SOCl2 catalyzed cyclization of chalcones: Synthesis and spectral studies of some bio-potent 1H pyrazoles

Article abstract of DOI:10.4314/bcse.v28i2.11

Some aryl-aryl ¹H pyrazoles have been synthesised by cyclization of aryl chalcones and hydrazine hydrate in the presence of SOCl₂. The yields of the pyrazoles are more than 85%. These pyrazoles are characterized by their physical con

Full text of DOI:10.4314/bcse.v28i2.11

Bull. Chem. Soc. Ethiop. 2014, 28(2), 271-288.
Printed in Ethiopia
DOI: http://dx.doi.org/10.4314/bcse.v28i2.11
ISSN 1011-3924
 2014 Chemical Society of Ethiopia
SOCl2 CATALYZED CYCLIZATION OF CHALCONES: SYNTHESIS AND
SPECTRAL STUDIES OF SOME BIO-POTENT 1H PYRAZOLES
Kaliyaperumal Ranganathan1, Ramamoorthy Suresh1, Ganesan Vanangamudi1,*,
Kannan Thirumurthy2, Perumal Mayavel2 and Ganesamoorthy Thirunarayanan2
1PG & Research Department of Chemistry, Government Arts College, C-Mutlur, Pin-608102,
Chidambaram, India
2Department of Chemistry, Annamalai University, Annamalainagar-608002, India
(Received March 16, 2013; revised December 6, 2013)
ABSTRACT. Some aryl-aryl 1H pyrazoles have been synthesised by cyclization of aryl chalcones
and hydrazine hydrate in the presence of SOCl2. The yields of the pyrazoles are more than 85%.
These pyrazoles are characterized by their physical constants and spectral data. The infrared,
NMR spectral group frequencies of these pyrazolines have been correlated with Hammett
substituent constants, F and R parameters. From the results of statistical analyses the effects of
substituent on the spectral frequencies have been studied. The antimicrobial activities of all
synthesised pyrazolines have been studied using Bauer-Kirby method.
1
KEY WORDS: SOCl2, H Pyrazolines, IR spectra, NMR spectra, Hammett substituent constants,
Antimicrobial activities
INTRODUCTION
The prominent nitrogen containing five membered heterocyclic compounds, such as pyrazolines
are extensive important synthons [1] in the synthetic organic chemistry and drug designing.
Pyrazoline refers to both the classes of simple aromatic ring organic compounds of the
heterocyclic series characterized by a five membered ring structure composed of three carbon
atoms and two nitrogen atoms in adjacent positions, and the unsubstitued parent compound.
These pyrazolines have played an important role in the development of theoretical heterocyclic
chemistry and organic synthesis. So these compounds with pharmacological effects on humans
are classified as alkaloid, although they are rare in nature. Many pyrazoline shows various
pharmacological-multipronged properties [2, 3]. Some pyrazoline derivatives are used as
pesticides [4], fungicides [5], antibacterial [6], antifungal [7], antiamoebic [8], and
antidepressant activity [9] and insecticides. Heterocyclic of the type 3-hetaryl-1H-4,5-
dihydropyrazoles arouse particular interest because the properties determined by the pyrazoline
fragment are combined with the features of the hetarene [9, 10]. Therefore, it should be noted
that 3-(4-hydroxy-3-coumarinyl)-1H-4,5-dihydropyrazolesare structural analogs of 3-substituted
4-hydroxy-coumarins some representatives of which are effective blood anticoagulants. The
pyrazoline function is quite stable, and has inspired chemists to utilize the mentioned stable
fragment in bioactive moieties to synthesize new compounds possessing biological activity.
Some pyrazoline related compounds possess anticonvulsant activity and was evaluated by
medicinal bio-chemistry researchers [11]. The antidepressant activities of these compounds
were evaluated by the “Porsolt Behavioural Despair Test” on Swiss-Webster mice [12]. The α,β-
unsaturated ketones can play the role of versatile precursors in the synthesis of the
corresponding pyrazoline derivatives [13, 14]. The reaction of hydrazine and its derivatives with
α,β-unsaturated ketones and α,β-epoxy ketones is one of the preparative methods for the
synthesis of pyrazolines and pyrazoles derivatives [15]. Alternatively, the reaction of substituted
__________
*Corresponding author. E-mail: drgvsibi@gmail.com

272
Kaliyaperumal Ranganathan et al.
