Tandem Lewis/Br?nsted homogeneous acid catalysis: conversion of glucose to 5-hydoxymethylfurfural in an aqueous chromium(iii) chloride and hydrochloric acid solution

Article abstract of DOI:10.1039/c5gc01257k

A kinetic model for the tandem conversion of glucose to 5-hydroxymethylfurfural (HMF) through fructose in aqueous CrCl₃-HCl solution was developed by analyzing experimental data. We show that the coupling of Lewis and Br?nsted acids in a single pot overcomes equilibrium limitations of the glucose-fructose isomerization leading to high glucose conversions and identify conditions that maximize HMF yield. Adjusting the HCl/CrCl₃ concentration has a more pronounced effect on HMF yield at constant glucose conversion than that of temperature or CrCl₃ concentration. This is attributed to the interactions between HCl and CrCl₃ speciation in solution that leads to HMF yield being maximized at moderate HCl concentrations for each CrCl₃ concentration. This volcano-like behavior is accompanied with a change in the rate-limiting step from fructose dehydration to glucose isomerization as the concentration of the Br?nsted acid increases. The maximum HMF yield in a single aqueous phase is only modest and appears independent of catalysts' concentrations as long as they are appropriately balanced. However, it can be further maximized in a biphasic system. Our findings are consistent with recent studies in other tandem reactions catalyzed by different catalysts.

Full text of DOI:10.1039/c5gc01257k

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Page 1 of 32
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TANDEM LEWIS/BRØNSTED HOMOGENEOUS ACID CATALYSIS:
CONVERSION OF GLUCOSE TO 5-HYDOXYMETHYLFURFURAL IN AN
AQUEOUS CHROMIUM(III) CHLORIDE AND HYDROCHLORIC ACID SOLUTION
a
a
b
a*
a*
T. Dallas Swift, Hannah Nguyen, Andrzej Anderko, Vladimiros Nikolakis, and Dionisios G. Vlachos
aDepartment of Chemical and Biomolecular Engineering
Catalysis Center for Energy Innovation, University of Delaware
221 Academy Street, Newark, DE 19176 (USA)
bOLI Systems Inc., 240 Cedar Knolls Road, Suite 301, Cedar Knolls, NJ 07927, USA
Abstract
A kinetic model for the tandem conversion of glucose to 5-hydroxymethylfurfural (HMF) through
fructose in aqueous CrCl -HCl solution was developed by analyzing experimental data. We show that the
3
coupling of Lewis and Brønsted acids in a single pot overcomes equilibrium limitations of the glucose-
fructose isomerization leading to high glucose conversions and identify conditions that maximize HMF
yield. Adjusting the HCl/CrCl
glucose conversion than that of temperature or CrCl
between HCl and CrCl speciation in solution that leads to HMF yield being maximized at moderate HCl
concentrations for each CrCl concentration. This volcano-like behavior is accompanied with a change in
3
concentration has a more pronounced effect on HMF yield at constant
3
concentration. This is attributed to the interactions
3
3
the rate-limiting step from fructose dehydration to glucose isomerization as the concentration of the
Brønsted acid increases. The maximum HMF yield in a single aqueous phase is only modest and appears
independent of catalysts’ concentrations as long as they are appropriately balanced. However, it can be
further maximized in a biphasic system. Our findings are consistent with recent studies in other tandem
reactions catalyzed by different catalysts.
Keywords: Cascade reactions; Glucose; HMF; CrCl
3
; Kinetics
*
Corresponding authors: vlad@udel.edu; vlachos@udel.edu
1

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Introduction
Recently, there has been an increased interest in the production of fuels and chemicals from
renewably produced biomass derivatives. Glucose, the building block of cellulose, is an attractive
feedstock since its furanic dehydration product, 5-hydroxymethylfurfural (HMF), is considered a very
[
1]
important platform chemical as it can be upgraded in high selectivity to drop-in products like dimethyl
furan,[2,3] paraxylene , organic solvents , etc. A main current barrier to commercialization includes the
high cost, largely due to byproduct formation.[6,7] In addition, HMF is an unstable product and can easily
decompose into levulinic acid and formic acid, or form polymeric compounds, especially in the presence
[4]
[5]
[
7]
of water. Thus improving the conversion of glucose to HMF can have a significant impact on future
biorefineries.
Unlike fructose, the Brønsted acid-catalyzed dehydration of glucose to HMF is slow.[8,9] It is then
common to first isomerize glucose to fructose. This isomerization employs the largest industrial use of
immobilized enzymes; over 10 million tons of glucose isomerase are produced annually for glucose to
fructose isomerization.[10] Furthermore, it is an equilibrium-limited reaction, with an equilibrium
constant of approximately unity[11] which unfortunately limits glucose conversion. To get around this
limitation, Simeonov and coworkers have combined enzymatic isomerization of glucose to fructose in a
first reactor with Brønsted acid catalyzed fructose dehydration to HMF in a second reactor[12] where
fructose dehydrates to HMF and HMF is extracted to an organic phase, while the glucose is recycled to
the isomerization reactor. This two-pot approach employs high glucose recycle to reach complete
conversion and the operating range of the isomerization reactor is constrained from the sensitivity of
the enzyme.
[
13]
Lewis acids have been shown to be active for glucose-fructose isomerization , and can also
tolerate Brønsted acidity and high temperature, thus providing a promising alternative for the
production of HMF from glucose in a single-pot.[14,15] The Davis group obtained HMF yields in excess of
5
0% in a one-pot reactor containing Lewis acidic Sn-Beta and HCl.[15] Following Davis’ group pioneering
work, many other tandem Lewis/Brønsted acid catalysts were investigated,[16] including aluminosilicate
2

