Highly efficient dehydration of carbohydrates to 5-(chloromethyl)furfural (CMF), 5-(hydroxymethyl)furfural (HMF) and levulinic acid by biphasic continuous flow processing

Article abstract of DOI:10.1039/c1gc15107j

Using a continuous flow reactor, the dehydration of d-fructose and other carbohydrates to 5-(chloromethyl)furfural (1) is achieved in reaction times as short as 60 s. The biphasic flow process allows for high-yielding multigram scale production of CMF (1) which is obtained with excellent purity after a simple extractive work-up. Efficient conversion of d-fructose into 5-(hydroxymethyl)furfural (2) and levulinic acid (6) is also demonstrated using flow reactor techniques.

Full text of DOI:10.1039/c1gc15107j

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Highly efficient dehydration of carbohydrates to 5-(chloromethyl)furfural
(CMF), 5-(hydroxymethyl)furfural (HMF) and levulinic acid by biphasic
continuous flow processing†
Malte Brasholz,* Karin von Ka¨nel, Christian H. Hornung, Simon Saubern and John Tsanaktsidis*
Received 27th January 2011, Accepted 17th February 2011
DOI: 10.1039/c1gc15107j
Using a continuous flow reactor, the dehydration of D-
fructose and other carbohydrates to 5-(chloromethyl)-
furfural (1) is achieved in reaction times as short as 60 s. The
biphasic flow process allows for high-yielding multigram
scale production of CMF (1) which is obtained with
excellent purity after a simple extractive work-up. Efficient
conversion of D-fructose into 5-(hydroxymethyl)furfural (2)
and levulinic acid (6) is also demonstrated using flow reactor
techniques.
aqueous hydrochloric acid, and the solution was pumped into
R
the flow reactor (Vapourtecꢀ),6 where it was mixed with either
dichloromethane (CH2Cl2) or 1,2-dichloroethane (DCE), prior
to entering a heated flow coil (PFA tubing, volume 10 mL,
1 mm inner diameter). Under these biphasic conditions, the
aqueous and the organic phase enter the flow reactor in defined
alternating segments. A back pressure regulator (8 bar) was
connected to the reactor outlet. When a 0.12 M solution of
sucrose in 32% HCl aq. was processed using CH2Cl2 as the
organic solvent, and at 100 ◦C for 2.5 min (Table 1, entry
1), CMF 1 was isolated in 51% yield after work-up, and with
excellent purity. The crude product contained no HMF 2, while
unreacted sugar remained in the aqueous phase. Reaction of
D-fructose and D-glucose under identical conditions (entries 2
and 3) led to CMF 1 in 80% and 15% yield, respectively, showing
that under these conditions D-fructose reacts ca. five times faster
than D-glucose.
The conversion of biological feed stock into functional chemical
intermediates and renewable fuels plays an increasingly impor-
tant role in the context of today’s efforts to make chemistry
more sustainable and to address the global issue of fossil
fuel depletion.1 For example, the dehydration of carbohydrates
readily leads to substituted furans, levulinic acid derivatives, and
other functional small molecules. While these transformations
have been known for decades, only recently has their impact been
fully recognised.2 We were interested to study the dehydration
reactions of sugars under continuous flow conditions, as micro-
and mesoscale flow reactors can offer increased efficiency
and safety compared to conventional chemical reactors, com-
bined with lower costs and environmental impact of chemical
production.3 Another notable advantage of flow reactors is
their considerably smaller footprint compared to conventional
batch reactors – an important factor for production of chemical
intermediates on scale.
Herein we report a new highly efficient methodology for the
dehydration of feed stock carbohydrates to the value-added
furan derivatives 5-(chloromethyl)furfural “CMF” 14 and 5-
(hydroxymethyl)furfural “HMF” 25 as well as levulinic acid
“LA” 6 by biphasic continuous flow reactor processing.
