Solid-state Synthesis, electronic Structure Studies, Solvent Interaction through Hydrogen Bonding, and Molecular Docking Studies of 2,2’-((1,2-Phenylenebis(Azaneylylidene))Bis (Methaneylylidene))Diphenol from o-Phenylenediamine and Salicylaldehyde

Abstract The compound was synthesized and characterized with Infrared, UV, and NMR studies. The present work is theoretically investigated using B3LYP/cc-pVDZ basis set. The LED has been performed using PBE0-D3/deft-TZVP basis set and DLPNO-CCSD(T). The DFT was used to define the structure and geometry of the compound. To identify the primary binding sites and weak interactions, the Multiwfn-3.8 was subjected to a topological analyses, including ELF, LOL, ALIE, and RDG. The UV-Visible spectrum was theoretically analyzed using the TD-SCF method. The B3LYP/cc-pVDZ was used to measure the HOMO-LUMO, MEP, NBO, and NLO. The NBO calculations investigate the intermolecular and intramolecular movement of charges, as well as the molecule stability. To determine whether the CS1 molecule has the potential to become a drug, a pharmacological investigation is performed using a Swiss-ADME. The docking study done against the 1NXU protein is performed using the Auto-dock.


Introduction
The chemistry of the imine group acting a key part in the activity of Schiff bases.Schiff bases were known since 1864.They were invented by Hugo Schiff and are named after him.The nitrogen atom in a Schiff base is bonded to either an aryl or an alkyl group, but not to hydrogen (i.e.R 1 R 2 C ¼ N-R 3 ). 1 R groups attached to the carbon or nitrogen of an imino can only be alkyl or aryl groups, or hydrogen.You may also hear these referred to as anils, imines, or azomethines.Because of their carbon-nitrogen (-C ¼ N) double bond, Schiff bases are also classified as azomethines. 2Primary amines (-NH 2 ) are the starting materials for forming Schiff bases, which are then typically condensed with active carbonyl compounds like aldehydes or ketones (>C ¼ O) to produce Schiff bases. 3It is also possible to think of them as a dehydration reaction.This reaction can be reversed by adding an acid, a base, or heat.While most Schiff bases are weak bases, some of them can form insoluble salts with strong acids. 4Schiff bases are flexi-dentate ligands that coordinate via the phenolic oxygen and azomethine nitrogen.
The aromatic amine and aromatic aldehyde-derived Schiff bases found use in many different areas of chemistry, including organic, inorganic, and analytical. 5To detect with increased selectivity and sensitivity, Schiff bases are used in a wide variety of sensors, most commonly in optical and electrochemical as well as certain chromatographic methods.Primary amine Schiff bases and carbonyl compounds both have applications in chemical analysis.Because of their ability to form stable complexes with transition metal ions, they are also vital in the field of coordination chemistry.Schiff base reactions are used to form carbon-nitrogen bonds in organic synthesis. 6][9][10] Many bioactive heterocyclic compounds can be synthesized using Schiff bases as a starting material.][13] Because of wide interest in the activity of Schiff bases derived from o-phenylenediamine and salicylaldehyde, we intended to study the synthesis of a new compound CS1 and its characterization employing FTIR, UV-Vis, 1 HNMR, and 13 CNMR.We also carried out theoretical studies with the help of DFT/B3LYP/cc-pVDZ techniques and performed studies concerning Molecular Electrostatic Potential, Molecular Docking, Nonlinear optical properties, Mulliken analysis, and NBO analysis.The autodock software is used to do perform the docking studies.We also studied solvation study through water solvent using DLPNO-CCSD(T) coupled cluster.

Material and instrumentation
Sigma Aldrich supplied both the o-phenylenediamine and salicylaldehyde used in this experiment.Direct use of the solvents ensued after their purchase from a nearby chemical supplier.An KBr model FTIR spectrophotometer was used to record the infrared spectrum.Perkin Elmer Lambda-35 data were used to record the emission spectrum.The Bruker Avance-400 MHz was used to record the NMR spectrum in DMSO-D6.

