Spectral and structural studies of the anti-cancer drug Flutamide by density functional theoretical method

Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 604–613

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Spectral and structural studies of the anti-cancer drug Flutamide by density functional theoretical method G. Mariappan, N. Sundaraganesan ⇑ Department of Physics (Engg.), Annamalai University, Annamalainagar 608 002, India

555

1018 1718

1602

IR intensity (arb units) 4 0 0 0

3 5 0 0

3 0 0 0

2 0 0 0

1 5 0 0

1345

1139

1244

655

903

839 2 5 0 0

1541

1717

Experimental

713

2642 2563 2468 3127 3055 2984 2919

1975

1496

1339

1127

B3LYP/6-31G(d,p)

3360

calculated by DFT method and compared.  UV–Vis spectra were recorded and compared with calculated ones.  NMR and NBO analysis were also carried out.

Transmittance (%)

Flutamide were recorded.  The vibrational frequencies were

3484

 The FTIR and FT-Raman spectra of

880

g r a p h i c a l a b s t r a c t 2999 2932

h i g h l i g h t s

1 0 0 0

5 0 0

Wavenumber (cm -1)

a r t i c l e

i n f o

Article history: Received 5 July 2013 Received in revised form 4 September 2013 Accepted 7 September 2013 Available online 18 September 2013 Keywords: Flutamide DFT Vibrational assignments UV–Vis HOMO–LUMO NMR

a b s t r a c t A comprehensive screening of the more recent DFT theoretical approach to structural analysis is presented in this section of theoretical structural analysis. The chemical name of 2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide is usually called as Flutamide (In the present study it is abbreviated as FLT) and is an important and efficacious drug in the treatment of anti-cancer resistant. The molecular geometry, vibrational spectra, electronic and NMR spectral interpretation of Flutamide have been studied with the aid of density functional theory method (DFT). The vibrational assignments of the normal modes were performed on the basis of the PED calculations using the VEDA 4 program. Comparison of computational results with X-ray diffraction results of Flutamide allowed the evaluation of structure predictions and confirmed B3LYP/6-31G(d,p) as accurate for structure determination. Application of scaling factors for IR and Raman frequency predictions showed good agreement with experimental values. This is supported the assignment of the major contributors of the vibration modes of the title compound. Stability of the molecule arising from hyperconjugative interactions leading to its bioactivity, charge delocalization have been analyzed using natural bond orbital (NBO) analysis. NMR chemical shifts of the molecule were calculated using the gauge independent atomic orbital (GIAO) method. The comparison of measured FTIR, FT-Raman, and UV–Visible data to calculated values allowed assignment of major spectral features of the title molecule. Besides, Frontier molecular orbital analyze was also investigated using theoretical calculations. Ó 2013 Elsevier B.V. All rights reserved.

Introduction Flutamide (FLT) is an unusual example of an antiandrogenic drug lacking a steroidal structure. Flutamide, a widely used ⇑ Corresponding author. Tel.: +91 9442068405. E-mail address: [email protected] (N. Sundaraganesan). 1386-1425/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.saa.2013.09.043

nonsteroidal antiandrogen drug for the treatment of prostate cancer, has been associated with rare incidences of hepatotoxicity in patients. It is believed that bioactivation of FLT and subsequent covalent binding to cellular proteins is responsible for its toxicity. It is used increasingly as part of total androgen ablation therapy and in neoadjuvant treatment before radical prostatectomy [1]. Although very useful and almost indispensable, it can produce

G. Mariappan, N. Sundaraganesan / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 604–613

parameters, have become an accepted technique to gather insight into the molecular structure. Experimental details The compound Flutamide (solid state, light yellow crystalline powder) was obtained from Sigma–Aldrich Chemical Company with a stated purity 99% and used as such without any further purification. The FTIR spectrum of the sample was carried out between 400 and 4000 cm1 on a JASCO FT-IR-6300, spectrometer. The FT-Raman spectrum of the sample recorded using 1064 nm line of an Nd–YAG laser as the excitation wavelength in the region of 50–3500 cm1 on a Bruker RFS 100/S FT-Raman spectrometer. The detector is a liquid nitrogen cooled Ge detector. Five hundred scans were accumulated at 1 cm1 resolution using a laser power of 100 mW. The UV absorption spectrum of FLT molecule dissolved in Methanol and Ethanol is examined in the range 200–800 nm using Shimadzu UV-1800 PC, UV–Vis recording spectrometer. Data were analyzed by UV PC personal spectroscopy software, version 3.91. The experimental FT-IR and FT-Raman spectra along with the theoretically simulated IR and Raman spectra using DFT/ B3LYP/6-31G(d,p) level of calculations are shown in Figs. 1 and 2. The spectral measurements were carried out at Indian Institute of Technology, Chennai, India. Computational details

555

1018 1718

1602

IR intensity (arb units)

880

Quantum chemical calculations were used for FLT to carry out the optimized geometry and vibrational wavenumbers with 03 version of the Gaussian program [11]. The vibrational modes were assigned by means of visual inspection using the Gauss View

2999 2932

3484

adverse biological effects such as clinical photosensitization which has been recognized to result from FLT [2]. FLT can cross the placental barrier and thus can have an impact on fetal development [3]. The capabilities of DFT method to reproduce the structural features of benzamides, particularly in relation with intramolecular and intermolecular C–H- - - -O hydrogen bonds, were also evaluated. Crystal and molecular structure analysis of FLT and then bifurcated helicoidal C–H. . .O hydrogen bonds have been analyzed by Cense et al. [4]. Vargas et al. [5] have investigated photochemistry and phototoxicity studies of Flutamide, a phototoxic anti-cancer drug. Payen et al. [6] studied synthesis and biological activity of ferrocenyl derivatives of the non-steroidal antiandrogens Flutamide and bicalutamide. A comparison between two doses of Flutamide (250 mg/d and 500 mg/d) in the treatment of hirsutism have analyzed by Muderris et al. [7]. The detailed study and an electrochemical evidence of free radicals formation from Flutamide and its reactivity with endo/xenobiotics of pharmacological relevance investigated by Vergara et al. [8]. In the present study, we have used the density functional theory approach which was preferred in order to include exchange correlation functions and to obtain an accurate electron density from the Kohn–Sham equations [9,10]. FTIR and FT-Raman spectroscopy have been established as a useful technique to obtain information about the influence of structural analysis of certain molecule in the solid-state. The experimental wave numbers of both FTIR and FT-Raman were reproduced fairly well by DFT calculations at the B3LYP/6-31G(d,p) level. In addition to the theoretical vibrational spectrum, density functional methods have also been used to calculate the molecular geometry, the atomic charges and some other molecular properties. Furthermore, the combination of DFT calculations of chemical shifts and harmonic vibrations with nuclear magnetic resonance (NMR), FTIR and FT-Raman experimental

3500

3000

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3127 3055

Transmittance (%)

2642 2563 2468

1496

1339

1127

B3LYP/6-31G(d,p)

4000

605

1000

-1

Wavenumber (cm ) Fig. 1. Comparison of experimental and theoretical (B3LYP/6-31G(d,p)) FT-IR spectra for FLT.

