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Quantum chemical calculations and analysis of FTIR, FT–Raman and UV–Vis spectra of temozolomide molecule
Accepted Manuscript Quantum chemical calculations and analysis of FTIR, FT-Raman and UV-Vis spectra of temozolomide molecule Sheeraz Ahmad Bhat, Shabbir Ahmad PII:
S0022-2860(15)30114-9
DOI:
10.1016/j.molstruc.2015.07.002
Reference:
MOLSTR 21656
To appear in:
Journal of Molecular Structure
Received Date: 14 February 2015 Revised Date:
1 July 2015
Accepted Date: 1 July 2015
Please cite this article as: S.A. Bhat, S. Ahmad, Quantum chemical calculations and analysis of FTIR, FT-Raman and UV-Vis spectra of temozolomide molecule, Journal of Molecular Structure (2015), doi: 10.1016/j.molstruc.2015.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Quantum chemical calculations and analysis of FTIR, FT-Raman and UV-Vis spectra of temozolomide molecule Sheeraz Ahmad Bhat, Shabbir Ahmad* Department of Physics, Aligarh Muslim University, Aligarh-202002, India
Abstract
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A combined experimental and theoretical study of the structure, vibrational and electronic spectra of temozolomide molecule, which is largely used in the treatment of brain tumours, is presented. FTIR (4000–400 cm-1) and FT-Raman spectra (4000 50 cm-1) have been recorded and analysed using anharmonic frequency calculations using VPT2, VSCF and CC-VSCF levels of theory within B3LYP/6-311++G(d,p) framework. Anharmonic methods give accurate frequencies of fundamental modes, overtones as well as Fermi resonances
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and account for coupling of different modes. The anharmonic frequencies calculated using VPT2 and CC-VSCF methods show better agreement with the experimental data. Harmonic frequencies including solvent effects are
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also computed using IEF-PCM model. The magnitudes of coupling between pair of modes have been calculated using coupling integral based on 2MR-QFF approximation. Intermolecular interactions are discussed for three possible dimers of temozolomide. UV-Vis spectrum, examined in ethanol solvent, is compared with the calculated spectrum at TD-DFT/6-311++G(d,p) level of theory. The electronic properties, such as excitation energy, frontier molecular orbital energies and the assignments of the absorption bands are also discussed. Keywords: Temozolomide, VPT2, VSCF, FTIR, FT-Raman, UV-Vis *Corresponding Author
[email protected]
Tel.: +91 9412501430
Introduction
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E-mail address:
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One of the most severe forms of human cancer is glioblastoma, which is a primary brain tumor [1]. Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma)
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occur more frequently than other types of primary central nervous system tumours. The media reported survival is less than 1 year even if these cancers are treated with surgery, radiation and chemotherapy [2]. Temozolomide (TMZ) is an orally administered alkylating agent, used largely in the therapy of malignant brain tumours including glioblastoma and astrocytoma, which are serious and aggressive types of brain cancers [3]. It readily crosses the blood-brain barrier and has a broad spectrum of antineoplastic activity [4 6]. Owing to the vast pharmaceutical importance, an attempt has been made in this study to interpret the vibrational and electronic spectra of TMZ.
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ACCEPTED MANUSCRIPT For proper understanding of vibrational spectra of molecules, theoretical methods ranging from semiempirical to DFT approaches are invaluable tools for reliable assignments of vibrational bands [7,8]. Structural and vibrational parameters predicted by theoretical methods often depend on the level of the theory, basis set and inclusion of correlation effects. DFT computations have become important in predicting the molecular structure and
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properties of biologically important compounds and drugs [9 12]. Harmonic frequency approximation is sometimes useful for rigid molecules, but has limited accuracy for flexible systems. Vibrational frequencies computed by the usual harmonic approximation overestimate the observed values partly because of strong anharmonic character of some
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vibrations [13 15]. Vibrational self-consistent field (VSCF) method is one of the approaches used to perform anharmonic vibrational calculations, which provides excellent results. The VSCF algorithm is included in GAMESS-US program [16] and has been extensively and
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successfully applied in recent years [17–20]. In the VSCF approach, each mode is assumed to be vibrating in the average field of other modes. Although, anharmonic frequency calculations using second-order perturbation (PT2) theories are of high computational cost, but the results are in close agreement with the experimental data [21–26]. The vibrational second order perturbation theory (VPT2) theory implemented by Barone in Gaussian package
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of programs is very useful and reasonably accurate for approximate calculations of low lying vibrational levels [27]. The correlation corrected vibrational self-consistent field (CC-VSCF) [28] method uses second order perturbation theory [29] and is more accurate than VSCF method within the separable approximation [30]. The CC-VSCF method employs directly ab
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initio potentials and for simple analytic force fields, it is viable for systems up to hundreds of normal modes [31].
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Extensive literature survey revealed that a little amount of work has been done on
TMZ [32–40]. The anticancer, antitumor activity and skin delivery potency of TMZ ester prodrugs have been reported [32,33]. Synthesis and structural evolution of TiO2 nanostructured reservoir with TMZ are reported [34]. UV spectrophotometric method has been developed for the quantitative determination of TMZ in bulk and capsule [35]. Highperformance liquid chromatographic analysis is carried out [36]. Some cocrystals of TMZ have been characterised by XRD, FTIR and FT-Raman analysis [37]. The feasibility of encapsulating TMZ into polybutylcyanoacrylate nanoparticles by polymerisation is reported [38]. The physiochemical characteristics of TMZ process-related impurities and their structure are studied [39]. Recently, the interaction between TMZ and water has been 2
ACCEPTED MANUSCRIPT reported [40]. To the best of our knowledge, the quantum chemical calculations and vibrational studies of TMZ molecule have not been carried out so far. In the present work, the optimised molecular geometrical parameters of the monomer and dimer structures of TMZ have been calculated using DFT method with 6-311++G(d,p) basis set. The anharmonic effects in the vibrational spectra are considered by VPT2 approach implemented by Barone
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[27], VSCF [30,41,42] based on two-mode representation quartic force field (2MR-QFF) potential energy function and CC-VSCF [28,43] methods. The effects of the intermolecular interactions on the vibrational spectra are studied by considering the three possible dimers of TMZ. Anharmonicity, which causes coupling between different vibrational modes, shifts the
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frequencies of the modes. In order to understand the coupling behaviour between pair of modes in TMZ, the magnitudes of two-mode coupling for the ground state are computed and discussed [44]. The electronic absorption spectrum in solution phase was also simulated
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using integral equation formalism of the polarisation continuum model (IEF-PCM) model at TD-B3LYP/6-311++G (d,p) level of theory. The theoretical results have been compared with experimental data (FTIR, FT-Raman, UV-Vis) and found to be in good agreement. Molecular electrostatic potential (MEP) mapping and HOMO–LUMO (highest occupied molecular
Experimental details
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orbital–lowest unoccupied molecular orbital) analysis of TMZ have also been presented.
The TMZ sample in solid form was obtained from Aldrich Chemicals, USA and used as such without further purification to record FTIR, FT-Raman and UV-Vis spectra. The
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FTIR spectrum was recorded at room temperature on Bruker tensor-37 spectrometer in the mid IR region (4000–400 cm-1) using KBr pellet technique, with a spectral resolution of 2
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cm-1. To increase the signal-to-noise ratio, a minimum of 32 scans were accumulated. The absorbance Aλ at a given wavenumber in FTIR spectrum was converted into epsilon value ελ (Lmol-1cm-1) using the Lambert-Beer law,
where, b is the thickness of the pellet and c is the concentration of the sample in mol L-1. The FT-Raman spectrum in solid phase was recorded at room temperature on Bruker RFS spectrometer in the region 4000-50 cm-1, with a spectral resolution of 2 cm-1, using 1064 nm line of Nd:YAG laser as excitation wavelength. The UV-Vis spectrum was recorded in
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solvent
in
the
region
800–200
nm
using
Lambda-950
UV-Vis-NIR
spectrophotometer. Computational details The theoretical computations for the monomer and dimer structures of TMZ have
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been carried out by Gaussian 09 program using DFT level of theory with 6-311++G(d,p) basis set [45]. Electron correlations in the DFT are included using the Becke's threeparameter hybrid exchange functional (B3) [46–48] and the Lee Yang Par (LYP) correlation functional [49]. The optimized geometries were taken as the input structure for calculations , corresponding to an ith normal mode
the following relationship [50].
is the laser exciting wavenumber; f (a constant equal to 10–12) is a suitably chosen
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where,
, was converted into intensity Ri by
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Raman activity
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of harmonic and anharmonic vibrational frequencies, IR intensities and Raman activities. The
common normalization factor for all peak intensities; h is the Planck constant; k is the Boltzmann constant; c and T are the speed of light and temperature (298 Kelvin) respectively. Since, the vibrational spectra not only depend upon the bond strengths within molecules, but,
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also on the environments around them. The solvation methods are attractive due to their reliability coupled to computational costs comparable with those of the corresponding
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computations in gas phase [51]. Therefore, in order to provide an insight into solute-solvent interactions and to figure out to which extent the calculated results in solvent agree with the experimental observations, the harmonic frequencies in the monomer structure of TMZ were also computed in dimethyl sulfoxide (DMSO) using IEF-PCM model [52]. For the dimer structures, only harmonic approximation in gas phase was taken into account. Anharmonic corrections in vibrational frequencies for TMZ monomer were computed using VPT2 approach implemented by Barone, as well as, VSCF/2MR-QFF and CC-VSCF (PT2-VSCF) methods implemented into GAMESS-US package [16]. The broadening in computed IR and Raman spectra was simulated using Lorentzian line shape with FWHM as 6 cm-1. The vibrational spectra have been interpreted by means of visual inspection of animated modes 4
ACCEPTED MANUSCRIPT and potential energy distribution (PED) using VEDA 4 program [53]. In order to understand the coupling between pair of modes, the magnitudes of mode-mode coupling for the ground state have been estimated. The 2MR-QFF potential energy function was used for calculating anharmonic mode-mode coupling strengths [44,54]. For a reasonable estimate of the modemode coupling strengths, the two mode coupling terms can be expressed as quartic force field
,
,
,
are obtained by numerical differentiations of an analytical Hessian available in
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and
are the mass weighted normal coordinates, the coefficients
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where,
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(QFF) as
GAMESS-US package. The expression for the two mode coupling integral for the first order correction of the ground state is then defined as
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where, |0⟩ is the ground state harmonic oscillator wavefunction [44]. TD-DFT/6-311++G(d,p) method, in combination with IEF-PCM model [51] in ethanol solvent, was used to calculate the excitation energies and oscillator strengths in TMZ. Furthermore, the HOMO and LUMO energies were predicted to interpret the orbital overlapping and the possibility of charge
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transfer within the molecule. The group contributions to the HOMO and LUMO orbitals were obtained by Gauss-sum 2.2 program [55].
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Results and discussion Geometric structure
The optimized geometries of TMZ monomer and dimer structures (D1, D2 and D3)
with atom numbering scheme are shown in Fig.1 and Fig.1S (supplementary data). respectively. The optimized bond lengths and bond angles of TMZ are given in Table 1S (supplementary data). Most of the calculated bond lengths and bond angles in monomer and dimer structures are same. The C H bond lengths in methyl group, C5 C8, C5 C10, N12 N15 and N14 N15 bonds in the monomer and dimer structures are equal. The 5
ACCEPTED MANUSCRIPT elongation of N13 H4 and C8=O7 bond lengths in D1 structure is due to intermolecular hydrogen bonding and electron withdrawing nature of carboxylic group respectively. The high value of the dipole moment, 3.4974 Debye in TMZ monomer favors the intermolecular hydrogen bonding.
