CaCl2molten salt hydrate-promoted conversion of carbohydrates to 5-hydroxymethylfurfural: an experimental and theoretical study

Article abstract of DOI:10.1039/d0gc04356g

Alkaline earth metal salts are environmentally friendly and economical. They have attracted much attention in the process of biomass conversion, especially for isomerization and dehydration. However, the lack of understanding of the alkaline earth metal-mediated catalytic mechanism prevents the achievement of high HMF yields from glucose or fructose. Herein, we performed experimental and theoretical studies on CaCl₂-catalyzed glucose-to-fructose isomerization and fructose-to-HMF dehydration. In CaCl₂solution, the highest fructose yield (33.6%) from glucose can be achieved at 80 °C. Meanwhile, the presence of CaCl₂in fructose-to-HMF dehydration notably improved fructose conversion. A “one-pot” isomerization-dehydration of glucose to prepare HMF was designed and 100% conversion and 52.1% HMF yield were obtained. The CaCl₂solution can be reused for five runs while maintaining catalytic activity without regeneration. Through¹H NMR,¹³C NMR, DOSY-NMR and DFT calculations, we concluded that the coordination between the C1/C2 sites of the β-glucopyranose tautomer and CaCl₂promoted the 1,2-intramolecular hydride shift of glucose, thus rapidly converting glucose into fructose. Similarly, Ca²⁺can complex with the C2/C6-OH of β-d-fructofuranose and stabilize this tautomer, which easily forms HMF. This is the main reason that CaCl₂can promote the preparation of HMF from fructose.

Full text of DOI:10.1039/d0gc04356g

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CaCl2 molten salt hydrate-promoted conversion of
carbohydrates to 5-hydroxymethylfurfural: an
experimental and theoretical study†
Cite this: Green Chem., 2021, 23,
2058
Changqu Lin,‡a Chaoqun Chai,‡b Yuanzhang Li,a Jiao Chen,a Yanyu Lu,a Hongli Wu,a
Lili Zhao, *b Fei Cao, *a Kequan Chen, a Ping Weia and Pingkai Ouyanga
Alkaline earth metal salts are environmentally friendly and economical. They have attracted much atten-
tion in the process of biomass conversion, especially for isomerization and dehydration. However, the
lack of understanding of the alkaline earth metal-mediated catalytic mechanism prevents the achieve-
ment of high HMF yields from glucose or fructose. Herein, we performed experimental and theoretical
studies on CaCl2-catalyzed glucose-to-fructose isomerization and fructose-to-HMF dehydration. In
CaCl2 solution, the highest fructose yield (33.6%) from glucose can be achieved at 80 °C. Meanwhile, the
presence of CaCl2 in fructose-to-HMF dehydration notably improved fructose conversion. A “one-pot”
isomerization–dehydration of glucose to prepare HMF was designed and 100% conversion and 52.1%
HMF yield were obtained. The CaCl2 solution can be reused for five runs while maintaining catalytic
activity without regeneration. Through 1H NMR, 13C NMR, DOSY-NMR and DFT calculations, we con-
cluded that the coordination between the C1/C2 sites of the β-glucopyranose tautomer and CaCl2 pro-
moted the 1,2-intramolecular hydride shift of glucose, thus rapidly converting glucose into fructose.
Similarly, Ca2+ can complex with the C2/C6-OH of β-D-fructofuranose and stabilize this tautomer, which
easily forms HMF. This is the main reason that CaCl2 can promote the preparation of HMF from fructose.
Received 25th December 2020,
Accepted 8th February 2021
DOI: 10.1039/d0gc04356g
rsc.li/greenchem
charides is a selective oxygen removal method and can
produce functional platform chemicals, such as 5-hydroxy-
Introduction
Climate changes caused by the continued emission of carbon methylfurfural (HMF), furfural, lactic acid, and levulinic acid.6
dioxide from fossil resource utilization have accelerated the HMF is a triple dehydration product derived from glucose and
development of carbon-balanced processes for the conversion fructose and was evaluated to be one of the “top 10 + 4” bio-
of renewable resources to fuels, chemicals, and/or materials.1–3 based chemicals.7 At present, HMF is regarded as an impor-
Non-edible lignocellulose, an abundant, cheap, and renewable tant platform for bridging the biomass chemistry and petro-
biomass resource, is a promising feedstock for the preparation chemical industry and can be used to prepare various value-
of fuels and chemicals and can be obtained by plant photosyn- added furan-based compounds, polymers, and alkane
thesis, which results in a “closed carbon balance” through CO2 molecules.8
capture.4 However, the high oxygen content in biomass is one
In addition to various acid catalysts, metal salts play an
of the biggest obstacles to its conversion into fuel and tra- important role in the selective conversion of glucose and fruc-
ditional petrochemical products.5 Dehydration of monosac- tose to HMF and its derivatives.9 The addition of inorganic
salts in the aqueous phase not only improves the partition
coefficient of HMF in the organic phase to prevent undesired
side reactions10 but also provides Lewis acid catalysts to carry
out glucose isomerization.11 Among them, alkaline earth
metal salts have shown some special properties because they
aCollege of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University,
30 South Puzhu Road, Nanjing, 211816, P. R. China.
can form bidentate complexes with different saccharides and
act as honorary transition metals in actions reported by Zhou
and co-workers.12 Wyman13 et al. showed that the rate constant
of degradation of xylotriose into furfural when treated with
CaCl2 and MgCl2 was higher than that with sodium chloride.
