Journal of Molecular Structure 1134 (2017) 770e780

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Journal of Molecular Structure

journal homepage: http://www.elsevier.com/locate/molstruc

Comparative theoretical and experimental study on novel tri-

quinoline system and its anticancer studies
Kasirajan Gayathri a, Ramachandran Radhika b, Ramasamy Shankar b,
Mahalingam Malathi c, Krishnaswamy Savithiri a, Hazel A. Sparkes d, Judith A.K. Howard e,
Palathurai Subramaniam Mohan a, *
a
Department of Chemistry, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
b
Department of Physics, Bharathiar University, Coimbatore, 641 046, Tamil Nadu, India
c
Department of Chemistry, Bannari Amman Institute of Technology, Sathyamangalam, 638 401, Tamil Nadu, India
d
School of Chemistry, University of Bristol, Cantock's Close, Bristol, BS8 1TS, UK
e
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK

a r t i c l e i n f o a b s t r a c t

Article history: A novel compound 2-chloro-3,6-bis-(quinolin-8-yloxymethyl)-quinoline 3 bearing a tri-quinoline moiety

Received 14 October 2016 has been synthesized from 2-chloro-3,6-dimethyl quinoline 1 and 8-hydroxy quinoline 2 using dry
Received in revised form acetone and K2CO3 as a base. 3 has been characterized by using FT-IR, FT-Raman, UVeVis, 1H NMR, 13C
7 January 2017
NMR spectra and single crystal X-ray diffraction methods. We have also made a combined experimental
Accepted 8 January 2017
Available online 10 January 2017
and theoretical study on the molecular structure, vibrational spectra, NMR, FT-IR, FT-Raman and UVeVis
spectra of 2-chloro-3,6-bis-(quinolin-8-yloxymethyl)-quinoline. The theoretical studies of the title
compound have been evaluated by using density functional theory calculations using B3LYP/6-31þG(d,p)
Keywords:
2-Chloro-3,6-bis-(quinolin-8-yloxymethyl)-
and M06-2X/6-31þG(d,p) level of theories. The calculated theoretical values were found to be in good
quinoline agreement with the experimental findings. The single crystal structure 3 crystallized in the orthorhombic
Spectroscopic studies space group Pna21. The compound 3 exhibits higher cytotoxicity in human cervical cancer cell lines
Single crystal XRD (HeLa) than human breast cancer cell lines (MCF7).
MEP © 2017 Elsevier B.V. All rights reserved.
HOMO-LUMO
Cytotoxicity

1. Introduction [13,14]. Also the special properties of quinolates were illustrated by

The compounds of quinoline based derivatives find extensive
applications such as medicinal usage, material utility, optoelec-
tronic properties etc. Specifically, 8-hydroxy quinoline (8HQ) is
used as one of the components in organic light emitting diode
(OLED) fabrication [1,2] since the organic materials have photo-
conductive, photorefractive and hole transporting properties [3].
8HQ is extensively used as the best chelator [4e7] for metal ions
after Ethylenediaminetetraacetic acid (EDTA) due to its chromo-
genic behavior. Derivatives of 8-hydroxy quinoline have been
popular in the field of organometallic chemistry [8,9] and as a
fluorescent sensors [10,11] because of the ease of complex forma-
tion with various metal ions such as Agþ [12], Cd2þ [10], Cu2þ
* Corresponding author.
E-mail addresses: ps_mohan_in@yahoo.com, psmohan59@gmail.com
(P.S. Mohan).
simple Werner -type complexes and have been useful in the syn-
thesis of metallosupramolecular materials [15,16]. 8HQ derivatives
and their quinolates are known to possess therapeutic properties
for Alzheimer's disease [17], widely used as antimicrobial [18,19]
and antitumor agents [20,21] To prepare newer derivatives, an
elaborate knowledge of spectroscopic and stability behavior is
required in order to promote the utility value in medicinal
properties.
In recent years, density functional theory (DFT) [22] has been
extensively used for optimized structural studies. In the present
work, Becke's three parameter hybrid functional [23,24] with cor-
relation functional of Lee-Yang-Parra [25] (B3LYP) and the hybrid
meta-GGA functional M06-2X with 6-31þG(d,p) basis set have
been used for comparing the experimental values of geometry,
vibrational spectra, electronic and NMR spectra etc.
In this communication, we report the first ever synthesis of the
novel tri-quinoline based compound 3 which was synthesized from

http://dx.doi.org/10.1016/j.molstruc.2017.01.030
0022-2860/© 2017 Elsevier B.V. All rights reserved.
 K. Gayathri et al. / Journal of Molecular Structure 1134 (2017) 770e780 771

2-chloro-3, 6-dimethyl quinoline and 8-hydroxy quinoline using Table 1

dry acetone and anhydrous K2CO3 as a base. Subsequently, we Crystal data and structure refinement of compound 3.

