Conversion of D-fructose to 5-acetoxymethyl-2-furfural Using Immobilized Lipase and Cation Exchange Resin

Article abstract of DOI:10.3390/molecules24244623

5-Acetoxymethyl-2-furfural (AMF) was prepared from D-fructose via 1,6-diacetylfructose (DAF) through a simple two-step reaction pathway. Immobilized enzyme (Novozym 435) was found to be the best enzymatic catalyst for the trans-esterification step (yielding 94.6% DAF). In the dehydration step, while soluble H₂SO₄ was found to be the best acidic catalyst (yielding 86.6% AMF), we opted to utilize heterogeneous cation exchange resin (Amberlyst 15) together with recyclable industrial solvents (1,4-dioxane) for a more sustainable AMF synthesis procedure. Although the total yield of AMF was a little lower, both the enzyme and the solid acid catalyst could be recycled for five cycles without a significant loss of activity, which has a major contribution to the cost-efficient aspect of the entire process.

Full text of DOI:10.3390/molecules24244623

molecules
Article
Conversion of D-fructose to 5-acetoxymethyl-2-furfural
Using Immobilized Lipase and Cation Exchange Resin
Nhan Thanh Thien Huynh 1
,2
, Kyung Won Lee , Jin Ku Cho 1,2, Yong Jin Kim 1,2
,
1,3
Se Won Bae 1 , Jong Shik Shin and Seunghan Shin
3
1,2,
*
1
Green Chemistry & Materials Group, Korea Institute of Industrial Technology (KITECH), 89 Yangdaegiro-gil,
Ipjang-myeon, Seobuk-gu, Cheonan, Chungnam 31056, Korea; huynhthanhthiennhan@gmail.com (N.T.T.H.);
c7512999@kitech.re.kr (K.W.L.); jkcho@kitech.re.kr (J.K.C.); yjkim@kitech.re.kr (Y.J.K.);
swbae@kitech.re.kr (S.W.B.)
2
3
Department of Green Process and System Engineering, Korea University of Science and Technology (UST),
2
17 Gajeong-ro, Yuseong-gu, Daejeon 34113, Korea
Department of Biotechnology, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea;
enzymo@yonsei.ac.kr
*
Correspondence: shshin@kitech.re.kr; Tel.: +82-41-5898-422; Fax: +82-41-5898-580
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
Received: 18 November 2019; Accepted: 15 December 2019; Published: 17 December 2019
ꢀ
ꢁꢂꢃꢄꢅꢆ
Abstract: 5-Acetoxymethyl-2-furfural (AMF) was prepared from D-fructose via 1,6-diacetylfructose
DAF) through a simple two-step reaction pathway. Immobilized enzyme (Novozym 435) was
found to be the best enzymatic catalyst for the trans-esterification step (yielding 94.6% DAF). In the
dehydration step, while soluble H SO was found to be the best acidic catalyst (yielding 86.6% AMF),
(
2
4
we opted to utilize heterogeneous cation exchange resin (Amberlyst 15) together with recyclable
industrial solvents (1,4-dioxane) for a more sustainable AMF synthesis procedure. Although the total
yield of AMF was a little lower, both the enzyme and the solid acid catalyst could be recycled for five
cycles without a significant loss of activity, which has a major contribution to the cost-efficient aspect
of the entire process.
Keywords: D-Fructose; 5-Acetoxymethyl-2-furfural (AMF); 5-Hydroxymethyl-2-furfural (HMF);
trans-esterification; dehydration.
1
. Introduction
Since the 19th century, fossil fuel exploitation and refinery have been established and well
developed. Currently, many aspects of the modern industry, ranging from energy and bulk chemicals
to refined materials, are dependent on petroleum. Therefore, these non-renewable resources are being
overly exhausted. Recent research shows great interest in using biomass resources as starters for the
production of polymeric materials, organic chemicals, and fuel [1]. 5-Hydroxymethyl-2-furfural (HMF)
and its derivatives are among the promising biomass-derived platform chemicals, which have the
potential to become “carbon-neutral” feedstock or building blocks in a green, renewable, and sustainable
industry [
2
,3]. Numerous studies on the synthesis of HMF from different sources of carbohydrates
were conducted over the past three decades [4–7] and many of these synthesis procedures involved
the dehydration of simple hexoses, such as glucose and fructose, using diverse reaction media
and reaction conditions. However, reactions using polar solvents, like N,N-dimethylformamide
(
DMF) [
8
,
9
], dimethylsulfoxide (DMSO) [
8
,
10
,
11], and sulfolane [12], present problems in HMF isolation
13], ionic liquids [14 16], or
,18], would create a burden on the synthesis cost. In addition, HMF’s low
while reactions with special conditions, such as microwave heating [
supercritical-state solvents [17
melting point (30–34 C) and good miscibility in both hydrophilic and hydrophobic solvents also reduce
7
,
–
◦
Molecules 2019, 24, 4623; doi:10.3390/molecules24244623
www.mdpi.com/journal/molecules

Molecules 2019, 24, 4623
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the options for purification procedures. Compared to HMF, 5-acetoxymethyl-2-furfural (AMF) [
2
],
◦
an ester derivative of HMF with a higher melting point (53–55 C) and higher hydrophobicity, could
be more appealing as a furan-based synthesized target. Despite the advantage, AMF has rarely been
a compound of interest and was only identified as a side-product from the oxidation reaction of
HMF to 2,5-furandicarboxaldehyde (FDA) [19]. Recently, Kang et al. realized that AMF has more
potential as an alternative to HMF and proposed a synthesis procedure from lignocellulosic biomass via
5-chloromethyl-2-furfural (CMF) and alkylammonium acetates in biphasic solvent [20]. Furthermore,
several patents on AMF’s functional group transformation were reported in the last decade [21 23],
–
which makes AMF a very promising substitution for HMF since it can be converted to useful furanic
monomers using similar procedures to HMF.
In this study, we aimed to synthesize AMF from D-fructose via an indirect pathway that involves
the formation of 1,6-diacetylfructose (DAF). DAF is a di-ester derivation, which can be selectively
converted from D-fructose using enzymes. Albeit briefly, the synthesis and characterization of DAF
were mentioned in D’Antona et al.’s study regarding lipase-catalyzed regioselective acylation [24].
Since DAF can be selectively produced from D-fructose and easily handled, it would make an ideal
intermediate for the AMF synthesis procedure. Scheme 1 explains the synthesis pathway, which consists
of two reaction steps: 1) Trans-esterification of D-fructose into DAF, and 2) dehydration of DAF into
AMF. This is a very new and unique approach for the synthesis of AMF since recent studies only
describe a synthesis route of AMF from CMF [20,25]. Kim et al. produced AMF using a substitution
reaction of CMF in DMF, with acetic acid catalyzed by a weak inorganic base. This procedure resulted
in a fairly good yield of AMF, but the use of high boiling polar solvent and soluble inorganic base
made the isolation of AMF quite complicated. Kang et al. greatly improved the production of AMF
from CMF by combining alkylammonium acetates supported on anion exchange resin with a biphasic
reaction system. This method was able to push the yield of AMF to over 90%; however, the use of
CMF as substrate was not preferred, since this compound is hard to synthesize from carbohydrate
sources and easily decomposes in the presence of moisture. Our approach to the AMF synthesis
pathway from D-fructose via the DAF intermediate helps to avoid the problems encountered when
using CMF as the starting material. The advantages of this pathway also include simple reaction steps,
mild reaction conditions, environmentally friendly catalysts, and commercially available solvents.
In addition, compared to the direct transformation of D-fructose into HMF, this approach, which targets
the production of AMF, might help avoid the difficulties related to HMF purification since AMF can be
separated from the reaction mixture by recrystallization or vacuum distillation [20]. Overall, the goal of
this research was to utilize immobilized enzyme catalysts (e.g., lipase) and heterogeneous acid catalysts
(e.g., Ambelyst 15) together with common industrial solvents (such as ethyl acetate, tetrahydrofuran,
1
,4-dioxane) in order to establish an efficient synthesis procedure of AMF from D-fructose.

