key: cord-0022910-2kuhne09
authors: Medimagh, Mouna; Issaoui, Noureddine; Gatfaoui, Sofian; Antonia Brandán, Silvia; Al-Dossary, Omar; Marouani, Houda; J. Wojcik, Marek
title: Impact of non-covalent interactions on FT-IR spectrum and properties of 4-methylbenzylammonium nitrate. A DFT and molecular docking study
date: 2021-10-19
journal: Heliyon
DOI: 10.1016/j.heliyon.2021.e08204
sha: 51114e3d42eedda7d66227ca0b15d16d11033e89
doc_id: 22910
cord_uid: 2kuhne09

In this research, the impact of non-covalent interactions on the FT-IR spectrum and structural, electronic, topological and vibrational properties of hybrid 4-methylbenzylammonium nitrate (4MBN) have been studied combining B3LYP/CC-PVTZ calculations with molecular docking. 4MBN was synthesized and characterized by using the FT-IR spectrum while the optimized structures in gas phase and in ethanol and aqueous solutions have evidenced monodentate coordination between the nitrate and methylbenzylammonium groups, in agreement with that experimental determined for this species by X-ray diffraction. Here, non-covalent interactions were deeply analyzed in terms of topological parameters (AIM), electron localization function (ELF), localized orbital locator (LOL), Hirshfeld surface and reduced density gradient (RDG) method. Weak interactions such as H-bonds, VDW and steric effect in 4MBN were visualized and quantified by the independent gradient density (IGM) based on the promolecular density. The hyper-conjugative and the delocalization of charge in 4MBN have been elucidated by natural bonding orbital (NBO) while its chemical reactivity was studied and discussed by using molecular electrostatic potential surface (MESP), frontier molecular orbital (FMOs), density of state (DOS) and partial density of state (PDOS). The complete vibrational assignments of 69 vibration modes expected for 4MBN are reported together with the scaled force constants while the electronic transitions were evaluated by TD-DFT calculations in ethanol solution. Thermal analysis (DTA and DSC) was also determined. Molecular docking calculations have suggested that 4MBN presents biological activity and could act as a good inhibitor against schizophrenia disease.

In recent years, molecular modelling has become a widely used tool for research and modelling new chemical compounds because it is a handy technical to reconstruct the structures of molecules from experimental data. Numerous experimental and theoretical studies have been carried out for a better prediction and understanding of the structures, molecular interactions and various properties of chemical species [1] . Thus, many studies on the most important inter and intra-molecular interactions have allowed describing, measure and comprehending their nature [1, 2] . In particular, the weak interactions are well known in various physical, chemical and biological fields [2] while the non-covalent interactions exist in the crystal structure of hybrids to ensure maintain the geometry of large molecules. In fact, the concept of "hybrid material" is utilized in many applications because it combines both organic and inorganic entities. In this research work, we have studied the hybrid material, 4-4-methylbenzylammonium nitrate (4MBN) whose structure was already determined by X-ray diffraction [3] . This material consists of an organic unit which is 4-methylbenzylammonium and an inorganic unit which is nitric acid. This type of material which combines the nitrate anion with the organic molecule has attracted attention due to their many uses in different fields, such as biomolecular science, liquid crystals, catalysts and fuel cells [4] . So far, the vibrational study, complete vibrational assignments and properties of 4MBN even not were reported yet. Hence, one of aim of this work is the vibrational study of 4MBN by using the FT-IR spectrum, the normal internal coordinates and the SQMFF methodology in order to analyze the coordination mode between inorganic and organic species based on the corresponding vibration modes and taking into account assignments for similar species [5, 6, 7, 8] . To achieve this purpose, DFT calculations were employed to study the structure and physico-chemical properties in order to reproduce with great precision the experimental structure and the FT-IR spectrum of 4MBN. Other of the objectives is to study the non-covalent interactions from a theoretical point of view using atoms in molecule (AIM) approach, electron localization function (ELF) and localized orbital locator (LOL). Hirshfeld surface have been used in order to analyze intra and intermolecular interactions in the crystal structure 4MBN. Reduced density gradient (RDG) and independent gradient density (IGM) were performed also to reveal the weak interactions. Natural bonding orbitals (NBO) analysis was used to determine the different donor-acceptor interactions presents in 4MBN while the molecular electrostatic potential surface (MESP) was displayed to identify its electrophilic and nucleophilic sites. The reactive sites were evaluated by using the frontier molecular orbital (FMOs) while the character of the molecular orbitals (MO) and the contribution of each group in 4MBN were illustrated by means of graphics of density of state (DOS) and partial density of state (PDOS). The UV-Visible absorption spectroscopy computes the major absorption features: excitation energy (E), Absorption wavelength (λ), oscillator force (f) and major contribution of the electronic transitions using TD-DFT method. Further, thermal analysis was reported here. In the pharmaceutical field, the 4MBN has promising use, as an intermediate pharmaceutical compound. It is popularly used to treat anxiety disorders as Schizophrenia diseases. Because of this, and because of the very important properties of this compound, we were encouraged to study the biological activities of our compound. Thus, by using the molecular docking method to assess the activity of quarter ligands (4MBN, BEZ, FAD and 98B) described in the literature as potential inhibitors of DAO protein. The objective of this method is to understand the mechanisms of action of this protein (DAO) and its role in the treatment of schizophrenia disease.

