Stacking in 5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl ester through C-H···π, C-H···O and C-H···N networks

Article abstract of DOI:10.1016/j.molstruc.2008.12.063

Nature contains things abundant in aromatic moieties which are sustained and controlled by non-covalent/aromatic interactions. Their extent of involvement provides stability and flexibility simultaneously to the systems like biological or chemical systems

Full text of DOI:10.1016/j.molstruc.2008.12.063

Journal of Molecular Structure 921 (2009) 251–254
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Stacking in 5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-3-methyl-1-
phenyl-1H-pyrazole-4-carboxylic acid ethyl ester through C–Hꢀꢀꢀ , C–HꢀꢀꢀO
p
and C–HꢀꢀꢀN networks
a
Ashish Kumar Tewari a, , Priyanka Srivastava , Carmen Puerta b,1, Pedro Valerga b
*
a Department of Chemistry, Faculty of Science, Banaras Hindu University, Varanasi 221 005, India
b Departamento de Ciencia de los, Materiales e Ingenieria Metalurgica, Facultad de Ciencias, Campus Universitario del Rio San Pedro, Puerto Real 11510, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
Nature contains things abundant in aromatic moieties which are sustained and controlled by non-cova-
lent/aromatic interactions. Their extent of involvement provides stability and flexibility simultaneously
to the systems like biological or chemical systems. Therefore, the need for designing of flexible models
arises for better understanding of such interactions which can be implemented in rational drug designing
concepts and in material sciences including many more fields. We report here the single crystal X-ray
study of 5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propoxy]-3-methyl-1-phenyl-1H-pyrazole-4-car-
boxylic acid ethyl ester for understanding weak interactions. The structure was stabilized through
Received 3 November 2008
Received in revised form 18 December 2008
Accepted 24 December 2008
Available online 10 January 2009
Keywords:
Aromatic interactions
Crystal structure
Self assembly
C–Hꢀꢀꢀ , C–HꢀꢀꢀO and C–HꢀꢀꢀN interactions.
p
Ó 2009 Elsevier B.V. All rights reserved.
C–Hꢀꢀꢀp interactions
1. Introduction
example, benzene dimer [8] and porphyrin [8] based models were
the most studied models but still as awareness for these interac-
tions increases due to their unavoidable significant involvement
in many systems, especially in drug designing, pharmaceuticals
and in bioanalysis, more models are needed to be designed for bet-
ter understanding of these aromatic interactions. Therefore, in or-
der to study weak interactions inspired due to above mentioned
findings, X-ray studies of a pyrazole based heterodimer is reported
here, involving phthalimide moiety attached through a trimethyl-
ene linker. The compound (2) generates an intramolecularly self
Molecular units organize themselves in an ordered structure
through non-covalent interactions leading to self assembled [1]
structures. The whole process is reversible and spontaneous. Weak
aromatic interactions play an important role in it. These non-cova-
lent interactions facilitate the make and break processes in chem-
ical, material and biological systems. The contribution of several
weak interactions ensures a flexible and stable system. So the
understanding of non-covalent interactions between molecules
will help in understanding the molecular recognition process. Aro-
matic moieties present in abundance everywhere in nature and
hence aromatic interactions control diverse phenomena such as
vertical base–base interactions which stabilize the double helical
structure of DNA [2], the intercalation of drugs into DNA [2,3],
the packing of aromatic molecules in crystals [4], the tertiary struc-
ture of proteins [5], the conformational preferences and binding
properties of polyaromatic macrocycles [6], complexes in many
host–guest systems [7] and porphyrin aggregates [8]. Among dif-
assembled architecture which is stabilized through C–Hꢀꢀꢀ
p, C–
HꢀꢀꢀO and C–HꢀꢀꢀN networks.
2. Experimental
2.1. Preparation and characterization
Preparation of 5-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-pro-
poxy]-3-methyl-1-phenyl-1H-pyrazole-4-carboxylic acid ethyl es-
ter (2): (Scheme 1) Phthalimide (0.20 g, 0.0014 mol) and
anhydrous K2CO3 (0.19 g, 0.0014 mol) were stirred in 15 ml DMF
for 20 min and (1) (0.5 g, 0.0014 mol) was added. The reaction
was stirred at r.t. for 24 h and TLC checked. After completion of
reaction, solvent was removed via rota vapour and the product
was extracted with CHCl3/H2O (30/30 ꢁ 2 ml). The CHCl3 layer
was dried (Na2SO4), filtered and evaporated and pure (2) was ob-
tained from 3% ethyl acetate in hexane mixture. Mp = 78–80 °C.
ferent non-covalent interactions,
p
ꢀꢀꢀ
p
, C–Hꢀꢀꢀ
p
and C–HꢀꢀꢀO are
most studied. C–Hꢀꢀꢀ
p
interactions are more common in proteins.
Various models were designed to study such interactions as for
* Corresponding author. Tel.: +91 0542 6702476; fax: +91 0542 2368127.
E-mail addresses: tashish2002@yahoo.com (A.K. Tewari), priyanka_netsoft@ya
hoo.co.in (P. Srivastava), carmen.puerta@uca.es (C. Puerta), pedro.valerga@uca.es
(P. Valerga).
1
Tel.: +34 956 016350; fax: +34 956 016288.
0022-2860/$ - see front matter Ó 2009 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2008.12.063

