Programming of microwave-assisted synthesis of new isophthalate derivatives using ZrOCl2 as a catalyst under solvent-free condition by experimental design

Article abstract of DOI:10.1016/j.molcata.2014.06.014

In this investigation, isophthalate derivatives were prepared by the reaction of isophthaloyl dichloride with various alcohol derivatives using ZrOCl₂ as an efficient, green and a heterogeneous catalyst under microwave irradiation and solvent- free condition. Optimization of the reaction condition was studied by the response surface method (Box Behnken Design (BBD)) with three replicates at a central point for developing a second order model. Predicting response values using the obtained model were in a good accordance with the experimental results. Clean reaction, easy workup procedure, the reusability of the catalyst, short reaction times and high yields were some advantages of this work.

Full text of DOI:10.1016/j.molcata.2014.06.014

Journal of Molecular Catalysis A: Chemical 393 (2014) 142–149
Contents lists available at ScienceDirect
Journal of Molecular Catalysis A: Chemical
journal homepage: www.elsevier.com/locate/molcata
Programming of microwave-assisted synthesis of new isophthalate
derivatives using ZrOCl2 as a catalyst under solvent-free condition by
experimental design
Mohammad Ali Zolfigola,∗, Ardeshir Khazaeia,∗, Negin Sarmastia, Jaber Yousefi Seyfb,
Vahid Khakyzadeha, Ahmad Reza Moosavi-Zarec
a Faculty of Chemistry, Bu-Ali Sina University, Hamedan 6517838683, Iran
b Pharmaceutical Engineering Laboratory, School of Chemical Engineering, College of Engineering, University of Tehran, P.O. Box 11155/4563, Tehran, Iran
c Department of Chemistry, University of Sayyed Jamaleddin Asadabadi, Asadabad 6541835583, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 June 2013
Received in revised form 13 May 2014
Accepted 11 June 2014
Available online 19 June 2014
In this investigation, isophthalate derivatives were prepared by the reaction of isophthaloyl dichloride
with various alcohol derivatives using ZrOCl2 as an efficient, green and a heterogeneous catalyst under
microwave irradiation and solvent- free condition. Optimization of the reaction condition was studied
by the response surface method (Box Behnken Design (BBD)) with three replicates at a central point for
developing a second order model. Predicting response values using the obtained model were in a good
accordance with the experimental results. Clean reaction, easy workup procedure, the reusability of the
catalyst, short reaction times and high yields were some advantages of this work.
Keywords:
Microwave
Design of experiment
Optimization
Isophthalate
ZrOCl2
© 2014 Published by Elsevier B.V.
1. Introduction
The relationship between response of natural process,
phenomena and the factors which affect them can be catego-
High-speed synthesis under microwave irradiations has
attracted a remarkable amount of attention in recent years.
Microwave-assisted organic synthesis (MAOS) has been introduced
as an effective technique in organic transformations. The efficiency
of “microwave flash heating” in dramatically reducing reaction
times (from days and hours to minutes and seconds) is just
one of the many advantages for this protocol [1,2]. Increased
yields, easier workup, compliance with Green Chemistry protocols
[3], and enhancement of the regioselectivity and stereoselectiv-
ity of reactions [4] are some of important advantages of this
method. Moreover, the unique capabilities of MAOS method allow
it to be applied in reactions which are difficult or impossible to
carry out by conventional methods. In fact, the high usefulness
of microwave-assisted synthesis, was increased the efficiency in
organic transformations [5–7].
rized into three levels. In the top level, all factors are known and
in the low level, all factors are known, but their interrelationships
are partly known. The lower level is the case in which part of
all factors is known to us. In this case, researchers consider to
experiments and the results are empirical formula such as Ergan’s
equation [8]. The top level is a deterministic phenomenon and the
second and third levels are stochastic phenomena. Researchers, to
achieve a random relationship, use experiment and then interpret
the obtained results statically [9]. Synthesis in organic chemistry
falls down in the lower level. A planned and powerful approach
for determining causes and effects is design of experiments (DOE).
The traditional way to look at chemical data tables is one variable
at a time (OVAT). Optimization by OVAT method is valid only when
there are not any interactions between variables. In the real world,
almost all cases have interaction term and the contours of response
are elliptical. Unfortunately, many of the chemists optimize their
reactions by OVAT method. If there are interactions between vari-
ables, OVAT procedure is doomed to fail. In Microwave-assisted
Synthesis:
∗
Corresponding authors. Fax: +98 811 8272404.
E-mail addresses: mzolfigol@yahoo.com, zolfi@basu.ac.ir (M.A. Zolfigol),
yield = f (P, Vc, εꢀ, εꢀꢀ, Dp, T, Cp, m, . . .)
(1)
Khzaei 1326@yahoo.com (A. Khazaei).
http://dx.doi.org/10.1016/j.molcata.2014.06.014
1381-1169/© 2014 Published by Elsevier B.V.

