Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

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Spectrochimica Acta Part A: Molecular and

Biomolecular Spectroscopy
journal homepage: www.elsevier.com/locate/saa

Spectroscopic, quantum chemical and molecular docking studies on

1-amino-5-chloroanthraquinone: A targeted drug therapy for thyroid
cancer
T. Valarmathi a, R. Premkumar a, M.R. Meera b, A. Milton Franklin Benial a,⇑
a
P.G. and Research Department of Physics, N.M.S.S.V.N. College, Madurai 625019, Tamil Nadu, India
b
Department of Physics, Sree Ayyappa College for Women, Chunkankadai, Kanyakumari 629003, Tamil Nadu, India

h i g h l i g h t s g r a p h i c a l a b s t r a c t

FT-IR, FT-Raman and FT-NMR spectra

of 1-Amino-5-chloroanthraquinone
were reported.

Fukui functions and FMOs analysis
indicates the chemical reactivity of
the molecule.

MEP analysis confirms the reactive
sites of the ACAQ molecule.

Docking results show that the
molecule can be useful for the
Thyroid cancer remedy.

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

Article history: The DFT studies of the 1-Amino-5-chloro-anthraquinone (ACAQ) molecule have been carried out with
Received 5 October 2020 extensive and accurate investigations of detailed vibrational and spectroscopic investigations and
Received in revised form 7 January 2021 validated by experimentally. The optimized molecular structure and harmonic resonance frequencies
Accepted 28 February 2021
were computed based on DFT/B3LYP method with 6-311G++(d,p) basis set using the Gaussian 09
Available online 9 March 2021
program. The experimental and calculated vibrational wavenumbers were assigned on the basis of PED
calculations using VEDA 4.0 program. The 13C NMR isotropic chemical shifts of the molecule were
Keywords:
calculated using Gauge-Invariant-Atomic Orbital (GIAO) method in DMSO solution and compared with
1-Amino-5-chloro-anthraquinone
DFT
the experimental data. The absorption spectrum of the molecule was computed in liquid phase (ethanol),
FT-IR which exhibits k to k* electronic transition and compared with observed UV–Vis spectrum. Frontier
FT-Raman molecular orbitals analysis shows the molecular reactivity and kinetic stability of the molecule. The
FT-NMR Mulliken atomic charge distribution and molecular electrostatic potential surface analysis of the
Molecular docking molecule validate the reactive site of the molecule. The natural bond orbital analysis proves the
Thyroid cancer bioactivity of the molecule. Molecular docking analysis indicate that ACAQ molecule inhibits the action
of c-Met Kinase protein, which is associated with the thyroid cancer. Hence, the present study pave
the way for the development of novel drugs in the treatment of thyroid cancer.
Ó 2021 Elsevier B.V. All rights reserved.

1. Introduction

Anthraquinones are a group of natural compounds that are

⇑ Corresponding author at: Department of Physics, N.M.S.S.V.N. College, Naga- classified as the most abundant quinones in the universe. They
malai, Madurai 625019, Tamil Nadu, India. are found in all plant parts, particularly roots, rhizomes, fruits and
E-mail address: miltonfranklin@yahoo.com (A. Milton Franklin Benial).

https://doi.org/10.1016/j.saa.2021.119659
1386-1425/Ó 2021 Elsevier B.V. All rights reserved.
T. Valarmathi, R. Premkumar, M.R. Meera et al.
flowers, and are found in a variety of foods, including peas, cabbage,
lettuce and beans [1]. Anthraquinones are the largest group of nat-
ural pigments described in approximately 700 compounds, and
about 200 of these compounds were isolated from plants and the
remainder isolated from lichens and fungi [2,3]. Anthraquinones
and their derivatives, produced as secondary metabolites in plants,
lichens, insects, and higher filamentous fungi, occur either in a free
form or as glycosides. They are used in a wide range of applications,
for example, as coloring agents in the food and textile industries
and as therapeutic agents for various diseases [4,5]. Clinically, they
show a wide range of bioactivity. Most of them are called laxatives
for constipation. Besides the activity of laxatives, the most studied
anthraquinone: emodin, catalyst, anti-inflammatory, anticancer,
antimicrobial, diuretic, DNA-binding and vaso-relaxant activities
have been reported [6–9]. Generally, anthracyclines are used in
the treatment of myeloid leukemia, malignant lymphomas, and
breast cancer [10–12]. Anthraquinone glycosylated derivatives
such as daunorubicin, doxorubicin, and carminomycin have been
used as the most active anthracycline antibiotics in the treatment
of multiple tumors. These molecules have been already in use for
many decades [13–15]. Anthraquinones are used as dyes in the
textile industry, providing a variety of shades depending on the
character and condition of the oxychromic groups in their base
skeleton [16–18].
Cancer is the second most widespread serious disease all over
the world and it is characterized by uncontrolled growth of abnor-
mal cells [19]. In recent years, cancer treatment has been a major
venture of research and development. So that, the search for potent
and selective anticancer drugs are needed due to the limitation of
available anticancer drugs [20] Recently, the bioactive anthraqui-
none derivatives were reported that which inhibits the harmful
disease associated targeted proteins, significantly cancer causing
proteins such as c-Met Kinase [21], Epidermal Growth Factor
Receptor (EGFR) [22], Histone deacetylase 6 (HDAC6) [23] and pro-
tein p53 [24]. The c-Met is a receptor tyrosine kinase, which is the
product of the MET proto-oncogene and it is expressed on the sur-
faces of various cells [25]. The structure-function relationships in
the c-Met kinase pathway have considerable importance in the
development of inhibitors for cancer therapy. Recently, an inhibi-
tor of c-Met kinase was reported as a clinically important thera-
peutic target for the development of metastatic medullary
thyroid cancer drugs [26]. Moreover, anthraquinone derivatives
inhibit the actions of c-Met kinase [21]. Thus, the anthraquinone
derivatives can be used as a inhibitor of c-Met kinase, which will
be useful for the designing of thyroid cancer drugs. EGFR is a mem-
ber of the ErbB protein family, which is deregulated and overex-
pressed in ovarian cancer cells [27]. Recently, the anthraquinone
derivatives inhibit the EGFR activity, which will be useful for the
development of ovarian cancer drugs [22]. HDAC6 was over
expressed in oral squamous cell carcinoma and it was also impli-
cated in several non-epigenetic cancer-related intracellular func-
tions [28]. The anthraquinone-based compounds were reported
as inhibitor of HDAC6 protein [23]. The anthraquinone derivatives
have the ability to treat the oral squamous cell carcinoma. After
that, an activation of tumor suppressor protein p53 is a most com-
mon genetic mechanism in lung cancer and also p53 was reported
as a novel targeted protein for the lung cancer treatment [24].
Anthraquinone derivatives including aloe-emodin, emodin, and
rhein have antitumor properties through the activation of p53
pathway [24].
Recently, a new anthraquinone [1-(2-Aminoethyl)piperazinyl-
9,10-dioxo-anthraquinone] derivative was synthesized and charac-
terized by density functional theory calculations, which shows
highest anti-bacterial activity against Gram-positive bacteria in-
cluding Staphylococcus aureus and S. epidermidis [29]. Renjith et.
al. reported that spectroscopic and molecular docking
2
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659
investigations of 1-hydroxy-4,5,8-tris(4-methoxyphenyl) anthra-
quinone, which exhibit inhibitory activity against Phosphoinosi-
tide 3-kinase (PI3K) and can act as an anti-neoplastic agent [30].
Recently, a DFT quantum chemical and molecular docking study
on 1-Hydroxyanthraquinone molecule was reported [31], which
acts as a good ovarian cancer drug. Valarmathi et al. reported that
DFT and molecular docking studies on 1,4-bis(methylamino)anthra
quinone molecule [32], which confirms that this molecule can act
as a potent drug for the treatment of pancreatic cancer. The struc-
tural, vibrational spectroscopic and molecular docking investiga-
tion on 1-(Methylamino) anthraquinone was reported [33],
which can act as a potential inhibitor against c-Met kinase.
Quantum chemistry calculation helps to understand the molec-
ular geometry and electronic properties at its atomic level by sup-
porting spectroscopic techniques. Furthermore, computational
modelling such as molecular docking tool can be very useful in
accelerating pharmacological research and improving selection
and persistence to answer specific questions about biological or
behavioural interventions. Although there are many therapeutic
agents available, finding analogies is the most effective and com-
plete treatment. This can be successfully achieved in the medical
field by suggesting new formulas, administration methods and
new analogues of existing drugs. The sophisticated vibrational
spectroscopy helps to understand the molecular geometry and
the intrinsic properties of the molecule at its atomic level. Inte-
grated DFT and experimental vibrational frequency calculations
were performed to characterize the properties of the molecule
[34]. Further, the molecular docking analysis is helpful to study
the affinity, selectivity, and stability of the molecule, which is
mainly useful for the pharmacology research to answer specific
questions about biomedical or behavioral intervention. Recently,
the vibrational spectroscopic and molecular docking analyses of
anthraquinone derivatives have been reported due to their poten-
tial importance in biological and pharmaceutical applications
[25–29]. There is no quantum chemical, vibrational spectroscopic
and molecular docking studies of the title molecule, 1-Amino-5-
chloro-anthraquinone were not reported yet. Therefore,
considering all of these special features, in the present study, vibra-
tional spectral analyses, NMR studies, ultraviolet–visible (UV–Vis)
spectral analysis, Mulliken atomic charge distribution analysis,
frontier molecular orbitals (FMOs) analysis, molecular electrostatic
potential surface (MEP) and natural bond orbital (NBO) analysis of
the ACAQ molecule were carried out and compared with the exper-
imental results. In addition, molecular docking analysis of the
ACAQ molecule was performed against the various harmful cancers
associated targeted proteins.
2. Materials and methods
2.1. Experimental characterizations
The ACAQ compound with 99% purity was purchased from
Sigma-Aldrich, chemicals Co, St. Louis, Mo, USA. Fourier
transform-infrared (FT-IR) spectrum of the compound was
recorded with Perkin Elmer Spectrum 1 FT-IR spectrometer by
using a KBr pellet technique at room temperature with a resolution
of 1.0 cm1. FT-Raman spectrum of the sample was recorded using
BRUKER RFS 27: Stand-alone Raman spectrometer at room temper-
ature with a resolution of 2 cm1. The FT-IR and FT-Raman spectra
were recorded in the wavenumber region 3500–400 cm1. The
UV–Vis spectrum of the sample was recorded by the Shimadzu
UV-3600 UV Vis-NIR spectrophotometer (Shimadzu Scientific
Instruments, Columbia, MD) in the wavelength region
200–600 nm using ethanol as a solvent. The 13C nuclear magnetic
T. Valarmathi, R. Premkumar, M.R. Meera et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

