Quantum mechanical and spectroscopic (FT-IR, FT-Raman) study, NBO analysis, HOMO-LUMO, first order hyperpolarizability and molecular docking study of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine by density functional method

Accepted Manuscript Quantum mechanical and spectroscopic (FT-IR, FT-Raman) study, NBO analysis, HOMO-LUMO, first order hyperpolarizability and molecular docking study of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine by density functional method

Tintu K. Kuruvilla, Johanan Christian Prasana, S. Muthu, Jacob George, Sheril Ann Mathew PII: DOI: Reference:

S1386-1425(17)30588-7 doi: 10.1016/j.saa.2017.07.029 SAA 15316

To appear in:

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Received date: Revised date: Accepted date:

31 December 2016 10 March 2017 18 July 2017

Please cite this article as: Tintu K. Kuruvilla, Johanan Christian Prasana, S. Muthu, Jacob George, Sheril Ann Mathew , Quantum mechanical and spectroscopic (FT-IR, FT-Raman) study, NBO analysis, HOMO-LUMO, first order hyperpolarizability and molecular docking study of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine by density functional method, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2017), doi: 10.1016/j.saa.2017.07.029

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ACCEPTED MANUSCRIPT Quantum Mechanical and Spectroscopic (FT-IR, FT-Raman) study, NBO analysis, HOMO-LUMO, first order hyperpolarizability and Molecular Docking study of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine by density functional method. Tintu K Kuruvilla 1, Johanan Christian Prasana1, S. Muthu2*, Jacob George1, Sheril Ann Mathew1 Department of Physics, Madras Christian College, East Tambaram 600059, Tamil Nadu, India.

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Department of Physics, Arignar Anna Govt. Arts College, Cheyyar 604407, Tamil Nadu, India.

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Corresponding author Email: [email protected] (Dr.S.Muthu)

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ABSTRACT

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Quantum chemical techniques such as density functional theory (DFT) have become a powerful tool in the investigation of the molecular structure and vibrational spectrum and are finding increasing use in application related to biological systems. The Fourier transform infrared (FT-IR) and Fourier transform Raman (FT-Raman) techniques are employed to characterize the title compound.The vibrational frequencies were obtained by DFT/B3LYP calculations with 6-31G(d,p) and 6-311++G(d,p) as basis sets. The geometry of the title compound was optimised. The vibrational assignments and the calculation of Potential Energy Distribution (PED) were carried out using the Vibrational Energy Distribution Analysis (VEDA) software. Molecular electrostatic potential was calculated for the title compound to predict the reactive sites for electrophilic and nucleophilic attack. In addition, the first-order hyperpolarizability, HOMO and LUMO energies, Fukui function and NBO were computed. The thermodynamic properties of the title compound were calculated at different temperatures, revealing the correlations between heat capacity (C), entropy (S) and enthalpy changes (H) with temperatures. Molecular docking studies were also conducted as part of this study.The paper further explains the experimental results which are in line with the theoretical calculations and provide optimistic evidence through molecular docking that the title compound can act as a good antidepressant. It also provides sufficient justification for the title compound to be selected as a good candidate for further studies related to NLO properties.

DFT; FT-IR; FT-Raman; HOMO-LUMO; Anti-depressant; Molecular Docking. 1. Introduction

The structural and chemical composition of the title compound methyl[(3R)-3-(2methylphenoxy)-3-phenylpropyl]amine is similar to a drug that is commercially available for use i.e. Atomoxetine. Atomoxetine is a drug used for the treatment of attention deficit hyperactivity disorder (ADHD) in children age six and older, adolescents and adults[1]. Its primary advantage over the standard stimulant treatments for ADHD is that it has little known abuse potential [2]. Atomoxetine is a drug manufactured and marketed by the brand name Strattera by Eli Lilly and Company. The chemical formula of atomoxetine is C17H21NO. Atomoxetine is a selective norepinephrine reuptake inhibitor which works by

ACCEPTED MANUSCRIPT increasing the levels of norepinephrine, a natural substance in the brain that is needed to control the behaviour. Compared to the various neuro transmitter receptors atomoxetine has a high affinity and selectivity for norepinephrine transporters. It has demonstrated ability to inhibit norepinephrine uptake in humans and animals selectively. Studies have shown that it preferentially binds to areas of known high distributions of noradrenergic neurons. Atomoxetine increases the ability to pay attention and decrease impulsiveness and hyper activity. It may also be used to treat symptoms associated with depression since both ADHD and depression are linked with a lower level of mental arousal [3].

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The literature review revealed that no detailed quantum chemical study was carried out for the title compound. Hence, this study was carried out and the spectroscopic characterisation of atomoxetine is reported by means of IR and Raman spectra. These experimental measurements were complimented with quantum chemical calculations. This has been carried out using density functional theory (B3LYP) method with 6-311++G(d,p) and 6-31G(d,p) basis set. Molecular properties like dipole moment, polarizability, first order hyperpolarizability, molecular electrostatic potential and thermodynamic parameters have been calculated for the title compound. The frontier molecular orbitals such as HOMO and LUMO determine the way the molecule interacts with other species which enable us to characterise the chemical reactivity of the molecule. The natural bond orbital (NBO) analysis has been applied to analyze the stability of molecule arising from hyper conjugative interaction and charge delocalization. Molecular docking studies are also reported due to its biological activity.

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2. Experimental Details

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The title compound was procured from the Sigma–Aldrich Chemical Company (USA) in the solid form. The title compound methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine without any further purification was used to record the FT-IR and FT-Raman spectra. The FT-IR spectrum of the compound was recorded in the region 4000-400 cm-1 in the spectrophotometer. The FT-Raman spectrum was recorded in the region 4000-100 cm-1 in Bruker RFS 27 spectrophotometer at the Sophisticated Analytical Instrumentation Facility (SAIF) in IIT Chennai, India. The observed experimental and stimulated FT-IR and FTRaman spectra using the basis sets 6-31G(d,p) and 6-311++G(d,p) are shown in Figs 1 and 2 respectively. 2.1 Computation Details The optimized structure of title compound, its energy and vibrational harmonic frequencies were calculated by DFT (B3LYP) with 6-31G(d,p) and 6-311++G(d,p) basis sets using GAUSSIAN 09W program package [4]. The gradient corrected density functional theory with the three parameter hybrid function (B3) was utilised for the exchange part and the LeeYang-Parr (LYP) correlation function [5-7] (the correlation functional of Lee, Yang, and Parr, which has both local and non-local terms). The Lee-Yang-Parr (LYP) correlation function is accepted as the cost-effective approach for the computation of molecular structure, vibrational frequencies and energy of optimized structures. The energy of the title

ACCEPTED MANUSCRIPT compound was minimized and the intra molecular forces were brought to zero without any constraint on the geometry. This is followed by the study of the harmonic vibrational frequencies at the same level of theory for the optimized structures (opt). Subsequently, the resultant frequencies were then scaled by the factor of 0.960 (above 3000 cm-1) and 0.961 (below 3000 cm-1) for B3LYP/6-311++G(d,p) [8] to compensate for the errors arising from the basis set incompleteness and neglect of vibrational anharmonicity.

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The symmetry considerations, the vibrational assignments and the calculation of the potential energy distribution (PED) were made with a high degree of accuracy using the Vibrational Energy Distribution Analysis (VEDA) software [9]. The GABEDIT software and ORIGIN 6.1 software were used to compare the theoretical and experimental results of IR and Raman spectrum. The geometric structure as well as parameters such as bond angle and bond length was obtained from CHEMCRAFT software.

