%, and 29% were achieved over CH₃COOK, KCl, HCl, and CrCl₃, respectively. It is suggested that H⁺ cooperating with Cl⁻ plays a significant role in improving the MF yield. Additionally, MF yields of 64%, 57%, and 35% were achieved over CoCl₂, CoBr₂, and CoSO₄, respectively, indicating that halide ions especially Cl⁻ as the superior nucleophilic reagent show more excellent performance on enhancing the MF yield than that of SO₄⁻, which may be due to the formation of a stable intermediate promoted by Cl⁻ ions, as previously studied by Marcotullio et al. in the dehydration of carbohydrates to furfural [27]. Among all tested catalysts, CuCl₂ was proved to be the best, with a l-rhamnose conversion of 100% and MF yield of 69%, which may be due to the formation of stable copper ions coordinated intermediates, reducing the energy barrier [28,29]. Additionally, the existence of MF was also verified by HPLC, GC-MS and ¹H NMR results, as shown in Figures S1–S3, respectively. Therefore, CuCl₂ was chosen for the following l-rhamnose dehydration experiments (

Table 2. Synthesis of MF from l-rhamnose ^a.

Entry	Catalyst	Concentration	Solvent	Volume Ratio	MF Yield
	Species	mol/L			(%)
1	/	0.1	Toluene	1	5
2	CuCl2	0.1	/	1	27
3	CuCl2	0.1	CCl4	1	54
4	CuCl2	0.1	DIPE	1	85
5	CuCl2	0.1	MIBK	1	82
6	CuCl2	0.1	1-butanol	1	47
7	CuCl2	0.1	DIPE	0.25	65
8	CuCl2	0.1	DIPE	2	94
9	CuCl2	0.05	DIPE	2	63
10	CuCl2	0.15	DIPE	2	91
11	CuCl2	0.2	DIPE	2	83

^a Reaction conditions: reaction temperature: 160 °C, heat-up time: 120 min, cool-down time: 5 min.

).

2.2. Effect of Extraction Solvent on l-Rhamnose Conversion to MF

Although aqueous CuCl₂ solution can be used as the solvent for l-rhamnose dehydration to MF, the MF yield of only 27% was achieved with a great amount of levulinic acid (yield: 15%) generated without extraction (Figure 2a). When the extraction solvent of toluene was added into the reaction system, the MF yield was enhanced to 69% with the total conversion of l-rhamnose. This enhancement can be ascribed to the migration of MF from the aqueous phase to the organic phase, which restricted the condensation of MF with l-rhamnose and the intermediates in the reaction. Other organic solvents including CCl₄, DIPE, MIBK, cyclohexane, and 1-butanol were also used as the extraction solvents for l-rhamnose dehydration. It was found that the biphasic CuCl₂ aqueous solution plus DIPE system achieved the highest MF yield of 85% and the lowest levulinic acid yield of 3%, which was attributed to the fact that the highest p value for the biphasic H₂O-DIPE system was observed. As shown in Figure 2b, the values of P_MF vary significantly for different organic solvents, whose order from the largest to the smallest is as follows: DIPE, MIBK, toluene, cyclohexane, CCl₄, and 1-butanol, which is consistent with the empirical “like-dissolves-like” rule in terms of the polarity [30]. MF with very weak polarity and a similar structure is prone to dissolve in DIPE and MIBK, instead of 1-butanol. Interestingly, the p values decreased after the reaction. We hypothesized that this is because some soluble polymers generated in the dehydration process are dissolved in water, increasing the solubility of MF in water phase, exacerbating the condensation side reactions of MF, substrate, and intermediates, and diminishing the MF yield. Additionally, a part of organic solvents, especially a part of 1-butanol, is dissolved in the water phase at a high temperature (160 °C), diminishing the P_MF value and MF yield, which is similar to the phenomenon in the fructose dehydration process [31,32]. Therefore, factors in addition to the ambient partition coefficient, such as the altered solvent polarity and other high-temperature effects, may also contribute to the overall success of the biphasic extraction process.

When DIPE was applied as the extraction solvent for l-rhamnose dehydration to MF in the concentrated CuCl₂ solution, the volume ratio of the extraction solvent to the aqueous solution (R) also has a significant impact on the product yield. From Figure 2c, it is found that the MF yield increases from 65% to 94% when the R values are increased from 0.25 to 2. However, with the further increase in R values above 2, the MF yield exhibits minimal variation. Therefore, to reduce the amount of organic solvent and increase the MF yield, an R value of 2 is suitable for the subsequent studies.

