Structural, spectroscopic, Hirshfeld surface and charge distribution analysis of 3-(1H-imidazole-1-yl)-1-phenylpropan-1-ol complemented by molecular docking predictions: An integrated experimental and computational approach

Article abstract of DOI:10.1016/j.molstruc.2019.07.003

The optimized structure of title compound 3-(1H-imidazole-1-yl)-1-phenylpropan-1-ol (3HIP) was predicted according to the density functional theory (DFT) using the B3LYP method with 6-311G (d,p) basis set. Computed structural parameters of 3HIP were compared with X-ray diffraction data. Recorded and computed wavenumbers were assigned according to the total energy distribution (TED) using VEDA software. The natural bond orbital (NBO) analysis was used to characterize intramolecular rehybridization and delocalization of the electron density within the title molecule. Predictions of the NMR (¹H and ¹³C) chemical shift assignments obtained by applying the gauge including atomic orbital (GIAO) approach were consistent with the corresponding experimental values. Ultraviolet-visible spectra of the title compound were simulated and validated experimentally. A molecular electrostatic potential (MEP) diagram visualized the electrophilic and nucleophilic sites of the 3HIP molecule. Hirshfeld surface analysis assessed the potential interactions of each atom inside the 3HIP molecule. Moreover, molecular docking analysis simulated the potential binding site pose of 3HIP within the active site of its target protein. The resulting 3HIP–target protein model can provide guidance for the development of new potent antifungal treatments.

Full text of DOI:10.1016/j.molstruc.2019.07.003

Accepted Manuscript
Structural, spectroscopic, Hirshfeld surface and charge distribution analysis of 3-(1H-
imidazole-1-yl)-1-phenylpropan-1-ol complemented by molecular docking predictions:
An integrated experimental and computational approach
Maha S. Almutairi, K. Jayasheela, S. Periandy, Alwah R. Al-Ghamdi, S. Sebastian, S.
Xavier, Adnan A. Kadi, Ali S. Abdelhameed, Mohamed I. Attia
PII:
S0022-2860(19)30837-3
DOI:
https://doi.org/10.1016/j.molstruc.2019.07.003
MOLSTR 26756
Reference:
To appear in: Journal of Molecular Structure
Received Date: 5 September 2018
Revised Date: 1 May 2019
Accepted Date: 1 July 2019
Please cite this article as: M.S. Almutairi, K. Jayasheela, S. Periandy, A.R. Al-Ghamdi, S. Sebastian, S.
Xavier, A.A. Kadi, A.S. Abdelhameed, M.I. Attia, Structural, spectroscopic, Hirshfeld surface and charge
distribution analysis of 3-(1H-imidazole-1-yl)-1-phenylpropan-1-ol complemented by molecular docking
predictions: An integrated experimental and computational approach, Journal of Molecular Structure
(2019), doi: https://doi.org/10.1016/j.molstruc.2019.07.003.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Structural, spectroscopic, Hirshfeld surface and charge distribution analysis of 3-(1H-
imidazol-1-yl)-1-phenylpropan-1-ol complemented by molecular docking predictions: an
integrated experimental and computational approach
a
b
b
a
c
Maha S. Almutairi , K. Jayasheela , S. Periandy , Alwah R. Al-Ghamdi , S. Sebastian , S.
c
a
a*
a,d*
Xavier , Adnan. A. Kadi , Ali S. Abdelhameed and Mohamed I. Attia
a
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O.
Box 2457, Riyadh 11451, Saudi Arabia
b
Department of Physics, Kanchi Mamunivar Center for Post Graduate Studies and Research,
Lawspet, Puducherry, 605 008, India
c
Department of Physics, St. Joseph College of Arts and Science, Cuddalore, Tamilnadu 607001,
India
d
Medicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries
Research Division, National Research Centre (ID: 60014618), El Bohooth Street, Dokki, Giza
1
2622, Egypt
Keywords: Imidazole; DFT; molecular docking; antifungals; Hirshfeld surface
1

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Abstract
The optimized structure of title compound 3-(1H-imidazol-1-yl)-1-phenylpropan-1-ol
(3HIP) was predicted according to the density functional theory (DFT) using the B3LYP method
with 6-311G(d,p) basis set. Computed structural parameters of 3HIP were compared with X-ray
diffraction data. Recorded and computed wavenumbers were assigned according to the total
energy distribution (TED) using VEDA software. The natural bond orbital (NBO) analysis was
used to characterize intramolecular rehybridization and delocalization of the electron density
1
13
within the title molecule. Predictions of the NMR ( H and C) chemical shift assignments
obtained by applying the gauge including atomic orbital (GIAO) approach were consistent with
the corresponding experimental values. Ultraviolet-visible spectra of the title compound were
simulated and validated experimentally. A molecular electrostatic potential (MEP) diagram
visualized the electrophilic and nucleophilic sites of the 3HIP molecule. Hirshfeld surface
analysis assessed the potential interactions of each atom inside the 3HIP molecule. Moreover,
molecular docking analysis simulated the potential binding site pose of 3HIP within the active
site of its target protein. The resulting 3HIP–target protein model can provide guidance for the
development of new potent antifungal treatments.
1
. Introduction
A significant increase in the use of antifungal agents in recent years led to the emergence
of resistance to the currently available antifungal drugs [1], which necessitates the search for new
antifungal agents that act on novel targets and have a broad spectrum, high potency, and few side
effects. Computational chemistry has become a source for critical tools that are used not only in
organic chemistry but also in other areas of chemical research, as well as in biology or material
science. It improves our understanding of the molecular structure of bioactive organic
compounds and provides predictions for their potential reaction mechanisms, as well as their
geometrical and electronic properties. Moreover, combining computational and experimental
chemistry has already solved an array of organic problems. In addition, the development of the
density functional theory (DFT) has contributed significantly to the advances in organic
synthesis and has been extensively utilized for computing the geometrical and electronic
properties of bioactive organic compounds [2-4].
The azole moiety (imidazole or triazole) is the pharmacophore fragment in azole-
containing antifungal lead compounds that inhibit cytochrome P450-dependent 14α-lanosterol
2

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demethylase, which subsequently suppresses sterol synthesis in fungi [5]. A literature survey
indicated that available azole antifungal candidate compounds often have an aromatic moiety
linked to the azole nitrogen via an ethyl group [6], whereas a limited number have a propyl group
instead of the ethyl group. Hence, we were interested in synthesizing the title compound using a
propyl group to link the imidazole and phenyl moieties, which created a precursor for the
synthesis of new imidazole-containing antifungal agents.
Considering the potential pharmaceutical properties of the title compound, 3-(1H-
imidazol-1-yl)-1-phenylpropan-1-ol (3HIP), we performed vibrational analyses using DFT
1
computations that have not been reported previously. Spectroscopic (FT-IR, FT-Raman, UV, H
1
3
and C NMR) analyses were recorded and compared with simulated results. In addition, we
examined intermolecular and intramolecular interactions, molecular geometry, and orbital energy
levels of the 3HIP molecule. A natural bond orbital (NBO) analysis explored potential hyper-
conjugation or intermolecular delocalization of the title molecule. Studies on molecular orbitals,
i.e., HOMO and LUMO, were performed to characterize potential intermolecular interactions of
the 3HIP molecule. Furthermore, the Hirshfeld analysis generated a graphical image for in-depth
exploration of the intermolecular interactions of the title molecule, while reduced density
gradient (RDG) analysis and color-filled electron density diagrams assessed its non-covalent
interactions. We also used a molecular docking tool to predict the binding pose of the title
compound in the target protein.
2
2
. Experimental details
.1. Synthesis
A reaction mixture containing dimethylamine hydrochloride (2.2 g, 27 mmol),
paraformaldehyde (0.81 g, 9 mmol), acetophenone (2.4 g, 20 mmol), and a catalytic amount of
concentrated hydrochloric acid (0.1 mL) in absolute ethanol was stirred under reflux for two
hours. Acetone (30 mL) was added to the cooled reaction mixture to precipitate the Mannich
base hydrochloride 1 as a white powder, which was filtered off, washed with cold acetone (10
mL), and dried. Compound 1 (2.1 g, 10 mmol) was dissolved in water and imidazole (1.4 g, 20
mmol) was added under stirring; the resulting solution was heated under reflux for five hours.
The reaction mixture was cooled, and the precipitated solid was recovered by filtration to obtain
compound 2. Subsequently, sodium borohydride (1.14 g, 30 mmol) was added in aliquots to
compound 2 (2.0 g, 10 mmol) dissolved in methanol (100 mL). The reaction mixture was stirred
3

