Catalysis Today 404 (2022) 201–218

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Catalysis Today
journal homepage: www.elsevier.com/locate/cattod

Optimization of reaction parameters by using response surface

methodology (RSM) for the selective dehydration of glucose to 5-hydrox-
ymethylfurfural (5-HMF), a valuable platform chemical over a mesoporous
TiO2 catalyst in dimethylsulfoxide (DMSO) medium
Richa Tomer , Prakash Biswas *
Department of Chemical Engineering, Indian Institute of Technology Roorkee, Roorkee 247667, Uttarakhand, India

A R T I C L E I N F O A B S T R A C T

Keywords: A highly active and selective mesoporous TiO2 was developed by the sol-gel hydrolysis technique for the selective
Glucose dehydration transformation of glucose to 5-hydroxymethylfurfural (5-HMF). The catalytic performance was tested in a glass
5-HMF tube reactor, and the reaction parameters were optimized using response surface methodology (RSM). The best-
Optimization
optimized reaction conditions were obtained using four-factors, four-responses, and the 5-level central composite
Catalyst recycle
Separation
design (CCD) integrated with the desirability approach. At the optimum reaction condition, RSM predicted
Power-Law kinetics complete conversion of glucose and a very high 5-HMF yield of ~56% in the dimethylsulfoxide (DMSO) solvent.
The predicted yield of other major products, including formic acid (FA) and levulinic acid (LA), was ~18% and
~2%, respectively. The empirical process model developed by RSM was validated by the experimental data
generated. Experimental results demonstrated that the TiO2 catalyst developed can easily be recycled with a
constant glucose conversion and 5-HMF yield. Further, a new liquid-liquid extraction method (LLE) is proposed
to extract 5-HMF from the product. The results depicted that 5-HMF can easily be extracted from the product
mixture with very high purity (~96%). Additionally, the Power-Law kinetic study suggested that the conversion
of glucose over TiO2 followed the first-order kinetics, and the calculated activation energy was 67.5 kJ mol−1.

1. Introduction β-1,4-glucosidic bonds [7]. This biomass-derived glucose has been

Global demand for energy and chemicals is increasing day by day
due to the growing population and urbanization. Energy Information
Administration (EIA, U.S.) projected ~50% increase in world energy
consumption by 2050 [1]. Till today, nonrenewable sources such as
crude oil (~29%), coal (~27%), and natural gas (~23%) are the primary
contributor to global energy demand and chemical supply [2,3]. Be-
sides, nuclear (~4%) and renewable sources (~14%), including wind,
solar, hydro, and biomass, also contribute significantly. Future global
energy utilization projection also shows an increasing trend to utilize
more renewables due to the depletion of fossils as well as environmental
issues [4,5]. For the last two decades, renewable lignocellulose biomass
has gained significant attention as a potential substitute for the pro-
duction of energy and valuable chemicals [6]. Lignocellulosic biomass
contains approximately 40–50% cellulose, 25–35% hemicellulose, and
5–30% lignin [3], where cellulose is a D-glucose unit polymer linked by
regarded as a feedstock for many valuable building block chemicals like
5-hydroxymethylfurfural, fructose, and organic acids like formic acid,
levulinic acid, acetic acid (AA), lactic acid, etc. [8]. Among all the
biomass-derived chemicals, 5-HMF comes in the top ten building block
chemical list given by the US department of energy [9] because of its
versatility and outstanding chemical reactivity [10–12]. 5-HMF can be
used as an intermediate for many industries such as bulk chemicals,
biofuel, pharmaceuticals, polymer/rubber, food packaging, agrochemi-
cals, cosmetic, and textile industries. It could also be widely used to
produce various high-value compounds like 2,5-furandicarboxylic acid
(2,5-FDCA), 2, 5-dimethylfuran, caprolactam, caprolactone, adipic acid,
etc. [13].
5-HMF is generally synthesized via the conversion of biomass-
derived carbohydrates, i.e., cellulose, glucose, and fructose, in the
presence of an acid catalyst. A higher 5-HMF yield (~90%) can easily be
achieved from fructose [14]. However, fructose availability and its high

* Corresponding author.
E-mail addresses: prakash.biswas@ch.iitr.ac.in, prakashbiswas@gmail.com (P. Biswas).

