Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 126 (2014) 339–348
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FT-IR, FT-Raman spectra, and DFT computations of the vibrational spectra and molecular geometry of chlorzoxazone q Sß enay Yurdakul a,⇑, Murat Yurdakul b a b
Department of Physics, Faculty of Sciences, Gazi University, Teknikokullar 06500, Ankara, Turkey Department of Mathematics, Faculty of Arts and Sciences, Middle East Technical University, Çankaya 06800, Ankara, Turkey
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
Spectroscopic, structural, and
electronic analysis on chlorzoxazone are reported. DFT calculated data such as IR and NMR are consistent with the experimental data. Spectroscopic data suggest the presence of monomer and dimer forms in the sample. Experimental IR spectrum in ethanol is recorded and compared with solid phase data. Experimental IR data are best represented by a hybrid solvation model in theory.
a r t i c l e
i n f o
Article history: Received 29 November 2013 Received in revised form 21 February 2014 Accepted 23 February 2014 Available online 12 March 2014 Keywords: Chlorzoxazone DFT IR and Raman spectra Tautomers Solvent effects
a b s t r a c t Far-IR, mid-IR, and FT-Raman spectra of the chlorzoxazone (CZX) were recorded. The observed vibrational wavenumbers were analyzed and assigned to different normal modes of vibration of the molecule. Density functional calculations were performed to support wavenumber assignments of the observed bands. The equilibrium geometry and harmonic wavenumbers of CZX were calculated by the DFT B3LYP method. All tautomeric forms and dimer form of CZX were determined and optimized. Additionally, experimental FT-IR spectrum in ethanol solution was recorded and compared with solid phase experimental data for the first time. The combination of the DFT B3LYP with polarized continuum model (PCM) was employed to characterize the solvent effects in ethanol solution. Ó 2014 Elsevier B.V. All rights reserved.
Introduction The chlorzoxazone is a centrally acting skeletal muscle relaxant. It acts primarily at the level of spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex arcs involved in
q Selected paper presented at XIIth International Conference on Molecular spectroscopy, Kraków–Białka Tatrzan´ska, Poland, September 8–12, 2013. ⇑ Corresponding author. Tel.: +90 312 202 12 38; fax: +90 312 212 22 79. E-mail address: [email protected] (S ß . Yurdakul).
http://dx.doi.org/10.1016/j.saa.2014.02.156 1386-1425/Ó 2014 Elsevier B.V. All rights reserved.
producing and maintaining skeletal muscle spasm of variety etiology [1,2]. It was found to be exclusively catalyzed by cytochrome P-4502E1 in human liver microsomes [3]. It was also proposed that chlorzoxazone could be used in vitro and in vivo as a tool to screen for cytochrome P-4502E1 activity and the ability of other drugs or compounds to induce or inhibit cytochrome P-4502E1 in humans [4]. Tautomerism, a particular case of isomerism plays an important role in pharmacology, molecular biology, organic chemistry, biochemistry, and medicinal chemistry. Tautomerization is an important step of many organic reactions [5]. Many biochemical
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processes, including those involving specific interactions with proteins, enzymes, and receptors requires an understanding of tautomerization [6]. Investigations on chlorzoxazone have shown that this molecule exhibits four tautomeric forms (Fig. 1) [7,8]. Based _ and Topaçlı [9] agreed that the amion crystal structure results, Ide no form (I) is predominant tautomer. Harikrishnan and Bhoopathy have investigated the most stable tautomeric form by using vibrational spectroscopy and theoretical methods [10]. There is also growing interest in the construction of supramolecular assemblies with hydrogen bands as the building blocks [11,12]. An example is the cocrystal of chlorzoxazone with carboxylic acid [13]. However, to the best of our knowledge, a complete detailed vibrational study on chlorzoxazone has not been reported yet. Due to the importance of this molecule, the interest in the present manuscript was to carry out analysis of the chlorzoxazone and its tautomeric forms’ energies, geometries and vibrational wavenumbers with the attention focused on the spectroscopic side. The infrared and Raman spectra were used for the comparison with the theoretical spectra. The 