Synthesis of 2,2'-((1,2-phenylenebis(azaneylylidene)) bis(methaneylylidene)) diphenol (CS1)
Over half an hour, salicylaldehyde (2.4 ml, 0.02 mm) and o-phenylenediamine (0.76 g, 0.01 mm) were grained together after being dissolved in a minimum amount of methanol.After the mixture has been transferred to a 100 ml RB flask, it is both reflexed in a water bath for 5h.At room temperature, the mixture is cooled.Recrystallization of the CS1 product is done in dimethyl sulfoxide (DMSO) after filtration and washing with ethanol. 14,15The reaction scheme are shown in Figure 1.

Computational
Gaussian-09W and Gauss view-06 are the softwares that are used to study the necessary DFT calculations and visualizations. 16,17Chemcraft was used to create a visual of the new, better structure. 18Gaussian calculations are carried out using the B3LYP/cc-pVDZ basis set.The local energy decomposition (LED) has been performed using PBE0-D3/deft-TZVP basis set and DLPNO-CCSD(T) coupled cluster level using Orca.5 software. 19To identify the binding regions and reactive sites, a wave functional analysis was carried out using the Multiwfn program. 19The compound pharmacological efficacy is determined with the help of the web-based Swiss-ADME tool.
PASS study was used to preserve the molecule bioactivity before target protein selection. 20The docked poses were visualized using Discovery Studio Visualizer after a MD study was performed on the target protein with the support of autodock software.

Structural analysis
As a first step, we performed a confirmation analysis on the compound structure, getting at the lowest negative value we can used for further DFT calculations. 21Its molecular formula is C 20 H 16 N 2 O 2 .DFT calculations using the B3LYP/cc-pVDZ basis set to yield the best results for this compound. 22Figure 2 depicts the enhanced structure that occurs in the gas phase. 23The structural parameters of the CS1 compound have been optimized and are detailed in Table S1.In DFT calculation (C10-C11), (N8-C10-H34), and (C11-C12-C22-C21) were found to have the longest bond length, angle, and dihedral angle, and their bond distances were measured as 1.46, 122.91, and 179.99, respectively. 24The Sankarganesan et al. previously synthesized same method and we compared. 257][28] Physical properties of temperature, heat capacity, and entropy are observed at 298, 97.07, and 177, respectively.

Solvation with water
The molecule contains significant site for the formation of hydrogen bond, close to the -OH functional group.This section investigates solvated by the water molecule in order to determine whether there is a higher probability of forming a hydrogen bond in a medium consisting of water. 19In order to optimize the geometry, a water molecule is positioned near -OH (O41 … .H39) position (Figure 3).This process is carried out using PBE0-D3/def2-TZVP basis set and DLPNO-CCISD(T).The solvation enthalpy is observed at water, synthesized compound and complex (water and synthesized compound) the final single point energy is À76.409(a.u),À1028.8698(a.u), and À1105.1279(a.u),respectively. 29The complex total interaction energy is À10.74 kcal/mol.The total interaction energy is calculated by following formula DE ¼ E xyÀ E xÀ E y (x ¼ water, y ¼ synthesized compound, xy ¼ complex).This is supported by the fact that the input orientation has no effect on the values of the solvation energies. 30Potential non-covalent interactions between the Schiff base and the water POLYCYCLIC AROMATIC COMPOUNDS solvation complex are presented qualitatively in Figure 4.The hydrogen-bond interaction, which are denoted by the color green, are more prevalent, whereas the van der Waal interactions, which are denoted by the color blue, are more prevalent.The steric repulsion, denoted by the color red, is virtually identical.In order to determine the precise characteristics of the solvation energy, an Energy Decomposition analysis was carried out with the help of ORCA 5.0 software at the DLPNO-CCISD(T) coupled cluster level. 31The Foster-Boys scheme was utilized in this situation for the purpose of localizing the molecular orbitals.Along with this, we used the Pipek-Merzy orbital localization scheme to pinpoint exactly where PNO should be situated within the EDA/LED framework.There are several techniques for breaking down the solvation energy.
where DE prep is the energy expended in preparing the solvation and DE int is the energy expended in interacting with the molecule, which includes the energy expended due to electrostatic repulsion, the energy expended due to Pauli repulsion, and the energy expended due to attractive orbital repulsion.The first term represents the solvation preparation energy, while the second term represents the interaction energy.Steric effects are responsible for Pauli's repulsion, while charge transfer and polarization are responsible for orbital interaction.The data collected is shown in Table S2.