Yang14 et al. found that MgCl2 was the most efficient catalyst
E-mail: csaofeiw@njtech.edu.cn
bInstitute of Advanced Synthesis, School of Chemistry and Molecular Engineering,
Nanjing Tech University, 30 South Puzhu Road, Nanjing, 211816, P. R. China.
E-mail: llzhao@njtech.edu.cn
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
d0gc04356g
‡These authors contributed equally to this work.
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among ested metal chlorides (NaCl, CaCl2 and MgCl2) for
agarose degradation and resulted in both the highest yield of
40.7% and the highest selectivity of 49.1% at 200 °C. The clea-
Experimental
Materials
vage of the C–O–C bond in agarose with the subsequent iso- Glucose, mannose, and fructose were obtained from Aladdin
merization of galactose to its ketose was considered as a poss- Industries Corporation. MgCl2, CaCl2, SrCl2, BaCl2, and other
ible mechanism for the formation of HMF. Combs and co- inorganic salts were purchased from Sigma-Aldrich.
workers15 found that the introduction of alkaline earth metal 2-Methyltetrahydrofuran (2-MeTHF), tetrahydrofuran (THF),
salts (CaCl2 and MgCl2) into acidic media can enhance the γ-valerolactone (GVL), and dimethyl sulfoxide (DMSO) were
glucose conversion rate and the HMF yield via the complexa- purchased from Sigma-Aldrich. HMF was purchased from
tion of glucose and alkaline earth metal salts. The presence of Adamas.
CaCl2 notably improved the catalytic performance of Al2O3 as
the catalyst.16 However, to fully understand the reaction
mechanism, defining the role of the alkaline earth metal in
Isomerization of glucose in molten salt hydrates
the isomerization and dehydration processes is still necessary.
Different molten salt hydrates (concentrated aqueous salt solu-
A molten salt hydrate (MSH) is an inorganic salt aqueous tions), including MgCl2, CaCl2, CaBr2, SrCl2, and BaCl2, were
solution with a high concentration determined by the coordi- investigated for glucose isomerization. 2 mL of the mixture
nation number of the salt cation. In a perfect MSH, all water solutions (100 g L−1 glucose and 25.6 wt% salts) were loaded
molecules are tightly bound to the inner coordination sphere in a 10 mL ACE pressure tube. The isomerization was con-
of the cation of the salt, leaving the anion naked (uncoordi- ducted at 40–120 °C for 120 min with a magnetic stirrer in an
nated) in the system. MSHs possess similar characteristics to oil bath. After the isomerization reaction, the reactor was
organic ionic liquids, including high thermal stability and low cooled in a water bath for 10 min and then the contents were
toxicity and volatility, and are also low cost and easy to diluted for the quantitation of sugars using high-performance
prepare. MSHs have mainly been employed for the swelling ion chromatography (HPIC), as described below.
and dissolution of lignocellulosic biomass, cellulose hydro-
lysis, and the conversion of mono sugars into platform chemi-
cals such as HMF, 1-(furan-2-yl)-2-hydroxyethanone and isosor-
The dehydration of carbohydrates into HMF
bide.9 Pan’s17 team investigated glucose isomerization in five 1 mL 100 g L−1 fructose or glucose, 9.5 to 37.8 wt% salts, and
halide salt MSHs (LiCl, LiBr, LiI, CaBr2, and ZnCl2), and 4 mL 2-MeTHF were weighed out into a 10 mL ACE pressure
results indicated that 31% of fructose was produced from tube. The mixtures were reacted at 140 °C–200 °C for 30 min–
glucose in LiBr trihydrate. Bhaumik18 et al. demonstrated 240 min with a magnetic stirrer in an oil bath. After the reac-
using a eutectic ternary LiNO3-NaNO3-KNO3 molten salt melt tion, the aqueous layer and the organic solvent layer were sep-
under mild conditions for HMF production directly from arated and filtered with a 0.2 μm syringe filter. The aqueous
biomass-derived saccharides such as fructose and glucose in a phase was diluted with water prior to analysis and the organic
biphasic system. The solubility of CaCl2 is 137 g per 100 mL at phase was diluted with 2-MeTHF prior to analysis.
50 °C, which exceeds the requirement of the coordination
number of the salt cation, so a high concentration CaCl2 solu-
tion can form a new MSH. Compared with the lithium salt
Computational details
MSH, the new type of CaCl2 MSH is cheaper (CaCl2 is over 10 Geometry optimizations without symmetry restriction were
times cheaper than LiCl) and the calcium content reserve in carried out using the Gaussian 16 program. Specifically, geo-
the crust is more abundant (about 3.45%, while the lithium metry optimization was first performed at the B3LYP/BSI level,
content is only 0.0065%). Meanwhile, 72% fructose conversion where BSI denotes the combination of the Aug-cc-pVDZ basis
and 32% HMF yield were obtained in 10% CaCl2 solution set for C, H, O, Cl, Br, and Mg, the cc-pVDZ basis set for Ca
using microwave irradiation in our previous studies.19 and the cc-pVDZ-X2C basis set for Sr and Ba. Note that
Therefore, we believe that the use of CaCl2 MSH can realize the Grimme’s D3 dispersion corrections and Becke–Johnson
potential of glucose isomerization into fructose and then damping (DFT-D3BJ) are also included. The solvation effects of
further dehydrate to yield HMF.