resonance (NMR) spectrum was documented on a BRUKER AVIII

500 instrument using DMSO solvent.

2.2. Computational details

The molecular structure of the ACAQ molecule was optimized

by DFT/B3LYP method with basis set 6-311G++ (d,p) using Gaus-
sian 09 program [35]. The most stable optimized structure of the
molecule was predicted by the DFT/B3LYP method with 6-311G+
+ (d.p) basis set. The vibrational wavenumbers were calculated
for the most stable optimized molecular structure of the molecule.
Raman scattering activities of the fundamental modes were con-
verted in to the relative Raman intensities using Gauss-Sum 3.0
program [36]. The calculated vibrational wavenumbers were
assigned on the basis of potential energy distribution (PED) calcu-
lation using VEDA 4.0 program [37]. The UV–vis spectrum was
simulated by the time dependent (TD)-DFT/B3LYP method associ-
ated with the polarizable continuum model (PCM) using 6-311G++
(d,p) basis set using ethanol as the solvent. The optimized molecu-
lar structure, calculated vibrational wavenumbers and UV–Vis
spectrum, NMR spectrum, Mulliken atomic charge distribution,
MEP surface and FMOs were visualized by the GaussView 05 [38]
program. All the calculations were executed at the ground state
energy level of the ACAQ molecule without applying any restraint
on the potential energy surface. In addition, the molecular docking
analysis was carried out to understand the inhibitory nature of the
ACAQ molecule against various cancer associated targeted proteins
such as c-Met Kinase [PDB ID: 4XMO], EGFR [PDB ID: 1M17],
HDAC6 [PDB ID: 5EF7] and protein p53 [PDB ID: 1YCS].

3. Results and discussion

3.1. Molecular geometry and symmetry

The molecular structure of ACAQ was optimized by the DFT/
B3LYP method with 6-311G++ (d.p) basis set. The energy values
of the optimized molecular geometries were calculated as
1203.94 a.u. by the 6-311G++ (d.p) basis set. The before and after
optimized molecular structure of the ACAQ molecule were shown
in Fig. 1. The global minimum energy of ACAQ was predicted by the
DFT/B3LYP method with 6-311G++ (d.p) basis set. The calculated
molecular geometry parameters such as bond length, bond angle
and dihedral angle of ACAQ structure for the two different basis
sets cc-pVDZ, 6-311G++ (d,p) and the calculated structural param-
eters were compared with the available X-ray diffraction data of
the 1-Dimethylamino-9,10-anthraquinone [39] were shown in
Table 1. The molecular geometry of the ACAQ molecule possesses
C1 point group symmetry. All the vibrational modes are found to
be IR and Raman active, which suggest that the ACAQ molecule
possesses a non-centro symmetric structure. The optimized molec-
ular geometry of the ACAQ molecule lies in the local minimum on
the potential energy surface, which was confirmed by the absence
of negative values in the calculated vibrational wavenumbers.
3.2. Vibrational spectral analysis
The chosen molecule has 26 atoms and 72 normal modes of
vibrations, which belongs to the same symmetry species. The
vibrational frequencies, IR intensity, Raman scattering activity,
reduced mass and force constant values were calculated for the
most stable optimized structure of the ACAQ molecule, which were
listed in Table 2. The ACAQ molecule possesses C1 point group
symmetry, which has no symmetry other than identity. So, the nor-
mal modes of vibrations belong to the symmetry species (A). In
order to account anharmonicity in DFT calculations, the calculated
3
Fig. 1. The molecular structure of the ACAQ molecule (a) before optimization and
(b) after optimization.
vibrational frequencies were scaled by scaling factors. The different
scaling factors were used for different modes of vibrations for
better agreement [40]. The scaling factor of ACAQ calculated by
[41] the formula,
C ¼ Rðmi  xi Þ=Rx2i
where C is the scaling factor, mi and xi are experimental fundamen-
tal frequency and theoretical harmonic frequency respectively. The
scaling factors used for stretching and bending vibrations were
0.9672 and 0.9847 respectively. The experimentally recorded and
theoretically simulated infrared and Raman spectra of the molecule
were shown in Fig. 2 and Fig. 3, respectively. The various vibrational
modes of experimental and theoretical values were consigned on
the basis of PED calculations and also listed in Table 2. The calcu-
lated and experimentally observed vibrational wavenumbers were
correlated well by using scaling factor value of 0.9672 and 0.9847.
The deviation between the experimental and calculated values is
approximately 5%. The vibrational assignments of the ACAQ mole-
cule were performed using VEDA 4.0 program, which has been used
as a good tool for vibrational assignments by many researchers
[42–51]. The potential energy distributions (PED) analysis using
VEDA 4.0 program concerning the internal symmetric coordinates,
force constants and frequencies of vibrational modes, which can
provide the accurate vibrational assignments.
3.2.1. CAH vibrations
In aromatic compounds, CAH stretching band appear in the
range 3100–3000 cm1 [42]. The CAH asymmetric stretching
vibration band of the selected molecule was found to be the
T. Valarmathi, R. Premkumar, M.R. Meera et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