The dehydration of sucrose, D-fructose and D-glucose to
CMF 1 in continuous flow using a biphasic solvent system
is presented in Table 1. The carbohydrates were dissolved in
The reaction mixtures obtained from sucrose, D-fructose
and D-glucose after a reaction time of 2.5 min (entries 1–
3) contained ca. 1 weight% of carbon particles, which were
easily removed by filtration through a short plug of silica
gel. However, when sucrose and D-glucose were processed for
longer periods of time or at higher temperatures to improve
conversion, greater amounts of carbon formed through product
decomposition, which eventually led to reactor blockage. To
address this limitation in the process so as to allow large scale
processing and in a truly continuous fashion, a particle filter
was incorporated into the flow stream (Scheme 1). The filter
R
consisted of a glass column (Omnifitꢀ),7 without the usual teflon
frit in its upper end piece, and filled with a short bed of sand.
Overhead space above the sand bed would allow particles to
sediment gently, rather than being forced into a dense filter plug
which would lead to pressure increase. Hence, this simple device,
connected to the outlet of the reactor coil, and placed before the
back pressure regulator, enabled effective in-line filtration of the
otherwise problematic carbon particles.
The process was subsequently optimized for carbohydrate
concentration, reaction time and yield (entries 4–8). Acid
concentration of 32% HCl aq. was retained, as experiments with
more dilute HCl produced mixtures of CMF 1 with HMF 2.8
D-Glucose could be converted into CMF 1 in 58% yield when
CSIRO Materials Science and Engineering, Bayview Avenue, Clayton,
VIC 3168, Australia. E-mail: john.tsanaktsidis@csiro.au; Tel: +61 3
9545 2222
† Electronic supplementary information (ESI) available: Full experimen-
tal detail and analytical data. See DOI: 10.1039/c1gc15107j
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Table 1 Conversion of carbohydrates into CMF 1 by biphasic continuous flow processing
Entry
Sugar
g/10 mL (conc.)a
Solvent
T/◦C
Flow rate (mL min-1)
rtb (min)
Yield (%)
1
2
3
4
5
6
7
8
Sucrose
0.2 (0.12 M)
0.2 (0.11 M)
0.2 (0.11 M)
0.2 (0.11 M)
0.2 (0.11 M)
0.5 (0.28 M)
1 (0.56 M)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CH2Cl2
CH2Cl2
CH2Cl2
100
100
100
100
120
100
100
100
2 ¥ 2
2 ¥ 2
2 ¥ 2
2 ¥ 0.5
2 ¥ 1
2 ¥ 2
2 ¥ 3
2 ¥ 5
2.5
2.5
2.5
10
51
80
15
47c
58c
69
81
76
D-Fructose
D-Glucose
D-Glucose
D-Glucose
D-Fructose
D-Fructose
D-Fructose
5
2.5
1.67
1
1 (0.56 M)
a Reactions were run using 10 mL solutions of the carbohydrates in 32% HCl aq. b rt = residence time. c Reaction was run with particle filter.
Scheme 1 Continuous flow conversion of sucrose and D-fructose into
CMF 1 on a 10 gram scale.
Scheme 2 Reactions of CMF 1 in batch and continuous flow. Condi-
tions: (a) 1 0.5 M in THF, H2O, flow-heating, 100 ◦C, 2.5 min. (b) 69%
HNO3 aq., 80 ◦C, 24 h. (c) NaBH4, Bu3PC16H33+Br-, TBME/H2O, 5 ◦C
reacted at 120 ◦C for 5 min, and using the particle filter (entry
˚
to rt, 2 h. (d) (i) Et3N, BnNH2, 4 A MS, DCE, rt, 16 h. (ii) NaBH(OAc)3,
5). In case of D-fructose, the concentration could be increased
to 1 g per 10 mL of aqueous solvent (0.56 M), and reaction
times as short as 60 s were sufficient to achieve conversion into
1 in ca. 80% yield (entries 6–8).9 As shown in Scheme 1, we also
performed the dehydration of D-fructose and sucrose on a 10
gram scale. Under optimum conditions, 6.32 g of 1 (79% yield)
were produced from 10 g of D-fructose, in only 20 min of total
process time. Likewise, 10 g of sucrose were converted into 5.13 g
of 1 (61% yield) using DCE as the organic solvent and at 130 ◦C.
Employing these procedures, a single flow channel would thus
produce an output of ca. 300 mg of product 1 per minute.
