Crystal and molecular structure analysis of (2-((6-Chloro pyridin-3-yl)methoxy)-5-methylphenyl)(p-tolyl)Methanone

Article abstract of DOI:10.1080/15421400903359116

The title compound, (2-((6-chloropyridin-3-yl)methoxy)-5-methylphenyl)(p- tolyl) methanone, was synthesized and characterized spectroscopically and finally confirmed by (XRD) study. The title compound crystallizes in the monoclinic space group P21/c with

Full text of DOI:10.1080/15421400903359116

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Crystal and Molecular
Structure Analysis of (2-
((6-Chloro pyridin-3-
yl)methoxy)-5-methylphenyl)
(p-tolyl)Methanone
B. N. Lakshminarayana a , J. Shashidhara Prasad a ,
T. D. Venu b , B. K. Manuprasad b , M. A. Sridhar a &
Sheena Shashikanth b
a Department of Studies in Physics , University of
Mysore , Mysore, India
b Department of Studies in Chemistry , University of
Mysore , Mysore, India
Published online: 17 Dec 2009.
To cite this article: B. N. Lakshminarayana , J. Shashidhara Prasad , T. D. Venu , B.
K. Manuprasad , M. A. Sridhar & Sheena Shashikanth (2009) Crystal and Molecular
Structure Analysis of (2-((6-Chloro pyridin-3-yl)methoxy)-5-methylphenyl)(p-
tolyl)Methanone, Molecular Crystals and Liquid Crystals, 515:1, 207-214, DOI:
10.1080/15421400903359116
To link to this article: http://dx.doi.org/10.1080/15421400903359116
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Mol. Cryst. Liq. Cryst., Vol. 515, pp. 207–214, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 1542-1406 print=1563-5287 online
DOI: 10.1080/15421400903359116
Crystal and Molecular Structure Analysis of
(2-((6-Chloro pyridin-3-yl)methoxy)-5-methylphenyl)
(p-tolyl)Methanone
B. N. Lakshminarayana1, J. Shashidhara Prasad1,
T. D. Venu2, B. K. Manuprasad2, M. A. Sridhar1,
and Sheena Shashikanth2
1Department of Studies in Physics, University of Mysore, Mysore, India
2Department of Studies in Chemistry, University of Mysore, Mysore,
India
The title compound, (2-((6-chloropyridin-3-yl)methoxy)-5-methylphenyl)(p-tolyl)
methanone, was synthesized and characterized spectroscopically and finally con-
firmed by (XRD) study. The title compound crystallizes in the monoclinic space
˚
˚
˚
group P21=c with cell parameters a ¼ 9.4420(1) A, b ¼ 7.9810(6) A, c ¼ 23.777(4) A,
a ¼ 90 , b ¼ 90.883(3) , c ¼ 90 , V ¼ 1791.5(4) Aꢁ3, and Z ¼ 4. The structure exhibits
ꢀ
ꢀ
ꢀ
˚
intermolecular hydrogen bond of the type CꢁH ꢂ ꢂ ꢂ O.
Keywords: anti-cancer; anti-inflammatory; benzophenone; crystal structure; pyridine
ring
INTRODUCTION
Functionalized phenols, such as 2-hydroxy benzophenones, represent
important building blocks in organic [1] and medicinal chemistry [2].
Benzophenone is a prototypical aromatic carbonyl compound that has
been extensively studied [3]. The great importance of these substances
is fundamentally due to the diverse biological and chemical properties
that they possess [4–13]. Benzophenones are usually obtained from
natural products [14–17] or by synthetic methods. Subsequently,
benzophenones are frequently used in medicine and industry [18,19].
The proficiency of benzophenone analogues as chemotherapeutic
agent, especially as anti-inflammatory, is well documented [20].
Benzophenone analogues which are synthesized by several scientists
Address correspondence to Prof. J. Shashidhara Prasad, Department of Studies
in Physics, Manasagangotri, University of Mysore, Mysore 570 006, India. Fax:
þ91-821-2419333. E-mail: jsp@physics.uni-mysore.ac.in
207