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Scheme 1. Reaction pathway for synthesis of 5-acetoxymethyl-2-furfural (AMF) from D-fructose via
,6-diacetylfructose (DAF).
1
2
. Materials and Methods
2
.1. Materials and Equipment
D-Fructose (99%), 5-hydroxymethyl-2-furfural (HMF, 99%), 5-acetoxymethyl-2-furfural
AMF, 99%), vinyl acetate (99%), tetrahydrofuran (anhydrous, 99.9%, abbreviated as THF henceforth),
,4-dioxane (anhydrous, 99.8%, abbreviated as dioxane henceforth), DMSO (anhydrous, 99.9%), sulfuric
acid (H SO 95-98%), p-toluenesulfonic acid monohydrate (pTSA, 98.5%), alumina (Al O , activated,
(
1
2
4
2
3
acidic, Brockmann I), and Amberlyst 15 (hydrogen form, dry) were purchased from Sigma-Aldrich.
Immobilized lipase, such as Novozym 435 and Lipozyme TL IM, were purchased from Novozymes
(Denmark). Lipozyme RM IM was purchased from Sigma-Aldrich.
The main reaction system was a Carousel 12 Plus Reaction Station (Radleys, UK) equipped
with a 20-mL reaction glass tube and PTFE cap. Heating, magnetic stirring, and a water-cooling
system are all integrated in the Carousel 12 Plus. For scaling up the procedures, 100-mL round flasks
(Schott DURAN, Wertheim am Main, Germany) were used instead of glass tubes and the reaction
temperature was adjusted using an IKA-RTC basic hot plate with magnetic stirring (IKA Works
GmbH & Co. KG, Staufen, Germany). The system can easily be connected with a water-cooling
®
reflux (WiseCircu WCH – 12 Liter, Heidelberg, Germany) for long reactions at high temperatures
(
e.g., dehydration). In the case of the 600 time scale-up of trans-esterification, a 5-L jacket-type glass
×
reactor was used. The reactor was specifically designed with two layers: The outer layer was filled
with temperature-controlled water (WiseCircu ® WCH – 22 Liter, Heidelberg, Germany) to heat the
reaction mixture in the inner layer. The reactor was also equipped with mechanical stirring (SM 3000D,
Global Lab, Gyeonggi-do, South Korea), a reflux system, and a bottom valve to collect the mixture
after reaction.
Analysis of the samples was conducted on a high-performance liquid chromatography (HPLC)
system (Agilent, 1200 series equipped with diode-array detector – DAD and refractive index
detector – RID) and a GC-MS system (Shimadzu GC-2010 Plus equipped with a QP2010 Ultra
mass spectrometer detector). The analysis of D-fructose, DAF, AMF, and HMF in the product mixtures
was performed using HPLC equipped with a Bio-rad Animex HPX-87P column with H O as the eluent.
2