https://doi.org/10.1016/j.cattod.2022.03.019
Received 31 August 2021; Received in revised form 9 March 2022; Accepted 24 March 2022
Available online 30 March 2022
0920-5861/© 2022 Elsevier B.V. All rights reserved.
R. Tomer and P. Biswas
cost limit its industrial applications. Alternatively, glucose can be
considered a sustainable feedstock due to its more accessibility and
lower cost [2]. The dehydration of glucose follows a tandem process,
including the formation of fructose via glucose isomerization in the
presence of Lewis acid sites (L-sites) accompanied by fructose dehy-
dration to 5-HMF in the presence of Brønsted acid sites (B-sites) of a
catalyst [15]. Various heterogeneous solid acid catalysts such as zeolites,
sulfated zirconia, phosphate-titania, chromium catalysts, ion-exchanged
resins, heteropolyacids, and metal-organic frameworks (MOFs) had
been synthesized and used for glucose dehydration reaction [3,16–19].
Among all these catalysts, various phosphated and sulfated metal oxide
catalysts were widely used due to their tunable properties and acidity. A
higher (53–81%) yield of 5-HMF was reported in a biphasic medium
(THF: water) in the presence of phosphated TiO2 catalyst synthesized by
sol-gel method [18,20,21]. WO3-TiO2 catalyst synthesized by
microwave-assisted hydrothermal method and demonstrated 58% yield
of 5-HMF in MIBK: H2O medium at 175 ◦ C after 2 h [22]. The phosphate
group and WO3 enhanced the B-sites. It has been shown that the anatase
phase of TiO2 was very active for glucose dehydration because of the
presence of both L-sites and B-sites [18,23]. The electron pair accepting
nature of Ti+4 corresponded to the Lewis acidic sites, and the proton
donor sites (-O-H) available corresponded to Brønsted acidic sites. The
ratio of these two different acidic sites played a vital role in the selective
transformation of glucose or fructose to 5-HMF.
The glucose dehydration reaction is a solid acid-catalyzed reaction in
various reaction mediums/solvents. Various reaction mediums such as
aqueous, ionic liquid ([BMIM]Cl, [EMIM]Cl), biphasic medium (THF:
H2O, DMSO: H2O, THF/H2O/NaCl), and organic solvents (DMSO, MIBK,
THF) have been explored [10,24–26]. Among all these solvents, water is
known as a green and polar protic solvent that provides protons and high
polarity [27]. However, in a water medium, a lower yield of 5-HMF was
reported because of more side reactions [10]. It has been reported that a
higher yield of 5-HMF could be obtained in ionic liquids. However, the
higher cost and separation inefficiency made the ionic liquids
commercially less attractive. Instead, the biphasic medium often gave a
better performance than the monophasic system. However, solvent
recycling and product separation are the main issues with the biphasic
medium [28]. Among all other solvents, DMSO, as the organic solvent,
have been reported [16,18,25] as a promising dehydration medium due
to its advantageous properties such as strong dehydration capacity,
ability to prevent rehydration reaction, and favorable solvation property
of the substrate, etc. [29].
Previous literature mainly discussed the experimental optimization
of the glucose dehydration process based on one factor at a time. This is
not a very appropriate approach to determine the true optimum region.
This technique does not account for the interaction effect of different
parameters. Therefore, few statistical techniques such as response sur-
face methodology and the Taguchi method have been proposed to
determine the optimum region mathematically. These mathematical
techniques reduce the time of analysis, chemical consumption, and the
number of experiments considerably. RSM is the statistical tool that
helps to find out the appropriate relationship between multiple variables
factors that affect the reaction with their response in the working
domain by using statistics, optimization, and regression techniques [30].
RSM provides a large amount of information by performing a minimum
set of runs to elucidate the experimental performance [31]. Very few
literature information is available on the RSM optimizations for trans-
forming glucose to 5-HMF in various reaction mediums [11,32–34]. In
the aqueous medium, a simplex-centroid (SC) method was used by
Catrinck et al. [33] for the optimization of 5-HMF yield in the presence
of niobium acid (NbO) and niobium phosphate (NbP). A 55% glucose
conversion with 56% selectivity of 5-HMF was obtained at 151.8 ◦ C in
120 min. The actual 5-HMF yield and the information regarding catalyst
stability are missing. In a [BMIM]Cl (ionic liquid) medium, Utami et al.
[32] optimized the glucose dehydration process in the presence of Yb
(OTf)3. A 3-level CCD was used. A 52% yield of 5-HMF was attained at
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Catalysis Today 404 (2022) 201–218
105 ◦ C after 2.7 h with 39.7 mg of catalyst. The information regarding
the catalyst reusability and stability is not reported. Similarly, Sarwono
et al. [34] optimized the reaction process in [BMIM]Cl with the CrCl3
catalyst using an RSM IV optimal design with three variables, i.e.,
temperature, time, and catalyst amount, respectively. Although the
obtained 5-HMF yield was high, however, the cost of ionic liquid (IL)
and the product separation difficulties make it less attractive. In the
organic DMSO medium, only one research paper was reported by Mo-
rales et al. [11]. A 3-level CCD model was used to optimize the glucose
dehydration reaction by considering run time, temperature, and catalyst
amount as the primary factors. The maximum 5-HMF yield of ~33% was
obtained at 147 ◦ C with 23 wt% catalyst loading after 24 h of reaction
time. However, the catalyst activity was reduced by 25% after the sec-
ond cycle due to a significant loss of acidic sites, and their reaction time
was too long.
In this study, the TiO2 was developed by the sol-gel hydrolysis
method and examined for glucose dehydration in a DMSO medium. The
reaction parameters were optimized using RSM coupled with a 5-level
central composite design. The effect of variable reaction variables, i.e.,
time, temperature, catalyst quantity, glucose loading on the conversion,
and products (5-HMF, LA, and FA) yield, was evaluated. The signifi-
cance of independent variables and the interaction effect between in-
dependent factors were also examined using RSM contour plots. The
optimization of the process was performed based on the desirability
approach. The model was validated with the experimental data gener-
ated at the optimum condition suggested by the RSM. In addition to that,
a catalyst regeneration and recycle strategy was developed, which
demonstrated that the TiO2 catalyst synthesized can easily be reused in
several cycles without much deactivation and loss of 5-HMF yield.
Furthermore, a new liquid-liquid extraction method is proposed to
separate the 5-HMF, and the results revealed that 5-HMF could be
separated from the product mixture with very high purity. Finally, the
experimental data were fitted with a Power-Law model, and the kinetic
parameters were calculated for the dehydration of glucose over the TiO2
catalyst.
2. Experimental
2.1. Catalyst synthesis
The TiO2 catalyst was developed by the sol-gel hydrolysis method
[18]. In the typical synthesis, 20 mL of titanium isopropoxide (97%,
Aldrich, India) was added to 40 mL of 2-propanol (99%, Thomas Baker,
India) and stirred for 5 min to make the solution homogeneous. Further,
distilled water was added drop by drop to the titanium isopropoxide
homogeneous solution for hydrolysis. The resulting mixture was stirred
for two hours, followed by the slow addition of 100 mL of 0.5 M HCl
(35–38%, Thomas Baker, India) for complete hydrolysis of titanium
isopropoxide. The solution was stirred for 3 h and aged overnight at
room temperature. The white color slurry obtained was diluted and
decanted a number of times with deionized water till the pH of the so-
lution reached ~2–3. The white-colored suspension obtained was
heated at 70 ℃ for 3 h to make a white gel. Afterward, the prepared gel
was dried at 120 ℃ overnight in a conventional oven. The shiny white
agglomerated particles obtained were grounded and calcined at 200 ℃
for 2 h in a muffle furnace in the presence of air. The resulting solid
power catalyst was designated as TiO2.
2.2. Catalyst characterization
The specific surface area (Brunauer-Emmett-teller) pore dimensions
of the TiO2 catalyst were determined by the N2 adsorption-desorption
