The production of 5-hydroxymethylfurfural from fructose in isopropyl alcohol: A green and efficient system

Article abstract of DOI:10.1002/cssc.201100489

Solving problems: An isopropyl alcohol-mediated reaction system for the production of 5-hydroxymethylfurfural (HMF) from fructose reaches a yield of up to 87 %. The solvent can be easily recycled by evaporation, giving the HMF product. The system avoids the use of large amounts of organic solvent, has a minimal environmental impact, and offers a new route to large-scale economically viable processes.

Full text of DOI:10.1002/cssc.201100489

DOI: 10.1002/cssc.201100489
The Production of 5-Hydroxymethylfurfural from Fructose in Isopropyl
Alcohol: A Green and Efficient System
Linke Lai and Yugen Zhang*[a]
Fossil fuels are still the primary carbon feedstock for a wide va-
riety of commodity and specialty chemicals, as well as thermal
energy and transportation fuels. However, after one century of
heavy industrial consumption hydrocarbon reserves are dimin-
ishing and concerns regarding their future scarcity of are well-
new system avoids the use of large volumes of organic solvent
and has a minimal environmental impact. It enables a simple
production and isolation of HMF, and offers a new opportunity
for a large-scale economically viable process.
Our reasoning for using an alcohol as solvent for the trans-
formation of sugars into HMF was two-fold: Firstly, alcohols are
environmentally friendly, cost efficient, and easy-to-use reac-
tion media. Their capacity to dissolve sugars is also high. Sec-
ondly, alcohols may further react with HMF to form HMF
ethers, which could prevent decomposition or oligomerization
of HMF (Scheme 1). Thus, methanol was first tested as a
medium for the transformation of fructose to HMF, with HCl as
founded. Biomass-derived carbohydrates are
a promising
carbon-based alternative, both as energy source and as sus-
tainable feedstock for chemicals.[1,2] Recently much effort has
been devoted to the conversion of biomass into 5-hydroxyme-
thylfurfural (HMF), a versatile and key intermediate in the bio-
fuel and petrochemical industries.[3,4] However, the large-scale
application of biomass-sourced HMF is still limited due to
some critical challenges, such as costs, supply, and
the environmental impact of industrial activity. Low
efficiency in synthesis and high solubility in water
pose difficulties in HMF mass production processes,
especially for isolation and purification.[5] In most re-
ported methods for the transformation of biomass or
derivatives into HMF, the HMF is obtained in solution
and the yield is reported by using HPLC or GC. How-
ever, developing efficient separation methods is very
important in order to make the industrial-scale pro-
duction of HMF economically viable.
Scheme 1. Equilibria between HMF and its alcohol derivatives.
Reaction media used for the synthesis of HMF from biomass
include water,[6] polar organic solvents such as dimethyl sulfox-
ide (DMSO) or dimethylformamide (DMF),[7] ionic liquids,[8] or
mixtures.[9] HMF can be isolated by extraction with various or-
ganic solvents, such as methyl isobutyl ketone (MIBK),[9a,b] di-
chloromethane (DCM),[9c] ethyl acetate,[10] tetrahydrofuran
(THF),[10] diethyl ether,[11] and acetone.[6c] Due to the high polari-
ty of HMF, its isolation typically requires multiple runs of vigo-
rous extraction processes. In this context, aqueous–organic
and ionic liquid–organic biphasic solvent systems are great im-
provements;[9,10] however, they still suffer from inefficient ex-
traction. The use of large volumes of organic solvent is costly
and has negative impacts on the environment.[12] Other chal-
lenges faced by biphasic systems are complex plant designs
and the difficulty of recycling the reaction system (e.g., ionic
liquids and catalyst).
catalyst. Fructose (0.45 g) and HCl (12.5m aqueous solution,
10 mol%) were added into methanol (5 mL). The mixture was
stirred at 808C for 8 h. NMR analysis showed that products A–
D in Scheme 1 were formed in a ratio of 1:3:4:17 (Table 1,
entry 8). The formation of products B, C, and D was not sur-
prising because the reaction conditions are suitable for acetali-
zation and ether formation. However, the total yield of furfural
products was only 25%. With these results in hand, other alco-
hols were also tested. In ethanol (entry 8), only HMF (A) and
ether (B) were produced in yields of 24% and 14%, respective-
ly. When isopropyl alcohol and tert-butanol were used as sol-
vent, HMF was produced as sole furfural product in yields of
67% and 62%, respectively. The high selectivity towards HMF
in isopropyl alcohol and tert-butanol is likely due to their bulki-
ness. Mixed solvents of methanol and isopropyl alcohol im-
proved neither the selectivity nor the yield of the reaction
(Supporting Information, Table S1). These results suggest that
isopropyl alcohol could be a suitable solvent for the dehydra-
tion of fructose to HMF.