1H- and 13C- NMR measurements were performed, and compared with the computed data. Solvent effects draw much attention since years. Shifts in the infrared frequencies and appearance of the new bands are due to the solute–solvent interactions. Besides, supporting experimental results by employing quantum chemical calculations produce good outcome. There are three main approaches in studying solvent effects computationally. Implicit solvation is one of them and known as PCM (polarized continuum model). PCM considers the medium as a dielectric continuum and it is first proposed by Miertuš et al. [14]. Another approach is calculating any given molecular structure in the gas phase with neighboring hydrogen bonded solvent molecules. A third approach is to combine the latter approaches by employing PCM model for a system of several solvent molecules hydrogen bonded to solute molecule. Here in this work, we also report the experimental FT-IR spectrum of CZX in ethanol solution and its interpretation using DFT PCM calculations for the first time. Experimental The pure sample of chlorzoxazone was obtained from Sigma, and used as such without any further purification. Mid-IR
spectrum was recorded in the regions 3800–550 cm1 on Bruker Vertex 80 FT-IR spectrometer with Pike MIRacle ATR apparatus. The resolution of the spectrometer was 2 cm1. Far-IR spectrum was recorded in the region 500–30 cm1 on a Bruker IFS 66 V/S spectrometer. FT-Raman spectrum was obtained on a Bruker FRA 106/S spectrometer using 1064 nm excitation from an Nd:YAG laser. The detector was a Ge-diode cooled to liquid nitrogen temperature. The upper limit for wavenumbers was 3800 cm1 and the lower wavenumbers is around 150 cm1. The 1H- and coupled 13 C NMR measurements were performed by using a Bruker Biospin UltraShield 300 MHz spectrometer at the natural abundance of the nuclei of interest. Dimethyl sulfoxide (DMSO) was the solvent. For liquid sample analysis, a solution of CZX was prepared at 50 mg/mL and the pure solvent spectrum was recorded as reference before sample measurement. Computational methods The calculations were carried out by using density functional theory, with the Becke’s three parameter exchange functional [15] in combination with the correlation functional of Lee, Yang and Parr (LYP) [16]. 6-311++G(d,p) basis set was used. These procedures are implemented in the Gaussian 03 W program package [17]. All calculations submitted via GaussView [18]. Counterpoise correction (CP) is included in calculation of the dimer form. Assignments of the calculated normal modes were made from the corresponding total energy distributions (TEDs). The TEDs were calculated using the Parallel Quantum Solutions software [19]. For the relative DE energies of chlorzoxazone tautomers, QCISD method using cc-pVDZ basis set was also employed. Atomic charges were determined with the Natural Bond Orbital (NBO) [20] and the Merz–Kollman (MK) procedures [21]. The 1H- and 13C-chemical shifts were calculated based on the gauge independent atomic orbital (GIAO) method by using the B3LYP/6-311++G(d,p) level considering the solvent effects. The chemical shifts were derived with respect to the isotropic shielding tensors of the TMS (tetramethylsilane). The structure used was re-optimized according to the same level with considering solvent effects, before the NMR calculations done. The solvent environment was evaluated by using the polarized continuum model (PCM) in all computations for investigating the
Fig. 1. Tautomeric forms of chlorzoxazone.
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Sß. Yurdakul, M. Yurdakul / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 126 (2014) 339–348 Table 1 Calculated total energies Etot (Hartree) and relative DE (kcal/mol) energies of the forms studied. In vacuo
In ethanol
B3LYP/6-311++G(d,p)// B3LYP/6-311++G(d,p)
CZX-1 CZX-2 CZX-3 CZX-4 a
QCISD/cc-pVDZ// B3LYP/6–311++G(d,p)
B3LYP/6-311++G(d,p)// B3LYP/6-311++G(d,p)
QCISD/cc-pVDZ// B3LYP/6-311++G(d,p)
Etot
DE
Etot
DE
Etot
DE
Etot
DE
934.727619054 934.705738360 934.684735170 934.680707790
0.00 13.73 26.91 29.44
932.73353518 932.71469681 932.69606681 932.69220649
0.00 11.82 23.51 25.93
934.73977758 934.71378085 934.69963450 934.69471591
0.00 16.31 25.19 28.28
932.74343838 932.72172162 932.70672750 932.70146733
0.00 13.63 23.04 26.34
DE = EnE1 are the total energy differences between the nth tautomer (n = 2, 3, 4) and the first tautomer.