technique in an ASAP 2060 (Mircomertics, USA) instrument. The BET
area and the catalyst’s pore size distributions were investigated using
the Brunauer-Emmett-teller (BET) and Barret-Joyner-Halenda (BJH)
methods. Before the analysis, the powdered sample was outgassed by
R. Tomer and P. Biswas
flowing helium (20 mL min−1) gas under vacuum at 150 ℃ for 2 h.
The powdered X-ray diffraction (P-XRD) pattern was recorded in a
D8-Advance diffractometer (Bruker, Germany) equipped with Ni filtered
radiation (Cu-Kα, λ = 1.5406 Å, voltage: 40 kV, current: 40 mA). The
diffraction pattern was recorded at a 2θ value of 5–90◦ . The step size and
scan speed were 0.02◦ and 4◦ min−1, respectively. The XRD peaks were
identified with the help of X′ pert-pro software and a joint committee of
powder diffraction standards (JCPDS). The line width of the XRD peaks
corresponding to different crystal planes was used in the Scherrer for-
mula to determine the average crystallite size of the TiO2.
The acidity of the catalyst sample was determined by NH3-TPD
(ammonia temperature-programmed desorption) technique on a
Micromeritics instrument (pulse chemisorb 2750, USA) coupled with a
TCD (thermal conductivity detector). In each experiment, a small
amount of catalyst (~40 mg) was pretreated for 2 h under helium flow
(20 mL min−1) at 150 ℃ followed by cooling at ambient conditions.
After the pretreatment, the catalyst sample was flooded with ammonia
by flowing a mixture of gas (10% NH3-He) (20 mL min−1) for 45 min at
room temperature. Further, the catalyst was purged with helium for 1 h
to remove the physically adsorbed ammonia on the catalyst’s surface.
The saturated sample was further heated from 25 to 900 ℃ at 10 ℃
min−1, and the amounts of NH3 desorbed were continuously recorded
with a TCD.
The Brønsted (B) and Lewis (L) acidity of the catalyst were analyzed
by the pyridine-FTIR (Py-FTIR) in a spectrophotometer (Bruker Tensor
II, Germany). In the distinctive process, initially, an appropriate amount
of catalyst dried for 1 h under vacuum at 120 ◦ C followed by cooling to
room temperature. Further, 50 mg of dried sample was saturated with
pyridine (100 µL) in a glass vial for 1 h. Then pyridine saturated sample
was heated at 120 ◦ C in the oven to evaporate the excess amounts of
pyridine adsorbed. The prepared catalyst sample (5 wt%) was mixed
with KBr (95:5 wt%) and pressed to a pellet of 13 mm diameter. Before
the analysis, the pellet weight was noted, and then the prepared pellet
was fixed in the IR cell of the FTIR instrument. After that, the FTIR
spectra of the pyridine adsorbed catalyst sample were collected at the
wavenumber of 500–4000 cm−1. The resolution and scan were 4 cm−1
and 64, respectively. The B/L ratio was obtained following the method
described in our previous work [35].
The catalyst morphology was analyzed by scanning electron micro-
scopy (FE-SEM, Carl-Zeiss-Ultra-Plus, Germany) armed with energy-
dispersive X-ray (EDX). EDX was used to determine the elements pre-
sent in the sample and their percentage. Before the FE-SEM analysis, the
crushed sample spread on the specimen holder and coated with gold
with the help of a sputter coater (Edwards S150, USA). The gold coating
was done under the flow of argon to eliminate the charging of particles.
The analysis was performed under vacuum at an accelerated voltage (20
kV).
2.3. Catalytic reaction test
The catalytic activity of TiO2 was carried out in a 15 mL borosilicate
glass tube connected with a tight screw cap. The appropriate amount of
glucose was dissolved in 5 mL DMSO (99.7%, Loba Chemie, India) and
added to the glass tube reactor (Borosil, India). After that, a pre-
determined amount of catalyst was added to the reaction mixture. The
glass reactor was tightly closed and kept in a preheated oil bath equip-
ped with a magnetic stirrer (Spinot digital model MC 02, Tarsons, India).
The dehydration reaction was done in the temperature range of
100–180 ◦ C. The glucose weight percentage in the feed, catalyst amount,
and reaction time varied in the range of 10–50 wt%, 0.15–0.965 g, and
2.5–8.5 h, respectively. After completion of the reaction, the glass tube
reactor was shifted from the oil bath and quenched with iced water to
end the reaction instantly. Further, the catalyst and products were
separated in a centrifuge (R-8C, Remi, India) at 4000 rpm, and the
composition of the product was measured in high-performance liquid
chromatography (HPLC, Waters, USA). The HPLC system was equipped
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Catalysis Today 404 (2022) 201–218
with a binary pump (Waters, 515, USA), RI detector (Waters 2414, USA),
a column (HPX 87-H+, 4.6 mm × 350 mm, Bio-Rad, USA). The column-
heater was used to maintain the desired temperature of the column. The
temperature of the column and the detector were kept at 65 ◦ C and
55 ◦ C, respectively. For HPLC analysis, degassed 5 mmol H2SO4 was
used as a mobile phase. The mobile phase flow rate, as well as the in-
jection volume, were 0.6 mL min−1, and 20 µL, respectively. In every
analysis, prior to the injection of the liquid product into the HPLC for
analysis, it was filtered using a 0.22 µm syringe filter. The concentration
of reactants and products was determined with the help of a standard
calibration curve of all known compounds. The following formula was
used for the calculation of glucose conversion and products yield.
% Conversion = [((Moles fed − Moles remaining)/Moles fed) ×100] (1)
% Yield = [(Product moles formed/ Glucose moles fed) ×100] (2)
3. Results and discussion
3.1. Catalyst characterization
In the nitrogen adsorption-desorption isotherm (Fig. 1(a)) of TiO2, a
hysteresis loop was detected at the relative pressure range of 0.4 < P/Po
< 0.7. These results represented the type-IV isotherm and H2 type hys-
teresis loop, which demonstrated the mesoporous characteristics of TiO2
[36]. Moreover, this hysteresis loop also confirmed the
ink-bottled-shaped pore structure of the TiO2 [37]. For TiO2 catalyst,
Nui et al. [38] reported a similar type of loop at a P/P0 of 0.4–1. The BET
surface area, cumulative pore volume, and pore diameter of the TiO2
catalyst were 272.66 m2 g−1, 0.189 cm3 g−1, and 2.3 nm, respectively.
The distributions of the pore size of catalyst are shown in Fig. 1(a) (inset
image). Raj et al. [39] reported a similar surfaced area of 277 m2 g−1 for
TiO2 catalyst without calcination. After calcination in the presence of air
at 500 ◦ C for 2 h, the BET area of TiO2 was found to be decreased to 100
m2 g−1.
In the XRD pattern (Fig. 1(b)) of TiO2, the major crystalline peaks
were identified at the two theta values of 25.4◦ , 37.8◦ , 48.0◦ , 55.3◦ ,
62.8, 69.0◦ , 75.3◦ , and 82.7◦ corresponding to the (101), (112), (200),
(105), (204), (116), (215), and (303), crystal planes of tetragonal TiO2,
respectively (JCPDS: 04–0477) [18]. These crystalline peaks of TiO2
were well matched with the anatase phase with the tetragonal structure
of TiO2. Similar two theta values corresponding to anatase TiO2 were
also reported by Muniandy et al. [40]. The Scherrer formula was applied
to estimate the average crystallite size of the TiO2. The calculated
average value based on the line width of their respective XRD peaks was
~22.4 nm.
The NH3-TPD profile (Fig. 1(c)) of TiO2 displayed the desorption
peaks at three different temperature regions, i.e., at 45–200 ℃,
200–300 ℃, and > 600 ℃, respectively. The desorption peaks repre-
sented weak, moderate, and strong-strength acidic sites on the TiO2
surface [41]. The total acidity of the TiO2 was calculated based on the
desorbed volume of NH3. For TiO2, the estimated total acidity was
0.76 mmol g−1, comparable with the value (0.87 mmol g−1) reported
earlier for anatase titania [20].
Pyridine FTIR study was performed to identify the nature of acidic
sites of TiO2 synthesized. The FTIR spectra of the pyridine adsorbed TiO2
catalyst demonstrated four peaks in the wavenumber range of
~1420–1705 cm−1, as shown in Fig. 1(d). The peak at the wavenumber
of ~1443.5 cm−1 and ~1536.5 cm−1 was associated with L-sites and B-
sites, respectively [42,43]. While the peak allied at ~1484.9 cm−1
represented both (B+L) sites of TiO2 catalyst [10]. These peaks
(1443.5 cm−1, ~1536.5 cm−1, and ~1484.9 cm−1) were attributed to
the coordinated pyridine molecule with L-sites and B-sites, respectively
[2,22]. The peak observed at ~1616 cm−1 was assigned to the physi-
cally adsorbed pyridine ring on the catalytic surface [19,44]. The B/L
R. Tomer and P. Biswas Catalysis Today 404 (2022) 201–218