Table 1
The optimized structrual parameters of the ACAQ molecule calculated by the DFT/B3LYP method with cc-pVDZ and 6-311 G++ (dp) basis set.

Structural Parameters 6-311G++ (d,p) CC-PVDZ Ref. [39]

Bond length (Ǻ)
C1-C2 1.42 1.42 1.41
C1-N13 1.35 1.36 1.37
C1-C15 1.43 1.43 1.43
C2-C3 1.38 1.38 1.36
C2-H19 1.09 1.09 0.93
C3-C4 1.40 1.40 1.37
C3-H20 1.08 1.09 0.93
C4-C16 1.39 1.39 1.37
C4-H21 1.08 1.09 0.93
C5-C6 1.39 1.40 1.37
C5-Cl14 1.75 1.75 –
C5-C18 1.41 1.41 1.39
C6-C7 1.39 1.39 1.38
C6-H22 1.08 1.09 0.93
C7-C8 1.39 1.39 1.38
C7-H23 1.08 1.09 0.93
C8-C17 1.39 1.40 1.39
C8-H24 1.08 1.09 0.93
C9-O11 1.23 1.24 1.23
C9-C15 1.46 1.46 1.47
C9-C17 1.50 1.50 1.48
C10-O12 1.22 1.22 1.23
C10-C16 1.50 1.50 1.48
C10-C18 1.50 1.50 1.47
N13-H25 1.01 1.02 –
N13-H26 1.00 1.01 –
C15-C16 1.42 1.42 1.42
C17-C18 1.41 1.42 1.39
Bond angle (degree)
C2-C1-N13 119.75 120.16 119.50
C2-C1-C15 118.25 118.27 117.70
N13-C1-C15 122.00 121.56 122.80
C1-C2-C3 121.10 121.03 121.70
C1-C2-H19 118.60 118.62 119.10
C3-C2-H19 120.29 120.35 119.10
C2-C3-C4 120.92 120.95 120.80
C2-C3-H20 119.38 119.32 119.60
C4-C3-H20 119.71 119.72 119.60
C3-C4-C16 119.51 119.48 119.90
C3-C4-H21 121.68 121.81 120.10
C16-C4-H21 118.81 118.72 120.10
C6-C5-Cl14 115.36 115.36 –
C6-C5-C18 121.02 120.99 120.90
Cl14-C5-C18 123.62 123.65 –
C5-C6-C7 120.37 120.38 119.80
C5-C6-H22 118.83 118.71 120.10
C7-C6-H22 120.80 120.91 120.10
C6-C7-C8 119.87 119.86 120.20
C6-C7-H23 119.69 119.68 119.90
C8-C7-H23 120.45 120.46 119.90
C7-C8-C17 120.18 120.15 120.50
C7-C8-H24 121.74 121.86 119.80
C17-C8-H24 118.08 117.99 119.80
O11-C9-C15 122.80 122.84 122.30
O11-C9-C17 118.52 118.44 119.20
C15-C9-C17 118.68 118.72 119.20
O12-C10-C16 119.74 119.71 120.80
O12-C10-C18 122.36 122.34 120.70
C16-C10-C18 117.90 117.95 118.50
C1-N13-H25 118.46 117.64 –
C1-N13-H26 120.08 120.11 –
H25-N13-H26 121.46 122.25 –
C1-C15-C9 120.87 120.73 123.70
C1-C15-C16 119.21 119.29 117.80
C9-C15-C16 119.92 119.98 117.70
C4-C16-C10 116.82 116.95 117.50
C4-C16-C15 121.02 120.98 121.40
C10-C16-C15 122.17 122.06 121.10
C8-C17-C9 116.55 116.64 119.80
C8-C17-C18 121.12 121.16 119.00
C9-C17-C18 122.32 122.20 121.10
C5-C18-C10 123.54 123.46 120.70
C5-C18-C17 117.44 117.46 119.60

4
T. Valarmathi, R. Premkumar, M.R. Meera et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

Table 1 (continued)

Structural Parameters 6-311G++ (d,p) CC-PVDZ Ref. [39]

C10-C18-C17 119.02 119.08 119.70
Dihedral angle (degree)
N13-C1-C2-C3 179.99 179.99 172.00
N13-C1-C2-H19 0.01 0.01 –
C15-C1-C2-C3 0.00 0.00 6.60
C15-C1-C2-H19 180.00 180.00 –
C2-C1-N13-H25 180.05 180.05 –
C2-C1-N13-H26 0.07 0.07 –
C15-C1-N13-H25 0.06 0.05 –
C15-C1-N13-H26 180.06 180.06 –
C2-C1-C15-C9 179.99 179.99 159.70
C2-C1-C15-C16 0.00 0.00 9.80
N13-C1-C15-C9 0.02 0.02 –
N13-C1-C15-C16 179.99 179.99 –
C1-C2-C3-C4 0.00 0.00 0.20
C1-C2-C3-H20 180.00 180.00 –
H19-C2-C3-C4 180.00 180.00 –
H19-C2-C3-H20 0.00 0.00 –
C2-C3-C4-C16 0.00 0.00 3.70
C2-C3-C4-H21 180.00 180.00 –
H20-C3-C4-C16 180.00 180.00 –
H20-C3-C4-H21 0.00 0.00 –
C3-C4-C16-C10 180.00 180.00 177.50
C3-C4-C16-C15 0.00 0.00 0.20
H21-C4-C16-C10 0.00 0.00 –
H21-C4-C16-C15 180.00 180.00 –
Cl14-C5-C6-C7 180.00 180.00 –
Cl14-C5-C6-H22 0.00 0.00 –
C18-C5-C6-C7 0.00 0.00 1.00
C18-C5-C6-H22 180.00 180.00 –
C6-C5-C18-C10 180.01 180.01 176.60
C6-C5-C18-C17 0.00 0.00 0.90
Cl14-C5-C18-C10 0.01 0.01 –
Cl14-C5-C18-C17 180.01 180.01 –
C5-C6-C7-C8 0.00 0.00 1.90
C5-C6-C7-H23 180.00 180.00 –
H22-C6-C7-C8 180.00 180.00 –
H22-C6-C7-H23 0.00 0.00 –
C6-C7-C8-C17 0.00 0.00 1.00
C6-C7-C8-H24 180.00 180.00 –
H23-C7-C8-C17 180.00 180.00 –
H23-C7-C8-H24 0.00 0.00 –
C7-C8-C17-C9 180.01 180.00 179.90
C7-C8-C17-C18 0.00 0.00 0.90
H24-C8-C17-C9 0.01 0.00 –
H24-C8-C17-C18 180.00 180.00 –
O11-C9-C15-C1 0.01 0.00 13.80
O11-C9-C15-C16 180.01 180.01 155.60
C17-C9-C15-C1 180.01 180.01 169.20
C17-C9-C15-C16 0.02 0.01 21.30
O11-C9-C17-C8 0.01 0.00 14.80
O11-C9-C17-C18 180.00 180.00 164.10
C15-C9-C17-C8 180.01 180.01 168.10
C15-C9-C17-C18 0.01 0.00 12.90
O12-C10-C16-C4 0.02 0.02 0.40
O12-C10-C16-C15 180.02 180.02 178.10
C18-C10-C16-C4 180.02 180.01 179.50
C18-C10-C16-C4 0.02 0.01 1.80
O12-C10-C18-C5 0.02 0.02 8.30
O12-C10-C18-C17 180.03 180.03 169.20
C16-C10-C18-C5 180.02 180.01 171.80
C16-C10-C18C-C17 0.03 0.02 10.70
C1-C15-C16-C4 0.00 0.00 6.60
C1-C15-C16-C10 180.00 180.00 175.80
C9-C15-C16-C4 180.01 180.01 163.50
C9-C15-C16-C10 0.00 0.01 14.10
C8-C17-C18-C5 0.00 0.00 1.90
C8-C17-C18-C10 180.01 180.01 175.70
C9-C17-C18-C5 180.01 180.01 179.20
C9-C17-C18-C10 0.02 0.01 3.30

