N-Methylimidazolium perchlorate as a new ionic liquid for the synthesis of bis(pyrazol-5-ol)s under solvent-free conditions

Article abstract of DOI:10.1016/j.cclet.2015.07.027

N-Methylimidazolium perchlorate ([MIm]ClO₄) was synthesized and some of its physico-chemical properties, such as density, surface tension were investigated. A thermo gravimetric analysis (TGA) and solvent performance were also studied. The resu

Full text of DOI:10.1016/j.cclet.2015.07.027

Accepted Manuscript
Title: N-Methylimidazolium perchlorate as a new ionic liquid
for the synthesis of bis(pyrazol-5-ol)s under solvent-free
conditions
Author: Nader Ghaffari Khaligh Sharifah Bee Abd Hamid
Salam J.J. Titinchi
PII:
S1001-8417(15)00335-6
DOI:
Reference:
http://dx.doi.org/doi:10.1016/j.cclet.2015.07.027
CCLET 3415
To appear in:
Chinese Chemical Letters
Received date:
Revised date:
Accepted date:
12-6-2015
15-7-2015
21-7-2015
Please cite this article as: N.G. Khaligh, S.B.A. Hamid, S.J.J. Titinchi, N-
Methylimidazolium perchlorate as a new ionic liquid for the synthesis of
bis(pyrazol-5-ol)s under solvent-free conditions, Chinese Chemical Letters (2015),
http://dx.doi.org/10.1016/j.cclet.2015.07.027
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Graphical Abstract
N-Methylimidazolium perchlorate as a new ionic liquid for the synthesis of bis(pyrazol-5-ol)s under solvent-free conditions
Nader Ghaffari Khaligh,a* Sharifah Bee Abd Hamid,a Salam J. J. Titinchib
a Nanotechnology & Catalysis Research Centre, NANOCAT, University Malaya, Kuala Lumpur, Malaysia
bDepartment of Chemistry, University of the Western Cape, Cape Town, South Africa
CH3
CH3
N
N
r.t. 24 h
ClO4
HClO4 (70%)
+
N
N
H
[MIm]ClO4
Cl
Cl
H3C
CH3
H
N
O
O
[MIm]ClO4
NH2
N
N
N
N
+
+
H3C
O
CH3
OH HO
CHO
N-Methylimidazolium perchlorate ([MIm]ClO4) was synthesized and some of its physico-chemical properties, such as density, surface tension
were investigated. A thermo gravimetric analysis (TGA) and solvent performance were also studied. The results show that this ionic liquid is
an excellent catalyst for the synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol) derivatives under solvent-free conditions. This method has
the advantages of high yield, clean transformation, simple operation and short reaction time. The ionic liquid can be recycled without
significant loss of activity.
Page 1 of 7