Fig. 1. (a) N2 isotherm with pore-size variation, (b) XRD pattern, (c) NH3-TPD pattern, (d) Pyridine FTIR spectra, (e) FESEM images at different magnification, (f)
Particle size histogram, (g) EDX Plot.

204
R. Tomer and P. Biswas
ratio was calculated based on the absorbance area of the peaks detected
at 1484.9 cm−1 and 1536.5 cm−1, respectively. The obtained B/L ratio
was 2.73. Pyridine-FTIR study demonstrated the total acidity (B+L) of
0.031 mmol g−1, which was much lower than the total acidity value
(0.76 mmol g−1) obtained from the NH3-TPD analysis.
The surface morphology of TiO2 was determined by FE-SEM equip-
ped with EDX. Results dictated small and uniform spherical-shaped
particles of TiO2 at different magnifications (Fig. 1(e)). Smaller and
uniform particles were formed due to the stable gel formation during the
synthesis via the sol-gel method [45]. For TiO2, Narabe et al. [46] re-
ported the agglomerated morphology at lower magnification with a
scale of ~5 µm and smaller spherical particles at higher magnification of
the scale size 200 nm. In this study, the average particle size of
10–20 nm was observed (Fig. 1(f)) for TiO2, which was very similar to
the value obtained in XRD (22.4 nm). Furthermore, the EDX equipped
with FE-SEM analysis was done to obtain the elemental composition of
TiO2. The presence of titania, oxygen, and trace amounts of chlorine was
confirmed by the results reported in Fig. 1(g). In the EDX plot, the peak
detected at 4.5 eV corresponded to bulk titania, and the peak at 5 eV was
due to the surface titania. Similar findings were also reported in the
previous literatures [35,47].
3.2. Experimental design by using response surface methodology (RSM)
Among the various RSM methodology known, CCD is better because
the region of operability is more than the region of interest [31,48,49].
The CCD gives excellent prediction on the center point and is insensitive
to any missing data point. Therefore, the CCD method was chosen to
design the glucose dehydration reaction in this study. From the previous
literature, it has been observed that reaction temperature (A), reaction
time (B), catalyst amount (C), and glucose amount (D) was the primary
reaction parameter that affected the glucose conversion as well product
yield. Thus, these reaction parameters were considered as the main
factors, and the corresponding decided responses were the conversion of
glucose, the yield of 5-HMF, the yield of FA, and the yield of LA,
respectively. For experimental design, five-level coded factors (−α, −1,
0, +1, +α) were considered, the corresponding values are reported in
Table 1. The ranges of factors for the initial design of the experiments
were decided based on a few preliminary experiments performed. The
design matrix of the experiments included 31 runs containing 16
factorial points, 6 center points, and 9 axial points, respectively. The
obtained design matrix and the actual value of all the responses are
presented in Table 2. To design the experiment runs and to evaluate the
R2 value, Design-Expert (Version 11) was used.
The quadratic (second-order) polynomial model equation developed
by RSM correlates the responses (Y1, Y2, Y3, Y4) as a function of the
factors (X1, X2, X3, X4) as Eq. (3) [2,49].
n
∑ n
∑ n
∑ precision should be > 4 for a better prediction of the model. Adequate
Y = ß0 + ßi Xi + ßii X 2ii + ßij Xi Xj + e
i=1 i=1 i=1
i<j
Where Y (Y1, Y2, Y3, and Y4) represent the predicted responses of glucose
conversion, yield of 5-HMF, yield of FA, and yield of LA, respectively. Xi
and Xj are the real values of the independent factors, i.e., reaction
Table 1
Selected factors with their corresponding levels.
Coded value Factor-A [h] Factor-B [℃] Factor-C [g]
− α (−2) 2.5 100 0.105
−1 4.0 120 0.32
0 5.5 140 0.535
1 6.5 160 0.75
+ α(-2) 7.0 180 0.965
A
Reaction time, Breaction temperature, Ccatalyst amount, Dglucose amount
Catalysis Today 404 (2022) 201–218
temperature (A), reaction time (B), catalyst amount (C), and glucose
amount (D). These independent factors were symbolized as X1(A), X2(B),
X3(C), and X4(D), respectively. Besides, ß0, ßi, ßii and ßij, and e repre-
sented the model constant, linear, quadratic and interaction coefficients,
and the error term, respectively. To understand the effect of independent
factors on responses with real and coded dimensionless factors, the
empirical model equations developed in CCD are shown in Table TS1
(supplementary information).
To determine the suitability of the selected model, the statistical
analysis of the experimental data obtained for each response was eval-
uated by the analysis of variance (ANOVA) [33]. ANOVA also measures
the significance of each independent factor, the goodness of fit, lack of
fit, Fisher’s test (F-value), and probability (P-value) [50]. The goodness
of fit was judged by the determination coefficient (R2), and correlation
coefficient values obtained [51]. F-value was used to analyze the sta-
tistical importance of the proposed model with the help of a P-value with
a 95% confidence interval. Further, the lack of fit approach was used to
verify the acceptability and data variation. The acceptability of the
model was also verified by conducting the required runs at the antici-
pated conditions given by the CCD. The goodness of fit of the model was
improved by the RSM by tuning the respective P-value and F-values. The
interaction terms with a high P-value (> 0.05) were considered insig-
nificant in the model. Therefore, insignificant terms (P > 0.05) were
neglected, which enhanced the model’s fitness. The modified empirical
model for glucose conversion and yield of products (FA, LA, 5-HMF)
yield is shown in Table TS2, TS3, TS4, and TS5 (supplementary infor-
mation). The significance of the modified models for all the responses
was confirmed with the help of the F-value (48.4, 35.8, 21.8, and 28.6
for conversion of glucose, 5-HMF yield, FA yield, LA yield, respectively),
and p-value (< 0.0001).
The goodness of the model’s fit was also determined with the help of
the coefficient of determination (R2), which represented the nearness of
the experimental, and the anticipated response [49]. A higher R2 value
(> 0.80) obtained for the glucose conversion, the yield of 5-HMF, and
the yield of LA indicated the higher importance of the model and better
predictability of the responses. The R2 value (0.94) for glucose conver-
sion revealed that 94% of experimental data were well explained by the
model. Similarly, 92% of experimental data were explained by the
model for 5-HMF and LA yield with the R2 value of 0.92. However, a
comparatively lower R2 value (0.61) was obtained for FA yield because
of the fluctuation in the concentration of FA throughout the design
matrix. It might be because of the decomposition of FA to other com-
pounds such as furfural and CO2, H2, CO, and H2O with the variation of
temperature [52,53]. According to the ANOVA fit statistics, the differ-
ence between predicted R2 and adjusted R2 should be < 0.2 for a better
fitting of the model. The observed difference was much lower
(0.06–0.09) for the glucose conversion, 5-HMF yield, the yield of LA,
and the yield of FA, respectively, indicating a better fit. The adequate
(3) precision suggests the domain of anticipated response with respect to its
connected error, i.e., signal/noise ratio. In this study, the adequate
precision value was in the range of 16.3–28.4, which was much higher
than the limiting value for all the responses. These results also suggested
better model prediction. The obtained statistical parameters for all
models are shown in Table 3, and the experimental and model-predicted
values are compared in Fig. 2.
3.3. Catalytic performance
Factor-D [wt%] 3.3.1. Temperature and time interaction effect
10
The combined effect of temperature (100–180 ℃) and time
20 (2.5–8.5 h) on the conversion of glucose and yield of the product were
30 determined by keeping the other reaction parameters such as glucose
40 amount (30 wt%) and catalyst amount (0.535 g) constant. The volume
50
of DMSO was also kept constant at 5 mL for all the runs. The obtained
conversion of glucose and yield of the product is displayed in Fig. 3(a)-
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Table 2
Experiment design in the presence of TiO2 catalyst.
Run Space type Factor Response

Time (h) Temperature ( C)

◦
Catalyst Amount (g) Glucose % Glucose conversion 5-HMF yield FA yield LA yield

1 Factorial 7.0 160 0.320 40 94.8 36.8 6.4 2.3

2 Factorial 4.0 160 0.320 20 93.2 40.6 16.7 1.4
3 Center 5.5 140 0.535 30 83.5 25.2 10.7 0.6
4 Center 5.5 140 0.535 30 82.4 33.8 10.6 1.1
5 Factorial 7.0 160 0.320 20 93.7 46.5 17.9 2.6
6 Axial 8.5 140 0.535 30 88.8 31.5 11.1 1.9
7 Factorial 4.0 120 0.320 20 64.3 13.0 5.5 0.9
8 Center 5.5 140 0.535 30 84.2 27.6 10.1 0.3
9 Factorial 7.0 120 0.320 20 75.2 26.0 12.5 2.4
10 Axial 5.5 180 0.535 30 100.0 35.6 60.2 4.2
11 Axial 5.5 140 0.535 50 89.2 33.3 21.9 1.4
12 Factorial 4.0 160 0.320 40 90.6 32.1 14.4 1.8
13 Axial 6.5 140 0.535 30 83.7 26.3 7.1 1.6
14 Factorial 4.0 120 0.750 40 77.0 15.7 10.0 0.2
15 Factorial 4.0 160 0.750 40 94.1 34.5 14.3 2.5
16 Factorial 4.0 120 0.750 20 71.0 27.7 8.6 0.3
17 Axial 5.5 140 0.535 10 92.1 52.3 7.6 2.8
18 Center 5.5 140 0.535 30 76.6 32 21.2 0.0
19 Factorial 4.0 120 0.320 40 74.4 7.6 3.7 0.2
20 Factorial 7.0 120 0.320 40 83.0 10.4 6.5 0.0
21 Factorial 7.0 160 0.750 40 99.1 32.2 16.3 3.4
22 Center 5.5 140 0.535 30 83.7 26.4 9.1 0.6
23 Factorial 4.0 160 0.750 20 97.9 40.7 53.3 3.0
24 Factorial 7.0 120 0.750 40 79.1 17.2 10.0 0.7
25 Axial 2.5 140 0.535 30 82.3 18.5 11.7 0.0
26 Axial 5.5 140 0.965 30 89.6 33.1 11.8 1.0
27 Factorial 7.0 160 0.750 20 97.8 42.5 35.0 3.4
28 Axial 5.5 140 0.105 30 79.3 14.1 8.7 0.5
29 Factorial 7.0 120 0.750 20 74.7 30.9 11.8 1.8
30 Axial 5.5 100 0.535 30 48.6 8.7 1.1 0.2
31 Center 5.5 140 0.535 30 82.5 26.8 11.4 0.7