the experimentally used solvent (i.e., water) were taken into
In this article, we report that (1) the isomerization of consideration by using the Cramer–Truhlar continuum sol-
glucose to fructose, followed by the dehydration of fructose vation model SMD. Therefore, the computational level can be
were investigated in CaCl2 solution. (2) NMR and DFT calcu- termed as B3LYP+D3BJ/BSI (SMD, solvent = water). Vibrational
lations were conducted to characterize the mechanism of frequency calculations were performed for all stationary points
CaCl2 isomerizing glucose into fructose and catalyzing the de- to identify whether they were local minima (no imaginary fre-
hydration of fructose. (3) Isomerization–dehydration of quencies) or transition structures (only one imaginary fre-
glucose catalyzed by CaCl2 was conducted to prepare HMF. We quency) and to derive the thermochemical corrections for the
believe that this work will provide new insights into the enthalpies and free energies. Intrinsic reaction coordinate
mechanism and application of dehydration or isomerization (IRC) calculations were conducted to verify the critical reaction
of glucose over alkaline earth metal catalysts.
steps involved in our proposed mechanisms.
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Table 1 Glucose isomerization in various alkaline earth metal salt
solutions
Analytical methods
The quantitation of glucose and its isomers including fructose
and mannose was conducted using a HPIC system (Dionex
ICS-3000, Sunnyvale, CA) equipped with an integrated ampero-
metric detector and CarboPac® PA1 guard and analytic
columns (Dionex, Sunnyvale, CA). Reaction product samples in
the aqueous phase were quantitated using a high-performance
liquid chromatography (HPLC) system (Dionex, Sunnyvale, CA)
with a Biorad Aminex HPX-87H sugar column and ultraviolet
(UV) detector at 210 nm. Glucose and fructose were detected
with an RI detector (1260 RID). The mobile phase was 0.005 M
Distribution of isomers or epimer (%)
Decomposition
Salts
Glucose
Fructose
Mannose
products (%)
NaCl
100.0
98.7
56.9
84.3
95.2
100.0
0.0
1.3
24.2
8.5
4.8
0.0
0.0
0.0
1.1
1.6
0.0
0.0
0.0
0.0
17.8
5.6
0.0
0.0
MgCl2
CaCl2
CaBr2
SrCl2
BaCl2
Reaction conditions: 25.6 wt% salts, 100 g L−1 glucose, 120 min,
H2SO4 flowing at a rate of 0.6 mL min−1. The column oven was 120 °C.
set to 30 °C. Reaction product samples in the organic phase
were analyzed using
a
Shimadzu gas chromatograph
(GC-2010Plus) with a Restek Rtx-VMS capillary. A 1 μL sample
was injected into the GC column with a split ratio of 49 : 1.
The carrier gas was helium and the flow rate was 1.0 mL
min−1. The oven temperature started at 40 °C and was held for
5 min, then raised to 240 °C at a rate of 7.5 °C min−1. The
temperature was held at 240 °C for 15 min. The conversion of
monosaccharide and yield of HMF were calculated with the
following equations.
tion. Due to the low solubility of some salts (the solubility of
BaCl2 is 35.8 g per 100 g water at 20 °C), 25.6 wt% salt solu-
tions were prepared as standards. The results of glucose iso-
merization in these salt solutions are presented in Table 1.
The aqueous CaCl2 solution gave a higher fructose yield
(>20%) than the aqueous Mg, Sr, and Ba chloride salt solu-
tions did. MgCl2 and SrCl2 solutions only isomerized 1.3%
and 4.8% glucose into fructose, respectively. No glucose
isomer (fructose) or epimer (mannose) was detected in the
BaCl2 solution. It was observed that glucose isomerization was
affected by cations in the systems. The halide anions also had
an effect on glucose isomerization because the aqueous CaBr2
solution gave a lower fructose yield than the aqueous CaCl2
solution did. Among all these alkaline earth salts, CaCl2 had
the best performance in catalyzing glucose isomerization.
Therefore, the subsequent investigations focused on the CaCl2
hydrate system.
½ Conversionꢀfructose or glucoseð%Þ ¼ 100
moles of reserved fructose or glucose
initial moles of fructose or glucose
ꢁ
moles of product fructose
½Yieldꢀfructoseð%Þ ¼ 100 ꢁ
initial moles of glucose
½YieldꢀHMFð%Þ ¼ 100
moles of product HMF
initial moles of fructose or glucose
ꢁ
To better understand the effects of CaCl2 concentration and
temperature on glucose isomerization, CaCl2 solutions with
different concentrations were tested to catalyze glucose into
fructose at 20, 80, and 120 °C. As shown in Fig. 1a, increasing
the CaCl2 concentration resulted in higher glucose conversion
and fructose yields from 20.1% to 33.6% could be achieved
when the CaCl2 concentration was elevated from 17.9 wt% to
Results and discussion
Isomerization of glucose in CaCl2 MSH
Alkaline earth salt solutions, including MgCl2, CaCl2, SrCl2,
CaBr2, and BaCl2, were tested to investigate glucose isomeriza-
Fig. 1 Isomerization of glucose (a) with various concentrations of CaCl2 solution at different temperatures (reaction conditions: 100 g L−1 glucose,
120 min) and (b) at different reaction times in 37.8 wt% CaCl2 solution (reaction conditions: 100 g L−1 glucose, 80 °C).