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Electronic spectra The TD-DFT method has become one of the most popular and widely used approaches for the calculation of properties, such as excitation energies, oscillator strengths and excited state geometries of medium to large molecular systems [56]. TD-DFT has been
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widely used to find out the low lying excited states of molecules on the basis of fully optimized ground-state structure [57]. The vertical excitation energies, absorption wavelengths and oscillator strengths (f) of TMZ molecule along with their assignments are
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given in Table 1. The pictorial representation of HOMO LUMO orbitals and energy gap of TMZ are shown in Fig.2 and the density of state spectrum is shown in Fig.2S. (supplementary data). The HOMO–LUMO energy gap characterizes the chemical activity, optical polarizibility and chemical hardness softness of the molecule [58]. The frontier molecular orbital energy gap is found to be 4.45 eV. The energy gap of (HOMO 1)–(LUMO+1) has
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been calculated to be 5.69 eV. A large HOMO–LUMO energy gap is an indication of high stability of TMZ. It can be seen from the HOMO–LUMO plots that HOMO is spread over the entire molecule except the NH2 group. The LUMO is also spread over the entire molecule except CH3 group. The experimental and simulated electronic spectra of TMZ are shown in
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Fig.3. The TD-DFT calculations in ethanol solution show three intense bands at 315, 252 and 207 nm having the oscillator strengths as 0.334, 0.1077 and 0.2545 respectively. These
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absorptions are found to be in good agreement with the experiment values. The maximum absorption wavelength, 317 nm, corresponds to HOMO→LUMO(94%) electronic transition. The absorption wavelengths, 245 and 206 nm, are assigned to HOMO→LUMO+1(83%) and HOMO→LUMO+2(50%) transitions respectively. The assignments of other transitions have also been shown in Table 1. Vibrational analysis The TMZ molecule consists of 20 atoms and, therefore, possesses 54 normal modes of vibration. Since the molecule is considered having C1 symmetry, all the vibrations are expected to be both IR and Raman active. The observed and calculated IR and Raman spectra 6
ACCEPTED MANUSCRIPT of TMZ have been compared in Fig.4 and Fig.5 respectively. It is observed from Fig. 4 that a large deviation between the experimental and theoretical IR intensities (Lmol-1cm-1) is observed, which may be due to the reason that computed values for epsilon only take account of the dipole term and various experimental colligative effects are not included. The comparison between computed harmonic and anharmonic wavenumbers is also shown in
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Fig.6. The calculated harmonic and anharmonic frequencies along with intensities and vibrational assignments are shown in Table 2. It is observed from Table 2, that the computed frequencies in gas phase at harmonic level overestimate the experimental data. However, the harmonic frequencies computed using IEF-PCM model show better performance than
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harmonic frequencies computed in gas phase. The RMS and MAD values also indicate higher precision of the DMSO computed harmonic frequencies with the experimental data for TMZ molecule. VPT2 and CC-VSCF theories within B3LYP frame work give better results than
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VSCF, as revealed by comparatively low RMS and MAD values. VPT2 method is of less computational cost, and performs better than VSCF and CCVSCF methods for most vibrational modes. VSCF and CC-VSCF methods perform well for the NH2 stretching modes. However, for lower wavenumbers, involving bending and torsional vibrations, no significant agreement is observed between VSCF and CC-VSCF computed frequencies and the
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experimental data. Also, overall average percentage error of 1.76% is observed for VPT2 as compared to an error of 2.16 and 1.99% for VSCF and CC-VSCF methods respectively. In the region, above 1500 cm-1, CC-VSCF method shows less percentage error (1.40%) as compared to 1.86 and 1.71% by VPT2 and VSCF methods respectively. However, in the
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regions, 1500–800 cm-1 and below 800 cm-1, VPT2 gives less percentage error of 1.61 and 1.99 % respectively, between experimental and computed anharmonic frequencies.
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Mode pair coupling strengths in the 2-mode coupling representations of the 2MR-
QFF, coupling strengths between some important pairs of modes and modes having the coupling strength larger than 30 cm-1 for TMZ are shown in Fig.3S (a), (b) and (c) (supplementary data) respectively. The assignments of the fundamental modes of TMZ molecule are discussed in the following sections. Carbonyl (C=O) group vibrations The carbonyl stretching vibrations have been widely studied by infrared spectroscopy. Since C=O group is highly polar in nature, strong and intense absorption bands are observed in the region 1700–1750 cm-1 [59,60]. C=O stretching vibrations are also very important as 7
ACCEPTED MANUSCRIPT they take part in hydrogen bonding. The C9=O6 stretching mode (mode 7) is observed at 1758 cm-1 with strong intensity in the IR spectrum of TMZ. The computed anharmonic wavenumbers are in agreement with the experimental frequency. The assignment is also in agreement with the literature [61–63]. The carbonyl group, C9=O6, is involved in hydrogen bonding in D3. The harmonic frequencies for this mode are 1779, 1778 cm-1 in D3. It is clear
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from Fig. 3S, that carbonyl vibrations are either not involved or weakly involved (< 30 cm-1). in coupling with other modes. Amide (CONH2) group vibrations
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The title molecule contains only one NH2 group. Therefore, one can expect six internal modes of vibration as symmetric (νsym) and asymmetric stretching (νasym), the symmetric planar deformation or scissoring (βs), the anti-symmetric planar deformation or
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rocking, the symmetric non-planar deformation or wagging (ω) and the anti-symmetric nonplanar deformation or torsion (τ). In all aromatic amines, NH2 stretching occurs in the 3300– 3500 cm-1 region [64]. In solid phase, the asymmetric and symmetric NH2 stretching vibrations appear at 3350 cm-1 and 3200 cm-1 respectively [64]. In TMZ, the medium intensity bands, observed in the IR spectrum at 3420 cm-1 (mode 1) and 3385 cm-1 (mode 2), are
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assigned to NH2 asymmetric and symmetric stretching vibrations respectively. Large deviations between the observed and calculated (VPT2) NH2 stretching frequencies are observed. The deviations are due to strong coupling of NH2 stretching modes (1 and 2) with mode 46 [Fig.3S]. These may also be due to the intermolecular hydrogen bonding, N H···O
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or N H···N, in D1 and D2 respectively. In dimer D1, the calculated frequencies for mode 1(3651,3650 cm-1) and mode 2 (3351,3311 cm-1) show better agreement to respective
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observed frequencies than those are in D2 and D3. The NH2 stretching modes show significant anharmonic corrections in VSCF and CC-VSCF levels of theory. The calculated frequencies of NH2 asymmetric and symmetric modes are 3483 and 3368 cm-1 respectively at CC-VSCF level of theory.
The NH2 scissoring vibration is usually observed in the region 1650 1620 cm-1 [65].
According to PED calculations, the NH2 scissoring mode is mixed with C C and C N stretching vibrations and contributes to mode 9 (57% PED) and 10 (22% PED). The vibrational frequencies observed at 1677 cm-1 and 1672 cm-1 in IR and Raman spectrum, respectively, are assigned to mode 9. Mode 10 has been observed at 1567 cm-1 in IR spectrum and at 1577 cm-1 in Raman spectrum. The computed anharmonic frequencies for mode 9 are 8
ACCEPTED MANUSCRIPT deviated from the observed frequencies. The deviation may be associated to the high anharmonicity of this mode [30]. Also, significant coupling strengths (>30 cm-1) are observed between mode pairs 9 and 1 as well as 9 and 2 [Fig.3S]. The deviations between the computed and observed wavenumbers for mode 9 are lower in D1 and D2 dimers. The NH2 rocking vibrations are observed in the region 1125 ± 45 cm-1 [66,67]. In the present study,
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this vibration is observed in mode 25 at 1095 cm-1 in the Raman spectrum. The anharmonic frequency, 1090 cm-1, calculated using VPT2 theory, is in close agreement with observed one. The non-planar modes (36 and 38) of the NH2 group have, respectively, 64% and 66% PED contribution from NH2 twisting vibrations. These modes are observed at 636 cm-1 in IR
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spectrum and at 583 cm-1 in Raman spectrum respectively. Mode 38 is strongly coupled to modes 46 and 48. The large deviations of the experimental and simulated anharmonic frequencies, corresponding to modes 36 and 38, may be due to the improper definition of
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potential energy surface or limitations in the Cartesian coordinate system [68]. The harmonic vibrational frequencies in monomer and D3, corresponding to mode 38, are in agreement with the observed frequency. The twisting vibration of NH2 group about C8–O7 bond (mode 54) is observed at 66 cm-1 in Raman spectrum. The NH2 wagging vibration, observed at 360 cm-1, is assigned to mode 45.
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The band due to the C=O stretching vibrations is often referred as the amide I band. It is generally observed in the region 1670–1650 cm-1 having strong intensity [65]. In the present study, C8=O7 stretching vibration (mode 8) is observed at 1733 cm-1 in IR spectrum. The corresponding anharmonic frequency, 1727 cm-1, predicted at VPT2 theory, is in
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agreement with the experimental frequency. Significant coupling between modes 8 and 54
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has also been predicted [Fig. 3S]. Methyl (CH3) group vibrations
Methyl groups are generally referred as an electron donating substitution in the
aromatic ring system. Since the title molecule contains only one CH3 group attached to the aromatic ring, nine fundamentals are expected. The C H stretching vibrations in CH3 group normally appear in the region 3010 2880 cm-1 [69–71]. In the present study, the anharmonic C H stretching frequencies of CH3 group, computed at VPT2 theory, have better agreement with the experimental wavenumbers. The C H asymmetric stretching vibration has been assigned to mode 4. The computed VPT2 anharmonic frequency, 3018cm-1, is ascribed to this mode. The symmetric C–H stretching vibration, computed at 2938 cm-1, is assigned to mode 9
ACCEPTED MANUSCRIPT 6. These vibrations are pure stretching vibrations as evident by PED values. The assignment of the CH3 stretching frequencies clearly signifies that these frequencies do not significantly depend on the surroundings of the functional group. The CH3 asymmetric bending modes, 12 and 14, have been observed at 1476 cm-1 and at 1403 cm-1 in Raman spectrum respectively. The CH3 symmetric bending frequency
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(umbrella motion) is not observed in IR and Raman spectra. The anharmonic frequencies, calculated at 1422 cm-1 (CC-VSCF), 1424 cm-1 (VSCF) and 1427 cm-1 (VPT2), correspond to the umbrella motion of methyl group. The CC-VSCF anharmonic frequencies, 1478 cm-1 and 1468 cm-1, are assigned to CH3 asymmetric bending vibrations. These assignments are within
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the region as reported in the literature [72–74,20]. The CH3 torsional mode generally appears in the low frequency region and is assigned to mode 52 with 72% PED contribution. The
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Raman frequency for this mode is observed at 105 cm-1. The harmonic wavenumbers, 104 and 103 cm-1 in D3, are in agreement with the observed wavenumbers. C-X vibrations
The C–H stretching vibrational bands normally appear in the region 3080–3010 cm-1 [65,71]. The intense band, observed at 3121 cm-1 in the IR spectrum and at 3115 cm-1 in
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Raman spectrum, shows the presence of C1–H17 stretching frequency. It is animated as pure stretching and is assigned to mode 3. The frequency, 3129 cm-1, computed at VPT2 level of theory, is in agreement with the observed frequency. As evident from Fig.3S, strong coupling
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is observed between modes 3 and 30. Mode 3 is also significantly coupled to mode 22 and 14. The C1 H17 in-plane bending vibrations, mixed with other vibrations, have contributions in mode 22, 23 and 26. The IR bands observed at 1176, 1143 and 1046 cm-1 are assigned to
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these bending modes. These assignments are well within the reported regions [20,75]. Ring vibrations
The ring stretching vibrations are complicate combinations of mainly C C, C N and
N N vibrations. The assignment of these vibrations is a difficult task, since the mixing of the vibrations occurs. In our work, mode 10 has been assigned to C C stretching vibration mixed with NH2 scissoring and C N stretching vibrations. The most important ring stretching vibration is the ring breathing in which all bonds of the ring stretch and contract inphase. It is predicted at 699 cm-1 in mode 33 using CC-VSCF method. The computed frequency for the breathing mode is in close agreement with the literature [76,77]. Another 10
ACCEPTED MANUSCRIPT important vibration is the butterfly motion in TMZ. This vibration presents a mixed profile and has been assigned to mode 48. The frequency of this mode has been observed at 261 cm-1 in Raman spectrum and well predicted at 257 cm-1 by DFT method. Conclusions
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In the present study, the geometrical parameters of the monomer and dimer structures of temozolomide have been calculated using DFT method with 6-311++G(d,p) basis set. The hydrogen bonding interactions between two monomeric units of the title molecule are also studied. The assignments of FTIR and FT-Raman spectra are supported by the anharmonic
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calculations using VPT2 method, VSCF and CC-VSCF approaches within the DFT framework. VPT2 and CC-VSCF theories within B3LYP framework give better results than VSCF, as revealed by comparatively low RMS and MAD values. However, VPT2 has lesser
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computational cost, at least an order of magnitude cheaper than VSCF and CC-VSCF. The harmonic frequencies computed using IEF-PCM model have a better agreement than the DFT/6-311++G(d,p) computed harmonic frequencies. In general, a good agreement between the experimental and calculated frequencies has been achieved. The deviations of the NH2 stretching modes from the experiment are observed due to the high anharmonicity associated
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with these modes or the neglect of higher order terms in potential expression. These modes are corrected well by VSCF and CC-VSCF approaches than VPT2 algorithm. UV Vis experimental and calculated data are in agreement with each other. The HOMO and LUMO energy eigenvalues support the charge transfer within the molecule.
