VIBRATIONAL SPECTROSCOPY INVESTIGATION AND HYBRID COMPUTATIONAL (HF &DFT) ANALYSIS ON THE STRUCTURE OF CHLORZOXAZONE

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1 International Journal of Metallurgical & Materials Science and Engineering (IJMMSE) ISSN Vol. 3, Issue 3, Aug 2013, TJPRC Pvt. Ltd. VIBRATIONAL SPECTROSCOPY INVESTIGATION AND HYBRID COMPUTATIONAL (HF &DFT) ANALYSIS ON THE STRUCTURE OF CHLORZOXAZONE S. HARIKRISHNAN & T. J. BHOOPATHY PG and Research Department of Physics, Pachaiyappa s College, Chennai, Tamil Nadu, India ABSTRACT In this work, the spectral properties of 5-chloro-3H-benzooxazol-2-one (Chlorzoxazone) are studiedusing density functional theory (DFT) employing B3LYP/ G (d,p) and ab initio HF/ G(d,p) levels of theory. The optimized geometrical parameters obtained by B3LYP/ G (d, p) methodshow good agreement with experimental X-ray data. Satisfactory vibrational assignments were made for the stable conformer of the molecule using Hartree Fock (HF) and density functional theory DFT-B3LYP methods with the G(d,p) basis set. Comparison of the observed fundamental vibrational wave numbers of the molecule and calculated results by RHF and DFT methods indicates that B3LYP is superior for molecular vibrational problems. A study on theelectronic properties, such as HOMO and LUMO energies, is performed. The isotropicchemical shift computed by 1H and 13C nuclear magnetic resonance (NMR) chemical shiftsof the Chlorzoxazone calculated using the gauge invariant atomic orbital (GIAO) method also showsgood agreement with ChemDraw Ultra. The natural bond order analysis and thermodynamic functions of the title molecule were also performed using the RHF and DFT methods. KEYWORDS: FTIR, FT-Raman and UV Spectra, ab Initio and DFT, Chlorzoxazone, Chemical Shift INTRODUCTION Chlorzoxazone is a compound with skeletal muscle relaxant property. It is used to decrease muscle tone and tension and thus to relieve spasm and pain associated with musculoskeletal disorders [1, 2]. It is a centrally acting muscle relaxant used to treat muscle spasm and the resulting pain or discomfort. It acts on the spinal cord by depressing reflexes. It is sold as Muscol or Parafon Forte, a combination of chlorzoxazone and acetaminophen (Paracetamol). Possible side effects include dizziness, light-headedness, malaise, nausea, vomiting, and liver dysfunction. Used with acetaminophen it has added risk of hepatoxicity, which is why the combination is not recommended. It can also be administered for acute pain in general and for tension headache (muscle contraction headache). However, this medicine does not take the place of rest, exercise, physical therapy, or other treatments that your doctor may recommend for your medical condition. Extensive experimental and theoretical investigations have focused on elucidating the structure and normal vibrations of Chlorzoxazone. Vibrational assignment based FT-IR and Raman spectra and theoretical DFT and HF calculations have been studied for Chlorzoxazone. The literature survey reveals that to the best of our knowledge, no experimental and computational vibrational spectroscopic study on Chlorzoxazone is published in the literature yet. This inadequacy observed in the literature encouraged us to make this theoretical and experimental vibrational spectroscopic research based on the conformers of Chlorzoxazoneto give a correct assignment of the fundamental bands in experimental FT-IR and FT-Raman spectra. Therefore, present study aims to give a complete description of the molecular geometry and molecular vibrations of the Chlorzoxazone. The optimized geometry and vibrational frequencies of Chlorzoxazone are calculated at DFT/B3LYP level and HF of theory using the G (d,p) basis set. The results of the theoretical and spectroscopic studies are reported herein. These calculations are valuable for providing insights into the vibrational