hydrazine with α,β-unsaturated ketones has been reported to form regioselective pyrazolines
[16]. The synthesis of pyrazoline rings from chalcone derivatives containing anisole and the 3,4-
methylenedioxyphenyl ring by the conventional method using acetic acid was reported with low
yields [17]. Some 1-(4-arylthiazol-2-yl)-3,5-diaryl-2-pyrazoline derivatives have been
synthesized by the reaction of 1-thiocarbamoyl-3,5-diaryl-2-pyrazoline derivatives with
phenacetylbromide in ethanol. The structural elucidations of the compounds were performed by
1
IR, HNMR and mass spectral data and elemental analysis [18]. Semicarbazide (hydrochloride)
and thiosemicarbazide on reaction with α,β-unsaturated ketones of the ferrocene series in excess
of t-But-OK gave 1-carbamoyl and 1-thiocarbamoyl (ferrocenyl)-4,5-dihydropyrazoles. Ten new
fluorine-containing 1-thiocarbamoyl-3,5-diphenyl-2-pyrazolines have been synthesized in 80-85%
yields by a microwave- promoted solvent–free condensation of 2,4-dichloro-5-fluoro chalcones
with thiosemicarbazide over potassium carbonate [19]. Nanoparticles of 1-phenyl-3-naphthyl-5-
(dimethylamino) phenyl)-2-pyrazolines ranging from tens to hundreds of nanometres have been
prepared by the reprecipitation method [20]. Five new 1,3,5-triphenyl-2-pyrazolines have been
synthesized by reacting 1,3-diphenyl-2-propene-1-one with phenyl hydrazine hydrochloride and
another five new 3-(2"-hydroxy naphthalen-1"-yl)-1,5-diphenyl-2-pyrazoline have been
synthesized by reacting 1-(2'-hydroxylnaphthyl)-3-phenyl-2-propene-1-one with phenyl
hydrazine hydrochloride [21]. Also some new 1,3,5-triphenyl-2-pyrazolines have been
synthesized by reacting 1,3-diphenyl-2-propene-1-one with phenyl hydrazine hydrochloride and
another five new 3-(2"-hydroxy naphthalen-1"-yl)-1,5-diphenyl-2-pyrazoline have been
synthesized by reacting 1-(2'-hydroxylnaphthyl)-3-phenyl-2-propene-1-one with phenyl
hydrazine hydrochloride [22]. The effect of substituents on the group frequencies have been
1
studied, through UV-Vis, IR, H and 13C NMR spectra of ketones [23], unsaturated ketones
[24-28], acyl bromides-esters [29] and naphthyl and 5-bromo-2-thienyl pyrazolines [30] by
spectral analysts and organic chemists. The effect of substituents on the infrared, proton and
carbon-13 group frequencies of pyrazoline derivatives are not been studied so far. Hence, the
authors have taken efforts to synthesise some pyrazoline derivatives by cyclization of 5-chloro-
2-thienyl chalcones and hydrazine hydrate in the presence of SOCl2 and to study the spectral
linearity and also the antimicrobial activities.
EXPERIMENTAL
All chemicals used were procured from Sigma-Aldrich and E-Merck. Melting points of all
pyrazoles were determined in open glass capillaries on Mettler FP51 melting point apparatus
and are uncorrected. Infrared spectra (KBr, 4000-400 cm-1) were recorded on Bruker (Thermo
Nicolet) Fourier transform spectrophotometer. The NMR spectra of all pyrazolines were
1
recorded on Bruker Avance III 500 MHz spectrometer operating at 500 MHz for recording H
spectra and 125.46 MHz for 13C spectra in DMSO solvent using TMS as internal standard. Mass
spectra were recorded on Shimadzu spectrometer using chemical ionization technique.
Synthesis of chalcones
An appropriate equi-molar quantities of 2-acetyl-5-chlorothiophene (2 mmol), substituted
benzaldehydes (2 mmol) and silica: H2SO4 (0.4 g) were taken in borosil tube and tightly capped.
The mixture was subjected to microwave heated for 8-10 min in a microwave oven (LG Grill,
Intellowave, Microwave Oven, 160-800 W) and then cooled to room temperature. The organic
layer was separated with dichloromethane and the solid product was obtained on evaporation.
The solid, on recrystallization with benzene-hexane mixture gave glittering solid. The insoluble
catalyst was recycled by washing the solid reagent remained on the filter by ethyl acetate (8 mL)
followed by drying in an oven at 100 °C for 1 h and it was made reusable for further reactions.
Bull. Chem. Soc. Ethiop. 2014, 28(2)

SOCl2 catalyzed cyclization of chalcones
273
Synthesis of pyrazolines derivatives: [1H-3-(substituted aryl)-5-(substituted phenyl)-2-
pyrazolines]
An appropriate equi-molar quantities of substituted styryl aryl ketones (2 mmol), hydrazine
hydrate (2 mmol) and SOCl2 (0.5 mL) was warmed (60 °C,) in (15 mL) of diethylether for 30
min (Scheme 1) in water bath. The progress of the reaction was monitored by TLC. The reaction
mixture was cooled, and poured into cold water. The precipitate was filtered, dried and
subjected to column chromatography using hexane and ethyl acetate (3:1) as eluent. The yield,
analytical and mass spectral data are presented in Table 1. The IR and NMR spectral data are
given in Table 2.
Hd
N
O
C
N
Hc
Ar'
SOCl2/ Ether
Warm
Ar
H2N-NH2 . H2O
+
Ar
C
H
C
H
Ar'
Ha
Hb
(1-50)
Scheme 1. Synthesis of pyrazolines.
Table 1. Analytical, yield, physical constants and mass spectral data of 3,5-disubstituted 1H pyrazoline
derivatives.
Entry
1
Ar
Ph
Ar′
Ph
M.F.
