Experimental and DFT studies on the molecular structure, spectroscopic properties, and molecular docking of 4-phenylpiperazine-1-ium dihydrogen phosphate

Journal Pre-proof Experimental and DFT studies on the molecular structure, spectroscopic properties, and molecular docking of 4-phenylpiperazine-1-ium dihydrogen phosphate Olfa Noureddine, Sofian Gatfaoui, Silvia Antonia Brandan, Abir Sagaama, Houda Marouani, Noureddine Issaoui PII:

S0022-2860(20)30086-7

DOI:

https://doi.org/10.1016/j.molstruc.2020.127762

Reference:

MOLSTR 127762

To appear in:

Journal of Molecular Structure

Received Date: 13 November 2019 Revised Date:

17 January 2020

Accepted Date: 20 January 2020

Please cite this article as: O. Noureddine, S. Gatfaoui, S.A. Brandan, A. Sagaama, H. Marouani, N. Issaoui, Experimental and DFT studies on the molecular structure, spectroscopic properties, and molecular docking of 4-phenylpiperazine-1-ium dihydrogen phosphate, Journal of Molecular Structure (2020), doi: https://doi.org/10.1016/j.molstruc.2020.127762. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Published by Elsevier B.V.

CREDIT AUTHORSHIP CONTRIBUTION STATEMENT Manuscript title: Experimental and DFT studies on the molecular structure, spectroscopic properties, and molecular docking of 4-phenylpiperazine-1-ium dihydrogen phosphate. Corresponding author’s full name: Noureddine ISSAOUI Olfa NOUREDDINE The majority of theoretical studies except the parts cited for other authors. Sofian GATFAOUI Synthesis of the compound and realization of the IR spectra Silvia Antonia Brandan Vibrational analysis and Force Fields studies Abir SAGAAMA Biological activities of the compound: Molecular docking Houda MAROUANI NMR spectral studies Noureddine ISSAOUI supervisor of the work

Experimental and DFT studies on the molecular structure, spectroscopic properties, and molecular docking of 4-phenylpiperazine-1-ium dihydrogen phosphate. c

Olfa NOUREDDINEa, Sofian GATFAOUIb, Silvia Antonia Brandan , Abir SAGAAMAa, Houda MAROUANIb, Noureddine ISSAOUIa* a

University of Monastir, Laboratory of Quantum and Statistical Physics (LR18ES18), Faculty of Sciences, Monastir 5079, Tunisia. b

University of Carthage, Laboratory of Chemistry of Materials (LR13ES08), Faculty of Sciences of Bizerte, 7021, Tunisia. c Cátedra de Química General, Instituto de Química Inorgánica, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho 471, (4000), San Miguel de Tucumán, Tucumán, Argentina

Abstract: In this work, the organic material4-Phenylpiperazine-1-ium dihydrogen phosphate (4PPHP)has been characterized by 13C and 31P nuclear magnetic resonance (NMR) spectra, UV-visible and infrared spectroscopy. Structural, electronic, topological and vibrational properties were predicted for this compound by using quantum chemical calculations via the density functional theory. The molecular geometry of 4PPHP was optimized by Becke’s three parameter hybrid functional with Lee-Yang-Parr correlation functional LYP (B3LYP) theory with the 6-311++G** basis set. Intermolecular interactions were analyzed by the reduced density gradient (RDG), natural bond orbital (NBO) and topological AIM approaches. The NBO analysis was carried out to provide information about the delocalization of charge and energy density of atoms. The chemical structure of the molecule was elucidated by the electron localization function (ELF) analysis. Besides, the intermolecular interactions of crystal of 4PPHP were analyzed using fingerprint plots of Hirshfeld surface. Nonlinear optical properties for 4PPHPwere predicted. The electronic properties (HOMO and LUMO) were computed. The local reactivity analyses (Fukui functions, electrophilicity indices, among others...) were evaluated to identify the reactive sites. The nucleophilic and electrophilic sites were identified by using the molecular electrostatic potential and the Fukui's functions.The strong band observed in the IR spectrum at 2493 cm-1, assigned to O33-H26 stretching mode of H2PO4 group, clearly supports the formation of an H bond between the H2PO4 and NH groups. The complete vibrational assignments of 96 vibrations modes expected for 4PPHP were reported together with the harmonic force constants. In addition, the biological activities of 4PPHP wereinvestigated by using molecular docking analysis. These studies show that4PPHP could have a great effect in the treatment of Parkinson and schizophrenia diseases. Keywords: DFT; HOMO-LUMO; NMR; ELF; NLO; Docking calculations.

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1. Introduction: The combination of inorganic and organic compounds was the starting point for developing new hybrid materials. The concept of hybrid materials is revealed with the birth of soft chemistry. This latter can undoubtedly provide relevant answers to several problems associated with the fields of environment, energy and health. Thanks to their new and remarkable properties, hybrid materials of organic-inorganic or biological nature, have attracted the interest of many researches in various fields such as biomedical imaging and intelligent therapeutic vectors, micro-optics and microelectronics, construction and insulation, functional coatings, etc. In particular, the hybrid materials containing phosphate groups are very important in pharmacology and medicine, because the frequent use of drugs containing those groups, with time, can produce pathological micro calcifications in various tissues. For instance, with the use of antiviral drug foscarnet, different kinds of diseases were observed [14].Hence, the characteristics and identifications of these phosphate groups are important for the treatment of the corresponding disease[5,6].In the present work, we focus on the theoretical and experimental study of the hybrid (C10H15N2)H2PO4 (4PPHP) material. This system consists of an organic entity which is the phenylpiperazine and an inorganic entity, which has trifunctional oxoacid: the phosphoric acid. Due to his trifunctional oxoacid; the phosphoric acid has very interest physical and chemical properties [6,7]. These properties make it a fundamental element in inorganic chemistry and in biochemistry and also avery interesting compound for several fields of research, such as in nonlinear optics [8,9].While, phenylpiperazine and its derivatives have been the principal elements of many research projects (mainly because they have many good properties in several areas, such as in biological area. They are considered as the new anticancer agents, anthelmintics, antidepressants, antihistamines [10]. In the pharmaceutical field, this element has promising use, as an intermediate pharmaceutical compound. Phenylpiperazine is popularly used to treat anxiety disorders, Parkinson and Schizophrenia diseases [11,12]. Because of this, and because of the very important properties of these two entities, we were encouraged to study the biological activities of our compound. We have determined the biological activity of our compound through a molecular docking calculation [13-16]. It is important torecall that this method is used to predict the affinity of a ligand for a protein, especially the most favourable position for a ligand interacting with a protein ofa known 3D structure. In this work two proteins, which have very important biological activities, are selected and which are monoamine oxidase B (MAOB) and phosphodiesterase 10A (PDE10). The study of these two

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proteins provides therapeutic approaches for the treatment of Parkinson's disease [17] and schizophrenia [18], respectively. 2. Computational details For better description of the conformational space of the 4-phenylpiperazine-1-ium dihydrogen phosphate, the Gaussian 09 software [19] and their interface GaussView [20] were used. All calculations were made by using 6-311++G** basis set in Density Functional Theory (DFT) and B3LYP method[21,22].Firstly, Potential Energy Surface (PES) was obtained to determine the optimized geometry of the studied compound. For this task, the selected torsion angle (C22-C13-C14-H15) was changed every 10° and molecular energy profile was calculated from 0°to 360°. Then, the lowest energy structure on PES of 4PPHP compound was optimized. After the optimization of 4PPHP molecule, the vibrational frequencies were calculated, and their vibrational assignments were made. The vibrational analysis was performed by using the normal internal coordinates, transferable scaling factors and the harmonic force fields calculated with the scaled mechanical force field (SQMFF) method and the Molvib program [26-28].Also, the electronic transitions and analyses of the structures were examined using UV-Vis and 13C-31P NMR spectroscopic techniques and TDDFT and DFT/gauge-including atomic orbitals (GIAO) methods, respectively. Furthermore, the information about the reactive nature of the studied compound was obtained by using their Molecular Electrostatic Potential (MEP) and the HOMO-LUMO transitions. Weak interactions analysis and topological analysis were also performed to see the interactions between the anionic and the cationic entities. The analysis of AIM, ELF and RDG were carried out using Multiwfn software [23].A study of natural bond orbital was performed using the NBO program [24].Hirshfeld surface analysis was carried out using Crystal Explorer 3.1[25].A UV-Visible study has been carried out via time dependent-density functional theory (TD-DFT).For docking calculations two softwares are used: iGEMDOCKprogram [29], for the calculations of ligand-protein interactions,and Discovery Studio Visualizerto determine the best docked poses and the different interactions between ligand-protein complexes. But above all, several steps are used to evaluate these ligand/protein interactions: the 3D crystalline structures of the proteins and the Ligand are determined from the Protein Data Bank (PDB) [30]. There is software that also allows determining ligand called ZINC database [31]. 3. Experimental A combination of an aqueous solution ofH3PO4 (Sigma Aldrich, 2 mmol), 1phenylpiperazine (Sigma Aldrich, 2 mmol), ethanol (10 mL) and water (10 mL) was added 3

together and was stirred during one hour. The chemical reaction can be written as follows (Scheme 1):

N

NH

+

H3 P O4

EtOH/H2 O

N

25°C Scheme 1: Synthesis of 4PPHP compound.

