Synthesis and crystal structure analysis of substituted 2-(3-(hydroxymethyl)quinolin-2-yl)phenol derivatives

Article abstract of DOI:10.1016/j.molstruc.2012.02.054

Two novel quinoline derivatives e.g. 2-(3-(hydroxymethyl)-7-methylquinolin- 2-yl)phenol (1) and 2-(3-(hydroxymethyl)-6-methoxyquinolin-2-yl)phenol (2) were synthesized. These compounds were characterized by IR, ¹H NMR and mass spectroscopy. The

Full text of DOI:10.1016/j.molstruc.2012.02.054

Journal of Molecular Structure 1016 (2012) 126–133
Contents lists available at SciVerse ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis and crystal structure analysis of substituted
2-(3-(hydroxymethyl)quinolin-2-yl)phenol derivatives
D. Rambabu a,b, G. Rama Krishna c, Srinivas Basavoju d, M.V. Basaveswara Rao e, C. Malla Reddy c,
Manojit Pal a,
⇑
a Institute of Life Sciences, University of Hyderabad Campus, Hyderabad 500 046, Andhra Pradesh, India
b Department of Chemistry, K.L. University, Vaddeswaram, Guntur 522 502, Andhra Pradesh, India
c Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, West Bengal 741 252, India
d Department of Chemistry, National Institute of Technology (NIT), Warangal 506 004, Andhra Pradesh, India
e Department of Chemistry, Krishna University, Machilipatnam 521 001, Andhra Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Two novel quinoline derivatives e.g. 2-(3-(hydroxymethyl)-7-methylquinolin-2-yl)phenol (1) and 2-(3-
(hydroxymethyl)-6-methoxyquinolin-2-yl)phenol (2) were synthesized. These compounds were charac-
terized by IR, 1H NMR and mass spectroscopy. Thermal analyses (DSC and TGA) and PXRD patterns were
collected for the supporting data. Finally the crystal structures were solved by single crystal X-ray diffrac-
tion data and the structures were analyzed in terms of supramolecular interactions. Compound 1 consists
of two symmetry independent molecules in the asymmetric unit. These two molecules are conformational
isomers (A and B) and form different hydrogen bonding in the crystal structure. The Hirshfeld surfaces and
associated 2D fingerprint plots were analyzed to differentiate the two conformers (A and B). Compound 2
form a helical structure with O–Hꢀ ꢀ ꢀO and O–Hꢀ ꢀ ꢀN hydrogen bond synthons along the c-axis.
Ó 2012 Elsevier B.V. All rights reserved.
Received 24 December 2011
Received in revised form 19 February 2012
Accepted 21 February 2012
Available online 3 March 2012
Keywords:
2-(3-(Hydroxymethyl)quinolin-2-yl)phenol
derivatives
Spectroscopic characterization
Single crystal X-ray diffraction
Supramolecular interactions
Conformational isomers
Helical structure
1. Introduction
rial and antituberculosis activities when tested in vitro. Their
screening results revealed that all the compounds showed
The quinoline core is considered as a key pharmacophore respon-
sible for the diverse pharmacological properties demonstrated by
quinoline derivatives. Thus a wide variety of quinoline derivatives
have been prepared and evaluated for their anticancer, antimyco-
bacterial, antimicrobial, anticonvulsant, anti-inflammatory and car-
diovascular activities [1]. Various quinoline alkaloids such as
quinine, chloroquine, mefloquine and amodiaquine have been used
as effective drugs for the treatment of malaria [2]. Development of
resistance by plasmodia parasites has compromised the widespread
use of these antimalarial drugs. Aryl substitution at C-2 position of
the quinoline ring has been reported to induce good antibacterial
activity [3,4]. These derivatives were found to be useful biological
synthons and have attracted much attention in the development
of new drugs [5,6]. In addition, they are ideally suitable for further
modifications to obtain more efficacious antibacterial and antitu-
berculosis agents.