Page 3 of 32
Green Chemistry
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DOI: 10.1039/C5GC01257K
zeolites,[17] activated carbons,[18] and homogeneous metal chlorides,[19] such as CrCl
[14,20–23]
and AlCl
.[24]
3
3
For the homogeneous Lewis acid CrCl /Brønsted acid HCl single pot catalysis, we revealed rather
3
complex and unexpected interactions that render understanding experimentally challenging.[14]
The aim of the present work is to further understand the interactions of coupled Lewis and
Brønsted acids in tandem reactions and specifically how to optimize the yield and rate of HMF. At the
fundamental level, we are interested in understanding the kinetic regimes of tandem reactions
catalyzed by different catalysts as these are commonplace in biomass processing. Toward this goal, we
perform select experiments and develop the first skeleton model of coupled dual catalysts to acquire
insights.
Methods
Reaction kinetics
A typical reaction was conducted in a sealed 5 mL thick walled glass vial, containing 2 mL
aqueous solution of a reactant and a catalyst heated at desired reaction temperature. Reactants were
fructose, mannose and HMF purchased from Sigma Aldrich and used a received. Catalysts were
CrCl
3
.6H O (Sigma Aldrich) and hydrochloric acid (Fisher Scientific). Details on the amounts of reactants
2
and catalysts were listed on experiment 1-8 in Table 1. Kinetic study was performed by placing multiple
glass reactors into a preheated aluminum reactor block (Chemglass) consisting on 17 wells, filled with
mineral oil placed on a magnetic hot plate (Fisher Scientific) for control of temperature and stirring
speed. Each well contained one reactor. At a specific time point, a reactor was taken out of the oil bath
and immediately immersed in an ice bath to stop reaction.
Post reaction solutions, which contained brownish particles, were filtered with a 0.2 µm
membrane nylon filter (Thermo Scientific) before being analyzed with high-performance liquid
chromatography (HPLC - from Waters Alliance Instruments). Sugar compounds were detected by two
Biorad HPX 87C columns in series heated to 75 ⁰C, and HPLC grade water flowing at 0.5 mL/min was the
mobile phase. Glucose, mannose and fructose eluted at 25, 29.5, and 32.7 minutes respectively. HMF,
3

Green Chemistry
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levulinic acid, and formic acid were detected by a Biorad HPX 87H column heated to 50 ⁰C and 0.005 M
sulfuric acid flowing at 0.5 mL/min was the mobile phase. HMF, levulinic acid, and formic acid eluted at
1
7, 19.6 and 38.3 minutes respectively. In the HPLC chromatograms, besides peak signals of glucose,
fructose, mannose, HMF, levulinic acid and formic acid, other peaks were also observed indicating the
formation of other soluble by-products. Most of these extra peak signals were only observed when
reactants were sugars instead of HMF. Therefore, we believe that these by-products form via side
reactions involving sugars or intermediates of them. In addition, since the area of these peaks was very
small (less than 1% of the total HPLC area), quantification of these by-products was neglected in the
reaction kinetic modelling study (no significant fractions of 5,5′-oxy(bismethylene)-2-furaldehyde were
formed, consistent with the reaction being carried in water solvent).[25] Reactant conversion and yields
of identified products were calculated as follows:
t=0
reactant
c
− creactant
t=0
Conversion
(
%
)
=
)
×100%
c
reactant
c
i
Yieldi
(
%
=
×100%
t=0
c
reactant
where ꢀ is the concentration of species i.
ꢁ
A significant amount of carbon loss was accounted for by the formation of insoluble polymeric materials
during the reaction, which were filtered out before the HPLC analysis. They are generally referred to as
humins, formed from polymerization reactions of hexoses and HMF on either Brønsted acid or Lewis
acid centers. The mechanism of humins formation as well as their structure have not yet been well
[
7]
determined and are subject to debate. For our purposes, the humins’ yield was estimated from the
carbon balance of quantified products; thus it also accounts for the non-identified soluble products.
Experimental conditions
The experimental conditions, exploiting different temperatures, substrates, and catalyst
concentrations, are listed in Table 1. Procedures of experiments conducted herein are reported in Ref.
4

