Efficient one-pot synthesis of 5-chloromethylfurfural (CMF) from carbohydrates in mild biphasic systems

Article abstract of DOI:10.3390/molecules18077675

5-Halomethylfurfurals can be considered as platform chemicals of high reactivity making them useful for the preparation of a variety of important compounds. In this study, a one-pot route for the conversion of carbohydrates into 5-chloromethylfurfural (CMF) in a simple and efficient (HCl-H ₃PO₄/CHCl₃) biphasic system has been investigated. Monosaccharides such as D-fructose, D-glucose and sorbose, disaccharides such as sucrose and cellobiose and polysaccharides such as cellulose were successfully converted into CMF in satisfactory yields under mild conditions. Our data shows that when using D-fructose the optimum yield of CMF was about 47%. This understanding allowed us to extent our work to biomaterials, such as wood powder and wood pulps with yields of CMF obtained being comparable to those seen with some of the enumerated mono and disaccharides. Overall, the proposed (HCl-H₃PO₄/CHCl₃) optimized biphasic system provides a simple, mild, and cost-effective means to prepare CMF from renewable resources.

Full text of DOI:10.3390/molecules18077675

Molecules 2013, 18, 7675-7685; doi:10.3390/molecules18077675
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Communication
Efficient One-Pot Synthesis of 5-Chloromethylfurfural (CMF)
from Carbohydrates in Mild Biphasic Systems
Wenhua Gao 1,2, Yiqun Li 3, Zhouyang Xiang 1, Kefu Chen 2, Rendang Yang 2 and
Dimitris S. Argyropoulos 1,4,
*
1
Departments of Chemistry and Forest Biomaterials, North Carolina State University, Raleigh,
NC 27695-8005, USA
2
State Key Laboratory Pulp and Paper Engineering, South China University of Technology,
Guangzhou 510460, China
3
4
Department of Chemistry, Jinan University, Guangzhou 510632, China
Center of Excellence for Advanced Materials Research (CEAMR), King Abdulaziz University,
P.O. Box 80203, Jeddah 21589, Saudi Arabia
* Author to whom correspondence should be addressed; E-Mail: dsargyro@ncsu.edu;
Tel.: +1-919-515-7708.
Received: 22 May 2013; in revised form: 24 June 2013 / Accepted: 25 June 2013 /
Published: 2 July 2013
Abstract: 5-Halomethylfurfurals can be considered as platform chemicals of high
reactivity making them useful for the preparation of a variety of important compounds. In
this study, a one-pot route for the conversion of carbohydrates into 5-chloromethylfurfural
(CMF) in a simple and efficient (HCl-H3PO4/CHCl3) biphasic system has been
investigated. Monosaccharides such as D-fructose, D-glucose and sorbose, disaccharides
such as sucrose and cellobiose and polysaccharides such as cellulose were successfully
converted into CMF in satisfactory yields under mild conditions. Our data shows that when
using D-fructose the optimum yield of CMF was about 47%. This understanding allowed
us to extent our work to biomaterials, such as wood powder and wood pulps with yields of
CMF obtained being comparable to those seen with some of the enumerated mono and
disaccharides. Overall, the proposed (HCl-H3PO4/CHCl3) optimized biphasic system
provides a simple, mild, and cost-effective means to prepare CMF from renewable resources.
Keywords: 5-chloromethylfurfural; carbohydrates; biphasic system