ACCEPTED MANUSCRIPT
at room temperature (RT) for 18 hours and concentrated under vacuum before adding water (50
mL) to the residue. The aqueous solution was extracted with ethyl acetate (3 x 50 mL), and the
organic phases were collected, dried (Na SO ), and evaporated under reduced pressure,
2
4
generating the title compound 3HIP at an almost quantitative yield as a white powder, m.p. 107–
1
09 °C [7, 8].
2
.2. Spectral characterization
The FT-IR spectrum of 3HIP was recorded with the IFS66V spectrophotometer in the
-1
range of 4000-400 cm using the KBr pellet technique. The Nerus 670 spectrophotometer
Thermo Electron Corporation, Waltham, MA) was used to measure the FT-Raman spectrum of
(
-1
the title compound with the Nd-YAG laser as excitation source in the range of 3500-50 cm . The
1
3
1
NMR ( C and H) spectra of the 3HIP molecule were measured in CDCl
3
using the Bruker
1
13
NMR spectrometer (Bruker, Billerica, MA) at 500 MHz for H and 125.76 MHz for C at the
Research Center, College of Pharmacy, King Saud University, Saudi Arabia. The ultraviolet
absorption spectrum of the 3HIP molecule was measured in chloroform in the range of 200-600
nm using the UV-1650 PC spectrophotometer (Shimadzu, Kyoto, Japan). Single crystal data
collection of the 3HIP molecule was carried out at 100 K on an APEX-II D8 Venture area
diffractometer (Bruker) equipped with a graphite monochromatic Mo Kα radiation source, λ =
0
.71073 Å. Data reduction and cell refinement were executed using the SAINT software
(Bruker). The 3HIP structure was solved with the aid of the SHELXT program [9].
2
.3. Computational data processing
The optimized geometry of the 3HIP molecule and its vibrational wavenumbers were
calculated using the Gaussian 09W program package with the 6-311G(d,p) basis set [10]. Total
energy distribution (TED) calculations with the VEDA 4 program [11] were used for vibrational
assignments of the normal modes for the title compound. The calculated vibrational
wavenumbers were scaled down by the scale factor 0.967 [12] to offset the systematic error
caused by negating electron density and anharmonicity, which allowed the comparison between
the calculated data and the experimental results. The NBO calculations were carried out using
the NBO 3.1 program [13] as implemented in the Gaussian 09W [10] package at the B3LYP/6-
3
11G(d,p) level of the basis set. The UV-Vis spectrum, vertical excitation, electron transition
energies, and oscillator strength were computed by applying the time-dependent density
functional theory (TD-DFT) method, and the electronic properties were specified by the TD-
4

ACCEPTED MANUSCRIPT
DFT approach [14]. The reduced density gradients (RDG) and the electrostatic potential (EPS)
were plotted using the Multiwfn software [15] and the VMD 1.9.1 program [16], respectively.
3
3
. Results and discussion
.1. Synthesis
The synthesis of title compound 3HIP was initiated using commercially available
acetophenone as a substrate in the Mannich reaction as illustrated in Scheme 1. The Mannich
base hydrochloride 1 was converted to imidazole derivative 2, which was subsequently reduced
by sodium borohydride to generate 3HIP.
O
O
O
CH3
N(CH
3
)
2
.HCl
N
N
i
ii
1
2
iii
OH
N
N
3HIP
3 2 2 n
Reagents and conditions: i) HN(CH ) .HCl, (CH O) , conc. HCl, ethanol, reflux, 2 h; ii)
imidazole, water, reflux, 5 h; iii) NaBH , methanol, RT, 18 h.
4
Scheme 1: Synthesis of title compound 3HIP.
3
.2. Optimized structure
The 3HIP molecule crystallizes as P21/c space group with the following cell constants: a
9.0352(5) Ǻ, b = 11.8521(7) Ǻ, c = 10.3462(6) Ǻ, a = 90.00º, b = 109.6880(10)º, c = 90.00º, V
=
=
3
1043.17(10) Ǻ , and Z = 4 as reported previously [9]. The optimized molecular structure is
shown in Fig. 1. The 3HIP molecule was optimized using the B3LYP/6-311G(d,p) method; the
optimized parameters (bond lengths, bond angles, and dihedral angles) are summarized in Table
1
. The presence of an O-H group in a small molecule affects its structural and vibrational
5

ACCEPTED MANUSCRIPT
properties. The 3HIP molecule contains two rings, i.e., the phenyl and imidazole rings, and
possesses a total of four C-N bonds, thirteen C-H bonds, and one O-H bond.
The propane chain substitution linking the phenyl and imidazole rings distorted the
phenyl ring as indicated by the bond angle C1-C6-C5 = 118.937º, which deviated from the
normal value of 120º. However, the bond angle C23-N22-C24 = 106.253º in the imidazole ring
indicated that it was not much affected by the propane chain. In the phenyl ring, the C-C bond
lengths were C1-C2 = 1.393 Å, C1-C6 = 1.398, C2-C3 = 1.394 Å, C3-C4 = 1.393 Å, C4-C5 =
1
.393 Å, and C5-C6 = 1.397 Å according to the B3LYP/6-311G(d,p) method, and the
corresponding X-ray diffraction (XRD) values were 1.391, 1.399, 1.398, 1.388, 1.394, and 1.393
Å, respectively.
The C-O (C12-O14) bond length of 1.431 Ǻ was in a good agreement with the standard
literature value of 1.400 Ǻ [17]. The bond lengths of C6-C12 = 1.519 Å, C12-C16 = 1.532 Å,
C16-C19 = 1.534 Å, and C19-N22 =1.459 Å indicated a large repulsion in the propane chain,
which might lead to a push-pull electron effect in this title compound region.
As reported previously, deviations in the aromatic C-H bond lengths upon substitution
may be caused by changes in the charge distribution on the carbon atoms of the benzene ring
[18]. In addition, the substitution of hydrogen atoms can increase the electron density of aromatic
ring carbons, which decreases the C-H force constants will occur and increases the bond lengths.
The title compound C-H bond length was 1.084 Ǻ for C1-H7, C2-H8, C3-H9, and C4-H10 and
1
.086 Ǻ for C5-H11 according to the B3LYP/6-311G(d,p) method. These values differed slightly
from the XRD values, which might be related to the low scattering factor of hydrogen atoms
involved in the X-ray diffraction experiment [18].
Table 1: Molecular geometry [bond length (Å), bond angle (◦) and dihedral angle (◦)]
of 3HIP by B3LYP/6-311G(d,p).
a
Parameter
Bond length(Å)
C1-C2
Calculated
XRD
1.393
1.398
1.084
1.394
1.084
1.393
1.391
1.399
0.950
1.398
0.950
1.388
C1-C6
C1-H7
C2-C3
C2-H8
C3-C4
6