+ NH2

. H2 PO4

The obtained solution was allowed to evaporate at room temperature for numerous days until the creation of single crystals of 4PPHP.The IR spectrum of 4PPHP is recorded in the region 4000–400 cm-1by means of pellets containing the sample in question and KBr as adispersant with 1.0 cm−1 resolution on a PERKIN ELMER FTIR Spectrophotometer. The NMR spectra were recorded on a Bruker DSX-300 spectrometer operating at 121 MHz for 31P and 75.49 MHz for 13C. All measurements were carried out at room temperature, with H3PO4 (85%) as an external standard reference. Phosphorus spectra were recorded under classical MAS conditions, while the carbon ones were recorded by use of cross-polarization from protons. 4. Results and discussion 4.1. Determination of optimized structure and structural parameters To study a molecular system, the first step is to identify the equilibrium structures, since the prediction of the physicochemical properties can be considered only on stable structure. Based on energetic considerations, a conformational study was done to locate the absolute minimum (the lowest energy) which refers to the most stable configuration of 4PPHP compound. To determine the most energetical conformation of 4PPHP molecule, the curve of potential energy versus dihedral angle is illustrated in Fig. S1.This surface shows the existence of four locales minima (I, II, III and IV). The third minima (III), which has the lowest energy (-1143.42 a.u), corresponds to the most stable structure. The geometrical structure corresponding to the lowest minima in the potential energy scan has been used as the starting point for the optimization of the structure at a higher level of theory as well as the basis set. The calculated parameters have been compared with the spatial coordinates of 4PPHP as obtained from X-ray structure analysis. The energetic parameters of the optimized structures (show Fig. 1), calculated by B3LYP/6-311++G**and WB97XD levels of theory in both gas phase and in water, were summarized in Table 1.The examination of this table shows that the global energies take negative values, which confirms the stability of the studied system. The dipole moment, reflecting the polarity of a molecule, shows the order µwater>µgas. 4

Using the B3LYP/6-311++G**method, for example, the dipole moment in gas and in water is 4.9852 Debye and 14.3195 Debye, respectively. In Table 2, we present a comparative study of the calculated parameters along the experimental one. According to the computed values, the longer the bonds lengths and angles, the bigger the experimental values. This differenceis expected because the experimental results are realized on the solid phase while the calculations are performed on isolated molecule. In the gas phase, the carbon-nitrogen bond lengths, C1-N24, C4-N27, C7-N27, C10-N24 and C13-N27 are 1.475Å, 1.460 Å, 1.469 Å, 1.475 Å and 1.415 Å, respectively. In solution, we notice the increase ofthe bonds lengths values.Hence, it is observed that carbon-carbon bond lengths vary between 1.091Å for C4-C6 and 1.526 Å for C4-C1. Moreover the examination of the geometric parameters which are characteristic of hydrogen bonds (depicted in Table 3), shows that there are two types of hydrogen bonding O-H…O and N-H…O: two strong H-bond types O-H…O and two types N-H…O. Theoretically, the intermolecular distances between hydrogen and oxygen (O−H) are: 0.96 Å and2.60 Å for H…O bond. We notice also that the computed O-H and H…O distances are larger than the observed distances. Concerning the N-H…O bonds, the calculated distances are: 1.01 Å for N24−H25; 1.58 Å for N24−H26; 2.93 Å for H25…O29 and 2.93 Å for H26…O29. On the other hand, RMSD (Root-Mean-Square Deviation) is a technique used to compare the theoretical geometric parameter values with the corresponding experimental ones. The predicted values of the RMSD in gas and in water are given in table 2. Calculations show that the RMSD increases by adding the solvent for bond lengths while using WB97XD basis set decreases the bond distances in gas and water, therefore, the RMSD value decreases. In the gas phase, the RMSD value is equal to 0.079by using B3LYP/6311++G**while using the WB97XD functional the value is 0.011. On the other hand, in water the RMSD value is 0.088 by using B3LYP/6-311++G**while it changes to 0.085when the otherWB97XD basis set is employed. Using WB97XD basis set, we find that the bond lengths have the lowest values of RMSD (0.011).However, this is not the case for bond angles because according to table 2 lower RMSD values are observed by using B3LYP/6-311++G** level. 4.2. Study of intermolecular interactions 4.2.1. Interaction analysis with AIM R. Bader [32,33] has developed the innovative approach AIM (Atoms In Molecules) [34], which proposes that the electron density ρ(r) is a local function of the molecular system. This approach is widely used to determine the inter and intra-atomic interaction calculations. The topological parameters which are: the electron density ρ(r), the Laplacian ∇2ρ(r), the 5

eigenvalues (λ1, λ2, λ3), the λ1/λ3 ratio, the kinetic energy densities G(r), the total energy densities H(r), the potential V(r) and the bond energy E give a lot of information on the properties of RCPs and BCPs. Hence, the different topological properties of 4PPHP compound are collected in detail in Table 4, whereas the graphical molecular is illustrated in Fig. 2.The electron density ρ(r) and it's Laplacian ∇2ρ(r) allows to determine the nature of the interactions. Generally speaking, the great values of ∇2ρ(r) and ρ(r) express the great strength of the hydrogen interactions. When ∇2ρ(r) is negative, the electron density ρ(r) is important in values and it also shows the concentration of charge in the internuclear region. The negative sign of ∇2ρ(r) (-2.4809a.u) at the CP of binding is indicative of a strong covalent character. Conversely, the Laplacian's positive values are attributed to weakening of charge in the internuclear region. Our study shows thatthe bond critical points are located in the hydrogen interactions O29…H25-N24 and N24…H26-O33, where the electron density values are equal to 0.2814 a.u and 0.2374 a.u; the laplacian equal to -0.9675 a.u and 1.4748 a.u, respectively. As seen, the hydrogen bond O29...H25-N24 has a negative laplacian (∇2ρ(r)= -0.9675 a.u) and a negative total energy density (H(r)= -0.2803a.u), we can conclude in this case, that this hydrogen bond is strong[35]. While the hydrogen bondN24…H26-O33 has a positive laplacian (∇2ρ(r)= 1.4748 a.u) and negative total energy densities (H(r)= -0.1826 a.u), so we have moderate hydrogen bonds.Note also, that this analysis explicitly describes two RCPs and a new ring critical point (NRCP1). All associated ρ(r) values are positive, likewise for laplacian except for NRCP1, which has a negative value equal to -2.4809 a.u. So, in this case we are talking about a concentration of charge around this point. 4.2.2. Electron localization function analysis In order to understand and precise the chemical structure of our molecule, the electron localization function (ELF) analysis is performed [36,37].This analysis allows us to distinguish the basins that correspond to the attractors, which are of great importance in chemistry. Figs. 3.a and 3.b shows the ELF maps using Multiwfn program. The dashed lines in graph 3-a (blue colour) correspond to the regions that have experience decrease in electron density whereas Fig. 3.b shows the colour filled ELF map. The blue and particularly dark blue areas revealed a decrease in ELF in the corresponding regions. This graph shows that the localization of electrons is limited in regions of intermolecular interaction, maybe this is related to the consequence of Pauli's repulsive effect. The areas of electron depletion are located between the inner layer and the valence layer; they are represented by blue circles around the nuclei. It is seen that the hydrogen and carbon regions have the lowest values of 6

the localized orbital locator. Generally, when the ELF has a higher value this corresponds to a higher electronic location. 4.2.3. Reduced density gradient analysis The non covalent interactions (NCI) method can be used to analyze all types of interactions and, in particular, in areas or regions of low density [38]. This method is based on the study of the reduced density gradient (RDG). Fig. S2 presents RDG as a function of ρ multiplied by the sign of λ2 (λ2 is the second eigenvalue of laplacian density). Generally, according to the sign of the eigenvalue λ2, we can determine the nature of the interaction since it characterizes density fluctuations. Thus, the sign of λ2 is a good indicator of the stabilizing or destabilizing nature of an intermolecular interaction. The sign (λ2) <0 informs about the interesting contributions to non-covalent interactions, while the sign (λ2)> 0 has repulsive contributions. From the sign (λ2)*ρ, it is possible to evaluate the bond strength. For example, the hydrogen bonds have a density ρ that is more negative than the van der Waals interactions, while we will see the repulsive zones for positive values. This made it possible to classify these interactions as well as their strength. The three-dimensional isosurfaces of 4PPHP are represented in Figure. 4whichpresent a colour code, that differentiates the different interactions types. The blue color indicates the hydrogen bond, whereas the green one corresponds to Van Der Waals interaction and the red denotes the steric cyclic effect. As it is clearly seen, in the RDG graph of 4PPHP compound, the crystal stability of our molecule is ensured by hydrogen bonds type C-H...O and N-H...O. These bonds appeared with a sign λ2*ρ ranging from -0.015 to -0.005 Å, as shown in figures 4.a and S2.a. To better study crystal stability of our complex, we have been examining interactions among two adjoining cations. According to the literature, if the distance between two neighbouring cations is over 3.8 Å there is no VDW interaction type. In the title compound, although the distance between cation-cation is greater than average distance (3.8Å), the bright intensity of green color in RDG isosurface (figure. 4b) proves the presence of strong VDW interaction. This latter associated with a distance equal to 4.870 Å. 4.2.4. Natural Bond Orbital study Natural Bonding Orbital (NBO) analysis characterizes the inter and intra molecular Hbonding interactions between a wide variety of chemical systems [40,41]. In the NBO analysis, the interaction between donor-acceptor is characterized by a significant energy E(2) [42] given by: E 2 = q i