aimed to compare the structural and spectroscopic properties of CCDC number 1005001
compound 3 obtained experimentally with theoretical results from Empirical formula C29H20ClN3O2
density functional theory calculations using B3LYP and M06-2X Formula weight 477.93
Temperature/K 100(2)
level of theories. We optimized the structure of compound 3 and Crystal system orthorhombic
the calculations were performed to calculate 1H NMR, 13C NMR, FT- Space group Pna21
IR, FT-Raman and UVeVis spectra at the B3LYP and M06-2X level of a/Å 6.61280(10)
theories. Furthermore, the frontier molecular orbital energies of b/Å 38.2988(7)
c/Å 9.8231(2)
compound 3 have been calculated and various molecular properties
a/ 90
such as chemical hardness, softness, electrophilicity, electronega- b/ 90
tivity, ionization potential, chemical potential and electron affinity g/ 90
have also been observed at these theory levels. From the molecular Volume/Å3 2487.82(8)
electrostatic potential (MEP), the lowest unoccupied molecular Z 4
rcalcg/cm3 1.276
orbital (LUMO) and highest occupied molecular orbital (HOMO) m/mm1 0.185
were plotted to visualize the charge distributions and electronic F(000) 992.0
transport properties of compound 3. The comparisons between Crystal size/mm3 0.48  0.18  0.11
experimental and theoretical calculations have also been done. Radiation MoKa (l ¼ 0.71073)
2q range for data collection/ 5.232 to 52.814
Index ranges 8  h  8,
2. Materials and methods 47  k  47,
12  l  9
Reflections collected 18435
2.1. Experimental
Rint 0.0455
Data/restraints/parameters 4616/1/316
2.1.1. General Goodness-of-fit on F2 1.020
All reagents and chemicals were of analytical grade and pur- Final R indexes [I  2s (I)] R1 ¼ 0.0421,
wR2 ¼ 0.0919
chased from Sigma Aldrich. The solvents were purified by standard
Final R indexes [all data] R1 ¼ 0.0539,
methods. Thin layer chromatography (TLC) plates coated with silica wR2 ¼ 0.0966
gel containing 13% calcium sulfate as a binder were used to test the Largest diff. peak/hole/e Å3 0.33/0.20
purity of the compound. Melting point (M.P.,  C) was determined
using Mettler FP 51 apparatus (Mettler Instruments, Switzerland)
and remains uncorrected. Microanalyses were performed on a 2.4. DFT computational analysis
Vario EL III model CHNS analyzer (Vario, Germany).
The molecular geometry for the compound 3 has been extracted
2.2. FT-IR, FT-Raman, UV spectra and NMR analysis of compound 3 from the single crystal X-ray analysis data. The compound 3 was
optimized by using B3LYP and M06-2X level of theories with 6-
The IR spectrum of compound 3 was recorded using KBr pellets 31þG(d,p) basis set in the Gaussian 09 suite of program [31]. The
in the scan range of 4000e400 cm1 with a resolution of 4 cm1 on vibrational frequencies were found at these theory levels and no
a Nicolet Avatar Model FTIR spectrometer (with ESP DTGS detec- imaginary frequencies were observed which confirmed that the
tor). Raman spectrum was measured using JY-1058 Raman spec- structure is on the real minima. Due to the absence of anharmo-
trometer (with CCD detector) in the scan range of 4000e50 cm1 nicity in the system, calculated stretching frequencies were higher
with resolution of 2 cm1. 1H NMR and 13C NMR were recorded than experimental values. The values were scaled by 0.964 [32] and
using a Bruker 400 MHz and 100 MHz spectrometers respectively 0.979 [33] at the B3LYP and M06-2X level of theories respectively
using tetramethyl silane (TMS) as an internal standard reference and agreed well with the experimental values. The UVeVis spectra
and dimethyl sulfoxide-d6 as solvent. The chemical shift values were calculated using polarizable continuum model (PCM) [34] in
were recorded as d (ppm). UVeVisible absorption spectrum of ethanol solution by using the time-dependent density functional
compound 3 (1  103 M solution in EtOH/H2O 1:1(v/v)) was theory (TD-DFT). The NMR chemical shift calculations were done by
recorded at 24 ± 1 C using JASCO-V- 630 spectrophotometer. using the Gauge- Independent Atomic Orbital (GIAO) method [35]
at B3LYP and M06-2X level of theories with 6-31þG(d,p) basis
set. The molecular electrostatic potential map is plotted for the
2.3. Single crystal X-ray analysis
optimized structure of the title compound 3 and it shows the
probable electrophilic and nucleophilic sites of the molecule.
X-ray diffraction data for 3 were collected at 100(2) K on a
Bruker APEX II CCD diffractometer using Mo-Ka radiation
(l ¼ 0.71073 Å). Absorption corrections were based on equivalent 2.5. Cytotoxicity study by MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-
reflections using SADABS [26]. The structure was solved using diphenyltetrazolium bromide) assay
SHELXS [27] and refined against F2 in SHELXL [28] using Olex2 [29].
All of the non-hydrogen atoms were refined anisotropically, while A cytotoxicity study of compound 3 was carried out on human
all of the hydrogen atoms were located geometrically and refined liver cancer cells (A549) which were collected from National Centre
using a riding model. There was disordered solvent present in the for Cell Science (NCCS), Pune, India. Cell viability was carried out
lattice which could not be sensibly modelled so Squeeze within using the MTT assay method. Cells were maintained in Eagles
Platon [30] was used to treat this. Crystal structure and refinement minimum essential medium containing 10% fetal bovine serum
data are given in Table 1. The structure has the CCDC number (FBS). For the screening experiment, the cells were seeded into 96-
1005001. Copies of the data can be collected, free of charge, on well plates in 100 mL of the respective medium containing 10% FBS,
application to CCDC, 12 Union Road, Cambridge, CB2 1EZ, UK. plates with a density of 10000 cells/well and incubated in a hu-
[Fax: þ44(0)-1223-336033 or e-mail: deposit@ccdc.cam.ac.uk]. midified incubator at 37  C, using conditions of 5% CO2, 95% air and
772 K. Gayathri et al. / Journal of Molecular Structure 1134 (2017) 770e780
100% relative humidity for 24 h prior to the addition of compound.
The compound 3 was dissolved in DMSO and diluted in the
respective medium containing 1% FBS. After 24 h, the medium was
changed with the respective medium with 1% FBS containing the
compounds at various concentrations and incubated at 37  C with
conditions of 5% CO2, 95% air and 100% relative humidity for 48 h.
Triplication was maintained and the medium not containing the
compound served as the control. After 48 h, 10 mL of MTT (5 mg/mL)
in phosphate buffered saline (PBS) was added to each well and
incubated at 37  C for 4 h. The medium with MTT was then flicked
off and as a result formazan crystals were dissolved in 100 mL of
DMSO. The absorbance was then measured at 570 nm using a
microquant plate reader (Bio-Tek Instruments). The percentage of
cell inhibition was determined using the formula