Molecules 2019, 24, 4623
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D-fructose and DAF were detected by the RID detector while AMF and HMF were detected at 254 nm
on the DAD detector. The formation of AMF and HMF was also verified using the GC-MS NIST
2
011 database.
2
.2. Synthetic Procedures and Analysis
1,6-Diacetylfructose (DAF): Enzymatic trans-esterification of D-fructose was performed using
several types of commercially available lipase (Novozym 435, Lipozyme TL IM, and Lipozyme RM IM)
as catalyst and vinyl acetate as an acyl donor. Reaction conditions were: 50 mg D-fructose, 80
µ
L vinyl
◦
acetate (3 equiv), 50 mg lipase, 5 mL solvent, magnetic stirring at 300 rpm, 45 C for 5 h. After the
reaction, lipase was filtered out and the filtrate was evaporated through rotary vaporization and
vacuum in order to give the final product in a slightly yellow syrup form. For NMR analysis, a small
portion of DAF was further purified using column chromatography. In total, 30 mg of DAF were
washed through a 4-cm normal phase silica column with Et O:MeOH (98:2) as the eluent. The recovered
2
1
DAF was dried again in vacuum before being dissolved in an appropriate solvent for analysis. H NMR
of DAF (300 MHz, CDCl ): 4.44–4.33 (m, 1H on C2), 4.30–4.23 (m, 2H of C5-CH ), 4.21–4.13 (m, 2H on
3
2
C3 and C4), 4.05–4.00 (m, 2H of C2-CH ), 2.17–2.12 (m, 6H of 2 –COOCH ; major anomer: 2.14 and
2
3
13
2
.13; minor anomer: 2.17 and 2.12) (Figure S1). C NMR of DAF (300 MHz, DMSO-d ): 170.83–170.47
6
(d, 2C in –COO– groups), 100.86 (s, C5 in the ring), 78.85 (s, C2 in the ring), 76.49 (s, C4 in the ring),
7
5.57 (s, C3 in the ring), 66.16 (s, C6 in –CH group), 64.62 (s, C1 in –CH group), 21.04 (m, 2C in –CH
2
2
3
groups) (Figure S2). LC-MS analysis with API-ES positive mode +70 V (in HCOOH 0.001 M) shows
−
m/z: 282.2 (M + H O, 38%), 247.1 (M – OH , 100%) (Figure S3).
2
5-Acetoxymethyl-2-furfural (AMF): Dehydration of DAF into AMF was performed in organic
solvent using heterogeneous acid catalyst and a high temperature. Amberlyst 15, a type of cation
exchange resin, was chosen as the acidic catalyst. Reaction conditions were: 50 mg DAF dissolved in
◦
5
mL solvent, 50 mg Amberlyst 15, stirring at 300 rpm, 120 C for 8 h. After dehydration, Amberlyst 15
was filtered out and the qualification and quantification of AMF in the reaction mixture was analyzed
by HPLC and GC-MS (Figures S7 and S8). AMF was also isolated through vacuum distillation and
1
analyzed with H NMR (300 MHz, THF-d ): 9.62 (s, 1H on –CHO), 7.31–7.30 (d, 1H of C4 on furan ring),
8
13
6
.68–6.67 (d, 1H of C3 on furan ring), 5.13 (s, 2H of –CH ), 2.06 (s, 3H of –CH ) (Figure S4). C NMR
2 3
of AMF (300 MHz, THF-d ): 176.91 (s, C in –CHO group), 169.23 (s, C in –COO– group), 155.57 (s, C2
8
in the furan ring), 155.37 (s, C5 in the furan ring), 120.62 (s, C4 in the furan ring), 112.06 (s, C3 in the
furan ring), 57.27 (s, C in –CH group), 19.32 (s, C in –CH group) (Figure S5). GC-MS analysis with EI
2
3
+
scan mode from -2.0 to +2.0 kV shows m/z: 282.2 (M - COCH + H , 100%) (Figure S6).
3
In the reusability test, after each reaction cycle, the solid catalyst (lipase or Amberlyst 15)
was filtered off using a Buchner funnel and Whatman filter paper grade 3. In the case of lipase,
the immobilized enzyme was washed with THF and dried at room temperature before being reused.
◦
As for Amberlyst 15, it was washed with acetone and then dried in a vacuum oven at 25 C before
being reused.
3
. Results and Discussion
3
.1. Trans-Esterification of D-fructose
Lipases (triacylglycerol ester hydrolase, EC 3.1.1.3) are very commonly used in synthetic organic
chemistry [24,26–30]. Beside the ubiquitous ability to catalyze the hydrolysis of fats and oils, lipases
can catalyze enantioselective derivatization of chiral compounds, esterification, trans-esterification,
and inter-esterification reactions [29]. Although lipases from different sources are able to catalyze
the same reaction, their catalytic activity might be very different even under the same reaction
conditions [31]. Table 1 presents the results when three types of commercially available lipases
were used for the trans-esterification of D-fructose in various solvents, with vinyl acetate as the
acyl donor. Since trans-esterification is a reversible reaction, the use of vinyl acetate as an acyl

Molecules 2019, 24, 4623
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donor would make it become irreversible, as the by-product, vinyl alcohol, is labile and immediately
converts to acetaldehyde [29]. It should be noted that lipase was chosen as the catalyst because
the enzyme’s characteristics favor the trans-esterification of primary alcohol groups, which would
lead to the formation of the desired di-ester derivation of D-fructose. The three particular types of
immobilized lipase used for this trans-esterification were Novozym 435 (1000 PLU/g), Lipozyme TL
IM (250 IUN/g), and Lipozyme RM IM (300 IUN/g). It was noticed that all three types of lipase could
catalyze the trans-esterification when an ether-type solvent (THF or dioxane) was used as media for
the reaction. When Novozym 435 together with THF or dioxane was used, the formation of DAF was
most favorable (Entry 5,6—Table 1; 96.2% and 90.4% of DAF yield in THF and dioxane, respectively).
Meanwhile, water and solvents containing –OH functional groups unsurprisingly prohibited the
reaction (Entry 1,2,3—Table 1) since the –OH group of these solvents interferes with the exchange of the
acetyl group from the acyl donor and primary –OH groups of D-fructose. On the other hand, solvents
with a medium and low polarity index gave little or no yield of DAF (Entry 4,8,9,10,11—Table 1)
because they can hardly dissolve D-fructose, thus the reaction remains stagnated when D-fructose
could not be dissolved and came into contact with the immobilized lipase. It was also observed
that using an excess amount of acyl donor (5 equiv. of vinyl acetate) did not improve the yield of
DAF (Entry 12,13—Table 1). This screening result is consistent with the literature [24], and therefore,
Novozym 435 was chosen as the source of catalyst while both THF and dioxane were used as solvents
for the scaling-up procedure.
Table 1. D-Fructose trans-esterification in various solvents a.
DAF yield (%)
Entry
Solvent
Lipozyme TL IM
Lipozyme RM IM
Novozym 435
1
2
3
4
5
6
7
8
9
H O
MeOH
EtOH
Acetone
THF
Dioxane
DMSO
Ethyl acetate
MIBK
Hexane
Dichloromethane
THF
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
0.0
2
7.4 ± 1.2
44.3 ± 2.7
37.4 ± 3.2
0.0
9.1 ± 2.1
5.7 ± 1.9
0.0
12.7 ± 2.4
96.2 ± 2.8
90.4 ± 2.5
0.0
14.4 ± 2.2
9.7 ± 1.8
0.0
30.1 ± 2.3
22.5 ± 1.8
0.0
0.0
0.0
0.0
0.0
-
1
1
0
1
0.0
-
-
0.0
b
1
1
2
3
95.5 ± 2.9
b
Dioxane
-
92.2 ± 2.3
a
◦
Conditions: D-fructose 50 mg, immobilized lipase 50 mg, vinyl acetate 80
00 rpm. Using 5 equiv. of vinyl acetate.
µL (3 equiv.), solvent 5 mL, 45 C, 5 h,
b
3
Scaling up of the trans-esterification reactions (
×
10 to 600 time) was performed based on the
×
screening results. After the scaling-up reactions, the catalyst was filtered off and recovered, the solvent
was removed with rotary vaporization and vacuum, and DAF was then obtained in a yellow syrup
form and stocked up as material for the dehydration step. Results in Table 2 show that scaling up
the procedure had very little effect on the conversion of D-fructose as well as the formation of DAF.
With some minor adjustments of the reaction time and stirring speed, we managed to achieve an 88.0%
yield of DAF with 92% of D-fructose conversion (Entry 11—Table 2) in a 600 time scale-up reaction.
This result indicates that trans-esterification of D-fructose with immobilized enzyme catalyst is a quite
stable procedure and can be utilized for sustainable production of DAF. One major setback of this
procedure is that when the concentration of the starting material was increased (from 1% w/v to 5%
w/v), the yield of DAF started to decrease accordingly (a 22.9% yield drop in THF and 21.9% yield drop
in dioxane was recorded). In other words, it was hard to achieve a high yield of DAF without using a
large amount of solvent to fully dissolve D-fructose at the beginning state of the reaction. This was due

