Accepted Manuscript Single crystal XRD, Vibrational and Quantum Chemical Calculation of pharmaceutical drugs Paracetamol: a new synthesis form R. Anitha, M. Gunasekaran, S. Suresh Kumar, S. Athimoolam, B. Sridhar PII: DOI: Reference:

S1386-1425(15)00704-0 http://dx.doi.org/10.1016/j.saa.2015.05.091 SAA 13759

To appear in:

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy

Received Date: Revised Date: Accepted Date:

28 November 2014 20 May 2015 24 May 2015

Please cite this article as: R. Anitha, M. Gunasekaran, S. Suresh Kumar, S. Athimoolam, B. Sridhar, Single crystal XRD, Vibrational and Quantum Chemical Calculation of pharmaceutical drugs Paracetamol: a new synthesis form, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy (2015), doi: http://dx.doi.org/10.1016/j.saa. 2015.05.091

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Single crystal XRD, Vibrational and Quantum Chemical Calculation of pharmaceutical drugs Paracetamol: a new synthesis form R. Anitha a, M. Gunasekaran a, S. Suresh Kumar b, S. Athimoolam b* and B. Sridhar c a

Department of Physics, Regional Centre, Anna University Tirunelveli Region, Tirunelveli 627 007, India b

Department of Physics, University College of Engineering Nagercoil, Anna University, Nagercoil 629 004, India

c

Laboratory of X-ray Crystallography, Indian Institute of Chemical Technology, 500 007 Hyderabad, India

*E-mail: [email protected] Abstract The common house hold pharmaceutical drug, Paracetamol (PAR), has been synthesized from 4-chloroaniline as a first ever report. After the synthesis, good quality single crystals were obtained for slow evaporation technique under the room temperature. The crystal and molecular structures were re-determined by the single crystal X-ray diffraction. The vibrational spectral measurements were carried out using FT-IR and FT- Raman spectroscopy in the range of 4000–400 cm-1. The single crystal X-ray studies shows that the drug crystallized in the monoclinic system polymorph (Form-I). The crystal packing is dominated by N–H···O and O–H···O classical hydrogen bonds. The ac diagonal of the unit cell features two chain C(7) and C(9) motifs running in the opposite directions. These two chain motifs are cross-linked to each other to form a ring R44(22) motif and a chain C22(6) motif which is running along the a-axis of the unit cell. Along with the classical hydrogen bonds, the methyl group forms a weak C–H···O interactions in the crystal packing. It offers the support for molecular assembly especially in the hydrophilic regions. Further, the strength of the hydrogen bonds are studied the shifting of vibrational bands. Geometrical optimizations of the drug molecule were done by the Density Functional Theory (DFT) using the B3LYP function and Hartree-Fock (HF) level with 6-311++G(d,p) basis set. The optimized molecular geometry and computed vibrational spectra are compared with experimental results which show significant agreement. The factor group analysis of the molecule was carried out by the various molecular symmetry, site and factor group species using the standard correlation method. The natural bond orbital (NBO) analysis was carried out to interpret hyperconjucative interaction and intramolecular charge transfer (ICT). The chemical softness, chemical hardness, electro-negativity, chemical potential and 1

electrophilicity index of the molecule were found out first time by HOMO-LUMO plot. The frontier orbitals shows lower band gap values signify the possible biological/pharmaceutical activity of the molecule. The thermodynamical properties are also obtained from the calculated frequencies of the optimized structures. Keywords: Paracetamol, FT-IR, FT-Raman, DFT, NBO and HOMO - LUMO Introduction Paracetamol (N-(4-hydroxyphenyl) acetamide), is a well known aniline based drug, it is an analgesic and antipyretic agent which is acting at pain path way such as both the central and peripheral [1-4]. It is commonly used for the relief of fever, headaches and other minor aches [5]. Paracetamol (PAR) is usually classified under non-steroidal anti-inflammatory drugs [6, 7]. Its main mechanism of action is the inhibition of cyclo-oxygenase (COX) [8, 9], an enzyme responsible for the production of prostaglandins, which are important mediators of inflammation, pain and fever [10, 11]. PAR is also using as a suitable medicine for the treatment of postoperative pain [12]. From Cambridge Structural Database (CSD ver. 5.35), it is observed that there are nearly 39 PAR structures already reported so far [13]. Though there are more reports for the pure paracetamol structures, it is observed that pure PAR crystallized only in two polymorphic forms (Form I & II) [14-18]. Form I crystallize in the monoclinic cell setting whereas the form II in orthorhombic cell [19, 20]. Further, a non-crystallographic report claims a new form III [21] which is highly unstable and difficult to investigate the structural features. The present study is the ever first report in which the PAR is crystallized in Form I polymorph from the 4-chloroaniline as a starting material. Further, as a new approach, the hydrogen bonding interactions in the crystal is analyzed through graph-set motif concept [22]. Further, the present investigation focuses on theoretical optimization and vibrational analyses by the quantum chemical calculations. Hence, a combined theoretical and experimental molecular feature of the medicine, paracetamol, is present here. The theoretical vibrational analyses of the molecule are crucial for understanding the strength of the intermolecular forces and delocalization of electron density inside the molecule. The quantum chemical calculations using Hartree Fock (HF) and Density Functional Theory (DFT) methods have been performed to identify various vibrational modes with their wavenumbers and it has been correlated with experimental data. As the stabilization energy has played an important role in the pharmaceutical activity, it is calculated 2

using the Natural Bond Orbital (NBO) analyses. The chemical softness, chemical hardness, chemical potential, electronegativity and electrophilicity index were calculated by the Frontier Molecular Orbital (FMO) analyses. The thermodynamical properties reveal the total thermal energy and the lowest possible energy of the quantum mechanical system. Materials and Methods Preparation The single crystals of PAR were synthesized from an aqueous mixture of 4-chloroaniline (4CA) as a starting material, in an unexpected and unprecedented reaction. Initially, 4CA is heated with ethanol solution at room atmosphere and NaOH was taken as a base solution. The solution was further treated with formic acid to undergo hydrolysis process. This leads to 4-amino phenol solution which is further heated with four drops of acetic acid. This leads to dehydration process and the product (PAR) is obtained in solution form. The resulting solution was stirred half an hour and filtered at room temperature. This filtered solution was allowed slowly to evaporate at a room temperature. After a two week period, a good quality light brown colour crystals of PAR were obtained. The scheme of the reaction is given below, NH2

