Synthesis and crystal structure of bis-chalcone-derived fused-ring pyrazoline having an unusual substitution pattern

Article abstract of DOI:10.1007/s00706-017-1995-8

Abstract: Pyrazolines are an important class of heterocyclic compounds with diverse applications. A novel bis-chalcone-derived fused ring pyrazoline has been obtained by the reaction of bis-chalcone with hydrazine hydrate in acetic acid solvent having a catalytic amount of HCl and characterized by IR, ¹H and ¹³C NMR, GC–MS, and finally by X-ray single crystal analysis. Interestingly, the in situ post-cyclization substitution pattern on pyrazoline ring nitrogen is entirely different from the previously reported related pyrazoline derivatives. The new compound crystallizes out from its ethanolic solution, which has monoclinic crystal lattice with P2₁/c space group, a?=?6.1001(4)??, b?=?38.602(2)??, c?=?7.7332(5)??, α?=?90°, β?=?113.039(3)°, γ?=?90°, V?=?1675.73(19)??³, Z?=?4, crystal size?=?0.38?×?0.30?×?0.18?mm³, and R_int?=?0.043. Graphical abstract: [Figure not available: see fulltext.].

Full text of DOI:10.1007/s00706-017-1995-8

Monatsh Chem
DOI 10.1007/s00706-017-1995-8
ORIGINAL PAPER
Synthesis and crystal structure of bis-chalcone-derived fused-ring
pyrazoline having an unusual substitution pattern
Shumaila Ashraf1 Shahid Hameed1 Muhammad Nawaz Tahir2
Muhammad Moazzam Naseer1
•
•
•
Received: 22 February 2017 / Accepted: 9 May 2017
Ó Springer-Verlag Wien 2017
Abstract Pyrazolines are an important class of heterocyclic
compounds with diverse applications. A novel bis-chalcone-
derived fused ring pyrazoline has been obtained by the reaction
of bis-chalcone with hydrazine hydrate in acetic acid solvent
having a catalytic amount of HCl and characterized by IR, 1H
and 13C NMR, GC–MS, and finally by X-ray single crystal
analysis. Interestingly, the in situ post-cyclization substitution
pattern on pyrazoline ring nitrogen is entirely different from the
previously reported related pyrazoline derivatives. The new
compound crystallizes out from its ethanolic solution, which
has monoclinic crystal lattice with P21/c space group,
Keywords Heterocycles Á Fused-ring pyrazoline Á
Structure elucidation Á X-ray structure determination
Introduction
Pyrazoline derivatives have a unique place in realm of
heterocyclic bioactive compounds [1–4]. They possess
anti-fungal [5], anti-depressant [6], anticonvulsant [7], anti-
inflammatory [8], anti-bacterial [9], anti-tumor [10],
antiarrhythmic [11], antitubercular [12], antidiabetic [13],
antipyretic [14], anticancer [15], antiviral [16], and so on
[17] properties. In addition to their applications in medic-
inal chemistry, the pyrazoline derivatives carrying a phenyl
substitution at 5-position have shown good film-forming
properties and displayed excellent photophysical properties
[18, 19]. The 2-pyrazolines (Fig. 1) can be synthesized
from a number of different synthetic precursors such as
Mannich bases [20], a,b-unsaturated esters [21], more
commonly from a,b-unsaturated ketones known as ‘‘chal-
cones’’ [22–27] and more recently from bis-chalcones [28].
However, the 2-pyrazolines prepared from bis-chalcones
are still limited in their number in comparison to the
derivatives obtained from simple mono-chalcones despite
of having an additional advantage of further functional-
ization through its double bond [29, 30]. Owing to this
additional double bond, the properties and functions of the
2-pyrazoline derivatives can further be tuned by introduc-
ing desired functionalities. Therefore, this sub-class of
2-pyrazolines requires a lot of attention from synthetic and
medicinal chemistry community.
˚
˚
˚
a = 6.1001(4) A, b = 38.602(2) A, c = 7.7332(5) A, a =
3
˚
90°, b = 113.039(3)°, c = 90°, V = 1675.73(19) A , Z = 4,
crystal size = 0.38 9 0.30 9 0.18 mm3, and Rint = 0.043.