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1. Introduction
Locating new and versatile platform chemicals and biofuels from sustainable resources to replace
those derived from petrochemicals is a central ongoing and urgent task prompted by depleting fossil
fuel reserves and growing global warming concerns [1–4]. Alternative fine chemicals and biofuels that
have been suggested to address some of these issues are butanol [5], ethanol [5], dimethylfuran [1],
5-ethoxymethylfurfural [2], γ-valerolactone, and alkanes produced from biomass [6,7]. Many of these
alternatives rely on the efficient conversion of biomass carbohydrates into furfural derivatives. This is
because biomass carbohydrates constitute 75% of the World’s renewable biomass and cellulose [4] and
as such, they represent a promising alternative energy and sustainable chemical feedstock. In this
regard, 5-halomethyfurfurals such as 5-chloromethylfurfural (CMF) and 5-bromomethylfurfural
(BMF) has received significant attention as platform chemicals for synthesizing a broad range of
chemicals and liquid transportation fuels [8,9].
CMF and BMF are extremely reactive [9] so that when subjected to further chemistries the provide
a variety of important compounds for fine chemicals, pharmaceuticals, furan-based polymers and
biofuels. These compounds include hydroxymethylfurfural (HMF) [9,10], 2,5-dimethylfuran (DMF) [1],
and 5-ethoxymethylfurfural (EMF) [2], and some biologically active compounds [11]. Among them, DMF
and EMF stand out since they possess excellent properties, including high energy density, high boiling
point and water stability. For these reasons, they have been promoted as novel biofuels. In particular,
EMF has been the subject of considerable attention since it possesses an energy density of 8.7 kWhL−1,
substantially higher than that of ethanol (6.1 kWhL−1), and comparable to that of standard gasoline
(8.8 kWhL−1) and diesel fuel (9.7 kWhL−1) [12]. Although, CMF and BMF themselves are not
biofuels, they could readily be converted into EMF biofuels in ethanol in nearly quantitative yields.
The conventional synthesis of CMF involves the treatment of HMF or cellulose with dry hydrogen
halide. More specifically, the hydroxyl group in HMF undergoes a facile halogen substitution reaction.
Examples in the literature include those of Sanda et al. who obtained CMF from the reaction of
ethereal gaseous hydrogen chloride with HMF [13]. Furthermore, while the conversion of cellulose
into CMF was low (12%) [14,15], a substantially higher yield (48%) was obtained for the preparation
of BMF when dry HBr was employed [16]. Considering the importance of these compounds, Mascal
et al. recently reported the synthesis of CMF from cellulose treated by HCl-LiCl and successive
continuous extraction [2]. Unfortunately, 5-(chloromethyl)furfural, 2-(2-hydroxyacetyl)furan,
5-(hydroxylmethyl), furfural and levulinic acid were also produced with this system. More recently,
Kumari et al. reported the preparation of BMF from cellulose by a modified procedure using HBr-LiBr
involving continuous extraction [17]. Despite the numerous efforts aimed at these transformations,
each of them suffers from at least one of the following limitations: diverse by-products in significant
yields that reduce the selectivity of the reaction and its economics, low conversions and yields, harsh
reaction conditions (dry hydrogen halide, relative high temperature), requirements for large amounts of
costly reagents (LiCl, LiBr), prolonged reaction times and tedious operations with complex set ups
(continuous extraction) [18]. These drawbacks seriously hamper their potential industrial applications.
Consequently, as part of our program aimed at developing new biofuels and fine chemicals based on
biomass, we embarked our research for the development of efficient and economical methods aimed at
converting carbohydrates to CMF under mild reaction conditions.