F(i, j) , where qi, F (i. j) and εi,εj represent, respectively, the occupation εi − ε j

of the orbital i, the Fock matrix element outside diagonal and the diagonal elements. 7

The NBO results obtained for the 4PPHS compound in the gaseous state and in the water are computed and presented in Table 5. This table lists the energy E(2) between the local orbitals which are the occupied bonding orbitals BD, the empty anti bonding orbitals BD*, the lone pairs LP and the anti-lone pairs LP*. The comparison shows that by adding the solvent the value of the stabilizing energy, it slightly decreases. Taking it as an example, in gas the total stabilization energy ∆ET of the interaction between the bonding donor orbital σ with the anti-bonding orbital σ* equals to 119.78 kcal/mol. Adding water, the energy decreases a little towards 119.65 kcal/mol. Interactions between the bonding orbital σ (C13 - C14), σ (C13 - C14), σ (C16 - C18), σ (C16 - C18), σ (C20 - C22), σ (C20 - C22) and σ (C1 -C4) and the anti- bonding orbital σ* (C16 - C18), σ* (C20 - C22), σ* (C13 - C14), σ* (C20 - C22), σ* (C13 - C14), σ* (C16 C18) and σ* (N24 - H25) possess medium stabilization energy roughly equal to 17.11 kcal/mol in gas and 17.09 kcal/mol in water. Concerning the interactions between the lone- pairs LP and the anti-bonding orbital σ*, they have approximately an average stabilization energy of around 12.65 kcal/mol in the gas phase, while, it is equal to 12.50 kcal/mol in water. NBO analysis confirms the existence of X-H…Y hydrogen bonds between the different interaction donor-acceptor, as, for example, the interaction between the lone pair LP(1)-N24 and LP*(1)H2 which is characterized by a stabilizing energy that equals to 75.07 kcal/mol (in gas) and 79.37 kcal/mol (in water). From this table, it is possible to observe that the BD→BD* interaction has bigger average E(2)energy than that of LP→BD*. For BD →BD* interaction, it is ranged between 1.94 to 22.23 kcal/mol; and between 1.90 to 22.63 kcal/mol in water. While, the LP→BD* interaction varies between 5.32-26.52 kcal/mol in gas phase and between 5.34-25.49 kcal/mol in water. 4.2.5. Hirshfeld investigation In order to perceive the intermolecular interactions in the crystal of 4PPHP, a Hirshfeld surface (HS) analysis [43] was executed by CrystalExplorer 3.1. In the HS plotted over dnorm (Fig. 5a), the white surface indicates contacts with distances equal to the sum of the van der Waals (VDW) radii, the red colour specifies distances shorter than the VDW radii and are considered as close contact but the blue colour identifies distances longer than the VDW radii and are considered as distinct contact. The overall two-dimensional (2D) fingerprint plot [44] (Fig. 5b) and those depicted into H…H, H…O/O…H, H…C/C…H and H…N/N…H interactions are illustrated in Figs. 5(c)– (f), respectively. The H…H contacts emerge in the middle of the scattered points in 2D fingerprint maps with a single broad peak at de = di = 1.1Å and have the most significant contribution to the HS 8

with a percentage contribution of 48.4%. The O…H/H…O contacts, which are attributed to O-H…O, N-H…O and C-H…O hydrogen bonding interactions, appear as two sharp symmetric spikes in the 2D fingerprint maps with a prominent long spike at de + di = 1.6 Å. They have the second significant contribution to the total HS (32.5%). The 17.1% contribution from the C…H/H…C contacts to the HS, generally slightly favoured in a sample of CH aromatic molecules, which results in a symmetric pair of wings, Fig. 5e. The enrichment ratio (ER) of a chemical element pair (X, Y) is defined as the ratio between the percentage of the actual contacts in the crystal and the theoretical percentage of the random contacts [45]. The enrichment ratio (ER) values are tabulated in Table 6. The H…O/O…H, H…C/C…H and H…N/N…H contact appears with equal enrichment ER = 1.35. Accordingly, this type of contacts are most recurrent interactions due to the great quantity of hydrogen on the molecular surface (% SH = 74.2%). Quantitative measures of HS of 4PPHP were completed akin to molecular volume (303.57 Å3), surface area (277.77 Å2), globularity (0.790) as well as asphericity (0.182). 4.3. Electronic properties 4.3.1. Molecular electrostatic potential (MESP) MEPs allowed us to determine the behaviour and the chemical activity of molecules in both electrophilic and nucleophilic reactions [46-49].To evaluate reactive sites for electrophilic and nucleophilic attack for the title molecule 4PPHP, the MESP is obtained based on B3LYP/6-311++ G** optimized result and it is shown in the Fig. S3. A spectrum of colours exists on the surface of the MEP, the total electron density ranging between two extreme limits:-6.98210-2a.u to 6.98210-2a.u. Where, the red colour reveals the strongest repulsion and the blue colour indicates the strongest attraction it contains several possible sites of nucleophilic and electrophilic attack. From the Figure, it is predicted that this molecule has several possible sites for electrophilic attack. Negative regions, in the title molecule,are found around the oxygen atom O34 of the anionic uniteand the potential V(r) value is -0.07098a.u, -0.0144 a.u -0.0069 a.u respectively.

The maximum positive

regionislocalized around thehydrogen atoms H30and H34and the potential V(r) values are +0.068892 a.u, +0.06135 a.u respectively, indicating possible sites for nucleophilic attack. 4.3.2. UV-Visible spectrum analysis UV-Visible spectroscopy is one of the most widely used analytical techniques, since it is able to detect almost every molecule. The UV spectrum ranges from 100 to 400 nm while the visible spectrum extends from 400 to 700 nm. When these molecules absorb photons, the energy of the valence electrons increases. The absorption in this region is related to the 9

variations of the energy of electronic transitions [50].The theoretical UV-visible spectrum of (C10H15N2)H2PO4, computed with the TD-DFT method at room temperature [51],is presented in Fig. S4.This later shows two maxima of absorption at 212.8 nm and 252.4 nm. In the Table S1we give the predicted energies, wavelength, oscillator strength, major and minor contributions of theoretical UV-visible spectrum. The major and minor contributions of the transitions were determined using GaussSum program [52].As illustrated in table S1, calculations reveal that the first intense band at 249.26 nm has f= 0.109 oscillator strength and HOMO->LUMO (21%); HOMO->L+2 (70%) major contribution. The second most intense band observed at 261.15 nm has f= 0.130 oscillator strength and HOMO->LUMO (75%); HOMO->L+2 (16%) major contribution. 4.3.3. Frontier Molecular Orbital analysis The frontier molecular orbitals (FMOs) makes it possible to understand the local reactivity of molecules. According to Fukui [53], to study a chemical reaction, only the two molecular orbitals HOMO (Highest Occupied Molecular Orbital) and LUMO (Lowest Unoccupied Molecular Orbital) are of real interest. The HOMO provides information on the electrondonor character (nucleophilic site) whereas the LUMO indicates the electro-receptor character of the molecule (electrophilic site).The 3D graphical representation of LUMO, LUMO+1, HOMO, HOMO-1 of 4PPHP compound (calculated with B3LYP/6-311++G**) is provided in Fig.6. The orbital density diagram (DOS) of 4PPHP is presented in Fig. S5. According to this diagram, it is possible to prepare the state of the orbital density. To discover the energetic behaviour of our compound, we have determined the quantum chemical parameters between the possible combinations of 4PPHP compound (the energies HOMO and LUMO, chemical potential µ, electro negativity χ, global hardness η, softness S and electrophilicity) using TDDFT calculations (show Table 7). All these parameters can be calculated from the energies of the frontier molecular orbitals [54, 55]. EHOMO is a size reflecting the transfer of electrons between two reactants. As it is illustrated in Fig. 6, HOMO and LUMO are very intriguing. In gas phase, EHOMO= -5.9029 eV; ELUMO= -0.7311eV and energy gap ∆E is determined to be 5.1718 eV, EHOMO-1= -7.1239 eV; ELUMO+1= -0.5621 eV, and energy gap ∆E is determined to be -6.5618 eV. In water, EHOMO=-5.8153 eV; ELUMO= -0.4658 eV and ∆E=-5.3495 eV. Concerning orbital HOMO-1 and LUMO+1, we found EHOMO-1= -7.0529 eV; ELUMO+1= 0.3698 eV and energy gap ∆E= -6.6831 eV. By examining this table, we find that gap energy in gas is larger than that in water. Similarly, for other orbitals, in water EHOMO-1-ELUMO+1 are weaker than the gap EHOMO-1-ELUMO+1in gas. In conclusion, we notice that the gap energy value is very low, which makes our system more reactive and less stable in water. 10

