Research Article pubs.acs.org/journal/ascecg
Biocatalytic Upgrading of 5‑Hydroxymethylfurfural (HMF) with Levulinic Acid to HMF Levulinate in Biomass-Derived Solvents Ye-Zhi Qin, Min-Hua Zong, Wen-Yong Lou, and Ning Li* School of Food Science and Engineering, South China University of Technology, 381 Wushan Road, Guangzhou 510640, China S Supporting Information *
ABSTRACT: Valorization of biomass-based platform chemicals into high value-added products has attracted increasing attention recently. In this work, upgrading of 5-hydroxymethylfurfual (HMF) and levulinic acid, two important biomass-based platform chemicals, to HMF levulinate via a green and efficient enzymatic approach was reported. Novozym 435 was found to be the best biocatalyst for the enzymatic esterification. The enzymatic esterification progressed smoothly in t-butanol, 2-methyl-2butanol, and cyclopentyl methyl ether as well as in the ecofriendly biomass-derived 2-methyltetrahydrofuran (2-MeTHF), while no enzymatic reaction occurred in deep eutectic solvents. When HMF concentration was up to 500 mM, a good conversion of 72% was achieved in 2-MeTHF. The reaction temperature exerted a significant effect on the enzymatic esterification. When the reaction temperature is below 40 °C, high HMF conversions (>85%) were obtained. Besides, significant inactivation of the enzyme was observed at more than 50 °C, resulting in poor conversions. KEYWORDS: Biorefineries, Cyclopentyl methyl ether, Enzyme-catalyzed esterification, 5-Hydroxymethylfurfural, Immobilized lipases, 2-Methyltetrahydrofuran, Platform chemicals
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INTRODUCTION Biomass-based fuels and platform chemicals have emerged as promising alternatives to conventional fossil-based counterparts, because they can be produced from abundant, readily available, carbon-neutral and renewable lignocellulosic biomass. 5-Hydroxymethylfurfural (HMF) that can be synthesized via carbohydrate dehydration is among the U.S. Department of Energy (DOE) “Top 10 + 4” list of platform chemicals.1,2 Upon chemical modifications, this useful chemical could be transformed into many high value-added products,3 since there are active functional groups such as hydroxyl and formyl groups in this compound. For example, HMF could be oxidized to 2,5diformylfuran (DFF), 5-hydroxymethyl-2-furancarboxylic acid (HMFCA), and 2,5-furandicarboxylic acid (FDCA) with promising application potential in fuels, polymers, and drugs.4−6 Besides, it also could be reduced to 2,5-bis(hydroxymethyl)furan, which is a key building block of biomass-based furan polymers with self-healing ability and multishape memory.7,8 In addition to oxidation and reduction, esterification is also an efficient approach for valorization of HMF, thus affording © XXXX American Chemical Society
HMF esters. HMF esters may be used as fuel additives, surfactants, and fungicides.9,10 However, HMF esters, especially HMF acetate and propionate, were synthesized mainly through chemical esterification of HMF and highly active acyl donors under basic conditions, or through esterification of HMF and acids in the presence of sulfuric acid or solid-phase catalysts.3,10 Nonetheless, side reactions such as oligomerization and rehydration readily occurred under the above chemical esterification conditions due to the intrinsic reactivity of HMF, thus resulting in low yields.3,11 Enzyme-catalyzed esterification is a promising alternative to chemical methods, because enzymes are active under mild reaction conditions, are environmentally friendly, and display excellent selectivity.12−14 However, there are limited reports on enzymatic synthesis of HMF esters in the literature. Krystof et al. reported lipasecatalyzed synthesis of a series of HMF esters via (trans)esterification with good yields.11 Received: May 9, 2016 Revised: May 28, 2016
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DOI: 10.1021/acssuschemeng.6b00996 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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ACS Sustainable Chemistry & Engineering Like HMF, levulinic acid (LA) is also one of the DOE “Top 10 + 4” platform chemicals, and it can be produced through HMF hydrolysis in acidic media.2 In addition, this versatile chemical could be upgraded to many valuable compounds. For example, alkyl levulinates were proven to be efficient and green solvents in food industry; in addition, they might be appropriate fuel additives for gasoline and diesel fuels.15 Although significant advances in chemical synthesis of alkyl levulinates have been achieved,15 biocatalytic esterification of LA received little attention.16,17 The reason may be that, as described by Dominguez de Maria and co-workers,11 the costly enzymes have been generally used for synthesis of enantiopure and high value-added building blocks or drugs. Driven by environmental concerns, enzymatic synthesis of bulk commodities such as biodiesel and biobased polyesters has received more attention.18,19 To our knowledge, enzymatic synthesis of HMF levulinate via esterification of HMF and LA has not been reported yet. In this work, therefore, we described efficient enzymatic synthesis of HMF levulinate via lipase-catalyzed esterification of HMF and LA in biomass-based 2-methyltetrahydrofuran (2-MeTHF), which is depicted as Figure 1.
