3-deoxy-glucosone is an intermediate in the formation of furfurals from D-glucose.

Article abstract of DOI:10.1002/cssc.201100249

The acid-catalyzed dehydration of glucose to hydroxymethylfurfural (6) can occur via two possible mechanisms. 3-deoxy-D-erythro-hex-2-ulose (3) is found to be an intermediate in the formation of 6 from glucose (1). This finding implies that elimination of the glucose 3-OH group is the important step, rather than isomerization of the carbonyl group.

Full text of DOI:10.1002/cssc.201100249

DOI: 10.1002/cssc.201100249
3
-Deoxy-glucosone is an Intermediate in the Formation of Furfurals
from d-Glucose.
[
a]
Harishchandra Jadhav, Christian Marcus Pedersen, Theis Sølling, and Mikael Bols*
There is a consensus that the current heavy dependence on
fossil fuels is untenable because it both leads to an increase in
atmospheric CO and climate change, and because fossil fuels
2
are a limited resource. Therefore much attention has been
given to research in biofuels, combustable organic compounds
obtained from the biosphere, that is, plants. Because most of
the organic material in the biosphere consists of carbohy-
drates, especially cellulose, the majority of this research is di-
rected at solving the problems associated with the conversion
of the carbohydrate biomass into fuels.
Methods based on established fermentation technologies
that convert carbohydrates into bioethanol are a more imme-
[
1]
diate solution. However, it is by no means certain that etha-
nol is a good or even efficient solution to the problem. Ethanol
is corrosive and fermentation has a poor carbon economy (glu-
Scheme 1. 3-Deoxy-2-ketohexose mechanism for formation of 6.
[
2]
cose=2EtOH+2CO2). Therefore, much attention has been
paid to the direct chemical conversion of carbohydrates, and
particularly dehydrative reactions to furfurals are considered
promising. The main furfural of interest is the product of the
acidic dehydration of glucose: hydroxymethylfurfural (HMF).
This compound has generated particular recent interest as an
[
3]
intermediate for new biofuels such as dimethylfuran and as a
[
4]
platform for biobased chemicals. Of course, realizing efficient
[5]
ways to obtain HMF from biomass is the key to success, and
this requires a deep understanding of the process.
The acid-catalyzed dehydration of glucose to HMF is a multi-
step process that has been known for many years. From older
literature it is clear that there are two possible mechanisms of
the conversion, between which it was not possible to distin-
[
6]
guish: one mechanism is the 3-deoxy-2-keto pathway shown
in Scheme 1, where elimination of the 3-OH of glucose (1)
leads to 3-deoxy-d-erythro-hex-2-ulose 3 (3-deoxyglucosone)
that undergoes ring-closure and eliminations to HMF (6). The
alternative mechanism is the fructose pathway shown in
Scheme 2, where 1 isomerizes to fructose (8) that undergoes
cyclization, reisomerization, and elimination to form 6. The
latter mechanism is supported by observations that 6 is
formed much faster and in higher yield from 8 than from 1,
and that 8 has been observed in dehydrations of 1, so in most
recent literature reports the fructose mechanism appears to
Scheme 2. Fructose mechanism for formation of 6.
good a source of HMF is 3? Older work shows that 3 does de-
[8]
hydrate to HMF, but otherwise little has been done in the
[9]
area.
Compound 3 has previously been prepared by El Khadem
[10]
et al. by reaction of glucose with benzoyl hydrazine to form
the oxazone S1 (Scheme S1, Supporting Information) followed
by rehydrazoniation with benzaldehyde. We followed this pro-
cedure with minor changes, obtaining S1 in 75% yield, while
the second step gave us 80% yield of 3. The product gave
very poor NMR spectra consisting of at least eight compounds
in aqueous solution, and previously 3 has only been character-
[
7]
prevail. Yet, the 3-deoxy mechanism is in fact more logical
because it does not include any “back and forth” isomerization
between C-1 and C-2. In this paper we ask the question: How
[
a] Dr. H. Jadhav, Dr. C. M. Pedersen, Prof. T. Sølling, Prof. M. Bols
Department of Chemistry, University of Copenhagen
Universitetsparken 5, 2100 Kbh Ø (Denmark)
Fax: (+45)35 32 02 12
[10]
ized by conversion to the dinitrophenyl hydrazone. We per-
formed a NaBH reduction of the material and obtained a mix-
4
ture of d-ribo- and d-arabino-3-deoxy-hexitols (S2 and S3) in
E-mail: bols@chem.ku.dk
7
4% yield, which is consistent with the compound being es-
Supporting Information for this article is available on the WWW under
http://dx.doi.org/10.1002/cssc.201100249.
sentially only 3.
ChemSusChem 2011, 4, 1049 – 1051
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1049