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C3-H9
C4-C5
C4-H10
C5-C6
1.084
1.393
1.084
1.397
1.086
1.519
1.101
1.431
1.532
0.963
1.094
1.094
1.534
1.090
1.094
1.459
1.380
0.950
1.394
0.950
1.393
0.950
1.518
1.001
1.417
1.527
0.964
0.990
0.990
1.526
0.990
0.990
1.464
1.377
C5-H11
C6-C12
C12-H13
C12-O14
C12-C16
O14-H15
C16-H17
C16-H18
C16-C19
C19-H20
C19-H21
C19-N22
N22-C23
N22-C24
C23-C25
C23-H26
C24-H27
C24-N29
C25-H28
1.367
1.371
1.078
1.080
1.314
1.079
1.375
1.357
1.367
0.950
0.950
1.322
0.950
1.380
C25-N29
o
Bond angle ( )
C2-C1-C6
C2-C1-H7
C6-C1-H7
C1-C2-C3
C1-C2-H8
C3-C2-H8
C2-C3-C4
C2-C3-H9
C4-C3-H9
C3-C4-C5
C3-C4-H10
C5-C4-H10
C4-C5-C6
C4-C5-H11
C6-C5-H11
C1-C6-C5
120.462
120.421
119.114
120.225
119.764
120.011
119.670
120.189
120.141
120.036
120.107
119.856
120.668
119.713
119.619
118.937
120.42
119.80
119.79
120.16
119.91
119.93
119.55
120.19
120.26
120.22
119.90
119.88
120.59
119.71
119.70
119.04
7

ACCEPTED MANUSCRIPT
C1-C6-C12
C5-C6-C12
120.534
120.516
108.187
112.295
112.059
109.577
108.462
106.185
108.039
109.148
108.581
112.277
107.181
109.833
109.679
109.859
110.290
112.832
107.287
108.849
107.544
126.728
126.941
106.253
105.699
121.778
132.521
121.743
112.427
125.826
127.979
110.569
121.450
105.052
120.64
120.32
108.70
112.56
110.39
108.68
108.71
107.72
107.68
108.83
108.76
113.82
107.70
108.75
108.81
109.04
109.02
112.79
107.78
109.03
109.06
126.59
126.45
106.94
105.80
127.14
127.06
123.99
111.96
124.06
124.89
110.28
124.83
105.02
C6-C12-H13
C6-C12-O14
C6-C12-C16
H13-C12-O14
H13-C12-C16
O14-C12-C16
C12-O14-H15
C12-C16-H17
C12-C16-H18
C12-C16-C19
H17-C16-H18
H17-C16-C19
H18-C16-C19
C16-C19-H20
C16-C19-H21
C16-C19-N22
H20-C19-H21
H20-C19-N22
H21-C19-N22
C19-N22-C23
C19-N22-C24
C23-N22-C24
N22-C23-C25
N22-C23-H26
C25-C23-H26
N22-C24-H27
N22-C24-N29
H27-C24-N29
C23-C25-H28
C23-C25-N29
H28-C25-N29
C24-N29-C25
o
Dihedral angle ( )
C6-C1-C2-C3
-0.136
179.913
-179.485
0.564
-1.16
178.81
178.86
-1.17
C6-C1-C2-H8
H7-C1-C2-C3
H7-C1-C2-H8
8

ACCEPTED MANUSCRIPT
C2-C1-C6-C5
-0.218
178.520
179.139
-2.124
1.20
C2-C1-C6-C12
H7-C1-C6-C5
-178.30
-178.82
1.68
H7-C1-C6-C12
C1-C2-C3-C4
0.277
-0.15
C1-C2-C3-H9
179.986
-179.772
-0.063
179.89
179.88
-0.08
H8-C2-C3-C4
H8-C2-C3-H9
C2-C3-C4-C5
-0.061
1.41
C2-C3-C4-H10
H9-C3-C4-C5
179.511
-179.770
-0.198
-178.56
-178.63
1.41
H9-C3-C4-H10
C3-C4-C5-C6
-0.299
-1.37
C3-C4-C5-H11
H10-C4-C5-C6
H10-C4-C5-H11
C4-C5-C6-C1
179.396
-179.871
-0.177
178.59
178.60
-1.44
0.436
0.06
C4-C5-C6-C12
H11-C5-C6-C1
H11-C5-C6-C12
C1-C6-C12-H13
C1-C6-C12-O14
C1-C6-C12-C16
C5-C6-C12-H13
C5-C6-C12-O14
C5-C6-C12-C16
C6-C12-O14-H15
H13-C12-O14-H15
C16-C12-O14-H15
C6-C12-C16-H17
C6-C12-C16-H18
C6-C12-C16-C19
H13-C12-C16-H17
H13-C12-C16-H18
H13-C12-C16-C19
O14-C12-C16-H17
O14-C12-C16-H18
O14-C12-C16-C19
C12-C16-C19-H20
-178.302
-179.259
2.003
179.56
-179.91
-0.40
155.861
34.805
-84.616
-25.421
-146.478
94.102
170.33
49.88
-70.52
-9.17
-129.62
109.99
39.65
-80.81
161.57
-62.48
54.59
55.923
-64.332
178.720
-55.779
60.747
-177.810
63.583
176.07
56.67
-179.891
-58.448
-178.725
-62.199
59.245
173.74
-64.78
174.27
-68.67
52.81
-57.362
-62.23
9

ACCEPTED MANUSCRIPT
C12-C16-C19-H21
60.697
-179.014
-179.002
-60.943
59.346
63.451
-178.491
-58.202
80.793
-95.531
-41.429
142.247
-157.356
26.320
-177.220
3.278
-179.66
C12-C16-C19-N22
H17-C16-C19-H20
H17-C16-C19-H21
H17-C16-C19-N22
H18-C16-C19-H20
H18-C16-C19-H21
H18-C16-C19-N22
C16-C19-N22-C23
C16-C19-N22-C24
H20-C19-N22-C23
H20-C19-N22-C24
H21-C19-N22-C23
H21-C19-N22-C24
C19-N22-C23-C25
C19-N22-C23-H26
C24-N22-C23-C25
C24-N22-C23-H26
C19-N22-C24-H27
C19-N22-C24-N29
C23-N22-C24-H27
C23-N22-C24-N29
N22-C23-C25-H28
N22-C23-C25-N29
H26-C23-C25-H28
H26-C23-C25-N29
N22-C24-N29-C25
H27-C24-N29-C25
C23-C25-N29-C24
H28-C25-N29-C24
59.04
176.28
58.84
-62.45
-58.21
59.22
-179.51
71.41
-107.01
-49.86
131.71
167.31
14.27
-179.01
1.00
-0.280
-0.34
-179.782
-3.360
179.68
-1.02
177.302
179.709
0.370
-179.377
0.115
178.99
-179.69
0.31
-179.71
0.26
0.049
0.28
179.540
-0.294
-179.600
0.104
-179.76
-0.15
179.85
-0.07
179.634
179.89
a
Taken from reference [16].
.3. Hirshfeld surface analysis
Intermolecular interactions of 3HIP molecules were characterized using the Hirshfeld
3
surface analysis, which simulates the surface character of the molecule [19, 20]. The Hirshfeld
surfaces are associated with the 2D fingerprint plot as a quantitative measure of intermolecular
interactions on the molecule surface [21, 22]. There are two critical distances in the Hirshfeld
surfaces, de as the distance from the nearest nucleus exterior to the surface, and di as the distance
1
0