2-MeTHF containing 200 mM HMF (0.4 mmol), 11 mM 9fluorenone (as the internal standard), and 100 mg of 4 Å molecular sieves. After mixing drastically, the immobilized lipases (10 mg/mL) were added, and then the mixtures were incubated at 40 °C and 200 r/ min. Aliquots were withdrawn from the reaction mixtures at specified time intervals and diluted 40-fold with the corresponding mobile phase prior to HPLC analysis. The conversion was calculated according to C −C the following equation: conversion(%) = 0C t × 100, in which C0 0
and Ct are the HMF concentrations at 0 and t h, respectively. All the experiments were carried out in duplicate, and all the values were the averages of repeated experiments. Purification and Characterization of HMF Levulinate. After reaction, the immobilized lipase and molecular sieves were filtered off by centrifugation, and the supernatant was washed 4−5-times with equal volume of deionized water to remove most HMF and LA. The organic phase was dried over anhydrous MgSO4. After removing solvent, the residues were subjected to silica gel column chromatography with ethyl acetate/n-hexane (1/6 to 1/1.8, v/v). The desired product was obtained as lightly yellow oil. Its structure was characterized by 1H and 13C NMR (Bruker AVANCE III HD 600, Germany), and its NMR spectra (Figures S1 and S2) were available as Supporting Information. 1H NMR (600 MHz, CDCl3) δ: 2.20 (s, 3H), 2.63 (t, J = 6.0 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H), 5.14 (s, 2H), 6.60 (d, J = 3.6 Hz, 1H), 7.22 (d, J = 3.6 Hz, 1H), 9.64 (s, 1H). 13C NMR (150 MHz, CDCl3) δ: 27.84, 29.94, 37.92, 58.16, 112.61, 121.87, 152.93, 155.52, 172.25, 177.91, 206.45. Assessing Thermostability of Novozym 435. A Novozym 435 portion of 10 mg was added into the mixtures of 0.5 mL of 2-MeTHF and 0.5 mL of LA, and the mixtures were incubated at 40 and 60 °C, respectively. At specified time intervals, the immobilized lipase was isolated from the mixtures, and washed by acetone 3 times. After being dried under reduced pressure at 50 °C for 30 min, the residual activity of this immobilized lipase was determined. The relative activity of the native lipase was defined as 100%. Assay of the Residual Activity of the Immobilized Lipase. The lipase activity was determined spectrophotometrically using pNPP as a substrate according to a previous method,22 with some modifications. Briefly, 0.1 mL of 60 mM p-NPP dissolved in isopropanol was added into 0.6 mL of phosphate buffer (50 mM, pH 7.5); then, the immobilized lipase was added, and the mixtures were incubated at 45 °C for 15 min. The reaction was terminated by adding 5.3 mL of ethanol. A control without enzyme was run simultaneously. Absorbance of the resulting yellow product was measured at 405 nm. One unit (1 U) of lipase activity was defined as the amount of enzyme catalyzing the release of 1 μmol of pnitrophenol per min from p-NPP under the standard assay conditions. HPLC Analysis. The reaction mixtures were analyzed by reversed phase HPLC on an Eclipse PlusC18 column (4.6 mm × 250 mm, 5 μm, Agilent) using a Waters 1525 pump and a 2489 UV detector. The mobile phase was a mixture of acetonitrile and 0.1% phosphoric acid (PA) with a flow rate of 1 mL/min. A gradient elution program was used as follows: 0−12 min, increasing acetonitrile/PA of 10/90 (v/v) to 90/10 (v/v) under 284 nm; 12−15 min, keeping acetonitrile/PA of 90/10 (v/v) under 254 nm. The retention times of HMF, HMF levulinate, and 9-fluorenone are 4.6, 7.9, and 12.5 min, respectively.
