ZnO: An Ecofriendly, Green Nano-catalyst for the Synthesis of Pyrazole Derivatives under Aqueous Media

Article abstract of DOI:10.1002/jccs.201400170

An efficient nano ZnO catalyzed green protocol for the synthesis of pyrazol derivatives by condensation of different substituted phenyl hydrazines/semicarbazide/thiosemicarbazide with 1,3-diketone/ketoester at ambient temperature has been achieved. ZnO na

Full text of DOI:10.1002/jccs.201400170

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Communication
ZnO: An Ecofriendly, Green Nano-catalyst for the Synthesis of Pyrazole Derivatives
under Aqueous Media
Yarabally R. Girish, Kothanahally S. Sharath Kumar, Heggadihalli S. Manasa and
Sheena Shashikanth*
Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570006, India
(Received: Apr. 15, 2014; Accepted: Jun. 25, 2014; Published Online: Sept. 12, 2014; DOI: 10.1002/jccs.201400170)
An efficient nano ZnO catalyzed green protocol for the synthesis of pyrazol derivatives by condensation
of different substituted phenyl hydrazines/semicarbazide/thiosemicarbazide with 1,3-diketone/ketoester
at ambient temperature has been achieved. ZnO nanocatalyst was prepared by low temperature solution
combustion method. From the Scherrer method, the crystallite size of ZnO was estimated and found to be
in the range of 30-50 nm. The main advantage of this protocol is an excellent yield, short reaction time and
easy work-up procedure. The catalyst was found to be reusable up to five catalytic cycles without any ap-
preciable loss in activity of the catalyst.
Keywords: Nanocatalyst; ZnO nanoparticles; Heterocyclic compounds; Water; Green synthesis.
INTRODUCTION
In recent year, material science has gained much at-
tones to synthesize pyrazole derivatives.10-12 However, all
the above-mentioned methods suffer from one or other dis-
advantages like tedious workup procedures, difficulty in
purification, low yield, harsh reaction conditions and pro-
longed heating. Hence, a protocol to overcome these diffi-
culties is still in demand.
tention for developing environmentally-benign procedures
for the synthesis of various heterocyclic compounds.1 As
we know, the properties of metal oxide nanoparticles are
very attractive when compared to its bulk counterparts due
to their high surface to volume ratio and their active surface
atoms2 Pyrazoles represent an important class of hetero-
cyclic compounds due to their widespread biological activ-
ities such as neurodegenerative agents for Alzheimer’s dis-
ease, anti-tumour, anti-convulsant and anti-microbial agents.
They have been used for pain relief and have shown suc-
cess in the inhibition of the human immune deficiency vi-
rus and some other biological activities as well.3
On the other hand, ZnO nanoparticles have been ex-
tensively used in the synthesis of various heterocyclic com-
pounds due to its environmentally friendly nature.13-16 ZnO
is a non-hygroscopic, highly reactive, inexpensive, non-
toxic and low processed metal oxide. By inspiring with the
high reactivity of ZnO nanoparticles we attempted, ZnO
nanoparticles catalysed one-pot two component synthesis
of pyrazole derivatives. This process involves condensa-
tion between hydrazine (1a) and 1,3-diketone (2a) under
mild reaction conditions (Scheme I) and the results are pre-
sented in Table 1.
Pyrazoles have also received considerable attention
because of their widespread applications in the fields of co-
ordination chemistry as ligands,4 chelators,5 as precursor
for the synthesis of various nitrogen containing hetero-
cycles,6 in material science as explosives.7 Because of its
diverse pharmaceutical activities, several synthetic efforts
have been made to develop this ring. The most common
method is one-pot cyclo-condensation of hydrazines with
1,3-diketone.8 Many heterogeneous catalysts such as
Mg(ClO4)2, Zn[(L) proline]2, PTC, p-toluene sulfonic acid
(PTSA), P2O5.SiO2 have been used for the synthesis of
pyrazoles. In addition, microwave irradiation using resins
and polymer supported systems9 has also been developed.