M.W. Yield
(%)
M.p. (°C)
Mass (m/z)
C15H14N2
222
256
252
236
267
301
85
85
83
83
85
84
85
84
85
85
85
84
83
85
199-200
(199)[31]
---
---
---
---
---
---
---
---
---
---
---
---
---
---
2
Ph
4-ClPh
4-OCH3Ph
4-CH3Ph
4-NO2Ph
Ph
C15H13ClN2
C16H16N2O
C16H16N2
218-219
(217)[31]
3
Ph
214-215
(212-214)[32]
184-185
4
Ph
(183-184)[32]
235-236
5
Ph
C15H13N3O2
C15H13BrN2
(234-236)[32]
215-215
(215)[31]
6
4-BrPh
4-BrPh
4-BrPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
4-CH3Ph
7
4-ClPh
4-CH3Ph
Ph
C15H12BrClN2 335
250-251
(248-250)[31]
245-246
8
C15H15BrN2
C15H13ClN2
C15H12Cl2N2
315
256
291
(244-245)[31]
220-221
(217)[31]
9
10
11
12
13
14
4-ClPh
4-OCH3Ph
4-CH3Ph
4-NO2Ph
Ph
231-232
(230-232)[31]
222-223
C16H15ClN2O 286
C15H15ClN2 271
C15H12ClN3O2 302
C16H16N2 236
Bull. Chem. Soc. Ethiop. 2014, 28(2)
(220-222)[31]
237-238
(236-237)[32]
234-235
(233-234)[32]
184-185

274
Kaliyaperumal Ranganathan et al.
(183-184)[31]
237-238
15
16
4-CH3Ph
4-CH3Ph
4-ClPh
4-CH3Ph
Ph
C15H15ClN2
C17H18N2
270
250
252
85
84
85
84
82
83
80
80
82
81
80
80
83
80
85
85
85
83
81
84
85
84
85
82
85
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
---
(236-237)[31]
237-238
(236-237)[31]
182-182
17 3-CH3-4-OHPh
18 3-CH3-4-OHPh
19 3-CH3-4-OHPh
20 3-CH3-4-OHPh
C16H16N2O
(182)[31]
142-143
2-ClPh
4-ClPh
4-FPh
C16H15N2OCl 286
C16H15N2OCl 286
(142)[33]
141-142
(141)[33]
145-146
C16H15N2OF
C18H21N3O
C17H18N2O2
C16H15N3O3
270
295
282
297
(144)[33]
162-163
21 3-CH3-4-OHPh 4-N(CH3)2Ph
(162-163)[33]
149-150
22 3-CH3-4-OHPh
23 3-CH3-4-OHPh
24 3-CH3-4-OHPh
4-OCH3Ph
3-NO2Ph
2,6-Cl2Ph
(149)[33]
151-152
(151)[33]
141-142
C16H14N2OCl 321
(141)[33]
121-122
25 3-CH3-4-OHPh 3,4-(OCH3)2Ph C18H20N2O3
26 3-CH3-4-OHPh 3,4,5-(OCH3)3Ph C19H22N2O4
312
342
242
322
242
272
312
322
322
341
328
312
358
388
(121)[33]
103-104
(103)[33]
163-164
27 3-CH3-4-OHPh
2-Furyl
1-Naphthyl
2-Thienyl
2-Naphthyl
Ph
C14H14N2O2
C23H18N2
(163)[33]
196-197
28
29
30
31
32
33
34
35
36
37
38
39
1-Naphthyl
Ph
(195-196)[34]
260-262
C15H14N2S
C20H16N2
(260-262)[35]
247-248
Ph
(247-248)[36]
102-103
Biphenyl
Biphenyl
Biphenyl
Biphenyl
Biphenyl
Biphenyl
Biphenyl
Biphenyl
5-Cl-2-Th
C21H18N2
(102)[37]
114-115
2-ClPh
C21H17ClN2
C21H17ClN2
C23H23N3
(114)[37]
124-125
4-ClPh
(124) )[37]
166-167
4-N(CH3)2Ph
4-OCH3Ph
4-CH3Ph
(166)[37]
158-159
C22H20N2O
C22H20N2
(158)[37]
164-165
(164)[37]
128-129
3,4-(OCH3)2Ph C23H22N2O2
2,4,6-(OCH3)2Ph C24H24N2O3
(128)[37]
190-191
(190)[37]
79-82
Ph
C13H11ClN2S 262
262[M+], 264[M2+],
227, 185, 145, 117,
77, 69, 55
40
5-Cl-2-Th
3-BrPh
C13H11BrClN2 341
S
84
80-83
341[M+], 343[M2+],
305, 261, 223, 185,
Bull. Chem. Soc. Ethiop. 2014, 28(2)

SOCl2 catalyzed cyclization of chalcones
275
155, 117, 79, 77,
69, 55
41
42
43
44
45
46
47
48
49
50
5-Cl-2-Th
5-Cl-2-Th
5-Cl-2-Th
5-Cl-2-Th
5-Cl-2-Th
5-Cl-2-Th
5-Cl-2-Th
5-Cl-2-Th
5-Cl-2-Th
5-Cl-2-Th
3-Cl Ph
2-F Ph
C13H10Cl2N2S 297
C13H10ClFN2S 280
C13H10ClN2S 280
C13H11ClN2OS 278
C14H13ClN2OS 293
C14H13ClN2OS 293
C14H13ClN2S 277
C14H13ClN2S 277
C14H10ClN3OS 307
C19H15ClN2OS 354
80
81
83
85
82
84
84
82
84
84
88-92
86-91
74-79
83-86
66-70
68-72
82-86
68-72
208-212
70-75
297[M+], 299[M2+],
261, 179, 185, 117,
111,77, 69, 55
280[M+], 282[M2+],
261, 185, 163, 117,
95, 77, 69, 55
280[M+], 282[M2+],
261, 185, 163, 117,
95, 77, 69, 55
278[M+], 280[M2+],
261, 243, 185, 161,
117, 93, 77, 69, 55
293[M+], 295[M2+],
261, 257, 185, 175,
117, 107, 77, 69, 55
293[M+], 295[M2+],
261, 257, 185, 175,
117, 107, 77, 69, 55
277[M+], 279[M2+],
261, 241,185,117,
159, 91, 77, 69, 55
277[M+], 279[M2+],
261, 241,185,117,
159, 91, 77, 69, 55
307[M+], 309[M2+],
261, 190, 185, 122,
117, 77, 69, 55
4-F Ph
4-OHPh
2-OCH3Ph
4-OCH3Ph
2-CH3Ph
4-CH3Ph
4-NO2Ph
3-OC6H5
354[M+], 356[M2+],
319, 277 ,261, 237,
185, 169, 93, 77,
69, 55
Table 2. IR and NMR spectral data of 3-(5-chlorothiophen-2-yl)-4,5-dihydro-5-(substituted phenyl)-1H-
pyrazoline derivatives(entries 39-50).
