Structural and vibrational study of primidone based on ...

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Structural and vibrational study of primidone based on monomer and dimer calculations a

b

b

Sefa Celik , Serda Kecel-Gunduz , Aysen E. Ozel & Sevim Akyuz

c

a

Engineering Faculty, Electrical-Electronics Engineering Department, Istanbul University, Avcilar 34320, Istanbul, Turkey b

Science Faculty, Physics Department, Istanbul University, Vezneciler 34134, Istanbul, Turkey c

Science and Letters Faculty, Physics Department, Istanbul Kultur University, Atakoy Campus, Bakirkoy 34156, Istanbul, Turkey Accepted author version posted online: 09 Apr 2014.Published online: 07 May 2014.

Click for updates To cite this article: Sefa Celik, Serda Kecel-Gunduz, Aysen E. Ozel & Sevim Akyuz (2015) Structural and vibrational study of primidone based on monomer and dimer calculations, Journal of Biomolecular Structure and Dynamics, 33:4, 911-923, DOI: 10.1080/07391102.2014.913505 To link to this article: http://dx.doi.org/10.1080/07391102.2014.913505

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Journal of Biomolecular Structure and Dynamics, 2015 Vol. 33, No. 4, 911–923, http://dx.doi.org/10.1080/07391102.2014.913505

Structural and vibrational study of primidone based on monomer and dimer calculations Sefa Celika*, Serda Kecel-Gunduzb, Aysen E. Ozelb and Sevim Akyuzc a

Engineering Faculty, Electrical-Electronics Engineering Department, Istanbul University, Avcilar 34320, Istanbul, Turkey; Science Faculty, Physics Department, Istanbul University, Vezneciler 34134, Istanbul, Turkey; cScience and Letters Faculty, Physics Department, Istanbul Kultur University, Atakoy Campus, Bakirkoy 34156, Istanbul, Turkey b

Downloaded by [Istanbul Universitesi Kutuphane ve Dok] at 23:44 24 February 2015

Communicated by Ramaswamy H. Sarma (Received 16 December 2013; accepted 6 April 2014) Primidone (Mysoline), with the chemical formula 5-ethyl-5-phenyl-hexahydropyrimidine- 4,6-dione (C12H14N2O2), has been a valuable drug in the treatment of epilepsy. In the present work, the experimental IR and Raman spectra of solid phase primidone were recorded, and the results were compared with theoretical wavenumber values of monomer and dimer forms of the title molecule. Vibrational spectral simulations in the dimer form were carried out to improve the assignment of the bands in the solid phase experimental spectra. The possible stable conformers of free molecule were searched by means of torsion potential energy surfaces scan studies through two dihedral angles. The molecular geometries of the monomer and dimer forms of title molecule were optimized using DFT method at B3LYP/6-31++G(d,p) level of theory. Using PEDs determined the contributions of internal (stretching, bending, etc.) coordinates to each normal mode of vibration. Further, HOMO–LUMO energy gap and NBO properties of the investigated molecule in monomer and dimer forms were also calculated. Keywords: primidone; DFT; BSSE; NBO; IR; Raman spectra

1. Introduction Primidone or 2-desoxyphenobarbital (5-ethyl-5-phenylhexahydropyrimidine- 4,6-dione) is an active anticonvulsant that works in the brain tissue to stop seizures (Katzung, 1989). It is used as a drug in the treatment of epilepsy. Primidone, either alone or used concomitantly with other anticonvulsants, is indicated in the control of grand mal, psychomotor and focal epileptic seizures Brodie & Dichter, 1996; Katzung, 1989). Essential tremor is one of the most common movement disorders in the world. Primidone is considered an effective agent that treats essential tremor (Zesiewicz et al., 2013). Primidone occurs in two polymorphic forms; form A and B (Payne, Roberts, Rowe, & Docherty, 1999). The crystal structure of form A is monoclinic, (has P21/c space group, with four molecules per unit cell, Schönflies notation of the point group is C2h) (Yeates & Palmer, 1975), and the crystal structure of form B is orthorhombic (has Pbca space group, with eight molecules per unit cell, Schönflies notation of the point group is D2h) (Payne, Roberts, Rowe, McPartlin, & Bashal, 1996). The packing motifs are different in the two forms, due to the difference in crystal structure; form A takes on a rhombic shape, whilst form B grows as plates. Form A has two types of hydrogen bonds: One creating dimers and the other linking those dimers into sheets of *Corresponding author. Email: [email protected] © 2014 Taylor & Francis

molecules. Form B has one type of hydrogen bondforming sheets (Yeates & Palmer, 1975). Recently, Paulraj, Muthu and Arjunan et al. calculated the harmonic vibrational wavenumbers for the optimized geometry of primidone, using HF and DFT/ B3LYP method with the 6-31G(d,p) basis set (Paulraj & Muthu, 2013) and, DFT/ B3LYP method with 6-31G(d,p), 6-311++G(d,p), cc-pVTZ and LanL2dz basis sets (Arjunan, Santhanam, Subramanian, & Mohan, 2013), respectively. In these previous studies, conformational analysis of primidone was not performed, just optimized geometry was used, although Primidone has a number of rotatable bonds, particularly dihedral angle ω (8C, 7C, 5C, 4C) adopts a significantly different value in A and B forms: In Primidone A, ω is 27.4°, whilst in primidone B it is 68.4° (Payne et al., 1999). On the other hand, up till now, no study has been reported on the dimer forms of primidone. Considering the biological activity of the title molecule it was found to be important to calculate the low energy conformers depending on the conformational analysis. It is well known that vibrational wavenumbers are strongly dependent on the conformational changes, for this reason, vibrational behaviour of the lowest energy conformer of primidone monomer was investigated. In this study, in addition to an isolated molecule, dimer models have also been studied to have an explicit


912

S. Celik et al.

approximation to the intermolecular interactions present in the crystal. In the present work, the possible stable conformers of free molecule were searched by means of torsion potential energy surface (PES) scan studies through two dihedral angles; ω (8C, 7C, 5C and 4C) and ϕ (14C, 13C, 5C and 4C) were varied from 0° to 360° by steps of 10°. The vibrational modes and wavenumbers of the most stable conformer were calculated. Afterwards, possible dimer forms were formed and three dimers with low energy were obtained resulting from the optimization process. The counterpoise (CP) method of Boys and Bernardi (1970) for correction of the basis set superposition error (BSSE) has been included in the calculations of dimer forms to take into account the BSSE effects on structure during geometry optimization. The purpose of this work is to obtain the most stable conformation of primidone and investigate the effects of intermolecular hydrogen bonding on the molecular stability and on vibrational properties.