ACCEPTED MANUSCRIPT
from the nearest nucleus interior to the surface. The normalized contact distance (dnorm) is based
on de and di as written below:
vdW
vdW
(
di − ri
)
(de − re
)
dnorm
=
+
vdW
vdW
ri
re
(1)
vdW
vdW
where ri
and re
represent the van der Waals radii of the atoms. Negative dnorm values are
indicated in red, denoting a shorter distance than the sum of the van der Waals radii. White
marks intermolecular distances close to the van der Waals radii and a dnorm value of zero.
Positive dnorm values are marked in blue, indicating a longer distance than the sum of the van der
Waals radii. The Hirshfeld surface was generated with Crystal Explorer 3.0 [23] as shown in
Figs. 2 and 3. The surface maps dnorm (A), shape index (B), curvedness (C), di, and de are
presented in the range of -0.593–1.159 Ǻ, -1.000–1.000 Ǻ, -4.000–0.400 Ǻ, 0.741–2.375 Ǻ, and
0
.740–2.452 Ǻ, respectively. Deep red (circular depression) on the Hirshfeld surface indicates
the presence of O…H hydrogen bond contacts; specifically, the concave regions around the
acceptor hydrogens are labeled in red, and the convex regions around the oxygen are marked in
blue. The π…..π interactions are absent in the 3HIP crystal as supported by the shape index,
which does not have adjacent red and blue triangle patterns [24]. In the 2D fingerprint, the C-H,
C-O, N-H, and H-O interactions are indicated by spikes at the bottom, and the H-C, O-C, N-H,
and O-H interactions are represented as spikes in the top left region. Two sharp peaks close to
the lower left of the plot represent H…H hydrogen bonding. The short distance minimum value
(di + de) = 1.0 Ǻ indicates the importance of hydrogen bond interactions. The proportions of
H…H, C…H, and N...H are 59.5%, 23.7%, and 12.0% in the 2D fingerprint plot. The
characteristic wing of (di + de) ~ 1.2 Ǻ corresponds to C…H/H…C bonds as shown in Fig. 2.
3
.4. Mulliken charge analysis
Mulliken charge analysis predicts the characteristics of molecules based on atomic
charges that affect their molecular properties, including dipole moment, electronic structure, and
molecular polarizability. The Mulliken charges of the 3HIP molecule were computed using the
B3LYP/6-311G(d,p) method as shown in Fig. 4. All phenyl ring carbon atoms have negative
charges (C1 = -0.052 e, C2 = -0.090 e, C3 = -0.087 e, C4 = -0.090 e, C5 = -0.065 e and C6 = -
0
.157 e). The atom C6 has the strongest negative charge, which could be attributed to its direct
bond to the propane group. The atom H15 has the highest positive charge among all hydrogen
1
1

ACCEPTED MANUSCRIPT
atoms because of its bond to the electronegative oxygen atom. The atom O14 shows the strongest
negative charge (-0.408 e) due to its high inherent electronegativity. In the imidazole ring, the
atom C24 has the highest positive charge (0.158 e) because of its covalent bonds to the
electronegative atoms N22 and N29. All hydrogen atoms are inherently positive as shown in Fig.
4
.
3
.5. Natural bond orbital (NBO) analysis
NBO analysis assesses intramolecular and intermolecular bonding and the interactions
among bonds. It is also a tool for investigating charge transfer or conjugative interactions in
(
2)
molecular systems. The larger the E value, the stronger is the interaction between electron
donors and acceptors, i.e., the higher the donating tendency from electron donors to electron
acceptors, the stronger the covalent bonds of the whole system. Delocalization of electron
density between occupied Lewis-type (bond or lone pair) NBOs and formally unoccupied
(antibond or Rydgberg) non-Lewis NBOs stabilizes donor–acceptor interactions [25]. The NBO
analysis of the title molecule at the DFT/B3LYP/6-311+G (d,p) level assessed the molecule’s
intramolecular rehybridization and electron density delocalization within the molecule. The
second order Fock matrix was performed to evaluate the donor–acceptor interactions of the
NBOs. These interactions can cause a loss of occupancy converting the localized NBO of an
idealized Lewis structure of a molecule into an empty non-Lewis orbital. For each donor (i) and
(
2)
acceptor (j), the stabilization energy E associated with delocalization i→j is estimated as:
F (i, j)2
E = ∆E = q
2
ij
i
ε j
−
εi
(2)
where q
i
is the donor orbital occupancy, ε
i
and ε
j
are diagonal elements, and F (i, j ) is the off-
diagonal NBO Fock matrix element. Intramolecular hyperconjugative interactions occur during
overlaps between bonding and antibonding orbitals, i.e., (C-C), (C-N), (C-H), (C-O), and (O-H),
which results in an intramolecular charge transfer (ICT) that stabilizes the molecular system.
These interactions are indicated by an increase in electron density (ED) in the bonding orbitals
(C-C) and (C-N) and the antibonding orbital (C-C) that weakens the respective bonds. The
electron density (∼ 1.9 e) of the conjugated bonds in the 3HIP molecule is an indicator of strong
delocalization.
1
2

ACCEPTED MANUSCRIPT
The strong intramolecular hyperconjugative interactions between the σ and π electrons of
C-C bonding and antibonding orbitals of the aromatic ring in the 3HIP molecule partially
stabilizes the ring structure as shown in Table 2. For example, the intramolecular
hyperconjugative interactions of σ(C1-C2) distributed to σ*((C1-C6), (C2-C3), (C3-H9), and
(C6-C12)) were stable at 3.96, 3.07, 2.38, and 3.79 KJ/mol, respectively. This stability promoted
further conjugation with the antibonding orbital π(C1-C2), which caused strong delocalization of
*
π ((C3-C4) and (C5-C6)) at 20.31 and 21.71 KJ/mol, respectively, as shown in Table 2. The
same type of interaction was observed for the C3-C4 bond that distributed energy to σ*((C2-C3),
(C2-H8), (C4- C5) and (C5-H11)) with stabilization energy values of 3.00, 2.45, 3.12 and 2.53
KJ/mol, respectively, as shown in Table 2. This stimulated conjugation with antibonding orbital
*
π(C3-C4), leading to strong delocalization to π ((C1-C2) and (C5-C6)) with a stabilization
energy of 20.67 and 20.33 KJ/mol, respectively, as presented in Table 2. Similar behavior was
computed for the C5-C6 and C23-C25 bonds. Moreover, the charges transferred from lone pairs
LP(2)O14, LP(1)N22, and LP(1)N29 had stabilization energy values of 5.44, 6.98, 5.83, 2.46,
3
1.27, 46.55, 8.32, 5.51, 2.23, and 2.19 KJ/mol for (C6-C12), (C12-H13), (C16-C19), (C19-
H20), (C23-C25), (C24-N29), (N22-C24), (C23-C25), (C24-H27), and (C25-H28), respectively.
1
3

ACCEPTED MANUSCRIPT
Table 2: Second order perturbation theory analysis of Fock matrix on NBO of 3HIP using the B3LYP/6-311G(d,p) method.
Donor (i)
Type
ED/e
Acceptor (j)
Type
ED/e
E(2) (Kj/Mol)
E(j)-E(i) (a.u)
F(i,j) (a.u)
C1-C2
C1-C2
C1-C2
C1-C2
C1-C2
C1-C2
C1-C6
C1-C6
C1-C6
C1-C6
C1-C6
C1-H7
C1-H7
C2-C3
C2-C3
C2-C3
C2-C3
C2-H8
C2-H8
C3-C4
C3-C4
C3-C4
C3-C4
C3-C4
C3-C4
σ
σ
σ
σ
π
π
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
π
π
1.97708
1.97708
1.97708
1.97708
1.66191
1.66191
1.97172
1.97172
1.97172
1.97172
1.97172
1.97851
1.97851
1.97914
1.97914
1.97914
1.97914
1.97956
1.97956
1.97889
1.97889
1.97889
1.97889
1.66013
1.66013
C1-C6
C2-C3
C3-H9
C6-C12
C3-C4
C5-C6
C1-C2
C2-H8
C5-C6
C5-H11
C6-C12
C2-C3
C5-C6
C1-C2
C1-H7
C3-C4
C4-H10
C1-C6
C3-C4
C2-C3
C2-H8
C4-C5
C5-H11
C1-C2
C5-C6
σ*
σ*
σ*
σ*
π*
π*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
π*
π*
0.02635
0.01708
0.01462
0.03918
0.33025
0.35496
0.01639
0.01466
0.02438
0.01595
0.03918
0.01708
0.02438
0.01639
0.01596
0.01691
0.01446
0.02635
0.01691
0.01708
0.01466
0.01628
0.01595
0.32468
0.35496
3.96
3.07
2.38
3.79
20.31
21.71
3.50
2.20
4.22
2.54
2.23
3.75
4.76
3.13
2.48
3.01
2.47
4.10
3.81
3.00
2.45
3.12
2.53
20.67
20.33
1.27
1.27
1.14
1.10
0.28
0.28
1.27
1.14
1.27
1.13
1.10
1.09
1.09
1.28
1.15
1.27
1.14
1.09
1.09
1.27
1.14
1.27
1.13
0.28
0.28
0.063
0.056
0.047
0.058
0.068
0.070
0.060
0.045
0.065
0.048
0.044
0.057
0.064
0.056
0.048
0.055
0.047
0.060
0.058
0.055
0.047
0.056
0.048
0.069
0.068
1
4