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37.8 wt% at 80 °C. Although higher glucose conversion was Mechanism of the interaction between CaCl2 and glucose
(NMR characterization)
obtained when the temperature rose from 20 °C to 80 °C, the
fructose yield was reduced at 120 °C and more carbohydrate
degradation was observed. It was assumed that partial fructose
was converted into HMF (13.1% HMF in 37.8 wt% CaCl2 solu-
tion at 120 °C) and HMF was subsequently condensed to
humins. This conclusion will be studied in detail in the follow-
ing chapters on fructose dehydration. Meanwhile, only a small
amount of mannose, a glucose epimer, was detected in all
tests.
Although resonance appeared at d = 99 ppm and d = 103 ppm
in the 13C NMR spectrum and the presence of fructose was cor-
roborated by the appearance of resonance at d = 4.1 ppm and
1
d = 4.2 ppm in the H NMR spectrum when glucose was iso-
merized in CaCl2 solution (Fig. 2), no direct and strong evi-
dence has supported that there is a strong interaction between
the CaCl2 and the glucose to catalyze the glucose isomeriza-
tion. Recently, diffusion ordered spectroscopy (DOSY),
a
The process of glucose isomerizing into fructose in
37.8 wt% CaCl2 solution at 80 °C is shown in Fig. 1b. Within
15 min of the initial reaction, glucose content sharply
decreased while fructose content quickly increased accordingly
(∼28.8%). After 30 min, both glucose conversion and fructose
yield slowed down. Fructose content did not increase but con-
trarily decreased at a prolonged reaction time. In the whole
process, the carbon yield remains above 90%. Meanwhile, the
mannose content is not shown in this figure because its yields
were consistently about 1%.
pseudo two-dimensional (2D) NMR technique, was introduced
to measure host–guest complex formation and study inter-
mediates in lignocellulosic biomass biorefining. For instance,
Qiao et al. proved the interaction between Sn4+ and fructose
using this method.20 Herein, we used 2D DOSY-NMR to
characterize the strong interaction between Ca2+ and glucose.
According to the Stokes–Einstein equation, the diffusion
coefficient of a species in solution is dependent on its weight
and size.21,22 If a strong interaction exists between the Ca2+
and glucose and a complex is formed, this larger and heavier
complex species will diffuse more slowly than the substrate.
Our research has shown that the isomerization of glucose
to fructose in CaCl2 solution can occur at a low temperature
(80 °C) and the selectivity for fructose reaches 80%. Compared
with the previously reported non-enzymatic glucose isomeriza-
tion (shown in Table S1†), CaCl2 exhibited good performance.
In particular, we obtained higher fructose yield in the presence
of CaCl2 than with a typical Lewis acid such as CrCl3, AlCl3,
SnCl4, or ZrCl2 as isomerization catalyst (entries 1 to 5). These
catalysts with Lewis acid sites immobilized on solid acid need
a higher reaction temperature to achieve similar results
(entries 6 to 9) which creates challenges for both catalyst stabi-
lity and removal of unwanted impurities. For example, using
graphite oxide or graphene oxide supported Al as catalysts, the
yield and selectivity of fructose can reach 34.6% and 63.4%,
respectively, at 140 °C under microwave irradiation. A product
distribution of 46 wt% glucose, 31 wt% fructose, and 9 wt%
mannose was obtained after 12 min of reaction at 140 °C when
Sn-beta was used as the glucose isomerization catalyst.
Obviously, CaCl2 is a very competitive glucose isomerization
catalyst when compared with the existing ones.
Correspondingly,
a smaller diffusion coefficient will be
obtained in the DOSY-NMR spectrum’s F1 dimension. As
shown in Fig. 3, two sets of signals were present in glucose’s
DOSY-NMR spectrum in the CaCl2 containing solution. The
signals on the top of the spectrum (smaller diffusion coeffi-
cient) belong to the β-glucopyranose tautomer (molecular
weight of 180) which more easily formed a heavier complex
with Ca2+ (ionic weight of 40), while the signals (bigger
diffusion coefficient) on the bottom of the spectra come from
the α-glucopyranose tautomer. Thus, DOSY NMR results
clearly suggest that there is a stronger interaction between the
Ca2+ and the β-glucopyranose tautomer. Additionally, the pro-
portion of β-glucopyranose tautomer was reduced from 71% in
the glucose stock solution (Fig. S1†) to 25% after adding the
CaCl2 (Fig. S2†) in the peak area ratio calculation of α-H1 and
β-H1. This indicated that a 1,2-intramolecular hydride shift is
easily realized after the coordination of β-glucopyranose tauto-
mers with Ca2+, resulting in the decrease of the proportion of
β-glucopyranose tautomers. García-Sancho16 and co-workers
Fig. 2 13C spectra of (a) glucose, (b) mixed sugars (glucose and fructose), and (c) glucose and CaCl2. 1H spectra of (d) glucose, (e) fructose, and
(f) glucose and CaCl2 in D2O.