Page 5 of 32
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[14].
Experiments 1-16 were used for parameter estimation and experiments 17-27 were employed for
model assessment.
Table 1. Experimental conditions. Data are from this work unless otherwise stated.
o
Experiment Temperature ( C)
Substrate (wt%)
Catalyst
Ref. Used for parameter
estimation
Yes
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
*
110
130
110
130
110
130
110
130
130
130
140
150
140
130
140
140
130
150
130
130
130
130
140
140
130
130
140
Mannose (5)
5 mM CrCl
3
3
3
3
3
3
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Mannose (5)
Fructose (5)
Fructose (5)
HMF (5)
5 mM CrCl
5 mM CrCl
5 mM CrCl
5 mM CrCl
5 mM CrCl
HMF (5)
Mannose (5)
Mannose (5)
Glucose (5)
45 mM HCl
45 mM HCl
5 mM CrCl
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
Glucose (5) + HMF (1.5) 5 mM CrCl
3
[
[
[
[
[
[
14]
14]
14]
14]
14]
14]
Yes
Yes
Yes
Yes
Yes
Yes
No
No
No
No
No
No
No
No
No
No
No
Fructose (10)
Glucose (10)
Glucose (10)
Glucose (10)
Glucose (10)
Fructose (10)
Glucose (1)
Glucose (1)
Glucose (5)
Glucose (5)
Glucose (5)
Glucose (5)
Glucose (10)
Glucose (10)
Glucose (5)
Glucose (5)
Glucose (10)*
17 mM CrCl
17 mM CrCl
17 mM CrCl
17 mM CrCl
17 mM CrCl
17 mM CrCl
3
3
3
3
3
3
+ 0.1 M HCl
+ 0.1 M HCl
2 mM CrCl
2 mM CrCl
5 mM CrCl
5 mM CrCl
5 mM CrCl
5 mM CrCl
3
3
3
3
3
3
+ 5 mM HCl
+ 10 mM HCl
+ 34 mM HCl
+ 120 mM HCl
[
[
14]
14]
8.5 mM CrCl
25 mM CrCl
3
3
5 mM CrCl
5 mM CrCl
3
+ 0.01 M HCl
+ 0.1 M HCl
3
[
14]
17 mM CrCl
Biphasic reactor used (20 wt% NaCl in aqueous phase + 2:1 THF:H O)
3
+ 0.1 M HCl
2
5

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Reaction network and kinetic modeling
We simulated the Brønsted acid chemistry using the reaction network shown with solid arrows
in Scheme 1, leveraging previous work for reactions 1-5[26,27] and 6-7[28] whose temperature range and
explicit pH dependence make them consistent with this work. Brønsted catalyzed mannose conversion
to HMF and humins (reactions 8 and 9) have been quantified here for first time. The parameters of all
Brønsted acid-catalyzed reaction rate laws are given in Table 2.
Scheme 1. Reaction network for tandem reaction of glucose conversion to HMF by CrCl and HCl in aqueous phase.
3
A kinetic model for CrCl -catalyzed reactions has not yet been published. Building on the
3
mechanistic insights proposed for glucose isomerization in Sn-BEA by the Davis group[29] and the
reaction network of Rajabbeigi et al.,[30] we propose a Lewis acid catalyzed reaction network shown by
dashed lines in Scheme 1 (reactions 10-16). The parameters of the Lewis acid-catalyzed reaction rate
laws are also given in Table 1. The speciation of CrCl in solution was calculated using the OLI Analyzer
3
Studio version 9.2 (OLI Systems, 2012), which is based on the aqueous electrolyte model presented by
Wang et al.[31] and was also used in our previous work.[14]
Parameter estimation involves fitting the transient profiles of glucose, mannose, fructose, HMF,
and LA using the fminunc minimization routine in Matlab R2013a. A similar procedure for parameter
estimation was previously employed for fructose dehydration kinetics in HCl.[26]
6

Page 7 of 32
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Results and discussion
Kinetic Parameters
The reaction kinetics of Brønsted acid-catalyzed chemistry has been reported before, except for
the Brønsted acid-catalyzed reactions of mannose. Thus, below we focus on the mannose chemistry in
HCl and on the Lewis acid-catalyzed reactions.
Mannose conversion in HCl
Mannose dehydration is considerably less studied compared to that of glucose and fructose.
Figure 1 shows the experimental concentration profiles (points) and model predictions (lines) using the
fitted parameters. HMF, FA/LA and humins are the main products, with humins being the most
abundant. As noted by van Putten et al., aldose sugars, including glucose and mannose, react similarly in
[
8]
aqueous solutions. The estimated parameters of Brønsted catalyzed mannose dehydration to HMF are
shown in Table 2 . While no literature is available for direct comparison, the activation energy of
mannose dehydration to HMF (175 kJ/mol) is similar to reported values of glucose dehydration to HMF
152-160 kJ/mol),[28,32] supporting the conclusion that mannose and glucose react similarly. The
[8]
(
activation energy for mannose degradation to humins (58 kJ/mol) is also consistent with the activation
energy for glucose degradation to humins (51 kJ/mol).[28] As mannose is a minor product, no further
experiments and model assessment were conducted.
7