2. Experimental and computational methods 2.1. Experimental part The compound primidone was purchased from SigmaAldrich Chemical Company with a stated purity of greater than 98% was received and was used without further purification. The FT-IR spectrum was recorded on a Jasco 300E FT-IR spectrometer (2 cm−1 resolution) in the range of 4000–400 cm−1 using the KBr pellet technique. The micro-Raman spectra were recorded using a micro-Raman Jasco NRS-3100 spectrometer (1200 lines/ mm grating and high sensitivity cooled CCD). A 532 nm Line of the diode lasers were used as the excitation wavelength in the region of 4000–50 cm−1. The spectral resolution was 3.9 cm−1. Baseline corrections and band-fitting procedures were performed using GRAMS/AI 7.02 (Thermo Electron Corporation) software package. Band fitted were done using Gaussian spectral functions and fitting was undertaken until reproducible and converged results were obtained with squared correlations better than r2 ~ .9999. The second derivative profile gives valuable information about the position of the bands and band widths. Thus for the band-fitting procedure (to locate the position of the peaks), the second derivative of the absorption spectrum was used as a guide. The second derivatives of the spectra were obtained using Savitzky–Golay function (two polynomial degrees, 17 points).

2.2. Computational part The conformational and vibrational calculations were carried out with Gaussian03© program suite (Frisch

et al., 2004) using the DFT method (Becke, 1993) at B3LYP/6-31++G(d,p) level of theory. The force fields in Cartesian coordinates were transformed to ‘natural’ internal coordinates using the MOLVIB programme (Sundius, 1990, 2002). The harmonic force field for primidone molecule was evaluated at the B3LYP/6-31++G(d,p) level with the scaled quantum mechanical force field procedure (Pulay, Fogarasi, Pongor, Boggs, & Vargha, 1983). The scale factors used are as follows: N–H stretch C–H stretch N–H and C–H deformation C=O stretch N–H stretch (involving Hbonds) All others

.84 Monomeric and forms .91 Monomeric and forms .92 Monomeric and forms .91 Monomeric and forms .98 Dimeric form

dimeric dimeric dimeric dimeric

.98 Monomeric and dimeric forms

The IR intensities, Raman activities and the potential energy distributions (PED) were computed using the MOLVIB programme (Sundius, 1990, 2002). The Raman activities calculated by Gaussian and adjusted during scaling procedure with MOLVIB were converted to relative Raman intensity using the Simirra Simulation program (Istvan, 2002). For the plots of simulated IR and Raman spectra, pure Lorentzian band shapes were used with a bandwidth (FWHM) of 10 cm−1 (Keresztury et al., 1993; Michalska & Wysokinski, 2005).

3. Result and discussion 3.1. Conformational stability The structure of the molecule, with numbering scheme for the atoms and torsion angles, is presented in Figure. 1. In order to reveal all possible conformations of primidone, a rigid PES scan for the two dihedral angles; ω (8C, 7C, 5C and 4C) and ϕ (14C, 13C, 5C and 4C), was performed. The initial input geometrical data of primidone are taken from the X-ray study given by DGR Yeates and RA Palmer. PES scan studies have been carried out by DFT calculations with 6-31G(d,p) basis set. During the calculations, all the geometrical parameters were simultaneously fixed while two dihedral angles ω (8C, 7C, 5C and 4C) and ϕ (14C, 13C, 5C and 4C) were varied from 0° to 360° by steps of 10°. The shape of the potential energy, as functions of the two dihedral angles, is illustrated in Figure. 2. The most stable conformer is obtained with the energy –725.70714 a.u. (–19747.506 eV), and with the torsion angles ω and ϕ; 29.7° and 61.58°, respectively. The dihedral angles and energies, obtained by PES scan studies at DFT/ 6-31G(d,p) level,


Structural and vibrational study of primidone based on monomer and dimer calculations

Figure 1. The molecular structure of conformation with global minimum of energy, with flexible dihedral angle definitions.

Figure 2.

913

of the 12 conformers with low energy are given in Figure 3. The computational processes were then followed by the geometry optimization carried out by DFT/ B3LYP/6-31++G(d,p) level of theory, and the energy of the most stable conformer and dihedral angles (ω; ϕ) are found to be –725.7358 a.u. (–19748.286 eV) and 31.54° (ω) and 61.17° (ϕ), respectively. From the crystallographic results on form A of primidone (Yeates & Palmer, 1975), the dihedral angles were found to be 27° (ω) and 60° (ϕ). Thus, the obtained dihedral angles for the most stable conformer of primidone are comparable with crystallographic results for primidone form A. In the previous calculations on primidone (Arjunan et al., 2013; Paulraj & Muthu, 2013) only optimized bond lengths and angles were given. Nevertheless, the examination of the optimized molecule schemes of primidone molecule in both papers indicates that the relative orientation of the methyl group with respect to the benzene ring is different in our study than those of previous studies (Arjunan et al., 2013; Paulraj & Muthu, 2013) as seen in Figure S1 (see in Supplementary Material). Furthermore energetically preferred conformations of dimers were investigated by DFT/B3LYP/6-31++G(d,p) level of theory calculations. The geometrical structures of three conformers with low energy of dimer forms of

PES scan studies for the 1296 energy conformers of primidone.


914

Figure 3.