In further, few nanoparticles are used to accelerate the
cyclocondensation of phenyl hydrazine’s and 1,3-dike-
Nano ZnO catalyzed synthesis of 3-methyl-
1-phenyl-1H-pyrazol-5-ol
Scheme I
RESULTS AND DISCUSSION
Initially, a model reaction was conducted between
* Corresponding author. E-mail: shashis1956@gmail.com
J. Chin. Chem. Soc. 2014, 61, 1175-1179
© 2014 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1175

Communication
Girish et al.
Proposed mechanism for the synthesis of
pyrazoles
Table 1. Synthesis of 3a under different reaction conditions
Scheme II
Amount
Entry
Catalyst
Timeb (min) Yieldc (%)
(mol %)
1
Bulk ZnO
Bulk ZnO
TiO2
5
10
5
45
90
40
40
45
50
25
25
15
15
15
60
50
52
30
45
55
70
85
88
95
94
93
20
2
3
4
Zn:Al2O4
Al2O3
Bi2O3
ZnO
5
5
5
6
5
7
5
8
ZnO
7.5
10
15
20
---
9
ZnO
10
11
12
ZnO
ZnO
----
a Reaction conditions: phenyl hydrazine (1 mmol), ethyl aceto-
acetate (1 mmol), 10 mol% of ZnO nano-catalyst; Solvent: water;
r.t. b Reaction progress monitored byTLC. c Isolated yield.
case of aqueous medium yield as well as reaction time were
significantly improved (Table 2, entry 10). ZnO nanoparti-
cles were prepared according to procedure reported by
Jagannatha Reddy, A. et al.17
phenyl hydrazine (1a) (1 mmol) and ethyl acetoacetate (2a)
(1 mmol) in water at room temperature using bulk ZnO (5
mol %) for about 25 minutes to synthesize 3-methyl-1-
phenyl-1H-pyrazol-5-ol. Thus the reaction between (1a)
and (2a) gave the required product (3a) in very low yield
(Table 1, Entry 1). Even after using 10 mol% of catalyst and
increasing in reaction time (90 min), it doesn’t give consid-
erable change in product yield (Table 1, Entry 2). Then, we
examined the reaction using ZnO nanoparticles (5 mol %)
as catalyst at room temperature. After 25 minutes, the reac-
tion yielded the required product in moderate yield (Table
1, Entry 7). Further increase in molar ratio of the catalyst
yielded the desired product in good yield (Table 1, Entry 9)
in shorter reaction time. Later, we diverted our interest to
explore the different nanocatalyst for the synthesis of pyra-
zoles, thus the reaction was screened in different nanocata-
lyst – TiO2, Al2O3, Bi2O3, Zn: Al2O4 gave the desired prod-
uct in low yield (Table 1, Entry 3-6).
Aromatic hydrazines containing both electron donat-
ing and electron withdrawing groups underwent reaction
smoothly. The substituted phenyl hydrazines having elec-
tron donating substituents require moderate reaction time
(Table 4, entry 2, 9) as donating substituent on aromatic
ring increases the nucleophilic character of hydrazine. The
thiosemicarbazide (Table 4, entry 12) requires longer reac-
tion time than that of semicarbazide because of presence of
electron withdrawing thione group (C=S) in thiosemicar-
bazide. The shorter reaction time of 15 min with 78% yield
was observed for 3-methyl-1-(3-nitrophenyl)-1H-pyrazol-
Table 2. Synthesis of (3a) using various solvents
Catalyst
Entry
Solvent
Timeb (min) Yieldc (%)
(Mol %)
Next, we studied the effect of solvent on reaction. Ini-
tially, the reaction was carried out with different solvents
such as acetic acid (AcOH), dimethyl sulfoxide (DMSO),
dimethyl formamide (DMF), tetrahedronfuran (THF),
methanol (MeOH), ethanol (EtOH), 1,4-dioxane and ethyl
acetate. When reaction was carried in presence of DMF,
DMSO and ethyl acetate, lower yield of the product 3a was
obtained after long time (Table 2, entries 2, 3, 7). In case of
acetic acid product yield was high (Table 2, entry 4) at 100
°C. When the reaction was carried out in alcoholic media,
the yield was moderate (Table 2, entries 1, 8, 9), where in
1
10
10
10
10
10
10
10
10
10
10
MeOH
DMF
90
150
150
30
75
55
48
91
80
87
70
78
85
95
2
3
DMSO
4
AcOH(100 °C)
THF
5
120
60
6
1,4-Dioxane
Ethylacetate
EtOH (70 °C)
EtOH
7
120
30
8
9
90
10
Water
15
a Reaction conditions: phenyl hydrazine (1 mmol), ethyl
acetoacetate (1 mmol), 10 mol% of ZnO nano-catalyst; Solvent:
water; r.t. b Reaction progress monitored by TLC. c Isolated yield.