NH2

+ NaOH

 C2H5OH

Cl

O-Na+

Hydrolysis Formic acid / H2O

O

HN

CH3

NH2

CH3COOH Dehydration

OH

OH

Paracetamol

Scheme 1. Chemical reaction of PAR

3

Density Measurement The density of the crystal was measured by sink and swim method (flotation technique) using a liquid mixture of xylene and carbon tetrachloride. Initially, xylene (5 ml) was taken in a test tube and a good three dimensional crystal was placed on it. Due to the more density than the liquid, the crystal started to sink. Then, drops of carbon tetrachloride were added drop-by-drop with continuous agitation to get uniform density over the liquid. When the density of the crystal and the liquid is matches the crystal starts to levitate on the middle of the test tube. Then, the density of the liquid was found with specific gravity bottle from the concept of relative density. Thus, the density of the crystal was founded to be 1.32 (2) Mg.m-3. Single crystal XRD studies The unit cell parameters of PAR and full data collections were done from single-crystal X-ray diffraction with Bruker SMART APEX CCD area detector diffractometer [23] (graphitemonochromated, MoK = 0.71073 Å). Crystallographic information, details of data collection and refinement statistics are given in Table S1 (Supplementary material). The structure was solved by direct methods using SHELXTL/PC [24]. All the non-H atoms were refined anisotropically and all the H atoms attached to carbon were positioned geometrically and refined using a riding model, with C−H = 0.93 Å and Uiso(H) = 1.2 Ueq (parent atom). Other H atoms, which are participating in the hydrogen bonding interactions, were located from different fourier map and refined isotropically. The re-determined structure matches well with the reported Form I polymorph of the PAR [25]. Vibrational spectroscopic measurements A Jasco FT-IR spectrometer, model 410 under a resolution of 4 cm-1 and with a scanning speed of 2 mm/sec was used for IR spectral measurements. The samples were prepared using pellet technique and the spectra were recorded over the range 4000–400 cm-1. The FT-Raman spectrum was recorded in the frequency range of 50–4000 cm-1 using a BRUKER RFS 27 FT-Raman Spectrometer module. The Nd: YAG Laser source was operated at 1064 nm with the resolution of 2 cm–1.

4

Computational details The geometries and electronic structure for PAR were carried out theoretically by the 6-311++G(d,p) method on a Intel Core i5/3.20 GHz computer using Gaussian 09W [26] program package without any constraint on the geometry optimization [27]. Initial geometry was taken from the single crystal X-ray studies and it was minimized (optimized) by Hartree−Fock (HF) method using the 6-311++G(d,p) basis set. Further, molecular geometries also have been optimized by the Density Functional Theory (DFT) using the Beckes three - parameters exchange functional (B3) [28] in combination with the Lee - Yang - Parr correlation functional (LYP) [29]. It is accepted as a cost-effective approach for the computation of molecular structure, vibrational frequencies and energies of optimized structures. The optimized structural parameters were used in the vibrational frequency calculations at the same level to characterize all stationary points as minima. Then vibrationally averaged nuclear positions of the structure were used for harmonic vibrational frequency calculations resulting in IR and Raman frequencies. Finally, the calculated normal mode vibrational frequencies provide thermodynamic properties through the principle of statistical mechanics. By combining the results of the GAUSSVIEW program [30] with symmetry considerations, vibrational frequency assignments were made with a high degree of accuracy. There is always some ambiguity in defining internal coordination. However, the defined coordinate from complete set matches quite well with the motions observed using the GAUSSVIEW program. Also the Natural Bond Orbital (NBO) calculation was carried out using HF and DFT method with the 6-311++G(d,p) basis set to get more detailed information about the chemical bonds of the molecule. The frontier molecular orbitals (FMO) has been computed and analyzed by the HF and DFT method with the 6-311++G (d,p) basis set. Results and Discussion Molecular Geometry The molecular structure of PAR consists of a benzene ring, a substituted hydroxyl group and a acetamide group in the asymmetric unit. It was crystallized in monoclinic P21/n space group. The unit cell parameters are a=7.066 (6) Å, b = 9.337 (7) Å, c = 11.651 (9) Å, and β = 97.410 (3)

.

Though the overall comparison of bond lengths and bond angles were appreciably matched with 5

the reported data, the present work was investigated the molecular and crystal structure in new approach. The optimized molecular structures of PAR along with ORTEP diagram are shown in Fig. 1. The optimized bond lengths, bond angles and torsion angles of PAR are listed in Table S2 (Supplementary material) with the comparison to experimental data. From the table, it is observed that the most of the optimized bond lengths and bond angles slightly deviated from the experimental values. Because theoretical calculations was carried out for the molecule in free gaseous state, whereas the experimental results corresponds to the molecule in the solid crystalline state. The optimized bond lengths of C–C in benzene ring are in the range 1.381 - 1.391 Å at the HF level and 1.391 - 1.402 Å by the DFT method whereas the single crystal XRD reveals that the C–C bond lengths are in the range of 1.371 (2) –1.380 (2) Å. This result shows that the theoretical results are in good agreement with the experimental values. The optimized bond length of the C–N is observed as 1.417 and 1.416 Å in HF and DFT levels respectively. This bond length is slightly shortened in the experimental results (1.408 (2) Å), which is due to the N–H···O intermolecular hydrogen bonds. The optimized bond length of the C–C bond in acetamide group is 1.514 and 1.520 Å in both HF and DFT respectively whereas the bond length in single crystal XRD is 1.494 (2) Å. This is also attributed to the weak C–H···O interactions in the crystal packing. Hydrogen Bonding features Intermolecular forces play an important role in the formation of supramolecular systems with pharmaceutical drugs, especially through hydrogen bonds. The phenomenon of hydrogen bonding gives more information about the molecular recognition and crystal-engineering. The crystal structure of PAR is stabilized through a three dimensional hydrogen bonding network formed through N–H···O and O–H···O hydrogen bonds. The hydrogen bond table is listed in Table 1. The N–H···O intermolecular hydrogen bonds form an infinite chain C(7) motif running along the ac- diagonal of the unit cell. Another chain C(9) motif is observed through the O–H···O intermolecular hydrogen bonds running along the same ac diagonal in opposite direction. These two primary chain motifs are cross-linked to each other to form a ring R44(22) 6

motif and a chain C22(6) motif, which is running along the a-axis of the unit cell (Fig. 2). These ring and chain motifs leads to the hydrophilic layers at z = 1/4 and 3/4 which are sandwiched between the two alternate hydrophobic layers at z = 0 and 1/2 (Fig. 3). Interestingly methyl group from the acetamide form a weak C–H...O interactions in the crystal packing. It offers an additional support for molecular assembly in the hydrophilic regions. One of the C–H...O interactions connect the molecules through the methyl and hydroxyl group (C13–H15···O17). Thus form a 'head-to-tail' like a chain extending along the a-axis of the unit cell. Another C–H···O interaction link the molecule along the b-axis of the unit cell. Mulliken charge analysis

The Mulliken charge analysis is the most common method for population analysis. This charge analysis is leading to the application of quantum mechanical calculations to the molecular systems. This calculation represents that the charge distribution of the each atom and explain the increase or decrease of bond length between the atoms. It also has significant influence on dipole moment, polarizability, electronic structure and vibrational modes [31]. The Mulliken atomic charge distribution was calculated at the HF and DFT level with the 6-311++G(d,p) basis set. The illustration of atomic charges plotted is shown in Fig. 4 and the predicted charge values are listed in the Table 2. Both positive and negative charges of carbon atoms shows that they are highly influenced by their substitutents. The three carbon (C1, C7 and C13) atoms have negative charges, out of them, the methyl C13 carbon (-0.609 e in HF and -0.661 e in DFT) atom superior than the other. Because this carbon atom surrounded by three electropositive hydrogen (H14, H15 and H16). This electronegative C atom of methyl group leads to the weak C–H···O interactions in the hydrophilic regions of the crystal. All the hydrogen atoms are positive. Moreover, mulliken charges are shows that the H20 (0.286 e in HF and 0.257 e in DFT) atom is more positive than others which is due to the hydrogen atom is surrounded by the two electronegative atoms nitrogen (N11) and oxygen (O17). This hydrogen atom is playing a key role in solid state packing through the N–H···O intermolecular hydrogen bond. Another hydrogen atom H19 (0.263 e in HF and 0.257 e in DFT) have superior than the other hydrogen atom because this hydrogen atom actively participate in O–H···O intermolecular hydrogen bond in the solid crystalline state.