500

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212

667

1345

851

1099 1015

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1496 1718

3002 2934

3115

3485

Raman Intensity (arb units)

B3LYP/6-31G(d,p)

106

1586

1338

606

3500

3000

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2000

1500

86

1000

458

761

901

1245

1123 1040

1721

2948

3081

1598

Experimental

500

Wavenumber (cm -1) Fig. 2. Comparison of experimental and theoretical (B3LYP/6-31G(d,p)) FT-Raman spectra for FLT.

program [12]. The basis set 6-31G(d,p) augmented by ‘d’ polarization functions on heavy atoms and ‘p’ polarization functions on hydrogen atoms were used for better description of polar bonds of molecules [13–14]. It should be emphasized that ‘p’ polarization functions on hydrogen atoms are useful not only for reproducing the out-of-plane vibrations involving hydrogen atoms but also for a better description of the molecular geometry and other normal vibrational modes. The vibrational assignments of the normal modes were also made on the basis of the PED calculated by using the VEDA 4 program [15]. Subsequent potential energy distribution (PED) to each observed frequencies, predicts well the purity of the fundamental modes and shows the reliability and accuracy of the spectral analysis. The graphical presentation of the calculated Raman and IR spectra were made using Gauss View program [12]. The absence of imaginary frequency modes for the optimized structure of FLT at DFT level confirms a true minimum on the potential energy surface. As the hybrid B3LYP functional tends to overestimate the fundamental normal modes of vibration, the computed frequencies were scaled with appropriate values to bring harmonization between theoretical and experimental wavenumbers [16–18]. We know that DFT potentials systematically overestimate the vibrational wavenumbers. These discrepancies are corrected either by computing anharmonic corrections explicitly or by introducing a scaled field or directly scaling the calculated wavenumbers with the proper factor [19,20]. In our present study, we have followed the scale factor of 0.9608 [19] for B3LYP/6-31G(d,p) method. The TD-DFT calculations were also performed using the Gaussian program in Methanol and Ethanol as solvent medium. To simulate the solvent effect the IEFPCM (Polarization Continum Model) is used [21,22]. To investigate the reactive sites of the title compound the MEP were evaluated using the B3LYP/6-31G(d,p) method. 1H and 13C NMR chemical shifts were calculated using the GIAO method [23,24] in deuterated DMSO.

Results and discussion Structural analysis The optimized parameters (bond lengths, angles, and dihedral angles) of the title compound have been obtained by using the B3LYP/6-31G(d,p) level of theory. The obtained results are compared with exact crystal structure of the title molecule [4] and listed in Table S1 (Supplementary information). The B3LYP geometry-optimized structure of FLT (Fig. 3) shows very close resemblance of the actual crystal structure of this molecule. The optimized structure of the molecule is mainly planar, except the NO2, CF3 and CH3 groups, in agreement with the experimental results and in contrast with molecular mechanics calculations [25]. The calculated values of bond lengths are very close to the X-ray diffraction results of the FLT molecule. The minimum deviation identified due to the crystal forces deforming the ring structure, exactly at the substitution position of C5–C6 bond length (1.398 Å) differs from the C5–C10 bond (1.386 Å). The theoretical data reproduced with the X-ray diffraction value on C–H- - - -O hydrogen bonds exactly at 2.18 Å [4] in O3–H21 bond distance. While the high positive charge H21 (0.158 e) can also be calculated theoretically using B3LYP/6-31G(d,p) level of theory, which is demonstrated the intramolecular hydrogen bonding interaction with carbonyl group. The influence of this intramolecular C–H- - - -O hydrogen bonding feature, results in the C10–H21 bond length contracted 1.080 Å among the other aromatic C–H bond lengths which are calculated around 1.083 Å. Both the nitrogen atoms are bonded in para position of aromatic ring in which amino (C–N = 1.471 Å) group dominates the increasing bond length than the secondary amide (C–N = 1.400 Å) group. It is noted that the high electronegativity and steric interaction between the NO2 and CF3 group and also the C–H- - - -O hydrogen bonding interactions with the O16–H20 (2.378 Å). Two methyl

G. Mariappan, N. Sundaraganesan / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 117 (2014) 604–613

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PED of the title molecule is given in Table 1. A complete assignment of the fundamentals was proposed based on the calculated PED values, infrared and Raman intensities. Any inadequacy noted between the observed and the calculated frequencies may be due to the two facts: one is that the experimental results belong to solid phase and theoretical calculations belong to gaseous phase; the another one is that the calculations have been actually done on a single molecule contrary to the experimental values recorded in the presence of intermolecular interactions.

Fig. 3. Optimized molecular structure and atomic numbering of FLT.