moderate to very good activity against pathogenic strains such as
Escherichia coli (ATTC-25922), Staphylococcus aureus (ATTC-
25923), Pseudomonas aeruginosa (ATCC-27853), Klebsiella pneumo-
niae and Mycobacterium tuberculosis H37Rv [7]. Kategaonkar et
al., reported the synthesis and biological evaluation of 2-chloro-
3-((4-phenyl-1H-1,2,3-triazol-1-yl)methyl)quinoline derivatives
via click chemistry approach [8]. These molecules were evaluated
in vitro for their antifungal and antibacterial activities. Most of
these compounds displayed significant activities against all the
tested strains. Quinoline derivatives, protoberbines and 8-oxober-
bines are known to possess biological properties such as antineo-
plastic activity [9]. The potent antitumor agents e.g. Dynamicin A
and Virantmycin are important natural products containing the
quinoline core [10]. Ahmed et al. synthesized the naturally occur-
ring quinolone alkaloids and their inhibitory properties (antiprolif-
erative activity) were evaluated against CEM-GFP cells [11]. These
results have attracted the attention to synthesize the quinoline
derivatives.
Recently, Sumesh et al., reported the synthesis and evaluation of
1,3-oxazolo[4,5-c]quinoline derivatives which showed antibacte-
Recently,
(Scheme 1) has been reported to exhibit significant cytotoxic
activities when tested in vitro (IC50 = 42.5 and 47.4 g/mL on HeLa
(2-chloro-6-methoxyquinolin-3-yl)methanol,
8
⇑
Corresponding author. Tel.: +91 40 66571633.
E-mail address: manojitpal@rediffmail.com (M. Pal).
l
0022-2860/$ - see front matter Ó 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.molstruc.2012.02.054

D. Rambabu et al. / Journal of Molecular Structure 1016 (2012) 126–133
127
Scheme 1. Synthesis of compounds 1 and 2.
and Vero cells, respectively) [12]. Due to our continuing interest
2.4. Infrared spectroscopy
in the identification of quinoline derivatives as cytotoxic agents
we became interested to prepare the derivatives of compound 8
such as compound 9 (Scheme 1) for in vitro pharmacological eval-
uation. Herein, we report the synthesis and characterization of 2-
(3-(hydroxymethyl)-7-methylquinolin-2-yl)phenol (1) and 2-(3-
(hydroxymethyl)-6-methoxyquinolin-2-yl)phenol (2) along with
their single crystal X-ray analysis data.
Jasco FT–IR 4200 (Easton, Maryland) type-A Fourier transform
infrared spectrophotometer was used to record the IR spectra of
the samples (sample concentration is 2 mg in 20 mg of KBr). The
spectra were recorded over the range of 4000–600 cmꢁ1. Data were
analyzed using spectrum version 2 software (JASCO, Easton, Mary-
land, USA).
2. Experimental
Table 1
2.1. Chemicals
Salient crystallographic data and structure refinement parameters of compounds 1
and 2.
m-Toluidine (4) (purity > 99.8%) and p-anisidine (6) (pur-
ity > 99.8%) were purchased from Aldrich Co. Ltd. 4-Chloro-3-form-
ylcoumarin (3) (purity > 99.8%) was synthesized according to the
literature procedures [13]. All the commercially available reagents
(purity > 99%) were used without further purification. The solvent
THF was dried over sodium-benzophenone before use.
1
2
Empirical formula
Formula weight
Crystal system
Space group
T/K
a/Å
b/Å
c/Å
C
17H15NO2
C17H15NO3
281.30
Tetragonal
I-4
265.30
Monoclinic
P21/c
100(2)
296(2)
16.8103(10)
12.9741(8)
12.9263(8)
90.00
17.4497(7)
17.4497(7)
8.9605(4)
90.00
2.2. General methods
a
/°
b/°
99.911(4)
90.00
8
2777.1(3)
1.269
1120.0
90.00
90.00
8
2728.4(3)
1.370
1184
All reactions were carried out under nitrogen atmosphere. Melt-
ing points were determined on a Büchi B-540 melting point appa-
ratus and are uncorrected. All compounds were routinely checked
by TLC and 1H NMR. TLC was performed on aluminum-backed sil-
ica gel plates (Merck DC, Alufolien Kieselgel 60 F254) with spots
visualized by UV light.
c/°
Z
V/Å3
Dcalc/g/cm3
F(000)
l
/mmꢁ1
0.083
0.094
h/°
2.36–26.99
ꢁ20 ꢂ h ꢂ 20
ꢁ15 ꢂ k ꢂ 15
ꢁ15 ꢂ l ꢂ 15
59,742
1.65–26.99
ꢁ22 ꢂ h ꢂ 22
ꢁ18 ꢂ k ꢂ 22
ꢁ11 ꢂ l ꢂ 11
9762
Index ranges
2.3. 1H and 13C NMR spectroscopy
N-total
1H and 13C NMR spectra were determined in CDCl3, DMSO-d6
and TFA solutions using 400 and 100 MHz spectrometers, respec-
tively. Proton chemical shifts (d) are relative to tetramethylsilane
(TMS, d = 0.0) as internal standard and expressed in parts per mil-
lion. Spin multiplicities are given as s (singlet), d (doublet), t (trip-
let), and m (multiplet) as well as b (broad). Coupling constants (J)
are given in hertz.