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Figure 1. Concentration profiles of 5 wt% mannose dehydration in aqueous HCl (45 mM, pH = 1.35) at 110 oC
o
(
(
a) and 130 C (b) from experiments 7-8 in Table 1. Measurable compounds include mannose (circles), HMF
triangles), LA (diamonds), and FA (not shown).
HMF degradation in CrCl
3
The products and mechanisms of HMF degradation in aqueous CrCl
3
solutions have not yet been
extensively studied. Figure 2 shows the HMF conversion and carbon yield of LA, FA, and humins. At 110
oC, the yield to humins is much higher than that to either LA or FA. This differs significantly from
Brønsted acid catalyzed chemistry, where the FA and LA account for over 80% of the HMF degradation
products.[26] At 130 C, the FA/LA yield is higher but humins remain the dominant product. The activation
energies of Brønsted-acid catalyzed HMF rehydration to FA/LA and HMF degradation to humins are
o
[
7]
similar, so the change in selectivity of the HMF consumption paths with temperature underscores that
8

Page 9 of 32
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there is a Lewis acid-catalyzed path of humin formation from HMF. This finding is corroborated by the
fact that FA forms in excess of LA, especially at lower temperatures (see supporting information Figure
S1), where the Lewis acid chemistry is dominant. This situation differs from typical Brønsted acid
rehydration chemistry that produces an equimolar amount of FA and LA.[26] Given the high yield to
humins, we hypothesize that FA is mainly produced as a byproduct of HMF condensation leading to
humins via a Lewis-acid catalyzed path. This is reminiscent of the additional retro-aldol path in glucose
[
9]
dehydration in HCl. The Lewis acid catalyzed reaction network (shown with dotted lines in Scheme 1)
accounts for this finding.
9

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o
o
Figure 2. HMF conversion and carbon yield of products at (a) 110 C and (b) 130 C in the presence of 5 mM
aqueous CrCl3. Data (points) from experiments 5 and 6 in Table 1. Lines represent model predictions.
Sugar isomerization and epimerization reactions in CrCl
3
Typical concentration profiles in aqueous CrCl starting from glucose and fructose are shown in
3
Figure 3a and b, respectively. Glucose primarily isomerizes to fructose at short times. As the reaction
proceeds, fructose dehydrates to HMF, which further rehydrates to LA and FA. Humins also form. In
order to rationalize the formation of HMF, LA, and FA, which are considered as Brønsted acid-catalyzed
products, we previously showed, using the speciation model,[14] that hydrolysis of the hydrated
3+
2
Cr(H O)
6
ion
3
+
2
+
+
Cr
( (
H O)6 + H O ⇔ Cr H O)5 OH + H O
2
2
2
3
1
0

Page 11 of 32
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decreases the pH. The reaction shown above, and other similar ones, is sufficient to drop the pH of the
solution to ~1.7 at reaction conditions, leading to Brønsted acid-catalyzed chemistry.
It is now well established that homogeneous Brønsted acids, such as HCl, decrease the reactivity
of CrCl
3
in glucose-fructose isomerization based on reversing the hydrolysis reaction (shown above).[14,23]
O)
OH 2+ is the active species for
To explain this phenomenon, we proposed that the ionic species Cr(H
2
5
the isomerization and the addition of HCl shifts the hydrolysis reaction reducing the concentration of the
active centers.[14] Consistent with the earlier results, Mushrif et al. showed that Cr(H
OH catalyzes
2+
2
O)
5
3+
glucose-fructose isomerization more effectively than Cr(H
simulations.[33,34] These findings are consistent with HCl reducing CrCl
speciation distribution of CrCl ·6H O in aqueous solutions the Cr(H O)
2
O)
6
using first-principles molecular dynamics
3
activity, since based on the
OH 2+ ion is most abundant
3
2
2
5
o
[36]
between pH 2-4 at 100 C.
In addition to the effect of Brønsted acids on the rate of Lewis acid-catalyzed sugar
isomerization, Lewis acid catalysts also affect the rate of fructose dehydration and HMF degradation
indirectly by promoting new paths leading to humins (Table 2). Aside from these negative couplings
between Lewis and Brønsted acid catalysts, the one-pot reactor drives the equilibrium-limited glucose-
fructose isomerization to high conversions via dehydrating fructose to HMF thus overcoming the
otherwise very slow glucose dehydration to HMF via Brønsted acid-catalyzed chemistry alone. Given
these tradeoffs, understanding the effect of interplay of the two catalysts on HMF yield and rate is
important to determine the optimal catalyst concentrations.
In attempting to correlate the glucose consumption rate with the active species concentration
over a wide pH range, we found that the change in Cr(H
2
O)
5
OH 2+ concentration is significantly greater
O)
OH 2+
than the change in the reaction rate (not shown). Indeed, Choudhary et al. concluded that Cr(H
2
5
must be the active species based on kinetics measurements mainly without HCl (and a single experiment
when 0.1 M HCl was added).[14] The OLI speciation model relies on thermodynamic parameters
determined in aqueous solution at higher pH.[36–39] Formation of oligomers is expected at low pH that
1
1