In an effort to develop an economically viable HMF synthesis
process, we disclose herein an isopropyl alcohol-mediated re-
action system for the production of HMF from fructose.[13] The
A time-dependent analysis indicated that the reaction in iso-
propyl alcohol generally proceeded fast in the first few hours
and then slowly ran to completion (Figure 1). The reaction con-
ditions were then further optimized. The reaction was found to
quickly reach a yield of more than 82% at 1208C (less than
1 h). The yield slowly decreased after 4 h, possibly due to the
HMF decomposition/oligomerization. At 1008C, it took 3 h to
reach a yield of 82%. A yield of 85% was achieved in 5–6 h
[a] L. Lai, Dr. Y. Zhang
Institute of Bioengineering and Nanotechnology
31 Biopolis Way, The Nanos
Singapore 138669 (Singapore)
Fax: (+65)6478-9020
E-mail: ygzhang@ibn.a-star.edu.sg
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201100489.
ChemSusChem 2011, 4, 1745 – 1748
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1745

ieved. This result is comparable
to the efficiency of other solvent
Table 1. The transformation of fructose to HMF in alcohols with HCl.[a]
Methanol
Yield[b]
[%]
Ethanol
Yield[b]
[%]
Isopropyl alcohol
tert-Butanol
systems.[4]
High-boiling-point
Entry
t
[h]
Ratio[c]
A/B/C/D
Ratio[c]
A/B/C/D
Yield[b]
[%]
Ratio[c]
A/B/C/D
Yield[b]
[%]
Ratio[c]
humin was the main by-product
of this process, and could be re-
moved by filtration of the reac-
tion mixture.
A/B/C/D
1
2
3
4
5
6
7
1
2
3
4
5
6
7
8
4
7
11
14
19
20
23
23
25
50
0.7:0.2:4:2
1:1:4:5
1:1:4:8
1:2:5:11
1:2:5:12
2:3:4:14
1:3:4:15
1:3:4:17
8:10:11:21
14
22
28
29
33
35
37
38
57
12:2:0:0
17:5:0:0
21:7:0:0
21:8:0:0
23:10:0:0
23:12:0:0
24:13:0:0
24:14:0:0
15:42:0:0
30
39
44
50
56
59
63
67
61
30:0:0:0
39:0:0:0
44:0:0:0
50:0:0:0
56:0:0:0
59:0:0:0
63:0:0:0
67:0:0:0
21:40:0:0
43
53
55
60
60
61
62
61
59
43:0:0:0
53:0:0:0
55:0:0:0
60:0:0:0
60:0:0:0
61:0:0:0
62:0:0:0
61:0:0:0
29:30:0:0
Recycling experiments for this
homogeneous system were car-
ried out with 4.5 g of fructose.
To a 150 mL flask equipped with
stirrer bars were added fructose,
isopropyl alcohol (50 mL), and
hydrochloric acid (5 mol%). The
reaction flask was heated on an
oil bath to 1208C with stirring
8
9[d]
[a] Reaction conditions: fructose (0.45 g), ROH (5 mL), HCl (10 mol%), T=808C. [b] Total furfural yields (isolated).
[c] The structures of A, B, C, and D are shown in Scheme 1. The ratios were determined by NMR with internal
standard. [d] With Amberlyst 15 as catalyst (20 mol%), T=1008C.
Figure 2. Effects of different alcohol solvents on HMF production from fruc-
tose. Reaction conditions: fructose (0.45 g), HCl (5 mol%), ROH (5 mL),
T=1208C, t=2 h.
Figure 1. Influence of temperature on HMF yield at different reaction times.
~
&
*
: 808C; : 1008C; : 1208C. Reaction conditions: fructose (0.45 g), HCl
(5 mol%), isopropyl alcohol (5 mL).
for 4 h. Raw HMF product was obtained simply by filtration
and evaporation. Evaporated isopropyl alcohol and HCl catalyst
were collected and used for the next batch reaction. The water
content of the reaction system could also be adjusted by azeo-
tropic evaporation of the solvent. As shown in Figure 4, using
recycled solvent directly for the reaction caused the HMF yield
to decrease slightly in subsequent runs. This is due to the par-
tial loss of HCl catalyst during the evaporation process. After
correcting the amount of HCl catalyst in the recycled solvent,
the HMF yield was successfully maintained at a high level. This
simple product isolation and solvent recycling process makes
the reaction system particularly suitable for large-scale opera-
tion (see Supporting Information).