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Fig. 3 2D DOSY NMR spectrum of glucose with CaCl2 in D2O at 25 °C.
proved this point from the disappearance of β-glucopyranose tau- glucose to fructose. As shown in Scheme 1, it starts with the
tomer with the addition of CaCl2. The isomerization of glucose addition of CaCl2 to glucose in acidic conditions to form the
proved that CaCl2 has a good isomerization ability at room temp- more thermodynamically stable intermediate IM1, a process
erature, therefore the complexation of calcium ions with which is highly exergonic by 111.0 kcal mol−1, providing the
β-pyranose tautomer does not stabilize the glucose configuration driving force for the following ring-opening step. After crossing
with the β-pyranose tautomer, but instead it directly isomerizes a barrier of 22.9 kcal mol−1 (i.e., IM1 → TS1), the ring opening
glucose and the β-pyranose tautomer of glucose decreases.
of the cyclic pyranose substrate can be achieved to provide its
We confirmed the binding site of the interaction between open-chain isomer IM2. Note that the O–H⋯Cl hydrogen
glucose and Ca2+ by the nuclear magnetic titration of glucose bonding (2.157 Å) and Ca–O (3.740 Å) interactions play an
with different concentrations of CaCl2 solutions. The chemical important role in stabilizing the six-membered-ring TS1 and
shifts of 5.1–5.3 ppm, 4.6–4.8 ppm, and 3.2–3.3 ppm in the 1H the key bond distance of the C–O bond (3.197 Å), as well as the
NMR glucose spectrum were assigned to the α-C1-H, β-C1-H and vibration mode of the only imaginary frequency, confirmed
C2-H positions, respectively, and continuously shifted in the the correct transition state TS1 (see Fig. 5). Note that the direct
various amounts of CaCl2, as shown in Fig. 4B, C and Da–d. conversion of glucose to fructose without a catalyst can be
This shows that CaCl2 and glucose complex with C1 and C2 to excluded because of the very high barrier (40.3 kcal mol−1
,
promote hydrogen transfer at C1 and C2, which are the key Scheme S1†). We also explored other reaction pathways
points for aldose-to-ketose isomerization in aqueous media. (Scheme S1†) for the ring-opening step, but the very high bar-
Meanwhile, with the increase of CaCl2 concentration, the peaks riers (>47.9 kcal mol−1) prevented such possibilities.
at d = 4.1 and 4.2 ppm also increased significantly, indicating
Subsequently, the isomerization from the open-chain form
that more fructose was formed. Based on the all the above NMR of glucose (i.e., IM2) to the open-chain isomer of fructose (i.e.,
characterizations, we can infer that a 1,2-intramolecular hydride IM4) proceeded by two successive H-transfer steps via tran-
shift promoted by the formation of coordination between Ca2+ sition states TS2 and TS3. These two barriers are 4.7 and
and the C1/C2 sites of the β-glucopyranose tautomer is the main 9.9 kcal mol−1, respectively. The process is also downhill: IM3
reason that CaCl2 has good catalytic activity for glucose isomeri- and IM4 are 6.8 and 13.3 kcal mol−1 more stable than IM2.
zation at room temperature.
Therefore, the H-transfer process is both kinetically and
thermodynamically favorable. Finally, after overcoming a very
small barrier of 1.0 kcal mol−1 (i.e., IM4 → TS5), the ring-
closure step is completed, generating the cyclic fructose
Mechanism of glucose isomerization in CaCl2 MSH (DFT
calculations)
DFT calculations were further conducted to gain insight into complex IM5. The whole reaction is highly exergonic by
the mechanism of the CaCl2-mediated isomerization from 102.1 kcal mol−1, which can provide the thermodynamic
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Fig. 4 Nuclear magnetic titration of CaCl2 and glucose. (A) 1H NMR spectra of solutions containing CaCl2 and glucose: (a) 100 g L−1 glucose,
(b) 100 g L−1 glucose and 9.5 wt% CaCl2, (c) 100 g L−1 glucose and 17.9 wt% CaCl2, (d) 100 g L−1 glucose and 25.6 wt% CaCl2 in D2O. The (B) α-C1-H,
(C) β-C1-H and (D) C2-H chemical shifts of glucose with various amounts of CaCl2 (0, 9.5, 17.9, 25.6 wt%).
driving force to reach the fructose species. The most favorable observed that other salts, such as MgCl2, CaBr2, SrCl2, and
catalytic cycle can be found in Scheme S2.†
BaCl2, also show different catalytic activities. We thus studied
The detailed mechanistic study above indicated that the other salts to mediate the ring-opening of cyclic pyranose. As a
ring-opening step of cyclic pyranose is the rate-determining comparison, in Table 2 and Scheme S3,† the barriers for the
step (RDS) for the whole catalysis and the barrier was predicted MgCl2, BaCl2, CaBr2, and SrCl2 mediated processes were pre-
to be 22.9 kcal mol−1 (i.e., IM1 → TS1). It was experimentally dicted to be 26.9, 29.2, 30.1, and 33.8 kcal mol−1, respectively,
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Scheme 1 Computed free energy profiles (in kcal mol−1) for the isomerization process. The electronic energies are given in brackets for reference.
Fig. 5 Optimized structures of the transition states TS1–TS4, along with key bond distances in Å. Other structures are given in Fig. S3 and S4†
(color code: C, gray; H, white; O, red; Cl, green; Ca, yellow).
Table 2 The comparison of the barriers (ΔG‡, ΔE‡ in kcal mol−1) of the
rate-determining step (RDS) in CaCl2, MgCl2, BaCl2, CaBr2, and SrCl2
hydration process of fructose than did chloride ion in our
studies.