N-independent
N-observed
Parameters
Rint
5188
3748
367
0.110
0.0490
0.1443
1.037
826,485
1593
1515
198
0.050
0.0330
0.0904
1.052
R1 (I > 2
r
(I))
wR2 (all data)
GOF
CCDC
826,484

128
D. Rambabu et al. / Journal of Molecular Structure 1016 (2012) 126–133
Table 2
Geometrical Parameters of Hydrogen bonds in 1 and 2.
a
Compound
1
D–Hꢀ ꢀ ꢀA
Dꢀ ꢀ ꢀA (Å)
Hꢀ ꢀ ꢀA (Å)
1.90
1.94
1.94
1.91
2.52
2.42
D–Hꢀ ꢀ ꢀA (°)
170
170
175
169
109
102
Symmetry code
O(1)–H(1)ꢀ ꢀ ꢀO(2)
2.713(2)
2.755(2)
2.759(2)
2.716(2)
2.982(3)
2.761(2)
2.671(2)
2.758(2)
2.778(2)
3.400(3)
ꢁx, 2 ꢁ y, 1 ꢁ z
O(2)–H(2)ꢀ ꢀ ꢀN(1)
ꢁx, 1/2 + y, 3/2 ꢁ z
O(3)–H(3A)ꢀ ꢀ ꢀO(4)
O(4)–H(4A)ꢀ ꢀ ꢀN(2)
Intra C(16)–H(16A)ꢀ ꢀ ꢀO(1)
Intra C(20)–H(20)ꢀ ꢀ ꢀO(4)
O(1)–H(1)ꢀ ꢀ ꢀO(2)
1 ꢁ x, 1/2 + y, 1/2 ꢁ z
x, 1/2 ꢁ y, 1/2 + z
–
–
2
1.77(3)
1.83(4)
2.43
173(3)
168(4)
102
ꢁy, x, 1 ꢁ z
O(2)–H(2)ꢀ ꢀ ꢀN(1)
1/2 ꢁ y,ꢁ1/2 + x, 1/2 ꢁ z
C(3)–H(3)ꢀ ꢀ ꢀO(2)
–
C(17)–H(17C)ꢀ ꢀ ꢀO(1)
2.58
144
y, ꢁx, ꢁz
a
All of the C–H and O–H distances are neutron normalized to 1.083 and 0.983 Å.
2.5. Differential Scanning Calorimetry (DSC)
Thermal analyses of these samples were performed on a Ther-
mal Advantage DSC Q2000 V9.8 Build 296 (TA Instrument, USA)
module which was calibrated for temperature and cell constants
using indium and sapphire. The instrument was equipped with
refrigerator cooling system (RCS). The crystals (3–5 mg) were
crimped in aluminum pans (non-hermetic) (30 lL) scanned at a
heating rate of 10 °C/min in the range 30–300 °C under a dry nitro-
gen atmosphere (flow rate 50 mL/min). The data were collected by
TA Instruments Universal Analysis 2000 V4.3A software.
2.6. Thermogravimetric Analysis (TGA)
Thermal analyses of these samples were carried out by TA
Instrument (USA) TGA Q5000 module with refrigerator cooling sys-
tem (RCS). The crystals (5–10 mg) were placed in aluminum cruci-
bles (30 lL) under a dry nitrogen atmosphere (flow rate is 25 mL/
min). The data were collected by TI Universal Analysis software.
2.7. Powder X-ray Diffraction (PXRD)
Fig. 1. ORTEP representation of conformers A and B of compound 1. Thermal
ellipsoids are drawn at 50% probability level.
PXRD patterns were collected on a Rigaku D/MAX 2200 (The
Woodlands, Texas) powder diffractometer with a Cu K
a radiation
2.9. Synthesis
(1.54056 Å). The tube voltage and amperage were set at 50 kV
and 34 mA respectively. The divergence slit and antiscattering slit
settings were variable for the illumination on the 20 mm sample
size. Each sample was scanned 3° and 45° in 2h with a step size
of 0.02°. The instrument had previously been calibrated using a sil-
icon standard.