Green Chemistry
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are not accounted for.[40] To overcome these limitations, we employ an empirical representation for the
activity of the catalytically active Lewis acid species:
1
/3
2
+

CrOH  


a = 



L
+



H



1
The concentrations of the species are determined using the OLI software. The exponent in
Equation 1 was determined by regressing data of Experiments 1-6 and 9-16 in Table 1. Figure S2 shows
the predicted value of ꢂ for Experiments 9 and 19-22 in Table 1. The functional form of ꢂ captures
ꢃ
ꢃ
well the change in apparent rate constant, considering Experiments 19-22 were not used to determine
the exponent in Equation 1.
Figure 3b shows the concentration profiles when fructose is the substrate. The major product of
this reaction is HMF, followed by LA and FA, formed from Brønsted acid-catalyzed dehydration whereas
the glucose and mannose concentrations are low. The CrCl -induced Brønsted acidity is therefore strong
3
enough that the fructose dehydration is faster than the Lewis acid-isomerization to glucose.
The hexose sugars may follow two different isomerization paths catalyzed by Lewis acids. First
glucose can convert to fructose and fructose to mannose via an intramolecular hydride transfer between
C1 to C2.[41,42] Glucose may also convert directly to mannose via the Bilik mechanism through a 1-2
intramolecular carbon shift.[42,43] Figure 3 shows that fructose produces glucose and mannose in similar
molar amounts after five minutes, indicating that both intramolecular hydride transfer pathways are
active in solution. On the other hand, glucose produces fructose with much higher selectivity than
mannose, indicating that intrahydride transfer dominates over Bilik reaction. This finding is consistent
with prior work using Sn-BEA for glucose chemistry.[43] Rajabbeigi et al. also found that glucose
conversion to mannose is an order of magnitude slower than glucose-fructose isomerization and
fructose-mannose isomerization.[30] Glucose, fructose, and mannose may all also degrade to humins.
Therefore, we can conclude that our data are in agreement and support the reaction network shown
with dashed arrows in Scheme 1.
1
2

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Figure 3. Representative concentration profiles starting with (a) 10 wt% glucose and (b) 10 wt% fructose in
o
[14]
1
7 mM CrCl
3
at 140 C taken from (experiments 11 and 13 in Table 1). Lines represent predicted
concentration profiles.
1
3

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Table 2. Reactions, rate laws, and estimated parameters determined herein unless otherwise stated for reactions shown in Scheme 1. Parity
plot for select experiments is shown in Figure S3.
-
1
-
/min-1
Reaction
Catalyst
Rate expression
Activation
energy, kJ/mol
ln(k403K/min M
)
log10(A
M )
0
Reference
1
-1
a
Glucose → Fructose
Fructose → Mannose
Mannose → Glucose
Fructose → Humins
Mannose → Humins
Glucose → Humins
HMF → Humins
CrCl
CrCl
CrCl
CrCl
CrCl
CrCl
CrCl
HCl
3
3
3
3
3
3
3
100 ± 5
-4.62 ± 0.03
-5.44 ± 0.03
-6.08 ± 0.03
-5.33 ± 0.03
-5.43 ± 0.11
-6.60 ± 0.10
-6.73 ± 0.11
-4.98 ± 0.02
-4.45 ± 0.13
1.44 ± 0.04b
11.0
9.4
k a C
i
L
Glu
Fru
Man
Fru
Man
Glu
a
a
91 ± 2
k a C
i
L
80 ± 11
114 ± 6
68 ± 7
7.7
k a C
i
L
9.5
k a C
i
L
6.4
k a C
i
L
71 ± 19
56 ± 9
6.4
k a C
i
L
4.2
k a C
HMF
i
L
Mannose → HMF
Mannose → Humins
Fructose → HMF
175 ± 3
58 ± 12
127 ± 2
20.5
5.6
k C C
i
+
Man
Man
H
HCl
k C C
i
+
H
18.1c
[26,27]
HCl
C +
H
kiφ
f
CFru
C
H O
2
-4.22 ± 0.16 b
-3.25 ± 0.02 b
-5.14 ± 0.21 b
16.4
11.9
6.6
[26,27]
[26,27]
[26,27]
Fructose → Humins
HMF → FA/LA
HCl
HCl
HCl
133 ± 7
97 ± 1
64 ± 8
k C C
Fru
i
+
H
k C C
i
+
HMF
HMF
H
HMF → Humins
k C C
i
+
H
1
4

