Spectral characterization, computed frequencies analysis and electronic structure calculations on (1E)–N-hydroxy-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine: An oxime-bearing precursor to potential antifungal agents

Article abstract of DOI:10.1016/j.molstruc.2018.05.022

(1E)–N-Hydroxy-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (H3IPI) is a precursor to potential antifungal agents and was subjected to experimental and simulated spectroscopic (UV, FT-IR, FT-Raman as well as ¹H and ¹³C NMR) characterization. Density functional theory, Hartree-Fock fundamental wavenumbers and intensity of the modes are interpreted with the aid of structure optimizations and normal force field computations. The complete wavenumbers assignments of H3IPI were made on the basis of potential energy distribution of each vibrational mode. The electronic and excited state properties have been determined by time dependent-density functional theory method. The responsiveness parameters as chemical potential, global hardness, and electrophilicity index have also been calculated. The scaled B3LYP/6–311++G (d,p) calculations showed better coincidence with the experimental findings of H3IPI over the other computation method. Molecular electrostatic potential and thermodynamic properties of the title compound were also investigated. In addition, Mulliken and natural charges distribution, non-linear optics properties as well as natural bond orbital analysis of the title molecule were calculated and interpreted. Theoretical calculations of the NMR chemical shifts of H3IPI were carried out through GIAO method at B3LYP/6–311++G (d,p) level and the results were compared with the experimental values.

Full text of DOI:10.1016/j.molstruc.2018.05.022

Accepted Manuscript
Spectral characterization, computed frequencies analysis and electronic structure
calculations on (1E)-N-hydroxy-3-(1H-imidazole-1-yl)-1-phenylpropan-1-imine: An
oxime-bearing precursor to potential antifungal agents
Reem I. Al-Wabli, Munusamy Govindarajan, Maha S. Almutairi, Mohamed I. Attia
PII:
S0022-2860(18)30582-9
10.1016/j.molstruc.2018.05.022
MOLSTR 25194
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 6 March 2018
Revised Date: 23 April 2018
Accepted Date: 7 May 2018
Please cite this article as: R.I. Al-Wabli, M. Govindarajan, M.S. Almutairi, M.I. Attia, Spectral
characterization, computed frequencies analysis and electronic structure calculations on (1E)-N-
hydroxy-3-(1H-imidazole-1-yl)-1-phenylpropan-1-imine: An oxime-bearing precursor to potential
antifungal agents, Journal of Molecular Structure (2018), doi: 10.1016/j.molstruc.2018.05.022.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Spectral characterization, computed frequencies analysis and electronic structure
calculations on (1E)-N-hydroxy-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine: An oxime-
bearing precursor to potential antifungal agents
Reem I. Al-Wablia, Munusamy Govindarajanb,c, Maha S. Almutairia and Mohamed I. Attiaa,d*
aDepartment of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O.
Box 2457, Riyadh 11451, Saudi Arabia
bDepartment of Physics, Avvaiyar Government College for Women (AGCW), Karaikal,
Puducherry 609602, India
cDepartment of Physics, Arignar Anna Government Arts and Science College for Women
(AAGASC), Karaikal, Puducherry 609602, India
dMedicinal and Pharmaceutical Chemistry Department, Pharmaceutical and Drug Industries
Research Division, National Research Centre, Dokki, Giza 12622, Egypt
Keywords: Imidazole; FT-IR; FT-Raman; HOMO-LUMO; DFT/B3LYP and HF.
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Abstract:
(1E)-N-Hydroxy-3-(1H-imidazol-1-yl)-1-phenylpropan-1-imine (H3IPI) is a precursor to
potential antifungal agents and was subjected to experimental and simulated spectroscopic (UV,
1
FT-IR, FT-Raman as well as H and 13C NMR) characterization. Density functional theory,
Hartfock fundamental wavenumbers and intensity of the modes are interpreted with the aid of
structure optimizations and normal force field computations. The complete wavenumbers
assignments of H3IPI were made on the basis of potential energy distribution of each vibrational
mode. The electronic and excited state properties have been determined by time dependent-
density functional theory method. The responsiveness parameters as chemical potential, global
hardness, and electrophilicity index have also been calculated. The scaled B3LYP/6-
311++G(d,p) calculations showed better coincidence with the experimental findings of H3IPI
over the other computation method. Molecular electrostatic potential and thermodynamic
properties of the title compound were also investigated. In addition, Mulliken and natural
charges distribution, non-linear optics properties as well as natural bond orbital analysis of the
title molecule were calculated and interpreted. Theoretical calculations of the NMR chemical
shifts of H3IPI were carried out through GIAO method at B3LYP/6-311++G(d,p) level and the
results were compared with the experimental values.
1. Introduction
The incidence of systemic fungal infections (IFIs) has significantly escalated over the
past two decades giving rise to high rates of morbidity and mortality particularly in
immunocompromised individuals such as patients taking anticancer chemotherapy or undergoing
organ transplants and patients with AIDS [1-3]. Polyenes [4], echinocandins [5], antimetabolites
[6] and azoles [7] are the major categories of the currently available antifungal drugs in clinic in
which azoles constitute a milestone in the antifungal therapy.
Since the appearance of imidazole-bearing antifungal agents in late 1980s, they are
widely applied as efficient antifungal drugs but resistance development limits their current
therapeutic use in clinic [8]. In addition, the antifungal agents manifested certain toxicity to
human systems due to similarity between the human and fungi molecular processes [9].
Therefore, the development of new azole-bearing antifungal agents remains an open interesting
research area to acquire safer antifungal candidates capable of countering resistance of the
serious fungal infections
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Most of the currently available antifungal agents feature a two carbon bridge between
aromatic and azole pharmacophore moieties, while a limited number of the available antifungal
agents have a three carbon spacer between the aromatic and the azole pharmacophore fragments
[10-13]. Moreover, some potent azole-bearing antifungal agents were prepared from starting
materials having oxime functionality [14].
Amalgamation of two or more biologically active pharmacophore fragments in one
molecular hybrid chemical entity became a popular approach in medicinal chemistry to get
modified scaffolds endowed with much improved and amazing biological properties [15].
The aforementioned premises persuaded us to synthesis the title molecule as an
amalgamated molecular hybrid bearing oxime functionality as well as the aromatic and
imidazole pharmacophore moieties with a three carbon chain spacer. The title molecule
compromises the required structural features to be functionalized in the synthesis of new
imidazole-bearing antifungal agents. Vibrational analysis and spectral (FT-IR, FT-Raman, UV,
1H and 13C NMR) characterization of the title compound was carried out in the current study
with the aid of ab initio Hartree-Fock (HF) and DFT computational approaches. Furthermore,
Molecular electrostatic potential (MEP), natural bond orbital (NBO) analysis, nonlinear optic
(NLO) activity and HOMO-LUMO analysis were also computed for the title molecule. We
believe that the results of the current investigations might support the development of improved
potent and safer antifungal agents.
2. Experimental details
2.1. General
The title molecule H3IPI was synthesized as previously reported [13]. The FT-IR spectrum
H3IPI has been recorded in Perkin-Elmer 180 spectrometer in the range of 4000–400 cm−1. The
spectral resolution is ± 2 cm-1. The FT-Raman spectrum of H3IPI was also recorded using the
same instrument with FRA 106 Raman module equipped with Nd: YAG laser source operating
in the region 100-4000 cm–1 at 1.064 ꢀm line widths with 200 mW powers. The spectra were
recorded with scanning speed of 30 cm-1/min and spectral width of 2 cm-1. The frequencies of all
sharp bands are accurate within ± 1 cm-1. Bruker NMR spectrometer was used to record NMR
1
spectra of the title compound in deuterated chloroform (CDCl3) at 500 MHz for H and 125.76
MHz for 13C at the Research Center, College of Pharmacy, King Saud University, Saudi Arabia.
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2.2. Synthesis
The commercially available acetophenone (2.4 g, 20 mmol) was dissolved in absolute
ethanol (35 mL). Paraformaldehyde (0.81 g, 9 mmol), dimethylamine hydrochloride (2.2 g, 27
mmol) and a catalytic amount of concentrated hydrochloric acid (0.1 mL) were added to the
ethanolic reaction solution. The reaction mixture was stirred and refluxed for two hours, cooled
and acetone (30 mL) was added. Mannich base hydrochloride (1) was precipitated, collected by
filtration and dried. Imidazole (1.4 g, 20 mmol) was added to the aqueous solution of compound
1 (2.1 g, 10 mmol) in water (10 mL). The reaction mixture was stirred and refluxed for five
hours and cooled. Compound 2 was precipitated and collected by filtration to give the ketone 2
in 77% yield which were pure enough to be used in the next step. The ketone 2 (2.00 g, 10
mmol), hydroxylamine hydrochloride (1.39 g, 20 mmol), and KOH (1.12 g, 20 mmol) in ethanol
(10 mL) were heated to reflux under stirring for 18 h. The reaction mixture was cooled to room
temperature and the insolubles were filtered off. The filtrate was concentrated under vacuum and
the residue was poured onto ice-cold water (15 mL). The precipitated solid was filtered, dried,
and recrystallized from ethanol to give 1.51 g (70%) of the oxime 3 as colorless crystals mp 427-
429 K (lit. 428-430 K [13]). 1H-NMR (CDCl3): δ 7.58 (s, 1H, -N-CH=N-), 7.29–7.49 (m 5H, Ar-
H), 7.07 (s, 1H, -N-CH=CH-N=), 6.96 (s, 1H, -N-CH=CH-N=), 4.28 (t, J = 7.1 Hz, 2H, -CH2-
CH2-N), 3.31 (t, J = 7.1 Hz, 2H, -CH2-CH2-N).
2.3. Quantum chemical calculations
The entire quantum chemical calculations have been performed at DFT (B3LYP) and ab
initio HF methods with 6-311++G(d,p) basis set using the Gaussian 09 program [16]. The
optimized structural parameters have been evaluated for the calculations of wavenumbers at
different level of theories. At the minimum geometry for the H3IPI molecule no negative
wavenumber modes were obtained, therefore a true minimum was found on the potential energy
of the molecule. Consequently, the computed wavenumbers, reduced masses, force constants,
infrared intensities, Raman activities, Raman intensities, and depolarization ratios were obtained.
The computed harmonic frequencies were scaled down to improve the computed values.
Therefore, the calculated wavenumbers at HF level were scaled by 0.905 [17] and the range of
wavenumbers were scaled by 0.958 and 0.983 above and below 1700 cm-1, respectively, for
B3LYP/6-311++G(d,p) [18, 19]. After using this scaling factor, the deviation from the
experimental values is less than 10 cm-1 with a few exceptions. The appointments of the
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calculated normal modes have been made on the basis of the corresponding PEDs. The PEDs
were calculated from the quantum chemically computed wavenumbers using VEDA program
[20]. GaussView program [21] has been considered to get visual animation and also for the
verification of the normal modes assignment.
The electronic absorption spectra for optimized H3IPI molecule calculated with time
dependent density functional theory (TD-DFT) at B3LYP/6-311++G (d,p) level. The molecular
electrostatic potential of H3IPI was evaluated to investigate its reactive sites. Furthermore, in
order to show the nonlinear optic (NLO) activity of the H3IPI molecule, the dipole moment,
linear polarizability and first hyperpolarizability were obtained from its molecular polarizabilities
based on theoretical calculations. Moreover, the changes in the thermodynamic functions (the
heat capacity, entropy and enthalpy) of H3IPI were investigated at different temperatures.
2.4. Prediction of Raman intensities
The calculated Raman activities (SRa) with Gaussian 03 program were converted to the
relative Raman intensities (IRa) using the following relationship derived from the intensity theory
of Raman scattering [22]:
f ν −ν 4 Si
(
)
0
i
Ii =
(1)
ν 1−exp −hcν / kT 
(
)
i
i