% of inhibition ¼ ½mean OD of untreated cells ðcontrolÞ=mean OD of treated cells
 100 and a graph was plotted as the percentage of cell inhibition versus concentration and from this the
IC50 value was calculated:
3. Results and discussion
3.1. Chemistry
8-hydroxy quinoline (0.025 g, 0.26 mmol) was added to the
solution of 3,6-bis(bromomethyl)-2-chloroquinoline [36] (0.048 g,
0.13 mmol) in dry acetone along with anhydrous K2CO3 (10 mg)
(Scheme 1). The reaction mixture was refluxed at 100e120  C for
8 h. After completion of the reaction, the mixture was cooled to
room temperature and using reduced pressure the excess solvent
was removed to get a yellow oil that was separated by silica gel
column chromatography (80:20 v/v Petroleum ether: Ethyl Acetate)
to give pure compound 3 in 64% yield; Mp: 223  C; IR (KBr, cm1)
3041, 1699, 1559, 1378, 1008, and 702; 1H NMR (300 MHz, DMSO,
ppm): d 8.84e8.85 (m, 2H, Ar-H), 8.33 (m, 2H, Ar-H), 8.29 (d, 2H,
J ¼ 8.4 Hz, Ar-H), 8.05 (s, 1H, Ar-H), 7.94 (d, 2H, J ¼ 8.8 Hz, Ar-H),
7.87 (d, 2H, J ¼ 8.8 Hz, Ar-H), 7.45e7.53 (m, 4H, Ar-H), 7.29 (d, 1H,
J ¼ 7.2 Hz, Ar-H), 5.48 (s, 4H, CH2); 13C NMR (100 MHz, DMSO,
ppm): 154.07, 153.70, 149.64, 149.51, 146.84, 136.80, 136.22, 136.10,
136.01, 129.72, 129.63, 129.43, 129.03, 128.75, 127.29, 126.65, 126.53,
125.78, 121.88, 121.74, 120.83, 120.36, 110.12, 110.10, 70.33, 67.37;
C29H20N3O2Cl: Calculated C 72.88%; H 4.22%; N 8.79%; Found, C
72.84%; H 4.49%; N 8.28%.
3.2. Single crystal X-ray diffraction studies
The structure of 3 was confirmed by single crystal X-ray
diffraction, see Fig. 1. It crystallized in the orthorhombic space
group Pna21 with one molecule in the asymmetric unit. One of the
Scheme 1. Synthesis of 2-Chloro-3,6-bis-(quinolin-8-yloxymethyl)-quinoline 3.
terminal quinolines (N2, C11eC19) was in almost the same plane as
the central Cl substituted quinoline (N1, C1eC9) with a plane to
plane angle of ~2 while the second terminal quinoline (N3,
C21eC29) was twisted significantly, ~62 , out of the place of the
rest of the molecule. The structure contained p-p stacking in-
teractions between the central quinolone (N1, C1eC9) and terminal
quinolone (N2, C11eC19), with centroid-centroid distances of
~3.6 Å and a shift of ~1.4 Å. Disordered solvent was removed
through the use of Squeeze.
3.3. FT NMR analysis
1
H NMR and 13C NMR spectra were observed in DMSO-d6 using
TMS as an internal standard. 1H NMR and 13C NMR data of com-
pound 3 are tabulated in Table 3. In 1H NMR, four protons of two
CH2 groups appeared in the upfield region of d 5.48 ppm. All other
aromatic proton peaks were observed in the downfield region be-
tween d 7.45 and 8.85 ppm. 13C NMR spectrum showed the pres-
ence of 26 carbon atoms. The characteristic signals at d 67.37 and
d 70.33 ppm were due to eCH2 group carbon atoms. The aromatic
carbons appeared in the region between d 110.10 and d 154.07 ppm
(Fig. S2).
3.4. In vitro cytotoxicity assay
By using MTT assay, the in vitro cytotoxicity of the compound 3
was done against human cervical cancer cell lines (Hela) and hu-
man breast cancer cell lines (MCF7).
3.5. XRD studies and structural analysis
The bond lengths, bond angles and dihedral angles of compound
3 from the single crystal XRD data are tabulated in accordance with
the atom numbering scheme as shown in Fig. 1. The experimental
and theoretical results of bond lengths, bond angles and dihedral
angles are compared and tabulated in Tables S1, S2 and S3. The
optimized bond lengths and bond angles are calculated and are
slightly varied from the experimental values because the structure
of compound 3 is optimized in gas phase while in X-ray diffraction
the molecule is packed in a crystal in addition the crystal structure
contained disordered solvent that was squeezed out but may alter
the molecular geometry, although this does not appear to have
been very significant here.
 K. Gayathri et al. / Journal of Molecular Structure 1134 (2017) 770e780
Fig. 1. (a) Structure of 3 with ellipsoids depicted at the 50% probability level. (b) Optimized electronic structure of molecule 3 calculated by using B3LYP/6-31þG(d,p) level of theory.
Both the experimental and theoretical X-ray data show single
and double bonds for CeC in the quinoline heterocyclic com-
pounds. The experimental X-ray structure showed CeC bond length
in the range of aromatic 1.346(6)-1.436(5) Å, single 1.498(5)-
1.506(5) Å and their corresponding theoretical CeC bond lengths
are formed around aromatic 1.375e1.439 Å, single 1.51e1.509 Å
using B3LYP and M06-2X level of theories. The experimental CeCl
and CeN bond lengths in compound 3 are 1.776(3) Å and 1.300(4)-
1.376(4) Å respectively with the related theoretical bond lengths
1.775 Å and 1.28e1.367 Å respectively. Hence a good agreement is
found between the bond lengths of experimental and theoretical
results.
In quinoline ring, almost all the bond angles of carbon lie around
120 , with sp2 hybridization for their corresponding carbon atoms.
The :CCC was found in the range of 116.5(3)-123.9(4) and
116.1e123.2 for experimental and theoretical data respectively.
The experimental bond angles of C11eO1eC10 and C21eO2eC20
were found as 115.8(3) Å and 116.9(3) Å respectively while the
theoretical values were calculated as 116.2 Å and 118.7(B3LYP) and
119.5 Å and 119.5 Å(M06-2X). The bond lengths of CeN, C]N, CeCl,
CeO, CeH, CeC agree well with the correlation coefficient of 0.9742
while the correlation coefficients of bond angles of CeCeC, CeCeN,
CeNeC, CeCeCl, OeCeH, CeOeC is 0.9612. The correlation coef-
ficient of experimental and theoretical dihedral angles of
773
OeCeCeC, NeCeCeC, and NeCeCeO is 0.9988 (Fig. S1). From the
obtained results almost all the experimental bond lengths, bond
angles and dihedral angles quite agreeable with theoretical
observations.
Quantum Theory of Atoms In Molecules (QTAIM) [37] is an
important tool to describe the chemical bonding between the
atoms. To observe the orientation of the molecule, QTAIM calcu-
lation were done to investigate the contributions of the intra-
molecular hydrogen bonds and Van der Waals interactions by using
MORPHY 98 program package [38]. Surprisingly, no such in-
teractions were observed in compound 3. Thus for the orientation
of the compound 3, the impact of non-covalent interaction is
lacking.
3.6. FT-IR and FT-Raman assignments
The infrared and Raman spectra of compound 2-chloro-3,6-bis-
(quinolin-8-yloxymethyl)-quinoline 3 are carried out in the fre-
quency range of 4000e400 cm1 and 4000-50 cm1 respectively.
The FT-IR and FT-Raman spectra of the molecule have been calcu-
lated by using B3LYP and M06-2X level of theories with 6-
31þG(d,p) basis set. The calculated vibrational frequencies of FT-IR
and FT-Raman, their IR intensities, Raman activities and their cor-
responding experimental frequencies were compared in Table 2.
774 K. Gayathri et al. / Journal of Molecular Structure 1134 (2017) 770e780

