Spectroscopic (FT-IR, FT-Raman, UV, ¹H and ¹³C NMR) insights, electronic profiling and DFT computations on ({(E)-[3-(1H-imidazol-1-yl)-1-phenylpropylidene] amino}oxy)(4-nitrophenyl)methanone, an imidazole-bearing anti-Candida agent

2.1 General

The FT-IR spectrum of the IPAONM molecule has been recorded with a Perkin-Elmer 180 Spectrometer in the range of 4000–400 cm⁻¹ with spectral resolution ± 2 cm^-1. Its FT-Raman spectrum was also recorded in 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 μm line widths with 200 mW powers. The spectra were recorded with scanning speed of 30 cm^-1. min^-1 with spectral width of 2 cm^-1. The frequencies of all sharp bands were accurate to ± 1 cm^-1. NMR spectra of the IPAONM were recorded on a Bruker NMR spectrometer (Bruker Biospin, Billerica, MA, USA). ¹H spectrum was run at 500 MHz and ¹³C spectrum was run at 125 MHz in deuterated dimethyl sulfoxide (DMSO-d6). The UV–Vis spectrum of the title molecule was registered in the range of 200–400 nm in acetonitrile using Shimadzu UV-2101 PC, UV–Vis recording spectrometer. All solvents and reagents were purchased from Sigma-Aldrich Chemie GmbH (Taufkirchen, Germany) and were pure enough to be used without further purification.

2.2 Synthesis

Preparation of ({(E)-[3-(1H-imidazol-1-yl)-1-phenylpropylidene] aminooxy)(4-nitro phenyl)methanone (5)

The title compound 5 was prepared according to the previously reported method [8]. The NMR spectral data of compound 5 are in agreement with the previously reported ones [8].

2.3 Quantum Chemical Calculations

The entire quantum chemical calculations have been performed using Hartree Fock (HF) and density functional theory (DFT, B3LYP) methods with 6-311G(d,p) basis set using the Gaussian 09 W program [9]. The optimized structural parameters have been evaluated for the calculations of vibrational frequencies at different level of theories. At the optimized geometry for the IPAONM molecule no imaginary wavenumbers were obtained, so there is a true minimum on the potential energy surface. As a result, the calculated frequencies, reduced masses, force constants, infrared intensities, Raman activities and depolarization ratios were obtained. In order to improve the computed values to be in agreement with the observed experimental values, it was necessary to scale down the calculated harmonic frequencies. Hence, the wavenumbers calculated at HF level were scaled by 0.9067 and the range of wavenumbers above 1700 cm^-1 were scaled by 0.958 and below 1700 cm^-1 by 0.983 for the B3LYP method [10,11]. The assignments of the calculated modes have been made on the basis of the corresponding PEDs. The vibrational frequencies were calculated using VEDA program [12]. GaussView program [13] was used in order to get visual animation and also for the verification of the normal modes assignments. The electronic absorption spectra for the optimized molecule were calculated with the time dependent density functional theory (TD-DFT) at B3LYP/6-311G(d,p) level.

Ethical approval: The conducted research is not related to either human or animals use.

3.1 Synthesis

The title compound 5 was prepared by adopting the previously reported literature procedure [8] as illustrated in Scheme S1. The spectral data of the title compound 5 are consistent with the previously reported ones [8].

3.2 Molecular Geometry

Molecules bearing oxygen or nitrogen substituents on their ring systems have the mono substituent co-planar with the ring. The selected optimized DFT geometries of the IPAONM molecule are calculated by HF and B3LYP methods with 6-311G(d,p) as a basic set with atom numbering as shown in Figure 1. The calculations are converged to optimized geometries, which correspond to the true energy minima, as revealed by the lack of imaginary frequencies in the vibrational mode calculations.

Figure 1

The optimized possible geometric structure with atoms numbering of the IPAONM molecule.

3.3 Geometric Structure

A conformation analysis was carried out on the IPAONM molecule in order to determine its most stable conformation. The crystal structure of the title compound is indicated in the Figure 2. The potential energy obtained by the rotation of the two dihedral angles C5-C7-C8-C9 and O16-C17-C18-O19 group from 0° to 360° in PM6 method is depicted in Figure 3. The most stable conformers are at 90° for SC1 and at 320° for SC2 with energy value = 0.0761424 a.u. The optimized geometry of the title molecule afforded one conformer at this stage. The selected optimized parameters were collected and compared with the experimental X-ray data [8] as illustrated in Table 1. The most stable conformer possesses the global minima on its potential energy surface as its calculated vibrational spectrum contains no imaginary wavenumbers.