Figure 1. Enzymatic esterification between HMF and LA.
HMF levulinate may have potent application potential as a fuel additive. In addition, the levulinyl group is a common and promising protecting group for hydroxyl group, since it is stable and can be selectively cleaved with hydrazine hydrate in pyridine−acetic acid.20 As a result, HMF levulinate may act as the precursor for further upgradations of HMF.
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EXPERIMENTAL SECTION
Materials. HMF was purchased from J&K Scientific Ltd. (Guangzhou, China). LA was from Macklin Biochemical Co., Ltd. (Shanghai, China). 2-MeTHF was purchased from Alfa Aesar Co. (Tianjin, China). Cyclopentyl methyl ether (CPME) was from Aladdin Industrial Inc. (Shanghai, China). 9-Fluorenone was purchased from TCI (Japan). p-Nitrophenyl palmitate (p-NPP) was from Sigma-Aldrich (St. Louis, MO). Candida antarctica lipase B immobilized on a macroporous acrylic resin (Novozym 435), Thermomyces lanuginosus lipase immobilized on silica gel (Lipozyme TL IM), and Rhizomucor miehei lipase immobilized on a macroporous acrylic resin (Lipozyme RM IM) were from Novozymes Co., Ltd. (China). Pseudomonas cepacia lipases immobilized on ceramic (PSL-C) and diatomite (PSL-D) were from Amano Co. (Japan). Crude Penicillium expansum lipase (PEL) was purchased from Leveking Bioengineering Co., Ltd. (Shenzhen, China). PEL immobilization on a macroporous adsorbent resin D4020 (cross-linked polystyrene) was conducted as described previously.21 All other chemicals were from commercial sources and of the highest purity available. The solvents were dried with 4 Å molecular sieves with gentle shaking overnight prior to use. Synthesis of Deep Eutectic Solvents (DES). Choline chloride (ChCl, 0.05 mol) and hydrogen bond donor (0.1 mol) were added to a 20-mL vial and heated at 100 °C until a clear and homogeneous liquid formed. DES were dried over P2O5 under vacuum at 50 °C for 24 h and stored over P2O5 in a desiccator at room temperature. The mixtures were dried with 4 Å molecular sieves with gentle shaking overnight prior to use. Enzymatic Esterification of HMF and LA. In a typical experiment, 1 mL of LA (9.8 mmol) was added to 1 mL of anhydrous
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RESULTS AND DISCUSSION Enzyme Screening. Initially, six immobilized lipases including Novozym 435, Lipozyme TL IM, Lipozyme RM IM, PSL-C, PSL-D, and immobilized PEL were examined for esterification of HMF and LA (Table 1). It could be found that, except for Novozym 435, almost all lipases gave pretty poor results, with the maximal HMF conversion of approximately 4%. LA has the pKa value of 4.59 at 25 °C,23 suggesting that its acidity is comparable to those of short-chain carboxylic acids such as acetic acid (pKa, 4.76) and propionic acid (pKa, 4.87).24 Excess LA was used for esterification of HMF in the reaction B
DOI: 10.1021/acssuschemeng.6b00996 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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95% was obtained after 12 h (Table 2). However, no clear correlation between the enzyme performance and log P value of the solvent was observed in this work. Since the pioneering work reported by Srienc and co-workers,32 DES have attracted growing interest as green reaction media for biocatalysis.33 Unfortunately, no reaction happened in the tested DES (Table 2). The reason might be that both reactants were good hydrogen bond donors, and they would form strong hydrogen bond interactions with Cl− present in choline chloride,34 thus significantly reducing the intrinsic reactivity of both hydroxyl present in HMF and carboxylic acid present in LA. In addition, Maugeri et al. reported that DES were extremely hygroscopic, and the water content increased significantly from 1.2% to 9.5% within 1 h when the mixture was open to air.34 It has been wellknown that a trace amount of water present in the solvents results in remarkable inhibition to the enzymatic esterification.12−14 So, water present in DES that was adsorbed from air during the reaction might be partially responsible for the above results. Effect of HMF Concentrations. Figure 2 shows the effect of HMF concentrations on the enzymatic reaction when its
Table 1. Esterification of HMF and LA Catalyzed by Various Immobilized Lipasesa lipase
time (h)
HMF conversion (%)
Novozym 435 Lipozyme RM IM Lipozyme TL IM PSL-C PSL-D immobilized PEL
7 24 24 24 24 24
92 3 1 4 2 1
a
Reaction conditions: 1 mL of 2-MeTHF, 1 mL of LA, 50 mM HMF, 20 mg of immobilized enzyme, 100 mg of 4 Å molecular sieves, 11 mM 9-fluorenone, 40 °C, 200 r/min.