5
T. Valarmathi, R. Premkumar, M.R. Meera et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

Table 2
Experimentally observed and calculated vibrational frequencies (cm1), IR intensities (Km mol1), Raman scattering activity (Å4 amu1), reduced mass (amu), force constants
(mDyne/Å1) and vibrational assignments based on PED calculations for the ACAQ molecule.

Wavenumber (cm1) Wavenumber

(cm1)
Experimental Theoretical
FT-IR FT-Raman Unscaled Scaled Reduced mass Force constant IR intensity Raman activity Assignment with PED%
3444m 3706 3584 1.10 8.89 78.13 111.02 mas NAH (100)
3326m 3522 3406 1.05 7.69 71.94 329.06 ms NAH (100)
3218 3113 1.09 6.66 2.26 100.89 m U CAH (97)
3215 3110 1.09 6.66 4.65 110.47 m U CAH (93)
3205 3099 1.09 6.62 2.91 181.54 m U CAH (89)
3180 3075 1.09 6.49 6.07 158.35 m U CAH (87)
3074w 3071s 3180 3075 1.09 6.51 24.39 219.33 ms U CAH (96)
3159 3055 1.09 6.39 10.17 120.95 mas U CAH (99)
1666m 1664vs 1738 1681 12.50 22.25 135.25 172.97 m U O@C (83)
1634m 1634s 1685 1629 7.82 13.08 149.84 208.35 m U O@C (59)
1601s 1602w 1649 1623 3.31 5.31 254.59 42.61 m U C@C (11),m U CAC (10), b HNH (22)
1617 1592 4.51 6.94 58.39 55.07 ms U CAC (50)
1573m 1576vs 1609 1584 2.90 4.42 84.43 174.57 mas U CAC (23), b HNH (18)
1601 1576 6.43 9.70 41.67 5.81 m U CAC (34), b U CCC (16)
1539s 1581 1557 3.18 4.68 163.30 16.88 mas U CAC (17), mas U C@C (10), b HNH (20)
1491 1469 3.11 4.07 8.19 9.28 m U CAC (25), b U HCC (17)
1482 1459 2.56 3.31 43.47 10.06 b U HCC (25), b U HNH (13)
1457m 1453vw 1472 1449 2.41 3.08 4.38 44.22 b U HCC (51)
1430w 1451 1428 3.43 4.25 23.34 2.82 ms U CAC (11), b U HCC (33)
1377m 1381vw 1396 1375 5.39 6.19 32.60 59.23 ms U CAC (22), ms U C@C (21)
1343vw 1368 1347 3.72 4.10 1.28 79.61 m U CAN (27)
1335 1314 8.96 9.40 79.27 9.94 mas U CAC (60)
1304s 1306vw 1314 1294 2.84 2.89 151.58 29.02 mas U CAC (22), b U HCC (10), b U HNC (10)
1257vs 1278 1259 3.77 3.63 529.77 27.14 mas U CAC (26), b U HCC (12)
1206m 1228 1210 2.00 1.78 54.37 3.76 m U CAC (20), b U HCC (24)
1206 1187 1.81 1.55 6.44 84.35 m U CAC (10), b U HCC (43)
1178vs 1194 1176 1.29 1.08 16.61 60.09 m U C@C (11), b U HCC (60)
1166s 1189 1171 1.40 1.17 11.81 20.11 m U CAC (11), b U HCC (41)
1131s 1129vw 1147 1130 3.70 2.87 44.55 32.79 m U CAC (16), m U ClAC (10), b U CCC (13)
1131 1113 1.72 1.30 8.93 65.50 m U CAC (14), b U HNC (16)
1072vs 1096 1079 2.20 1.56 0.57 92.55 ms U CAC (39), b U HCC (21)
1051m 1068 1051 2.63 1.76 9.70 7.96 m U CAC (11), b U HNC (16), b U CCC (26)
1016m 1027 1011 2.58 1.60 51.09 3.82 m U CAC (15), b U HNC (23)
1017 1002 1.34 0.82 0.41 0.13 g U HCCC (74), g U CCCC (13)
1001 985 1.33 0.78 0.34 0.58 g U HCCC (76), g U HCCN (11)
953 939 1.38 0.74 0.02 0.14 g U HCCC (79)
921w 933 919 6.36 3.26 7.21 41.04 m U CAC (16), b U CCC (10)
917w 919 905 1.45 0.72 0.39 0.53 g U HCCC (46), g U HCCN (31)
883w 900 886 7.04 3.36 17.03 18.80 Ring breathing mode
845w 848 835 3.95 1.67 1.23 0.61 g U OCCC (27), g U HCCN (14)
824 812 1.69 0.67 35.66 0.13 g U HCCC (39), g U HCCN (15)
808vs 820 807 7.33 2.90 27.89 3.15 b U CCC (20)
789 777 1.67 0.61 3.18 0.96 g U HCCC (12), g U OCCC (13), g U CCCC (10)
757vw 776 765 4.09 1.45 31.91 0.76 g U OCCC (42), g U NCCC (10)
738m 750 739 7.81 2.59 51.56 2.20 m U CACl (18), b U CCC (29)
705s 722 711 2.85 0.88 31.07 0.11 g U CCCC (41)
708 697 7.04 2.08 1.83 7.22 b U OCC (36)
674 663 4.48 1.20 0.03 0.16 g U CCCC (49),g U OCCC (11), g U NCCC (11)
640 630 1.08 0.26 25.35 0.09 g U HNCC (100)
614w 623 613 6.37 1.46 2.56 0.90 b U CCC (52)
569vw 571 562 6.41 1.23 0.69 18.66 b U CCC (18)
547m 563 554 4.00 0.75 6.88 0.64 g U CCCC (24), g U NCCC (23)
514 506 5.27 0.82 2.37 0.33 g U ClCCC (31), g U CCCC (22)
476vs 486 478 8.11 1.13 0.86 50.41 b U CCC (55)
483 475 3.84 0.53 5.77 0.11 g U CCCC (44)
468 461 5.62 0.73 11.18 4.39 m U ClAC (14), b U NCC (26)
435 429 5.12 0.57 0.16 0.81 g U CCCC (47), g U OCCC (27)
433 427 11.86 1.31 23.05 0.68 b U OCC (38),b U CCC (12)
416vw 419 413 6.13 0.63 0.53 4.83 b U OCC (17),b U CCC (10), b U NCC (17)
389 383 6.10 0.54 1.39 3.68 b U ClCC (29),b U CCC (20), b U NCC (10)
351vw 359 354 11.93 0.91 1.82 5.34 m U ClAC (11), b U CCC (14),b U OCC (14)
354 348 6.82 0.50 0.05 0.70 b U OCC (14),b U CCC (51)
266vw 262 258 6.79 0.27 4.41 5.37 g U CCCC (57), g U NCCC (11)
256 252 7.12 0.28 0.27 1.91 m U CAC (14),m U ClCC (19),b U CCC (14)
236 232 1.32 0.04 110.80 0.13 g U CCCC (26), g U HNCC (45)
208vw 212 209 4.77 0.13 14.27 0.38 g U ClCCC (22),g U CCCC (15), g U HNCC (13)
186 183 4.56 0.09 3.99 4.96 g U CCCC (53)
177 174 9.90 0.18 0.99 1.06 b U ClCC (31), b U CCC (29)
140 138 3.22 0.04 28.27 1.13 Butterfly mode
80 79 10.53 0.04 7.36 0.76 Butterfly mode