7

Factor group analysis The factor group analysis of PAR, (C8H9NO2), was carried out by standard and group theory [32]. It was crystallized in the monoclinic system with centrosymmetric space group P21/n. It has four formula units per unit cell. Totally 221 genuine normal modes of vibrations were identified excluding

acoustic

modes.

These

genuine

total . Γoptical crystal  Γ crystal  Γ acoustic  56A g + 56Bg + 55A u + 54Bu

modes

These

can

results

be

distributed

as

are

tabulated

in

Table S3 (Supplementary material). The Au species is IR active whereas the Ag species is IR and Raman active. The number of modes calculated from the factor group method is well coinciding with the theoretical methods. Vibrational Assignment Vibrational studies are one of the most powerful techniques for the characterization of materials. It gives the valuable information about the bonding forces and strength of intermolecular bonds in addition to symmetry of the individual species. The effect of hydrogen bond is very important in crystal environment and affects the vibrational spectra to large extent. The vibrational studies not only investigate the symmetry and geometry of the atomic arrangement, it also analyses the chemical composition. Thus it gives information about the bonding mechanisms of the complexes. The assignment of the vibrational spectra was carried out on the basis of a set of locally symmetrized vibrational modes that can be easily correlated with characteristic group wavenumbers. PAR has 20 atoms and 54 normal modes of vibrations. The experimental FTIR and FT-Raman spectra of present molecule along with theoretical spectra are shown in the Figs. 5 and 6 respectively. The calculated harmonic vibrational frequencies by the DFT/B3LYP and HF methods have been compared with experimental results. The assignments are shown in the Table 3. In the present investigation, few functional groups associated with the PAR have been discussed separately, such as –CH3, C–H, N–H, C–N, C=O and O–H. The vibrational modes of these groups are conventional to change in their intensity and position due to their crystalline environment and the nature of the bonding.

8

Vibration of the CH3 group The present molecule PAR has one CH3 group in the acetamide group. This methyl group has C–H stretching vibrations which lie in the region 2975–2840 cm–1 [33, 34]. The assignment of methyl group frequencies consist of nine fundamentals modes which are associated with stretching (symm.stretch and asymm.stretch), bending (in-plane and out-of plane), deformation (symm. def and asymm. def), rocking (in-plane and out-of plane) and twisting modes. The substituted aromatic structure shows the presence of C–H stretching vibrations in the region 3100–3000 cm−1 and this is the characteristic region for the identification of the C–H stretching vibrations. Also, the bands are not affected appreciably by the nature of the substitutents in this region [35]. In the present molecule, a doublet was observed at 3072 and 3084 cm-1 in FT-Raman spectra corresponding to the asymmetric C–H stretching mode. This peak is absent in the experimental IR spectra. i.e., the experimental stretching modes are down shifted due to the intermolecular interaction. The same stretching vibration is computed at 3114 cm-1 in the B3LYP and at 3249 cm-1 in the HF method. This results shows that the theoretical values are slightly deviated from the experimental values. These asymmetric C–H stretching vibrations are also observed in the 3278 cm-1 in the HF method and 3115 cm-1 in B3LYP method. This vibration is inactive in the experimental results. The band at 1492 and 1402 cm-1 in IR spectra is assigned to the C–H scissoring vibration, this vibration is inactive in the FT-Raman spectra. The in-plane C–H vibrations are observed at 1089 cm-1 in IR spectra and at 1090 cm-1 in Raman spectra. The C–H rocking vibration is observed at 1041 cm-1 as a weak and medium peak in IR spectra and at 1044 cm-1 as a strong peak in Raman spectra. These two vibrations are well correlated with the theoretical results. The very strong, weak and medium bands are observed at 819, 692 and 636 cm-1 respectively in IR spectra. It is assigned to the in-plane C–H vibrations, out-of-plane C–H and wagging vibration respectively. The corresponding vibration is observed as strong, weak and medium band at 802, 709 and 634 cm-1 respectively in the Raman spectra. These bands are in appreciable matches with the theoretical results. In the lower wavenumber region, most of the bands are assigned to the wagging, rocking and twisting vibration in both B3LYP and HF methods respectively. It is not present in the experimental results.

9

C–C, N–H, C–N, C=O and O–H vibrations Generally, the C–C stretching vibration is observed in the region 1650–1200 cm-1. In the present case, the band at 1620, 1543 and 1149 cm-1 in IR spectra and 1602, 1536 and 1175 cm-1 in Raman spectra are identified as C–C stretching vibrations. The corresponding vibrations are predicted at 1637, 1558, 1539 and 1187 cm-1 in B3LYP and 1786, 1700, 1673 and 1231 cm-1 in HF methods respectively. The upshifting in the wavenumbers is due to the overlapping of N–H and O–H in plane bending vibration. The weak band at 1205 cm-1 in IR spectra and 1208 cm-1 in Raman spectra is assigned as C–N stretching vibration. This vibration is also replicated in both the theoretical calculations. The C=O stretching vibrations normally occur in the region 1725 ± 65 cm-1 [36, 37]. The stretching vibrations of C=O are observed as medium and weak bands at 1751 cm-1 in IR spectra, similar vibration is Raman inactive. This vibration is also elucidated in both the quantum chemical calculations. The weak band observed at 3663 cm-1 in IR spectra is assigned to the N–H stretching vibration, similar vibration is Raman inactive. This vibration is also replicated in both the theoretical calculation. The O–H stretching vibration is observed at 3839 cm-1 in B3LYP and 4191 cm-1 in HF method. This vibration is not present in the experimental results. NBO analysis The natural bond orbital analysis (NBO) is supportive tool for understanding the hydrogen bonding interactions and delocalization of electron density from the occupied donor and unoccupied acceptor within the molecule. It is also estimate the energy of the molecule with the same geometry in the absence of electronic delocalization. The stabilization of orbital interaction is proportional to the energy difference between interacting orbital and it is play an important role in the biological field. The second order Fock matrix was carried out to evaluate the donor–acceptor interactions in the NBO analysis [38]. The interactions result is a loss of occupancy from the localized NBO of the idealized Lewis structure into an empty non‐Lewis orbital. For each donor (i) and acceptor (j), the stabilization energy E(2) associated with the delocalization i → j is estimated as E(2) = qi