low temperature (< 140 ◦ C) and at < 4 h (Fig. 3(c)). However, at a

Table 3
higher temperature (> 160 ◦ C) and after a longer reaction time (> 6 h),
Statistical parameter for the glucose conversion to 5-HMF.
the LA was detected. The maximum LA yield of ~5% was observed at
Response R2 Adjusted R2 Predicted R2 Adequate precision > 160 ◦ C after a reaction time of more than 7 h. Morales et al. [11]
Glucose conversion 0.94 0.92 0.84 28.4 reported the maximum LA yield of < 4% at 150 ◦ C with Amberlyst-70
5-HMF yield 0.92 0.89 0.83 25.8 catalyst after the reaction time of 24 h in the DMSO medium. The
LA yield 0.92 0.89 0.83 20.3 lower yield of LA was observed because the DMSO restricted the rehy-
FA yield 0.61 0.58 0.49 16.3
dration of 5-HMF. Previous reported density functional theory (DFT)
calculation on the stability of 5-HMF in DMSO/water mixture dictated
(d), respectively. As expected, glucose conversion was found to be that DMSO increased the LUMO energy of 5-HMF, which reduced the
increased with temperature (Fig. 3(a)) [10,52]. The conversion was very probability of the nucleophilic attack and stabilized the 5-HMF in the
high (~80%) even at low temperatures (~140 ℃), and it was achieved DMSO medium. The molecular simulation study also suggested that the
~100% at > 160 ℃. Conversion also displayed an increasing trend with carbonyl group of 5-HMF solvated in DMSO prevented the rehydration
increasing reaction time. After 8.5 h, glucose conversion was ~80–86% of 5-HMF to other side products, including levulinic acid, formic acid,
in the temperature range of 120–140 ℃, and it reached ~90% at etc. [55,56]. The yield observed for FA is shown in Fig. 3(d). Initially, at
~160 ℃ in less than 3 h of reaction. These results revealed that the rate low temperature (< 140 ◦ C), in the entire reaction time domain
of glucose conversion was ~1.4 times (3.9 × 10−3 mmol mL−1 min−1) (2.5–8.5 h), the FA yield was very low (< 14%). However, FA yields
higher at 160 ◦ C concerning the rate (2.7 × 10−3 mmol mL−1 min−1) increased significantly (~20–40%) at 160–180 ◦ C. The formation rate of
observed at 120 ◦ C. At higher temperatures, the favorable electron ex- FA was also calculated, and it was observed that formation rate (7.2 ×
change rate facilitated, which enhanced the glucose conversion rate [2]. 10−4 mmol mL−1 min−1 at 160 ◦ C) was ~3 fold higher at high tem-
The time and temperature interaction results suggested that, in the perature (160–180 ◦ C) with respect to the rate (2.3 × 10−4 mmol mL−1
presence of the TiO2 catalyst, very high glucose conversion (~80–100%) min−1 at 120 ◦ C) calculated at low temperature (100–140 ◦ C). These
can be achieved in the temperature range of 140–180 ◦ C, and after a results revealed that higher reaction temperature with prolonged reac-
reaction time of 4–8 h. The variation of the yield of 5-HMF with tem- tion time facilitated the formation of FA and LA, which was formed due
perature and time is manifested in Fig. 3(b). The yield of 5-HMF was to the rehydration/degradation of 5-HMF/glucose. A similar type of
found to be very low (< 20%) at low temperature (< 140 ◦ C) and in the rehydration product was also observed mainly at high temperatures in
entire time domain (2.5–8.5 h). At this low-temperature range, the various previous studies [11,12,57]. The contour plots reported in Fig. 3
calculated 5-HMF formation rate with time was also low (~5.5 × 10−4 (a)-(d) suggested that the influence of the reaction temperature was
mmol mL−1 min−1 at 120 ◦ C). However, at high temperatures (> more significant with respect to the reaction time on glucose conversion
160 ◦ C), the calculated rate of formation increased to approximately 3.6 along with the products (5-HMF, LA, and FA) yield.
times (2 × 10−3 mmol mL−1 min−1 at 160 ◦ C). Similar results were re-
ported previously over several solid acid catalysts and reaction solvents 3.3.2. Glucose amount and temperature interaction effect
[22,54]. A maximum ~43% yield of 5-HMF was achieved at As discussed in Section 3.2, the interaction terms with a high P-value
160–180 ◦ C, and after a reaction time of 5.5 h. LA was not observed at (> 0.05) were considered insignificant in the model. Therefore,

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R. Tomer and P. Biswas
Fig. 2. Experimental vs. predicted values (a) conversion of glucose, (b) yield of 5-HMF, (c) yield of LA, and (d) yield of FA.
negligence of insignificant terms (P > 0.05) from the model improved
the model’s fitness. The ANOVA statistics suggested that the combined
effect of glucose amount and temperature on 5-HMF and FA yield was
negligible. Therefore, the obtained interaction effect of glucose amount
(10–50 wt%) and reaction temperature (100–180 ◦ C) on glucose con-
version and LA yield with a fixed amount of catalyst (0.535 g) and re-
action time (5.5 h) is shown in Fig. 4. It was found that the conversion of
glucose was ~60% at a low temperature (< 120 ◦ C) in the entire region
of glucose amount (10–50 wt%) studied. However, a slight increase
(~72%) in conversion was observed with 50 wt% glucose at < 120 ◦ C
because of higher accessibility of glucose molecules [10,20]. The cur-
vature of contours lines was found to be increased at a high temperature
(> 140 ◦ C), which indicated the enhanced interaction of glucose amount
with temperature [2]. The complete conversion (100%) of glucose was
observed in the temperature region of ~160–180 ◦ C at a low glucose
amount (< 20 wt%). However, at higher glucose concentration (> 30 wt
%), the maximum conversion was ~95% at 160–180 ◦ C. Glucose con-
version decreased because of the presence of an insufficient amount of
active sites since the catalyst amount was constant [58]. LA was not
detected at higher glucose concentration (> 30 wt%) and lower tem-
perature region (~100–140 ◦ C). However, the formation of LA was
found to be favorable at high temperatures (~140–180 ◦ C) in the entire
glucose amount domain, as shown in Fig. 4(b) [11]. The formation of LA
via 5-HMF rehydration was favorable at high reaction temperatures. The
maximum yield of LA (~5%) was obtained at the temperature region of
160–180 ◦ C. This interaction study suggested that complete glucose
conversion can be achieved in the presence of a lower glucose amount
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Catalysis Today 404 (2022) 201–218
(< 20 wt%) at the temperature of < 160 ◦ C. Also, the high reaction
temperature facilitated the rehydration of the desired 5-HMF to side
products such as LA.
3.3.3. Glucose amount and time interaction effect
To determine the combined interaction effect, glucose amount and
time were varied in the range of 10–50 wt%, and 2.5–8.5 h, respectively.
The catalyst amount (0.535 g) and the reaction temperature (140 ◦ C)
were kept constant. As shown in Fig. 5(a), glucose conversion was
observed to be increased with time, and it decreased with glucose con-
centration. It has been seen that in the reaction time domain of 7–8.5 h,
glucose conversion decreased from ~92% at < 20 wt% glucose to ~87%
at 20–40 wt% glucose. Further, at a higher glucose amount (> 40 wt%),
the conversion was found to be increased marginally because the con-
centration (> 40 wt%) was beyond the design space. Conversion
decreased with increasing glucose amount was caused by the less
availability of active centers in the presence of a constant amount of
catalyst. The comparable observations were stated by Sarwono et al.
[58]. The glucose conversion rate was calculated with the variation of
reaction time as well as glucose amount. The rate was found to be
decreased with reaction time and increased with glucose amount. At
140 ◦ C in the presence of 30 wt% of glucose, the conversion rate
decreased from 5.9 × 10−3 to 4.4 × 10−3 mmol mL−1 min−1 in the re-
action time domain of 2.5–8.5 h. Moreover, after 5.5 h, the calculated
glucose conversion rate was observed to be increased from 9.1 × 10−4 to
3.9 × 10−3 mmol mL−1 min−1 in the glucose amount range of 10–50 wt
%. The decreasing trend of the yield of 5-HMF with increasing glucose
R. Tomer and P. Biswas Catalysis Today 404 (2022) 201–218

Fig. 3. 3-D surface and contour plots represent the temperature-time interaction effect on (a) Glucose conversion, (c) 5-HMF yield, (d) LA yield, (d) FA yield.
Reaction condition: 0.535 g catalyst, 30 wt% glucose in the solvent, 5 mL DMSO solvent.

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R. Tomer and P. Biswas
Fig. 4. 3-D surface and contour plots represent the temperature-glucose amount interaction effect on (a) Glucose conversion (b) LA yield. Reaction condition: 0.535 g
catalyst, 5.5 h, 5 mL DMSO solvent.
amount in the reaction mixture was observed (Fig. 5(b)). The value
decreased from ~52% to ~32% on increasing the glucose concentration
from 10 wt% to 50 wt%. It has been observed from previous literature
that, in the presence of a constant amount of catalyst, beyond a certain
glucose concentration, conversion of glucose/5-HMF to other undesired
products such as humin facilitated [58,59]. Because of this reason, the
5-HMF yield decreased at a high concentration of glucose. However,
with increasing reaction time, the yield of 5-HMF increased marginally
due to the availability of sufficient time to obtain the equilibrium con-
version. In the presence of a limited amount of catalyst, prolonged re-
action time helps achieve equilibrium conversion [2]. The highest
(~52%) yield of 5-HMF was detected within 4–8 h of reaction time at
lower glucose concentration (< 20 wt%). The curvature of lines in Fig. 5
(c) indicated the interaction of glucose amount and reaction time on LA
yield. The overall yield of LA was very low (< 4%). LA was formed due to
the rehydration of 5-HMF; very low LA yield suggested that the rehy-
dration reaction was negligible. However, the results reported in Fig. 5
(c) suggested that LA formation was facilitated at a higher reaction time
(> 7 h) and in the presence of a lower amount of glucose (< 20 wt%)
[19]. The interaction effect of glucose amount and reaction time
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Catalysis Today 404 (2022) 201–218
suggested that glucose concentration of < 20 wt% and the reaction time
of 4–8 h was beneficial for higher glucose conversion and 5-HMF yield.
3.3.4. Temperature and catalyst amount interaction effect
The combined effect of catalyst amount and temperature on the
glucose conversion and FA yield was insignificant as the P-value was
> 0.5. Therefore, the obtained interaction effect of reaction temperature
(100–180 ◦ C) and catalyst amount (0.105–0.965 g) on the 5-HMF and
LA yields are shown in Fig. 6. The other reaction factors, such as glucose
concentration (30 wt%) and reaction time (5.5 h), were constant. It was
observed from Fig. 6(a) that the yield of 5-HMF was negligible (< 10%)
at a lower amount of catalyst (0.105–0.32 g) and a low reaction tem-
perature (< 120 ◦ C). The 5-HMF yield was lower at low temperatures
due to low activation energy. However, in the low-temperature region
(< 120 ◦ C), at high catalyst loading (> 0.75 g), ~19% yield of 5-HMF
was obtained because of the accessibility of more active centers [25].
It was observed that in the high-temperature region (> 140 ◦ C), the
5-HMF yield decreased with the increasing catalyst amount (> 0.535 g).
At > 160 ◦ C, in the low catalyst amount region (0.105–0.32 g), the
maximum 5-HMF yield of ~41% was obtained. Moreover, the 5-HMF
R. Tomer and P. Biswas Catalysis Today 404 (2022) 201–218