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Acknowledgements
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We gratefully acknowledge the UGC (DRS) and DST (FIST) for the sanction of grants for FTIR and UV-Vis-NIR spectrophotometer. We also acknowledge the SAIF IIT Chennai for using FT-Raman facility. The author (Sheeraz Ahmad Bhat) is thankful to the UGC, New Delhi, India for the financial assistance. References
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K.N. Kudin, V.N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J.C.
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[77]. A.Y. Hirakawa, H. Okada, S. Sasagawa, M. Tsuboi, Spectrochim. Acta A 41 (1985) 209–216.
15
ACCEPTED MANUSCRIPT
206
5.96
B3LYP/6-311++G(d,p) Composition (˃5%)
320
0.001
3.87
H-1→LUMO (89%), H-3→LUMO (9%)
315
0.334
3.94
HOMO→LUMO (94%)
296
0.004
4.19
H-3→LUMO (89%), H-1→LUMO (8%)
275
0.0246
4.50
H-2→LUMO (99%)
252 243 233
0.1077 0.0007 0.0001
4.93 5.11 5.32
HOMO→L+1 (83%), H-4→LUMO (7%) H-5→LUMO (98%) H-3→L+1 (23%), H-1→L+1 (66%), H-7→LUMO (8%)
231
0.0001
5.38
H-7→LUMO (73%), H-1→L+1 (15%)
230
0.0125
5.38
H-6→LUMO (13%), H-4→LUMO (76%)
223
0.0005
5.56
217
0.0026
5.72
H-7→LUMO (12%), H-3→L+1 (68%), H-1→L+1 (14%) H-2→L+1 (89%), HOMO→L+2 (7%)
216
0.000
214
0.0896
207
0.2545
202
0.003
SC
5.01
E (ev)
M AN U
245
3.87
(f)
TE D
317
λcal(nm)
5.75
H-1→L+2 (86%)
5.80
5.98
H-6→LUMO (37%), H-4→LUMO (13%), HOMO→L+2 (33%), H-2→L+1 (9%), H-6→LUMO (41%), HOMO→L+2 (50%)
6.13
H-5→L+1 (84%), H-7→L+1 (9%)
EP
Experimental λobs(nm) E (ev)
RI PT
Table 1 Theoretical and experimental UV spectral characteristics of temozolomide.
AC C
Abbreviations used: λ- Excitation wavelength, E-Excitation energy, H-Homo, L-Lumo, f-Oscillator strength
ACCEPTED MANUSCRIPT
A VPT2 km/mol 3544 84.9 3427 60.3 3129 6.4 3018 0.2 2973 8.4 2938 23.3 1760 559.2 1727 346.1 1571 275.5 1549 4.6 1504 20.6 1485 15.5 1451 121.5 1449 12.3 1427 0.3 1375 2.1 1337 217.7 1300 1.8 1282 69.7
R 18.914 58.592 31.229 24.478 42.451 138.989 42.578 77.902 272.066 476.751 429.468 69.893 164.019 31.767 27.860 411.713 276.603 138.330 127.154
D1 3651,3650 3351,3311 3268,3268 3169,3169 3124,3124 3058,3058 1795,1794 1740,1720 1635,1621 1588,1585 1537,1537 1506,1506 1491,1491 1481,1481 1447,1447 1432,1426 1391,1388 1346,1345 1319,1319
D2 3672,3672 3476,3476 3268,3268 3170,3170 3126,3126 3060,3059 1796,1795 1751,1749 1636,1635 1583,1583 1537,1537 1506,1506 1491,1487 1481,1481 1448,1448 1416,1415 1378,1374 1345,1344 1319,1318
CCVSCF VSCF D3 3723,3723 3493 3483 3585,3585 3379 3368 3251,3249 3064 3090 3170,3170 2989 2980 3125,3125 2932 2904 3059,3059 2919 2899 1779,1778 1759 1759 1760,1760 1720 1720 1608,1607 1573 1596 1583,1583 1554 1553 1540,1539 1518 1516 1506,1506 1477 1478 1490,1488 1468 1469 1482,1482 1471 1468 1448,1448 1424 1422 1411,1410 1387 1384 1374,1372 1349 1344 1335,1335 1311 1308 1323,1322 1299 1295
Aa km/mol R 85.2 23.7 55.16 52.4 5.16 32.6 0.15 16.3 7.98 33.2 30.81 147.5 554.21 44.0 334.76 76.5 275.09 275.5 7.03 423.8 7.33 528.2 27.01 44.1 17.94 27.7 119.47 784.3 7.01 19.4 0.88 327.2 225.92 299.4 0.14 165.7 60.47 175.0
SC
Har 3723 3586 3270 3170 3125 3059 1795 1760 1607 1580 1537 1506 1489 1481 1448 1410 1372 1339 1317
M AN U
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
B3LYP/6-311++G(d,p) Har/Vacuum
TE D
M
Observed wavenumbers (cm-1) IEF-PCM/DMSO FTIR FT-Raman A Har km/mol R 3420m 3706 135.0 28.268 3385m 3576 133.0 102.531 3121s 3115m 3275 10.3 68.873 3007w 3179 1.0 52.429 2961m 3139 10.1 81.947 3068 29.3 280.716 1758vs 1763 1046.5 178.823 1733vs 1732m 1692 768.6 201.251 1677vs 1672m 1600 482.2 1239.815 1567sh 1577vs 1580 11.0 1925.051 1528 29.6 1384.831 1476m 1495 65.8 228.208 1452s 1454s 1488 219.7 615.391 1403m 1403s 1470 20.3 56.664 1445 3.5 139.182 1411 26.1 1618.421 1356s 1356vvs 1377 418.9 1266.650 1300vw 1304s 1349 11.7 503.462 1264s 1269s 1308 135.3 632.473
RI PT
Table 2 Comparison of the calculated and experimental (FTIR and FT-Raman) vibrational spectra of temozolomide.
20 21 1215w 22 1176vw
1224s 1183w
1285 1237 1232
266.6 62.4 20.3
167.946 986.661 77.528
1279 1249 165.2 1236 1207 21.2 1227 1200 6.5
50.351 274.673 21.053
1290,1287 1283,1280 1243,1241 1238,1237 1231,1230 1228,1226
1285,1283 1233,1232 1243,1241
1258 1221 1209
1256 1218 1206
175.13 68.8 28.22 220.8 41.16 49.4
23 1143vw 24 1109vw 25 26 1046m
1112w 1095w 1050w
1195 1146 1092 1052
26.7 0.1 6.3 85.8
69.895 1.691 328.060 198.206
1191 1150 1094 1051
9.8 0.2 3.7 38.8
17.179 2.627 113.560 65.603
1192,1192 1149,1149 1136,1132 1055,1054
1193,1192 1149,1149 1094,1094 1056,1054
1161 1146 1084 1038
1157 1143 1077 1036
2.9 0.4 3.58 38.25
19.3 23.5 102.3 99.6
27 1005w
1003w
1013
40.8
104.748
1010 989
24.5
18.066
1013,1013 1014,1012
1010,1010
996
994
33.28
23.3
28 29 30 31 32 33 34 35 36
946s
955w
850w 804w 736m
847w 791m
707m
703s
946 852 841 795 744 704 701 665 665
376.8 9.3 9.5 8.7 37.3 2.6 4.6 100.4 20.7
349.599 152.749 15.817 78.539 7.871 143.128 41.342 220.613 2.775
929 852 831 793 742 699 697 689 665
179.4 12.0 8.1 4.3 22.0 0.7 1.2 55.8 14.6
57.326 25.612 2.458 20.000 1.411 56.051 14.105 62.719 1.666
929,927 852,852 831,831 805 743,743 700,700 697,694 722,711 652,649
926,923 852,850 875,871 791,791 741,741 700,699 695,695 690,690 667,667
917 838 900 812 743 701 707 686 695
913 836 893 814 743 699 705 684 684
120.46 13.66 9 3.71 21.42 1.16 0.72 60.04 12
65.0 34.5 67.7 16.1 5.7 46.1 28.7 60.4 0.2
636w
898 836 842 814 746 689 709 682 659
EP
1191,1190 1150,1150 1101,1094 1056,1053
AC C
1162 1126 1090 1029
928,928 852,852 835,835 815,803 742,739 703,702 686,679 697,697 648,630
PED ( ≥5%)
νas [NH2] (99) νsy [NH2] (99) ν [C1-H17] (99) νas [CH3] (90) νas [H20-C2-H18] [in CH3] (100) νsy [CH3] (90) ν [C9=O6] (83) ν [C8=O7] (80) scis [NH2] (57) + ν [C5-C10 + C5-C8] (15)] + ν [C8-N13] (6) ν [C5-C10] (45) + scis [NH2] (22) + ν [C5-C8] (6) + ν [C1-N11] (5) ν [N14-N15] (61) + ν [C1-N11 + C9-N12] (10) βas [CH3] (66) ν [N11-C1 +N16-C1] (33) +β [H17-C1-N16] (23) + ν [C10-N16] (9) βas [CH3] (75) umb [CH3] (84) ν [N16-C1 + N13-C8] (28) + ν [C5-C8] (5) ν [NC] (34) + ν [C5-C8] (12) + β [NH2] (5) ν [N16-C10 + N13-C8] (30) + β (CNN) (16) + β (C10-C5-N11) (11) + β [H14-N13-C8] (6) ν [N12-C2 + N12-C9] (23) + ν [N13-C8 + N11-C1] (19) + β [CNN] (15) + β [C10-C5-N11] (10) + β [CH3] (9) ν [N11-C5 + N13-C8] (43) + β [N16-C1-N11] (8) + β [C8-N13-H4] (8) + roc [CH3] (6) τ [HCNC] (25) + ν [N-C] (21) + roc [CH3] (10) + β [N13-C8-O7] (4) β [C1-H17](29) + τ [H18-C2-N12-C9] (15) + ν [N11-C1 + N11-C5 + N13-C8 ] (17) + roc [CH3] (7) + β [C5-N10-N14] (5) β [C1-H17] (19) + roc [NH2] (10) ν [N-C] (7) + roc [CH3] (7) + ν [N-N] (5) τ [H18-C2-N12-C9 + H19-C2-N12-C9 + H20-C2-N12-C9] (60) + roc [CH3] (26) roc [NH2] (58) + ν [O7-C8] (9) + ν [N11-C5 + N13-C8 + N16-C1] (8) β [N16-C9-O6] (23) + ν [N12-C2] (15) + β [C1-H17] (7) + β [ C1-N11-C5 + C10-C5-C11 + C10-N14N15] (6) ν [N12-C9 + N13-C8 + N16-C1] (31) + β [N16-C9-O6] (11) + β [C5-C8-N13+ C5-C10-N14+ C1N11-C5] (7) ν [N12-N15] (21) + τ [H17-C1-N11-C5] (17)β [N16-C9-O6] (11) + ν [N16-C1] (8) + roc [CH3] (5) β [Rr] (52) + ν [N12-CH3] (22) + β [CCN] (7) + β [C10-N14-N15] (5) γ [H17-C1] (86) τ [C1-N11-C5-C10] (71) + γ [C8-C10-N11-C5] (6) γ [O6-N12-N16-C9] [85] ν [Rr] (43) τ [C1-N11-C5-C10] (72) + γ [O6-N12-N16-C9] (6) + γ [N14-C5-N16-C10] (7) β [N13-C8-O7] (25) + ν [C8-C5] (15) + roc [NH2] (7) + β [N12-N14-N15] (7) twi [NH2] (64) + τ [H17-C1-N11-C5] (9) + γ [N14-C5-N16-C10] (8)