2 24 S. Harikrishnan & T. J. Bhoopathy spectrum and molecular parameters. The calculated HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) energies show that charge transfer occurs in Chlorzoxazone. Density functional theory calculations are reported to provide excellent vibrational frequencies of organic compounds if the calculated frequencies are approximate treatment for electron correlation, for basis set deficiencies and for the anharmonicity [3, 4]. EXPERIMENTAL DETAILS The sample Chlorzoxazone was provided by the Lancaster Chemical Company, (UK), with a purity of greater than 98%, and it was used as such without further purification. The room temperature FT-IR spectrum of Chlorzoxazone was recorded in the frequency region cm 1 at a resolution of ±1 cm-1 using BRUKER IFS 66V FTIR spectrometer equipped with an MCT detector, a KBr beam splitter and globar source. The FT-Raman spectrum of Chlorzoxazone was recorded on a computer interfaced BRUKER IFS 66V model interferometer equipped with FRA-106 FT-Raman accessories. The spectrum was measured in the Stokes region cm 1 using Nd: YAG laser at 1064 nm of 200 mw output as the excitation source and with a liquid nitrogen-cooled Ge-diode detector with the powder sample in a capillary tube. The UV vis spectral measurements were carried out using a Variancary 5E-UV-NIR spectrophotometer. The spectral measurements were carried out at sophisticated instrumentation Analysis Facility, IIT, Chennai, India. COMPUTATIONAL DETAILS In order to obtain stable structures, the geometrical parameters of Chlorzoxazone in the ground state were obtained at DFT by the B3LYP and HF level of theory using the G (d,p) basis sets Moreover, the vibrational wavenumbers of Chlorzoxazone conformation have also been calculated to improve simulation of the experimental spectra. The computed bond lengths and bond angles by both levels show satisfactory agreement with experimental [5] observation. The tabulated calculations that are performed using Gauss view molecular visualization program [6] and Gaussian 03W program package on the personal computer [7]. The Becke s three-parameter hybrid density functional, B3LYP [8, 9], was used to calculate harmonic vibrational wavenumbers with G (d, p) basis set. It is well known in the quantum chemical literature that among available B3LYP function yields a good description of harmonic vibrational wavenumbers for small and medium-sized molecules. Natural bond orbital analysis was also performed by thegaussian 03W program at the B3LYP level of theory analysis which transforms the canonical delocalized Hartee Fock (HF) molecular orbital (MOs) into localized MOs that are closely tiedto chemical bonding concepts. Interaction between both filled and virtual orbital spaces information correctly is explained by the NBO analysis, and it could enhance the analysis of intra- and intermolecular interactions. RESULTS AND DISCUSSIONS The optimized structures and numbering of the atoms of Chlorzoxazoneare shown in Figure 1. We reported same geometric parameters for Chlorzoxazoneusing DFT (B3LYP) and HF compared with the available datas (bond lengths, bond angles) [10]. Geometric Structure The optimized bond lengths and bond angles of Chlorzoxazone calculated by using B3LYP/ G (d) and HF/ G (d, p) basis sets are listed in Table 1 in accordance with atom numbering scheme as shown in Fig. 1. Since the exact crystal structure of Chlorzoxazone is not available till now, the optimized structure can only be compared with available data [10] for which the crystal structures have been solved. From thetheoretical values we can find that most of the optimized bond lengths are slightly larger and shorter than experimental values. Comparing bond lengths and bond