CMF 1 is a valuable small molecule for synthesis,10 and
Scheme 2 shows some examples of new useful transformations of
1 we developed, e.g. the aqueous hydrolysis of 1 to yield HMF
2 (performed in a flow reactor),11 the oxidation of 1 leading
to furan dicarboxylic acid 3, the reduction of 1 with sodium
borohydride (under phase transfer conditions)12 to afford (5-
methylfuran-2-yl)methanol 4, and bis-amination of 1 to the
symmetrical furan diamine 5 by a one-pot substitution-reductive
amination procedure, respectively.
HOAc, rt, 16 h.
The aqueous hydrolysis of 1 to HMF 2 in continuous flow
(Scheme 2) was only moderately selective as 2 was accompanied
by 20% of levulinic acid (LA) 6.11 LA 6 itself is a valuable
platform chemical,2d and it can be accessed directly from D-
fructose as shown in Scheme 3. A 10% aqueous solution of
carbohydrate in a 1 : 2 mixture of 2 M HCl aq. and methanol
◦
was heated to 140 C for 80 min in a flow reactor, to produce
levulinic acid 6 in 72% yield (along with 11% of isolated
HMF 2).13
Scheme 3 Continuous flow dehydration of D-fructose to LA 6.
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As the formation of HMF 2 by hydrolysis of CMF 1
proceeded with only moderate selectivity under flow conditions,
we turned our attention to its direct preparation from D-
fructose. The production of HMF 2 from biological feedstock
has been extensively investigated,2,5 as one of its important
applications is the heterogeneous hydrogenation leading to the
biofuel 2,5-dimethylfuran (DMF).5c,e,f Previous work has shown
that, analogously to the formation of CMF 1 from sugars, the
selectivity of this dehydration is increased by employing biphasic
solvent systems; HMF 2 is readily extracted into the organic
phase as it forms, preventing it from reacting further to LA
6. High boiling solvents like DMSO5d,14 or dimethylacetamide5e
have been employed in the process, as well as speciality solvents
like ionic liquids5b and Lewis acid additives.5b,f Instead, we have
used here the simple biphasic solvent system of 0.25 M aqueous
HCl and methyl isobutyl ketone (MIBK).5a The dehydration of
D-fructose to HMF 2 was readily achieved with good selectivity
and high yield under these reaction conditions (Scheme 4), and
no formation of carbon particles occurred when a 10% aqueous
solution of the carbohydrate was used. The best results were
obtained when the organic phase was mixed into the flow stream
with a flow rate 3 ¥ higher than the aqueous solution ◦of the
carbohydrate. Heating the resulting flow stream to 140 C for
15 min gave, after work-up and filtration through silica, 74% of
isolated HMF 2 (the crude product contained HMF 2 and LA
6 in a ratio of 87 : 13 with less than 3% of other side products).14
Notes and references
1 (a) Selected books: D. L. Klass, Biomass for Renewable Energy Fuels
and Chemicals, Academic Press, San Diego 1998; (b) P. Anastas, J.
Warner, Green Chemistry: Theory and Practice, Oxford University
Press, Oxford 2000; (c) Biofuels: Global Impact on Renewable Energy
Production Agriculture and Technological Advancements, D. Tomes, P.
Lakshmanan, D. Songstad, (Ed.; Springer, New York 2010); (d) G.
W. Huber, S. Iborra and A. Corma, Chem. Rev., 2006, 106, 4044;
(e) A. J. Ragauskas, C. K. Williams, B. H. Davison, G. Britovsek, J.
Cairney, C. A. Eckert, W. J. Frederick, Jr., J. P. Hallett, D. J. Leak, C.
L. Liotta, J. R. Mielenz, R. Murphy, R. Templer and T. Tschaplinski,
Science, 2006, 311, 484; (f) M. Sto¨cker, Angew. Chem., 2008, 120,
9340, (Angew. Chem., Int. Ed., 2008, 47, 9200); (g) D. M. Alonso, J.
Q. Bond and J. A. Dumesic, Green Chem., 2010, 12, 1493.
2 Selected reviews: (a) F. W. Lichtenthaler, Carbohydr. Res., 1998, 313,
69; (b) F. W. Lichtenthaler, Acc. Chem. Res., 2002, 35, 728; (c) C.
Moreau, M. N. Belgacem and A. Gandini, Top. Catal., 2004, 27, 11;
(d) A. Corma, S. Iborra and A. Velty, Chem. Rev., 2007, 107, 2411.