ACCEPTED MANUSCRIPT
562m 512m 479vw
508w 472s
360m 333m 280w
620 587 578 547 512 469 331 324 316 303 269
10.6 8.3 13.8 0.3 46.6 3.9 11.2 11.5 323.0 2.4 11.2
245.723 7.718 96.142 1.249 25.889 227.123 209.133 160.537 41.209 32.904 9.636
605 590 574 541 510 468 331 319 301 300 251
591 561 566 557 503 461 329 323 377 294 280
5.5 4.9 10.8 0.2 26.1 2.0 6.3 6.9 202.3 1.0 8.4
64.712 6.008 54.147 0.193 22.343 98.635 115.832 50.588 21.881 19.196 3.611
612,609 552,550 589,587 552,550 515,512 477,476 357,353 322,320 526,522 308,305 259,255
604,580 599 581,580 556,551 508,508 471,463 338,338 319,319 445 301,301 258,254
604,604 591,591 575,574 542,542 511,510 470,469 331,331 322,322 296,295 302,302 250,249
596 732 572 582 502 464 348 329 307 571 313
5.17 8.38 10.48 1.12 27.52 1.79 12.78 1.51 3.31 147.01 23.42
74.6 11.6 57.3 5.1 31.2 82.6 6.0 153.5 38.1 65.1 2.2
ν [N12-N15] (42) + β [CNN] (14) + β [N12- C9-O6] (7) twi [NH2] (66) + τ [C10-N14-N15-N12] (20) β [N13-C8-O7] (47) + ν [N12-N15] (10) + β [C9-N12-N15] (9) + roc [NH2] (5) τ [C10-N14-N15-N12] (66) + twi [NH2] (17) + τ [C5-N11-C1-N16] (7) β [CNN] (50) + β [CCN] (6) β [CCN] (25) + ν [C5-C8] (12) + β [N13-C8-O7] (9) + β [C5-C8-N13] (5) β [C5-C8-N13] (28) + ν [C8-C5] (18) + ν [C5-C10] (11) + N16-C9-O6 ] (7) +β [CNC] (10) β [N15-N12-CH3] (48) + [N16-C9-O6] (9) ω [NH2] (82) + τ [N13-C8-C5-C10] (5) β [NCO] (41) + β [C5-C8-N13 + C5-C10-N14] (26) + β [C10-N14-N15] (7) γ [C2-C9-N15-N12] (63) + γ [N14-C5-N16-C10] (16) + τ [H18-C2-N12-C9 + H19-C2-N12-C9 + H20-C2N12-C9] (7) τ [Rr] (68) + ω [NH2] (12) + γ [C8-C10-N11-C5] (5) γ [C2-C9-N5-N12] (67) + γ [C8-C10-N11-C5] (6) β [C5-C8- N13] (76) + β [C15-C12-CH3] (6) + β [C5-C10-N14] (5) τ [C1-N11-C5-C10] (56) + γ [C2-C9-N15-N12] (12) + γ [N14-C5-N16-N10] (8) τ [CH3] (72) + τ [N15-N14-C10-N16] (7) γ [C8-C10-N11-C5] (70) + τ [C1-N11-C5-C10] (11) + γ [O6-N12-N16-C9] (5) twi [O7-C8-NH2] (85)
242 0.5 9.290 236 257 7.1 3.695 255,245 242,240 235,235 343 316 9.99 29.3 210 11.2 147.160 194 242 4.9 31.635 203,200 202,198 190,189 272 246 15.15 174.4 22.176 178,175 151,145 138,137 141 139 8.32 27.8 142 13.7 33.755 136 134 8.3 116 3.3 1.620 111 123 4.9 0.047 114,112 118,113 114,110 319 272 0.26 244.8 105sh 102 3.0 103.919 95 174 1.1 52.654 96,93 92,92 104,103 122 122 5 118.0 40.956 69,67 116 95 0.84 164.6 81vvs 73 0.01 104.445 67 75 0.1 71 69 66s 50 13.2 167.531 47 70 3.1 69.057 78,76 47,44 98 93 2.29 64.8 77 RMS 78 81 36 36 31 MAD 45 47 23 25 23 Abbreviation used: M-modes, Har-harmonic wavenumbers,Anh-Anharmonic wavenumbers, A- harmonic IR intensity, R- Raman intensity (arb. unit), ν- stretching, sy- symmetric, as- asymmetric, β- bending, βas - antisymmetric bending, τ- torsional, τ Rr-butterfly motion, scis- scissoring, roc- rocking, ω- wagging, twi- twisting, umb- umbrella motion, γ- out of plane vibrations, w- weak, m- medium strong, sh- shoulder, s- strong, vs- very strong , vvs- very very strong, Aa-VSCF anharmonic IR intensity, bold letter specifies the frequency having high IR intensity than the other one in dimer.
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595 726 569 576 501 463 347 327 304 570 290
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molecule. Fig. 4. Comparison of the experimental FTIR and theoretical anharmonic spectra of temozolomide molecule at B3LYP/6-311++G(d,p) level of theory.
Fig. 5. Comparison of the experimental FT-Raman and theoretical Raman spectra of
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temozolomide molecule at B3LYP/6-311++G(d,p) level of theory.
Fig. 6. Comparison of the computed harmonic and anharmonic spectra of temozolomide
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molecule at B3LYP/6-311++G(d,p) level of theory
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Research highlights FTIR, FT-Raman and UV-Vis spectra were recorded and analysed.
•
Anharmonic frequencies were computed by VPT2, VSCF and CC-VSCF methods.
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Mode-Mode coupling strengths were computed using 2MR-QFF.
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The existence of intermolecular hydrogen bonding was investigated.
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Supplementary Materials
Bond length
Bond
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Table 1S. Optimized geometrical parameters (bond lengths and bond angles) of monomer and dimer structures of temozolomide at B3LYP/6-311++G(d,p) level of theory. Monomer
D1
D2
D3
C1 N11
1.313
1.312
1.316
1.313
N11 C1 N16
110.7
C1 N16
1.367
1.368
1.364
1.367
N11 C1 H17
127.1
C1 H17
1.078
1.078
1.078
1.078
N16 C1 H17
122.2
122.2
C2 N12
1.463
1.463
1.464
1.463
N12 C2 H18
110.1
C2 H18
1.091
1.091
1.091
1.091
N12 C2 H19
106.8
C2 H19
1.087
1.087
1.087
1.087
N12 C2 H20
C2 H20
1.091
1.091
1.091
1.091
H18 C2 H19
H3 N13
1.008
1.009
1.016
1.008
H4 N13
1.007
1.025
1.008
1.007
C5 C8
1.493
1.492
1.495
1.493
1.387
Monomer
D1
D2
110.7
110.6
110.7
127.0
127.1
122.4
122.2
110.2
110.1
110.1
106.8
106.8
106.8
110.1
110.2
110.1
110.1
110.3
110.3
110.3
110.3
H18 C2 H20
109.0
109.0
109.0
109.0
H19 C2 H20
110.3
110.3
110.4
110.3
C8 C5 C10
128.8
129.0
127.7
128.8
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Angle (0)
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1.387
1.387
1.387
1.374
1.373
1.374
1.374
C8 C5 N11
121.8
121.7
123.2
121.8
C10 C5 N11
109.3
109.3
109.1
109.3
C9 O6
1.207
1.207
1.207
C8 O7
1.218
1.232
1.22
1.207
C5 C8 O7
122.6
120.9
121.3
122.6
1.218
C5 C8 N13
113.1
114.4
114.5
113.1
C8 N13
1.362
1.344
C9 N12
1.381
1.381
1.358
1.362
O7 C8 N13
124.3
124.7
124.2
124.3
1.38
1.381
O6 C9 N12
125.5
125.4
125.7
125.5
1.405
1.403
O6 C9 N16
124.0
124.1
123.9
124.0
1.365
1.365
N12 C9 N16
110.5
110.5
110.4
110.5
1.399
1.399
C5 C10 N14
134.1
134.1
133.9
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127.1
D3
1.403
1.403
1.365
1.365
C10 N16
1.399
1.4
N12 N15
1.396
1.396
1.397
1.396
C5 C10 N16
105.0
105.0
105.2
105.0
N14 N15
1.260
1.26
1.259
1.26
N14 C10 N16
120.9
120.9
120.9
120.9
1.876
C1 N11 C5
107.6
107.6
107.7
107.6
1.876
C2 N12 C9
118.7
118.7
118.7
118.7
O27···H4 O7···H24
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C9 N16 C10 N14
O6···H37
2.228
C2 N12 N15
114.7
114.7
114.7
114.7
O26···H17
2.228
C9 N12 N15
126.7
126.6
126.7
126.7
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2.140
H3 N13 H4
120.7
121.0
119.1
120.7
N11···H23
2.140
H3 N13 C8
120.8
119.4
124.0
120.8
118.5
119.6
116.9
118.5
119.8
119.8
119.8
119.8
N12 N15 N14
120.0
119.9
120.0
120.0
C1 N16 C9
130.4
130.4
130.3
130.4
C1 N16 C10
107.4
107.3
107.4
107.4
C9 N16 C10
122.2
122.3
122.3
122.2
H17 O26···C29
161.4
158.0
N13 H3. ···N31
161.4
N13 H4···O27 N33 H24···O7
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H37 O6···C9
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172.3
172.3
158.0
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Fig. 1S. The optimized dimer structures of temozolomide molecule at DFT/6-311++G(d,p) level of theory.
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Fig. 2S. Density of state (DOS) spectrum of temozolomide molecule at DFT/6-311++G(d,p).