208
B. N. Lakshminarayana et al.
have been reported as effective anti-inflammatory agents [21–24].
Recently, synthesis and structural activity relationship of benzophe-
nones as novel class of p38 MAP kinase inhibitors with high anti-
inflammatory activity have been reported [25]. The in-vitro and in-vivo
studies of novel nitro and amino substituted benzophenones have been
investigated as potential anticancer agents with low cytotoxicity [26].
These observations and our exploration for new molecules with
anti-inflammatory activity, encouraged us to integrate 2-chloro-5-
chloromethyl pyridine moiety in benzophenone framework, since these
systems possess well-documented anti-inflammatory activity.
EXPERIMENTAL
Synthesis of (2-((6-Chloropyridin-3-yl)methoxy)-
5-methylphenyl)(p-tolyl)methanone
4-Methyl-benzoic acid 4-methyl-phenyl ester (3) was synthesized
by benzoylation of 4-methyl-phenol (1) with 4-methyl benzoyl
chloride (2) using 10% sodium hydroxide solution. (5-Methyl-2-
hydroxy-phenyl)-(4-methyl-phenyl)-methanone (4) was synthesized
by Fries rearrangement of the above ester in presence of anhydrous
aluminium chloride. A mixture of 4 (1 g, 4.41 mM) and 2-chloro-5-chlor-
omethyl pyridine (0.95 g, 4.41 mM) was refluxed in dry acetonitrile for
5 h, in presence of anhydrous potassium carbonate (1.83 g, 13.25 mM).
When the reaction was completed (TLC), the reaction mass was cooled,
and the solvent was removed under reduced pressure. The residual
mass was triturated with ice-cold water to remove potassium carbonate
and then extracted with dichloromethane (3 ꢃ 20 ml). The organic layer
was washed with 10% sodium hydroxide solution (3 ꢃ 10 ml) followed
with water wash (3 ꢃ 15 ml) and then dried over anhydrous sodium
sulfate and evaporated to dryness under reduced pressure to obtain
the crude solid, which upon recrystallization with ethanol afforded
(2-((6-chloropyridin-3-yl) methoxy)-5-bromophenyl) (4-chlorophenyl)
methanone (5) as pale yellow crystals, in good yield. A schematic
diagram of the molecule is shown in Figure 1.
ꢁ1
1
Yield 1.40 g (88%): M.p. 165ꢀC; IR (Nujol): 1718 cm (C O); H NMR
(CDCl3): d 2.31(s, 3 H, CH3), 2.41(s, 3 Hm CH3), 4.91 (s, 2 H, CH2),
6.70–8.71 ppm (m, 10 H, J ¼ 7 Hz, Ar-H). Anal. Calc. for C21H18ClNO2:
C, 71.69; H, 5.16; N, 3.98. Found: C, 71.68; H, 5.13; N, 3.98%.
=
CRYSTAL STRUCTURE DETERMINATION
Single crystals of suitable size were chosen for X-ray diffraction (XRD)
studies. The data were collected at room temperature on a DIPLabo

Crystal and Molecular Structure
209
SCHEME 1 Schematic diagram of the molecule.
Image Plate system with graphite monochromated radiation MoKa.
Each exposure of the image plate was set to a period of 400 s. Thirty-six
frames of data were collected in the oscillation mode with an oscillation
range of 5ꢀ and processed using Denzo [27]. The reflections were

210
B. N. Lakshminarayana et al.
merged with Scalepack. All the frames could be indexed using a
primitive monoclinic lattice. The structure was solved by direct
methods using SHELXS-97 [28]. Least-squares refinement using
SHELXL-97 [28] with isotropic displacement parameters for all the
non-hydrogen atoms converged the residual to 0.1659. Subsequent
refinements were carried out with anisotropic thermal parameters
for non-hydrogen atoms. After eight cycles of refinement the residuals
converged to 0.0583. The hydrogen atoms were fixed at chemically
acceptable positions and were allowed to ride on their parent atoms.
RESULTS AND DISCUSSION
The details of crystal data and refinement are given in Table 1. The
bond lengths and bond angles of all the non-hydrogen atoms are given
TABLE 1 Crystal Data and Structure Refinement Table
CCDC Deposition Number
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
CCDC 719332
21H18NO2Cl
351.81
C
293(2) K
˚
0.71073 A
Monoclinic
P21=c
˚
Cell dimensions
a ¼ 9.4420(15) A
˚
b ¼ 7.9810(6) A
˚
c ¼ 23.777(4) A
b ¼ 90.883(3)
3
˚
Volume
1791.5(4) A
Z
4
Density (calculated)
Absorption coefficient
F000
1.304 Mg=m3
0.227 mmꢁ1
736
Crystal size
Theta range for data collection
Index ranges
0.3 ꢃ 0.27 ꢃ 0.25 mm
2.69ꢀ to 25.02ꢀ
ꢁ9 ꢄ h ꢄ 9
ꢁ8 ꢄ k ꢄ 7
ꢁ28 ꢄ l ꢄ 28
Reflections collected
4451
Independent reflections
Absorption correction
Refinement method
Data=restraints=parameters
Goodness-of-fit on F2
Final R indices [I > 2r(I)]
R indices (all data)
2500 [R(int) ¼ 0.0254]
None
Full-matrix least-squares on F2
2500=0=230
1.073
R1 ¼ 0.0583, wR2 ¼ 0.1599
R1 ¼ 0.0729, wR2 ¼ 0.1775
0.020(5)
Extinction coefficient
Largest diff. peak and hole
ꢁ3
˚
0.186 and ꢁ0.274 e ꢂ A