groups are super-imposed well in terms of structural data because commonly all the C–H bond lengths of methyl group are calculated around 1.09 Å. Noveron et al. [26] reported the bond lengths for the benzamide derivatives C5–N4, C1–N4, C1–C2, N4–H18 and C1–O3 as 1.395, 1.370, 1.494, 0.733 and 1.225 Å respectively and also Dereli et al. [27] calculated for 4-phenylsemicarbazide molecule as C5–N4 (1.410 Å), N4–H18 (1.020 Å) and C1–O3 (1.240 Å) where as the corresponding values for our title molecule is 1.400, 1.387, 1.531, 1.010 and 1.222 Å respectively calculated by DFT/B3LYP level of theory. These values are well in agreement with the experimental counterparts (XRD) of C5–N4, C1–N4, C1–C2 and C1–O3 as 1.401, 1.379, 1.503, 1.213 Å respectively. According to the experimental and the literature data [28,29] the changes in bond lengths of C@O and C–N are consistent with the following interpretation: that is, hydrogen bond decreases the double bond character of C@O bond and increases the double bond character of C–N bond. On this basis of C1 atom the bond angles are found to be C2–C1–O3 = 121.9° (120.7°), C2–C1– N4 = 114.8° (115.5°) and N4–C1–O3 = 123.3° (123.7°) [30] and this asymmetry of exocyclic angles reveals both the interaction between H18 and H30 (2.101 Å) and O3 and H21 (2.18 Å). While the bond angle C10–C5–N4 is increased by 3.6° and N4–C5–C6 is reduced by 2.82° from 120° and this asymmetry reveals the interaction between the amide moiety and the phenyl ring in which the number in parentheses is from the literature data [30]. Within the CF3 group FCF (F12–C11–F14) angle is increased to 108.9° compared to other FCF angles due to the steric interaction. As it is evident from the dihedral angle values C7–C8–N15–O16 (153.4°) and C9–C8–N15–O17 (150.1°) give non-planarity of NO2 group.

Vibrational assignments The most-significant calculated and experimental fundamental vibrational modes, together with their IR and Raman intensities, are summarized in Table 1. As one can notice, the calculated values agree well with the experimental data; however, some deviations were observed for the vibrations involving electronegative atoms. All the calculated wavenumbers are in very good agreement with the experimental values after which are scaled. The task of the vibrational analysis is to find out the different vibrational modes connected with specific molecular structure of title molecule. The FLT consists of 30 atoms; hence it undergoes 84 normal modes of vibrations. Of the 84 normal modes of vibrations, 29 modes are stretching vibrations, 28 are bending modes of vibrations and the remaining 27 modes are tensional vibrations. The potential energy distribution (PED) was calculated and the fundamental vibrational modes were characterized by their PED. The recorded (FT-IR, FT-Raman) and calculated vibrational wavenumber along with their relative intensities and probable assignments along with

Amide group vibrations The characteristic secondary amide bands in the stretching region, associated with N–H stretch and the overtone of N–H in-plane bending, can be observed in the IR spectrum. Usually the N–H stretching vibrations for secondary amides appear strong and broad in the region 3390 ± 60 cm1 [31]. For the title compound, the very strong band at 3360 cm1 in the IR spectrum is assigned as N–H stretching mode. The calculated wavenumber for this mode is at 3485 cm1. The lowering of the N–H stretching wavenumber can be attributed to the red shifting by 125 cm1 in the IR spectrum with a strong intensity from the computed wavenumber, which indicates the weakening of the N–H bond resulting in proton transfer to the neighboring oxygen [32]. As expected, this mode is a pure stretching mode, and as it is evident from the PED column they are almost contributing 100%. The first overtone of the N–H in-plane bending mode (3110 cm1) falling on the N–H stretching band positions produces two bands of comparable intensities, equally displaced on either side of this wavenumber resulting from Fermi resonance with one or more N–H stretching [33]. In the present study, the NH2 bending frequency was found at 1497 cm1 by B3LYP method is matching with medium FT-IR band at 1495 cm1 showed good agreement in the FT-IR and FTRaman spectra respectively. C–H vibrations The C–H stretching vibration occurs above 3000 cm1 and is typically exhibited as a multiplicity of weak to moderate bands, compared with the aliphatic C–H stretch [34]. According to Roeges [31], the C–H stretching vibrations of the phenyl ring are expected in the region 3120–3000 cm1. In the present study, one can expect three C–H stretching vibrations. Among the three stretching vibrations the blue shifting of the ring C–H stretching wavenumbers are at 3148 and 3115 cm1 (mode nos. 2 and 3) which indicates the weakening of C–H bond resulting the intramolecular C–H- - - -O interactions to the neighboring oxygen atoms as O3–H21 (2.183 Å) and O16–H20 (2.378 Å) respectively. Substantially, the observed FTIR bands at 3207 and 3127 cm1 are supported our calculated wavenumbers. As expected, this mode is a pure stretching mode, and as it is evident from the PED column they are almost contributing 98%. Among the three aromatic C–H stretching vibrations, the remaining one is observed within the spectral range at 3055 and 3080 cm1 in FTIR and FT-Raman spectra respectively. The calculated wavenumber also gives good correlation with the observed wavenumber at 3092 cm1 with 99% of contribution. The C–H in plane bending vibration usually occurs in the region 1390–990 cm1 and is very useful for characterization purpose [35]. The calculated frequencies are at 1287, 1245 and 1218 cm1 by B3LYP/6-31G(d,p) level are assigned to C–H in plane bending vibrations. The C–H in plane bending vibration are observed at 1274, 1244 cm1 in FTIR and 1244 cm1 in FT-Raman spectra for the title compound. The C–H out of plane deformation is usually observed between 1000 and 700 cm1 [31]. The C–H out of plane bending mode is observed in FTIR spectrum at 963 and 839 cm1 and 840 cm1 in FT-Raman spectrum for the title compound. The theoretical values are calculated for out of plane bending vibrations are at 966, 850 cm1 B3LYP/6-31G(d,p) level of theory.

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Table 1 Comparison of the experimental and calculated vibrational spectra and proposed assignments of FLT. Mode Nos.

Experimental wavenumbers/cm1 FT-IR

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 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

FT-Raman

3360vs 3207w 3127s 3055m

3080w

2984s 2941m

2985w 2947w

2880w 1716vs 1611s 1597w 1541s 1495w 1470w

2907w 1721m 1610s 1597s 1540m

1446w 1391

1344s

1345vs

1321vs 1274m

1319s

1244vs

1244s

1173m

1187w

1138w

1143m 1123s

1102w

1040s 963w 931w 902vs

1041s

901w

862s 839s

840w

754s 712s 655vs

478m 456w

227w

Theoretical wavenumbers/cm1/B3LYP/6-31G(d,p) Unscaled

Scaled

a

3627 3276 3242 3218 3142 3138 3123 3121 3053 3050 3024 1789 1667 1652 1626 1558 1533 1528 1516 1507 1499 1436 1429 1410 1400 1393 1362 1339 1337 1296 1268 1229 1211 1205 1173 1168 1144 1121 1117 1058 1006 977 969 941 917 900 886 885 847 769 760 755 714 694 669 660 657 605 579 551 520 480 465 417 386 354 325 320 314 274 257 245 220