Molecules 2019, 24, 4623
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to the low solubility of D-fructose in organic solvents and was hard to compromise. However, almost
all of the solvent could be recovered and reused after the reaction.
Table 2. Scale up trans-esterification of D-fructose a.
D-Fructose
Conversion (%)
DAF Selectivity
(%) *
Entry
Solvent
D-Fructose (g)
DAF Yield (%)
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
0.5
1.0
1.5
2.0
2.5
0.5
1.0
1.5
2.0
2.5
30.0
100
98.3
90.1
83.5
76.7
100
95.7
88.8
79.9
73.4
92.0
94.6
90.1
82.8
77.3
71.7
91.3
86.7
80.2
75.4
69.4
88.0
◦
94.6
91.6
91.9
92.6
93.5
91.3
90.6
90.3
94.4
94.6
95.6
b
THF
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
THF
1
0
b
1
a
1
Conditions: mD-fructose = mNovozym 435, vinyl acetate (3 equiv.), solvent 50 mL, 45 C, 5 h, 300 rpm; Conditions:
D-fructose 30 g, Novozym 435 30 g, vinyl acetate 46 mL (3 equiv.), THF 3 L, 45 C, 6 h, 500 rpm; * DAF selectivity
◦
DAF yield (%)
was calculated using this formula: DAF selectivity (%) =
× 100.
D−fructose conversion (%)
Experiments to investigate the reusability of the immobilized lipase were also performed in
THF. After each cycle, the enzyme in the small bead form was simply filtered off, washed with THF,
and dried at room temperature for 12 h before reuse. It was observed that Novozym 435 can be reused
for up to five cycles with less than 9% of weight loss while still giving a stable yield of DAF (less than
5% decline in DAF yield—Figure 1). Further recycling of the enzyme led to a higher drop in DAF
yield (10.4% and 13.7% drop in DAF yield at the sixth and seventh recycling circle, respectively) as
well as over a 10% loss of the catalyst amount. The loss of catalyst could be explained by the partial
fragmentation of catalyst beads during the long reaction and these fragments were lost in the recovery
and transferring process between the cycles. As observed in Figure 1, the increment in catalyst loss
correlated well with the drop in DAF yield.
DAF
Catalyst loss
100
9
2.5
91.0
8
9.9
8
8.2
87.7
82.1
7
8.8
80
60
40
20
0
16.1
1
1.8
8
.8
6
.0
3
.9
2
.4
0
.0
1
st
2nd
3rd
4th
5th
6th
7th
Cycle
Figure 1. Reusability of immobilized lipase (conditions: D-fructose 500 mg, Novozym 435 500 mg
◦
(
reused through all seven cycles), vinyl acetate 800 µL, THF 50 mL, 45 C, 5 h, 300 rpm).

Molecules 2019, 24, 4623
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3
.2. Dehydration of DAF
DAF could be converted to AMF by removing three molecules of water and one molecule of
acetic acid under acidic conditions as depicted in Scheme S1 (Supplementary Materials). The DAF
obtained from the prior trans-esterification step was dissolved in organic solvent media prior to
the dehydration reaction. Based on previous studies of catalytic dehydration of sugars into furan
compounds [9,14,32], Amberlyst 15 was chosen as the heterogeneous acidic catalyst for the dehydration
step. Multiple experiments were conducted in order to optimize the reaction parameters, such as the
reaction time, catalyst ratio, and reaction media.
In order to study the course of the reaction, a time-dependent experiment was performed.
◦
DAF diluted in dioxane was heated at 120 C and samples were taken at certain time intervals for
HPLC analysis. It was observed that both AMF and HMF were formed under this condition, with AMF
being the major product. After 8 h of reaction, we achieved the highest yield of AMF with 23.6% and
8
.2% of HMF (Figure 2). Further prolongation of the reaction showed no increment of the AMF quantity.
We suspected that the relatively low yield of AMF could be improved when reaction conditions, such as
the solvent media or catalyst amount, were to be adjusted. In addition, the simultaneous formation of
AMF and HMF in the reaction media suggested that both dehydration and hydrolysis were catalyzed
in the presence of Amberlyst 15 (Scheme S2).
HMF yield
AMF yield
DAF conversion
40
35
30
25
20
15
10
5
0
3
7.5
2
3.6
8.2
0
100
200
300
400
500
Time (min)
Figure 2. Effect of reaction time on the dehydration of DAF (Conditions: DAF 50 mg, Amberlyst 15
◦
1
0 mg, 1,4-dioxane 5 mL, 120 C, 300 rpm).
Since DAF is synthesized and easily dissolved in THF or dioxane, these solvents were tested to see
if they are suitable for the dehydration of DAF. DMSO was also examined because AMF, unlike HMF,
can be easily separated from DMSO by liquid-liquid extraction [20]. The results in Table 3 show that
THF was inferior to dioxane and DMSO as a solvent for dehydration. It was understandable since THF
◦
possesses a low boiling point (66 C) and therefore would not be very effective for the dehydration of
◦
DAF, which was performed at a much higher temperature (120 C). Compared to the time-dependent
experiment, we increased the amount of Amberlyst 15 used in this experiment to 50 mg, but the yield
of AMF in dioxane was not significantly improved (23.6% compared to 29.2%). At the same time,
the yield of HMF in dioxane, when increasing the amount of Amberlyst 15, was quite noticeable (from
8.2% to 15.6%). This could be an indication that the hydrolysis reaction in dioxane is a little more
favorable when more acid catalyst is added.