Table 2
Experimental and theoretical vibrational frequencies of compound 3 using B3LYP and M06-2X functionals and 6-31þG (d,p) as basis set.

Vibrational assignments IR frequency (cm1) Raman frequency (cm1)

using Fig. 1b
Theoretical Experimental Theoretical Experimental

B3LYP/6-31þG(d,p) M06-2X/6-31þG(d,p) B3LYP/6-31þG(d,p) M06-2X/6-31þG(d,p)

Scaled IR intensity Scaled IR intensity Scaled Raman activity Scaled Raman activity

ns CH2 (41,42,43) 2851 25.42 2969 19.3475 2851 285.54 2969 223.99
ns CH2(21,22,23) 2869 19.03 2986 15.7657 2869 254.50 2986 207.24
nas CH2(41,42,43) 2898 23.34 3018 18.8447 2898 31.96 3018 33.72
nas CH2(21,22,23) 2903 14.89 3031 11.0659 3041 2903 48.00 3031 49.28 3064
CH2 (41,42,43)Rocking 1006 8.02 1023 2.09 1008 1006 0.27 1023 3.52
CH2(21,22,23)Rocking 1015 0.45 1027 0.33 1015 0.50 1027 0.57
CH2 (41,42,43)Twisting 1224 3.8 1236 5.56 1282 1224 48.68 1236 26.51
CH2(21,22,23)Twisting 1226 1.13 1241 5.81 1226 6.09 1241 7.27
CH2 41,42,43)Scissoring 1470 4.60 1489 95.28 1470 3.14 1489 3.51
CH2(21,22,23)Scissoring 1467 2.00 1489 18.12 1428 1467 2.12 1489 3.37 1422
CH2 (41,42,43)Wagging 1252 495.46 1272 423.77 1282 1252 4.84 1272 5.33
CH2(21,22,23)Wagging 1257 168.59 1276 127.97 1257 6.94 1276 8.86
CeC 1379e1355 69.13 1403e1381 56.87 1428e1378 1380e1355 179.52 1403e1381 176.22 1422
t Ph twisting 997 15.06 1018 10.06 945 997 5.26 1019 1.65
n C36H37 3005 22.59 3113 16.0549 3048 108.67 3114 101.38
n C38H39 3006 22.99 3108 15.2286 3049 122.43 3107 112.11
n C17H18 3015 11.12 3112 6.3201 3057 52.79 3111 55.37
n C15H16 3024 3.72 3121 7.0096 3066 3.58 3121 112.88
n C50H51 3025 6.01 3120 0.1259 3067 17.13 3121 65.20
n C48H49 3026 7.89 3135 6.0476 3068 176.61 3135 88.21
n C32H33 3027 5.51 3131 2.4733 3070 159.07 3132 82.05
n C54H55 3041 34.68 3136 20.1632 3041 3084 206.24 3136 196.38
n C7H8 3043 33.10 3148 16.9058 3086 218.29 3149 193.08
n C52H53 3049 30.17 3147 13.7926 3091 333.39 3145 300.09
n C24H25 3050 26.72 3135 6.0476 3093 267.58 3135 88.21
n C19H20 3050 0.55 3144 1.2778 3092 90.71 3144 73.30
n C10H11 3055 2.22 3162 13.2667 3098 111.16 3162 278.45
n C26H27 3065 3.77 3161 1.6869 3108 212.11 3161 213.8
n C28H29 3068 9.01 3165 4.7244 3188 3111 127.35 3165 134.97
n C44H45 3068 13.42 3159 7.8557 3110 128.18 3159 151.46
n CeCl 746 36.72 773 53.4720 702 746 5.18 773 3.37 768
n C40eO3 1316 495.46 1332 423.7792 1378 1316 4.85 1332 5.33 1385
n C12eO2 1316 168.59 1330 127.9720 1317 6.95 1330 8.86
n C6eN4 1602 27.35 1656 30.09 1699 1602 6.51 1656 5.46 1568
n C31eN34 1601 29.41 1633 19.89 1600 7.55 1633 12.00
n C47eN5 1590 61.08 1641 71.38 1590 36.60 1641 32.87

