# Spectroscopic Investigations, DFT Calculations, and Molecular Docking Studies of the Anticonvulsant (2E)-2-[3-(1H-Imidazol-1-yl)-1-phenylpropylidene]-N-(4-methylphenyl)hydrazinecarboxamide

Authors: Reem I. Al-Wabli; Devarasu Manimaran; Liji John; Isaac Hubert Joe; Nadia G. Haress; Mohamed I. Attia
Journal: Journal of Spectroscopy
 (2016)

---

## Abstract

Drug discovery for the management of neurological disorders is a challenging arena in medicinal chemistry. Vibrational spectral studies of (2E)-2-[3-(1H-imidazol-1-yl)-1-phenylpropylidene]-N-(4-methylphenyl)hydrazinecarboxamide ((2E)-IPPMP) have been recorded and analyzed to identify the functional groups and intermolecular/intramolecular interactions of the title molecule. The blue shift of the C-H stretching wavenumber reveals the presence of improper C-H⋯O hydrogen bonding. The equilibrium geometry, harmonic vibrational wavenumbers, Frontier orbital energy, and natural bond orbital analyses have been carried out using density functional theory with a B3LYP/6-311++G(d,p) level of the basis set. The vibrational modes have been unambiguously assigned using potential energy distribution analysis. The scaled wavenumbers are in good agreement with the experimental results. Natural bond orbital analysis has confirmed the intermolecular/intramolecular charge transfer interactions. HOMO-LUMO analysis was carried out to explore charge delocalization on the (2E)-IPPMP molecule. A molecular docking study has supported the anticonvulsant activity of the title molecule.


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## Body

## 1. Introduction

Epilepsy is a rather neurobiological group of disorders. It has multiple origins and aspects depending upon the affected brain areas. It affects nearly 50 million people of the world’s population [1–3]. The hydrazinecarboxamide derivatives have a wide spectrum of biological activities. Among these activities are anticancer and antioxidant [4], antifertility [5], antimicrobial [6, 7], anticonvulsant [8, 9], and anti-inflammatory [10] activities. The title molecule (2E)-2-[3-(1H-imidazol-1-yl)-1-phenyl-propylidene]-N-(4-methylphenyl)hydrazinecarboxamide ((2E)-IPPMP) was synthesized in our laboratory and its crystal structure was previously reported [11]. (2E)-IPPMP exhibited anticonvulsant activity with 83% and 50% seizure protection at a dose level of 718 μmol/kg in subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock seizure (MES) screens, respectively, without any neurotoxicity [9].Literature screening indicated that computational studies on the (2E)-IPPMP molecule have not yet been reported. Therefore, detailed investigations of structural properties and vibrational spectral analysis of the (2E)-IPPMP molecule were carried out in the present study using density functional theory (DFT) computations. Moreover, the biological activity of the title molecule has been predicted by molecular docking analysis. It is expected that the current investigations might support the development of new potent anticonvulsant agents.


## 2. Experimental

### 2.1. General

Melting point was recorded on a Gallenkamp melting point instrument and it is uncorrected. The Fourier transform infrared spectrum of MMIMI was recorded on a Perkin Elmer RXL spectrometer (Waltham, Massachusetts, USA) in the region 4000–400 cm−1, with samples in the KBr pellet method. The resolution of the spectrum was 2 cm−1. The FT-Raman spectrum was measured in the range 3500–50 cm−1 using a Bruker RFS 100/S FT-Raman spectrophotometer (Ettlingen, Germany) with a 1064 nm Nd:YAG laser source of 100 mW power (Göttingen, Germany).


### 2.2. Synthesis

A solution containingN-(4-methylphenyl)hydrazinecarboxamide [12] (1.65 g, 10 mmol), 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one (2.00 g, 10 mmol) [13], and a few drops of glacial acetic acid in ethanol (15 mL) was stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure and the residue was crystallized from ethanol to give 1.67 g (48%) of the title compound as colorless crystals (m.p. 476–478 K) which were suitable for single crystal X-ray analysis. 1H and 13C NMR as well as the mass spectral data of the title compound2 are in accordance with the previously reported ones [9].


### 2.3. Theoretical Calculations

All DFT calculations of the (2E)-IPPMP molecule were performed using the Gaussian 09 program package [14] at the Becke3-Lee-Yang-Parr (B3LYP) level with a 6-311++G(d,p) basis set [15–17]. The structural parameters were computed in the gas phase as well as in the liquid phase using a polarizable continuum model (PCM) method. In order to correct the overestimations arising from some negative factors such as basis set truncation effect, neglecting electron correlations, and anharmonicity characters of the vibrational modes, the calculated wavenumbers were scaled using a uniform scaling factor of 0.9673 [18, 19]. Theoretical NMR calculation was performed on the basis of the GIAO (gauge-independent atomic orbitals) theory method using a Gaussian program.


## 2.1. General

Melting point was recorded on a Gallenkamp melting point instrument and it is uncorrected. The Fourier transform infrared spectrum of MMIMI was recorded on a Perkin Elmer RXL spectrometer (Waltham, Massachusetts, USA) in the region 4000–400 cm−1, with samples in the KBr pellet method. The resolution of the spectrum was 2 cm−1. The FT-Raman spectrum was measured in the range 3500–50 cm−1 using a Bruker RFS 100/S FT-Raman spectrophotometer (Ettlingen, Germany) with a 1064 nm Nd:YAG laser source of 100 mW power (Göttingen, Germany).


## 2.2. Synthesis

A solution containingN-(4-methylphenyl)hydrazinecarboxamide [12] (1.65 g, 10 mmol), 3-(1H-imidazol-1-yl)-1-phenylpropan-1-one (2.00 g, 10 mmol) [13], and a few drops of glacial acetic acid in ethanol (15 mL) was stirred at room temperature for 18 h. The reaction mixture was evaporated under reduced pressure and the residue was crystallized from ethanol to give 1.67 g (48%) of the title compound as colorless crystals (m.p. 476–478 K) which were suitable for single crystal X-ray analysis. 1H and 13C NMR as well as the mass spectral data of the title compound2 are in accordance with the previously reported ones [9].


## 2.3. Theoretical Calculations

All DFT calculations of the (2E)-IPPMP molecule were performed using the Gaussian 09 program package [14] at the Becke3-Lee-Yang-Parr (B3LYP) level with a 6-311++G(d,p) basis set [15–17]. The structural parameters were computed in the gas phase as well as in the liquid phase using a polarizable continuum model (PCM) method. In order to correct the overestimations arising from some negative factors such as basis set truncation effect, neglecting electron correlations, and anharmonicity characters of the vibrational modes, the calculated wavenumbers were scaled using a uniform scaling factor of 0.9673 [18, 19]. Theoretical NMR calculation was performed on the basis of the GIAO (gauge-independent atomic orbitals) theory method using a Gaussian program.


## 3. Results and Discussion

### 3.1. Synthesis

The target compound (2E)-IPPMP was obtained in a three-step reaction sequence as given in Scheme 1.Scheme 1
Synthesis of the title molecule (2E)-IPPMP. Reagents and conditions: (i) HN(CH3)2·HCl, (CH2O)n, conc. HCl, ethanol, reflux, 2 h; (ii) imidazole, water, reflux, 5 h; (iii)N-(4-methylphenyl)hydrazinecarboxamide, few drops of acetic acid, ethanol, RT, 18 h.