Ion chromatography (IC) of 3 on a Dionex ICS-3000 system
Table 2. Relative rates (determined from initial rates) of reaction for for-
mation of furfurals determined by normal-phase HPLC (EtOAc/heptane
1:9). The dehydration methods used were those of Scheme 3.
using a carbopac PA1 column and NaOH (0.15m)/NaOAc
À1
(
0.5m)/water (60:5:35, 10 mLmin ) as eluent showed 3 as a
broad peak at 8.2 min, clearly distinguishable from glucose
3.6 min) and fructose (3.8 min). When 6 was prepared from 1
Starting
material
Relative rate of reaction
(
HMF (6)
CMF (12)
BMF (13)
[
11]
by the H SO , DMA–LiCl protocol, stopped after 3 h and sep-
2
4
3
8
1
61
22
1
329
181
1
3268
2945
1
arated into an aqueous and toluene layer, IC showed the pres-
ence of both 3 and 8 in the aqueous phase in a ratio of 2:1.
This shows that both compounds are formed during the reac-
tion and could be intermediates.
[
11]
Reaction of 3 with H SO (95–97%) in DMA/LiCl for 3 h
2
4
gave a 92% yield of 6 (Scheme 3, Table 1). Similarly reaction of
[
13]
3
with HCl(37%)/LiCl or HBr(48%)/LiBr gave chloromethylfur-
2 4
Scheme 3. Synthesis of furfurals from 3-deoxy-glucusone 3. a) H SO , DMA/
LiCl, 92%; b) HCl/LiCl, 91%; c) HBr/LiBr, 91%,
À1
Figure 1. Free energies (kJmol , 298.15 K) calculated at the G3MP2 level for
the central species involved in the transformation of glucose (1) via the fruc-
tose (8, grey line) and 3-deoxy (3, black line) pathways. For the structures of
compound numbers, see Schemes 1 and 2.
[
12]
Table 1. Yields of furans obtained from 3 and 8, respectively.
Starting material
-DG
Method
Product
Yield
3
(3)
(8)
(3)
(8)
(3)
(8)
a
a
b
b
c
HMF
HMF
CMF
CMF
BMF
BMF
(6)
(6)
(12)
(12)
(13)
(13)
92%
61%
91%
72%
91%
74%
Fructose
-DG
Fructose
-DG
Fructose
are clearly favored over the fructose route (grey line). Accord-
ing to these data there is little doubt that the 3-deoxy route is
the preferred mechanism of HMF formation from glucose.
Altogether we find that both 3 and 8 are formed when glu-
cose is converted to HMF, but 3 is converted faster to product.
This can only mean that the pathway through 3 is active,
though the presence of 8 suggests that some HMF is also
formed through 8. The theoretical results support this conclu-
sion and indicate that the 3-deoxy pathway is actually domi-
nant. These results are important and should be taken into ac-
count in the ongoing work to improve furfural synthesis.
3
3
c
fural (CMF, 12) or bromomethylfurfural (BMF, 13), both in 91%
yield. All experiments show that 3 is an excellent starting ma-
terial for 6, because 12 and 13 are most likely formed from 6,
and 3 is essentially quantitatively converted to these furfural
products. The yields from fructose are also lower under identi-
cal conditions (Table 1).
For these reactions the rates of formation of 6, 12, and 13
from 3 or 8 were determined by following the concentration
Acknowledgements.
of the three furfurals by normal-phase HPLC (EtOAc/heptane
À1
We thank the FTP for financial support.
1
:9, 1 mLmin , see Supporting Information). The initial rates
of reaction determined from these data are shown in Table 2. 6
is formed three times faster from 3 than from 8. Halogen deriv-
atives 12 and 13 are formed 1.8 and 1.1 times faster, respec-
tively, from 3 than from 8 (Table 2). Taken together with IC re-
sults that showed 3 is present during the HMF reaction, this
means that 3 must be an intermediate.
Keywords: biofuels · biomass · dehydration · elimination ·
furanics
[1] C. Somerville, Biofuels Curr. Biol. 2007, 17, R115–R119.
[
2] M. Mascal, E. B. Nikitin, Angew. Chem. 2008, 120, 8042–8044; Angew.
Chem. Int. Ed. 2008, 47, 7924–7926.
Finally we wished to compare the two mechanisms theoreti-
cally and carried out calculations with the Gaussian 03 suite of
[
3] Y. Romꢁn-Leshkov, C. J. Barrett, Z. Y. Liu, J. A. Dumesic, Nature 2007, 447,
982.
[
14]
programs. To provide relative free energies to within chemi-
[4] A. Corma, S. Iborra, A. Velty, Chem. Rev. 2007, 107, 2411–2502.
[5] H. Zhao, J. E. Holladay, H. Brown, Z. C. Zhang, Science 2007, 316, 1597.
À1
cal accuracy (2 kcalmol ; 1 kcal=4.184 kJ) the G3MP2 method
[
[
6] E. F. L. J. Anet, Adv. Carbohydr. Chem. 1964, 19, 181–218.
was employed and thus the obtained geometries are at the
7] a) T. Stꢂhlberg, S. Rodriguez-Rodriguez, P. Fristrup, A. Riisager, Chem.
Eur. J. 2011, 17, 1369–1378; b) Y. Zhang, E. A. Pidko, E. J. M. Hensen,
Chem. Eur. J. 2011, 17, 5210–5217; For a Review of the arguments for
[
15]
MP2(FULL)/6-31G(d) level of theory. The results are shown in
Figure 1. All the intermediates in the 3-deoxy-route (black line)
1
050
www.chemsuschem.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemSusChem 2011, 4, 1049 – 1051