Vibrational analysis
There are a total of 40 atoms in the CS1 compound.The structure was refined in the gas phase by scaling factor of 0.9651 and using B3LYP/cc-pVDZ as the basis set. 32The FTIR spectrum (calculated and observed) shows good agreement. 33For a more accurate assignment of IR active modes of vibration, it is helpful to compare experimental FTIR and computed results. 34In Table 1, we presented both the experimentally observed infrared frequencies and the scaled of selected vibrational modes of CS1.There is good agreement between the observed and scaled FTIR spectra. 35The spectral comparison of the infrared is presented in Figure 5.In an experiment, the stretching frequency of the azomethine group in the CS1 compound was found to be 1614 cm À1 and scaled is 1610 cm À1 , respectively. 36

NMR spectroscopy
Figure 6 displays the 1 HNMR chemical shifts.The 1 HNMR spectrum reveals the number and nature of hydrogen isotopes present in a compound and their relative abundances in its surrounding environment. 38The difference between a nucleus resonance frequency and the standard indicates the absorption peak in a 1 HNMR spectrum. 39The singlet, doublet, triplet and multiplet chemical shifts are  40 The chemical shifts of the various forms of carbon in a compound are what that reveals its structure in 13 CNMR absorption peaks. 41The 13 CNMR chemical shifts are depicted in Figure 7.The chemical shift of carbon is set by the types   of carbon bonds themselves. 42Ketone and aldehyde groups have a chemical shift of roughly 200 ppm, while aromatic carbons have a value between 110 to 160 ppm. 43Double-bonded carbon atoms have chemical shift values between 100 to 50 ppm. 44The aliphatic and aromatic carbons have been observed to have chemical shifts of 133.S3.

UV-Visible spectral analysis
To learn more about the electronic transitions in CS1, we used TD-SCF/B3LYP/cc-pVDZ basis set with IEFPCM solvent model. 45Absorption spectra were also run in a chloroform solvent for comparison with the experimental one (Figure 8).The calculated section show that the chloroform solvent has an absorption peak at 342 nm. 46UV absorption peak was found to be significantly stronger than visible light absorption. 47The experimental results show good agreement compared to the simulated one. 48The experimental results show that the chloroform solvent has an absorption peak at 361 nm.The both absorption peak is very close.The wavelength, oscillator strength, energy and HOMO-LUMO contributions are listed in Table 2.

Reactive descriptor analysis
The B3LYP/cc-pVDZ basis set was used to calculate the HOMO and LUMO orbitals are shown in Figure 9.The enthalpy gap, or the difference between the energies of the molecule highestand lowest-filled orbitals (HOMO and LUMO), was calculated. 49If you want to know what is going on in a chemical reaction, look no further than the HOMO and LUMO orbitals. 50When one orbital (the HOMO) donates an electron, the other (the LUMO) accepts it.The chemical stability and reactivity of a compound can be indirect from its energy gap. 51This results in a compound that is both highly reactive and not very stable; this is due to the smaller energy gap that exists between the orbitals. 52It is thought that the band gap in the gas phase is 2.18 eV. 53The bioactivity of a compound increases as its HOMO-LUMO energy gap decreases, as a result of charge transfer between the molecule. 54The LUMO and HOMO orbital can be found in the benzyl ring, the azomethine group, and OH group.The color red is used to denote the positive phase, and the color green is used to denote the negative phase.The fact that it is both chemically hard and soft indicates stability.Table S4 displays the frontier molecular properties of the titled compound CS1.Gauss-sum 2.2 program O'Boyle et al. were used to calculated group contributions to the molecular orbital (HOMO and LUMO) and prepare the density of states (TDOS and PDOS) spectrum. 55The TDOS and PDOS spectra were created by convoluting the molecular orbital  information with Gaussian curves of unit height.The green and blue line in the DOS spectrum (Figure 10) indicated the HOMO and LUMO levels. 56In Figure 11, the blue and green color indicate the overlapping of orbitals, the red color indicate occupied orbitals and light blue color indicate virtual orbitals.

