Experimental and theoretical study of ornidazole

Experimental and theoretical study of ornidazole

    Experimental and Theoretical study of Ornidazole P. Rajesh, S. Gunasekaran, T. Gnanasambandan, S. Seshadri PII: DOI: Reference: S138...

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    Experimental and Theoretical study of Ornidazole P. Rajesh, S. Gunasekaran, T. Gnanasambandan, S. Seshadri PII: DOI: Reference:

S1386-1425(15)30190-6 doi: 10.1016/j.saa.2015.08.032 SAA 14042

To appear in: Received date: Revised date: Accepted date:

11 August 2014 8 August 2015 14 August 2015

Please cite this article as: P. Rajesh, S. Gunasekaran, T. Gnanasambandan, S. Seshadri, Experimental and Theoretical study of Ornidazole, (2015), doi: 10.1016/j.saa.2015.08.032

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ACCEPTED MANUSCRIPT Experimental and Theoretical study of Ornidazole P.Rajesh1* S. Gunasekaran2 T.Gnanasambandan3 S.Seshadri4 1

Department of Physics,Pachaiyappa’s College, Chennai 600030, India Research & Development, St.Peter’s Univerisity, Avadi, Chennai-600 054, India. 3 Department of Physics, Pallavan College of Engineering, Kanchipuram-63150, India 4 Department of Physics, L.N.Govt. Arts College , Ponneri- 601204. India

Abstract

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The Fourier transform infrared (FT-IR) and the Fourier transform Raman (FT-Raman) spectra of the title molecule in solid phase were recorded in the region

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4000–400 cm-1 and 4000–100 cm-1respectively. The geometrical parameters and energies were investigated with the help of Density Functional Theory (DFT) employing B3LYP method and 6-31G(d,p) basis set. The analysis was supported by electrostatic potential maps

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and calculation of HOMO-LUMO. UV, FT-IR and FT-Raman spectra of Ornidazole were

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calculated and compared with experimental results. Thermodynamic properties like entropy, heat capacity, have been calculated for the molecule. The predicted first hyperpolarizability

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also shows that the molecule might have a reasonably good non-linear optical (NLO) behaviour. The intramolecular contacts have been interpreted using natural bond orbital (NBO) and natural localized molecular orbital (NLMO) analysis. Keywords: FT-IR, FT-R, DFT, NBO * Corresponding author: [email protected] ( P.Rajesh) Tel: +91 8189823556

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1. Introduction Ornidazole is a nitroimidazole which is an antibacterial and antiprotozoal drug used to treat anaerobic

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enteric protozoa. Also used in the treatment of prophylaxis susceptible anaerobic infections in dental and gastrointestinal surgery. Chemically, ornidazole is 1-Chloro-3-(2-methyl-5-nitroimidazol-1-yl) propan-2-ol.

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The molecular formula is C7H10ClN3O3. Ornidazol is available in the brand name of Avrazor, Biteral, Mebaxol, Oniz, Orni, and Ornid.

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The ornidazole and its derivatives are studied by several authors. Investigation of the Formation Process of In vivo and real time determination of ornidazole and tinidazole and pharmacokinetic study by

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capillary electrophoresis with microdialysis was done by Zhang et al. [1]. A comparative study of the use of ornidazole hemihydrate was investigated by Deng et al. [2]. Toxicity of ornidazole and its analogues to rat spermatozoa as reflected in motility parameters were studied by Bone et al. [3]. Thermodynamic characteristics of solutions of ornidazole in different organic solvents at different temperatures was done by Bhesaniya et

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al.[4] Enantioselective determination of ornidazole in human plasma by liquid chromatography–tandem mass

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spectrometry on a Chiral-AGP column was investigated by Jiangbo Du et al.[5] Synthesis and characterization of PH-sensitive hydrogel composed of carboxymethyl chitosan for colon targeted delivery of ornidazole were

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studied by Vaghaniet et al.[6],

Literature survey reveals that so far there is no complete experimental and theoretical study for the title compound ornidazole. In this work, we mainly focus on the detailed spectral assignments and vibrational thermodynamic properties based on the experimental Fourier transform infrared (FT-IR) and Fourier transform Raman (FT-Raman) spectra as well as DFT/B3LYP calculations for ornidazole. The redistribution of electron density (ED) in various bonding, antibonding orbitals and E(2) energies have been calculated by the natural bond orbital (NBO) analysis to give clear evidence of stabilization originating from the hyper conjugation of various intra-molecular interactions. Conformational analysis is the examination of the position of a molecule and the energy changes it undergoes as it converts among the different conformations. The study of HOMO and LUMO analysis has been used to elucidate the information regarding the charge transfer within the molecule. Finally, the UV–vis spectra and the electronic absorption properties were explained and illustrated from the frontier molecular orbitals. Here, the calculated results have been reported in the text. The experimental and theoretical results supported each other and the calculations are valuable for providing insight into the vibrational spectra and molecular properties.

