Synthesis and an evaluation of molecular conformation and crystal packing in two substituted 4-phenylquinolines

Article abstract of DOI:10.1007/s10870-012-0284-y

The title compounds, namely Methyl 2-methyl- 4 -phenylquinoline-3- carboxylate (I), C₁₈H₁₅NO₂, and (2E)-3-(3,4-dimethoxyphenyl)-1-(2-methyl-4 -phenylquinolin- 3-yl)prop-2-en-1-one (II), C₂₇H₂₃NO₃, comprising of the phenyl ring, exhibit differences in conformational behaviour with respect to the plane of the quinoline fragment. (I) contains the methyl ester moiety whereas (II) contains the chalcone fragment, consisting of a double bond and phenyl group containing dimethoxy groups as substituents. The dihedral angles between the phenyl group and the quinoline ring is 82.77 (7)° in (I), and 79.02 (8)° in (II) respectively. It is the weak C-H···O=C H-bond and C-H··· π interactions which dictate packing of molecules in (I). In (II), it is C-H···N and C- H··· π, involving the dimethoxy ring, which controls packing of molecules in the crystal lattice. In addition, p·· ·p aromatic stacking interactions involving the quinoline fragment is present in all the molecules. Springer Science+Business Media, LLC 2012.

Full text of DOI:10.1007/s10870-012-0284-y

J Chem Crystallogr (2012) 42:583–587
DOI 10.1007/s10870-012-0284-y
ORIGINAL PAPER
Synthesis and an Evaluation of Molecular Conformation
and Crystal Packing in Two Substituted 4-Phenylquinolines
•
S. Sarveswari R. Prasath P. S. Mathew
•
•
•
Deepak Chopra T. Narasimhamurthy
•
V. Vijayakumar
Received: 5 December 2011 / Accepted: 7 February 2012 / Published online: 1 March 2012
Ó Springer Science+Business Media, LLC 2012
Abstract The title compounds, namely Methyl 2-methyl-
4 -phenylquinoline-3-carboxylate (I), C18H15NO2, and
(2E)-3-(3,4-dimethoxyphenyl)-1-(2-methyl-4 -phenylquin-
olin-3-yl)prop-2-en-1-one (II), C27H23NO3, comprising of
the phenyl ring, exhibit differences in conformational
behaviour with respect to the plane of the quinoline frag-
ment. (I) contains the methyl ester moiety whereas (II)
contains the chalcone fragment, consisting of a double
bond and phenyl group containing dimethoxy groups as
substituents. The dihedral angles between the phenyl group
and the quinoline ring is 82.77 (7)° in (I), and 79.02 (8)° in
(II) respectively. It is the weak C–HÁÁÁO=C H-bond and
C–HÁÁÁp interactions which dictate packing of molecules in
(I). In (II), it is C–HÁÁÁN and C–HÁÁÁp, involving the
dimethoxy ring, which controls packing of molecules in the
crystal lattice. In addition, pÁÁÁp aromatic stacking inter-
actions involving the quinoline fragment is present in all
the molecules.
Introduction
The treatment of different diseases today involves the
screening of small organic molecules for their biological
activity which finds subsequent applications as compounds
for therapeutic purposes. One such dangerous disease is
malaria, which affects half of the world population. People
living in tropical and subtropical areas are most affected by
this disease (e.g. [1, 2]). A large number of molecules
namely chloroquine, mefloquine, primaquine and amodia-
quine [3] are used for the prevention and treatment of
malaria. All these contain the quinoline ring, a functional
group which has been most effective for malarial therapy.
This nucleus is found in many organic molecules, either
synthetic or natural and exhibiting a wide range of phar-
macological activities, such as anti-viral, anti-cancer, anti-
bacterial, anti-fungal, and anti-inflammatory activities (e.g.
[4–7]) and are valuable reagents for the synthesis of nano
and mesostructures with enhanced electronic and photonic
properties [8].
Keywords Phenylquinolines Á Molecular conformation Á
Intermolecular interactions Á Hydrogen bonds
In view of clinical applications of these classes of
compounds, single crystal structure determinations and the
subsequent supramolecular perspectives have been delin-
eated in detail in substituted chloroquinine [9] and related
biologically active phosphate compounds exhibiting anti-
malarial activity [10]. A majority of these structures con-
tain a molecular skeleton corresponding to the 4-quinoline
moiety. The molecular skeleton is divided into three parts,
namely the quinoline ring, the phenyl ring and most of the
crystallographic investigations involve varying substituents
on the quinoline fragment (Scheme 1).