Molecules 2019, 24, 4623
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Table 3. DAF dehydration in different solvents.
Solvent
DAF Conversion (%)
AMF Yield (%)
HMF Yield (%)
THF
Dioxane
DMSO
12.9 ± 1.0
51.2 ± 1.2
59.2 ± 1.4
6.1 ± 1.6
29.2 ± 2.1
38.7 ± 2.4
3.8 ± 0.8
15.6 ± 1.7
14.9 ± 1.9
◦
Conditions: DAF 50 mg, Amberlyst 15 50 mg, solvent 5 mL, 120 C, 8 h,300 rpm.
The AMF yield was the highest in the case of DMSO, which has been widely and effectively used
as a solvent for the dehydration of ketose-type sugars into furan compounds [33 35]. Several researches
also mentioned that DMSO could stabilize HMF, and reduce side reactions during dehydration [36 37].
–
,
Thus, it was understandable that DMSO gave a higher total yield of HMF and AMF. On the other
hand, the yield of AMF in dioxane was not so far behind when compared to in DMSO (29.2% to
◦
3
8.7%), especially considering dioxane has a much lower boiling point than DMSO (101 C compared
◦
to 189 C). Therefore, we purposely combined DMSO and dioxane as a mixture solvent for further
investigation, with the aim of maximizing the yield of AMF while limiting the formation of HMF.
As the results show in Figure 3, using DMSO as a co-solvent greatly enhanced the formation of AMF
while still keeping HMF at low yields. The best condition for solvent was at 15% DMSO in dioxane,
which resulted in a 55.8% and 9.0% yield of AMF and HMF, respectively. It was not expected that when
we increased the ratio of DMSO in dioxane to over 20%, the yield of AMF started to decline. As we
mentioned that AMF and HMF were simultaneously formed during the reaction, we highly suspected
that when DMSO was mixed in as co-solvent at a specific ratio, the combined solvent media had
positive effects on the dehydration of DAF into furan compounds. Firstly, it was clear that the added
DMSO possessed the benefit of increasing the boiling point of the reaction media, which made the
◦
combined solvent more suitable for dehydration at high temperature (120 C). Secondly, the presence
of DMSO was suggested to have a catalytic activity in the removal of H O molecules from the furanose
2
ring [33
,38] as well as reducing the formation of by-products and stabilizing the formed AMF and
HMF in the reaction mixture [39].
DAF
AMF
HMF
80
60
40
20
0
7
1.6
71.0
7
0.7
70.5
6
9.4
68.9
6
4.2
55.8
55.3
4
9.3
4
8.8
48.7
46.7
4
4.8
44.2
29.2
15.6
15.0
1
4.4
1
2.7
12.8
1
1.9
1
0.7
9
.0
0
10
20
30
40
50
%
DMSO in 1,4-dioxane
Figure 3. Effect of reaction media on the dehydration of DAF (Conditions: DAF 50 mg, Amberlyst 15
◦
5
0 mg, solvent 5 mL, 120 C, 8 h, 300 rpm).
Since Amberlyst 15 is a cation exchange resin in the H+ form with a macro-reticular pore
structure [40], dehydration of DAF in this case is catalyzed heterogeneously at hydrogen ion sites

Molecules 2019, 24, 4623
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located throughout the resin beads. It is expected that higher amounts of catalyst during long reaction
times will lead to a better yield of AMF. With that in mind, we investigated the effect of the catalyst
ratio on the dehydration reaction. Upon varying the mass ratio between catalyst/substrate while
maintaining the composition of reaction media at 15% DMSO in dioxane (Figure 4), it was observed that
when the catalyst/substrate ratio ranged from 0.6 to 1.0 (w/w), the formation of AMF was significantly
improved and stabilized (over 50% yield of AMF) compared to using a lower catalyst/substrate mass
ratio. This means that when optimizing the procedure for sustainable production, we can slightly
adjust the amount of catalyst in order to lower the cost of the reaction.
AMF
HMF
60
45
30
15
0
55.8
5
2.0
51.9
42.0
2
4.8
9.0
7.6
7.4
5.4
3.2
0
.2
0.4
0.6
0.8
1
R(Cat/Sub)
Figure 4. Effect of the catalyst ratio, RCat/Sub, on the dehydration of DAF (Conditions: DAF 50 mg,
◦
Amberlyst 15, solvent 5 mL, 120 C, 8 h, 300 rpm).
Various scaling-up dehydrations of DAF were also performed based on the best reaction media
(15% DMSO in dioxane) with the ratio of Amberlyst 15/DAF (RCat/Sub) at 0.6. The results in Table 4
confirm that this procedure could be effectively scaled up to 100 times without any effect on the yield of
the desired AMF product (Entry 5). It was noticed that since the amount of DAF and Amberlyst 15 was
increased while the solvent volume was kept at a constant value, the stirring speed had to be slightly
adjusted (ranging from 300 to 500 rpm) for better heat regulation during the entire reaction course.
Table 4. Scaling-up dehydration of DAF using 15% DMSO in dioxane as solvent.
Entry
DAF (g)
DAF Conversion (%)
AMF Yield (%)
HMF Yield (%)
1
2
3
4
5
0.5
1.0
2.0
4.0
5.0
69.9
71.2
73.8
74.7
74.9
54.7
54.2
56.1
55.4
57.9
◦
9.8
11.2
13.7
15.5
15.8
Conditions: RCat/Sub = 0.6, solvent 50 mL, 120 C, 8 h, 300–500 rpm.
The recycling of catalyst would have an impact on the cost of the reaction. Therefore, we conducted
an experiment to test the reusability of Amberlyst 15 in this particular reaction since it could affect the
possibility for commercialization of this procedure. After each cycle of dehydration, Amberlyst 15
◦
was filtered, washed with acetone, and dried in a vacuum oven (25 C) overnight before being reused.
The results showed that Amberlyst 15 can be reused for up to five cycles without a remarkable change

Molecules 2019, 24, 4623
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in the yield of AMF and HMF (Figure 5). It should be noted that all the cycles in the reusability test
were performed using 15% DMSO in dioxane as the reaction media.
AMF
HMF
6
4
3
1
0
5
0
5
0
5
2.0
52.1
5
0.2
4
9.4
4
7.0
1
2.9
11.9
11.5
1
0.3
7
.6
1
st
2nd
3rd
4th
5th
Cycle
Figure 5. Reusability of Amberlyst 15 (Conditions: DAF 50 mg, Amberlyst 15 30 mg, solvent 5 mL,
◦
1
20 C, 8 h, 300 rpm).
Additional experiments using different acidic catalysts were also performed as an attempt
to improve the yield of AMF from DAF dehydration. Two homogeneous acid catalysts and one
heterogeneous acid catalyst were used, and the results are shown in Table 5. Concentrated sulfuric
acid (H SO ) and p-toluenesulfonic acid (pTSA) displayed relatively high catalytic activity for the
2
4
dehydration in DMSO solvent (over 73% of AMF yield, Entry 4, 5, 6, and 12—Table 5). On the other
hand, alumina (Al O —acidic form) possessed quite low activity even when used at a higher molar
2
3
ratio and longer reaction time (DAF conversion was lower than 50% and AMF yield was lower than
0%, Entry 13–20 in Table 5). Overall, DMSO proved to be a better solvent for DAF dehydration since
most of the experiments performed in DMSO gave a higher conversion of DAF as well as a higher
yield of AMF. When applying a mixed solvent system (15% DMSO in dioxane), only the case of Al O
4
2
3
displayed a noticeable improvement in AMF yield (entry 23—Table 5). It could be concluded that the
use of a co-solvent would have little effect on dehydration with homogeneous acid catalyst. We also
noticed that when the amount of homogeneous acid catalysts (from 25 mol% to 50 mol% of DAF) was
increased, the yield of AMF was not much improved, or even decreased (in the case of Entry 5 and 6 in
Table 5) so we conducted blank experiments to examine the stability of AMF in the presence of these
acids. The results showed that when the catalyst amount was doubled, the formation of HMF from
AMF was tripled (Entry 21–24 in Table 5) and a small amount of levulinic acid was detected in the
reaction mixture.