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The hyperpolarisability for the title compound was also calculated at B3LYP level using the basis set 6-311++G(d,p). This was done to explore the non linear optical behaviour of the title compound. Various non-linear optical properties of the title compound such as dipole moment, anisotropy of polarizability and first order hyper polarizability were also computed on theoretical computations. The electronic properties such as Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO) energies were determined. They are called frontier orbitals as we can determine the way in which the molecule interacts with other species. The Molecular Electrostatic Potential (MEP) was also calculated using Gauss View [10].

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The Natural Bond Orbital (NBO) [11] was calculated on the title compound at B3LYP level using the basis set 6-311++G(d,p). This analysis was done to give clear evidence of stabilization originating from hyper conjugation of various intramolecular interactions.

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The thermodynamic properties of the title compound were calculated at different temperatures, revealing the correlation between heat capacity (C), enthalpy (H) and entropy (S) with temperatures. The molecular docking (ligand-protein) simulations had been performed by AutoDock 4.2.6 free software package.

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3. Results and Discussions 3.1 Molecular geometry

The geometrical parameters (bond length and bond angle) of methyl[(3R)-3-(2methylphenoxy)-3-phenylpropyl]amine are listed in Table 1 using DFT/B3LYP method with 6-31G(d,p), 6-311++G(d,p) as basis sets. The optimized molecular structure of the title compound obtained from Gaussian 09W and CHEMCRAFT software are shown in Fig 3. To the best of our knowledge, exact experimental data on the geometrical parameters of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine are not available in the literature. Therefore, the crystal data of a closely related molecule such as 1-Benzoyl-Nphenylcyclopropane carboxamide is compared with that of title compound [12-13]. It is observed that the calculated C-C bond distances and the O-C bond lengths are found to be

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similar at all levels of calculations. The C-H bond length varied from 0.93A to 1.106A. The N-C bond length varied from 1.456A to 1.502A. The molecular geometry in gas phase may differ from the solid phase owing to the extended hydrogen bonding and stacking interactions (attractive non-covalent interactions between two aromatic rings). The difference between the theoretical and experimental geometry can mostly be attributed to the fact that calculations were performed using isolated molecule in the gaseous phase to obtain theoretical results and in solid state for experimental results. Thus, it is found that most of the optimized bond lengths and the bond angles are in reasonable agreement with the corresponding experimental values (Table 1). Hence, DFT theory results in geometrical parameters which are in agreement with the experimental values.

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3.2 Vibrational analysis

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The IR and Raman spectra consist of various bands at specific wave numbers. The aim of vibrational analysis is to predict which vibrational modes give rise to each of these observed bands. The title compound consists of 40 atoms and has 114 normal vibrational modes. Figs. 1 and 2 show comparative representations of theoretically predicted FTIR and FT- Raman spectra at B3LYP/6-311++G(d,p) and B3LYP/6-3lG(d,p) level of theory along with the experimental results of FT-IR and FT-Raman spectra respectively.

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The theoretical and experimental frequencies are presented in Table 2. The relative intensity is calculated for each of these theoretical frequencies. The absolute intensity is a ratio of relative intensities corresponding to each frequency and the peak value in the relative intensities data set.

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The theoretical intensities show slight deviations from the experimental values since the theoretical wavenumbers are obtained from the isolated molecule in the gaseous phase and the experimental wavenumbers are obtained from the isolated molecule in solid state.

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The fundamental mode of title compound had been assigned based on vibrational concept and the detailed explanations are provided in the following sections. 3.2.1 C-H Vibrations

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The aromatic derivatives result in C-H stretching and bending vibrations. These derivatives exhibit multiple weak bands in the spectral region of 3100 to 3000 cm-1 [14]. They are not affected by the nature of the substituents to a great extend [15-16]. In the present study, the title compound has 20 C-H stretching vibrations. For the title compound, the peak corresponding to C-H stretching vibration occurs at frequencies of -1 3060,2981,2905,2888,2812 cm by B3LYP/6-311++G(d,p) method. This results show excellent agreement with recorded spectral values. The PED corresponding to this vibration is in pure mode contributing to 90-100% as shown in Table 2. 3.2.2 C-C Vibrations The aromatic ring modes are influenced by C-C bands. The ring stretching vibrations (C-C) are within the region 1300 to 1000 cm-1 [17-19], based on experiments. In the present study,

ACCEPTED MANUSCRIPT the bands which are of different intensities were observed at 1602, 1166, 1070, 1034 and 876 cm-1 in FT-IR. Raman bands were identified at 1600, 1264, 1048, 998 and 876 cm-1. The theoretical values were obtained in the range of 1578 to 874 cm-1 by B3LYP/6-311++G(d,p) method. The above results show that the theoretical values are in good agreement with experimental data. 3.2.3 N-H Vibrations

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The N–H stretches of amines are in found in the region 3000 to 3500 cm-1 [20,21]. These bands are weaker but sharper than those of the alcohol O–H stretches which are also present in the same region. For the title compound, the band corresponding to N-H stretching vibration occurs at 3393 cm-1 by B3LYP/6-311++G(d,p) method. This shows excellent agreement with recorded FT-IR value at 3380 cm-1 and this pure mode shows 100% PED contribution as in the Table 2. 3.2.4 O-C Vibrations

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The O-C stretching vibrations of carboxylic acids & its derivatives are in the region 1000 to 1300 cm-1 [22]. In the present study, the peaks corresponding to O-C stretching vibration was observed at 1202 cm-1 by theoretical method and a band of strong intensity was observed at 1201 cm-1 in FT-IR. 3.2.5 HCC Vibrations

3.2.6 HCH Vibrations

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For the title compound the H-C-C bending is observed in the region 1465 to 1064 cm-1. In the present study, 19 HCC bending vibrations were observed and the FT-IR spectra peaks at 1342, 1201 and 1070 cm-1. The Raman bands were identified at 1468, 1415, 1345 and 1264 cm-1.

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For the title compound the H-C-H bending is observed in the region 1460 to 965 cm-1. In the present study, 12 HCH bending vibrations were observed and the FT-IR spectra peaks at 1433 and 1360 cm-1. The Raman bands were identified at 1415 and 1379 cm-1. 3.2.7 CCC Vibrations

For the title compound the C-C-C bending is observed in the region 1561 to 58 cm-1. In the present study, 17 CCC bending vibrations were observed and the FT-IR spectra peaks at 755, 630 and 607 cm-1. The Raman bands were identified at 772, 615, 378, 223 and 184 cm-1. 3.2.8 HCCC Vibrations For the title compound the H-C-C-C torsion is observed in the region 1420 to 134 cm-1. In the present study, 21 HCCC torsion vibrations were observed and the FT-IR spectra peaks at 1201, 915, 899 and 876 cm-1. The Raman bands were identified at 909, 876, 356 cm-1. 3.2.9 HCNC Vibrations

ACCEPTED MANUSCRIPT For the title compound the H-C-N-C torsion is observed in the region 1428 to 235 cm-1. In the present study, 9 HCNC torsion vibrations were observed and the FT-IR spectra peaks at 1433, 1243, 1115, 1093 cm-1. The Raman bands were identified at 1120 and 262 cm-1. 3.2.10 CCCC Vibrations For the title compound the C-C-C-C torsion is observed in the region 968 to 29 cm-1. In the present study, 9 CCCC torsion vibrations were observed. CCCC out of plane torsion is found between the region 1018 to 56 cm-1. The Raman bands were identified at 262 cm-1.

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3.2.11 Other Vibrations

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COC, NCC, CNC, CCO, and OCC are the other bending vibrations that are seen in the title compound. CNCC, OCCC, CCOC, HCOC, HNCC, COCC, NCCC are the other torsion vibrations that are seen in the study. The occurrences of these vibrations are less than five. 3.3 Nonlinear optical effects

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Quantum chemical calculations have been useful in the description of the relationship between electronic structure of systems and its NLO response [23]. NLO is at the forefront of the recent research because of its significance in bestowing the key functions of optical modulation, optical logic, optical memory, optical switching and frequency shifting in areas such as telecommunications, signal processing, and optical interconnections [24-25].