Reagents were purchased from Sigma Aldrich Company. The IR spectrum was obtained on a Perkin-Elmer Spectrum BX II FT-IR spectrometer using a sample dispersed in a spectroscopically pure KBr pellet in the 400-4000 cm À1 region. The spectral resolution was 4 cm À1 . UV-Vis spectrum was recorded on a Perkin Elmer Lambda 19 spectrophotometer using quartz cuvettes with 1cm optical path in the 200-800 nm range. This technique involves adding to the cuvette a solution of the sample in 2 mL of ethanol with a concentration of 2.10 À3 mol.L À1 . The spectral resolution was 2 nm.

The thermal analysis of the synthesized compound is carried out using a multimodule 92 Setaram analyzer under argon. The mass of product was 10.2 mg for DTA-TG and 11.21 mg for DSC placed in a platinum crucible from room temperature up to 880 K for DTA-TG and in the range temperature [298-535 K] for DSC with a heating rate of 5 K.min À1 .

The experimental structure of 4MBN was determined by X-ray diffraction at room temperature (293 K) [3] . This analysis revealed that 4MBN belongs to the monoclinic crystal system with the space group P2 1 /c and their lattice parameters are as follows: a ¼ 15.097 (2) Å, b ¼ 5.812 (10) Å, c ¼ 10.486 (2) Å and β ¼ 99.75 (2) [3] . Figure 1 shows an ORTEP plot of 4MBN with displacement ellipsoids drawn at the 30% probability level. The molecular structure consists of an organic cation which is 4-methylbenzylammonium and an inorganic anion NO 3 -. In the crystal structure, molecules develop in parallel layers along the b axis and along the c axis are described by a succession of cationic and anionic layers ( Figure 2 ). In addition Figures 3 and 4 indicates that the crystal cohesion and stability between cationic and anionic entities is ensured by two types of weak hydrogen bonds: C-H…O and N-H… O. These two interactions were evaluated by different computational and experimental methods, as we will see later.

In the present study, all calculations were performed by using Gaussian 09 [9] program and GaussView 6.0 [10] as interface visualization. The molecular geometry structure has been optimized with density functional theory (DFT) using the hybrid functional B3LYP (Becke's three parameter hybrid functional using the LYP correlation functional) [11, 12] with CC-PVTZ basis set. The non-covalent interactions were examined in detail with AIM, ELF, LOL, RDG and IGM analysis using Multiwfn program [13] and the isosurfaces are visualized via VMD software package [14] . Also, the Hirshfeld surface has been generated using Crystal Explorer 3.1 program [15] . A natural orbital bond (NBO) analysis was carried out to study the transfer of electronic charge (donor-acceptor) in the molecule and the bond orders. The molecular electrostatic potential surface (MESP) was mapped to identify the electrophilic and nucleophilic sites which promote the formation of hydrogen bonds in 4MBN. The complete vibrational assignments of all bands observed in the experimental FT-IR spectrum of 4MBN in gas phase were performed with the calculated harmonic force fields by using the scaled quantum mechanical force field (SQMFF) methodology and taking into account the normal internal coordinates, transferable scaling factors and the Molvib program [16, 17, 18] . The experimental structure has evidenced that NH 2 group is coordinate to H atom of OH of acid and, hence, it is as NH 3 group, for which this group was considered with C 3V symmetry while the NO 3 group with C 2V symmetry because it group was optimized with two double bonds character and the other one as simple bond, as was observed in similar species [5, 6, 7, 8] . Also, UV-Vis spectra and electronic properties such as frontier molecular orbital analysis (HOMO-LUMO) were computed with the help of time-dependent DFT (TD-DFT) method. Plots of state density (DOS) and partial state electron density (PDOS) were obtained using GaussSum software [19] . Finally, the molecular docking has been performed for the determination of biological activity and to analyze various ligand-receptor interactions. In addition, the structures ligands and protein are extracted from the PDB data bank (Protein Data Bank) [20] . The docking calculations were carried out by using iGEMDOCK program [21] and the results obtained were visualized using discovery studio software [22] .

The optimized structure of 4MBN obtained with the B3LYP/CC-PVTZ method is depicted in Figure 5 . Table 1 presents the effect of dispersion on the values of minimum energies and dipolar moment (μ) in the gas phase and in the presence of a solvent (water). The examination of this table shows that the optimization in the gas without dispersion is the most stable because it has the minimum energy value (E ¼ -647.440 a.u).

The dipole moment is high in water (μ (dispersion) ¼ 15 D and μ (without dispersion) ¼ 14.2 D) compared to gas (μ (dispersion) ¼ 4.6 D and μ (without dispersion) ¼ 5.7 D), which indicate the increase of the polar character and charge separation in water.

To see how well the theoretical model represents reality, an RMSD (Root Mean Square Deviation) calculation was performed to compare between the experimental and theoretical values. RMSD values (Table 2) shows that the dispersion has a weak effect on the calculated bond lengths in the gas phase unlike the solvent (water). For bond angles, the dispersion shows a small change in gas phase and solvent. The lowest RMSD values are noted for bond lengths (0.012 Å) and 0.965 for angles in water with and without dispersion, respectively. The graphs of correlations between theoretical and experimental distances and bond angles in gas phase and in solvent with and without dispersion are shown in Figures 6, 7, 8, and 9 . The values of R 2 ( Table 2) are very close to 1, so we can say that all the parameters calculated are agreeing well with the experiment. The geometric parameters such as the bond length and bond angle are compared with the experimental results as presented in Table 2 . The bond angle of intramolecular hydrogen bonding interaction (N-H ⋯... O) has found to be 106.550 . 4MBN has eight C-C bond lengths, three O-N bond lengths, a single C-N bond and hydrogen bonds. Theoretically, the C-C intermolecular bond lengths of the benzene group are: C 9 -C 14 (1.392 Å), C 9 -C 12 (1.391 Å), C 11 -C 20 (1.398 Å), C 11 -C 12 (1.392 Å), C 15 -C 20 (1.386 Å) and C 14 -C 15 (1.397 Å) . It is noticed that the values of the computed geometric parameters are slightly different compared to the experimental ones. This difference is explained by the fact that the experimental results are obtained from a solid state where the packing forces were not considered because the calculations were performed in the gaseous state for the molecules isolated. These differences also are observed in the broad band observed in the FT-IR spectrum in the 4000-2000 cm À1 region. [23, 24] . This approach has extensively been applied to identify the nature of bond critical points (BCPs) and to evaluate their energies. Generally, topological analysis has been used to classify hydrogen bond (weak, moderate, strong) and analyze the nature of interactions in terms of electron density ρ (r) and his Laplacien r 2 ρ (r) inside the molecular systems [25] .