3485 3148 3115 3092 3019 3015 3001 2999 2933 2930 2905 1719 1602 1587 1563 1497 1473 1468 1456 1448 1440 1380 1373 1355 1345 1339 1309 1287 1285 1245 1218 1181 1163 1158 1127 1122 1099 1077 1074 1016 966 939 931 904 881 865 852 850 814 739 730 726 686 667 642 634 631 582 556 529 500 461 447 400 371 340 312 307 302 263 247 235 211

24.37 10.20 1.62 3.44 25.27 1.61 38.88 16.24 16.06 28.73 31.88 131.92 132.32 126.49 62.02 558.23 116.15 3.40 15.19 1.41 1.02 14.55 0.66 2.72 146.15 299.09 86.27 331.19 1.33 73.91 89.99 225.85 43.26 103.26 307.41 74.75 43.32 0.11 16.82 62.37 0.96 0.26 10.14 2.33 32.61 30.20 1.82 14.04 33.21 10.69 7.28 0.06 9.05 4.81 1.50 8.24 2.62 4.19 58.76 2.31 3.00 4.34 1.07 4.91 8.36 1.12 0.80 1.34 8.14 2.53 2.81 5.11 0.50

IIR

Vibrational assignments with PED (P10%)

b

IRA

4.98 3.02 3.88 3.49 6.28 0.71 10.13 1.95 18.35 0.17 4.01 17.76 28.62 62.25 8.53 34.35 0.14 2.22 9 3.01 7.25 1.57 2.3 0.78 52.3 100 33.2 26.41 3.46 7.79 32.94 0.89 13.69 1.56 4.1 3.46 31.32 2.27 4.47 23.21 0.64 3.41 2.56 0.01 6.61 1.46 4.32 3.31 8.23 2.45 3.83 0.3 5.29 9.74 1.41 1.96 3.5 1.92 0.83 2.26 2.04 1.03 3.66 0.19 3.79 0.2 1.77 3.62 1.62 3.83 1.9 2.41 14.63

tNH(100) tCH(98) tCH(98) tCH(99) tCH(36) tCH(38) tCH(29) tCH(30) tCH(39) tCH(35) tCH(98) tOC(82) tCC(20) + tON(15) tON(18) + tCC(16) tCC(22) + tON(17) + dHNC(10) dHNC(41) dHCC(24) dHCH(29) + dHCC(14) + cCHCH(15) dHCH(27) + cCHCH(15) cCHCH(29) + dHCH(27) + dHCC(12) dHCH(31) tCC(22) + + dHCH(20) + dHCC(11) dHCC(16) + dHCH(12) + cCHCH(11) dHCC(20) + dHCH(17) + cCHCH(13) tON(23) + dHCC(14) dHCC(37) + tON(18) tCC(25) tCC(18) + tNC(16) + dHCC(12) sHCCN(72) dHCC(28) + tCC(10) tNC(22) + dHCC(21) tFC(44) cCHCH(18) + cCCCC(12) tFC(22) + dHCC(11) tNC(13) + dHCC(13) + tFC(12) tNC(21) + tCC(15) + dHCC(15) tNC(15) + dCCC(15) + dHCC(14) + tFC(11) tCC(24) + cCHCH(12) + dHCC(11) dHCC(29) + cCHCH(14) + tCC(11) dCCC(28) + tFC(15) cCCCH(52) + sHCCC(43) cCHCH(25) + dHCC(22) + tCC(18) tCC(19) + dNCO(11) cCHCH(32) + dHCC(16) + sHCCN(16) tCC(20) sHCCN(84) tCC(25) cCCCH(32) + sHCCC(32) dONO(48) cOCON(51) cCFFF(14) + tFC(13) + dCCC(12) cOCNC(61) sCCCC(24) + cOCON(16) tCC(19) dCCC(24) + dONO(15) + tNC(10) dCCC(16) + cCFFF(14) sCCCC(24) + sCCCN(13) dCNO(18) + dFCF(10) sHNCC(86) cCCFF(38) + dCNO(16) dFCF(45) + dCNO(11) tNC(14) sCCCC(52) cCCCC(20) + dNCO(16) + dCCN(12) dCCF(23) dCCF(19) + cCCCC(18) dCCF(33) + sCCCC(25) sCCCC(15) + dCCC(14) + sCCCN(12) + sCCNC(10) dCCC(33) + dNCO(10) tCC(14) + dCCF(15) + cCFFF(12) sHCCC(40) dCCC(26) + sHCCC(11) + cOCNC(11) dCCN(15)

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Table 1 (continued) Mode Nos.

74 75 76 77 78 79 80 81 82 83 84

Experimental wavenumbers/cm1

Theoretical wavenumbers/cm1/B3LYP/6-31G(d,p)

FT-IR

Unscaled

FT-Raman

134m

86s

216 207 176 157 110 98 88 54 43 36 17

Scaled 207 199 169 151 106 94 84 52 41 34 16

a

IIR 1.01 1.23 0.52 0.09 0.32 0.40 1.21 3.89 2.01 1.25 0.00

Vibrational assignments with PED (P10%)

b

IRA 0.25 4.04 8.12 5.99 38.55 10.25 5.96 26.06 27.24 5.63 39.68

sHCCC(47) dCCN(31) + sHCCC(10) dCCC(38) + dCCN(13) sCCCC(51) sCCCN(31) + sCCNC(20) + sCCCC(10) sCCCF(36) + sCCCN(13) + dCCF(10) dCCN(23) + dCNC(19) + dCCC(12) + sCCCF(11) sCNCC(29) + sCCNO(24) + sCCCC(13) sCCNO(36) + sCNCC(26) + sCCCF(22) sCCNC(35) + sCNCC(19) + sCCCN(19) sCCCN(80)

m-Stretching; d-in-plane-bending; c-out-of-plane bending; s-torsion; w-weak; s-strong; vs-very strong; vw-very weak; m-medium. a b

IIR-IR Intensity (Km mol1). IRa-Raman intensity (Arb units) (intensity normalized to 100%).