Original article
N-Methylimidazolium perchlorate as a new ionic liquid for the synthesis of
bis(pyrazol-5-ol)s under solvent-free conditions
Nader Ghaffari Khaligh a, , Sharifah Bee Abd Hamid a, Salam J. J. Titinchi b
a Nanotechnology & Catalysis Research Centre, NANOCAT, University Malaya, Kuala Lumpur, Malaysia
bDepartment of Chemistry, University of the Western Cape, Cape Town, South Africa
ARTICLE INFO
ABSTRACT
Article history:
N-Methylimidazolium perchlorate ([MIm]ClO4) was synthesized and some of its physico-
chemical properties, such as density, surface tension were investigated. A thermo gravimetric
analysis (TGA) and solvent performance were also studied. The results show that this ionic
liquid is an excellent catalyst for the synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)
derivatives under solvent-free conditions. This method has the advantages of high yield, clean
transformation, simple operation and short reaction time. The ionic liquid can be recycled
without significant loss of activity.
Received 12 June 2015
Received in revised form 15 July 2015
Accepted 21 July 2015
Available online
Keywords:
Ionic liquid
N-Methylimidazolium perchlorate
Bis(pyrazol-5-ol)s
Recycle
1. Introduction
Ionic liquids (ILs) are used in many fields due to their unique physical and chemical properties. Their recycle-ability and low
environment impact are the most impressive factors in the present era. In the past few years significant progress has been made in the
preparation, characterization and application of ILs [1]. The physicochemical properties of ILs depend on the nature and size of both
their cation and anion constituents; therefore, different ILs can be fine-tuned using different cations and anions to meet the
requirements of the application of interests. Fluorinated ionic liquids were investigated for recovery/recycling of perfluorocarbon
contaminants such as greenhouse perfluorocarbons gases and perfluoroalkyl acids of industrial effluents that are persistent,
bioaccumulative, and toxic. The partial or total replacement of inert perfluorocarbons in oxygen therapeutic emulsions was achieved by
enhancing the emulsion stability and increasing the solubility of respiratory gas [2]. 1-Butyl-3-methylimidazolium perchlorate,
[BMIM][ClO4] was used as a reducing agent to upgrade a selected heavy oil [3].
Although ILs with perfluoroanions are stable, during reaction they would produce HF, which is a toxic and corrosive gas [4] and the
costs of perfluoroanions are high. On the other hand, chloroaluminated ionic liquids are cheaper but they are extremely sensitive to air
and water. Bearing these aspects in mind, additional effort is needed to search for new environment-protective ionic liquids for
academic and industrial applications, which should meet the technically desired properties. To introduce new, low cost ionic liquids,
we synthesized N-methylimidazolium perchlorate to explore its catalytic activity.
Pyrazoles, including 4,4'-(arylmethylene)bis(1H-pyrazol-5-ol) derivatives appear widely in various molecules exhibiting significant
antipyretic, analgesic and anti-inflammatory [5], anticancer [6], antiviral [7], anti-proliferative [8], hypoglycemic [9] and antioxidant
[10] activities. These compounds have been employed as inhibitors of Mycobacterium tuberculosis [11], antibacterial and antifungal
[12,13], pesticides [14] and dyestuffs [15].
Consequently, a variety of synthetic strategies have been developed for the preparation of 4,4'-(arylmethylene)bis(1H-pyrazol-5-ol)
derivatives [16,17].
In our view, the one-pot multi-component reaction of a tandem Knoevenagel-Michael reaction or Mannich type reaction [17] is the
most appropriate method for the preparation of 4,4′-(arylmethylene)-bis(1H-pyrazol-5-ols) since 1,3-disubstituted-1H-pyrazol-5(4H)-
ones are expensive, especially 3-methyl-1H-5-pyrazolone.
2. Experimental
2.1 Synthesis of N-methylimidazolium perchlorate ([MIm]ClO4)
———
Corresponding author.
E-mail address: ngkhaligh@gmail.com
Page 2 of 7