Graphical abstract
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-017-1995-8) contains supplementary
material, which is available to authorized users.
& Muhammad Moazzam Naseer
moazzam@qau.edu.pk
1
In recent years, most of the derivatives of 2-pyrazoline
have been obtained either by incorporating a substituent at
N1 position or by introducing different substituents at 3-
Department of Chemistry, Quaid-i-Azam University,
Islamabad 45320, Pakistan
2
Department of Physics, University of Sargodha, Sargodha
40100, Pakistan
123

S. Ashraf et al.
In FT-IR spectroscopy, two characteristic absorption
bands appeared at 1600 and 1176 cm-1 were assigned to
the carbon nitrogen double bond (C=N) and carbon nitro-
gen single bond (C–N), respectively. Both of these
indicated the formation of pyrazoline ring. Another
stretching band at 1688 cm-1 showed the presence of
carbonyl moiety of N-acetyl group [32, 33]. The formation
of five membered pyrazoline ring was further confirmed by
the 1H NMR spectroscopy. All protons were found at their
expected regions and the chemical shift values for these
protons are provided in the experimental section. The 13C
NMR spectrum complimented the results further with the
observation of all the carbon signals. Finally, a molecular
ion peak (M?Á) observed at m/z = 316 in its GC–MS
spectrum confirmed the formation of pyrazoline derivative
2.
Fig. 1 Different isomeric forms of pyrazoline
and 5-positions. Considering the synthesis of 2-pyrazoline
from chalcone, N1 position is always the nitrogen con-
nected to the carbon coming from aldehyde component of
the chalcone. In this context and to best of our knowledge,
the substitution at N2 of 2-pyrazoline, whether it is pre-
pared from simple chalcones or bis-chalcones, has not been
reported so far. Herein, in this communication, as a result
of our continuous interest in pyrazoline derivatives
[22–27], we report the synthesis and crystal structure of a
novel bis-chalcone derived fused ring pyrazoline 2 having
an unusual substitution at N2 position.
The structure of compound 2 was further characterized
unambiguously by growing the single crystals suitable for
X-ray diffraction analysis from its ethanolic solution. The
ORTEP diagram of 2 with the numbering scheme is shown
in Fig. 2. The phenyl ring [C(1)–C(6)] directly attached to
the pyrazoline ring is nearly in the same plane as pyrazo-
line ring, making a dihedral angle of 8.47° [C(1)–C(6)–
C(7)–N(1)]. The other phenyl ring [C(16)–C(21)] that is
directly attached to the cyclopentane ring through a double
bond is tilted, making a dihedral angle of 34.87° [C(14)–
C(15)–C(16)–C(17)] with the double bond. All of the bond
lengths and bond angles related to the phenyl rings are in
the normal range. Selected bond lengths and bond angles
are provided in Table 1. In the cyclopentananopyrazolinyl
Results and discussion
The N2-substituted pyrazoline derivative 2 was obtained in
good yield by the reaction of bis-chalcone intermediate 1
with hydrazine hydrate in acetic acid solvent containing
catalytic amount of hydrochloric acid in reflux conditions
(Schemes 1, 2). The bis-chalcone intermediate 1 in turn was
obtained by Claisen–Schmidt condensation reaction of two
equivalents of benzaldehydes with one equivalent of
cyclopentanone in ethanol solvent and in the presence of
30% NaOH. It is worth addressing here that we [22–27] and
various others previously prepared pyrazoline derivatives
from simple or mono-chalcones under similar conditions
where the acyl substituent always goes to N1 position.
Similarly, Azam et al. [31] and Song et al. [28] reported some
bis-chalcone derived pyrazoline derivatives that also have
substitution at N1 position. The structure of this somewhat
usual that bis-chalcone-derived pyrazoline 2 was deduced on
˚
ring, the N(1)=C(7) bond length [1.284(2) A] is slightly
shorter than those found in a similar fused cyclohex-
˚
ananopyrazoline derivative [1.287(3) A] [28] and the
˚
related simple pyrazoline derivatives [1.290(2) A,
˚
1.293(3) A] [25], while the bond lengths of N(1)–N(2)
˚
˚
[1.389(2) A] and N(2)–N(10) [1.471(2) A] are comparable
to those with pyrazolines prepared from both mono- and
bis-chalcones.