where; ν0 is the laser exciting wavenumber in cm−1 (ν0 = 9398.5 cm−1, which corresponds to the
wavelength of 1064 nm of a Nd:YAG laser), νi the vibrational wavenumber of the ith normal
mode (cm−1), while Si is the Raman scattering activity of the normal mode νI, f is a constant
equal to 10−12 and was suitably chosen with common normalization factor for all peak intensities.
h, k, c and T are Planck constant, Boltzmann constant, speed of light and temperature in Kelvin,
respectively.
3. Results and discussion
3.1. Synthesis
The title molecule
3 was prepared in a three step reaction sequence as presented in
Scheme 1 using the commercially available acetophenone as a starting material according to the
reported procedure [13]. The spectral data of the synthesized H3IPI are in accordance with the
recorded ones.
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O
O
O
N(CH3)2 .HCl
N
CH3
N
i
ii
1
2
iii
NOH
N
N
3
Reagents and conditions: i) HN(CH3)2.HCl, (CH2O)n, conc. HCl, ethanol, reflux, 2 h; ii) Imidazole, water, reflux, 5
h; iii) H2NOH.HCl, KOH, ethanol, reflux, 18 h.
Scheme 1: Synthesis of the title compound
3.2. Molecular geometry
3.
The optimized DFT geometries of the H3IPI molecule by B3LYP/6-311++G(d,p) and its
molecular structure with atoms numbering are shown in Figure 1. The internal coordinates
described the position of atoms in terms of distances, angles and dihedral angles with respect to
an origin atom. By allowing the relaxation of all parameters, the calculations were made up of
scan coordinate 1 (C6-C5-C7-C8) and scan coordinate 2 (C5-C7-C8-C9) by rotating angle from
0 to 360°. It met the optimized geometries, which correspond to the true energy minima, as
revealed by the lack of imaginary frequencies in the vibrational mode calculations. The
symmetry coordinates were constructed using a set of internal coordinates. A full set of 81
standard internal coordinates for the H3IPI molecule are presented in Figure 2. The molecules
were linked together by a strong intermolecular O16· · ·N13 bond with 0.900 Å bond length.
The optimized geometry of H3IPI was calculated by PM3 and was re-calculated by B3LYP
and HF methods. The bond lengths evaluated by B3LYP method were longer than that obtained
by HF and PM3 methods. The H3IPI molecule has one O-H, one O-N, five C-N, ten C-C and
twelve C-H bond lengths. The optimized parameters of H3IPI by B3LYP and HF methods at 6-
311++G(d,p) level as well as the experimental values [23] are indicated in Table 1. The
B3LYP/6-311++G(d,p) method overestimates bond lengths, particularly the C-H bond lengths.
The average aromatic C–H bond lengths in the H3IPI molecule were calculated as 1.083 Å using
B3LYP/6-311++G(d,p) method and 1.093 Å in the propylidene side chain. The aromatic C–H
bond lengths are shorter in both HF method and experimental. The shortest C11–H26 bond
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length is presented as 1.069 Å in the HF/6-311++G (d,p) method. On the other hand, the C-C
bond distances of H3IPI were found to have higher values in case of B3LYP calculations with
respect to HF computations. The longest C-C bond length was calculated for C8-C9 using
B3LYP /6-311++G(d,p) to be 1.546 Å, while the shortest C-C bond length was found in the C11-
C12 (1.371 Å) using the same computation method. The shortest experimental C-N bond was
found to be 1.285 Å for N15-C7 bond, while the O16-H29 bond is the shortest (0.900 Å)
experimental O-H vibration. The calculated O–N bond lengths were found to be 1.381 and 1.372
Å using B3LYP and HF methods, respectively, at 6-311++G(d,p) level of theory.
Table 1: Optimized structural parameters (bond lengths (Å), bond angles and dihedral angles (°))
of H3IPI calculated by HF and B3LYP methods with 6-311++G(d, p) level.
Bond
HF
B3LYP
Exp.a
Bond
HF
B3LYP
Exp.a
Bond lengths (Å)
O16-N15
O16-H29
N15-C7
1.372
0.943
1.260
1.447
1.350
1.373
1.369
1.291
1.381
1.395
1.073
1.388
1.076
1.382
1.076
1.381
0.970
1.286
1.454
1.370
1.382
1.375
1.311
1.388
1.405
1.082
1.395
1.084
1.391
1.084
1.403
0.900
1.285
1.466
1.350
1.374
1.378
1.319
1.391
1.398
0.950
1.389
0.950
1.389
0.950
C3-C4
C3-H19
C4-C5
C4-H20
C5-C7
1.386
1.076
1.390
1.075
1.463
1.515
1.535
1.082
1.082
1.083
1.080
1.072
1.351
1.069
1.070
1.393
1.084
1.402
1.083
1.489
1.516
1.546
1.089
1.097
1.092
1.092
1.081
1.371
1.078
1.079
1.388
0.950
1.400
0.950
1.485
1.511
1.534
0.990
0.990
0.990
0.990
0.950
1.359
0.950
0.950
N10-C9
N10-C14
N10-C11
N13-C12
N13-C14
C6-C1
C6-C5
C6-H21
C1-C2
C1-H17
C7-C8
C8-C9
C8-H22
C8-H23
C9-H24
C9-H25
C14-H28
C11-C12
C11-H26
C12-H27
C2-C3
C2-H18
Bond angles (°)
C7-N15-O16
C14-N10-C11
C14-N13-C12
C1-C6-C5
C1-C6-H21
C6-C1-H17
C2-C1-C6
C2-C1-H17
C5-C6-H21
C3-C2-C1
113.19 112.66
105.94 105.26
105.05 105.18
120.60 120.73
120.18 120.57
119.63 119.56
120.34 120.41
120.03 120.02
119.22 118.61
119.57 119.46
111.57
106.95
105.09
120.45
119.8
119.8
120.27
119.9
C5-C4-H20
C6-C5-C4
C6-C5-C7
C4-C5-C7
C5-C7-C8
C7-C8-C9
C7-C8-H22
C9-C8-H22
C7-C8-H23
C9-C8-H23
120.56
118.57
120.34
121.09
120.89
112.10
108.35
108.86
110.24
109.73
120.62
118..30
119.84
121.86
120.14
110.22
110.55
109.00
111.84
109.30
119.6
118.63
120.40
120.90
120.70
114.95
108.5
108.5
108.5
108.5
119.9
119.75
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C3-C2-H18
C1-C2-H18
C4-C3-C2
C4-C3-H19
C2-C3-H19
C3-C4-C5
C3-C4-H20
120.22 120.25
120.21 120.29
120.12 120.26
119.64 119.51
120.23 120.18
120.80 120.83
118.64 118.53
120.1
120.1
120.14
119.9
119.9
120.72
119.6
N10-C9-C8
N10-C9-H24
C8-C9-H24
N10-C9-H25
C8-C9-H25
C11-C12-N13
C12-C11-N10
112.11
107.71
110.71
108.89
109.78
110.33
105.78
112.76
107.92
110.21
108.97
109.66
110.60
105.64
114.23
108.7
108.7
108.7
108.7
110.14
105.94
Dihedral angles (°)
C5-C6-C1-C2
C6-C1-C2-C3
C1-C2-C3-C4
C3-C4-C5-C6
C1-C6-C5-C4
C1-C6-C5-C7
C3-C4-C5-C6
C3-C4-C5-C7
O16-N15-C7-C5
O16-N15-C7-C8
C6-C5-C7-C8
C6-C5-C7-N15
C6-C5-C7-C8
0.0662 -0.085
0.1261 0.1987
-0.1301 -0.1224 -1.3
0.5
1.1
N15-C7-C8-C9
C5-C7-C8-C9
C14-N10-C11-C12 -0.1929 -0.2625 -0.1
C9-N10-C11-C12
N13-C12-C11-N10 0.1027 0.146
C9-N10-C14-N13
77.72
-83.378 66.1
-102.51 -91.935 -114.85
-0.504
-0.069
-0.1
-1.9
175.03
1.7
177.57 176.98
176.87
0.1
-0.2458 -0.019
179.49 179.95
-177.60 -177.03 -176.95
0.504
0.049
-178.93 -179.48 -175.24
-179.27 -176.83 -178.52
0.8549 -1.33
-156.49 -151.84 -145.59
23.62 23.85 31.3
-156.49 -151.84 35.2
aAtoms numbering as indicated in Figure 1.
0.6
The experimental values of the angles are C1–C6–C5 (120.45°), C2–C1–C6 (120.27°), C3–
C2–C1 (119.75°), C4–C3–C2 (120.14°), C3–C4–C5 (120.72°) and C6-C5-C4 (118.63°) in which
they are closer to the values calculated by the HF method than that calculated by B3LYP
method. The smallest experimental dihedral angle was manifested for C14-N10-C11-C12 to be
-0.1° in the H3IPI molecule. The calculated bond angles of the title molecule suggest a distortion
in its aromatic ring which might be due to steric and electronic factors. The graphical expression
between the experimental and calculated bond lengths and bond angles are represented in Figure
S1.
Bond length
2
µ
cal= 0.34267+0.75043
µ
exp
(R =0.98064)HF
(2)
(3)
µcal= 0.35321+0.75123
µ
exp
(R2 =0.98631)B3LYP
Bond angle
φ
cal= 2.99553+0.97437
φ
exp
(R2 =0.97165)HF
(4)
(5)
φcal= 4.94878+0.95750
φ
exp
(R2 =0.94707)B3LYP
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3.3. Mulliken and natural charges distribution
The wavenumbers of the molecule is directly related to its Mulliken charges, and quantifies
how the electronic behavior alters under atomic displacement. Therefore, it is directly related to
the chemical bonds present in the molecule. Major contribution of Mulliken charges involves
dipole moment, polarizability, electronic structure of the molecule. The Mulliken and natural
charge distribution of the H3IPI molecule are calculated on HF and B3LYP levels at gaseous
phase and the values are given in Table 2, while their graphs are presented in Figure 3. The
Mulliken charges distribution on the title compound showed that all carbon atoms attached with
hydrogen atoms are negatively charged expect C7, which manifested about 0.275722 and
0.119624 in HF and B3LYP, respectively. The natural charges distribution also exhibited the
same trend. Moreover, the Mulliken and natural charges distribution on N10 and N13 possesses
more negative values than on N15. In both Mulliken and natural charges using HF/6-
311++G(d,p), the H29 atom showed the highest positive value (0.366224 and 0.43835,
respectively) due to its attachment to the electronegative oxygen atom. The natural charges of all
hydrogen atoms are positive with higher values than Mulliken charges.
Table 2: Muilliken and natural charges distribution using B3LYP and HF methods at
311++G(d,p) level.
Atom Muilliken charges distribution Natural charges distribution
B3LYP
-0.093994
-0.079357
-0.097622
-0.072321
-0.100630
-0.027714
0.119624
-0.272107
-0.052193
-0.313809
-0.009793
-0.057939
-0.301359
0.155669
-0.116732
-0.275306
0.101489
0.099648
0.097239
HF
B3LYP
-0.19308
-0.19771
-0.19293
-0.18681
-0.08195
-0.18301
0.17243
-0.43674
-0.16634
-0.43523
-0.07053
-0.06196
-0.49821
0.20112
-0.09361
-0.50814
0.20793
0.20771
0.20759
HF
C1
C2
C3
C4
C5
C6
C7
C8
C9
N10
C11
C12
N13
C14
N15
O16
H17
H18
H19
-0.152501
-0.142897
-0.151905
-0.154646
-0.038884
-0.121181
0.275722
-0.266487
-0.003425
-0.623881
0.046267
0.000234
-0.544873
0.339315
-0.212585
-0.514838
0.155698
0.155858
0.155654
-0.18190
-0.18732
-0.18164
-0.17478
-0.09191
-0.16974
0.21458
-0.38944
-0.09397
-0.52231
-0.03810
-0.03532
-0.55605
0.29621
-0.09796
-0.55960
0.19697
0.19682
0.19660
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H20
H21
H22
H23
H24
H25
H26
H27
H28
H29
0.091674
0.110464
0.142537
0.120154
0.136121
0.150257
0.105427
0.102980
0.108512
0.229082
0.147615
0.179439
0.178108
0.146813
0.140600
0.173627
0.170017
0.145350
0.151563
0.366224
0.20871
0.21366
0.23188
0.18916
0.21136
0.22023
0.20943
0.20355
0.19597
0.42554
0.19763
0.20341
0.20790
0.16761
0.18661
0.19775
0.19973
0.19391
0.18595
0.43835
3.4. Thermodynamic properties
The global minimum energies obtained for structure optimization of H3IPI are ca -
704.68625 a.u. and -700.1511 a.u. using B3LYP and HF methods, respectively, with 6-
311++G(d,p) basis set without any symmetric constrains. The mean energy difference between
the two computational methods is ca 4 a.u. only. The thermal energies are also in the same trend
with global minimum energies of the H3IPI molecule. The rotational constants are falling in
values from HF to B3LYP method and the entropy values are more eminent in the B3LYP/6-
311++G(d,p) method. The biggest value of zero point vibrational energy of the H3IPI molecule
is 146.95501 (Kcal/Mol) obtained at B3LP/6-311++G(d,p). The charge distribution of a
molecule counts on the dipole moment in the three dimensions and the direction of the dipole
moment in the H3IPI molecule shows the focus on the positive and negative charges.
The thermodynamic parameters, heat capacity (C), entropy (S) and enthalpy changes (ꢁH)
of H3IPI by DFT/B3LYP method at different temperatures and 1.00 atm pressure were obtained
from the theoretical harmonic frequencies are listed in Table 3. These thermodynamic functions
are changing with temperature ranging from 100 to 1000 K due to the fact that the molecular
vibrational wavenumbers increase with temperature [24]. Correlation equations between heat
capacities, entropies, enthalpy changes and temperatures were fitted by quadratic polynomial
formulas, and the corresponding fitting factors (R2) for these thermodynamic properties are
0.999967, 0.9999 and 0.9999, respectively. The corresponding fitting equations are as follows
and their correlation graphics are illustrated in Figure 4.
10