2.3. Effect of the Reaction Temperature and Time

The effects of operation conditions (reaction temperature and time) on the homogeneous dehydration of l-rhamnose to MF over CuCl₂ catalysts were also investigated, and the results are shown in Figure 3. The l-rhamnose conversion increases continuously with increasing reaction time, while the maximum MF yield shows an upward trend and then a downward trend from 150 to 180 °C (Figure 3a,b). The rising temperature can accelerate both main and side reactions but to different extents. Although the dehydration rate of l-rhamnose to MF is significantly accelerated at high temperatures, the polymerization of l-rhamnose, intermediates, and MF into polymers or humins and MF rehydration to levulinic acid are also exacerbated. The MF yield reaches the maximum value at 160 °C, which is relatively higher than the optimum temperature (~130 °C) of the fructose dehydration to HMF [33,34]. It is suggested that the dehydration of l-rhamnose to MF is more difficult than that of fructose. Additionally, the total carbon balance decreases at the early stage of the reaction and then increases after the complete conversion of l-rhamnose, while the selectivity of MF increases gradually, indicating the formation of undetectable intermediates (Figure 3c and Figure 4). The intermediates are relatively quickly generated from l-rhamnose, but they are slow to be consumed. Only a very small amount of levulinic acid (yield of 2%) was observed, suggesting that the rehydration of MF is significantly suppressed under experimental conditions.

2.4. Effect of the Catalyst and Substrate Concentration

The effects of catalyst concentration from 0.05 to 0.20 mol/L on the l-rhamnose conversion to MF were evaluated. As shown in Figure 5a, when CuCl₂ concentration of 0.05 mol/L was adopted, the MF yield of 63% was achieved with a l-rhamnose conversion of 87%. When CuCl₂ concentration was increased from 0.05 to 0.20 mol/L, the MF yield was first improved and then it diminished. CuCl₂ concentration of 0.10 mol/L was suitable for achieving a high MF yield of 94%. Although a higher catalyst concentration can accelerate the dehydration process, it will also intensify the condensation reactions among the substrate, intermediates and MF, reducing the MF yield. With the increasing substrate concentration from 10 to 50 wt % in the aqueous phase, the total MF yield shows a continuous downward trend, due to the aggravated condensation side reactions (Figure 5b,c).

2.5. Recyclability of the Concentrated CuCl₂ Solution

The reusability of the catalytic system is a significant characteristic and highly related to the applicability of this process in industry. Experiments were conducted to investigate the recyclability of the reaction system. In a typical recycling test, the DIPE phase was removed after the reaction, and the residual MF in the water phase was completely extracted using fresh DIPE. Finally, MF was separated from the DIPE phase via rectification. As displayed in Figure 6, the MF yield exhibits a decline from 94% to 90% after six consecutive runs, which may be ascribed to the fact that the accumulation of soluble polymers, thereby diminishing the extraction efficiency of the DIPE phase and exacerbating the condensation reactions in the water phase.

2.6. Mechanism of l-Rhamnose Dehydration to MF

At present, the understanding of structure and reaction energetics of catalytic dehydration reactions of sugar to desired platform chemical MF is necessary to compliment experimental efforts. However, few studies have been performed on the reaction mechanism and energies of l-rhamnose conversion to MF. Here, the chemical structures and free energies of all possible intermediates were computed at the B3LYP/6-31G (2df, p) level of theory with the SMD solvation model to further understand the reaction mechanism, and optimized structures of all the intermediates including four transition states (1–14) are shown in Figure 7. Similar to fructose, l-rhamnose exists in the form of cyclic and open-chain structures (L1 and L2) at a dynamic equilibrium, where the reciprocal transformation is via the nucleophilic addition reaction. Then, the dehydration process is initiated by the protonation of the terminal aldehyde group in species L2. Then, deprotonation from the transition state L3 results in the formation of the species L4. Of the four secondary hydroxyl groups of species L4, the C3-OH has a higher proton affinity than C2-OH, C4-OH and C5-OH, which is favorable for the occurrence of protonation of the C3-OH, generating the transition state L5. However, the protonation of L4 (L4 → L5) is significantly endergonic (22.2 kcal/mol). Furthermore, the subsequent reaction L5 → L6 is exergonic with the removal of water (−11.9 kcal/mol). Then, thermodynamically stable L7 is generated from the deprotonation of L6, which is also accompanied by the formation of a conjugated double bond with the aldehyde group and increasing entropy. Subsequently, the protonation of the C4-OH in L7 is also endergonic (2.0 kcal/mol), and the transition state L8 is converted into L10 via L9 by the removal of water and deprotonation in turn. With the acyloin condensation reaction of hydroxyl and carbonyl groups, L10 was then transformed into L11, which will further undergo protonation, dehydration and deprotonation successively, generating the final product MF. The coordinates of all intermediates are available in Table S1.