solvent effects. To investigate the effects of solvation on CZX, the following calculations were carried out: (i) PCM implicit solvation model calculation on the most stable tautomer (Model A), (ii) hybrid (both implicit and explicit solvation model) calculation on 1:1 CZX:Ethanol complex in which an ethanol molecule is bound to chlorine (Model B), (iii) hybrid calculation on 1:1 CZX:Ethanol complex in which an ethanol molecule is bound to ring oxygen (Model C), and (iv) hybrid calculation on 1:2 CZX:Ethanol complex in which two ethanol molecules are bound to chlorine and oxygen (Model D).
Results and discussion Tautomerism of chlorzoxazone The structures and the nomenclature of the studied tautomers were depicted in Fig. 1. To obtain more accurate results which
are comparable with experimental data, the B3LYP/6311++G(d,p) level of computations are used. On the other hand, in view of relative energy differences, we also considered the QCISD method because of its reproducibility of the experimentally measured energy differences [23,24]. The B3LYP/6-311++G(d,p) and QCISD/cc-pVDZ calculated single point energy predictions of four tautomers are compared in Table 1 which shows that CZX-1 has the lowest energy value (934.727619054 and 932.73353518 Hartree, respectively) among four tautomers. The relative abundances of possible CZX tautomers were calculated using Boltzmann Distribution equation. The abundance of the most stable tautomer, CZX-1 equals 100% at 298 K. The remaining species have zero total population and are expected to be of no importance in relation to the experimental spectra. Single point energy predictions are also obtained for ethanol solution. The results have shown that when CZX is solvated in ethanol, CZX-1 stays as the most stable tautomer. Besides, the relative energy difference between CZX-1 and the second most
Table 2 Calculated bond lengthsa and bond anglesa of CZX in various media. Coordinate
Calculated Experimentalb
CL12AC5 N7AC8 N7AC1 O9AC2 O9AC8 O15AC8 C2AC1 C2AC3 C1AC6 C6AC5 C5AC4 C4AC3 CL HAO O HAO C8AN7AC1 C2AO9AC8 O9AC2AC1 O9AC2AC3 C1AC2AC3 N7AC8AO9 N7AC8AO15 O9AC8AO15 N7AC1AC2 N7AC1AC6 C2AC1AC6 C1AC6AC5 CL12AC5AC6 CL12AC5AC4 C6AC5AC4 C5AC4AC3 C2AC3AC4 CL HAO O HAO a b
1.7384 1.3515 1.3866 1.3905 1.3776 1.2036 1.3926 1.3687 1.3716 1.3837 1.3957 1.3796
110.74 107.83 108.44 128.64 123.04 107.54 130.55 122.04 105.44 133.54 121.04 116.24 118.73 118.54 122.84 120.44 116.64
In vacuo 1.7582 1.3845 1.3899 1.3762 1.3919 1.1955 1.3964 1.3772 1.3853 1.3983 1.3933 1.4008
110.57 108.25 109.60 128.06 122.33 106.37 129.38 124.23 105.18 133.41 121.39 116.20 118.29 119.03 122.67 120.29 117.09
All bond lengths are in Angstroms and all bond angles are in degrees. Taken from Ref. [9].