Isopropyl group vibrations The isopropyl group consists of two methyl groups attached to a carbon that also has a C–H bond. The C–H moiety in the isopropyl functional group is called methane group [36]. The antisymmetric C–H stretching mode of CH3 is expected around 2980 cm1 and CH3 symmetric stretching is expected at 2870 cm1 [37,38]. For the methyl group compound, the asymmetric stretching mode appears in the range 2825–2870 cm1, lower in magnitude compared to its value in CH3 (compounds) (2860–2935 cm1) whereas the asymmetric stretching modes for both the type of compounds lie in the same region 2925–2985 cm1 [37,38]. In the present calculation, these modes are at the following wavenumbers: 3019, 3015, 3001 and 2999 cm1 for CH3 asymmetric stretching vibrations and 2933, 2930 cm1 for CH3 symmetric vibrations, while the experimental observation for asymmetric CH3 stretching mode is observed at 2984 cm1 and 2985 cm1 in FTIR and FT-Raman spectra respectively. Furthermore the symmetric stretching mode is observed in both the spectra at 2941 and 2947 cm1 respectively. The asymmetric bending vibrations of the methyl groups should appear between 1410 and 1550 cm1 [39]. In many molecules the symmetric deformation appears with an intensity from medium to strong and expected in the range of 1380 ± 25 cm1 [31]. The title molecule obeys this statement. Asymmetric deformation vibration contributes to the bands calculated at 1468, 1456, 1448 and 1440 cm1, the symmetric deformation vibrations (umbrella mode) are calculated at 1380, 1373 and 1355 cm1 calculated by B3LYP level. Experimentally, asymmetric mode is observed at 1446 cm1 and symmetric mode is observed at 1391 cm1 in FTIR spectrum. No bands are appeared in the FT-Raman spectrum. Carbonyl group vibrations The carbonyl stretching wavenumber have been extensively studied by infrared spectroscopy [40]. This multiple bonded group is highly polar and therefore gives rise to an intense infrared absorption band in the region 1700–1800 cm1. The carbon–oxygen double bond is formed by pp–pp bonding between carbon and oxygen. Because of the different electronegativities of carbon and oxygen atoms, the bonding electrons are not equally distributed between the two atoms. The intensity of these bands can increase due to conjugation or formation of hydrogen bonds. The following two resonance forms contribute to the bonding of the carbonyl group >C@O M C+AOA. The lone pair of electrons on oxygen also determines the nature of the carbonyl group [40]. In our present case, one can expect only one C@O stretching vibration corresponding to the C1@O3 mode. The experimental wavenumber observed as a very strong band in the FT-IR and FT-Raman spectrum at 1716 and 1721 cm1 respectively, are assigned to C@O stretching vibration, which shows good agreement with that of calculated value by B3LYP level at 1719 cm1. In this study, according

to PED (82%), this mode is not contaminated with other vibrations suggesting that it is a pure mode. In keto-groups, the C@O in-plane bending vibration is found theoretically at 400 cm1 by B3LYP/631G(d,p) level of theory. However, the experimental observation does not support this kind of vibration. The C@O out-of-plane bending vibration computed by B3LYP level at 235 cm1 show good agreement with recorded weak FT-Raman band at 227 cm1. An analysis by PED calculations shows that this vibration is coupled with ring bending mode as shown in Table 1. Nitro group vibrations Commonly aromatic nitro compounds have strong absorptions due to asymmetric and symmetric stretching vibration of the nitro group at 1570–1485 and 1370–1320 cm1 respectively [41]. Usually the symmetric vibration is stronger than the asymmetric one in the Raman spectra and contrary holds in infrared [42,43]. This could be due to the electron withdrawing substituent adjacent to the nitro group that tends to increase the frequency of asymmetric vibration and decrease symmetric vibration. Based on the above observation and literature data the strong asymmetric stretching bands are measured at 1611, 1597 and 1541 cm1 in FTIR and 1610, 1597 and 1540 cm1 in FT-Raman spectrum. And the symmetric bands are observed at 1344 and 1345 cm1 in FTIR and FT-Raman spectra respectively. The calculated wavenumbers are well reproduced in the experimental observations which are assigned as asymmetric and symmetric stretching modes at 1602, 1587, 1563 cm1 and 1345, 1339 cm1 respectively. The in-plane bending modes are calculated at 814 and 642 cm1 while the out-of-plane bending vibrations are assigned at 739, 726 and 686 cm1. As expected, these modes are pure modes as it is evident from the PED column. Trifluromethyl group vibrations The trifluromethyl group stretching vibrations are falling in the range of 1290–1200 cm1 [44,45]. In the present study, the medium and weak bands are observed in FTIR and FT-Raman spectra at 1173 and 1187 cm1 respectively. The CF3 stretching wavenumbers are calculated in our theoretical study are at 1181, 1158, and 1099 cm1 are assigned to the C–F stretching modes. Furthermore, the calculated wavenumbers are at 582 and 500 cm1 in our title compound is assigned to CF3 in-plane-bending modes. Mode nos. 56, 60 and 70 are assigned as CF3 out-of-plane bending vibrations at 529 and 263 cm1. And also the CF3 torsional modes are calculated at 84 and 41 cm1. Phenyl ring modes The aromatic carbon–carbon stretching vibration occurs in the region 1620–1400 cm1 called ring modes. Usually the bands appear between the range of 1630–1680 cm1, it is most likely a

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C@C (double bond) stretching vibration. Ring modes are lower in wavenumber than C@C stretches because the bond order of aromatic carbon–carbon bonds is lower than in alkenes. The lowering of the force constant causes the difference between the spectra of the two functional groups [36]. In the present work, the frequencies observed in the FT-IR spectrum at 1611, 1541, 1391 and 1321 cm1 and predicted wavenumber by B3LYP level at 1602, 1563, 1380 and 1309 were assigned to C–C stretching vibrations. The same vibrations in the FT-Raman spectrum are observed at 1610, 1540 and 1319 cm1. The ring breathing mode at 1040 cm1 in FT-IR and the same vibration in FT-Raman at 1041 cm1 coincide exactly with the predicted value at 1016 cm1. The PED of this vibration is a mixed mode as it is evident from Table 1 mixed with C–F stretching mode. The in-plane deformations are at higher frequencies than those of out-of-plane vibrations. Shimanouchi et al. [46] gave the frequency data for these vibrations for different benzene derivatives as a result of normal coordinate analysis. The calculated values of mode nos (51, 55–56) are assigned to C–C–C deformation of phenyl ring. The theoretically computed C–C–C out-of-plane and inplane bending vibrational modes have been found to be consistent with recorded spectral value. The PED of these vibrations is not pure modes as it is evident from the last column of PED in Table 1. C–N vibrations The identification of C–N stretching vibrations is a very difficult task, since the mixing of several bands is possible in this region. However, with the help of the animation option of Gauss View 3.0 graphical interface for Gaussian programs and PED value from VEDA 4 program, the C–N stretching vibrations are identified and assigned in this study. In the present work, the bands observed at 1138 and 1102 cm1 in FT-IR spectrum and at 1143 and 1123 cm1 in FT-Raman spectrum have been assigned to, C–N stretching vibrations for amide and nitro group respectively. The corresponding calculated wavenumbers are assigned at 1127, 1122 and 1099 cm1 for C–N stretching modes which gives good correlation with the experimental one. Correlation coefficient In order to investigate the performance and vibrational wavenumbers for the title compound, the correlation coefficient between the calculated harmonic and observed fundamental vibrational frequencies are 0.999 for both the cases by B3LYP method 6-31G(d,p) basis set were also calculated which are shown in Fig. S2 (Supplementary information). As we can see the correlation graph, experimental fundamentals are in good agreement with the scaled fundamental and are found to be better correlation for DFT method. 1