The -G (r)/V (r) ratio in AIM analysis which describes the nature of the hydrogen bond [26] . In fact, when -(G (r)/V (r)) > 1, the hydrogen bond has a character non-covalent, whereas for 0.5 <-(G (r)/V (r)) <1, the hydrogen bond is covalent. Further, the topological properties are handy tool to characterize the strength of hydrogen bond such as: electron density ρ (r), and its Laplacian r 2 ρ (r), kinetic energy density G (r), potential V (r), total energy H (r) and the bond energy E HB ¼ V (r)/2 (proposed by Espinosa and his collaborators [27] ) are also the efficient parameters to characterize the hydrogen bonding. The various bond critical points (BCPs), new ring critical points (NRCPs) and ring critical points (RCPs) were identified as shown in Figure 10 . Their corresponded topological parameters are provided in Tables 3 and 4 . Inspection of the table shows that the low values of the ellipticity at the RCP points confirm that there is delocalization of electrons in the aromatic nucleus. In addition, the high value of ellipticity suggests that there is a strong delocalization in NRCP structures. As shown in Figure 3 , the interactions between the monomer, dimer, around organic cation and around inorganic anion are mainly ensured by two types of hydrogen bonds: N-H⋯O and C-H⋯O. Basing on the values of r 2 ρ(r) et G(r) þV(r) are all positive in various cases as well as the E interaction is less than 12.0 kcal/mol (50 kJ/mol). These results confirm that the hydrogen bonds forming within our compound are considered weak. The ratio 0.5 <-(G (r)/V (r)) <1, indicating also that low hydrogen bonds existing in our compound are non-covalent nature. Moreover, the interactions of hydrogen bonds can be characterized by various important aspects, including the energy of ΔE bonds in the case of charged and neutral complexes [28] . In this context, the values of ΔE < 2.5 kcal/mol, therefore the hydrogen bonds of our compound are weak and dominated by dispersions and electrostatic interactions. [29, 30] is a powerful tool for determining the localization of electron pairs probability. It also helps to understand the behavior of electrons in multielectronic systems. This approach was generated by Silvi and Savin [30] , it allows to decide if the electrons are localized. In fact, when the electrons are perfect localized the value of ELF varies in the range [0.5, 1], whereas an ELF 1/2 shows the delocalized electronic region [31] . Furthermore, ELF furnishes some local measure of Pauli repulsion which is associated directly with the kinetic energy of electrons. Usually, the ELF value is close to 1 for the regions with the highest Pauling repulsion and is close to 0 for the regions with the lowest Pauling repulsion. The Figure 11 illustrates the ELF map of the title compound 4MBN on the plane C 22 , N 5 , N 2 atoms. A color code is represented with the ELF map varies from blue to red which show the scale range from 0 to 1. We can see from the 2D carte that the areas presented by a blue color around some carbon such as C 22 , C 14 , C 11 and oxygen atoms (O 3 ) represent the delocalized electron. Whereas, the red and orange color around the hydrogen atoms of the organic group C 8 H 12 N þ have comparatively large ELF values. Therefore, this region can be associated with a covalent bond character which is characterized by an appreciable electron density (a region of maximum Pauli repulsion). Generally, the elevated ELF regions are indicated a high localization of electrons, and may be identified with presence of a covalent bond, a lone pair of electrons, or a nuclear shell in that region. The visualization of the ELF can also indicate the non-covalent interactions (hydrogen bonds).

Here, we noted that the ELF value is high around N 5 -H 8 bond of the organic group (red region) and low around the O 1 atom of the inorganic group (blue circle). In addition, the blue region between the hydrogen atom H 8 and oxygen O 1 gave evidence for occurrence of interaction in this region, leading to a hydrogen bond of N-H ⋯ O type. Not only, the other types of hydrogen bonds can be displayed in the crystal structure of our compound. Therefore, we can conclude that this method is in agreement with the AIM approach.