Figure 2

The crystal structure of the IPAONM molecule.

Figure 3

The potential energy scan picture the IPAONM molecule.

These optimized parameters are in agreement with the crystallographic values (Table 1). The aromatic N-O bond distances of IPAONM were found to have lower values in case of HF calculations with respect to B3LYP computations. The oxygen–carbon bonds are not of the same length. The elongation of O16-C17 could be attributed to its presence in the main chain. The N-C bond distances are present between 1.469 to 1.265 Å. The N42-C22 is the longest bond among the N-C bonds and its length is 1.469 Å. In the imidazole ring, the bonds N10-C9, N13-C12, N13-C14, N10-C11 and N10-C14 are 1.453, 1.355, 1.371, 1.309 and 1.414 Å in length, respectively.

The HF and B3LYP calculations also gave dihedral angles values that are consistent with the selected experimental values (Table 1). The highest value was 127.82° in case of C9-N10-C11, while the bond angle C14-N10-C11 possesses the smallest selected bond angle being about 104.9°. Moreover, the bond angles, O19-C17-O16 and O25-N42-O43 have the values of 125.13° and 123.17°, respectively.

3.4 Mulliken Atomic Charges

Mulliken atomic charge calculations have a substantial role in the quantum chemical calculations of molecular systems because they affect a lot of their properties. The calculated Mulliken charge values of the title compound IPAONM are listed in Table S1 and its charge distribution is shown in Figure 4. The Mulliken charges of the IPAONM molecule presumably occur due to polarization on the molecule. The charges of the NO₂ moiety are -0.258427 e^_ on one oxygen atom, -0.259955 e^- on the other oxygen atom and 0.173708 e^- on the nitrogen atom using B3LYP/6-311G(d,p) method which are less than the values obtained by HF/6-311G(d,p) method. All nitrogen atoms are negatively charged except for N42. The Mulliken charges on nitrogen atoms N10 and N13 are more negative than that on N15. All aromatic carbon atoms are negatively charged using B3LP/6-311G(d,p) method except C22 due to its bonding with the nitro group . C7 and C17 are the highest positively charged carbon atoms by B3LYP method due to their bonding to nitrogen and oxygen atoms, respectively. All hydrogen atoms are positively charged using both HF and B3LP methods (Figure 4).

Figure 4

The Mulliken charge distribution for the IPAONM molecule.

3.5 Frontier Molecular Orbitals (FMOs)

HOMO is the highest occupied molecular orbital and LUMO is the lowest-lying unoccupied molecular orbital and together they are named frontier molecular orbitals (FMOs). The FMOs play a crucial role in many optical and electric properties as well as in quantum chemistry and UV–Vis spectra of molecules [14]. The HOMO makes up the ability to donate electrons, while LUMO as an electron acceptor. The energy gap between HOMO and LUMO decides the kinetic stability, chemical reactivity, optical polarizability and chemical hardness–softness of a molecule [15].

The energies of the four important molecular orbitals, the highest and the second highest occupied MO’s (HOMO and HOMO–1) as well as the lowest and the second lowest unoccupied MO’s (LUMO and LUMO+1), of the IPAONM molecule were calculated using B3LYP method at 6-311G(d,p) level. The 3D plots of the HOMO-1, HOMO, LUMO and LUMO+1 orbitals computed at the B3LYP/6-311G(d,p) level for the IPAONM molecule are illustrated in Figure 5. The positive phase is red and the negative one is green. It is clear from Figure 5 that while the HOMO is localized on the imidazole moiety of the IPAONM molecule, the LUMO is localized on the nitrophenyl ring. However, the HOMO-1 is localized on the other phenyl ring, LUMO+1 is localized on both phenyl ring and the nitro group of the title molecule. Both the HOMOs and the LUMOs are mostly π-antibonding type orbitals.

Figure 5

The molecular orbitals and energies for the HOMO-1, HOMO, and LUMO and LUMO+1 of the IPAONM molecule.

The calculated energy values of the title molecule are HOMO = −6.5688 and LUMO = −3.1197 eV. The value of energy separation between the HOMO and LUMO is -3.4491 eV (Table 2). The HOMO–LUMO energy gap of the title molecule explains the charge transfer interaction inside the molecule, which influences its bioactivity. Increasing the value of the energy gap indicates more stability of the molecule.