### 3.2. Structural Geometry Analysis

The structure of the (2E)-IPPMP molecule was optimized using the B3LYP method with a 6-311++G(d,p) basis set. The optimized molecular structure of the isolated molecule is shown in Figure 1. The optimized geometrical parameters of the isolated (2E)-IPPMP molecule in the gas and water phases are given in Table 1. The calculated values were compared with the X-ray diffraction results. In the (2E)-IPPMP molecule the two phenyl rings are bridged by a hydrazinecarboxamide skeleton containing an imidazole ring. The C-N bond lengths C17-N16 (1.4179 Å) and C17-N19 (1.3792 Å) are shorter than the normal single C-N bond length 1.480 Å [20]. This discrepancy is due to the conjugation of p-type electrons of the carbonyl group and nitrogen atom, allowing the electrons to smear out along the C-N bond. In thepara-disubstituted phenyl ring, the calculated C25-H44 (1.0789 Å) bond length is shorter than that of the other C-C bonds; also, O18⋯H44 distance is 2.25 Å, which is significantly shorter than the van der Waals radius (2.72 Å) [21] between O and H atoms, which indicates the possibility of C-H⋯O hydrogen bonding. The elongation of the C20-C21 (1.4004 Å) bond is due to the transfer of a lone pair of electrons from the amide nitrogen to the carbon atom. In the other phenyl ring, the C5-H31 (1.0825 Å) bond is shorter than that of the other C-C bonds; also, N15⋯H31 distance is 2.56 Å, which is significantly shorter than the van der Waals radius (2.75 Å) between N and H atoms, which indicates the possibility of C-H⋯O hydrogen bonding. In addition, C5-C6 (1.4024 Å) and C4-C5 (1.4012 Å) bond distances on either side of the cyanide group are appreciably greater than the other C-C bonds due to the resonance effect between the cyanide group and phenyl ring. In the imidazole ring, C14-N10 (1.3676 Å) and C14-N13 (1.3139 Å) bonds are relatively shorter due to the lone pair interaction from the nitrogen atom. The deviation of bond lengths of N15-H39 (1.0123 Å) and N19-H40 (1.0092 Å) is due to the different environment of the nitrogen atom. Conjugation of the carbonyl group with the hydrazine moiety would favor planarity, but the van der Waals repulsion between H39 and H40 hinders the achievement of coplanarity. A small deviation was obtained within the calculated structural parameters in the gas and liquid phases, which were due to the solvent interactions over the solution phase calculations.Table 1
Structural geometry parameters of (2E)-IPPMP compared with their experimental X-ray diffraction results.
Bond length (Å)
Bond angle (°)
Dihedral angle (°)
Parameter
Calc.
Exp.a
Solution phase
Parameter
Calc.
Exp.
Solution phase
Parameter
Calc.
Exp.
Solution phase
C4-C5
1.4012
1.386
1.402
C2-C1-C6
120.31
120.52
120.25
C6-C1-C2-C3
0.16
0.21
0.3706
C5-C6
1.4024
1.382
1.4035
C2-C1-H27
120.00
119.72
120.05
C6-C1-C2-H28
−179.76
179.84
−179.83
C1-C6
1.3903
1.384
1.3912
C6-C1-H27
119.69
119.77
119.70
H27-C1-C2-C3
−179.89
179.84
−179.44
C1-C2
1.3956
1.361
1.3965
C1-C2-C3
119.62
119.51
119.65
H27-C1-C2-H28
0.19
−0.13
0.36
C2-C3
1.3928
1.363
1.3937
C1-C2-C28
120.20
120.24
120.17
C2-C1-C6-C5
−0.63
0.23
−0.50
C3-C4
1.3934
1.388
1.3942
C3-C2-H28
120.18
120.26
120.18
C2-C1-C6-H31
179.22
179.80
179.97
C5-C7
1.4919
1.487
1.4924
C2-C3-C4
120.13
120.76
120.19
H27-C1-C6-C5
179.42
179.79
179.31
C8-C7
1.5135
1.508
1.5128
C2-C3-H29
120.15
119.63
120.18
H27-C1-C6-C31
−0.73
0.18
−0.21
C8-C9
1.5434
1.525
1.5428
C4-C3-H29
119.71
119.63
119.64
C1-C2-C3-C4
0.48
0.42
0.25
C8-H32
1.0883
0.958
1.0877
C3-C4-C5
120.69
120.32
120.59
C1-C2-C3-H29
−179.3
179.61
−179.76
C8-H33
1.0932
0.948
1.0932
C3-C4-H30
119.24
119.89
119.12
H28-C2-C3-C4
−179.6
−179.60
−179.54
C9-H34
1.0907
0.970
1.0895
C5-C4-H30
120.05
119.79
120.28
H28-C2-C3-H29
0.61
0.36
0.44
C9-H35
1.0923
0.971
1.0909
C4-C5-C6
118.67
117.99
118.75
C2-C3-C4-C5
−0.65
−0.72
−0.76
N10-C9
1.4584
1.452
1.4623
C4-C5-C7
120.71
120.05
120.75
C2-C3-C4-H30
−178.94
179.25
−179.59
N10-C14
1.3677
1.348
1.3628
C6-C5-C7
120.61
121.06
120.49
H29-C3-C4-C5
179.13
179.31
179.26
N10-C11
1.3810
1.364
1.3800
C1-C6-C5
120.57
120.95
120.57
H29-C3-C4-H30
0.84
0.71
0.42
N13-C12
1.3749
1.366
1.3794
C1-C6-H31
120.54
119.58
120.27
C3-C4-C5-C6
0.18
0.75
0.62
N13-C14
1.3677
1.304
1.3196
C5-C6-H31
118.89
119.58
119.15
C3-C4-C5-C7
−178.58
179.34
−178.67
C11-C12
1.3718
1.345
1.3713
C5-C7-C8
118.92
118.08
118.76
H30-C4-C5-C6
178.46
179.22
179.44
C12-H37
1.0790
0.930
1.0792
C5-C7-N15
115.01
115.92
115.26
H30-C4-C5-C7
−0.31
0.68
0.15
C11-H36
1.0776
0.931
1.0775
C8-C7-N15
125.99
125.96
125.92
C4-C5-C6-C1
0.46
0.51
0.002
C14-H38
1.0803
0.930
1.0799
C7-C8-C9
112.37
112.66
112.28
C4-C5-C6-H31
−179.4
179.51
179.53
C7-N15
1.2849
1.287
1.2860
C7-C8-H32
109.46
109.95
109.63
C7-C5-C6-C1
179.22
179.58
179.30
N15-N16
1.4036
1.367
1.4072
C7-C8-H33
110.05
111.01
109.68
C7-C5-C6-C31
−0.63
−0.39
−1.17
N16-H39
1.0123
0.899
1.0129
C9-C8-H32
108.19
106.60
108.53
C4-C5-C7-C8
−36.92
−29.26
−37.14
C17-N16
1.4179
1.362
1.4056
C9-C8-H33
110.37
110.76
109.71
C4-C5-C7-N15
146.04
152.80
145.29
C17-O18
1.2131
1.230
1.2222
H32-C8-H33
106.18
105.53
106.85
C6-C5-C7-C8
144.33
150.64
143.58
C17-N19
1.3792
1.350
1.3747
C8-C9-N10
111.95
113.52
111.52
C6-C5-C7-N15
−32.7
27.30
−33.99
N19-H40
1.0093
0.889
1.0104
C8-C9-H34
111.61
108.87
111.63
C5-C7-C8-C9
−52.66
−68.80
−55.35
N19-C20
1.4143
1.419
1.4123
C8-C9-H35
109.97
108.87
110.26
C5-C7-C8-H32
−172.89
49.95
−176.06
C20-C21
1.4005
1.384
1.4028
N10-C9-H34
108.78
108.88
108.21
C5-C7-C8-H33
70.77
166.33
66.90
C21-C22
1.3895
1.381
1.3897
N10-C9-H35
107.24
108.83
107.44
C15-C7-C8-C9
124.02
108.92
121.94
C22-C23
1.3984
1.380
1.4006
H34-C9-H35
107.08
107.71
107.60
N15-C7-C8-H32
3.79
−15.96
1.23
C23-C24
1.3972
1.376
1.3974
C9-N10-C11
127.03
126.90
126.69
N15-C7-C8-H33
−112.55
−132.34
−115.80
C24-C25
1.3931
1.384
1.3953
C9-N10-C14
126.64
126.29
126.56
C5-C7-N15-N16
−177.68
179.43
−178.97
C20-C25
1.3987
1.384
1.3999
C11-N10-C14
106.28
106.52
106.69
C8-C7-N15-N16
5.53
1.67
3.66
C21-H41
1.0864
0.929
1.0855
N10-C11-C12
105.73
105.44
105.79
C7-C8-C9-N10
−174.09
−26.97
−178.38
C22-H42
1.0853
0.930
1.0852
N10-C11-H36
122.10
127.32
122.03
C7-C8-C9-H34
63.7
66.15
60.44
C24-H43
1.0855
0.930
1.0855
C12-C11-H36
132.17
124.35
132.18
C7-C8-C9-H35
−54.99
−176.68
−59.11
C25-H44
1.0790
0.929
1.0788
C11-C12-N13
110.47
111.35
110.26
H32-C8-C9-N10
−53.12
175.97
−57.03
C23-C26
1.5095
1.608
1.5097
C11-C12-H37
127.96
124.35
127.94
H32-C8-C9-H34
−175.33
62.64
−178.21
C26-H45
1.0928
0.960
1.0928
N13-C12-H37
121.56
124.30
121.80
H32-C8-C9-H35
65.98
54.53
62.24
C26-H46
1.0926
0.960
1.0922
C12-N13-C14
105.20
104.06
105.21
H33-C8-C9-N10
62.66
−54.53
59.38
C26-H47
1.0957
0.960
1.0956
N10-C14-N13
112.32
112.62
112.05
H33-C8-C9-H34
−59.55
−54.53
−61.80
aTaken from [11].Figure 1
Optimized structure of (2E)-IPPMP.