H and

13

C NMR spectral analysis

The characterization of the title compound was further enhanced by the use of 1H and 13C NMR spectroscopy. In the present investigation we took the experimental chemical shift values from the literature data [47] as shown in Table 2. The isotropic chemical shifts are frequently used as an aid in identification of reactive organic as well as ionic species. It is recognized that accurate predictions of molecular geometries are essential for reliable calculations of magnetic properties. Therefore, full geometry optimization of FLT were performed by using B3LYP/6-31G(d,p) level of theory. Then, Gauge-Including Atomic Orbital (GIAO) 1H and 13C chemical shift calculations of the compound have been made by the same level of theory. Density functional theory shielding calculations are rapid and applicable to large systems, but the paramagnetic contribution to the shielding tends to be overestimated. In this sense, theoretical calculations of the chemical shifts may be used as an

Table 2 The observed (in deuterated DMSO) and predicted 1H and 13C NMR isotropic chemical shifts (with respect to TMS, all values in ppm) for FLT.

a

Atom position

a Experimental (DMSO)

B3LYP/631G(d,p)

Atom position

a Experimental (DMSO)

B3LYP/631G(d,p)

C1 C2 C5 C6 C7 C8 C9 C10 C11 C22 C23

176.4 35.2 144.0 117.1 126.1 141.1 127.6 122.0 123.4 19.1 19.1

179.31 49.24 148.08 123.49 133.31 148.15 135.02 124.42 135.11 30.17 30.52

H18 H19 H20 H21 H24 H25 H26 H27 H28 H29 H30

10.62 8.29 8.17 8.06 1.13 1.13 1.13 1.13 1.13 1.13 2.63

8.09 7.79 8.38 9.01 1.62 1.22 1.23 1.28 1.22 1.27 3.01

Taken from Ref No. [47].

aid for the assignment of the experimental data and for the study of our title molecule. The range for 13C NMR chemical shift of the typical organic molecule usually is >100 ppm [48,49], the accuracy ensures reliable interpretation of spectroscopic parameters. It is true from the above literature value, in our present study, the title molecule FLT also falls with the above literature data except with the isopropyl carbon atoms (C2, C22 and C23). Usually, the carbonyl carbon enhanced the chemical shift to the shielded region. Notwithstanding the fact and the adjacent electronegativity environment of nitrogen impact to the present case for C1 chemical shift as it is observed at shielded region of 176.4 ppm in the experimental value and 179.31 ppm for calculated value. Among the ring carbon chemical shifts, C5 and C8 carbon atoms fall in deshielding region at 144.0 and 141.1 ppm and which is exactly correlated with the calculated chemical shifts at 148.08 and 148.15 ppm respectively. The signals for aromatic carbons were observed at 117.1– 144 ppm in 13C NMR spectrum for the title molecule, since those carbon atoms which belong to phenyl also exactly correlate with theoretically predicted value at 123.49–148.15 ppm. The H atom is the smallest of all atoms and mostly localized on the periphery of molecules. Therefore their chemical shifts would be more susceptible to intermolecular interactions in the aqueous solution as compared to that for other heavier atoms. Another important aspect is that, hydrogen attached or nearby electron withdrawing atom or group can decrease the shielding and moves the resonance of attached proton towards to a higher frequency. By contrast electron donating atom or group increases the shielding and moves the resonance towards to a lower frequency. In this study, the signals of the aromatic proton were observed at 8.06– 8.29 ppm it is well known the aromatic protons fall in the shielded region. The calculated proton NMR chemical shifts show moderate agreement with the experimental values except for isopropyl and amide protons. The chemical shifts obtained and calculated for the hydrogen atoms of methyl groups are quite low. All values are 63 ppm [50] due to shielding effect. It is true from above literature data in our present study all the isopropyl protons at C22 and C23 appear as doublet with six protons integral at 1.13 ppm shows good agreement with computed chemical shift values and are shown in Table 2. The computed methine H atom (H30) chemical shift by B3LYP level (3.01 ppm) is in good agreement with experimental value at 2.63 ppm which is also fall in shielding region.

Natural bond orbital analysis The Natural bond orbital analysis provides an efficient method for studying intra and intermolecular bonding and interaction

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among bonds, and also provides a convenient basis for investigating charge transfer or conjugative interaction in molecular systems. Some electron donor orbital, acceptor orbital and the interacting stabilization energy resulting from the second order micro disturbance theory are reported. The interaction result is a loss of occupancy from the localized NBO of the idealized Lewis structure into an empty non-Lewis orbital. For each donor (i) and acceptor (j), the stabilization energy E(2) associated with the delocalization i ? j is estimated as

Electronic properties

2

Eð2Þ ¼ DEij ¼ qi

C8–C9 (24.45 kJmol1); C6–C7 ? C5–C10 (19.04 kJmol1), C8–C9 (16.89 kJmol1); C8–C9 ? C5–C10 (17.03 kJmol1), C6–C7 (22.38 kJmol1); on the phenyl ring of the title molecule. While the oxygen and nitrogen lone pairs (O3, O16, O17 and N4), have the greater interactions energy contribution in their (r⁄, p⁄) antibonding orbitals. Furthermore, the p⁄ (C15–O17) NBO conjugates with respective bonds of p⁄ (C8–C9) resulting to maximum stabilization of 14.49 kJ mol1 in the antibonding interactions.