Electron localization descriptor such as localized orbital locator (LOL) is widely used to describe the molecular bonding, reactivity and chemical structure. This tool is similar to the ELF as both depend on the kinetic energy density [32] . LOL analysis was introduced by Silvi and Savin [30] and carried out by using Multiwfn software. Also, the LOL map is a simpler and clearer picture than ELF. Moreover, ELF explains the electron pair density and LOL illustrates highestlocalized orbitals overlapping owing to the gradients of orbitals. Color filled map of the LOL for the atoms of the title compound is summarized in the Figure 12 . According to this figure, we observed that the high limit for LOL is 0.8 (red) and the lower limit is 0 (blue). LOL achieves in high regions (superior in 0.5) when the electron density is dominated by electron localization. It is seen in the Figure 11 that the region represented by the blue color around the carbon and nitrogen atoms provides LOL values 0.5 (region where the electron density is considerably depleted). Therefore the bonds could be classified in this region as weakly covalent bond or van der Waals bonds. Furthermore, the red color region near carbon atoms of the benzene ring with strong LOL values are due covalent bonds between the atoms (region where the electron density is much concentrated). As a result of the presence of a covalent bond in that area results in high localization of electrons, which proves great value in that region [32] . Also the small white circles present at the central part of the hydrogen atoms with maximum range caused to electron density (a region exceeds the high limit 0.8). As it is shown also in the figure of LOL that the low blue region between hydrogen H 8 and nitrogen N 5 displays the formation of a weak hydrogen bond of the N-H⋯ O type. Similar to ELF, LOL confirms also the results found in AIM analysis.

3D Hirshfeld surfaces (HS) and 2D fingerprint maps are unique for every molecule in the asymmetric unit of crystal structures. Indeed, (HS) provide a three-dimensional image of intermolecular interactions in crystals, while two-dimensional plots obtained by analysis of (HS) can identify each type of intermolecular interaction. The d norm molecular (HS), "d e ", Shape index and "Curvedness" of (C 8 H 12 N) NO 3 are respectively shown in Figure 13 . These surfaces are shown transparent to highlight the visualization of the orientation and conformation of functional groups in the crystal. The normalized contact distance (d norm ) of the produced compound displays a surface with a color scheme (red, blue, white), where the red spots highlight the shortest intermolecular outlines on the curvedness map exclude the presence of π-π and C-H… π interactions in our crystal structure [36] .

Electrostatic potential plays a key role in molecular recognition processes, including interactions with drug receptors. Again it exhibits important properties for the evaluation of lattice energy in crystals [37, 38] . The electrostatic potentials of (C 8 H 12 N) NO 3 were mapped on the (HS) using the STO-3G base fixed at the level of Hartree-Fock theory over a range of AE0.20 AU. Indeed, the presence of interactions and hydrogen bonds C-H… O and N-H… O between anions and cationic groups are observed through their (HS) mapped to the electrostatic potential (Figure 13 c). This map shows donor atoms (Nitrogen and Carbon of C 8 H 12 N þ ) in blue regions with positive potential and acceptor atoms (Oxygen of NO 3 -) with negative potential in red regions [39, 40, 41] . The overall two-dimensional fingerprint plot as well as the percentages of the various contacts existing in the (C 8 H 12 N) NO 3 compound is Table 3 . Topological parameters of critical points in monomer and dimer from. Table 4 . Topological parameters of critical points around organic cation and around inorganic anion.

Interactions The ER XY enrichment ratio of a chemical element pair (X, Y) is defined as the ratio of the percentage of actual contacts in the crystal to the theoretical percentage of random contacts. The enrichment ratios (ER) of the intermolecular contacts existing in the asymmetric unit are calculated and given in Table 5 

The reduced density gradient method (RDG) is also a most efficient technique for analyzing non-covalent interactions (NCI) [43] . This approach was developed by Johnson et al. [44] and it enables to identify and visualize zones of weak interactions in a molecular system, such as the van der Waals (VDW) interaction, hydrogen bonds (H-B) and steric effect. His expression is a dimensionless quantity coming from the density and its first derivative [43] :

The RDG represents a color code to examine the interaction within the systems molecular. Blue zone indicates the presence of strong attractive interactions (ρ > 0; λ 2 < 0), such as hydrogen bond, red zone indicates the presence of strong repulsive interactions (ρ > 0; λ 2 > 0), such as steric effect and green zone shows the presence of weak interaction (ρ % 0, λ 2 % 0) such as VDW interaction [45] . Showing the 2D and 3D RDG plots ( Figure 15 ) proves that the blue isosurface located between the H atom and the O-H group indicates the presence of H-B. In three dimensional spaces (3D), the values of sign (λ 2 ) ρ allow to determine the nature of interactions. In fact, hydrogen bond (H-B) was located between -0.035 a.u < sign (λ 2 ) ρ < -0.020 a.u. The force between hydrogen atoms and NO 3 group is the VDW interaction (green isosurface). This region located between -0.015 a.u < sign (λ 2 ) ρ < -0.010 a.u. While, red color indicates the steric effect which is found in center aromatic rings (strong repulsion). These repulsive interactions were observed within 0.020 a.u < sign (λ 2 ) ρ < 0.035 a.u. Waals interaction presents in chemical systems. It also defined the independent gradient function (δg), the inter-fragment (δg inter ) and intrafragment (δg intra ) to show interaction regions in the IGM. The multiwfn program was used to carry out the IGM analysis to reveal the noncovalent interactions (Figure 16 ) of our compound 4MBN [45] . This figure shows the range of δg values with an upper limit 0.2 (red color) and a lower limit is 0 (blue color). From this figure we see that the blue color around the carbon atoms indicates the charge depletion zone. Red color round hydrogen atoms present high electron density and the green color around the nitrogen atoms indicate the neuter zone. In addition, the white color indicates all chemical interactions that have bigger values of δg (a region with δg > 0.2). The plots which are presented by δg intra , δg inter and δg versus sign (λ 2 ) ρ values are depicted in Figure 17 . Figure 17 .a associated for inter-fragment (δg inter ) interactions indicates the presence of remarkable peak about 0.393 a.u with sign (λ 2 ) ρ is equal to -0.025.