(Figure 1). When lowering the HCl catalyst loadings to 5 mol%
and 2.5 mol%, the reactions took 2 h and 5 h, respectively, to
reach maximum HMF yields (81% and 82%) at 1208C (Table 2).
With these optimized reaction conditions, other alcohols were
tested again as solvents for fructose dehydration. Under the
same conditions (T=1208C, t=2 h), methanol, ethanol, 1-
propanol, and 1-butanol gave yields of a mixture of products
A (HMF) and B (ether) of 40%, 64%, 69% and 65%, respective-
ly, while isopropyl alcohol and tert-butanol gave yields of HMF
(A) of 83% and 70%, respectively (Figure 2). A larger-scale re-
action (with 13.5 g fructose) was carried out under the same
conditions in isopropyl alcohol and 7.6 g of HMF (80.4%, puri-
fied by flash column chromatography, EtOAc/hexane=1:1) was
obtained.
Other Brønsted-acidic catalysts were also screened, and HCl
proved the best catalyst for fructose dehydration in isopropyl
alcohol. Under standard conditions (T=1208C, 10% catalyst
loading, t=2 h), H2SO4 gave 68% yield (57% A and 17% B),
while other acids, such as HNO3, H3PO4, HCOOH, CH3COOH,
and B(OH)3, gave trace or zero yields of HMF. Accounting for
the different catalyst recycling pathways for a large-scale pro-
cess, a solid acid catalyst (Amberlyst 15) was also evaluated.
The reaction was tested in methanol, ethanol, isopropyl alco-
hol, and tert-butanol (Table 1, entry 9). Reaction in methanol
gave a 50% yield of a mixture of A, B, C, and D. Reactions in
In the dehydration process, three water molecules are gen-
erated during the reaction. The effect of traces of water in the
reaction system was further investigated. Notably, the reaction
system did not require strict water-free conditions. With traces
of water (6 vol%) present in the system, the yield of HMF in-
creased to 87%, but more than 10 vol% of water resulted in a
low HMF yield (Figure 3). Under optimized reaction conditions,
an HMF yield of up to 87% and a conversion of 99% were ach-
1746
www.chemsuschem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1745 – 1748

Table 2. Transformation of fructose to HMF in isopropyl alcohol with Am-
berlyst 15.[a]
Entry
t
[h]
Yield[b]
[%]
Ratio[c]
A/B/C/D
1
2
3[d]
4[d]
5[e]
6[e]
1
4
1
4
1
4
40
60
46
62
50
57
31:9:0:0
24:28:5:3
35:11:0:0
39:22:1:0
27:7:12:5
45:12:0:0
[a] Reaction conditions: fructose (0.45 g), Amberlyst 15 (20 mol%), isopro-
pyl alcohol (5 mL), T=1208C. [b] Total furfural yield. [c] Structures of
product A, B, C, D as shown in Scheme 1, composition was determined
by NMR. [d] First run recycled catalyst; [e] Second run recycled catalyst.
Figure 3. Effects of water content on HMF yield. Reaction conditions: fruc-
tose (0.45 g), HCl (5 mol%), isopropyl alcohol (5 mL), T=1208C, t=2 h.
sequent run: for the third run, a 57% furfural yield was ach-
ieved in 4 h with an A/B/C/D product ratio 45:12:0:0.
In conclusion, an isopropyl alcohol-mediated reaction
system for the production of HMF from fructose is reported.
Using isopropyl alcohol as solvent and HCl as catalyst, an HMF
yield of up to 87% from fructose is achieved. The solvent and
catalyst can be easily recycled by evaporation, giving the HMF
product. The new system avoids the use of large amounts of
organic solvent and has a minimal impact on the environment.
It allows for efficient and convenient HMF production and iso-
lation, and provides a new opportunity for a large-scale eco-
nomically viable process. A recyclable solid acid catalyst (Am-
berlyst 15) was also used, but a lower yield and lower selectivi-
ty to HMF were found.
Experimental Section
^
Figure 4. Recycling experiments. : Evaporated solvent was directly used for
HCl-catalyzed conversion of fructose to HMF and HMF derivatives
in alcohols: To a 15 mL sealed tube equipped with stirrer bars, fruc-
tose (0.45 g, 2.5 mmol), alcohol (5 mL), and hydrochloric acid
(12.5m aqueous solution, 0.01 mL) were added. The sealed tube
was heated on an oil bath to 1008C with stirring. The reaction was
stopped at the desired reaction time. For product isolation, the re-
action mixture was cooled in an ice/water bath and addition of
sodium hydroxide (6.25m, 0.04 mL) to neutralize the catalyst. Sol-
vents in the reaction mixtures were removed under vacuum. 1 mL
of distilled water was then added to the residue and the product
was extracted with 10 mL of ethyl acetate. The organic layer was
collected and evaporated to obtain the crude product to which
mesitylene (0.1 g, 0.83 mmol) was added as internal standard. The
composition of the samples was then analyzed by NMR.