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In this communication we demonstrate the use of the biphasic mixture HCl-H3PO4/CHCl3 for the
one-pot conversion of carbohydrates into CMF. The rational for the use of this biphasic approach is
based on the thinking that as CMF is generated from HMF it is immediately transported and extracted
from the aqueous acidic phase into the organic phase significantly minimizing by-product yields [9].
2. Results and Discussion
Initial efforts using the biphasic treatment (HCl(37%)-H3PO4(85%)/CHCl3) of the monosaccharide
D-fructose at 45 °C for 20 h, offered a CMF yield of 35.8%. we then attempted to further optimize this
result by systematically varying the volume ratio of HCl and H3PO4 (Table 1), the nature of the
non-aqueous solvent, the reaction time and temperature. This is due to the fact that Table 1 deals
only with the volume ratio of HCl and H3PO4. The effects of changing other variables are reported in
Tables elsewhere.
Table 1. The effect various reaction variables on CMF yields from D-fructose a.
Entry
HCl/H3PO4 (v/v)
Temperature (°C)
Time (h)
Yields (mol%) b
1
2
3
4
1/0
2/1
3/1
4/1
5/1
45
45
45
45
45
20
20
20
20
20
28.4
36.9
42.1
46.8
45.5
5
a
D-fructose (5.0 mmol) was added in a mixture with specific volume ratio of 37% HCl and 85% H3PO4
(5.0 mL), and CHCl3 (5.0 mL). The system was stirred continuously at 45 °C for 20 h. b Isolated yields based
on D-fructose.
The data of Table 1 indicates that the amount of hydrochloric acid in the biphasic medium plays an
important role in this transformation. Increasing the amount of HCl in the system seemed to
concomitantly increase the yield of CMF (Table 1, entries 1–5). Even at lower volume ratios of
HCl/H3PO4 such as 2:1, the yield of CMF was seen to increase by 8.5%, compared with the reaction
with just hydrochloric acid (Table 1, entries 1,2). H3PO4 offered enough hydrogen ions to promote the
fructose selective conversion to CMF. The D-fructose molecule needs catalytic hydrogen ions to form
fructofuranosyl intermediates, and the acid-induced elimination of three moles of water from this
intermediate leads to the conversion to 5-hydroxymethyl-2-furaldehyde (HMF) [19,20]. As
hydrochloric acid existed in the system, HMF could easily be transformed to 5-chloromethylfurfural
(CMF). Increasing the mixed acid ratio (HCl/H3PO4) to 3:1 offered a CMF yield of 42.1% (Table 1,
entry 3). Further increases in the mixed acid ratio (HCl/H3PO4) offered only marginal yield increases
in the CMF yield (Table 1, entries 4,5). Therefore, in the dehydration reaction to produce CMF from
fructose, HCl performed as a good mineral acid catalyst and provided the essential chloride for the
production of CMF. Román-Leshkov et al. also observed various acid catalysts used to implement the
dehydration reaction, while HCl showed the highest catalytic ability amongst common mineral acids [21].
The effect of reaction temperature was examined in detail by conducting CMF yield studies at 35,
45, and 55 °C at different ratios of HCl/ H3PO4 (Table 2).

Molecules 2013, 18
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a
Table 2. Effect of reaction temperature on the yields of CMF at different ratios of HCl/H3PO4 .
Entry
HCl/H3PO4 (v/v)
Temperature (°C)
Time (h)
20
CMF Yield (mol %) b
1
2
3
4
5
6
7
8
3/1
3/1
3/1
4/1
4/1
4/1
5/1
5/1
5/1
35
45
55 c
35
45
55
35
45
55
38.5
42.1
38.8
43.9
46.8
42.8
43.2
45.5
40.2
20
20
20
20
20
20
20
9
a
20
D-fructose (5.0 mmol) was added in a mixture with specific volume ratio of HCl(37%) and H3PO4(85%)
(5.0 mL), and CHCl3 (5.0 mL). The system stirred continuously at the special temperature for 20h. b Isolated
yields based on D-fructose. c Slightly below the CHCl3-water azeotrope boiling point (56.1 °C).
Upon increasing the temperature from 35 to 45 °C, the yields of CMF were seen to increase, when
the mixed acid ratio of HCl/H3PO4 was varied from 3:1, 4:1 and 5:1 (Table 2, entries 1–9). At the
temperature of 55 °C, however, all the CMF yields decreased somewhat compared to 45 °C (Table 2,
entries 1–9). This could be rationalized on the basis of different energies of activation for the different
side-reactions being more pronounced at the slightly higher temperatures.
In the presence of acid catalysts, fructose could dehydrate to produce CMF and various by-products.
Increasing temperatures improved the yields of by-products. The cyclic fructofuransyl intermediate
pathway degraded by means of secondary reactions, such as fragmentation, condensation or
other dehydration reactions. In this respect our data was consistent with similar research by
Moreau et al. [22] and Antal et al. [23] that dealt with the D-fructose dehydration mechanism and the
formation of HMF. Overall, at lower reaction temperatures, the mixed acids did not offer their catalytic
role, and the yield of CMF was not high.
CMF yields obtained from the acid ratio (HCl/H3PO4) of 4:1 at different temperatures were seen to
be higher than when the acid ratio was 3:1 or 5:1 (Table 2, entries 1–9). As such the acid volume ratio
and the reaction temperature were established to be 4:1 and 45 °C, respectively, for this transformation.
The immiscible organic solvent plays an important role in extracting the products formed during the
acidic aqueous phase reaction, thud significantly reducing side reactions. The nature of the extraction
solvent was thus further explored and it was verified that indeed chloroform (Table 3, entry 1) was the
extraction solvent of choice amongst all screened solvents. For example, 1, 2-dichlororethane (Table 3,
entry 2) and 1-chlorobutane (Table 3, entry 3) were not able to extract all the CMF from the acidic
aqueous phase, while toluene promoted a multitude of side reactions manifesting themselves in the
complexity of the isolated product mixture. Unlike toluene, chloroform showed an excellent selectivity
for extracting CMF from the acidic aqueous phase, simultaneously promoting reaction uniformity and
reducing by-product diversity. Overall, this makes the work-up with chloroform and purification steps
convenient with potential practical applications.