Molecules 2019, 24, 4623
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Table 5. Dehydration of DAF using various acid catalysts.
Catalyst - mol%
of DAF
DAF
Conversion (%)
AMF Yield
HMF Yield
Entry
Solvent
Time (h)
(%)
(%)
1
2
3
4
5
6
7
8
9
H SO -10%
Dioxane
Dioxane
Dioxane
DMSO
DMSO
DMSO
Dioxane
Dioxane
Dioxane
DMSO
DMSO
DMSO
Dioxane
Dioxane
Dioxane
Dioxane
DMSO
DMSO
DMSO
DMSO
2
2
2
2
2
2
4
4
4
4
4
4
8
8
8
8
8
8
8
8
2
4
8
2
2
4
4
◦
69.1 ± 2.3
84.6 ± 1.8
94.5 ± 2.2
88.2 ± 1.2
98.4 ± 1.6
100 ± 0.0
66.6 ± 1.1
85.2 ± 1.3
97.0 ± 0.9
66.8 ± 2.4
83.4 ± 2.7
100 ± 1.7
29.2 ± 1.4
30.7 ± 1.7
34.7 ± 1.3
42.8 ± 2.4
33.1 ± 1.4
33.8 ± 0.9
40.9 ± 1.9
49.6 ± 1.5
99.1 ± 0.7
96.6 ± 1.4
60.9 ± 2.1
-
49.9 ± 1.9
61.7 ± 1.5
59.4 ± 2.8
73.2 ± 2.7
86.6 ± 1.7
78.1 ± 3.4
49.3 ± 2.0
60.9 ± 1.0
63.7 ± 3.0
52.2 ± 2.5
69.1 ± 2.0
73.0 ± 2.3
22.8 ± 1.1
23.9 ± 1.5
26.1 ± 1.4
31.6 ± 2.0
24.5 ± 1.5
24.9 ± 1.3
28.6 ± 1.5
39.9 ± 2.3
85.3 ± 0.9
76.2 ± 2.9
48.3 ± 1.8
95.7
15.2 ± 2.5
17.6 ± 2.2
22.7 ± 3.4
11.7 ± 1.4
10.4 ± 1.3
14.9 ± 3.8
12.4 ± 1.8
19.4 ± 2.4
24.5 ± 3.3
10.3 ± 1.2
10.2 ± 1.2
19.9 ± 1.6
3.9 ± 0.6
3.8 ± 1.7
4.4 ± 0.8
6.9 ± 1.5
5.2 ± 1.0
5.0 ± 1.2
7.0 ± 1.1
6.2 ± 1.9
11.0 ± 1.3
14.8 ± 2.2
6.6 ± 1.5
3.9
2
4
H SO -25%
2
4
H SO -50%
2
4
H SO -10%
2
4
H SO -25%
2
4
H SO -50%
2
4
pTSA-10%
pTSA-25%
pTSA-50%
pTSA-10%
pTSA-25%
pTSA-50%
Al O -10%
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
1
1
1
1
1
1
1
1
1
2
2
2
2
2
3
Al O -25%
2
3
Al O -50%
2
3
Al O -100%
2
3
Al O -10%
2
3
Al O -25%
2
3
Al O -50%
2
3
Al O -100%
2
3
H SO -25%
15%DMSO in dioxane
15%DMSO in dioxane
15%DMSO in dioxane
DMSO
DMSO
DMSO
2
4
pTSA-50%
Al O -100%
2
3
24*
25*
26*
27*
H SO -25%
2 4
H SO -50%
-
-
-
83.4
94.4
82.1
12.3
4.3
13.9
2
4
pTSA-25%
pTSA-50%
DMSO
Conditions: DAF 50 mg, acid catalyst, solvent 5 mL, 120 C, 300 rpm; * blank experiment: AMF 50 mg, acid catalyst,
solvent 5 mL, 120 C, 300 rpm.
◦
3
.3. Two-Step Synthesis Procedure and Separation of AMF
Scheme 2 describes the complete synthesis procedure of AMF from D-fructose based on the
results from both the trans-esterification step and dehydration step. The trans-esterification step can
be performed efficiently in both THF (Scheme 2a) and dioxane (Scheme 2b) while the dehydration step
required a mixture of DMSO in dioxane as the reaction media. In both cases, the final yield of AMF
was similar (53.7% and 50.4%, respectively) and the solvents (THF, dioxane) can be recovered through
rotary vaporization and reused after distillation. After removing most of the solvent, the final reaction
◦
mixture can be distilled under vacuum at 106 to 109 C to achieve AMF with 99% purity (the analysis
results of AMF are given in the Supplementary Material).
When combining the enzymatic trans-esterification and the acidic homogeneous dehydration,
the yield of AMF was significantly boosted (Scheme 2c). However, the purification step for AMF in
this case is more complicated since H SO needs to be neutralized and a larger amount of DMSO
2
4
needs to be removed. The reaction mixture was first diluted in ethyl acetate, washed with aqueous
NaOH ( 3 times), and then water ( 5 times) to transfer H SO and DMSO to the aqueous phase while
×
×
2
4
retaining AMF in the organic phase. Ethyl acetate was then evaporated, and the remaining product
was further distilled under vacuum to achieve AMF (70.3% yield with 99% purity). Although this
procedure resulted in a higher yield of the desired product, the catalyst and solvent for the dehydration
step could only be discarded after the reaction. Thus, it was less favorable to use this as a green and
sustainable manufacturing method for AMF.

Molecules 2019, 24, 4623
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Scheme 2. Complete synthesis procedure of AMF from D-fructose via DAF with (
followed by Amberlyst 15/DMSO-dioxane reaction system, ( ) Novozym 435/dioxane followed by
Amberlyst 15/DMSO-dioxane reaction system, and ( ) Novozym 435/THF followed by H SO /DMSO
reaction system.
a) Novozym 435/THF
b
c
2
4
4
. Conclusions
In this research, a simple two-step synthesis of AMF from D-fructose was investigated.
D-fructose was purposely converted to DAF using lipase and then dehydrated to achieve AMF.