S. Celik et al.

Twelve conformations with lowest energy determined by the 6-31G(d,p) calculation.

the primidone are given in Figure 4. The structural parameters of the most stable primidone, in monomer and dimer forms are presented in Table 1. Crystal data on primidone form A (Yeates & Palmer, 1975) and a related molecule phenobarbital (C12H12O3N2) (Platteau et al., 2005) are included for comparison. Comparison of the computed bond lengths at B3LYP/6-31++G(d,p) method with those of experimental bond lengths (Yeates & Palmer, 1975) indicates that the computed bond lengths are slightly longer. The small difference between the computed and experimental data is due to the fact that calculation belongs to gaseous phase while an experimental result belongs to solid phase. However, rather big deviations obtained between experimental and theoretical values of CH and NH bond lengths are probably due to the experimental error in determining the positions of hydrogen atoms by X-ray diffraction in 1975 (Yeates & Palmer, 1975). The NH (N3–H20) and CO (C4–O15) bonds, which are involved in intermolecular H-bonding, are affected in dimer formation. The other

two NH (N1–H17) and CO (C6–O19) bonds, that do not involve intermolecular H-bonding, thus, are not affected by the dimerization. The geometric parameters altered by the dimerization are marked in bold in Table 1. The new bond lengths, formed in the dimeric structure, are also presented in Table 1.

3.2. BSSE-corrected calculations An accurate determination of interaction energies in hydrogen-bonded complexes such as a dimeric structure is not an easy task. Using finite basis sets lead to the well-known BSSE in quantum chemical calculations (Boys & Bernardi, 1970). It is known that the BSSE effect is rather significant on the structure and energy of dimer form. Thus, BSSE correction is necessary in order to provide a convergence to the uncorrected result at the complete 6-31++G(d,p) basis set. The calculated energies of monomer form and dimers (I–II–III) of primidone and



915

Figure 4. The geometrical structures of three low energy conformers (I–III) of dimeric forms of the primidone, predicted by the DFT calculations.

the interaction energy of primidone dimers are presented in Table 2. The interaction energies (ΔE) of the dimers are computed as the difference between the calculated total energy of the dimer and the energies of the two isolated monomers {ΔE = Edimer – 2 * Emonomer}. The interaction energies of primidone dimers are changed properly, after BSSE correction via the standard CP method (Boys & Bernardi, 1970). The BSSE values of the three low-energy dimers (I–III) are .76, .75 and .78 kcal/mol, respectively, and the BSSE/ΔEuncorrected ratios are 5.00, 4.99 and 5.14%, respectively. These results indicate that BSSE is large and should be considered in calculations of the interaction energies. Dimer I is the most stable, due to its strong interaction energy and lower relative energy.

3.3. IR and Raman spectra Although the experimental and calculated vibrational spectra of primidone have been reported previously Arjunan et al., 2013; Paulraj & Muthu, 2013), some spectral assignments were in doubt and needed to be clarified. On the other hand, the most stable primidone conformer obtained by PES scan for two dihedral angles; ω (8C, 7C, 5C and 4C) and ϕ (14C, 13C, 5C and 4C), has different conformations than those of previous studies. Since it is well known that the simulated vibrational spectrum depends crucially on the molecular conformation, an extensive experimental and theoretical vibrational study is undertaken in order to obtain complete, reliable and accurate vibrational assignments of the title molecule.

1.450 1.367 1.011 1.450 1.093 1.101 1.368 1.011 1.550 1.225 1.550 1.552 1.553 1.225 1.404 1.405 1.397 1.086 1.397 1.086 1.397 1.086 1.397 1.086 1.086 1.534 1.094 1.094 1.094 1.094 1.095

Mono

1.451 1.364 1.012 1.449 1.092 1.101 1.348 1.031 1.546 1.242 1.551 1.552 1.553 1.226 1.404 1.404 1.397 1.085 1.396 1.086 1.397 1.086 1.397 1.086 1.085 1.533 1.094 1.093 1.094 1.093 1.096 1.829

Dimer-I

This study

1.441 1.329 .84 1.441 .98 1.00 1.329 .85 1.543 1.230 1.540 1.533 1.540 1.223 1.387 1.390 1.393 .97 1.359 .99 1.361 .99 1.392 .94 1.02 1.532 .96 1.00 1.00 1.02 .97

[1]

1.393

1.393

1.393

1.528 1.221 1.528 1.547 1.547 1.221 1.393 1.393 1.393

1.372

1.372

[2] R(20,48) R(47,55) A(2,1,6) A(2,1,17) A(6,1,17) A(1,2,3) A(1,2,18) A(1,2,19) A(3,2,18) A(3,2,19) A(18,2,19) A(2,3,4) A(2,3,20) A(4,3,20) A(3,4,5) A(3,4,15) A(5,4,15) A(4,5,6) A(4,5,7) A(4,5,13) A(6,5,7) A(6,5,13) A(7,5,13) A(1,6,5) A(1,6,16) A(5,6,16) A(5,7,8) A(5,7,12) A(7,8,21) A(9,8,21) A(8,9,22) A(10,9,22)

Bonding/structural parameters

123.04 119.99 116.43 108.87 108.87 110.85 108.87 110.86 108.48 123.05 119.98 116.42 115.37 121.72 122.90 111.02 108.27 110.12 108.22 110.11 109.05 115.37 121.72 122.90 120.77 120.67 119.99 119.29 119.40 120.19

Mono 1.829 1.031 122.98 119.96 116.43 109.49 109.00 110.86 108.48 110.54 108.42 122.47 119.24 118.16 116.63 122.01 121.34 110.54 108.52 110.59 108.12 109.98 109.02 115.26 122.01 122.72 120.99 120.48 120.06 119.19 119.42 120.20

Dimer-I

This study

122.10 116.00 122.00 110.00 107.00 112.00 112.00 110.00 107.00 121.8 117.00 121.00 116.00 122.90 121.00 108.80 108.40 111.70 109.00 111.00 107.80 115.80 122.20 122.00 119.80 119.80 117.00 123.00 115.00 125.00

[1]

