3.1. Synthesis
The title compound
2 was prepared in a three-step reaction sequence as depicted in
Scheme 1.
Scheme 1.
Synthetic pathway for the target compound 2.
Scheme 1.
Synthetic pathway for the target compound 2.
Reagents and conditions: (i) HN(CH3)2∙HCl, (CH2O)n, conc. HCl, ethanol, reflux, 2 h; (ii) imidazole, water, reflux, 5 h; (iii) N-phenylhydrazinecarboxamide, drops of acetic acid, ethanol, rt, 18 h.
3.3. Potential Energy Surface Scan Grid
A potential energy surface scan was used to determine the optimized molecular structure of the (2
E)-HIPC molecule in its equilibrium state and to determine the most stable structure at the global minimum of the potential energy surface. The energy surface scan grid for the title molecule was performed using the AM1 method, and the N16–C17–N18–C20 and C9–C8–C7–C5 dihedral angles were rotated for various geometries. The rotation angles of the two benzene rings with respect to the imidazole ring were computed by varying the dihedral angles. A potential energy scan of the (2
E)-HIPC molecular geometry was performed by freezing the N16–C17–N18–C20 (SCAN1) and C9–C8–C7–C5 (SCAN2) dihedral angles and varying the dihedral angles values in 18 steps of 20° from −179° to 179° and from 0° to 180° for N16–C17–N18–C20 and C9–C8–C7–C5, respectively. A 3D view of the (2
E)-HIPC rotational conformer is shown in
Figure 1. This scan revealed that the optimized molecular geometries at 170 out of 361 with N16–C17–N18–C20 and C9–C8–C7–C5 dihedral angles of −19.42° and 440.713°, respectively, were the ground state conformations. The potential energy surface (PES) scan grid and the calculated optimized conformers were determined in the gas phase. The PES scan of the dihedral angle rotations resulted in 361 conformers. Two rotational global minimum energy conformers were identified for the title compound.
Figure 1 illustrates the various levels of energies using colors where dark blue indicates the global minimum, light blue indicates a local minimum, red indicates a local maximum, and dark red indicates a global maximum.
Figure 1.
Potential energy surface grid of (2E)-HIPC.
Figure 1.
Potential energy surface grid of (2E)-HIPC.
Rotational conformers
I and
II, which are shown in
Figure 2, were optimized with the AM1 and B3LYP methods in the gas phase, DMSO, and acetonitrile. The global minimum energies and dipole moments for the conformers are presented in
Table S1. Conformer
I exhibited the lowest global minimum energies of 0.1695246 and −1084.70550 Hartree in DMSO solution using AM1 and B3LYP, respectively, compared with the obtained values in the gas phase and in acetonitrile. This result was confirmed by the computed dipole moment values in DMSO, which were 7.1931 and 7.4136 Debye using the AM1 and B3LYP methods, respectively. Therefore, conformer
I was computed to have the minimum global energy, and this optimized molecular structure was used for further analysis.
Figure 2.
Rotational conformers of (2E)-HIPC. (A) Conformer I by rotation of scan 1 = −71.425° and scan 2 = 0° or 360°. Energy (B3LYP) = 1084.7055 hartree; (B) Conformer II by rotation of scan 1 = −71.574° and scan 2 = 0° or 360°. Energy (B3LYP) = 1084.6857 hartree.
Figure 2.
Rotational conformers of (2E)-HIPC. (A) Conformer I by rotation of scan 1 = −71.425° and scan 2 = 0° or 360°. Energy (B3LYP) = 1084.7055 hartree; (B) Conformer II by rotation of scan 1 = −71.574° and scan 2 = 0° or 360°. Energy (B3LYP) = 1084.6857 hartree.
3.4. Geometry of the Title Molecule
The optimized molecular structure of (2
E)-HIPC with labeled atoms is shown in
Figure 3. Selected optimized theoretical parameters in the gas phase and X-ray diffraction geometrical parameters of (2
E)-HIPC are listed in
Table S2. The optimized bond lengths of the C–C bond in the phenyl ring of (2
E)-HIPC fall in the range of 1.390–1.409 Å and 1.380–1.391 Å in the B3LYP and HF methods, respectively. The observed XRD data for these bond lengths in (2
E)-HIPC fall in the range from 1.368 to 1.393 Å, which are in good agreement with the values obtained using the HF method. The mean aromatic ring C–C bond distance is 1.385 Å by the HF method, which is consistent with the experimental value (1.382 Å). The optimized C–C bond length in the imidazole ring of (2
E)-HIPC is 1.353 Å using the HF method, which is slightly longer than the observed XRD value (1.350 Å).