NLO properties
The NLO properties of substances and their varied applications in industry, optics, and other fields have attracted more attention in recent years. 57A molecule nonlinearity is caused by the possibility of charge transfer between the donor and acceptor levels and the polarization of the p orbitals. 58To determine whether or not a substance is NLO active, nonlinear properties of the substance are typically measured and compared to those of the prototype substance, which is urea. 59It has been discovered that organic materials have high NLO activity and are resistant to harm from visual submissions. 60These numerical results are sufficiently close to experimental data to be practically applicable. 61In this work, we use B3LYP/cc-pVDZ calculations in the gas phase to determine the NLO properties.The CS1 has a larger dipole moment in the gas phase than urea (I ¼ 6.9264 D vs.I ¼ 1.3732 D).Our compound has a greater NLO property when compared to urea.

MEP study
MEP is related to electron density, dipole moment, electronegativity, and molecule reactive sites. 62he electrostatic potential is plotted in a straight line on a surface with uniform electron density. 63The MEP map shows the molecule electrostatic potential by varying the colors.Each level of electrostatic potential is shown by a different color.The colors blue, green, yellow, orange, and red make up the spectrum of the electrostatic potential. 64The electrophilic and nucleophilic sites of the compound are revealed as a result of interactions with hydrogen, which in turn reveals the intermolecular interactions of the compound as well as its biological activity. 65All hydrogen atoms in a molecule are open targets for electrophilic attack. 66The nucleophilic and electrophilic forces are shown to be at work in the attack depicted in Figure 12.

Mulliken analysis
The Mulliken atomic charges were calculated by using the number of electrons in each atom. 67he charges on the atoms are crucial in the quantum mechanical calculations of a molecular system. 68Dipole moments, electronic parameters, polarization, and transparency are just some of the properties that are altered by these charges. 69The MPA determined with the DFT/B3LYP/cc-pVDZ level is displayed in Table S5.In addition to being more numerically stable, NPA provides a better description of the spreading of electrical charges in the scheme. 70Table 3 displays an NPA analysis.We compared the distribution of charge using three distinct approaches because it appears to be method dependent. 71MPA, 10 C (0.1737) has the highest positive charge and 25 O (À0.3291) has the highest negative charge; in NPA, 41H (0.4887) and 23 O (À0.6896) have the highest positive and negative charges, respectively. 72In addition, C and H atoms exhibit both þ ve and À ve charges, whereas the N and O atoms exhibit a À ve charge in MPA. 33According to the NPA analysis, C atoms exhibit both þ ve and À ve charges, while all H atoms exhibit only þ ve charges and all O and N atoms exhibit only negative charges.

NBO analysis
NBO analysis calculates electron transfer stabilization energies E(2) from Lewis-type donor orbitals to acceptor orbitals. 73Stronger donor-acceptor interactions and more delocalized electron coupling across the whole system are indicated by larger E(2) values. 74Because the orbitals are chosen through a mathematical process that takes priority having the highest ratio of electron density, NBO provide an accurate representation of the Lewis structure. 75There are significant interactions between the energies of the donor and the acceptor, Table S6 represents these interactions. 76he various type of interactions, such as p-p Ã , r-p Ã , n-p Ã , n-p Ã , n-r Ã and p Ã -p Ã were appeared in the theoretical result, while only p-p Ã , and n-p Ã interactions were observed in electronic spectral analysis as expected. 77Thus, the NBO results revealed that the calculated above two transitions are in good agreement with the observed electronic spectrum.9][80] The sp 2.62 hybrid on carbon atom was interacted with a sp 1.86 hybrid of nitrogen atom for the formation of r(C4-N8) bond.The sp 2.90 hybrid orbital of carbon (74.16%, p-character) was interacted with sp 1.85 hybrid on oxygen (64.84%, pcharcter) and formed r(C17-O23) bond.
The maximum amount of stabilization energy was found to be 75.