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µtot = µ0+αijEj + βijkEjEk

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The non-linear optical response of an isolated molecule in the electric field Ei(ω) is represented as a Taylor series expansion of total dipole moment, µtot, induced by the field:

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where α is the linear polarizability, µ0 the permanent dipole moment and βijk are the first hyperpolarizability tensor components [26]. The first order hyperpolarizability, is a tensor of rank 3 that can be described by a 3 x 3 x 3 matrix. Owing to the Kleinman symmetry the 27 components of 3D matrix can be reduced to

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10 components [27].

The total molecular dipole moment (µ), linear polarizability (α) and first-order hyperpolarizability (β) were computed at DFT level using Gaussian 09 program package and are shown in Table 3 [28]. DFT is a tool used to investigate the organic NLO materials [2933]. The first order hyperpolarizability of the title compound is 1.2034x10-29 esu. The calculated hyperpolarizability of the title compound is 32.52 times that of standard NLO material Urea (0.37x10-30). Hence, we can conclude that the title compound and its derivatives are important for future studies of nonlinear optical properties. 3.4 Frontier Molecular Orbital Analysis

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One of the most important tools used in quantum chemistry are the highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO). HOMO, which can be considered as the outer most orbital containing electrons, tends to give these electrons away as an electron donor. On the other hand, LUMO can be thought of as the inner most orbital containing free places to accept electrons [34]. Energy of HOMO is directly related to the ionization potential and LUMO energy is directly related to the electron affinity. The pictorial representation of HOMO and LUMO is shown in Fig 4. The HOMO energy is -6.0434 eV and LUMO energy is -0.7992 eV. The energy difference between the HOMO and LUMO orbitals is called the energy gap which serves as an important stability factor for the compound [35]. The HOMO-LUMO energy gap for the title compound is 5.2442 eV which confirms that the molecule has stable structure. Lower the energy gap, more easily electrons are excited from the ground state to excited state.

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Chemical potential (µ) = 2(ELUMO + EHOMO)

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By using the HOMO and LUMO energy values, the global chemical reactivity descriptors such as Electronegativity (χ), chemical potential (μ), global hardness (η), and softness (S) can be defined. The concept of these parameters is related to each other [36-39] where:

Electro negativity (χ) = -µ = - 2(ELUMO + EHOMO) 1

Electrophilicity =

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Global hardness (η) = 2(ELUMO - EHOMO) µ

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Using the above equations, the chemical potential, hardness and electrophilicity index have been calculated for title compound and their values are shown in Table 4. The IP value indicates that energy of 6.04 eV is required to remove an electron from the HOMO. The lower value of electron affinity shows higher molecular reactivity with the nucleophiles. Higher hardness and lower softness values confirm the higher molecular hardness associated with the molecule. The electrophilicity index helps in describing the biological activity of title compound [40-42]. The mesh diagrams of HOMO and LUMO are given in Fig 4. 3.5 Molecular Electrostatic Potential Molecular electrostatic potential are three-dimensional diagrams which can be used to visualize charge distributions and the charge related properties of the molecules. It illustrates the possible sites for electrophillic and nucleophillic attacks and is useful in biological recognition processes and hydrogen bonding interactions [43]. Visual understanding of the relative polarity of the molecule is also achieved. Different colours represent the electrostatic potential of the region on the surface of the compound: red represents areas of most electro negative electrostatic potential; blue represents areas of most positive electrostatic potential; and green represents areas of zero potential.

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The electrostatic potential value ascends in the order of red < orange < yellow < green < blue [44]. At DFT level the MEP surface (Fig. 5) is plotted for the title compound [45]. The negative electrostatic potential corresponds to an attraction of a proton by the aggregate electron density in the molecule (shades of red and yellow) and the positive electrostatic potential corresponds to the repulsion of a proton by the nuclei (shades of blue). The colour code of these maps ranges from -4.297 eV to 4.297 eV. Fig 5 reveals that negative regions (red) are mostly localized over the O and N atoms which are the most reactive sites for an electrophillic attack, whereas most of the positive regions (blue) are around the H atoms which are most reactive sites for a nucleophillic attack. The contour map of electrostatic potential confirms the different negative and positive potential sites of the molecule in accordance with the total electron density surface map. 3.6 Fukui Function

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f j - = q j (N)-q j( N-1) f j+ =q j(N+1)-qj(N) f j0 =1/2 [q j(N+1)-q j(N -1)

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The Fukui function is accepted as the local density functional descriptors to depict both the chemical reactivity and selectivity. It is a local reactivity descriptor that shows the regions where a chemical group will alter its density when the number of electron changes. Hence it shows the propensity of the electronic density to deform at a given position upon accepting or donating electrons [46-48]. The condensed or atomic Fukui functions on the jth atom site are given as per the following equations for an electrophilic fj-(r), nucleophilic and free radical attack fj+(r), on the reference molecule, respectively.

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In the above equations, qj is the atomic charge (calculated from Mulliken population analysis, electrostatic derived charge, etc.) at the jth atomic site in the corresponding neutral (N), anionic (N + 1) or cationic (N - 1) chemical species. Chattaraj et al. [49] proposed the concept of generalized philicity. It contains almost all the information about known various global, local reactivity and the selectivity descriptors in addition to the information regarding electrophilic or nucleophilic power of a given atomic site in a molecule. Morell et al. [50] proposed a dual descriptor (Df(r)), defined as the difference between the nucleophilic and electrophilic Fukui function and is given by: Δf(r) = [f + (r) - f - (r)]

If Δf(r) > 0, the site is favoured for a nucleophilic attack. If Δf(r) < 0, the site may be favoured for an electrophilic attack. Dual descriptors Δf (r) gives a clear difference between nucleophilic and electrophilic attack at a particular region with their sign. It gives positive value for site where nucleophilic attack is possible and a negative value where electrophilic attack is possible. From the values reported in Table 6, the nucleophillic attacking sites for the title compound are N1, C2, C3, C4, C7, C8, C9, C10, C12, C14, C15, C16, C17, C18, C19 (positive value i.e. Df (r) > 0) and the electrophillic attacking sites are C5, C6, O11, C13, H20, H21, H22,

ACCEPTED MANUSCRIPT H23, H24, H25, H26, H27, H28, H29, H30, H31, H32, H33, H34, H35, H36, H37, H38, H39, H40 (negative value i.e. Df (r) < 0). 3.7 Natural Bond Orbital (NBO) Analysis

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A natural bond orbital or NBO is the calculated bonding orbital with highest electron density. Natural (localized) orbitals are used in computational study to calculate the distribution of electron density in atoms and in bonds in between the atoms. The most important advantage of the natural bond orbital (NBO) method is the information obtained about the interactions in both filled and the virtual orbital which supplement the analysis of both the intra and inter molecular interactions [51]. The strength of the interaction between electron donors and the electron acceptors, or the donating tendency which is from electron donors to electron acceptors and hence the degree of conjugation of the system is measured by the value of energy of the hyperconjugative interactions, E(2) .

qi ( Fij )2 εj −εi

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E2 = ΔEi j =

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In order to evaluate the donor–acceptor interactions, the second-order Fock matrix was carried out in NBO analysis [52]. For each donor (i) and acceptor (j), the stabilization energy E(2) associated with the delocalization i→j is estimated as:

where, qi is the donor orbital occupancy, εj and εi are diagonal elements and Fij is the off diagonal NBO Fock matrix element.