ACCEPTED MANUSCRIPT
C=1.07395+0.21048 T−8.53284x10−5 T2
S=61.35032+0.21623 T−4.40243x10−5 T2
(R2 =0.99967)
(R2 =0.99995)
(6)
(7)
(8)
ꢁH=−1.2347+0.01048 T+7.14841x10−5 T2 (R2 =0.99906)
The thermodynamic data furnished helpful information for further study on the H3IPI
molecule. The thermodynamic data can be used to compute the early thermodynamic energies
according to the relationships of thermodynamic functions and calculate directions of chemical
reactions according to the second law of thermodynamics in the thermo chemical field [25].
Table 3: Thermodynamic properties at different temperatures of H3IPI at the B3LYP/6-
311++G(d,p) level.
Temperature Heat capacity Entropy
Enthalpy changes
1.347
100
200
300
400
500
600
700
800
900
1000
21.654
39.292
56.846
70.560
85.316
97.643
106.452
114.339
121.550
126.197
82.808
102.236
122.740
140.396
158.777
175.196
191.087
206.222
220.289
233.530
3.213
7.826
14.160
21.613
30.649
41.105
54.629
65.976
79.926
3.5. Ultraviolet spectra analysis and Frontier molecular orbitals (FMOs)
The highest occupied molecular orbitals (HOMOs) and the lowest-lying unoccupied
molecular orbitals (LUMOs) are named as frontier molecular orbitals (FMOs). The FMOs play a
key role in the optical and electric properties, as well as in UV–Vis spectra of the molecules [26].
Gauss-Sum 2.2 program [27] was used to calculate group contributions to the molecular orbital
(HOMO and LUMO) of the H3IPI molecule as shown in Figure 5. The HOMO represents the
power to give an electron, while LUMO as an electron acceptor represents the ability to obtain
an electron. The gap between HOMO and LUMO energies determines the kinetic stability,
chemical responsiveness, optical polarization and chemical hardness–softness of the molecule.
In order to measure the energetic behavior of H3IPI, the calculations were carried out in
11