3.6 Electrostatic Potential, Total Electron Density and Molecular Electrostatic Potential

The electrostatic potential (ESP), total electron density (TED) and molecular electrostatic potential (MEP) of the title molecule are illustrated in Figure 6. The yellowish blob in the ESP Figure reflects the negative portion of the title molecule. However, the MEP diagram represents the constant electron density surface of the IPAONM molecule. The MEP diagram is a useful tool to analyze the reactivity of the molecules toward electrophiles and nucleophiles. In the majority of the MEPs, the maximum positive and negative regions in the molecule are indicated by red and green colors which are the preferred sites to be attacked by electrophiles and nucleophiles, respectively. The importance of the MEPs resides in the fact that they display at the same time the molecular size, shape as well as positive, negative and neutral electrostatic potential regions of the molecule in terms of color grading. They are also a very useful tool correlating molecular structure with the physiochemical properties of the molecule [16,17,18].

Figure 6

Electrostatic potential (ESP), electron density (ED) and the molecular electrostatic potential map (MEP) for the IPAONM molecule.

The electrostatic potential at the surface of the IPAONM molecule is represented by different colors in the order red < orange < yellow < green < blue in the range between -0.0568 a.u. (deepest red) to 0.0568 (deepest blue). The blue color indicates the strongest attraction, while the red color indicates the strongest repulsion. The negative potential was manifested over the electronegative oxygen atoms of the nitro group in the MEP diagram of the title molecule with values of -0.04086 and -0.04019 a.u.

3.7 Natural Bond Orbital (NBO) Analysis

The larger the stabilization energy value of the molecule, the more significant is the interaction between the donors and acceptors, i.e. the more giving tendency there is from donors to acceptors, the greater the extent of conjugation of the entire system. The intramolecular interactions of the title molecule are formed by the orbital overlap between σ(C-N), σ*(C-N), σ(N-C), σ*(N-C), σ(C-O), σ*(C-O), σ(O-N), σ*(O-N), σ(N-O), σ*(N-O) and π(C-C), π*(C-C) bond orbitals. These fundamental interactions were observed as a gain in the electron density (ED) in the C-C antibonding orbitals that weaken the respective bonds. These intramolecular charge transfers (σ → σ*, π → π*) can induce large nonlinearity of the IPAONM molecule.

Natural bond orbital (NBO) analysis has been carried out on the IPAONM molecule at the B3LYP/6-311G(d,p) level in order to elucidate its possible intramolecular, rehybridization and delocalization of the electron density within the molecule. The intramolecular hyperconjugation interactions of the σ and π electrons of C-N, N-C, C-O, O-N and N-O to the anti C-C, C-H, C-N and N-O bonds in the title molecule lead to stabilization of the respective moieties within the molecule as evident from Table S2. The strong hyperconjugative interactions of the σ electron of σ (N10–C11) are distributed to σ*(C9-N10), N10-C14, C11-C12, C12-N13, C12-H36, N13-C14 and C14-H37 of the imidazole ring with energy values of 1.86, 2.47, 1.47, 0.73, 3.19, 0.63 and 2.89 kcal/mol, respectively. On the other hand, the σ (C17-O19) and π (C17-O19) bonds are distributed to π*(C18-C20) with energy values of 1.08 and 4.36 kcal/mol, respectively. In addition, in the LP N10 and LP N13 are distributed to the LP*(1) (C11-C12) bond with energy values of 30.68 and 5.46 kcal/mol, respectively.

3.8 Electronic Absorption Spectra

Based on a fully optimized ground-state structure of the of the IPAONM molecule, B3LYP/6-311G(d,p) calculations have been carried out to determine its low-lying excited states. The experimental (in acetonitrile) and theoretical UV absorption wavelengths (in acetonitrile, aniline, chloroform, DMSO, ethanol, methanol and toluene) of the title compound are shown in Figure S1 and Table 3. Calculations involving the vertical excitation energies, oscillator strengths (f) and wavelengths (λ) have been performed and the results were compared with experimental values [19]. The major contributions of the transitions of the IPAONM molecule were designated with the aid of SWizard program [20]. The predicted wavelengths using B3LYP/6-311G(d,p) calculations in acetonitrile are 411.65, 358.21, 318.02, 315.99 and 299.80 nm, whereas the experimental wavelengths in acetonitrile are 235.10 and 282.80 nm. In view of the calculated absorption spectra of the title compound, the maximum absorption wavelengths correspond to the electronic transitions from the highest occupied molecular orbital HOMO to the lowest unoccupied molecular orbital LUMO with 100% contribution and the transitions from HOMO-9 to LUMO with 85% except with chloroform and toluene.