The negative sign (λ 2 ) ρ implies attraction interaction (H-bond). The δg inter shows also another low intensity peak about 0.098 a.u with sign (λ 2 ) ρ is equal to 0.035 a.u which indicates the presence of a repulsive interaction correspond to a steric effect. From the scattering plots of intra-fragment interaction (Figure 17 .b), when sign (λ 2 ) ρ is equal to -0.035 a.u, the δg intra has an intense peak which implies the presence of hydrogen bonds in our compound 4MBN. Two weak peaks are equal to 0.080 a.u and 0.050 a.u which are associated to sign (λ 2 ) ρ % 0 essentially corresponding to VDW interactions.

NBO analysis is considered the most useful technique to describe and determine the different donor-acceptor interactions between the atoms of the studied molecular system. Its applies to study electronic transitions, charge transfer or hyper-conjugative interactions. It is also enables to identify the possible interactions between filled Lewis-type NBOs (donors) and Lewis unfilled NBOs (acceptors) for a molecule [46] . The stabilization energy of 2 nd order E (2) related from any donor (i) and acceptor (j), can be estimated by the following equation [47] .

where q i is the donor occupancy, F (i, j) is the Fock matrix element, ε i , ε j are the diagonal elements of the orbital energies. An NBO analysis was performed at the DFT level on the 4MBN structure optimized with the B3LYP/CC-PVTZ method. Table 6 enumerated the various interactions between Lewis (donor), non-Lewis (acceptor) orbits and second-order interaction energy E (2) ! 6 kcal/ mol corresponding to monomer and dimer. The greater E (2) values representing the high intensive interaction between electron donors and electron acceptors [48] . Referring to the results summarized in Table 6 , it has noted the presence of strong interactions between electron-donors in the monomer and dimer. hydrogen bonded interaction promotes the charge transfer in 4MBN and conserve the molecular stability. Hence, the monodentate coordination is clearly justified by this analysis. On the other hand, the study of bond orders, expressed as Wiberg bond index matrix in the NAO basis shows that of the two predicted hydrogen C15-H16⋅⋅⋅O1 and N5-H8⋅⋅⋅O1 bonds, suggested by AIM and Hirshfeld surfaces analyses, only one of them (N5-H8⋅⋅⋅O1) has a higher bond order value (0.5873), as compared with the other one C15-H16⋅⋅⋅O1 (0.0019) justifying this way, the monodentate coordination by means of the N5-H8⋅⋅⋅O1 bond.

In this part, surface of molecular electrostatic potential (MESP) is created to predict and analyzed the molecular reactive behaviour of a studied molecule. It is related to the electronic density and is a very useful to study hydrogen bonding interactions and for determining electrophilic and nucleophilic attack sites [49, 50] . The MESP map of 4MBN was constructed by using B3LYP/CC-PVTZ method and it mapped in Figure 18 . The image of MESP was represented with color code located between two extremes: -4,671 10 À2 (red indicates strongest repulsion) to 4,671 10 À2 (blue indicates strongest attraction). Red regions represent the most appropriate sites for nucleophilic attack, blue region indicates sites for highest reactivity about electrophilic attack and green color corresponds to a neutral zone. Positive electrostatic potential (blue region) in 4MBN is found around NH 3 þ of the methylbenzylammouim cation group. Whereas, negative electrostatic potential (red and yellow regions) is localized around oxygen and nitrogen atoms of the NO 3 group.

In addition, the electrophilic and nucleophilic sites explain the formation of hydrogen bonds between the nitrate groups and the methylbenzylammouim and its importance in the stability of 4MBN.

Theory of frontier molecular orbital (FMOs) is an invaluable tool to discuss the energy transition of the charge density because these FMOs play a key role in optical, electrical and chemical properties of compounds [51, 52] . Thus, HOMO (electron donor) represents the highest occupied molecular orbital, while lowest unoccupied orbital LUMO (electron acceptor) that takes part in chemical stability [53] . These two bands describe the capacity of a molecule to offer an electron and to gain an electron respectively. Furthermore, HOMO-LUMO are energetically separated by an energy gap, also they plays an important role to characterize the chemical reactivity and chemical hardness-softness as well as optical polarizability of 4MBN [54] . Hence, the HOMO-LUMO plots of 4MBN were carried out in gas phase and in solvent effect (ethanol and water) which are given in Figure 19 . As seen this figure, two important molecular orbital (MO) was examined which presented by two colors: green color represents negatively charged surfaces (nucleophilic sites), while red color indicates positively charged surfaces (electrophilic sites).

It is clear that the HOMO iso-density plots are located on (C 8 H 12 N þ ), while the LUMO iso-density plots are located on (NO 3 -). In addition, the global reactivity descriptors: global hardness (η), maximum load transfer index (ΔN max ), electronegativity χ and moment dipolar (μ) were defined by Parr R.G and colleagues [55] . Table 7 summarized these values, and indicates that the gap energies of 4MBN are equal to: 5.59 eV (gas), 4.04 (water) and 4.98 eV (ethanol). Since a compound with a higher-gap energy value is more polarizable, associated with high chemical reactivity, indicates low kinetic stability and is also called a soft molecule [56] . ΔN max ¼ 2.36 eV is maximum in presence of water, which means that 4MBN acquires a maximum of charges in its structure unlike gas and ethanol. To examine the character of the molecular orbitals (MO) of our compound we have calculated the density of states (DOS) (Figure 20) . It can be clearly seen from this figure that DOS spectrum shows two peaks in the presence of ethanol: one is very intense and well localized on LUMO orbital with energy equal to -0.89 eV, and other less intense localized on HOMO orbital with E HOMO ¼ -6.2 eV. In the gas phase, the two peaks HOMO and LUMO are less intense such that the energies E HOMO ¼ -6.99 eV and E LUMO ¼ -1.41 eV. In water, the band HOMO is located at E HOMO ¼ -6.98 eV and the band LUMO is located at E LUMO ¼ -1. (water) ¼ -6.80 eV, E LUMO (water) ¼ -0.62 eV. From all these results we can conclude that our compound 4MBN is more reactive in water.