S. Sarveswari Á R. Prasath Á P. S. Mathew Á V. Vijayakumar
Organic Chemistry Division, School of Advanced Sciences,
VIT University, Vellore 632 014, Tamil Nadu, India
D. Chopra (&)
Department of Chemistry, Indian Institute of Science Education
and Research Bhopal, ITI (Gas Rahat Building), Bhopal 462
023, Madhya Pradesh, India
e-mail: dchopra@iiserbhopal.ac.in
In the current article, we report the crystal and molec-
ular structure of 4-phenyl-quinoline containing methyl
and methyl ester moiety in (I), and the chalcone frag-
ment containing dimethoxy groups in (II). The chalcone
T. Narasimhamurthy
Materials Research Centre, Indian Institute of Science,
Bangalore 560012, Karnataka, India
123

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J Chem Crystallogr (2012) 42:583–587
Data Collection and Refinement
Single crystal X-ray diffraction data were collected on a
Bruker AXS SMART APEX CCD diffractometer using
˚
graphite monochromated MoKa (k = 0.7107 A) radiation
at 290(2) K and the intensities were measured using x scan
with a scan width of 0.3°. A total of 606 frames per set
were collected in different settings of / (/ = 0°, 90° and
180° if the system is monoclinic; / = 0°, 90°, 180°)
keeping the sample to detector distance of 6.03 cm. The
data were reduced by SAINTPLUS [11] and an empirical
absorption correction was applied using the package
SADABS [11] available in the Bruker software package.
All the crystal structures were solved by direct methods
using SIR92 [12] and refined by full matrix least squares
method using SHELXL97 [13] present in the program suite
WinGX (Version 1.63.04a) [14]. All the H-atoms were
positioned geometrically and refined using a riding model
Scheme 1 Molecular structure of the investigated compounds
functionality is also biologically very potent and exhibits
broad range of biological activites. All the related functions
along with crystallographic investigations involving chal-
cones are summarized in an article [20]. It is of interest to
investigate structurally two highly relevant biological
fragments in the same molecule for their molecular
geometry and packing preferences in crystalline solids. In
the light of the above mentioned statements, we present in
this article, the pertinent structural highlights obtained
from crystallographic investigations performed on com-
pounds (I)–(II).
˚
with d(C–H) = 0.93/0.96 A, Uiso = 1.2–1.5 Ueq (C) for
aromatic, methyl hydrogens. ORTEP diagrams of all the
compounds were generated using ORTEP32 [15] and
packing diagrams were generated using CAMERON [16]
available in the WinGX program suite and MERCURY
[17]. Geometrical calculations were done using PARST95
[18] and PLATON [19]. Crystallographic data (excluding
structure factors) for the structural analysis has been
deposited with the Cambridge Crystallographic Data Cen-
tre, Nos. CCDC-856600 (I), and CCDC-856601 (II).
Copies of this information may be obtained free of charge
from: The Director, CCDC, 12 Union Road, Cambridge,
CB2 1EZ, UK, e-mail:deposit@ccdc.cam.ac.uk, or
www.ccdc.cam.ac.uk.
Experimental
Synthesis
The title compound was synthesized by the following
procedures.
(I): A mixture of 2-aminobenzophenone (1.9 g, 0.01 M)
and methyacetoacetate (1.2 g, 0.01 M) with 0.15 ml con-
centrated HCl taken in a beaker was subjected to microwave
irradiation (240 W) for about 6 min. After completion of
the reaction (TLC), the reaction mixture was washed with
saturated NaHCO3 solution (10 ml), dried, washed with
petroleum ether and re crystallized with chloroform (Yield:
74%; M.P: 408–411 K; IR data (in cm-1): 1703 (C=O
stretching frequency), 1198 (C–O stretching frequency of
O–CH3 group). The observed crystals were colourless and
block morphology was observed.
Results and Discussion
Table 1 highlights the relevant crystallographic data. Fig-
ures 1 and 2 depicts the atom-numbering scheme for all the
compounds of current investigation. Figures 3 and 4
depicts the corresponding packing diagrams of all the
molecules for (I) and (II) in the unit cell.