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2. Experimental Details The compound under investigation was obtained from the Lancaster Chemical Company of UK with a

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stated purity of greater than 98% and it was used as such for the spectral measurements. In room temperature the Fourier transform infrared spectra of ornidazole was recorded in the region 4000–400 cm-1 at a resolution of 1

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cm-1 using BRUKER IFS-66V Fourier transform spectrometer equipped with a MCT detector, a KBr beam splitter and global source. The FT-Raman spectrum was recorded with FRA-106 Raman accessories in the

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region 4000–100 cm-1 Nd: YAG laser operating at 200mW power with 1064 nm excitation was used as a source. The UV–visible absorption spectrum of the sample was recorded using a Shimadzu UV-1800 PC, UV-Vis

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spectrophotometer in the range 200–400 nm using water as solvent. 3. Methods of analysis

The molecular geometry optimization and vibrational frequency calculations were carried out for ornidazole, with GAUSSIAN 03W software package [7] Becke’s three parameter exchange functional (B3)

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[8,9], and combination with the correlation functional of Lee, Yang and Parr (LYP) [10] with standard

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6-31G(d,p) basis sets. The potential energy distribution (PED) corresponding to each of the observed frequencies is calculated using VEDA 4 program [11] and it shows the reliability and accuracy of the spectral

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analysis. The atomic charge, electric dipole moment, polarizability, first hyperpolarizability, HOMO, LUMO and other thermodynamic parameters were also calculated theoretically. The natural bonding orbital (NBO) calculation were performed using NBO 3.1 program as implemented in the GAUSSIAN 03W package at the DFT level in order to understand the various second-order interactions between the filled orbital of subsystem and the vacant of another subsystem, which is a measure of the intermolecular delocalization or hyperconjugation. Finally, the calculated normal mode of vibrational frequencies will provide the thermodynamic properties through the principle of statistical mechanics. 4. Results and discussion 4.1 Geometrical structure In order to find the most optimized geometry, the energies were carried out for ornidazole using B3LYP/6-31G(d,p) method for various possible conformers. There are three conformers for ornidazole. The computationally predicted various possible conformers obtained for the compound ornidazole . The total energies obtained for these conformers were listed in Table 1. It is clear in Table 1, the structure optimizations have shown that the conformer C3 have produced the global minimum energy of -2947736.83 kJ/mol.

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ACCEPTED MANUSCRIPT Therefore, C3 form is the most stable conformer than the other conformers. The optimized molecular structure with the numbering of atoms of the ornidazole is shown in Fig. 1. The most optimized structure parameters of ornidazole calculated by DFT-B3LYP levels with the 6-31G(d,p) basis set are listed in the Table 2 in

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accordance with the atom numbering scheme given in Fig. 2. The optimized molecular structure of ornidazole belongs to C1 point group symmetry. Table 2 compares the calculated bond lengths and angles for ornidazole

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with those experimentally available from literature value [12]. The C-N bond length is 1.33 Å, which is shorter than that of normal C-N bond (1.417 Å). The calculated bond length values for C-C and C-H in the

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nitroimidazole ring vary from 1.3804 to 1.522 Å and 0.9658to 1.0964Å by B3LYP/6-31G(d,p) basis set, respectively and well agreed with the experimental values [12]. In this study the optimized bond length of C-Cl

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are high and for C-C is low (0.965 Å), with the electron donating and withdrawing substituent on the nitroimidazole ring, the symmetry of the ring is distorted, yielding variation in bond angles at the point of substitution. It is clearly shown that the angles at the point of substitution C-C-C, C-C-H, C-C-O, H-C-H O-N-O are 112 Å, 126 Å, 111 Å, 109 Å and 124 Å respectively. The small difference between experimental and

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theoretical bond lengths and bond angles may be due to presence of intermolecular hydrogen bonding or the

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experimental results belong to solid phase and theoretical calculations belong to gaseous phase. 4.3 Vibrational assignments

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The title molecule consists of 24 atoms, hence undergoes 66 normal modes of vibrations, all are active in infrared and Raman spectra. The molecule under investigation possesses C1 point group symmetry. The observed and calculated wavenumbers along with the relative intensities, probable assignments and total energy distribution (PED) are presented in Table 3. The experimental and theoretical FTIR and FT-Raman spectra are shown in Figs. 3 and 4. The scaling factor of 0.963 for B3LYP/6-31G (d, p) is used in the present work. 4.3.1 C-H Vibrations Aromatic compounds commonly exhibit multiple weak bands in the region 3100–3000 cm-1 due to aromatic CH stretching vibrations [13–16]. The bands appeared at 3028 cm-1 in FT-IR spectrum and 3021 cm-1 in FT-Raman spectrum are assigned to CH ring stretching vibrations. The band identified at 3030 cm-1 in B3LYP methods are assigned to CH ring stretching vibrations. The CH in-plane and out-of-plane bending vibrations generally lie in the range 1000–1300 cm-1 and 950–800 cm-1 [17, 18] respectively. In the present case, the two CH in-plane bending vibrations of the compound is identified at 1030, 1045 and 1149 cm-1 in the B3LYP methods are assigned to CH in-plane bending vibrations. The two CH out-of-plane bending vibrations are observed at 868 and 882 cm-1 in FT-IR spectrum.

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ACCEPTED MANUSCRIPT 4.3.2 C-C Vibrations The ring CC and CC stretching vibrations, known as semicircle stretching usually occurs in the region 1400–1625 cm-1. The CC stretching vibrations found at 1442, 1467 cm-1in B3LYP/6-31G (d,p) methods

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are assigned to CC stretching vibrations and it is also observed at 1435,1467and1431,1470 cm-1 in FT-IR and

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FT-Raman respectively. In the present work, the computed two strong bands present at 899,947 cm-1 in B3LYP/6-31G (d,p) are assigned CCC in-plane bending vibrations. These assignments are in line with the

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literature [19].