The target compound 1 was prepared following a two-step pro-
cedure, the reaction of 4-chloro-3-formylcoumarin (3) with m-
toluidine (4) being the key step (Scheme 1). Thus 9-methyl-6H-
chromeno[4,3-b]quinolin-6-one (5) was prepared by AlCl3-medi-
ated condensation reaction of 3 with 4 according to a known pro-
cedure [17]. A similar procedure was used for the preparation of
compound 7, by using 3 and 6.
2.8. Single crystal X-ray diffraction
The single-crystal X-ray diffraction data of the crystals were col-
lected on a Bruker Kappa APEX-II CCD DUO diffractometer at
296(2)
K using graphite-monochromated Mo Ka radiation
(k = 0.71073 Å). No absorption correction was applied. The lattice
parameters were determined from least-squares analysis, and
reflection data were integrated using the program SHELXTL [14].
The crystal structures were solved by direct methods using SHEL-
XS-97 and refined by full-matrix least-squares refinement on F2
with anisotropic displacement parameters for non-H atoms using
SHELXL-97 [15]. The OꢁH hydrogens were located from difference
Fourier maps. Aromatic and aliphatic CꢁH hydrogens were gener-
ated by the riding model in idealized geometries. The software
used to prepare material for publication was Mercury 2.3 (Build
RC4), ORTEP-3 and X-Seed [16]. Table 1 gives the pertinent crystal-
lographic data, and Table 2 gives hydrogen bond parameters.
Fig. 2. An overlay diagram of conformers A (blue) and B (purple) of the two
molecules of asymmetric unit of compound 1. It is visible that the two phenyl rings
are not in coplanar with the quinoline moiety. (For interpretation of the references
to colour in this figure legend, the reader is referred to the web version of this
article.)

D. Rambabu et al. / Journal of Molecular Structure 1016 (2012) 126–133
129
Fig. 3. (a and b) Different hydrogen bonding patterns in two symmetry independent molecules (conformers A and B) of asymmetric unit in compound 1.
Spectral data for compound 5, white solid; yield (90%); Rf = 0.60
(30% EtOAc-n-Hexane); m.p. 228–230 °C; 1H NMR (400 MHz,
CDCl3): d 9.12 (s, 1H), 8.77 (dd, J = 8.0 and 1.6 Hz, 1H), 8.14 (d,
J = 8.4 Hz, 1H), 7.76–7.74 (m, 2H), 7.58–7.56 (m, 1H), 7.45–7.38
(m, 2H), 2.59 (s, 3H); 13C NMR (100 MHz, DMSO-d6): d 160.9,
152.8, 150.8, 149.6, 145.1, 140.9, 132.9, 130.3, 129.9, 128.0,
125.8, 125.3, 124.9, 119.8, 117.7, 115.6, 22.3; MS (ES mass): m/z
262.3 (M+1, 100%); IR (KBr) tmax (cmꢁ1): 3449, 3055, 2923, 1735,
1599, 1497, 1462, 1378, 1310, 1188, 900, 826, 754.
Spectral data for compound 7, white solid; yield (91%); Rf = 0.71
(20% EtOAc-n-Hexane); mp 236–238 °C; 1H NMR (400 MHz,
CDCl3): d 9.1 (s, 1H), 8.76 (dd, J = 10 and 1.6 Hz, 1H), 8.14 (d,
J = 9.2 Hz, 1H), 7.60–7.55 (m, 2H), 7.45–7.39 (m, 2H), 7.23 (d,
J = 2.8 Hz, 1H), 3.99 (s, 3H); 13C NMR (100 MHz, TFA): d 159.6,
153.8, 151.6, 147.6, 142.2, 138.9, 134.7, 134.6, 127.2, 124.8,
124.0, 122.1, 121.8, 118.9, 105.9, 105.6, 58.8; MS (ES mass): m/z
278.3 (M+1, 10%); IR (KBr) tmax (cmꢁ1): 3100, 2990, 2836, 1737,
1601, 1496, 1384, 1237, 835, 749.