Model A 1.7636 1.3720 1.3903 1.3807 1.3866 1.2052 1.3948 1.3773 1.3857 1.3973 1.3942 1.4007
110.35 108.04 109.14 128.14 122.72 107.02 129.85 123.12 105.44 133.18 121.38 115.84 118.17 118.73 123.10 120.15 116.80
Model B 1.7629 1.3689 1.3909 1.3837 1.3943 1.2036 1.3940 1.3770 1.3857 1.3971 1.3942 1.4006 2.6138 110.59 108.10 108.93 128.27 122.81 106.75 130.39 122.86 105.63 133.00 121.37 115.84 118.19 123.07 120.21 116.71 110.59 175.38
Model C 1.7629 1.3689 1.3909 1.3837 1.3943 1.2036 1.3940 1.3770 1.3857 1.3971 1.3942 1.4006 2.0808 110.59 108.10 108.93 128.27 122.81 106.75 130.39 122.86 105.63 133.00 121.37 115.84 118.19 123.07 120.21 116.71 110.59 175.41
Model D 1.7663 1.3691 1.3906 1.3831 1.3947 1.2033 1.3942 1.3769 1.3856 1.3965 1.3935 1.4007 2.6145 2.0857 110.58 108.11 108.92 128.22 122.86 106.74 130.41 122.85 105.65 133.01 121.34 115.73 118.07 118.64 123.29 120.07 116.71 175.83 175.96
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Fig. 2. Experimental (a) Mid-IR, (b) Far-IR, and (c) Raman spectra of CZX.
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Table 3 Vibrational modes of CZX and their approximate assignments. Mode
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
Symmetry
00
A A00 A0 A00 A00 A00 A00 A00 A00 A0 A0 A00 A0 A00 A0 A00 A00 A00 A0 A0 A00 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0
Experimental (cm1)
Calculated
IR
Ra
Frequency*
IIR (SRA)
TED (%)
116 m 202 m 237 vs 279 m 343 sh,w 353 s 394 s 417 s 434 w 549 m 592 s 639 sh,m 688 vs 708 s 737 m 751 sh,w 800 vs 842 s 868 w 920 s – 959 vs 1061 m 1102 m 1147 s 1230 sh,w 1255 s 1295 s 1361 m – 1456 sh,m 1473 s 1616 s 1704 sh,m 1764 vs 3053 w 3082 w 3147 w 3472 vw
– 226 w 241 vw 297 w – 362 s 401 s 438 vw – 578 vs 610 vw – 721 s – – 774 vw 824 vw 855 sh 879 s 939 vw – 980 m 1080 w 1118 vw 1178 vw 1239 sh,w 1267 vs 1333 w 1384 w – 1474 m 1492 m 1639 m 1706 vw 1746 w – 3094 w – –
90 (90) 171 (171) 212 (212) 253 (253) 346 (345) 358 (357) 385 (384) 413 (412) 450 (449) 558 (557) 588 (587) 601 (600) 710 (709) 714 (713) 718 (717) 749 (748) 815 (814) 849 (847) 868 (866) 918 (916) 933 (931) 937 (935) 1075 (1073) 1101 (1099) 1154 (1152) 1254 (1252) 1271 (1269) 1294 (1292) 1343 (1341) 1378 (1376) 1485 (1482) 1506 (1503) 1652 (1649) 1659 (1656) 1878 (1875) 3203 (3197) 3210 (3204) 3215 (3209) 3669 (3662)
1.6 (0.2) 2.3 (0.01) 1.7 (1.2) 0.3 (0.7) 0.8 (7.6) 13.6 (1.3) 1.4 (4.8) 12.2 (0.2) 92.7 (0.3) 5.4 (8.0) 17.0 (0.3) 2.1 (0.2) 15.9 (8.6) 0.9 (0.1) 21.8 (13.2) 9.2 (0.1) 38.0 (0.2) 26.9 (0.2) 0.8 (15.5) 62.2 (1.7) 0.7 (0.02) 103.9 (5.1) 26.5 (13.1) 23.8 (1.5) 27.1 (3.9) 6.6 (7.3) 159.4 (36.9) 42.8 (4.2) 18.4 (4.6) 14.2 (20.7) 11.1 (25.8) 214.8 (13.9) 35.1 (9.1) 17.2 (27.3) 1110.0 (39.0) 0.3 (50.9) 0.4 (63.2) 0.1 (168.4) 96.6 (118.4)