4.4. NMR spectral studies Nuclear Magnetic Resonance spectroscopy (NMR) is a technique that uses the magnetic properties of atomic nuclei to identify the structure of the compounds. Our system contains 5 types of atoms: carbon, hydrogen, oxygen, nitrogen and phosphate, but only the nuclei of phosphate and carbon that are subjected by NMR spectroscopy. 13

C carbon NMR: Theoretical and experimental C13-NMR spectrum of (C10H15N2)H2PO4 are provided in

Fig.7. The calculated chemical shifts of 13C by using the GIAO [56] method as a reference at the TMS B3LYP/6-311+G (2d,p), the TMS HF/6-31G(d) and CH4 HF/6-31G(d) levels can be seen from Table 8 as well as the experimental shifts. To see that it is the best reference, we will use, we calculated the RMSD. As illustrated in table 8, the value of RMSD is lower using B3LYP/6-31G(d) level or CH4 HF/6-31G(d) level since they contain the same displacement values(RMSD6-311+G (2d,p)= 12.565; RMSD6-31G (d)= 8.199), so we will finish our work with this reference. As noted, the observed chemical shifts were found from 44.81 to 149.18 ppm, while the calculated shifts were identified from 43.08 to 171.42 ppm. This difference is due to the fact that the molecule is in the solid state experimentally, and, on the other hand it is in gas phase theoretically. The analysis of C13-NMR curves shows that theoretically there are ten carbon rays, while experimentally we observe seven rays. This can be explained by the presence of carbon atoms having the same chemical shifts which are the pairs (C10, C1) and (C7, C4). Usually, the chemical shift of carbon, which corresponds to the aromatic ring is in the range of 115-150 ppm. But as noted in table 8, the carbon C13 theoretically takes the value 171.42 ppm and the value 149.18 ppm experimentally. In fact, the C13 carbon that is adjacent to the nitrogen atom is the most unblocked since it is close to an electron-with drawing group. 31

P phosphate NMR: We represent in Fig. 8 (a and b), the experimental and theoretical

31

P-NMR spectrum of

4PPHP compound. As clearly seen, the NMR spectrum consists of a single ray at 3 ppm, which is in good agreement with those of monophosphates which vary between -10 and 5 ppm [57,58]. The presence of a single ray shows that the elementary cell of 4PPHP compound contains a single phosphoric site. 4.5. Fukui functions In quantum chemistry, Fukui functions (FF) [59] can be an adequate tool to investigate the reactivity behaviour of the molecule. They are among the most useful reactivity indices that derive from the most useful DFT. In order to identify the most reactive sites for electrophilic or nucleophilic reactions within a molecule Fukui functions are introduced [60]. Fukui 11

function, proposed by Parr and Yang in 1984 is a tool for understanding and predicting the relative reactivity of different sites in a molecule [61]. To get Fukui's functions, the first step: the neutral molecule is calculated to know the corresponding molecular structure to of the lowest energy and its multiplicity. The second step: the molecular geometry obtained above makes it possible to calculate on its anion and its cation while changing the charge and the multiplicity in each case. These geometries have been optimized using B3LYP theory. In Fig. 9, Fukui functions (f0,f+ and f-) of (C10H15N2)H2PO4 compound are shown. The atomic charge of cationic, anionic and neutral of 4PPHP calculated by B3LYP/6-311++G**level of theory are tabulated in Table S2. Fukui indices with higher values correspond to efficient electrophilic and nucleophilic sites. Therefore, more than the Molecular Electrostatic Potential (MEP) that allows recognizing nucleophilic and electrophilic sites, these sites can be identified from these Fukui's functions. From table S2, it is observed that the higher FF f+ values are in the order of C1> C10> P28> C20>…ect, these are the nucleophilic attack sites. Likewise, the higher FF f- values are in the order of C13> N24> C7> C20>…etc. Also, we have calculated ∆f (∆f=f+-f-) which represents an excellent factor to identify the properties of electrophilicity and nucleophilicity: if ∆f> 0 the site has a nucleophilic property and if ∆f< 0 the site has an electrophilic character. For that, we have shown in Fig. S6, the variation of ∆f in functions of the atoms. Results reveal that, from the calculated values of ∆f given in table S2, the atoms H2, H3, C4, H6, C7, H8, H9, H11, H12, C13, C16, H17, H21, C22, H23, N24, H25, H30 and H32 present electrophilic sites since the value of ∆f is negative. It is seen that the atoms N24 (∆f =-0.940358) and C7 (∆f =-0.742047) are the favourablesites for electrophilic attack. While, C1, H5, C10, C14, H15, C18, H19, C20, H26, N27, P28, O29, O31, O33 and O34 correspond to the positive ∆f so they present the nucleophilic sites. C1 and C10 are the favourablesites for nucleophilic attack where ∆f equal to 1.738856 and 1,736162, respectively. 4.6. Non-linear optical properties study Nonlinear optics (NLO) concerns the phenomena of the non-linearity of a material medium to the action of an electromagnetic wave in an optical domain. According to the literature, organic materials have higher nonlinear optical properties than inorganic materials [62].According to Buckingham's [63], density functional theory allows to calculate the polarizability

(α),

the

hyperpolarizability(β)

and

the

electric

dipole

moment.

Hyperpolarizability β is very sensitive to the molecular structure. α and β present a very important tool in the field of pharmacology since they can be used in drug design. In this study, the non-linear optical properties of present, molecule were investigated. Table S3 12

shows the calculated values of the exact polarizability (αxx, αxy, αyy, αxz, αyz, αzz), the hyperpolarizability (βxxx, βxxy, βxyy, βyyy, βxxz, βxyz, βyyz, βxzz, βyzz, βzzz) and the dipole moment determined from electronic structural calculations. The molecular hyper polarizability β of the our studied compound has been calculated as 5351.97×10-33 esuwith dipole moment 12.865 Debyeand 22.6907 ×10-24esuusing Gaussian output by DFT/B3LYP/6-311++G(d,p) set and the values have been shown in Table S3. The β value of 4PPHR has been compared with the β value of Urea (372.8 .10-33esu) which is a standard NLO reference material. This large β value (more than 14 times larger than the Urea) indicates the potential of 4PPHP to exhibit second order optical effects. The increase of the polarizability isdue to inter and intra molecular interactions that have been discussed in topology analysis. Results have shown that our compound has a higher dipole moment than for urea, which can be explained by the noncentrosymmetric of this molecule. We can conclude that, due to low band gap energy which has been explained in electronic properties section, high β and µ, 4PPHP can have industrial application in the form of NLO material. 4.7.Molecular docking Docking is one of the powerful theoretical methods for studying molecular interactions between ligand and protein, which are very important in biological process [80-82], such as the tumors and the bacterial[83-84]diseases. In the present work, the docking calculation were conducted using iGEMDOCK program, whose population size is 800, the number of generations is 80, as well as the number of solutions is 10.Our goal is to very quickly evaluate the energy for the various configurations, and to determine the lowest energy which shows the stability of the compound. Using iGEMDOCK program, we can determine the interaction energy of a ligand with a protein (also called free energy binding). Generally, this interaction energy is not found from a single structure. In fact, it corresponds to the average of the energy of several stable structures. Results reveal 10 docked poses, so 10 energy values. The best position that has the lowest energy, which corresponds to the most stable protein/ligand complex. Docking calculations of interaction energies were subsequently clustered in Table 9. The Fig. 10-a represents the molecular docking of MAOB protein with the four ligand that are Farnesol (2BK3) [64], Deprenyl (2BYB) [65], Zonisamide(3PO7) [66] and 4PPHP. In this context, several research studies have been carried out on molecular docking [67,68]. These researchers have found that the derivatives of thiophenic acid play an important role as inhibitors of human MAOB. The different types of these complexes interactions are illustrated in Fig. S7.Molecular docking led to the following results: the total energies equal to -92.493, 13