In order to understand the electronic transitions between the molecular orbits HOMO-LUMO in 4MBN, a TD-DFT calculation in the solvent ethanol was affected. UV-Visible absorption spectroscopy is an analytical method used to characterize a molecule, to find the nature of electronic transitions and oscillatory strength. The simulated and experimental UV-Visible absorption spectra of our compound in ethanol are shown in Figure 22 . The effect of the solvent (ethanol) was taken into account by using the polarizable continuum model of the integral equation formalism (IEFPCM). The major absorption features: excitation energy E (eV), oscillator strength (f), wavelength λ (nm) and major contributions (%) of the molecular orbitals involved in each transition are reported in Table 8 . In comparison with experimental study, UVvisible spectrum shows two peaks: the first is the most intense, located at λ max ¼ 277 nm (E ¼ 4.48 eV) and 274 nm for spectra theoretical and experimental respectively is due to HOMO→LUMO transition with (97%) contribution. This electronic transition can be carried out at the П→П * transition relative to the organic group, due to the presence of the benzene ring. The second peak, was observed at λ max (theoretical) ¼ 235 nm (5.26 eV) and λ max (experimental) ¼ 307 nm corresponding to H-1→Lþ1, H-1→Lþ2, HOMO→Lþ1, HOMO→Lþ2 with (27%), (12%), (20%), (41%) contributions respectively. All these transition appear to be due to n →П * of group nitrate.

The differential and thermogravimetric thermal analysis of 4-Methylbenzylammonium nitrate is carried out in a temperature range from ambient up to 880 K on a sample of mass is equal to 10.2 mg with a heating rate of 5 K.min À1 and under an argon atmosphere. The DTA curve given in Figure 23 . a shows the presence of an endothermic peak located at 397 K without loss of mass observed by TG curve. To better understand the nature of this phenomenon or of this transformation, the starting product was heated to a temperature slightly below 397 K for a few minutes, which causes the melting of our product and the start of its decomposition. A second exothermic peak is observed at 497 K. This peak is accompanied, on the TG curve, by a great loss of mass which corresponds to the total decomposition during which our compound undergoes an ignition and an explosion which leads to at the end of handling with nitrogen oxides [57, 58, 59] . The differential scanning calorimetry analysis (DSC) (Figure 23 b) of (4-CH 3 C 6 H 4 CH 2 NH 3 )NO 3 compound is carried out under a stream of nitrogen using a Setaram "multimodule 92" type thermo-analyzer. This analysis is carried out on 11.21 mg of product placed in an alumina crucible from room temperature up to 535 K with a heating rate of 5 K. min À1 . The DSC analysis shows the presence of two peaks one endothermic located at 416 K and the other exothermic at 507 K corresponding respectively to the melting and decomposition of our product; these two phenomena are also observed by DTA/TG.

The optimization of 4MBN with the B3LYP/CC-PVTZ method and the previous studies for this species have clearly evidenced the presence of NH 3 þ group belonging to methylbenzylammonium cation and the NO 3 group where the coordination mode is clearly monodentate. The experimental FT-IR spectrum of 4MBN in the solid phase was compared in Figure 24 with the corresponding predicted for the compound in the gas phase and with the Raman spectrum also predicted in the same medium and level of theory. The Raman spectrum predicted in activities was transformed to intensities with suggested equations [61, 62] . The complete assignments of 69 vibration modes expected for the structure of 4MBN with C 1 symmetry were carried out with the calculated harmonic force field in the gas phase by using the scaled quantum mechanical force field (SQMFF) methodology and taking into account the normal internal coordinates, transferable scaling factors and the Molvib program [16, 17, 18] . In the construction of the normal internal coordinates, as detailed in computational section, the NH 3 group was considered with C 3V symmetry while the NO 3 group with C 2V symmetry. In the assignments of all vibrations modes were considered the SQM calculations performed here, potential energy distribution (PED) contributions !10 % and assignments reported for species with similar groups [5, 6, 7, 8] . Observed and calculated wavenumbers for 4MBN in the gas phase by using B3LYP/CC-PVTZ calculations together with the corresponding assignments can be seen in Table 9 . Note that the intense IR band predicted with the B3LYP/CC-PVTZ method at 2492 cm À1 and by SQM calculations at 2390 cm À1 is quickly assigned by its intensity to the N-O⋯H stretching mode of acid coordinate to NH 2 group, as was reported for the p-xylylenediaminium bis(nitrate) at 2651 cm À1 [6] . Thus, the experimental IR bands between 2615 and 2346 cm À1 (with red circle in Figure 13 ) can be assigned to O1-H8 stretching mode although the intensity of band in the experimental spectrum is different from the theoretical one probably due to that the dimeric species is also present in the solid phase, as was reported for p-xylylenediaminiumbis (nitrate) [6] . Discussions of some assignments for the most important groups are presented below. characteristic than the other two N5-H6 and N5-H7 ones. Many theoretical studies show that this mode are more sensitive to the presence of the hydrogen bond [63, 64, 65] . Hence, an anti-symmetric stretching mode of this group is predict at 3408 cm À1 while the other one at 251 cm À1 due to the coordination with the H8 atom of acid. The corresponding symmetric mode is predicted at 3329 cm À1 . Hence, these NH 3 stretching modes are assigned in different positions. The coordinate N⋅⋅⋅H bonds in p-xylylenediaminiumbis (nitrate) are predicted between 271 and 119 cm À1 [6] . The anti-symmetric and symmetric deformation modes corresponding to these groups in the dimer of p-xylylenediaminiumbis (nitrate) [6] are predicted between 1793 and 1639 cm À1 while for the monomer between 1597 and 1591 cm À1 . In 4MBN, both anti-symmetric and symmetric deformation modes are predicted at 1565 cm À1 while the other anti-symmetric mode due to the coordination appears at 435 cm À1 . In p-xylylenediaminium bis(nitrate) [6] , the rocking modes of these groups due to the monodentate coordination are predicted in the lower wavenumbers region. Here, these modes are predicted at 1144 and 51 cm À1 while the twisting mode is predicted coupled with other vibration modes between 489 and 448 cm À1 . In the dimer of p-xylylenediaminium bis(nitrate) this modes is assigned between 476 and 419 cm À1 while for the monomeric species these modes are predicted around 30 cm À1 [6] .