M.A. Zolfigol et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 142–149
143
Scheme 1. The preparation of isophthalate derivatives.
2. Experimental
Fig. 1. The general structures of isophthalate derivatives which exhibited anti pro-
liferative and non-necrotic cytotoxic effects on HeLa cells.
2.1. Characterization methods
where P is the power of the microwave, Vc the volume of the cav-
ity, εꢀ the dielectric constant, εꢀꢀ dielectric loss, Dp the penetration
depth, T the temperature, Cp the heat capacity, and m the total mass
of the reaction medium. Deriving an analytical expression to get
out from kinetic, electromagnetic theory and energy balance is dif-
ficult. So, the chemists can use the Taylor expansion and relate the
response to the variables such as [10]:
All chemicals were purchased from Merck and Fluka Chemical
Companies. The products were identified by 1H, 13C NMR, mass
analysis and melting points as well as IR spectra. The corresponding
spectral data have been reported in the Experimental section. The
1H, 13C NMR (400 MHz) was recorded on a Bruker Avance DPX-
400 FT-NMR spectrometer (ı in ppm). Mass spectra were recorded
on a Shimadzu GC MS-QP 1000 EX 85 apparatus. Melting points
were recorded on a Büchi B-545 apparatus in open capillary tubes.
Infrared spectrum of products was recorded by Perkin Elmer PE-
1600-FTIR. Progress of the reactions was monitored by TLC using
silica gel SIL G/UV 254 plates.
Y = ˇ0 + ˇ1x1 + ˇ2x2 + · · · + ˇkxk + ˇ12x1x2 + ˇ13x1x3 + · · ·
+ ˇk−1,k
x
k−1xk + ˇ11x12 + ˇ22x22 + · · · + ˇkkx22 + ε
(2)
This model is often called response surface model and the
coefficients (ˇ) show the magnitude effects of variables. Vector of
ˇ can be obtained from optimization in that X is the model matrix
[11]:
2.2. General procedure for the synthesis of isophthalate
derivatives (1a–g)
To a well-ground mixture of isophthaloyl dichloride (0.203 g,
1 mmol) and 2-phenylethanol (0.276 g, 2.23 mmol) in a microwave
vessel, zircon (IV)-oxidchlorid (0.003 g, 0.01 mmol) was added and
mixed carefully with a small rod. The mixture was irradiated in a
microwave oven for the appropriate times in optimum condition.
The reaction progress was monitored by TLC. After completion of
the reaction, the reaction mixture was cooled to room tempera-
ture, extracted with ethyl acetate (25 ml) and then transferred to
a separatory funnel containing 25 ml of H2O. The organic layer
was separated and dried with MgSO4. The solvent was evapo-
rated to give a crude product and the crude product was purified
by column chromatography on silica gel and eluted with ethyl
acetate/n-hexane (2/8).
ˇ = (XT X)−1XT Y
(3)
In summary, experimental design has three stages: Screening for
determining the important variables which have major effects
[12–14], using statistical methods to develop a model and opti-
mization to find an optimal condition [15–19].