3 Vibrational Spectroscopy Investigation and Hybrid Computational (HF &DFT) Analysis on the Structure of Chlorzoxazone 25 angles of C 1 point groupsymmetry at B3LYP/ G (d, p) method leads to geometric parameters that which are much closer to experimental values. Several researchers [11, 12] have explained the changes in the frequency or bond length of the C H bond on substitution due to a change in the charge distribution on the ring carbon atom of the benzene ring. The carbon atoms are bonded to the hydrogen atoms with s bond in benzene and substitution of a Cl atom for hydrogen reduces the electron density at the ring carbon atom. The ring carbon atoms in substituted benzene exert a large attraction on the valence electron cloud of the hydrogen atom resulting in an increase in the C H force constant and a decrease in the corresponding bond length which would be influenced by the combined effects on the inductive mesmeric interaction and the electric dipole field of the polar substituent. In this study, the C H bond lengths were calculated as 1.1 and 1.1 Å for the ring.the optimized parameters obtained by B3LYP method using G (d, p) basis set are approximately similar than to those observed experimentally. At all levels reported here, the calculated bond lengths and bond angles are very close to experimental values, except for the angle at the point of substitution. Natural Bond Orbital Analysis The calculation of effective atomic charges plays an important role in the application of quantum mechanical calculations to molecular systems. Our interest here is in the comparison of different methods (RHF and DFT) to describe the electron distribution in Chlorzoxazone as broadly as possible, and to assess the sensitivity of the calculated charges to change the choice of quantum chemical method. The calculated natural atomic charge values from the natural population analysis (NPA) and Mulliken population analysis (MPA) procedures using the RHF and DFT methods are listed in Table 2. The NPA from the natural bonding orbital (NBO) method is better than the MPA scheme. Table 2 compares the atomic charge site of Chlorzoxazone from both MPA and NPA methods. The NPA of Chlorzoxazone shows that the presence of two oxygen and nitrogen atoms [O10 = (RHF) and (DFT); O1 = (RHF) and (DFT); N3 = (RHF) and (DFT)] imposes large positive charges on the carbon atom [C2 = (RHF) and (DFT)]. However, the nitrogen atom N3 possess large negative charges, resulting in the positive charges on the carbon atoms C2. Moreover, there is no difference in charge distribution observed on all hydrogen atoms except the H12 hydrogen atom (H12 = in RHF and in DFT). HOMO-LUMO Band Gap The energies of four important molecular orbitals of Chlorzoxazone: the highest and second highest occupied MO s (HOMO and HOMO 1), the lowest and the second lowest unoccupied MO s (LUMO and LUMO+1) were calculated and are presented in Table 3. The lowest singlet singlet spin-allowed excited states of Chlorzoxazone were taken into account for the TD-DFT calculation in order to investigate the properties of electronic absorption. The experimental λ max values are obtained from the UV/visible spectra recorded in methanol. The calculations were also performed with methanol solvent effect. The calculated absorption wavelengths (λ max ), oscillator strength, excitation energies and the experimental wavelengths are also given in Table 3. The energy gap between HOMO and LUMO is a critical parameter in determining molecular electrical transport properties [13]. In the electronic absorption spectrum of Chlorzoxazone, there are three absorption bands with a maximum 260, 235 and 210 nm. The strong absorption band 260 nm is caused by the n π* and the other two moderately intense bands are due to π π* transitions. The π π* transitions are expected to occur relatively at lower wavelength, due to the consequence of the extended aromaticity of the benzene ring. The HOMO and LUMO of Chlorzoxazone are represented in Figure 2.