Molecules 2013, 18
7679
Table 3. Effect of extraction solvent on reaction yields a.
Entry
Extraction Solvent
Temperature (°C)
Time (h)
CMF Yield (mol%) b
1
2
3
Chloroform
1,2-Dichloroethane
1-Chlorobutane
Toluene
45
45
45
45
20
20
20
20
46.8
28.8
22.6
--- c
4
a
D-fructose (5.0 mmol) was added in a mixture with 4/1 (v/v) of 37% HCl (4.0 mL) and 85% H3PO4
(1.0 mL), and organic solvent (5.0 mL ) and stirred continuously at 45 °C for 20 h. b Isolated yields based on
D-fructose. c Complex mixture of compounds was formed as indicated by GC-MS.
Finally the effect of reaction time was investigated using the optimized reaction conditions
determined so far. A 10 h reaction time offered a CMF yield of only 34.6% (Table 4, entry 1).
Extending the reaction time to 20 h, dramatically increased the CMF yield by 12.2% (Table 4,
entries 1,2). Further extension of the reaction time did not offer additional CMF yield improvements
(Table 4, entries 3,4).
Table 4. Effect of reaction time on reaction yields a.
Entry HCl/H3PO4 (v/v)
Extractant
CHCl3
Temperature (°C) Time (h) CMF Yield (mol%) b
1
2
3
4
4:1
4:1
4:1
4:1
45
45
45
45
10
20
30
40
34.6
46.8
44.9
45.2
CHCl3
CHCl3
CHCl3
a D-fructose (5.0 mmol) was added in a mixture with 4/1 (v/v) of 37% HCl (4.0mL) and 85% H3PO4 (1.0 mL),
and CHCl3 (5.0 mL ) and stirred continuously at 45 °C for special time. b Isolated yields based on D-fructose.
From the above analysis, a possible route of the fructose dehydration to form CMF as illustrated in
Scheme 1 can be suggested.
Scheme 1. Possible route depicting the fructose dehydration to form CMF. Structures (a),
(b) and (c) are fructofuransyl intermediates referred to in the text.
CH2OH
CH2OH
OH
CH2OH
CH2OH
CH2OH
OH
OH
H+
- H2O
O
O
O
OH
+
+OH2
OH
OH
OH
OH
(a)
H
CH2OH
CH2OH
CH2OH
Cl-
OH
+
OH
OH
O
O
OH
O
OH
OH
+
Cl
OH
OH
OH
(b)
(c)
-HCl
CH2OH
OH
HCl
O
OH
Cl
OH
OHC
O
OHC
O
OH
In an effort to further understand and chart the selectivity and general applicability of the proposed
methodology a series of mono-saccharine, two disaccharides and a poly-saccharide were examined.

