Glucose activation by transient Cr2+ dimers

Article abstract of DOI:10.1002/anie.201000250

[Figure Presented] Cat waiting in the wings: The transient formation of Cr²⁺ dimers through coordination to a second molecule of the catalyst promotes the isomerization of glucose to fructose and explains the unique ability of CrCl₂ to catalyze the dehydration of glucose to 5-hydroxymethylfurfural (HMF) in ionic-liquid media. The active-site environment during the rate-controlling step resembles that in hexose isomerase enzymes.

Full text of DOI:10.1002/anie.201000250

Communications
DOI: 10.1002/anie.201000250
Reaction Mechanisms
Glucose Activation by Transient Cr2+ Dimers**
Evgeny A. Pidko, Volkan Degirmenci, Rutger A. van Santen, and
Emiel J. M. Hensen*
Angewandte
Chemie
2530
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 2530 –2534

Angewandte
Chemie
Concerns about global warming and energy security have led
to the exploration of alternatives to fossil hydrocarbon
resources to supply chemicals and energy.[1] Biomass is a
promising renewable feedstock. Efficient routes are required
for the conversion of carbohydrates, the main constituents of
biomass, into fuels and chemicals.[2,3] 5-Hydroxymethylfurfu-
ral (HMF) is considered a key biorenewable platform
molecule.[3,4] Although HMF can be obtained from fructose
in high yield by using Brønsted and Lewis acid catalysts,[5,6]
the selective transformation of glucose, the dominant sugar in
cellulosic biomass, remains a challenge. Only recently,
unprecedented HMF yields were reported for glucose dehy-
dration by chromium(II) chloride in the ionic liquid (IL)
1-ethyl-3-methylimidazolium chloride (EMIMCl).[6]
Lewis acid catalyzed transformations in ionic liquids are
thought to involve mononuclear metal complexes.[6–9] For the
dehydration of glucose to HMF, a CrCl3ꢀ anion was proposed
to coordinate an enediolate intermediate, which undergoes
the hydrogen transfer (H shift) required for the isomerization
of glucose to fructose.[6,8] Usually, it is assumed that the role of
the ionic-liquid medium is to provide a noncoordinating polar
environment to stabilize catalytically active low-coordinate
metal species.[7] The direct involvement of the organic cations
of the ionic liquid in the catalytically active complex has also
been mentioned;[8] however, evidence of the formation of
metal–carbon bonds is lacking. Besides this chemocatalytic
system, some enzymes readily promote glucose conversion.
Typical enzymes capable of isomerizing glucose to fructose
with high selectivity contain an active site involving two metal
centers.[10–14]
Figure 1. a) Concentration of the reactant and of the fructose and
HMF products during glucose dehydration catalyzed by CrCl2 in
EMIMCl at 1008C. b) Ring opening and mutarotation of a-d-glucopyr-
anose. c) Isomerization and dehydration of a-d-glucopyranose.
In this study, we combined kinetic experiments, in situ
X-ray absorption spectroscopy (XAS), and density functional
theory (DFT) calculations to unravel the molecular-level
details of the unique reactivity of chromium(II) chloride
towards selective glucose dehydration in an ionic-liquid
medium. As a starting point, we investigated the kinetics of
glucose dehydration by CrCl2 in EMIMCl at 1008C. The
reaction proceeds through glucose isomerization to fructose,
followed by dehydration to give HMF (Figure 1). The HMF
yield after a reaction time of 3 hours is 62%. An experiment
with fructose gave HMF in 59% yield under identical
conditions. In both cases, the starting sugar underwent
almost complete conversion. Thus, the CrCl2/EMIMCl cata-
lyst converts glucose into fructose with high selectivity, and
then catalyzes the dehydration of fructose to give HMF.[6] The
poorly characterized humin-type side products are due to
condensation reactions of intermediates formed during fruc-
tose dehydration.[6]
X-ray absorption spectroscopy at the Cr K edge was used
to resolve the nature and coordination properties of Cr
species involved in the conversion of glucose. We used an in
situ cell for liquid-phase experiments (see the Supporting
Information). Absorption spectra in the CrCl2/EMIMCl/
glucose system were recorded at 808C, as glucose is not
converted under these conditions. Spectra were recorded
before reaction, after reaction at 1008C for 10 minutes, and
after reaction at 1008C for 180 minutes (the fit results are
given in Table 1 and spectra in the Supporting Information).