UCCCN(22)+UCCNO(19)+UCCCO(17)+UClCCC(17) UClCCC(25)+UCCNO(17)+UCCCO(13)+ UCCHCl(12) dClCC(53) UCCCN(39)+UCCNO(16)+UCCCC(15) mCCl(27)+dCCC(17)+dCCCl(11) UCCNH(30)+UCCCO(26)+UCCCCl(12) dCCCl(26)+mCCl(13)+mCN(10) UCCCC(33)+UCCNH(18)+UCONH(16) UCONH(42)+UCCNH(12) dCCC(27)+mCO(13)+mCCl(12) dCNO(47)+dCCO(22)+dCCN(10) UCCCC(35)+UCCCH(30) mCCl(21)+dCCC(21)+dCCO(14) UCCCC(44)+UCCCH(21) dCCC(19)+dCCN(14) UCCNO(40)+UCONH(30)+UCCOO(11) UCCCH(52)+UCCHO(20)+UCCHCl(18) UCCCH(34)+UCCNH(28)+UCCHCl(26) mCC(34)+dCNO(15)+mCO(13) mCO(66) UCCHH(42)+UCCCN(29)+UCCHO(12) dCCC(23)+mCN(20) mCC(46)+dCCH(24)+mCCl(12) mCN(26)+dCCH(17)+mCO(10)+dCCC(10) dCCH(54)+mCC(24) dCCH(36)+dCNH(24)+mCC(10) mCC(34)+mCO(21)+dCCH(20) mCN(21)+mCC(15)+dCCN(13)+mCO(10) dCCH(34)+mCC(28)+dCNH(24) mCC(48)+dCNH(19) mCC(36)+dCCH(22)+mCN(14) dCCH(44)+mCC(28) mCC(68) mCC(62) mCO(80) mCH(100) mCH(99) mCH(99) mNH(100)
m: stretch, d: bending, C: torsion, vw: very weak, w: weak, m: medium, sh: shoulder, s: strong, vs: very strong. *
Values shown in parenthesis are scaled wavenumbers, scale factor is 0.9982.
Fig. 3. Dimer form of chlorzoxazone.
stable tautomer CZX-2 is larger in ethanol. Hence, CZX-1 is the most abundant tautomer even in the solvation phase. Molecular parameters The optimized bond lengths and bond angles in various media obtained for the most stable tautomer of chlorzoxazone (CZX-1)
using the B3LYP functional with 6-311++G(d,p) basis set are given in Table 2. The optimized geometry is compared with the struc_ and Topaçlı [9]. The tural parameters obtained in the study of Ide conformation of the molecule is planar. Table 2 shows that some bond lengths (O9AC2 and O15AC8) in vacuum are shorter than the experimental values. Some others; like CL12AC5, N7AC8, or O9AC8, are overestimated. These
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Fig. 4. Experimental mid-IR spectrum of CZX in ethanol.
It has been seen that when passed from gas phase to solvation phase the bond lengths of the most stable tautomer CZX-1 have not been changed significantly. The biggest differences were determined in N7AC8 (|D| 0.015 Å) and in O15AC8 (|D| 0.010 Å). Considering solvent effects in implicit or in mixed fashion has not been created much difference. Solvent effects were determined clearer on bond angles, though mostly the differences between the gas phase and solvation phase are small. Significant changes were determined in N7AC8AO15 and in O9AC8AO15. Vibrational analysis
Fig. 5. Optimized geometries of considered CZX:EtOH complexes in ethanol; (a) Model B, (b) Model C, and (c) Model D.
deviations are because of the fact that experimental data belong to the solid phase of the molecule while the calculations referred to a structure in the gas phase. N7AC1, C2AC1, and C5AC4 bond lengths are predicted very well. On the benzene ring, the valence angles between non-hydrogen atoms are in the range of 116– 123°, referring to a significant ring distortion.