### 3.3. Natural Bond Orbital Analysis

Natural bond orbital (NBO) analysis was performed using the NBO 3.1 program [22] as implemented in the Gaussian 09 program package for the DFT method. The corresponding results are presented in Table 2. NBO analysis has proved to be an effective tool for chemical interpretation of hyperconjugative interaction and electron density transfer (EDT) from a filled lone pair to an unfilled antibonding orbital in the hydrogen bonding system [23–25]. The intramolecular C-H⋯O hydrogen bonding is formed due to the orbital overlap between n
(
O
) and σ
∗
(
C-H
) which results in intramolecular charge transfer (ICT) causing stabilization of H-bonded systems. This interaction results in increased electron density (ED) of the C-H antibonding orbital, which strengthens the C-H bond. NBO analysis confirms C-H⋯O intramolecular hydrogen bonding formed by the orbital overlap between a lone pair n
2
(
O
18
) and σ
∗
(
C
25
-
H
44
) antibonding orbital with stabilization energy of 0.78 kcal/mol. The most important interaction (
n
-
π
∗
) and (n
-
σ
∗) energies of n
1
(
N
10
)
→
π
∗
(
N
13
-
C
14
) and n
2
(
O
18
)
→
σ
∗
(
N
16
-
C
17
) are 46.48 and 26.84 kcal/mol, respectively. This larger E
(
2
) value shows ICT interactions of the molecule.Table 2
Second-order perturbation theory analysis of Fock matrix in natural bond orbital (NBO) basis for (2E)-IPPMP.
Donor (i)
Occupancy (e)
Acceptor (j)
Occupancy (e)
E
(
2
)
a
kcal/mol
E
(
j
)
-
E
(
i
)
b
(a.u)
E
(
i
,
j
)
c
(a.u)
n
1(N10)
1.55554
π
∗(C11-C12)
1.85684
30.62
0.29
0.087
n
1(N10)
1.55554
π
∗(N13-C14)
1.86721
46.48
0.28
0.103
n
1(N13)
1.9234
σ
∗(C11-C12)
1.98419
5.1
0.95
0.063
n
1(N15)
1.92552
σ
∗(C7-C8)
1.97792
11.4
0.79
0.086
n
1(N15)
1.92552
σ
∗(N16-H39)
1.97686
2.02
0.77
0.036
n
1(N16)
1.79578
π
∗(C7-N15)
1.94162
9.06
0.36
0.052
n
2(O18)
1.83834
σ
∗(N16-C17)
1.98245
26.84
0.63
0.118
n
2(O18)
1.83834
σ
∗(C17-N19)
1.98641
24.58
0.69
0.119
n
2(O18)
1.83834
σ
∗(C25-H44)
1.97725
0.78
0.73
0.022
n
1(N19)
1.70657
π
∗(C20-C25)
1.64309
30.72
0.31
0.089
π(C2-C3)
1.6583
π
∗(C4-C5)
1.64969
20.62
0.28
0.069
π(C4-C5)
1.64969
π
∗(C1-C6)
1.66001
19.97
0.29
0.067
π(C11-C12)
1.85684
π
∗(N13-C14)
1.86721
15.01
0.28
0.061
π(N13-C14)
1.86721
π
∗(C11-C12)
1.85684
21.59
0.33
0.078
π(C20-C25)
1.64309
π
∗(C21-C22)
1.70752
19.29
0.28
0.066
π(C20-C25)
1.64309
π
∗(C23-C24)
1.64872
20.41
0.3
0.069
π(C23-C24)
1.64872
π
∗(C20-C25)
1.64309
20.68
0.27
0.068
π(C23-C24)
1.64872
π
∗(C21-C22)
1.70752
22.11
0.27
0.069
π(N13-C14)
1.86721
π
∗(C11-C12)
1.85684
107.4
0.01
0.06
σ(C26-H46)
1.98674
σ
∗(C23-C24)
1.64872
0.84
0.54
0.021
σ(C26-H47)
1.97658
σ
∗(C23-C24)
1.64872
4.34
0.54
0.047
π(C20-C25)
1.64309
π
∗(C23-C24)
1.64872
254.22
0.01
0.082
π(C21-C22)
1.70752
π
∗(C23-C24)
1.64872
230.93
0.01
0.084
a
E(2) means energy of hyperconjugative interactions. bEnergy difference between donor and acceptor i and j NBO. c
F
(
i
,
j
) is the Fock matrix element between i and j NBO.


### 3.4. Vibrational Spectral Analysis

Computed vibrational wavenumbers and atomic displacements corresponding to the different normal modes are used to identify vibrational modes. The vibrational modes are assigned on the basis of potential energy distribution analysis using the VEDA4 program [26]. The experimental infrared (IR) and Raman spectra are shown in Figures 2 and 3. The calculated vibrational wavenumbers, measured IR, and Raman band positions and their detailed assignments are given in Table 3.Table 3
Vibrational assignment of (2E)-IPPMP based on potential energy distribution method.
Calculated wavenumber (cm−1)
Experimental wavenumber (cm−1)
Assignment with PED%
Unscaled
Scaled
FT-IR
FT-Raman
3610
3497
3207w
—
ν N-H (92)
3565
3453
3141vw
3140vw
ν N-H (99)
3265
3163
3138vw
3138w
ν C-H imd (83)
3241
3140
3119w
3121w
ν C-H ph (99)
3202
3102
3118w
ν C-H ph (86)
3182
3082
3083vw
—
ν C-H ph (67)
3164
3066
—
3065m
ν C-H ph (27)
3105
3008
—
3018w
ν
a
s C-H (55)
3073
2977
—
2977w
ν
s
y C-H (36)
3059
2964
—
2941w
ν
s
y C-H (48)
3019
2925
—
2917w
ν
s
y C-H (18)
1776
1720
1654vs
—
ν C=O (78)
1639
1588
1589m
1593vs
ν C-C ph (42)
1614
1564
—
1569m
ν C-C ph (36)
1553
1504
1523vs
1527vw
β N-H (32)
1496
1449
1449m
—
ω N-H (33)
1492
1445
—
1447vw
δ
s
c
i C-H (19)
1468
1422
1401m
—
δ
s
c
i C-H (79)
1399
1355
1352w
1361vw
ω C-H (51)
1382
1339
—
1338vw
ν C-C imd (20)
1327
1286
1288w
—
β C-H ph (22)
1307
1267
—
1275w
β C-H ph (12)
1263
1223
—
1222w
β C-H ph (46)
1258
1219
1218m
—
β C-H ph (56)
1209
1171
1174vw
—
β C-H ph (28)
1177
1140
1141s
1177w
t C-H (18)
1118
1084
1089m
1088vw
ν N-N (23), β C-H ph (12)
1101
1067
—
1069vw
β C-H ph (10)
1075
1041
1039vw
—
ν N-N (19)
1061
1028
1020vw
1027vw
τ CHCH (70)
1043
1011
1011w
—
β C-H imd (32)
1023
991
—
998w
ν N-C (14)
985
954
947vw
—
τ HCCH (81)
947
918
931vw
—
τ CCCH (49)
940
911
911w
—
τ HCCC (47)
917
888
876vw
875vw
β CC imd (72)
820
794
797vw
796vw
τ HCCN (55)
785
761
769w
ν C-C (14)
673
652
660s
663vw
τ CNCN (63),
652
632
—
640w
β CC ph (24)
636
617
615m
—
τ CCNC (34), β CC ph (21)
614
595
590vw
586vw
τ CCNN (17)
414
401
—
401vw
τ CCCC (29)
370
359
—
354vw
τ CCNN (14)
199
193
—
204vw
τ CCCC (23)
71
69
—
71m
τ CNCN (14), τ NNCN (19)
ν, stretching; ν
a
s, asymmetric; ν
s
y, symmetric stretching; ph, phenyl ring; imd, imidazole ring: δ
s
c
i, scissoring; t, twisting; ω, wagging; β, in-plane bending; τ, Torsion; vs, very strong; s, strong; m, medium; w, weak; vw, very weak.Figure 2
(a) Calculated (b) experiment infrared spectra of (2E)-IPPMP.
(a)
(b)Figure 3
(a) Calculated (b) experiment Raman spectra of (2E)-IPPMP.
(a)
(b)