4.3.3 C-N Vibrations

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The identification of CN, CN vibrations is a difficult task, since the mixing of vibrations is possible in this region. Silverstein et al. [20] assigned the CN stretching absorption in the range 1382–1266 cm-1 for aromatic amines. In the present work, the band observed at 1270,1295,1350 and 1394 cm-1 in FT-IR spectrum

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and 1270,1296,1364,1386 and 1421 cm-1 in FT-Raman are assigned to CN stretching vibrations. The

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theoretically computed value of CN and CN stretching vibrations also falls in the region 1261,1307,1344 and 1384cm-1 by both the B3LYP/6-31G(d,p) methods. 4.3.4 C–Cl vibrations

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The vibrations belonging to the bond between the ring and the halogen atoms are worth to discuss here, since mixing of vibrations are possible due to the lowering of the molecular symmetry and the presence of heavy atoms on the periphery of the molecule [21]. Mooney [22, 23] assigned the vibrations of C–X group (X = C1, Br and I) in the frequency range of 1129–480cm−1. Generally the C–Cl stretching vibration gives strong bands in the region 710–505cm−1. Compounds with more than one chlorine atom exhibit strong bands due to the asymmetric and symmetric stretching modes. Vibrational coupling with other groups may results in a shift in the absorption to as high as 840cm−1. The C–Cl stretching vibrations in the compound under study are observed at 728 and 670cm-1 in Raman and the corresponding bands are observed at 727, 670 cm−1 in IR. The PED corresponding to C–Cl stretching vibration is 31% [24]. The theoretical calculation by B3LYP6-31G (d, p) method gives the C-Cl stretching mode at 711,673cm-1. 4.3.5 O-H Vibrations Bands due to O-H stretching are of medium to strong intensity in the infrared spectrum, although it may be broad. In Raman spectra the band is generally weak. For solids, liquids and concentrated solutions a broad band of less intensity is normally observed [25]. The very weak FT-IR band at 3696 cm-1 and FT-Raman

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ACCEPTED MANUSCRIPT 3688 cm-1 is assigned to the O–H stretching vibrations. Normally free O–H stretching vibrations appeared around 3600 cm-1 for phenol [26]. The PED corresponding to this vibration is a pure stretching mode and it is exactly contributing to 100%. The characteristic bands corresponding to in-plane bending vibration and out-of-

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plane bending are identified at 1431 cm-1 in Raman and 1325,1435cm-1 in infrared with pure and mixed modes [27,28]. In the case of electron-accepting or almost neutral groups, the band is found above 400 cm-1 whereas

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with electron donating substituents the band occurs below 400cm-1 for solid samples. In the present study, this band is observed in Raman spectrum at 254,281 cm-1 and 251,271 cm-1 in infrared (Table 3) for ornidazole.

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5. Other molecular properties 5.1 Non-Linear optical effects

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Non-linear optical (NLO) effects arise from the interactions of electromagnetic fields in various media to produce new fields altered in phase, frequency, amplitude or other propagation characteristics from the incident fields [29]. NLO is at the forefront of current research because of its importance in providing the key functions of frequency shifting, optical modulation, optical switching, optical logic, and optical memory for the

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emerging technologies in areas such as telecommunications, signal processing and optical interconnections [30–

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33].

The non-linear optical response of an isolated molecule in an electric field Ei () can be presented as a ; induced by the field:

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Taylor series expansion of the total dipole moment,

Where  is the linear polarizability, o the permanent dipole moment and ijk are the first hyperpolarizability tensor components. The isotropic (or average) linear polarizability is defined as [34]:

First hyperpolarizability is a third rank tensor that can be described by 3  33 matrix. The 27 components of 3D matrix can be reduced to 10 components due to the Kleinman symmetry [35] likewise other permutations also take same value). The output from

the

Gaussian

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provides

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components

respectively.

The

of

this

components

matrix of

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as first

hyperpolarizability can be calculated using the following equation:

Using the x, y and z components of, the magnitude of the first hyperpolarizability tensor can be calculated as:

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The complete equation for calculating the magnitude of  from the Gaussian 03W output is given as follows:

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The calculations of the total molecular dipole moment (), linear polarizability () and first-order hyperpolarizability () from the Gaussian output have been explained in detail previously [36] and the DFT has

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been extensively used as an effective method to investigate the organic NLO materials [37]. Table 4 shows the calculated values of tot , tot and tot for the title compound are 1.7106 D, 16.86

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10-12 and 0.997  10-30 esu, obtained by the B3LYP/6-31G(d, p) method. The calculated first hyperpolarizability of title compound is about 3 times greater than those of urea. The above results show that ornidazole might have the NLO applications [38-41]. 5.2 Electrostatic potential

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Molecular electrostatic potential (MESP) at a point in the space around a molecule gives an indication

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of the net electrostatic effect produced at that point by the total charge distribution (electron + nuclei) of the molecule and correlates with the dipole moment, electronegativity, partial charge and chemical reactivity of the

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molecules. It provides a visual method to understand the relative polarity of the molecule. An electron density isosurface mapped with electrostatic potential surface depicts the size, shape, charge density and the site of chemical reactivity of the molecules. The different values of the electrostatic potential represented by different colour; red represents the regions of the most negative electrostatic potential, blue represents the regions of the most positive electrostatic potential and green represents the region of zero potential. Potential increases in the order red < orange < yellow < green < blue. Such mapped electrostatic potential surfaces have been plotted for title molecule in B3LYP/6-31G (d, p) basis set using the computer software Gauss view. Projections of these surfaces along the molecular plane and a perpendicular plane are given in Fig 5. This figure provides a visual representation of the chemically active sites and comparative reactivity of atoms. It may be seen that, in the method, a region of zero potential envelopes the p-system of the aromatic rings, leaving a more electrophilic region in the plane of hydrogen atoms in ornidazole molecule [42].