HCl-catalyzed conversion of fructose to HMF in isopropyl alcohol
(recycle and larger scale): To a 150 mL flask equipped with stirrer
bars, fructose (4.5 g, 25 mmol), isopropyl alcohol (50 mL), and hy-
drochloric acid (12.5m aqueous solution, 0.1 mL) were added. The
reaction flask was heated on an oil bath to 1208C with stirring. For
larger-scale experiments, fructose (13.5 g, 75 mmol), isopropyl alco-
hol (150 mL) and hydrochloric acid (12.5m aqueous solution,
0.3 mL) were added in a 500 mL flask. The reaction was stopped
after 4 h. The reaction mixture was filtrated to remove insoluble
humin by-product. Solvent in the reaction mixture was then dis-
tilled to give the crude HMF product. The recycled solvent was
either directly used or used with additional 2 mol% HCl for next
~
the next reaction run; : an additional 2 mol% of HCl was added to the re-
cycled solvent for subsequent run. Reaction conditions: fructose (4.5 g), HCl
(5 mol%), isopropyl alcohol (50 mL), T=1208C, t=4 h.
ethanol, isopropyl alcohol, and tert-butanol gave a yield of ca.
60% of a mixture of A and B. The reactions in bulky alcohols
had a better selectivity to HMF. These results indicate that
using Amberlyst 15 as catalyst (in different alcohols) leads to
the formation of more ether or acetalization products (B, C,
D),[13] compared to HCl catalyst systems. This may be due to
the stronger acidity of Amberlyst 15. For comparison, the reac-
tion conditions with Amberlyst 15 as catalyst in isopropyl alco-
hol were further optimized (see Table 2 and the Supporting In-
formation, which also includes the results of catalyst recycling
tests). For the first run, at 1208C, the total furfural yield
reached 40% in 1 h and increased to a maximum of 60% in
4 h. The ratio of products A/B/C/D was 24:28:5:3. The second
run with recycled catalyst gave slightly better results: 62% of
furfural yield was achieved in 4 h with an A/B/C/D product
ratio of 39:22:1:0. More HMF was produced in the second run,
with recycled catalyst. This change indicated that the acidity of
recycled catalyst had decreased, which was reflected in a sub-
ChemSusChem 2011, 4, 1745 – 1748
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
1747

2009, 52, 297; c) X. H. Qi, M. Watanabe, T. M. Aida, R. L. Smith, Green
Chem. 2008, 10, 799; d) C. Carlini, P. Patrono, A. M. R. Galletti, G. Sbrana,
Appl. Catal. A: Gen. 2004, 275, 111.
run. The crude HMF product was purified by flash column chroma-
tography, EtOAc/hexane=1:1.
[7] a) H. P. Yan, Y. Yang, D. M. Tong, X. Xiang, C. W. Hu, Catal. Commun.
2009, 10, 1558; b) A. Takagaki, M. Ohara, S. Nishimura, K. Ebitani, Chem.
Commun. 2009, 6276; c) G. A. Halliday, R. J. Young, V. V. Grushin, Org.
Lett. 2003, 5, 2003; d) K. Shimizu, R. Uozumi, A. Satsuma, Catal.
Commun. 2009, 10, 1849.
[8] a) M. E. Zakrzewska, E. Bogel-Lukasik, R. Bogel-Lukasik, Chem. Rev. 2011,
111, 397; b) T. Stꢁhlberg, W. Fu, J. M. Woodley, A. Riisager, ChemSusChem
2011, 4, 451; c) Y. G. Zhang, J. Y. G. Chan, Energy Environ. Sci. 2010, 3,
408; d) C. Moreau, A. Finiels, L. Vanoye, J. Mol. Catal. A: Chem. 2006,
253, 165; e) H. B. Zhao, J. E. Holladay, H. Brown, Z. C. Zhang, Science
2007, 316, 1597.
[9] a) S. Lima, P. Neves, M. M. Antunes, M. Pillinger, N. Ignatyev, A. A. Val-
ente, Appl. Catal. A: Gen. 2009, 363, 93; b) Y. Romꢂn-Leshkov, C. J. Bar-
rett, Z. Y. Liu, J. A. Dumesic, Nature 2007, 447, 982; c) J. N. Chheda, Y.