10

where qi is the donor orbital occupancy, εi and εj are orbital energies and F(i,j) is the off diagonal NBO Fock matrix element. Natural bond orbital analysis gives the information about intra‐ and intermolecular bonding and interaction among bonds and also it supply the convenient basis for investigating charge transfer or conjugative interaction in molecular systems. Some of the electron donor orbital, acceptor orbital and the interacting stabilization energy resulting from the second‐order micro‐disturbance theory are already reported [39, 40]. The NBO calculation was performed at HF and B3LYP calculations with 6-311++G(d,p) basis set in order to investigate the electronic structure of the present molecule. The intramolecular charge transfers (ICT) of present molecule are leading to the C = C bond atom in the benzene ring, this intramolecular charge transfers are carried out by the overlapping between the bonding (C–C) and anti bonding (C–C) orbitals within the benzene ring. The strong intramolecular hyperconjugative interaction of the π electrons of C–C to the anti C–C bond of the ring leads to more stabilization of the aromatic ring as listed in the Table 4. The occupancies at π bonds for the (C–C) benzene ring are ~ 1.677 – 1.993 for HF and ~ 1.672- 1.990 for DFT and π* bonds of (C–C) benzene ring are ~0.007- 0.324–for HF and ~ 0.009 – 0.397 for DFT. It is clearly indicates that the strong delocalization takes place around the aromatic ring. This delocalization is leading to the more stabilization energy such as 1.24–46.79 kcal/mol for HF method and 1.18 – 22.46 kcal/mol for DFT method. Another most important interaction energies, that related to the resonance in the benzene ring are electron donating from the LP(N11), LP(O17) and LP (O18) to the anti-bonding acceptor BD*(C12–O18), BD*(C1–C9), BD*(N11–C12) and BD*(C12–C13) orbital. The interaction energies reported for the mentioned conjugative interactions are 31.01, 94.55, 30.21 and 23.06 kcal/mol in HF and 65.69, 6.27, 23.33 and 18.59 kcal/mol in B3LYP level respectively. These most interacting hyperconjugative interactions are responsible for the stability of PAR molecule. The above results shows that more electron delocalization is take place around the benzene ring which is leads to the molecule as possible bio active. These analyses reiterate the bio activity of the present molecule.

Frontier molecular orbitals (FM) studies The FMO (frontier molecular orbitals) are called as a Highest Occupied Molecular Orbital (HOMO) and Lowest Unoccupied Molecular Orbital (LUMO). It is participated a crucial part in 11

the chemical stability of the molecule [41]. The FMOs are playing an important role in the optical and electric properties [42]. It is also used to determine the interaction of the molecule with the other species. The HOMO is characterized by the ability to donate an electron and LUMO corresponds to the electron acceptor [43]. The energy gap between HOMO and LUMO determines the chemical stability, chemical reactivity and chemical hardness–softness of a molecule [43]. The FMOs were computed by HF/DFT method with the 6-311++G(d,p) basis set. The calculated energies of HOMO, LUMO, chemical softness, chemical hardness, electronegativity, chemical potential and electrophilicity index were listed in the Table 5. The energy level diagrams of the present molecule are shown in the Fig. 7. From that figure, it was observed those 296 energy levels and 304 energy levels with the energy ranges -20.588 au to 51.761 au and -19.160 to 50.026 au in HF and DFT methods respectively. The calculated HOMO and LUMO energy values of the present molecule at the HF / DFT levels are -0.300 au/-0.218 au and 0.053 au/ -0.025 au, respectively. The energy gap value between the frontier orbitals are 0.406 au/ 0.193 au. Considering frontier orbitals energy gap, the present molecule have lower band gap which leads to the more charge delocalization. This large charge transfer influences the biological activity of the molecule. Thermodynamical properties Thermodynamics properties was carried out by the HF and B3LYP calculations with the 6-311++G(d,p) basis set in order to investigate the total thermal energy of a present molecule. The calculated thermodynamical parameters are listed in the Table 6. The thermal energy arises from the sum of translational, rotational, vibrational and electronic energies. This energy is less in the

B3LYP/6-311++G(d,p) level. The zero point vibrational energy reveals that the lowest

possible energy of the quantum mechanical system. From that table, it is observed that zero point vibrational energy much higher in HF/6-311++G(d,p) level than by the B3LYP/6-311++G(d,p) level. This result shows that, the optimized structure from the B3LYP method more stable than the HF level. The entropy is the quantitative measure of disorder in a system which is less in the B3LYP/6-311++G(d,p) level. Conclusion The molecular structure of the crystallized material PAR has been re-determined by the single crystal X-ray diffraction. This studies shows that the crystal packing is dominated by N–H···O 12

and O–H···O classical hydrogen bonds leading to hydrogen bonded ensemble. The theoretical study was attempted to predict the optimized geometry and computed spectra by the HF and DFT method with the 6-311++G(d,p) basis set. The shifting of vibrational bands due to the intermolecular hydrogen bonds was analyzed with experimentally and theoretically computed vibrational spectra. According to this, the calculated results for the molecular geometry show a good agreement with the results from the X-ray diffraction. Natural bond orbital analysis indicates the strong intermolecular interactions which are in agreement with the experimental intermolecular hydrogen bonding results. Natural bond orbital analysis of the molecule confirms that the charge transfer caused by π electron cloud movement from the donor to acceptor must be responsible for bioactivity. The value of the energy gap between the HOMO and LUMO give the information about chemical softness, chemical hardness, electronegativity, chemical potential and electrophilicity index of the molecule. The thermodynamical properties grant information about the lowest possible energy of the quantum mechanical system. Acknowledgement The authors SA and SSK thanks the Department of Science and Technology, SERB for the financial support of this work in the form of Fast track Research Project scheme. References [1]. A. Bertolini, A Ferrari, A. Ottani, S. Guerzoni , R. Tacchi, S. Leone, CNS Drug Rev 12 (3–4) (2006) 250–275. [2]. K. Bergman, L. Muller, S.W. Teigen, Mutat. Res 349 (2) (1996) 263– 288. [3]. S. Sweetman Martindale: The complete drug reference. Electronic version. London UK: Pharmaceutical Press; Greenwood Village, Colorado: Thomson MICROMEDEX, (2004). [4]. J. Bonnefont J, J P. Courade, A. Alloui, Drugs 63 (Spec. Iss. 2) (2003) 1-4. [5]. S.T. Duggan, L.J. Scott, Drugs 69 (1) (2009) 101–13. [6]. G.I Juhl, S.E. Norholt, E. Tonnesen, O. Hiesse-Provost, T.S. Jensen, Eur J Pain 10(4) (2006) 371–377. [7]. Martindale, The Extra Pharmacopoeia, 31st ed. Pharmaceutical, press, London (2007). [8]. G.G.Graham and K.F. Scott KF, Am J Ther 12 (1) (2005) 46-55.