2.10. Preparation of 2-(3-(hydroxymethyl)-7-methylquinolin-2-
yl)phenol (1)
A solution of 9-methyl-6H-chromeno[4,3-b]quinolin-6-one, 5
(200 mg, 1.0 mmol) in dry THF (15 mL) was cooled to 0 °C and
LiAlH4 (40 mg, 1.2 mmol) was added portion wise with stirring un-
der a nitrogen atmosphere. The duration of addition was 15 min.
The mixture was then warmed to room temperature and stirring
continued. After completion of the reaction the mixture was
quenched with water (15 mL) and extracted with ethyl acetate
(2 ꢃ 100 mL). The organic layers were collected, combined, washed

130
D. Rambabu et al. / Journal of Molecular Structure 1016 (2012) 126–133
Fig. 4. ORTEP representation of compound 2. Thermal ellipsoids are drawn at 50% probability level.
with cold water (2 ꢃ 50 mL), dried over anhydrous Na2SO4, filtered
and concentrated under vacuum. The residue was purified by flash
chromatography using 1:1 n-hexane/ethyl acetate to give the re-
quired product 1. The pure compound 1 was crystallized from ace-
tonitrile to give needle shaped crystals.
Spectral data for compound 1, white solid; yield (150 mg, 74%);
Rf = 0.60 (30% EtOAc-n-Hexane); m.p. 185–187 °C; 1H NMR
(400 MHz, DMSO-d6): d 10.02 (s, 1H), 8.30 (s, 1H), 7.91–7.84 (m,
1H), 7.40–7.34 (m, 1H), 7.32–7.20 (m, 3H), 6.94–6.87 (m, 2H),
5.25 (t, J = 5.6 Hz, 1H), 4.47 (d, J = 5.2, 2H), 3.88 (s, 3H); 13C NMR
(100 MHz, DMSO-d6): d 157.9, 157.2, 144.7, 138.3, 132.5, 131.2,
130.4, 129.8, 127.6, 127.5, 127.1, 126.7, 121.3, 119.1, 118.2, 62.9,
21.30. MS (ES mass): m/z 266.1 (M+1, 10%); IR (KBr) tmax (cmꢁ1):
3120, 3079, 2941, 2470, 2028, 1796, 1493, 1435, 1025, 1068,
740, 637; HPLC: 99.5%.
that the presence of –OH group in the molecule that is involved
in hydrogen bonding and this was confirmed by single crystal X-
ray structure analysis. The disappearance of strong absorption at
1735 and 1737 cmꢁ1 corresponding to the lactone carbonyl group
of compounds 5 and 7 respectively, showed that they were com-
pletely reduced to give compound 1 and 2 respectively. The peaks
in compound 1 appeared at 2941 and 2804 cmꢁ1 were due to the –
CH3 and –CH2 groups. The stretching frequencies at 2994 and
2836 cmꢁ1 were due to the –CH3 and –CH2 groups respectively
in compound 2. A broad peak at 3100 cmꢁ1 was due to the –OH
group present in compound 2 and involved in strong hydrogen
bonding. This was later confirmed by single crystal X-ray structure.
A peak at 1456 cmꢁ1 accounts for the –OCH3 linkage in compound
2.
3.2. DSC and TGA analyses
2.11. Preparation of 2-(3-(hydroxymethyl)-6-methoxyquinolin-2-
yl)phenol (2)
DSC and TGA thermograms (Supplementary material Fig. S23–
S26) show the thermal behavior of the compounds 1 and 2. DSC
thermogram of compound 1 shows that a sharp endothermic peak
at 175.82 °C (melting point: 185–187 °C) attributed to its melting
point and no endothermic peak below the melting point shows
that there was no inclusion of solvent in the crystal. In compound
2, an endothermic peak at 203.99 °C (melting point: 230–232 °C)
corresponds to its melting range and a small endotherm at
198.6 °C shows a phase transition. TGA shows that there was no
weight loss in the two compounds and found that they are anhy-
drous in nature. It was finally confirmed by single crystal X-ray
diffraction.
A similar procedure as described above was followed for the
preparation of 2. The pure compound 2 was crystallized from ace-
tonitrile to give needle shaped crystals.