120.4 120.4

118.5

109.5 107.7

111.6

118.5

125.4

115.9

125.4

[2] A(8,7,12) A(7,8,9) A(8,9,10) A(9,10,11) A(9,10,23) A(11,10,23) A(10,11,12) A(10,11,24) A(12,11,24) A(7,12,11) A(7,12,25) A(11,12,25) A(5,13,14) A(5,13,26) A(5,13,27) A(14,13,26) A(14,13,27) A(26,13,27) A(13,14,28) A(13,14,29) A(13,14,30) A(28,14,29) A(28,14,30) A(29,14,30) D(C2-N1-C6-C5) D(N1-C6-C5-C4) D(C6-C5-C4-N3) D(C2-N3-C4-C5) D(C4-N3-C2-N1) D(C6-N1-C2-N3)

Bonding angles 118.45 120.71 120.41 119.31 120.34 120.35 120.40 120.19 119.41 120.72 119.94 119.33 115.66 106.87 106.86 109.74 109.76 107.62 111.45 111.47 109.46 109.26 107.52 107.53 3.73 33.82 −33.76 −3.84 40.40 −40.33

Mono

118.45 120.75 120.37 119.31 120.34 120.35 120.41 120.18 119.40 120.71 119.88 119.41 115.73 106.96 106.77 109.88 109.59 107.58 111.56 111.37 109.49 109.19 107.55 107.53 4.28 33.07 −34.77 −1.47 38.41 −40.04

Dimer-I

This study

118.30 120.10 121.00 119.50 122.00 118.00 121.00 122.00 118.00 120.10 116.00 124.00 114.80 107.00 107.00 111.00 107.00 111.00 111.00 107.00 109.00 110.00 107.00 112.00

[1]

113.7

119.7

119.7

119.7 119.7 119.7

[2]

The optimized (DFT/6-31G++(d,p) level) bond lengths (R/Å ), angles (A/°), and dihedral angles (D/°) with experimental X-ray data from literature [1] and related data

a For atomic numbers refer to Figure 1 (for monomer) and Figure 4 (for dimer). Yeates and Palmer (1975). Platteau et al. (2005).

R(1,2) R(1,6) R(1,17) R(2,3) R(2,18) R(2,19) R(3,4) R(3,20) R(4,5) R(4,15) R(5,6) R(5,7) R(5,13) R(6,16) R(7,8) R(7,12) R(8,9) R(8,21) R(9,10) R(9,22) R(10,11) R(10,23) R(11,12) R(11,24) R(12,25) R(13,14) R(13,26) R(13,27) R(14,28) R(14,29) R(14,30) R(15,55)

Bonds

Table 1. [2]a.


916 S. Celik et al.


917

Table 2. The calculated energies of monomeric, dimeric (I-II-III) forms of primidone and the interaction energy (kcal/mol) of primidone dimers at DFT-RB3LYP /6-31++G(d,p) level of theory. The interaction energy (ΔE) of primidone dimers

Energies of most stable monomer and dimers


Monomer Dimer I Dimer II Dimer III

Hartree

kcal/mol

Relative energy of dimers (kcal/mol)

BSSE uncorrected ΔE (kcal/mol)

BSSE Corrected ΔE (kcal/mol)

BSSE (kcal/mol)

−725.73583952 −1451.49606264 −1451.49589192 −1451.49588630

−455401.4165063 −910818.1337948 −910818.0266675 −910818.0231409

0 .1071273 .1106539

−15.301 −15.194 −15.190

−14.519 −14.419 −14.393

.766 .759 .782

The optimized structural parameters were used to compute the vibrational frequencies of the stable conformer of primidone in monomeric and dimeric structures at the DFT (B3LYP)/6-311++G(d,p) level of calculations. The detailed vibrational assignment of the experimental wavenumbers is based on normal mode analyses and a comparison with theoretically scaled wavenumbers. The results of energy calculations show that the energy of free primidone molecule at C1 symmetry is lower than that of Cs symmetry. Thus, due to the low symmetry of the molecule (C1), several internal coordinates contribute to each of the normal modes. The observed and scaled theoretical frequencies, IR and Raman intensities are listed in Table 3. Since primidone crystal, in form A, has P21/c space group that corresponds to C2h point group, and 4 molecules are present per unit cell, the factor group analysis indicates that all the vibrational modes should split into four, but due to centrosymmetric structure (C2h), two should be IR, and the other two should be Raman active. As seen in Table 3 we did not observe coincidences in IR and Raman active modes of experimental vibrational spectra of primidone in solid phase. The experimental IR and Raman spectra of primidone in solid phase in the 4000–2750 cm−1, 1800–200 cm−1(Ra) or 1800–400 (IR) cm−1 regions are presented in Figures 5 and 6, respectively. The simulated IR and Raman spectra of monomer form of primidone in the corresponding spectral regions are given in Figures S2– S5. There are two NH bonds in the primidone monomer (N1–H17 and N3–H20), only one (N3–H20) is involved in intermolecular H-bonding for dimer formation. In form A of primidone crystal, however, both are involved in intermolecular H-bonding interaction, but in different strengths. In the experimental vibrational spectra, we expect to observe eight ν(N–H) stretching modes, due to factor group splitting; four of them IR and the other four should be Raman active. The strong and broad IR band observed at 3206 cm−1 and the medium band at 3099 cm−1 are assigned to IR active and the weak Raman bands at 3189 cm−1 and 3152 cm−1 are assigned to Raman active components of NH stretching vibrations of primidone. We do not observe further splitting but observe broadening in the IR and Raman active