Molecules 2019, 24, 4623
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Both synthesis steps utilized commercially available catalyst, such as Novozym 435 (immobilized
Lipase B) and Amberlyst 15, together with common industrial solvents in order to establish a
sustainable manufacturing procedure of AMF from D-fructose. In addition, the organic solvents
(
THF, dioxane) could be recovered and both catalysts reused for five cycles, which is a big advantage
when determining the cost of AMF production. To the best of our knowledge, there has been no
precedent study that utilizes both immobilized enzyme and cation exchange resin for the synthesis
of 5-acetoxymethyl-2-furfural.
Supplementary Materials: Analysis results are available for HPLC, LC-MS, GC-MS, and NMR. Schemes for
plausible mechanism from DAF to AMF and for a suggested pathway for the formation of AMF and HMF are
also provided.
Author Contributions: Conceptualization, N.T.T.H., J.K.C. and S.S.; methodology, N.T.T.H. and K.W.L.; validation,
Y.J.K., S.W.B. and J.S.S.; formal analysis, N.T.T.H.; investigation, N.T.T.N. and K.W.L.; data curation, N.T.T.H.;
writing—original draft preparation, N.T.T.H.; writing—review and editing, N.T.T.H. and S.S.; supervision, S.S.
Funding: This research was funded by the Big Issue Program (Project No. EO190029) and Internal Research
Program (Project No. EO190028) of Korea Institute of Industrial Technology (KITECH).
Acknowledgments: We express our appreciation to the late Cho, whose contribution of this work was of
great significance.
Conflicts of Interest: The authors declare no conflict of interest.
References
1
.
Narayan, R. Biomass (Renewable) Resources for Production of Materials, Chemicals and Fuels. Symp. A Q. J.
Mod. Foreign Lit. 1992. [CrossRef]
2
.
Van Putten, R.; van Der Waal, J.C.; de Jong, E.; Rasrendra, C.B.; Heeres, H.J.; de Vries, J.G.
Hydroxymethylfurfural, A Versatile Platform Chemical Made from Renewable Resources. Chem. Rev.
2
013, 113, 1499–1597. [CrossRef] [PubMed]
3
.
Werpy, T.; Petersen, G. Top Value Added Chemicals from Biomass Volume I: Results of Screening for Potential
Candidates. In Top Value Added Chemicals from Biomass Volume I—Results of Screening for Potential Candidates
from Sugars and Synthesis Gas; National Renewable Energy Lab.: Golden, CO, USA, 2004; 76p.
4.
5.
6.
Papers, G. Synthesis, chemistry and applications of 5-hydroxymethyl-furfural and its derivatives. Arkivoc
2
005, 2001, 17.
Yu, I.K.M.; Tsang, D.C.W. Conversion of biomass to hydroxymethylfurfural: A review of catalytic systems
and underlying mechanisms. Bioresour. Technol. 2017, 238, 716–732. [CrossRef] [PubMed]
Toftgaard Pedersen, A.; Ringborg, R.; Grotkjær, T.; Pedersen, S.; Woodley, J.M. Synthesis of
5-hydroxymethylfurfural (HMF) by acid catalyzed dehydration of glucose-fructose mixtures. Chem. Eng. J.
2
015, 273, 455–464. [CrossRef]
7.
8.
9.
Hansen, T.S.; Woodley, J.M.; Riisager, A. Efficient microwave-assisted synthesis of 5-hydroxymethylfurfural
from concentrated aqueous fructose. Carbohydr. Res. 2009, 344, 2568–2572. [CrossRef] [PubMed]
Seri, K.; Inoue, Y.; Ishida, H. Highly Efficient Catalytic Activity of Lanthanide (III) Ions for Conversion of
Saccharides to 5-Hydroxymethyl-2-furfural in Organic Solvents. Chem. Lett. 2000, 29, 22–23. [CrossRef]
Takagaki, A.; Ohara, M.; Nishimura, S.; Ebitani, K. A one-pot reaction for biorefinery: Combination of solid
acid and base catalysts for direct production of 5-hydroxymethylfurfural from saccharides. Chem. Commun.
2
009, 41, 6276–6278. [CrossRef]
1
1
1
1
0. Bao, Q.; Qiao, K.; Tomida, D.; Yokoyama, C. Preparation of 5-hydroymethylfurfural by dehydration of
fructose in the presence of acidic ionic liquid. Catal. Commun. 2008, 9, 1383–1388. [CrossRef]
1. Shimizu, K.I.; Uozumi, R.; Satsuma, A. Enhanced production of hydroxymethylfurfural from fructose with
solid acid catalysts by simple water removal methods. Catal. Commun. 2009, 10, 1849–1853. [CrossRef]
2. Caes, B.R.; Raines, R.T. Conversion of Fructose into 5-(Hydroxymethyl) furfural in Sulfolane. ChemSusChem
2
011, 4, 353–356. [CrossRef] [PubMed]
3. Qi, X.; Watanabe, M.; Aida, T.M.; Smith, R.L. Catalytic dehydration of fructose into 5-hydroxymethylfurfural
by ion-exchange resin in mixed-aqueous system by microwave heating. Green Chem. 2008, 10, 799–805.
[CrossRef]