The experimental FT-IR and FT-Raman spectra are presented in Fig. 2. The experimental frequencies are also gathered in Table 3, together with the TED (%) values. Theoretical data were calculated at B3LYP/6-311++G(d,p) level and a uniform scaling factor 0.9982 was applied [22]. Calculations achieved a good agreement with the experimental spectrum. The experimental FT-IR spectrum is dominated by a single tautomer as expected, and it would be interpreted accordingly. The FT-IR spectrum of CZX investigated exhibits several broad and intense absorption bands in the range 550–1750 cm1. This absorption is due to the NAH and CAN bending, and C@O stretching vibrations of the oxazole and carbonyl groups. On the other hand, Raman spectrum presents only narrow bands because highly polar bonds like C@O give weak (virtually nonexistent) scattering. Hence, the Raman spectrum of CZX is unaffected. In the FTIR spectrum the band observed at 202 (Ra 226, calc. 171) cm1 is a medium band which is due to the CACL bending of benzene ring. The strong band at 353 (Ra 362, calc. 357) cm1 is the butterfly motion of benzoxazole skeleton. At 417 (Ra 438, calc. 412) cm1 wavenumber a strong band is observed and assigned as a mix of deformation in benzene ring and the NH bending of oxazole. A C@O bending mode is observed at 592 (Ra 610, calc. 587) cm1 as a strong band. A very strong band at 688 (Ra 721, calc. 709) cm1 is assigned to CACL stretch and ring deformation vibrations. Skeletal CH and NH bendings are observed at 842 (Ra 855, calc. 847) cm1 as a strong band. Another CH bending is observed at 1147 (Ra 1178, calc. 1152) cm1, again as a strong band. The medium band at 1102 (Ra 1118, calc. 1099) cm1 is due to the
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Table 4 Vibrational modes of CZX in various media and approximate assignments in ethanol solution. a
Experimental (cm1)
Calculated
(cm1)
Solid
EtOH soln.
Model A
Model B
Model C
Model D
% TEDb
592 s 688 vs 737 m 800 vs 842 s 868 w 920 s 959 vs 1061 m 1102 m 1147 s 1255 s 1295 s 1361 m 1456 sh,m 1473 s 1616 s 1704 sh,m 1764 vs 3472 vw
558 m 590 m 708 m 756 m 801 m 845 m 865 w 918 m 944 m 1064 w 1105 w 1149 m 1256 s 1295 m 1364 w 1451 sh,w 1483 s 1623 m 1694 sh,w 1776 vs 3499 w
555 (12.8) 587 (35.8) 706 (36.1) 750 (13.4) 813 (62.6) 862 (39.8) 868 (1.7) 921 (50.7) 936 (245.3) 1071 (38.8) 1109 (27.5) 1156 (63.6) 1265 (253.1) 1293 (91.2) 1376 (30.9) 1478 (28.4) 1497 (351.9) 1649 (87.2) 1654 (13.1) 1800 (1890.1) 3640 (178.3)
554 (12.1) 589 (33.7) 706 (35.4) 750 (13.1) 813 (61.2) 862 (38.6) 869 (1.7) 918 (63.4) 936 (234.1) 1069 (33.2) 1111 (22.8) 1157 (62.4) 1265 (233.8) 1293 (91.3) 1380 (31.9) 1479 (41.4) 1498 (335.1) 1649 (81.1) 1654 (13.1) 1802 (1897.6) 3638 (181.4)
554 (8.1) 591 (38.0) 708 (43.2) 749 (13.5) 813 (62.6) 862 (36.1) 870 (7.8) 910 (139.6) 933 (177.4) 1071 (40.4) 1111 (24.4) 1157 (59.6) 1264 (288.5) 1293 (88.7) 1375 (31.7) 1478 (26.4) 1498 (351.9) 1649 (87.7) 1655 (14.2) 1810 (1852.6) 3634 (186.8)
554 (9.1) 592 (36.8) 707 (44.5) 749 (13.4) 816 (62.1) 863 (37.9) 870 (6.6) 910 (143.7) 934 (175.9) 1071 (36.7) 1111 (23.0) 1158 (58.7) 1265 (261.7) 1293 (86.3) 1380 (34.2) 1479 (39.9) 1499 (335.6) 1649 (85.5) 1656 (14.1) 1811 (1853.5) 3637 (191.4)