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Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J.A. Montgomery, 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, O. Farkas, J.B. Foresman, J.V. Ortiz, J. Cioslowski, D.J. Fox (2013). Gaussian 09, Revision A.1, Gaussian, Inc., Wallingford CT. [27]. H.B. Schlegel, J. Comput. Chem 3(1982) 214-218. [28]. P. Hohenberg, W. Kohn, Phys.rev B 136 (1964) 864-871. [29]. A.D. Becke, J.Chem. Phys 98 (1993) 5648-5653. [30]. R. Dennington, T. Keith, J. Millam GaussView, Version 5. J. Semichem Inc., Shawnee Mission (2009). [31]. I. Sidir, Y.G. Sidir, M. Kumalar, E. Tasal, J. Mol. Struct: 964 (2010) 134–138. [32]. W.G. Fateley, F.R. Dollish, N.T. McDevitt, F.F. Bentley, Infrared and Raman Selection Rules for Molecular and Lattice Vibrations. Wiley: New York (1972). [33]. G. Varsanyi, Vibrational Spectra of Benzene Derivatives, Academic Press, NewYork (1969). [34]. G. Socrates, Infrared Characteristics Group Frequencies, John Wiley, (1980). [35]. M.R. Rosenthal, J. Chem. Educ: 50 3 (1973) 31. [36]. J.B. Lambert, H.F. Shurvell, D.A. Lightner, R.G. Cooks, Organic Struc. Spect, Simon & Schuster/A Viacom company, New Jersey (1998). [37]. A. K. Raju, H.T. Varghese, C. M. Granaderio, I.S. Helena, C. Nogueiradand, Y. Panicker, J. Brazil Chem. Soc (2009) 549–559. [38]. M. Szafran, A. Komasa, E.B. Adamska, J. Mol. Struct. (THEOCHEM) 827 (2007) 101–107. [39]. C. James, A. Amal Raj, R. Reghunathan,

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Spectrosc 37 (2006) 1381‐1392. [40]. L.J. Na, C.Z. Rang, Y.Z.J. Fang, Zhejiang Univ. Sci B 6 (2005) 584‐589. 15

[41]. B. Kosar, C. Albayrak, J. Spectrochim. Acta 78A (2011) 160–167. [42]. I. Fleming, Frontier Orbitals and Organic Chemical Reactions, John Wiley & Sons, New York (1976). [43]. P. Senthil kumar, K. Vasudevan, A. Prakasam, M. Geetha, P.M. Anbarasan, J.Spectrochim. Acta 77A (2010) 45–50.

16

Tables

Table 1 Hydrogen Bonding geometry of PAR molecule D-H···A (Å, )

(D-H) (Å)

(H···A) (Å)

(D···A) (Å)

(D–H···A) ()

N11– H20···O17 (i)

0.87 (1)

2.08 (1)

2.92 (1)

163

O17– H19···O18 (ii)

0.88 (2)

1.79 (2)

2.65 (14)

165

C13 – H15···O17 (i)

0.96 (2)

2.70 (1)

3.54 (2)

146

C13 – H16···O18 (iii)

0.96 (2)

2.89 (1)

3.83 (2)

167

Equivalent Positions: i. x-1/2, -y-3/2, z-1/2 ii. x-1/2, -y-3/2, z+1/2 iii. -x+1/2, y-1/2, -z+3/2

17

Table 2 Atomic charges for optimized geometry of PAR molecule

Atom

HF/6311++G(d,p)

B3LYP/6311++G(d,p)

C1

-0.319

-0.347

C2

0.123

-0.176

H3

0.144

0.195

C4

0.011

0.523

H5

0.172

0.248

C6

0.543

-0.371

C7

-0.852

-0.374

H8

0.116

0.128

C9

0.207

-0.002

H10

0.114

0.142

N11

-0.324

-0.071

C12

0.485

0.349

C13

-0.609

-0.661

H14

0.165

0.184

H15

0.114

0.117

H16

0.169

0.184

O17

-0.353

-0.238

O18

-0.453

-0.344

H19

0.263

0.257

H20

0.286

0.257

18

Table 3 Experimental, HF and B3LYP levels computed vibrational frequencies (cm-1) obtained for PAR molecule Mode Number

Experimental

HF/6-311++G(d,p) νcal

a IR

b Raman

I

1

15

4.176

2

37

3

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

Assignment

νcal

a IR

b Raman

1.999

42

1.683

0.579

t (CH3) + γ (C-H+N-H)

1.608

0.425

47

3.246

0.284

t (CH3)

78

4.118

0.467

79

1.121

0.411

ρ (CH3)

4

142

3.169

0.137

155

3.85

0.488

ω (CH3) + β (C-H+O-H + N-H)

5

206

3.772

0.526

183

0.333

0.218

ρ (CH3) + γ (C-H+N-H+O-H)

6

241

126.06

1.717

262

108.504

1.69

γ (O-H)

7

337

2.899

2.904

313

4.526

3.965

β (C-H+O-H + N-H)

8

352

7.589

0.719

326

3.736

0.917

ω (CH3)

9

411

1.744

2.128

375

1.002

1.797

γ (C-H+N-H)

457

7.183

0.221

421

2.803

0.084

t (C-H)

469

6.734

0.301

429

8.38

0.48

β (C-H+O-H)

504

73.404

1.879

507

25.542

4.651

ω (CH3)

13

545

28.804

4.449

521

28.233

0.065

γ (C-C)

14

575

27.512

0.206

527

50.126

1.038

γ (N-H)

15

673

4.577

1.616

627

4.464

0.257

ρ (CH3) + γ N-H

683

1.733

3.193

629

0.972

3.895

ω (CH3)+ β (C-H)

706

2.5

4.345

657

1.878

6.036

ν (C-C)

709 w

774

0.337

2.786

705

0.239

1.952

γ (C-H)

730 w

859

31.448

9.294

797

29.017

0.065

γ (C-H)

802 s

903

22.366

2.562

801

25.047

16.38

ν (C-C) + β (C-H + N-H)

10

FT-IR

Raman

414 w

11 12

16

493 vs

636 m

634 m

17 18

692 w

19 20

819 vs

I

19

I

I

21

922

2.346

29.452

855

43.423

0.087

γ (C-H)

22

944

60.038

0.709

863

4.218

28.488

Ring breathing

23

1031

0.52

0.437

909

1.35

0.072

γ (C-H)

24

1045

2.856

2.134

965

3.983

2.232

ν (C=O) + ν (C-N)

25

1089

0.318

0.264

985

1.151

0.011

γ (C-H)

1100

6.293

2.631

1013

24.381

6.001

(C-H)

1108

27.863

5.743

1027

2.481

0.523

ν (C-C)

26

1014 m

27 28

1041 m

1044 vs

1154

10.674

0.81

1050

6.219

0.146

ρ (CH3)

29

1089 w

1090 s

1177

33.814

2.452

1133

15.301

0.986

β (C-H + O-H)

30

1149 m

1175 m

1231

38.293

1.023

1187

190.068

8.476

ν (C-C) + β (C-H + O-H)

1285

12.374

7.647

1197

10.354

24.423

β (C-H )

1330

34.663

32.742

1234

26.968

14.915

ν (C-N) + β (C-H) + ω (CH2)

1337

6.23

1.082

1260

165.114

55.658

β (C-H + N-H+ O-H)

1377

446.845

1.592

1283

33.864

60.71

ν (C-C) + β (C-H + N-H)