Fig. 5. 3-D surface and contour plots represent the glucose amount-reaction time interaction effect on (a) glucose conversion, (b) 5-HMF yield, (c) LA yield. Reaction
condition: 140 ◦ C, 0.535 g catalyst, 5 mL DMSO solvent.

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R. Tomer and P. Biswas
Fig. 6. 3-D surface and contour plots represent the temperature-catalyst amount effect on (a) 5-HMF yield (b) LA yield. Reaction condition: 5.5 h, 30 wt% glucose,
5 mL DMSO solvent.
yield decreased to ~34% at higher catalyst loading (> 0.75 g) in the
same temperature region. These results suggested that increasing the
catalyst amount and temperature facilitated the formation of 5-HMF up
to an optimum value. Beyond that, excess catalyst amount and high
temperature facilitated the side reactions, i.e., rehydration of 5-HMF.
The variation of the yield of LA is shown in Fig. 6(b). LA was not
formed at a low-temperature region (< 140 ◦ C) in the complete domain
of catalyst amount (0.105–0.965 g) studied. However, LA formation was
observed predominantly at the high-temperature region (> 160 ◦ C). The
maximum percentage yield of LA was ~5.5% at a high catalyst amount
(> 0.535 g) and a high temperature (160–180 ◦ C) because of the rehy-
dration of 5-HMF [60]. The combined effect of temperature and catalyst
amount study suggested that a high 5-HMF yield (~41%) can be ach-
ieved in the reaction temperature range of 140–160 ◦ C and the presence
of an optimum amount of catalyst (0.32–0.535 g), respectively.
3.3.5. Time and catalyst amount interaction effect
The combined effect of reaction time (2.5–8.5 h) and catalyst
amount (0.11–0.97 g) on conversion and product yield at a constant
glucose concentration (30 wt%) and reaction temperature (140 ◦ C) is
shown in Fig. 7. The obtained straight contour lines in all Fig. (7(a)-(d))
indicated a more negligible interaction effect between these two factors
on all the responses. Glucose conversion increased from ~77–84%,
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Catalysis Today 404 (2022) 201–218
increasing reaction time from 2.5 to 8.5 h. Conversion also increased
from ~77–90%, with the catalyst loading increasing from 0.105 to
0.965 g (Fig. 7(a)). These results suggested that both factors had an
effective linear outcome on glucose conversion. A similar outcome of
time and the amount of catalyst was also observed on the yield of 5-
HMF, as manifested in Fig. 7(b). The yield of 5-HMF increased from
17% to 25%, increasing the time from 2.5 h to 8.5 h at low catalyst
loading (0.105–0.32 g). A maximum yield of 5-HMF of ~18–35% was
achieved using the catalyst amount of 0.105–0.965 g. High catalyst
loading (> 0.75 g) and reaction time (> 5.5 h) enhanced the yield of LA
(2%) and FA (18%), as depicted in Fig. 7(c) and (d), respectively. These
results suggested that glucose conversion and 5-HMF yield increased
with time and catalyst amount because of the accessibility of more active
centers at higher catalyst loading for a more extended period. However,
the higher accessibility of active centers also enhanced the yield of
rehydrated products such as LA and FA, respectively [61,62]. The time
and catalyst amount interaction effect suggested that the optimum
catalyst amount of < 0.75 g and the reaction time of < 7 h were favor-
able for a higher 5-HMF yield.
As discussed earlier, the B/L ratio of the catalyst played an important
role in product distribution. The B-L acidic sites of TiO2 were identified
based on the functional group obtained in FTIR spectroscopy, as re-
ported in Fig. 9(b). The FTIR spectrum of TiO2 catalyst demonstrated
R. Tomer and P. Biswas Catalysis Today 404 (2022) 201–218

Fig. 7. 3-D surface contour plots represent the catalyst amount-reaction time interaction effect on (a) the conversion of glucose, (b) the yield of 5-HMF, (c) the yield
of LA, and (d) the yield of FA. Reaction condition: 140 ◦ C, 30 wt% glucose, 5 mL DMSO as solvent.

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three significant bands at the wavenumber of 3374.1, 1619.5, and value for Yi response. All individual desirability (di(Yi)) functions for all
1021–500 cm−1, corresponding to the H-O-H stretching of adsorbed the responses were combined to obtain the maxima, a unique function
water molecules, Ti-O-H stretching, and Ti-O fingerprints, respectively. named overall desirability (DI), which was found by using the following
An O-Ti group was responsible for Lewis (L) acidic sites, while the Ti-O- equation:
H group was responsible for Brønsted (B) acidic sites. The proposed /
∑n ( )
structure of the TiO2 catalyst is shown in Fig. S1 (Supplementary file). 1 si n
∏
Similar types of B and L sites are also reported earlier [63]. Based on the
s1 s2
DI = (d1 d2 .dn )sn i=1
= di si (5)
product distribution obtained over the TiO2 catalyst, a probable reaction i=1