1176
www.jccs.wiley-vch.de
© 2014 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2014, 61, 1175-1179

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
ZnO Catalyzed Synthesis of Pyrazole
5-ol (Table 4, entry 3), which might be due to the presence
of electron withdrawing (NO2) group. This catalytic sys-
tem also worked well for (4-(trifluoromethyl) phenyl)
hydrazine to afford the corresponding products in 94%
yield (Table 4, entries 7) within short period of time (10
min) without forming OEt functionality. The nano ZnO
was chosen as catalyst because of its inexpensive, biode-
gradable and easy accessibility. All the synthesized com-
pounds have been characterized by its physical constant,
FTIR, 1H NMR, and mass spectroscopy and compared with
literature.
Morphology and characteristics of ZnO nanoparticles
were compared by SEM. (Fig. 2). The mean diameter of
ZnO is about 30–70 nm with an almost hexagonal shape. It
can be observed from the ?gure that nanocatalyst is com-
posed of tiny porous nanoparticles of dimension 10 mm and
the particles are uniformly distributed throughout the spec-
imen. From TEM image (Fig. 3), the particle size was
found to be 30 nm.
With the optimal multicomponent protocol in hand,
we next explored the generality of the protocol by reacting
a variety of structurally variable phenyl hydrazine’s pos-
sessing a wide range of functional groups. Thus phenyl
hydrazines bearing various electron donating and electron
withdrawing substituent’s underwent reaction smoothly
and produced respective pyrazole derivatives in good
yields (Table 3, Entry 1-10) interestingly reaction of 1,3-
diketones with semicarbazide and thiosemicarbazide are
also gave the desired product in excellent yield (Table 3,
Entry 11 and 12). Most of the synthesized compounds have
The crystal structure of the ZnO was also studied by
XRD analysis (Fig. 1). The XRD patterns of the ZnO nano-
particles indicate eleven characteristic peaks at 2q = 31.8,
34.45, 36.15, 47.42, 56, 62.8, 66.4, 67.9, 69.1, 72.5, and
77.1, corresponding to (100), (002), (101), (102), (110),
(103), (200), (112), (201), (004) and (202) planes, respec-
tively, as shown in Fig. 1. All diffraction peaks and posi-
tions match well with those from the JCPDS card (Joint
Committee on Powder Diffraction Standards no. 36–1451)
for the hexagonal wurtzite-type structure of ZnO. This
shows that the prepared ZnO nanoparticles are pure with a
hexagonal wurtzite-type structure and the size of the parti-
cles was found to be 30 nm was calculated from the
Scherer’s equation:
1
been characterized by its physical constant, FTIR, H
NMR, 13C NMR and mass spectroscopy and compared with
literature
CONCLUSIONS
We have developed an efficient, concise, quick and
environmentally benign protocol for the synthesis of sub-
stituted pyrazole derivatives. The nano ZnO catalyst has
high catalytic activity for the generation of a diverse range
0.9l
d =
bcos q
where d is the average grain size of the crystallites, l, the
incident wavelength, q, the Bragg angle and b, the dif-
fracted full-width at half-maximum (FWHM) in radians
caused by the crystallites.
Fig. 2. SEM images of nano ZnO (a) and (b).
Fig. 1. XRD spectra of nano ZnO prepared by combus-
tion method.
Fig. 3. TEM images of ZnO nanoparticle.
J. Chin. Chem. Soc. 2014, 61, 1175-1179
© 2014 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
1177

Communication
Girish et al.
