Conformational, vibrational and DFT studies of a newly synthesized arylpiperazine-based drug and evaluation of its reactivity towards the human GABA receptor

Article abstract of DOI:10.1016/j.molstruc.2017.06.107

This study reports a computational assessment of important biochemical properties and vibrational assignments for the synthesized 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone (MNPE). MNPE is related to the commonly used arylpiperazine-based drugs

Full text of DOI:10.1016/j.molstruc.2017.06.107

Accepted Manuscript
Conformational, vibrational and DFT studies of a newly synthesized arylpiperazine-
based drug and evaluation of its reactivity towards the human GABA receptor
A.T. Onawole, A.F. Al-Ahmadi, Y.S. Mary, C.Y. Panicker, N. Ullah, S. Armaković, S.J.
Armaković, C.V. Alsenoy, A.A. Al-Saadi
PII:
S0022-2860(17)30888-8
10.1016/j.molstruc.2017.06.107
MOLSTR 23993
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 20 May 2017
Revised Date: 21 June 2017
Accepted Date: 21 June 2017
Please cite this article as: A.T. Onawole, A.F. Al-Ahmadi, Y.S. Mary, C.Y. Panicker, N. Ullah, S.
Armaković, S.J. Armaković, C.V. Alsenoy, A.A. Al-Saadi, Conformational, vibrational and DFT studies of
a newly synthesized arylpiperazine-based drug and evaluation of its reactivity towards the human GABA
receptor, Journal of Molecular Structure (2017), doi: 10.1016/j.molstruc.2017.06.107.
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ACCEPTED MANUSCRIPT
Conformational, vibrational and DFT studies of a newly synthesized arylpiperazine-based
drug and evaluation of its reactivity towards the human GABA receptor
a
a
b
b
a
c
A. T. Onawole , A. F. Al-Ahmadi Y.S. Mary , C.Y. Panicker , N. Ullah , S. Armaković , S. J.
,
d
e
a,*
Armaković , C.V. Alsenoy , A. A. Al-Saadi
a
Department of Chemistry, King Fahd University of Petroleum and Minerals, Dhahran 31261,
Saudi Arabia
Department of Physics, Fatima Mata National College, Kollam, Kerala, India
b
c
University of Novi Sad, Faculty of Sciences, Department of Physics, Trg D. Obradovića 4,
2
1000 Novi Sad, Serbia
University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and
d
Environmental Protection, Trg D. Obradovića 3, 21000 Novi Sad, Serbia
e
Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, B-2020, Antwerp,
Belgium
*
Corresponding Author: asaadi@kfupm.edu.sa
1

ACCEPTED MANUSCRIPT
Abstract
This study reports a computational assessment of important biochemical properties and
vibrational assignments for the synthesized 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-
yl)ethanone (MNPE). MNPE is related to the commonly used arylpiperazine-based drugs that
exhibit a wide range of pharmacological activities. The characterization of MNPE is based on
-1
-
the readily sighted 1363 cm infrared band (associated with piperazine ring stretching), 1308 cm
1
-1
-1
Raman line (associated with the phenyl ring breathing), 1242 cm Raman line and 1092 cm
infrared band (both associated with C-N stretching) as key modes in its vibrational spectra. First
principle calculations revealed that MNPE could exist in sixteen different plausible
conformations, which were used as basis to understand the possible molecular docking
A
mechanism of the molecule as an agonist in the human GABA receptor. The best binding
scenarios showed the presence of intramolecular hydrogen bonding in MNPE and was
comparable with the most stable configuration. It was further evaluated for its reactivity
properties by utilizing the concepts of Average Local Ionization Energies (ALIE) and Fukui
functions. The autoxidation and hydrolysis degradation likelihood of MNPE estimated from the
computed bond dissociation energies and radial distribution functions predicted that MNPE is to
be readily biodegradable in aqueous solutions.
Keywords: Arylpiperazine; Human GABA
A
receptor; Molecular docking; Vibrational
spectroscopy; Density functional theory.
2

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1
. Introduction
Arylpiperazines and its derivatives have demonstrated an alluring pharmacological framework
that is found in different branded drugs. The inclusion of piperazine motif is a vital synthetic
procedure in drug discovery. This is due to its solubility, proper alkalinity, and hydrogen bond
formation capability. All these attributes in turn lead to its ease in the modification of molecular
physicochemical properties [1, 2]. Moreover, arylpiperazine derivatives have found extensive
applications in the pharmaceutical chemistry such as anticancer [3, 4], antiviral [5], antifungal
[6], anti-oxidative [7], anti-histamine [8], anti-parasitic [9] psychotolytic [10] and as an agonist
for the human GABA receptor [11]. Contrary, the frequent usage and improper disposal of this
class of compounds can act as organic pollutants and pose threat to the environment especially in
water and hence become toxic to aquatic organisms [12-14]. In general, arylpiperazine
derivatives are quite stable and hence their degradation under normal conditions is very slow.
This in turn make the conventional water purification methods unsuitable for efficient and
economic removal of these compounds [15]. Therefore, considerable synthetic efforts have been
devoted to design new arylpiperazines which are both medicinally effective and water-
degradable. In the light of above, we have synthesized an arylpiperazine derivative and have
studied it computationally and spectroscopically as well as by means of bond dissociation energy
(BDE), radial distribution function (RDF) and molecular docking approaches to gain some
insights on its electronic properties and side effects.
Given the fact that the advanced oxidation is considered a widely used method in water
purification technology [16], understanding the reactive properties of MNPE (Fig. 1) and the
possible auto-oxidation locations within the molecule is essential. This in turn can be achieved
by calculating BDEs during hydrogen abstraction. Thus, the BDE of the rest of the single acyclic
bonds can be used for classification of bonds according to their strength and prediction of
locations where degradation can occur. Considering the importance of water as solvent,
molecular dynamics (MD) simulations can provide valuable information to ascertain the
interaction with water molecules and different type of atoms of MNPE. In this case, RDF shall
be particularly quite useful.
In addition, arylpiperazine derivatives are known as agonist to naturally occurring γ-
aminobutyric acid (GABA) receptor, which in turn produces a synergistic anti-stress and anti-
3

ACCEPTED MANUSCRIPT
anxiety effect. The GABA
A
receptor is one of the Ligand-gated Ion Channels (LICs) that are
+
+
referred to as ionotropic receptors because they allow the passage of ions such as Na and K
through the membrane as a response to the stimulus effect when a ligand binds to them. [17–19].
Since most drugs often imitate the action of endogenous ligands [20a], the conformational
analysis and the molecular docking study of can thus provide a deeper understanding of the
mode of action by which drugs act on such a target protein.
2
. Experimental
Melting Points were determined on a Büchi apparatus (Büchi Labortechnik AG,
Switzerland) and are uncorrected. Elemental analysis was carried out on a Perkin Elmer
1
13
Elemental Analyzer Series 11 Model 2400 (PerkinElmer Inc. USA). H and C NMR spectra
were measured in CDCl using TMS as internal standard on a JEOL JNM-LA 500 MHz
3
spectrometer (JEOL USA Inc.). Analytical TLC was carried out on silica gel 60 F254 plates (E.
Merck); column chromatography was carried out on silica gel (200-400 mesh, E. Merck).
DR/Jasco FT-IR 6300 spectrometer employing KBr tablets was used to record the infrared
spectrum (Fig. 2) of MNPE while a Bruker RFS 100/s, Germany was used to record the Raman
spectrum (Fig. 3). The emission of Nd:YAG laser at the wavelength of 1064 nm was utilized for
sample excitation with a maximal power of 150 mW.
2
.1 Synthesis of MNPE (6)
o
To a suspension of compound 5 [20b] (1.05 g, 3 mmol) in CH
2
2
Cl (20 mL) at 0 C was added
Et N (1.1 mL, 8 mmol) followed by the dropwise addition of acetyl chloride (0.32 mL, 4.5
3
mmol). The mixture was stirred for three hours at room temperature until completion (TLC
3
analysis). The reaction was quenched with saturated NaHCO (10 mL) and the organic layer was
separated, washed with H O (10 mL) and then dried over Na SO followed by evaporation under
2
2
4
reduced pressure to obtain a yellow solid, which was re-crystallized with ethanol to afford the
1
title compound 6 as yellow crystalline solid. H NMR (500 MHz, CDCl ): δ 2.16 (s, 3H,
3
COCH ), 3.41 (m, 4H, piperazine H), 3.68 (2H, t, piperazine H), 3.80 (2H, t, piperazine H), 3.91
3
(s, 3H, OCH
3
), 6.35 (d, J = 1.9 Hz, 1H, H-2), 6.41 (dd, J = 1.9, 8.6 Hz, 1H, H-6), 8.01 (d, J = 8.6
Hz, 1H, H-5). Anal. Calcd for C H N O : C, 55.91; H, 6.14; N, 15.05%. Found: C, 55.87; H,
1
3
17
3
4
6
.17; N, 15.01.
4