#### 3.4.1. Phenyl Ring Vibrations

Aromatic C-H stretching vibrations generally absorb in the region 3080–3010 cm−1 [27]. The observed weak IR band at 3119 cm−1 and Raman band at 3121 cm−1 correspond to aromatic C-H stretching mode. The blue shift of the C-H stretching wavenumber is due to weak intramolecular C-H⋯O hydrogen bonding. Aromatic C=C stretching vibrations occur in the region 1625–1430 cm−1 [28]. A medium IR band at 1539 cm−1 and a strong Raman band at 1591 cm−1 are observed, which correspond to aromatic C=C stretching mode. In-plane C-H deformation vibrations appear in the region 1290–1000 cm−1 [27]. Observed IR and Raman bands at 1288 and 1275 cm−1 are assigned to in-plane C-H deformation. In-plane ring deformation vibrations appear in the region 650–615 cm−1. Observed IR and Raman bands at 615 and 640 cm−1 are assigned to in-plane ring deformation.


#### 3.4.2. Methylene Vibrations

Asymmetric and symmetric CH2 stretching vibrations normally appear strongly at about 2926 and 2855 cm−1 [29]. The Raman band at 2941 cm−1 is assigned to CH2 symmetric stretching vibration. Methylene scissoring vibrations normally appear in the region 1465–1445 cm−1 [29]. A medium band observed in IR at 1401 cm−1 is attributed to methylene scissoring mode. The twisting, wagging vibrations appear in the region 1422–719 cm−1 [30]. The observed strong IR band at 1141 cm−1 and weak Raman band at 1177 cm−1 are assigned to CH2 twisting modes for methylene. Wagging is observed in IR at 1352 cm−1 and Raman at 1361 cm−1.


#### 3.4.3. Methyl Vibrations

The asymmetric C-H stretching mode of CH3 generally occurs at 2982–2962 cm−1 and CH3 symmetric stretching at 2882–2862 cm−1 [29]. A weak Raman band at 2977 cm−1 is attributed to CH3 symmetric stretching. Asymmetric bending vibrations of methyl groups occur in the region 1470–1450 cm−1 [28]. The observed weak Raman band at 1447 cm−1 is assigned to methyl scissoring vibration.


#### 3.4.4. Secondary Amide Vibrations

Carbonyl stretching vibration in a secondary amide is expected in the region 1680–1630 cm−1 [28]. A very strong band at 1654 cm−1 is assigned to C=O stretching. N-H stretching vibrations generally appear in the region 3370–3170 cm−1. Observed IR and Raman bands at 3141 and 3140 cm−1 are attributed to N-H stretching. The in-plane N-H bending vibration usually appears from 1570 to 1515 cm−1 [28]. The observed very strong IR band at 1523 cm−1 and weak Raman band at 1527 cm−1 are assigned to in-plane N-H bending vibration.


#### 3.4.5. Imidazole Vibrations

Imidazole C-H stretching vibrations are expected in the region 3145–3115 cm−1 [31, 32]. Observed Raman bands at 3121 and 3138 cm−1 and IR bands at 3119 and 3138 cm−1 are assigned to C-H stretching mode. The observed Raman band at 1338 cm−1 is attributed to C-C stretching mode [33].


#### 3.4.6. Hydrazine Vibrations

In accordance with earlier reports and in agreement with the calculation, a weak band observed at 3207 cm−1 is assigned to hydrazine N-H stretching [27, 34]. Observed bands in IR and Raman at 1089 and 1088 cm−1 are assigned to N-N stretching vibration.


#### 3.4.7. Skeletal Mode Vibrations

C-N and C-C stretching vibrations generally occur in the region 1150–850 cm−1 [34]. The weak IR and Raman bands observed at 1011 and 998 cm−1 are attributed to C-C stretching.


### 3.5. Frontier Molecular Orbital Energy Analysis

HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) are important in defining the reactivity of a chemical species. The energy of HOMO indicates nucleophilicity and LUMO indicates electrophilicity [35]. HOMO is spread over the methyl phenyl, hydrazinecarboxamide fragment and LUMO is located on ph 2. This shows the charge transfer between the two rings through the hydrazinecarboxamide path. The HOMO (−6.61 eV) and LUMO (−1.61 eV) energies reflect the charge transfer within the molecule. The HOMO-LUMO energy gap is 4.46 eV. The frontier molecular orbital diagrams are shown in Figure 4.Figure 4
(a) HOMO and (b) LUMO plots of (2E)-IPPMP.
(a)
(b)


### 3.6. Natural Population Analysis

Natural population analysis provides an effective method to calculate atomic charges and electron distribution within a molecule [36]. The net atomic charges of the (2E)-IPPMP molecule obtained by natural population analysis are plotted in Figure 5. All hydrogen atoms have a net positive charge. The atoms H40 (0.3852e) and H39 (0.3788e) show more positive charge than other hydrogen atoms due to their attachment with a nitrogen atom. Among the hydrogen atoms (~0.2023e) of the phenyl ring, H44 (~0.2452e) shows the highest positive charge, being involved in C-H⋯O intramolecular hydrogen bonding. All carbon atoms are negatively charged except C7, C14, C17, and C20 due to their attachment with electronegative nitrogen or oxygen atoms. The atom C17 (0.7991e) shows more positive charge and N19 (−0.6181e) shows more negative charge, indicating charge delocalization in the molecule.Figure 5
Natural charge distribution chart of the (2E)-IPPMP molecule.


### 3.7. NMR Analysis

The scaled and experimental NMR (1H and 13C) chemical shift values for the (2E)-IPPMP molecule are presented in Table 4. The phenyl and imidazole ring carbon signals usually appear in the region 115–150 ppm. In this molecule, imidazole ring carbon signals are obtained at 119.4, 126.4, and 137.3 ppm, which are predicted at 119.36, 128.75, and 140.01 ppm, respectively.Table 4
NMR chemicals shift values of13C and 1H.
13C
1H
Atom
δ
e
x
p
.
δ
c
a
l
c
.
Atom
δ
e
x
p
.
δ
c
a
l
c
.
C1
128.3
128.01
H27
7.39
7.16
C2
128.9
129.41
H28
7.43
7.19
C3
128.3
127.48
H29
7.39
7.16
C4
128.4
128.13
H30
7.84
7.50
C5
136.8
138.17
H31
7.84
7.63
C6
128.4
126.71
H32
3.33
2.61
C7
153.6
168.87
H33
3.33
2.89
C8
28.3
33.31
H34
4.14
3.77
C9
42.1
44.26
H35
4.14
3.19
C11
119.4
119.36
H36
6.87
6.87
C12
126.4
128.75
H37
7.29
6.56
C14
137.3
140.01
H38
7.65
6.82
C17
144.9
150.09
H39
10.24
6.70
C20
131.5
137.03
H40
8.79
5.70
C21
120.0
115.12
H41
7.13
6.27
C22
128.8
128.43
H42
7.53
6.80
C23
136.3
132.85
H43
7.53
6.85
C24
128.8
128.53
H44
7.13
7.90
C25
120.0
114.58
H45
2.28
1.78
C26
20.4
18.25
H46
2.28
1.80
H47
2.28
2.08Phenyl carbon signals were observed at 120.0, 128.4, 128.8, 128.9, 131.5, 136.3, 136.8, and 137.3 ppm, while their respective calculated ones were obtained at 115.12, 128.13, 128.53, 129.41, 137.03, 132.85, 138.17, and 140.01 ppm. A carbonyl carbon signal was seen at 144.9 ppm and its computed one was obtained at 150.09 ppm. This deviation may occur due to the presence of amide⋯amide interactions in the crystalline state. On the other hand, the computed1H chemical shift values for the title molecule showed good agreement with the experimental ones (Table 4).