ACCEPTED MANUSCRIPT
C3-H9
C3-H9
C4-C5
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
π
π
π
π
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
1.97954
1.97954
1.97716
1.97716
1.97716
1.97716
1.97952
1.97952
1.97220
1.97220
1.97220
1.97220
1.97220
1.66000
1.66000
1.66000
1.66000
1.97910
1.97910
1.97018
1.97018
1.97018
1.97018
1.97601
1.97601
1.96474
1.96474
1.98847
C1-C2
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
π*
π*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
π*
σ*
σ*
0.01639
3.86
3.87
3.04
2.39
3.97
3.83
3.79
4.08
4.26
2.44
3.57
2.16
2.14
19.77
20.73
2.28
2.90
4.66
3.69
2.54
2.40
2.45
2.40
3.81
2.66
2.53
2.33
2.53
1.10
1.09
1.27
1.14
1.27
1.10
1.09
1.09
1.27
1.15
1.27
1.14
1.10
0.29
0.29
0.53
0.62
1.09
1.10
1.21
1.20
1.21
1.21
1.08
0.92
0.65
0.96
1.09
0.058
0.058
0.063
0.047
0.063
0.058
0.058
0.060
0.066
0.047
0.060
0.044
0.043
0.067
0.069
0.034
0.041
0.064
0.025
0.050
0.048
0.049
0.048
0.057
0.044
0.039
0.042
0.047
C4-C5
C3-C4
0.01628
0.01691
0.01462
0.02438
0.03918
0.01708
0.02438
0.02635
0.01596
0.01628
0.01446
0.03918
0.32468
0.33025
0.02735
0.02512
0.02635
0.01691
0.01639
0.02635
0.01628
0.02438
0.02635
0.01595
0.35496
0.02790
0.02512
C4-C5
C3-H9
C5-C6
C6-C12
C2-C3
C5-C6
C1-C6
C4-C5
C4-C5
C4-H10
C4-H10
C5-C6
C5-C6
C5-C6
C1-H7
C4-C5
C5-C6
C4-H10
C6-C12
C1-C2
C5-C6
C5-C6
C5-C6
C5-C6
C3-C4
C12-O14
C12-C16
C1-C6
C5-C6
C5-H11
C5-H11
C6-C12
C6-C12
C6-C12
C6-C12
C12-H13
C12-H13
C12-C16
C12-C16
O14-H15
C3-C4
C1-C2
C1-C6
C4-C5
C5-C6
C1-C6
C16-H18
C5-C6
C19-N22
C12-C16
1
5

ACCEPTED MANUSCRIPT
C16-H17
C16-H17
C16-H18
C16-H18
C16-C19
C19-H20
C19-H20
C19-H21
C19-H21
N22-C23
N22-C23
N22-C23
N22-C24
N22-C24
C23-C25
C23-C25
C23-H26
C24-H27
C24-H27
C24-N29
C24-C29
C24-C29
C25-H28
C25-N29
C25-N29
LP(2)O14
LP(2)O14
LP(1)N22
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
π
σ
σ
σ
σ
σ
π
σ
σ
σ
n
n
n
1.97475
1.97475
1.97600
1.97600
1.97528
1.98004
1.98004
1.98064
1.98064
1.98140
1.98140
1.98140
1.98605
1.98605
1.98381
1.85770
1.98543
1.98380
1.98380
1.98501
1.98501
1.86725
1.98550
1.97835
1.97835
1.95456
1.95456
1.55711
C12-O14
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
σ*
π*
σ*
σ*
σ*
σ*
σ*
π*
σ*
σ*
σ*
σ*
σ*
σ*
0.02735
3.83
2.53
2.74
2.64
2.07
2.62
3.81
2.59
4.51
2.19
2.67
3.06
2.12
2.70
5.85
15.12
3.12
3.29
3.18
3.78
3.27
21.55
2.86
3.43
5.19
5.44
6.98
5.83
0.77
0.91
0.88
0.89
1.02
0.92
0.98
0.93
0.98
1.25
1.21
1.24
1.25
1.24
1.04
0.28
1.01
1.00
1.05
1.15
1.27
0.33
1.10
1.18
1.17
0.72
0.70
0.62
0.049
0.043
0.444
0.043
0.041
0.044
0.055
0.044
0.059
0.047
0.051
0.055
0.046
0.052
0.070
0.062
0.051
0.051
0.052
0.059
0.058
0.078
0.050
0.057
0.069
0.056
0.062
0.060
C19-H20
C12-H13
C19-H21
C6-C12
0.01635
0.03607
0.01485
0.03918
0.01156
0.04255
0.01595
0.02372
0.04255
0.02243
0.01815
0.02372
0.01277
0.02790
0.38194
0.04255
0.02372
0.01136
0.02790
0.01815
0.30719
0.38194
0.01277
0.02243
0.03918
0.03607
0.01988
C16-H17
N22-C24
C16-H18
N22-C23
N22-C24
C24-H27
C25-H28
N22-C23
C23-H26
C19-N22
C24-N29
N22-C24
N22-C23
C25-N29
C19-N22
C25-H28
C23-C25
C24-N29
C23-H26
C24-H27
C6-C12
C12-H13
C16-C19
1
6

ACCEPTED MANUSCRIPT
LP(1)N22
LP(1)N22
LP(1)N22
LP(1)N29
LP(1)N29
LP(1)N29
LP(1)N29
n
n
n
n
n
n
n
1.55711
1.55711
1.55711
1.92411
1.92411
1.92411
1.92411
C19-H20
σ*
π*
π*
σ*
σ*
σ*
σ*
0.01635
2.46
31.27
46.55
8.32
0.66
0.29
0.28
0.81
0.94
0.77
0.80
0.041
0.088
0.103
0.074
0.065
0.037
0.038
C23-C25
C24-N29
N22-C24
C23-C25
C24-H27
C25-H28
0.30719
0.38194
0.04255
0.01884
0.02243
0.01815
5.51
2.23
2.19
1
7