and against the two mechanisms see: c) M. J. Antal, W. S. L. Mok, G. N.
Richards, Carbohydr. Res. 1990, 199, 91–109.
8] E. F. L. J. Anet, Aust. J. Chem. 1965, 18, 240.
heated for 3 h at 658C; c) 250 mg carbohydrate in 10 mL PhMe, 240 mg
LiBr and 0.5 mL HBr (48%), heated for 3 h at 658C.
[13] N. Kumari, J. K. Olesen, C. M. Pedersen, M. Bols, Eur. J. Org. Chem. 2011,
1266–1270.
[
[
9] C. Perez Locas, V. A. Yaylayan, J. Agric. Food Chem. 2008, 56, 6717–6723.
[
10] a) H. El Khadem, D. Horton, M. H. Meshreki, M. A. Nashed, Carbohydr.
Res. 1971, 17, 183–192; b) T. Henle, A. A. Bachmann, Lebensm. Unters.
Forsch. 1996, 202, 72–74.
[14] M. J. Frisch et.al. , Gaussian 03, Revision B.03, Gaussian, Inc., Wallingford
CT, 2004.
[
15] A. G. Baboul, L. A. Curtiss, P. C. Redfern, K. Raghavachari, J. Chem. Phys.
999, 110, 7650.
1
[11] J. B. Binder, R. T. Raines, J. Am. Chem. Soc. 2009, 131, 1979–1985.
12] Methods: a) 137.5 mg carbohydrate in 1 mL DMA, 120 mg LiCl, 10 mL
[
PhMe and 2.5 mL H
2
SO
4
(95–97%), heated for 3 h at 808C; b) 250 mg
Received: May 17, 2011
carbohydrate in 10 mL PhMe, 110 mg LiCl and 0.5 mL HCl (37%),
Published online on June 29, 2011
ChemSusChem 2011, 4, 1049 – 1051
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemsuschem.org
1051