6
T. Valarmathi, R. Premkumar, M.R. Meera et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

Table 2 (continued)

Wavenumber (cm1) Wavenumber

(cm1)
Experimental Theoretical
FT-IR FT-Raman Unscaled Scaled Reduced mass Force constant IR intensity Raman activity Assignment with PED%
47 46 7.24 0.01 3.33 0.12 Butterfly mode
19 18 10.65 0.00 3.17 0.36 Butterfly mode

s – strong, vs – very strong, w – weak, vw – very weak, b – broad, m – medium, m – stretching, ms – symmetrical stretching, mas – asymmetrical stretching, b – in-plane bending,
d – Scissoring, q – rocking, s – Torsion, g – out of plane bending, U – ring, r – deformation.

and calculated as 1259 cm1. Moreover, the same vibrational

modes were observed as weak peaks at 1206, 1166, 1016 cm1
in FT-IR and the corresponding vibrational modes were calculated
as 1210, 1171 and 1011 cm1 respectively. The two very strong
peaks were observed at 1178 and 1072 cm1 in FT-Raman spec-
trum and the corresponding vibrational modes were calculated at
1176 and 1079 cm1 respectively. These assignments were
correlated well with the reported literature values [42,43].

3.2.2. C@O, CACAC group vibrations

Fig. 2. The infrared spectra of ACAQ molecule.
The carbonyl stretching vibrational modes mostly expected in
the region 1725 ± 65 cm1 [44,45]. The strength of C@O stretching
vibrations depend on the conjugation, hydrogen bonding, and elec-
tronic effects of the molecule [46,47]. The C@O stretching vibra-
tional modes of the title molecule were observed as two medium
peaks at 1666 and 1634 cm1 in FT-IR spectrum and observed as
strong peaks at 1664 and 1634 cm1 in FT-Raman spectrum,
respectively. The corresponding peaks were calculated as 1681
and 1629 cm1 respectively. The CCC and OCC in-plane bending
vibrational mode of the molecule was observed as weak band at
351 cm1 in FT-Raman spectrum and the corresponding vibra-
tional mode was calculated as 354 cm1. The OCC in plane bending
vibrational mode was observed as strong band at 705 cm1 in FT-IR
spectrum and the corresponding vibrational mode was calculated
at 711 cm1. The OC coupled with HCN out-of plane bending vibra-
tional modes was observed as very weak band at 757 cm1 in
FT- IR spectrum and which was calculated at 765 cm1
respectively.

3.2.3. CAC, HACAC and NACAH vibrations

Fig. 3. The Raman spectra of the ACAQ molecule.
weakest band at 3074 cm1 in FT-IR spectrum, and the strongest
band at 3071 cm1 in FT-Raman spectrum, and its corresponding
vibrational mode was observed at 3075 cm1. The aromatic CAH
in-plane bending vibrational modes of benzene and its derivatives
were observed in the region 1300–1000 cm1. The very strong
peak was observed at 1257 cm1 in FT-IR spectrum of the molecule
7
The aromatic ring CAC stretching vibrational mode normally
appear in the region between 1608 and 1040 cm1 [48]. The CAC
stretching coupled with the C@C stretching vibrational modes of
the molecule were observed as a medium to weak bands at 1601,
1573, and 1377 cm1 in FT-IR spectrum and the corresponding
peaks were calculated at 1623, 1584, and 1375 cm1. The very
strong to very weak bands observed at 1602, 1576, 1381, 1129
and 921 cm1 in FT-Raman spectrum and calculated at 1623,
1584, 1375, 1130 and 919 cm1 which were assigned to CAC
stretching vibrational mode coupled with other stretching and
bending vibrational modes of the molecule. The CAC in-plane
bending vibrational modes were obtained as very weak peak at
614 cm1 in FT-IR spectrum and the corresponding peaks were cal-
culated at 613 cm1. The very weak peak at 569 cm1 and a very
strong peak was observed at 476 cm1 in FT-Raman spectrum
and the corresponding peaks were calculated at 562 and
478 cm1. The HACAC in-plane bending vibrational modes were
obtained as weak to medium peaks at 1457, 1430, 1304, 1131,
and 1051 cm1 in FT-IR spectrum and the corresponding peaks were
calculated at 1449, 1428, 1294, 1147 and 1051 cm1. The corre-
sponding vibrational modes were observed as very weak peaks at
1453 cm1 and 1306 cm1 in FT-Raman spectrum. The correspond-
ing peaks were calculated at 1449 and 1294 cm1 respectively. The
T. Valarmathi, R. Premkumar, M.R. Meera et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

CC coupled with CN out-of plane bending vibrational mode was

observed as a very weak band at 547 cm1 in FT- IR spectrum
and which was calculated as 554 cm1 and the same vibrational
mode was observed as a very weak band at 266 cm1 in FT- Raman
spectrum, which was calculated at 259 cm1. These assignments
were correlated well with the reported literature values [42,43].

3.2.4. CACl vibrations

The CACl stretching vibrations give normally strong bands in
the region 760–505 cm1. Vibrational coupling with other groups
results in a shift as high as 840 cm1 [49]. In the present study,
the CACl stretching vibrational mode of the ACAQ molecule was
observed as a weak band at 738 cm1 in FT-IR spectrum and the
corresponding peak was calculated at 739 cm1. The CACl out of
plane bending vibrational mode of the molecule was observed as
a very weak peak at 208 cm1 in FT-Raman spectrum, which
correlates exactly with the calculated value 209 cm1.