ACCEPTED MANUSCRIPT
3
.6. Vibrational analysis
The maximum number of potentially active fundamental vibrations of a non-linear
molecule consisting of atoms is 3 – 6, apart from three translational and three rotational
N
N
degrees of freedom. The title molecule has 29 atoms with 81 normal vibrations and displays C1
point group symmetry. The simulated and experimental FT-IR and FT-Raman spectra of the
3
6
HIP molecule are shown in Figs. S1 and S2. The observed and scaled theoretical frequencies of
-311+G(d,p) basis sets and the respective TEDs are listed in Table 3. The 3HIP molecule was
subjected to vibrational analyses using the B3LYP/6-311G(d,p) method. The computed
wavenumbers were generally higher than the recorded (FT-IR and FT-Raman) wavenumbers,
which might be related to the neglect of the anharmonicity in the built-in real calculation system
of the software. These discrepancies can be corrected by either computing anharmonicity
corrections explicitly or introducing a scaled field or directly scaling the wavenumbers using a
proper scale factor [12]. However, tentative assignments are often made using the non-scaled
frequencies by assuming that the observed frequencies are in the same magnitude as the
calculated values.
3
.6.1. C-H vibrations
Carbon-hydrogen stretching vibrations are assigned on the basis of scaled ab initio
predicted frequencies and known “group frequencies.” The 3HIP molecule has one imidazole
substructure and one phenyl ring linked by a propane bridge as shown in Fig. 1. The imidazole
moiety has three C-H bonds, and the phenyl ring has five. The heterocyclic aromatic
-1
substructures have C-H stretching vibrations in the range of 3100–3000 cm [26]. In this range,
the substituents do not significantly affect the vibration bands. The scaled vibrations (mode nos.:
2
-9) correspond to the stretching modes of the C-H bonds in the imidazole and phenyl rings.
Computing of these vibrations for the title compound by using the B3LYP/6-311G(d,p) method
-1
generated the following values, 3155, 3126, 3121, 3087, 3080, 3069, 3060, and 3047 cm , which
-1
were in good agreement with the recorded FT-IR spectrum band at 3166 cm and the FT-Raman
-1
spectrum bands at 3135, 3117, and 3074 cm . The computed TED contribution for the C-H
vibration was 100% as shown in Table 3. The aromatic C-H stretching bands were weak because
of the low dipole moment based on the weak negative charge on the carbon atoms, which is
caused by increasing the chain length of the substituent [27].
1
8

ACCEPTED MANUSCRIPT
-
Substitution-sensitive C-H in-plane-bending vibrations are in the range of 1300–1000 cm
1
-1
[
26]. For the title compound, the medium and strong bands at 1292, 1255, and 1147 cm in the
-1
FT-IR spectrum and at 1280, 1210, 1109, and 1076 cm in the FT-Raman spectrum were
assigned as C-H in-plane-bending vibrations. The theoretically computed wavenumbers for this
mode were 1282, 1277, 1264, 1243, 1236, 1216, 1174, 1158, 1144, 1129, 1102, 1074, and 1058
-1
cm using B3LYP/6-311G (d,p) method. The computed C-H out-of-plane bending vibrations for
both rings of the 3HIP molecule are in good agreement with recorded wavenumbers as shown in
Table 3.
3
2
.6.2. CH vibrations
Assigning of methylene group vibrations is based on spectral similarity to amino acids,
-1
2
which have expected CH symmetric and antisymmetric vibrations of ~3100–2900 cm [28].
The calculated CH symmetric and antisymmetric stretching modes of the title compound were
2
-1
3
015, 2983, 2954, 2943, and 2863 cm (mode nos. 10–14, respectively) with TED contributions
of ~95% indicating a pure mode. The wavenumbers of the recorded FT-IR and FT-Raman
-1
spectra of the 3HIP molecule show bands near 2981, 2927, and 2943 cm , which were assigned
to CH antisymmetric and symmetric stretching vibrations. Position shift and changes in the
2
intensity of the C-H stretching and bending modes can be caused by electronic effects including
back donation due to a nitrogen atom adjacent to the methylene group. The CH bending
2
-1
(
scissoring) mode is in the range of 1450–875 cm , and its wagging mode is approximately 1340
-1
-1
±
25 cm [28, 29]. The CH wagging mode calculated for the 3HIP molecule was at 1350 cm
2
with a TED contribution of ~35% using the B3LYP/6-311+G(d,p) method. A weak band
-1
recorded at 1352 cm of the 3HIP FT-Raman spectrum of the title compound was assigned as
-1
CH wagging mode. The band recorded at 1456 cm of the 3HIP FT-Raman spectrum was
2
categorized as CH
contribution of ~60% as shown in Table 3.
.6.3. O-H vibrations
The O-H group induces vibrations in stretching, in-plane bending, and out-of-plane
2
scissoring mode, and its computed TED indicated a pure mode with a
3
bending modes. Vibrations of the O-H group are most sensitive to the surrounding environment;
they show pronounced shifts in the spectra of hydrogen-bonded molecule species. The
-1
frequencies of O-H stretching vibrations are approximately 3500 cm [30]; however, in un-
-1
substituted phenol derivatives, they appear in the gas phase at approximately 3657 cm [31]. The
1
9

ACCEPTED MANUSCRIPT
-1
3
HIP molecule analysis detected a strong FT-IR band at 3166 cm , which was categorized as O-
H stretching vibration. The measured O-H stretching band value had a negative deviation of
-1
approximately 500 cm from the literature values, which could be related to the absence of the
harmonic approximation as a vibration parameter of atomic groups involved in intramolecular
-
hydrogen bonds as shown in Table 3. The computed wavenumber of this vibration was 3698 cm
1
(
mode no. 1) with a 100% TED contribution.
The O-H in-plane-bending vibration of phenols is in the range of 1250–1150 cm , and it
is not significantly affected by intramolecular hydrogen bonding unlike the stretching and out-of-
-1
-1
plane bending vibrations [30]. The observed bands at 1292 and 1280 cm in the FT-IR and FT-
Raman spectra, respectively, of the 3HIP molecule were classified as O-H in-plane-bending
-1
vibrations. The corresponding computed wavenumber was 1282 cm with a TED contribution of
approximately 35%.
-1
The free O-H group has vibrations in out-of-plane bending mode at 300 cm , which was
beyond the infrared spectral range of this investigation. However, in compounds, the O-H out-of-
-1
plane bending vibrations are in the range of 517–710 cm in intermolecular and intramolecular
interactions. For the title compound, the O-H out-of-plane bending vibrations computed using
the B3LYP/6-311+G(d,p) method were in good agreement with the recorded spectral data.
3
.6.4. Ring vibrations
Ring mode vibrations are affected by substitutions in the ring system. Due to different
-1
substituents, the imidazole ring absorbs strongly in the range of 1630–1300 cm [30]. Typically,
-1
the indole ring has several bands of variable intensities in the range of 1530-1013 cm due to
-1
ring stretching vibrations [31]. The bands at 958 and 889 cm in the FT-IR spectrum of the title
-1
compound and at 1000, 978, 779, 750 cm in its FT-Raman spectrum were categorized as C-C
stretching vibrations, which were in good agreement with the following wavenumber values
computed using the B3LYP/6-311+G(d,p) method, 1048, 1017, 1014, 1012, 1005, 983, 973, 954,
-1
9
12, 899, 889, and 835 cm . The computed C-C-C in-plane and out-of-plane bending vibration
wavenumbers were in a good agreement with recorded spectra data as shown in Table 3.
3
.7. UV-Vis and Frontier molecular orbital (FMO) analysis
The UV-Vis spectral data of the 3HIP molecule in the gas and chloroform phases were
computed according to the time-dependent density functional theory (TD-DFT) using the
B3LYP/6-311G (d,p) method. Fig. S3 shows the UV-Vis absorption spectrum of 3HIP in
2
0