5.3. NBO/NLMO analysis NBO (Natural Bond Orbital) analyses provides an efficient method for studying intra and inter molecular bonding and interaction among the bonds. It also provides a convenient basis for the investigation of

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ACCEPTED MANUSCRIPT charge transfer or conjugative interactions in the molecular system [43]. Another useful aspect of the NBO method is that it gives information about the interactions in both filled and virtual orbital spaces that could enhance the analysis of intra and intermolecular interactions. The second order Fock matrix was carried out to

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evaluate the donor–acceptor interactions in the NBO analysis [44]. For each donor NBO (i) and acceptor NBO

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(j), the stabilization energy associated with ij delocalization can be estimated as,

Where qi is the donor orbital occupancy, i and j are diagonal elements (orbital energies) and F(i, j) is the off-

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diagonal NBO Fock matrix element.

In Table 5, the perturbation energies of significant donor–acceptor interactions are present. The larger

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the E (2) value, the intensive is the interaction between electron donors and electron acceptors. In ornidazole, the interactions between the first lone pair of oxygen O12 and the antibonding of N10-O11 have the highest E (2) value around 150.34 kcal/mol. The other significant interactions giving stronger stabilization energy value of

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51.64 kcal/mol to the structure are the interactions between antibonding of C5-N6 between the first lone pair of

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nitrogen N9. Table 5 gives the occupancy of electrons and p-character [45] in significant NBO natural atomic hybrid orbitals. In C–H bonds, the hydrogen atoms have almost 0% of p character. The 100% p-character was observed in the first lone pairs of N6, N9, O11 and O12 and in the second lone pair of O4, O11 and O12 and in the

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third lone pair of O12. The natural localized molecular orbital (NLMO) analysis has been carried out since they show how bonding in a molecule is composed from orbitals localized on different atoms. The derivation of NLMOs from NBOs gives direct insight into the nature of the localized molecular orbital’s ‘‘delocalization tails’’ [46, 47]. Table 5 shows significant NLMO’s occupancy, percentage from parent NBO and atomic hybrid contributions of Ornidazole calculated at the B3LYP level using 6-31G (d, p) basis set. The NLMO of third lone pair of Oxygen atom O12 is the most delocalized NLMO and has only 72% contribution from the localized LP(3) O12 parent NBO, and the delocalization tail (27%) consists of the hybrids of N10 and O11. Similarly, the first lone pair of nitrogen atom N9 has delocalization tail (23%) consists of hybrids of N5 and N6. 5.4 Mulliken population analysis The natural population analysis of Ornidazole is obtained by Mulliken [48] population analysis with B3LYP using the basis set 6-31G (d, p). Calculation of effective atomic charges plays an important role in the application of quantum chemical calculations to molecular systems. Our interest here is in the comparison of B3LYP 6-31G(d, p) basis sets methods to describe the electron distribution in Ornidazole as broadly as possible, and assess the sensitivity, the calculated charges to changes in (i) the choice of the basis set; (ii) the choice of

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ACCEPTED MANUSCRIPT the quantum mechanical method. Mulliken charges, calculate the electron population of each atom defined in the basic functions. The Mulliken charge calculated using B3LYP 6-31G (d, p) basis set are listed in Table 6. The C8 atom has more positive charge B3LYP/6-31G (d, p), whereas the N9 atom has more negative charge than

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the other atoms which is reported in Table 6. The result suggests that the atoms bonded to H atom and all O and N atoms are electron acceptor and the charge transfer takes place from H to O. The C8 and C5 atoms by

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B3LYP/6-31G (d, p) methods are more positive than the other atoms. 5.5 UV-spectral analysis

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The UV–Vis spectral analysis of Ornidazole have been calculated by TD-B3LYP/6-31G (d, p) method along with measured UV–Vis data are summarized in Table 7. The UV–Vis spectrum of Ornidazole is shown in

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SF1 (supplementary Material) was examined using water as solvent. Gauss-Sum 2.2 Program [49] has been used to calculate the group contributions to the molecular orbitals and prepare the density of the state (DOS) as shown in Fig. 7. The DOS spectra were created by convoluting the molecular orbital information with the GAUSSIAN cures of unit height. The Highest Occupied Molecular Orbitals (HOMOs) and Lowest–Lying

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Unoccupied Molecular Orbitals (LUMOs) are named as Frontier molecular orbitals (FMOs). The energy gap

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between the HOMOs and LUMOs is the critical parameter in determining the molecular electrical transport properties which helps in the measure of electron conductivity as shown in the Fig.7. The absorption maxima max for the low lying singlet states of the Ornidazole have been calculated by both the B3LYP/6-31G(d,p)