n- Stretching; ns e Symmetric stretching; nas- Asymmetric stretching; t- Twisting.

Scaling factor for B3LYP/6-31þG (d,p) ¼ 0.964.
Scaling factor for M06-2X/6-31þG (d,p) ¼ 0.979.

The experimental and theoretical FT-IR and FT-Raman were shown
in Figs. 2 and 3.
3.7. CeC vibrations
The FT-IR and FT-Raman stretching frequencies for the aromatic
ring and CeC were calculated by using B3LYP/6-31þG(d,p) and
M06-2X/6-31þG(d,p) level of theories. The carbon-carbon
stretching vibrations in phenyl ring are identified with reference
to the previously reported vibrations of the benzene molecule
[39,40]. The CeC stretching vibrations are very important modes in
carbon skeleton molecule. From the literature studies [41], the CeC
stretching vibrations are observed in the region 1625-1430 cm1. In
our present study, the experimental CeC stretching vibrations were
observed between 1428 and 1378 cm1 for FT-IR and 1422 cm1 for
FT-Raman. For the titled compound, the corresponding theoretical
FT-IR and FT-Raman stretching vibrations were observed at 1379-
1355 cm1 and 1403-1381 cm1 using B3LYP and M06-2X level of
theories respectively which agree well with the experimental FT-IR
and FT-Raman values.
3.8. CeH and C]N vibrations
In most of the aromatic compounds, CeH stretching vibrations
[42] are usually observed at 3100-2850 cm1 and in the present
investigation, they were observed at 3165-3005 cm1 in FT-IR and
FT-Raman spectra by B3LYP/6-31þG(d,p) and M06-2X/6-31þG(d,p)
methods. Experimentally, the bands observed at 3188 and
3041 cm1 were attributed to CeH stretching modes. According to
Silverstein et al. [43], the C]N ring stretching bands are observed
in the region of 1600e1430 cm1. The experimentally calculated
C]N stretching vibrations were observed at 1699 and 1568 cm1
for FT-IR and FT-Raman values respectively and theoretical values
of FT-IR and FT-Raman spectra were calculated around 1602, 1601
and 1590 cm1 at B3LYP level of theory which has been associated
to C]N stretching vibrations of compound 3. While, by using M06-
2X functional the values were calculated at 1633, 1641 and
1656 cm1.
3.9. CeCl and CeO vibrations
In quinoline ring, CeCl stretching is observed as a very intense
and narrow peak in the range of 850e550 cm1 [44]. Arjunan et al.
[45] reported CeCl stretching vibration at 734 cm1 for IR and
735 cm1 for Raman. In our current investigation, CeCl stretching
vibrations of the compound 3 have been observed at 702 cm1 and
768 cm1 for FT-IR and FT-Raman respectively and the corre-
sponding theoretical values have been calculated at 746 and
 K. Gayathri et al. / Journal of Molecular Structure 1134 (2017) 770e780 775

Table 3
Experimental and theoretical 1H NMR and 13
C NMR chemical shifts of compound 3.

NMR assignments of compound 3 using Fig. 1

1 13
H NMR chemical shifts (d) C NMR chemical shifts (d)

Atom No Experimental Theoretical (B3LYP) Theoretical (M06-2X) Atom No Experimental Theoretical (B3LYP) Theoretical (M06-2X)