ACCEPTED MANUSCRIPT
chloroform. The computed electronic properties such as absorption wavelength, excitation
energy, oscillator strength, and the major contribution of each transition along with its
assignment are shown in Table 4. Single peaks were calculated for the title compound in the gas
and chloroform phases at 245.49 and 232.29 nm, respectively. The recorded UV-Vis spectrum
peak of the title compound in chloroform at 258 nm was attributed to the hyperconjugation
interactions in the ring substructures and assigned to n→π* electronic transition, i.e., the lone
pair electrons of the electronegative phenyl ring in the 3HIP molecule underwent the transition to
the π electrons of this ring. The computed UV-Vis spectrum of the title compound is presented in
Fig. 5.
Among the two frontier orbitals, the HOMO is the outermost orbital occupied by
electrons that tends to donate them, whereas the LUMO represents the free, unoccupied space
that tends to accept electrons [32, 33]. The interaction between the frontier orbitals of 3HIP was
based on the n→π* transition. The energy difference between HOMO and LUMO orbitals
determines critical electronic parameters such as ionization potential, electron affinity, global
hardness, chemical potential, electrophilic index, and chemical softness. The respective
electronic parameters of 3HIP in the gas and chloroform phases were computed using the
B3LYP/6-311G(d,p) method as shown in Table 5. The computed parameters indicated that the
3
HIP molecule is chemically soft and may possess certain biological activities.
2
1

ACCEPTED MANUSCRIPT
Table 3: Vibrational wavenumbers obtained for the 3HIP molecule at B3LYP /6-311G(d,p) method.
Theoretical
TED (≥10%)
Experimental
Mode
nos.
-1
Wavenumber (cm )
Assignments
-1
Wavenumber (cm )
B3LYP/6-311G(d,p
FT-IR FT-Raman
Wavenumber IRIntinisty
RamanActivity
1
2
3
4
5
6
7
8
9
3698
3155
3126
3121
3087
3080
3069
3060
3047
3015
2983
2954
2943
2863
1592
1573
1486
1480
29.2539
2.4972
5.2045
4.107
νOH(100)
νCH(99)
νCH(82)
νCH(96)
νCH(98)
νCH(95)
νCH(93)
νCH(80)
νCH(97)
νCH(88)
νCH(99)
νCH(96)
νCH(97)
νCH(98)
νCH(55)
νCH(68)
1
9
1
4
10.465
7.0936
15.062
6.2067
3166 s
3135 s
3117 s
13.4354
20.0083
16.6743
0.1181
8.9797
11.3894
7.942
3
01.6916
8.807
02.9361
3074 ms
3
1
8
4.8434
5.1221
4.4454
3052 s
4
10
11
12
13
14
15
16
17
18
2
2981 s
4
5.95
32.7296
1.8283
41.1782
2.7215
0.7586
24.7969
40.5059
3
9
7
3
7.3686
0.3903
8.9794
9.2626
2927 ms
2943 ms
1599 s
1567 w
1499 m
6
.6279
.7773
.0339
νNC(24)+νCC(30)+βHCC(14)
2
νCC(21)+βCNC(16)+βHCC(16)+βHCH(11)
8
2
2

ACCEPTED MANUSCRIPT
1
2
2
2
2
9
0
1
2
3
1473 s
1476
1450
1436
1429
1367
12.0087
21.8502
10.5121
8.2081
βHCC(61)
1
3
0
.2192
.0912
.5984
14560 vw
βHCH(60)
νCC(22)+βHCC(38)
βHCH(87)
2
1.2675
1379 ms
15.2077
νNC(17)+γCCNH(11)+τHCCC(23)
βHOC(16)+βHCN(10)+βHCC(12)+τHCCN(22)+
γCCCH(13)
5.4671
24
1364
25.1505
8.668
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
1352 w
1280 m
1350
1339
1334
1305
1282
1277
1264
1243
1236
1216
1174
1158
1144
1129
1102
1074
1058
1048
1017
1014
1012
3.0391
9.0834
4.2829
2.9689
23.6727
1.6797
27.9995
25.1309
15.0415
32.8976
1.4703
1.0541
0.0744
1.652
βHCN(19)+τCCCH(35)
νNC(25)+βHCC(19)
νNC(26)+βHCN(13)+βHCC(15)
βHCC(57)
1
9.882
1
7.8578
1
5.36
0.8004
1292 s
βHOC(11)+βHCC(35)
νCC(20)
5.9097
2
.73
1255 ms
νNC(11)+βHCC(43)
βHOC(18)+βHCC(18)+τHCCN(12)
βHCC(19)+τHCCN(16)
νNC(23)+βHCN(57)
νCC(41)+βHCC(10)
βHCC(73)
1
6.0403
1
.6211
.7916
.9564
0
1210 w
4
1
6.7514
6
.1533
.9517
.6986
.7934
.6161
.7708
.8649
1147 vs
νCC(10)+βHCC(73)
νNC(11)+βHCN(12)+τHCCC(11)
νNC(58)+βHCC(22)
νCC(24)+νOC(10)
νCC(20)+βHCC(49)
νOC(21)
3
3
6
1
9
6
1109 w
1076 m
17.1502
8.755
24.6236
37.4455
41.6054
6.3276
6.4814
νCC(34)+βHOC(10)
νCC(57)
1
1
4.3775
1.2528
νCC(12)+βCCN(36)
4.5923
2
3

ACCEPTED MANUSCRIPT
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
1000 vs
978 m
1005
983
973
954
912
899
889
835
835
817
787
758
748
709
706
694
656
622
614
608
535
495
403
378
354
333
326
237
36.515
0.5324
0.4591
0.025
νCC(52)+βCCN(14)
1
3
3.0964
5.3427
νCC(21)+βCCC(66)
τHCCH(70)
0
.0314
.0318
.6857
.1793
.2132
958 s
τHCCC(24)+τHCCH(40)
νCC(15)+νOC(28)
0
10.4503
1.0808
11.8444
1.5913
0.0468
3.3625
30.0652
1.6371
26.8554
28.2746
4.5605
37.8496
16.4995
1.4825
0.5227
14.4752
27.6639
4.8639
1.7212
26.8244
48.702
38.8219
29.5431
1.1241
2
2
3
τHCCC(17)+τHCCH(45)
νNC(10)+βCNC(72)
889 vs
τHCNC(14)+τHCCH(80)
τHCCC(21)+τHCCH(71)
νCC(27)+βCCC(19)
0
.349
.0064
.6934
.8395
1
5
0
779 w
γCNNH(88)
βHCC(15)+γCCNH(25)+τHCCN(16)
τHCCC(28)+τCCCC(42)
τHCNC(76)+τHCCH(14)
νNC(21)+βCNC(23)
0
1
.53
.05
750 vw
712 vw
639 ms
0
1
0
0
1
.6865
.4101
.4733
.1766
.9923
τHCCC(64)+τCCCC(20)
τCNCN(93)
τCNCC(63)
βCCC(74)
4
.962
βCCC(19)+βCCO(14)+τCNCC(17)
τCCCC(45)
1
0
0
0
2
2
0
0
3
.9587
.6824
.3753
.0716
.3942
.4366
.4046
.9495
.5421
562 m
βCCC(10)+γOCCC(32)
τCCCC(85)
377 w
βCCO(11)+βCCN(14)+τHCOH(12)+τCCCC(21)
βCCN(13)+τHCOH(39)
βCNC(45)+τHCOH(25)
βCNC(31)+βCCO(13)+τHCOH(19)
βCCC(25)+τCCCC(26)+τCNCN(11)
362 vw
2
4