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method with gas and shows that the visible absorption maxima of  which are functions of electron availability for the range of 292.68 and 292.79 nm for Water. As concluded from the UV–Vis Table 7,the maximum absorption wavelength corresponding to the electronic transition from HOMO -5->L(12%), HOMO-4-> LUMO (-23%) ,HOMO->LUMO (74%)and HOMO -8-> LUMO (19%), HOMO -5-> LUMO (-15%) with contribution. The observed transition from HOMOLUMO is n*. 5.6 Molecular properties of Ornidazole The energy gap between HOMO and LUMO is a critical parameter to determine molecular electrical transport properties. By using HOMO and LUMO energy values for a molecule, the global chemical reactivity descriptors of the molecules such as hardness, chemical potential, softness, electronegativity and electrophilicity index as well as local reactivity have been defined [50–54]. Pauling introduced the concept of electronegativity as the power of an atom in a molecule to attract electrons to it. Hardness (), chemical potential () and electronegativity () and softness are defined follows.

= 9

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Where E and V(r) are electronic energy and external potential of an N-electron system respectively. Softness is a property of molecule that measures the extent of chemical reactivity. It is the reciprocal of hardness.

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S=

Using Koopman’s theorem for closed-shell molecules,,  and  can be defined as

=

=

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=

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Where A and I are the ionization potential and electron affinity of the molecules respectively. The ionization energy and electron affinity can be expressed through the HOMO and LUMO orbital energies as I = EHOMO and A = ELUMO. Electron affinity refers to the capability of a ligand to accept precisely one electron from a donor. The ionization potential calculated by B3LYP/6-31G(d,p) method for Ornidazole is 4.58243343 eV.

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Considering the chemical hardness, large HOMO–LUMO gap means a hard molecule and small

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HOMO–LUMO gap means a soft molecule. One can also relate the stability of the molecule to hardness, which means that the molecule with least HOMO–LUMO (4.5824) gap means it, is more reactive. If the HOMO – LUMO energy gap is small, the interaction is strong and the reaction is rapid, whereas if the HOMO- LUMO

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energy gap is large, the interaction is weak and the reaction is slow. Recently Parr et al. [50] have defined a new descriptor to quantify the global electrophilic power of the molecule as electrophilicity index (), which defines a quantitative classification of the global electrophilic nature of a molecule Parr et al. [50] have proposed electrophilicity index () as a measure of energy lowering due to maximal electron flow between donor and acceptor. They defined electrophilicity index (x) as follows:

Using the above equations, the chemical potential, hardness and electrophilicity index have been calculated for Ornidazole and their values are shown in ST1(supplementary Material). The usefulness of this new reactivity quantity has been recently demonstrated in understanding the toxicity of various pollutants in terms of their reactivity and site selectivity [55–57]. 5.7 Thermodynamic properties The standard thermodynamic functions such as, entropy and enthalpy were calculated using perl script THERMO.PL [58] and are listed in ST2(supplementary Material). As observed from the ST2(supplementary

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ACCEPTED MANUSCRIPT Material), the values of CP, H and S all increase with the increase of temperature from 100 to 1000 K, which is attributed to the enhancement of the molecular vibration as the temperature increases. The correlation equations between heat capacity, entropy, enthalpy changes and temperatures were fitted by quadratic formulas and the

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corresponding fitting factors (R2) for these thermodynamic properties are 0.9999, 0.9998 and 0.9998, respectively. The corresponding fitting equations are as follows and the correlation graphs of those shown in

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SF2(supplementary Material).

Cp,mo =  9.4708+0.11333 T+1.94436  10-4 T2 (R2 = 0.9998)

34.7703+0.726797 T3.67732  10-4 T2 (R2 = 0.9998)

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Smo =

Hmo = 253.44324+0.91669 T2.48752 10-4 T2 (R2 = 0.9999)

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All the thermodynamic data provide helpful information to further study of the title compound. They compute the other thermodynamic energies according to relationships of thermodynamic functions and estimate directions of chemical reactions according to the second law of thermodynamics in thermo chemical field. 6. Conclusions

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FT-IR, FT-Raman, UV spectra and DFT quantum chemical calculations studies were performed on

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Ornidazole, in order to identify its structural and spectroscopic features. Every individual normal mode vibrations were compared and characterized by simulated FT- IR and FT-Raman spectrum which promotes the

frequencies

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conclusion on deriving. The molecular geometry parameters such as bond length, bond angle, and vibrational are calculated using B3LYP methods using 6-31G (d, p) basis set brings out a close agreement

between the theoretical calculations and experimental values. A computation of the first hyperpolarizability indicates that the compound may be a good candidate as a NLO material. Stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. Finally the calculated HOMO and LUMO energies shows that charge transfer occur in the molecules, which are responsible for the bioactive property of the biomedical compound Ornidazole. Thermodynamic analysis reveals that all the thermodynamic parameters calculated are directly proportional to temperature.

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ACCEPTED MANUSCRIPT References [1] L. Zhang, Z. Zhang , Journal of Pharmaceutical and Biomedical Analysis, 41 (2006) 1453–1457. [2] L. Deng,W. Wang ,Jianguo Lv, Acta Cryst. (2007). E63, 4204-4206.

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[3] W. Bone, C. H. Yeung, R. Skupin, G. Haufe T.G. Cooper, Int. journal of andrology, 20 (1997) 347-355. [4] K.D. Bhesaniya, K.V. Chavda, C.H. Sadhu, S. Baluja, J.Mol. Liquids 191 (2014) 124 –127.