Fði; jÞ ej  ei

Some electron donor orbital, acceptor orbital and the interacting stabilization energy resulted from the second-order-micro-disturbance theory, where qi is the donor orbital occupancy, ei and ej are diagonal elements and F(i,j) is the off diagonal NBO Fock matrix element reported [51,52]. The intramolecular hyperconjugative interactions are formed by the orbital overlap between p(C–C) and geminal p⁄(C–C) bond orbitals which results intra-molecular charge transfer (ICT) causing stabilization of the system are presented in Table 3. These interactions are observed as an increase in electron density (ED) in (C–C) and (N–O) antibonding orbital that weakens the respective bonds. The electron density of conjugated double bond of FLT (1.6 e) clearly demonstrates strong delocalization as evident from Table 3. The exception of the electron density (ED) value of 1.985 e occurs for N15–O17 may be the reason of high electronegativity environment. We could see the strong intramolecular hyperconjugative interaction of p-electrons with the greater energy contributions from C5–C10 ? C6–C7 (19.16 kJmol1),

The TD-DFT method is able to detect accurate absorption wavelengths at a relatively small computing time which correspond to vertical electronic transitions computed on the ground state geometry, especially in the study of solvent effect for vertical excitation energy of electronic spectra [53–55]. To investigate the nature of electronic transitions, the electronic spectra of FLT molecule were calculated using the time-dependent density functional theory (TD-DFT) approach at the B3LYP/6-31G(d,p) level on the basis of fully optimized ground-state structure. Calculations are performed for Methanol and Ethanol environment. Molecules allow strong p– p⁄ and r–r⁄ transitions in the UV–Vis region with high extinction coefficients. It is targeted to understand the nature of electronic transitions, positions of experimental absorption peaks, calculated absorption peaks (kmax), vertical excitation energies, oscillator strengths (f) and assignments of the transitions of the FLT molecule were calculated according to Frank Condon principle and the results are presented in Table 4 along with experimental UV–Vis spectrum recorded in ethanol and methanol as solvent are shown

Table 3 Second order Perturbation theory analysis of Fock Matrix in NBO basis for FLT. Donor (i)

ED (i)(e)

Acceptor (j)

ED (j)(e)

E(2)a kJ mol1

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

F(i,j)c a.u

p(C5–C10)

1.599

p(C6–C7)

1.707

p(C8–C9)

1.650

p⁄(C6–C7) p⁄(C8–C9) p⁄(C5–C10) p⁄(C8–C9) r⁄(C11–F12) r⁄(C11–F14) p⁄(C5–C10) p⁄(C6–C7)

p(N15–O17)

1.985

LP(3)O16

LP(2)O3

1.976 1.861

p⁄(N15–O17) r⁄(C7–C8) r⁄(C1–C2) r⁄(C1–N4)

LP(1)O3 LP(1)N4

1.974 1.659

LP(2)O16

1.895

LP(2)O17

1.895

p⁄(N15–O17)

0.613

0.338 0.370 0.366 0.370 0.104 0.107 0.366 0.338 1.444 0.613 0.029 0.068 0.080 0.018 0.250 0.366 0.103 0.063 0.103 0.062 0.370

19.16 24.45 19.04 16.89 3.75 6.32 17.03 22.38 11.72 6.85 5.02 19.38 27.53 16.45 55.92 37.89 13.11 18.76 12.78 19.72 14.49

0.28 0.28 0.29 0.29 0.51 0.52 0.29 0.28 0.19 0.34 1.07 0.62 0.69 1.5 0.29 0.29 0.56 0.7 0.56 0.7 0.12

0.066 0.074 0.068 0.064 0.041 0.054 0.063 0.071 0.078 0.051 0.065 0.1 0.125 0.141 0.115 0.094 0.077 0.103 0.076 0.106 0.054

r(C9–H20)

RY⁄(1)C1

p⁄(C1–O3) p⁄(C5–C10) r⁄(C8–N15) r⁄(N15–O17) r⁄(C8–N15) r⁄(N15–O16) p⁄(C8–C9)

ED means Electron Density. a E(2) means energy of hyper conjugative interactions. b Energy difference between donor and acceptor i and j NBO orbitals. c F(i,j) is the Fock matrix element between i and j NBO orbitals.

Table 4 The experimental and computed absorption wavelength k (nm), excitation energies E(eV), absorbance and oscillator strengths (f) of FLT in ethanol, methanol solutions. Experimental

TD-DFT/B3LYP/6-31G(d,p)

Ethanol

Methanol

Ethanol

Methanol

k(nm)

Abs.

k(nm)

Abs.

k(nm)

E(eV)

F(a.u)

k(nm)

E(eV)

F(a.u)

– 296 229

– 0.885 1.22

– 293 231

– 0.575 0.808

343.95 308.69 303.18

3.605 4.016 4.089

0.288 0.014 0.102

344.21 309.35 303.09

3.602 4.008 4.091

0.289 0.012 0.099

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1.4

1.0

Absorbance (a.u)

Absorbance (a.u)

0.8

Ethanol

1.2

0.8 0.6 0.4

Methanol

0.6

0.4

0.2 0.2 0.0

0.0 200

250

300

350

400

450

300

400

Wavelength (nm)

Wavelength (nm) Fig. 4. The UV–Visible spectrum (Ethanol and Methanol) of FLT.