Topological analysis
Molecular orbitals can be seen on ELF and LOL maps, which also depict localized electron density.These maps show the intramolecular covalent bond.Software from the Multiwfn was used to create both the ELF and LOL maps. 81The colored ELF and LOL maps can be seen in Figure 13, both of which can be found in the same file. 82Maximum ELF line values fall between 0.0 and 1.0 Bohr, indicating a highly localized region within the molecule. 83However, a very low value indicates that electrons are highly distributed throughout the molecule.The carbon, and nitrogen, atoms of the molecule have the highest localized electron densities. 12An explanation of the compound localized and delocalized molecular orbital positions are provided using the LOL map.The counter map of LOL is colored based on a range from 0.0 to 0.8 Bohr.The weak n-delocalized orbital is shown in blue, while the strong one is shown in red. 84The carbon, and nitrogen atoms in this molecule are colored blue, the hydrogen atoms are colored red, all of which indicate that the electron density in these atoms is higher than the upper limit of the LOL scale.

ALIE study
After confirming the structure of the CS1 molecule, the wavefunction file was generated for the molecule.The structure was optimized with the help of this file. 85This study found that electrons can contribute to a molecule stability and bioactivity either localized or delocalized, depending on the molecule context. 86Figure 14 shows the CS1 reactivity sites, which range from À12.99 to 12.99 Bohr3, and are depicted by the colors blue (0.00) to red (2.00).The greenish-blue color indicates that all hydrogen atoms have delocalized electrons.The blue color stands for the sigma bond between hydrogen atoms.

RDG study
RDG is determined by Multiwfn software and used in NCI molecular analyses.RDG is a dimensionless quantity (r) that can be computed using the density and its first derivative.This picture shows that the distribution of electrons has become more uneven. 87As you move away from the  molecule, the RDG has a high positive value because the electron density falls off exponentially until it reaches zero. 11Covalent bonds and NCI lead to nearly insignificant RDG.When you look at the second value of the Hessian of the second derivative of the electron density (k2), you can see how the electron density interacts. 88Electron density versus molecule-specific Hessian plots can be used to generate color-coded maps of intra-and intermolecular attractive and repulsive forces. 89DG maps were made using Multiwfn 3.8 software to depict weak interaction.The red areas are those where the steric effect predominates, while the green ones are those where van der Waals interactions are minimal.Figure 15 illustrates the RDG surface map of the compound CS1.

Molecular docking
Molecular docking is applied to the docked compound to determine the specific protein-ligand interactions. 90Docking was performed against Dehydro-L-gulonate decarboxylase inhibitor because the PASS web tool predicted that the title compound would have highly probability activity is Dehydro-L-gulonate decarboxylase inhibitor (Table S7). 91The crystal structure of 1NXU was selected as one of the targets for the Dehydro-L-gulonate decarboxylase inhibitor. 92We accessed the RCSB database online to retrieve target structures in PDB format.All docking analyses and representations were carried out in Discovery Studio and autodock software. 93Table 4 shows the binding energies of protein-ligand interactions, and Table 5 displays the nonbonded interactions of the synthesized compound.The Auto-Dock Grid Box parameters for this study were selected with the assistance of the autodock software. 94The docked interactions of the entire 1NXU protein chain are depicted in Figure 16.The study findings include a negative binding energy and a positive inhibition constant for protein-ligand interactions.The docking of CS1 against the inhibitor of 1NXU protein has an atomic contact energy of À3.80 kcal/mol.The synthesized compound interacted with different types of amino acids such as LYS91, GLU31, and ARG35 with bond distance is 2.3, 1.9, 3.8, 5.0, 4.0, and 5.1, respectively.

Conclusion
The DFT/B3LYP/cc-pVDZ calculations have a very good correlation with the experimental IR, UV, and NMR data.The local energy decomposition (LED) has been performed with highest binding energy is À10.74 kcal/mol.The most characteristic azomethine group of compound showed a band at 1614 cm À1 as expected.The theoretical and experimental values of infrared and UV-VIS spectra for the studied compound were almost same.The molecular electrostatic potential of the studied compound showed suitable regions to attack for electrophilic and nucleophilic substance.The mentioned compound is highly chemically reactive and acts as a soft molecule.Both benzene rings of the compound were aromatic in character due to calculated HOMO value.The molecular docking analysis showed that the compound has relatively more binding affinity with the target protein.Moreover, the compound followed all the parameters of Lipinski's rule of five.It also showed good ADME properties and toxicity profile that makes the compound a potential drug candidate and may be considered for further drug development.