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[15] G. Varsanyi, Vibrational Spectra of Benzene Derivatives, Academic Press, New York, 1969. [16] V. Krishnakumar, R. John Xavier, Indian J. Pure Appl. Phys. 41 (2003) 597–602. [17] V. Krishnakumar, V.N. Prabavathi, Spectrochim. Acta, Part A 71 (2008) 449–457. [18] A. Altun, K. Golcuk, M. Kumru, J. Mol. Struct. 637 (2003) 155–169. [19] F.R. Dollish, W.G. Fateley, Characteristic Raman Frequencies on Organic Comp, Wiley, New York, 1997. [20] R.M. Silverstein, R.M. Clayton Bassler, T.C. Morril, Spectroscopic Identification of Organic Compounds, John Wiley, New York, 1991. [21] R.A. Yadav, I.S. Singh, Indian J. Pure Appl. Phys. 23 (1985) 626-635. [22] E.F. Mooney, Spectrochim. Acta 20 (1964) 1343-1349. [23] J.E. Burch, E. Gerrard, M. Goldstein, E.F. Mooney, Spectrochim.Acta 19 (1963) 889-899. [24] R. Krishnana, H. Saleema, S. Subashchandrabosea, Spectrochimica Acta Part A 78 (2011) 582–589. [25] R.M. Silverstein, G.C. Bassler, T.C. Morrill, Spectrometric Identification of Organic Compounds, 5th Ed., John Wiley & Sons, Inc., New York, 1981.

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ACCEPTED MANUSCRIPT [56] R. Parthasarathi, J. Padmanabhan, V. Subramanian, B. Maiti, P. Chattaraj, Curr.Sci. 86 (2004) 535–542. [57] R. Parthasarathi, J. Padmanabhan, V. Subramanian, Internet Electron. J. Mol. Des. 2 (2003) 798–813.

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[58] K.K. Irikura, THERMO.PL, National Institute of Standards and Technology, 2002.

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ACCEPTED MANUSCRIPT Table 1 Total energies of different conformations of ornidazole Conformer

Hartrees

KJ/mol

Energy difference (J/mol)

1

C1

-1118.132

-2935656.978

0.000000

2

C2

-1118.188

-2935803.231

146.2531

3

C3

-1122.733

-2947736.836

12079.85

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Sl.No.

Bond length

B3LYP

Expt

Bond Angle

Expt

C1-C2

1.5226

1.518

C2-C1-Cl14

113.72

112.27

C1-Cl14

1.8174

1.770

C2-C1-H15

110.57

109.86

C1-H15

1.0909

0.970

C2-C1-H16

109.44

109.81

C1-H16

1.0895

0.970

H15-C1-H16

109.89

109,54

C2-C3

1.5385

1.522

C1-C2-C3

112.45

110.50

C2-C4

1.4209

1.354

C1-C2-O4

108.45

110.20

C2-H17

1.0996

0.980

C1-C2-H17

105.40

108.26

C3-H9

1.0467

0.960

C3-C2-O4

111.58

110.69

C3-H18

1.0891

0.960

C3-C2-H17

107.85

108.00

C3-H19

1.0896

0.960

O4-C2-H17

110.92

109.81

C4-H20

0.9658

0.930

C2-C3-N9

111.71

111.71

C5-N6

1.3334

1.340

C1-C2-H18

110.37

109.63

C5-N9

1.3694

1.370

C2-C3-H19

109.45

109.22

C5-C13

1.4932

1.522

N9-C2-H18

108.65

109.01

N6-C7

1.3558

1.351

N9-C2-H19

107.33

108.27

C7-C8

1.3804

1.353

H18-C3-H19

109.23

109.55

1.0798

0.980

C2-O4-H20

108.17

106.76

1.3936

1.414

N6-C5-N9

112.11

111.71

1.4179

1.419

N6-C5-C13

124.03

124.81

1.2327

1.218

N9-C5-C13

123.83

123.64

N10-O12

1.2433

1.224

C5-N6-C7

106.08

106.46

C13-H22

1.0903

0.980

N6-C7-C8

109.91

109.48

C13-H23

1.0935

0.970

N6-C7-H21

123.19

124.20

C13-H24

1.0964

0.970

C8-C7-H21

126.88

125.32

C7-C8-N10

106.65

107.59

C7-C8-N10

127.75

127.17

N9-C8-N10

125.58

125.40

C3-N9-C8

129.18

129.73

C5-N9-C8

105.23

106.46

C8-N10-O11

116.85

117.21

C8-N10-012

118.77

119.36

O11-N10-O12

124.36

124.10

C7-H21 C8-N9 C8-N10 N10-O11

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Table2 Optimized geometrical parameters like bond length and bond angles of ornidazole

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Table 3 Vibrational assignments of ornidazole

intensity (km)Mol-1

activity (km)Mol-1

21.74 0.814 1.049 2.006 4.341 3.606 10.78 7.529 8.342 216.1 23.60 141.5 50.85 10.42 24.21 10.24 172.5 48.91 49.14 23.23 15.13 14.86 26.63 156.9 4.357 22.19 36.61 24.46 17.60 30.51 4.464