Roman-Leshkov, J. A. Dumesic, Green Chem. 2007, 9, 342; d) M. Chidam-
baram, A. Bell, Green Chem. 2010, 12, 1253; e) C. Lansalot-Matras, C.
Moreau, Catal. Commun. 2003, 4, 517; f) Q. X. Bao, K. Qiao, D. Tomida, C.
Yokoyama, Catal. Commun. 2008, 9, 1383; g) J. B. Binder, R. T. Raines, J.
Am. Chem. Soc. 2009, 131, 1979; h) A. I. Torres, P. Daoutidis, M. Tsapatsis,
Energy Environ. Sci. 2010, 3, 1560.
[10] a) S. Q. Hu, Z. F. Zhang, J. L. Song, Y. X. Zhou, B. X. Han, Green Chem.
2009, 11, 1746; b) J. Y. G. Chan, Y. G. Zhang, ChemSusChem 2009, 2, 731.
[11] a) G. Yong, Y. G. Zhang, J. Y. Ying, Angew. Chem. 2008, 120, 9485; Angew.
Chem. Int. Ed. 2008, 47, 9345; b) L. Lai, Y. G. Zhang, ChemSusChem 2010,
3, 1257; c) M. X. Tan, L. Zhao, Y. G. Zhang, Biomass Bioenergy 2011, 35,
1367.
Acknowledgements
This work was funded by the Institute of Bioengineering and
Nanotechnology (Biomedical Research Council), Agency for Sci-
ence, Technology and Research, Singapore).
Keywords: alcohols · biofuels · carbohydrates · catalysis ·
renewable resources
[1] a) A. Corma, S. Iborra, A. Velty, Chem. Rev. 2007, 107, 2411; b) P. Gallezot,
Green Chem. 2007, 9, 295; c) C. H. Christensen, J. Rass-Hansen, C. C.
Marsden, E. Taarning, K. Egeblad, ChemSusChem 2008, 1, 283.
[2] a) B. Kamm, Angew. Chem. 2007, 119, 5146; Angew. Chem. Int. Ed. 2007,
46, 5056; b) F. W. Lichtenthaler, in Biorefineries—Industrial Processes and
Products (Eds.: B. Kamm, P. R. Gruber, M. Kamm), Wiley-VCH, Weinheim
2006.
[3] G. W. Huber, J. N. Chheda, C. J. Barrett, J. A. Dumesic, Science 2005, 308,
1446.
[4] Selected reviews on HMF production and chemistry: a) B. F. M. Kuster,
Starch/Staerke 1990, 42, 314; b) L. Cottier, G. Descotes, Trends Heterocycl.
Chem. 1991, 2, 233; c) J. Lewkowski, ARKIVOC 2001, 2, 17; d) C. Moreau,
M. N. Belgacem, A. Gandini, Top. Catal. 2004, 27, 11; e) A. Boisen, T. B.
Christensen, W. Fu, Y. Y. Gorbanev, T. S. Hansen, J. S. Jensen, S. K. Klit-
gaard, S. Pedersen, A. Riisager, T. Stꢁhlberg, J. M. Woodley, Chem. Eng.
Res. Des. 2009, 87, 1318; f) J. C. Serrano-Ruiz, R. M. West, J. A. Dumesic,
Annu. Rev. Chem. Biomol. Eng. 2010, 1, 79; g) M. J. Climent, A. Corma, S.
Iborra, Green Chem. 2011, 13, 520; h) A. A. Rosatella, S. P. Simeonov,
R. F. M. Frade, C. A. M. Afonso, Green Chem. 2011, 13, 754; i) X. L. Tong, Y.
Ma, Y. D. Li, Appl. Catal. A: Gen. 2010, 385, 1.
[12] a) C. Moreau, R. Durand, S. Razigade, J. Duhamet, P. Faugeras, P. Rivalier,
P. Ros, G. Avignon, Appl. Catal. A: Gen. 1996, 145, 211; b) Y. Romꢂn-Lesh-
kov, J. A. Dumesic, Top. Catal. 2009, 52, 297.
[13] G. J. M. Gruter, F. Dautzenberg, Method for the Synthesis of 5-Alkoxyme-
thylfurfural Ethers and Their Use, European Patent 06075564.2, 2006.
[5] A. Cukalovic, C. V. Stevens, Green Chem. 2010, 12, 1201.
[6] a) F. Ilgen, D. Ott, D. Kralisch, C. Reil, A. Palmberger, B. Konig, Green
Chem. 2009, 11, 1948; b) Y. Romꢂn-Leshkov, J. A. Dumesic, Top. Catal.
Received: August 25, 2011
Published online on October 21, 2011
1748
www.chemsuschem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1745 – 1748