3.2.5. NAH and CAHAN vibration

In amines, the NAH stretching vibrations occur in the region
3500–3300 cm1. Normally asymmetric stretching vibrational
modes are more intense due to large change in dipole moment
and appear at higher wavenumber region whereas symmetric
stretching mode appears at lower wavenumber region [50]. In this
case, the NAH asymmetric and symmetric stretching vibrational
modes were observed at 3444 and 3326 cm1 in FT-IR spectrum
and the corresponding peaks were calculated as 3584 and
3406 cm1. The very weak band was observed at 1343 cm1 in
FT-Raman and the corresponding peak was calculated at
1347 cm1, which is due to the CAN stretching vibrational mode
of the molecule. The CAH coupled with CN out-of plane bending
vibrational mode was observed as a weak band at 917 cm1 in
FT-IR spectrum, which was calculated as 905 cm1 [51].
3.2.6. Ring vibrations
Ring breathing vibrational modes are most commonly occurring
in the wavenumber region 900–780 cm1 [41]. In ACAQ molecule,
the benzene ring breathing vibrational mode was observed as a
weak band at 883 cm1 in FT-IR spectrum and the corresponding
vibrational mode was calculated as 886 cm1. The ring out-of plane
bending vibrational mode was observed as a weak peak at
845 cm1 in FT-IR spectrum and the corresponding vibrational
mode was calculated as 835 cm1. The CAC in plane bending vibra-
tional mode was observed as very strong peak at 808 cm1 in FT-IR
spectrum and the corresponding vibrational mode was calculated
as 807 cm1.
3.3. UV–Visible analysis
The study of the UV–Vis spectra is a powerful method to obtain
characteristic information about the electronic states of molecules
[64,65]. The UV–Vis electronic absorption spectrum of the ACAQ
molecule was simulated using TD-DFT method with B3LYP/6-
311G++ (d,p) basis set in ethanol environment. The experimental
UV–Vis absorption spectrum of the title compound was recorded
in liquid phase using ethanol as a solvent and the simulated in both
gas and liquid phase, which were shown in Fig. 4. The calculated
optical parameters such as excitation wavelength (k), excitation
energy (E), oscillator strength (f) and the corresponding orbital
contribution for the electronic transition were listed in Table 3.
Results indicate that theoretically calculated main transition with
maximum absorption values observed in gas phase as f-value of
0.12, E-value of 2.12 eV for the transition from HOMO ? LUMO
(99%). For liquid phase, f- value was calculated as 0.15 and E-
value was calculated as 2.58 eV for the transition from
HOMO ? LUMO (99%). The UV–Vis absorption peaks of the ACAQ
8
Fig. 4. The UV–Vis spectra of ACAQ molecule (a) Experimental (liquid phase), (b)
Theoretical (liquid phase) and (c) Theoretical (Gas phase).
molecule were calculated at 456 and 481 nm in gas phase and
liquid phase, respectively. The corresponding peak was experimen-
tally observed at 500 nm, which was assigned to p ? p* transition
of the title molecule.
3.4. NMR spectral investigations
NMR spectroscopy is a unique spectroscopic method widely
used to determine the structure of organic compounds. Density
functional theory (DFT) shielding calculations are rapid and suit-
able to large systems. The ‘‘gauge independent atomic orbital”
(GIAO) method [52–55] has proven to be quite accepted and accu-
rate. 13C NMR spectrum of the title compound was recorded exper-
imentally and used to study the structure of the title compound,
which is shown in Fig. 5. Generally, the aromatic carbons give sig-
nals with chemical shift values from 100 to 200 ppm [56–58]. The
observed experimental chemical shift positions of ring carbons
atoms lie in the range 182.78–116.14 ppm. The external magnetic
field experienced by the carbon nuclei is affected by the elec-
tronegativity of the atoms attached to them. Generally, the chem-
ical shift value of the carbon atom increases when the carbon atom
is attached to an electronegative atom. In the present case, the car-
bonyl carbon atoms C9 and C10 show very downfield effect and the
corresponding chemical shift was observed at 182.78 and
182.16 ppm, which were calculated at 186.20 and 184.36 ppm,
respectively as shown in the Table 4. The more electronegative
character of the oxygen atoms renders a positive charge to the car-
bon and thus the carbon atom C1 chemical shift is observed in the
more downfield shift at 152.32 ppm and calculated at 155.85 ppm.
Moreover, the upfield chemical shift was observed for the carbon
atom C15 at 116.14 ppm and calculated at 114.12 ppm, which is
due to the coupling of a carbon atom C1 associated with the amino
group. The chemical shift values of the other carbon atoms includ-
ing C3, C6 and C16 of the ACAQ molecule were observed at 135.23,
135.50 and 135.06 ppm, respectively. The corresponding chemical
shift values were calculated at 139.75, 141.51 and 138.98 ppm.
T. Valarmathi, R. Premkumar, M.R. Meera et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

Table 3
The calculated and observed UV–Vis spectral parameters in ethanol solution for ACAQ molecule with its assignments.

Calculated Observed (Liquid Assignment

Phase)
Gas Phase Liquid Phase
k (nm) E (eV) f Orbital contribution k (nm) E (eV) f Orbital contribution k (nm) E (eV) p ? p*
456 2.72 0.12 H ? L (99%) 481 2.58 0.15 H ? L (99%) 500 2.48

13
Fig. 5. The observed C NMR spectrum of the ACAQ molecule.

Table 4
13
The experimental and calculated C isotropic chemical shifts (ppm) with respect to
TMS of ACAQ molecule.
13
C Assignment riso Calculated (ppm) Experimental (ppm)
C1 26.62 155.85 152.32
C2 56.90 125.57 126.62
C3 42.72 139.75 135.23
C4 62.67 119.80 123.34
C5 35.45 147.02 137.55
C6 40.96 141.51 135.50
C7 44.69 137.78 134.76
C8 51.50 130.97 129.33
C9 3.73 186.20 182.78
C10 1.89 184.36 182.16
C15 68.35 114.12 116.14
C16 43.49 138.98 135.06
C17 40.89 141.58 136.89
C18 50.67 131.80 133.42

Fig. 6. Mulliken atomic charge distribution of the ACAQ molecule.

3.5. Mulliken atomic charge distribution analysis

The Mulliken atomic charge distribution of a molecule has sig-
nificant influence on dipole moment, polarizability and electronic
structure [59,60]. In the present work, the Mulliken atomic charge
distribution was predicted for the ACAQ molecule by using the
DFT/B3LYP method with 6-311G++ (d,p) basis set. The Mulliken
atomic charge distributions of the title molecule were shown in
Fig. 6. The carbon atom C9 (0.364) has very high positive charge
value, which is due to that the C9 atom is attached with an elec-
tronegative oxygen atom O11. Moreover, the nitrogen atom N13
(-0.534) has the highest negative charge value. The computed
Mulliken atomic charge values were listed in Table S1. In the ACAQ
molecule, all hydrogen atoms have positive charge values and the
electronegative oxygen, chlorine and nitrogen atoms have negative
charge values, but carbon atoms have both positive and negative
charge values, so carbon atoms are dominated by their sub-
stituents. If all electronegative atoms bonded with carbon, the
charge of the carbon atom changes from negative to positive,
which indicates that the delocalization of charges mainly arises
via the oxygen and nitrogen atoms. Among all the hydrogen atoms,
H25 (0.254) and H26 (0.215) has the highest value since it is
attached to the nitrogen atom N13. This variations further confirms
the electron back donation from the amino group to benzene ring.