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(b)
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Fig. 3S. (a) Graphical representation of mode-mode coupling strength (b) Mode-mode coupling strength between some important modes (c) 2D
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graphical representation of anharmonic mode-mode coupling strength higher than 30 cm-1 in temozolomide molecule
S0022-2860(15)30114-9
DOI:
10.1016/j.molstruc.2015.07.002
Reference:
MOLSTR 21656
To appear in:
Journal of Molecular Structure
Received Date: 14 February 2015 Revised Date:
1 July 2015
Accepted Date: 1 July 2015
Please cite this article as: S.A. Bhat, S. Ahmad, Quantum chemical calculations and analysis of FTIR, FT-Raman and UV-Vis spectra of temozolomide molecule, Journal of Molecular Structure (2015), doi: 10.1016/j.molstruc.2015.07.002. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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ACCEPTED MANUSCRIPT Quantum chemical calculations and analysis of FTIR, FT-Raman and UV-Vis spectra of temozolomide molecule Sheeraz Ahmad Bhat, Shabbir Ahmad* Department of Physics, Aligarh Muslim University, Aligarh-202002, India
Abstract
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A combined experimental and theoretical study of the structure, vibrational and electronic spectra of temozolomide molecule, which is largely used in the treatment of brain tumours, is presented. FTIR (4000–400 cm-1) and FT-Raman spectra (4000 50 cm-1) have been recorded and analysed using anharmonic frequency calculations using VPT2, VSCF and CC-VSCF levels of theory within B3LYP/6-311++G(d,p) framework. Anharmonic methods give accurate frequencies of fundamental modes, overtones as well as Fermi resonances
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and account for coupling of different modes. The anharmonic frequencies calculated using VPT2 and CC-VSCF methods show better agreement with the experimental data. Harmonic frequencies including solvent effects are
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also computed using IEF-PCM model. The magnitudes of coupling between pair of modes have been calculated using coupling integral based on 2MR-QFF approximation. Intermolecular interactions are discussed for three possible dimers of temozolomide. UV-Vis spectrum, examined in ethanol solvent, is compared with the calculated spectrum at TD-DFT/6-311++G(d,p) level of theory. The electronic properties, such as excitation energy, frontier molecular orbital energies and the assignments of the absorption bands are also discussed. Keywords: Temozolomide, VPT2, VSCF, FTIR, FT-Raman, UV-Vis *Corresponding Author
[email protected]
Tel.: +91 9412501430
Introduction
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E-mail address:
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One of the most severe forms of human cancer is glioblastoma, which is a primary brain tumor [1]. Malignant gliomas (glioblastoma multiforme and anaplastic astrocytoma)
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occur more frequently than other types of primary central nervous system tumours. The media reported survival is less than 1 year even if these cancers are treated with surgery, radiation and chemotherapy [2]. Temozolomide (TMZ) is an orally administered alkylating agent, used largely in the therapy of malignant brain tumours including glioblastoma and astrocytoma, which are serious and aggressive types of brain cancers [3]. It readily crosses the blood-brain barrier and has a broad spectrum of antineoplastic activity [4 6]. Owing to the vast pharmaceutical importance, an attempt has been made in this study to interpret the vibrational and electronic spectra of TMZ.
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ACCEPTED MANUSCRIPT For proper understanding of vibrational spectra of molecules, theoretical methods ranging from semiempirical to DFT approaches are invaluable tools for reliable assignments of vibrational bands [7,8]. Structural and vibrational parameters predicted by theoretical methods often depend on the level of the theory, basis set and inclusion of correlation effects. DFT computations have become important in predicting the molecular structure and
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properties of biologically important compounds and drugs [9 12]. Harmonic frequency approximation is sometimes useful for rigid molecules, but has limited accuracy for flexible systems. Vibrational frequencies computed by the usual harmonic approximation overestimate the observed values partly because of strong anharmonic character of some
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vibrations [13 15]. Vibrational self-consistent field (VSCF) method is one of the approaches used to perform anharmonic vibrational calculations, which provides excellent results. The VSCF algorithm is included in GAMESS-US program [16] and has been extensively and
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successfully applied in recent years [17–20]. In the VSCF approach, each mode is assumed to be vibrating in the average field of other modes. Although, anharmonic frequency calculations using second-order perturbation (PT2) theories are of high computational cost, but the results are in close agreement with the experimental data [21–26]. The vibrational second order perturbation theory (VPT2) theory implemented by Barone in Gaussian package
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of programs is very useful and reasonably accurate for approximate calculations of low lying vibrational levels [27]. The correlation corrected vibrational self-consistent field (CC-VSCF) [28] method uses second order perturbation theory [29] and is more accurate than VSCF method within the separable approximation [30]. The CC-VSCF method employs directly ab
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initio potentials and for simple analytic force fields, it is viable for systems up to hundreds of normal modes [31].
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Extensive literature survey revealed that a little amount of work has been done on
TMZ [32–40]. The anticancer, antitumor activity and skin delivery potency of TMZ ester prodrugs have been reported [32,33]. Synthesis and structural evolution of TiO2 nanostructured reservoir with TMZ are reported [34]. UV spectrophotometric method has been developed for the quantitative determination of TMZ in bulk and capsule [35]. Highperformance liquid chromatographic analysis is carried out [36]. Some cocrystals of TMZ have been characterised by XRD, FTIR and FT-Raman analysis [37]. The feasibility of encapsulating TMZ into polybutylcyanoacrylate nanoparticles by polymerisation is reported [38]. The physiochemical characteristics of TMZ process-related impurities and their structure are studied [39]. Recently, the interaction between TMZ and water has been 2
ACCEPTED MANUSCRIPT reported [40]. To the best of our knowledge, the quantum chemical calculations and vibrational studies of TMZ molecule have not been carried out so far. In the present work, the optimised molecular geometrical parameters of the monomer and dimer structures of TMZ have been calculated using DFT method with 6-311++G(d,p) basis set. The anharmonic effects in the vibrational spectra are considered by VPT2 approach implemented by Barone
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[27], VSCF [30,41,42] based on two-mode representation quartic force field (2MR-QFF) potential energy function and CC-VSCF [28,43] methods. The effects of the intermolecular interactions on the vibrational spectra are studied by considering the three possible dimers of TMZ. Anharmonicity, which causes coupling between different vibrational modes, shifts the
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frequencies of the modes. In order to understand the coupling behaviour between pair of modes in TMZ, the magnitudes of two-mode coupling for the ground state are computed and discussed [44]. The electronic absorption spectrum in solution phase was also simulated
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using integral equation formalism of the polarisation continuum model (IEF-PCM) model at TD-B3LYP/6-311++G (d,p) level of theory. The theoretical results have been compared with experimental data (FTIR, FT-Raman, UV-Vis) and found to be in good agreement. Molecular electrostatic potential (MEP) mapping and HOMO–LUMO (highest occupied molecular
Experimental details
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orbital–lowest unoccupied molecular orbital) analysis of TMZ have also been presented.
The TMZ sample in solid form was obtained from Aldrich Chemicals, USA and used as such without further purification to record FTIR, FT-Raman and UV-Vis spectra. The
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FTIR spectrum was recorded at room temperature on Bruker tensor-37 spectrometer in the mid IR region (4000–400 cm-1) using KBr pellet technique, with a spectral resolution of 2
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cm-1. To increase the signal-to-noise ratio, a minimum of 32 scans were accumulated. The absorbance Aλ at a given wavenumber in FTIR spectrum was converted into epsilon value ελ (Lmol-1cm-1) using the Lambert-Beer law,
where, b is the thickness of the pellet and c is the concentration of the sample in mol L-1. The FT-Raman spectrum in solid phase was recorded at room temperature on Bruker RFS spectrometer in the region 4000-50 cm-1, with a spectral resolution of 2 cm-1, using 1064 nm line of Nd:YAG laser as excitation wavelength. The UV-Vis spectrum was recorded in
3
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solvent
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the
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spectrophotometer. Computational details The theoretical computations for the monomer and dimer structures of TMZ have
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been carried out by Gaussian 09 program using DFT level of theory with 6-311++G(d,p) basis set [45]. Electron correlations in the DFT are included using the Becke's threeparameter hybrid exchange functional (B3) [46–48] and the Lee Yang Par (LYP) correlation functional [49]. The optimized geometries were taken as the input structure for calculations , corresponding to an ith normal mode
the following relationship [50].
is the laser exciting wavenumber; f (a constant equal to 10–12) is a suitably chosen
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of harmonic and anharmonic vibrational frequencies, IR intensities and Raman activities. The
common normalization factor for all peak intensities; h is the Planck constant; k is the Boltzmann constant; c and T are the speed of light and temperature (298 Kelvin) respectively. Since, the vibrational spectra not only depend upon the bond strengths within molecules, but,
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also on the environments around them. The solvation methods are attractive due to their reliability coupled to computational costs comparable with those of the corresponding
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computations in gas phase [51]. Therefore, in order to provide an insight into solute-solvent interactions and to figure out to which extent the calculated results in solvent agree with the experimental observations, the harmonic frequencies in the monomer structure of TMZ were also computed in dimethyl sulfoxide (DMSO) using IEF-PCM model [52]. For the dimer structures, only harmonic approximation in gas phase was taken into account. Anharmonic corrections in vibrational frequencies for TMZ monomer were computed using VPT2 approach implemented by Barone, as well as, VSCF/2MR-QFF and CC-VSCF (PT2-VSCF) methods implemented into GAMESS-US package [16]. The broadening in computed IR and Raman spectra was simulated using Lorentzian line shape with FWHM as 6 cm-1. The vibrational spectra have been interpreted by means of visual inspection of animated modes 4
ACCEPTED MANUSCRIPT and potential energy distribution (PED) using VEDA 4 program [53]. In order to understand the coupling between pair of modes, the magnitudes of mode-mode coupling for the ground state have been estimated. The 2MR-QFF potential energy function was used for calculating anharmonic mode-mode coupling strengths [44,54]. For a reasonable estimate of the modemode coupling strengths, the two mode coupling terms can be expressed as quartic force field
,
,
,
are obtained by numerical differentiations of an analytical Hessian available in
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where,
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(QFF) as
GAMESS-US package. The expression for the two mode coupling integral for the first order correction of the ground state is then defined as
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where, |0⟩ is the ground state harmonic oscillator wavefunction [44]. TD-DFT/6-311++G(d,p) method, in combination with IEF-PCM model [51] in ethanol solvent, was used to calculate the excitation energies and oscillator strengths in TMZ. Furthermore, the HOMO and LUMO energies were predicted to interpret the orbital overlapping and the possibility of charge
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transfer within the molecule. The group contributions to the HOMO and LUMO orbitals were obtained by Gauss-sum 2.2 program [55].