35

1396

31.866

33.167

1335

66.775

45.757

β (C-H + N-H)

36

1461

13.549

2.972

1362

54.522

8.27

β (C-H + O-H)

1529

24.035

1.359

1400

35.097

18.248

δ CH3

1571

166.214

2.134

1452

167.147

13.989

ν (C-C) + β (C-H + N-H + O-H)

1588

9.991

6.077

1470

7.511

7.574

δ CH3

1608

17.485

6.832

1490

13.592

4.378

δ CH3

1673

112.062

1.275

1539

118.131

9.941

ν (C-C)

1700

488.427

5.549

1558

368.66

59.503

ν (C-C) + ν (C-N)

1786

45.074

12.661

1637

44.636

30.153

ν (C-C) + β (C-H +N-H)

31 32

1205 w

1208 m

33 34

37

1288 w

1402 w

38

1424 w

39 40

1492 s

41

1536 w

42

1543 m

43

1620 w

1602 m

20

44

1811

6.439

67.581

1660

3.235

172.363

Planar Ring Distortion

1929

336.434

19.8

1746

277.219

63.974

ν (C=O)

3184

10.244

160.184

3041

11.058

254.605

νs C-H (methyl)

3249

20.022

56.97

3114

16.116

82.119

νas C-H(methyl)

48

3278

12.712

72.862

3115

5.779

91.07

νas C-H (methyl)

49

3307

20.556

57.714

3148

19.314

63.743

νs C-H (Benzene)

50

3327

15.068

121.194

3165

12.448

147.069

ν C-H (Benzene)

51

3352

5.378

97.452

3192

3.778

113.663

ν C-H (Benzene)

52

3405

0.513

57.976

3243

6.58

50.619

ν C-H (Benzene)

3889

37.005

55.754

3628

19.847

80.613

ν N-H

4191

109.533

89.819

3839

75.067

155.176

ν O-H

45

1751 m

46 3072 & 3084 m

47

53

3663 w

54

w-weak; vs - very strong; m- medium; ν, Stretching; νs, sym.stretching; νas, asym.stretching; β- in plane bending; γ- out -of- plane bending; ω-Wagging; t- twisting;

δ - Scissoring; ρ -Rocking;

21

Table 4. Second order perturbation theory analysis of Fock Matrix in NBO for PAR molecule Donor (i)

Type

ED (i) /e HF

DFT

Acceptor (j)