4 26 S. Harikrishnan & T. J. Bhoopathy Computed IR Intensity Analyses Computed vibrational spectral IR intensities of Chlorzoxazone for corresponding wavenumbers by DFT method at B3LYP and HF with G (d,p) basis set have been listed in Table 4. VIBRATIONAL SPECTRAL ANALYSIS In the present study, C and H atoms of CH group are taken to bein plane group. With this assumed structural model, the molecule under consideration would belong to C 1 point group and the 42 normal modes of vibrations. The harmonic vibrational frequencies calculated for Chlorzoxazone at B3LYP and HF level using the G (d,p) basis sets along with infrared intensities have been summarized in Table 4. Comparison of the frequencies calculated at B3LYP and HF with experimental values (Table 4) reveals the overestimation of the calculated vibrational modes due to neglect of anharmonicity in real system. Inclusion of electron correlation in density functional theory to a certain extent makes the frequency valuessmaller in comparison with the HF/ G(p,d) data. The experimental FTIR, FT-Raman and calculated (B3LYP, HF) vibrational spectra were shown in Figures C H Vibrations For simplicity, modes of vibrations of aromatic compounds are considered as separate C H or ring C C vibrations. However, as with any complex molecules, vibrational interactions occur and these levels only indicate the predominant vibration. Substituted benzenes have large number of sensitive bands, i.e., bands whose position is significantly affected by the mass and electronic properties, mesmeric or inductive of the substituents. According to the literature [14, 15], in infrared spectra, most mononuclear and polynuclear aromatic compounds have peaks in the region cm 1, these are due to the stretching vibrations of the ring CH bands. Accordingly, in the present study, the FT- IR bands identified at 3002 cm 1 and FT Raman bands at 2930 cm 1 are assigned to C H stretching vibrations of Chlorzoxazone which are in good agreement with calculated values by B3LYP/ G (d,p) 3090 cm 1. The FT-IR bands at 1336, 1399, and 1454 cm 1 and the FT Raman bands at 1395 and 1445 cm 1 are assigned to C H in-plane bending vibration of Chlorzoxazone. The C H out-of-plane bending vibrations of the Chlorzoxazoneare well identified at 921 and 927 cm 1 in the FTIR and 950 cm 1 in the FT-Raman spectra which are found tobe well within their characteristic region. C C Vibrations The ring C=O and C C stretching vibrations, known as semicircle stretching usually occur in the region cm 1 [16, 17]. Hence in the present investigation, the FT-IR bands identified at 1614 cm 1 and the FT-Raman bands at 1648 cm 1 are assigned to C C stretching vibrations of Chlorzoxazone. The calculated modes found at 1652 cm 1 and 1802 cm 1 in B3LYP/ G (d,p) and HF/ G(d,p) are assigned to C C vibrations, respectively. CH Wagging As it was pointed out the methyl group deformations are superimposed with the ones of the CH groups and cannot be easily identified. The CHwagging, frequently were assigned to the bands at (FTIR) 1119, 1165, 1260 and 1274 cm -1 and in FT-Raman at 1235 and 1273 cm -1 and similarly B3LYP/ G(d,p) calculated values at 1075, 1100, 1154, 1254 and 1271 cm-1 and 1151, 1199, 1250, 1272 and 1358 cm-1 at HF/ G(d,p) respectively. This interaction, which is able to induce a deformation in the molecule, may also fix the methyl group by making its rotation around the threefold axis more difficult with the consequent hardening of the vibrational modes. The CH and wagging, frequently combined with CH deformations, were assigned to the bands at 890 cm -1 in IR and 895 cm -1 in Raman spectra.

5 Vibrational Spectroscopy Investigation and Hybrid Computational (HF &DFT) Analysis on the Structure of Chlorzoxazone 27 1 H and 13 C NMR Spectral Analyses The molecular structure of Chlorzoxazone is optimized by using B3LYP and HF method with G (d,p). Then, gauge invariant atomic orbital (GIAO) 1 H and 13 C calculations of Chlorzoxazoneare calculated and compared with ChemDraw Ultra data which are shown in Table 5. The 1 H and 13 C NMR spectra are presented in Figs. 6a & 6b. The result shows that the range of 1 H and 13 C NMR chemical shift of the typical organic molecule is usually > 100 ppm [18, 19] the accuracy ensures reliable interpretation of spectroscopic parameters. It is true from the above literature value in our present study; Chlorzoxazonealso shows the same. The molecular structure of Chlorzoxazoneshows that the Chlorine atom presents at 7th position of the ring carbon. This Chlorine atom shows electronegative property (they attract the other atom towards), but the chemical shift of C7 seems to be (C7 = 158.3) by B3LYP/ G (d,p) and (C7 = 148.3) by HF/ G (d,p) method which is same for other carbon atoms but in C2 the chemical shift has higher value i.e ppm using B3LYP/ G (d,p) and ppm using HF/ G (d,p) method. On the other hand the isotropic chemical shifts for the other carbon and hydrogen atoms are shown in Table 5. Thermodynamic Properties Several calculated thermodynamic parameters at room temperature are presented in Table 6. According to Koopmanns theorem, ionization potential (I) is the negative of the highest occupied molecular orbital (HOMO) energy, i.e. I = -EHOMO, and affinity potential (A) is the negative of the lowest unoccupied molecular orbital (LUMO) energy, i.e. A = -ELUMO, which are summarized in Table 6. Knowledge of permanent dipole moment of a molecule provides a wealth of information to determine the exact molecular conformation. The total dipole moment of Chlorzoxazone in HF method is exactly twice the dipole moment value of DFT method was observed. In general, the LUMO becomes less bound while the HOMO becomes more bound. From Table 6, it is concluded that the lowest energy gap was found at the DFT method. The variations in the entropy and zero-point vibrational energies seem to be insignificant. CONCLUSIONS We have carried out density functional theory calculations on the structure, vibrational spectrum, NBO, HOMO LUMO analyses and 1H and 13C NMR of Chlorzoxazone. The equilibrium geometry by B3LYP/ G (d,p)for both the bond lengths and bond angles is performed better than HF/ G(d,p) level. The vibration frequency analysis by B3LYP/ G (d, p) method agrees satisfactorily with experimental results. The energies of important MO s, absorption wavelength (λ max ), oscillator strength and excitation energies of the compound were also determined from TD-DFT method and compared with the experimental values. On the basis of agreement between the calculated and experimental results, assignments of selected the fundamental vibrational modes of Chlorzoxazoneare examined and proposed in this investigation. Therefore, the assignments made at higher level of theory with higher basis set with only reasonable deviations from the experimental values, seems to be correct. The high degree of stabilization emanating from strong mesomeric effects has been well demonstrated by NBO analysis. The lowering of HOMO LUMO band gap supports bioactive property of the molecule. 1H and 13C NMR isotropic chemical shifts were calculated and the assignments made are compared with the ChemDraw Ultra values. The calculated normal-mode vibrational frequencies provide thermodynamic properties by way of statistical mechanics. REFERENCES 1. The Merck Index, Thirteenth Edition, Merck and Co. Inc. USA, 2001,