Esters of carboxylic acid derivatives have gained special atten-
tion in the last few years since millions of tons of polyesters are
constructed via the reaction of dicarboxylic acid derivatives with
diols, and a wide variety of mono- and di-esters are used in the
synthesis of important and specialty chemicals such as pesticides,
fragrances and pharmaceuticals [20].
Accordingly, some isophthalate derivatives were synthesized
(Fig. 1) and their effects on HeLa human cervical cancer cell viabil-
ity and proliferation were investigated. The prepared compounds
exhibited anti proliferative and non-necrotic cytotoxic effects on
HeLa cells [21].
3. Results and discussion
3.1. Quick screening of the variables
Generally, esterification reactions are very slow; and require
several days to give expected product in the absence of a catalyst.
Water which forms during the reaction, works against the equi-
librium. It means that product hydrolyzes and converts to starting
materials. Therefore, the rate of the reaction is increased in the pres-
enceofcatalyst. Mineralacids, such asH2SO4, HCl andHI, andstrong
organic acids, such as HCOOH, can be used as homogeneous cata-
lysts in this transformation. Use of homogeneous catalysts suffers
from several disadvantages. For example, the catalysts are diffi-
cult to be separated from the reaction medium [22]. Therefore, it
is important to apply an effective catalyst that does not have the
above mentioned problems. Having above facts, we have reported a
clean, facile and rapid solvent-less method for the synthesis of new
categories of isophthalate derivatives in the presence of catalytic
amount of ZrOCl2 under microwave condition (Scheme 1). Also, the
optimization of the reaction condition was studied by experimental
design.
First of all, to find the reaction conditions for the synthesis
of isophthalate derivatives, the reaction of 2-phenylethanol with
isophthaloyl dichloride was selected as a model reaction. To com-
pare the efficiency of the solvent-free versus solvent conditions, the
model reaction was examined in various solvents at 25 ◦C and 45 ◦C.
Isophthaloyl dichloride melted at 45 ◦C and created a homogeneous
reaction media that resemblance is not far from that of ionic liq-
uids (Table 1). As it is shown from Table 1, lower yields and longer
reaction times were obtained in solution conditions at 25 ◦C and
45 ◦C. Therefore, the solvent-free condition is more successful than
the other conditions (entry 1). In the next step, the effect of kind
of catalyst on the model reaction was investigated at 45 ◦C. With
this issue in mind, various Bronsted acids ([Msim]Cl, [Dsim]Cl) and
Lewis acids (ZrOCl2, ZrO2, AlCl3 and FeCl3) as catalyst were applied
in this reaction (Table 2) [23]. As it is shown in Table 2, higher yield
and shorter reaction time were obtained when the reaction was
carried out using ZrOCl2 (10 mol%) as a catalyst.