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3
. Computational Details
An extensive conformational analysis was done for MNPE using Density Functional Theory
DFT) with Gaussian 09 program [21] at the Becke’s three-parameter half-and-half model and
the Lee-Yang-Parr connection useful (B3LYP) level of theory using both 6-311G(d,p) and 6-
11++G(d,p) as the basis sets which are good for medium-size organic molecules. Sixteen
possible structures (Fig. 4) of MNPE were determined, and their energies were computed (Table
) [22]. The 6-311++G(d,p) basis set was employed to predict the geometrical parameters in
(
3
1
details (Tables 2-5) and calculate the vibrational wavenumbers (Table 5) [23], [24] of the most
stable conformer (Fig. 1) using a scaling factor of 0.9613 [25]in order to acheive a better
correlation with experimental values. The assignments of the figured wavenumbers are supported
by the atomic displacements visulized with GAUSSVIEW [26] and the Potential Energy
Distribution (PED) values computed with the GAR2PED software [27].
Moreover, the Jaguar program 9.0 embedded in the Schrödinger Materials Science Suite [28]
was utilized for DFT calculations of Average Local Ionization Energies (ALIE), Fukui capacities
and BDE. For MD simulations of RDFs, the Desmond program [29]–[32] was utilized, likewise
as executed in the Schrödinger Materials Science Suite. For all DFT estimations B3LYP
exchange correlation functionals were employed [33]. . Concerning MD simulations, OPLS 2005
force field [34] was used. The system was modeled by placing one molecule of MNPE in a cubic
box with ~3000 water molecules and treated with NPT (where N is constant particle number, P is
pressure and T is temperature) ensemble class. The Pressure was set to 1.0325 bar while the
temperature was set to be 300 K, with simulation time of 10 ns. The cut-off radius was set to 12
Å, while the solvent description was done by employing the Simple Point Charge (SPC) model
[
35]. The molecular docking analysis was performed with the CLC Drug Discovery program
36] while the Moleman 2 [37] was used to validate the crystal structure of the human GABA
[
A
receptor which is the target protein in this study.
4
4
Results and Discussion
.1 Synthesis of 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone
The desired compound MNPE (6) was synthesized as outlined in scheme 1. In brief, O-
methylation of phenol 1 with iodomethane in DMF rendered 2, which in turn was condensed
5

ACCEPTED MANUSCRIPT
with 1-boc-piperazine 3 to produce coupled product 4. Acid induced removal of boc protection
of 4 furnished salt 5, which was reacted with acetic anhydride in CH Cl to yield the desired 6 in
2
2
4
4% overall yield from 1 [38].
Scheme 1. Synthesis of 1-(4-(3-methoxy-4-nitrophenyl)piperazin-1-yl)ethanone (MNPE)
4
.2. Conformational Analysis
Exploring conformational properties of organic-based drugs is extremely useful in order to
understand the structure-activity relationship. Detailed conformational analysis of the multi-rotor
MNPE has led to 16 possible unique conformations depicted in Fig. 4. The variation of bond
lengths, bond angles and dihedral angles among the stable forms are listed in Tables 2-4.
Generally, the steric effect when the methoxy and nitro groups repel each other pushes the
energy 1-2 kcal/mol to the higher side (Table 1). Consequently, the position of the methoxy with
respect to the nitro groups is the main factor that influences the overall energy of the molecule.
The average distance between O and O in A and B conformations is about 0.2 Å shorter than
1
3
37
in corresponding C and D conformations (Table 2). The internal rotation of the OCH group,
3
6

ACCEPTED MANUSCRIPT
3
presented in Fig. 5(A), has shown that the eclipsing position of the CH group is 3-4 kcal higher
in energy than when the methoxy and nitro group oxygens repel each other. On the other hand,
the molecule seems more flexible flipping along the aromatic ring-piperazine ring linkage and
the nitro group-aromatic ring linkage. The piperazine ring in its lowest energy form positons
itself in the same plane of the benzene ring with about 42º tilting angle. The stable position of the
methoxy group in C and D configurations represents a metastable arrangement with 5 kcal/mol
barrier (Fig. 5) to interchange to A and B conformations.
The conformer B4 is predicted to be the most stable form, and its detailed structural parameters
are listed in Table S1. There is no significant difference between the results obtained by the
B3LYP/6-311G(d,p) and B3LYP/6-311++G(d,p) basis sets in terms of bond angles and
9
distances, yet some major dihedral angles, such as O37-N15-C10-C and O36-N15-C10-C11 (Table 4)
showed a notable difference (up to 6º in some cases) when these two different basis sets are
utilized. This perception demonstrates the impact of the electronic properties of the nitro group
when long-range repulsion parameters are considered in the basis set.
The molecular electrostatic potential (MEP) map (Fig 6a) indicates that the nitro and
carbonyl groups demonstrate an electronegative region in the molecule whereas the
electropositive region occurs at the piperazine ring vicinity. This map has given an insight into
possible interactions between MNPE and the amino acid in the target protein. The HOMO
(highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energy
values were calculated to be -7.83 eV and -4.55 eV, respectively, with an energy gap of 3.28 eV.
Due to the relatively small gap in MNPE, the charge transfer process is predicted to be feasible
and supports the docked pose of the compound in the molecular docking analysis, which will be
discussed later in this script.
4
.3
Geometrical Parameters for B4 Conformer
4 5
For the piperazine ring of the title compound, the bond lengths are computed as N -C =
1
1
.4586 Å, N -C = 1.4567 Å, C -C = 1.5293 Å, N -C = 1.4633 Å, N -C = 1.4675 Å, C -C =
4 3 3 2 1 6 1 2 5 6
.5284 Å and corresponding reported bond lengths are 1.465, 1.463, 1.514, 1.458, 1.471, 1.511Å
[39] and 1.4488, 1.485, 1.535, 1.488, 1.477, 1.547 Å [40]. The DFT calculations predict the bond
angles within the piperazine ring N -C -C = 110.4°, N -C -C = 111.1°, N -C -C = 110.9°, N -
4
3
2
4
5
6
1
6
5
1
C
2
-C
3
= 111.3°, C
6
-N
1
-C
2
= 112.4° whereas the corresponding reported values are 110.4, 113.1,
7

ACCEPTED MANUSCRIPT
1
10.7, 109.7, 114.8° [40] and 110.0, 109.7, 109.7, 110.0, 110.0° [39].The dihedral angles of the
piperazine ring, C -N -C -C = -54.7°, C -N -C -C = -55.1°, N -C -C -N = 53.9°, C -N -C -C
5
5
4
3
2
6
1
2
3
4
3
2
1
2
1
6
=
54.6°, C -N -C -C = 54.9°, N -C -C -N = -53.6° are in agreement with the reported values
3 4 5 6 1 6 5 4
[41]. The C-O bond lengths of MNPE are C
9
-O13 = 1.346 Å and C14-O13 = 1.424 Å and the
increase in bond length of C -O is due to the noticeable hydrogen bonding experienced by the
1
4
13
molecule as reported in literature [42], [43]. In the present case, the C=O bond length is 1.2225
Å which is in agreement with literature [44]. The C-C bond lengths in the phenyl ring are in the
range 1.3792-1.4118 Å and the bond lengths are somewhere in between the normal values for a
single (1.54 Å) and a double (1.33 Å) bond [44]. For the title compound the N-O bond lengths
are 1.2246 Å and 1.2324 Å which was in agreement with reported values [45].
The C-N-O angles are reported as 117.7° and 117.5° [45] where as for the title
compound, the angles are 118.9° and 117.0°. At N position, the bond angles are, C -N -O =
1
5
10
15
37
1
18.9°, C -N -O = 117.0° and O -N -O = 124.1° and this asymmetry in angles is due to the
10 15 36 36 15 37
3 9
adjacent OCH group. At C10 position, the bond angle C -C10-C15 increased by 2.9° and C11-C10-
N is decreased by 2.5° from 120°, which reveals the hydrogen bonding with the H atom. At
1
5
31
C
9
position, the bond angles are, C
8
-C
9
-C10 = 118.5°, C
8
-C
9
9
-O13 = 122.9° and C10-C -O13 =
1
18.5° and the increase in C -C -O is due to the interaction between CH and H atom. At C
8 9 13 3 30 7
position the bond angles are C -C -C = 118.0°, C -C -N = 121.4° and C -C -N = 120.5° and
8
7
12
8
7
1
12
7
1
the asymmetry in angles is due to the interaction between the phenyl ring and the CH
piperazine ring. Similarly, at C position, the bond angles are, N -C -C = 117.5°, N -C -O
17
2
groups of
1
6
4
16 18
4
16
=
3 2
121.5°, C18-C16-O17 = 121.0° and this asymmetry is due to the CH group and CH groups of
piperazine ring. The methoxy group is slightly tilted from the phenyl ring as is evident from the
torsion angles, C -C -C -O = 177.6°, C -C -O -C = 1.9°, C -C -C -O = -175.9° and C -
7
8
9
13
8
9
13 14
11 10
9
13
10
C
9
-O13-C14 = 178.8° and the phenyl ring and piperazine ring are tilted from each other as is
evident from the torsion angles, C -C -N -C = -4.7°, C -C -N -C = 139.3°, C -C -N -C = -
8
7
1
6
8
7
1
2
12
7
1
2
4
7 1 6 3
2.2° and C12-C -N -C = 173.7°. The COCH and the piperazine ring are tilted from each other
as is evident from the torsion angles, C -N -C -O = 4.1°, C -N -C -O = 174.7°, C -N -C -
5
4
16
17
3
4
16
17
5
4
16
C = -176.4° and C -N -C -C = -5.8°.
18
3
4
16 18
4
.4
Molecular Reactivity
4
.4.1 ALIE Surfaces and Fukui Functions
8