The reference spectrum of CrCl2 dissolved in EMIMCl at
808C showed that Cr2+ is coordinated by four chlorine atoms
at an average bond length of 2.39 ꢀ. This distance is typical
for four-coordinate chlorine-containing CrII complexes.[15] Cr–
Cr coordination, as present in solid CrCl2 and in a mixed
crystal of CrCl2 and EMIMCl,[16] is absent. DFT calculations
confirmed the structure of chromium(II) chloride in
EMIMCl. Geometry optimization of a cluster model con-
taining two CrCl2 units and five ion pairs of the ionic liquid (a
model constructed from X-ray diffraction data[16]) led to two
[*] Dr. E. A. Pidko, Dr. V. Degirmenci, Prof. Dr. R. A. van Santen,
Prof. Dr. E. J. M. Hensen
Schuit Institute of Catalysis
Eindhoven University of Technology
P.O. Box 513, NL-5600 MB, Eindhoven (The Netherlands)
Fax: (+31)40-245-5054
E-mail: e.j.m.hensen@tue.nl
[**] This research was performed within the framework of the CatchBio
program. We gratefully acknowledge the support of the Smart Mix
Program of the Netherlands Ministry of Economic Affairs and the
Netherlands Ministry of Education, Culture and Science. E.J.M.H.
and V.D. thank the Technology Foundation STW, the applied-science
division of NWO. NWO-NCF and NWO-Dubble are acknowledged
for access to computing and XAS facilities, respectively.
2ꢀ
noninteracting square-planar CrCl4 units. This geometry is
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201000250.
typical for four-coordinate CrII complexes.[15] The average
Angew. Chem. Int. Ed. 2010, 49, 2530 –2534
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2531

Communications
Table 1: EXAFS fit parameters of the CrCl2/EMIMCl system.
molecular mechanism of the chromium(II)-catalyzed glucose
isomerization. On the basis of a mechanism similar to that
proposed for enzymes,[10] we considered three steps in the
conversion of glucose into fructose: 1) ring opening,
2) H transfer between C2 and C1, and 3) ring closure
(Figure 1c). The replacement of a Clꢀ ligand and coordina-
Backscatter
N[a]
R [ꢀ][b]
Ds2 [ꢀ2][c]
DE0 [eV][d]
ꢀ8.4
CrCl2/EMIMCl, 808C
ꢀ
Cr Cl
3.9
2.39
0.008
CrCl2/EMIMCl/glucose, 808C
ꢀ
tion of a-d-glucopyranose (a-d-GP) to Cr through the O1
Cr Cl
ꢀ
Cr O
2.9
1.0
2.38
2.13
0.007
0.015
ꢀ3.4
ꢀ7.4
o;IL
atom (Figure 2c) is favorable (DG
¼ꢀ10 kJmolꢀ1). Such
100ꢁC
a coordination mode of glucose to the Cr center was
considered because it enables the opening of the glucopyr-
anose ring through H+ transfer from O1 to O6. This choice is
supported by the observation that the mutarotation of a-d-
glucose to b-d-glucose occurs in the presence of a CrII catalyst
even under conditions (808C) that do not promote its
conversion into fructose or HMF. Mutarotation requires
opening of the glucopyranose ring. The DFT-computed
bonding parameters of the respective complexes correspond
well with the structural parameters determined by EXAFS
(see the Supporting Information). The coordination of a
second Cr center at this step of the reaction is unfavorable.
In the enzyme-catalyzed process, the initial proton trans-
fer is catalyzed by a basic histidine moiety (His53) located in
the cavity of the enzyme active site (Figure 2a).[10,11] In the
chemocatalytic system, the mobile chloride anions of the ionic
liquid play the role of basic mediators. The chloride anions
CrCl2/EMIMCl/glucose, 1008C, 10 min
ꢀ
Cr Cl
2.4
2.0
0.6
2.36
2.04
3.45
0.004
0.004
0.006
ꢀ
Cr O
ꢀ
Cr Cr
CrCl2/EMIMCl/glucose, 1008C, 180 min
ꢀ
Cr Cl
2.4
1.4
2.35
2.02
0.005
0.003
ꢀ5.2
ꢀ
Cr O
[a] Coordination number (ꢂ20%). [b] Coordination distance (ꢂ0.02 ꢀ).
[c] Debye–Waller factor (ꢂ10%). [d] Inner potential.
ꢀ
computed Cr Cl bond length of 2.39 ꢀ agrees with the
experimental values.