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Results of NBO analysis that was performed on the title compound at the DFT/B3LYP/6311++G(dp) DFT level are presented in Table 6.

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The strong intramolecular hyper conjugative interactions of σ and π electrons of C-C to the anti C-C bond of the ring give rise to stabilization of some part of the ring. The interaction of σ (C5-C6) distributed to σ (C6-H34) results in a stabilisation of 56.77 kcal/mole. A notable interaction related to the resonance in the molecule is electrons donating from bonding donor σ (C6-H34) to the bonding receptor σ (C6-H26) with large stabilization energy of 334.44 kcal/mole as shown in Table 6. 3.8 Thermodynamic Properties Based on vibrational analysis and statistical thermodynamics, the standard thermodynamic functions of heat capacity (Cp), entropy (S) and enthalpy changes (H) for the title compound were obtained using perl script THERMO.PL, and are listed in Table 8. From Table 8, it can be observed that these thermodynamic functions increase with temperature in the range of 100 to 1000 K. The correlation equations between heat capacity, entropy, enthalpy changes and temperatures were fitted by quadratic formulae, and the corresponding fitting factors (R2) for these thermodynamic properties are 0.9987, 0.99998 and 0.99953 respectively. The corresponding fit equations are as follows and the correlation graphs are shown in Fig 6. C = 5.87775 + 1.19675T – 4.63046 x 10 -4 T2(R2 = 0.9987)

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3.9 Molecular Docking Studies

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Atomoxetine (title compound) increase the brain activity by inhibiting the re-uptake of norepinephrine and could provide anti-depressant property [54]. Hence, the molecular docking method was adopted to conduct further study to obtain additional experimental evidence to justify further research in using the title compound as an anti-depressant relief drug.

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Molecular docking is a powerful computational tool in predicting the binding affinity of a ligand with proteins which is useful in modern structure based drug designing. In the present work, molecular docking study was carried out for protein associated with anti-depressant. The structure of target protein 2QEI was obtained from RCSB PDB format [55] and all molecular docking calculations were performed on Auto Dock-Vina software. Co- crystalized ligands, waters and co-factors were removed before preparing protein for docking.

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To calculate Kollman charges and polar hydrogens, the Auto Dock Tools (ADT) graphical user interface was used. The ligand was prepared for docking by minimizing its energy at B3LYP/6-311++G(d,p) level of theory and partial charges were computed by Geistenger method. The Lamarckian Genetic Algorithm (LGA) feature in Auto Dock software was utilized for docking process[56]. Subsequently, the docking protocol was tested by extracting out the co-crystallized inhibitor from the protein followed by docking the same. The first three rank docking parameters such as binding energy, inhibition constant and intermolecular energy of molecule with respect to protein 2QEI are listed in Table 8. Discover Studio Visualizer 4.0 software was used to analyse the detailed interaction of the best conformation. The preferred orientation of the ligand with respect to the target protein is shown in Fig 7. These results indicate that the docked ligand title compound forms a stable complex with 2QEI with a binding affinity value of -6.73 kcal/mol. Hence, we can conclude that title compound can have anti-depressant property. 4. Conclusion Spectroscopic (FT-IR, FT-Raman,), NLO, NBO, MEP and thermodynamic function of [(3R)3-(2-methylphenoxy)-3-phenylpropyl]amine was analysed using B3LYP/6-311++G(d,p) and B3LYP/6-31G(d,p) methods. The vibrational assignments and the calculation of Potential Energy Distribution (PED) were carried out using the Vibrational Energy Distribution Analysis (VEDA) software. The experimental results are in line with the theoretical values derived from structural parameters, vibrational frequencies, infrared intensities and Raman

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activities. The Non-Linear Optical (NLO) properties were calculated theoretically and it was found that the predicated first order hyperpolarizability value is greater than that of Urea. This shows that the title compound has large NLO property. The HOMO and LUMO energies were calculated and the energy gap was determined as 5.2442 eV. The electrophilicity values were calculated from the HOMO and LUMO energies and found to be significantly high. This confirms that the title compound is biologically active. The predicted MEP Fig revealed the negative and positive regions of the molecule. NBO analysis was done on the title compound and it showed that the intra molecular charge transfer occurs between the bonding and antibonding orbitals. The thermodynamic properties of the title compound were calculated for different temperatures, and the correlations among the properties and temperatures were obtained. This data provides useful information for further study on the title compound with relation to thermodynamic properties. They can be used to compute other thermodynamic energies and can estimate directions of chemical reactions in accordance with the second law of thermodynamics. Molecular docking study was carried out for protein associated with anti-depressant. The structure of target protein 2QEI was obtained from RCSB PDB format and all molecular docking calculations were performed on Auto Dock-Vina software. These results indicate that the docked ligand title compound forms a stable complex with 2QEI with a binding affinity value of -6.73 kcal/mol. Hence, molecular docking analysis reveals that the title compound can act as a good antidepressant.

5. References

ACCEPTED MANUSCRIPT [1] Purper-Ouakild D, Fourneret P, Wohl M, Reneric JP. Encephale. 2005 May-June; 31 (3): 337-48. [2] Michelson D, Adler L, Spencer T, Reimherr FW, West SA, Allen AJ, Kelsey D, Wernicke J, Dietrich A, Milton D. Bio Psychiatry. 2003 Jan 15;53(2): 112-20. [3] Garnock-Jones K.P.,Keating G.M. Paediatr.Drugs.2009;11(3):203-26

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[4] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, Ö. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian 09 (Gaussian, Inc., Wallingford CT, 2009).

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Inc., Shawnee Mission, KS, 2009. [11] E.D.Glendenning, A.E.Reed, J.E Carpenter, Weinhold, NBO version 3.1,TCL,University of Wisconsin,Madison,1998. [12] Frank H. Allen,” Olga Kennard, and David G. Watson, Tables of Bond Lengths determined by X-Ray and Neutron Diffraction. Part I. Bond Lengths in Organic Compounds (2008), Acta Crystallographica. [13] Wen-Liang Li and Zhi-Guo Zhu*,1 EW 1-Benzoyl-N-phenylcyclopropanecarboxamide, Acta Crystallographica Section E, 2008 [14] V. Krishnakumar, R.J. Xavier, Indian J. Pure Appl. Phys. 41 (2003) 597–601.

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[22] Y. Sun, Y. Wang, Z. Liu, C. Yu, Spectrochim. Acta 96 (2012) 42-50

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[35] D. F. V. Lewis, C. loannides, D. V. Parke, 401–408 (1994). [36] R. G. Parr, R. A. Donnelly, M. Levy, and W. E. Palke, The Journal of Chemical Physics, vol. 68, no. 8, pp. 3801–3807, 1977. [37]R. G. Parr and R. G. Pearson, Journal of the American Chemical Society, vol. 105, no. 26, pp. 7512–7516, 1983. [38] R. G. Pearson, Inorganic Chemistry, vol. 27, no. 4, pp. 734–740, 1988..

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[39] P. Geerlings, F. De Proft, and W. Langenaeker, “Conceptual density functional theory,” Chemical Reviews, vol. 103, no. 5, pp. 1793–1873, 2003.

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[42] R. Parthasarathi, J. Padmanabhan, V. Subramanian, U. Sarkar, B. Maiti, P. Chattaraj, Internet Electron. J. Mol. Des. 2 (2003) 798–813.

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[43] P. Politzer, J.S. Murray, in: D.L. Beveridge, R. Lavery (Eds.) Theoretical Biochemistry and Molecular Biophysics, A comprehensive Survey, protein, Vol. 2, Adenine Press, Schenectady, New York 1991.

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[44] P. Thul, V.P. Gupta, V.J. Ram, P. Tandon, Spectrochim. Acta 75 (2010) 251.