Molecules 2013, 18
7680
The data of Table 5 showed that fructose offered the highest yields of CMF (Table 5, entry 1),
while glucose and cellulose the lowest (Table 5, entries 2–6). Interestingly -fructose and -glucose,
while they are chemically very similar (Scheme 2), they produced significantly different yields of
CMF (Table 5, entries 1,2). This is most likely because with the ketohexose ( -fructose) was easier to
form the fructofuransyl intermediate than with the aldohexose ( -glucose), due to the higher reactivity
of ketohexoses. It is likely that -glucose could not dehydrate directly and transform into
D
D
D
D
D
fructofuransyl intermediates under our conditions. The glucose to fructose isomerization reaction
seems to be a pre-requisite for the formed fructose to dehydrate and yield CMF under the mixed acid
catalytic system we propose. Our contention is supported by Rosatella et al. who proposed two
methods to form the fructofuransyl intermediates, and the main one was the glucose to fructose
isomerization reaction [24]. Furthermore, Zhao et al. [25] and Huang et al. [26] observed that in order
to obtain high HMF yields from glucose the selective in situ isomerization of fructose was essential.
Table 5. Effect of different carbohydrate substrate on CMF yields a.
Entry
Carbohydrate
Fructose
CMF Yield (mol %) b
1
2
3
4
5
6
46.8
7.3
Glucose
Sorbose
16.4
43.1
19.3
7.8
Sucrose
Cellobiose
Cellulose
a all reactions were performed in HCl-H3PO4/CHCl3 biphasic system at 45 °C for 20 h. b isolated yield based
on carbohydrate.
Scheme 2. Structures of carbohydrates used and discussed in this work.
The monosaccharide sorbose offered a better CMF yield than
D
-glucose (Table 5, entry 3), since it
-fructose (Scheme 2), it had
is a ketohexose. Although sorbose is one of the epimers (C-2 and C-3) of
D

Molecules 2013, 18
7681
similar reactivity to D-glucose. Our data is further supported by that of Khajavi et al. who has also
documented that sorbose and glucose showed almost the same ability to produce HMF, but much
lower than fructose [27].
The disaccharide sucrose (Scheme 2) comprised of linked fructose and glucose units afforded CMF
yields similar to fructose (Table 5, entry 4, 43.1 mol%). In the mixed acid aqueous medium, the sucrose
molecule was quickly hydrolyzed into fructose and glucose. Almost all of the fructose could be selectively
converted into CMF in the biphasic system, due to the higher CMF yield from sucrose. Literature data also
reports that 90% fructose solutions (obtained from sucrose hydrolysis) can be converted into fructofuransyl
intermediates, while the glucose residue remains nearly unchanged [28]. Therefore, the overall
activating nature of the carbonyl group in the C-2 position of the sugar seems to be apparent. Its
absence (glucose and cellulose) dramatically reduces the reaction yields toward the production of CMF.
Cellobiose consists of two glucose molecules joined by equatorial C1-C4 glycosidic bonds (Scheme 2).
In an aqueous mixed acid solution, cellobiose was easily hydrolyzed to glucose molecules and as such
it showed a somewhat higher CMF yield of 19.3% (Table 5, entry 5), while the polysaccharide
cellulose only showed similar yields as glucose (Table 5, entry 6). The possible explanation for this
observation was that cellulose is a high molecular weight linear polysaccharide, and its degradation
involves the breaking of bonds between glucose units within the chain. As such the mixed acidic
aqueous system might produce many random chain scissions, leading to many secondary reactions.
Similar data have also been addressed in the literature by Emsley et al. [29] and Scheiding et al. [30].
Finally we examined various pulps and a wood powder for their potential to prepare CMF with the
proposed methodology. Hardwood kraft pulp with the highest total sugar content (Table 6), containing
mostly cellulose and hemicellulose, (which can hydrolyze into glucose and xylose) offered a yield of
CMF of 21.3 mol% (based on the glucose of the pulp). This was a much higher than either glucose or
cellulose could offer by themselves (Table 7, entry 1; Table 5, entries 2,6). The softwood (Norway
spruce) thermomechanical pulp offered CMF yields of 22.8% while the hardwood powdered wood
gave a CMF yield of 31.4% (both figures based on total sugar contents of these samples) (Table 7).
These yields may be explained on the basis that mannose and other hexoses present in wood may also
convert to fructofuransyl intermediates besides glucose. This data is supported by earlier efforts, where
it was shown that mannose and glucose was of similar reactivity transforming to fructofuransyl
intermediates producing hydroxymethylfurfural (HMF) [27]. Overall, our data with the complete
lignocellulosic substrate is encouraging since all wood components were present during the reaction
(cellulose, lignin and hemicelluloses). Under these circumstances, we believe that the obtained yields
of CMF were encouraging. Efforts in our laboratory are continuing to further promote these yields in
the presence of selective catalysts in the system [31].
Table 6. Sugar contents present in the examined lignocellulosic materials.
Lignocellulose
Sample
Rhamnose Arabinose Galactose Glucose Xylose Mannose
Total
Sugars (%)
85.7
(%)
(%)
(%)
(%)
(%)
(%)
Eucalyptus Kraft pulp
Norway Spruce
0.0
0.0
0.0
75.9
20.8
0.0
0.0
0.0
0.0
0.0
1.8
1.3
44.2
45.0
6.3
11.8
0.9
64.1
64.7
Softwood TMP
Eucalyptus Hardwood
17.5