ACCEPTED MANUSCRIPT
acetonitrile, chloroform, toluene and ethanol. According to the probe of FMO energy levels of
the H3IPI molecule, the corresponding electronic shifts between HOMO and LUMO as well as
between HOMO-1 and LUMO+1 can be found. The energies of the four important molecular
orbitals (the highest occupied MO’s (HOMO and HOMO−1) and the lowest unoccupied MO’s
(LUMO and LUMO+1)) of H3IPI were calculated using B3LYP/6-311++G(d,p) and presented
in Table 4. The calculated HOMO energy value of H3IPI is -6.1819, -6.1328, -6.0816 and -
6.1784 eV in acetonitrile, chloroform, toluene and ethanol, while its LUMO is -1.1767, -1.1829,
-1.1946 and -1.1770 eV, respectively. The value of the energy gap between the HOMO and
LUMO is -5.0052, -4.9499, -4.8870 and -5.0014 eV in acetonitrile, chloroform, toluene and
ethanol, respectively.
Table 4: Calculated energy values of H3IPI in acetonitrile, chloroform, toluene and ethanol
using B3LYP/6-311++G(d,p).
Parameter
Acetonitrile Chloroform Toluene
Ethanol
Etotal (Hartree)
EHOMO (eV)
ELUMO (eV)
-704.529
-6.1819
-1.1767
-5.0052
-6.3253
-0.1653
-6.1600
2.5026
3.6793
0.8511
4.8683
-704.525 -704.522 -704.529
-6.1328
-1.1829
-4.9499
-6.3286
-0.1735
-6.1551
2.4749
3.6579
0.8372
4.7206
-6.0816
-1.1946
-4.8870
-6.3392
-0.1873
-6.1518
2.4435
3.6381
0.8205
4.5647
-6.1784
-1.1770
-5.0014
-6.3253
-0.1659
-6.1594
2.5007
3.6777
0.8501
4.8584
∆EHOMO-LUMO gap (eV)
EHOMO-1 (eV)
ELUMO+1 (eV)
∆
EHOMO-1-LUMO+1 gap (eV)
Electronegativity (eV)
Chemical hardness (eV )
Electrophilicity index (eV )
Dipole moment (Debye)
χ
η
ψ
The energy break of HOMO–LUMO explains the charge shift interaction within H3IPI,
which influences its biological activity. 3D plots of the HOMO and LUMO orbitals of H3IPI
computed at the B3LYP/6-311++G(d,p) level are illustrated in Figure 5. The red color indicates
positive sites, while the green color indicates the negative ones. It is authorizing that, while the
HOMO is placed on the whole H3IPI molecule especially localized on the imidazole ring and
CNO group, the LUMO is placed on the benzene ring CNO and CH2 groups. The
HOMO
→LUMO transition implies an electron density transfer from oxygen atom.
The value of electronegativity, chemical hardness and electrophilicity index of H3IPI in
acetonitrile are 2.5026, 3.6793 and 0.8511 eV, respectively, which are higher than the values
12

ACCEPTED MANUSCRIPT
calculated in chloroform, toluene and ethanol. The dipole moment in a molecule is another
important electronic property. For example, the bigger the dipole moment, the stronger will be
the intermolecular interactions. The calculated dipole moment values for the title molecule are
also given in Table 4. Based on the predicted dipole moment values, it was found that, the
highest value (4.8683 Debye) was obtained in acetonitrile.
Ultraviolet spectra analyses of H3IPI have been investigated in acetonitrile, chloroform,
toluene and ethanol by theoretical calculations. On the basis of fully optimized ground-state
structure, TD-DFT/B3LYP/6-311++G(d,p) calculations have been used to determine the low-
lying excited states of H3IPI. The theoretical electronic excitation energies, oscillator strengths
and absorption wavelengths of H3IPI are listed in Table 5 and its theoretical as well as
experimental UV spectra are presented in Figure S2. Calculations of the molecular orbital
geometry of H3IPI showed that its absorption maxima corresponds to the electron transition
between frontier orbitals such as translation from HOMO to LUMO. As can be seen from Table
5, the calculated absorption maxima values have been found to be 272.75, 252.55, 251.91,
237.83 and 220.49 nm for acetonitrile, 276.36, 252.75, 252.64, 238.28 and 222.81 nm for
chloroform, 280.44, 253.13, 252.66, 238.82 and 225.49 nm for toluene and 272.99, 252.57,
252.05, 237.87 and 220.63 nm for ethanol at DFT/B3LYP/6-311++G(d,p) level.
Table 5: Theoretical electronic absorption spectra of E3IYLPI absorption wavelengths λ (nm),
excitation energies E (eV) and oscillator strengths ( f )) using TD-DFT/B3LYP/6-311++G(d,p)
method in different solvents.
Solvent E (eV)
λ (nm)
( f )
4.5457eV 272.75nm f=0.0058
4.9094 eV 252.55nm f=0.0374
Acetonitrile 4.9217eV 251.91 nm f=0.3606
5.2131eV 237.83nm f=0.0050
5.6232eV 220.49nm f=0.0240
4.4864 eV 276.36 nm f=0.0057
4.9054 eV 252.75 nm f=0.2418
Chloroform 4.9075 eV 252.64 nm f=0.1729
5.2033eV 238.28 nm f=0.0064
5.5645 eV 222.81nm f=0.0045
4.4211 eV 280.44 nm f=0.0055
4.8980 eV 253.13 nm f=0.2892
Toluene
4.9071 eV 252.66 nm f=0.1326
5.1916 eV 238.82 nm f=0.0086
13