3 Books and book chapters on flow reactors in synthesis: (a) W.
Ehrfeld, V. Hessel, H. Lo¨we, Microreactors: New Technology for
Modern Chemistry, Wiley-VCH, Weinheim 2000; (b) New Avenues to
Efficient Chemical Synthesis: Emerging Technologies. Ernst Schering
Foundation Symposium Proceedings (Ed.: P. H. Seeberger, T. Blume),
Springer, Berlin, Heidelberg, 2007; Vol. 1, 2006–3; (c) Microreactors
in Organic Synthesis and Catalysis (Ed.: T. Wirth), Wiley-VCH,
Weinheim, 2008; (d) J. C. Brandt, T. Wirth, in Recoverable and
Recyclable Catalysts (Ed.: M. Benaglia), John Wiley & Sons, 2009,
411; (e) S. Ceylan, A. Kirschning, in Recoverable and Recyclable
Catalysts (Ed.: M. Benaglia), John Wiley & Sons, 2009, 379; (f) V.
Hessel, A. Renken, J. C. Schouten, J. Yoshida, Micro Process
Engineering, Wiley-VCH, Weinheim 2009; (g) Chemical Reactions
and Processes under Flow Conditions RSC Green Chemistry Series
No. 5 (ed.: S. V. Luis, E. Garcia-Verdugo), The Royal Society of
Chemistry, Cambridge, 2010Selected reviews: (h) G. Jas and A.
Kirschning, Chem.–Eur. J., 2003, 9, 5708; (i) K. Ja¨hnisch, V. Hessel,
H. Lo¨we and M. Baerns, Angew. Chem., 2004, 116, 410, (Angew.
Chem., Int. Ed., 2004, 43, 406); (j) B. Ahmed-Omer, J. C. Brandt
and T. Wirth, Org. Biomol. Chem., 2007, 5, 733; (k) B. P. Mason,
K. E. Price, J. L. Steinbacher, A. R. Bogdan and D. T. McQuade,
Chem. Rev., 2007, 107, 2300; (l) V. T. N. Glasnov and C. O. Kappe,
Macromol. Rapid Commun., 2007, 28, 395; (m) F. Benito-Lo´pez, R.
J. M. Egberink, D. N. Reinhoudt and W. Verboom, Tetrahedron,
2008, 64, 10023; (n) S. V. Ley and I. R. Baxendale, Chimia, 2008, 62,
162; (o) P. H. Seeberger, Nat. Chem., 2009, 1, 258; (p) F. E. Valera,
M. Quaranta, A. Moran, J. Blacker, A. Armstrong, J. T. Cabral and
D. G. Blackmond, Angew. Chem., 2010, 122, 2530, (Angew. Chem.,
Int. Ed., 2010, 49, 2478).
Scheme 4 Biphasic continuous flow dehydration of D-fructose to HMF
2.
4 Conversion of carbohydrates into CMF 1, ‘early’ examples: (a) H.
J. H. Fenton and M. Gostling, J. Chem. Soc. Trans., 1901, 79, 807;
(b) E. Fischer and H. von Neyman, Ber. Dtsch. Chem. Ges., 1914,
47, 973; (c) W. N. Haworth and W. G. M. Jones, J. Chem. Soc.,
1944, 667‘Recent’ examples: (d) H. H. Szmant and D. D. Chundury,
J. Chem. Technol. Biotechnol., 1981, 31, 205; (e) K. Hamada, H.
Yoshihara and G. Suzukamo, Chem. Lett., 1982, 617; (f) C. Fayet and
J. Gelas, Carbohydr. Res., 1983, 122, 59; (g) K. Sanda, L. Rigal and A.
Gaset, J. Chem. Tech. Biotechnol., 1992, 55, 139; (h) M. Mascal and
E. B. Nikitin, Angew. Chem., 2008, 120, 8042, (Angew. Chem., Int.
Ed., 2008, 47, 7924); (i) M. Mascal and E. B. Nikitin, Green Chem.,
2010, 12, 370; (j) Patents: K. Hamada, H. Yoshihara, G. Suzukamo,
Pat. US4424390 A1, 1984; (k) S. Prasad, T. K. Chakraborty, M.
Jaggi, A. C. Burman, R. Mukherjee, A. C. Kunwar, A. Mathur, Pat.