IR
1H
δHb (dd)
13C
Entry
X
H
δHa (dd)
δHc (dd)
δHd (s) δC=N
νC=N νC-Cl
39
40
41
42
43
44
1645.22 792.95 2.770, J = 21 Hz 2.962, J = 21 Hz 4.005, J = 14 Hz 7.126 155.43
3-Br 1653.96 781.83 2.931, J = 18 Hz 3.177, J = 18 Hz 4.085, J = 12 Hz 7.140 155.54
3-Cl 1653.18 785.57 2.788, J = 21 Hz 2.968, J = 21 Hz 4.057, J = 14 Hz 7.131 155.19
2-F
4-F
1652.42 790.30 2.790, J = 21 Hz 2.975, J = 21 Hz 4.038, J = 15 Hz 7.112 155.23
1651.82 789.11 2.770, J = 21 Hz 2.964, J = 21 Hz 4.063, J = 14 Hz 7.181 155.29
4-OH 1647.36 786.42 2.893, J = 21 Hz 3.044, J = 21 Hz 3.858, J = 16 Hz 7.026 158.80
45 2-OCH3 1646.77 789.75 2.995, J = 17 Hz 3.158, J = 17 Hz 3.905, J = 20 Hz 7.099 155.65
46 4-OCH3 1653.19 794.08 2.745, J = 21 Hz 2.935, J = 21 Hz 3.983, J = 14 Hz 7.117 155.41
47
48
49
2-CH3 1647.32 788.02 2.756, J = 21 Hz 2.932, J = 21 Hz 4.216, J = 14 Hz 7.106 155.60
4-CH3 1652.48 788.26 2.753, J = 21 Hz 2.936, J = 21 Hz 3.979, J = 14 Hz 7.014 155.43
4-NO2 1648.72 783.88 2.939, J = 22 Hz 3.125, J = 22 Hz 4.078, J = 14 Hz 6.787 155.86
50 3-OC6H5 1654.46 784.40 2.791, J = 21 Hz 2.958, J = 21 Hz 4.061, J = 14 Hz 7.138 155.21
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Kaliyaperumal Ranganathan et al.
RESULTS AND DISCUSSION
in-situ
+ H+ + OH-SOCl + Cl-
NH3
H2N
H2N
NH2 H2O
SOCl2
Et2O, Warm, Stir
OH
O
C
'
R
R
C
N
C
H
C
H
'
R
R
C
H
C
H
H
N
H
H
H2N
NH2
OH
C
'
R
R
C
C
C
H2O
H
H
'
R
R
C
H
C
H
N
N
N
H
H
H
H
N
H
H
H
'
R
R
C
C
C
H
H
C
C
R'
H
N
R
C
N
N
H
H
H
N
H
C
H
H
H
H
C
R'
C
C
R
'
H
R
C
R
C
N
N
H
H
N
N
Figure 1. The proposed general mechanism for synthesis of 3,5-diaryl-1H-pyrazolines.
Hd
N
N
O
C
Hc
SOCl2/ Ether
Warm
Cl
H2N-NH2 . H2O
+
C
H
C
H
Cl
S
S
X
X
Ha
Hb
(39-50)
X=H, 3-Br, 3–Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3, 2-CH3, 4-CH3, 4-NO2, 3-OC6H5
Scheme 2. Synthesis of 3-(5-chlorothiophen-2-yl)-4,5-dihydro-5-(substituted phenyl)-1H-
pyrazoline derivatives.