The dehydration of fructose to HMF catalyzed by alkaline
RDS
CaCl2
MgCl2
BaCl2
CaBr2
SrCl2
and alkaline earth metal salts (NaCl, MgCl2, CaCl2, SrCl2,
BaCl2) was investigated at 150 °C under autonomous pressure
for 120 min in a biphasic reactor system consisting of an
aqueous layer with metal chlorides and a 2-MeTHF extracting
organic layer. In Fig. 6, the addition of alkaline earth metal
salts (17.9 wt%) clearly leads to a significant increase in fruc-
tose conversion and HMF yield, although fructose can be con-
verted without any metal chloride (16% fructose conversion
and 3.1% HMF yield) or with NaCl (61.4% fructose conversions
and 31.6% HMF yield). Among the alkaline earth metal salts, a
better result (100% fructose conversion and 61.6% HMF yield)
can be achieved by using CaCl2 as the catalyst.
ΔG‡
ΔE‡
22.9
23.5
26.9
28.4
29.2
28.3
30.1
30.2
33.8
36.3
all higher than that of CaCl2 (ΔG‡ = 22.9 kcal mol−1). The
corresponding energy profiles and optimized structures are
given in Scheme S3 and Fig. S5.† This agrees well with the
experimental observations, in which CaCl2 had the best
performance.
The dehydration of fructose into HMF in CaCl2 MSH
It is generally believed that chloride ion plays a key role in the
The influence of different CaCl2 concentrations on the de-
preparation of HMF using alkali metal and alkaline earth hydration of fructose is shown in Fig. 7. With higher CaCl2
metal salts to catalyze the dehydration of fructose. For concentrations employed, higher values of fructose conversion
example, Wang23 et al. found that the Cl− can promote the de- and HMF yield are achieved. The maximum values were
hydration of fructose, thus driving the selective formation of reached 100% and 61.6%, respectively, in 17.9 wt% CaCl2 solu-
HMF. Mellmer24 and co-workers proved from molecular tion. When the concentration of CaCl2 was further increased,
dynamics simulations that highly localized negative charge on the yield of HMF decreased gradually, although fructose could
Cl− allows the chloride anion to more readily approach and be completely converted. Obviously, a high concentration of
stabilize the formed oxocarbenium ion and the deprotonation CaCl2 is not conducive to the formation of HMF because of the
transition state to promote the dehydration of fructose. degradation of HMF or the easy formation of humins.
However, Ca2+ showed better catalytic performance in the de- Meanwhile, neither increasing the reaction temperature nor
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Fig. 6 Dehydration of fructose in various salt solutions. Reaction
conditions: 17.9 wt% salts, 100
water : 2-MeTHF = 1 : 4.
g 2 h,
L−1 fructose, 150 °C,
Fig. 8 Recyclability of CaCl2 solution for HMF preparation. Reaction
conditions: 100 g L−1 fructose, 150 °C, 2 h, water : 2-MeTHF = 1 : 4.
Mechanism of CaCl2 catalyzing the dehydration of fructose
Compared with other salts, CaCl2 has a special positive effect
in promoting the dehydration of fructose. From the 2D
DOSY-NMR results of fructose with CaCl2 in D2O, we can infer
that there is a strong interaction between Ca2+ and the fructose
based on the two separate signals in the spectrum (Fig. S7†).
Therefore, we speculated that the combination of Ca2+ and
fructose stabilizes the optimal fructose configuration to form
HMF and is the main reason for the higher catalytic ability of
CaCl2 in the process of fructose dehydration.
In general, β-D-fructopyranose is the main structure among
the fructose tautomers, which also include β-D-fructofuranose
and α-D-fructofuranose in D2O at 20 °C. These tautomers’ dis-
tribution in fructose can be analyzed using the C2 signals in
the 13C NMR spectrum at 98.1 ppm (β-D-fructopyranose),
101.6 ppm (β-D-fructofuranose), and 104.5 ppm (α-D-fructofura-
nose) in Fig. 9A. This is the same as those reported by Shi,25
who found that the ratios of the three configurations of β-D-
pyranfructose, β-D-furanfructose, and α-D-furanfructose were
Fig. 7 Effect of CaCl2 concentration on fructose conversion and
HMF yield. Reaction conditions: 100
water : 2-MeTHF = 1 : 4.
g 2 h,
L−1 fructose, 150 °C,
prolonging the reaction time is beneficial to the HMF respectively 68.23%, 22.25%, and 6.24%. This is further sup-
yield (Table S2†). Additionally, when using other organic ported by DFT calculations which show that β-D-fructopyranose
solvents like GVL, THF, MIBK, and DMSO as the is the most stable configuration in pure water (Table S3†).
extracting phase, the yields of HMF reached 58.5%, 42.8%,
In CaCl2 solution, the 13C NMR spectrum of fructose has an
57.5%, and 65.0%, respectively (Fig. S6†). Although the yield of obvious change (Fig. 9B). The original three peaks of the C2
HMF was improved in DMSO, it was difficult to separate the signal turn into one peak located at 101.6 ppm and assigned
two phases.