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M.A. Zolfigol et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 142–149
Table 1
Table 5
Effect of various solvents on the reaction of 2-phenylethanol (2 mmol) with isoph-
thaloyl dichloride (1 mmol) (without the microwave irradiation).
Analysis of variance for the response surface quadratic model for yield and time.
Source
P-value prob > F
Source
P-value prob > F
Entry
Solvent
Time (min)
Yielda (%)
Model (yield)
X1
X2
X3
0.0002
0.4419
0.4076
<0.0001
0.3535
0.3981
0.1044
0.0354
0.1171
0.0001
Model (time)
X1
X2
X3
<0.0001
0.0024
<0.0001
0.0042
0.0033
0.0414
0.0077
0.0010
0.1396
0.0082
25 ◦
C
45 ◦
C
1
2
3
4
5
6
–
40
>70
>70
>70
>70
>70
30
70
<40
<40
<40
<40
<40
EtOAc
CHCl3
THF
n-Hexane
Acetonitrile
Trace
Trace
Trace
Trace
Trace
X1X2
X1X3
X2X3
X12
X1X2
X1X3
X2X3
X12
X22
X22
X32
X32
a
Isolated yield.
Table 2
order model was employed [24]. Three variables that can affect the
yield and time of the reaction are molar ratio of 2-phenylethanol
to isophthaloyl dichloride (X1), the amount of catalyst (X2), and
microwave power (X3). These variables were coded to three levels
of +1, 0, and 1. The levels of the variables and the corresponding
response values of the BBD are shown in Table 4.
Yield and reaction time were used as the dependent variables
and were fitted to a quadratic polynomial model. Based on BBD
method, there were 15 runs for deriving objective function for
time and yield. Table 5 shows the ANOVA (Analysis of Variance)
of responses. The correlation coefficients (R2) for time and yield
are 0.9788 and 0.9709, respectively, with the derived model, which
demonstrates that theoretical values are in a good accordance with
the experimental values. Polynomial response surface models for
time and yield, based on significant levels and actual values are
obtained from the experimental design:
Effect of different catalysts on the reaction of 2-phenylethanol (2 mmol) with isoph-
thaloyl dichloride (1 mmol) at 45 ◦C using 10 mol% of catalyst under solvent-free
condition (without the microwave irradiation).
Entry
Catalyst
Amount of catalyst (mol%)
Time (min)
Yielda (%)
1
2
3
4
5
6
ZrOCl2
ZrO2
AlCl3
FeCl3
[Msim]Cl
[Dsim]Cl
10
10
10
10
10
10
12
>30
>30
>30
>30
>30
75
<50
<50
<50
<50
<50
a
Isolated yield.
Table 3
Investigation of different condition on the reaction of 2-phenylethanol (2 mmol)
with isophthaloyl dichloride (1 mmol) and ZrOCl2 (10 mol%).
Entry Reaction condition
Temperature (◦C) Time (min) Yielda (%)
1
2
3
Solvent-free
Solvent-free
25 ◦
45 ◦
C
C
C
>60
12
<2
Trace
75
80
Y1(time) = 1030.68 − 850.83X1 − 11.99X2 + 0.93X3 + 3.33X1X2
Microwave/Solvent-free 45 ◦
+ 0.75X1X3 − 0.08X2X3 + 180.00X12 + 0.37X22 − 0.02X32
a
Isolated yield.
(4)
Afterward, two different reaction conditions were investigated.
Y2(yield) = −303.02 + 253.56X1 − 2.46X2 + 3.51X3 + 1.30X1X2
Accordingly, we studied the model reaction in the presence of
ZrOCl2 as a catalyst under solvent-free condition and solvent-
free condition under microwave irradiation. As Table 3, indicates
that microwave and solvent-free condition is more effective than
solvent-free condition.
− 0.04X1X3 − 0.03X2X3 − 57.11X12 + 0.11X22 − 0.02X32
(5)
It can be seen from Y1 that the X1 has the main linear effect on
the reaction time and there is a considerable interaction between
X1 and X2. Altogether, the terms that have minus and plus sign
have a negative and positive effect on Y, respectively. The magni-
tude of the effect of X is related to the value of ˇ in Y. To check
3.2. Statistical analysis and the model fitting
The Box Behnken Design (BBD) of the response surface method,
with three replicates at the central point for developing a second
Table 4
Levels of the experimental variables and the corresponding response values of the BBD.
Runs
Independent variables
Dependent variables
X1
X2
X3
Time
Yield
Coded levels
0
+1
+1
0
Actual levels
Coded levels
Actual levels
Coded levels
Actual levels
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2.25
2.50
2.50
2.25
2.25
2.00
2.50
2.25
2.00
2.00
2.25
2.00
2.25
2.50
2.25
+1
+1
0
10.00
10.00
5.50
5.50
10.00
1.00
1.00
1.00
5.50
10.00
5.50
5.50
1.00
5.50
5.50
+1
70.00
50.00
30.00
50.00
30.00
50.00
50.00
30.00
30.00
50.00
50.00
70.00
70.00
70.00
50.00
60.00
84.95
84.33
57.61
82.21
60.55
80.70
76.43
58.32
54.36
82.74
83.63
80.25
93.93
82.60
81.53
0
−1
0
75.00
75.00
75.00
60.00
120.00
120.00
75.00
75.00
60.00
75.00
75.00
105.00
90.00
75.00
0
0
+1
−1
−1
−1
0
+1
0
0
−1
−1
+1
0
−1
−1
0
0
0
−1
−1
0
0
−1
+1
+1
+1
0
0
−1
+1
0
0
0