In our organic chemistry research laboratory, we attempted to synthesize aryl pyrazoline
derivatives by cycloaddition of chalcones and hydrazine hydrate using vigorous acidic catalyst
SOCl2 except acid or base or its salt in warming condition. Hence, we have synthesised the
pyrazoline derivatives by the reaction between 2 mmol of chalcones and 2 mmol of hydrazine
hydrate, 0.5 mL of SOCl2 and 15 mL of diethyl ether in water bath warming at 60 °C (Scheme
Bull. Chem. Soc. Ethiop. 2014, 28(2)

SOCl2 catalyzed cyclization of chalcones
277
1). During the course of this reaction the acidic SOCl2 catalyses for the cycloaddition reaction
between chalcone and hydrazine hydrate. The catalyst SOCl2 abstracts water and it produce H+
and Cl- ions in-situ from the hydrazine hydrate. The hydrazine molecule attacks the carbonyl
carbon of the chalcones and further rearranges leads to the formation of pyrazoline molecule.
The yield of the reaction is more than 80%. The proposed general mechanism of this reaction is
given in Figure 1. Further we investigated this reaction with equimolar quantities of the styryl 5-
chloro-2-thienyl ketone with hydrazine hydrate (Scheme 2). In this reaction the obtained yield is
85%.
IR spectral study
The synthesized pyrazoline derivatives are shown in Scheme 1. The infrared νC=N and C-Cl
stretching frequencies (cm-1) of the pyrazolines (entries 39-50) have been recorded and are
presented in Table 2. These data are [24-29, 38, 39] with Hammett substituent constants and
Swain-Lupton’s [40] parameters. In this correlation the structure parameter Hammett equation
employed is as shown in equation (1).
ν = ρσ + νo
(1)
where νo is the frequency for the parent member of the series.
The observed νC=N and C-Cl stretching frequencies (cm-1) are correlated with various
Hammett substituent constants, F and R parameters through single and multi-regression analyses
including Swain-Lupoton’s [40] parameters. The results of statistical analysis of single
parameter correlation are shown in Table 3. The correlation of νC=N (cm-1) frequencies of
pyrazolines with Hammett σR substituent constants is found to be satisfactory with negative ρ
value. The remaining constants were failing in correlation with positive ρ values. This implies
that there is a normal substituent effect operates in all systems. This is due to the absence of
inductive and resonance effects of the substituent and is associated with the conjugated
structure shown in (Figure 2). In short some of the single parameter correlations of νC=N (cm-1)
frequencies with Hammett substituent constants of resonance and inductive effects fail. So, we
think that it is worthwhile to seek the multi regression analysis and which produce a satisfactory
correlation with Resonance, Field and Swain-Lupton’s [40] constants. The corresponding
equations are given in (2 and 3).
νC=N(cm-1) = 1648.25( 1.904) + 5.472( 4.280) σI – 2.083( 4.243) σR
(R = 0.932, n = 12, P > 90%)
(2)
νC=N(cm-1) = 1657.07( 3.568) – 3.260( 6.674)F + 2.036( 2.925)R
(3)
(R = 0.957, n = 12, P > 95%)
The correlation of νC-Cl (cm-1) frequencies of pyrazolines with Hammett σ, σI, σR, F and R
parameters were found to be satisfactory except σ+ constants. All correlations produce negative
ρ values. The remaining constants were fails in correlation with negative ρ values. The fail in
correlation with σ+ is due to the absence of polar effects of the substituent and is associated with
the conjugated structure shown in (Figure 2). Also the authors observed the worth full multi-
regression analysis and which produce a satisfactory correlation with Resonance, Field and
Swain-Lupton’s [40] constants. The corresponding equations are given in (4 and 5).
νC-Cl(cm-1) = 788.92( 1.964) – 8.018( 4.417) σI – 5.387( 4.379) σR
(R = 0.967, n = 12, P > 95%)
(4)
νC-Cl(cm-1) = 788.34( 1.718) – 5.566( 3.848)F – 5.615( 2.987)R
(R = 0.930, n = 12, P > 90%)
(5)
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Kaliyaperumal Ranganathan et al.
Table 3. Results of statistical analysis of infrared νC=N and C-Cl (cm-1) modes of 3-(5-chlorothiophen-2-
yl)-4,5-dihydro-5-(substituted phenyl)-1H-pyrazoline derivatives (entries 39-50) with Hammett σ,
σ+, σI, σR constants and F and R parameters.
Frequency Constants
r
I
ρ
s
n Correlated derivatives
νC=N
σ
σ+
σI
σR
F
0.833 1650.30 3.026 3.17 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
0.811 1650.55 0.690 3.34 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
0.834 1648.75 5.480 3.09 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
0.913 1649.77 -2.570 3.31 10 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
0.835 1648.94 4.330 3.14 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
R
0.814 1650.85 1.336 3.33 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
νC-Cl
σ
0.998 788.25 -6.112 3.08 12 H, 3-Br, 3–Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
σ+
σI
σR
F
0.837 787.63 -2.517 3.56 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
0.945 790.16 -7.191 3.42 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
0.926 786.71 -4.177 3.70 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
0.937 789.28 -3.921 3.68 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
R
0.943 786.62 -4.633 3.46 12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH, 2-OCH3, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
r = correlation co-efficient; ρ = slope; I = intercept; s = standard deviation; n = number of substituents.
Figure 2. The resonance – conjugative structure.