Crystal and Molecular Structure
211
ꢀ
˚
TABLE 2 Selected Bond Lengths (A) and angles ( )
Atoms
Length
Atoms
Length
Cl16ꢁC13
O18ꢁC17
O8ꢁC3
1.737(3)
1.224(3)
1.375(3)
1.413(4)
1.315(5)
1.482(4)
1.385(4)
C2ꢁC17
1.500(4)
1.364(4)
1.373(4)
1.385(4)
1.340(4)
1.384(4)
C10ꢁC15
C10ꢁC11
C23ꢁC22
N14ꢁC15
C1ꢁC6
O8ꢁC9
N14ꢁC13
C19ꢁC17
C2ꢁC1
C3ꢁO8ꢁC9
119.0(2)
120.5(2)
121.2(2)
107.8(2)
124.8(3)
115.5(2)
119.2(3)
119.5(3)
121.0(2)
119.3(2)
C20ꢁC19ꢁC17
C24ꢁC19ꢁC17
O8ꢁC9ꢁC10
O8ꢁC3ꢁC4
C13ꢁN14ꢁC15
C6ꢁC1ꢁC2
116.4(3)
121.8(3)
124.1(3)
116.3(3)
119.6(3)
121.0(3)
121.2(2)
124.5(3)
119.7(2)
N14ꢁC13ꢁC12
N14ꢁC13ꢁCl16
C12ꢁC13ꢁCl16
C23ꢁC22ꢁC25
C3ꢁC2ꢁC17
O8ꢁC3ꢁC2
C1ꢁC2ꢁC3
C1ꢁC2ꢁC17
O18ꢁC17ꢁC19
O18ꢁC17ꢁC2
N14ꢁC15ꢁC10
C19ꢁC17ꢁC2
in Table 2, which are in good agreement with the standard values.
Figure 2 represents the ORTEP [29] diagram of the molecule with
thermal ellipsoids drawn at 50% probability.
In the title compound, (2-((6-chloropyridin-3-yl)methoxy)-5-methyl
phenyl)(p-tolyl) methanone, the ring twist angle of 70.29(1)ꢀ between
the phenyl rings bridged by the keto carbonyl is less compared with
the corresponding value of 83.72(6)ꢀ reported for [2-amino-20,5-
dichlorobenzophenone] [30], and high as compared with other reported
compounds [30]. The dihedral angle between the pyridine ring and
phenyl ring (C19ꢁC20ꢁC21ꢁC22ꢁC23ꢁC24) is 82.97(1)ꢀ, which
FIGURE 1 Schematic diagram of the title compound.

212
B. N. Lakshminarayana et al.
FIGURE 2 ORTEP of the molecule with thermal ellipsoids drawn at 50%
probability.
shows that it is an indication of equatorial conformation. The pyridine
ring is at axial position to the phenyl ring (C1ꢁC2ꢁC3ꢁC4ꢁC5ꢁC6)
as indicated by the dihedral angle of 16.22(1)ꢀ between them. The bond
˚
=
length O18 C17 ¼ 1.244(3) A is comparable with other reported com-
pounds [30]. Another indication of the conformation is the values of
the torsion angles for C1ꢁC2ꢁC17ꢁO18 and C20ꢁC19ꢁC17ꢁO18
are 53.5(4)ꢀ and 24.4(4)ꢀ, respectively, and these values vary with
the other reported compounds [30]. For benzophenone, these torsion
angles take the same sign and are each reported to be 30% in energy
minimized benzophenones [31]. The C9ꢁO8 bond is in an
þanti-periplanar conformation, as indicated by the torsion angle value
of 174.2(3)ꢀ for C10ꢁC9ꢁO8ꢁC3. The structure exhibits an intermole-
cular hydrogen bond of the type CꢁH ꢂ ꢂ ꢂ O which holds the molecules
together in the crystal lattice resulting in a hydrogen bonded dimer as
shown in Fig. 3. The intermolecular hydrogen bond C23ꢁH23 ꢂ ꢂ ꢂ O18
is between the central methyl phenyl ring and the keto carbonyl
˚
group. The C23ꢁH23 ꢂ ꢂ ꢂ O18 has a distance of 0.93 A and a distance
˚
˚
of 2.51 A to the acceptor atom with a bond length of 3.427(4) A and a
bond angle of 167ꢀ with symmetry code x, 1 þ y, z.

Crystal and Molecular Structure
213
FIGURE 3 Packing of the molecules down a axis.
ACKNOWLEDGMENTS
The authors are grateful to DST and Government of India project SP=
I2=FOO=93 and University of Mysore, Mysore for financial assistance.
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