(II): A mixture of 3-acetyl-2-methyl-4-phenylquinoline
(2.6 g 0.01 M) and 3,4-dimethoxybenzaldehyde (1.66 g,
0.01 M) and a catalytic amount of KOH in distilled ethanol
was stirred for about 24 h, the resulting mixture was con-
centrated to remove ethanol then poured on to ice and
neutralized with dilute acetic acid. The resultant solid was
filtered, dried and purified by column chromatography
using 1:1 mixture of ethyl acetate and petroleum ether and
recrystallized from acetone (Yield: 66%; M.P: 412–413 K:
IR data (in cm-1): 1638 (stretching frequency of C=O for
a, b- unsaturated ketone), 1588 (C=C stretching frequency
for a, b- unsaturated ketone). Block shaped colorless
crystals were obtained.
In (I), the torsion angle C18–C9–C8–C10, between the
ester moiety and methyl fragment is 2.1 (2)°. The ester
group makes a torsion of 74.5 (2)° with the quinoline
moiety. The crystal structure is stabilized by weak, yet
highly directional C–HÁÁÁO hydrogen bonds (involving
H15) and C–HÁÁÁp interactions (involving H12) of the
4-phenyl ring forming dimeric motifs in the solid state
(Fig. 3; Table 2). There exists pÁÁÁp interactions between
the quinoline motifs, the stacking distance being 3.8671
˚
(19) A. In (II), the torsion C17–C9–C8–C10 is -2.4 (3)°
between the chalcone fragment and the methyl group. The
˚
configuration of the C18=C19 double bond [1.329 (2) A] is
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J Chem Crystallogr (2012) 42:583–587
585
Fig. 3 Packing diagram in (I) depicting C–HÁÁÁO and C–HÁÁÁp
interaction dimers. The molecules at ‘i’ and ‘ii’ have the symmetry
code (-x, -y ? 1, -z ? 2) and (-x ? 2, -y, -z ? 1). Cg2 depicts
the center of gravity of the six-membered phenyl ring C1/C6.
Hydrogen atoms not taking part in the interaction have been omitted
for clarity
Fig. 1 The structure of (I) showing the atom-numbering scheme.
Displacement ellipsoids are drawn at 50% probability level
Fig. 2 The structure of (II) showing the atom-numbering scheme.
Displacement ellipsoids are drawn at 50% probability level
E and the chalcone residue is approximately perpendicular
to the quinolinyl residue, the torsion angle C7–C8–C10–
C18 being -93.91 (19)°. The packing is dictated by weak
but linear C–HÁÁÁN hydrogen bonds, involving H14, form-
ing chains along the crystallographic [110] direction along
with C–HÁÁÁp interactions, involving H21 and the 4-phenyl
ring, forming chains along a axis (Fig. 4; Table 2). Aro-
matic pÁÁÁp interactions between the quinoline motifs is
Fig. 4 Packing diagram in (II) depicting C–HÁÁÁN and C–HÁÁÁp
interactions. Molecules at i and ii are located at (x ? 1, y ? 1, z) and
(x ? 1, y, z). Cg3 depicts the center of gravity of the six-membered
phenyl ring C11/C16. Hydrogen atoms not taking part in the
interaction have been omitted for clarity
˚
also present, the stacking distance being 3.7991 (10) A.
along with absence of bis-methoxy group followed by
presence of a chlorine atom in the 6-position. The quino-
line ring forms a dihedral angle of 62.53(5)° with the
benzene ring. The torsion angle between the keto group of
the chalcone fragment and methyl group is approximately
5.2°. Structurally related compounds containing the chal-
cone moiety along with different functional groups have
also been recently reported in the literature [24–30].
Such interactions involving the p-rings are of significance
in crystal packing and have been investigated both from an
experimental and theoretical perspective [21, 22].