Molecules 2013, 18
Table 7. Preparation of CMF with wood pulp and wood powder a.
7682
Entry
Lignocellulose Sample
Eucalyptus Kraft pulp
CMF Yield (mol %) b
CMF Yield (mol %) c
1
2
3
21.3
33.7
47.4
16.0
22.8
31.4
Norway Spruce softwood TMP
Eucalyptus hardwood
a
Lignocellulose sample (1.0 mg) was added in a mixture with 4/1 (v/v) of 37% HCl (4.0 mL) and 85%
H3PO4 (1.0 mL), and CHCl3 (5.0 mL) and stirred continuously at 45 °C for special time at 45 °C for 20 h.
b Isolated yield based on the glucose in the lignocellulose sample. c Isolated yield based on the total sugars in
the lignocellulose sample.
3. Experimental
3.1. Materials and Instruments
All solvents and chemicals used were as obtained from commercial suppliers, unless otherwise
indicated. 1H-NMR spectra were recorded on a Bruker Avance 300 instrument using CDCl3 as solvent
and TMS as the internal standard. GC-MS spectra were performed on an HP G1800B GCD system.
Eucalyptus globulus wood powder and its ensuing kraft pulp were examined as well as a Norway
Spruce sample of unbleached thermomechanical pulp, which was sampled in a Swedish mill of
approximate 38% consistency and 85 mL Canadian Standard Freeness prepared by one-stage refining
and a subsequent reject refining (about 20%) stage. All wood materials used in this work represent
standard samples, being the subject of Cost action E 41 entitled; “Analytical tools with applications for
wood and pulping chemistry” operated by the European Union. The sugar profiling for these materials
was examined according to the procedure of Min et al. followed by ion chromatography (Dionex
IC-3000; Dionex, Sunnyvale, CA, USA) (Table 6) [32,33].
3.2. General Procedure for the Synthesis of CMF from Model Carbohydrates
The selected carbohydrate (5.0 mmol) was added in a mixture of 37% HCl (4.0 mL), 85% H3PO4
(1.0 mL), and CHCl3 (5.0 mL) and it was stirred continuously at 45 °C for 20 h. Then an equal volume
of water (5.0 mL) was added to quench the reaction. The reaction mixture was then extracted with
CHCl3 3 times. The combined organic extracts were then dried with anhydrous Na2SO4 for 4 h.
Finally, the organic extracts were subjected to liquid chromatography (silica gel, CH2Cl2 as eluent) to
offer the desired 5-chloromethylfurfural. The procedure of treating lignocellulose sample (Table 6)
was almost the same as the carbohydrate, except adding the selected simple 1.0 mg each trial. The
1
1
structure of 5-chloromethylfurfural was confirmed using H-NMR and GC-MS as follows: H-NMR
(CDCl3): δ = 4.60 (s, 2H), 6.58 (d, J = 3.6 Hz, 1H), 7.18 (d, J = 3.6 Hz, 1H), 9.64 (s, 1H) ppm. GC-MS
+
(EI, 80 eV): m/z 146 (M+, 37Cl, 10.53), 144 (M+, 35Cl, 32.0), 109 (C6H5O2 , 100), 81 (C5H5O+, 17.3).
4. Conclusions
In summary, this note describes an optimized biphasic system (HCl-H3PO4/CHCl3) that may pave
the way for the development of a simple, mild, and cost-effective protocol for the conversion of
various carbohydrates to CMF. The systematic optimization effort undertaken here delineates the

Molecules 2013, 18
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structural features of carbohydrate residues that offer optimum CMF yields. Overall, the described
procedure offers several advantages over other methodologies including mild reaction conditions;
satisfactory product yields; and a simple experimental and isolation process.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (21072077), the Guangdong
Natural Science Foundation (10151063201000051), and the Guangzhou Science & Technology Project
(2010Y1-C511) for financial support.
Conflict of Interest
The authors declare no conflict of interest.
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