ACCEPTED MANUSCRIPT
Two representative Average Local Ionization Energy (ALIE) surfaces of MNPE are
depicted in Fig. 7a. ALIE is frequently used as a quantum molecular descriptor for the
understanding of local reactivity properties of molecular systems. This quantity was introduced
by Sjoberg et al. [46, 47], and it is useful when its values are mapped to the electron density
surface. In that case the certain areas of the surface indicate the molecule locations where
electrons are the least tightly bound, i.e. the most easily removed. Therefore these locations are
the most prone to electrophilic attacks. ALIE is defined as followed:
r
ρi
(
r
)
εi
)
I
(
r
)
=
(1)
εi
∑
r
ρ
(
r
i
r
r
where ρi
(
r
)
r
represents the electronic density of the i-th molecular orbital at the point ,
r
represents the orbital energy and
ρ
(
r
)
is the total electronic density function.
The results obtained for MNPE revealed that the locations at the benzene ring and NO group
2
are prone to possible electrophilic attack. This implied that electrons in the regions near vicinity
of carbon atoms C and C (belonging to benzene ring), nitrogen atom N (belonging to
8
12
1
piperazine ring) and oxygen atoms of NO group are less tightly bound. At all these locations,
2
the ALIE values were somewhat lower than 200 kcal/mol, exhibiting possible reactive sites.
Besides MEP and ALIE analysis, values of Fukui functions (Fig. 7b) can also serve as
indicators of possible reactive centers in the molecule. They provide insight on how electron
+
–
density changes with the addition or removal of the charge. Two Fukui functions, f and f ,
were calculated with infinite difference approach as follows:
N +
δ
N
N
(
ρ
(
r
)
δ
−
−
ρ
ρ
(
r
)
)
+
f =
(2)
N −
δ
(ρ
(
r
)
δ
(
r
)
)
−
f =
(3)
where N is the number of electrons in the reference state of the molecule and
δ
represents the
fraction of electron, which is set to be 0.01 [48].
+
According to the results presented in Fig.6a, purple region of Fukui f function is located
2
at oxygen atoms of NO group, which indicated an increase in the electron density with the
addition of charge. On the other side, the negative color was generated at the methyl group in the
near vicinity of benzene ring and in the near vicinity of oxygen atom O , which revealed these
1
3
9

ACCEPTED MANUSCRIPT
locations as interesting possible reactive centers. It is evident that the regions indicated by Fukui
functions corresponded to the regions where MEP surfaces have the highest or lowest values.
4
.4.2 NBO Analysis
The natural bond orbitals (NBO) calculations were performed using NBO 3.1 program
49] as implemented in the Gaussian 09 [21] package, and various hyper-conjugative interaction
parameters are given in tables 7 and 8. The intra-molecular hyper-conjugative interactions in the
title compound are: C -C from N of n (N )→π*(C -C of n (N )→π*(C16
(O13)→π*(C (O17)→σ*(N -C16), N15-O37
(O36)→π*(N15-O37), N15-O36 from O37 of n (O37)→σ*(N15-O36) having electron
densities, 0.42457, 0.28120, 0.46950, 0.08444, 0.62299, 0.06304e and stabilization energies,
[
7
8
1
1
1
7
8
), C16-O17 from N
4
1
4
-
O
17), C
9
-C10 from O13 of n
2
9
-C10), N
4
-C16 from O17 of n
2
4
from O36 of n
3
2
3
2.39, 62.42, 35.28, 26.34, 148.77, 19.69 KJ/mol.
From Table 7, the natural hybrid orbital with higher energies, considerable p-character
(
nearly 100%) and low occupancy were predicted to be n (O ), n (O ), n (O ) and n (O ) with
2 13 2 17 3 36 2 37
energies, -0.31933, -0.24010, -0.25443, -0.26721a.u and p-characters, 99.99, 99.99, 99.84,
9.97% and occupation numbers, 1.81466, 1.86423, 1.46681, 1.89783, respectively. On the
other hand, the orbitals with lower energies and high occupancy are: n
n (O ) with energies, -0.54441, -0.77681, -0.66876, -0.77363a.u and p-characters, 62.67, 41.68,
9
1
1 1
(O13), n (O17), n (O36),
1
37
2
4.97, 25.40% and occupation numbers, 1.96232, 1.97565, 1.98127, 1.98091, respectively.
Thus, a nearly pure p-type lone pair orbital is predicted to participate in the electron
donation to the n (N ) → π*(C -C ), n (N ) → π*(C -O ), n (O ) → π*(C -C ), n (O ) →
1
1
7
8
1
4
16
17
2
13
9
10
2
17
σ*(N -C ), n (O ) → π*( N -O ), and n (O ) → σ*(N -O ) interactions in MNPE.
4
16
3
36
15
37
2
37
15
36
4
.5
Degradation Properties
The degradation properties based on the autoxidation and hydrolysis processes of MNPE
can be perceived with the help of computed Bond Dissociation Energy (BDE) values as obtained
by DFT calculations [50, 53]. BDE is a valuable tool for primary assessment of molecular sites
wherein the mechanism of autoxidation could initiate. In addition, the efficiency of autoxidation
process is related to the abstraction of hydrogen atom by peroxy radical from the parent drug
molecule [50, 51]. It is well established that all peroxy radicals have similar BDE values (in the
1
0

ACCEPTED MANUSCRIPT
range of 87 kcal/mol to 92 kcal/mol). When the calculated BDE for hydrogen abstraction is
within this range, corresponding molecule location is considered a candidate for the initiation of
the autoxidation process. BDE values for peroxy radicals can be considered independent of the
chemical surrounding [51, 52]. When the BDE value of the hydrogen abstraction is in the
interval of 75 kcal/mol to 85 kcal/mol, then the molecule is considered to be highly prone to
autoxidation mechanism [50], [53]. BDE values of all single acyclic bonds of the title molecule
are presented in Fig. 8. All BDE values related to hydrogen abstraction are higher than 92
kcal/mol, thus it indicates that MNPE is highly stable in open air, in the presence of oxygen. On
the other hand, two BDE values for the rest of the single acyclic bonds were predicted to have
values of ~66 and ~69 kcal/mol, indicating that acetyl-phenyl linkage and O-CH bond are
3
dissociable and hence can be a potential site of degradation.
Furthermore, molecular areas that are likely to interact with water molecules are
presented in Fig. 9 in the form of Radial Distribution Functions (RDFs), which was obtained
from MD simulations. RDF, g(r), is the probability of finding a particle in the distance r from
another particle [54]. When the obtained curve profile is sharp and when its peak is at a short
distance, it indicates interactions between certain atoms and water molecules.
RDF curves shown in Fig. 9a indicate that the carbon atoms C , C and C could have
1
0
14
18
pronounced interactions with water molecules. Atoms C and C are very similar in terms of
1
0
18
the highest g(r) value, ranging between 1.3 and 1.5, and its peak distance, which has a value of
around 3.6 Å. On the other side carbon atom C shows the highest g(r) value of 1.1 and a peak
1
4
distance at around 4.7 Å. Moreover, RDFs of non-carbon atoms demonstrate that they are more
apt to interact with water molecules (Fig. 9b). The shortest peak distances in these cases were
calculated to be for N and O atoms, both less than 3 Å, with maximal g(r) values of around 0.5
1
17
and 1.0, respectively. O36 and O37 are very similar in terms of g(r) value and peak distance,
around 1.1 and 3.2 Å, respectively. Nitrogen atom N has scored the highest g(r) value of almost
1
5
1
4
.4, while its peak distance is located at somewhat less than 4 Å. Nitrogen atom N has maximal
g(r) value of around 1.2 with its peak distance located at around 4.7 Å. The facts that BDE
values are the lowest for bonds that connect nitro and methoxy moieties to the benzene ring and
that RDF curves show pronounced interactions for certain atoms belonging to these groups,
indicate the role of these groups in terms of degradability of the title molecule.
1
1

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4
.6
MNPE Docking Analysis towards GABA Receptor
4
.6.1 Protein Structure Validation
The validation of the structure of the target protein is an essential step in the drug discovery
process [55]. The crystal structure of a human GABA receptor (PDB ID: 4COF) shown in Fig.
1
0a was done at a resolution of 2.97 Å and was used as the target protein [17]. The target protein
contains 5 possible binding sites, namely chains A, B, C, D and E. Each chain is consisted of
about five α-helices which are spiral in shape and about 8 β-pleated sheets. Ramachandran plot
(
Fig. 10b) checked a total number of 1574 residues out of the 1665 amino residues present in the
target protein, which is tantamount to about 95% of the total residues. The total number of core
regions and outliers are 1546 and 28 respectively, which gave a rise to a percentage outlier of 1.8
%
. The Ramachandran plot uses percentage outlier to ascertain the validity of a protein structure.
The recommended range for the percentage outlier for a valid protein structure is between 0 to 5
[56]. Hence, the target protein (PDB ID: 4COF) used for the molecular docking was valid.
%
4
.6.2 Molecular Docking
The five binding sites of the benzamidine molecule, A, B, C, D and E, complexed with
the crystal structure of the target protein (PDB ID: 4COF) were used for docking analysis.
Benzamidine is an agonist for the human GABA receptor [17] and hence its binding site was
used as a reference for the molecular docking analysis. Table 8 lists the molecular docking
results of MNPE and human GABA receptor. Binding site C which is the reference site for BEN
C in the original crystal structure had the highest total docking score value which implies that
MNPE exhibits the best binding affinity towards the target protein within this binding site. The
total score value is the sum of the Hydrogen Bond (HB) score, the Steric Interaction (SI) score
and the ligand penalty conformation. It was also predicted that the ligand in binding cite C has
the lowest ligand conformation penalty value (7.910) and the most negative steric interaction
score (-59.781) among the different binding sites. Four types of favorable interactions (Fig. 11)
between MNPE and the target protein could be established. The favorable interactions between
MNPE and the target protein included conventional hydrogen bonding with amino acids THR
2
02 and GLN 64, π-π stacking and π-alkyl interactions with PHE 200, TYR 62 and TYR 205,
and carbon hydrogen bond with ASP 43 and TYR 157 (Fig. 11).
1
2