Table 3. Synthesis of pyrazole derivatives (3a-l)
Table 4. Catalyst recycle studies
NHNH
2
Catalyst recycle
Timeb (minutes)
Yieldc (%)
R
10 mol% ZnO nanoparticles
water, r.t
1(a-k)
1
2
3
4
5
15
15
15
15
20
95
94
92
90
88
N
O
O
1
R
N
1
R
R
3(a-l)
2(a-b)
Time
/min
Yield
/ (/%) b
a Reaction conditions: phenyl hydrazine (1 mmol), ethyl aceto-
acetate (1 mmol) 10 mol% ZnO Nano-catalyst, 3 mL water.
b Reaction progress monitored by TLC. c Isolated yield.
aEntry
R1
R2
Product
3a
1
C6H5
OEt
(2a)
OEt
(2a)
OEt
(2a)
OEt
(2a)
OEt
(2a)
OEt
(2a)
OEt
(2a)
OEt
(2a)
Me
15
10
15
5
9518a
(1a)
2
2-MeC6H5
(1b)
3b
3c
93
for 2 h and used for the next catalytic cycle. The catalyst
was found to be reusable up to five catalytic cycles without
any significant loss in catalytic activity (Table 4).
3
3-NO2C6H5
(1c)
7818a
85
4
2,5-diClC6H5
(1d)
3d
3e
ACKNOWLEDGEMENTS
5
4-CNC6H5
(1e)
5
9318b
9318c
9718d
95
We are thankful to the UGC-BSR (Order no DV-5/
662/RFSMS/2012-13), New Delhi, India for financial sup-
port and we are also thankful to SAIF, IITM and SAIF,
IITB for their support in carrying out research work regard-
ing the HRMS-TEM analysis.
6
4-FC6H5
(1f)
3f
5
7
4-CF3C6H5
(1g)
3g
10
15
10
5
8
3-CF3C6H5
(1h)
3h
3i
9
4-OMeC6H5
(1i)
9618e
85
REFERENCES
(2b)
Me
1. Clark, J. H. Green Chem. 1999, 1, 1–8; Sheldon, A. R. Green
Chem. 2005, 7, 267–278; Sreedhar, B.; Suresh Kumar, A.;
Divya Yada. Tetrahedron Lett. 2011, 52, 3565–3569.
2. Narayanan, R.; El-Sayed, M. A. J. Phys. Chem. B 2005, 109,
12663.
10
11
12
4-CNC6H5
(1e)
3j
(2b)
OEt
(2a)
OEt
(2a)
NH2CO
(1j)
3k
3l
4
9618f
9318g
NH2CS
(1k)
45
3. Rajeshwar, N.; Marcus, P.; Stefanie, L.; Karlheinz, B.;
Sabine, K.; Thomas, D.; Sascha, W.; Eckhard, M.; Boris, S.
ChemMedChem 2008, 3, 165-172; Fraley, M. E.; Hoffman,
W. F.; Rubino, R. S.; Hungate, R. W.; Tebbon, A. J.;
Rutledge, R. Z.; McFall, R. C.; Huckel, W. R.; Kendall, R.
L.; Coll, K. E.; Thomas, K. A. Bioorg. Med. Chem. Lett.
2002, 12, 2767; Kaymakcioglu, B. K.; Rollas, S.; Korcegez,
E.; Aricioglu, F. Eur. J. Pharm. Sci. 2005, 26, 97.
4. Anuradha, M.; Amitabha, S. Tetrahedron Lett. 2005, 46,
15–18.
a Reaction conditions: phenyl hydrazine (1 mmol), ethyl aceto-
acetate (1 mmol), 10 mol% of ZnO nano-catalyst; Solvent: water;
r.t. a Reaction progress monitored by TLC. b Isolated yield.
of pyrazoles in excellent yields. The experimental simplic-
ity, ease of product isolation, reusability of the catalyst and
ready availability of the reagents, wide functional group
tolerance are note-worthy features of this protocol. The
method is very economical and makes this process very
useful.
5. Vitor, R. F.; Alves, S.; Correia, J. D. G.; Paulo, A.; Santos, I.
J. Organomet. Chem. 2004, 689, 4764–4774.
6. Fawzia, A. Q.; Faisal, M.; Mervat, M. A.; Abeer, A. B. Mole-
cules 2009, 14, 78-88; Thomas, M, K.; Alexander, P.;
Carolin, P.; Jörg, S.; Muhamed, S. Eur. J. Inorg. Chem. 2013,
26, 4667–4678; Pasupala, R.; Girish, M. G.; Surya, P. T.;
Arun, K. S. J. Mol. Model. 2011, 17, 2475–2484.