M.A. Zolfigol et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 142–149
145
Fig. 2. Two and three dimensional response surfaces for the effect of factors on the reaction time.
the significance of each coefficients the P-value can be used as a
tool. The smaller the P-value, the more significant the terms. From
Table 5 for time, it is evident that linear terms of X1, X2 and X3,
quadratic terms of X12 and X32 are significant. Among the interac-
tion terms, X1 with X3, and X2with X3 are more significant. The
R2-predicted values are 0.88 and 0.84 for time and yield, respec-
tively, showing the ability of these particular models to be used as
a basis for future prediction. Two and three-dimensional profiles
of time, which generated by the model are illustrated in Fig. 2. For
example, the upper part of Fig. 2 shows that the minimum reaction
time occurs at the high levels of power and catalyst (blue region).
Lower part of Fig. 2 shows that at a high level of catalyst and the ratio
of 2-phenylethanol to isophthaloyl dichloride in the vicinity of 2.2
corresponding reaction time is minimal (blue region). Correspond-
ing profiles is illustrated in Fig. 3 for yield which can be interpreted
as time.

146
M.A. Zolfigol et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 142–149
Fig. 3. Two and three dimensional response surfaces for the effect of factors on the reaction yield.
3.3. Optimization of operational condition and validation of the
model
The validity of models for predicting response values was tested
using the optimal condition. The predicted and experimental opti-
mum responses are shown in Table 6. A mean value of 60.00 second
(N = 3) for time and 90.81% (N = 3) for yield was obtained from
experimental results that are in a good accordance with predicted
responses. To investigate the effect of ZrOCl2 as a catalyst on the
Programming showed that optimal operational conditions are
X1 = 2.23, X2 = 10.00 and X3 = 61.10. Corresponding minimum time
and maximum yields are 60.66 seconds and 91.77%, respectively.