A related compound, namely, (2E, 4E)-1-(6-Chloro-
2-methyl-4-phenyl-3-quinolyl)-5-phenylpenta-2,4-dien-1-
one, has also been investigated [23]. It contains a double
bond in conjugation with the C18=C19 double bond in (II)
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J Chem Crystallogr (2012) 42:583–587
Table 1 Crystal data, data
collection and structure
refinement
Compound
I
II
Formula
C18H15NO2
0.2 9 0.2 9 0.15
277.31
C27H23NO3
0.3 9 0.2 9 0.10
409.46
Size of crystal (mm)
Formula weight
Crystal System
Space group
T(K)
Triclinic
Monoclinic
P21/n
P-1
292(2)
292(2)
˚
a(A)
8.9412 (2)
9.2235 (2)
10.7903 (2)
6.2373(2)
8.5718(3)
2162.36(12)
˚
b(A)
˚
c(A)
3
˚
a (°), b(°), c(°), V (A )
73.026 (1)°, 66.519 (1)°, 63.341 (1)°,
722.43 (3)
90, 90.961(2), 90,
2162.36(12)
Z
2
4
Dx (g cm-3
)
1.275
1.258
864
F(000)
292
l(mm-1
h range (°)
h, k, l range
)
0.083
0.082
2.0, 26.0
2.5, 26.0
(-11, 11), (-11, 11), (-13, 13)
(-7, 7), (-10, 10),
(-49, 49)
Reflections Collected
11521
34511
Unique Reflections(Rint
)
2798 (0.0164)
2208
4261(0.0505)
3057
Observed Reflections (with
I [ 2r(I))
Number of Parameters
R_obs, R_all
192
283
0.0432, 0.0568
0.1121, 0.1248
1.031
0.0450, 0.0702
0.1043, 0.1183
1.017
wR2_obs, wR2_all
G.O.F
-3
˚
Dqmax, min (e A
)
0.168, -0.141
0.205, -0.168
Table 2 List of H-bonding geometry
D
H
A
D–H
HÁÁÁA
DÁÁÁA
D–HÁÁÁA
Symmetry code
I
C15
C12
C14
C21
H15
H12
H14
H21
O1
0.93
0.93
0.93
0.93
2.81
2.85
2.60
2.74
3.733(2)
3.648(2)
3.518(3)
3.837(2)
173
144
171
162
(-x, -y ? 1, -z ? 2)
(-x ? 2, -y, -z ? 1).
(x ? 1, y ? 1, z)
Cg2
N1
II
Cg3
(x ? 1, y, z)
A search of the Cambridge Structural Database (CSD,
hydrogens on the carbon atom (part of the cyclic ring
system) with the hydrogens ortho to the carbon atom of the
phenyl ring. In case of the five membered ring, the ring size
being smaller results in decreased steric interactions and
hence greater flexibility with respect to rotation about the
C–C bond connected to the phenyl ring. These values are
also comparable with those reported for compounds
(I)-(II). The determination of the molecular conformation
for compounds reported in references [22] and [23]
essentially has the same chalcone moiety [with different
substitutions] and phenyl ring [no substitution], wherein
the dihedral angles between the phenyl ring with the
Version 5.31, November 2009) performed for search-
ing the structures containing the 6-chloro-4-phenyl-
quinoline moiety, gave three hits. The compounds are
6-Chloro-10-phenyl-1,2,3,4-tetrahydroacridine [31], 2,3-
Trimethylene-4-phenyl-6-chloroquinoline [32], and 2-Chloro-
12-phenyl-6,7,8,9,10,11-hexahydrocycloocta(b)quinoline [33]
containing cyclohexene, cyclopentene and cyclooctene ring
in the 2,3-position of the quinoline ring. The torsion angles
between the phenyl and the quinoline ring are 73°, 62° and
77° in the three related compounds, respectively. This is
because of the increased steric interactions between the
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quinoline ring vary between 54° and 88°. The differences
essentially stem from the different intermolecular interac-
tions which govern crystal packing when a different
functional group is introduced on a fixed molecular scaf-
fold. In fact this forms the basis of the problem of crystal
engineering wherein the importance of weak interactions in
dictating molecular conformation in organic solids is
realised. The chalcone moiety is close to being orthogonal
[dihedral angle varies from 70° to 105°] with respect to the
plane of the quinoline ring, indicating free rotation about
the C–C bond to minimize steric interaction of the methyl
hydrogens with the hydrogen atoms of the conjugated
double bond of the chalcone moiety.
In conclusion, it is of interest to investigate molecular
conformation, strong and weak intermolecular H-bonds
along with Van der Waals interactions operating between
different functional groups present in an organic solid.
Such studies provide suitable pointers to the fact that all the
above-mentioned factors are significant to decide the
overall packing of molecules in the crystal lattice. These
are again of importance during docking processes (protein–
ligand interactions) as both are events of molecular
recognition.
Acknowledgments We thank the Department of Science and
Technology, the funding agency for supporting the CCD facility at
IISc Bengaluru for data collection on the instrument under the
IRHPA-DST program. The authors DC and VV are grateful to
DST-India for funding through the Young Scientist Scheme (Fast
Track Proposal).
26. Prasath R, Sarveswari S, Vijayakumar V, Narasimhamurthy T,
Tiekink ERT (2010) Acta Cryst E66:o1110
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Tiekink ERT (2010) Acta Cryst E66:o3284
29. Shahani T, Fun HK, Sarveswari S, Vijayakumar V, Ragavan RV
(2010) Acta Cryst E66:o374
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