7. Tahir, M.; Corey, R. H.; Brian, P.; Nicola, C. Tetrahedron
Lett. 2004, 45, 2137–2139.
Recycling study of the catalyst
We also investigated reusability of catalyst under wa-
ter using model phenyl hydrazine 1a with ethyl acetoace-
tate 2a in presence of 10 mol % of nano ZnO. After comple-
tion of the reaction, the mixture was dissolved in ethyl ace-
tate (10 mL) and filter off the catalyst . The catalyst was
treated with ethanol, acetone, and then finally washing
with distilled water. It was then dried in an oven at 80 °C,
8. Mirjalili, B. B. F.; Bamoniri, A.; Amrollahi, M. A.; Emtiazi,
H. Dig. J. Nanomater. Biostruct. 2010, 5, 897-902; Kidwai,
M.; Jain, A.; Poddar, R. J. Organomet. Chem. 2011, 696,
1178
www.jccs.wiley-vch.de
© 2014 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2014, 61, 1175-1179

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
ZnO Catalyzed Synthesis of Pyrazole
1939-1944; Wen, J.; Fu, Y.; Zhang, R. Y.; Zhang, J.; Chen, S.
Y.; Yu, X. Q. Tetrahedron 2011, 67, 9618-9621; Heravi, M.;
Javanmardi, N. O.; Hossein, A.; Baghernejad, B. G.; Univ. J.
Sci. 2011, 24(2), 227; BamoniriI, A.; Mirjalili, B. B. F.;
Jafari, A. A.; Abasaltian, F. Iran. J. Catal. 2012, 2(2), 75-78;
Vaddula, B. R.; Varma, R. S.; Leazer, J. Tetrahedron Lett.
2013, 54, 1538–1541; Donohue, A. C.; Pallich, S.; McCar-
thy, T. D. J. Chem. Soc. Perkin Trans. 2001, 1, 2817–2822;
Polshettiwar, V.; Varma, R. S. Tetrahedron Lett. 2008, 49,
397–400.
2013, 27(2), 309-314.
13. Hosseini-Sarvari, M. J. Iran. Chem. Soc. 2011, 8, S119-
S128.
14. Safaei-Ghomi, J.; Ghasemzadeh, M. A.; Zahedi, S. J. Mex.
Chem. Soc. 2013, 57(1), 1-7.
15. Vinay Kumar, B.; Bhojya Naik, H. S.; Girija, D.; Vijaya
Kumar, B. J. Chem. Sci. 2011, 123, 615–621.
16. Thornburgh, S.; Graupner, P. R.; Cooper, D. H. J. Hetero-
cycl. Chem. 2007, 44(6), 1389-1393; Shetty, M. R.; Samanth,
S. D. Synth. Commun. 2012, 42(10), 1411-1418; Dandia, A.;
Parewa, P.; Gupta, S. L.; Rathore, K. S. J. Mol. Catal. A:
Chem. 2013, 373, 61–71; Chandak, H. S.; Lad, N. P.; Dange,
D. S. Green Chem. Lett. Rev. 2012, 5(2), 135-138.
17. Jagannatha Reddy, A.; Kokila, M. K.; Nagabhushana, H.;
Rao, J. L.; Shivakumara, C.; Nagabhushana, B. M.;
Chakradhar, R. P. S. Spectrochim. Acta, Part A. 2011, 81 53–
58.
9. Mamta, S.; Thierry, J.; Julia, J. N.; Frank, G. Green Chem.
2012, 14, 2193.
10. Dissanayake, A. A.; Odom, A. L. Chem. Commun. 2012, 48,
440–442.
11. Polshettiwar, V.; Varma, R. S. Tetrahedron 2010, 66,
1091–1097.
12. Baghernejad, B.; Khorshidi, M. Bull. Chem. Soc. Ethiop.
J. Chin. Chem. Soc. 2014, 61, 1175-1179
© 2014 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.jccs.wiley-vch.de
1179