US2005/32707 A1, 2005; (l) M. Mascal, Pat. US2009/234142 A1,
2009.
Conclusions
We have developed efficient and practicable procedures for
the dehydration of carbohydrates to the value-added products
5-(chloromethyl)furfural 1, 5-(hydroxymethyl)furfural 2 and
levulinic acid 6 under biphasic continuous flow conditions.
The flow reactor-assisted conversion of D-fructose, D-glucose
and sucrose into CMF 1 is superior to previously published
procedures4h,i in terms of overall efficiency: a reaction time of
60 s is sufficient to produce 1 with 80% isolated yield from
D-fructose and 60% yield from sucrose. Likewise, the biphasic
continuous flow protocol for the conversion of D-fructose into
HMF 2 proceeds with high isolated yield, in a reaction time of
only 15 min, and avoids high boiling solvents like DMSO5d,14 or
other additives like Lewis acids,5b,f or special phase modifiers.5a
In summary, this study has shown that by using flow reactor
processing, carbohydrates can readily be converted into the
important platform chemicals 1, 2 and 6 with good efficiency
and a high state of purity. This was achieved using inexpensive
reagent systems, in short reaction times and with simple work-up
procedures.
5 Recent examples: (a) Y. Roma´n-Leshkov, J. N. Chheda and J. A.
Dumesic, Science, 2006, 312, 1933; (b) H. Zhao, J. E. Holladay, H.
Brown and Z. C. Zhang, Science, 2007, 316, 1597; (c) Y. Roma´n-
Leshkov, C. J. Barrett, Z. Y. Liu and J. A. Dumesic, Nature, 2007,
447, 982; (d) J. N. Chheda, Y. Roman-Leshkov and J. A. Dumesic,
Green Chem., 2007, 9, 342; (e) J. B. Binder and R. T. Raines, J. Am.
Chem. Soc., 2009, 131, 1979; (f) T. Thananatthanachon and T. B.
Rauchfuss, Angew. Chem., 2010, 122, 37, (Angew. Chem. Int. Ed.,
2010, 49, 37).
6 VapourtecꢀR R2/R4 systems were used, see www.vapourtec.co.uk and
Supporting Information for detail.
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7 For detail, see www.omnifit.com and Supporting Infor-
mation.
8 Use of 4 M HCl aq. led to the formation of 1 and 2 in 1 : 1
ratio.
9 No unreacted carbohydrate was isolated after these
reactions.
10 For examples, see: (a) M. K. Jogia, V. Vakamoce and R. T. Weavers,
Aust. J. Chem., 1985, 38, 1009; (b) L. L. Klein and M. S. Shanklin, J.
Org. Chem., 1988, 53, 5202; (c) T. K. Chakraborty, S. Tapadar and
S. K. Kiran, Tetrahedron Lett., 2002, 43, 1317; (d) B. Das, S. Rudra,
A. Yadav, A. Ray, A. V. S. R. Rao, A. S. S. V. Srinavas, A. Soni, S.
Saini, S. Shukla, M. Pandya, P. Bhateja, S. Malhotra, T. Mathur, S.
K. Arora, A. Rattan and A. Mehta, Bioorg. Med. Chem. Lett., 2005,
15, 4261.
However, we could not obtain a comparable result by flow reactor
processing despite extensive optimization.
12 F. Rolla, J. Org. Chem., 1981, 46, 3909.
13 The overall yield of the reaction reflects the formation of carbon
particulates which occurs in batch experiments to the same extend.
Conducting the reaction in flow at higher temperatures would lead
to shorter reaction time, but would generate more carbon particles
and also require steel tubing. PFA tubing has a lower pressure rating
(140 ◦C at 16 bar are close to the material’s stability limit), but the
advantage of transparency of the flow channel and a lesser propensity
for blockages.
14 Dehydrations of D-fructose and D-glucose to HMF 2 in continuous
flow using DMSO/HCl aq. have been recently reported, yields based
on HPLC conversion measurements: M. Scho¨n, M. Schnu¨rch and
M. D. Mihovilovic, Mol. Divers., 2010, DOI: 10.1007/s11030-010-
9295-9.
11 The batch mode hydrolysis of CMF 1 to HMF 2 has been reported
previously, see ref. 4 (i), with a yield of 86% of 2 and 10% of LA 6.
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