3.5.1.2. Nitrate groups. In 4MBN, two N¼O and one N-O stretching modes are expected due to the monodentate coordination of N-O⋯H bond. In some inorganic nitrate salts, the N¼O stretching modes are observed between 1672 and 1460 cm À1 [66, 67] , in niobyl nitrate are assigned between 1763 and 1753 cm À1 [68] while in species containing NO 2 groups these modes are assigned between 1584 and 1335 cm À1 [5, 69] . Here, due to the monodentate coordination the very strong band at 1305 cm À1 is clearly assigned to symmetric mode because the SQM calculations predict this mode at 1277 cm À1 while the anti-symmetric mode is assigned to the shoulder at 1652 cm À1 because this mode is coupled with the τH8-N5 and τO1-H8 torsion modes. The stretching mode related to simple N2-O1 bond is predicted at 930 cm À1 and, for this reason, the weak band at 923 cm À1 is assigned to this vibration mode. The O¼N¼O deformation mode is predicted and assigned at 681 cm À1 while the wagging and rocking modes are assigned at 743 and 686 cm À1 , respectively The torsion modes for the monodentate form of p-xylylenediaminiumbis (nitrate) [6] are predicted at 76 cm À1 while in 4MBN this mode is predicted at 51 cm À1 , as indicated in Table 9 .

3.5.1.3. CH 3 and CH 2 groups. 4MBN has one CH 3 and CH 2 groups, later; the corresponding anti-symmetric and symmetric stretching modes are predicted between 2976 and 2896 cm À1 and, for these reasons, the shoulders and group of IR bands in that region are assigned to these vibration modes, as is detailed in Table 9 [6, 7, 8, 69] . The symmetries of these modes cannot be verified because in this work the Raman spectrum was not recorded. The deformation modes of these groups are predicted between 1449 and 1356 cm À1 while the wagging CH 2 and rocking CH 3 modes are predicted at 1403/1393 and 1043/981 cm À1 , respectively. The SQM calculations predicted the twisting CH 2 mode at 851 cm À1 whiles the corresponding to CH 3 group at 39 cm À1 . This way, only the twisting CH 2 mode is assigned at 888 cm À1 .

3.5.1.4. Skeletal groups. The C¼C stretching modes corresponding to the benzyl rings of p-xylylenediaminium at 1622 cm À1 , as reported in other similar compounds [5, 6, 8] while in 4MBN are predicted between 1605 and 1563 cm À1 . Hence, these modes are assigned to the IR bands at 1609 and 1522 cm À1 . On the other hand, the C-C stretching modes are predicted by SQM calculations between 1293 and 1111 cm À1 while the C-N stretching mode is predicted at 953 cm À1 and assigned to the shoulder at 966 cm À1 . The deformation and torsion of benzyl ring are assigned in the expected 1000-200 cm À1 region, as predicted by SQM calculations [5, 6, 8, 69] .

The harmonic force constants are interesting and useful parameters to analyze the forces of different bonds and, especially when the molecule under study presents monodentate coordination as in 4MBN. These constants were calculated for 4MBN in the gas phase from the harmonic force field with the SQMFF methodology and by using B3LYP/ CC-PVTZ method and the Molvib program [16, 17, 18] . The scaled force constants for 4MBN in the gas phase are compared in Table 10 with reported for species with monodentate coordinations, such as p-xylylenediaminium bis(nitrate) [6] and chromyl nitrate [67] . These comparisons are interesting because these compounds present the same coordination modes but different chemical characteristics, thus p-xylylenediaminium bis (nitrate) is a hybrid as 4MBN [6] while chromyl nitrate is an inorganic compound [67] . Comparing first the constants for both hybrid species we observed practically the same values for the two species and only slight changes in the f(δN-O-H) force constants values are observed. Such differences could be attributed in part to the different basis sets used in the calculations. When the f(νN ¼ O) and f(νN-O) force constants values for 4MBN are compared with the corresponding to chromyl nitrate we observed that the f(νN ¼ O) force constant value is lower in 4MBN while the other f(νN-O) force constant is lower in chromyl nitrate [67] . Obviously, these differences are quickly associated to different nature of atoms linked to NO 3 group because in chromyl nitrate this group is coordinated to Cr while in 4MBN is coordinated to H. Hence, the Cr atom is most electropositive than H and, for this reason, the coordination is stronger between Cr and O (Cr←O) than H and O (H←O) [67] .