6 28 S. Harikrishnan & T. J. Bhoopathy 2. Bailey L C, Remington, The Science and Practice of Pharmacy, Nineteenth edition. 3. N.C. Handy, C.W. Murray, R.D. Amos, (1993) J. Phys. Chem P.J. Stephans, F.J. Devlin, C.F. Chavalowski, M.J. Frisch, (1995) J. Phys. Chem S. Gunasekaran, S. Seshadri, S. Muthu, (2007) Asian J. Chem A. Frisch, A.B. Niesen, A.J. Holder, GaussView user Manual, Gaussian Inc., (2008). 7. M.J. Frisch, G.W. Trucks, H.B. Schlegal, G.E. Scuseria, M.A. Robb, et al. Gaussian 03, Revision A. 02, Gaussian, inc, Wallingford CT, (2003). 8. A.D. Becke, (1993) J. Chem. Phys C. Lee, W. Yang, R.G. Parr, (1993) Phys. Rev. B J.V. Prasad, S.B. Rai, S.N. Thakur, (1998) Chem. Phys. Lett H. Scot,A.M. Brewer, S.E. Allen, T.L. Lappi, K.A. Chase, C.B. Briggman, S. Gorman, Franzen, (2004) Langmuir R.M. Silverstein, G.C. Bassler, T.C. Morrill, Spectrometric Identification of Organic Compounds, 5th ed., John Wiley & Sons, Inc., New York, (1981). 14. G. Socrates, Infrared and Raman Characteristic Group Frequencies, 3rd ed., Wiley, New York (2001). 15. V. Krishnakumar, V. Balachandran, (2006) Spectrochim. Acta 63A V. Krishnakumar, R. John Xavier, (2003) Indian J. Pure Appl.Phys K. Furic, V. Mohacek, M. Bonifacic, I. Stefanic, (1992) J. Mol. Struct H.O. Kalinowski, S. Berger, S. Brawn, Carbon- 13NMR Spectroscopy, John Wiley and Sons, Chichester, (1988). 19. K. Pihlajer, E. Kleinprter (Eds), Carbon-13Chemical Shifts in Structure and Spectrochemical analysis, VCH Publishers, Deerfield Beach, (1994). APPENDICES Figure 1: Atom Numbering Scheme of Chlorzoxazone

7 Vibrational Spectroscopy Investigation and Hybrid Computational (HF &DFT) Analysis on the Structure of Chlorzoxazone 29 Figure 2: The HOMO and LUMO of Chlorzoxazone Figure 3: FTIR Spectrum of Chlorzoxazone Figure 4: FT-Raman Spectrum of Chlorzoxazone