### 3.8. Molecular Docking Analysis

The title molecule (2E)-IPPMP was energy minimized based on the DFT method. Molecular docking was performed using AutoDock 4.2. A target protein (PDB ID: 1EOU) for antiepileptic agents was selected for the present docking analysis [37, 38]. The protein data bank file of the target protein was downloaded from the Research Collaboratory for Structural Bioinformatics (RCSB) database, with a resolution of 2.1 Å. Protein preparation was carried out by the following steps: (i) all water molecules were removed, (ii) hydrogen atoms were added to the crystal structure, (iii) Kollman charge was added, and (iv) a previously docked inhibitor (fructose-based sugar sulfamate RWJ-37497) was removed from the protein. Rigid protein and flexible ligand dockings were carried out using the AutoDock 4.2 program package [39] with the Lamarckian genetic algorithm, applying the following protocol: trials of 100 dockings, energy evaluations of 25000000, population size of 200, mutation rate of 0.02, crossover rate of 0.8, and elitism value of 1. The docking results were evaluated by sorting the docked conformations according to their predicted binding free energy. The protein-ligand interaction complex is given in Figure 6, displaying the conformer with the best predicted binding free energy (−7.94 kcal/mol). The amino acids ASN11, TYR7, and LYS169 in the active sites of the target protein bind with the (2E)-IPPMP ligand by N-H⋯O and N-H⋯N hydrogen bonds. These preliminary results support the exhibited anticonvulsant activity of the title molecule.Figure 6
Binding pose diagrams of the (2E)-IPPMP molecule with its target protein.


## 3.1. Synthesis

The target compound (2E)-IPPMP was obtained in a three-step reaction sequence as given in Scheme 1.Scheme 1
Synthesis of the title molecule (2E)-IPPMP. Reagents and conditions: (i) HN(CH3)2·HCl, (CH2O)n, conc. HCl, ethanol, reflux, 2 h; (ii) imidazole, water, reflux, 5 h; (iii)N-(4-methylphenyl)hydrazinecarboxamide, few drops of acetic acid, ethanol, RT, 18 h.


## 3.2. Structural Geometry Analysis

The structure of the (2E)-IPPMP molecule was optimized using the B3LYP method with a 6-311++G(d,p) basis set. The optimized molecular structure of the isolated molecule is shown in Figure 1. The optimized geometrical parameters of the isolated (2E)-IPPMP molecule in the gas and water phases are given in Table 1. The calculated values were compared with the X-ray diffraction results. In the (2E)-IPPMP molecule the two phenyl rings are bridged by a hydrazinecarboxamide skeleton containing an imidazole ring. The C-N bond lengths C17-N16 (1.4179 Å) and C17-N19 (1.3792 Å) are shorter than the normal single C-N bond length 1.480 Å [20]. This discrepancy is due to the conjugation of p-type electrons of the carbonyl group and nitrogen atom, allowing the electrons to smear out along the C-N bond. In thepara-disubstituted phenyl ring, the calculated C25-H44 (1.0789 Å) bond length is shorter than that of the other C-C bonds; also, O18⋯H44 distance is 2.25 Å, which is significantly shorter than the van der Waals radius (2.72 Å) [21] between O and H atoms, which indicates the possibility of C-H⋯O hydrogen bonding. The elongation of the C20-C21 (1.4004 Å) bond is due to the transfer of a lone pair of electrons from the amide nitrogen to the carbon atom. In the other phenyl ring, the C5-H31 (1.0825 Å) bond is shorter than that of the other C-C bonds; also, N15⋯H31 distance is 2.56 Å, which is significantly shorter than the van der Waals radius (2.75 Å) between N and H atoms, which indicates the possibility of C-H⋯O hydrogen bonding. In addition, C5-C6 (1.4024 Å) and C4-C5 (1.4012 Å) bond distances on either side of the cyanide group are appreciably greater than the other C-C bonds due to the resonance effect between the cyanide group and phenyl ring. In the imidazole ring, C14-N10 (1.3676 Å) and C14-N13 (1.3139 Å) bonds are relatively shorter due to the lone pair interaction from the nitrogen atom. The deviation of bond lengths of N15-H39 (1.0123 Å) and N19-H40 (1.0092 Å) is due to the different environment of the nitrogen atom. Conjugation of the carbonyl group with the hydrazine moiety would favor planarity, but the van der Waals repulsion between H39 and H40 hinders the achievement of coplanarity. A small deviation was obtained within the calculated structural parameters in the gas and liquid phases, which were due to the solvent interactions over the solution phase calculations.Table 1
Structural geometry parameters of (2E)-IPPMP compared with their experimental X-ray diffraction results.
Bond length (Å)
Bond angle (°)
Dihedral angle (°)
Parameter
Calc.
Exp.a
Solution phase
Parameter
Calc.
Exp.
Solution phase
Parameter
Calc.
Exp.
Solution phase
C4-C5
1.4012
1.386
1.402
C2-C1-C6
120.31
120.52
120.25
C6-C1-C2-C3
0.16
0.21
0.3706
C5-C6
1.4024
1.382
1.4035
C2-C1-H27
120.00
119.72
120.05
C6-C1-C2-H28
−179.76
179.84
−179.83
C1-C6
1.3903
1.384
1.3912
C6-C1-H27
119.69
119.77
119.70
H27-C1-C2-C3
−179.89
179.84
−179.44
C1-C2
1.3956
1.361
1.3965
C1-C2-C3
119.62
119.51
119.65
H27-C1-C2-H28
0.19
−0.13
0.36
C2-C3
1.3928
1.363
1.3937
C1-C2-C28
120.20
120.24
120.17
C2-C1-C6-C5
−0.63
0.23
−0.50
C3-C4
1.3934
1.388
1.3942
C3-C2-H28
120.18
120.26
120.18
C2-C1-C6-H31
179.22
179.80
179.97
C5-C7
1.4919
1.487
1.4924
C2-C3-C4
120.13
120.76
120.19
H27-C1-C6-C5
179.42
179.79
179.31
C8-C7
1.5135
1.508
1.5128
C2-C3-H29
120.15
119.63
120.18
H27-C1-C6-C31
−0.73
0.18
−0.21
C8-C9
1.5434
1.525
1.5428
C4-C3-H29
119.71
119.63
119.64
C1-C2-C3-C4
0.48
0.42
0.25
C8-H32
1.0883
0.958
1.0877
C3-C4-C5
120.69
120.32
120.59
C1-C2-C3-H29
−179.3
179.61
−179.76
C8-H33
1.0932
0.948
1.0932
C3-C4-H30
119.24
119.89
119.12
H28-C2-C3-C4
−179.6
−179.60
−179.54
C9-H34
1.0907
0.970
1.0895
C5-C4-H30
120.05
119.79
120.28
H28-C2-C3-H29
0.61
0.36
0.44
C9-H35
1.0923
0.971
1.0909
C4-C5-C6
118.67
117.99
118.75
C2-C3-C4-C5
−0.65
−0.72
−0.76
N10-C9
1.4584
1.452
1.4623
C4-C5-C7
120.71
120.05
120.75
C2-C3-C4-H30
−178.94
179.25
−179.59
N10-C14
1.3677
1.348
1.3628
C6-C5-C7
120.61
121.06
120.49
H29-C3-C4-C5
179.13
179.31
179.26
N10-C11
1.3810
1.364
1.3800
C1-C6-C5
120.57
120.95
120.57
H29-C3-C4-H30
0.84
0.71
0.42
N13-C12
1.3749
1.366
1.3794
C1-C6-H31
120.54
119.58
120.27
C3-C4-C5-C6
0.18
0.75
0.62
N13-C14
1.3677
1.304
1.3196
C5-C6-H31
118.89
119.58
119.15
C3-C4-C5-C7
−178.58
179.34
−178.67
C11-C12
1.3718
1.345
1.3713
C5-C7-C8
118.92
118.08
118.76
H30-C4-C5-C6
178.46
179.22
179.44
C12-H37
1.0790
0.930
1.0792
C5-C7-N15
115.01
115.92
115.26
H30-C4-C5-C7
−0.31
0.68
0.15
C11-H36
1.0776
0.931
1.0775
C8-C7-N15
125.99
125.96
125.92
C4-C5-C6-C1
0.46
0.51
0.002
C14-H38
1.0803
0.930
1.0799
C7-C8-C9
112.37
112.66
112.28
C4-C5-C6-H31
−179.4
179.51
179.53
C7-N15
1.2849
1.287
1.2860
C7-C8-H32
109.46
109.95
109.63
C7-C5-C6-C1
179.22
179.58
179.30
N15-N16
1.4036
1.367
1.4072
C7-C8-H33
110.05
111.01
109.68
C7-C5-C6-C31
−0.63
−0.39
−1.17
N16-H39
1.0123
0.899
1.0129
C9-C8-H32
108.19
106.60
108.53
C4-C5-C7-C8
−36.92
−29.26
−37.14
C17-N16
1.4179
1.362
1.4056
C9-C8-H33
110.37
110.76
109.71
C4-C5-C7-N15
146.04
152.80
145.29
C17-O18
1.2131
1.230
1.2222
H32-C8-H33
106.18
105.53
106.85
C6-C5-C7-C8
144.33
150.64
143.58
C17-N19
1.3792
1.350
1.3747
C8-C9-N10
111.95
113.52
111.52
C6-C5-C7-N15
−32.7
27.30
−33.99
N19-H40
1.0093
0.889
1.0104
C8-C9-H34
111.61
108.87
111.63
C5-C7-C8-C9
−52.66
−68.80
−55.35
N19-C20
1.4143
1.419
1.4123
C8-C9-H35
109.97
108.87
110.26
C5-C7-C8-H32
−172.89
49.95
−176.06
C20-C21
1.4005
1.384
1.4028
N10-C9-H34
108.78
108.88
108.21
C5-C7-C8-H33
70.77
166.33
66.90
C21-C22
1.3895
1.381
1.3897
N10-C9-H35
107.24
108.83
107.44
C15-C7-C8-C9
124.02
108.92
121.94
C22-C23
1.3984
1.380
1.4006
H34-C9-H35
107.08
107.71
107.60
N15-C7-C8-H32
3.79
−15.96
1.23
C23-C24
1.3972
1.376
1.3974
C9-N10-C11
127.03
126.90
126.69
N15-C7-C8-H33
−112.55
−132.34
−115.80
C24-C25
1.3931
1.384
1.3953
C9-N10-C14
126.64
126.29
126.56
C5-C7-N15-N16
−177.68
179.43
−178.97
C20-C25
1.3987
1.384
1.3999
C11-N10-C14
106.28
106.52
106.69
C8-C7-N15-N16
5.53
1.67
3.66
C21-H41
1.0864
0.929
1.0855
N10-C11-C12
105.73
105.44
105.79
C7-C8-C9-N10
−174.09
−26.97
−178.38
C22-H42
1.0853
0.930
1.0852
N10-C11-H36
122.10
127.32
122.03
C7-C8-C9-H34
63.7
66.15
60.44
C24-H43
1.0855
0.930
1.0855
C12-C11-H36
132.17
124.35
132.18
C7-C8-C9-H35
−54.99
−176.68
−59.11
C25-H44
1.0790
0.929
1.0788
C11-C12-N13
110.47
111.35
110.26
H32-C8-C9-N10
−53.12
175.97
−57.03
C23-C26
1.5095
1.608
1.5097
C11-C12-H37
127.96
124.35
127.94
H32-C8-C9-H34
−175.33
62.64
−178.21
C26-H45
1.0928
0.960
1.0928
N13-C12-H37
121.56
124.30
121.80
H32-C8-C9-H35
65.98
54.53
62.24
C26-H46
1.0926
0.960
1.0922
C12-N13-C14
105.20
104.06
105.21
H33-C8-C9-N10
62.66
−54.53
59.38
C26-H47
1.0957
0.960
1.0956
N10-C14-N13
112.32
112.62
112.05
H33-C8-C9-H34
−59.55
−54.53
−61.80
aTaken from [11].Figure 1
Optimized structure of (2E)-IPPMP.