N-Methylimidazole (8.21 g, 100 mmol) was added to a solution of perchloric acid 70% (8.6 mL, 100 mmol) and the mixture was
stirred continuously for 24 h at room temperature. The product was dried by rotary evaporation and a colorless liquid was obtained in
94% yield. The obtained ionic liquid was dried in vacuum at 80 °C for 24 h; IR (KBr): νmax 3390, 3150, 3120, 2950, 2940, 1570, 1465,
1
1170, 1108, 1078, 616, 465 cm-1; H NMR (400 MHz, DMSO-d6):
δ
3.845 (s, 3H, NCH3), 7.611 (dd, 1H, J = 1.6 Hz, NCHCHN),
7.662 (dd, 1H, J = 1.6 Hz, NCHCHN), 9.014-9.015 (d, 1H, J = 0.4 Hz, NCHN), 14.222 (br s, 1H); 13C NMR (400 MHz, DMSO-d6):
35.805, 120.147, 123.610, 136.218; ESI(+)-MS (m/z) for [MIm] 83; ESI(-)-MS (m/z) [ClO4] 99 and 101.
δ
2.2 Preparation of 4,4'-(arylmethylene)bis(1H-pyrazol-5-ol) derivatives
In a 25 mL round bottom flask a mixture of ethyl acetoacetate (10 mmol), aromatic aldehyde (5 mmol), phenylhydrazine or
hydrazine hydrate (10 mmol) was stirred in the presence of N-methylimidazolium perchlorate (50 mg) at 60 °C under solvent-free
conditions for an appropriate period of time. After the completion of the reaction (monitored by TLC analysis), the reaction mixture
was cooled to room temperature and water (5 mL) was added with stirring. The precipitate was collected by filtration and evaporation
of the mother liquors under reduced pressure led to the recovery of the catalyst, which could be reused in the next run. The crude
products were purified by recrystallization from ethanol (95%).
3. Results and discussion
The focus of our research is to develop an eco-efficient methodology that decreases both the amount of waste generated and use of
hazardous materials. Recently, 4-(succinimido)-1-butane sulfonic acid (SBSA) was prepared in our laboratory by stirring succinimide
and 1,4-butanesultone for 10 h at 40-60 °C using solar energy [18]. The current synthesis of N-methylimidazolium perchlorate
([MIm]ClO4) involved merely stirring N-methylimidazole and perchloric acid at room temperature for 24 h (Scheme 1). The structure
of ionic liquid was confirmed by FT-IR and 1H NMR.
CH3
CH3
N
N
r.t. 24 h
ClO4
HClO4 (70%)
+
N
N
H
[MIm]ClO4
Scheme 1. Synthesis of N-methylimidazolium perchlorate ([MIm]ClO4).
The peaks at 3150 and 3120 cm-1 in ionic liquid were assigned to the stretching for C-H vibrations of the imidazole ring in the FT-IR
spectrum of [MIm]ClO4. Stretching vibration peaks of C-H from the methyl group of imidazole ring appeared at 2950 and 2940 cm-1. Skeletal
vibration peaks of imidazole ring were seen at 1570 and 1465 cm-1; in-plane bending vibration peak of C-H from imidazole ring was located at
1170 cm-1. On the other hand, the asymmetric and symmetric stretching vibration peaks of anion perchlorate were located at 1108, 1078 and
1
1
616 cm-1, respectively. The bending vibration peak also was seen at 461 cm− [19]. In addition, a broad, intense band centered on 3390 cm−
indicated the presence of water.
1H NMR spectrum of [MIm]ClO4 showed two deshielded ring protons at 7.611 and 7.662 ppm (two overlapped doublets respectively). The
protons of the methyl group attached to the ring were shown at 3.845 ppm (singlet). However, the signal of the CH- group attached to the
electronegative N atom ring was detected at 9.014 ppm. The signal of acidic proton was not clear and was detected at 14.222 ppm. The ESI-
MS of [MIm]ClO4 in methanol of a concentration of ca. 3 × 10-8 M - 4 × 10-8 M was determined. Characteristic signals were detected
-
corresponding to the IL cation (C+) in ESI(+) (MIm+ at m/z 83) and IL anion (A-) in ESI(-) (ClO4 at m/z 99 and 101). For [MIm]ClO4, two
weak signals (m/z 265) and (m/z 281) corresponding to a C2A+ and CA2- cluster were also observed in ESI(+) and ESI(-), respectively. The rest
of the peaks in the spectra, such as m/z 180, m/z 222, m/z 296 in ESI(+) and m/z 143, m/z 199, m/z 255, m/z 267 in ESI(-), were also observed
by ESI-MS of methanol, and therefore might not be related to [MIm]ClO4.
The water content in [MIm]ClO4 was determined to be less than 0.3% by the Karl–Fischer titration method. The density was measured to be
approximately 1.22 g/mL at 20 °C using the bottle method and the surface tension was 47.9 mN/m at 20 °C measured by the method of
bubbling. Also, water absorption of ionic liquid was tested and it was seen from the fact that the mass of [MIm]ClO4 ionic liquid increased
with the prolonged exposure but the mass gain was insignificant, and changes slowed after 8 h with just 3.2% mass fraction after 24 h.
The TGA results of [MIm]ClO4 showed that the obtained ionic liquid is comparably stable to 325 °C. Evaporation of some water causes the
mass loss around 100 °C, which is consistent with the results of the water absorption experiments. The mass loss of 80% around 325 °C is
hypothesized to be caused by the decomposition of the ionic liquid. These results indicate that ionic liquid has good thermal stability with high
decomposition temperature and can be used at a wide temperature range. [MIm]ClO4 was soluble in water, methanol, ethanol, acetone and
ethyl acetate. However it was immiscible with non-polar solvents such as toluene and diethyl ether. Consequently the catalyst can be separated
conveniently from products by simple phase separations.
Page 3 of 7