mixture, which may strongly inactivate the lipases. It may well explain the pretty low activities of most lipases observed above. Novozym 435 is known as a stable and versatile biocatalyst for synthesis of chiral alcohols, amines, and acids.25 Graebin et al. reported that the immobilized Candida antarctica lipase B was able to catalyze esterification of acetic acid and butanol at acid concentration of up to 0.5 M,26 indicating that this lipase is highly tolerant to acids of high concentrations. As a result, Novozym 435 provided a good HMF conversion of 92% in the enzymatic esterification of HMF and LA of approximately 4.9 M. Effect of Reaction Media. Reaction medium is one of the key factors affecting enzyme catalysis in nonaqueous media. Therefore, the effect of reaction media on the enzymatic esterification of HMF and LA was studied (Table 2). Several Table 2. Effect of Reaction Media on the Enzymatic Esterificationa reaction media
log Pb
time (h)
conversion (%)
t-butanol 2-methyl-2-butanol 2-MeTHF CPME acetone ChCl:LA (1:2)c ChCl:urea (1:2)c ChCl:glycerol (1:2)c
0.35 0.89 1.85 1.59 −0.24 n.a.d n.a. n.a.
12 12 12 24 48 n.r.e n.r. n.r.
94 92 95 92 24 n.r. n.r. n.r.
Figure 2. Effect of HMF concentrations on the enzymatic esterification. Reaction conditions: 1 mL of 2-MeTHF, 1 mL of LA, 20 mg of Novozym 435, 11 mM 9-fluorenone, 100 mg of 4 Å molecular sieves, HMF of designated concentrations, 40 °C, 200 r/ min. The reaction time is 12 h, except for 48 h with 500 mM.
concentrations varied from 50 to 500 mM. It was interestingly found that high conversions of >88% were obtained within 12 h when HMF concentration was up to 200 mM. When HMF concentration was 500 mM, the conversion (approximately 72%) remained good after 48 h. Previously, Krystof et al. reported that HMF propionate was afforded with an approximately 50% yield at 300 mM HMF in the mixture of propionic acid and t-butanol (1:1, v/v) by using immobilized lipase B from Candida antarctica, and a lower yield (approximately 30%) was obtained at 400 mM HMF.11 Apparently, the results reported in this work were better than the previously results, since a higher conversion (72%) was obtained at 500 mM HMF. As mentioned above, LA is slightly more acidic than propionic acid (pKa values, 4.59 and 4.87, respectively); thus, the inactivation effect of LA on the lipase may be stronger than that of propionic acid. Indeed, higher substrate conversions were achieved with LA as the acyl donor in this work, compared to those with propionic acid in the previous work.11 Therefore, the higher HMF conversions obtained in this work may be attributed to use of 2-MeTHF as cosolvent, since it has been demonstrated that this biomassbased solvent not only has much better enzyme-compatibility
a
Reaction conditions: 1 mL of solvent, 1 mL of LA, 50 mM HMF, 20 mg of Novozym 435, 11 mM 9-fluorenone, 100 mg of 4 Å molecular sieves, 40 °C, 200 r/min. bAt 25 °C.29,35 cChCl, choline chloride; the ratios mentioned are the molar ratios. dNot available. eNo reaction.