Figure 3.
Optimized molecular structure of (2E)-HIPC.
Figure 3.
Optimized molecular structure of (2E)-HIPC.
The optimized bond length for the C=O bond in the title compound is 1.221 Å by the HF method, which is in a good agreement with the experimental value (1.227 Å). It is interesting that the calculated N15–N16 bond length in the side chain of the title molecule is almost the same as the observed XRD value (1.384 Å). Based on the above comparisons, although there are some differences between our values and the literature data, the optimized geometric parameters can reproduce the literature values well and are the basis for subsequent discussion. The theoretical optimized C–H bond lengths show large deviation from the experimental values, which may originate from the low scattering factors of hydrogen atoms in the XRD. The C–H bond lengths determined using the HF method lead to geometric parameters that are much closer to the experimental data. The ring C–N bond distances are in the range of 1.353 to 1.412 Å using both the HF and B3LYP methods, while the observed XRD values are in the range of 1.347 to 1.418 Å. The longest bond length was found in C20–N18 due to the close C=O group. The influence of different groups in the title compound on the bond length and dihedral angle parameters seems to be negligibly small. The mean angle deviation of the phenyl ring carbon atoms C–C–C was found to be greater by 0.2° in the HF method and by 0.1° in the B3LYP method than the corresponding XRD values. A large deviation was observed between theoretical and experimental XRD values in the bond angles of H38–N16–N15 and H35–C11–C12. The hydrogen bonding geometrical parameters [
14] are presented in
Table S3. The N–H···N and C–H···O bonds are identified as the NH and CO groups of (2
E)-HIPC. These bonds are overestimated compared with the XRD values, whereas the H···N and H···O bonds are best fit with the HF and B3LYP values. Additionally, most of the intramolecular bond angles are in good agreement with the experimental values.
3.5. Frontier Molecular Orbitals (FMOs) and Ultraviolet Spectral Analysis
The excitation energies obtained using the TD-DFT/B3LYP method were computed for five excited electronic states. To enable a more relevant comparison between the theoretical and experimental data, the calculated transition energies were uniformly blue shifted such that the calculated and measured energies of the most intense transitions matched. The UV calculations were performed for a single molecule in the gas phase, DMSO, and acetonitrile without interactions with the environment, and the computed results were directly compared to the measured UV data for (2E)-HIPC in acetonitrile solution.
Figure 4.
Theoretical (B3LYP) and experimental UV-Vis spectra of (2E)-HIPC.
Figure 4.
Theoretical (B3LYP) and experimental UV-Vis spectra of (2E)-HIPC.
The major energy contribution was approximately 0.98 in HOMO to LUMO for all three UV analyses. The 100–400 nm wavelength regions of the theoretical and experimental UV spectra of (2
E)-HIPC are illustrated in
Figure 4. The observed electronic absorption wavelengths at 250–320 nm were assigned to the π-to-π* transitions. The computed electronic absorption wavelengths were calculated to be 347.13, 304.34, 283.91, 274.33, and 267.55 nm in the gas phase; 318.40, 286.17, 278.08, 262.57, and 252.13 nm in DMSO; and 319.90, 287.47, 279.77, 265.00, and 254.05 nm in acetonitrile. The corresponding dipole moment values were 6.6951, 8.4925, and 8.6364 Debye. Based on a comparison of the dipole moments of DMSO and acetonitrile, more electronic transitions occur in acetonitrile due to its value. It is worth mentioning that the experimental and calculated absorption wavelengths are in good agreement, as shown in
Figure 4.