9
T. Valarmathi, R. Premkumar, M.R. Meera et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

3.6. Fukui functions
The local reactivity descriptor like Fukui function indicates pre-
ferred regions where the molecule will amend its density when
numbers of electrons are modified or it indicates tendency of elec-
tronic density to deform at a given position upon accepting or
donating electrons [60,61]. Furthermore, the molecular reactivity
study plays a key role in the design of new pharmaceutical com-
pounds and used to confirms the bioactivity of the molecule
[62,63]. The Mulliken population analysis (MPA) was used to calcu-
late the Fukui functions [63]. The calculated Mulliken atomic
charge distributions of the neutral, anionic and cationic state of
the molecule were listed in Table 5. The calculated values of the
Fukui functions used for identifying the possible regions of elec-
trophilic, neutrophilic and radical attack, which were listed in
Table 5. Fukui function defines the more reactive regions, which
leads to the selectivity towards specific chemical events in a mole-
cule. The most higher Fukui function f+k values for nucleophilic
reactive atoms of the ACAQ molecule were in the order of
13 N > 4C > 14Cl > 2C > 26H > 21H. The higher Fukui function f k interaction between molecules presents the distribution of electro-
values for electrophilic reactive atoms were identified to be in
the order of 12O > 14Cl > 11O > 9C > 10C. The
13 N > 14Cl > 12O > 4C > 2C and 11O atoms are favorable sites
for the radical attack f0k.
3.7. Frontier molecular orbitals (FMOs) analysis
The frontier molecular orbitals (FMOs) analysis determines the
way in which the molecule interacts with other species. The high-
est occupied molecular orbital (HOMO) and the lowest unoccupied
molecular orbital (LUMO) are said to be the frontier molecular
orbitals. From Koopmans’s theorem, the theoretical concepts like
chemical potential, hardness, electrophilicity and electronegativity
are derived from FMOs orbitals. Generally, a molecule with the
smallest energy gap indicates that it was highly polarizable and
highly reactive [64]. The colors red and green indicate the positive
and negative phase, respectively. Table 6 shows the HOMO, LUMO
energies, energy gap and the related molecular properties of the
ACAQ molecule calculated based on the B3LYP method with
6311G++ (d,p) basis set. The calculated energy gap value
(3.151 eV) indicates that the ACAQ molecule has stable structure
and the value was comparable with the band gap energy value of
the reported bioactive molecules [69]. The calculated high ioniza-
tion potential value of the ACAQ molecule shows the ability to per-
form nucleophilic attack. In addition, the calculated higher
hardness and lower softness value indicate the stability of the
molecule. The obtained FMOs plot was shown in Fig. 7a. DOS spec-
trum was also simulated by convoluting the molecular orbitals
with Gaussian curves of unit height. These results further validated
by the FMOs analysis. The green and red lines in the DOS spectrum
represent the occupied and virtual orbitals respectively. The simu-
lated DOS spectrum was shown in Fig. 7b.
3.8. Molecular electrostatic potential (MEP) analysis
The molecular electrostatic potential (MEP) analysis reveals the
static potential (electron + nucleus). The color in the MEP surface is
a measure of the electrostatic potential value. The MEP surface of a
molecule measures the molecular interaction with its surround-
ings and provides a visual understanding of size, shape, charge
density and relative polarity of the molecule [66–68]. This three
dimensional mapping helps in locating the reactive sites of the
molecule by understanding its color codes. The different values
of the electrostatic potential energy are represented by the differ-
ent colors; red color indicates the highest negative potential sites
whereas the blue color indicates the highest positive potential
sites. The green color indicates the site which has a zero potential.
Fig. 8 shows the MEP surface of the ACAQ molecule, which pro-
vides a visual method to understand the relative polarity of the
molecule. The area around the oxygen atom of the carbonyl group
are found to be electron rich (red), which is due to the lone pair
electrons of oxygen atom. The area lying around chlorine and
amino group hydrogen atoms were found to be electron deficient

Table 5
The calculated Fukui functions values of the ACAQ molecule.

Atom Fukui functions Relative Relative

electrophilicity nucleophilicity
þ  þ   þ
ðf k Þ ðf k Þ 0
ðf k Þ ðf k Þ=ðf k Þ ðf k Þ=ðf k Þ

C1 0.011 0.012 0.001 0.885 1.130

C2 0.071 0.046 0.059 1.531 0.653
C3 0.016 0.022 0.019 0.713 1.402
C4 0.087 0.035 0.061 2.525 0.396
C5 0.007 0.004 0.006 1.726 0.579
C6 0.028 0.038 0.033 0.730 1.371
C7 0.015 0.032 0.024 0.462 2.166
C8 0.024 0.024 0.024 0.980 1.020
C9 0.025 0.063 0.044 0.394 2.538
C10 0.020 0.061 0.040 0.332 3.015
O11 0.021 0.080 0.051 0.266 3.761
O12 0.040 0.089 0.065 0.455 2.199
N13 0.156 0.019 0.088 8.041 0.124
Cl14 0.073 0.088 0.080 0.833 1.200
C15 0.059 0.005 0.032 12.682 0.079
C16 0.005 0.005 0.005 0.974 1.026
C17 0.006 0.013 0.004 0.425 2.353
C18 0.004 0.019 0.011 0.218 4.578
H19 0.059 0.054 0.056 1.102 0.908
H20 0.057 0.053 0.055 1.079 0.926
H21 0.061 0.044 0.052 1.386 0.721
H22 0.034 0.052 0.043 0.654 1.528
H23 0.033 0.053 0.043 0.623 1.605
H24 0.025 0.043 0.034 0.580 1.725
H25 0.048 0.018 0.033 2.593 0.386
H26 0.063 0.037 0.050 1.710 0.585