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4
.6.3 Binding Mode Conformation
The molecular docking analysis involved the generation of five low energy
conformational scenarios known as poses. Unlike regular conformations, a pose structure is
dependent on the target protein. Each pose was screened against the target protein in each of the
five binding sites, A thru E. The binding mode conformation of MNPE in a binding site C have
shown the best binding affinity (Fig. 11). During molecular docking analysis, the molecule
orientated itself such that there exist an intramolecular hydrogen bonding between one of the
hydrogens of the piperazine ring and the oxygen of the carbonyl group. The comparison between
the most stable conformer (B4) and the best binding pose from the molecular docking analysis is
depicted in Fig. 12. It was evident that the docked pose and most stable conformer of MNPE
were similar with respect to the position of the various functional groups except that the structure
of the binding pose is contracted due to the presence of intramolecular hydrogen bonding along
with its orientation of the flexible bonds in the molecule. The difference in the structure of the
binding pose arises because in molecular docking the molecule would orientate itself such that it
best-fit into the binding pocket of the target protein to ensure adequate binding.
4
.7
Vibrational Assignments of the IR and Raman Spectra
Understanding the detailed infrared and Raman features of newly synthesized, biologically active
molecules is essential for tracing purposes as well as gaining advanced structural comprehension.
In order to further elaborate on the vibrational spectral properties of MNPE, the calculated scaled
wavenumbers, observed IR, Raman bands and detailed vibrational assignments for MNPE were
provided in table 5.
4
2
.7.1 NO Modes
According to literature, the NO stretching modes are normally observed in the regions
2
-1
1
580 ± 80 (asymmetric) and 1330 ± 30 cm (symmetric) [57]. For the title compound, NO
2
-
1
-1
stretching modes are assigned at 1502, 1310 cm in the IR spectrum, 1492, 1308 cm in the
-1
Raman spectrum and at 1495, 1307 cm theoretically with PEDs 66 and 49%. Both the modes
-1
possess a high IR intensity and the mode at 1307 cm has a high Raman activity. Mary et al.
-1
reported the NO stretching modes at 1429, 1363 (DFT), 1435, 1368 (IR), 1435, 1367 cm
2
2
(Raman) [58]. The NO deformation modes (scissoring, out-of-plane wagging, in-plane rocking
1
3

ACCEPTED MANUSCRIPT
-1
and torsion) are expected in the regions 855 ± 40, 760 ± 30, 540 ± 30 and 70 ± 20 cm ,
-1
-1
respectively [57]. The bands at 844, 808 cm in the Raman spectrum and 842, 807 and 549 cm
DFT) are assigned as the deformation modes of the NO group for MNPE. These modes have
(
2
3
9, 38, 47% PEDs, and the first two modes possess a medium-strength IR and Raman intensities.
The reported values of the NO deformations modes are: 778, 692, 533 (DFT), 773, 522 (IR),
2
-1
-1
7
73 cm (Raman) [58] and at 800, 727, 534 (DFT), 809, 727, 524 cm (experimentally) [59].
4
.7.2 C-O-C and C=O Modes
The C-O-C stretching vibrations are expected in the ranges, 1310-1110 and 1050-1010
-1
-1
cm [57], [60]. In the present case the C-O-C stretching modes are assigned at 1240, 1008 cm
-1
theoretically with a PED of 40% and correspond experimentally to 1010 cm in the IR and 1242
-1
cm in the Raman spectra. Mary et al. reported the C-O-C stretching modes at 1042, 1016, 982
-1
-1
cm in the IR spectrum and at 1135, 1132, 1080, 1046, 1012, 984 cm theoretically [61].
-
1
-1
Moreover, the C=O stretching mode in MNPE is assigned at 1648 cm in IR, 1649 cm in
-1
Raman and 1655 cm theoretically which is in agreement with the expected region of 1750-1600
-1
cm [57], [62], [63]. The carbonyl stretching mode is predicted to have minimum coupling from
other modes with a PED of 75% and of high infrared and Raman intensities [57].
4
3
.7.3 CH Modes
-1
For the title compound, the CH stretching modes are assigned at 2977, 2944 cm in the
3
-1
infrared spectrum, 3032, 2950, 2900 cm in the Raman spectrum and in the range 3030-2895
-1
cm theoretically. The deformation modes of the methyl groups of the title compound are
normally highly coupled with other bending modes. In MNPE the infrared bands observed at
-1
-1
1
430 and 1339 cm and Raman lines observed at 1428, 1159, 970 cm are assigned as CH
3
-1
deformations (Table 5). The corresponding theoretical values are in the range 1443-1338 cm
-1
(
scissoring) and 1161-967 cm (rocking) [57].
4
.7.4 C-N and C-C Modes
The C-N stretching modes are observed in the range 1300-1000 cm [62], [63] and for
-1
-1
the title compound these modes are assigned at 1178, 1073 cm in the IR spectrum, 1224, 1077
-1
-1
cm in the Raman spectrum and at 1220, 1185, 1074 cm theoretically with PEDs of 44, 41 and
1
4

ACCEPTED MANUSCRIPT
3
9
1
6%, respectively. El-Azab et al. [43] reported the C-N stretching modes at 1232, 1146, 1108,
-1
-1
66 cm in the IR spectrum, 1232, 1149, 1108, 967 cm in the Raman spectrum and in the range
-1
235-965 cm theoretically. For the title compound the C-C stretching mode is assigned at 904
-1
-1
cm in the Raman spectrum and at 902 cm theoretically as expected [63].
4
.7.5 Piperazine Ring Modes
The CH stretching modes in the piperazine ring could be assigned to 3014, 2977, 2876,
2
-1
-1
2
820 cm in the infrared and to 2999, 2981, 2885, 2843 cm in the Raman spectra. El-Emam et
-1
2
al. [39] reported stretching CH vibrations in the piperazine ring in the range 3033-2834 cm .
Renjith et al. reported the CH stretching modes in the piperazine ring at 2986, 2976, 2965, 2923
2
-1
-1
-1
cm (theoretical), 2990, 2923 cm (IR) and 2988, 2924 cm (Raman) [64]. The corresponding
-1
deformation modes could be assigned to 1363, 1202, 1178, 1092, 1036, 829 cm in the IR and to
-1
1
452, 1364, 1333, 1242, 1224, 1196, 1091, 1040, 829 cm in the Raman spectra. According to
H. L. Spell [65] the CH deformation modes associated with the piperazine ring are usually
observed ass harp, well defined absorptions at 1380-1345 cm , 125-1170 cm and 1050-1025
2
-1
-1
-1
cm regions in the infrared spectrum. It prompted us to assign the strong peak observed in the
-1
infrared spectrum of MNPE at 1363 cm (Fig. 2) to the CH wagging mode of the piperazine
2
-1
ring in agreement with the DFT value (1361 cm ). Furthermore, another intense band observed
-1
2
at 1036 cm in the IR spectrum was assigned to the ring CH rocking vibration, in consistency
with previously reported finding da Silva et al. [66]. According to H. L. Spell [65], this is one of
the key bands useful for the detection of the presence of di-substituted piperazines.
-1
Piperazine ring stretching modes in MNPE could be observed at 1131, 960, 697 cm in
-1
the ir spectrum and at 1196, 1018, 954, 904, 701 cm in the Raman spectrum. The PED analysis
-1
predicts these modes in the range 1193-699 cm . Renjith et al. reported the piperazine ring
-1
-1
stretching modes 1099, 985, 930 cm in the IR spectrum, 1100, 924, 905 cm in the Raman
-1
spectrum and 1159, 1098, 1020, 982, 924 and 914 cm theoretically [64]. The C-C stretching
-1
vibrations in the piperaizne ring were previously reported at 972 and 903 cm [58] while the C-
-1
N stretching modes were reported in the range 1154-756 cm [58].
4
.7.6 Phenyl Ring Modes
1
5

ACCEPTED MANUSCRIPT
-1
The C-H stretching modes of the phenyl ring are expected above 3000 cm [57] and, for
-1
-1
the title compound, the bands at 3118, 3078 cm (Raman) and 3120, 3094, 3081 cm (DFT) are
assigned as the C-H stretching vibrations of the phenyl ring. The phenyl ring stretching modes
-1
-1
are assigned at 1574, 1550, 1476, 1288 cm in the IR spectrum, 1577, 1392 cm in the Raman
-1
spectrum and at 1576, 1553, 1473, 1391, 1291 cm theoretically which are expected in the
-1
-1
region 1250-1600 cm [57]. The ring breathing mode of the phenyl ring is assigned at 1010 cm
-1
in the IR spectrum and at 1008 cm theoretically as reported in literature [57], [67]. The reported
-1
-1
values of the ring breathing mode of poly substituted phenyl ring at 978 cm [43], 1025 cm in
-1
the Raman spectrum and 1032 cm theoretically [68]. The C-H in-plane and out-of-plane
-1
bendings of the phenyl ring are expected above and below 1000 cm [57] and for the title
-1
-1
-1
compound, the bands at 1258, 1073 cm (IR), 1077 cm (Raman), 1257, 1146, 1074 cm (DFT)
-1
-1
and 932, 801 cm (IR), 935, 799, 789 cm (DFT) are assigned as the in-plane and out-of-plane
CH deformation modes, respectively.
5
.
Conclusions
The synthesis and vibrational spectroscopic properties of 1-(4-(3-methoxy-4-
nitrophenyl)piperazin-1-yl)ethanone (MNPE) have been accomplished. MEP studies revealed the
most reactive sites in the molecule. The low HOMO-LUMO energy gap is associated with the
high chemical reactivity and existence of charge transfer within the molecule. ALIE surfaces
indicated that significant reactive centers, prone to electrophilic attacks, could be located at
carbon atoms of the benzene ring, nitrogen atom of the piperazine moiety and oxygen atoms of
the nitro group. Bond dissociation energy values of hydrogen abstraction indicated that MNPE is
highly stable in open air and in the presence of oxygen, however, the calculated RDF curves
revealed that MNPE is dissociable in aqueous systems. The molecular docking analysis showed
that binding site C had the best binding affinity towards the GABA receptor
Acknowledgment
Experimental and computational resources provided by King Fahd University of Petroleum and
Minerals (KFUPM) to support this work are appreciated. Support received from Schrödinger Inc.
is appreciated. Part of this study was conducted within the projects supported by the Ministry of
1
6