3.9 Topological Analysis

The structure of the IPAONM molecule was also analysed by Bader’s charge electron density topological analysis [21,22]. In the topological atoms in molecules (AIM) theory, the chemical bonds and molecular reactivity are interpreted in terms of the total molecular electronic density ρ(r) and its corresponding Laplacian ∇²ρ(r). The ρ(r) and ∇²ρ(r) values at the bond critical points (BCP1 and BCP2) allow the characterization of the chemical bonds between atoms of the molecule. Different studies have pointed out that formation of hydrogen bonds was associated with the appearance of BCP1 and BCP2 between hydrogen atoms and the acceptor atoms, which are linked by the concomitant bond path [23,24,25]. The positive Laplacian value of the electron density ∇²ρ(r) indicates that the interaction is dominated by the contraction of charge away from the interatomic surface toward each nuclei. Figure 7 illustrated the AIM molecular graphic of the title molecule showing its different bonds and ring critical points obtained by B3LYP/6-311G(d,p) method. The Laplacian values of the IPAONM molecule at the BCP1 and BCP2 of H37-H38 and H30-H32 bonds are 0.0069 and 0.0473 a.u., respectively, while their Lagrangian kinetic energy density G(r) and energy density H(r) values are 0.0013, 0.0096 and 0.0004, 0.0022 a.u., respectively.

Figure 7

The topological diagram of the IPAONM molecule.

3.10 Vibrational Analysis

All vibrations are active in both Raman and infrared absorptions. The detailed vibrational assignments of the experimental wavenumbers are based on normal mode analyses and a comparison with theoretically scaled wavenumbers with PED by B3LYP method. Since the scaled wavenumbers following B3LYP/6-311G(d,p) method were found to be close to the experimental data than the results obtained using HF method, so only the PEDs from this set of data are discussed in detail. The observed and simulated FT-IR and laser Raman spectra of the IPAONM molecule are shown in Figures 8 and 9, respectively. The observed and scaled theoretical frequencies using HF and DFT (B3LYP) with 6-311G(d,p) basis set, infrared intensities and Raman activities of B3LYP/6-311G(d,p) are listed in Table 4.

Figure 8

Experimental FT-IR and FT-Raman and spectra of the IPAONM molecule.

Figure 9

Simulated FT-IR and FT-Raman and spectra of the IPAONM molecule.

3.11 NMR Analysis

The calculated ¹H and ¹³C NMR chemical shift values of the IPAONM molecule are presented in Table 5 and have been compared with the experimental data. ¹H and ¹³C NMR chemical shifts are reported in ppm relative to TMS. Full geometry optimization of the IPAONM molecule was carried out at the gradient corrected density functional level of theory using the hybrid B3LYP method based on Becke’s three parameters functional of DFT. Thereafter, gauge-including atomic orbital (GIAO) ¹H and ¹³C chemical shift calculations of the title compound was performed by the same method using 6-311G(d,p) basis set and integral equation formalism-polarizable continuum model (IEF-PCM)/DMSO variant.

Aromatic carbons gave calculated signals in the overlapped areas of the ¹³C spectrum of the title molecule with chemical shift values in the range of 134.4 to 158.1 ppm. Their corresponding experimental chemical shift values occurred in the range of 128.5-150.4 ppm. Moreover, the highest ¹³C chemical shift values were observed for C17 and C7 to be 165.1 and 161.4 ppm due to their connection to oxygen and nitrogen atoms, respectively, while the imidazole carbons C11, C12 and C14 were noticed at 119.4, 127.3 and 137.2 ppm, respectively, in which C14 is the most downfield carbon atom due to its bonding with two nitrogen atoms. One the other hand, the ethylene carbons, C8 and C9, manifested the lowest chemical shift values at 30.1 and 43.0 ppm, respectively, in the ¹³C NMR spectrum of the IPAONM molecule.

The calculated chemical shift values for the aromatic hydrogens of the title compound lie in the range of 7.7-8.7 ppm and their respective observed values occurred in the range of 7.5-8.4 ppm. The aromatic protons H38, H39, H40 and H41 are the most downfield protons due to their connection to the nitro-substituted aromatic ring, whereas the ethylene protons H31, H32, H33 and H34 appear in the range of 3.6-4.3 ppm being the most upfield protons in the ¹H NMR spectrum of the IPAONM molecule. There is a good agreement between the experimental and theoretical chemical shift values of the title compound.