commonly used organic solvents for enzymatic acylation of polar compounds including t-butanol, 2-methyl-2-butanol, and acetone were examined. It was found that both t-butanol and 2methyl-2-butanol were good solvents for the enzymatic esterification of HMF and LA, affording >92% conversions. In addition to these conventional organic solvents, some novel and interesting reaction media were also tested for the enzymatic esterification. Recently, 2-MeTHF, a commercially available biomass-derived solvent, and CPME have emerged as green and promising alternatives to conventional ether solvents for organic synthesis,27−29 because they have a lot of favorable physicochemical properties such as lower miscibility with water, higher boiling points, and good stability as well as low environmental impact.28−31 Interestingly, it was found that the enzymatic esterification proceeded smoothly in the two green solvents, particularly, 2-MeTHF, in which a high conversion of C
DOI: 10.1021/acssuschemeng.6b00996 ACS Sustainable Chem. Eng. XXXX, XXX, XXX−XXX
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ACS Sustainable Chemistry & Engineering than t-butanol, but also the enzyme has much higher substrate affinity in 2-MeTHF than in t-butanol.36 Effect of Reaction Temperature. Then, the effect of reaction temperature on the enzymatic esterification was explored (Figure 3). As shown in Figure 3A, the reaction
potential. Use of biomass-derived 2-MeTHF as cosolvent not only facilitates the enzymatic reaction, but also has a promising environmental footprint. Good conversions were achieved at high HMF concentrations, which is promising to envisage an industrially sound biocatalytic process for valorization of both HMF and LA. Nonetheless, more experiments such as lowering LA concentrations or/and improving the immobilized methods should be conducted to reduce the enzyme inactivation. In addition, the rational process optimization is also necessary to further improve the productivity as well as the conversions,38,39 particularly at high substrate concentrations, prior to its successful large-scale applications.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acssuschemeng.6b00996. NMR spectra of HMF levulinate (PDF)
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Figure 3. Effect of reaction temperature on the enzymatic esterification (A) and the thermostability of Novozym 435 (B). Conditions for enzymatic reaction (A): 1 mL of 2-MeTHF, 1 mL of LA, 200 mM HMF, 20 mg of Novozym 435, 11 mM 9-fluorenone, 100 mg of 4 Å molecular sieves, at the designated temperature, 200 r/min, the reaction time is 48, 36, 12, 72, and 7 h for 20, 30 40, 50, and 60 °C, respectively. Conditions for thermostability assay (B): Novozym 435 was added into the mixture of 2-MeTHF and LA (1:1, v/v), and then the mixtures were incubated at the designated temperature. At the designated time, the residual activity of the immobilized enzyme was assayed.
AUTHOR INFORMATION
Corresponding Author
*Phone/fax: +86 20 2223 6669. E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This research was financially supported by the Natural Science Foundation of Guangdong Province (2014A030313263).
temperature exerted a remarkable effect on the enzymatic reaction. When the reaction temperature was less than 40 °C, high HMF conversions (>85%) were obtained. The reaction rates increased significantly with the increment of reaction temperature when reaction temperature was less than 40 °C. For example, the reaction time for reaching a good conversion of 85% was 48 h at 20 °C, while being only 12 h at 40 °C. However, fewer conversions (26−48%) were obtained when the reaction temperature increased to more than 50 °C, which was in good agreement with the previous results.11 To explain the above results, the inactivation kinetics of the immobilized enzyme was studied at 40 and 60 °C in the mixture of LA and 2-MeTHF (Figure 3B). It could be found that the residual activities of the immobilized enzyme decreased significantly with increasing incubation time. At 40 °C, the residual activity markedly reduced to 36% after 12 h, and to approximately 20% after 48 h. In addition, inactivation of the immobilized enzyme appeared to be more significant at 60 °C, with the residual activity of approximately 7% after 12 h. Although Novozym 435 has been known as an extremely thermostable lipase, highly acidic LA with a concentration of up to 4.9 M was present in the reaction mixture, which would cause the severe enzyme inactivation. In addition, a high concentration of HMF (200 mM) would readily form Schiff bases with the ε-amino groups of lysine residues present in the lipase,37 thus resulting in the enzyme inactivation, especially at higher temperature.
REFERENCES
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CONCLUSIONS A green and efficient enzymatic approach has been successfully established for upgrading the two important biomass-based HMF and LA to HMF levulinate with potent application D
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