Spectral data for compound 2, white solid; yield (145 mg, 65%);
Rf = 0.60 (30% EtOAc-n-Hexane); m.p. 230–232 °C; 1H NMR
(400 MHz, DMSO-d6): d 10.02 (s, 1H), 8.30 (s, 1H), 7.85 (d, J = 8.8,
1H), 7.36 (d, J = 9.2, 1H), 7.27–7.20 (m, 3H), 6.93–6.87 (m, 2H), 5.25
(t, J = 5.6, 1H), 4.47 (d, J = 5.2, 2H), 3.88 (s, 3H); 13C NMR (100 MHz,
DMSO-d6): d 154.8, 141.9, 135.4, 131.6, 130.3, 129.8, 129.5128.6,
128.1, 126.6, 121.2, 118.9, 115.6, 105.4, 59.9, 55.3, 29.0; MS (ES mass):
m/z 282.1 (M+1, 10%); IR (KBr) t
max (cmꢁ1): 3074, 2994, 2754, 1621,
1596, 1496, 1456, 1227, 1051, 926, 756; HPLC: 99.9%.
3.3. PXRD analysis
2.12. Preliminary characterization
The PXRD patterns of compounds 1 and 2 were given in Supple-
mentary Information (Fig. S19–S22).
The shapes of the crystals of the compounds 1 and 2 were ob-
served under the LEICA DFC295 polarizing microscope.
3.4. Crystal structure analysis
3. Results and discussion
With regard to structural analysis of compound 1, it crystallizes
in the centrosymmetric monoclinic P21/c space group with two
symmetry independent molecules in the asymmetric unit (Z0 = 2)
(Fig. 1). The two o-hydroxyphenyl rings of the molecules in the
asymmetric unit are not coplanar with quinoline moieties of the
two molecules. The torsion angles of the phenyl ring and quinoline
3.1. Infrared spectroscopy analysis
IR spectra of the compounds 1 and 2 are given in supplementary
material (see Fig. S3 and S4). A broad peak at 3151 cmꢁ1 shows

D. Rambabu et al. / Journal of Molecular Structure 1016 (2012) 126–133
131
Fig. 6. Shows (a) Hirshfeld surface and (b) 2D fingerprint plot of compound-1.
molecules of the conformer-B interact with each other via H2C–
OHꢀꢀꢀN (d = 1.91 Å, h = 169°) and Ph–OHꢀ ꢀ ꢀOH–CH2 (d = 1.94 Å,
h = 175°) hydrogen bonds to form a tetramer. These interactions
propagate in 1D and 2D to form a corrugated layered structure
(Fig. 3b). The corrugated layers of the two conformers arranged
alternatively along the (100) plane. Missing the dimer in con-
former-B indicate that the two molecules in the asymmetric unit
in compound-1 are conformational isomers.
Fig. 5. A helical structure with O–Hꢀ ꢀ ꢀO and O–Hꢀ ꢀ ꢀN hydrogen bonds in compound
2. (a) viewdown c-axis; (b) spacefill model to show the helical structure with O–
Hꢀ ꢀ ꢀO and O–Hꢀ ꢀ ꢀN interactions (viewdown a-axis).
Compound 2 crystallizes in the tetragonal I-4 space group with
one molecule in the asymmetric unit (Fig. 4). The o-hydroxyphenyl
moiety is not in coplanar with the quinoline moiety. The torsion
angle between the o-hydroxyphenyl and quinoline moieties (N1–
C1–C10–C15) is ꢁ112.69°. The molecules in the crystal structure
form helical structure with the phenolic –OH groups of one mole-
cule, –CH2–OH group of another molecule and quinoline nitrogen
of the another molecule via O–Hꢀ ꢀ ꢀO (d = 1.77(3) Å, h = 173(3)°)
and O–Hꢀ ꢀ ꢀN (d = 1.83(4) Å, h = 168(4)°) synthons along the c-axis
(Fig. 5a and b). These interactions are extended along a and b axes
and form a helical structures. Notably, the –OCH3 group of com-
pound 2 was not involved in any hydrogen bonding.
moieties are ꢁ124.66° (N1–C1–C10–C15) and 99.49° (N2–C18–
C27–C28). Interestingly, the two molecules in the asymmetric unit
of compound 1 form different hydrogen bonding patterns in the
crystal structure. These two molecules of compound 1 are con-
formationally different (Fig. 2). The inversion related molecules
of conformer-A, form a supramolecular dimer with robust O–
Hꢀ ꢀ ꢀO synhons (d = 1.90 Å, h = 170°) with the phenolic –OH and –
CH2OH groups. The free hydrogens of the phenolic O–H and –
CH2OH groups of this dimer interact with screw related molecules
via O–Hꢀ ꢀ ꢀN hydrogen bonds (d = 1.94 Å, h = 170°) to form a super-
molecule. These interactions propagate in 2D and form a corru-
gated layered structure (Fig. 3a). Two pairs of inversion related

132
D. Rambabu et al. / Journal of Molecular Structure 1016 (2012) 126–133
Fig. 8. Shows (a) Hirshfeld surface and (b) finger print picture of conformer-B of
compound-1.