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SOCl2 catalyzed cyclization of chalcones
279
1H NMR spectral study
The 1H NMR spectra of twelve pyrazoline derivatives under investigation have been recorded in
deuteraated dimethyl sulphoxide solution employing tetramethylsilane (TMS) as internal
standard. The signals of the pyrazoline ring protons have been assigned. They have been
calculated as AB or AA' systems, respectively. The chemical shifts (ppm) of Ha are at higher
fields than those of Hb, Hc and Hd in this series of pyrazolines. This is due to the deshielding of
protons which are in different chemical as well as magnetic environment. These Ha protons gave
an AB pattern and the Hb proton doublet of doublet in most cases was well separated from the
signals Hc and the aromatic protons. The assigned chemical shifts (ppm) of the pyrazoline ring
Ha, Hb, Hc and Hd protons are presented in Table 2.
In nuclear magnetic resonance spectra, the 1H or the 13C chemical shifts (δ) (ppm) depend on
the electronic environment of the nuclei concerned. These chemical shifts have been correlated
with reactivity parameters. Thus the Hammett equation may be used in the form as shown in (6).
Log δ = Log δ0 + ρσ
(6)
where δ0 is the chemical shift of the corresponding parent compound.
The assigned Ha, Hb, Hc and Hd proton chemical shifts (ppm) of pyrazoline ring have been
correlated [24-29, 38-42] with various Hammett sigma constants. The results of statistical
analysis are presented in Table 4. The Ha proton chemical shifts (ppm) with Hammett
substituent constants and F and R parameters fail in correlation except σ values. All correlations
gave positive ρ values. This shows that the normal substituent effect operates in all systems. The
failure in correlation is associated with the conjugative structure shown in Figure 2.
Table 4. Results of statistical analysis of 1H NMR δHa, δHb, δHc and δHd and 13C NMR δC=N (ppm) of 3-
(5-chlorothiophen-2-yl)-4,5-dihydro-5-(substituted phenyl)-1H-pyrazoline derivatives with
Hammett substituent constants σ, σ+, σI, σR, F and R parameters(entries 39-50).
Chemical
shifts
Constants
r
I
ρ
s
n
Correlated derivatives
δHa (ppm)
σ
0.915
0.715
2.854
2.829
0.036
0.025
0.09
0.09
10 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OCH3,
2-CH3, 4-CH3, 4-NO2, 3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
σ+
σI
σR
F
0.840
0.701
0.826
0.808
0.825
0.728
2.777
2.824
2.795
2.820
3.007
3.015
0.155
0.007
0.086
-0.021
0.065
0.047
0.08
0.09
0.08
0.09
0.09
0.09
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
R
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
δHb (ppm)
σ
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
σ+
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
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Kaliyaperumal Ranganathan et al.
σI
σR
F
0.904
0.807
0.729
0.805
0.950
0.905
0.907
0.840
0.805
0.846
0.837
0.818
0.917
0.756
0.810
0.825
2.954
3.019
2.974
3.007
4.019
4.035
4.017
4.072
4.026
4.061
7.088
7.076
7.106
7.011
7.095
7.060
0.176
0.029
0.105
-0.005
0.130
0.086
0.029
0.160
0.019
0.125
-1.108
-0.055
-0.086
-0.250
-0.039
-0.077
0.08
0.09
0.09
0.09
0.08
0.08
0.09
0.08
0.09
0.08
0.10
0.10
0.10
0.09
0.10
0.10
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
R
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
δHc (ppm)
σ
11 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 4-CH3, 4-NO2,
3-OC6H5
σ+
σI
σR
F
11 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 4-CH3, 4-NO2,
3-OC6H5
9
3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 4-NO2,
3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
R
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
δHd (ppm)
σ
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
σ+
σI
σR
F
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
11 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
R
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
δCN (ppm)
σ
0.934
0.709
155.77
155.46
-0.958
-0.038
0.97
0.23
10 H,3-Cl, 2-F, 4-F, 4-OH, 2-OCH3,
4-OCH3, 2-CH3, 4-CH3, 3-OC6H5
σ+
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
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SOCl2 catalyzed cyclization of chalcones
281
σI
σR
F
0.806
0.731
0.794
155.48
155.55
155.51
-0.062
0.306
0.23
0.22
0.23
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
-0.123
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
R
0.709
155.45
-0.060
0.23
12 H, 3-Br, 3-Cl, 2-F, 4-F, 4-OH,
2-OCH3, 4-OCH3, 2-CH3, 4-CH3,
4-NO2, 3-OC6H5
r = correlation co-efficient; ρ = slope; I = intercept; s = standard deviation; n = number of substituents.
The results of statistical analysis of Hb proton chemical shifts (ppm) with Hammett
substituents are shown in Table 4. The Hb proton chemical shifts with Hammett σIconstants give
satisfactory correlation. The remaining Hammett substituent constants, F and R parameters were
failed in correlation. This is due to the absence of inductive and resonance effect of substituents
and it is associated with the conjugative structure shown in Figure 2.
The results of statistical analysis of Hc proton chemical shifts (ppm) with Hammett
substituents are presented in Table 4. The Hc proton chemical shifts with Hammett σ, σ+ and σI
constants gave satisfactory correlation. The remaining σR, F and R parameters fail in correlation.