Type

ED (j) /e HF

DFT

E(2)a (kcal/mol) HF

DFT

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

DFT

F(i,j)c (a.u) HF

DFT

C1 - C2

ζ

1.979

1.977

C1 - C9

ζ*

0.024

0.028

4.74

3.77

1.8

1.29

0.083

0.062

C1 - C2

ζ

1.979

1.977

C2 - H3

ζ*

0.015

0.011

3.76

2.98

1.94

1.44

0.076

0.059

C1 - C2

ζ

1.979

1.977

C2 - C4

ζ*

0.015

0.016

3.96

2.96

1.82

1.31

0.076

0.056

C1 - C2

ζ

1.979

1.977

C4 - H5

ζ*

0.009

0.011

1.64

1.54

1.96

1.47

0.051

0.043

C1 - C2

ζ

1.979

1.977

C9 - H10

ζ*

0.01

0.012

2.17

1.98

1.91

1.42

0.058

0.047

C1 - C2

ζ

1.979

1.977

O17 - H19

ζ*

0.004

0.005

1.57

1.31

1.81

1.28

0.048

0.037

C1 - C9

ζ

1.980

1.98

C1 - C2

ζ*

0.022

0.025

4.91

3.95

1.82

1.3

0.084

0.064

C1 - C9

ζ

1.980

1.98

C2 - H3

ζ*

0.015

0.011

1.82

1.7

1.95

1.45

0.053

0.045

C1 - C9

ζ

1.980

1.98

C7 - H8

ζ*

0.01

0.012

1.87

1.74

1.93

1.43

0.054

0.045

C1 - C9

ζ

1.980

1.98

C7 - C9

ζ*

0.016

0.017

4.74

3.56

1.82

1.32

0.083

0.061

C1 - C9

ζ

1.980

1.98

C9 - H10

ζ*

0.01

0.012

3.88

3.11

1.93

1.43

0.077

0.06

C1 - C9

π

1.663

1.659

C2 - C4

π*

0.324

0.327

36

17.56

0.51

0.31

0.122

0.066

C1 - C9

π

1.663

1.659

C6 - C7

π*

0.382

0.403

46.79

21.99

0.5

0.29

0.138

0.073

C1 - O17

ζ

1.995

1.994

C2 - C4

ζ*

0.015

0.016

1.4

1.29

2.07

1.53

0.048

0.04

C1 - O17

ζ

1.995

1.994

C7 - C9

ζ*

0.016

0.017

1.23

1.1

2.06

1.52

0.045

0.037

C2 - H3

ζ

1.981

1.978

C1 - C2

ζ*

0.022

0.025

2.65

1.85

1.65

1.17

0.059

0.041

C2 - H3

ζ

1.981

1.978

C1 - C9

ζ*

0.024

0.028

4.14

3.64

1.65

1.17

0.074

0.058

C2 - H3

ζ

1.981

1.978

C2 - C4

ζ*

0.015

0.016

3.07

2.08

1.67

1.19

0.064

0.044

C2 - H3

ζ

1.981

1.978

C4 - C6

ζ*

0.021

0.024

4.04

3.56

1.66

1.17

0.073

0.058

C2 - C4

ζ

1.973

1.969

C1 - C2

ζ*

0.022

0.025

4.2

3.15

1.79

1.28

0.077

0.057

22

C2 - C4

ζ

1.973

1.969

C1 - O17

ζ*

0.018

0.025

4.64

4.08

1.56

1.05

0.076

0.059

C2 - C4

ζ

1.973

1.969

C2 - H3

ζ*

0.015

0.011

3.59

2.83

1.92

1.43

0.074

0.057

C2 - C4

ζ

1.973

1.969

C4 - H5

ζ*

0.009

0.011

3.31

2.59

1.95

1.45

0.072

0.055

C2 - C4

ζ

1.973

1.969

C4 - C6

ζ*

0.021

0.024

4.72

3.57

1.79

1.29

0.082

0.061

C2 - C4

ζ

1.973

1.969

C6 - N11

ζ*

0.027

0.035

5.66

4.95

1.61

1.11

0.085

0.066

C2 - C4

π

1.682

1.689

C1 - C9

π*

0.369

0.397

45.74

22.46

0.49

0.28

0.135

0.072

C2 - C4

π

1.682

1.689

C6 - C7

π*

0.382

0.403

40.21

20.24

0.48

0.28

0.126

0.069

C4 - H5

ζ

1.980

1.977

C1 - C2

ζ*

0.022

0.025

3.8

3.31

1.65

1.16

0.071

0.055

C4 - H5

ζ

1.980

1.977

C2 - C4

ζ*

0.015

0.016

3.03

2.09

1.67

1.18

0.064

0.044

C4 - H5

ζ

1.980

1.977

C4 - C6

ζ*

0.021

0.024

2.85

2.02

1.65

1.17

0.061

0.043

C4 - H5

ζ

1.980

1.977

C6 - C7

ζ*

0.019

0.022

4.43

3.92

1.64

1.16

0.076

0.06

C4 - C6

ζ

1.977

1.975

C2 - H3

ζ*

0.015

0.011

1.68

1.57

1.94

1.44

0.051

0.043

C4 - C6

ζ

1.977

1.975

C2 - C4

ζ*

0.015

0.016

4.15

3.05

1.82

1.32

0.078

0.057

C4 - C6

ζ

1.977

1.975

C4 - H5

ζ*

0.009

0.011

3.89

3.14

1.96

1.47

0.078

0.061

C4 - C6

ζ

1.977

1.975

C6 - C7

ζ*

0.019

0.022

5.54

4.27

1.8

1.29

0.089

0.066

C4 - C6

ζ

1.977

1.975

C6 - N11

ζ*

0.027

0.035

1.58

1.08

1.63

1.12

0.045

0.031

C4 - C6

ζ

1.977

1.975

C7 - H8

ζ*

0.01

0.012

2.05

1.86

1.91

1.42

0.056

0.046

C4 - C6

ζ

1.977

1.975

N11 - H20

ζ*

0.01

0.013

1.52

1.32

1.92

1.4

0.048

0.038

C6 - C7

ζ

1.976

1.974

C4 - H5

ζ*

0.009

0.011

2.03

1.84

1.96

1.47

0.057

0.047

C6 - C7

ζ

1.976

1.974

C4 - C6

ζ*

0.021

0.024

5.32

4.09

1.81

1.3

0.088

0.065

C6 - C7

ζ

1.976

1.974

C7 - H8

ζ*

0.01

0.012

3.91

3.15

1.92

1.42

0.078

0.06

C6 - C7

ζ

1.976

1.974

C7 - C9

ζ*

0.016

0.017

4.71

3.48

1.81

1.31

0.083

0.06

C6 - C7

ζ

1.976

1.974

C9 - H10

ζ*

0.01

0.012

1.84

1.71

1.92

1.42

0.053

0.044

23

C6 - C7

ζ

1.976

1.974

N11 - C12

ζ*

0.056

0.07

3.06

2.68

1.73

1.22

0.066

0.052

C6 - C7

π

1.677

1.672

C1 - C9

π*

0.369

0.397

37.51

19

0.5

0.29

0.124

0.067

C6 - C7

π

1.677

1.672

C2 - C4

π*

0.324

0.397

42.56

20.37

0.52

0.3

0.132

0.07

C6 - N11

ζ

1.986

1.984

C2 - C4

ζ*

0.015

0.016

1.36

1.25

1.92

1.41

0.046

0.037

C6 - N11

ζ

1.986

1.984

C4 - C6

ζ*

0.021

0.024

1.71

1.3

1.9

1.39

0.051

0.038

C6 - N11

ζ

1.986

1.984

C7 - C9

ζ*

0.016

0.017

1.15

1.55

1.89

1.4

0.042

0.041

C6 - N11

ζ

1.986

1.984

N11 - C12

ζ*

0.056

0.07

3.07

2.35

1.83

1.31

0.068

0.05

C6 - N11

ζ

1.986

1.984

N11 - H20

ζ*

0.01

0.013

2.14

1.72

2.02

1.49

0.059

0.045

C6 - N11

ζ

1.986

1.984

C12 - C13

ζ*

0.041

0.055

1.93

1.74

1.69

1.2

0.051

0.041

C7 - H8

ζ

1.981

1.978

C1 - C9

ζ*

0.024

0.028

3.56

3.14

1.67

1.18

0.069

0.055

C7 - H8

ζ

1.981

1.978

C4 - C6

ζ*

0.021

0.024

4.47

3.94

1.68

1.19

0.077

0.061

C7 - H8

ζ

1.981

1.978

C6 - C7

ζ*

0.019

0.022

2.66

1.89

1.67

1.18

0.059

0.042

C7 - H8

ζ

1.981

1.978

C7 - C9

ζ*

0.016

0.017

2.93

2.02

1.68

1.19

0.063

0.044

C7 - C9

ζ

1.972

1.968

C1 - C9

ζ*

0.024

0.028

4.76

3.58

1.8

1.29

0.083

0.061

C7 - C9

ζ

1.972

1.968

C1 - O17

ζ*

0.018

0.025

5.26

4.67

1.57

1.06

0.081

0.063

C7 - C9

ζ

1.972

1.968

C6 - C7

ζ*

0.019

0.022

5.1

3.8

1.79

1.29

0.086

0.063

C7 - C9

ζ

1.972

1.968

C6 - N11

ζ*

0.027

0.035

4.52

3.91

1.62

1.12

0.077

0.059

C7 - C9

ζ

1.972

1.968

C7 - H8

ζ*

0.01

0.012

3.61

2.85

1.91

1.42

0.074

0.057

C7 - C9

ζ

1.972

1.968

C9 - H10

ζ*

0.01

0.012

3.94

3.11

1.91

1.42

0.078

0.06

C9 - H10

ζ

1.981

1.978

C1 - C2

ζ*

0.022

0.025

4.01

3.53

1.67

1.18

0.073

0.058

C9 - H10

ζ

1.981

1.978

C1 - C9

ζ*

0.369

0.028

2.59

1.83

1.67

1.18

0.059

0.042

C9 - H10

ζ

1.981

1.978

C6 - C7

ζ*

0.019

0.022

3.82

3.38

1.67

1.18

0.071

0.056