The condensation between ethyl acetoacetate, 4-chloro-benzaldehyde (1b) and phenylhydrazine was carried out in the presence of different
amount of [MIm]ClO4 (2.2, 5.4 and 10.8 mol%) under solvent-free conditions (Scheme 2). It was observed that 5.4 mol% of ionic liquid was
the optimum amount to furnish the desired product in high yield. Increasing the amount of the catalyst to 10.8 mol% did not increase the yield
significantly. In addition different reaction temperatures (room temperature-80 °C) were employed to identify the optimum temperature of the
reaction. Results illustrated that 92% yield of 4,4′-[(4-chlorophenyl)-methylene]bis(3-methyl-1-phenyl-1H-pyrazol-5-ol) was obtained in the
presence of 5.4 mol% [MIm]ClO4 at 50 °C within 20 min. Higher temperatures caused more spots on the TLC, which led us to conclude that
by-products were being produced. In a control experiment without [MIm]ClO4, the reaction did not go to completion at the same temperature
even after 8 h and only 26% of product 2b was produced. In the presence of 5.4 mol% imidazole and perchloric acid as catalysts 34% of 2b
with fewer spots was observed within 8 h at 50 °C. Consequently, it seems that the superior catalytic performance is due to the synergistic
effect of imidazolium cation and perchlorate anion.
Cl
Cl
H3C
CH3
H
O
O
[MIm]ClO4
N
NH2
N
N
N
N
+
+
H3C
O
CH3
Different parameters
OH HO
CHO
1b
2b
Scheme 2. Synthesis of 4,4'-[(4-chlorophenyl)methylene)]bis(1H-pyrazol-5-ol) derivatives in presence of [MIm]ClO4 under various reaction
conditions.
In order to evaluate the generality of the present method, a range of hetero and aryl aldehydes 1(a-l) were mixed with ethyl
acetoacetate and phenylhydrazine or hydrazine hydrate under the optimized reaction conditions in the presence of [MIm]ClO4 (Table
1). The aryl aldehydes that possess electron-donating and electron-withdrawing substituents provided the desired products in good to
high yields without little by-products (Table 1, entries 1-16). The shorter reaction times and higher yields were observed for the
substrates with electron-withdrawing substituents (–NO2) compared to those with electron-donating substituents (CH3O-) (Table 1,
entries 4, 12 and 6, 14). Furthermore, acid sensitive aldehydes, such as furfural and 2-thienaldehyde, were smoothly converted into the
corresponding products, a conversion that is otherwise problematic in the presence of acidic catalysts (Table 1, entries 7, 8 and 15, 16).
Aliphatic aldehydes produced two or more spots on the TLC and GC-MS spectrum under the optimized conditions. New products were
1
characterized by IR, H NMR, 13C NMR and elemental analysis while known products were characterized by comparison of their
melting points and spectral data with those of authentic samples. Ionic liquid was isolated and could be recycled up to five times
without any significant loss of activity (Table 1, entry 2).
Based on mechanisms reported in the literature [20c], a proposed mechanism for formation of the product is outlined in Scheme 3.
In the first step, pyrazolone would be anticipated from the very fast condensation between phenylhydrazine or hydrazine hydrate with
ethyl acetoacetate catalyzed by [MIm]ClO4. The activated carbonyl group of the aldehyde again by ionic liquid [MIm]ClO4 condenses
with two equivalents of pyrazolone through a pyrazolenone intermediate resulting in the formation of 4,4′-(arylmethylene)bis(1H-
pyrazol-5-ol)s via a tandem Knoevenagel-Michael reaction.
To validate the proposed mechanism, the synthesis of 2b was carried out in two steps. Firstly, pyrazolone was obtained by
condensation between phenylhydrazine or hydrazine hydrate reacted with ethyl acetoacetate, then 2 equivalent of pyrazolone were
reacted with one equivalent 4-chlorobenzaldehyde under the optimization reaction conditions to give the product 2b (88%) within 20
min.
To the best of our knowledge, there is only a few papers in the synthesis of 4,4'-(arylmethylene)bis(3-methyl-1H-pyrazol-5-ols) [20b
and 23a]. To evaluate the overall utility of the current methodology, we compared our results with those of the methods reported in
literature for the synthesis of 2d and 2g as shown in Table 2. It is clearly illustrated that the reaction in presence of [MIm]ClO4 affords
a comparable yield and requires smaller mol% of catalyst and lower temperature than other protocols.
Table 1
Synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s in the presence of SBSA.a
Page 4 of 7