ACCEPTED MANUSCRIPT
5.4984 eV 225.49 nm f=0.0032
4.5418 eV 272.99 nm f=0.0058
4.9090 eV 252.57 nm f=0.0444
4.9190 eV 252.05 nm f=0.3565
5.2123 eV 237.87 nm f=0.0051
5.6195 eV 220.63 nm f=0.0178
Ethanol
3.6. Molecular electrostatic potential
A 3D plot of molecular electrostatic potential (MEP) map of H3IPI is illustrated in Figure 6.
This MEP is a plot of electrostatic potential mapped onto the constant electron density surface.
The importance of MEP lies in the fact that the molecular shape as well as the positive, negative
and neutral electrostatic potential regions of the molecule can be displayed in one figure in terms
of color grading which is very useful to generate a relationship between molecular structure and
its physiochemical properties [28, 29]. In addition, the MEP is a useful property to study the
reactivity of the molecule as an approaching electrophile will be attracted to the negative regions
and the nucleophile will attack the positive regions in the molecule. In the majority of MEPs, the
maximum negative regions are indicated as red colors, while the positive regions are indicated as
blue colors. The negative electrostatic potential is preferred on nitrogen occupied regions, while
the positive electrostatic potential is preferred on (CH2)2 occupied regions.
The different values of the electrostatic potential at the surface of the H3IPI molecule are
represented by different colors. The potential increases in the order red < orange < yellow <
green < blue. The color code of the H3IPI map is in the range between -0.05929 a.u. (deepest
red) to 0.05929 a.u. (deep blue color). Where the blue color indicates the strongest attraction and
the red color indicates the strongest repulsion. The electron density (ED) value of H3IPI was
found to be within the range of -0.01766 to +0.01766 a.u. As can be seen from the MEP map of
the title molecule, while regions having the negative potential are over the nitrogen and oxygen
atoms, the regions having the positive potential are over all hydrogen atoms. The front and side
views of ethylene group in H3IPI have a green color indicating neutral potential.
3.7. Non-Linear optics (NLO) properties
The first hyperpolarizability (
for H3IPI using HF/6-311++G(d,p) basis set on the basis of the finite-field approach. The
complete equations for calculating the magnitude of total static dipole moment ( ), the mean
β), dipole moment (ꢀ) and polarizability (α) were calculated
ꢀ
14

ACCEPTED MANUSCRIPT
polarizability (α0), the anisotropy of the polarizability (∆α) and the mean first polarizability (β0),
using the x, y, z components from Gaussian 03W program output are as follows:
1
(9)
α
=
(α
+ α + α
)
tot
xx
yy
zz
3
1
2
1
2
2
(
)
(
)
∆
α
=
=
[
α xx
−
α yy
+
α yy
−
α zz
+
(
α zz
−
α xx
2 +6α x2z +6α x2y +6α y2z
)
]
(10)
(11)
2
1
2
2
2
2
β
[
(
βxxx
+
βxyy
+
βxzz
)
+
(
β yyy
+
β yzz
+
β yxx
)
+
(
βzzz
+
βzxx
+
βzyy
)
]
The total dipole moment was calculated using the following equation:
1
2
µtot
=
(
µx2
+
µy2
+
µz2
)
(12)
The calculated parameters described above for the title compound were listed in Table 6. It
is well known that the higher values of dipole moment, molecular polarizability, and
hyperpolarizability result in more active NLO properties. The polarizabilities and
hyperpolarizability are reported in atomic units (a.u.), the calculated values have been converted
into electrostatic units (esu) (for α β
, 1 a.u. = 0.1482 x 10-24 esu and for , 1 a.u. = 8.6393 x 10-33
esu). The calculated value of the total dipole moment (µtotal) of H3IPI was found to be 1.8915
Debye. The highest value of dipole moment was observed for component µz (0.0995 D). The
calculated polarizability of H3IPI is 1363.48 x 10-33 esu. The magnitude of molecular
hyperpolarizability (
first hyperpolarizability of the title molecule are about 1.32 and 3.66 times greater than those of
the standard NLO compound, urea ( and
of urea are 1.3732 Debye and 372.8 x 10−33 esu
obtained by HF/6-311++G(d,p) method).
Table 6: The electric dipole moment, polarizability and first hyperpolarizability of H3IPI.
β) is an important key factor in the NLO system. The dipole moment and
ꢀ
β
Parameter
a.u.
196.54
12.86
170.51
3.02
esu (×10−24) Parameter
a.u.
10.816
esu (×10−33
93.44526
-218.966
-428.244
-1161.25
105.1887
-143.947
-332.238
86.22042
-89.2461
)
αxx
αxy
αyy
αxz
αyz
αzz
αtotal
µx
29.12781
1.90606
25.2698
0.448769
-0.24436
16.23113
19.002
βxxx
βxxy
βxyy
βyyy
βxxz
βxyz
βyyz
βxzz
βyzz
-25.345
-49.569
-134.145
12.1756
-16.661
-38.456
9.9800
-1.64
109.85
128.221
-1.5816
-0.8939
µy
-10.330
15

ACCEPTED MANUSCRIPT
µz
µtotal
0.995
1.8915
βzzz
β0
9.0154
157.823
77.88726
1363.48
3.8. Natural bond orbital (NBO) analysis
Natural bond orbital (NBO) analysis has been expressed away to explain the delocalization
of charges due to interactions among bonds, and also it provides a convenient basis for looking
into conjugative interactions in molecular systems. The presence of electron donor orbitals and
electron acceptor orbitals in the molecular system gives rise stabilization energy resulting from
the second-order micro disturbance theory is reported [30]. The greater the stabilization energy
value, the more intensive is the fundamental interaction between electron donors and electron
acceptors, i.e. the more donating trend from electron donors to electron acceptors and the greater
the extent of junction of the whole system. Delocalization of electrons concentration between
occupied Lewis-type (bond or lone pair) NBO orbitals and formally unoccupied (anti bond or
Rydberg) non-Lewis NBO orbitals is corresponding to the stabilizing donor–acceptor interaction.
These interactions were observed in case of increasing the ED in C-C anti-bonding orbital that
weakens the respective bonds. These intramolecular charge transfer (σ→σ* π→π*) can induce
,
large nonlinearity of the molecule.
The strong intramolecular hyperconjugation interactions of
σ and π electrons of the C-C, C-
H, C-N and N-C bonds to the anti C-C, C-H, C-N and N-C bonds lead to stabilization of some
parts of the H3IPI molecule as evident from Table 7. NBO analysis has been performed on the
title molecule at the B3LYP/6-311++G(d,p) level in order to elucidate its intramolecular
hyperconjugation interactions, re-hybridization and delocalization of the electron density within
the molecule. The interaction was formed by the orbital convergence between the bonding (C-C)
and the anti-bond (C-C) orbital which results intramolecular charge transfer (ICT) causing
stabilization of the system. These interactions were observed as an increase in the electron
density in the C–C anti-bonding orbital that weakens the respective bonds. The solid
intramolecular hyperconjugative interaction of the
C6, C1–H17, C2–C3, C2–H18, C3–H19 and C6–H21) of the aromatic moiety of H3IPI. On the other
hand, the
(C1–C6) in the aromatic ring conjugates to the anti-bonding orbital of π*(C2–C3 and
C4–C5) leading to strong delocalization of 0.28 kJ/mol. The (C2-C3) is interacting with
∗(C1-C6
and C4-C5) with the energies 0.29 and 0.28 kcal/mol, respectively. The (C1–C6) is contributing
(C2–C3) is contributing energy
σ
electrons of (C1–C2) distributed to σ*(C1–
π
π
π
π
energy by 0.28 kcal/mol with π*(C2–C3). In a reverse trend, the
π
16