252
A.K. Tewari et al. / Journal of Molecular Structure 921 (2009) 251–254
O
O
H3C
H3C
O
OCH2CH3
O
OCH2CH3
N
(i). K2CO3/ DMF
(ii). 24 Hr/ R.T.
N
H
Br +
N
O
N
O
N
N
O
O
(1)
(2)
Scheme 1.
Yield = 0.30 g (51%). 1H NMR (300 MHz, 25 °C, Si(CH3)4, CDCl3): d
1.32–1.37 (t, 3H, CH2CH3) (J = 6.9, 7.2 Hz); d 2.03–2.08 (t, 2H,
CH2) (J = 6.9, 6.9 Hz); d 2.46 (s, 3H, CH3); d 3.69–3.73 (t, 2H,
NCH2) (J = 7.2, 7.2 Hz); d 4.25–4.32 (q, 4H, OCH2, OCH2CH3)
Table 2
Geometry of non-covalent interactions in (2).
S. No. Interactions
C–H/N/OꢀꢀꢀO/p/N in Å
(angle in degree)
(J = 7.5, 6.9, 6.6 Hz);
d
7.26–7.84 (m, 9H, Ar-H). 13C NMR
(i) Intramolecular interactions
(300 MHz, 25 °C, Si(CH3)4, CDCl3): d 14.32 (CH3); d 15.29 (CH3); d
28.84 (CH2); d 34.73 (CH2); d 59.79 (CH2); d 73.42 (CH2); d 99.45
(C); d 123.25 (CH); d 127.38 (CH); d 128.94 (CH); d 131.94 (C); d
133.84 (CH); d 137.43 (C); d 150.87 (C); d 154.95 (C); d 162.87
(C); d 168.01 (C). MS (m/z) M+ 434. Element analysis: (i) Calculated:
N = 9.69%; C = 66.51%; H = 5.31%. (ii) Found: N = 9.76%; C = 67.34%;
H = 5.40%.
1.
2.
3.
4.
5.
6.
7.
8.
9.
C–H(10A)ꢀꢀꢀO(2)
C–H(20)ꢀꢀꢀO(1)
C–H(20)ꢀꢀꢀO(3)
C–H(9B)ꢀꢀꢀO(3)
3.248 (104.98)
3.234 (118.16)
2.525 (108.41)
2.671 (181.68)
3.716 (66.97)
3.412 (83.96)
3.414 (159.78)
3.519
C–H(11B)ꢀꢀꢀ
p
(pyrazole)
C–H(11A)ꢀꢀꢀ
p (pyrazole)
C–H(9B)ꢀꢀꢀp (pyrazole)
N(3)ꢀꢀꢀO(3)
N(2)ꢀꢀꢀO(3)
O(3)ꢀꢀꢀO(4)
2.331
2.942
10.
2.2. Crystal structure determinations
(ii) Intermolecular interactions
1.
2.
3.
4.
5.
6.
7.
8.
9.
C–H(24)ꢀꢀꢀ
p
p
(phthalimide-6-membered ring)
(phthalimide-5-membered ring)
3.012 (136.48)
3.116 (100.79)
3.439 (90.31)
3.401 (133.63)
3.195 (124.46)
2.528 (130.80)
2.510 (152.19)
3.609 (110.64)
3.070
The cell parameters, space group and crystal structure were
determined from single crystal X-ray diffraction data collected at
ambient temperature on Bruker SMART APEX CCD area detector dif-
fractometer at the Servicio Central de Ciencia y Technologia de la
Universidad de Cadiz. Crystal data, experimental conditions and
structure refinement parameters for (2) are mentioned in Table 1.
The structure was solved and refined by using SHELXTL (Sheldrick,
2001) program. Molecular graphics were designed by using OR-
TEP-3 vers. 1.08. Some importantintermolecular and intramolecular
distances and hydrogen bonds are summarized in Table 2. Lists of
atomic coordinates and complete geometry have been deposited
C–H(24)ꢀꢀꢀ
C–H(2)ꢀꢀꢀ
p
(pyrazole)
p
p
C–H(17C)ꢀꢀꢀ
(phthalimide-5-membered ring)
(phthalimide-6-membered ring)
C–H(16B)ꢀꢀꢀ
C–H(20)ꢀꢀꢀO(2)
C–H(11A)ꢀꢀꢀO(1)
C–H(5)ꢀꢀꢀp (pyrazole)
O(2)ꢀꢀꢀO(3)
10.
11.
12.
O(4)ꢀꢀꢀ
p
(phthalimide-5-membered ring)
3.479
3.193
2.512
C(12)ꢀꢀꢀO(2)
C–H(9A)ꢀꢀꢀO(1)
with the Cambridge Crystallographic Data Centre, CCDC 654473
and can be obtained upon request from CCDC, 12 Union Road, Cam-
bridge CB21EZ, England (Fax +44 1223 336033; e-mail:
deposit@ccdc.cam.ac.uk).
Table 1
Crystal data on structure (2).
Compound
Empirical formula
Formula weight
Crystal system
Space group
Cell length
a (Å)
(2)
C24H23N3O5
433.45
Monoclinic
P21/n
3. Results and discussion
X-ray quality crystal of (2) was grown from slow evaporation of
3% ethyl acetate in hexane mixture at room temperature.
15.788(2)
9.0235(11)
15.800(2)
b (Å)
c (Å)
Cell angle
3.1. Crystal structure analysis
a
(°)
b (°)
(°)
90.00
111.795(2)
90.00
2090.02(5)
1.378
912
Z: 4 Z’: 0
4.78
2.257–24.993
c
The cell parameters, space group and crystal structure were
determined from single crystal X-ray diffraction data collected at
ambient temperatures. Compound (2) possess monoclinic crystal
system with P21/n space group having a, b and c values of
15.788(2), 9.0235(11) and 15.800(2) Å, respectively.
The solid state single crystal X-ray diffraction data of (2) indi-
cated intramolecular interaction along with intermolecularly stabi-
lized self assembly of molecules in three-dimensions. The overall
structure of (2) as a single molecule and in packing of molecules
Cell volume, V (Å3)
Dcalc (mg/m3)
F(000)
Z, Z0
R factor (%)
H
range (°)
Index range
h
k
ꢂ18, 18
ꢂ10, 10
ꢂ16, 18
331–333
0.0478
0.1026
1.051
l
Mp (K)
R1
wR2
GOF
is sustained and controlled through a combination of C–Hꢀꢀꢀ
HꢀꢀꢀO, C–HꢀꢀꢀN, C–NꢀꢀꢀO, OꢀꢀꢀO, C–CꢀꢀꢀO and ꢀꢀꢀO interactions among
which C–Hꢀꢀꢀ , C–HꢀꢀꢀO and C–HꢀꢀꢀN interactions predominates. The
overall X-ray analysis revealed intramolecularly as well as inter-
p, C–
p
p