55.01 87.84 41.41 67.25 74.52 54.50 79.02 174.3 64.31 6.660 5.347 57.82 84.84 23.89 6.601 10.16 11.12 10.25 45.95 28.33 18.37 5.663 2.394 61.87 5.130 11.55 20.80 1.760 2.270 3.223 0.676

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Scaled 3686 3283 3182 3170 3123 3116 3111 3050 3030 1607 1561 1520 1508 1497 1487 1481 1467 1442 1426 1405 1384 1344 1337 1307 1261 1242 1227 1184 1130 1084 1069

υ OH(100) υ CH(99) υ CH2(84) υ CH2(97) υ CH2(95) υ CH2(90) υ CH2(98) υ CH3(100) υ CH(92) υ NOO(80) υ NC(20)+ υ CC(20)+ δ HCN(10) δ HCH(18) υ NC(17)+ υ CC(19)+ δ HCH(16) δ HCH(76)+ τ HCN(14) δ HCH(62)+ τ HCN(11) δ HCH(88) υ NC(13)+δ HCH(11)+ δ CCN(10) δ HOC(12)+ δ HCO(21)+ γ CCH(20) υ NC(13)+ δ HCH(10) υ CC(10)+ δ HCO(13)+ δ HCH(12)+ τ HCN (23)+ γ CCH(12) δ HCN(24)+ δ CCN(10) δ CCC(12)+ τ HCC(14)+ τ HCN(12) δ HOC(16)+ δ CCl(17)+τ HCC(30) υ ON(13)+ υ NC(31) δ HCN(24)+ τ HCNC(12) δ HCC(10)+ τ HCC(14) υNC(27)+ δ HOC(10)+ δ HCCl(13) δ HCN(49) υ CC(14)+υ OC(19)+δ HCN(10) + γ OCC(13) υ OC(22)+ δ HCCl(17)+ τ HCC(20) δ HCH(17)+τ HCN (58)

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υ (cm-1) 3688(vw) 3284(s) 3205(s) 3167(m) 3135(m) 3113(m) 3091(s) 3055(s) 3021(s) 1607(m) 1581 (s) 1531(s) 1495 (m) 1486 (m) 1470 (m) 1431 (m) 1421 (m) 1386 (m) 1364 (m) 1296 (s) 1270 (s) 1242 (s) 1235 (s) 1189 (s) 1150 (s) 1109 (s) 1055 (s)

Vibrational Assignments + PED (%)

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3696 (vw) 3291(s) 3184(m) 3177(m) 3126(m) 3114(m) 3112(s) 3059(s) 3028(s) 1610(m) 1558 (s) 1538(s) 1510 (s) 1495 (m) 1487 (m) 1474(m) 1467 (m) 1435 (m) 1426 (m) 1394 (m) 1382 (m) 1350 (m) 1325 (m) 1295 (s) 1270 (s) 1254 (s) 1232 (s) 1192 (s) 1149 (s) 1107 (s) 1045 (s)

B3LYP/6-31G(d,p) IR Raman

ED

(cm-1)

FTRaman

EP T

υ

AC C

FT-IR

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AC C

EP T

ED

MA

NU

SC RI PT

1030 (s) 1031 (s) 1025 6.251 10.65 υ CC(13)+ δ HCH(10)+τ HCN(28) 1003 (m) 973 (m) 993 8.739 1.839 υ CC(14)+ δ CNC(19) 978 (m) 947 (m) 947 8.626 2.174 υ CC(15)+ δ CNC(15)+ γ OCC(12) 909 (m) 912 (m) 899 20.23 4.688 υ OC(34)+ δ HCCl(12)+τ HCC(22) 882 (s) 882 (s) 895 5.641 1.952 τ HCNC (83) 868 (s) 859 (s) 864 4.265 5.266 υ CC(19)+τ HCNC (17) 828 (s) 828 (s) 834 24.38 9.440 δ CCN (11)+ δ ONC (50) 792 (m) 793 (m) 798 6.719 3.457 υ CC(11)+ υ NC(22)+ δ CNC (11) 742 (m) 743 (m) 748 13.59 0.828 γ ONON (90) 727 (m) 728 (m) 711 13.11 9.718 υ CC(24)+ υ ClC(12)+ δ NC N(14) 689 (s) 687 (s) 692 12.88 4.142 υ ClC(16)+τ HCCN (13)+ τ CNCN (37) 670 (s) 670 (s) 673 12.02 4.609 υ ClC(31)+ δ NCN(11)+ τ CNCN(10) 609 (s) 608 (s) 608 1.691 2.887 τ CCN (66) 479 (s) 483 (m) 485 13.55 3.392 δ CCN(13)+ γ OCC (16) 450 (s) 431 (s) 428 2.629 1.676 υ NC(13)+ δ ONO(15)+ δ OCC(14)+δ CNC(12) 35 3.270 0.681 τ CCCN (73) 65 (vw) 49 1.169 2.675 τ ONC (22) + γ CCN(42) 74 (vw) 83 2.029 1.389 δ ONC(22)+γ CCN(42) 84 (vw) 89 1.429 0.384 τ CCN (57) + γ NCC(10) 122 (vw) 112 0.855 0.302 τ ONC (33)+ τ ClCC(45) 151 (vw) 135 0.635 0.164 τ ONC (29) +τ ClCC (10) + γ CCN(18) 164 (vw) 166 0.701 0.973 δ CCN(13)+τ CNCN (14) + γ NCC(37) + γ CNC(14) 187 (m) 178 4.972 0.727 δ ClCC(50) 226 (m) 225 4.309 0.662 τ HCN(72)+ γ CNC(12) 254 (m) 257 47.31 2.893 τ HOC(44) 281 (m) 271 82.71 2.639 τ HOC(37)+ γ NCC(20) 311 (m) 316 9.244 0.985 δ OCC(17) +δ CCN(10)+ γ CNNC (14) 365 (m) 349 3.007 0.928 δ CCN(18) +δ CNC(17) 389 (s) 392 2.235 2.339 υ NC(14)+ δ ONC(20)+ δ CCN(32) 533 (s) 546 19.62 0.466 υ ClC(13)+ δ NCN(11)+ δ OCC(11) 566 (s) 586 4.086 7.023 υ ClC(11)+ δ ONC(24)+ δ NCC(11) 1219 (s) 1219 80.20 26.25 δ HCN(45) 1409 131.8 36.50 υ ON(25)+ υ NC(20)+ δ HCH(39) 3178(m) 3179 2.052 48.99 υ CH2(85) υ–stretching;δ–in-plane-bending;τ–torsion;γ–out-of-plane-bending;s-strong;vw-veryweak;w-weak;m-medium