3. Experimental Section

3.1. Materials

l-Rhamnose with 99% purity was bought from Macklin Biochemical Co., Ltd. (Shanghai, China). MF with 99% purity used in all experiments was bought from Ailan Chemical Technology Co., Ltd. (Shanghai, China). Solvents, such as toluene, carbon tetrachloride, cyclohexane, 1-butanol, diisopropyl ether (DIPE), and methyl isobutyl ketone (MIBK) were purchased from Aladdin Biochemical Co., Ltd. (Shanghai, China). CH₃COOK, KCl, HCl, CrCl₃, AlCl₃, FeCl₃, NH₄Cl, BaCl₂, CoCl₂, CoBr₂, MnCl₂, CuCl₂ and CoSO₄ were bought from Sinopharm Chemical Co., Ltd. (Shanghai, China).

3.2. Experimental Procedure

The catalytic dehydration experiments were carried out in a 20 mL stainless steel reactor equipped with a magnetic stirrer. In a typical experiment (Figure S4), l-rhamnose and catalysts were dissolved in water to form a homogeneous liquid. Then, the water solution and organic solvent were added into the reactor and the rotating speed of magnetic stirrer was set as 500 rpm. And then the reactor was heated to the desired value, and the temperature was maintained for the desired reaction time. After reaction, the reactor was cooled to the room temperature by the cold-water bath. The upper and lower phases were moved out to centrifuge tubes, followed by centrifugation, separation, and weighted, respectively. The upper and lower phases were sampled, diluted, filtrated, and analyzed by the high-performance liquid chromatography (HPLC) to determine the conversion of l-rhamnose and yield of MF.

For a typical recycling test, the CuCl₂ aqueous solution was reused in the next run with fresh l-rhamnose and DIPE. The reaction solution was heated in the stainless steel reactor. After reaction, the DIPE phase was then separated and the CuCl₂ aqueous solution was recycled for the next run.

3.3. Analytical Method

The MF and levulinic acid in the aqueous phase are quantified by HPLC using an external standard method and calibration curve (shown in Figure S5), while those in the organic phase are quantified by GC using an internal standard and calibration curve (shown in Figure S6). Shimadzu LC-2030 HPLC (Kyoto, Japan) was equipped with an Agilent ZORBAX Eclipse XDB-C18 column (Santa Clara, CA, USA) and an ultraviolet detector at 254 nm, as shown in Figure S1 in the Supporting Information (SI). The mobile phase of HPLC consisted of two eluents: V (water):V (acetonitrile) = 70:30 with a flow rate of 0.6 mL/min with a column oven temperature of 30 °C. Due to stable chemical properties and suitable volatility, para-xylene was selected as an internal standard, MF in the organic phase were quantified by Shimadzu Nexis GC-2030 GC (Kyoto, Japan) equipped with a Shimadzu SH-5 chromatographic column (60 m × 0.32 mm × 0.25 um) and a flame ionization detector (FID, Kyoto, Japan). The vaporization chamber temperature of the Shimadzu Nexis GC-2030 GC (Kyoto, Japan) is set at 240 °C. The column temperature program is as follows: 60 °C held for 5 min, then increased to 180 °C at a rate of 5 °C/min, and finally maintained at 180 °C for 6 min. The detector temperature is 250 °C. During the analyzing process, GC provides the quantitative analysis of MF (with para-xylene as an internal standard), while a GC-MS was also employed separately to confirm the identity of the products. l-Rhamnose was analyzed by Shimadzu LC-2030 HPLC (Kyoto, Japan) with an Aminex HPX-87H column (300 × 7.8 mm, Hercules, CA, USA) and an ultraviolet detector set at 210 nm. Aqueous H₂SO₄ solution (pH = 2) served as the mobile phase with a flow rate of 0.5 mL/min and a column temperature of 40 °C.

3.4. Computational Methods

Quantum chemical studies were performed using the density functional theory (DFT) as implemented in Gaussian 16 package [35,36]. Geometry optimization and Gibbs free energy were calculated at B3LYP functional with 6-31G (2df, p) basis sets at 298 K [37,38]. Geometries of reactants, intermediates, and products were fully calculated using the polarizable continuum model (PCM). Single-point energy calculations were performed with the SMD model.

3.5. Determination of Yields for Products and Partition Coefficient

For the aqueous phase, MF and levulinic acid were analyzed via HPLC (external standard calibration), and for the organic phase, MF was quantified by GC-FID using an internal standard (para-xylene). Reactant conversion and product yield are defined as shown in Equations (1) and (2). And the partition coefficient of MF (P) in a biphasic system is defined as the ratio of the concentration of MF dissolved by the organic phase to the concentration of MF in the aqueous solution at equilibrium, as shown in Equation (3). Before reaction, PMF is equal to MF in organic solvent/MF in pure water or 0.1 M-CuCl₂ aqueous solution. After reaction, PMF is equal to MF in organic solvent/MF in 0.1 M-CuCl₂ aqueous solution contained some by-product generated by the reaction.