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[45] A.D. Becke, J. Chem. Phys.l 98 (1993) 5648. [46] R.G. Parr, W. Yang, Functional Theory of Atoms and Molecules, Oxford University Press, New York, 1989.

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[47] P.W. Ayers, R.G. Parr, J. Am. Chem. Soc. 122 (2000) 2010.

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[48] R.G. Parr, W.J. Yang, Am. Chem. Soc. 106 (1984) 511–516 [49] P.K. Chattaraj, B. Maiti, U. Sarkar, J. Phys. Chem. A 107 (2003) 4973. [50] C. Morell, A. Grand, A. Toro-Labbe, J. Phys. Chem. A 109 (2005) 205 [51] F. Weinhold, C.R. Landis, Valency and Bonding: A Natural Bond Orbital Donor– Acceptor Perspective, Cambridge University Press, Cambridge, 2005 [52] I. Sidir, Y.G. Sidir, M. Kumalar, E. Tasal, J. Mol. Struct. 964 (2010) 134–151. [53] R.Zhang, B.Dub, G.Sun, Y.X.Sun, Spectrochim.Acta A 75 (2010) 1115-1124 [54] www.mentalhealthdaily.com [55] Singh, S.K., Yamashita,A., Gouaux,E.(2007) Nature 448: 952-956

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[56] Morris, G. M., Goodsell, D. S., Halliday, R.S., Huey, R., Hart, W. E., Belew, R. K. and Olson, A. J. (1998), J. Computational Chemistry, 19: 1639-1662.

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Fig 1 FT-IR spectra of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine (Experimental, B3LYP/6-31G(d,p) and B3LYP/6-311++G (d,p) )

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Fig 2 FT-Raman spectra of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine (Experimental, B3LYP/6-31G(d,p) and B3LYP/6-311++G (d,p)

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Fig 3 Numbering system adopted for methyl[(3R)-3-(2-methylphenoxy)-3phenylpropyl]amine

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ACCEPTED MANUSCRIPT

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Fig 4 The atomic orbital compositions of the frontier molecular orbital of the title compound

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Fig 5 The total electron density surface 3D mapped with electrostatic potential of the title compound

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Fig 6 Correlations graphs of entropy, heat capacity and enthalpy changes of the title compound with various temperatures.

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Fig 7 Schematic for the docked conformation of active site of title compound with antidepressant protein.

ACCEPTED MANUSCRIPT Table 1 Optimized parameters of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine ( bond length ( Å) and bond angle (˚) ). EXPERIMENTAL*

B3LYP/6-31G(d,p)

B3LYP/6-311++G(d,p)

N(1)-C(2)

1.456

1.462

1.463

N(1)-C(19)

1.502

1.457

1.458

N(1)-H(20)

0.95

1.016

1.014

C(2)-C(3)

1.524

1.535

1.534

C(2)-H(21)

1.092

1.106

C(2)-H(22)

1.092

1.098

PARAMETERS

PT

BOND LENGTH (Å)

1.103 1.096

1.531

1.543

1.092

1.096

C(3)-H(24)

1.092

1.096

C(4)-C(5)

1.556

1.524

1.523

C(4)-O(11)

1.431

1.432

1.434

C(4)-H(25)

1.096

1.099

1.097

C(5)-C(6)

1.397

C(5)-C(10)

1.397

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1.541

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C(3)-C(4) C(3)-H(23)

1.094 1.094

1.4

1.397

1.401

1.399

1.397

1.395

1.085

1.083

1.397 0.93

C(7)-C(8)

1.397

1.395

1.393

C(7)-H(27)

0.93

1.086

1.084

C(8)-C(9)

1.397

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C(6)-C(7) C(6)-H(26)

1.395

1.086

1.084

1.397

1.394

1.393

0.93

1.086

1.084

C(10)-H(30)

0.93

1.088

1.086

O(11)-C(12)

1.3759

1.375

1.373

C(12)-C(13)

1.397

1.411

1.409

C(12)-C(17)

1.397

1.397

1.396

C(13)-C(14)

1.397

1.395

1.394

C(13)-C(18)

1.524

1.507

1.507

C(14)-C(15)

1.397

1.398

1.396

C(14)-H(31)

0.93

1.087

1.085

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C(9)-C(10)

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1.396

0.93

C(8)-H(28)

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C(9)-H(29)

C(15)-C(16)

1.397

1.391

1.389

C(15)-H(32)

0.93

1.086

1.084

C(16)-C(17)

1.397

1.398

1.396

C(16)-H(33)

0.93

1.086

1.084

C(17)-H(34)

0.93

1.083

1.081

C(18)-H(35)

0.96

1.095

1.092

C(18)-H(36)

0.96

1.093

1.094

C(18)-H(37)

0.96

1.096

1.094

C(19)-H(38)

0.96

1.094

1.092

C(19)-H(39)

0.96

1.097

1.095

ACCEPTED MANUSCRIPT C(19)-H(40)

0.96

1.106

1.104

PARAMETERS

EXPERIMENTAL

B3LYP/6-31G(d,p)

B3LYP/6-311++G(d,p)

C(2)-N(1)-C(19)

113.2

112.6

113

C(2)-N(1)-H(20)

113.2

109.3

109.9

N(1)-C(2)-C(3)

110.32

112.7

112.9

N(1)-C(2)-H(21)

115.8

113.4

112.8

N(1)-C(2)-H(22)

107.1

106.9

106.9

C(19)-N(1)-H(20)

113.2

109

109.6

N(1)-C(19)-H(38)

109.5

109.6

109.6

N(1)-C(19)-H(39)

109.5

109.6

N(1)-C(19)-H(40)

115.8

114.6

C(3)-C(2)-H(21)

109.5

109.5

C(3)-C(2)-H(22)

107.5

107.9

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BOND ANGLE (˚)

109.6 114

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109.7 108

117.3

116.9

109

108.9

108.9

C(2)-C(3)-H(24)

108

108.5

108.6

H(21)-C(2)-H(22)

106.5

105.9

106.2

C(4)-C(3)-H(23)

106.5

106.1

106.1

C(4)-C(3)-H(24)

108.8

108.7

108.6

C(3)-C(4)-C(5)

114.1

114.4

114.5

C(3)-C(4)-O(11)

122.18

106.1

106.2

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C(2)-C(3)-C(4) C(2)-C(3)-H(23)

117.1

106.5

106.8

106.7

108

107.4

107.2

C(5)-C(4)-O(11)

122.18

112.3

112.3

108.8

108.4

108.3

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C(5)-C(4)-H(25)

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C(3)-C(4)-H(25) H(23)-C(3)-H(24)

121.8

121.7

121.9

119.46

119.5

119.3

O(11)-C(4)-H(25)

108.8

108.6

108.5

C(4)-O(11)-C(12)

120

120.1

120.4

C(6)-C(5)-C(10)

118.75

118.8

118.8

C(5)-C(6)-C(7)

120.41

120.4

120.5

C(5)-C(6)-H(26)

119.2

119.2

119.4

C(5)-C(10)-C(9)

120.62

120.7

120.8

C(5)-C(10)-C(30)

119.5

119.6

119.7

C(7)-C(6)-H(26)

120.7

120.3

120.1

C(6)-C(7)-C(8)

120.3

120.3

120.3

C(6)-C(7)-H(27)

119.5

119.6

119.6

C(8)-C(7)-H(27)

120.7

120.1

120

C(7)-C(8)-C(9)

119.59

119.6

119.5

C(7)-C(8)-H(28)

120.7

120.2

120.3

C(9)-C(8)-H(28)

120.7

120.2

120.2

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C(4)-C(5)-C(6)