ACCEPTED MANUSCRIPT
by 0.29 kcal/mol with π*(C1–C6). Similarly, the
σ
(C7-N15) is acting with σ*(C4–C5, C5–C7, C7–C8
and O16–H29) with energy values of 1.48, 1.37, 1.31 and 1.32 kcal/mol, respectively. The σ(N10-
C11 and N10-C14) are acting with σ*(C9–N10 and N13–C14) with values of 1.12, 1.36 and 1.14,
1.38 kcal/mol, respectively. The LP(1) of N15 and O16 are moving with LP*(1)(C5-C7) with
values of 0.89 and 1.15 kcal/mol, respectively.
Table 7: Second order perturbation theory analysis of Fock matrix in NBO basis for H3IPI.
Donor (i)
Type
of
Occupancy Acceptor (j) Type
Occupancy E2
(kJ.mol−1)a
E(j) −E(i) (a.u.)b F(i, j) (a.u.)c
of
bond
σ
bond
C1-C2
1.97923
1.97801
C1-C6
C1-H17
C2-C3
C2-H18
C3-H19
C6-H21
C1-C2
C1-H17
C2-H18
C5-C6
C5-C7
C6-H21
C2-C3
C 4-C5
C1-C2
C1-H17
C2-H18
C3-C4
C3-H19
C4-H20
C1-C6
C4-C5
C3-C4
C3-H19
C4-H20
C5-C6
C5-C7
C6-H21
C7-N15
C1-C6
C2-C3
C7-N15
C1-C6
C1-H17
C4-C5
C4-H20
C5-C7
C6-H21
C7-C8
C1-C6
C3-C4
C4-C5
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
*
*
*
*
*
*
*
*
*
*
*
*
0.01587
0.01468
0.01686
0.01457
0.01440
0.01457
0.01728
0.01468
0.01457
0.02473
0.03480
0.01457
0.32273
0.37586
0.01728
0.01468
0.01457
0.01599
0.01440
0.01487
0.29363
0.37586
0.01599
0.01440
0.01487
0.02473
0.03480
0.01457
0.01864
0.29363
0.32273
0.17579
0.01587
0.01468
0.02436
0.01487
0.03480
0.01457
0.03423
0.01587
0.01599
0.02436
3.07
1.09
2.96
1.10
2.52
2.39
3.08
1.14
2.36
3.66
3.60
1.20
20.72
20.10
2.94
2.43
1.13
3.14
1.15
2.44
19.09
20.66
3.44
2.12
1.30
4.33
2.81
2.26
1.46
18.78
19.89
15.99
3.25
2.22
4.42
2.67
2.95
1.19
2.42
2.01
2.27
2.49
1.28
1.14
1.27
1.14
1.14
1.16
1.27
1.15
1.15
1.26
1.16
1.16
0.28
0.28
1.27
1.15
1.15
1.28
1.14
1.14
0.29
0.28
1.27
1.14
1.14
1.25
1.15
1.15
1.28
0.29
0.29
0.27
1.27
1.13
1.25
1.13
1.14
1.15
1.08
1.24
1.23
1.22
0.056
0.031
0.055
0.032
0.048
0.047
0.056
0.032
0.046
0.061
0.058
0.033
0.068
0.068
0.055
0.047
0.032
0.057
0.032
0.047
0.067
0.069
0.059
0.044
0.034
0.066
0.051
0.046
0.039
0.067
0.068
0.062
0.058
0.045
0.066
0.049
0.052
0.033
0.046
0.045
0.047
0.049
C1-C6
σ
C1-C6
C2-C3
π
σ
1.66685
1.97907
π
π
*
*
σ
σ
σ
σ
σ
σ
*
*
*
*
*
*
C2-C3
C4-C5
π
σ
1.66136
1.97263
π
π
*
*
σ
σ
σ
σ
σ
σ
σ
*
*
*
*
*
*
*
C4-C5
C5-C6
π
σ
1.65090
1.97086
π
π
π
*
*
*
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
*
*
*
*
*
*
*
*
*
*
C5-C7
σ
1.96109
17

ACCEPTED MANUSCRIPT
C5-C6
C7-C8
C7-N15
N15-O16
C5-C6
C5-C7
C7-N15
C8-C9
C8-H22
C8-H23
C9-N10
N15-O16
C4-C5
C5-C7
C7-C8
O16-H29
C5-C7
C7-C8
C7-N15
C8-H22
N10-C11
N10-C14
C7-C8
N10-C11
N10-C14
C11-C12
N13-C14
C9-N10
N10-C14
C11-C12
C12-N13
C12-H27
N13-C14
C14-H28
C9-N10
C9-H24
N10-C11
C11-H26
N13-C14
C9-N10
N10-C11
C11-H26
C12-N13
C12-H27
N10-C11
N10-C14
C11-C12
C11-H26
N13-C14
C14-H28
C9-N10
N10-C14
C12-N13
C12-H27
C14-H28
C7-C8
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
σ
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
*
0.02473
0.03423
0.01864
0.02145
0.02473
0.03480
0.01864
0.02218
0.01514
0.01317
0.02891
0.02145
0.37586
0.03480
0.03423
0.00375
0.03480
0.03423
0.01864
0.01514
0.02391
0.04246
0.03423
0.01514
0.04246
0.01880
0.00912
0.02891
0.04246
0.01880
0.01133
0.01804
0.00912
0.02233
0.02891
0.01345
0.02391
0.01266
0.00912
0.02891
0.02391
0.01266
0.01133
0.01804
0.02391
0.04246
0.01880
0.01266
0.00912
0.02233
0.02891
0.04246
0.01133
0.01804
0.02233
2.79
1.31
2.35
5.23
2.29
2.00
1.80
0.71
0.59
0.60
2.33
0.64
1.77
2.27
2.03
0.51
1.04
0.97
3.25
0.59
0.53
1.28
1.29
1.47
1.39
0.75
0.86
1.70
2.17
1.25
0.66
3.03
0.62
2.66
1.86
0.52
2.12
2.67
0.67
5.86
0.98
2.06
0.59
1.51
0.96
1.19
1.20
3.41
0.62
5.15
3.80
0.83
0.61
3.23
1.13
0.61
1.21
1.05
1.24
0.87
1.20
1.10
1.23
0.99
1.05
1.05
0.98
0.86
1.48
1.37
1.31
1.32
1.07
1.02
0.64
1.03
1.07
1.08
1.16
1.22
1.23
1.36
1.34
1.12
1.25
1.38
1.29
1.24
1.36
1.21
1.14
1.19
1.25
1.24
1.38
1.04
1.15
1.14
1.20
1.16
1.20
1.21
1.34
1.18
1.32
1.17
1.15
1.28
1.32
1.27
1.24
0.65
0.052
0.033
0.048
0.060
0.047
0.042
0.042
0.024
0.022
0.022
0.043
0.021
0.046
0.050
0.046
0.023
0.030
0.028
0.042
0.022
0.021
0.033
0.035
0.038
0.037
0.029
0.030
0.039
0.047
0.037
0.026
0.055
0.026
0.051
0.041
0.022
0.046
0.051
0.027
0.070
0.030
0.043
0.024
0.037
0.030
0.034
0.036
0.057
0.026
0.069
0.059
0.029
0.025
0.057
0.033
0.020
C7-C8
σ
1.97455
C7-N15
C8-C9
σ
σ
1.98928
1.96602
C9-N10
σ
σ
1.98650
1.98151
N10-C11
N10-C14
C11-C12
C12-N13
σ
σ
σ
1.98610
1.98384
1.97842
N13-C14
N10
σ
1.98504
1.55892
LP(1)
LP*(1) 0.03423
18