pathway is proposed (Fig. 8), which depicts the different steps of

where ’n′ was the total number for responses, ’si’ was the relative
product formation via the interaction of molecules with the different
importance assigned to each response, which might be varied from 1 for
acidic sites of the catalyst [64]. DMSO acted as a reaction medium and
the least important response to 5 for a most important response. DI also
prevented the rehydration of 5-HMF via the solvation of its carbonyl
varied from zero to one. DI worked on a direct search method to
group [56].
maximize the desirability function [65]. The direct search method was
advantageous because, in this method, any information regarding the
3.4. Optimizations of reaction parameter and model validation gradient of the objective function is not required.
The individual desirability functions were defined for all the re-
The optimal reaction conditions for high glucose conversion and sponses as below:
high yield of 5-HMF were determined using the optimization (numeri- ⎧ ⎫
⎪ 0 if Yi ≤ 80 ⎪
cal) features of Design Expert-11 (software). The goal of the optimiza- ⎪
⎪
⎨
⎪
⎪
⎬
tion process was to maximize the glucose conversion and 5-HMF yield. Y1 − 80
d1 (Y1 ) = if 80 < Yi < 100 (6)
⎪ 100 − 80
The constraints and importance levels decided to achieve the selected ⎪
⎪ ⎪
⎪
⎩ ⎪
⎭
goals are shown in Table 4. The reaction parameter study demonstrated 1 if Yi ≥ 100
that the high conversion and the desired product (5-HMF) yield could be ⎧ ⎫
obtained at a higher temperature, reaction time, catalyst amount, and ⎪
⎪ 0 if Y2 ≤ 10 ⎪
⎪
⎪
⎨ ⎪
⎬
low glucose concentration. As a result, temperature, time, and amount of Y2 − 10
d2 (Y2 ) = if 10 < Y2 < 60 (7)
catalyst were set a goal as "in range", and the glucose amount was ⎪
⎪ 60 − 10 ⎪
⎪
⎪
⎩ ⎪
⎭
assigned with a goal of 10 wt% to achieve the maximum response for 1 if Y2 ≥ 60
feed (glucose) conversion and desired product (5-HMF) yield. The so-
lutions acquired with these four variables, including the desirability ⎧ ⎫
⎪
⎪ 1 if Y3 ≤ 1.5 ⎪
⎪
index, were generated by the software, and the results obtained are ⎪
⎨ ⎪
⎬
Y3 − 1.5
shown in Table 5. The individual desirability index (’di’) was set as an d3 (Y3 ) = if 1.5 < Y3 < 4.5 (8)
⎪
⎪ 4.5 − 1.5 ⎪
⎪
objective function ranging from 0 to 1 (0 ≤ di ≥ 1). When the response ⎪
⎩ ⎪
⎭
0 if Y3 ≥ 4.5
was at the target, ’di’ was equal to one (1), and when the response was
exterior of the desired region, then ’di’ was equal to zero (0). Then the ⎧ ⎫
⎪ 1 if Y4 ≤ 20 ⎪
individual desirability function was described as follows: ⎪
⎪
⎨
⎪
⎪
⎬
Y4 − 20
⎧ ⎫ d4 (Y4 ) = if 20 < Y4 < 30 (9)
⎪
⎪ 0 if Yi ≤ Yi min ⎪
⎪ ⎪
⎪ 30 − 20 ⎪
⎪
⎪
⎪ ⎪
⎪ ⎪
⎩ ⎪
⎭
⎨ min ⎬ 0 if Y4 ≥ 30
Yi − Yi
di(Yi ) = max min if Yi
min
< Y i < Yi
max (4)
⎪
⎪ Yi − Yi ⎪
⎪
⎪
⎪
⎩
⎪
⎪
⎭ To verify the model’s prediction ability, a glucose dehydration re-
1 if Yi ≥ Yi max action was performed at the optimal reaction conditions suggested by
the software. The comparison of model-predicted and experimental
Where di(Yi) was the desirability of Yi response, Yimin was the lower values for a particular solution is shown in Table 6. The results suggested
acceptable value for the Yi response, Yimax was the acceptable upper

Fig. 8. Reaction pathway of glucose dehydration in the presence of a TiO2 catalyst.

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Table 4
Constraints for numerical optimization by using the CCD method in RSM.
Factor Goal Lower limit Upper limit Lower weight Upper weight Importance

Time (h) In range 4 7 1 1 3

Temperature (◦ C) In range 130 160 1 1 3
Catalyst amount (g) In range 0.32 0.75 1 1 3
Glucose amount (wt%) Target= 10 10 30 1 1 3
Glucose conversion (%) Maximize 80 100 1 1 5
5-HMF yield (%) Maximize 10 60 1 1 5
LA yield (%) Minimize 1.5 4.2 1 1 3
FA yield (%) Minimize 20 30 1 1 4

Table 5
Possible solutions for the optimum conditions to maximize the 5-HMF yield and glucose conversion.
No. A (h) B (◦ C) C (g) D (wt%) Y1 (%) Y2 (%) Y3 (%) Y4 (%) Desirability index (DI)

1 4.0 159.3 0.320 10.0 100.0 56.4 18.4 2.4 0.921

2 4.0 158.0 0.320 10.0 99.2 55.8 17.6 2.4 0.913
3 4.0 155.8 0.320 10.0 97.9 54.8 16.5 2.3 0.899
4 5.6 155.7 0.320 10.0 100.0 57.3 16.5 3.1 0.857
5 5.8 160.0 0.320 12.8 100.1 54.0 18.7 3.0 0.838
6 5.4 149.6 0.321 10.0 95.9 53.9 13.7 2.9 0.825
7 5.8 160.0 0.385 14.5 99.3 51.1 20.0 2.9 0.811

4. Catalyst stability, reusability, and regeneration study

Table 6
Comparison between the experimental and model-predicted values at the opti-
The catalyst stability and the reusability were examined at the
mum condition.
optimized reaction conditions. After each experiment, the used catalyst
Response Experimental value Predicted Value % error
was separated via centrifuge from the reaction mixture. The catalyst was
(%) (%)
washed with distilled water and acetone several times to separate all the
Glucose conversion 98.2 100.0 1.8 deposited byproducts. After washing, it was filtered and heated at 80 ◦ C
(%)
overnight in a conventional oven for drying. The dried catalyst was
5-HMF yield (%) 56.1 56.4 0.54
LA yield (%) 2.38 2.4 0.84 further used in the subsequent cycle of the reaction. The results sug-
FA yield (%) 19.58 18.4 6.03 gested that the catalyst activity decreased in the subsequent cycle (Fig. 9
(a)), and conversion decreased from 98% to 64% in cycle-3. Glucose
Optimized reaction condition: 159.3 ◦ C, 4 h, 10 wt% glucose, 0.32 g catalyst,
5 mL DMSO solvent, and DI = 0.92. conversion decreased due to the deposition of humin or other organic
molecules formed on the catalyst active surface, which blocked the
active catalyst sites in every cycle. Therefore, after cycle-3, the catalyst
that the experimental values for reactant (glucose) conversion and
was regenerated by heating at 400 ◦ C in a furnace for 1 h in air presence.
product (5-HMF, LA, and FA) yield were very near the model’s predicted
Further, the activity of this regenerated catalyst was evaluated in the
value. The relative error between predicted and experimental values was
next run under the same reaction condition. Results dictated that con-
less than 2% for reactant (glucose) conversion and desired product (5-
version and yield further increased to 87% and 54%, respectively (Fig. 9
HMF) yield. It can be concluded that the developed model for conversion
(a)). These values were comparable with the conversion (98%) and yield
(glucose) and the main product (5-HMF) yield demonstrated very good
(56%) obtained over fresh catalysts. These results revealed that the TiO2
predictability with adequate accuracy within the experimental domain.
catalyst developed was very active, selective to 5-HMF, and easily

Fig. 9. (a) Recycle study of the TiO2 catalyst, (b) FTIR spectra of fresh, spent, and regenerated catalyst. Reaction condition: 160 ◦ C, 4 h, 0.32 g catalyst, 10 wt%
glucose, 5 mL DMSO solvent.