Fig. 7. Shows (a) Hirshfeld surface and (b) finger print plot of conformer-A of
compound-1.
hence the surfaces essentially reflect different intermolecular
interactions. A challenging task is to successfully differentiate the
conformational polymorphism by analyzing the crystal structures.
But the Hirshfeld surface analysis made easy to differentiate the
polymorphic forms and conformational polymorphism. Since the
Hirshfeld surfaces are directly depend on the molecular environ-
ment, these are unique in the given crystal structure and they de-
pend on the number of crystallographically independent molecules
present in the asymmetric unit. Here we have applied the Hirshfeld
surface and 2D fingerprint plots to analyze the conformers A and B
of compound-1.
The 2D fingerprint plots of compound-1 were derived from the
Hirshfeld surface by plotting the fraction of points on the surface as
a function of the pair (di, de). Each point on the standard 2D graph
represents a bin formed by discrete intervals of di and de
(0.01 ꢃ 0.01 Å), and the points are colored as a function of the frac-
tion of surface points in that bin, with a range from blue (relatively
few points) through green (moderate fraction). The Hirshfeld sur-
faces and 2D fingerprint plots are given in Figs. 6–8. It is obvious
from this analysis that the two conformers-A and B of com-
pound-1 are completely different and exhibit the conformational
isomerism. Inspection of the fingerprint plots in Figs. 7b and 8b
highlights the major differences between the two conformers.
The conformer-A features the diffuse region of the blue points
3.5. CSD analysis
Cambridge analysis database (ConQuest version 5.27, Nov 2005,
number of hits 3,55,064) search for 2-phenylquinoline moiety was
performed. Good-quality structures containing ordered, error-free,
and nonpolymeric organic compounds with 3D coordinates and
having R < 5% were chosen for the analysis. Only 5 molecules were
found the in the analysis. Among 5 molecules two molecules (ref-
codes: MENBAJ VIHGOI) are N-oxides. It is observed from the
search that there is no more than one same molecule in the asym-
metric unit, like in compound 1.
3.6. Hirshfeld surface analysis
It is difficult to understand the intermolecular interactions in
polymorphic structures by visualizing the three dimensional struc-
tures. However, graphical tools based on the Hirshfeld surface and
the two dimensional (2D) fingerprint plots [18] offered consider-
able promise for exploring packing patterns and intermolecular
interactions in molecular crystals. As emphasized in the literature
the size and shape of a Hirshfeld surface reflects the interaction be-
tween different atoms and intermolecular contacts in a crystal, and

D. Rambabu et al. / Journal of Molecular Structure 1016 (2012) 126–133
133
structure in the crystal structures with O–Hꢀ ꢀ ꢀO and O–Hꢀ ꢀ ꢀN
hydrogen bond synthons. The biological evaluation of these two
compounds is in progress in our laboratory. This work contributes
the synthesis of novel quinoline derivates and the use of Hirshfeld
surface analysis to identify the conformational isomers.
Acknowledgements
DRB thanks Prof. Javed Iqbal, Director of ILS for his continuous
support and encouragements. CMR thanks the DST, New Delhi, In-
dia for funding. GRK thanks IISER, Kolkata, India for a Senior Re-
search Fellowship.
Appendix A. Supplementary material
Spectral data (IR, MASS, NMR, HPLC, PXRD, DSC and TGA) of the
compounds 1 and 2 are available in the supporting information in
.pdf format. Crystallographic information files (.cif) for the com-
pounds 1 and 2 are available in the electronic format. Supplemen-
tary data associated with this article can be found, in the online
version, at doi:10.1016/j.molstruc.2012.02.054.
References
[1] S. Kumar, S. Bawa, H. Gupta, Mini Rev. Med. Chem. 9 (2009) 1648;
A. Robert, B. Meunier, Chem. Soc. Rev. 27 (1998) 273.
[2] M.E. Jason, W.C. Robert, C. Mark, G.C. Gary, H.H. Peter, A.J. Brian, A. MacLeod, M.