Page 15 of 32
Green Chemistry
-4.92 ± 0.19 b
15.5
[26,27]
[28]
Fructose →
FA/Humins
HCl
HCl
HCl
129 ± 10
160 ± 5
k C C
Fru
i
+
H
18.4 ± 1.0d
3.9 ± 0.5 d
1
.29
Glucose → HMF
k C
CGlu
i
(
H +
)
[28]
Glucose → Humins
2.76
51 ± 2


k 0.29 + C
CGlu
i
(
H +
)




a
[11,30]
Reverse reactions modeled based on literature equilibrium constants
Reference temperature of 381K used for these parameters
b
c
c
[28]
−1
Units of A
0
expressed in min
−n
−1
Units of A
0
expressed in M ⋅min , where n is the exponent associated with C +
H
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The activation energies of glucose-fructose and fructose-mannose isomerization are similar,
which may be expected given that both reactions proceed via the same mechanism of 1,2
intramolecular hydride transfer. Our reported value is in excellent agreement with the first-principles
predicted value of 104 kJ/mol.[33] In comparison to solid Lewis acid catalysts, Sn-BEA has a similar
activation energy (95 kJ/mol)[30] whereas Ti-BEA has a higher value (155 kJ/mol).[13] The activation energy
reported here for glucose-fructose isomerization differs from that reported by Choudhary et al.[14] (64
kJ/mol) because Table 2 includes the contribution of changing speciation equilibria with temperature
and also considers a wider dataset.
When HCl is added to aqueous CrCl
3
solution, Brønsted acid catalyzed reactions become more
- and HCl-catalyzed
prevalent. It is therefore important to understand the relative rates of CrCl
3
reactions, particularly how the rate of glucose isomerization compares to that of fructose dehydration.
o
, the apparent rate constant of glucose isomerization to fructose of 0.01 min-1
At 130 C with 5 mM CrCl
3
-
1
is higher than that of fructose dehydration to HMF of 0.0022 min (estimated considering the predicted
pH=2.3 of CrCl solution) by fivefold.
Effects of CrCl concentration and temperature on rate and yields
3
3
Figure 4 shows the experimentally observed glucose conversion, fructose yield, and HMF yield
as a function of time at different catalyst concentrations. The glucose consumption rate increases with
increasing CrCl concentration. Recently, Jia et al. found that the yields of fructose and HMF as a
3
o
[20]
function of glucose conversion do not change with catalyst concentration at 110 C. Our data at
higher temperatures (Figure 4b-c) also support this finding since fructose and HMF yields are not
sensitive to changes in the catalyst concentration at the same glucose conversion. These findings
indicate that the relative rates of desirable (isomerization and dehydration) and undesirable (humin
formation) reactions have weak dependence on CrCl
conversion rate must be balanced by similar enhancement in the other reactions. This trend is
consistent with each CrCl -catalyzed reaction having the same functional dependence on CrCl
concentration and potentially involving the same catalytically active species. The ꢂ term in Table 2
3
concentration. So the enhancement in glucose
3
3
ꢃ
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reflects these observations, since it does not change for different reactions (the model captures this
well; see Figure S4).
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Figure 4. (a) Glucose conversion as a function of time, and yield of (b) fructose and (c) HMF as a function of
o
glucose conversion at 140 C at three different CrCl
3
concentrations. Data from experiments 23-24 in Table 1.
Figure 5 shows that the yields of fructose, HMF and humins do not vary with reaction
temperature at the same glucose conversion. While the absolute rate of glucose conversion increases
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o
with increasing temperature over the range of 110-150 C, the relative rates of isomerization and
o
[20]
degradation reactions do not change consistent with the observation of Jia et al. at 90-130 C. The
temperature insensitivity of the yield suggests that the activation energies of the most important
reactions have similar values. These important reactions include glucose-fructose isomerization,
fructose dehydration to HMF, and humin-formation reactions. We determine the most important of
these degradation reactions by examining the predicted sources of the humins (Figure 6). Figure 6 shows
that most of the humins form from either fructose (>50% from Lewis acid-catalyzed reactions) or
glucose (25-40% from Lewis acid-catalyzed reactions). These reactions have comparable activation
energies (127 vs. 114 kJ/mol), and thus, as the temperature changes, the rates of fructose degradation
to humins and fructose dehydration to HMF vary proportionally. This rationalizes the temperature-
insensitivity of fructose and HMF yield in CrCl as shown in Figure 5 (see Figure S5 for model
3
predictions). These findings also agree with earlier work by Weingarten et al., who determined that
increasing the number of Lewis acid sites increases the formation of humins from glucose,[44] and
highlight the importance of reducing the Lewis acid-catalyzed humin formation reactions of sugars,
particularly of fructose.
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Figure 5. (a) Fructose yield, (b) HMF yield, and (c) humin carbon yield at different temperatures vs. glucose
conversion. Experiments 12-14 in Table 1.
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o
Figure 6. Humins yield after 1, 2, and 3 h of reaction (10 wt% glucose, 130 C, 5 mM CrCl ) broken down by
3
source. Hashes indicate Brønsted acid-catalyzed reactions; un-hashed bars indicate Lewis acid-catalyzed
reactions.
Taken together, these findings indicate that varying the concentration of CrCl or adjusting the
3
temperature are not effective strategies for improving HMF yield from glucose, a key factor in improving
the economic viability of this process.[45] Therefore, below we evaluate the possibility of improving HMF
yield by adding HCl to CrCl
3
in aqueous solution.
Optimizing HMF yield in tandem reactions
Unlike temperature and CrCl concentration, adding HCl to a reactor does change HMF yield
3
from glucose (Figure S6) by simultaneously increasing the rate of fructose dehydration and decreasing
the rate of glucose isomerization. The additional HCl would be beneficial if faster fructose dehydration
improved HMF selectivity more than the reduced glucose isomerization hurt it. In order to understand
which reactions control the HMF rate, Figure 7 shows the normalized sensitivity coefficient (NSC) of
HMF selectivity to changes in the rate constants of all reactions when only CrCl is present. Since the
3
NSC of fructose dehydration to HMF is higher than that of glucose-fructose isomerization, adjusting the
HCl concentration should have the most pronounced impact on HMF selectivity. However, these
sensitivities may change as the amount of HCl in the system increases.
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Figure 7. Normalized sensitivity coefficient of HMF selectivity after 5 h to rate constants of each reaction at
o
1
30 C with 5 mM CrCl
3
.
Recently, Patet et al. explored para-xylene production from dimethylfuran and ethylene, a
tandem reaction involving a homogeneous Diels-Alder cycloaddition followed by a Brønsted acid
catalyzed dehydration.[46] They observed a clear kinetic regime change upon increasing the amount of
Brønsted acid catalyst. At low catalyst concentrations the rate increases with increasing catalyst
concentration and eventually plateaus at high catalyst concentrations, accompanied with a change in
the rate-limiting step from Brønsted-acid catalyzed to the uncatalyzed Diels-Alder reaction. Similar
trends have been observed in forthcoming work studying glucose conversion to HMF using a
bifunctional H-BEA catalyst.[47] Like other tandem reactions, a change in kinetic regimes is observed
herein as the HCl concentration increases (Figure 8a), accompanied by a change in the rate-limiting step
Figure 8b). When the HCl concentration is low Brønsted catalyzed dehydration is the rate limiting step.
(
The opposite can be concluded in the case of solution with high HCl concetrations. The maximum of the
HMF reaction rate instead of the plateau arises from the enhancement of the HMF degradation
reactions at high Brønsted acid catalyst concentrations, while such degradation reactions in the case of
2
2