ACCEPTED MANUSCRIPT
74
75
76
77
78
79
80
81
225 w
226
202
116
99
0.6517
0.5978
0.3341
1.2795
1.622
βCCC(40)+γOCCC(11)
βCCC(50)+βCCO(14)
1
.19
0
.7708
.1871
τCCCC(39)+τCNCN(39)
τCCCC(52)+τCCNC(11)
τCCCC(33)+τCCCN(38)
βCCC(37)+βCCN(15)+τCCCC(20)+τCNCN(20)
τCCCC(49)+τCCNC(35)
τCCCC(21)
1
0
.303
.6069
.9525
61
1
6
44
0.6167
1.6557
0.6654
35
6
.62
23
4.3419
w–weak; vw–very weak; s–strong; vs–very strong; m–medium; br, sh–broad, shoulder; υ–stretching; υsym–symmetric stretching; υasy–
antisymmetric stretching ; β– in-plane bending; γ–out-of –plane bending; ω–wagging; t–twisting; δ–scissoring ; τ–torsion.
Table 4: Experimental and calculated absorption wavelengths, energies, and oscillator strengths of the 3HIP molecule according to
the TD-DFT method using the B3LYP/6-311G(d,p) method.
a
λ (nm)
E(eV)
(f)
Experimental
Major contributions
Assignment
Gas
245.49
241.98
232.22
5.0505 0.0043
5.1238 0.0001
5.3391 0.0007
H→L (100%)
H→L+1 (99%)
H-3→L(39%), H-1→L+1(44%)
n→π*
π →π*
π →π*
Chloroform
2
2
2
32.29
30.22
26.90
5.3376 0.0012
5.3854 0.0083
5.4643 0.0001
258
230
H-2→L (39%), H-1→L+1(48%)
H→L (97%)
H→L+1 (94%)
n→π*
π →π*
π →π*
a
H: HOMO; L: LUMO
2
5

ACCEPTED MANUSCRIPT
Table 5: Calculated energy values of HOMOs and LUMOs in the 3HIP molecule in the gas and
chloroform phases using the B3LYP/6-311G(d,p) method.
Parameter
Energy
Gas Phase
Chloroform Phase
E
E
E
E
E
E
E
E
(eV)
E
-
-
6.13
0.65
-6.33
-0.53
5.80
-6.93
-0.47
6.46
-7.16
0.5
2.90
3.43
1.45
2.028
6.1333
HOMO
LUMO
HOMO
(eV)
-
LUMO gap
5.48
-7.0
HOMO-1
-0.6
LUMO+1
E
(eV)
HOMO-1-
gap
6.4
LUMO+1
-7.11
HOMO-2
LUMO+2
0.59
2.74
3.39
1.37
2.0970
5.3521
Chemical hardness η (eV )
Electronegativity χ (eV)
Chemical softness ξ (eV )
Electrophilicity index ω (eV )
Dipole moment (Debye)
The density of state (DOS) spectra of the 3HIP molecule in the gas and chloroform
phases were predicted using the GaussSum [34] software for calculating the Gaussian curves
including their heights as shown in Fig. 5. The energy gap value between HOMO and LUMO of
the title compound was 5.48 and 5.80 eV in the gas and chloroform phases, respectively. An
increase in the electron donating properties caused by substituents on ring substructure leads
typically to an increase in the HOMO-LUMO energy and a decrease in the HOMO-LUMO
energy gap [35]. The energy gap between the HOMO-LUMO indicates the eventual charge
transfer within the molecule. The marginal lowering of the HOMO-LUMO energy gap in the
title compound could be attributed to the propane group substitution connecting the two ring
substructures. The frontier molecular orbitals of 3HIP are displayed in Fig. 6. Positively charged
regions are marked in green and negatively charged regions in red. The HOMO→LUMO
transitions indicated the occurrence of an electron density transfer from the imidazole ring to the
phenyl moiety.
3
.8. Molecular electrostatic potential
The molecular electrostatic potential (MEP), also called the molecular electrical potential
surface, represents the 3D charge distribution in the molecule by visualizing the electrophilic and
nucleophilic charged regions. The MEP surface of 3HIP was generated using the B3LYP/6-
2
6

ACCEPTED MANUSCRIPT
3
11G(d,p) method as shown in Fig. 7. Electron-rich regions with the lowest electrostatic
potential are marked in red, and areas with the lowest electron concentration and the highest
electrostatic potential are marked in blue. An intermediate color represents an intermediary
electrostatic potential. In the 3HIP molecule, all hydrogen atoms have an electrophilic site
whereas the imidazole ring represents a nucleophilic site.
3
.9. NMR analysis
Nuclear magnetic resonance (NMR) spectroscopic technique is used to investigate the
chemical structure of organic compounds. The molecular structure of the 3HIP molecule was
optimized using B3LYP/6-311G(d,p) method; then, the gauge including atomic orbital (GIAO)
1
13
method was adopted to determine H and C chemical shift values. The recorded and computed
1
3
(
gas and chloroform phase) chemical shift values are presented in Table 6. In C NMR spectrum
of the 3HIP molecule, the signal peak observed at 78.54 ppm was assigned to the C12 atom, and
its computed value was 77.96 ppm in the chloroform phase using the B3LYP/6-311G(d,p)
method. The chemical shifts of the shielded C16 and C19 atoms were observed at 38.9 and 42.7
1
3
ppm, and their computed values were 47.43 and 47.71 ppm, respectively. The C chemical shift
1
3
values for aromatic carbons are typically around 120–140 ppm [35]. The computed C NMR
chemical shifts of the phenyl ring carbons C1, C2, C3, C4, C5, and C6 were 128.28, 132.78,
1
31.74, 132.09, 129.49, and 151.35 ppm in chloroform, respectively. The chemical shift values
of the imidazole ring carbons C23, C24, and C25 in chloroform were calculated as 122.39,
1
1
39.21, and 132.84 ppm, respectively. The computed H chemical shift values of the methylene
protons were 1.67, 1.90, 4.37 and 3.90 ppm for the hydrogens H17, H18, H20, H21, respectively.
The recorded spectra peaked at 1.93 and 3.92 ppm corresponding to the methylene protons in
1
chloroform. The calculated H chemical shift values of the phenyl ring hydrogens were in the
range of 7.28–7.82 ppm using the B3LYP/6-311G(d,p) method.
Table 6: Computed NMR parameters of the 3HIP molecule using the B3LYP/6-311G(d,p)
method.
Atom
Number
C1
B3LYP/6-311G(d,p)
Exp.
Gas Phase
Chloroform Phase
128.28
128.09
132.94
131.88
132.06
128.99
126.5
127.8
124.7
127.8
126.5
C2
C3
C4
C5
132.78
131.74
132.09
129.49
2
7

ACCEPTED MANUSCRIPT
C6
150.80
78.54
47.75
47.67
120.35
137.95
134.64
7.79
7.48
7.34
7.35
7.15
4.67
1.61
1.93
4.37
3.69
6.78
7.18
7.03
151.35
77.96
47.43
47.71
122.39
139.21
132.84
7.82
7.55
7.42
7.44
7.28
4.82
1.67
1.90
4.37
3.90
7.01
7.33
6.98
143.6
68.9
38.9
42.7
117.8
136.2
127.5
7.14
7.19
7.20
7.19
7.14
4.41
1.93
1.93
3.92
3.92
6.79
7.25
6.79
C12
C16
C19
C23
C24
C25
H7
H8
H9
H10
H11
H13
H17
H18
H20
H21
H26
H27
H28
3
.10. Reduced density gradient (RDG)
Johnson et al. [36] were the first to develop the methodology for calculating the reduced
density gradient (RDG) from the electron density as a dimensionless quantity.
2
∆
ρ
(r)
1
RDG = (r) =
(3)
1
3
4
3
2
2(3
π
r )
ρ(r)
2
The plot of ρ(r) versus the sign of λ helps to characterize the nature and strength of the
interactions. The sign of λ , the second largest value of the Hessian matrix of electron density, is
2
used to define the interaction type; λ > 0 for non-bonded species and λ < 0 for bonded species.
2
2
The RDG isosurface of the 3HIP molecule was drawn using an isosurface value of 0.5 as shown
in Fig. 8. The software used for plotting the RDG surface was Multiwfn software supported by
the VMD program [16]. In Fig. 8, red indicates a strong repulsion that appears at the centers of
the phenyl and imidazole ring systems. As shown in the same figure, a strong van der Waals
interaction happened between the O-H group and phenyl ring hydrogens.
2
8