$$Conversion \left(mol \%\right)={\displaystyle \frac{\mathrm{m}\mathrm{o}\mathrm{l}\mathrm{e}\mathrm{s} \mathrm{o}\mathrm{f} \mathrm{L}-\mathrm{r}\mathrm{h}\mathrm{a}\mathrm{m}\mathrm{n}\mathrm{o}\mathrm{s}\mathrm{e} \mathrm{r}\mathrm{e}\mathrm{a}\mathrm{c}\mathrm{t}\mathrm{e}\mathrm{d}}{\mathrm{m}\mathrm{o}\mathrm{l}\mathrm{e}\mathrm{s} \mathrm{o}\mathrm{f} \mathrm{i}\mathrm{n}\mathrm{i}\mathrm{t}\mathrm{i}\mathrm{a}\mathrm{l} \mathrm{L}-\mathrm{r}\mathrm{h}\mathrm{a}\mathrm{m}\mathrm{n}\mathrm{o}\mathrm{s}\mathrm{e}}}\times 100\%$$

(1)

$$Yield \left(mol \%\right)={\displaystyle \frac{\mathrm{m}\mathrm{o}\mathrm{l}\mathrm{e}\mathrm{s} \mathrm{o}\mathrm{f} \mathrm{p}\mathrm{r}\mathrm{o}\mathrm{d}\mathrm{u}\mathrm{c}\mathrm{e}\mathrm{d} \mathrm{M}\mathrm{F} \mathrm{o}\mathrm{r} \mathrm{l}\mathrm{e}\mathrm{v}\mathrm{u}\mathrm{l}\mathrm{i}\mathrm{n}\mathrm{i}\mathrm{c} \mathrm{a}\mathrm{c}\mathrm{i}\mathrm{d} \mathrm{i}\mathrm{n} \mathrm{w}\mathrm{a}\mathrm{t}\mathrm{e}\mathrm{r} \mathrm{a}\mathrm{n}\mathrm{d} \mathrm{o}\mathrm{r}\mathrm{g}\mathrm{a}\mathrm{n}\mathrm{i}\mathrm{c} \mathrm{p}\mathrm{h}\mathrm{a}\mathrm{s}\mathrm{e}\mathrm{s}}{\mathrm{m}\mathrm{o}\mathrm{l}\mathrm{e}\mathrm{s} \mathrm{o}\mathrm{f} \mathrm{i}\mathrm{n}\mathrm{i}\mathrm{t}\mathrm{i}\mathrm{a}\mathrm{l} \mathrm{L}-\mathrm{r}\mathrm{h}\mathrm{a}\mathrm{m}\mathrm{n}\mathrm{o}\mathrm{s}\mathrm{e}}}\times 100\%$$

(2)

$$\mathrm{P}={\displaystyle \frac{\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{c}\mathrm{e}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n} \mathrm{o}\mathrm{f} \mathrm{M}\mathrm{F} \mathrm{i}\mathrm{n} \mathrm{a}\mathrm{n} \mathrm{o}\mathrm{r}\mathrm{g}\mathrm{a}\mathrm{n}\mathrm{i}\mathrm{c} \mathrm{s}\mathrm{o}\mathrm{l}\mathrm{v}\mathrm{e}\mathrm{n}\mathrm{t}}{\mathrm{c}\mathrm{o}\mathrm{n}\mathrm{c}\mathrm{e}\mathrm{n}\mathrm{t}\mathrm{r}\mathrm{a}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n} \mathrm{o}\mathrm{f} \mathrm{M}\mathrm{F} \mathrm{i}\mathrm{n} \mathrm{a}\mathrm{n} \mathrm{a}\mathrm{q}\mathrm{e}\mathrm{o}\mathrm{u}\mathrm{s}\mathrm{e} \mathrm{s}\mathrm{o}\mathrm{l}\mathrm{u}\mathrm{t}\mathrm{i}\mathrm{o}\mathrm{n}}}$$

(3)

4. Conclusions

An efficient approach to converting the concentrated l-rhamnose to MF in a biphasic “H₂O + extraction” system was investigated in this work. Among all tested catalysts, CuCl₂ was proven to be the most effective catalyst to provide the highest MF yield, which may be due to the formation of stable copper ions coordinated intermediates. DIPE with the highest P_MF value shows the most excellent performance, with an MF yield of 94% at 160 °C and a low volume ratio of extractant to water (extractant/water = 2:1). More importantly, it is found that the biphasic system of H₂O/DIPE is still effective, with only an MF yield loss of 4% after the fifth reuse due to the accumulation of soluble polymers. Finally, based on the quantum chemical calculation, the energy and structures of intermediates, and possible pathways for the l-rhamnose conversion to MF were proposed, and the first water molecule removal has the highest energy barrier. These findings reported here provide an efficient catalytic system for the production of MF from l-rhamnose.