87.140, -83.580 and -76.541 kcal/mol for 2BK3, 3PO7, 4PPHP, and 2BYB interacting with MAOB protein, respectively. We notice that the 4PPHP, 2BYB and 1-PPHS ligands have almost the same best positions, which are different to the other two ligands (3PO7 and 2BK3) which are ancrage at the same binding site. The 2BK3 ligand is the strongest binding since it possesses the strongest energy (in absolute value) -92.493 kcal/mol, the strongest van der Waals interaction -86.535 kcal/mol and the strongest averconpair 34.25 kcal/mol. Thereafter, the ligand 3PO7 is found with energy equal to -87.140 kcal/mol. We notice that there is not an important difference between the energy values of these two ligands, which justifies the localization of their best docked poses (show Fig. 10-a). The weakest bond is for 2BYB ligand with a total score energy equal to -76.541 kcal/mol.Accordingly, it is seen that the most similar best poses are for the 4PPHP and 2BYB ligands, in terms of the type of interactions and binding energies, similarly for the two ligands 3PO7 and 2BK3. This result is harmonious with the similarity of their structure. Following the previous observations, a new protein was studied called PDE10A in interaction with the following Ligand: Imadazopyrazine (5K9R) [69], Benzinidazole (3WS9) [70], Triazolopyrimidine (6KEO) [71] and 4PPHP. Localization of the best docked poses of these complexes estimated via docking calculations are given in Fig. 10-b. The interactions profiling between these complexes have been shown in Fig. S8.Table 9 analysis shows that our compound 4PPHP takes the highest energy value which is equal to -86.119 kcal/mol, also it presents the strongest van der Waals interaction (-63.292 kcal/mol). Likewise, it is the only compound that has an electronic interaction (equal to -1.8531 kcal/mol). The total energy of 5K9R ligand (E=-69.567 kcal/mol) is nearly equal to the energy of ligand 6KEO (-69.047 kcal/mol) and approximately 5 kcal/mol higher than that of 3WS9.We represent in Fig. S7 and S8, the docking calculations of H-bond interaction energies between protein-ligand . The analysis, of these figures, shows that the binding pose represents many hydrogen bonds. For example, our compound "4PPHP" contains two important interactions considered as hydrogen bonds; the first one is O29…H25-N24 (1.67 a.u) and the second is N24…H26-O33 (2.56 a.u). The electron acceptor-donor interaction promotes the formation of these bonds. For MAOB4PPHP interaction, H2SO4 compound plays the role of an electron acceptor, while the phenyl group plays the role of an electron donor. For PDE10A-4PPHP interaction, phenyl ring represents the character of an electron acceptor, whereas H2SO4 represents the character of an electron donor. Also, these figures depict the existence of π-π interactions which have many applications in various fields, such as in the biomedical field [72]. This type of interactions is used as a driving force for drug handling. We presented a comparative study of the results 14

obtained with our previously work [73], where we made the computation docking of another phenylpiperazine derivative which is the 1-Phenylpiperazine-1,4-dium bis (hydrogen sulfate) compound (abbreviated as1-PPHS) with the both proteins MAOB and PDE10A. The resulting docking conformations of this later are ranked in Figs. 10, S7 and S8, and the interactions energies are given in table 9. The comparison shows that 1-PPHS have the strongest binding ligand (EMAOB=-97.845 kcal/mol; EPDE10A=-99.378 kcal/mol) and the strongest van der Waals interaction. While, the studied compound 4PPHP has a total energy score equal to -83.580 kcal/mol for MAOB protein and -86.119 kcal/mol for PDE10A protein. Similarly, it can be noted that for PDE10A protein only these two compounds have electronic interactions. Whereas for MAOB, we find that 1-PPHS is the only compound that contains an electronic energy equal to -1.345 kcal/mol. This energy difference is due to the inorganic group in the 1PPHS compound. The main conclusion can be drawn, is that the molecular docking allows us to determine the biological activities of such a system. According to our results, we found that 4PPHP has a lot of biological activities. The different interactions observed between the complexes 4PPHP-PDE10A and 4PPHP-MAOB makes it clear that our compound can be an important inhibitor against Parkinson's and Alzheimer's diseases. 4.8. Vibrational analysis The B3LYP/6-311++G**calculations have optimized the structure of 4PPHP in gas phase with C1 symmetry. Hence, the 96 vibrations modes expected for 4PPHP present activities in both infrared and Raman spectra. The experimental infrared spectrum of 4PPHP in the solid phase in the 4000-400 cm-1 region can be seen in Fig. S9as compared to the corresponding predicted in gas phase by using the B3LYP/6-311++G**method while in Figure S10the predicted Raman spectrum of 4PPHP in the gas phase at the same level of theory is shown. Here, the predicted Raman spectrum in activities were corrected to intensities by using suggested equations [74,75]. The above studies on 4PPHPhave clearly evidenced the presence of intra-molecular H bonds formedbetween the N24-H25 and H2PO4groups (O-H26...N24 and NH25...O-P),for which, this analysis was performed taking into account the normal internal coordinates for the three NH2, HO-P-OH and P=O2groups with C2V symmetries, as in related compounds [5-7,76-77].The harmonic force fields were calculated with the normal internal coordinates by using transferable scaling factors, the scaled mechanical force field (SQMFF) procedure and the Molvib program [26-28]. To the assignments, only potential energy distributions (PED) contributions ≥ 10% and the experimental IR spectrum were considered. Observed and calculated wavenumbers and assignments for 4PPHP in gas phase by using the 15

B3LYP/6-311++G**method are summarized in Table S4. The assignments for the most important groups are discussed below. Band Assignments 4000-2000 cm-1 region. This region is typical of antisymmetric and symmetric stretching modes of NH2 and CH2 groups, of OH stretching modes and also of aromatic C-H bonds. In 4PPHP, two of three O-H stretching modes expected for the H3PO4 group (see Fig. S9) were predicted by SQM calculations at higher wavenumbers than the corresponding to NH2 groups, hence, the strong and broad band at3567 cm-1 is clearly assigned to those two vibration modes of OH and NH2 groups. Note that the two NH2 stretching modes undergo strong coupling between them due to that an N24-H26 bond of this group is linked to P-O33-H26 group and, for these reasons, they are also predicted at 462, 257, 197, 136 and 74 cm-1 for which the strong band at 512 cm-1 can be assigned to these modes. Here, a very important observation is the strong shifting of stretching mode related to O33-H26 bond because it is predicted by SQM calculation at 2298 cm-1due to the H bond formation (N24...H26), then it is observed at lower wavenumbers than the other ones. Hence, the strong band at 2493 cm-1is easily assigned to that vibration mode. The two stretching modes of CH2 groups are predicted in the expected regions and, for these reasons, they are assigned accordingly [76,77]. Note that the symmetries of these modes were not specified in this work because the Raman spectrum was not recorded. 2000-1000 cm-1 region. This region is characteristic of C=C, C-C and C-N stretching modes, deformation and rocking modes of NH2 and CH2 groups, wagging modes of CH2 groups and rocking modes of C-H groups. In 4PPHP, the IR band of medium intensity and the strong bands at 1640 and 1600 cm-1, respectively are clearly assigned to C=C stretching modes because these bonds are predicted by calculations with double bond character. Other C-C stretching modes, predicted with partial double bond character can be associated to the intense IR bands at 1260 and 1091 cm-1 while the shoulder and strong band respectively at 1233 and 1154 cm-1 can be assigned to C-N stretching modes, as detailed in Table S4. The CH2 deformation modes are predicted by calculations between 1445 and 1425 cm-1 while the wagging modes of the same group are predicted between 1400 and 1390 cm-1. Hence, these modes are assigned as predicted by SQM calculations. In 4PPHP, the vibration modes corresponding to NH2 groups are predicted in regions, different from the assignments reported for similar compounds [78,79] because an N24-H26 bond of this group is coordinated to P-O33H26 group. Hence, the NH2deformation mode is predicted at 17 cm-1 and, hence, it is not assigned. On the other hand, the coupling of NH2 wagging and rocking modes is clearly 16

predicted by calculations at 1459 cm-1, hence, the strong band at 1451 cm-1 can be assigned to these vibration modes. Also, the coordination’smodes observed between the N24-H26 and PO33-H26 groups justify the strong coupling between the corresponding O33-H26 and N24H26torsion modes observed in this region and, in the lower wavenumbers region. In this region, the PO2antisymmetric mode is predicted at 1238 cm-1 because the P=O bonds are predicted with double bond character, therefore, the strong band at 1260 cm-1 is also assigned to this vibration mode. 1000-10 cm-1 region. In this region, the SQM calculations predicted the PO2symmetric mode and, also, the two HPO2antisymmetric and symmetric modes respectively at 924, 817 and 757 cm-1 because these modes have simple bond character, for these reasons, the intense bands at919, 856 and 764 cm-1 are clearly assigned to these vibration modes. Two OH deformation modes of H3PO4 group are assigned respectively to the band and shoulder to 991 and 969 cm-1, as predicted by the SQM calculations. The deformation wagging, rocking and twisting of HPO2 group are predicted between 468 and 178 cm-1 while the PO2 deformation mode is predicted coupled with the corresponding to HPO2 group at 375 cm-1 and, hence, its mode cannot be assigned because the IR spectrum was recorded until 400 cm-1. The deformation and torsion modes of both phenyl (A1) and piperazine (A2) rings are predicted in this region and, assigned as in similar compounds and as predicted the calculations [70,75]. Other skeletal modes are also predicted by calculations at lower wavenumbers. 4.9. Force Fields The studies of different interactions in 4PPHP have clearly revealed the coordination modes of H3PO4 moiety to N-H group and, as a consequence the formation of different types of H bonds are observed. Therefore, it is expected that the force of NH2, P=O and P-O bonds are different among them, as supported by the vibrational analysis. Hence, the harmonic force constants for 4PPHP in gas phase were computed from the corresponding force field with the SQMFF methodology and the Molvib program [26-28] by using the B3LYP/6311++G**level of theory. The values are presented in Table 10 compared with those reported for species containing NH2 and phosphate groups at different level of theory. The compared species are foscarnet [5], aminoethyl phosphonic acid (AEP) [77], acetazolamide [76] and guanfacine [79]. Comparing first the f(νP=O) force constant value of 4PPHP with foscarnet, we observed a lower value in this antiviral drug because in the vibrational analysis of the acid specie a C3V symmetry was considered for the PO3 group [5]. If now the values are compared with the predicted for the AEPsimilar values are observed in the force constants of phosphate groups but different from the OH and NH2 groups [79]. These differences can be attributed to 17