ACCEPTED MANUSCRIPT
C8-C9
LP*(1) 0.02218
LP*(1) 0.01345
LP*(1) 0.01740
LP*(1) 0.02891
LP*(1) 0.04246
LP*(1) 0.01880
LP*(1) 0.01804
LP*(1) 0.02233
LP*(1) 0.03480
LP*(1) 0.03423
LP*(1) 0.00375
LP*(1) 0.03480
LP*(1) 0.01317
5.89
0.61
3.07
0.59
8.34
5.50
2.19
2.23
0.63
9.46
0.75
0.63
0.73
0.60
0.65
0.66
0.68
0.81
0.94
0.80
0.77
0.89
0.83
0.84
1.15
1.10
0.060
0.020
0.045
0.018
0.074
0.065
0.038
0.037
0.021
0.079
0.023
0.024
0.025
C9-H24
C9-H25
C9-N10
N10-C14
C11-C12
C12-H27
C14-H28
C5-C7
N13
LP(1)
1.92363
N15
O16
LP(1)
LP(1)
1.95757
1.99274
C7-C8
O16-H29
C5-C7
C8-H23
a E(2) means energy of hyper conjugative interactions; b Energy difference between donor and acceptor i. and j. NBO orbitals; c F(i,
j) is the Fock matrix element between i .and j. NBO orbitals.
3.9. NMR spectra and calculations
The experimental and theoretical 1H and 13C NMR chemical shifts of H3IPI are described in
ppm relative to TMS and the data are presented in Table 8 and their spectra are shown in Figures
S4 and S5. Full geometry optimization of H3IPI was firstly carried out at the gradient corrected
density functional level of theory using the hybrid B3LYP method based on Becke’s three
1
13
parameters functional of DFT. Thereafter, gauge-including atomic orbital (GIAO) H and C
chemical shift calculations of H3IPI was performed by the same method using 6-311G++(d,p)
basis set IEFPCM/CDCl3 solution.
Table 8: Experimental and theoretical probable 13C and 1H NMR chemical shifts of the H3IPI
molecule.
Atom* Experimental Theoretical Atom* Experimental Theoretical
C1
C2
C3
C4
C5
C6
C7
C8
128.9
135.1
128.9
128.8
137.0
128.8
155.4
28.3
132.7
133.3
131.5
128.5
137.6
131.4
160.7
32.4
H17
H18
H19
H20
H21
H22
H23
H24
H25
H26
H27
H28
7.3
7.4
7.3
7.5
7.5
3.3
3.3
4.3
4.3
6.9
7.1
7.6
6.8
7.1
7.0
7.1
7.1
3.3
2.1
3.5
4.1
6.6
6.6
7.7
C9
41.8
44.0
C11
C12
C14
119.1
126.1
139.5
120.6
128.3
139.8
* Atoms positions are numbered as in Figure 1.
19

ACCEPTED MANUSCRIPT
The aromatic ring carbon atoms committed signals in the covered areas of the 13C spectrum
with chemical shift values from 128.5-137.6 ppm, while their corresponding experimental values
were observed in the range of 128.8-137.0 ppm. The highest experimental chemical shift values
were noticed for C7 and C14 carbon atoms at 155.4 and 139.5 ppm, respectively. On the other
hand, the lowest chemical shift values were observed for C8 and C9 carbon atoms at 28.3 and
41.8 ppm, respectively.
The aromatic ring hydrogens of H3IPI were accumulated in the range of 6.8-7.1 ppm
(B3LYP) and are experimentally observed in the range of 7.3-7.5 ppm. The performance of the
B3LYP method with respect to the prediction of the NMR chemical shifts within the H3IPI
molecule is quite close to the experimental values.
3.10. Vibrational analysis
The maximum number of potentially active observable fundamentals of a non-linear
molecule containing N atoms is equal to (3N-6), apart from three translational and three
rotational degrees of freedom [31]. The H3IPI molecule is planar with 29 atoms and 81 normal
modes of vibrations and it is considered under Cs point group symmetry. The fundamental modes
are distributed in the Cs symmetry species as: Γvib = 55A
′+26A″. Here A′ represents symmetric
planer and A asymmetric non-planer vibrations. All vibrations are active in both Raman and
″
infrared absorptions. The detailed vibrational assignments of the experimental wavenumbers are
based on normal mode analyses of the title compound. The scaled wavenumbers following
B3LYP/6-311++G(d,p) method were found to be closer to the experimental data than the results
obtained using HF method. The observed and simulated FT-IR and FT-Raman spectra of H3IPI
are shown in Figures 7 and 8, respectively. The observed and scaled theoretical frequencies using
HF/6-311++G(d,p) and DFT/B3LYP/6-311++G(d,p) basis sets with their potential energy
distributions (PEDs) are listed in Table 9.
Table 9: Detailed assignments of theoretical and experimental wavenumbers of H3IPI along
with their potential energy distributions (PEDs) assignments.
B3LYP/6-311++G(d,p)
HF/6-
311++G(d,p)
scaled
Serial
number
FT-IR
FT-Raman
IIR
147.03
1.28
4.35
3.12
SRaman
163.60
94.08
unscaled
3835
3265
scaled
3674
3128
3102
3095
3072
assignments
1
2
3
4
5
3238
3148
3116
3805
3148 3126
3101
3090
3063 3078
γOH
γCH
γCH
γCH
γCH
107.87
37.32
3238
3231
3.47
110.43
3206
20

ACCEPTED MANUSCRIPT
6
7
8
9
3061
3052
3041
11.84
25.20
5.05
1.08
9.16
0.08
20.03
5.29
4.42
0.56
227.40
58.43
136.20
41.80
1.97
3193
3185
3174
3166
3125
3105
3075
3063
1677
1639
1612
1535
1528
1527
1503
1488
1473
1413
1402
1393
1382
1355
1332
1317
1310
1301
1279
1258
1207
1185
1181
1139
1109
1094
1086
1048
1046
1029
1023
1015
1010
991
3059
3051
3041
3033
2994
2974
2946
2934
1648
1611
1585
1509
1502
1501
1477
1462
1448
1389
1378
1369
1359
1332
1310
1295
1287
1279
1258
1237
1187
1165
1161
1120
1090
1075
1067
1030
1028
1012
1006
998
γ
γ
γ
γ
γ
γ
γ
γ
β
γ
γ
γ
γ
γ
CH
CH
CH
CH
CH
CH
CH
CH
OH
CC
CC
CC
CC
CC
3049
3002
3022 3031
2997
2974 2979
2859 2944
2933
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
52.75
4.39
132.42
94.29
259.14
18.56
5.44
12.68
21.90
4.30
1644
1600
1574
1749
1623 1640
1597 1611
1515 1566
1531
1497 1514
1476 1486
1475
1456
1400 1408
1399
1.99
28.56
22.61
21.35
10.86
50.91
3.99
1507
1474
1455
1441
γCN
γCN
γCN
γCN
γCN
γNO
16.48
4.35
3.58
16.62
79.12
40.51
32.33
2.77
4.08
2.38
13.23
20.40
34.73
5.92
4.62
6.07
23.96
6.82
1.24
17.36
8.66
39.10
3.21
18.95
24.21
1.99
2.61
12.30
0.60
51.37
20.25
65.56
40.69
2.89
0.34
1.68
18.83
3.78
18.18
27.00
10.38
10.44
49.65
7.81
1368
1351
1369 1390
1344 1386
1335
γ
γ
γ
CC
CC
CC
CC
CH
CH
CH
OH
CH
CH
CH
CH
CN
CN
CN
CN
1313
1296
1309
1300
1287
γ
β
β
β
φ
β
β
β
β
β
β
β
β
1277
1255
1279 1260
1247
1230 1214
1185 1180
1164 1160
1158 1112
1108
1102 1086
1077
1076
1050
1027 1024
1024
1016
998 1011
1004
988
924 959
951
908
854 903
876
1184
1105
1079
1040
1024
βNO
1.10
β
β
β
β
β
β
β
CN
CN
CH
CH
CH
CH
CH
21.37
56.12
0.82
0.25
2.36
0.50
1.38
1.75
1.31
997
972
1.28
0.71
0.42
123.71
12.30
8.09
2.42
0.27
992
974
926
921
902
855
841
832
942
937
917
870
855
846
810
924
893
852
βCCC
βCCC
βCCC
823
780
867
831
6.63
30.74
2.80
0.55
βNO
796
βCCC
21