ACCEPTED MANUSCRIPT
Education, Science and Technological Development of Serbia, grant numbers OI 171039 and TR
3
4019 (project period 2016-2019/20).
References
[1]
[2]
[3]
J. Cai, Y. Lu, L. Gan, Y. Zhang, and C. Zhou, “Recent advance in the research of
piperazine-containing compounds as antimicrobial agents,” Chin. J. Antibiot, 8 (2009) 3.
L. L. Gan, Y. H. Lu, and Zhou C.H., “Advances in the research of piperazine compounds
as enzyme inhibitors,” Chin. J. Biochem. Pharm, vol. 30, no. 6, pp. 127–131, 2009.
Y.-J. Shaw, Y.-T. Yang, J. B. Garrison, N. Kyprianou, and C.-S. Chen, “Pharmacological
Exploitation of the α1-Adrenoreceptor Antagonist Doxazosin to Develop a Novel Class of
Antitumor Agents That Block Intracellular Protein Kinase B/Akt Activation,” J. Med.
Chem., vol. 47, no. 18, pp. 4453–4462, 2004.
[4]
J. Chen, M. Lu, Y. Jing, and J. Dong, “The synthesis of L-carvone and limonene
derivatives with increased antiproliferative effect and activation of ERK pathway in
prostate cancer cells,” Bioorg. Med. Chem., 14 (2006) 6539-6547.
[
5]
6]
S. Richter, C. Parolin, and M. Palumbo, “Antiviral properties of quinolone-based drugs,”
Drug Targets-Infectious, 4 (2004) 111-116.
[
W. J. Watkins, L. Chong, A. Cho, R. Hilgenkamp, M. Ludwikow, N. Garizi, N. Iqbal, J.
Barnard, R. Singh, D. Madsen, K. Lolans, O. Lomovskaya, U. Oza, P. Kumaraswamy, A.
Blecken, S. Bai, D. J. Loury, D. C. Griffith, and M. N. Dudley, “Quinazolinone fungal
efflux pump inhibitors. Part 3: (N-methyl)piperazine variants and pharmacokinetic
optimization,” Bioorg. Med. Chem. Lett., vol. 17, no. 10, pp. 2802–2806, May 2007.
M. Kimura, T. Masuda, K. Yamada, N. Kawakatsu, N. Kubota, M. Mitani, K. Kishii, M.
Inazu, Y. Kiuchi, K. Oguchi, and T. Namiki, “Antioxidative activities of novel
diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter,”
Bioorg. Med. Chem. Lett., vol. 14, no. 16, pp. 4287–4290, 2004.
[7]
[8]
[9]
R. A. Smits, H. D. Lim, A. Hanzer, O. P. Zuiderveld, E. Guaita, M. Adami, G. Coruzzi, R.
Leurs, and I. J. P. Esch, “Fragment Based Design of New H 4 Receptor−Ligands with
Anti-inflammatory Properties in Vivo,” J. Med. Chem., vol. 51, no. 8, pp. 2457–2467,
2
008.
W. Cunico, C. R. B. Gomes, M. Moreth, D. P. Manhanini, I. H. Figueiredo, C. Penido, M.
G. M. O. Henriques, F. P. Varotti, and A. U. Krettli, “Synthesis and antimalarial activity
of hydroxyethylpiperazine derivatives,” Eur. J. Med. Chem., vol. 44, no. 3, pp. 1363–
1
368, 2009.
[
[
[
10] J. Penjišević, V. Šukalović, D. Andrić, S. Kostić-Rajačić, V. Šoškić, and G. Roglić, “1-
Cinnamyl-4-(2-methoxyphenyl)piperazines,” Arch. Pharm. (Weinheim)., vol. 340, no. 9,
pp. 456–465, 2007.
11] D. S. Wishart, C. Knox, A. C. Guo, S. Shrivastava, M. Hassanali, P. Stothard, Z. Chang,
and J. Woolsey, “DrugBank: a comprehensive resource for in silico drug discovery and
exploration.,” Nucleic Acids Res., vol. 34, no. Database issue, pp. D668–D672, 2006.
12] A. Golubović, B. Abramović, M. Šćepanović, M. Grujić-Brojčin, S. Armaković, I.
1
7

ACCEPTED MANUSCRIPT
Veljković, B. Babić, Z. Dohčević-Mitrović, and Z. V Popović, “Improved efficiency of
sol–gel synthesized mesoporous anatase nanopowders in photocatalytic degradation of
metoprolol,” Mater. Res. Bull., vol. 48, no. 4, pp. 1363–1371, 2013.
[
[
[
[
13] R. Ma, B. Wang, S. Lu, Y. Zhang, L. Yin, J. Huang, S. Deng, Y. Wang, and G. Yu,
“Characterization of pharmaceutically active compounds in Dongting Lake, China:
Occurrence, chiral profiling and environmental risk,” Sci. Total Environ., vol. 557–558,
pp. 268–275, Jul. 2016.
14] S. J. Armaković, S. Armaković, N. L. Finčur, F. Šibul, D. Vione, J. P. Šetrajčić, and B. F.
Abramović, “Influence of electron acceptors on the kinetics of metoprolol photocatalytic
degradation in TiO 2 suspension. A combined experimental and theoretical study,” RSC
Adv, vol. 5, no. 67, pp. 54589–54604, 2015.
15] D. Šojić, V. Despotović, D. Orčić, E. Szabó, E. Arany, S. Armaković, E. Illés, K. Gajda-
Schrantz, A. Dombi, T. Alapi, E. Sajben-Nagy, A. Palágyi, C. Vágvölgyi, L. Manczinger,
L. Bjelica, and B. Abramović, “Degradation of thiamethoxam and metoprolol by UV, O3
and UV/O3 hybrid processes,” J. Hydrol., vol. 472–473, pp. 314–327, 2012.
16] B. Abramović, S. Kler, D. Šojić, M. Laušević, T. Radović, and D. Vione, “Photocatalytic
2
degradation of metoprolol tartrate in suspensions of two TiO -based photocatalysts with
different surface area. Identification of intermediates and proposal of degradation
pathways,” J. Hazard. Mater., vol. 198, pp. 123–132, 2011.
[17] P. S. Miller and A. R. Aricescu, “Crystal structure of a human GABAA receptor,” Nature,
5
12 (2014) 270-275.
[18] P. R. Schofield, M. G. Darlison, N. Fujita, D. R. Burt, F. A. Stephenson, H. Rodriguez, L.
M. Rhee, J. Ramachandran, V. Reale, T. A. Glencorse, P. H. Seeburg, and E. A. Barnard,
“Sequence and functional expression of the GABAA receptor shows a ligand-gated
receptor super-family,” Nature, vol. 328, no. 6127, pp. 221–227, Jul. 1987.
19] W. Sieghart, “GABAA receptors: ligand-gated Cl− ion channels modulated by multiple
drug-binding sites,” Trends Pharmacol. Sci., vol. 13, pp. 446–450, Jan. 1992.
20] a) A. J. Pawson, J. L. Sharman, H. E. Benson, E. Faccenda, S. P. H. Alexander, O. P.
Buneman, A. P. Davenport, J. C. McGrath, J. A. Peters, C. Southan, M. Spedding, W. Yu,
and A. J. Harmar, “The IUPHAR/BPS Guide to PHARMACOLOGY: An expert-driven
knowledgebase of drug targets and their ligands,” Nucleic Acids Res., vol. 42, no. D1, pp.
[
[
1
098–1106, 2014. b) A. O. Ba-Salema, M. N. Shaikh, N. Ullah and M. Faiz, "Synthesis
and magnetic relaxation properties of new Gd(III) complexes derived from DTPA-
bis(amide) conjugates of arylpiperazinyl amines," Inorg. Chem. Commun., vol. 56, pp. 5-
7
, 2015.
[
21] G. E. S. M. J. Frisch, G. W. Trucks, H. B. Schlegel, B. M. M. A. Robb, J. R. Cheeseman,
G. Scalmani, V. Barone, H. P. H. G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, M. H.
A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, T. N. M. Ehara, K. Toyota, R.
Fukuda, J. Hasegawa, M. Ishida, J. Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A.
Montgomery, E. B. J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, J. N. K. N. Kudin,
V. N. Staroverov, T. Keith, R. Kobayashi, J. T. K. Raghavachari, A. Rendell, J. C. Burant,
S. S. Iyengar, J. B. C. M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, R. E. S. V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, J. W. O. O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, G. A. V. R. L. Martin, K. Morokuma, V. G. Zakrzewski, A. D. D. P.
Salvador, J. J. Dannenberg, S. Dapprich, J. C. O. Farkas, J. B. Foresman, J. V. Ortiz, and
and D. J. Fox, “Gaussian 09, Revision D.01,” Gaussian, Inc. Wallingford CT. 2013.
1
8