C(4)-C(5)-C(10)

C(8)-C(9)-C(10)

120.05

120.1

120.1

C(8)-C(9)-H(29)

120.7

120.1

120.1

C(10)-C(9)-H(29)

119.5

119.8

119.8

C(9)-C(10-H(30)

119.5

119.6

119.5

ACCEPTED MANUSCRIPT O(11)-C(12)-C(13)

114.26

114.8

115

O(11)-C(12)-C(17)

123.76

124.3

124.3

C(13)-C(12)-C(17)

120.99

120.9

120.7

C(12)-C(13)-C(14)

118.2

118

118

C(12)-C(13)-C(18)

120.05

120.1

120.2

C(12)-C(17)-C(16)

119.75

119.7

119.8

C(12)-C(17)-H(34)

120.7

120.7

120.8

C(14)-C(13)-C(18)

121.9

121.9

121.7

121.8

121.8

121.8

118.5

118.5

118.6

C(13)-C(18)-H(35)

111.3

111.3

C(13)-C(18)-H(36)

110.9

110.8

C(13)-C(18)-H(37)

111.5

111.5

C(15)-C(14)-H(31)

119.5

119.7

C(14)-C(15)-C(16)

119.29

119.3

C(14)-C(15)-H(32)

120.7

120.2

120.2

C(16)-C(15)-H(32)

120.7

120.5

120.5

120.4

120.4

120.4

120.4

119.2

119.2

119.6

119.4

PT

C(13)-C(14)-C(15) C(13)-C(14)-H(31)

110.7 111.4

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111.3 119.6 119.3

120.41 120.7

C(17)-C(16)-H(33)

119.2

C(16)-C(17)-H(34)

119.5

H(35)-C(18)-H(36)

108.5

108.5

108.3

H(35)-C(18)-H(37)

105.1

106.4

108.5

H(36(-C(18)-H(37)

108.4

108.2

106.5

H(38)-C(19)-H(39)

108

107.6

107.6

108

108.3

107.2

107.6

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H(38)-C(19)-H(40) H(39)-C(19)-H(40)

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* Ref [12,13]

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C(15)-C(16)-C(17) C(15)-C(16)-H(33)

108

ACCEPTED MANUSCRIPT

Table 2 Calculated and vibrational wavenumbers, measured IR and Raman band positions (cm-1) and assignments of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine Frequencies

2900 2889 2793 1602

1600

CE

1468

AC

1433

1415

1360

1379

1342

1345

1264 1243 1201 1166

Relative 115 109 140 221 175 90 91 82 85 39 68 80 72 64 244 112 207 67 40 123 118 31 40 11 12 2 3 9 5 4 4 6 1 7 2 6 3 8 2 1 7 2 16 15 1 1 5 15 17 1

Absolute 47 45 57 90 72 37 37 34 35 16 28 33 29 26 100 46 85 27 17 51 48 13 16 5 5 1 1 4 2 1 2 3 1 3 1 2 1 3 1 0 3 1 7 6 0 1 2 6 7 0

Vibrational assignments [PED] νNH(100) νCH(93) νCH(93) νCH(87) ν CH(85) ν CH(87) ν CH(97) ν CH(81) ν CH(97) ν CH(96) ν CH(91) ν CH(99) ν CH(99) ν CH(99) ν CH(96) ν CH(95) ν CH(99) ν CH(90) ν CH(94) ν CH(97) ν CH(97) ν CC(36) ν CC(52) ν CC(32)+ βCCC(10) ν CC(43) β HCC(56) β HCC(40) β HCH(62) β HNC(19)+ βHCH(50) β HCH(38) βHNC(28)+βHCH(22) βHCH(67)+δHCNC(13) βHCC(46) β HCH(76)+δHCCC(16) βHCC(35)+βHCH(14) βHCH(81) β HCH(88) β HCH (91) βHCC(10)+ δHCCC(20)+ δHCOC(18) β HCC(20)+ β HCO (23)+ δ HCOC(13) βHCO(41)+ δHCNC(16) βHCC(50) νCC(10)+ βHCC(12)+ δHCOC(12) νCC(27)+ βHCC(12) νCC(22)+ βHCC(11) νCC(14)+ βHCC(50) δHCOC(25)+ δHCNC(10) νCC(10)+ νOC(24) νOC(10)+ βHCC(30)+δHCCC(10) νCC(20)

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Absolute 8 3 3 11 18 11 7 0 6 4 15 18 16 10 34 30 19 17 7 44 59 3 24 9 4 5 63 4 25 6 1 13 9 6 14 5 1 1 2 11 11 3 3 8 2 5 6 100 66 23

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Relative 13 5 4 18 28 17 10 0 10 6 23 28 25 16 52 46 29 27 11 68 91 4 36 14 6 8 97 6 38 9 1 19 14 9 21 7 1 2 3 17 17 4 5 13 3 8 9 154 102 36

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2978

Scaled 3393 3082 3069 3060 3060 3048 3043 3038 3030 3027 2981 2967 2955 2951 2921 2920 2906 2905 2888 2826 2812 1578 1574 1561 1559 1465 1463 1460 1458 1443 1439 1428 1423 1420 1412 1409 1399 1362 1351 1339 1327 1299 1294 1285 1272 1263 1242 1210 1202 1165

Raman Activity

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3054

Unscaled 3535 3210 3197 3187 3187 3175 3169 3165 3156 3153 3105 3091 3078 3073 3043 3041 3027 3026 3008 2941 2926 1642 1638 1625 1622 1525 1522 1520 1517 1502 1497 1486 1480 1478 1469 1466 1456 1417 1406 1394 1380 1352 1347 1337 1324 1314 1292 1259 1251 1213

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IR Intensities

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IR 3380

Theorectical

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Experimental

ACCEPTED MANUSCRIPT

915 899 876

909 876 851

772 755

713

630 607

615

552

548

AC

475

378 356 262

223 184 142

72

58 43 40

56 42 38

0 0 0

0 0 0

2 6 3

νCC(24) βHCC(70) νCC(10)+ βHCC(73) βHCC(73) νNC(11)+ βHCC(13)+ δHCNC(28) νNC(17)+ δHCNC(31) νCC(11)+νNC (11)+ βHCC(21) νNC(34)+ δHCNC(14) νCC(32)+ βHCC(22) νNC(11)+ νCC(35) νCC(65) νOC(29)+ νCC(13) βHCH(23)+ δHCCC(60)+ OUT CCCC(11) νCC(45) νCC(12)+ βCCC(61) δHCNC(12) δHCCC(48)+ δCCCC(39) βHCH(10)+ βCCC(14)+ δHCCC(42) δHCCC(89) νOC(25) δHCCC(68) δHCCC(52) δHCCC(74) νCC(36)+ δHCCC(10) νNC(15)+ δHNCC(11) δHCCC(95) δHCCC(79) νOC(13)+ βCCC(13) νCC(12)+ βCCC(16) βCCC(11)+ δHNCC(22) δHCCC(51) δHCCC(68)+ δCCCC(11) δHNCC(22) δHCCC(15)+ δCCCC(57) δHCCC(26)+ δCCCC(36) βCCC(16)+ OUT CCOC(10) βCCC(80) βCCC(23)+ βCCO(19) βOCC(14) δCCCC(16)+ δCCCO (13) βCCC(12) βCOC(12)+ βCCO(10) βCNC(15)+ βNCC(18)+ βCCC(15) δHCCC(11)+ δCCCC(42)+ OUT CCCC(23) δHCCC(24)+δ CCC (67) βCCC(41)+ βOCC(10) βCNC(20)+ βCCO(15)+δ HCCC (12) βCNC(13)+ δCCCO(25)+ OUT CCCC(12) βCNC(11)+βCCC(12)+ δHCNC(22) δHCNC(42) βCCC(18) βCCC(23)+ βOCC(11)+ OUT CCCC(16) νCOC(13)+ βCCO(24)+ βCCC(16) δCCCC(32)+ δCCCO(15) βCCO(10)+ βCCC(10) δHCCC(71) νCOC(17)+ δCNCC(15)+ δNCCC(25) δCNCC (22)+ δNCCC(41) βCCC(10)+ δ CNCC(24)+ OUT CCOC(21)+ OUT CCCC(20) δCOCC (27)+ δOCCC(44) δCCOC (24)+ δCOCC(22)+ δOCCC(37)