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para-xylene example were slow. These results show that one needs to balance the Lewis acid and
Brønsted acid concentrations to optimize HMF yield and rate.
Figure 8. (a) Predicted reaction rates of glucose, fructose, and HMF as a function of HCl concentration and (b)
normalized sensitivity coefficient of HMF reaction rate at different HCl concentration after 1 hour of reaction.
o
Conditions: 10 wt% glucose, 5 mM CrCl
3
, 130 C.
Given the nonlinear dependence of HMF yield on HCl concentration and in order to understand
the interplay of the two catalysts, we performed parametric studies. Figure 9 shows the maximum HMF
yield and the corresponding time as a function of HCl concentration at fixed CrCl concentration (full
3
profiles of conversion and yield for select HCl concentrations are given in Figure S7). When more CrCl
3
is
present, the optimal HMF yield occurs at higher HCl concentration but the maximum HMF yield itself
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does not change. Interestingly, a volcano relationship with an optimum HCl concentration for each CrCl
concentration is observed, reflecting a change in the rate-limiting step from dehydration at low HCl
concentrations to isomerization at high HCl concentrations (sensitivity analysis shown in Figure 8b). As
shown in Figure 9a, HMF yield is maximized when HCl concentration is ~0.02 M, where the NSC of
isomerization and dehydration reactions are similar (Figure 8b), indicating the desirability of balancing
isomerization and dehydration. Generally, lower pH decreases processing time, so intermediate
concentrations of HCl can both increase HMF yield and decrease the time it takes to reach that yield.
3
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4