H-11 8.05 9.01 10.36 C-47 154.07 141.28 142.88

H-27 8.33 8.70 9.88 C-35 129.03 118.10 130.13
H-20 e 8.11 9.56 C-10 136.01 124.25 138.78
H-18 8.33 7.71 9.12 C-14 125.78 133.94 146.52
H-22 5.48 5.08 5.72 C-9 146.84 114.79 127.15
H-23 4.83 5.30
H-29 7.29 6.96 7.93 C-19 126.65 117.86 130.67
H-8 7.87 7.32 8.57 C-26 129.43 116.08 129.74
H-33 7.45e7.53 7.01 8.12 C-13 136.10 125.33 138.75
H-37 8.29 8.91 10.08 C-17 126.53 111.01 123.62
H-25 7.45e7.53 7.23 8.60 C-21 67.37 57.89 53.82
H-49 7.94 7.75 8.73 C-12 153.70 141.71 154.20
H-42 5.48 5.00 5.41 C-6 110.10 128.39 141.36
H-43 5.11 5.76
H-45 7.29 6.57 7.55 C-30 120.36 113.80 125.59
H-55 7.87 7.16 8.60 C-32 121.88 106.21 120.10
H-51 7.45e7.53 7.13 8.03 C-7 127.29 115.61 123.83
H-16 7.94 7.93 8.89 C-28 136.22 94.07 103.88
H-53 7.45e7.53 7.13 8.72 C-36 149.51 135.73 148.43
H-39 8.84 8.94 10.19 C-24 121.74 108.44 119.99
C-48 129.63 121.81 136.77
C-41 70.33 61.82 59.44
C-40 153.70 143.37 154.56
C-44 110.10 93.03 100.72
C-54 120.83 113.69 123.48
C-50 121.88 105.88 116.94
C-46 128.75 117.44 129.85
C-34 136.80 129.47 142.37
C-15 129.72 121.27 137.47
C-52 121.74 107.94 119.79
C-38 149.64 135.48 147.29

RMSD by Linear regression plot:

1
H NMR at B3LYP/6-31þG (d,p) ¼ 0.9538.
1
H NMR at M06-2X/6-31þG (d,p) ¼ 0.9661.
13
C NMR at B3LYP/6-31þG (d,p) ¼ 0.8751.
13
C NMR at M06-2X/6-31þG (d,p) ¼ 0.8750.

Fig. 2. (a) Theoretical and (b) Experimental FT-IR spectra of compound 3.

Fig. 3. (a) Theoretical and (b) Experimental FT-Raman spectra of compound 3.