EXAFS data recorded at 808C in the presence of glucose
provided evidence for the coordination of glucose to Cr
through one of its hydroxy groups. One of the chlorine ligands
was replaced with an oxygen ligand. The
ꢀ
ꢀ
Cr O and Cr Cl bond lengths were 2.13
and 2.38 ꢀ, respectively. The relatively
ꢀ
long Cr O distance indicates coordina-
tion of CrII to a hydroxy group of the
sugar.[15,17] The fructose concentration
was highest after a reaction time of
10 minutes at 1008C (Figure 1a). At this
stage, the coordination environment of
Cr had changed substantially. Chromium
coordinated two oxygen atoms at a dis-
tance of 2.04 ꢀ and two chlorine atoms at
ꢀ
2.36 ꢀ. The decrease in the Cr O dis-
tance is due to deprotonation of the sugar
hydroxy groups coordinated to Cr.[15] The
fit of this spectrum also contains a Cr–Cr
shell with a coordination number of 0.6 at
a distance of 3.45 ꢀ which points to the
presence of O- or Cl-bridged Cr
dimers.[15] When nearly all the glucose
had been converted, this Cr–Cr coordi-
nation was no longer observed. The
coordination environment of Cr con-
tained on average 1.4 oxygen ligands at
a distance of 2.02 ꢀ and 2.4 chlorine
ligands at 2.35 ꢀ.
The exceptional catalytic perfor-
mance of the CrCl2/EMIMCl system is
directly related to its ability to promote
the isomerization of glucose to fructose.
The EXAFS results imply dynamic evo-
lution of the catalytic CrII species during
the course of the reaction. DFT calcula-
Figure 2. a) Atomic-resolution XRD structure of glucose interacting with the binuclear active
site of a xylose isomerase enzyme.[10] b) DFT-optimized structure of the initial coordination
complex between glucose and chromium(II) chloride. c) Scheme showing the H shift that
takes place during glucose isomerization. d) DFT-computed binuclear CrII complexes with the
deprotonated sugar intermediates shown in (c). DG values are given in kJmolꢀ1. TS=transition
tions were carried out to unravel the state.
2532
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 2530 –2534

Angewandte
Chemie
form a hydrogen-bonding network with the hydroxy groups of
the carbohydrate. This proposition is supported by the
absence of fructose and HMF formation when the anion of
the ionic liquid is replaced with nonbasic PF6 (see the
Supporting Information).
Figure 3 shows the computed free-energy diagram for
glucose isomerization involving mono- and binuclear Cr
complexes. The free-energy barrier to the formation of the
open form of d-glucose is low and does not depend on the
nuclearity of the Cr complex. The free-energy change for the
ring opening of d-glucose coordinated to a single Cr center
compares favorably to that of the noncatalytic ring opening;
the difference in the free-energy change for these processes is
in line with optical-rotation results (see the Supporting
Information). The resulting complex of the open form of d-
glucose with Cr is the precursor to the following trans-
formation. The isomerization of glucose to fructose requires
an H shift between C2 and C1 of the open form of the sugar
(Figure 2c). This step is thought to involve an enediolate
intermediate.[6,8] Prior to the H shift, deprotonation of the
ꢀ
ꢀ
O2 H group is required. This step is strongly
endothermic (+ 68 kJmolꢀ1) when the open form
is stabilized by one Cr center. The energy cost of
the subsequent H shift is 51 kJmolꢀ1. The overall
free-energy barrier to the H shift is 120 kJmolꢀ1.
The O2-deprotonated glucose intermediate is
stabilized considerably when a second Cr center
becomes involved (Figure 3). In the resulting
binuclear complex, O1 bridges the two Cr centers
(Figure 2d). One of the chromium ions also
coordinates to O2. In this case, the free energy
required for the deprotonation of O2 is lowered
by 15 kJmolꢀ1. More importantly, the energy
barrier to the direct H shift from C2 to C1 in
this complex is negligible (9 kJmolꢀ1). The prod-
uct is also a Cr dimer, which now contains the
open form of d-fructose deprotonated at O1
(Figure 2d). This complex is much more stable
than its mononuclear counterpart. Thus, the
isomerization of glucose proceeds by the coordi-
nation of a second Cr center during the deproto-
nation of O2, followed by a rapid H shift.
The overall activation free-energy barrier of
only 63 kJmolꢀ1 for the binuclear pathway com-
pares favorably to the barrier of the mononuclear
pathway. The Cr–Cr distances observed in the
optimized structures of the stable Cr dimer
complexes of the O1-deprotonated and neutral
open forms of fructose agree well with the Cr–Cr
distance determined by EXAFS analysis (see the
Supporting Information). The transition state of
the direct H shift is stabilized by delocalization of
the electron density in the conjugated p system.