PT

5 2 3 1 1 1 1 1 0 1 14 1 0 6 14 3 0 2 0 1 0 0 0 1 1 0 0 1 8 3 2 1 1 0 0 2 1 1 1 1 2 1 1 0 0 1 0 0 1 0 1 1 0 1 0 0 0 0

RI

11 5 6 3 3 3 3 3 1 2 33 2 0 14 34 7 1 6 0 3 0 0 0 3 2 0 0 2 21 7 6 2 2 0 0 6 3 3 3 2 5 2 2 0 0 1 1 1 2 1 2 2 1 3 1 0 1 1

SC

998

1 7 4 0 6 36 20 22 5 1 11 49 1 5 1 4 1 5 0 22 1 1 2 5 1 0 1 5 2 19 26 39 13 8 26 2 0 2 3 2 3 0 2 2 0 1 0 1 1 1 0 3 0 0 0 0 1 2

NU

1048 1034

1 11 6 0 10 56 30 33 8 2 17 76 1 8 2 7 1 8 1 34 1 1 3 7 2 0 2 8 3 30 41 60 20 13 41 2 0 3 5 3 4 0 3 3 0 1 0 1 1 2 1 4 0 0 0 0 1 2

MA

1090

D

1093 1070

1159 1154 1139 1136 1128 1111 1099 1094 1064 1047 1031 1026 1018 1007 977 970 968 965 953 942 937 908 900 874 851 828 823 814 773 749 734 731 717 700 687 643 609 589 536 531 523 488 458 434 398 373 309 274 239 235 221 215 189 158 146 134 97 82

PT E

1120

CE

1115

1206 1201 1186 1182 1174 1156 1143 1138 1107 1090 1073 1067 1060 1048 1017 1009 1007 1005 992 980 975 945 937 910 885 862 857 847 804 779 764 761 747 728 715 669 633 613 558 553 544 508 477 451 414 388 322 285 249 245 229 224 196 164 152 139 101 85

1 3 1

ACCEPTED MANUSCRIPT 32 30

30 29

0 0

0 0

1 4

δ CCOC (31)+ δ CCCC (37) δCCOC(27)+ δCOCC(23)+ δCCCC(27)

1 1

Abbrevations: ν stretching, β bending, δ torsion.

PT

Table 3 The calculated electric dipole moments (Debye), polarizability (10-24 esu), β components and βtot (10-30esu) value of methyl[(3R)-3-(2-methylphenoxy)-3phenylpropyl]amine by B3LYP/6-311++G(d,p) method.

B3LYP/6-311++G(d,p) -0.91

Parameters βxxx

B3LYP/6-311++G(d,p) -349.48

μy μz μ(D) αxx αxy αyy αxz αyz αzz α(a.u)

-0.45 -0.96 1.40 251.24 39.00 240.16 64.96 3.65 229.04 240.15

βxxy βxyy βyyy βzxx βxyz βzyy βxzz βyzz βzzz βtot(a.u)

-2.02 -83.29 -149.98 -516.39 -74.46 -133.80 -474.71 140.55 -407.40 1393.61

α(e.s.u) ∆α(a.u)

3.55x10-23 435.58

∆α(e.s.u)

6.45x10-23

SC

NU

MA

D

PT E CE AC

RI

Parameters μx

βtot(e.s.u)

1.20x10-29

ACCEPTED MANUSCRIPT

PT

Table 4 Calculated energy values, chemical hardness, electronegativity and dipole moment of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine

AC

CE

PT E

D

RI

SC

MA

Electron affinity Energy gap(eV) Electronegativity Chemical potential Chemical hardness Chemical softness Electrophilicity index

NU

HOMO(eV) LUMO(eV) Ionization potential

B3LYP/6-311++G(d,p) -6.04 -0.79 6.04 0.80 5.24 3.42 -3.42 2.62 0.19 2.23

ACCEPTED MANUSCRIPT

Table 5 Values of the Fukui function considering Mulliken charges fj 0.413

0.012

0.401

C3

0.493

0.009

0.483

C4

0.190

0.101

0.088

C5

-0.434

-0.014

-0.420

C6

0.056

0.058

-0.002

C7

0.314

-0.141

0.455

C8

0.136

0.015

0.121

C9

0.437

-0.132

0.569

C10

0.068

-0.083

0.151

O11

-0.031

-0.021

-0.010

C12

0.354

-0.006

0.360

C13

-0.057

0.003

-0.060

C14

0.503

-0.028

0.531

C15

0.163

0.006

0.157

C16

0.378

-0.047

0.426

C17

0.600

-0.062

0.662

C18

0.337

-0.021

0.358

C19

0.303

-0.022

0.325

H20

-0.321

0.042

-0.363

H21

-0.124

-0.020

-0.104

H22

-0.164

-0.041

-0.123

H23

-0.165

-0.045

-0.120

-0.158

-0.021

-0.137

-0.202

-0.051

-0.151

H26

0.042

-0.074

0.116

H27

-0.164

-0.071

-0.093

H28

-0.142

-0.065

-0.077

H29

-0.154

-0.078

-0.076

H30

-0.134

-0.055

-0.079

H31

-0.196

-0.044

-0.152

H32

-0.162

-0.053

-0.109

H33

-0.165

-0.042

-0.123

H24 H25

RI

C2

SC

0.039

NU

0.024

PT E

D

0.063

AC

N1

PT

Δfk

MA

fj +

CE

Atoms

ACCEPTED MANUSCRIPT -0.311

0.093

-0.404

H35

-0.096

-0.030

-0.065

H36

-0.158

-0.008

-0.150

H37

-0.172

-0.029

-0.143

H38

-0.131

-0.002

-0.130

H39

-0.112

-0.031

-0.081

H40

-0.096

-0.026

-0.070

AC

CE

PT E

D

MA

NU

SC

RI

PT

H34

ACCEPTED MANUSCRIPT

Table 6 Second order perturbation theory analysis of Fock matrix in NBO basis TYPE 1

ED/e

ACCEPTOR

TYPE 2

ED/e

E(2) kcal/mol

E(j)-E(i) (a.u)

F(I,j) (a.u)