## 3.3. Natural Bond Orbital Analysis

Natural bond orbital (NBO) analysis was performed using the NBO 3.1 program [22] as implemented in the Gaussian 09 program package for the DFT method. The corresponding results are presented in Table 2. NBO analysis has proved to be an effective tool for chemical interpretation of hyperconjugative interaction and electron density transfer (EDT) from a filled lone pair to an unfilled antibonding orbital in the hydrogen bonding system [23–25]. The intramolecular C-H⋯O hydrogen bonding is formed due to the orbital overlap between n
(
O
) and σ
∗
(
C-H
) which results in intramolecular charge transfer (ICT) causing stabilization of H-bonded systems. This interaction results in increased electron density (ED) of the C-H antibonding orbital, which strengthens the C-H bond. NBO analysis confirms C-H⋯O intramolecular hydrogen bonding formed by the orbital overlap between a lone pair n
2
(
O
18
) and σ
∗
(
C
25
-
H
44
) antibonding orbital with stabilization energy of 0.78 kcal/mol. The most important interaction (
n
-
π
∗
) and (n
-
σ
∗) energies of n
1
(
N
10
)
→
π
∗
(
N
13
-
C
14
) and n
2
(
O
18
)
→
σ
∗
(
N
16
-
C
17
) are 46.48 and 26.84 kcal/mol, respectively. This larger E
(
2
) value shows ICT interactions of the molecule.Table 2
Second-order perturbation theory analysis of Fock matrix in natural bond orbital (NBO) basis for (2E)-IPPMP.
Donor (i)
Occupancy (e)
Acceptor (j)
Occupancy (e)
E
(
2
)
a
kcal/mol
E
(
j
)
-
E
(
i
)
b
(a.u)
E
(
i
,
j
)
c
(a.u)
n
1(N10)
1.55554
π
∗(C11-C12)
1.85684
30.62
0.29
0.087
n
1(N10)
1.55554
π
∗(N13-C14)
1.86721
46.48
0.28
0.103
n
1(N13)
1.9234
σ
∗(C11-C12)
1.98419
5.1
0.95
0.063
n
1(N15)
1.92552
σ
∗(C7-C8)
1.97792
11.4
0.79
0.086
n
1(N15)
1.92552
σ
∗(N16-H39)
1.97686
2.02
0.77
0.036
n
1(N16)
1.79578
π
∗(C7-N15)
1.94162
9.06
0.36
0.052
n
2(O18)
1.83834
σ
∗(N16-C17)
1.98245
26.84
0.63
0.118
n
2(O18)
1.83834
σ
∗(C17-N19)
1.98641
24.58
0.69
0.119
n
2(O18)
1.83834
σ
∗(C25-H44)
1.97725
0.78
0.73
0.022
n
1(N19)
1.70657
π
∗(C20-C25)
1.64309
30.72
0.31
0.089
π(C2-C3)
1.6583
π
∗(C4-C5)
1.64969
20.62
0.28
0.069
π(C4-C5)
1.64969
π
∗(C1-C6)
1.66001
19.97
0.29
0.067
π(C11-C12)
1.85684
π
∗(N13-C14)
1.86721
15.01
0.28
0.061
π(N13-C14)
1.86721
π
∗(C11-C12)
1.85684
21.59
0.33
0.078
π(C20-C25)
1.64309
π
∗(C21-C22)
1.70752
19.29
0.28
0.066
π(C20-C25)
1.64309
π
∗(C23-C24)
1.64872
20.41
0.3
0.069
π(C23-C24)
1.64872
π
∗(C20-C25)
1.64309
20.68
0.27
0.068
π(C23-C24)
1.64872
π
∗(C21-C22)
1.70752
22.11
0.27
0.069
π(N13-C14)
1.86721
π
∗(C11-C12)
1.85684
107.4
0.01
0.06
σ(C26-H46)
1.98674
σ
∗(C23-C24)
1.64872
0.84
0.54
0.021
σ(C26-H47)
1.97658
σ
∗(C23-C24)
1.64872
4.34
0.54
0.047
π(C20-C25)
1.64309
π
∗(C23-C24)
1.64872
254.22
0.01
0.082
π(C21-C22)
1.70752
π
∗(C23-C24)
1.64872
230.93
0.01
0.084
a
E(2) means energy of hyperconjugative interactions. bEnergy difference between donor and acceptor i and j NBO. c
F
(
i
,
j
) is the Fock matrix element between i and j NBO.