Rose, M.L. Georgina, M. Elena, M. Fraser, R. Michael, R. Inmaculada, G.N.R.
Michael, S. Bindi, L.T. Kwei, W. Brian, Bioorg. Med. Chem. Lett. 50 (2006) 5748.
[3] J. Nilsson, E.Ø. Nielsen, T. Liljefors, M. Nielsen, O. Sterner, Bioorg. Med. Chem.
Lett. 18 (2008) 5713.
[4] M. Simeon, N. John, L. Georgia, K. Eleni, G. Vasiliki, T. Dimitrios, N. Pavlos, Int. J.
Antimicrob. Agents 29 (2007) 738.
[5] N. Kaila, K. Janz, S. DeBernardo, P.W. Bedard, R.T. Camphausen, S. Tam, D.H.H.
Tsao, J.C. Keith Jr., C.N. Nutter, A. Shilling, R.Y. Sciame, Q. Wang, J. Med. Chem.
50 (2007) 21.
[6] K.E. Andersen, B.F. Lundt, A.S. Jørgensen, C. Braestrup, Eur. J. Med. Chem. 31
(1996) 417.
[7] S. Eswaran, A.V. Adhikari, R.A. Kumar, Eur. J. Med. Chem. 45 (2010) 957.
[8] A.H. Kategaonkar, P.V. Shinde, A.H. Kategaonkar, S.K. Pasale, B.B. Shingate, M.S.
Shingare, Eur. J. Med. Chem. 45 (2010) 3142.
[9] M.A. Matulenko, A.I. Meyers, J. Org. Chem. 61 (1996) 573.
[10] P. Magnus, D. Parry, T. Illiadis, S.A. Eisenbeis, R.A. Fairhuist, J. Chem. Soc., Chem.
Commun. (1994) 1543.
Fig. 9. Shows (a) Hirshfeld surface and (b) fingerprint picture of compound-2.
between the hydrogen bond spikes, while this feature is sharpened
in the fingerprint plot of conformer-B. The Hirshfeld surface and
fingerprint plots of compound-2 are given in Fig. 9a and b.
[11] N. Ahmed, K.G. Brahmbhatt, S. Sabde, D. Mitra, I.P. Singh, K.K. Bhutani, Bioorg.
Med. Chem. 18 (2010) 2872.
[12] S. M. Roopan, F. R. N. Khan, ARKIVOC, 2009, xiii, 161.
[13] S. Bairagi, A. Bhosale, M.N. Deodhar, E-J. Chemi. 6 (2009) 759.
[14] SHELXTL, Program for the Solution and Refinement of Crystal Structures,
(version 6.14), Bruker AXS, Wisconsin, USA, 2000.
[15] G.M. Sheldrick, SHELX-97: Program for the Solution and refinement of Crystal
Structures, University of Göttingen, Germany, 1997.
[16] (a) C.F. Macrae, I.J. Bruno, J.A. Chisholm, P.R. Edgington, P. McCabe, E. Pidcock,
L. Rodriguez-Monge, R. Taylor, J. van de Streek, P.A. Wood, J. Appl. Cryst. 41
(2008) 466;
(b) L.J. Farrugia, J. Appl. Cryst. 30 (1997) 565;
(c) L.J. Barbour, Supramol. Chem. 1 (2001) 189.
[17] Heber, Dieter Archiv der Pharmazie (Weinheim, Germany) 320 (1987) 595.
[18] (a) M.A. Spackman, J.J. McKinnon, CrystEngComm 4 (2002) 378;
(b) J.J. McKinnon, F.P.A. Fabbiani, M.A. Spackman, Crystal Growth Des. 7 (2007)
755.
4. Conclusions
The compounds 1 and 2 were synthesized and characterized by
spectral data (1H NMR, IR and Mass). The structures of the com-
pounds 1 and 2 were finally determined by single crystal X-ray dif-
fraction data. Due to the torsion angles of the phenyl ring and
quinoline moieties, the compound 1 exhibits conformational isom-
erism and the two conformers (A and B) form different hydrogen
bond synthons. The Hirshfeld surface analysis associated with 2D
finger plots were carried out on the two conformers (A and B) of
compound 1. It is evident from this analysis that the two conform-
ers are completely different and they form different hydrogen
bonds in the crystal structure. The compound 2 forms helical