A.K. Tewari et al. / Journal of Molecular Structure 921 (2009) 251–254
253
molecularly stacked arrangement of (2) in solid state. These weak
(but rather good to say strong) non-covalent forces were found to
stabilize the geometry of molecules in 3D-space which were indi-
cated in ORTEP and in packing diagrams through different axes. It
is an asymmetrical molecule consisting of phthalimide and pyra-
zole moieties attached together through a flexible (Leonard) tri-
methylene linker. The molecule is nonplanar and the pyrazole
ring lies in one plane while the N-phenyl ring bisects it with an an-
gle of 71.92°.
C–H(9B) of linker was in close contact with
p
electrons of N-
phenyl ring. This indicated that the molecule is oriented in such
a manner where the 20th proton of phenyl ring is interacting
with phthalimide oxygen means that phenyl ring is tilted to-
wards phthalimide moiety and the close contact between H(9)
and O(3) of linker generates a bent structure for (2). Also, the
distances between H(9) of linker and
p electron density over
phenyl ring and H(9) and O(3) of linker are 3.414 Å (159.78°)
and 2.671 Å (181.68°), respectively, which again support intra-
molecular stacking within the molecule (2) (Fig. 1). O(3) and
O(4) distance (2.942 Å) indicated that the OC2H5 side chain is
interacting with the linker oxygen.
X-ray diffraction quality Crystals of (2) were grown from slow
evaporation of 2% ethylacetate in hexane mixture at room tem-
perature. Compound (2) is intramolecularly stacked and the
stacking is stabilized through C–Hꢀꢀꢀ
p
, C–HꢀꢀꢀN and C–HꢀꢀꢀO net-
The trimethylene linker is not present in the plane possessing
pyrazole and phthalimide moieties which can be supported by
the fact that O(3) of linker is interacting strongly with N(2) and
N(3) of pyrazole moiety (2.331 Å and 3.519 Å) and also, both
works (Table 2). The distances between H(20) of phenyl and
1st oxygen of phthalimide moiety was 3.234 Å (118.16°) and
that of H(20) and O(3) of linker was 2.525 Å (108.41°). Also,
Fig. 1. (a) Single molecule; (b) ORTEP view; (c,e) represents herringbone packing through c axis; (d) indicate packing through a axis and (f) indicates opposite orientation of
molecules of (2).