45 d(CCC) + 12 m(CLC) 63 d(CCO) + 10 d(CCC) 22 m(CLC) + 19 d(CCO) + 13 m(CC) + 12 d(CCN) 87 C(OONC) 87 C(HCCO) 79 C(HCCC) 54 m(CC) + 23 d(CCN) 23 d(CCN) + 19 d(CCO) + 16 m(NC) 22 d(CCO) + 15 m(CC) + 12 d(CCC) 29 m(CC) + 14 d(HCC) 22 d(HCC) + 20 m(NC) + 13 d(CCN) + 13 m(CC) 44 d(HCC) + 11 m(NC) + 11 d(CCC) 16 d(HCC) + 14 m(NC) + 11 m(CC) 29 m(NC) + 16 m(CC) + 12 d(HCC) 34 m(CC) + 28 d(HNC) 16 d(HCC) + 12 d(CCC) + 11 m(NC) + 10 m(CC) 47 d(HCC) + 29 m(CC) 38 m(CC) + 13 d(CCN) + 13 d(CCC) 66 m(CC) 79 m(OC) + 13 m(NC) 100 m(NH)
m: stretch, d: bending, C: torsion, vw: very weak, w: weak, m: medium, sh: shoulder, s: strong, vs: very strong. a b
Calculated wavenumbers are belong to form B and they are scaled by 0.9982. Given assignments are for Model D.
Table 5 Energiesa (in eV) of HOMO and LUMO for the structures studied.
a
Structure
HOMO
LUMO
DELAH
CZX-1 CZX-2 CZX-3 CZX-4 Model Model Model Model
6.749 6.763 7.601 6.895 6.652 6.695 6.716 6.758
1.333 1.190 3.149 3.373 1.147 1.179 1.189 1.218
5.416 5.573 4.452 3.522 5.505 5.516 5.526 5.540
A B C D
Calculated at the B3LYP/6-311++G(d,p) level with the option pop = reg.
CAN and CAO stretchings in oxazole ring. 1361 (Ra 1384, calc. 1341) is mostly due to the ring deformations. The medium intensity shoulder at 1456 (Ra 1474, calc. 1482) cm1 is a similar band which is also contributed by CC stretching and CH bending vibrations. A CC stretching mode of benzene is observed at 1616 (Ra 1639, calc. 1649) cm1. The most important band of such a structure, the C@O stretch, is observed at 1764 (Ra 1746, calc. 1875) cm1 with a very strong intensity. The very strong band at 237 (Ra 241, calc. 212) cm1 is due to the CACL bending vibration. A medium band at 279 (Ra 297, calc. 253) cm1 is the ring puckering of oxazole. Another medium band is observed at 737 (Ra not observed, calc. 717) cm1, and it is contributed by the deformation of benzene and oxazole rings. The out of plane CH bending is observed at 800 (Ra 824, calc. 814) cm1 as a very strong band. Another CH bending mode is observed at 1473 (Ra 1492, calc. 1503) cm1 as a strong band. Two bands at 920 (Ra 939, calc. 916) cm1 and 959 (Ra 980, calc. 935) cm1 are assigned to the stretching vibrations of CAO and CAN. The mode at 1061 (Ra 1080, calc. 1073) cm1 is observed at medium intensity and assigned to deformation of benzene ring together with the CACL stretching vibration. Two strong bands at 1255 (Ra 1267, calc. 1269) cm1 and 1295 (Ra 1333, calc. 1292) cm1 are both ring stretching modes. The NH stretching mode of CZX is observed at 3472 (Ra not observed, calc. 3662) cm1.
Fig. 6. (a) HOMO and (b) LUMO of CZX.
The IR spectrum of CZX exhibits a broad contour in the 1800–3300 cm1 range. We may conclude that this contour is due to the overtones and combination bands of CZX fundamentals. On the other hand, it is known that CZX can be found as hydrogen bonded homomolecular dimers. Also, anti-parallel centrosymmetric dimers of CZX can be observed in cocrystal structures. And for the cocrystal structures, there are repulsive
346
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Table 6 MK and NBO charges (in e) of CZX-1 in vacuo and in ethanol. No.