## 3.4. Vibrational Spectral Analysis

Computed vibrational wavenumbers and atomic displacements corresponding to the different normal modes are used to identify vibrational modes. The vibrational modes are assigned on the basis of potential energy distribution analysis using the VEDA4 program [26]. The experimental infrared (IR) and Raman spectra are shown in Figures 2 and 3. The calculated vibrational wavenumbers, measured IR, and Raman band positions and their detailed assignments are given in Table 3.Table 3
Vibrational assignment of (2E)-IPPMP based on potential energy distribution method.
Calculated wavenumber (cm−1)
Experimental wavenumber (cm−1)
Assignment with PED%
Unscaled
Scaled
FT-IR
FT-Raman
3610
3497
3207w
—
ν N-H (92)
3565
3453
3141vw
3140vw
ν N-H (99)
3265
3163
3138vw
3138w
ν C-H imd (83)
3241
3140
3119w
3121w
ν C-H ph (99)
3202
3102
3118w
ν C-H ph (86)
3182
3082
3083vw
—
ν C-H ph (67)
3164
3066
—
3065m
ν C-H ph (27)
3105
3008
—
3018w
ν
a
s C-H (55)
3073
2977
—
2977w
ν
s
y C-H (36)
3059
2964
—
2941w
ν
s
y C-H (48)
3019
2925
—
2917w
ν
s
y C-H (18)
1776
1720
1654vs
—
ν C=O (78)
1639
1588
1589m
1593vs
ν C-C ph (42)
1614
1564
—
1569m
ν C-C ph (36)
1553
1504
1523vs
1527vw
β N-H (32)
1496
1449
1449m
—
ω N-H (33)
1492
1445
—
1447vw
δ
s
c
i C-H (19)
1468
1422
1401m
—
δ
s
c
i C-H (79)
1399
1355
1352w
1361vw
ω C-H (51)
1382
1339
—
1338vw
ν C-C imd (20)
1327
1286
1288w
—
β C-H ph (22)
1307
1267
—
1275w
β C-H ph (12)
1263
1223
—
1222w
β C-H ph (46)
1258
1219
1218m
—
β C-H ph (56)
1209
1171
1174vw
—
β C-H ph (28)
1177
1140
1141s
1177w
t C-H (18)
1118
1084
1089m
1088vw
ν N-N (23), β C-H ph (12)
1101
1067
—
1069vw
β C-H ph (10)
1075
1041
1039vw
—
ν N-N (19)
1061
1028
1020vw
1027vw
τ CHCH (70)
1043
1011
1011w
—
β C-H imd (32)
1023
991
—
998w
ν N-C (14)
985
954
947vw
—
τ HCCH (81)
947
918
931vw
—
τ CCCH (49)
940
911
911w
—
τ HCCC (47)
917
888
876vw
875vw
β CC imd (72)
820
794
797vw
796vw
τ HCCN (55)
785
761
769w
ν C-C (14)
673
652
660s
663vw
τ CNCN (63),
652
632
—
640w
β CC ph (24)
636
617
615m
—
τ CCNC (34), β CC ph (21)
614
595
590vw
586vw
τ CCNN (17)
414
401
—
401vw
τ CCCC (29)
370
359
—
354vw
τ CCNN (14)
199
193
—
204vw
τ CCCC (23)
71
69
—
71m
τ CNCN (14), τ NNCN (19)
ν, stretching; ν
a
s, asymmetric; ν
s
y, symmetric stretching; ph, phenyl ring; imd, imidazole ring: δ
s
c
i, scissoring; t, twisting; ω, wagging; β, in-plane bending; τ, Torsion; vs, very strong; s, strong; m, medium; w, weak; vw, very weak.Figure 2
(a) Calculated (b) experiment infrared spectra of (2E)-IPPMP.
(a)
(b)Figure 3
(a) Calculated (b) experiment Raman spectra of (2E)-IPPMP.
(a)
(b)


### 3.4.1. Phenyl Ring Vibrations

Aromatic C-H stretching vibrations generally absorb in the region 3080–3010 cm−1 [27]. The observed weak IR band at 3119 cm−1 and Raman band at 3121 cm−1 correspond to aromatic C-H stretching mode. The blue shift of the C-H stretching wavenumber is due to weak intramolecular C-H⋯O hydrogen bonding. Aromatic C=C stretching vibrations occur in the region 1625–1430 cm−1 [28]. A medium IR band at 1539 cm−1 and a strong Raman band at 1591 cm−1 are observed, which correspond to aromatic C=C stretching mode. In-plane C-H deformation vibrations appear in the region 1290–1000 cm−1 [27]. Observed IR and Raman bands at 1288 and 1275 cm−1 are assigned to in-plane C-H deformation. In-plane ring deformation vibrations appear in the region 650–615 cm−1. Observed IR and Raman bands at 615 and 640 cm−1 are assigned to in-plane ring deformation.


### 3.4.2. Methylene Vibrations

Asymmetric and symmetric CH2 stretching vibrations normally appear strongly at about 2926 and 2855 cm−1 [29]. The Raman band at 2941 cm−1 is assigned to CH2 symmetric stretching vibration. Methylene scissoring vibrations normally appear in the region 1465–1445 cm−1 [29]. A medium band observed in IR at 1401 cm−1 is attributed to methylene scissoring mode. The twisting, wagging vibrations appear in the region 1422–719 cm−1 [30]. The observed strong IR band at 1141 cm−1 and weak Raman band at 1177 cm−1 are assigned to CH2 twisting modes for methylene. Wagging is observed in IR at 1352 cm−1 and Raman at 1361 cm−1.


### 3.4.3. Methyl Vibrations

The asymmetric C-H stretching mode of CH3 generally occurs at 2982–2962 cm−1 and CH3 symmetric stretching at 2882–2862 cm−1 [29]. A weak Raman band at 2977 cm−1 is attributed to CH3 symmetric stretching. Asymmetric bending vibrations of methyl groups occur in the region 1470–1450 cm−1 [28]. The observed weak Raman band at 1447 cm−1 is assigned to methyl scissoring vibration.


### 3.4.4. Secondary Amide Vibrations

Carbonyl stretching vibration in a secondary amide is expected in the region 1680–1630 cm−1 [28]. A very strong band at 1654 cm−1 is assigned to C=O stretching. N-H stretching vibrations generally appear in the region 3370–3170 cm−1. Observed IR and Raman bands at 3141 and 3140 cm−1 are attributed to N-H stretching. The in-plane N-H bending vibration usually appears from 1570 to 1515 cm−1 [28]. The observed very strong IR band at 1523 cm−1 and weak Raman band at 1527 cm−1 are assigned to in-plane N-H bending vibration.


### 3.4.5. Imidazole Vibrations

Imidazole C-H stretching vibrations are expected in the region 3145–3115 cm−1 [31, 32]. Observed Raman bands at 3121 and 3138 cm−1 and IR bands at 3119 and 3138 cm−1 are assigned to C-H stretching mode. The observed Raman band at 1338 cm−1 is attributed to C-C stretching mode [33].


### 3.4.6. Hydrazine Vibrations

In accordance with earlier reports and in agreement with the calculation, a weak band observed at 3207 cm−1 is assigned to hydrazine N-H stretching [27, 34]. Observed bands in IR and Raman at 1089 and 1088 cm−1 are assigned to N-N stretching vibration.


### 3.4.7. Skeletal Mode Vibrations

C-N and C-C stretching vibrations generally occur in the region 1150–850 cm−1 [34]. The weak IR and Raman bands observed at 1011 and 998 cm−1 are attributed to C-C stretching.


## 3.4.1. Phenyl Ring Vibrations

Aromatic C-H stretching vibrations generally absorb in the region 3080–3010 cm−1 [27]. The observed weak IR band at 3119 cm−1 and Raman band at 3121 cm−1 correspond to aromatic C-H stretching mode. The blue shift of the C-H stretching wavenumber is due to weak intramolecular C-H⋯O hydrogen bonding. Aromatic C=C stretching vibrations occur in the region 1625–1430 cm−1 [28]. A medium IR band at 1539 cm−1 and a strong Raman band at 1591 cm−1 are observed, which correspond to aromatic C=C stretching mode. In-plane C-H deformation vibrations appear in the region 1290–1000 cm−1 [27]. Observed IR and Raman bands at 1288 and 1275 cm−1 are assigned to in-plane C-H deformation. In-plane ring deformation vibrations appear in the region 650–615 cm−1. Observed IR and Raman bands at 615 and 640 cm−1 are assigned to in-plane ring deformation.


## 3.4.2. Methylene Vibrations

Asymmetric and symmetric CH2 stretching vibrations normally appear strongly at about 2926 and 2855 cm−1 [29]. The Raman band at 2941 cm−1 is assigned to CH2 symmetric stretching vibration. Methylene scissoring vibrations normally appear in the region 1465–1445 cm−1 [29]. A medium band observed in IR at 1401 cm−1 is attributed to methylene scissoring mode. The twisting, wagging vibrations appear in the region 1422–719 cm−1 [30]. The observed strong IR band at 1141 cm−1 and weak Raman band at 1177 cm−1 are assigned to CH2 twisting modes for methylene. Wagging is observed in IR at 1352 cm−1 and Raman at 1361 cm−1.