8 30 S. Harikrishnan & T. J. Bhoopathy Figure 5: Calculated IR Spectrum of Chlorzoxazone Figure 6a: 13 C NMR Spectra of Chlorzoxazone Figure 6b: 1 H NMR Spectra of Chlorzoxazone

9 Vibrational Spectroscopy Investigation and Hybrid Computational (HF &DFT) Analysis on the Structure of Chlorzoxazone 31 Table 1: Structural Parameters of Chlorzoxazone Calculated by HF and DFT Methods Chlorzoxazone Structural Parameters Experimental 10 B3LYP/6- HF/ G(d,p) 311++G(d,p) Internuclear Distance (A ) R(1-2) R(1-5) R(2-3) R(2-10) R(3-4) R(3-12) R(4-5) R(4-6) R(5-9) R(6-7) R(6-13) R(7-8) R(7-11) R(8-9) R(8-14) R(9-15) Bond Angle ( ) A(2-1-5) A(1-2-3) A(1-2-10) A(1-5-4) A(1-5-9) A(3-2-10) A(2-3-4) A(2-3-12) A(4-3-12) A(3-4-5) A(3-4-6) A(5-4-6) A(4-5-9) A(4-6-7) A(4-6-13) A(5-9-8) A(5-9-15) A(7-6-13) A(6-7-8) A(6-7-11) A(8-7-11) A(7-8-9) A(7-8-14) A(9-8-14) A(8-9-15) Atom with Numbering Table 2: Natural Atomic Charges of Chlorzoxazone MPA NPA B3LYP/ G(d,p) HF/ G(d,p) B3LYP/ G(d,p) O C N C C HF/ G(d,p)

10 32 S. Harikrishnan & T. J. Bhoopathy Table 2: Contd., C C C C O Cl H H H H Table 3: Experimental and Calculated Absorption Wavelength (λ), Excitation Energies (E), Oscillator Strength (f) and Frontier Orbital Energies of Chlorzoxazone by TD-DFT Method λ(exp.;nm) λ(cal.;nm) E(eV) f Assignment E HOMO (ev) E LUMO (ev) E HOMO-1 (ev) E LUMO+1 (ev) n π * π π -* π π * Table 4: Observed and Theoretical Vibrational Assignments of Chlorzoxazone Experimental Theoretical Frequency FTIR B3LYP/6- RHF/6- FT- Vibrational Assignment 311++G(d,p) 311++G(d,p) RAMAN Freq. Int. Freq. Int Ring Torsion NH inplane bending CH out of plane Ring deformation Ring deformation CH out of plane CN wagging CH out of plane CH out of plane Ring deformation CO stretching CH out of plane CH out of plane CH wagging CH wagging CH wagging CH wagging CH wagging NH2 scissoring CH inplane bending CH inplane bending CH inplane bending CH wagging CC stretching CC stretching C=O stretching CH2 asymmetric stretching C-H stretching C-H stretching N-H stretching

11 Vibrational Spectroscopy Investigation and Hybrid Computational (HF &DFT) Analysis on the Structure of Chlorzoxazone 33 Table 5: The Calculated 13 C & 1 H NMR Chemical Shifts of Chlorzoxazone B3LYP/ HF/ Atom Absolute Chemical Absolute Chemical ChemDraw Position Shielding Shift Shielding Shift Ultra Assignment C1 in 1-amide C3 in 1-benzene C4 in 1-benzene C5 in Aliphatic C7 in 1-benzene C9 in 1-benzene C11 in 1-benzene H12 in sec. amide H13 in 1-benzene H14 in 1-benzene H15 in 1-benzene Table 6: The Calculated Thermodynamic Parameters of Chlorzoxazone Parameter B3LYP/ G(d,p) HF/ G(d,p) Total Energy(a.u) Zero point energy(kcal/mol) Rotational Constants(GHz) Entropy Total Translational Rotational Vibrational Dipole moment(debye) HOMO(eV) LUMO(eV) Energy gap(ev)

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