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Figure 9. (a) Maximum HMF yield and (b) time to reach the maximum yield as a function of HCl concentration
at different Lewis acid catalyst concentrations and temperatures.
In order to assess the model prediction, we conducted additional experiments. Figure 10
compares experimental data (symbols) and model predictions (lines) of glucose conversion and HMF
yield as a function of time for three HCl concentrations. While the glucose conversion is not captured as
well at long times, the HMF yield is predicted very well and underscores the non-monotonic dependence
of HMF yield on HCl concentration. This is the first model-based prediction indicating that there are
optimal catalyst concentrations.
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Figure 10. Experimentally observed (symbols) and model predictions (lines) (a) glucose conversion and (b)
o
HMF yield in aqueous CrCl
3
+HCl at 5 wt% glucose and 130 C with 5 mM CrCl
3
for various HCl concentrations
indicated. Experiments 25-26 in Table 1.
Reactive extraction
A disadvantage of high Brønsted acidity is that in addition to enhancing fructose dehydration
rate it also enhances the rates of HMF degradation reactions. The addition of an organic extracting
phase can reduce HMF degradation products[48] and was shown to work for this tandem reaction.[14]
Figure 11 shows the predicted concentration profile for this biphasic system compared to experimental
data for a reactor with a 2:1 volume ratio of THF:H
extraction, shown in dashed line). While glucose conversion and fructose yield are well-predicted, the
HMF yield is somewhat under-estimated. Wrigstedt et al. found that fructose in aqueous CrCl /HCl
2
O and for an infinite partition coefficient (ideal
3
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6

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reacts differently in the presence of different inorganic salts, such as NaCl and KCl.[23] We hypothesize
that the underestimation could be due to salt effects not captured by the model. Importantly, extraction
significantly enhances the HMF yield. Furthermore, even in the presence of an extractant, the HMF yield
is maximized at moderate HCl concentrations (Figure S8).
Figure 11. Predicted and experimental glucose conversion, fructose yield, and HMF yield as a function of time
in a biphasic reactor with 2:1 volume ratio of THF (partition coefficient = 7, shown by solid lines) and ideal
extractant (dashed lines). Experimental conditions given in Experiment 27 in Table 1.
Conclusions
We have conducted select experiments in order to develop and assess the first-of its kind model
describing the tandem conversion of glucose to HMF through fructose in aqueous CrCl -HCl.
3
Experimental data indicate that glucose converts to fructose and fructose converts to mannose mainly
via 1,2 intrahydride transfer, whereas epimerization (Bilik) reaction via intracarbon shift is considerably
slow under our conditions, consistent with the mechanism over Sn-BEA zeolite of the Davis group[43] and
in support of the NMR data on the glucose to fructose isomerization over CrCl
3
catalyst of our prior
work.[16] Brønsted-acid catalysis of mannose leads primarily to humins, and HMF in CrCl
undergoes
3
considerable loss to humins and formic acid especially at low temperatures. Consistent with recent
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work,[20] we find that increasing temperature and CrCl
concentration do not change either fructose or
3
HMF yield at constant glucose conversion and are not effective for HMF yield optimization.
In agreement with our previous work,[14] we show that Lewis acid metal salts interact with the
3+
homogeneous Brønsted acids in complex ways. Specifically, hydrolysis of the hydrated Cr releases
protons and drives endogenous Brønsted acid chemistry. Exogenous Brønsted acids retard the rate of
isomerization due to changing the speciation (reducing the active species concentration) but at the
same time increase the rate of fructose dehydration and HMF degradation. In turn, Lewis acid salts
accelerate the rate of glucose conversion to fructose mainly via isomerization but also open up new
channels, mainly Lewis-catalyzed humin formation from sugars (fructose > glucose > mannose) and to
less extent from HMF, which reduce HMF yield. Finally, the coupling of Lewis and Brønsted acids in a
single pot overcomes equilibrium limitations of the glucose-fructose isomerization leading to high
glucose conversions. Model predictions and assessment experiments clearly show for the first time that
the interplay of these complex interactions leads to HMF yield being maximized at moderate HCl
concentrations for each CrCl concentration. This volcano-like behavior is accompanied with a change in
3
the rate-limiting step from fructose dehydration to glucose isomerization as the concentration of the
Brønsted acid increases. The maximum HMF yield in a single aqueous phase is only modest and appears
independent of catalysts’ concentrations as long as they are appropriately balanced. Finally,
experiments and modeling indicate significant increase in yield using a biphasic system. Fundamentally,
as the concentration of the Brønsted acid increases, a change in kinetic regimes in the reaction rate of
HMF production is predicted, consistent with recent studies in other tandem reactions catalyzed by
different catalysts, underscoring that this is a generic behavior of cascade reactions.
Acknowledgements
The authors would like to thank Dr. Marta León, who conducted Experiments 17 and 18. This
work was supported as part of the Catalysis Center for Energy Innovation, an Energy Frontier Research
Center funded by the US Dept. of Energy, Office of Science, Office of Basic Energy Sciences under award
number DE-SC0001004.
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