The compound 2 packs in 1D-supramolecular chains in
the solid state driven mainly by CHÁÁÁO [C(13)–
˚
H(13A)ÁÁÁO(1) 2.590 A] and pÁÁÁp [34, 35] [C(1)ÁÁÁO(8)
1
the basis of its FT-IR, H and 13C NMR, GCMS data, and
˚
3.326 A] stacking interactions (Fig. 3a). These chains are
finally by X-ray single crystal diffraction analysis.
further connected to the neighboring chains by means of
Scheme 1
123

Synthesis and crystal structure of bis-chalcone-derived fused-ring pyrazoline having an…
Scheme 2
undergoes substitution at the nitrogen which is directly attached
to the ketone component of the bis-chalcone which has not been
previously reported. It packs in 1D-supramolecular chains in
the solid state driven mainly by CHÁÁÁO and pÁÁÁp stacking
interactions. We are currently investigating this reaction that
provided an unusual product, in more detail, and the results
regarding the reason of its formation, substrate scope, etc. will
be subject of our future paper.
Experimental
All the reagents and solvents were used as obtained from
the supplier or recrystallized/redistilled as required. Thin
layer chromatography (TLC) was performed using alu-
minium sheets coated with silica gel 60 F254 (Merck).
Melting point was determined in open capillary tube using
Gallenkamp apparatus (MP-D) and was uncorrected. IR
spectrum in the range of 4000–400 cm-1 was obtained on a
Fig. 2 Molecular structure (ORTEP diagram) of 2
˚
CHÁÁÁp [27] [C(9)–H(9A)ÁÁÁC(3) 2.874 A, C(9)–
˚
H(9A)ÁÁÁC(4) 2.788 A] interactions forming an overall 2D
network structure (Fig. 3b).
1
Thermo Nicolet-6700 FT-IR Spectrophotometer. The H
and 13C NMR spectra were recorded on a Bruker spec-
trometer at 300 and 75 MHz in CDCl3, respectively, using
residual solvent signals as a reference. The GC–MS spec-
trum was recorded on Agilent 5973 inert mass selective
detector in combination with Agilent 6890 N gas
chromatograph.
Conclusion
In conclusion, we have reported the synthesis and crystal
structure of a novel fused-ring pyrazoline 2 having an unusual
post-cyclization substitution pattern on pyrazoline nucleus. It
123

S. Ashraf et al.
˚
Table 1 Selected geometric parameters; bond lengths/A, bond
angles/°, and torsion angles/° for fused-ring pyrazoline 2
Compound
2
O(1)–C(8)
1.220(2)
N(1)–C(7)
1.284(2)
N(1)–N(2)
1.389(2)
N(2)–C(8)
1.361(2)
N(2)–C(10)
1.471(2)
C(6)–C(7)
1.471(2)
C(10)–C(14)
1.512(3)
C(14)–C(15)
1.329(3)
C(15)–C(16)
1.466(3)
C(7)–N(1)–N(2)
C(8)–N(2)–N(1)
C(8)–N(2)–C(10)
N(1)–N(2)–C(10)
N(1)–C(7)–C(6)
N(1)–C(7)–C(11)
N(2)–C(8)–C(9)
N(2)–C(10)–C(14)
N(2)–C(10)–C(11)
C(7)/N(1)/N(2)/C(8)
C(7)/N(1)/N(2)/C(10)
N(2)/N(1)/C(7)/C(6)
N(2)/N(1)/C(7)/C(11)
C(1)/C(6)/C(7)/N(1)
C(14)/C(15)/C(16)/C(17)
108.18(15)
122.79(16)
124.23(16)
112.79(15)
120.86(17)
114.61(16)
117.25(18)
112.10(16)
102.21(14)
170.81(18)
-4.4(2)
Fig. 3 Molecular packing of 2 in the solid state; a 1D supramolecular
chain, b 2D structure
Yield 70%; light yellow crystals; m.p.: 118–120 °C;
Rf = 0.52 (n-hexane:ethyl acetate, 4:1); IR: vꢀ = 1176 (C–
1
N), 1600 (C=N), 1688 (C=O) cm-1; H NMR (300 MHz,
CDCl3): d = 0.99–1.2 (1H, m), 1.33–1.39 (1H, m),
1.69–1.74 (2H, m), 1.85 (3H, s, CH3), 2.06 (1H, m), 5.9
(1H, m), 7.11 (1H, s), 7.30 (2H, dd, Ph), 7.46 (1H, t, Ph),
7.78 (2H, d, Ph), 7.79 (2H, dd, Ph), 7.80 (1H, t, Ph), 8.02
(2H, d, Ph) ppm;13C NMR (75 MHz, CDCl3): d = 22.7,
29.60, 29.65, 31.93, 53.19, 115.87, 119.99, 127.03, 128.55,
128.79, 128.88, 137.45, 141.89, 157.73, 164.89 ppm; EI-
MS: m/z = 316 (M? base peak).