ACCEPTED MANUSCRIPT
[
22] A. Irfan, R. Jin, A. G. Al-Sehemi, and A. M. Asiri, “Quantum chemical study of the
donor-bridge-acceptor triphenylamine based sensitizers,” Spectrochim. Acta Part A Mol.
Biomol. Spectrosc., vol. 110, pp. 60–66, 2013.
[
23] A. Irfan, A. G. Al-Sehemi, and M. S. Al-Assiri, “The effect of donors–acceptors on the
charge transfer properties and tuning of emitting color for thiophene, pyrimidine and
oligoacene based compounds,” J. Fluor. Chem., vol. 157, pp. 52–57, 2014.
24] E. F. J.B. Foresman, Exploring Chemistry with Electronic Structure Methods: A Guide to
Using Gaussian, no. 1 TS-CrossRef Metadata Search. Pittsburg: Gaussian Inc., 1996.
25] A. A. Al-Saadi and J. Laane, “Ab initio and DFT calculations for the structure and
vibrational spectra of cyclopentene and its isotopomers,” J. Mol. Struct., vol. 830, no. 1–3,
pp. 46–57, 2007.
[
[
[
[
[
26] R. Dennington, T. Keith, and J. Millam, “GaussView.” Semichem Inc, Shawnee Mission
KS, 2009.
27] C. V. A. J.M.L. Martin, “GAR2PED,” vol. 44, no. 2. University of Antwerp, Belgium,
2
007.
28] A. D. Bochevarov, E. Harder, T. F. Hughes, J. R. Greenwood, D. A. Braden, D. M.
Philipp, D. Rinaldo, M. D. Halls, J. Zhang, and R. A. Friesner, “Jaguar: A high-
performance quantum chemistry software program with strengths in life and materials
sciences,” Int. J. Quantum Chem., vol. 113, no. 18, pp. 2110–2142, 2013.
[
[
[
29] D. Shivakumar, J. Williams, Y. Wu, W. Damm, J. Shelley, and W. Sherman, “Prediction
of Absolute Solvation Free Energies using Molecular Dynamics Free Energy Perturbation
and the OPLS Force Field,” J. Chem. Theory Comput., vol. 6, no. 5, pp. 1509–1519, 2010.
30] Z. Guo, U. Mohanty, J. Noehre, T. K. Sawyer, W. Sherman, and G. Krilov, “Probing theα-
Helical Structural Stability of Stapled p53 Peptides: Molecular Dynamics Simulations and
Analysis,” Chem. Biol. Drug Des., vol. 75, no. 4, pp. 348–359, Apr. 2010.
31] K. J. Bowers, F. D. Sacerdoti, J. K. Salmon, Y. Shan, D. E. Shaw, E. Chow, H. Xu, R. O.
Dror, M. P. Eastwood, B. A. Gregersen, J. L. Klepeis, I. Kolossvary, and M. A. Moraes,
“Molecular dynamics---Scalable algorithms for molecular dynamics simulations on
commodity clusters,” in Proceedings of the 2006 ACM/IEEE conference on
Supercomputing - SC ’06, 2006, p. 84.
[
[
[
32] D. E. Shaw Research, “Schrödinger Release 2015-4: Desmond Molecular Dynamics
System.” 2015.
33] A. D. Becke, “Density‐functional thermochemistry. III. The role of exact exchange,” J.
Chem. Phys., vol. 98, no. 7, pp. 5648–5652, 1993.
34] J. L. Banks, H. S. Beard, Y. Cao, A. E. Cho, W. Damm, R. Farid, A. K. Felts, T. A.
Halgren, D. T. Mainz, J. R. Maple, R. Murphy, D. M. Philipp, M. P. Repasky, L. Y.
Zhang, B. J. Berne, R. A. Friesner, E. Gallicchio, and R. M. Levy, “Integrated Modeling
Program, Applied Chemical Theory (IMPACT),” J. Comput. Chem., vol. 26, no. 16, pp.
1
752–1780, 2005.
[
35] H. J. C. Berendsen, J. P. M. Postma, W. F. van Gunsteren, and J. Hermans, “Interaction
Models for Water in Relation to Protein Hydration,” in Intermolecular Forces, vol. 14, B.
Pullman, Ed. Dordrecht: Springer Netherlands, 1981, pp. 331–342.
[
[
36] T. Knudsen, Bjarne Knudsen, “CLC Drug Discovery Workbench.” pp. 1–367, 2016.
37] G. J. Kleywegt and T. A. Jones, “Phi/Psi-chology,” Structure, vol. 4, no. 12, pp. 1395–
1
400, 1996.
[38] I. P. Holmes, Y. Bergman, G. E. Lunniss, M. Nikac, N. Chol, C. F. Hemley, S. R. Walker,
1
9

ACCEPTED MANUSCRIPT
R. C. Foitzik, D. Ganame, and R. Lessene, US 20130022594, 2013.
[
39] A. A. El-Emam, A.-M. S. Al-Tamimi, K. A. Al-Rashood, H. N. Misra, V. Narayan, O.
Prasad, and L. Sinha, “Structural and spectroscopic characterization of a novel potential
chemotherapeutic agent 3-(1-adamantyl)-1-{[4-(2-methoxyphenyl)piperazin-1-
yl]methyl}-4-methyl-1H-1,2,4-triazole-5(4H)-thione by first principle calculations,” J.
Mol. Struct., vol. 1022, pp. 49–60, 2012.
[
40] K. S. Resmi, Y. S. Mary, H. T. Varghese, C. Y. Panicker, M. Pakosińska-Parys, and C.
van Alsenoy, “Spectral investigations, DFT computations and molecular docking studies
of 1,7,8,9-tetrachloro-10,10-dimethoxy-4-{3-[4-(2-methylphenyl)piperazin-1-yl]propyl}-
4
2
-azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione,” J. Mol. Struct., vol. 1098, pp. 130–145,
015.
[
41] Z. Karczmarzy and W. Malinka, “Crystal Structure of 4,6-Dimethyl-2-[4-(2,3-
dichlorophenyl)piperazin-1-ylmethyl]isothiazolo[5,4-b]pyridin-3(2H)-one,” Anal. Sci. X-
ray Struct. Anal. Online, vol. 23, pp. x151–x152, 2007.
[
42] Y. Sheena Mary, T. S. Yamuna, C. Y. Panicker, H. S. Yathirajan, M. S. Siddegowda, A. a
Al-Saadi, C. Van Alsenoy, and J. A. War, “Vibrational spectroscopic studies and
molecular docking of 10,10-Dimethylanthrone.,” Spectrochim. Acta. A. Mol. Biomol.
Spectrosc., vol. 135, pp. 652–61, 2015.
[
[
[
43] A. S. El-Azab, Y. Sheena Mary, C. Yohannan Panicker, A. A.-M. Abdel-Aziz, M. A. El-
Sherbeny, and C. van Alsenoy, “DFT and experimental (FT-IR and FT-Raman)
investigation of vibrational spectroscopy and molecular docking studies of 2-(4-oxo-3-
phenethyl-3,4-dihydroquinazolin-2-ylthio)-N-(3,4,5-trimethoxyphenyl) acetamide,” J.
Mol. Struct., vol. 1113, pp. 133–145, 2016.
44] Y. Sheena Mary, K. Raju, C. Y. Panicker, A. A. Al-Saadi, T. Thiemann, and C. van
Alsenoy, “Molecular conformational analysis, vibrational spectra, NBO analysis and first
hyperpolarizability of (2E)-3-phenylprop-2-enoic anhydride based on density functional
theory calculations,” Spectrochim. Acta Part A Mol. Biomol. Spectrosc., vol. 128, pp.
6
38–646, 2014.
45] C. Y. Panicker, H. T. Varghese, P. S. Nayak, B. Narayana, B. K. Sarojini, H. K. Fun, J. A.
War, S. K. Srivastava, and C. van Alsenoy, “Infrared spectrum, NBO, HOMO–LUMO,
MEP and molecular docking studies (2E)-3-(3-nitrophenyl)-1-[4-piperidin-1-yl]prop-2-en-
1
-one,” Spectrochim. Acta Part A Mol. Biomol. Spectrosc., vol. 148, pp. 18–28, 2015.
[
46] P. Sjoberg, J. S. Murray, T. Brinck, and P. Politzer, “Average local ionization energies on
the molecular surfaces of aromatic systems as guides to chemical reactivity,” Can. J.
Chem., vol. 68, no. 8, pp. 1440–1443, 1990.
[
47] P. Politzer, F. Abu-Awwad, and J. S. Murray, “Comparison of density functional and
Hartree-Fock average local ionization energies on molecular surfaces,” Int. J. Quantum
Chem., vol. 69, no. 4, pp. 607–613, 1998.
[
[
[
48] A. Michalak, F. Proft, P. Geerlings, and R. F. Nalewajski, “Fukui Functions from the
Relaxed Kohn−Sham Orbitals,” J. Phys. Chem. A, vol. 103, no. 6, pp. 762–771, 1999.
49] A. E. R. E.D. Glendening J.E. Carpenter, F.Weinhold, “NBO Version 3.1,” vol. 81 TS-C,
no. 32. Gaussian Inc., 2003.
50] A. B. T. Andersson E. Evertsson, “Prediction of drug candidates sensitivity toward
autoxidation:Computational estimation of C-H dissociation energies of carbon centered
radicals,” J. Pharm. Sci., vol. 103, p. 1949–1955.
[51] P. Lienard, J. Gavartin, G. Boccardi, and M. Meunier, “Predicting drug substances
2
0