C9 - H10

ζ

1.981

1.978

C7 - C9

ζ*

0.016

0.017

3.25

2.22

1.68

1.2

0.066

0.046

24

N11 - C12

ζ

1.99

1.988

C6 - C7

ζ*

0.019

0.022

1.31

1.22

1.98

1.45

0.046

0.038

N11 - C12

ζ

1.99

1.988

C6 - N11

ζ*

0.027

0.035

3.29

2.46

1.81

1.28

0.069

0.05

N11 - C12

ζ

1.99

1.988

N11 - H20

ζ*

0.01

0.013

2.61

2.28

2.11

1.55

0.066

0.053

N11 - H20

ζ

1.984

1.982

C4 - C6

ζ*

0.021

0.024

3.61

3.08

1.86

1.35

0.073

0.058

N11 - H20

ζ

1.984

1.982

C6 - N11

ζ*

0.027

0.035

1.46

1.04

1.68

1.17

0.044

0.031

N11 - H20

ζ

1.984

1.982

N11 - C12

ζ*

0.056

0.07

1.47

1.2

1.78

1.27

0.046

0.035

N11 - H20

ζ

1.984

1.982

C12 - O18

ζ*

0.013

0.016

4.6

4.19

1.89

1.36

0.083

0.067

C12 - C13

ζ

1.984

1.982

C6 - N11

ζ*

0.027

0.035

6.04

5.1

1.55

1.05

0.087

0.066

C12 - C13

ζ

1.984

1.982

C13 - H14

ζ*

0.007

0.008

1.74

1.74

1.68

1.22

0.048

0.041

C12 - C13

ζ

1.984

1.982

C13 - H15

ζ*

0.005

0.007

1.37

1.58

1.67

1.21

0.043

0.039

C12 - C13

ζ

1.984

1.982

C13 - H16

ζ*

0.006

0.008

1.58

1.62

1.69

1.23

0.046

0.04

C12 - O18

ζ

1.995

1.995

N11 - H20

ζ*

0.01

0.013

1.41

1.18

2.33

1.73

0.051

0.04

C12 - O18

π

1.993

1.990

C13 - H14

ζ*

0.007

0.009

1.24

1.18

1.34

0.95

0.036

0.03

C13 - H14

ζ

1.978

1.972

C12 - C13

ζ*

0.041

0.055

1.05

1

1.43

0.97

0.035

0.028

C13 - H14

ζ

1.978

1.972

C12 - O18

π*

0.228

0.292

6.92

5.02

0.97

0.59

0.077

0.052

C13 - H14

ζ

1.978

1.972

C13 - H15

ζ*

0.005

0.007

1.95

1.86

1.59

1.14

0.05

0.041

C13 - H14

ζ

1.978

1.972

C13 - H16

ζ*

0.006

0.008

2.41

2.2

1.6

1.16

0.056

0.045

C13 - H15

ζ

1.988

1.985

C12 - O18

ζ*

0.013

0.016

5.14

4.52

1.68

1.18

0.083

0.065

C13 - H15

ζ

1.988

1.985

C13 - H14

ζ*

0.007

0.009

1.98

1.93

1.6

1.16

0.05

0.042

C13 - H15

ζ

1.988

1.985

C13 - H16

ζ*

0.006

0.008

2.01

1.97

1.61

1.17

0.051

0.043

C13 - H16

ζ

1.988

1.979

N11 - C12

ζ*

0.056

0.07

2.85

2.4

1.56

1.08

0.06

0.046

C13 - H16

ζ

1.983

1.979

C12 - C13

ζ*

0.041

0.055

1.12

1.11

1.42

0.97

0.036

0.029

C13 - H16

ζ

1.983

1.979

C12 - O18

π*

0.228

0.292

3.22

2.31

0.97

0.58

0.053

0.035

25

C13 - H16

ζ

1.983

1.979

C13 - H14

ζ*

0.007

0.009

2.49

2.29

1.59

1.15

0.056

0.046

C13 - H16

ζ

1.983

1.979

C13 - H15

ζ*

0.005

0.007

2.12

2.07

1.58

1.14

0.052

0.043

O17 - H19

ζ

1.99

1.989

C1 - C2

ζ*

0.022

0.025

4.38

3.53

1.93

1.41

0.082

0.063

N 11

LP

1.737

1.673

C6 - C7

ζ*

0.019

0.022

1.02

26.57

1.27

0.3

0.034

0.082

N 11

LP

1.737

1.673

C12 - O18

π*

0.228

0.292

31.01

65.69

0.56

0.3

0.122

0.126

O 17

LP

1.982

1.977

C1 - C9

π*

0.369

0.397

94.55

6.27

0.6

1.17

0.214

0.077

O 17

LP

1.982

1.977

C1 - C9

ζ*

0.024

0.028

7.92

25.5

1.69

0.36

0.103

0.093

O 18

LP

1.981

1.879

N11 - C12

ζ*

0.056

0.07

1.51

1.31

1.73

1.19

0.046

0.036

O 18

LP

1.981

1.879

C12 - C13

ζ*

0.041

0.055

2.01

1.64

1.59

1.08

0.051

0.038

O 18

LP

1.907

1.981

N11 - C12

ζ*

0.056

0.07

30.21

23.33

1.22

0.76

0.173

0.12

O 18

LP

1.907

1.981

C12 - C13

ζ*

0.041

0.055

23.06

18.59

1.08

0.64

0.143

0.099

C1 - C9

π*

0.369

0.397

C2 - C4

π*

0.324

0.327

519.42

251.63

0.01

0.01

0.128

0.085

C6 - C7

π*

0.382

0.403

C2 - C4

π*

0.324

0.327

411.21

273.95

0.02

0.01

0.13

0.085

C12 - O18 π* 0.228 0.292 C13 - H14 ζ* 0.007 a E(2) means energy of hyperconjugative interactions b Energy difference between donor and acceptor i and j NBO orbitals c F(i,j) is the Fock matrix element between i and j NBO orbitals

0.009

1.51

1.28

0.62

0.57

0.08

0.062

26

Table 5. Calculated energy values of PAR molecule HF/ 6-311++G(d,p)

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

ELUMO

0.053

-0.025

EHOMO

-0.300

-0.218

Δ(ELUMO - EHOMO)

0.406

0.193

Chemical Softness (S)

2.173

4.115

Chemical Hardness (η)

0.230

0.122

Electronegativity (χ)

0.124

0.097

Chemical Potential (μ)

-0.124

-0.097

Electrophilicity Index

0.033

0.039

Parameters (au)

Table 6. The calculated thermodynamical parameters of PAR molecule Calculated Value Thermodynamic Parameter

HF/6311++G(d,p)

B3LYP/6311++G(d,p)

Total thermal energy (Kcal/Mol)

112.611

105.96

Vibrational energy (Kcal/Mol)

110.834

104.182

Zero Point vibrational energy (Kcal/Mol)

106.247

99.350

Heat capacity Cv (Cal/Mol-Kelvin)

36.670

39.110

Entropy S (Cal/Mol-Kelvin)

103.280

102.200

27

Fig. 1. The molecular structure of the PAR with the numbering scheme for the atoms and 50% probability displacement ellipsoids (a), Optimized molecular geometry and Atomic numbering scheme by (b) HF and B3LYP (c) levels

28

Fig. 2. Molecular aggregation formed through PAR ring and chain motifs. Hydrogen bonds are shown dashed lines.

29

Fig. 3. Packing diagram of the molecules viewed down the b-axis showing alternate hydrophilic and hydrophobic regions at z = 1/4 or 3/4 and z = 0 or 1/2 respectively. H bonds are drawn as dashed lines

Fig. 4. The atomic charges optimized molecular structure of the PAR using with by (a) HF and (b) B3LYP levels

30

Fig. 5. Experimental and theoretical FT-IR spectra for PAR

31

Fig. 6. Experimental and theoretical Raman spectra for PAR

32

Fig. 7. Energy level diagram of molecular orbits of PAR by (a) HF and (b) B3LYP levels

33

HIGHLIGHTS

 PAR was crystallized by the slow evaporation method.  The single crystal X-ray studies shows that the drug crystallized in the monoclinic system  The complete spectroscopic analysis of PAR has been carried out.  Natural bond orbital (NBO), HOMO/LUMO and Thermodynamical properties were analyzed.

Single crystal XRD, vibrational and quantum chemical calculation of pharmaceutical drug paracetamol: A new synthesis form.

The common house hold pharmaceutical drug, paracetamol (PAR), has been synthesized from 4-chloroaniline as a first ever report. After the synthesis, g...
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