10
T. Valarmathi, R. Premkumar, M.R. Meera et al.
Table 6
The calculated FMOs and related molecular properties of the ACAQ molecule.
Molecular Energy (eV) Molecular properties
properties
Energy (a.u.) 1203.940 Electron affinity (A)
EHOMO 6.099 Global hardness (g)
ELUMO 2.948 Chemical potential (m)
Energy gap 3.151 Electrophilicity index
(W)
Ionization energy (I) 6.099 Softness (S)
(blue). The MEP analysis predicts the probable sites available for
the electrophilic and nucleophilic reactions of the ACAQ molecule.
3.9. NBO analysis
The NBO analysis was carried out to identify and confirm the
possible intra- and inter-molecular interactions between the atoms
present in the molecule [69,72]. NBO analysis enables hybridiza-
tion, bond type (covalent vs. Dative vs. ionic etc.), Lewis structure,
atomic charge and the estimation of the energy of the molecule in
the absence of electronic delocalization [69]. Natural bond orbital
(NBO) analysis provides significant donor-acceptor interactions
with their second order perturbation energies E (2) [65,70,71].
The important donor-acceptor interactions with their second order
perturbation energies E (2) were listed in Table S2, which gives the
measure of hyperconjugation or delocalization. For each donor (i)
and acceptor (j), the stabilization energy E (2) associated with
the delocalization i ? j is calculated by:
F 2ði;jÞ
Eð2Þ ¼ DEij ¼ qi
ei  ej
where qi is the donor orbital occupancy, ei and ej are the energies of
the diagonal elements and F(i, j) is the off diagonal NBO Fock matrix
element. The strong stabilization interaction (52.83 kcal/mol) was
predicted between LP N13 ? p* (C1-C15), which further confirms
the electron donation from the amino group to the benzene ring
of the title molecule. The stabilization interactions between the LP
orbitals and anti-bonding r or p orbitals are accountable for the
biological activity of a molecule [69,72]. The stabilization interac-
tion was predicted between k (C1-C15) ? k*(C9-O11) with stabi-
lization energy of 28.34 kcal/mol accounts for the polarizabilty of
Fig. 7. (a) The frontier molecular orbitals of the ACAQ molecule and (b) DOS spectrum of the ACAQ molecule.
Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659
Energy
(eV)
2.948
1.575
4.523
6.496
0.635
Fig. 8. Molecular electrostatic potential surface of the ACAQ molecule.
the molecule. The obtained significant intra-molecular charge
transfer interactions from the lone pair electrons of electronegative
atom N13 to the anti-bonding orbitals of C1-C15 with higher
hybridization energy value is a characteristic feature of a pharma-
ceutical compound [72].
3.10. Molecular docking analysis
The molecular docking is an important tool used to identify the
interaction between a small ligand and a target protein, which has
been widely used for the structure-based drug design in pharma-
ceutical research [73,74]. In the present work, the title molecule,
ACAQ was used as a ligand and four cancer associated proteins
such as thyroid cancer (protein c-Met Kinase [PDB ID: 4XMO]),
ovarian cancer (EGFR [PDB ID: 1 M17]), oral squamous cell carci-
noma (HDAC6 [PDB ID: 5EF7]) and lung cancer (protein p53 [PDB
ID: 1YCS]) were used as targeted proteins, which are identified
based on the inhibitory nature of the anthraquinone derivatives
for the corresponding cancer diseases [21–28]. The ACAQ molecule
was docked with the four selected cancer associated targeted pro-
11
T. Valarmathi, R. Premkumar, M.R. Meera et al. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 255 (2021) 119659

Table 7
The obtained docking parameters of the ACAQ molecule on their rank calculated by Autodock.

Ligand Target protein (receptor) Docking Parameters based on the rank

Binding energy (Kcal/mol) Inhibition constant (lM) Intermolecular energy (Kcal/mol)
1 2 3 1 2 3 1 2 3
ACAQ 4XMO 6.18 6.06 5.89 29.33 35.97 48.12 6.48 6.36 6.19
1 M17 5.70 5.59 5.40 66.24 80.23 110.60 6.00 5.89 5.70
5EF7 5.06 5.01 4.95 195.34 212.21 235.87 5.36 5.31 5.25
1YCS 4.85 4.78 4.53 279.76 313.43 477.57 5.15 5.08 4.83

teins. The lowest binding energy, inhibition constant and inter-
molecular energy values of the four protein-ligand complexes were
calculated, which were listed in Table 7 and the lowest energy
docked poses of the protein-ligand complexes were shown in
Fig. 9. As shown in Fig. 9, the dotted yellow lines indicate the
hydrogen bonds formation between the ligand (ACAQ molecule)
and selected targeted proteins. The corresponding hydrogen bond
length values between ligand molecule and the amino acid resi-
dues in the targeted proteins were also depicted in Fig. 9. As listed
in Table 7, the calculated lowest binding energy, inhibition con-
stant and intermolecular energy values confirm that the ACAQ
molecule exhibits the lower binding energy and inhibition con-
stant value for the targeted protein c-Met Kinase. In docking stud-
ies, the binding energy is released when a drug molecule (ligand)
bound with a targeted protein, which leads to a lowering of the
overall energy of the protein-ligand complex. The lowering binding
energy value of the protein-ligand complex causes the greater
binding affinity between the ligand and targeted protein. As listed
in Table 7, the ACAQ molecule exhibits the lower binding energy
value of 6.18 kcal/mol for the protein target, protein c-Met Kinase
[PDB ID: 4XMO], which is known as thyroid cancer-associated pro-
tein. Moreover, the inhibition constant value of the ACAQ- protein
c-Met Kinase complex was calculated as very low value of
29.33 mM, which reveals that the obtained results will be useful
in the in vitro and in vivo studies for the development of effective
drugs in the treatment of thyroid cancer. The c-Met Kinase was
reported as a clinically important therapeutic target for develop-
ment of metastatic medullary thyroid cancer drugs. Hence, the pre-
sent investigations will be useful for the development of potent
drugs in the treatment of thyroid cancer.

Fig. 9. Lowest energy docked poses of the ACAQ molecule with various cancer associated targeted proteins such as (a) c-Met Kinase [PDB ID: 4XMO], (b) EGFR [PDB ID:
1 M17], (c) HDAC6 [PDB ID: 5EF7] and (d) protein p53 [PDB ID: 1YCS].

12
T. Valarmathi, R. Premkumar, M.R. Meera et al.
4. Conclusion
In the present work, 1-Amino-5-chloro-anthraquinone (ACAQ)
compound was investigated using the experimental FT-IR, FT-
Raman, NMR and UV–Vis spectroscopic methods and compared
with the DFT studies. The most stable molecular structure of the
molecule was optimized and the structural parameters including
bond length, bond angle and dihedral angle values of the molecule
were calculated and compared with the experimental results. The
vibrational wavenumbers of the molecule were calculated, which
are correlated well with the observed vibrational wavenumbers
using FT-IR and FT Raman analysis. The UV–Visible absorption
spectrum of the molecule indicates the k to k* electronic transition.
The 13C NMR isotropic chemical shift values of the molecule were
calculated and compared with the experimental data, which
reveals the molecular structure of the ACAQ molecule. The Mul-
liken atomic charge distribution analysis was performed, which
confirms the reactive site of the molecule. Fukui function calcula-
tions were carried out to investigate the reactive nature of the
HAQ molecule. FMOs analysis shows the molecular reactivity,
kinetic stability and intramolecular charge transfer of the mole-
cule, which influences the bioactivity to the HAQ molecule. The
MEP surface of the molecule also authenticates the reactive site
of the molecule. The natural bond orbital analysis predicts the
bioactive nature of the molecule. Molecular docking analysis con-
firms that the title molecule inhibits the action of c-Met Kinase
protein, which is associated thyroid cancer. Hence, the present
study will be useful for the development of novel drugs in the
treatment of thyroid cancer.
CRediT authorship contribution statement
T. Valarmathi: Theoretical Calculations, Writing - original draft.
R. Premkumar: Experimental characterization, Molecular docking
simulations and Result analysis. M.R. Meera: Reviewing and
Editing. A. Milton Franklin Benial: Supervision, Writing - review
& editing.
Declaration of Competing Interest
The authors declare that they have no known competing finan-
cial interests or personal relationships that could have appeared
to influence the work reported in this paper.
Acknowledgments
The authors thank the college management for encouragement
and permission to carry out this work and also thank the P.G. and
Research Department of Physics, N. M. S. S. V. N. College, Naga-
malai, Madurai-19, for providing the Gaussian 09 program pack-
age. The SAIF, IIT, Chennai shall be duly acknowledged for
recording the FT-IR, FT-Raman and FT-NMR spectra.
Appendix A. Supplementary material
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.saa.2021.119659.
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