vibrations in the experimental vibrational spectra of primidone. The DFT calculations give these modes at 3326 and 3325 cm−1 for monomer, and 3325 cm−1 (for non-hydrogen bonded NH pairs) and 3253 and 3207 cm−1 (for intermolecular hydrogen-bonded NH pairs, out of phase and in phase components, respectively) for dimer forms. The formation of two H-bonds between N3–H20…O48 and N47–H55 O15 bonds leads to an increase in electron density in the N–H antibonding orbitals and a decrease in N–H wavenumbers. Upon dimerization, the frequency shifts with respect to the corresponding monomeric frequencies are largely different, while the modes involving atoms participating in intermolecular H-bonding exhibit significant shifts (modes ν2, ν16, ν22, ν29, ν35, etc.), the others are shifted less than 5 cm−1. The largest dimeric effect is found for in-phase component of ν2, NH stretching vibration, which exhibits a downshift by 118 cm−1 upon the dimer formation (Δ = νNHmonomer – νNHdimer = 3325–3207 = 118 cm−1) as seen in Table 3. Primidone has two C=O bonds, thus has two C=O stretching modes in the monomer form. In form A, four molecules are present in the unit cell of primidone crystal and due to factor group splitting, out of eight C=O stretching modes, four IR and four non-coincident Raman bands are expected in the 1850–1600 cm−1 region of the spectra. But Paulraj and Muthu assigned two C=O stretching modes of primidone amazingly wrong; the 2944 and 2885 cm−1 bands observed in the IR and Raman spectra of solid primidone were assigned to C=O stretching modes, although they observed three strong bands around 1700–1650 cm−1 in the reported experimental IR spectrum (Paulraj & Muthu, 2013). On the other hand, Arjunan et al. (Arjunan et al., 2013) observed only one strong band at 1662 cm−1 in the IR spectrum of solid primidone and assigned it to one of the C=O stretching modes. The calculated scaled wavenumbers were 1661 and 1637 cm−1 (Arjunan et al., 2013). In the experimental IR spectrum of primidone, we clearly observed factor group splitting in C=O stretching vibrations and observed four bands at 1712, 1695, 1668 and 1653 cm−1. We revealed the four Raman active components of the C=O stretching modes by band component analysis. The band component analysis of

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47

υ(NH) υ(NH) υ(CH)phenyl υ(CH)phenyl υ(CH)phenyl υ(CH)phenyl υ(CH)phenyl υa(CH3) υa(CH2) υa(CH3) υa(CH2)cyclo υs(CH2) υs(CH3) υs(CH2)cyclo υ(CO) υ(CO) υ(CC)phenyl υ(CC)phenyl δ(CCH)phenyl δ(CH2)cyclo δ(CH3) δ(CNH)+ υ(CN) δ(CH3) δCCH+υCC(phe) w(CH2)cyclo δ(CH2) w(CH3) δCNH(cyclo) δCNH(cyclo) υCC(phenyl) wag(CH2) δCCH(phenyl) twist(CH2) twist(CH2)cyclo υCN(cyclo) δCCH(phenyl) υCC(phe-cyclo) δCCH(phenyl) δCCH+ twist(CH3) υCC(cyclo-CH2) υCN(cyclo) υCC(phenyl) rCH2(cyclo) νCC(CH2-CH3) υCC(phenyl) δCCC(phenyl) ΓCCCH 2999 2989 2970 2940 2926 2884 2853 1701; 1675 1660; 1619 1601 1582 1488 1469 1451 1441 1429 1408 1378 1342

1282 1198 1185 1160 1151 1102 1082 1038 1003

1458 1445

1438 1402 1374

1339

1315 1307 1277

1191 1182 1156 1149

1120 1100

1079

1034 1008 1000

3189 3152 3061 3057 3053

Raman νexp

2988 2974 2943 2930 2885 2859 1712; 1695 1668; 1653 1596 1579 1490 1464

3061

3206 3099

IR νexp

Solid phase Primidone

1008 975

1070

1310

1445

1600 1506

3015

3050

3070

IR νexp

1005

1075

1185

1209

1317

1355

1455

1605 1588 1505

3045 3015

3078 3060

Raman νexp

Phe. [1,2]

1184

1389

1774 1741

3485 3435

IR νexp

1167

1373

1810 1784

3490 3449

anh. νanh

Uracil[3,4,5]

3332 3332 3062 3065 3054 3042 3033 3003 2979 2980 2959 2937 2916 2851 1730 1700 1630 1609 1492 1480 1464 1456 1458 1450 1438 1420 1365 1341 1347 1334 1315 1311 1279 1248 1232 1183 1174 1147 1139 1134 1098 1088 1086 1075 1044 1006 995

Vcal

43 40 7 13 16 15 0 18 2 26 29 11 33 55 340 259 8 3 19 19 7 195 8 4 29 5 8 14 97 0 12 4 0 1 8 4 1 0 4 11 34 6 7 5 8 1 0

Iint 83 80 85 100 55 55 33 10 55 54 57 27 54 42 8 6 31 8 4 19 26 28 32 12 6 13 5 11 10 4 5 4 4 13 10 18 20 11 9 12 9 14 15 15 33 46 10

Rint

6-31G(d,p)

3326 3325 3062 3058 3052 3041 3032 2994 2971 2970 2964 2932 2909 2856 1707 1675 1619 1600 1484 1472 1453 1451 1448 1442 1432 1414 1359 1344 1341 1331 1310 1308 1274 1248 1231 1180 1169 1144 1134 1128 1097 1084 1082 1070 1038 1004 997

Vcal

49 42 15 7 10 11 0 18 0 28 23 12 40 47 364 337 10 2 17 19 52 128 11 4 26 6 10 105 12 0 11 3 1 1 13 3 1 0 5 12 32 7 6 3 10 1 0

Iint 73 74 100 73 47 50 28 9 62 66 64 28 65 40 11 7 32 10 3 12 13 14 14 7 3 9 3 11 10 3 4 4 2 7 5 11 20 8 8 14 6 9 10 17 43 56 22

Rint

6-31++G(d,p)

Monomer

DFT/B3LYP

3325; 3325 3253; 3207 3064; 3064 3060; 3060 3054; 3054 3042; 3042 3034; 3033 2995; 2995 2973; 2973 2969; 2969 2972; 2972 2933; 2933 2909; 2909 2861; 2860 1702; 1692 1662; 1643 1619; 1619 1600; 1600 1484; 1484 1472; 1471 1453; 1453 1494; 1489 1447; 1447 1441; 1441 1435; 1434 1413; 1411 1356; 1356 1347; 1347 1428; 1420 1332; 1332 1313; 1312 1309; 1309 1278; 1278 1249; 1248 1261; 1261 1181; 1181 1169; 1169 1144; 1144 1143; 1141 1130; 1129 1108; 1107 1083; 1082 1087; 1087 1071; 1071 1037; 1037 999; 999 997; 997