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Results and discussion Geometric structure
The optimized geometries of TMZ monomer and dimer structures (D1, D2 and D3)
with atom numbering scheme are shown in Fig.1 and Fig.1S (supplementary data). respectively. The optimized bond lengths and bond angles of TMZ are given in Table 1S (supplementary data). Most of the calculated bond lengths and bond angles in monomer and dimer structures are same. The C H bond lengths in methyl group, C5 C8, C5 C10, N12 N15 and N14 N15 bonds in the monomer and dimer structures are equal. The 5
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Electronic spectra The TD-DFT method has become one of the most popular and widely used approaches for the calculation of properties, such as excitation energies, oscillator strengths and excited state geometries of medium to large molecular systems [56]. TD-DFT has been
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widely used to find out the low lying excited states of molecules on the basis of fully optimized ground-state structure [57]. The vertical excitation energies, absorption wavelengths and oscillator strengths (f) of TMZ molecule along with their assignments are
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given in Table 1. The pictorial representation of HOMO LUMO orbitals and energy gap of TMZ are shown in Fig.2 and the density of state spectrum is shown in Fig.2S. (supplementary data). The HOMO–LUMO energy gap characterizes the chemical activity, optical polarizibility and chemical hardness softness of the molecule [58]. The frontier molecular orbital energy gap is found to be 4.45 eV. The energy gap of (HOMO 1)–(LUMO+1) has
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been calculated to be 5.69 eV. A large HOMO–LUMO energy gap is an indication of high stability of TMZ. It can be seen from the HOMO–LUMO plots that HOMO is spread over the entire molecule except the NH2 group. The LUMO is also spread over the entire molecule except CH3 group. The experimental and simulated electronic spectra of TMZ are shown in
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Fig.3. The TD-DFT calculations in ethanol solution show three intense bands at 315, 252 and 207 nm having the oscillator strengths as 0.334, 0.1077 and 0.2545 respectively. These
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absorptions are found to be in good agreement with the experiment values. The maximum absorption wavelength, 317 nm, corresponds to HOMO→LUMO(94%) electronic transition. The absorption wavelengths, 245 and 206 nm, are assigned to HOMO→LUMO+1(83%) and HOMO→LUMO+2(50%) transitions respectively. The assignments of other transitions have also been shown in Table 1. Vibrational analysis The TMZ molecule consists of 20 atoms and, therefore, possesses 54 normal modes of vibration. Since the molecule is considered having C1 symmetry, all the vibrations are expected to be both IR and Raman active. The observed and calculated IR and Raman spectra 6
ACCEPTED MANUSCRIPT of TMZ have been compared in Fig.4 and Fig.5 respectively. It is observed from Fig. 4 that a large deviation between the experimental and theoretical IR intensities (Lmol-1cm-1) is observed, which may be due to the reason that computed values for epsilon only take account of the dipole term and various experimental colligative effects are not included. The comparison between computed harmonic and anharmonic wavenumbers is also shown in
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Fig.6. The calculated harmonic and anharmonic frequencies along with intensities and vibrational assignments are shown in Table 2. It is observed from Table 2, that the computed frequencies in gas phase at harmonic level overestimate the experimental data. However, the harmonic frequencies computed using IEF-PCM model show better performance than
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harmonic frequencies computed in gas phase. The RMS and MAD values also indicate higher precision of the DMSO computed harmonic frequencies with the experimental data for TMZ molecule. VPT2 and CC-VSCF theories within B3LYP frame work give better results than
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VSCF, as revealed by comparatively low RMS and MAD values. VPT2 method is of less computational cost, and performs better than VSCF and CCVSCF methods for most vibrational modes. VSCF and CC-VSCF methods perform well for the NH2 stretching modes. However, for lower wavenumbers, involving bending and torsional vibrations, no significant agreement is observed between VSCF and CC-VSCF computed frequencies and the
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experimental data. Also, overall average percentage error of 1.76% is observed for VPT2 as compared to an error of 2.16 and 1.99% for VSCF and CC-VSCF methods respectively. In the region, above 1500 cm-1, CC-VSCF method shows less percentage error (1.40%) as compared to 1.86 and 1.71% by VPT2 and VSCF methods respectively. However, in the
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Mode pair coupling strengths in the 2-mode coupling representations of the 2MR-
QFF, coupling strengths between some important pairs of modes and modes having the coupling strength larger than 30 cm-1 for TMZ are shown in Fig.3S (a), (b) and (c) (supplementary data) respectively. The assignments of the fundamental modes of TMZ molecule are discussed in the following sections. Carbonyl (C=O) group vibrations The carbonyl stretching vibrations have been widely studied by infrared spectroscopy. Since C=O group is highly polar in nature, strong and intense absorption bands are observed in the region 1700–1750 cm-1 [59,60]. C=O stretching vibrations are also very important as 7
ACCEPTED MANUSCRIPT they take part in hydrogen bonding. The C9=O6 stretching mode (mode 7) is observed at 1758 cm-1 with strong intensity in the IR spectrum of TMZ. The computed anharmonic wavenumbers are in agreement with the experimental frequency. The assignment is also in agreement with the literature [61–63]. The carbonyl group, C9=O6, is involved in hydrogen bonding in D3. The harmonic frequencies for this mode are 1779, 1778 cm-1 in D3. It is clear
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from Fig. 3S, that carbonyl vibrations are either not involved or weakly involved (< 30 cm-1). in coupling with other modes. Amide (CONH2) group vibrations
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The title molecule contains only one NH2 group. Therefore, one can expect six internal modes of vibration as symmetric (νsym) and asymmetric stretching (νasym), the symmetric planar deformation or scissoring (βs), the anti-symmetric planar deformation or
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rocking, the symmetric non-planar deformation or wagging (ω) and the anti-symmetric nonplanar deformation or torsion (τ). In all aromatic amines, NH2 stretching occurs in the 3300– 3500 cm-1 region [64]. In solid phase, the asymmetric and symmetric NH2 stretching vibrations appear at 3350 cm-1 and 3200 cm-1 respectively [64]. In TMZ, the medium intensity bands, observed in the IR spectrum at 3420 cm-1 (mode 1) and 3385 cm-1 (mode 2), are
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assigned to NH2 asymmetric and symmetric stretching vibrations respectively. Large deviations between the observed and calculated (VPT2) NH2 stretching frequencies are observed. The deviations are due to strong coupling of NH2 stretching modes (1 and 2) with mode 46 [Fig.3S]. These may also be due to the intermolecular hydrogen bonding, N H···O
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or N H···N, in D1 and D2 respectively. In dimer D1, the calculated frequencies for mode 1(3651,3650 cm-1) and mode 2 (3351,3311 cm-1) show better agreement to respective
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observed frequencies than those are in D2 and D3. The NH2 stretching modes show significant anharmonic corrections in VSCF and CC-VSCF levels of theory. The calculated frequencies of NH2 asymmetric and symmetric modes are 3483 and 3368 cm-1 respectively at CC-VSCF level of theory.
The NH2 scissoring vibration is usually observed in the region 1650 1620 cm-1 [65].
According to PED calculations, the NH2 scissoring mode is mixed with C C and C N stretching vibrations and contributes to mode 9 (57% PED) and 10 (22% PED). The vibrational frequencies observed at 1677 cm-1 and 1672 cm-1 in IR and Raman spectrum, respectively, are assigned to mode 9. Mode 10 has been observed at 1567 cm-1 in IR spectrum and at 1577 cm-1 in Raman spectrum. The computed anharmonic frequencies for mode 9 are 8
ACCEPTED MANUSCRIPT deviated from the observed frequencies. The deviation may be associated to the high anharmonicity of this mode [30]. Also, significant coupling strengths (>30 cm-1) are observed between mode pairs 9 and 1 as well as 9 and 2 [Fig.3S]. The deviations between the computed and observed wavenumbers for mode 9 are lower in D1 and D2 dimers. The NH2 rocking vibrations are observed in the region 1125 ± 45 cm-1 [66,67]. In the present study,
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this vibration is observed in mode 25 at 1095 cm-1 in the Raman spectrum. The anharmonic frequency, 1090 cm-1, calculated using VPT2 theory, is in close agreement with observed one. The non-planar modes (36 and 38) of the NH2 group have, respectively, 64% and 66% PED contribution from NH2 twisting vibrations. These modes are observed at 636 cm-1 in IR
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spectrum and at 583 cm-1 in Raman spectrum respectively. Mode 38 is strongly coupled to modes 46 and 48. The large deviations of the experimental and simulated anharmonic frequencies, corresponding to modes 36 and 38, may be due to the improper definition of
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potential energy surface or limitations in the Cartesian coordinate system [68]. The harmonic vibrational frequencies in monomer and D3, corresponding to mode 38, are in agreement with the observed frequency. The twisting vibration of NH2 group about C8–O7 bond (mode 54) is observed at 66 cm-1 in Raman spectrum. The NH2 wagging vibration, observed at 360 cm-1, is assigned to mode 45.
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The band due to the C=O stretching vibrations is often referred as the amide I band. It is generally observed in the region 1670–1650 cm-1 having strong intensity [65]. In the present study, C8=O7 stretching vibration (mode 8) is observed at 1733 cm-1 in IR spectrum. The corresponding anharmonic frequency, 1727 cm-1, predicted at VPT2 theory, is in
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agreement with the experimental frequency. Significant coupling between modes 8 and 54
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has also been predicted [Fig. 3S]. Methyl (CH3) group vibrations
Methyl groups are generally referred as an electron donating substitution in the
aromatic ring system. Since the title molecule contains only one CH3 group attached to the aromatic ring, nine fundamentals are expected. The C H stretching vibrations in CH3 group normally appear in the region 3010 2880 cm-1 [69–71]. In the present study, the anharmonic C H stretching frequencies of CH3 group, computed at VPT2 theory, have better agreement with the experimental wavenumbers. The C H asymmetric stretching vibration has been assigned to mode 4. The computed VPT2 anharmonic frequency, 3018cm-1, is ascribed to this mode. The symmetric C–H stretching vibration, computed at 2938 cm-1, is assigned to mode 9
ACCEPTED MANUSCRIPT 6. These vibrations are pure stretching vibrations as evident by PED values. The assignment of the CH3 stretching frequencies clearly signifies that these frequencies do not significantly depend on the surroundings of the functional group. The CH3 asymmetric bending modes, 12 and 14, have been observed at 1476 cm-1 and at 1403 cm-1 in Raman spectrum respectively. The CH3 symmetric bending frequency
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(umbrella motion) is not observed in IR and Raman spectra. The anharmonic frequencies, calculated at 1422 cm-1 (CC-VSCF), 1424 cm-1 (VSCF) and 1427 cm-1 (VPT2), correspond to the umbrella motion of methyl group. The CC-VSCF anharmonic frequencies, 1478 cm-1 and 1468 cm-1, are assigned to CH3 asymmetric bending vibrations. These assignments are within
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the region as reported in the literature [72–74,20]. The CH3 torsional mode generally appears in the low frequency region and is assigned to mode 52 with 72% PED contribution. The
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Raman frequency for this mode is observed at 105 cm-1. The harmonic wavenumbers, 104 and 103 cm-1 in D3, are in agreement with the observed wavenumbers. C-X vibrations
The C–H stretching vibrational bands normally appear in the region 3080–3010 cm-1 [65,71]. The intense band, observed at 3121 cm-1 in the IR spectrum and at 3115 cm-1 in
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Raman spectrum, shows the presence of C1–H17 stretching frequency. It is animated as pure stretching and is assigned to mode 3. The frequency, 3129 cm-1, computed at VPT2 level of theory, is in agreement with the observed frequency. As evident from Fig.3S, strong coupling
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is observed between modes 3 and 30. Mode 3 is also significantly coupled to mode 22 and 14. The C1 H17 in-plane bending vibrations, mixed with other vibrations, have contributions in mode 22, 23 and 26. The IR bands observed at 1176, 1143 and 1046 cm-1 are assigned to
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these bending modes. These assignments are well within the reported regions [20,75]. Ring vibrations
The ring stretching vibrations are complicate combinations of mainly C C, C N and
N N vibrations. The assignment of these vibrations is a difficult task, since the mixing of the vibrations occurs. In our work, mode 10 has been assigned to C C stretching vibration mixed with NH2 scissoring and C N stretching vibrations. The most important ring stretching vibration is the ring breathing in which all bonds of the ring stretch and contract inphase. It is predicted at 699 cm-1 in mode 33 using CC-VSCF method. The computed frequency for the breathing mode is in close agreement with the literature [76,77]. Another 10
ACCEPTED MANUSCRIPT important vibration is the butterfly motion in TMZ. This vibration presents a mixed profile and has been assigned to mode 48. The frequency of this mode has been observed at 261 cm-1 in Raman spectrum and well predicted at 257 cm-1 by DFT method. Conclusions
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In the present study, the geometrical parameters of the monomer and dimer structures of temozolomide have been calculated using DFT method with 6-311++G(d,p) basis set. The hydrogen bonding interactions between two monomeric units of the title molecule are also studied. The assignments of FTIR and FT-Raman spectra are supported by the anharmonic
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calculations using VPT2 method, VSCF and CC-VSCF approaches within the DFT framework. VPT2 and CC-VSCF theories within B3LYP framework give better results than VSCF, as revealed by comparatively low RMS and MAD values. However, VPT2 has lesser
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computational cost, at least an order of magnitude cheaper than VSCF and CC-VSCF. The harmonic frequencies computed using IEF-PCM model have a better agreement than the DFT/6-311++G(d,p) computed harmonic frequencies. In general, a good agreement between the experimental and calculated frequencies has been achieved. The deviations of the NH2 stretching modes from the experiment are observed due to the high anharmonicity associated
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with these modes or the neglect of higher order terms in potential expression. These modes are corrected well by VSCF and CC-VSCF approaches than VPT2 algorithm. UV Vis experimental and calculated data are in agreement with each other. The HOMO and LUMO energy eigenvalues support the charge transfer within the molecule.