179.37(15)
-0.4(2)
-8.4(3)
-34.8(3)
(E)-1-(6-Benzylidene-3-phenyl-4,5,6,6a-tetrahydrocy-
clopenta[c]pyrazol-1(3aH)-yl)ethanone (2, C21H20N2O)
A round bottom flask containing 15 cm3 ethanol and
benzaldehyde (0.02 mol) was added 30% NaOH solution at
room temperature with stirring. After about 30 min of
continuous stirring, cyclopentanone (0.01 mol) was then
added and stirring was continued at room temperature for
another 3–4 h. The precipitates thus appeared after cooling
the reaction mixture with ice were filtered and washed
thoroughly with distilled water to obtain 2,5-dibenzyli-
denecyclopentanone (1).
Compound 1 (0.01 mol, 0.5 g) was dissolved in 15 cm3
glacial acetic acid containing few drops of concentrated
hydrochloric acid and heated to 60–65 °C for 30 min.
Hydrazine hydrate (0.03 mol) was then added and heated
the reaction mixture to reflux for 24 h. The reaction
mixture was then cooled to room temperature and poured
into crushed ice. The precipitates so obtained were filtered
off, washed with distilled water, and dried in desiccator to
get crude 2 which was further purified by column
chromatography using n-hexane/ethylacetate (4:1) as
eluent.
Crystallographic data collection and structural
refinement
Single crystals of 2 were mounted on a thin glass fiber at
room temperature and the reflection data were collected on
a Bruker kappa APE XII CCD diffractometer equipped
with graphite mono-chromated MoKa radiation
˚
(k = 0.71073 A). The data were also corrected to Lorentz
and polarization effect. The structure was solved using
SHELXS-97. Final refinement on F2 was carried out by
full-matrix least-squares techniques using SHELXL-97
[36].
Crystal
data
(CCDC
1529599):
C21H20N2O,
M = 316.39, crystal size 0.38 9 0.30 9 0.18 mm3, crystal
˚
system: monoclinic, space group: P21/c, a = 6.1001(4) A,
˚
˚
b = 38.602(2) A,
b = 113.039(3)°, c = 90°, V = 1675.73(19) A , Z = 4,
q = 1.254 g cm-3
T = 296(2) K, R1, wR2[-
c = 7.7332(5) A,
a = 90°,
3
˚
,
I [ 2r(I)] = 0.0556, 0.1172, R1, wR2 (all data) = 0.0891,
0.1321, quality of fit = 1.037.
123

Synthesis and crystal structure of bis-chalcone-derived fused-ring pyrazoline having an…
Acknowledgements We are grateful to HEC and QAU for financial
support.