1
773 cm for FT-IR and FT-Raman at B3LYP and M06-2X level of
theories respectively. According to the literature [46], the stretch- level of theories. The experimental values of CeO stretching vi-
ing mode of CeO is observed around 1350-1000 cm1. The bands brations are observed at 1378 cm1 and 1385 cm1 in FT-IR and FT-
observed around at 1317, 1316, 1332 and 1330 cm1 in FT- IR and FT- Raman values respectively.
Raman have been assigned to CeO stretching vibrations of the
compound which have been calculated at the B3LYP and M06-2X
776 K. Gayathri et al. / Journal of Molecular Structure 1134 (2017) 770e780
3.10. CH2 vibrations
Basically there are six fundamentals stretching modes linked
with each CH2 group. They are CH2 asym-asymmetric stretching,
CH2 sym-symmetric stretching, CH2 scis-scissoring and CH2 rock-
rocking modes and are expected to be polarized. The CH2 wag-
wagging and CH2 twist-twisting modes belong to depolarized for
out of plane bending vibrations [47]. In the present investigation,
the experimental CH2 symmetric and asymmetric FT-IR vibrational
frequencies were found at 3041 cm1 respectively and the corre-
sponding CH2 symmetric and asymmetric stretching frequencies of
FT-Raman are noted at 3064 cm1. The theoretical values of the FT-
IR and FT-Raman associated to symmetric CH2 stretching vibra-
tional frequencies of title compound have been calculated at 2851,
2869 and 2969, 2986 cm1 at B3LYP/6-31þG(d,p) and M06-2X/6-
31þG(d,p) level of theories. While the asymmetric CH2 stretching
vibrational frequencies were noticed at 2898 and 2903 cm1 for
B3LYP and 3018 and 3031 cm1 for M06-2X level of theories. Both
theoretical and experimental CH2 symmetric as well as asymmetric
stretching vibrational frequencies are in good agreement with each
other. Similarly all the possible modes of vibrations are tabulated in
Table 2 by using B3LYP and M06-2X level of theories with
6e31þ(d,p) as basis set. In addition, the CH2 bending and stretching
modes follow the order of decreasing wave number and the order is
CH2 scissoring > CH2 > wagging > CH2 twisting > CH2 rocking
[48,49]. All the CH2 vibrations were computed at the B3LYP and
M06-2X level of theories which agreed well with the experimental
values.
3.11. NMR analysis
1
H and 13C NMR spectra of the title compound were recorded by
using DMSO-d6 solvent and TMS as the internal standard and the
chemical shift values were (d) calculated by B3LYP/6-31þG(d,p) and
M06-2X/6-31þG(d,p) (Fig. S2). The experimental 1H and 13C
chemical shift values are compared with the theoretically calcu-
lated 1H and 13C chemical shift values and are presented in Table 3.
The theoretically calculated chemical shift values of aliphatic pro-
tons were observed in the shielded region of 4.83e5.11 ppm and
experimentally a sharp singlet is observed at 5.48 ppm which is
attributed to two CH2 protons. The experimental chemical shifts
were obtained in the deshielded region of 7.29e8.84 ppm which is
attributed to aromatic ring protons while the theoretical values are
found in the region of 6.57e9.01 and 7.55e10.36 ppm by using
B3LYP and M06-2X level of theories respectively.
In 13C NMR, the experimental chemical shift values of the aro-
matic carbons have appeared in the region of 120.36e149.64 ppm.
In the present investigation, theoretically calculated chemical shift
values of 13C aromatic carbons were found to be in the range of
105.88e143.37 ppm. In addition to that, aliphatic carbons C21 and
C41 (carbon atoms are numbered using Fig. 1b) give a signal in the
upfield region at 67.37 and 70.33 ppm respectively with the cor-
responding theoretical values of 57.89 and 61.82 ppm (B3LYP) and
53.82 and 59.44 ppm (M06-2X). As the compound 3 contains a Cl
group which is an electronegative functional group, it polarizes the
electron distribution. In 13C NMR, the experimental chemical shift
value of C47 bonded to Cl group is too high as observed in the
downfield region of 154.07 ppm and the corresponding theoretical
13
C NMR chemical shift of Cl group is noted at 141.28 ppm. From
Table 3, the difference between experimental and theoretical
values is in the range of 0.004e2.31 ppm and 0.3e32 ppm for the
1
H and 13C NMR respectively. Theoretical data of 1H and 13C
chemical shift values are in good agreement with the experimental
data since, the error between the theoretical and experimental
values can up to 30 ppm [50]. The experimental and theoretical
NMR chemical shift values are portrayed by using Root Mean
Square Deviation by Linear regression plot given in Fig. S3. From the
figure it is found that the correlation coefficient obtained for the 1H
and 13C NMR at B3LYP and M06-2X level of theories are found as
0.9538, 0.9661, 0.8751 and 0.8750 respectively which represent the
good correlation between the experimental and theoretical values.
3.12. Molecular electrostatic potential
The electrostatic potential map (MEP) is used to visualize the
charge distributions in molecules, the size and shape of molecules
along with the charge-related properties of molecules [51,52]. The
molecular electrostatic potential V(r) is defined as
X Z
ZA rðr0 Þ
VðrÞ ¼  dðr 0 Þ
ðRA  rÞ ðr 0  rÞ
A
where ZA is the charge of nucleus A, located at RA, r(r') is the
electronic density function of the compound. A molecular electro-
static potential map (MEP) was used to visualize the charge dis-
tributions over compound 3 and identify the reactive sites of the
compound.
Using the density functional B3LYP with 6-31þG(d,p) basis set,
the MEP was plotted over the optimized geometry of molecule 3. In
MEP, the red color refers to negative electrostatic potential regions
(electron-rich) which are related to electrophilic attack while blue
color refers to positive electrostatic potential regions (electron-
poor) which are related to nucleophilic attack. The green color re-
fers to zero electrostatic potential. From Fig. 4, it is observed that
compound 3 has several possible sites for electrophilic attack.
These negative sites in compound 3 were found around the N1, N2
and N3 atoms as 0.102, 0.190 and 0.178 a.u respectively in the
quinoline ring and negative potential is also found around O1 and
O2 atoms of ether linkage as 0.345 and 0.300 a.u. From the
obtained values, it is clear that a greater electrophilic region is
found around the oxygen atoms O1 and O2 of the ether linkage.
This might be due to the presence of delocalization of charge
around the oxygen atoms. The positive potential regions are highly
localized over the hydrogen atoms of the quinoline rings which are
susceptible to nucleophilic attack and the corresponding positive
charges are in the range of 0.176e0.248 a.u. In general, halogen
atoms are electronegative which favors electrophilic attack. How-
ever, in the present work, green color in the MEP indicates the
radical attacking site due to the Cl atom and the corresponding
Fig. 4. Molecular electrostatic potential (MEP) map of compound 3 calculated at
B3LYP/6-31þG(d,p) level of theory.
 K. Gayathri et al. / Journal of Molecular Structure 1134 (2017) 770e780
Table 4
The chemical reactivity parameters of compound 3 using B3LYP/6-31þG(d,p) and
M06-2X/6-31þG(d,p) level of theories.
Parameters B3LYP/6-31þG(d,p) M06-2X/6-31þG(d,p)
HOMO energy (a.u) 0.2235 0.22628
LUMO energy (a.u) 0.0659 0.06754
Ionization Potential (eV) 6.0836 6.1575
Electron Affinity (eV) 1.7956 1.8377
Global Hardness (eV) 2.1440 2.1598
Chemical potential (eV) 3.9396 3.9976
Electrophilicity (eV) 3.6196 3.6997
charge value is 0.088 a.u.
3.13. Frontier molecular orbitals (HOMO and LUMO)
The HOMO energy represents the electron donating ability
while the LUMO represents the electron-accepting ability of the
molecule. The Eigen values of HOMO and LUMO designate the
chemical stability and reactivity of a molecule [53]. The frontier
molecular orbitals play an important role in describing the HOMO,
LUMO energies and were calculated by using B3LYP/6-31þG (d,p)
and M06-2X/6-31þG (d,p).
The frontier molecular orbital [54] is very useful in determining
the electrical transport properties of the molecules. HOMO and
LUMO values are used in determining the chemical reactivity, ki-
netic stability, chemical hardness and softness of the compound,
properties that are used to describe the bioactivity of a molecule via
intermolecular charge transfer [55]. A molecule with a large
HOMO-LUMO energy gap is more stable, less polarizable and with
less chemical reactivity is said to be hard species while a molecule
with a small HOMO-LUMO gap is said to be soft species [56].
According to Koopmans theorem [57], from the HOMO and
LUMO energy values, ionization potential (I), chemical potential(m),
electron affinity (A), chemical hardness (h) and electrophilicity (u)
were calculated and the results are shown in Table 4. The calculated
HOMO and LUMO values of the compound 3 are 6.0836
and 1.7957 eV (B3LYP) and 7.3574 and 0.9377 eV (M06-2X). The
HOMO-LUMO energy gap of the compound 3 is 4.28800 eV
and 6.4197 eV at B3LYP and M06-2X level of theories. The energy
distributions and levels of HOMO-3, HOMO-2, HOMO-1, HOMO,
LUMOþ1, LUMOþ2, LUMOþ3 orbitals computed by using B3LYP/6-
31þG(d,p) level of theory are shown in Fig. 5 and Fig. S4. The HOMO
Fig. 5. Plots of the frontier orbital of molecule 3 using B3LYP/6-31þG(d,p).
777
of the compound 3 is localized over the 6-substituted quinoline and
LUMO is distributed over the Cl-substituted and 3-substituted
quinoline.
Electrophilicity (u) is used to determine the energy lowering
due to electron flow between an acceptor and donor [58]. Recently,
Bondarchuk et al. [59,60] reported the modern developments of
electrophilicity concepts. To calculate the global (u) and local
electrophilicity (uþk ) indexes, vertical and adiabatic approaches
have been used and the experimental data supports the adiabatic
approach. This index is also useful in finding out the toxicity value
in terms of site selectivity and reactivity [61]. In our present work,
the toxicity values (log 1/IC50) can be determined by the regression
equation given below
log½1=IC50  ¼ 3:3944  u  5:5788:
The above equation was tested for aliphatic amines, poly-
chlorinated dibenzofurans and polychlorinated biphenyls against
ciliate fresh water protozoa Tetrahymena pyriformis [62] where
electrophilicity index (u) is taken as an independent variable. Cell
viability graphs of compound 3 using MTT assay are shown in
Fig. S5. The IC50 value by MTT assay was calculated as 21.02 mM and
27.73 mM against HeLa and MCF-7 cancer cell lines. The toxicity
values (log 1/IC50) were observed as 19.61 mM and 10.48 mM at
B3LYP and M06-2X level of theories respectively which are com-
parable with the experimental values.
3.14. Electronic spectra
The electronic absorption spectrum of the title compound 3 was
recorded in the range 200e600 nm using the solvent as ethanol
and the representative spectrum is given in Fig. 6. From the figure, it
can be observed that the electronic absorption spectrum showed
one maximum at 233 nm are caused by the n-p* transitions and
two strong shoulder bands at 315 and 364 nm might be due to p-p*.
This spectral absorption is similar to those found in related quin-
oline compounds [63,64].
The TD-DFT/B3LYP/6-31þG(d,p) calculations were done for the
optimized structure of the compound 3 in ethanol solvent using
PCM model. The stimulated UVeVis spectra are shown in Fig. 6.
From the calculations, it is observed that by using the B3LYP level of
theory, the computed absorption wavelengths are obtained at
286.08, 291.31, 317.14, 319.96, 331.75 nm. For M06-2X, the theo-
retical absorption values were found to be 241.62, 258.81, 268.60,
778 K. Gayathri et al. / Journal of Molecular Structure 1134 (2017) 770e780