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Acknowledgements
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We gratefully acknowledge the UGC (DRS) and DST (FIST) for the sanction of grants for FTIR and UV-Vis-NIR spectrophotometer. We also acknowledge the SAIF IIT Chennai for using FT-Raman facility. The author (Sheeraz Ahmad Bhat) is thankful to the UGC, New Delhi, India for the financial assistance. References
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ACCEPTED MANUSCRIPT [73]. I.L. Tocon, M.S. Wooley, J.C. Oetero, J.I. Marcos, J. Mol. Struct. 470 (1997) 241 246. [74]. N.B. Colthup, L.H. Daly, S.E. Wiberley, Introduction to Infrared and Raman Spectroscopy, Second Edition, Academic Press, 1975. [75]. P.B. Nagabalasubramanian, S. Periandy, Spectrochim. Acta A 77 (2010) 1099 1107. [76]. R. Santamaria, E. Charro, A. Zacarias, M. Castro, J. Comput. Chem. 20 (1999) 511–530.
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[77]. A.Y. Hirakawa, H. Okada, S. Sasagawa, M. Tsuboi, Spectrochim. Acta A 41 (1985) 209–216.
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206
5.96
B3LYP/6-311++G(d,p) Composition (˃5%)
320
0.001
3.87
H-1→LUMO (89%), H-3→LUMO (9%)
315
0.334
3.94
HOMO→LUMO (94%)
296
0.004
4.19
H-3→LUMO (89%), H-1→LUMO (8%)
275
0.0246
4.50
H-2→LUMO (99%)
252 243 233
0.1077 0.0007 0.0001
4.93 5.11 5.32
HOMO→L+1 (83%), H-4→LUMO (7%) H-5→LUMO (98%) H-3→L+1 (23%), H-1→L+1 (66%), H-7→LUMO (8%)
231
0.0001
5.38
H-7→LUMO (73%), H-1→L+1 (15%)
230
0.0125
5.38
H-6→LUMO (13%), H-4→LUMO (76%)
223
0.0005
5.56
217
0.0026
5.72
H-7→LUMO (12%), H-3→L+1 (68%), H-1→L+1 (14%) H-2→L+1 (89%), HOMO→L+2 (7%)
216
0.000
214
0.0896
207
0.2545
202
0.003
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5.01
E (ev)
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245
3.87
(f)
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317
λcal(nm)
5.75
H-1→L+2 (86%)
5.80
5.98
H-6→LUMO (37%), H-4→LUMO (13%), HOMO→L+2 (33%), H-2→L+1 (9%), H-6→LUMO (41%), HOMO→L+2 (50%)
6.13
H-5→L+1 (84%), H-7→L+1 (9%)
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Experimental λobs(nm) E (ev)
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Table 1 Theoretical and experimental UV spectral characteristics of temozolomide.
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Abbreviations used: λ- Excitation wavelength, E-Excitation energy, H-Homo, L-Lumo, f-Oscillator strength
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A VPT2 km/mol 3544 84.9 3427 60.3 3129 6.4 3018 0.2 2973 8.4 2938 23.3 1760 559.2 1727 346.1 1571 275.5 1549 4.6 1504 20.6 1485 15.5 1451 121.5 1449 12.3 1427 0.3 1375 2.1 1337 217.7 1300 1.8 1282 69.7
R 18.914 58.592 31.229 24.478 42.451 138.989 42.578 77.902 272.066 476.751 429.468 69.893 164.019 31.767 27.860 411.713 276.603 138.330 127.154
D1 3651,3650 3351,3311 3268,3268 3169,3169 3124,3124 3058,3058 1795,1794 1740,1720 1635,1621 1588,1585 1537,1537 1506,1506 1491,1491 1481,1481 1447,1447 1432,1426 1391,1388 1346,1345 1319,1319
D2 3672,3672 3476,3476 3268,3268 3170,3170 3126,3126 3060,3059 1796,1795 1751,1749 1636,1635 1583,1583 1537,1537 1506,1506 1491,1487 1481,1481 1448,1448 1416,1415 1378,1374 1345,1344 1319,1318
CCVSCF VSCF D3 3723,3723 3493 3483 3585,3585 3379 3368 3251,3249 3064 3090 3170,3170 2989 2980 3125,3125 2932 2904 3059,3059 2919 2899 1779,1778 1759 1759 1760,1760 1720 1720 1608,1607 1573 1596 1583,1583 1554 1553 1540,1539 1518 1516 1506,1506 1477 1478 1490,1488 1468 1469 1482,1482 1471 1468 1448,1448 1424 1422 1411,1410 1387 1384 1374,1372 1349 1344 1335,1335 1311 1308 1323,1322 1299 1295
Aa km/mol R 85.2 23.7 55.16 52.4 5.16 32.6 0.15 16.3 7.98 33.2 30.81 147.5 554.21 44.0 334.76 76.5 275.09 275.5 7.03 423.8 7.33 528.2 27.01 44.1 17.94 27.7 119.47 784.3 7.01 19.4 0.88 327.2 225.92 299.4 0.14 165.7 60.47 175.0
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Har 3723 3586 3270 3170 3125 3059 1795 1760 1607 1580 1537 1506 1489 1481 1448 1410 1372 1339 1317
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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19
B3LYP/6-311++G(d,p) Har/Vacuum
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M
Observed wavenumbers (cm-1) IEF-PCM/DMSO FTIR FT-Raman A Har km/mol R 3420m 3706 135.0 28.268 3385m 3576 133.0 102.531 3121s 3115m 3275 10.3 68.873 3007w 3179 1.0 52.429 2961m 3139 10.1 81.947 3068 29.3 280.716 1758vs 1763 1046.5 178.823 1733vs 1732m 1692 768.6 201.251 1677vs 1672m 1600 482.2 1239.815 1567sh 1577vs 1580 11.0 1925.051 1528 29.6 1384.831 1476m 1495 65.8 228.208 1452s 1454s 1488 219.7 615.391 1403m 1403s 1470 20.3 56.664 1445 3.5 139.182 1411 26.1 1618.421 1356s 1356vvs 1377 418.9 1266.650 1300vw 1304s 1349 11.7 503.462 1264s 1269s 1308 135.3 632.473
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Table 2 Comparison of the calculated and experimental (FTIR and FT-Raman) vibrational spectra of temozolomide.
20 21 1215w 22 1176vw
1224s 1183w
1285 1237 1232
266.6 62.4 20.3
167.946 986.661 77.528
1279 1249 165.2 1236 1207 21.2 1227 1200 6.5
50.351 274.673 21.053
1290,1287 1283,1280 1243,1241 1238,1237 1231,1230 1228,1226
1285,1283 1233,1232 1243,1241
1258 1221 1209
1256 1218 1206
175.13 68.8 28.22 220.8 41.16 49.4
23 1143vw 24 1109vw 25 26 1046m
1112w 1095w 1050w
1195 1146 1092 1052
26.7 0.1 6.3 85.8
69.895 1.691 328.060 198.206
1191 1150 1094 1051
9.8 0.2 3.7 38.8
17.179 2.627 113.560 65.603
1192,1192 1149,1149 1136,1132 1055,1054
1193,1192 1149,1149 1094,1094 1056,1054
1161 1146 1084 1038
1157 1143 1077 1036
2.9 0.4 3.58 38.25
19.3 23.5 102.3 99.6
27 1005w
1003w
1013
40.8
104.748
1010 989
24.5
18.066
1013,1013 1014,1012
1010,1010
996
994
33.28
23.3
28 29 30 31 32 33 34 35 36
946s
955w
850w 804w 736m
847w 791m
707m
703s
946 852 841 795 744 704 701 665 665
376.8 9.3 9.5 8.7 37.3 2.6 4.6 100.4 20.7
349.599 152.749 15.817 78.539 7.871 143.128 41.342 220.613 2.775
929 852 831 793 742 699 697 689 665
179.4 12.0 8.1 4.3 22.0 0.7 1.2 55.8 14.6
57.326 25.612 2.458 20.000 1.411 56.051 14.105 62.719 1.666
929,927 852,852 831,831 805 743,743 700,700 697,694 722,711 652,649
926,923 852,850 875,871 791,791 741,741 700,699 695,695 690,690 667,667
917 838 900 812 743 701 707 686 695
913 836 893 814 743 699 705 684 684
120.46 13.66 9 3.71 21.42 1.16 0.72 60.04 12
65.0 34.5 67.7 16.1 5.7 46.1 28.7 60.4 0.2
636w
898 836 842 814 746 689 709 682 659
EP
1191,1190 1150,1150 1101,1094 1056,1053
AC C
1162 1126 1090 1029
928,928 852,852 835,835 815,803 742,739 703,702 686,679 697,697 648,630
PED ( ≥5%)
νas [NH2] (99) νsy [NH2] (99) ν [C1-H17] (99) νas [CH3] (90) νas [H20-C2-H18] [in CH3] (100) νsy [CH3] (90) ν [C9=O6] (83) ν [C8=O7] (80) scis [NH2] (57) + ν [C5-C10 + C5-C8] (15)] + ν [C8-N13] (6) ν [C5-C10] (45) + scis [NH2] (22) + ν [C5-C8] (6) + ν [C1-N11] (5) ν [N14-N15] (61) + ν [C1-N11 + C9-N12] (10) βas [CH3] (66) ν [N11-C1 +N16-C1] (33) +β [H17-C1-N16] (23) + ν [C10-N16] (9) βas [CH3] (75) umb [CH3] (84) ν [N16-C1 + N13-C8] (28) + ν [C5-C8] (5) ν [NC] (34) + ν [C5-C8] (12) + β [NH2] (5) ν [N16-C10 + N13-C8] (30) + β (CNN) (16) + β (C10-C5-N11) (11) + β [H14-N13-C8] (6) ν [N12-C2 + N12-C9] (23) + ν [N13-C8 + N11-C1] (19) + β [CNN] (15) + β [C10-C5-N11] (10) + β [CH3] (9) ν [N11-C5 + N13-C8] (43) + β [N16-C1-N11] (8) + β [C8-N13-H4] (8) + roc [CH3] (6) τ [HCNC] (25) + ν [N-C] (21) + roc [CH3] (10) + β [N13-C8-O7] (4) β [C1-H17](29) + τ [H18-C2-N12-C9] (15) + ν [N11-C1 + N11-C5 + N13-C8 ] (17) + roc [CH3] (7) + β [C5-N10-N14] (5) β [C1-H17] (19) + roc [NH2] (10) ν [N-C] (7) + roc [CH3] (7) + ν [N-N] (5) τ [H18-C2-N12-C9 + H19-C2-N12-C9 + H20-C2-N12-C9] (60) + roc [CH3] (26) roc [NH2] (58) + ν [O7-C8] (9) + ν [N11-C5 + N13-C8 + N16-C1] (8) β [N16-C9-O6] (23) + ν [N12-C2] (15) + β [C1-H17] (7) + β [ C1-N11-C5 + C10-C5-C11 + C10-N14N15] (6) ν [N12-C9 + N13-C8 + N16-C1] (31) + β [N16-C9-O6] (11) + β [C5-C8-N13+ C5-C10-N14+ C1N11-C5] (7) ν [N12-N15] (21) + τ [H17-C1-N11-C5] (17)β [N16-C9-O6] (11) + ν [N16-C1] (8) + roc [CH3] (5) β [Rr] (52) + ν [N12-CH3] (22) + β [CCN] (7) + β [C10-N14-N15] (5) γ [H17-C1] (86) τ [C1-N11-C5-C10] (71) + γ [C8-C10-N11-C5] (6) γ [O6-N12-N16-C9] [85] ν [Rr] (43) τ [C1-N11-C5-C10] (72) + γ [O6-N12-N16-C9] (6) + γ [N14-C5-N16-C10] (7) β [N13-C8-O7] (25) + ν [C8-C5] (15) + roc [NH2] (7) + β [N12-N14-N15] (7) twi [NH2] (64) + τ [H17-C1-N11-C5] (9) + γ [N14-C5-N16-C10] (8)