During the H shift, negative charge develops on
the O1 atom. The coordination of O1 to two
Lewis acidic Cr centers stabilizes this negative
charge better than coordination to a single Cr
center and results in a substantial decrease of the
free-energy barrier. Analysis of the computa-
tional results showed that the transferred H atom
has a positive charge of + 0.34eꢀ. The high
concentration of the free basic Clꢀ ions of the
ionic liquid should facilitate proton transfer. The
formation of fructose from the binuclear complex
o;IL
100
Figure 3. a) DFT-computed free-energy (DG ꢁ C) diagrams for glucose isomerization
with the open form of fructose involves the
protonation of C1, followed by ring closure. The
DFT-optimized structures of Cr2+ complexes with
the products of glucose dehydration, namely
HMF and H2O, are also in close agreement with
involving mono- (blue) and binuclear (orange) CrII complexes with the carbohydrate
in a model MMIM ionic-liquid medium. The red line highlights the path of lowest
free energy (the corresponding catalytic cycle is shown in (b)). b) Catalytic cycle for
the isomerization of glucose in the presence of CrCl2 in a model MMIM ionic-liquid
medium. d-FF=d-fructofuranose, d-GP=d-glucopyranose.
Angew. Chem. Int. Ed. 2010, 49, 2530 –2534
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
2533

Communications
the medium. Zero-point, finite-temperature, and entropic (TS)
energy contributions were computed by normal-mode analysis at
the EXAFS results after completion of the reaction (see the
Supporting Information).
the PBE0/Dz level. The reported Gibbs free energy differences,
Catalysis by chromium usually involves highly complex
redox and coordination chemistry of the metal center. In the
case of heterogeneous catalytic ethylene oligomerization, a
single-site CrII species has been accepted as the active site.[18]
Examples of homogeneous catalysis involve both mono- and
binuclear CrII complexes.[15,19] We are unaware of prior
observations of the transient self-organization of mononu-
clear Cr species into a binuclear complex with a reactant in a
chemocatalytic system. Our results show that the facile
reactions of sugar ring opening and closure involve coordi-
nation to a single Cr center. The rate-controlling H-shift
reaction of the open form of the carbohydrate is facilitated by
the transient self-organization of the Lewis acidic Cr2+ centers
into a binuclear complex with the open form of glucose. The
active site for this step resembles the active site of hexose
isomerase enzymes.[11] The exact role of the second metal site
in biological systems is still under debate. In the CrCl2/
EMIMCl system, the second Cr center stabilizes the reaction
intermediates involved in the H shift. The moderate basicity
and the high concentration and mobility of the chlorine ions
of the ionic-liquid reaction medium promote the various
(de)protonation reactions. In enzymes, such reactions are
catalyzed by basic amino acid residues at the active site. The
unique transient self-organization of Cr2+ dimers to facilitate
the rate-controlling H shift in glucose isomerization is possi-
ble as a result of the dynamic nature of the Cr complexes and
the presence of moderately basic sites in the ionic liquid.
o;IL
DG C, include solvation, thermal, entropic, and zero-point energy
100ꢁ
contributions. Extended computational and experimental details can
be found in the Supporting Information.
Received: January 15, 2010
Revised: February 17, 2010
Published online: March 15, 2010
Keywords: ab initio calculations · biomass ·
.
EXAFS spectroscopy · homogeneous catalysis ·
reaction mechanisms
[1] Y. C. Lin, G. W. Huber, Energy Environ. Sci. 2009, 2, 80.
[2] L. D. Schmidt, P. J. Dauenhauer, Nature 2007, 447, 914.
[3] J. N. Chheda, G. W. Huber, J. A. Dumesic, Angew. Chem. 2007,
119, 7298; Angew. Chem. Int. Ed. 2007, 46, 7164.
[4] G. W. Huber, J. N. Chheda, C. J. Barrett, J. A. Dumesic, Science
2005, 308, 1446.
[5] Y. Roman-Leshkov, J. N. Chheda, J. A. Dumesic, Science 2006,
312, 1933.
[6] H. Zhao, J. E. Holladay, H. Brown, Z. C. Zhang, Science 2007,
316, 1597.
[7] Z. C. Zhang, Adv. Catal. 2006, 49, 153.
[8] J. B. Binder, R. T. J. Raines, J. Am. Chem. Soc. 2009, 131, 1979.