M.A. Zolfigol et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 142–149
147
Table 6
As Table 8 shows that isophthalate derivatives could be obtained
in high to excellent yields (75.41–95.82%) within short reac-
tion times (60–195 s). Alcohol derivatives, including aliphatic as
well as aromatic alcohols containing electron-releasing, electron-
withdrawing substituents or halogens on their aromatic rings were
successfully tested in this reaction condition (Table 8, compounds
a–g).
Predicted and experimental value of responses at the optimum condition.
Optimum
Optimum variables
Optimum response
X1
X2
X3
Time
Yield
Predicted
Experimental
2.23
2.23
10.00
10.00
61.10
60.00
60.65
60.00
91.77
90.81
Table 7
3.5. Proposed mechanism (Scheme 2)
Checking optimum condition without catalyst.
Variables
Response
Time
Isophthaloyl dichloride (I) has two acyl groups that could be
activated by a Lewis acid as catalyst. Therefore, one or both of
them could be activated by the Zirconium(IV) oxychloride to pro-
duce IV (in the second process, two chlorine atoms were released
as counter ion). Two resonance forms of activated acyl groups (IV
and IVꢀ) could be produced and converted together in a reversible
reaction. Mechanistically, one group of acyl could be activated by
Zirconium(IV) oxychloride as a catalyst. However, it is possible that
the two groups of acyl were simultaneously coordinated with two
molecule of zircon (IV)-oxidchlorid and produce intermediate IV.
Based on, isophthaloyl dichloride was reacted with ZrOCl2 and IR
spectra of the carbonyl group in the isophthaloyl dichloride were as
follows: IR (Nujol): ꢀmax (cm−1) of C O in isophthaloyl dichloride
(1745.06 cm−1) decreased to (1724.42 cm−1) ꢀmax in the reaction
mixture (Fig. 4). It was noticeable that the wavelength absorption
of C O was decreased at about 20.64 cm−1 in intermediate IV that
X1
X2
X3
Yield
With catalyst
Without catalyst
2.23
2.23
10.00
0.00
60.00
60.00
60.00
315.00
90.81
90.50
responses, the optimum condition was repeated without catalyst
(X1 = 2.23, X2 = 0.00 and X3 = 60.00). The result shows that the pres-
ence of ZrOCl2 is vital to decreasing the reaction time (Table 7).
3.4. Using optimal condition
After optimization of the reaction conditions, the efficiency and
applicability of the presented method were studied by the reac-
tion of isophthaloyl dichloride with various alcohol derivatives in
the presence of ZrOCl2. The results were summarized in Table 8.
Table 8
Using optimal condition for some reagents.
Entry
Product
Time (s)/power of MW (W)
60.00/60.00
Yielda (%)
90.81
mp (◦C)
53–57
O
O
O
a
O
O
O
O
b
c
60.00/60.00
180.00/60.00
195.00/60.00
76.51
83.22
93.68
79–84
146–148
60–64
O
O
O
O
O2N
O
NO2
O
O
O
O
O
d
O
O
O
O
Me
O
e
f
150.00/60.00
75.41
73–76
Me
O
O
Cl
Cl
105.00/60.00
75.00/60.00
95.82
90.18
70–72
O
O
O
O
g
–
O
O
a
Isolated yield.

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M.A. Zolfigol et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 142–149
Scheme 2. The plausible mechanism for the synthesis of isophthalate derivatives catalyzed by ZrOCl2.
Fig. 4. IR spectrum of ZrOCl2 (a), IR spectrum of mixture of isophthaloyl dichloride and ZrOCl2 (b) and IR spectrum of mixture of isophthaloyl dichloride (c).
confirmed our suggestion. Then, two benzyl alcohols were attached
to intermediate V (in this process, two equivalents of HCl were
released and confirmed by determination of pH and measurement
of weight loss of reaction mixture (Table 9)). In this step, It was
possible that the released HCl acted as catalyst. For this purpose,
we tested the model reaction in the absence of ZrOCl2 and in the
presence of HCl. Long reaction time showed that HCl did not act
as an efficient catalyst for this reaction in comparison with ZrOCl2.
Finally, zircon (IV)-oxidchlorid was generated again in the cycle of
reaction by the reaction of two chlorine atoms with intermediate
VI. Although, the reaction could be mechanistically done step by
step on one carbonyl oxygen of isophthaloyl dichloride at a time to
give the desired product.
4. Conclusions
In conclusion, we have introduced a new protocol for the prepa-
ration of isophthalate derivatives using ZrOCl2 as a catalyst under
solvent-free condition. In this work, the correlation coefficients
(R2) for time and yield showed that theoretical values were in a
good accordance with the experimental values. The R2-predicted
values were 0.88 and 0.84 for time and yield, respectively, exhib-
ited the ability for these particular models to be used as a basis for
futurestudies. Repeating the optimal condition withoutthecatalyst
showed the presence of the catalyst was important in decreasing
the reaction time. The promising points for the presented proto-
col were efficiency, generality, high yields, short reaction times,
cleaner reaction profile and simplicity.
Table 9
Measurement of weight loss of the reaction mixture.
Reaction status (progress percent)
Weight of reaction mixture (g)
0.0000%
50.0000%
90.8100%
13.2536
13.1804
13.1210

M.A. Zolfigol et al. / Journal of Molecular Catalysis A: Chemical 393 (2014) 142–149
149
Acknowledgements
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Appendix A. Supplementary data
Supplementary data associated with this article can be
found, in the online version, at http://dx.doi.org/10.1016/j.molcata.
2014.06.014.
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