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recycled by simply heating in the presence of air. The removal of process proposed in this study may be very attractive for the production
deposited organics from the active sites of TiO2 catalyst was found to be and separation of 5-HMF on a larger scale.
very crucial for its regeneration. In Table 7, the result obtained in this study is compared with the
To understand the reason for the catalyst deactivation, the FTIR previously reported results in the DMSO solvent. In the previous studies
analysis of fresh, used, and regenerated catalysts were performed, and [5,10,16,17,26,44,69–73], the glucose conversion and 5-HMF yield
the obtained spectra were compared in Fig. 9(b). FTIR spectrum of fresh were reported in the span of 97–100% and ~26–67%, respectively. In
TiO2 catalyst demonstrated three significant bands at the wavenumber this study, a maximum of 56% yield was reached for 5-HMF with 98%
of 3374.1, 1619.5, and 1021–500 cm−1, assigned to the H-O-H stretch- glucose conversion at 160 ◦ C after the 4 h of reaction. Comparatively,
ing of water molecules adsorbed, Ti-O-H stretching, and Ti-O finger- Qu et al. [17] reported a higher yield (~67%) of 5-HMF in the presence
prints [38,66], respectively. In the used catalyst, besides these bands, of ionic liquid as a catalyst. However, the isolation of products and the
some other wide-stretching bands were observed at the wavenumber cost of ionic liquids were critical issues. The marginally higher yield
range of 2094.8–1795.2 and 1478.0–1278.5 cm−1. The broad spectrum (57%) of 5-HMF was also reported by Lu et al. [69]. Nevertheless, in
detected at 2094.8–1795.2 cm−1 represented the C– – O stretching, and their study, it was observed that the reaction time was higher, and most
at 1478.0–1278.5 cm−1 corresponded to C-O, C-O-C stretching of the importantly, the 5-HMF yield was found to be decreased approximately
furan ring, separately. These distinct results confirmed the existence of 21% after recycling. None of these studies discussed the extraction of
humin and/or other deposited organic molecules on the used catalyst 5-HMF. In the present study, ~54% 5-HMF yield was obtained even after
surface [35]. Furthermore, in the FTIR spectra of the regenerated cata- cycle-3 and 5-HMF were separated from the reaction mixture with very
lyst, the band (2094.8–1795.2 cm−1) corresponding to the humin high purity. Therefore, the results reported in this study are very
and/or other organic molecules was absent. These results confirmed that promising and may be very attractive commercially for the
the humin and/or other organics deposited on the catalyst surface were industrial-scale manufacturing of 5-HMF from glucose in the DMSO
removed entirely after regeneration. The peak intensity corresponding medium.
to the deposited organic species at the wavenumber of 5-HMF is an important platform chemical and is used as a feedstock
1478.0–1278.5 cm−1 was reduced significantly, and the FTIR spectra in various chemical industries, including bulk chemicals, biofuel,
resumed like a fresh catalyst (Fig. 9(b)-inset). pharmaceuticals, polymer/rubber, food packaging, agrochemicals,
The Power-Law kinetics of glucose conversion was developed cosmetic and textile industries, etc. Various important chemicals, i.e.,
following the Levenspiel method. The glucose concentration at different 2,5-furandicarboxylic acid (2,5-FDCA), adipic acid, 2,5-Dimethylfuran,
temperatures (120–140 ◦ C) was analyzed at the time interval of 10 min caprolactam, and caprolactone 5-HMF, can also be synthesized from
up to 1 h, as shown in Fig FS2(a) (supplementary file). The obtained 5-HMF. A high 5-HMF yield can easily be acquired from fructose.
results suggested first-order kinetics of glucose dehydration reaction However, the availability and the cost of fructose are major concerns.
with the Ea (activation energy) and A0 (Arrhenius factor) of Alternatively, the production of 5-HMF from the low cost and available
67.5 kJ mol−1 and 1.2 × 107 min−1, respectively (Fig. FS2(b)) (supple- glucose is very attractive. However, the pyranose structure of glucose
mentary file). The value of Ea obtained was less with respect to the hindered the formation of 5-HMF from glucose. The development of a
previously reported value for the same reaction systems demonstrating special type of catalyst, solvent, and catalytic process is highly desirable
excellent activity of the TiO2 catalyst in the DMSO medium. The detailed for the development of a commercial process. In addition to that, the
kinetics study is shown in Section S1 in the supplementary information. separation and purification of 5-HMF from the reaction mixture is also a
big challenge. In this study, a new promising, easily available, and
5. 5-HMF extraction from the product mixture recyclable TiO2 was synthesized for the manufacturing of 5-HMF from
glucose. Most importantly, a new product separation strategy is also
Previous literature discussed the formation of 5-HMF in different proposed. Therefore, the information reported in this study may be
reaction mediums in the presence of various types of catalysts. However, helpful for the large-scale production of 5-HMF from glucose in the near
none of the studies discussed the separation and purification of 5-HMF,
which is the major hurdle in the industrial manufacture of 5-HMF.
Therefore, in the present study, a new liquid-liquid extraction process Table 7
is proposed for the separation of 5-HMF. The process flow diagram of the Comparison of results obtained with previously reported literature in the DMSO
separation process proposed is displayed in Fig. FS3 (supplementary medium.
file). In the typical procedure, the TiO2 catalyst was segregated from the S. Temperature, Catalyst Glucose 5- Reference
product mixture by centrifuge. Further, the NaCl saturated water was no. Time Conversion HMF
added into the remaining product mixture to separate the humin/ yield
polymeric byproducts. Then the 5-HMF was removed from the super- 1. 140 ◦ C, 12 h UiO-66 – 49.7 [5]
natant by the Liquid-liquid extraction (LLE) in the separating funnel. 2. 130 ◦ C, 1 h PIL-Sn 99 51.1 [10]
Tetrahydrofuran (THF) was used as a low boiling solvent for the 3. 130 ◦ C, 4 h SO42−/ZrO2/ 99 47.6 [16]
Al2O3
extraction of 5-HMF from the product mixture containing DMSO. The 4. 180 ℃, 1 h [CO2HMIM]BF4 – 67.4 [17]
oxygen heterocyclic structure of THF facilitated the 5-HMF extraction 5. 170 ◦ C, 2 h Al-KCC-1 Silica 97 39.0 [26]
efficiency [67]. The addition of NaCl in the aqueous phase increased the 6. 140 ◦ C, 2 h Al2O3-B2O3(Al/ 98 41.5 [44]
partition coefficient due to the "salting-out effect" between the organic B=5:5)
7. 140 ◦ C, 10 h Hydroxylated 97 57.0 [69]
and aqueous layer [68], which enhanced the separation. After the
AlF3
addition of THF, two distinct aqueous-organic layers were visible, as 8. 150 C, 8 h
◦
APS/SiO2-ZrO2/ 100 34.0 a
[70]
shown in Fig FS4 (supplementary file). An evident color change, i.e., PAI-HF
from clear solution to the dark-brown color of the THF layer, was visible, 9. 195 ◦ C, 1.5 h SO42−/ZrO2/ – 25.8 [71]
which indicated the transport of 5-HMF to the THF layer. 5-HMF was ZSM-5
10. 80 ◦ C, 3 h Hydrotalcite/ – 25.0 [72]
extracted multiple times from the aqueous layer, and the HPLC results Amberlyst-15
demonstrated that ~95.7% of 5-HMF was extracted in the THF layer. 11. 120 C, 5 min
◦
Mesoporous TiO2 – 34.3 [73]
The extracted 5-HMF was separated from THF in a rotary evaporator. nanaopartclies
The purity (Fig. FS5) (supplementary file) of 5-HMF was also verified by 12. 160 ◦ C, 4 h TiO2 98 56.1 This
study
HPLC equipped with a Diode-array detector (DAD) and observed
~96.1% purity. The results depicted that the liquid-liquid extraction a
selectivity

215
R. Tomer and P. Biswas
future.
6. Conclusions
The mesoporous TiO2 was synthesized by sol-gel hydrolysis tech-
nique, and the properties of the catalyst were characterized by N2-
physisorption, XRD, FESEM, FTIR, NH3-TPD, Py-FTIR, etc. XRD results
revealed the anatase phase of the tetragonal TiO2. The Py-FTIR
confirmed the existence of both the B-sites and L-sites in the TiO2
catalyst, and the obtained B/L ratio was ~2.73. It was observed that the
B/L ratio played a crucial role in the transformation of glucose to 5-
HMF. The reaction parameters, including catalyst amount, tempera-
ture, time, and glucose concentration, were optimized using RSM with a
5-level CCD. The empirical model equations for all the responses were
developed by RSM software, and the models were found to be statisti-
cally well fitted with an R2 value of ~0.9 for the primary reaction
products. At the optimum reaction condition suggested by RSM, a higher
yield (~56%) of 5-HMF and glucose conversion (~98%) was achieved.
The relative error between the experimental and predicted response for
the glucose conversion and product (5-HMF and LA) yield was found to
be in the acceptable range (< 2%). However, a little higher relative error
(~6%) was observed for FA yield because of the decomposition of FA at
high temperatures. The catalysts recycle study revealed that humin
removal from the active centers of the titania catalyst was a very crucial
step. The regenerated catalyst showed a similar yield of 5-HMF even
after the 3rd cycle. The Power-law kinetic study suggested the first-order
dependency concerning glucose with a low activation energy of
67.5 kJ mol−1, which demonstrated the promising activity of the TiO2
catalyst. Finally, the new liquid-liquid extraction process proposed was
very effective in extracting the 5-HMF with high purity.
Funding
Indian Institute of Technology Roorkee, Uttarakhand, India, sup-
ported this work, and the Ministry of Education, Government of India,
provided the student fellowship.
CRediT authorship contribution statement
Richa Tomer: Conceptualization, Data curation, Formal analysis,
Investigation, Methodology, Validation, Visualization, Writing – orig-
inal draft, Writing – review & editing. Prakash Biswas: Conceptuali-
zation, Formal analysis, Funding acquisition, Investigation,
Methodology, Project administration, Resources, Supervision, Writing –
review & editing.
Declaration of Competing Interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influence
the work reported in this paper.
Acknowledgments
The authors generously acknowledge the Ministry of Education,
Government of India, for providing student fellowship and the Indian
Institute of Technology Roorkee, Uttarakhand, for supporting the
essential resources to conduct the work.
Appendix A. Supporting information
Supplementary data associated with this article can be found in the
online version at doi:10.1016/j.cattod.2022.03.019.
216
Catalysis Today 404 (2022) 201–218
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