16. Havrylyuk D, Zimenkovsky B, Vasylenko O, Lesyk R (2013) J
Heterocycl Chem 50:E55
17. Mete E, Comez B, Gul HI, Gulcin I, Supuran CT (2016) J Enz
Inhib Med Chem 31:1
18. Szukalski A, Haupa K, Miniewicz A, Mysliwiec J (2015) J Phys
Chem C 119:10007
References
19. Szukalski A, Miniewicz A, Haupa K, Przybyl B, Janczak J,
Sobolewski AL, Mysliwiec J (2016) J Phys Chem C 120:14813
20. Afsah EM, Kandeel EEDM, Khalifa MM, Hammouda WM
(2007) Z Naturforsch B 62:540
21. Levai A (2002) J Heterocycl Chem 39:1
22. Abbas A, Flores-Holguin N, Naseer MM (2015) New J Chem
39:4359
1. Elinson MN, Nasybullin RF, Ryzhkov FV, Zaimovskaya TA,
Nikishin GI (2015) Monatsh Chem 146:631
2. Albuquerque HMT, Santos CMM, Cavaleiro JAS, Silva AMS
(2014) Curr Org Chem 18:2750
3. Seebacher W, Michl G, Belaj F, Brun R, Saf R, Weis R (2003)
Tetrahedron 59:2811
4. Tong X, Chen R, Zhang TT, Han Y, Tang WJ, Liu XH (2015)
Bioorg Med Chem 23:515
23. Abbas A, Hussain S, Hafeez N, Naseer MM (2014) Spectrochim
Acta A 133:182
5. Montoya A, Quiroga J, Abonia R, Derita M, Sortino M, Ornelas
A, Zacchino S, Insuasty B (2016) Molecules 21:969
6. Kaplancikli ZA, Ozdemir A, Turan-Zitouni G, Altintop MD, Can
OD (2010) Eur J Med Chem 45:4383
7. Bhandari S, Tripathi AC, Saraf SK (2013) Med Chem Res
22:5290
8. Jadhav SY, Shirame SP, Kulkarni SD, Patil SB, Pasale SK,
Bhosale RB (2013) Bioorg Med Chem Lett 23:2575
9. Evranos-Aksoz B, Onurdag FK, Ozgacar SO (2015) Z Natur-
forsch C 70:183
10. Elmeligie S, Khalil NA, Ahmed EM, Emam SH, Zaitone SAB
(2016) Biol Pharm Bull 39:1611
24. Abbas A, Hussain S, Hafeez N, Hasan A, Naseer MM (2014)
Spectrochim Acta A 127:32
25. Abbas A, Nazir H, Naseer MM, Bolte M, Hussain S, Hafeez N,
Hasan A (2014) Spectrochim Acta A 120:176
26. Abbas A, Naseer MM (2014) Acta Chim Slov 61:792
27. Anam F, Abbas A, Lo KM, Zia-ur-Rehman, Hameed S, Naseer
MM (2014) New J Chem 38:5617
28. Song J, Zhao PS, Zhang WG (2010) Bull Korean Chem Soc
31:1875
29. Asiri AM, Khan SA (2012) J Heterocycl Chem 49:1434
30. Asiri AM, Khan SA (2011) Molecules 16:523
31. Azam MA, Gomathy S, Alam F, Suresh B (2008) Indian J
Heterocycl Chem 18:157
11. Bruno O, Bondavalli F, Ranise A, Schenone P, Losasso C, Cilenti
L, Matera C, Marmo E (1990) Farmaco 45:147
12. Harikrishna N, Isloor AM, Ananda K, Obaid A, Fun HK (2016)
New J Chem 40:73
32. Hadi S, Rilyanti M (2010) Orient J Chem 26:775
33. Hadi S, Afriyani H, Anggraini WD, Qudus HI, Suhartati T (2015)
Asian J Chem 27:1509
13. Ahn JH, Kim HM, Jung SH, Kang SK, Kim KR, Rhee SD, Yang
SD, Cheon HG, Kim SS (2004) Bioorg Med Chem Lett 14:4461
14. Amr AE, AL-Omar MA, Abdalla MM (2016) Lat Am J Pharm
35:950
34. Naseer MM, Hameed S (2012) Cryst Eng Comm 14:4247
35. Ahmad M, Pervez H, Hadda TB, Toupet L, Naseer MM (2014)
Tetrahedron Lett 55:5400
36. Sheldrick GM (2008) Acta Crystallogr A 64:112
15. Lee Y, Kim BS, Ahn S, Koh D, Lee YH, Shin SY, Lim Y (2016)
Bioorg Chem 68:166
123