Molecules 2019, 24, 4623
14 of 15
1
1
4. Lansalot-Matras, C.; Moreau, C. Dehydration of fructose into 5-hydroxymethylfurfural in the presence of
ionic liquids. Catal. Commun. 2003, 4, 517–520. [CrossRef]
5. Hu, S.; Zhang, Z.; Zhou, Y.; Han, B.; Fan, H.; Li, W.; Song, J.; Xie, Y. Conversion of fructose to
5
-hydroxymethylfurfural using ionic liquids prepared from renewable materials. Green Chem. 2008, 10,
280–1283. [CrossRef]
6. Zakrzewska, M.E.; Bogel-łukasik, E.; Bogel-łukasik, R. Ionic Liquid-Mediated Formation of
-Hydroxymethylfurfural s A Promising Biomass-Derived Building Block. Chem. Rev. 2011, 111, 397–417.
CrossRef] [PubMed]
1
1
5
[
1
1
1
7. Asghari, F.S.; Yoshida, H. Dehydration of fructose to 5-hydroxymethylfurfural in sub-critical water over
heterogeneous zirconium phosphate catalysts. Carbohydr. Res. 2006, 341, 2379–2387. [CrossRef] [PubMed]
8. Bicker, M.; Hirth, J.; Vogel, H. Dehydration of fructose to 5-hydroxymethylfurfural in sub-and supercritical
acetone. Green Chem. 2003, 5, 280–284. [CrossRef]
9. Carlini, C.; Patrono, P.; Galletti, A.M.R.; Sbrana, G.; Zima, V. Selective oxidation of 5-hydroxymethyl-2-
furaldehyde to furan-2,5-dicarboxaldehyde by catalytic systems based on vanadyl phosphate. Appl. Catal.
A Gen. 2005, 289, 197–204. [CrossRef]
2
0. Kang, E.S.; Hong, Y.W.; Chae, D.W.; Kim, B.; Kim, B.; Kim, Y.J.; Cho, J.K.; Kim, Y.G. From Lignocellulosic
Biomass to Furans via 5-Acetoxymethylfurfural as an Alternative to 5-Hydroxymethylfurfural. ChemSusChem
2
015, 8, 1179–1188. [CrossRef]
1. Sanborn, A.J. Archer Daniels Midland Company. Oxidation of Furfural Compounds. U.S. Patent 2,010,034,856,
8 November 2010.
2. Shaikh, A.; Janka, M.E.; Lange, D.M.; Morrow, M.C.; Bowers, B.R.; Parker, K.R.; Partin, L.R.; Jenkins, J.C.;
Moody, P.; Shanks, T.E.; et al. An Oxidation Process to Produce a Crude and/or Purified Carboxylic Acid
Product. U.S. Patent 13/228,797, 29 November 2012.
2
2
1
2
2
2
3. Frank, R.; Jostock, R.; Schick, H.; Theil, F.; Groeger, O.; Kudick, R.; Sonnenschein, H.; Henkel, B. Salts of
Substituted Allophanates and Their Use in Drugs. U.S. Patent 8,173,700, 8 May 2012.
4. D’antona, N.; El-Idrissi, M.; Ittobane, N.; Nicolosi, G. Enzymatic procedures in the preparation of
regioprotected D-fructose derivatives. Carbohydr. Res. 2005, 340, 319–323. [CrossRef]
5. Kim, J.; Kim, S.; Oh, K.; Ko, S.Y.; Kim, J.Y.; Lee, B.; Kim, B.T.; Lee, Y.S.; Min, Y.K.; Park, K. Furan Derivatives
For Preventing and Curing Osteoporosis and Pharmaceutical Compositions Containing the Same Technical
Field. U.S. Patent 12,125,841, 11 September 2018.
2
6. Stergiou, P.Y.; Foukis, A.; Filippou, M.; Koukouritaki, M.; Parapouli, M.; Theodorou, L.G.; Hatziloukas, E.;
Afendra, A.; Pandey, A.; Papamichael, E.M. Advances in lipase-catalyzed esterification reactions.
Biotechnol. Adv. 2013, 31, 1846–1859. [CrossRef] [PubMed]
2
7. Bornscheuer, U.T. Lipase-catalyzed syntheses of monoacylglycerols. Enzym. Microb. Technol. 1995, 17,
5
78–586. [CrossRef]
8. Neena, N.G.; Patil, N.S.; Sawant, S.B.; Joshi, J.B. Lipase Catalyzed Esterification. Catal. Rev. Sci. Eng. 2000
2, 439–480.
9. Reetz, M.T. Lipases as practical biocatalysts. Curr. Opin. Chem. Biol. 2002, 6, 145–150. [CrossRef]
0. Cao, L.; Bornscheuer, U.T.; Schmid, R.D. Lipase-Catalyzed Solid Phase Synthesis of Sugar Esters. Lipid/Fett
996, 98, 332–335. [CrossRef]
2
,
4
2
3
1
3
1. Yahya, A.R.M.; Anderson, W.A.; Moo-Young, M. Ester synthesis in lipase-catalyzed reactions.
Enzym. Microb. Technol. 1998, 23, 438–450. [CrossRef]
3
2. Jeong, J.; Antonyraj, C.A.; Shin, S.; Kim, S.; Kim, B.; Lee, K.-Y.; Cho, J.K. Commercially attractive process
for production of 5-hydroxymethyl-2-furfural from high fructose corn syrup. J. Ind. Eng. Chem. 2013, 19,
1
106–1111. [CrossRef]
3
3. Ren, L.K.; Zhu, L.F.; Qi, T.; Tang, J.Q.; Yang, H.Q.; Hu, C.W. Performance of Dimethyl Sulfoxide and
Brønsted Acid Catalysts in Fructose Conversion to 5-Hydroxymethylfurfural. ACS Catal. 2017, 7, 2199–2212.
[CrossRef]
3
3
4. Rong, C.; Ding, X.; Zhu, Y.; Li, Y.; Wang, L.; Qu, Y.; Ma, X.; Wang, Z. Production of furfural from xylose at
atmospheric pressure by dilute sulfuric acid and inorganic salts. Carbohydr. Res. 2012, 350, 77–80. [CrossRef]
5. Kuster, B.F.M. 5-Hydroxymethylfurfural (HMF). A Review Focussing on its Manufacture. Starch—Stärke
1
990, 42, 314–321. [CrossRef]

Molecules 2019, 24, 4623
15 of 15
3
6. Román-Leshkov, Y.; Chheda, J.N.; Dumesic, J.A. Phase modifiers promote efficient production of
hydroxymethylfurfural from fructose. Science 2006, 312, 1933–1937. [CrossRef] [PubMed]
3
7. Despax, S.; Maurer, C.; Estrine, B.; Le Bras, J.; Hoffmann, N.; Marinkovic, S.; Muzart, J. Fast and efficient
DMSO-mediated dehydration of carbohydrates into 5-hydroxymethylfurfural. Catal. Commun. 2014, 51, 5–9.
[CrossRef]
3
8. Amarasekara, A.S.; Williams, L.T.D.; Ebede, C.C. Mechanism of the dehydration of d-fructose to
◦
5
3
-hydroxymethylfurfural in dimethyl sulfoxide at 150 C: An NMR study. Carbohydr. Res. 2008, 343,
021–3024. [CrossRef] [PubMed]
3
4
9. Van Dam, H.E.; Kieboom, A.P.G.; van Bekkum, H. The Conversion of Fructose and Glucose in Acidic Media:
Formation of Hydroxymethylfurfural. Starch—Stärke 1986, 38, 95–101. [CrossRef]
0. Kunin, R.; Meitzner, E.F.; Oline, J.A.; Fisher, S.A.; Frisch, N. Characterization of amberlyst 15 macroreticular
sulfonic acid cation exchange resin. Ind. Eng. Chem. Prod. Res. Dev. 1962, 1, 140–144. [CrossRef]
Sample Availability: Samples of the compounds DAF and AMF are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
CC BY) license (http://creativecommons.org/licenses/by/4.0/).
(