[9] G. Yong, Y. Zhang, J. Y. Ying, Angew. Chem. 2008, 120, 9485;
Angew. Chem. Int. Ed. 2008, 47, 9345.
[10] T. D. Fenn, D. Ringe, G. A. Petsko, Biochemistry 2004, 43, 6464.
[11] F. Meilleur, E. H. Snell, M. J. van der Woerd, R. A. Judge,
D. A. A. Myles, Eur. Biophys. J. 2006, 35, 601.
[12] X. He, G. Agnihotri, H. Liu, Chem. Rev. 2000, 100, 4615.
[13] M. Garcia-Viloca, C. Alhambra, D. G. Truhlar, J. Gao, J. Am.
Chem. Soc. 2002, 124, 7268.
[14] G. C. Ferenczy, G. Nꢂray-Szabꢃ, P. Vꢂrnai, Int. J. Quantum
Chem. 1999, 75, 215.
Experimental Section
Dehydration procedure: Glucose or fructose (50 mg) and the ionic
liquid EMIMCl (500 mg) were placed in a glass reaction vial (15 ꢁ
45 mm), and CrCl2 (2 mg, 6 mol% with respect to the sugar) was
added. The vial was closed under an inert atmosphere and then
heated at 80 or 1008C in an oil bath. The reaction was quenched at
08C, and the product mixture was analyzed by HPLC analysis.
X-ray absorption spectroscopy (XAS): XAS spectra were
recorded in a home-built transmission cell for liquid samples. In a
typical experiment, hexose (50 mg), EMIMCl (500 mg), and CrCl2
(8 mg) were mixed at 608C. A 3 mL sample of this mixture was
transferred into the XAS cell. XAS spectra at the Cr K edge were
recorded in fluorescence mode at DUBBLE of the European
Synchrotron Radiation Facility (ESRF, Grenoble, France).
[15] P. A. Lay, A. Levina in Comprehensive Coordination Chemistry
II, Vol. 4 (Eds.: J. A. McCleverty, T. J. Meyer), Elsevier,
Dordrecht, 2003, pp. 313 – 413, and references therein.
[16] J. J. Danford, A. M. Arif, L. M. Berreau, Acta Crystallogr. Sect. E
2009, 65, m227.
[17] F. A. Cotton, L. M. Daniels, X. Feng, D. J. Maloney, C. A.
Murillo, L. A. Zfflæiga, Inorg. Chim. Acta 1995, 235, 21.
[18] a) E. Groppo, C. Lamberti, S. Bordiga, G. Spoto, A. Zecchina,
Chem. Rev. 2005, 105, 115; b) G. Agostini, E. Groppo, S.
Bordiga, A. Zecchina, C. Prestipino, F. DꢄAcapito, E. van Kim-
menade, P. C. Thüne, J. W. Niemantsverdriet, C. Lamberti, J.
Phys. Chem. C 2007, 111, 16437; c) C. N. Nenu, J. N. J. van Lin-
gen, F. M. F. de Groot, D. C. Koningsberger, B. M. Weckhuysen,
Chem. Eur. J. 2006, 12, 4756; d) C. N. Nenu, E. Groppo, C.
Lamberti, A. M. Beale, T. Visser, A. Zecchina, B. M. Weckhuy-
sen, Angew. Chem. 2007, 119, 1487; Angew. Chem. Int. Ed. 2007,
46, 1465, and references therein.
DFT calculations: Electronic energies of the ground and
transition states were calculated at the PBE0/Tz//PBE0/Dz level of
theory by using Gaussian03.[20] Dz denotes the basis-set combination,
whereby the 6-31 + G(d) basis set was used for Cr, Cl, and O atoms,
and C, N, and H atoms were treated with the 6-31G(d) basis set. In an
extended Tz combination, the 6-31 + G(d) basis set was used for Cr,
6-311 + + G(d,p) for Cl and the C, H, and O atoms of the carbohy-
drate molecule and its derivatives, and 6-311G(d,p) for the remaining
C, H, and N atoms of the 1,3-dimethylimidazolium (MMIM) cations
of the model ionic-liquid solvent. At least two MMIMCl ion pairs per
Cr atom were explicitly added to describe the reaction environment.
The polarizable continuum model (PCM) was used to approximate
[19] R. D. Köhn, Angew. Chem. 2008, 120, 251; Angew. Chem. Int.
Ed. 2008, 47, 245.
[20] Gaussian03, Revision D.01, M. J. Frisch et al., Gaussian, Inc.,
Pittsburgh, PA, 2003.
2534
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 2530 –2534