two factors: (i) in AEP the NH2 group is as zwitterionic species (NH3+), later a C3V symmetry was considered for this group and, (ii) in 4PPHP, the NH2 group is formed by a coordinated bond N24…H26-P. Thus, lower f(νO-H), f(νNH2) and f(δNH2) force constants values are predicted for 4PPHP, as compared with AEP. When the value is compared with the corresponding to acetazolamide, higher values are observed in the f(νNH2) and f(δNH2) force constants, as expected because in this species both N-H bonds are not coordinated [76]. For these same reasons, the f(νNH2) and f(νC-N) force constants predicted for the free base, cationic and hydrochloride species of guanfacine are higher than the corresponding to 4PPHP. However, similar values are observed for the other force constants. These results in the force constants for 4PPHP clearly confirm the different characteristics of N-H and P-O bonds. 5. Conclusions In the present paper, we have investigated the theoretical structural, electronic, topological and vibrational analysis of 4-Phenylpiperazine-1-ium dihydrogen phosphate computed by quantum chemical methods. A conformational study is presented in order to find the most stable structure. The optimized bond lengths and bond angles parameters are calculated and compared among B3LYP/6-311++G** and WB97XD for the optimized structure. We found that the equilibrium geometry by B3LYP/6-311++G** theory for the bond angles is performing better. NBO, AIM, ELF and RDG approach determines the nature and properties of molecular interactions and reveals clearly the different characteristics of N-H and P-O bonds. Hence, H bonds interactions between the N24-H25 and H2PO4groups (O-H26...N24 and N-H25...O-P) were clearly revealed by AIM studies. HS is evaluated in order to perceive the intermolecular interactions in the crystal. TD-DFT has been used to determine the electronic spectrum of 4PPHP compound. MEP mapping is determined to predict the nucleophilic and electrophilic reactions also the hydrogen bonding interactions of the molecule. It is seen that the positive potential sites are located on hydrogen and nitrogen atoms as well as the negative sites are the oxygen atoms in the sulfuric acid. The complete assignments of 96 normal vibration modes expected for 4PPHPare presented together with the force field and the force constants. The experimental and simulated UV-visible absorption spectra show a good correlation. The FMOs have been visualized and the energy separation between HOMO and LUMO that gives information about the chemical reactivity of 4PPHP has been calculated. The experimental and theoretical

13

C and

31

P NMR spectrum have been simulated, and then

we have obtained the calculated chemical shifts with the help of GIAO method. Based on the distribution of electron density in space, all the hydrogen bonds studied are weak. Molecular 18

docking analysis suggests that 4PPHP has a very important inhibitory activity for the treatment of Parkinson’s and schizophrenia diseases. Acknowledgements. This work was supported with grants from the Ministry of Higher Education and Scientific Research of Tunisia and CIUNT Project Nº 26/D608(Consejo de Investigaciones, Universidad Nacional de Tucumán). The authors would like to thank Prof. Tom Sundius for his permission to use MOLVIB. References : [1] Jan Sjovall, Anders Karlsson, Stephan Ogenstad, Sandström E, Saarimäki M Pharmacokinetics and absorption of foscarnet after intravenous and oral administration to patients with human immunodeficiency virus, Clin.Pharmacol.Ther. 44 (1988) 65-73. [2] L Gérard, D Salmon Céron, Pharmacology and clinical use of foscarnet, Int. J. Antimicrob. Agents. 5(1995) 209-17. [3] Erik De Clercq, Antiviral drugs in current clinical use,J. CLIN. VIROL. 30 (2004) 115. [4] Jocelyne Piret, Guy Boivin, Resistance of Herpes Simplex Viruses to Nucleoside Analogues: Mechanisms, Prevalence, and Management,ANTIMICROB. AGENTS. CH. 55 (2011) 459-472. [5] Maximiliano A. Iramain, Silvia A. Brandán, Structural and vibrational study on the acid, hexa-hydrated and anhydrous trisodic salts of antiviral drug Foscarnet, drug design: J. Intellect. Prop. 1 (2018) 1-17. [6] S. A. Brandán, S. B. Díaz, J. J. López González, E. A. Disalvo, A. Ben Altabef, Experimental and theoretical study of hydration of phosphates groups in esters of biologic interest, Spectroc. Acta A: Mol. Biomol. Spectrosc. 66 884-897 (2007). [7] S. A. Brandán, S. B. Díaz, R. Cobos Picot, E. A. Disalvo, A. Ben Altabef, Hydration of Inorganic Phosphates in Crystal Lattices and In Aqueous Solution. An Experimental and Theoretical Study, Spectroc. Acta A: Mol. Biomol. Spectrosc.66(2007) 1152-1164. [8] J.L. Oudar, R. Hierle, An efficient organic crystal for nonlinear optics: methyl‐(2, 4‐dinitrophenyl)- aminopropanoate, J. Appl. Phys. 48 (1977) 2699-2704. [9] R. Masse, J. Zyss, A new approach in the design of polar crystals for quadratic nonlinear optics exemplified by the synthesis and crystal structure of 2-amino-5-nitropyridinium dihydrogen monophosphate (2A5NPDP), Mol. Engineer. 1 (1991) 141-152. [10] POMPEU, E.T. Thais, ALVES, R.S. Fernando, FIGUEIREDO, D.M. Carolina, Synthesis and pharmacological evaluation of new N-phenylpiperazine derivatives designed as

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25

List of tables : Table 1: Energy, dipole moment, RMS Gradient Norm, Maximum force and force calculated at B3LYP6-311++G(d,p) and WB97D levels of theory. Table 2: Optimized bond lengths and bond angles (Å, °) parameters of 4PPHP. Table 3: Geometric characteristics of hydrogen bonds in (C10H15N2)H2PO4. Table 4: AIM analysis of the bond critical points (BCP) and ring critical points (RCP) for (C10H15N2)H2PO4. Table 5: Natural bond orbital analysis and the corresponding energies E(2) in gas phase and in water for (C10H15N2)H2PO4 using B3LYP/6-311++G (d. p) method. Table 6: Enrichment ratio (ER) of different inter-contact and percentage of each atom on the HS in 4PPHP. Table 7: Difference of energies between the possible combinations, chemical potential, Electronegativity, Global hardness, Softness and Electrophilicity. All values are in eV except for S which is given in eV-1. Table 8: Experimental and theoretical chemical shifts of 13C. Table 9: Docking calculations of interaction energies (in kcal/mol). Table 10. Scaled internal force constants for 4PPHP in gas phase by using the B3LYP/6311++G(d,p) method compared with other reported at different level of theory.

1

Table 1: Energy, dipole moment, RMS Gradient Norm, Maximum force and force calculated at B3LYP6311++G(d,p) and WB97D levels of theory.

B3LYP6-311++G(d,p) Energy (a.u) Dipole moment (Debye) RMS Gradient Norm (a.u) Maximum force RMS force

Gas -1143.418 4.985 4.86 .10-6 0.141296 0.030327

Water -1143.474 14.319 9.06 .10-6 0.014791 0.002266

WB97XD Gas -1143.143 4.938 4.15 .10-6 0.243910 0.047756

Water -1143.474 14.319 9.06 .10-6 0.016047 0.002379

Table 2: Optimized bond lengths and bond angles (Å, °) parameters of 4PPHP.

Theoretically calculated B3LYP6-311++G(d,p) Gas Water

Gas

WB97XD Water

Experimental

Bond lengths: (Å) C1-C2 C1-C3 C4-C1 C1-N24 C4-C5 C4-C6 C4-N27 C7-C8 C7-C9 C10-C7 C7-N27 C10-C11 C10-C12 C10-N24 C13-14 C13-C22 C13-N27 C14-H15 C14-C16 C16-H17 C16-C18 C18-H19 C18-C20 C20-H21 C20-C22 C22-H23 N24-H25 N24-H26 H26-O29 P28-O29 P28-O33 P28-O29 P28-O33 O29-H30 O33-H32 RMSD

1.098 1.092 1.526 1.475 1.103 1.091 1.460 1.088 1.102 1.524 1.469 1.092 1.098 1.475 1.403 1.407 1.415 1.081 1.395 1.084 1.390 1.083 1.396 1.084 1.388 1.083 1.017 1.585 1.039 1.630 1.633 1.567 1.475 0.964 0.964 0.079

1.090 1.089 1.519 1.498 1.100 1.089 1.466 1.087 1.100 1.517 1.474 1.089 1.090 1.497 1.405 1.409 1.419 1.081 1.396 1.084 1.391 1.083 1.397 1.084 1.390 1.083 1.021 1.053 1.692 1.631 1.643 1.517 1.509 0.968 0.967 0.088

1.098 1.092 1.520 1.469 1.100 1.092 1.456 1.089 1.098 1.519 1.464 1.092 1.098 1.470 1.397 1.401 1.413 1.082 1.392 1.084 1.386 1.083 1.392 1.084 1.384 1.084 1.014 1.598 1.028 1.625 1.613 1.557 1.468 0.960 0.960 0.011 2