Vcal

68; 19 2924; 0 0; 25 13; 4 0; 26 21; 1 0; 0 26; 18 0; 8 8; 48 26; 2 0; 24 79; 0 1; 80 649; 0 905; 0 3; 16 5; 1 0; 49 0; 52 0; 8 0; 76 0; 22 0; 6 127; 0 0; 39 0; 15 41; 0 0; 235 0; 0 0; 4 7; 0 0; 10 0; 50 5; 1 0; 5 4; 0 0; 0 19; 0 11; 0 50; 0 0; 14 0; 29 9; 0 0; 20 2; 0 0; 1

Iint

6-31++G(d,p)

Dimer

υNH(100) υNH(100) υCH(98) υCH(99) υCH(92) υCH(99) υCH(92) υCH(100) υCH(98) υCH(97) υCH(97) υCH(96) υCH(100) υCH(97) υCO(70) +δCCN(7)+ υCN(10) υCO(75) υCC(63)+ δCCC(10) υCC(70)+ δCCH(8)+ δCCC(10) δCCH(59)+ υCC(18) δHCH(94) δCCH(41)+δHCH(37) δCNH(26)+ υCN(21)+ δHCH(9)+ δCCH(8) δHCH(55)+ δCCH(43) υCC(30)+ δCCH(38)+ δCCC(6) δHCN(50)+ δCNH(12)+ υCN(18) δHCH(93) δHCH(78)+ υCC(9)+ δCCH(6) δCNH(28)+ δHCH(9)+ υCN(20)+ δNCO(8) δCNH(43)+ υCN(25)+ δNCH(17) υCC(72) δCCH(70)+ υCC(7) δCCH(50)+ υCC(19) δCCH(65) δHCN(83)+ υCN(12) υCN(51)+ δHCN(16) δCCH(78) υCC(39)+ δCCC(10) δCCH(81) δCCH(34)+ δHCH(11)+ δCCC(11)+ υCC(16) υCC(40)+ δCCN(13)+ δCCC(5) υCN(32)+ δHCN(20)+ δNCO(12) υCC(37)+ δCCH(34) δHCN(43)+ υCN(22) υCC(43)+ δHCH(9)+ δCCH(9)+ δNCH(7)+ δCCC(5) υCC(54)+ δCCC(9)+ δCCH(14) δCCC(61)+ υCC(12) ΓCCCH(80)+ ΓCCCC(15)

6-31++G(d,p)

MOLVIB PED% Primidone

Experimental (IR, Raman) and calculated and wavenumbes (cm−1), and the PED of the vibrational modes of the Primidone and the calculated wavenumbers of Dimer

Assignment

Table 3. I.


918 S. Celik et al.

ΓCCCH υCN(cyclo) ΓCCCH ΓCCCH υCC(cyclo) ΓCNCO ΓCCCH δCCN(cyclo) ΓCCCC rCH2(C-CH2) ΓCNCO ΓCCCC ΓCNCO υCC δCCC(phenyl) δCCC(phenyl) δNCO(cyclo) ΓCCCC δCCN(cyclo) ΓCCCC ΓCCNH ΓCCNH ΓCCCC δNCO(cyclo) δCCC δCCC δCCC ΓCNCC ΓCNCC ΓCCCH δCCC δCCC ΓCNCC ΓCNCC δCCC ΓCNCC ΓCCCC 394

419 406

174 137 124

269 241 210

327

697 661 622 597 583 532 510 466

763 713

917 843 802

928

962

708 696 653 621 598 580 528 513 463

911 843 800 785 761

986 955 942 925

James, Ravikumar, Jayakumara, and Joe (2008). Castro, Ramirez, Arenas, and Otero (2005). Elkin, Erman, and Pulin (2006). Susi and Ard (1970). Colarusso, Zhang, Bujin, and Bernath (1997).

48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 692

910

487

624 600

815

914

970

391

385

667 560

513

516 662 551

533

719

748

803 752

536

718

757

804 763

979 982 954 930 928 911 863 795 770 748 722 712 709 652 626 591 582 540 504 467 443 427 413 380 327 315 291 250 206 209 180 142 125 96 96 62 29

0 14 6 3 1 18 0 7 18 8 13 21 0 7 0 58 1 25 6 49 91 8 0 11 3 4 1 3 5 2 2 0 0 1 0 8 0

10 12 12 7 8 13 10 11 9 2 5 6 5 44 15 12 8 7 5 11 11 18 6 14 10 31 10 20 61 50 30 83 41 213 207 1030 4600

983 980 950 926 924 910 857 792 766 746 718 709 706 650 625 587 581 538 500 463 441 425 410 378 325 313 288 252 209 202 180 139 124 105 95 61 20

0 12 5 3 1 16 0 7 25 7 10 36 0 5 0 50 1 28 7 37 103 9 0 10 3 3 2 4 4 2 2 0 0 1 1 9 0

8 9 6 11 10 9 1 10 1 1 4 2 2 47 11 10 6 3 6 7 6 8 3 10 10 34 8 13 46 23 24 67 29 57 130 659 4710

984; 984 990; 989 951; 951 929; 928 926; 926 914; 914 859; 858 792; 789 765; 765 747; 746 716; 715 707; 707 704; 701 653; 651 620; 620 597; 589 579; 578 535; 535 506; 495 461; 460 442; 440 – 410; 410 395; 390 335; 330 314; 313 291; 290 257; 254 211; 211 206; 203 194; 186 146; 139 128; 125 153; 134 99; 97 74; 57 20; 19