HOMO-LUMO or frontier molecular orbitals (FMOs) are an important measure of the nonlinear optical and electric properties, which can be obtained from quantum chemistry, UV-Vis, and NMR spectra [
20]. The HOMO has the ability to donate an electron, and the LUMO, which acts as an electron acceptor, has the ability to receive an electron. GaussSum 2.2 software [
21] was used to calculate the minor and major energy contributions to the HOMOs and LUMOs. The energy gap between the FMOs determines the kinetic stability, chemical reactivity, optical polarizability, and chemical hardness/softness of a molecule. Chemical hardness and softness can be used as an additive tool to describe the thermodynamic aspects of chemical reactivity. To assess the trends in the transition energies of (2
E)-HIPC, we carried out calculations for (2
E)-HIPC in acetonitrile, DMSO, and the gas phase. The energies of the FMOs for (2
E)-HIPC (
i.e., HOMO, HOMO−1, LUMO and LUMO +1) were calculated at the B3LYP/6-311++G(d,p) level, and the results are listed in
Table S4. The values of the HOMO-LUMO energy gap were 4.3772, 4.3994, and 4.0621 eV for (2
E)-HIPC in acetonitrile, DMSO, and the gas phase, respectively.
The energy gap of the FMOs explains the ultimate charge transfer and interactions of atoms within the molecule. This activity influences the biological functions of the molecule. Three-dimensional plots of the HOMO and LUMO orbitals were computed at the B3LYP/6-311++G(d,p) level. Positive charge is shown in violet, and negative charge is shown in green. Based on the results shown in
Figure 5, although the HOMO was localized on one benzene ring, the LUMO was localized on a different benzene ring as well as on the chain linking the two rings.
Figure 5.
3D plots of the HOMO and LUMO of (2E)-HIPC at the B3LYP level.
Figure 5.
3D plots of the HOMO and LUMO of (2E)-HIPC at the B3LYP level.
The values of electronegativity, chemical hardness, softness, and electrophilicity index for (2E)-HIPC in acetonitrile were 3.9125, 2.1886, 1.0943, and 5.2418 eV, respectively. These values are between the corresponding values for (2E)-HIPC in DMSO and in the gas phase. The lowest value of the dipole moment was calculated for the gas phase. The stronger intermolecular interactions in acetonitrile are due to the dipole moment value being larger than those in DMSO and the gas phase.
The electronic transitions and UV spectra of (2
E)-HIPC were computed using the TD-DFT/IEFPCM approach at the B3LYP/6-311++G(d,p) level. The calculations were performed for (2
E)-HIPC in acetonitrile, DMSO, and the gas phase. The frontier orbital energies, absorption wavelengths (λ), oscillator strengths (
f), and excitation energies (E) for (2
E)-HIPC were computed in the gas phase, DMSO, and acetonitrile; the data are presented in
Table S5. TD-DFT calculations for (2
E)-HIPC predicted an intense electronic transition at 279.7 nm (
f = 0.4339) in acetonitrile, 278.0 nm (
f = 0.4700) in DMSO, and 284.9 nm (
f = 0.5114) in the gas phase. The observed differences are due to shifting of the bands in both DMSO and acetonitrile due to their permittivities. The results are better represented in graphical form, as shown in
Figure 4. Experimentally, absorption peaks of (2
E)-HIPC in acetonitrile were observed at 283.1, 234.9, and 199.4 nm. The observed values are shifted downfield compared with the corresponding computed values. The major energy contributions were computed.
3.6. Electrostatic Potentials, Total Electron Densities, and Molecular Electrostatic Potentials
The molecular electrostatic potentials (MEPs) of the title compound were calculated using the B3LYP and HF methods in the gas phase, as shown in
Figure 6. The MEP maps of (2
E)-HIPC indicate that the regions of negative electrostatic potential lie outside of the compound and near the oxygen atom. For the imidazole ring of (2
E)-HIPC, the negative electrostatic potential lies outside the ring.
Therefore, no favorable location exists for the formation of a normal cation above the ring. The molecular electrostatic potential (red color) was located on the N and O atoms belonging to the imidazole ring and C=O group, respectively. Less negative values were observed on the N–H groups (blue color). Both regions should be different because they are the principal acceptor and donor sites of the H bonds. In the vicinity of the nitrogen and oxygen atoms, the charge magnitude varies from −0.008 to −0.02. In the benzene ring, the charges vary from 0.008 to 0.8 from the inner to the outer contour. The electrostatic potential of different atoms on the surface is represented by different colors. The value of the electrostatic potential increased from red (more negative) to blue (more positive). The coloring of these maps represents a range of −0.06023 a.u. (deepest red) to 0.06023 a.u. (deepest blue) at the B3LYP/6-311++G(d,p) level and −0.06321 a.u. to 0.06321 a.u. at the HF/6-311++G(d,p) level. The atomic sites colored in the MEP map indicate the strongest attraction in blue and the strongest repulsion in red. The electrostatic potential of C17 is more positive (0.718286) due to the high electronegativity of the neighboring O19 atom. N18 is more negative (−0.638291) due to the nearby oxygen and intramolecular bonding of H39 with N15. All of the hydrogen atoms have positive potentials. C7 and C8 have positive potentials, and C9 has a negative potential in the side chain carbon atoms. All carbons in the rings have negative electrostatic potentials except for C14 due to its bonding with two nitrogen atoms.