254
A.K. Tewari et al. / Journal of Molecular Structure 921 (2009) 251–254
the protons at 11th carbon (H11A and H11B) are in close proxim-
ity with electron cloud of pyrazole ring (3.412 Å and 3.716 Å)
4. Conclusion
p
therefore, it showed zig-zag and not straight trimethylene chain.
Above all observations suggesting that (2) possess intramolecu-
larly stacked structure in solid state. The packing diagram re-
vealed interesting intermolecularly self assembled architecture
stabilized mainly through combination of weak forces. Packing
revealed that the molecules are arranged in opposite orientations
as indicated by arrows in Fig. 1(f). The phenyl and phthalimide
groups packs in the commonly observed herringbone motif
Compound (2) was synthesized under simple conditions and
characterized through spectroscopy. Diffraction quality single
crystal was obtained and single crystal X-ray diffraction data re-
vealed intermolecularly self assembled structure for (2) along with
intramolecular stacking. The overall structure was stabilized
through C–Hꢀꢀꢀ , C–HꢀꢀꢀN and C–HꢀꢀꢀO networks.
p
Acknowledgements
[4,8b,9], which mediates the CH/
tons and centroids of phthalimide-5 and 6-membered rings. The
electrons of aromatic moieties are known to act as H-bond
acceptor and therefore, molecules of (2) have shown C–Hꢀꢀꢀ net-
p networks between phenyl pro-
Author is gracefully acknowledged to Department of Science
and Technology, New Delhi for financial assistance in Young Scien-
tist scheme. Department of Chemistry, Faculty of Science, Banaras
Hindu University, Varanasi India is acknowledged for departmental
facilities.
p
p
works between donor–acceptor systems. The distances between
24th proton of phenyl ring and centroids of phthalimide 5- and
6-membered rings of two different molecules are 3.116 Å
(136.48°) and 3.012 Å (100.79°), respectively. Also, the H(2) of
phthalimide is only 3.439 Å apart from centroid of pyrazole which
is perpendicularly placed to it indicating that both the phenyl
ring and phthalimide moiety of different molecules of (2) are in
close proximity. H(2) of phthalimide is interacting with N(2)
and N(3) of pyrazole of different molecules with bond distances
and angles of 3.689 Å (82.30°) and 3.811 Å (72.67°). The OC2H5
side arm protons H(17 C) and H(16B) were also influenced by
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.molstruc.2008.12.063.
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