0; 0 25; 0 6; 0 0; 3 0; 5 22; 0 14; 0 38; 0 49; 2 0; 29 0; 13 0; 61 0; 9 12; 0 0; 0 20; 0 0; 38 0; 46 80; 0 13; 0 0; 161 – 0; 0 36; 0 0; 11 0; 7 0; 6 0; 6 4; 1 0; 8 0; 2 1; 0 0; 6 0; 1 0; 1 19; 0 0; 0

ΓCCCH(92)+ ΓCCCC(8) δHCN(20)+ υCN(21)+ υCC(8)+ δCCH(6)+ δHCH(6) υCC(17)+ ΓCCCH(27)+ δCCC(11) ΓCCCH(64)+ υCC(8) δCCH(25)+ δCCC(9)+ υCC(30)+ δHCH(8) ΓCNCO(14)+ ΓCNCC(8)+δCCH(8)+ δCCN(8)+ δNCH(9) ΓCCCH(100) δCCN(44)+ δCCC(11) ΓCCCH(35)+ ΓCCCC(45) δCCH(33)+ ΓCNCO(28)+ δHCH(6)+ δCCH(13)+ ΓCNCC(6) δCCC(21)+ ΓCNCO(30)+ υCC(15)+ ΓCNCC(9) ΓCCCC(67)+ ΓCCCH(30) ΓCNCO(46)+ ΓCCNC(10)+ δCCH(15)+ υCC(5) υCC(39)+ δCCC(14) δCCC(87) δCCC(48)+ ΓCNCO(10) δNCO(52)+ υCN(12) ΓCCCC(64)+ ΓCCCH(8) δCCN(56)+ ΓCCNH(14)+ δNCO(10) ΓCCCC(32)+ ΓCCNH(20)+ δCCC(18) ΓCCNH(46)+ δCCC(28) ΓCCNH(70)+ δCCN(19) ΓCCCC(82) δNCO(40)+ δCCC(17)+ υCC(22)+ δCCN(5) δCCC(57)+ δNCO(14)+ ΓCCCH(6) ΓCCCC(21)+ δCCC(30)+ υCC(14) δCCC(58)+ ΓCCCH(15)+ ΓCCCC(12) ΓCNCC(38)+ ΓCNCN(15)+ ΓCCCC(12)+ δCCC(7) ΓCNCC(29)+ ΓCNCN(19)+ ΓCCCC(11)+ δCCC(10)+ ΓCCNH(14) ΓCCCH(58)+ δCCC(28) ΓCNCC(20)+ ΓCCNH(25)+ δCCC(35) δCCC(35)+ ΓCCCC(23)+ ΓCCCH(9)+ ΓCCNH(14)+ ΓCNCO(5) ΓCNCC(32)+ ΓCCCC(24)+ δCCC(9)+ ΓCCNH(17)+ ΓCCCH(5) ΓCNCC(53)+ ΓCCNH(41) ΓCCCC(20)+ ΓCCNC(17)+ δCCC(36)+ ΓCCNH(6) ΓCNCC(41)+ ΓCNCN(26)+ ΓCCNH(16) ΓCCCC(64)+ δCCC(31)


Structural and vibrational study of primidone based on monomer and dimer calculations 919


920

S. Celik et al.

Figure 5. The Raman (a) and FT-IR (b) spectra of solid primidone in the region of 3500–2750 cm−1.

1710–1570 cm−1 region of the Raman spectrum of primidone, in comparison with the second derivative profile is given in Figure 7. Four bands are revealed at 1701, 1675, 1660 and 1619 cm−1 and are assigned to Raman active components of the C=O stretching vibrations. The calculated two C=O stretching modes of monomer form of primidone are 1707 (ν15) and 1675 cm−1 (ν16) (nonH-bonded C=O, out-of-phase and in-phase components, respectively). On going from monomer to dimeric structure, the formation of the intermolecular H-bonding CO…HN induced a downshift by 13 cm−1 {Δout-of-phase = 1675–1662} and 32 cm−1 {Δin-phase = 1675–1643} for the C=O stretching vibrational mode of out-of-phase and in-phase components, respectively. So increasing of electron density in σ*(C4–O15) and π*(C4–O15) characters can be confirmed again (Table S1). The simulated IR and Raman spectra are shown in Figures. S4 and S5, respectively. The band component analysis of

Figure 6. The Raman (a) and FT-IR (b) spectra of solid primidone in the region of 1800–200 cm−1.

1530–1370 cm−1 region of the Raman spectrum of solid Primidone is given in Figure 8. The 1451 and 1429 cm−1 bands are revealed from the band component analysis, which are not clearly observed in the original Raman spectrum and assigned to ν22 {δ(CNH)+ ν(CN)} and ν25 {CH2 wagging} modes. Dimerization leads to an increase in the wavenumbers of in-phase (i.p.) and out-of-phase (o.p.) components of both ν22{δ(CNH) + ν(CN)} {Δdimer-monomer = 38 (i.p.) and 43 (o.p.) cm−1} and ν81 {ΓCNCC}{Δdimer-monomer = 29 cm−1(i.p.) and 48 cm−1(o.p.)} modes, probably due to slight conformational alteration of the heterocyclic part. It



Figure 7.

The band component analysis of 1710–1570 cm−1 region of the Raman spectrum of solid primidone.

Figure 8.

Band component analysis of 1530–1370 cm−1 region of the Raman spectrum of solid primidone.

is important to note that the calculated structure of pyrimidine ring of dimeric form is only slightly closer to planar ring than in the monomer. The computed torsional angles (C2–N3–C4–C5) and (C4–N3–C2–N1) are shifted from – 3.84 and 40.40 to –1.47 and 38.41, respectively, by dimer formation (see Table 1). The increase of the frequency of the amide-II mode of diketopiperazine ring (mainly CN stretching) in dipeptides on going from boat conformation to planar form was reported by Mendham et al. (Mendham, Dines, Snowden, Withnall, & Chowdhry, 2009). In the experimental IR and Raman spectra of solid primidone, the CN stretching mode of the ring structure is assigned to 1458 cm−1 (IR) and 1451 cm−1 (Ra) bands, which are in accordance with the boat conformation

921

(Mendham et al., 2009). Thus, the increase in CN stretching and torsion vibrational wavenumbers on going from monomer to dimer form can be concluded as a result of going from near boat conformation to near-planar ring conformation. Ethyl group vibrations, aromatic C–C and C–H stretching modes are in the expected range and not strongly shifted with respect to the monomeric vibrations. The NCO (ν71) and CCC (ν78) in plane-bending vibrational modes are also affected by dimerization. The results of normal coordinate analysis are used to assign the NCO and CCC in plane-bending vibrations at 378 cm−1 (ν71) and 180 cm−1(ν78) for monomer and

922

S. Celik et al.

395–390 cm−1 and 194–186 cm−1 for dimer forms of primidone.