All correlations produce positive ρ values. This means that the normal substituent effect
operates in all systems. This failure in correlation is associated with conjugative structure shown
in Figure 2.
The results of statistical analysis of Hd proton chemical shifts (ppm) with Hammett
substituents are presented in Table 4. The Hc proton chemical shifts with Hammett σI constants
gave satisfactory correlation. The remaining σ, σ+, σR, F and R parameters fail in correlation.
This failure in correlation is associated with conjugative structure shown in Figure 2.
In view of the inability of the Hammett σ constants to produce individually satisfactory
correlation, the authors think that it is worthwhile to seek multiple correlations involving either
σI andσR constants or F and R parameters [40]. The correlation equations for Ha–Hd protons are
given in (7-14).
δHa(ppm) = 2.781( 0.051) + 0.157( 0.116)σI + 0.016( 0.011)σR
(R = 0.941, n = 12, P > 90%)
(7)
δHa (ppm) = 2.794( 0.048) + 0.084( 0.109)F – 0.006( 0.084)R
(R = 0.926, n = 12, P > 90%)
(8)
δHb(ppm) = 2.968( 0.052) + 0.185( 0.117)σI + 0.057( 0.116)σR
(R = 0.946, n = 12, P > 90%)
(9)
δHb(ppm) = 2.974( 0.050) + 0.103( 0.112)F + 0.002( 0.087)R
(R = 0.929, n = 12, P> 90%)
(10)
(11)
(12)
(13)
δHc(ppm) = 4.056( 0.054) + 0.055( 0.121)σI + 0.169( 0.120)σR
(R = 0.942, n = 12, P > 90%)
δHc (ppm) = 4.042( 0.046) + 0.059( 0.013)F + 0.136( 0.080)R
(R = 0.949, n = 12, P> 90%)
δHd(ppm) = 7.082( 0.019) + 0.069( 0.044)σI– 0.003( 0.044) σR
(R = 0.946, n = 12, P > 90%)
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Kaliyaperumal Ranganathan et al.
δHd(ppm) = 7.095( 0.017) + 0.054( 0.039)F + 0.031( 0.030)R
(R = 0.946, n = 12, P > 90%)
(14)
13C NMR spectra
Organic chemists and researchers [24-29, 38-42] have made extensive study of 13C NMR
spectra for a large number of different ketones, styrenes, styryl ketones and keto-epoxides. They
have studied linear correlation of the chemical shifts (ppm) of Cα, Cβ and CO carbons with
Hammett σ constants in alkenes, alkynes, acid chlorides and styrenes. In the present study, the
chemical shifts (ppm) of pyrazoline ring C=N carbon, have been assigned and are presented in
Table 2. Attempts have been made to correlate the δC=N chemical shifts (ppm) with Hammett
substituent constants, field and resonance parameters, with the help of single and multi-
regression analyses to study the reactivity through the effect of substituents.
The chemical shifts (ppm) observed for the δC=N have been correlated [24-29, 38-42] with
Hammett constants and the results of statistical analysis are presented in Table 4. The δC=N
chemical shifts (ppm) give satisfactory correlation with Hammett σ constants except 3-Br and 4-
substituents. When these are included in the correlation they reduce the correlation co-efficient
considerably. The remaining Hammett σ+, σI, σR, F and R parameters fail in correlation. This is
due to the reason stated earlier with resonance conjugative structure shown in Figure 2.
In view of inability of some of the σ constants to produce individually satisfactory
correlation, the authors think that it is worthwhile to seek multiple correlation involving all σI,
σR, F and R parameters [40]. The correlation equations are given in (15 and 16).
δC=N (ppm) = 155.68( 0.637) – 0.393( 1.432)σI – 0.568( 1.420)σR
(R = 0.914, n = 12, P > 90%)
(15)
(16)
δC=N (ppm) = 155.60( 0.525) – 0.575( 1.176)F – 0.116( 0.913)R
(R = 0.939, n = 12, P > 90%)
Microbial activities
Pyrazoline derivatives possess a wide range of biological activities [4, 6, 8, 10-12, 43, 44].
These multipronged activities are associated with different pyrazoline rings. Hence, it is
intended to examine their activities against respective microbes-bacterial and fungal strains.
Antibacterial sensitivity assay
The antibacterial screening effect of synthesized pyrazoline is shown in Figure 3 (Plates 1-10).
The antibacterial activities of all the synthesized pyrazolines have been studied against three
gram positive pathogenic strains Micrococcousluteus, Bacillus substilis, Staphylococcus aureus
and two gram negative strains Escherichia coli and Klebsiella species. The disc diffusion
technique was followed using the Kirby-Bauer [45] method, at a concentration of 250 µg/mL
with ampicillin taken as the standard drug. The measured zone of inhibition is shown in Table 5
and the clustered column chart is shown in Figure 4. All the compounds showed high activity
against Escherichia coli. Moderate activity was observed against Micrococcusluteus and
Klebsilla pneumoniae. The pyrazoline containing substituents 4-F, 2-CH3 and 4-NO2 have
shown high antibacterial activity against all the strains. The rest of the compounds displayed
lesser antibacterial activity against all the strains. However the activities of the test compounds
are less than that of standard antibacterial agent used.