1.090 1.088 1.514 1.487 1.100 1.090 1.461 1.087 1.098 1.513 1.470 1.088 1.090 1.487 1.399 1.403 1.419 1.081 1.393 1.084 1.387 1.083 1.393 1.084 1.386 1.083 1.019 1.051 1.678 1.631 1.619 1.511 1.502 0.963 0.964 0.085

0.970 0.970 1.498(5) 1.474(4) 0.970 0.970 1.469(3) 0.970 0.970 1.492(4) 1.450(4) 0.970 0.970 1,476(4) 1.405(4) 1.395(4) 1.403(4) 0.930 1.373(5) 0.930 1.375(6) 0.930 1.370(6) 0.930 1.366(5) 0.930 0.900 0.899 1.359 1.511(19) 1.496(2) 1.569(2) 1.5572(19) 0.900 0.899

Bond angles (°) H2-C1-H3 H2-C1-C4 H2-C1-N24 H3-C1-C4 H3-C1-N24 C4-C1-N24 C1-C4-H5 C1-C4-H6 C1-C4-N27 H5-C4-H6 H5-C4-N27 H6-C4-N27 H8-C7-H9 H8-C7-C10 H8-C7-N27 H9-C7-C10 H9-C7-N27 C10-C7-N27 C7-C10-C11 C7-C10-H12 C7-C10-N24 H11-C10-H12 H11-C10-N24 H12-C10-N24 C14-C13-C22 C14-C13-N27 C22-C13-N27 C13-C14-H15 C13-C14-C16 H15-C14-C16 C14-C16-H17 C14-C16-C18 H17-C16-C18 C16-C18-H19 C16-C18-C20 H19-C18-C20 C18-C20-H21 C18-C20-C22 H21-C20-C22 C13-C22-C20 C13-C22-H23 C20-C22-H23 C1-N24-C10 C1-N24-H25 C1-N24-H26 C10-N24-H25 C10-N24-H26 H25-N24-H26 C4-N27-C7 C4-N27-C13 C7-N27-C13 O29-P28-O33 O29-P28-O29 O29-P28-O33

108.551 109.169 110.941 109.669 108.535 109.948 109.285 108.373 110.199 107.951 111.950 108.987 107.494 109.047 109.710 109.368 110.478 110.672 109.798 109.403 109.497 108.644 108.559 110.918 117.909 122.478 119.582 120.507 120.730 118.757 119.057 120.861 120.076 120.639 118.814 120.546 120.028 120.721 119.241 120.957 119.713 119.302 111.152 109.971 112.439 109.874 113.605 99.155 111.635 117.825 116.764 100.530 100.954 116.581

109.281 111.352 107.268 110.417 107.887 110.518 109.614 106.822 111.141 107.862 111.587 109.644 107.645 107.257 110.356 109.653 110.230 111.576 110.459 111.529 110.108 109.354 107.864 107.406 117.853 122.430 119.673 120.743 120.733 118.523 118.899 120.948 120.149 120.667 118.702 120.630 120.038 120.809 119.148 120.949 120.024 119.010 111.127 109.256 109.972 109.378 109.701 107.322 110.684 116.634 115.260 99.526 105.289 111.958

108.822 109.417 110.963 109.573 108.576 109.466 109.264 108.577 109.843 108.461 111.924 108.699 107.515 108.563 109.574 109.682 110.718 110.705 109.362 109.436 109.885 108.978 108.532 110.621 118.235 122.659 119.091 120.449 120.555 118.990 119.148 120.797 120.050 120.536 118.958 120.503 119.995 120.569 119.425 120.876 119.419 119.681 110.803 109.441 108.679 109.320 114.685 103.606 111.586 116.629 114.863 101.014 105.956 112.684 3

109.265 111.654 107.678 110.145 108.024 109.972 109.199 107.008 111.360 108.047 111.466 109.603 107.712 106.927 110.346 109.779 110.043 111.900 110.206 111.507 110.276 109.224 108.141 107.381 118.026 122.642 119.320 120.935 120.638 118.424 118.906 120.920 120.170 120.619 118.757 120.623 120.100 120.726 119.170 120.925 120.017 119.048 110.788 109.684 108.592 109.695 110.226 107.794 110.195 115.295 113.083 99.516 109.594 109.934

108.0 109.4 109.4 109.4 109.4 111.2 (2) 109.5 109.5 110.7 (2) 108.1 109.5 109.5 107.9 109.2 109.2 109.2 109.2 112.0 (2) 109.2 109.2 112.1 (2) 107.9 109.2 109.2 116.2 (3) 121.1 (3) 122.6 (3) 119.4 121.2 (3) 119.4 119.4 121.3 (4) 119.4 121.0 118.0 (3) 121.0 119.1 121.7 (3) 119.1 121.5 (3) 119.2 119.2 110.3 (2) 109.6 109.6 109.6 109.6 108.2 110.8 (2) 116.4 (2) 117.0 (2) 115.26 (11) 109.38 (11) 111.40 (11)

O33-P28-O29 O33-P28-O33 O29-P28-O33 P28-O29-H30 P28-O33-H32 RMSD

106.880 112.276 117.645 112.774 110.720 1.764

109.860 109.659 118.780 113.157 112.210 1.627

102.077 115.968 117.278 110.744 113.153 1.834

105.513 111.857 118.666 112.635 113.508 1.764

110.60 (12) 106.11 (11) 103.41 (12) 109.5 109.5

Table 3: Geometric characteristics of hydrogen bonds in (C10H15N2)H2PO4.

O(N)−H (Å) H…O (Å) O(N)…O (Å) O(N)−H…O (°)

O33−H32…O33 0.82exp 0.96the 1.81exp 2.60the 2.58exp 2.58 the 158exp 77.88the

O29−H30…O33 0.82exp 0.96the 1.87exp 2.60the 2.64exp 2.64the 156exp 69.33the

N24−H25…O29 0.90exp 1.01the 1.79exp 2.93the 2.67exp 2.62the 167exp 64.59the

N24−H26…O29 0.90exp 1.58the 1.84exp 1.03the 2.73exp 2.62the 171exp 174.74 the

Table 4: AIM analysis of the bond critical points (BCP) and ring critical points (RCP) for (C10H15N2)H2PO4. Interactions

ρ(r)

∇2ρ(r)

λ1

λ2

λ3

|λ1/λ |λ λ3||

G

H

V

RCP1 RCP2 NRCP1 O29…H25-N24 N24…H26-O33

0.3571 0.1945 0.1701 0.2814 0.2374

-2.4809 0.8942 0.5951 -0.9675 1.4748

-1.7433 1.6043 -0.2769 -0.7481 2.3157

1.0318 -0.3668 -0.2973 0.5165 -0.4159

-1.7694 -0.3433 1.1693 -0.7360 -0.4250

0.9852 -4.7631 -0.2368 1.0164 -5.4487

0.0702 0.36725 0.2758 0.0384 0.5513

-0.6904 -0.1437 -0.1270 -0.2803 -0.1826

-0.7606 -0.5109 -0.4029 -0.3188 -0.7339

4

Ebond kJ.mol-1 -998.47 -670.55 -528.77 -418.50 -963.29

Table 5: Natural bond orbital analysis and the corresponding energies E(2) in gas phase and in water for (C10H15N2)H2PO4 using B3LYP/6-311++G (d. p) method.

Donor (i)

Acceptor

σ (C13 - C14) σ (C13 - C14) σ (C16 - C18) σ (C16 - C18) σ (C20 - C22) σ (C20 - C22) σ (C1 -C4) ∆ET σ -σ* LP (2)- O29 LP (2) -O29 LP (2) -O31 LP (2) -O33 LP (2) -O34 LP (2) -O34 LP (3) -O34 LP (3) -O34 LP (1)-N24 LP (1)-N27 LP(1)- N27 LP (1)-N27 ∆ETLP-σ* LP (1)-N24 LP (1)-O33 LP (3)-O33 LP (1)-O33 ∆ET LP -LP* LP*(1)-H26 ∆ET LP - σ* σ(P28-O31) σ(P28-O29) ∆ET σ - LP *

σ* (C16 - C18) σ* (C20 - C22) σ* (C13 - C14) σ* (C20 - C22) σ* (C13 - C14) σ* (C16 - C18) σ* (N24 - H25) σ* (P28 - O31) σ* (P28 - O34) σ* (P28 - O33) σ* (P28 - O31) σ* (P28 - O31) σ* ( P28 - O33) σ* (P28 - O29) σ* (P28 - O33) σ* (C10 - H12) σ* (C4 - H5) σ* (C7 - H9) σ* (C13 - C14) LP*(1)-H26 LP*(1)-H26 LP*(1)-H26 LP*(1)- H26 σ* (P28-O33) LP*( 1)-H26 LP*(1)-H26

E(2)a [kcal/mol] 22.23 17.45 17.99 21.95 20.86 17.36 1.94 119.78 8.50 5.32 9.07 13.99 24.37 11.85 26.52 9.22 5.47 8.40 7.92 21.27 151.9 75.07 18.21 378.10 18.21 489.59 9.88 9.88 0.05 0.12 0.17

Gas E(j)_E(i)b [a.u.] 0.29 0.29 0.28 0.28 0.28 0.29 1.01

F(i.j)c [a.u.] 0.072 0.063 0.064 0.070 0.070 0.064 0.040

0.57 0.74 0.62 0.54 0.48 0.53 0.47 0.53 0.72 0.65 0.65 0.30

0.064 0.056 0.068 0.080 0.097 0.072 0.100 0.064 0.058 0.069 0.067 0.075

0.45 0.67 0.65 0.67

0.178 0.112 0.454 0.112

0.18

0.067

0.92 0.93

0.007 0.011

Water E(2)a E(j)_E(i)b [kcal/mol] [a.u.] 22.63 0.29 17.54 0.29 17.68 0.28 21.77 0.28 20.71 0.28 17.42 0.29 1.90 1.02 119.65 8.66 0.56 5.66 0.73 9.17 0.61 13.98 0.54 22.93 0.50 12.13 0.55 25.49 0.49 8.47 0.55 5.34 0.73 8.40 0.65 7.94 0.65 21.88 0.30 150.05 79.37 0.43 17.39 0.68 365.07 0.66 17.39 0.68 479.22 9.77 0.17 9.77 0.05 0.92 0.12 0.93 0.17

Table 6: Enrichment ratio (ER) of different inter-contact and percentage of each atom on the HS in 4PPHP.