3.4. NBO analysis The importance of the NBO method stems from the fact that it gives information about the intra and intermolecular bonding and interactions among bonds and also it is a convenient method to understand rehybridization, electron density transfer or conjugative interactions in molecular system. NBO analysis has been performed for monomer and dimer forms of primidone using DFT/ B3LYP/6-31++G(d,p) level of theory. Due to formation of intermolecular hydrogen bonding between O15…H55 and O48…H20 atoms, the electron density of antibonding orbitals of N3–H20 and N47–H55 bonds increase; as a result, the corresponding bonds become weaker with an amount of elongation of about ~.02 Å and their stretching frequencies (ν2) decrease by 118 and 72 cm−1. On the other hand, the s character of N3–H20 hybrid orbitals increases (2.49%) from sp2.44 to sp2.17 that generates strengthening and contraction of the corresponding bonds (see Table S2). A strong intra-molecular hyperconjugative interaction from n1(N3) to π*(C4–O15) can form again an increased electron density at the N3 atom with 79.97 kcal/mol. Also the energy of hyper conjugative interaction, E(2), proves the extent of intermolecular hydrogen bonding in such a way that n1(O15) → σ*(N47–H55), n2(O15) → σ* (N47–H55), n1(O48) → σ*(N3–H20), n2(O48) → σ*(N3–H20) were equal to 6.86, 15.72, 6.86 and 15.73 kcal/mol, respectively. (Table S3) In addition, the electron density in C=O antibonding orbitals σ*(C4–O15) and π*(C4–O15) are increased significantly (.00279e and .06023e, respectively) upon dimerization which decreases the s-character of hybrid orbital (%–.81) and allows weakening and elongation (.017 Å) of corresponding bonds and the downshift of stretching frequency (ν16) (13 and 32 cm−1) as discussed above. 3.5. HOMO–LUMO analysis HOMO and LUMO energies are very important parameters for quantum chemistry. Homo energy characterizes the capability of electron giving and Lumo energy is related to the electron affinity. In order to evaluate the energetic behaviour of the compound, the energies of HOMO, LUMO and HOMO–LUMO energy gaps are calculated using 6-31++G(d,p) basis sets for monomeric and dimeric forms of primidone. It is clear from the figure that the HOMO is localized on the phenyl ring which splits up into two rings, while the LUMO is localized on the pirimidine ring, phenyl ring and substitution atom. The HOMO–LUMO transition implies an electron density transfer to N–C–N atom on the pirimidine ring

from the phenyl ring. The HOMO and LUMO plots of primidone monomer are given in Figure S6. The calculated energies of HOMO, LUMO and HOMO–LUMO gap are –6.993, –.789 and 6.204 eV, respectively. The chemical hardness and softness of a molecule is a good indication of the chemical stability of the molecule. The molecules having a large energy gap are known as hard molecule and molecules having a small energy gap are known as soft molecules. The soft molecules are more polarizable than the hard ones. Calculated energy gaps of dimeric forms of primidone are 6.15, 6.123 and 6.123 eV, respectively. Although TD-DFT accurately predicts the HOMO–LUMO gaps, time-independent DFT can provide an approximate information about the reactivity of the molecule (Zhang & Musgrave, 2007). We can conclude that dimer II and dimer III with a smaller frontier orbital gap than dimer I and more polarizable with a high chemical reactivity, low kinetic stability and is also termed as soft molecule.

4. Conclusions We conclude the following. (a) The possible 1296 conformers of free primidone molecule were searched by means of torsion PESs scan studies through ω (8C, 7C, 5C, 4C) and φ (14C, 13C, 5C, 4C) which were varied from 0° to 360° by steps of 10° and the most stable conformer of primidone was identified. (b) The geometric parameters and vibrational data have been employed for free and dimer I forms of primidone using DFT /B3LYP method with the 6-31++G(d,p) as basis set at harmonic level. The PED of the vibrational modes of the title molecule was calculated with Molvib program and the fundamental vibrational modes were characterized by their PED. (c) The calculated energies of monomeric and dimeric (I–II–III) forms of Primidone and the interaction energy of primidone dimers at DFTB3LYP /6-31++G(d,p) level of theory are presented in order to provide a convergence to the uncorrected result at the complete 6-31++G(d,p) basis set. Because of the difference in the BSSEcorrected (–14.519 kcal/mol) and uncorrected (–15.301 kcal/mol) interaction energy, Dimer-I has strong interaction energy and lower relative energy and its stability is also powerful. (d) The largest dimeric effect is found for N–H and C=O stretching vibrations which are shifted by 118 and 32 cm−1 to lower and higher frequencies, respectively. The N–H and C=O vibrations are reported to characterize the dimerization.



(e) The comparison of NBO analysis between dimer and monomer forms indicates that due to the increase of the electron density of N–H and C=O antibonding orbitals, corresponding bonds become weaker with an amount of elongation of about ~.02, ~.017 Å, respectively, and their stretching frequencies shifted to lower frequencies. (f) The HOMO–LUMO transition implies an electron density transfer from the phenyl ring to N–C–N atoms on the pyrimidine ring. Supplementary material The supplementary material for this paper is available online at http://dx.doi.10.1080/07391102.2014.913505. Acknowledgement This study was supported by the Research funds of the Istanbul University (ONAP-2423, N-3341, N-3875).

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