M.p. (°C)
Reported
Entry Substrate (
1
)
R2
Product (
2
)
Time (min)
Yield (%)b
Ref.
20a
20a
Found
1
2
C6H5-CHO
C6H5-
C6H5-
a
37
25
90
94
172-174
171-172
4-Cl-C6H4-CHO
b
214-216
207-209
(25,25,26,26) (94,94,92,92)
3
4
5
6
7
4-HO-C6H4-CHO
4-NO2-C6H4-CHO
4-CH3-C6H4-CHO
4-CH3O-C6H4-CHO
Furfural
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
C6H5-
H-
H-
H-
H-
H-
c
d
e
45
25
40
45
60
60
25
20
35
20
30
35
60
60
86
94
88
87
77
80
94
90
84
90
89
88
82
84
150-152
232-234
208-210
171-173
187-189
180-182
228-230
224-226
258-260
298-300
202-204
198-200
259-261
203-205
154-157
230-232
203-204
173-175
189-190
181-183
230-232
224-226
262-264
300-302
-
20d
20a
20a
20e
7
21b
20a
17a
20a
20a
-
f
g
h
i
j
k
l
m
n
o
p
8
9
2-Thienaldehyde
C6H5-CHO
10
11
12
13
14
15
16
4-Cl-C6H4-CHO
4-HO-C6H4-CHO
4-NO2-C6H4-CHO
4-CH3-C6H4-CHO
4-CH3O-C6H4-CHO
Furfural
H-
H-
H-
-
-
270-272
-
20e
-
2-Thienaldehyde
a Reaction conditions: ethyl acetoacetate (10 mmol), aromatic aldehyde (5 mmol), phenylhydrazine or hydrazine hydrate (10 mmol);
[MIm]ClO4(50 mg, 5.4 mol%); 50 °C; solvent-free.
b Isolated yield.
CH3
CH3
CH3
N
N
N
ClO4
N
ClO4
ClO4
R1
N
H
H
N
H
CH3
O
CH3
O
O
O
N
N
N
H
+
OH
NH
O
NH
-H2O
CH3
-C2H5OH
H3C
O
CH3
R2
R2
O
H3C
O
O
H
R2NH-NH2
H
H3C
R2HN
N
ClO4
N
-
H
H3C
2
ClO4
CH3
O
N
N
H
CH3
R1
N
O
R1
CH3
N
R2
R2
N
N
H3C
H3C
CH3
H
O
H
R1
N
N
R2
N
N
R2
N
N
R2
N
N
R2
H3C
O
OH
OH HO
Scheme 3. The proposed mechanism for the synthesis of 4,4′-(arylmethylene)bis(1H-pyrazol-5-ol)s in presence of [MIm]ClO4.
Table 2.
Comparison of the present method with other reported strategies for the synthesis of 2d and 2g.
Entry Catalyst
Amount of catalyst Conditions
Ref.
2d
2g
Time (min)
35
Yield (%)
91
Time (min) Yield (%)
Silica-bonded propylpiperazine sulfamic acid
(SBPPSA)
2-hydroxy ethylammonium propionate
(2-HEAP)
Silica-bonded S-sulfonic acid
(SBSSA)
1
2
3
4
8.7 mol% H+ 80 °C, neat
-
-
21a
17b
21b
20a
10 mol%
100 mg
90 °C, neat
50
40
60
77
90
20
-
92
-
Reflux,ethanol
Reflux, water
Sodium dodecyl sulfate
(SDS)
5.0 mol%
90.6
60
87
3-Aminopropylated silica gel
(AP-SiO2)
Xanthan sulfuric acid
1,3-Disulfonic acid imidazolium
tetrachloroaluminate
NH4OAc
Nano-SiO2/HClO4
1,3,5-Tris(hydrogensulfato) benzene
(THSB)
5
6
7
30 mol%
80 mg
r.t., CH3CN
Reflux, ethanol
50 °C, neat
10
15
40
98
90
91
-
-
-
-
-
-
21c
21d
21e
1 mol%
8
9
100 mol%
6 mg
r.t., grinding
Reflux, water
5
20
91.6
96
-
-
-
-
21f
21g
10
11
4 mol%
75 °C, ethanol
50 °C, neat
3
96
95
-
-
20c
N
-Methylimidazolium perchlorate
5.4 mol%
20
25
92
This work
([MIm]ClO4)
Page 5 of 7

4. Conclusion
A novel ionic liquid was synthesized and its catalytic activity was investigated for the synthesis of 4,4′-(arylmethylene)bis(1H-
pyrazol-5-ol)s under solvent-free conditions. The current protocol has the advantages of simple experimental procedures, good to high
yield of products, inexpensive substrates, reusability of the catalyst and being environmentally benign. The catalyst can be recycled up
to five times without any significant loss of activity.
Acknowledgment
The authors are thankful to the partial support from University Malaya to Project GC 001A-14-AET.
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