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ACCEPTED MANUSCRIPT Table 4 The calculated  ,  and  components of ornidazole

Table 5 NBO analysis of Ornidazole Donor

Accepot

E(2)a Kj/mol

Hybrid

ED(e)

π C5-N6

π*C7-O8

27.87

P1.00

π C7-C8

π *N10-O11

35.81

P1.00 1.00

B3LYP/6-31G(d,p) 30.893 37.231 14.437 -44.43 50.061 20.459 2.0268 2.0170 1.3724 21.801 0.997X10-30

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Parameters xxx xxy xyy yyy xxz xyz yyz xzz yzz zzz tot(esu)

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B3LYP/6-31G(d,p) -1.2486 0.9805 0.6364 1.7106 138.33 -7.1991 132.49 10.944 -0.6393 70.564 16.86X10-12

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Parameters x y z tot(Debye) xx xy yy xz yz zz tot (esu)

Contributions Atoms

Atom

%

C7,O8

44.21

C5-N6

1.00

1.74263

86.951

N10,O11

12.21

C7-C8

1.00

1.98371

57.682

O12

41.50

N10-O11

1.00

π N10-O11

LP O12

10.45

P

LP(1) N6

σ *C5-N9

9.221

P1.00

1.93194

96.559

C5,N9

2.773

N6

1.00

51.64

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Hybrid Atom

1.76356

%from Parent NBO 53.043

1.00

1.55216

75.223

C5,N6

23.72

N9

1.00

P1.00

1.90367

95.149

N10, O11

4.496

O11

1.00

P

1.00

1.98250

99.118

C8,N10

0.704

O12

1.00

P

1.00

1.91344

95.653

N10,O11

3.821

O12

1.00

P

1.00

1.49788

71.964

N10,O11

27.50

O12

1.00

π *C5-N6

LP(2) O11

σ * N10-O11 18.63

LP(2) O12 LP(3) O12

σ * C8-N10

4.312

σ * N10-O11 17.67 π * N10-O11 150.3

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LP(1) O12

P

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LP(1) N9

Table 6 Mulliken atomic charges of ornidazole Atoms C1 C2 C3 O4 C5 N6 C7 C8 N9 N10 O11 O12

B3LYP6-31G(d,p) -0.28776 0.14634 -0.04802 -0.52286 0.45083 -0.47283 0.07904 0.46204 -0.50451 0.33662 -0.39656 -0.43679

Atoms C13 Cl14 H15 H16 H17 H18 H19 H20 H21 H22 H23 H24

B3LYP6-31G(d,p) -0.39518 -0.08914 0.16128 0.18145 0.13241 0.14539 0.14323 0.32428 0.14044 0.15642 0.16100 0.13280

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ACCEPTED MANUSCRIPT Table 7 The UV–Vis excitation energy of ornidazole

Major Contributions

283 270 262

HOMO -5-> LUMO (12%), HOMO -4-> LUMO (-23%) HOMO->LUMO (74%) HOMO -8-> LUMO (19%), HOMO -5-> LUMO (-15%)

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Expt. obs(nm)

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S1 S2 S3

TD-B3LYP/6-31G(d,p) Water Gas Phase cal(nm) E(eV) cal(nm) E(eV) 292.79 3.9137 292.68 3.8304 274.83 4.0995 274.45 4.2395 265.81 4.3533 265.71 4.3394

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States

Fig.1 Optimized structure of Ornidazole

Fig.2 Different possible conformers of Ornidazole

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Fig.3 FT-IR spectra of Ornidazole

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Fig. 4 FT-Raman spectra of Ornidazole

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Fig.5 Molecular electrostatic potential of ornidazole

Fig.6 DOS spectrum of Ornidazole

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Fig.7 Frontier molecular orbital of Ornidazole

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GRAPHICAL ABSTRACT

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HIGHLIGHTS  The wavenumbers are assigned using PED analysis  The compound was characterized by FT-IR and FT-Raman and UV spectroscopy.

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 HOMO - LUMO energy gap were calculated.

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 Natural bond orbital (NBO) analysis has been carried out.

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