to β-D-fructofuranose. This indicates that the three co-existing
After HMF extraction, the CaCl2 solution can be reused. We configurations of fructose are transformed into the β-D-fructo-
reloaded fresh 2-MeTHF and fructose into the residual CaCl2 furanose configuration in the CaCl2 solution. This is sup-
solution and conducted five consecutive batch reactions. The ported by DFT calculations, which show that the calcium co-
results shown in Fig. 8 revealed no obvious loss in the yield of ordinated β-D-fructofuranose is the most stable structure
HMF. Compared to the first batch, the HMF yield increased among the Ca2+ + α-D-fructofuranose, Ca2+ + β-D-fructofura-
from 62% to 73% in the second run because some HMF nose, and Ca2+ + β-D-fructopyranose complexes (Table S4 and
remained in the aqueous phase and was extracted in the next Fig. S8†). In the literature, the configuration of β-D-fructofura-
runs. From the second run, the yields of HMF were over 70% nose is generally considered to be the best configuration for
in each subsequent cycle. This indicated that the CaCl2 solu- preparing HMF from fructose, as the other fructose configur-
tion was sufficiently recyclable.
ations will form by-products such as humins. Dumesic26 and
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tion path of fructose dehydration by isotope labeling and
found that β-D-furan fructose can be directly dehydrated to
form HMF.
To further prove the complexation of Ca2+ and fructose and
the specific binding sites of calcium and fructose, the energy
of different binding sites was examined by DFT calculations.
As detailed in Tables S5–S7,† the C2 and C6 positions of β-D-
fructofuranose complexed with Ca2+ have the lowest free
energy, compared with the C3 and C4 of β-D-fructopyranose or
the C3 and C4 of α-D-fructofuranose complexed with Ca2+.
Hence, we concluded that the tautomer distribution of fruc-
tose plays a key role in fructose dehydration into HMF. By com-
plexing with the C2 and C6 of β-D-fructofuranose, Ca2+ can
stabilize this tautomer to promote HMF formation, which
should be the main reason that CaCl2 can promote the prepa-
ration of HMF from fructose (Scheme 2).
The dehydration of glucose into HMF in CaCl2 MSH
Based on the glucose isomerization and fructose dehydration
abilities of CaCl2, it can be directly used to catalyze glucose de-
hydration to prepare HMF. From the glucose isomerization
results, we found that the higher the concentration of CaCl2,
the stronger the isomerization ability will be. However, exces-
sively high CaCl2 concentrations increase the side reactions in
fructose dehydration. In order to balance glucose isomeriza-
tion and fructose dehydration, the effect of CaCl2 concen-
tration on glucose dehydration into HMF was further studied.
Fig. 6a shows that the glucose conversion, HMF yield, and
HMF selectivity were 70.4%, 30.4%, and 44%, respectively, in
25.6 wt% CaCl2 solution. When increasing the CaCl2 concen-
tration from 25.6 to 31.8 wt%, the yield of HMF increased
from 30.4% to 39.7%, but the HMF selectivity decreased from
43.2% to 39.7%. When the CaCl2 concentration is further
increased to 37.8 wt%, the selectivity and yield of HMF are
only 28.5%. This indicated that high CaCl2 concentration is
unfavorable to form HMF.
Fig. 9 13CNMR spectra of fructose in D2O (A) before and (B) after
▲
●
:
addition of CaCl2.
■
:
β-D-fructopyranose,
β-D-fructofuranose,
: α-D-fructofuranose.
co-workers found that the predominance of β-D-fructofuranose
tautomers in DMSO facilitates HMF formation, whereas the
predominance of β-D-fructofuranose tautomers in water pro-
motes the isomerization of fructose to glucose and/or polymer-
ization to humins. The use of DHMTHF as a co-solvent has a
beneficial effect on the selectivity for HMF due to the fructose
tautomerization favoring the β-D-fructofuranose form in the
mixed solvent.27 Svenningsen et al. revealed that the primary
factor controlling selectivity in the dehydration reaction is the
fructose tautomer distribution and that β-D-fructofuranose can
be converted to HMF directly.28 Akien29 et al. studied the reac-
Scheme 2 The mechanism of HMF formation from fructose in CaCl2 MSH.
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Fig. 10 Dehydration of glucose to HMF in CaCl2 solution. Effect of (a) CaCl2 concentration, (b) temperature, and (c) time on glucose dehydration in
17.9 wt% CaCl2 solution. (d) Recycling of CaCl2 solution. Reaction conditions: 100 g L−1 glucose, water : 2-MeTHF = 1 : 4.
The effects of temperature and time on glucose dehydration 61.0% HMF yield were achieved in water/THF or in water/
into HMF were also studied. Fig. 10a shows that, in 25.6% DMSO by adding 30 wt% NaCl (entries 5–8). In addition, even
CaCl2 solution, the selectivity for HMF was highest. Hence, we compared with the expensive ionic liquid [BMIM]Cl, the yield
first chose 25.6% CaCl2 solution to investigate the effect of of HMF catalyzed by CaCl2 is comparable (52.1% vs. 58.8%,
temperature on the conversion of glucose. However, as shown entry 9). Hence, the cost-effective CaCl2 solution has good
in Fig. S9,† the carbonization is very serious in 25.6% CaCl2 application prospects as a catalyst to obtain satisfactory HMF
solution. In contrast, there is little carbonization in the 17.9% yield from glucose.
CaCl2 solution. We chose 17.9% CaCl2 solution to further
investigate the effect of time on the conversion of glucose. The
effects of the different reaction temperatures in 17.9 wt%
CaCl2 solution are shown in Fig. 10b. As the temperature
Conclusion
increased from 150 °C to 180 °C, the yield of HMF increased
from 19.1% to 42.7%, while the glucose conversion increased
from 57.2% to 100%. Fig. 10c shows that the glucose conver-
sion, HMF yield, and selectivity for HMF continuously
increased with prolonged reaction time and reached 93.6%,
52.1%, and 55.6%, respectively, at 60 min. Further extending
the reaction time to 120 min, the HMF yield and selectivity
decreased to 45.1% and 42.7%, although glucose was comple-
tely converted. For the five recycling experiments, the yields of
HMF were up to 50% (Fig. 10d), indicating that the CaCl2 solu-
tion has sufficient recyclability.