ACCEPTED MANUSCRIPT
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
768 780
768
24.36
19.92
31.14
14.45
39.73
14.41
26.79
4.74
2.74
14.49
3.45
24.15
88.65
1.58
2.92
0.92
1.28
1.78
1.17
0.26
1.45
1.01
2.29
0.52
1.62
1.70
0.26
0.10
3.58
0.69
2.91
8.69
2.70
1.41
1.32
0.15
2.76
0.59
0.47
3.59
0.72
1.31
2.02
3.00
1.05
1.44
0.92
2.02
3.08
785
772
732
730
705
673
658
644
634
623
513
462
422
412
401
357
326
300
297
210
156
122
89
771
759
720
717
693
661
646
633
623
612
504
454
415
405
394
351
321
295
292
206
153
120
88
βCCC
758
φ
CH
CH
CH
CH
CH
CH
CH
CN
CN
CN
CH
CN
CN
CH
NO
CH
CH
761
711
700
φ
φ
φ
φ
φ
φ
φ
φ
φ
φ
φ
φ
φ
φ
φ
φ
699
672
671 661
654 645
635
625
600
514
619
610
510
440
429 412
390
398 370
348
312 318
307
288
φCCC
φCCC
φCCN
φCCC
φCNC
φCNC
φCNC
φCCN
φCCN
223 206
144 152
102 123
87 92
76 81
37
1.44
1.43
1.45
0.87
78
36
28
21
77
36
27
21
80
81
30
25
0.33
γ
: stretching;
β: in-plane bending; φ: out-of-plane bending; IIR: IR intensity; S Raman: Raman scattering activity.
3.10.1. O–H vibrations
The OH group gives rise to three vibrations namely, stretching, in-plane bending and out-
of-plane bending vibrations. They are likely to be the most sensitive to the environment, so they
show pronounced shifts in the spectra of the hydrogen-bonded species. In case of un-substituted
phenols, it has been shown that the frequency of OH stretching vibration in the gas phase
appeared around 3657 cm−1 [32]. The H3IPI molecule manifested a weak band in its FT-IR
spectrum at 3208 cm−1, which was assigned to OH stretching vibration. A comparison of this
band with the literature data predicted that there is a negative deviation of about 300 cm−1. This
might be due to inter-molecular hydrogen bonding. The in-plane and out-of-plane bending
vibrations were observed at 1644 and 1230 cm−1, respectively.
3.10.2. C-H vibrations
22

ACCEPTED MANUSCRIPT
The aromatic derivatives give rise to C-H stretching, C-H in-plane and C-H out-of-plane
bending vibrations. Aromatic compounds commonly exhibit multiple weak bands in the region
3100–3000 cm−1 [33] due to aromatic C-H stretching vibrations and they are not appreciably
affected by the nature of the substituents [34]. The C–H vibrations of the title compound were
observed as very weak bands at 3148, 3116, 3049 and 3002 cm−1 in its FT-IR spectrum and at
3148, 3063, 3022, 2974 and 2859 cm−1 in its FT-Raman spectrum. This mode was calculated in
the range of 3038-3011 cm-1 with B3LYP/6-311++G(d,p) and in the range of 2934-3128 cm-1
with HF method. As expected, these modes (2-12 modes) are pure stretching modes as it is
evident from the PED assignment column.
The bands due to C-H in-plane bending vibrations appeared in the region of 1000–1300
cm−1 [35]. The C-H in-plane bending vibrations of H3IPI were noted at 1277, 1255, 1184, 1105,
997 and 972 cm−1 in the FT-IR spectrum and at 1279, 1164, 1158, 998 and 924 cm−1 in its FT-
Raman spectrum. The theoretically scaled vibrations by B3LYP/6-311++G(d,p) level method
showed good agreement with experimentally recorded data.
The C-H out-of-plane bending vibrations usually occur within the region of 980-717 cm−1
[35]. This vibration mode was identified at 758, 699 and 672 cm−1 in the FT-IR spectrum of the
H3IPI molecule and at 671, 654 and 398 in its FT-Raman spectrum.
3.10.3. Ring vibrations
The aromatic ring stretching vibrations are expected within the region of 1300-1000 cm−1
[36]. Most of the aromatic ring modes are altered by ring substitutions. The bands with different
intensities were observed at 1600, 1574, 1507, 1351, 1313 and 1296 cm-1 in the FT-IR spectrum
and at 1597, 1515, 1497 and 1344 cm-1 in the FT-Raman spectrum have been assigned to C-C
stretching vibrations of the H3IPI molecule. All these vibrations appeared with mixed modes in
the PED except three as evident by their strong intensities. The in-plane deformations were
observed as expected at higher frequencies than the out-of-plane vibrations. The theoretical
values exhibited excellent agreement with experimental ones.
3.10.4. C-N vibrations
The identification of C–N vibration bands is a very difficult task due to their overlapping
with other several bands. Silverstein [37] assigned C–N stretching absorption in the region of
1382–1266 cm-1. These vibration bands occurred at 1474, 1455 and 1441 cm-1 in the FT-IR
spectrum of H3IPI and were observed at 1476 and 1400 cm-1 in its FT-Raman spectrum.
23

ACCEPTED MANUSCRIPT
The C-N in-plane bending vibrations of H3IPI appeared at 1102 in its FT-Raman spectrum
and at 1079 and 1040 cm−1 in its FT-IR spectrum. The theoretically scaled vibrations by
B3LYP/6-311++G(d,p) level method also showed good agreement with experimentally recorded
data.
The C-N out-of-plane bending vibrations usually appear within the region of 980-717 cm−1 .
These vibrations were identified at 625, 600 and 514 cm−1 in FT-IR spectrum of H3IPI and at
429 cm−1 in its FT-Raman spectrum.
3.10.5. N-O vibrations
The characteristics group frequencies of the NO2 group are independent on the rest of the
molecule. In addition, wagging and twisting modes would be expected to be depolarized for out-
of-plane vibrations. Aromatic nitro compounds have strong absorptions due to stretching
vibrations of the NO2 group at 1570-1485 cm-1 and 1370-1320 cm-1 [38]. The NO stretching
mode of H3IPI was identified at 1368 in its FT-IR spectrum and at 1369 cm-1 in its FT-Raman
spectrum. The in-plane bending modes of the NO group of H3IPI were assigned at 1024 and
1027 cm-1 in its FT-IR and FT-Raman spectra, respectively.
3.11. Error analysis of different vibrational calculations
The unscaled theoretical wavenumbers of the H3IPI molecule are overestimated and hence
were scaled by different scaling factors. This is quite obvious, since the calculated frequencies
are harmonic in nature, whereas the experimental frequencies may involve anharmonicity. In
order to reduce the standard deviation between the unscaled and observed fundamentals, overall
scale factors were used. A close agreement between the experimental and scaled wavenumbers is
mostly achieved in the fingerprint region. Both HF and DFT (B3LYP) methods showed a
uniform deviation after scaling, but the HF method manifested more deviation than the DFT
(B3LYP) method. The correlation between the calculated and experimental frequencies using
both HF and DFT (B3LYP) methods are linear (Figure S3) and is described by the following
equations:
B3LYP
∂cal=−19.03218+1.02191 ∂exp
(R2 =0.99598)
(12)
HF
24

ACCEPTED MANUSCRIPT
∂cal=−17.1797+1.02827 ∂exp
(R2 =0.99310)
(13)
Therefore, the calculated frequencies by B3LYP/6-311++G(d,p) method seem to be more
closer to the experimental values than that calculated by the HF method.
4. Conclusions
The title compound H3IPI is an oxime-bearing precursor to potential antifungal agents
and has been thoroughly characterized with various spectroscopic tools. Perfect normal co-
ordinates of the title molecule were performed using DFT-B3LYP and HF methods with 6-
311++G(d,p) basis set. The calculated frequencies of H3IPI by B3LYP/6-311++G(d,p) method is
good fitted with the experimental values. The experimental X-ray diffraction data are quite close
to the optimized values. The calculated bond angles values of H3IPI suggest that the ring of the
molecule is deformed which might be due to steric and electronic factors. All hydrogen atoms of
H3IPI manifested positive natural charges which are greater in values than their corresponding
Mulliken charges. The correlation equations between heat capacities, entropies, enthalpy changes
and temperatures are represented by quadratic polynomial formulas. The energy break of
HOMO–LUMO of H3IPI explains the charge shift interactions within the molecule, which
influences its biological activity. The calculated dipole moment and first hyperpolarizability of
the title molecule are 1.32 and 3.66 times, respectively, as that of urea which gives the possibility
to be a new NLO compound. The molecular orbital coefficient studies of H3IPI proposed that its
electronic spectrum corresponds to the π → π* electronic transition. The NBO analysis has been
executed for the title compound at the B3LYP/6-311++G(d,p) level in order to clarify the
intramolecular, re-hybridization and delocalization of electron density within the molecule. The
performance of the B3LYP method with respect to the prediction of the NMR chemical shifts
within the H3IPI molecule is in a good agreement with the experimental values. The current
comprehensive spectroscopic characterization of H3IPI and the computations thereof could
support pharmacomodulation of the title compound to develop new potent antifungal candidates.
Acknowledgment: The authors would like to extend their sincere appreciation to the Deanship
of Scientific Research at King Saud University for its funding of this research through the
Research Group Project No. RG-1438-083.
25

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