Fig. 6. (a) Experimental UVeVisible spectra of compound 3 (1  103 M) in EtOH/H2O 1:1 (v/v). Theoretical UVeVisible spectra of compound 3 in ethanol phase calculated by (b)
B3LYP and (c) M06-2X level of theories using PCM model.

281.42, 349.77 nm. The calculated values along with their oscillator resolve the unambiguity of the structure both by theoretical and
strength (f) and the experimental values are listed in Table 5. Thus experimental studies, complete spectroscopic studies FT-IR, FT-
theoretical absorption values are in good agreement with the Raman, 1H NMR, 13C NMR, UV- Vis, HOMO and LUMO were un-
experimental value. dertaken and found to be in agreement with the experimental
values of the synthesized compound. By using the PCM model, the
absorption maximum (lmax) of the compound was found by TD-
4. Conclusion DFT calculations and compared with the experimental spectra.
Most of the experimental data were found to be in good agreement
The present work reports a novel tri-quinoline compound which with the theoretical results. It has been noticed that the experi-
has been synthesized to find out the anticancer activity. In order to mental data were obtained in solid phase while all the theoretical
calculations were done in gaseous phase except the electronic
Table 5
spectrum which was calculated in solvent phase. The small differ-
Experimental and theoretical electronic transitions and its oscillator strength of ence in the results might be due to the phase used. The study also
compound 3. revealed some interesting facts in terms of studying the possible
Wavelength(l) nm Oscillator strength(f)
electrophilic and nucleophilic sites of the compound using molec-
ular electrostatic potential map and showed that the positive po-
Theoretical Experimental
tential regions are around the hydrogen atoms while the negative
B3LYP M06-2X B3LYP M06-2X potential regions are on electronegative atoms. The eventual charge
286.08 241.62 233 0.0628 1.075 transfer interactions were studied using frontier orbital analysis.
291.31 258.81 e 0.0493 0.094 IC50 of the compound was found to be 21.02 mM and 27.73 mM
317.14 268.60 315 0.0816 0.1488 against HeLa and MCF-7 cancer cell lines using MTT assay and is in
319.96 281.42 0.1403 0.2592
agreement with the theoretical data.
e
331.75 349.77 364 0.0327 0.2678
 K. Gayathri et al. / Journal of Molecular Structure 1134 (2017) 770e780
Acknowledgement
Our sincere thanks go to the SIF, VIT-University, Vellore, for
providing access their NMR spectral facilities. P.S.M thanks, DRDO-
BU-CLS (DLS/86/50071/DRDO-BU centre/Phase-II) for funding. Two
of the authors R. S and R. R are thankful to DST-SERB-Fast Track
Project grant No: SR/FTP/PS-151/2011 & 22.05.2012 for financial
assistance. One of the authors K.S is thankful to the University Grant
Commission (UGC-SAP), New Delhi, for BSR - Senior Research
Fellowship, which is gratefully acknowledged.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2017.01.030.
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