Some reported results of glucose dehydration into HMF by
bifunctional catalysts with Lewis acid and Brønsted acid sites
are listed in Table S9.† Compared to those bifunctional cata-
lysts, the HMF yield from glucose in CaCl2 solution was higher
(entries 1–4). Only when large amounts of salt were added to
greatly improve the partition coefficient of HMF was the HMF
yield greatly increased. For example, 66.2%, 72.0%, 63.1% and
In summary, CaCl2, a non-typical Lewis acid, shows good cata-
lytic performance in both glucose-to-fructose isomerization
and fructose-to-HMF dehydration and is applied to catalyze
the “one-pot” isomerization–dehydration of glucose to prepare
HMF. Using CaCl2 alone as the catalyst, the highest fructose
yield from 10% glucose solution can reach 33.6% at 80 °C,
whereas the HMF yields from fructose and glucose were up to
61.6% and 52.1%, respectively. This yield is comparable to that
catalyzed by Lewis/Brønsted acid bifunctional catalysts.
Notably, the CaCl2 solution can be reused without any regener-
ation step and still maintains its catalytic activity after five
runs. This reaction system not only avoids the use of a corros-
ive acid catalyst but also reduces the pollution caused by waste-
water discharge. Through NMR analysis and DFT calculations,
we proved that a 1,2-intramolecular hydride shift promoted by
the formation of coordination between CaCl2 and the C1/C2
sites of β-glucopyranose tautomer is the main reason that
CaCl2 catalyzes glucose isomerization. The presence of CaCl2
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in the reaction medium notably improved the carbohydrate de-
hydration performance due to the interaction between Ca2+
9 N. R. Quiroz, A. M. Norton, H. Nguyen, E. Vasileiadou and
D. G. Vlachos, ACS Catal., 2019, 9, 9923–9952.
ions and the C2/C6-OH of fructose molecules favoring β-D-fruc- 10 G. Grundl, M. Müller, D. Touraud and W. Kunz, J. Mol.
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14 L. Yan, D. D. Laskar, S.-J. Lee and B. Yang, RSC Adv., 2013,
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Conflicts of interest
15 E. Combs, B. Cinlar, Y. Pagan-Torres, J. A. Dumesic and
B. H. Shanks, Catal. Commun., 2013, 30, 1–4.
16 C. García-Sancho, I. Fúnez-Núñez, R. Moreno-Tost,
J. Santamaría-González, E. Pérez-Inestrosa, J. L. G. Fierro
and P. Maireles-Torres, Appl. Catal., B, 2017, 206, 617–
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17 C. G. Yoo, N. Li, M. Swannell and X. Pan, Green Chem.,
2017, 19, 4402–4411.
18 P. Bhaumik, H. Chou, L. Lee and P. Chung, ACS Sustainable
Chem. Eng., 2018, 6, 5712–5717.
19 C. Lin, H. Wu, J. Wang, J. Huang, F. Cao, W. Zhuang, Y. Lu,
J. Chen, H. Jia and P. Ouyang, Ind. Eng. Chem. Res., 2020,
59, 4358–4366.
20 Y. Qiao, C. M. Pedersen, D. Huang, W. Ge, M. Wu, C. Chen,
S. Jia, Y. Wang and X. Hou, ACS Sustainable Chem. Eng.,
2016, 4, 3327–3333.
21 G. Colafemmina, H. Mateos and G. Palazzo, Curr. Opin.
Colloid Interface Sci., 2020, 48, 109–120.
22 W. Ge, J. H. Zhang, C. M. Pedersen, T. Zhao, F. Yue,
C. Chen, P. Wang, Y. Wang and Y. Qiao, ACS Sustainable
Chem. Eng., 2016, 4, 1193–1200.
There are no conflicts to declare.
Acknowledgements
This work was supported by the National Key Research and
Development Program of China (2019YFC1906603), The
Jiangsu Synergetic Innovation Center for Advanced Bio-
Manufacture (XTC1806), the National Natural Science
Foundation of China (22078152), and the Six Talent Peaks
Project in Jiangsu Province (SWYY-030 and SWYY-118). L. Z.
acknowledges the financial support from National Natural
Science Foundation of China (grant no. 21703099 and
21973044), Nanjing Tech University (grant number 39837123
and 39837132), and the high-performance center of Nanjing
Tech University for supporting the computational resources.
The authors would like to acknowledge Xin Li (Nanjing
Forestry University) for the help with detection of the glucose
fructose and mannose by HPIC system.
23 X. Li, Y. Zhang, Q. Xia, X. Liu, K. Peng,
S. Yang and Y. Wang, Ind. Eng. Chem. Res., 2018, 57, 3545–
3553.
24 M. A. Mellmer, C. Sanpitakseree, B. Demir, K. Ma,
W. A. Elliott, P. Bai, R. L. Johnson, T. W. Walker,
B. H. Shanks, R. M. Rioux, M. Neurock and J. A. Dumesic,
Nat. Commun., 2019, 10, 1132.
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