ACCEPTED MANUSCRIPT
autoxidation,” Pharm. Res., vol. 32, no. 1, pp. 300–310, 2015.
52] Y.-R. Luo, Handbook of bond dissociation energies in organic compounds. Boca Raton,
FL: CRC Press, 2003.
53] J. S. Wright, H. Shadnia, and L. L. Chepelev, “Stability of carbon-centered radicals:
Effect of functional groups on the energetics of addition of molecular oxygen,” J. Comput.
Chem., vol. 30, no. 7, pp. 1016–1026, May 2009.
[
[
[54] R. V. Vaz, J. R. B. Gomes, and C. M. Silva, “Molecular dynamics simulation of diffusion
coefficients and structural properties of ketones in supercritical CO at infinite dilution,” J.
2
Supercrit. Fluids, vol. 107, pp. 630–638, Jan. 2016.
[
[
[
[
55] M. E. Bunnage, A. M. Gilbert, L. H. Jones, and E. C. Hett, “Know your target, know your
molecule,” Nat. Chem. Biol., vol. 11, no. 6, pp. 368–372, 2015.
56] G. J. Kleywegt and T. A. Jones, “Phi/Psi-chology: Ramachandran revisited,” Structure,
vol. 4, no. 12, pp. 1395–1400, 1996.
57] N. P. G. Roeges, A guide to the complete interpretation of infrared spectra of organic
structures. Wiley, 1994.
58] Y. Sheena Mary, K. Raju, T. E. Bolelli, I. Yildiz, H. I. S. Nogueira, C. M. Granadeiro, and
C. van Alseony, “FT-IR, FT-Raman, surface enhanced Raman scattering and
computational study of 2-(p-fluorobenzyl)-6-nitrobenzoxazole,” J. Mol. Struct., vol. 1012,
pp. 22–30, 2012.
[
59] H. T. V. C.Y. Panicker L. Usha Kumari, T. Ertan, I. Yildiz, C.M. Granadeiro, H.I.S.
Nogueira, Y.S. Mary, “FT-IR, FT-Raman, SERS spectra and Computational calculations
of 4-Ethyl-N-(2’-hydroxy-5’-nitrophenyl)benzamide,” J. Raman Spectrosc., vol. 41, p.
3
81–390., 2010.
[60] B. Smith, Infrared spectral interpretation:A systematic approach, vol. 36 TS-C, no. 10.
Washington, DC: CRC Press, 1999.
[
61] Y. Sheena Mary, C. Yohannan Panicker, P. L. Anto, M. Sapnakumari, B. Narayana, and
B. K. Sarojini, “Molecular structure, FT-IR, NBO, HOMO and LUMO, MEP and first
order hyperpolarizability of (2E)-1-(2,4-Dichlorophenyl)-3-(3,4,5-trimethoxyphenyl)prop-
2
-en-1-one by HF and density functional methods,” Spectrochim. Acta Part A Mol.
Biomol. Spectrosc., vol. 135, pp. 81–92, 2015.
[
[
[
62] L. H. D. N.B. Colthup S.E. Wiberly, Introduction to IR and Raman Spectroscopy. New
York: Academic Press TS - CrossRef Metadata Search M4 - Citavi, 1990.
63] R. M. (Robert M. Silverstein, F. X. Webster, D. J. Kiemle, and D. L. (David L. Bryce,
Spectrometric identification of organic compounds. .
64] R. Renjith, Y. Sheena Mary, C. Yohannan Panicker, H. T. Varghese, M. Pakosinska-
Parys, C. van Alsenoy, and A. A. Al-Saadi, “Spectroscopic (FT-IR, FT-Raman)
investigations and quantum chemical calculations of 1,7,8,9-tetrachloro-10,10-dimethoxy-
4
-{3-4-(3-methoxyphenyl)piperazin-1-ylpropy l}-4-azatricyclo5.2.1.0(2,6)dec-8-ene-3,5-
dione,” Spectrochim. Acta. A. Mol. Biomol. Spectrosc., vol. 129, pp. 438–450, 2014.
65] H. L. Spell, “Determination of piperazine rings in ethyleneamines, poly(ethyleneamine),
and polyethylenimine by infrared spectrometry,” Anal. Chem., vol. 41, no. 7, pp. 902–905,
[
2
002.
[
66] S. P. M.A.S. da Silva T. Francisco, F.O.N. Da Silva, A.A. Batista, J. Ellena, I.M.M.
Varvalho, J.R. de Sousa, F.A. Dias-Filho, E. Longhinotti, I.C.N. Diogenes, “A novel and
simple synthetic route for a piperazine derivative,” J. Braz. Chem. Soc, vol. 21, pp. 1754–
1
759.
2
1

ACCEPTED MANUSCRIPT
[67] G. Varsanyi, Assignments for Vibrational Spectra of Seven Hundred Benzene Derivatives,
vol. 51 TS-C, no. 2. New York: Wiley, 1974.
[
68] A. Raj, Y. Sheena Mary, C. Yohannan Panicker, H. T. Varghese, and K. Raju, “IR,
Raman, SERS and computational study of 2-(benzylsulfanyl)-3,5-dinitrobenzoic acid,”
Spectrochim. Acta. A. Mol. Biomol. Spectrosc., vol. 113, pp. 28–36, 2013.
2
2

ACCEPTED MANUSCRIPT
LIST OF TABLES
Table 1. Conformations and relative energies of the title compound
Relative energy (kcal/mol)
Conformation
Computational Method B3LYP/6-311G(d,p)
B3LYP/6-311++G(d,p)
A1
A2
A3
A4
B1
B2
B3
B4
C1
C2
C3
C4
D1
D2
D3
D4
0.127
0.107
0.434
0.174
0.283
0.286
0.258
0.000
1.271
1.5
1.627
0.89
1.205
1.475
1.645
0.972
0.137
0.126
0.474
0.188
0.298
0.319
0.29
0.000
1.591
1.837
1.975
1.236
1.523
1.811
1.995
1.318

ACCEPTED MANUSCRIPT
Table 2. Bond lengths of selected atoms
Models N -O
N -C6 C -O
O -O
N -C7 N -C
C -O
16 17
1
5
37
1
9
13
13
37
1
4
16
A1
A2
A3
A4
B1
B2
B3
B4
C1
C2
C3
C4
D1
D2
D3
D4
1.224
1.462
1.346
2.665
1.399
1.378
1.222
(1.22)
1.222
(1.22)
1.222
(
(
1.223) (1.464) (1.346)
1.225 1.461 1.345
1.223) (1.464) (1.345) (2.622) (1.397) (1.379)
1.232 1.463 1.347 2.651 1.399 1.378
(2.64) (1.398) (1.379)
2.644 1.398 1.377
(
1.23) (1.465) (1.346) (2.627) (1.398) (1.378) (1.219)
1.232 1.46 1.346 2.657 1.397 1.378 1.222
1.231) (1.463) (1.346 (2.634) (1.396) (1.379) (1.219)
1.224 1.462 1.347 2.666 1.399 1.378 1.222
1.223 (1.465) (1.347) (2.64) (1.399) (1.379) (1.219)
1.225 1.461 1.346 2.643 1.397 1.378 1.222
1.223 (1.464 (1.346 (2.621) (1.397) (1.379) (1.219)
(
(
(
(
1.232
1.223 (1.465) (1.346) (2.627) (1.398) (1.379)
1.232 1.46 1.346 2.657 1.397 1.377
1.231) (1.463 (1.345 (2.635) (1.397) (1.379)
1.23 1.456 1.353 2.888 1.394 1.378
1.462
1.346
2.651
1.398
1.378
1.222
(1.22)
1.222
(1.22)
1.222
(
(
(
(
1.229) (1.458) (1.354) (2.864) (1.393 (1.379) (1.219)
1.23
1.229) (1.458) (1.353) (2.865) (1.395) (1.379)
1.23 1.456 1.354 2.882 1.393 1.378
1.456
1.352
2.89
1.396
1.378
1.222
(1.22)
1.222
1.228) (1.458) (1.355) (2.858) (1.392) (1.379) (1.219)
1.23
1.228 (1.457) (1.352) (2.877) (1.393) (1.379)
1.23 1.456 1.353 2.888 1.394 1.378
1.455
1.352
2.896
1.394
1.378
1.222
(1.22)
1.222
(
(1.229 (1.458 (1.354) (2.864) (1.393) (1.379) (1.219)
1.23
1.229) (1.458) (1.353) (2.864) (1.395) (1.379)
1.23 1.456 1.354 2.882 1.393 1.378
1.456
1.353
2.888
1.396
1.378
1.222
(1.22)
1.222
(
(
(
1.228) (1.458) (1.354) (2.859) (1.392) (1.379) (1.219)
1.23
1.228) (1.457) (1.352) (2.877) (1.394 (1.379)
1.455
1.352
2.897
1.394
1.378
1.222
(1.22)

ACCEPTED MANUSCRIPT
Table 3. Bond angles of selected atoms of the conformation
Model O -N -O O -N -C C -C -N
C -N -C
C12-N13-C16 O -C -C
17 16 18
1
2
3
3
2
4
8
7
10
15
10 11
A1
A2
A3
A4
B1
B2
B3
B4
C1
C2
C3
C4
D1
D2
D3
D4
124.2
124.4)
124.1
124.2)
124.2
124.3)
124.1
124.3)
124.3
124.4)
124.1
124.2)
124.2
124.3)
124.1
124.3)
123.9
117
(116.9)
117
(117)
118.8
(118.8)
118.8
(118.8)
117
122.1
(122.2)
120.5
(120.5)
120
(119.9)
121.5
(121.5)
122
112.1
(112.2)
112.3
(112.4)
112.1
(112.1)
112.3
(112.4)
112.1
119.6
(119.5)
119.9
(119.7)
119.7
(119.5)
119.7
(119.5)
125.9
121
(121)
121
(121.1)
121
(121)
121
(121)
121
(
(
(
(
(
(
(
(
(116.9)
117
(116.9)
118.8
(118.8)
118.9
(118.8
117.9
(122.1)
120.3
(120.3)
119.9
(119.9)
121.4
(121.4
122.1
(112.2)
112.2
(112.3)
112.1
(112.2)
112.4
(112.4
112.4
(126.2)
125.9
(126.3)
125.9
(126.3)
126.2
(126.5
119.7
(121)
121
(121)
121
(121)
121
(121.1
121
(
124)
123.9
124)
123.9
124)
123.9
124)
123.9
124)
123.9
124)
123.9
124)
123.9
124)
(117.8)
117.9
(122.2)
120.5
(112.6)
112.3
(119.5)
119.8
(121)
121
(
(117.8)
118.2
(118.1)
118.1
(118.1)
117.9
(117.9)
117.9
(120.5)
121.3
(121.3)
121.8
(121.8)
122
(122.1)
120.5
(112.3)
112.6
(112.7)
112.5
(112.6)
112.4
(112.6)
112.3
(119.6)
119.8
(119.6)
119.7
(119.6)
125.9
(126.2)
126.1
(121)
121
(121.1)
121
(121)
121
(121.1)
121
(
(
(
(
(117.8)
117.9
(120.5)
121.7
(112.3)
112.7
(126.4)
119.9
(121.1)
121
(
(118.1)
118.1
(118.1)
(121.2)
121.7
(121.7)
(112.8)
112.5
(112.5)
(126.5)
126.1
(126.4)
(121.1))
121
(
(121)