ER H O C N % Surface

H 0.88

O 1.35 -

C 1.35 -

74.2

16.25

8.55

5

N 1.35 1.0

F(i.j)c [a.u.] 0.072 0.064 0.064 0.070 0.070 0.064 0.039 0.064 0.057 0.068 0.080 0.096 0.073 0.100 0.062 0.058 0.069 0.067 0.076 0.179 0.110 0.452 0.110 0.065 0.007 0.011

Table 7: Difference of energies between the possible combinations, chemical potential, Electronegativity, Global hardness, Softness and Electrophilicity. All values are in eV except for S which is given in eV-1.

DFT/B3LYP/6–311++G(d.p)

Gas

Water

EHOMO (eV) ELUMO (eV)

-5.9029 -0.7311

-5.8153 -0.4658

∆EHOMO–LUMO gap (eV) EHOMO–1 (eV) ELUMO+1 (eV) ∆E (HOMO–1)–(LUMO+1) gap (eV) Chemical Potential µ (eV) Electronegativity χ (eV) Global hardness η (eV ) Softness S (eV )−1 Electrophilicity (eV )

-5.1718 -7.1239 -0.5621 -6.5618 -3.3170 -3.3170 2.5859 0.3867 2.1274

-5.3495 -7.0529 -0.3698 -6.6831 -3.1405 -3.1405 2.6747 0.3738 1.8437

Table 8: Experimental and theoretical chemical shifts of 13C.

δ Atoms

theoretical

(ppm)

δ

44.49 45.79 41.77 43.08 171.42 125.97 141.71 130.02 140.20 121.29

CH4 HF/631G(d) GIAO 44.49 45.79 41.77 43.08 171.42 125.97 141.71 130.02 140.20 121.29

Without reference 154.60 153.30 157.32 156.01 27.67 73.12 57.38 69.07 58.89 77.80

8.199

8.199

85.265

TMS B3LYP/6311+G (2d,p) GIAO

TMS HF/631G(d) GIAO

C10 C7 C4 C1 C13 C22 C20 C18 C16 C14

27.85 29.15 25.14 26.45 154.78 109.34 125.07 113.38 123.57 104.65

RMSD

12.565

experimental

(ppm) 44.81 44.81 44.81 44.81 149.18 113.36 129.63 119.94 131.24 131.24

Table 9: Docking calculations of interaction energies (in kcal/mol). Protein molecule

MAOB

PDE10A

Ligand molecule

Code

Total energy

VDW

H-bond

Electronic

AverConPair

1-PPHS [57] Farnesol Zonisamide 4PPHP Deprenyl 1-PPHS [57] 4PPHP Imadazopyrazine Triazolopyrimidine Benzimidazole

1-PPHS 2BK3 3PO7 4PPHP 2BYB 4PPHP 4PPHP 5K9R 6KEO 3WS9

-97.845 -92.493 -87.140 -83.580 -76.541 -99.378 -86.119 -69.567 -69.047 -64.750

-93.000 -86.535 -71.055 -76.580 -76.541 -72.938 -63.292 -43.825 -31.665 -54.250

-3.500 -5.958 -16.085 -7.000 0 -23.761 -20.973 -25.742 -37.381 -10.500

-1.345 0 0 0 0 -2.678 -1.853 0 0 0

29.909 34.250 35.000 33.882 33.500 26.545 28.117 43.333 39.666 36.111

6

Table 10. Scaled internal force constants for 4PPHP in gas phase by using the B3LYP/6311++G(d,p) method compared with other reported at different level of theory. B3LYP/6-311++G(d,p) Force constant

4PPHPa

B3LYP/6-31G*

Foscarnetb

AEPc

Guanfacinee

ACEd Free base B

Cationic E

HCl F

6.56

6.58

6.04

f(νO-H)

6.54

7.23

f(νNH2)

3.38

5.14

f(νP=O)

7.52

f(νP-O)

4.36

4.09

f(νC-N)

4.68

4.09

7.08

7.06

7.44

f(νCH2)

4.67

4.91

4.91

4.82

4.88

f(νC-H)R

5.10

5.23

5.26

5.24

f(νC=C)

6.31

6.55

6.56

6.55

f(δCH2)

0.71

0.75

0.74

0.74

f(δNH2)

0.28

6.40

6.45

7.51

0.84 0.60

0.76

-1

Units are mdyn Å for stretching and mdyn Å rad-2 for angle deformations a

This work; bFrom Ref [5]; cFor aminoethyl phosphonic acid from Ref [77]; dFor acetazolamide from Ref [76]; e For guanfacine from Ref [79].

7

Figures : Figure 1: The optimized geometry of (C10H15N2)H2PO4 compound B3LYP/6-311++G** theory. Figure 2: AIM molecular graph of (C10H15N2)H2PO4 compound. Figure 3: The electron localization function maps. Figure 4: Visualization in the molecular space of non covalent interaction in the monomer and between two cations of 4PPHP. Figure 5: Hirshfeld surfaces mapped with dnorm (-0.742 - 1.450) for 4PPHP (a). Fingerprint plots of all (b), H…H (c), O…H/H…O (d), C…H/H…C (e) and H…N/N…H (f) contacts; Surfaces to the side highlight the relevant surface patches associated with the specific contacts, with dnorm mapped in the same manner. (Dotted lines “red” represent hydrogen bonds). Figure 6: Frontier molecular orbital plots of 4PPHP compound calculated with B3LYP/6311++G**. Figure 7: Experimental (a) and theoretical (b) 13C-NMR spectrum of (C10H15N2)H2PO4. Figure 8: Experimental (a) and theoretical (b) 31P-NMR spectrum of (C10H15N2)H2PO4. Figure 9: Fukui function of 4PPHP compound. Figure 10: Molecular docking of MAOB protein (a) with the ligands Zonisamide, Deprenyl, Farnesol, 1-PPHS and 4PPHP; and of 1-PDE10A protein (b) with the Ligand Imadazopyrazine, Benzinidazole, Triazolopyrimidine, 1-PPHS and 4PPHP.

1

Figure 1: The optimized geometry of (C10H15N2)H2PO4 compound using B3LYP/6-311++G** method.

Figure 2 : AIM molecular graph of (C10H15N2)H2PO4 compound.

2

(a)

(b)

Figure 3: The electron localization function maps. (a)

(b) 4.870Å

Figure 4: Visualization in the molecular space of non covalent interaction in the monomer and between two cations of 4PPHP.

3

Figure 5: Hirshfeld surfaces mapped with dnorm (-0.742 - 1.450) for 4PPHP (a). Fingerprint plots of all (b), H…H (c), O…H/H…O (d), C…H/H…C (e) and H…N/N…H (f) contacts; Surfaces to the side highlight the relevant surface patches associated with the specific contacts, with dnorm mapped in the same manner. (Dotted lines “red” represent hydrogen bonds).

4

Figure 6: Frontier molecular orbital plots of 4PPHP compound calculated with B3LYP/6-311++G**.

5

(a)

(b)

Figure 7: Experimental (a) and theoretical (b) 13C-NMR spectrum of (C10H15N2)H2PO4.

(a)

(b)

Figure 8: Experimental (a) and theoretical (b) 31P-NMR spectrum of (C10H15N2)H2PO4.

Figure 9: Fukui function of 4PPHP compound.

6

(a)

(b)

Figure 10: Molecular docking of MAOB protein (a) with the ligands Zonisamide, Deprenyl, Farnesol, 1-PPHS and 4PPHP; and of 1-PDE10A protein (b) with the ligands Imadazopyrazine, Benzinidazole, Triazolopyrimidine, 1-PPHS and 4PPHP.

7

Highlights: • A detailed study on the DFT has been performed for the new hybrid material (4PPHP). • The optimized geometry of 4PPHP was determined by using B3LYP/6-311++G** theory. • The weak interactions were studied by AIM, RDG, NBO and HS analysis. • The local reactivity analysis are evaluated to determine the reactive sites. • Docking calculation were conducted using iGEMDOCK program.