in Fig. 4. As can be seen from the Table 4 TD-DFT/B3LYP method predicts one intense band in electronic transitions for the ethanol and methanol solvents at 4.016 eV (308.69 nm) and 4.008 eV (309.35) with the oscillator strength 0.014 and 0.012 respectively is in good agreement with the measured experimental data in ethanol at 0.885 eV (296 nm) and methanol at 0.575 eV (293 nm). The difference may be due to Bathochromic shift (red shift). Comparing these values with the corresponding experimental values, TD-DFT method for both the solvent media is useful to predict UV–Vis spectrum. The transitions that are formally forbidden by the selection rules are often not observed. However, theoretical treatments are rather approximate, and in certain cases forbidden transitions are observed, although the intensity of the absorption tends to be much lower than for transitions that are allowed by the selection rules. The n ? p⁄ transition is the most common type of forbidden transition. Here the energy required to bring about transitions from the highest occupied energy level (HOMO) in the ground state to the lowest unoccupied energy level (LUMO) is less than the energy required to bring about a transition from a lower occupied energy level. The typical carbonyl compound undergoes n ? p⁄ transition around 280–290 nm and p ? p⁄ transitions around 190 nm. Most of these n ? p⁄ transitions are forbidden and hence are of low intensity. Notwithstanding the fact, the title molecule having the possibilities of conjucation effect in the solution state and carbonyl group exhibits to the n ? p⁄ transitions. Molecular orbital coefficients analysis based on optimized geometry indicate that, for the title compound, the frontier molecular orbitals are mainly composed of p-atomic orbitals, so the electronic transitions are mainly derived from the contribution of bands n ? p⁄ within the FLT molecule. Frontier molecular orbital analysis Investigation of molecular orbitals and the spatial distribution of other molecular properties are useful for many purposes. MOs can provide important insight into bonding and other chemical properties. The analysis of the wave function indicates that the electron absorption corresponds to the transition from the ground to the first excited state and is mainly described by one-electron excitation from the highest occupied molecular orbital (HOMO) to the lowest unoccupied orbital (LUMO). Highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital (LUMO) are very important parameters for quantum chemistry. The HOMO–LUMO energy gap for FLT molecule was calculated

by B3LYP/6-31G(d,p) level of theory. The frontier orbital gap helps to characterize the chemical reactivity and kinetic stability of the molecule. A molecule with a small frontier orbital gap is more polarizable and is generally associated with a high chemical reactivity, low kinetic stability and is also termed as soft molecule [56]. The eigen values of HOMO and LUMO and their energy gap reflect the chemical activity of the molecule. A greater HOMO–LUMO energy gap has been taken as an indication of a high stability of the title molecule shown in Fig. S3 (Supplementary information). According to the DFT/B3LYP features the HOMO–LUMO energy values are calculated as

HOMO energy ¼ 7:0993 eV LUMO energy ¼ 2:5425 eV HOMO  LUMO energy gap ¼ 4:5568 eV The molecular orbitals show that the electron density in the HOMO mostly centered on the phenyl ring and carbonyl group while in LUMO the electron density predominantly located on the phenyl ring and nitro group, indicating a charge transfer of the type n ? p⁄ upon excitation. Conclusion The spectroscopic techniques such as FTIR, FT-Raman, NMR and UV–visible supported by the recent development of computational tool such as DFT method allow the structural analysis of our title molecule to be conducted in a seamless way. In this review, the experimental approach to molecular properties has been shown by some examples of FTIR, FT-Raman, NMR and UV–Visible spectroscopy. The theoretical support has been addressed by example of DFT/B3LYP/6-31G(d,p) calculations, and the peculiarities and limitations of the theoretical approach to the analysis have been considered. Both the nitrogen atoms are bonded in para position of aromatic ring in which amino (C–N = 1.471 Å) group dominates the increasing bond length than the secondary amide (C– N = 1.400 Å) group. It is noted that the high electronegativity and steric interaction between the NO2 and CF3 group and also the C– H- - - -O hydrogen bonding interactions with the O16–H20 (2.378 Å). The vibrational frequencies of the fundamental modes of the compound have been precisely assigned and analyzed and the theoretical results were compared with the experimental vibrations. The experimental data are deviated substantially from the calculated results according to the intermolecular hydrogen bonds and the crystal forces, which deforming the structure. The

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theoretically constructed IR and Raman spectra exactly coincide with experimentally observed counterparts which are proved by the correlation graphs. 1H and 13C NMR isotropic chemical shifts were calculated and compared with the experimental values. The UV–Visible spectrum was also recorded and the energies of important MO’s and the kmax of the compound were also determined from TD-DFT method. The relative stabilities, HOMO–LUMO energy gap and implications of the electronic properties are examined and discussed. Finally, a short survey on the determination of the Flutamide by the combined use of experimental techniques supported by quantum-chemical calculations has been presented to demonstrate the insight of the molecular analysis in molecular modeling. Acknowledgement Financial assistance from University Grants Commission (UGC), New Delhi is gratefully acknowledged. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.saa.2013.09.043. References [1] R.N. Brogden, P. Chrisp, Drug Aging 1 (1991) 104–115. [2] E.J. Small, Curr. Opin. Oncol. 9 (1997) 277–286. [3] M. Durlej, I. Kopera, K.K. Stwora, A. Hejmej, M. Duda, M. Koziorowski, Acta Histochem. 113 (2011) 6–12. [4] J.M. Cense, V. Agafonov, R. Ceolin, P. Ladure, N. Rodier, Struct. Chem. 5 (2) (1994). [5] F. Vargas, C. Rivas, H. Mendez, A. Fuentes, G. Fraile, M. Velas, J. Photochem. Photobiol. B: Biol. 58 (2000) 108–114. [6] O. Payen, S. Top, A. Vessières, E. Brulé, A. Lauzier, M.A. Plamont, M.J. McGlinchey, H.M. Bunz, G. Jaouen, J. Organomet. Chem. 696 (2011) 1049– 1056. [7] I.I. Miiderris, F. Bayram, Y. Qahin, F. Kelegtimur, Am. Soc. Rep. Med. 68 (4) (1997). [8] L.J.N. Vergara, D. Farias, S. Bollo, J.A. Squella, Bioelectrochemistry 53 (2000) 103–110. [9] W. Kohn, L.J. Sham, Phys. Rev. A 140 (1965) 1133–1138. [10] N.C. Handy, D.J. Tozer, G.J. Laming, C.W. Murray, R.D. Amos, Isr. J. Chem. 33 (1993) 331–334. [11] Gaussian Inc., Gaussian03 Program, Gaussian Inc.: Wallingford, 2004. [12] Gauss view, F. Weinhold, J. Am. Chem. Phys. Soc. 102 (1980) 7211–7218. [13] G.A. Petersson, M.A. Allaham, J. Chem. Phys. 94 (1991) 6081–6090. [14] G.A. Petersson, A. Bennett, T.G. Tensfeldt, M.A. Allaham, W.A. Shirley, J. Mantzaris, J. Chem. Phys. 89 (1988) 2193–2218. [15] M.H. Jamroz, Vibrational Enegy Distribution Analysis, VEDA 4 Computer Program, Poland, 2004. [16] N.C. Handy, C.W. Murray, R.D. Amos, J. Phys. Chem. 97 (1993) 4392–4396.

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