Figure 6.
A representative illustration of the molecular electrostatic potentials (MEPs) (A) and contour map of (2E)-HIPC (B).
Figure 6.
A representative illustration of the molecular electrostatic potentials (MEPs) (A) and contour map of (2E)-HIPC (B).
3.8. NMR Analysis
NMR parameters are used to determine the chemical environment of the molecule. The isotopic shifts provide essential information for understanding the microscopic environment of the molecules. DFT calculations were used to assign and analyze the experimental NMR spectra. DFT calculations were performed for (2
E)-HIPC in different solvents to improve the accuracy of the predicted NMR values. The observed and simulated
1H and
13C NMR spectra of (2
E)-HIPC are shown in
Figure 9. The observed and theoretical values from the
1H and
13C NMR spectra of (2
E)-HIPC are listed in
Table S7. The chemical shifts were calculated for (2
E)-HIPC in DMSO and acetonitrile, and the results were compared with the experimental data for (2
E)-HIPC in DMSO. In the
1H NMR spectrum, the signal at 145.1 ppm was due to the carbon atom (C17) attached to the oxygen atom. Similarly, the peaks located at 153.6 and 138.9 ppm were due to carbon atoms in the side chain, C7 and C14, respectively, located between the two nitrogen atoms in the imidazole ring. The chemical shifts for carbon atoms C20 and C5 in the benzene rings increased due to the attachment of the side chains. Of these two carbon atoms, C20 was upshifted due to its attachment to a nitrogen atom. In addition, the computed values were higher than the observed values. The chemical shifts of ring carbon atoms C2, C4, C6, C24, C22, C1, and C3 were observed at 128 ppm. The chemical shifts of the first two carbons (
i.e., C2 and C4) were estimated to be smaller than the calculated values. The more upfield-shifted carbon atoms in the benzene ring were C21, C23, and C25. The observed chemical shifts of the imidazole ring carbon atoms (
i.e., C11 and C12) were 119.4 and 126.4 ppm, respectively.
The 1H NMR spectrum of (2E)-HIPC contains five sets of peaks between 3.33 and 10.27 ppm. The 1H NMR signal splitting was caused by spin–spin coupling between nearest nuclei. The two triplets obtained at 3.33 and 4.13 ppm were due to the splitting of the signals of the side-chain hydrogen atoms and were assigned to the equivalent protons H31 and H32 and to the equivalent protons H33 and H34, respectively. The two triplets observed at 3.33 and 4.13 ppm were due to the splitting of the signals of the side-chain hydrogen atoms. The 1H NMR splitting from 6.87 to 7.43 ppm was due to the signals from the hydrogen atoms (i.e., H35, H36, and H37) attached to the imidazole ring. The observed signal due to NH38 at 10.27 ppm exhibited a large chemical shift compared with the calculated values for (2E)-HIPC in DMSO and acetonitrile. The signal of the other NH39 exhibited an upfield chemical shift (8.88 ppm) due to intramolecular hydrogen bonding with N15. This intramolecular hydrogen bonding was confirmed by comparison to the calculated values for (2E)-HIPC in both DMSO and acetonitrile. The root mean square deviations (RMSDs) for 13C NMR are 4.499 and 3.794 in DMSO and acetonitrile, respectively. However, a small deviation was observed for 1H NMR in both solvents. The calculated chemical shift values for both the 1H and 13C NMR spectra of (2E)-HIPC in DMSO exhibited good linear fits with the experimental values.
Figure 9.
Theoretical and experimental 13C and 1H NMR of (2E)-HIPC.
Figure 9.
Theoretical and experimental 13C and 1H NMR of (2E)-HIPC.