ACCEPTED MANUSCRIPT
Table 4. Dihedral angles of some selected atoms in the 16 possible conformations
Model O -N -C -C O -N -C -C
C -C -N -C C -N -C -C
8 7 1 6 5 4 16 18
37
15 10
9
36
15 10 11
A1
A2
A3
A4
B1
B2
B3
B4
C1
C2
C3
C4
D1
D2
D3
D4
23.37
23.9
-6.6
6.59
(8.24)
4.52
(27.43)
19.28
(23.67)
22.44
(25.84)
22.38
(27.04)
23.55
(27.71)
19.48
(23.84)
22.19
(27.26)
22.34
(28.65)
20.68
(-5.22)
42.89
(25.54)
21.35
(42.51)
44.59
(43.7)
-6.21
(5.78)
6.48
(27.59)
21.86
(7.9)
6.29
(25.64)
24.14
(-5.07)
-6.76
(7.85)
-175.8
(28.97)
20.85
(-5.34)
42.84
(42.52)
44.13
(43.33)
-5.87
(-175.26)
-175.95
(-175.38)
-176.21
(-175.46)
-176.34
(-176.40)
6.86
(25.7)
21.08
(25.51)
21.84
(27)
(25.61)
22.96
(-4.74)
-4.8
26.62
29.64)
26.62
29.66)
23.08
28.86)
23.8
(
(
(
(
(
(
(
(
(26.43)
23.89
(-4.09)
41.91
(41.93)
31.67
(-1.61)
-6.29
-8.24
5.88
(27.34)
25.81
(7.1)
6.57
(26.65)
27.33
(-4.96)
5.87
26.77)
26.67
29.65)
26.56
29.58)
23.1
(29.65)
23.03
(-5.51)
-4.83
(7.22)
-175.52
(-175.11)
-176.5
(26.45)
23.81
(-4.03)
40.98
(40.8)
31.17
(-2.22)
-5.88
(23.81)
25.84
(-175.87)
-175.84
(-187.62)
-176.19
(-176.64)
28.72)
23.83
26.83)
(26.52)
27.37
(29.71)
(-5.08)

ACCEPTED MANUSCRIPT
Table 5. Calculated scaled wave numbers, observed IR, Raman bands and assignments of
the title compound
B3LYP/6-311++G(d,p) (5D, 7F) IR
Raman
Assignmentsa
-1
-1
-1
υ(cm )
IRI
RA
υ(cm ) υ(cm )
3
3
3
120
094
081
1.69
4.66
4.65
44.38
112.93
38.68
υCHI(99)
υCHI(99)
υCHI(98)
-
-
3118
-
3
3
3
3
3
2
2
2
2
2
2
2
2
030
024
014
013
011
979
976
956
920
895
887
877
841
6.99
13.8
86.1
124.33
97.07
72.2
-
3078
υCH (99)
3
-
3032
υCH (91)
3
13.84
5.46
-
-
2
υCH (97)
3014
-
-
υCH (98)
2
8.77
42.83
47.35
43.68
42.82
158.49
152.5
104.31
71.25
267.53
-
υCH (95)
2
15.07
10.16
29.15
6.4
-
2977
2977
2944
-
2999
2981
-
υCH (96)
2
3
υCH (99)
υCH (100)
3
2950
-
υCH (100)
3
42.63
55.9
υCH
3
2
(100)
(93)
-
2900
2885
-
υCH
42.61
69.12
-
υCH (92)
2
2876
υCH (95)
2
2
1
1
838
655
576
26.23
417.22
492.6
25.36
20.08
212.72
-
2843
-
1649
2
υCH (95)
2820
1648
υC=O(75)
υPhI(59), δCHI(14)
1
553
252.25
41.74
1574
1577
υPhI(41), υNO (16)
2
1
1
495
473
175.89
65.07
31.98
18.48
1550
1502
-
υNO (66)
δCHI(28), υPhI(49)
2
1492
1
1
1
1
1
1
1
1
448
443
441
438
437
432
429
427
6.46
11.35
49.44
9.44
20.87
3.31
5.98
11.6
3.64
5.86
0.68
10.67
1476
-
δCH (83)
2
-
1452
2 3
δCH (48), δCH (37)
-
-
δCH (56), δCH (27)
3
2
-
-
δCH (99)
3
20.68
5.59
-
-
δCH (68), δCH (23)
2
3
-
-
-
-
δCH
2
(84)
24.57
5.64
δCH (56), δCH (19)
3 2
1430
1428
δCH (51), δCH (39)
3 2

ACCEPTED MANUSCRIPT
1
1
1
1
1
1
1
1
1
418
396
391
361
355
343
338
335
319
11.1
272.94
51.48
29.39
15.77
21.43
15.45
4.93
6.29
4.57
-
-
δCH (78), δCH (14)
3 2
-
1400
-
-
υCN(41), δCH (20), υPhII(11)
2
25.46
8.14
-
δCH (22), υPhI(52), δCHI(19)
3
1392
2
δCH (62)
6.35
1363
-
1364
δCH (73)
2
2.26
-
δCH (51), υCN(11)
2
4.95
1339
1339
-
-
-
3 2
δCH (62), δCH (11)
21.07
25.14
δCH (53), δCH (17)
2
3
13.94
1333
δCH (75)
2
υNO (49), υCN(11), υPhI(20),
2
1
1
307
291
369.53
212.78
605.65
91.72
-
-
δCH2(10)
1310
1308
2
υPhI(45), υNO (10)
1
1
261
257
75.88
37.56
11.49
12.93
1288
-
-
-
δCH (53), υPhII(17)
δCHI(46), υPhI(13)
2
1
1
1
1
1
1
240
220
198
193
185
161
282.66
268.29
46.22
168.39
63.25
18.12
11.38
9.44
1258
-
υCO(40), δCH (43)
2
-
-
1242
1224
1196
1196
-
δCH (39), υCN(44)
2
δCH (41), υPhII(14)
2
144.21
231.16
3.96
1202
-
2
δCH (48), υPhII(45)
δCH (46), υCN(41)
2
8.7
1178
δCH (53), δCHI(10), υPhI(11)
3
1
1
146
128
6.14
41.36
7.25
4.7
-
-
1159
-
δCHI(40), δCH
υPhII(68)
3
(19), υPhI(15)
1
119
0.76
2
1131
-
δCH (94)
3
1
1
088
074
6.79
112.68
3.47
77.08
-
-
δCH
υCN(36), δCHI(40), υPhI(11)
δCH (50), δCH (10), δPhII(10)
2
(40), τPhII(10), υCN(11)
1092
1091
1
034
8.76
5.27
1073
1077
2
3
1
1
027
020
11.45
26.42
3.91
54.01
1036
-
1040
-
δCH (56), υPhII(13)
υPhII(52), υCO(11)
2
1
1
009
008
2.46
48.37
0.67
18.85
-
-
1018
-
δCH
υCO(40), υPhI(45)
δCH (43), υPhII(16)
υPhII(56), δPhI(22)
υPhII(53), δPhI(24)
γCHI(86)
3
(76), γC=O(18)
9
9
9
9
9
67
56
42
35
02
72.77
100.35
8.18
9.15
5.74
0.68
0.76
1.5
0.37
2.35
1010
-
960
-
-
970
954
-
3
932
-
υCC(44), υPhII(44)

ACCEPTED MANUSCRIPT
8
42
27
12.39
6.2
24.42
4.32
-
-
904
844
δNO (39), δPhI(19), υPhII(13)
2
8
δCH (62)
2
8
7
07
99
17.69
40.12
14.09
1
829
-
829
808
δNO (38), υPhII(12)
2
γCHI(51), τPhI(21), γCN(11)
γCHI(54), γCO(10), τCN(18),
τPhI(12)
γCN(54), γCHI(21), τPhI(10)
υPhII(42), γCN(12)
789
733
699
692
680
1.93
12.62
10.3
4.53
8.5
5.3
2.57
22.31
3.28
8.97
801
-
-
-
728
697
-
731
701
-
δPhI(40), τPhI(25)
τPhI(41), γCN(12)
γCN(18), δPhI(15), γCO(19),
δPhII(24)
γCO(26), γCN(15), τPhI(15)
δC=O(43), δPhII(10), δCN(10)
γC=O(20), δC=O(17), δPhII(38)
646
627
594
578
15.24
8.13
6.65
9.37
3.83
1.7
4.37
3.56
-
-
651
620
592
650
620
596
567
7.9
1.44
-
-
γC=O(46), δCH (31)
3
549
497
461
457
452
416
400
381
362
305
289
273
4
7.1
2.09
0.91
1.7
566
-
567
-
δPhI(25), δNO (47)
2
1.49
0.22
3.35
9.7
δCN(25), δPhII(24), δPhI(18)
δCN(46), δPhII(11), τPhI(10)
δPhII(44), δCN(10)
-
-
501
464
-
7.8
457
τPhI(44), γCN(25)
2.42
4.3
5.7
-
444
414
-
-
-
δCN(38), τPhI(20)
δCO(39), δCN(23)
5.19
1.48
0.56
7.66
0.62
4.46
414
1.27
1.24
1.32
11.08
20.06
-
-
-
-
-
τPhII(60)
δPhII(27), δPhI(38), δCN(15)
τPhI(20), γCN(27), δCN(10)
τPhII(38), δCN(39)
306
286
τPhII(41), γCN(12), δCN(24)
257
232
212
3.19
4.81
0.32
2.58
1.11
4.69
-
-
-
-
-
-
τCH (46), τPhI(26)
τPhII(22), γCN(16), τCH3(11)
δPhI(31), δPhII(39)
3
188
183
165
3.78
1.13
1.02
1.68
1.24
3.96
-
-
-
-
190
-
τPhI(37), τCH (26)
δCN(40), τPhI(10), τPhII(10)
δCO(31), τPhII(23), δCN(15)
3
1
1
60
15
0.36
0.66
0.19
1.3
-
-
163
-
δCH (74), τCH (16)
τPhI(22), γCN(22), τPhII(10)
3
3
9
8
7
3.56
3.7
1.11
0.76
-
-
-
τC=O(54), τCH (17)
3
8
102
3
τCO(61), τCH (22)