σ

1.96349

C 5 - C 10

π*

0.32459

3.92

0.62

0.048

C 5-C 6

σ

1.9508

C 6 - H 26

σ

0.06536

3.07

0.5

0.067

C 6 - H 34

σ

0.12509

56.77

0.12

0.133

C 6-C 7

σ*

0.03451

8.86

1.21

0.093

C 6 - H 34

σ*

0.12509

15.25

2.05

0.161

C 6-C 7

π*

0.45047

4.53

0.77

0.056

C 6 - H 34

σ*

0.12509

3.55

1.59

0.069

C 8-C 9

π*

0.39068

12.82

0.28

0.056

C 6 - H 34

C 6-C 7

π

1.76544

SC

C 5 - C 10

148.97

0.45047

56.68

0.61

0.177

σ*

0.06536

20.19

0.49

0.107

σ*

0.12509

37.18

1.44

0.244

π*

0.39068

76.18

0.12

0.093

C 6-C 7

π

1.32031

292.98

0.11

0.207

C 6-C 7

π*

0.45047

314.93

0.72

0.43

C 6 - H 26

σ*

0.06536

27.9

0.6

0.131

C 6 - H 34

σ*

0.12509

15.65

1.55

0.154

C 16 - C 17

σ*

0.03514

4.38

0.71

0.057

C 16 - C 17

π*

0.4168

36.01

0.19

0.076

C 6-C 7

π

1.30231

56.1

0.49

0.187

C 6 - H 26

σ

1.49323

334.44

0.38

0.437

C 6-C 7

σ*

0.03451

3.74

1.09

0.066

C 6-C 7

π*

0.45047

95.71

1.1

0.298

C 6 - H 34

σ*

0.12509

4.01

1.93

0.089

1.98121

C 5-C 6

σ*

0.03168

3.57

1.01

0.054

C 8-C 9

σ*

0.01408

3.44

1.07

0.054

π

1.69261

C 5 - C 10

π*

0.32459

24.05

0.27

0.072

σ

1.97881

C 6-C 7

σ*

0.03451

3.56

1.01

0.054

C 9 - C 10

σ*

0.1353

3.7

1.07

0.056

σ

1.93726

C 5-C 6 π

C 6-C 7 C 6 - H 26 C 6 - H 34

σ

1.49323

C 8-C 9 C 8 - H 28

1.43463

CE

C 7 - H 27

σ

σ

AC

C 6 - H 34

PT E

D

C 6 - H 26

MA

C 8-C 9

σ

1.43463

0.09

0.183

σ*

0.03168

5.57

1.17

0.073

π*

NU

C 6-C 8

PT

N 1 - H 20

RI

DONOR

C 9 - C 10

σ

1.97926

C 4-C 5

σ*

0.03541

3.39

1.09

0.055

C 9 - H 29

σ

1.98062

C 5 - C 10

σ*

0.02135

3.65

1.04

0.055

C 7-C 8

σ*

0.01461

3.64

1.03

0.055

C 10 - H 30

σ

1.9771

C 5-C 6

σ*

0.03168

5.08

1.01

0.064

C 8-C 9

σ*

0.01408

3.41

1.07

0.054

C 12 - C 14

σ

1.96808

C 12 - C 17

σ*

0.04034

4.09

1.21

0.063

C 12 - C 13

π

1.6336

C 14 - C 15

π*

0.33191

18.65

0.28

0.065

C 16 - C 17

π*

0.41687

19.19

0.27

0.065

C 12 - C 17

σ

1.97105

C 6 - H 34

σ

1.43463

15.33

0.15

0.079

C 13 - C 14

σ

1.9746

O 11 - C 12

σ*

0.02985

3.77

1.06

0.056

ACCEPTED MANUSCRIPT

σ

1.67732

1.97753

C 18 - H 36

σ

1.98799

N 1

LP(1)

1.90615

O 11

O 11

LP(2)

LP(2)

1.95045

1.89057

π*

0.37027

20.6

0.27

0.067

C 16 - C 17

π*

0.41687

21.58

0.26

0.068

C 6 - H 34

σ

1.43463

9.89

0.14

0.06

C 6 - H 34

σ*

0.12509

3.48

2.07

0.078

O 11 - C 12

σ*

0.02985

3.41

1.07

0.054

C 12 - C 17

σ*

0.04034

3.42

1.21

0.058

C 6 - H 26

σ

1.49323

27.08

0.08

0.065

C 6 - H 26

σ*

0.06536

9.37

0.68

0.076

C 12 - C 13

π*

0.37027

19.51

0.28

0.067

C 14 - C 15

π*

0.33191

16.86

0.28

0.062

C 12 - C 17

σ*

0.04034

4.31

1.02

0.06

C 14 - C 15

σ*

0.01313

3.46

1.06

0.054

C 13 - C 14

σ*

0.02106

1.03

0.063

0.03654

4.78

C 2 - H 21

σ*

7.49

0.66

0.064

C 19 - H 40

σ*

0.02622

6.82

0.66

0.061

C 4-C 5

σ*

0.03541

3.2

0.96

0.05

C 12 - C 17

σ*

0.04034

5.72

1.02

0.068

C 4 - H 25

σ*

0.04208

7.86

0.75

0.07

σ*

0.03688

4.2

0.91

0.056

π*

0.37027

11.52

0.39

0.064

σ*

0.03451

8.33

0.57

0.089

C 12 - C 13 C 12 - C 13 0.92416

C 6-C 7

MA

LP(1)

C 6-C 7

π*

0.45047

5.36

0.59

0.06

C 6 - H 26

σ*

0.06536

14.99

0.47

0.106

C 6 - H 34

σ*

0.12509

59.28

1.42

0.357

O 11 - C 12

σ*

0.02985

7.21

0.42

0.071

C 12 - C 13

D

C 17

π*

0.03688

5.49

0.59

0.073

σ*

0.04034

3.59

0.56

0.057

C 15 - C 16

σ*

0.01736

6.61

0.59

0.081

C 16 - H 33

σ*

0.02067

6.18

0.47

0.07

0.45047

C 6 - H 34

σ*

0.12509

62.65

0.83

0.379

0.41687

C 6 - H 26

σ*

0.06536

7.2

0.41

0.098

PT E

π*

σ*

C 12 - C 17

AC

CE

C 6-C 7 C 16 - C 17

PT

C 16 - H 34

π

1.97573

C 12 - C 13

RI

C 16 - C 17

σ

1.65847

SC

C 16 - C 17

π

NU

C 14 - C 15

ACCEPTED MANUSCRIPT

H (kJ/mol)

384.18

134.85

8.76

502.42

217.42

606.6

312.51

300

608.54

314.37

52.79

400

712.51

411.54

89.16

500

813.64

495.39

134.64

600

910.24

700

1001.53

800

1087.45

900 1000

SC

26.29 52.21

564.02

187.73

620.05

247.02

666.38

311.41

1168.24

705.18

380.05

1244.29

737.97

452.25

PT E CE AC

NU

298.15

D

200

S (J/mol.K)

RI

Cp (J/mol.K)

100

MA

T (K)

PT

Table 7 Thermodynamic properties of the title compound at B3LY/6-311++G(d,p)

ACCEPTED MANUSCRIPT

Table 8 The obtained docking parameters of the title compound based on first (1), second (2),

Docking parametres based on their rank calculated by AutoDock

1

2

3

1

-6.73

-4.77

-4.76

11.68

MA D PT E CE AC

2QEI

Inhibition constant (micromolar)

SC

Binding energy (kcal/mol)

NU

Protein ID

RI

PT

third (3) rank calculated by the AutoDock

Intermolecular energy (kcal/mol

2

3

1

2

3

321.32

322.49

-8.52

-6.56

-6.55

ACCEPTED MANUSCRIPT GRAPHICAL ABSTRACT

AC

CE

PT E

D

MA

NU

SC

RI

PT

Experimental and theoretical calculations on the molecular structure, electronic and vibrational characteristics of methyl[(3R)-3-(2-methylphenoxy)-3-phenylpropyl]amine are presented .The vibrational frequiencies were obtained by DFT/B3LYP calculations using 6-31 G(d,p) and 6-311++G(d,p)basis set. Molecular docking studies were performed and shows that the compound exhibit antidepressant property.

ACCEPTED MANUSCRIPT HIGHLIGHTS

PT RI SC NU MA D PT E CE

 

IR, Raman spectra, NLO, HOMO LUMO, MEP, Fukui function and NBO analysis were reported Vibrational assignments were made using potential energy distribution Molecular Docking studies suggest that the compound exhibit antidepressant property.

AC