## 3.4.3. Methyl Vibrations

The asymmetric C-H stretching mode of CH3 generally occurs at 2982–2962 cm−1 and CH3 symmetric stretching at 2882–2862 cm−1 [29]. A weak Raman band at 2977 cm−1 is attributed to CH3 symmetric stretching. Asymmetric bending vibrations of methyl groups occur in the region 1470–1450 cm−1 [28]. The observed weak Raman band at 1447 cm−1 is assigned to methyl scissoring vibration.


## 3.4.4. Secondary Amide Vibrations

Carbonyl stretching vibration in a secondary amide is expected in the region 1680–1630 cm−1 [28]. A very strong band at 1654 cm−1 is assigned to C=O stretching. N-H stretching vibrations generally appear in the region 3370–3170 cm−1. Observed IR and Raman bands at 3141 and 3140 cm−1 are attributed to N-H stretching. The in-plane N-H bending vibration usually appears from 1570 to 1515 cm−1 [28]. The observed very strong IR band at 1523 cm−1 and weak Raman band at 1527 cm−1 are assigned to in-plane N-H bending vibration.


## 3.4.5. Imidazole Vibrations

Imidazole C-H stretching vibrations are expected in the region 3145–3115 cm−1 [31, 32]. Observed Raman bands at 3121 and 3138 cm−1 and IR bands at 3119 and 3138 cm−1 are assigned to C-H stretching mode. The observed Raman band at 1338 cm−1 is attributed to C-C stretching mode [33].


## 3.4.6. Hydrazine Vibrations

In accordance with earlier reports and in agreement with the calculation, a weak band observed at 3207 cm−1 is assigned to hydrazine N-H stretching [27, 34]. Observed bands in IR and Raman at 1089 and 1088 cm−1 are assigned to N-N stretching vibration.


## 3.4.7. Skeletal Mode Vibrations

C-N and C-C stretching vibrations generally occur in the region 1150–850 cm−1 [34]. The weak IR and Raman bands observed at 1011 and 998 cm−1 are attributed to C-C stretching.


## 3.5. Frontier Molecular Orbital Energy Analysis

HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) are important in defining the reactivity of a chemical species. The energy of HOMO indicates nucleophilicity and LUMO indicates electrophilicity [35]. HOMO is spread over the methyl phenyl, hydrazinecarboxamide fragment and LUMO is located on ph 2. This shows the charge transfer between the two rings through the hydrazinecarboxamide path. The HOMO (−6.61 eV) and LUMO (−1.61 eV) energies reflect the charge transfer within the molecule. The HOMO-LUMO energy gap is 4.46 eV. The frontier molecular orbital diagrams are shown in Figure 4.Figure 4
(a) HOMO and (b) LUMO plots of (2E)-IPPMP.
(a)
(b)


## 3.6. Natural Population Analysis

Natural population analysis provides an effective method to calculate atomic charges and electron distribution within a molecule [36]. The net atomic charges of the (2E)-IPPMP molecule obtained by natural population analysis are plotted in Figure 5. All hydrogen atoms have a net positive charge. The atoms H40 (0.3852e) and H39 (0.3788e) show more positive charge than other hydrogen atoms due to their attachment with a nitrogen atom. Among the hydrogen atoms (~0.2023e) of the phenyl ring, H44 (~0.2452e) shows the highest positive charge, being involved in C-H⋯O intramolecular hydrogen bonding. All carbon atoms are negatively charged except C7, C14, C17, and C20 due to their attachment with electronegative nitrogen or oxygen atoms. The atom C17 (0.7991e) shows more positive charge and N19 (−0.6181e) shows more negative charge, indicating charge delocalization in the molecule.Figure 5
Natural charge distribution chart of the (2E)-IPPMP molecule.


## 3.7. NMR Analysis

The scaled and experimental NMR (1H and 13C) chemical shift values for the (2E)-IPPMP molecule are presented in Table 4. The phenyl and imidazole ring carbon signals usually appear in the region 115–150 ppm. In this molecule, imidazole ring carbon signals are obtained at 119.4, 126.4, and 137.3 ppm, which are predicted at 119.36, 128.75, and 140.01 ppm, respectively.Table 4
NMR chemicals shift values of13C and 1H.
13C
1H
Atom
δ
e
x
p
.
δ
c
a
l
c
.
Atom
δ
e
x
p
.
δ
c
a
l
c
.
C1
128.3
128.01
H27
7.39
7.16
C2
128.9
129.41
H28
7.43
7.19
C3
128.3
127.48
H29
7.39
7.16
C4
128.4
128.13
H30
7.84
7.50
C5
136.8
138.17
H31
7.84
7.63
C6
128.4
126.71
H32
3.33
2.61
C7
153.6
168.87
H33
3.33
2.89
C8
28.3
33.31
H34
4.14
3.77
C9
42.1
44.26
H35
4.14
3.19
C11
119.4
119.36
H36
6.87
6.87
C12
126.4
128.75
H37
7.29
6.56
C14
137.3
140.01
H38
7.65
6.82
C17
144.9
150.09
H39
10.24
6.70
C20
131.5
137.03
H40
8.79
5.70
C21
120.0
115.12
H41
7.13
6.27
C22
128.8
128.43
H42
7.53
6.80
C23
136.3
132.85
H43
7.53
6.85
C24
128.8
128.53
H44
7.13
7.90
C25
120.0
114.58
H45
2.28
1.78
C26
20.4
18.25
H46
2.28
1.80
H47
2.28
2.08Phenyl carbon signals were observed at 120.0, 128.4, 128.8, 128.9, 131.5, 136.3, 136.8, and 137.3 ppm, while their respective calculated ones were obtained at 115.12, 128.13, 128.53, 129.41, 137.03, 132.85, 138.17, and 140.01 ppm. A carbonyl carbon signal was seen at 144.9 ppm and its computed one was obtained at 150.09 ppm. This deviation may occur due to the presence of amide⋯amide interactions in the crystalline state. On the other hand, the computed1H chemical shift values for the title molecule showed good agreement with the experimental ones (Table 4).


## 3.8. Molecular Docking Analysis

The title molecule (2E)-IPPMP was energy minimized based on the DFT method. Molecular docking was performed using AutoDock 4.2. A target protein (PDB ID: 1EOU) for antiepileptic agents was selected for the present docking analysis [37, 38]. The protein data bank file of the target protein was downloaded from the Research Collaboratory for Structural Bioinformatics (RCSB) database, with a resolution of 2.1 Å. Protein preparation was carried out by the following steps: (i) all water molecules were removed, (ii) hydrogen atoms were added to the crystal structure, (iii) Kollman charge was added, and (iv) a previously docked inhibitor (fructose-based sugar sulfamate RWJ-37497) was removed from the protein. Rigid protein and flexible ligand dockings were carried out using the AutoDock 4.2 program package [39] with the Lamarckian genetic algorithm, applying the following protocol: trials of 100 dockings, energy evaluations of 25000000, population size of 200, mutation rate of 0.02, crossover rate of 0.8, and elitism value of 1. The docking results were evaluated by sorting the docked conformations according to their predicted binding free energy. The protein-ligand interaction complex is given in Figure 6, displaying the conformer with the best predicted binding free energy (−7.94 kcal/mol). The amino acids ASN11, TYR7, and LYS169 in the active sites of the target protein bind with the (2E)-IPPMP ligand by N-H⋯O and N-H⋯N hydrogen bonds. These preliminary results support the exhibited anticonvulsant activity of the title molecule.Figure 6
Binding pose diagrams of the (2E)-IPPMP molecule with its target protein.


## 4. Conclusions

The geometry optimization and harmonic wavenumbers of the (2E)-IPPMP molecule have been performed at ground state calculations using the DFT method. FT-IR and FT-Raman measurements helped functional group identification of the title molecule. The fundamental wavenumbers are in good agreement with the theoretical results. Shifting of vibrational wavenumbers and hyperconjugative results confirmed the presence of intermolecular/intramolecular interactions in the molecule. The molecular docking results predicted the anticonvulsant activity of the (2E)-IPPMP molecule due to its ability to interact with a target protein (1EOU) for anticonvulsants. The results of the current study will support the development of new drug-like candidates in the anticonvulsant research area.



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*Source: 8520757-2016-05-25.xml*