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SOCl2 catalyzed cyclization of chalcones
283
Table 5. Antibacterial activity of 3-(5-chlorothiophen-2-yl)-4,5-dihydro-5-(substituted phenyl)-
1H-pyrazoline derivatives(entries 39-50).
Zone of Inhibition (mm)
Entry
X
Gram positive bacteria
Gram negative bacteria
Bacillus Micrococcus Staphylococcus Escherichia
Klebsilla
pneumoniae
substilis
luteus
aureus
coli
6
H
6
7
7
7
7
7
7
6
6
7
8
6
22
-
7
7
8
8
9
8
8
7
8
7
6
9
20
-
7
8
6
-
6
7
6
6
7
7
8
6
-
39
40
41
42
43
44
45
46
47
48
49
50
3-Br
8
3-Cl
6
2-F
8
4-F
6
-
7
4-OH
2-OCH3
4-OCH3
2-CH3
4-CH3
4-NO2
3-OC6H5
8
8
6
6
-
6
6
7
7
8
8
7
9
-
-
8
-
6
Standard Ampicillin
Control DMSO
12
-
10
-
Antifungal sensitivity assay
Antifungal sensitivity assay was performed using Kirby-Bauer [45] disc diffusion technique.
PDA medium was prepared and sterilized as above. It was poured (ear bearing heating
condition) in the petri-plate which was already filled with 1 mL of the fungal species. The plate
was rotated clockwise and counter clock-wise for uniform spreading of the species. The discs
were impregnated with the test solution. The test solution was prepared by dissolving 15 mg of
the pyrazoline in 1 mL of DMSO solvent (250 µg/L). The medium was allowed to solidify and
kept for 24 h. Then the plates were visually examined and the diameter values of zone of
inhibition were measured. Triplicate results were recorded by repeating the same procedure.
The antifungal activities of substituted pyrazoline synthesized in the present study are shown
in Figure 5 for plates (1-4) and the zone of inhibition values of the effect is given in Table 6.
The clustered column chart, shown in Figure 6 reveals that all the compounds have moderate
antifungal activity against Aspergillius niger, Mucor species, Trichoderma viridie. The
pyrazoline containing 3-Cl, 2-OCH3 and 2-OCH3 substituents have shown higher antifungal
activity than those with the other substituents present in the series.
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284
Kaliyaperumal Ranganathan et al.
Plate 1
Plate 3
Plate 5
Plate 7
Plate 9
Plate 2
Plate 4
Plate 6
Plate 8
Plate 10
Figure 3. Antibacterial activities of 3-(5-chlorothiophen-2-yl)-4,5-dihydro-5-(substituted
phenyl)-1H-pyrazoline derivatives-petri-dishes.
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SOCl2 catalyzed cyclization of chalcones
285
Figure 4. Antibacterial activities of 3-(5-chlorothiophen-2-yl)-4,5-dihydro-5-(substituted
phenyl)-1H-pyrazoline derivatives-clustered column chart.
Table 6. Antifungal
pyrazoline derivatives (entries 39-50).
activity of 3-(5-chlorothiophen-2-yl)-4,5-dihydro-5-(substituted phenyl)-1H-
Entry
X
Zone of inhibition(mm)
Aspergillius niger
Mucor species
Trichoderma viride
39
40
41
42
43
44
45
46
47
48
49
50
H
7
8
8
7
8
6
-
9
6
8
7
8
7
7
8
-
3-Br
3-Cl
6
2-F
6
4-F
7
4-OH
2-OCH3
4-OCH3
2-CH3
4-CH3
4-NO2
3-OC6H5
-
6
9
7
6
-
7
11
10
7
6
-
-
8
7
18
6
7
15
Standard Miconazole
Control DMSO
9
-
-
-
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286
Kaliyaperumal Ranganathan et al.
Plate 1
Plate 2
Plate 3
Plate 4
Plate 5
Plate 6
Figure 5. Antifungal activities of 3-(5-chlorothiophen-2-yl)-4,5-dihydro-5-(substituted phenyl)-
1H-pyrazoline derivatives-petri-dishes.
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SOCl2 catalyzed cyclization of chalcones
287
Figure 6. Antifungal activities of 3-(5-chlorothiophen-2-yl)-4,5-dihydro-5-(substituted phenyl)-
1H-pyrazoline derivatives-clustered column chart.
CONCLUSION
We have synthesized some aryl 1H pyrazolines including 3-(5-chlorothiophen-2-yl)-4,5-dihydro-
5-(substituted phenyl)-1H-pyrazoline derivatives by cyclization of aryl chalcones and hydrazine
hydrate in the presence of SOCl2. The yields of the pyrazoles are more than 85%. These
pyrazoles are characterized by their physical constants and spectral data. The infrared, NMR
spectral group frequencies of these pyrazolines have been correlated with Hammett substituent
constants, F and R parameters. From the results of statistical analyses the effects of substituent
on the spectral frequencies have been studied. The antimicrobial activities of all synthesised
pyrazolines have been studied using Bauer-Kirby method.
ACKNOWLEDGEMENT
The authors thank to SAIF, IIT Chennai-600036 for recording NMR spectra of all compounds.
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Bull. Chem. Soc. Ethiop. 2014, 28(2)

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