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562m 512m 479vw
508w 472s
360m 333m 280w
620 587 578 547 512 469 331 324 316 303 269
10.6 8.3 13.8 0.3 46.6 3.9 11.2 11.5 323.0 2.4 11.2
245.723 7.718 96.142 1.249 25.889 227.123 209.133 160.537 41.209 32.904 9.636
605 590 574 541 510 468 331 319 301 300 251
591 561 566 557 503 461 329 323 377 294 280
5.5 4.9 10.8 0.2 26.1 2.0 6.3 6.9 202.3 1.0 8.4
64.712 6.008 54.147 0.193 22.343 98.635 115.832 50.588 21.881 19.196 3.611
612,609 552,550 589,587 552,550 515,512 477,476 357,353 322,320 526,522 308,305 259,255
604,580 599 581,580 556,551 508,508 471,463 338,338 319,319 445 301,301 258,254
604,604 591,591 575,574 542,542 511,510 470,469 331,331 322,322 296,295 302,302 250,249
596 732 572 582 502 464 348 329 307 571 313
5.17 8.38 10.48 1.12 27.52 1.79 12.78 1.51 3.31 147.01 23.42
74.6 11.6 57.3 5.1 31.2 82.6 6.0 153.5 38.1 65.1 2.2
ν [N12-N15] (42) + β [CNN] (14) + β [N12- C9-O6] (7) twi [NH2] (66) + τ [C10-N14-N15-N12] (20) β [N13-C8-O7] (47) + ν [N12-N15] (10) + β [C9-N12-N15] (9) + roc [NH2] (5) τ [C10-N14-N15-N12] (66) + twi [NH2] (17) + τ [C5-N11-C1-N16] (7) β [CNN] (50) + β [CCN] (6) β [CCN] (25) + ν [C5-C8] (12) + β [N13-C8-O7] (9) + β [C5-C8-N13] (5) β [C5-C8-N13] (28) + ν [C8-C5] (18) + ν [C5-C10] (11) + N16-C9-O6 ] (7) +β [CNC] (10) β [N15-N12-CH3] (48) + [N16-C9-O6] (9) ω [NH2] (82) + τ [N13-C8-C5-C10] (5) β [NCO] (41) + β [C5-C8-N13 + C5-C10-N14] (26) + β [C10-N14-N15] (7) γ [C2-C9-N15-N12] (63) + γ [N14-C5-N16-C10] (16) + τ [H18-C2-N12-C9 + H19-C2-N12-C9 + H20-C2N12-C9] (7) τ [Rr] (68) + ω [NH2] (12) + γ [C8-C10-N11-C5] (5) γ [C2-C9-N5-N12] (67) + γ [C8-C10-N11-C5] (6) β [C5-C8- N13] (76) + β [C15-C12-CH3] (6) + β [C5-C10-N14] (5) τ [C1-N11-C5-C10] (56) + γ [C2-C9-N15-N12] (12) + γ [N14-C5-N16-N10] (8) τ [CH3] (72) + τ [N15-N14-C10-N16] (7) γ [C8-C10-N11-C5] (70) + τ [C1-N11-C5-C10] (11) + γ [O6-N12-N16-C9] (5) twi [O7-C8-NH2] (85)
242 0.5 9.290 236 257 7.1 3.695 255,245 242,240 235,235 343 316 9.99 29.3 210 11.2 147.160 194 242 4.9 31.635 203,200 202,198 190,189 272 246 15.15 174.4 22.176 178,175 151,145 138,137 141 139 8.32 27.8 142 13.7 33.755 136 134 8.3 116 3.3 1.620 111 123 4.9 0.047 114,112 118,113 114,110 319 272 0.26 244.8 105sh 102 3.0 103.919 95 174 1.1 52.654 96,93 92,92 104,103 122 122 5 118.0 40.956 69,67 116 95 0.84 164.6 81vvs 73 0.01 104.445 67 75 0.1 71 69 66s 50 13.2 167.531 47 70 3.1 69.057 78,76 47,44 98 93 2.29 64.8 77 RMS 78 81 36 36 31 MAD 45 47 23 25 23 Abbreviation used: M-modes, Har-harmonic wavenumbers,Anh-Anharmonic wavenumbers, A- harmonic IR intensity, R- Raman intensity (arb. unit), ν- stretching, sy- symmetric, as- asymmetric, β- bending, βas - antisymmetric bending, τ- torsional, τ Rr-butterfly motion, scis- scissoring, roc- rocking, ω- wagging, twi- twisting, umb- umbrella motion, γ- out of plane vibrations, w- weak, m- medium strong, sh- shoulder, s- strong, vs- very strong , vvs- very very strong, Aa-VSCF anharmonic IR intensity, bold letter specifies the frequency having high IR intensity than the other one in dimer.
TE D
M AN U
SC
261w 237w 130s
595 726 569 576 501 463 347 327 304 570 290
RI PT
610s 583w
EP
48 49 50 51 52 53 54
606sh
AC C
37 38 39 40 41 42 43 44 45 46 47
ACCEPTED MANUSCRIPT Fig. 1. The optimized structure of temozolomide molecule at DFT/6-311++G(d,p) level of theory with atom numbering scheme. Fig. 2. Frontier molecular orbitals of temozolomide molecule in gas phase at DFT/6-311++G(d,p) level of theory. Fig. 3. Experimental and simulated UV spectrum (TD-DFT/6311++G(d,p) of temozolomide
RI PT
molecule. Fig. 4. Comparison of the experimental FTIR and theoretical anharmonic spectra of temozolomide molecule at B3LYP/6-311++G(d,p) level of theory.
Fig. 5. Comparison of the experimental FT-Raman and theoretical Raman spectra of
SC
temozolomide molecule at B3LYP/6-311++G(d,p) level of theory.
Fig. 6. Comparison of the computed harmonic and anharmonic spectra of temozolomide
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M AN U
molecule at B3LYP/6-311++G(d,p) level of theory
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SC
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SC
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Research highlights FTIR, FT-Raman and UV-Vis spectra were recorded and analysed.
•
Anharmonic frequencies were computed by VPT2, VSCF and CC-VSCF methods.
•
Mode-Mode coupling strengths were computed using 2MR-QFF.
•
The existence of intermolecular hydrogen bonding was investigated.
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•
ACCEPTED MANUSCRIPT
Supplementary Materials
Bond length
Bond
RI PT
Table 1S. Optimized geometrical parameters (bond lengths and bond angles) of monomer and dimer structures of temozolomide at B3LYP/6-311++G(d,p) level of theory. Monomer
D1
D2
D3
C1 N11
1.313
1.312
1.316
1.313
N11 C1 N16
110.7
C1 N16
1.367
1.368
1.364
1.367
N11 C1 H17
127.1
C1 H17
1.078
1.078
1.078
1.078
N16 C1 H17
122.2
122.2
C2 N12
1.463
1.463
1.464
1.463
N12 C2 H18
110.1
C2 H18
1.091
1.091
1.091
1.091
N12 C2 H19
106.8
C2 H19
1.087
1.087
1.087
1.087
N12 C2 H20
C2 H20
1.091
1.091
1.091
1.091
H18 C2 H19
H3 N13
1.008
1.009
1.016
1.008
H4 N13
1.007
1.025
1.008
1.007
C5 C8
1.493
1.492
1.495
1.493
1.387
Monomer
D1
D2
110.7
110.6
110.7
127.0
127.1
122.4
122.2
110.2
110.1
110.1
106.8
106.8
106.8
110.1
110.2
110.1
110.1
110.3
110.3
110.3
110.3
H18 C2 H20
109.0
109.0
109.0
109.0
H19 C2 H20
110.3
110.3
110.4
110.3
C8 C5 C10
128.8
129.0
127.7
128.8
SC
Angle (0)
M AN U
(Å)
1.387
1.387
1.387
1.374
1.373
1.374
1.374
C8 C5 N11
121.8
121.7
123.2
121.8
C10 C5 N11
109.3
109.3
109.1
109.3
C9 O6
1.207
1.207
1.207
C8 O7
1.218
1.232
1.22
1.207
C5 C8 O7
122.6
120.9
121.3
122.6
1.218
C5 C8 N13
113.1
114.4
114.5
113.1
C8 N13
1.362
1.344
C9 N12
1.381
1.381
1.358
1.362
O7 C8 N13
124.3
124.7
124.2
124.3
1.38
1.381
O6 C9 N12
125.5
125.4
125.7
125.5
1.405
1.403
O6 C9 N16
124.0
124.1
123.9
124.0
1.365
1.365
N12 C9 N16
110.5
110.5
110.4
110.5
1.399
1.399
C5 C10 N14
134.1
134.1
133.9
134.1
EP
TE D
C5 C10 C5 N11
127.1
D3
1.403
1.403
1.365
1.365
C10 N16
1.399
1.4
N12 N15
1.396
1.396
1.397
1.396
C5 C10 N16
105.0
105.0
105.2
105.0
N14 N15
1.260
1.26
1.259
1.26
N14 C10 N16
120.9
120.9
120.9
120.9
1.876
C1 N11 C5
107.6
107.6
107.7
107.6
1.876
C2 N12 C9
118.7
118.7
118.7
118.7
O27···H4 O7···H24
AC C
C9 N16 C10 N14
O6···H37
2.228
C2 N12 N15
114.7
114.7
114.7
114.7
O26···H17
2.228
C9 N12 N15
126.7
126.6
126.7
126.7
ACCEPTED MANUSCRIPT N31···H3
2.140
H3 N13 H4
120.7
121.0
119.1
120.7
N11···H23
2.140
H3 N13 C8
120.8
119.4
124.0
120.8
118.5
119.6
116.9
118.5
119.8
119.8
119.8
119.8
N12 N15 N14
120.0
119.9
120.0
120.0
C1 N16 C9
130.4
130.4
130.3
130.4
C1 N16 C10
107.4
107.3
107.4
107.4
C9 N16 C10
122.2
122.3
122.3
122.2
H17 O26···C29
161.4
158.0
N13 H3. ···N31
161.4
N13 H4···O27 N33 H24···O7
SC
H37 O6···C9
RI PT
H4 N13 C8 C10 N14 N15
172.3
172.3
158.0
AC C
EP
TE D
M AN U
N11 H23···N33
Fig. 1S. The optimized dimer structures of temozolomide molecule at DFT/6-311++G(d,p) level of theory.
TE D
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SC
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AC C
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Fig. 2S. Density of state (DOS) spectrum of temozolomide molecule at DFT/6-311++G(d,p).
M AN U
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(b)
TE D
(a)
(c)
Fig. 3S. (a) Graphical representation of mode-mode coupling strength (b) Mode-mode coupling strength between some important modes (c) 2D
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graphical representation of anharmonic mode-mode coupling strength higher than 30 cm-1 in temozolomide molecule