With the development of computer tools in the last 20 years, molecular docking is becoming a very efficient tool for the determination of biological activities. The docking study is a critical step in understanding biological reactions and in drug design [54, 55, 56, 57, 58, 59] . The objective of the computational molecular docking was performed to find out the orientations in space and bonding conformations between ligands with the target receptor [58] . A bibliographic study shows that the protein amino acid oxidase (DAO) is usually used in the treatment of mental disorder. In this study, docking calculations was effected for targeted protein related to the treatment of schizophrenia. The prototypical DAO inhibitor has been shown to be Units are mdyn Å À1 for stretching and mdyn Å rad À2 for angle deformations. a This work. b From Ref. [6] . c From Ref. [63] .

effective in improving neurocognitive symptoms [60] and in the treatment of this disease [61, 62] . Molecular docking was used to evaluate the activity of quarter ligands: 4MBN, BEZ, FAD and 98B described in the literature as potential inhibitors of DAO. These ligands and protein structures are extracted from the PDB (Protein Data Bank) [14] . This database contains thousands of protein structures obtained either by crystallography (X-ray) or by NMR. Figure 25 and Figure 26 show the best pose which corresponds to the minimum energies of the ligands in the DAO protein and 2D interactions between the different complexes gained from the docking of all studied ligands inside DAO. The total energy, VDW interactions, electronics and H-bond values obtained are indicated in Table 11 . As reported clearly in this table that the predominant interaction is of VDW type. DAO-FAD complex showed the highest total energy (À304.288 Kcal/mol), with interaction energies of the order of: E VDW ¼ -232.615 kcal/mol, E H-bond ¼ -71.272 kcal/mol and E electronic ¼ -0.400 kcal/mol. The total energy scores of 4MBN, 98B and BEZ are respectively equal to: -76,828 kcal/ mol, -65,111 kcal/mol and -61,792 kcal/mol, respectively. As depicted in Figure 25 , all three ligands have almost the same positions in the protein.

Their VDW interactions are of the order of -50.987 kcal/mol, -58.135 kcal/mol and -47.198 kcal/mol, as well as their hydrogen bond energies are equal to -25.841 kcal/mol, -6.976 kcal/mol and -14,594 kcal/mol, respectively. In another important steps Figure 10 . C and Figure 27 show the presence of several types of interactions such as: Pi-alkyl, Pi-anion, hydrogen bonds and conventional hydrogen interactions which exist between the ligands and residues. In fact, electron acceptor-donor interactions promote the formation of these bonds. Therefore, these interactions mediate the stabilization of the complex with the residues (inhibitor stability).

Molecular docking studies have evidenced that 4MBN penetrates well into the active sites of the receptor while the interactions observed between the DAO protein and the 4MBN ligands prove a good degree of inhibition against schizophrenia disease.

In this research, the hybrid 4MBN compound has been synthesized in order to study the influence of non-covalent interactions on its experimental infrared spectrum and on its structural, electronic, topological and vibrational properties. For these purposes, the experimental IR spectrum and the structure previously determined by X-ray diffraction were employed in combination with B3LYP/CC-PVTZ level of theory to optimize 4MBN in gas phase and in ethanol and aqueous solutions. Then, the complete vibrational assignments of 69 vibration modes expected for the most stable structure of 4MBN was performed by using the SQMFF methodology together with the normal internal coordinates and scaling factors. Different computational and analytical methods, such as AIM, RDG, Hirsfeld surface analysis, NBO, MEP surfaces were used to describe the non-covalent interactions in 4MBN. The AIM analysis of topological parameters and Hirsfeld surfaces have showed the presence of two weak hydrogen bonds (N-H⋅⋅⋅O and C-H⋅⋅⋅O) in 4MBN while the study of bond orders support the higher value of N-H⋅⋅⋅O interaction. Hence, the monodentate coordination between cation and anion is also supported by the predicted strong IR band assigned to the N-O⋅⋅⋅H stretching mode of acid coordinate to NH 2 group of 4MBN. The RDG reduced density gradient method makes it possible to demonstrate, in addition to hydrogen bonds, the presence of van der Waals-type interactions and the steric effect. Natural orbital analysis (NBO) has shown that LP (O) → σ * (O-H) interactions (hydrogen bonds) stabilize the structure. Likewise, electronic properties were performed using the TD-DFT method. The nucleophilic and electrophilic sites were identified by calculating the Molecular Electrostatic Potential Surface (MESP). They clearly explain the monodentate coordination between nitrate and methylbenzylammonium groups and its importance in the stabilization of 4MBN. The Frontier Molecule Orbital Analysis (FMOs) of 4MBN in ethanol and aqueous solutions suggest that this species is most reactive in water. The UV-Visible spectra were studied 

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This work was supported by the Ministry of Higher Education and Scientific Research of Tunisia. The authors would like also to thank Prof. Tom Sundius for his permission to use MOLVIB.

Mouna Medimagh; Silvia Antonia Brand an: Analyzed and interpreted the data; Wrote the paper. Noureddine Issaoui; Omar Al-Dossary: Conceived and designed the analysis.Sofian Gatfaoui: Performed the experiments; Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data.Houda Marouani: Conceived and designed the experiments; Contributed reagents, materials, analysis tools or data.Marek. J. Wojcik: Conceived and designed the experiments; Analyzed and interpreted the data.

This work was supported by project number (RSP-2021/61), King Saud University, Riyadh, Saudi Arabia and with grants from CIUNT Project No 26/D608 (Consejo de Investigaciones, Universidad Nacional de Tucum an, Argentina).

The authors do not have permission to share data.

The authors declare no conflict of interest.

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