Atom
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
C C C C C C N C O H H Cl H H O
In vacuo
Model A
Model B
Model C
Model D
MK
NBO
MK
NBO
MK
NBO
MK
NBO
MK
NBO
0.27259 0.36733 0.38129 0.04962 0.07135 0.25066 0.67310 0.84653 0.40340 0.22771 0.14709 0.07650 0.19462 0.40822 0.55817
0.12924 0.27909 0.21436 0.22965 0.03632 0.25463 0.61416 0.90249 0.50286 0.23054 0.22629 0.00854 0.22986 0.42375 0.57782
0.19967 0.38325 0.38098 0.04743 0.08759 0.20259 0.58855 0.83156 0.40884 0.23598 0.15745 0.09968 0.20908 0.43083 0.63213
0.13450 0.27792 0.21526 0.23249 0.03771 0.24772 0.59597 0.91032 0.51065 0.24013 0.23394 0.00735 0.24416 0.44506 0.63887
0.22774 0.34172 0.36218 0.04292 0.05025 0.21022 0.61787 0.88554 0.41672 0.23640 0.14350 0.10438 0.20370 0.42999 0.64730
0.13514 0.27998 0.21452 0.23137 0.03732 0.24645 0.59546 0.91049 0.51041 0.24055 0.23481 0.01374 0.24540 0.44556 0.63750
0.30098 0.24072 0.35554 0.05468 0.02956 0.25842 0.59387 0.74882 0.27918 0.24045 0.15137 0.10864 0.21387 0.43156 0.59664
0.13541 0.27934 0.21433 0.23015 0.03660 0.24563 0.59351 0.91405 0.53450 0.24147 0.23470 0.00511 0.24500 0.44675 0.63058
0.27676 0.18862 0.29065 0.06325 0.00574 0.25861 0.55137 0.75118 0.27384 0.22625 0.14352 0.11115 0.21378 0.41774 0.59774
0.13613 0.28135 0.21357 0.22907 0.03578 0.24413 0.59313 0.91417 0.53406 0.24190 0.23555 0.01195 0.24619 0.44717 0.62942
CAH CLAC interactions in the packing motif [12]. Hence, the broad contour observed in CZX spectrum is the absorption of dimeric structures superimposed on the overtones and combinations of the monomeric form. A possible dimeric form of CZX (Fig. 3) which is stabilized by intermolecular hydrogen bonding was also computed. Complete lists of the vibrational frequencies of CZX dimer is given in Table S1 (Supp. Information. Table S1). We have looked forward for how CZX’s vibrational modes were affected when it solvated in ethanol. When the experimental solvation phase spectrum (see Fig. 4) was compared with the solid phase experimental data, we have spotted a peak at 558 cm1 which was not observed for the solid sample. Hence, we have concluded that CZX might have been established hydrogen bonded complexes with ethanol. Considered complexes are plotted in Fig. 5. Experimental and theoretical vibrational data of the solvated CZX are given in Table 4. We have gathered the most suitable results from Model D (see Fig. 5c). Hence, the basis of our conclusions is Model D. The band observed at 558 cm1 is calculated at 554 cm1 as a medium band and assigned as a mix of CLC bending and ring deformation of benzene. O@C stretching band was observed at 1764 cm1 in very strong intensity. This band is shifted to 1776 cm1 and it is observed in very strong intensity again. The calculated wavenumber for this band is 1811 cm1 and the intensity of the calculated band matches with our experimental results. NAH stretching band is also affected by the presence of solvent. It was observed at 3472 cm1 as a very weak band for the solid sample. When solvated, it is shifted to 3499 cm1 and the band shape is superimposed by the broad band of ethanol. The very strong CACL stretching band at 688 cm1 is shifted to 708 cm1 (calc. 707 cm1). This shift might have been occurred most probably due to the intermolecular hydrogen bonding interactions between the chlorine site of CZX and ethanol. Another significant shift is observed for the ring bending vibration of oxazole of 959 cm1. This band is detected at 944 cm1 (calc. 934 cm1) in medium intensity when in solvation phase. Similarly the band at 737 cm1 is shifted to 756 cm1 (calc. 749 cm1) in solution. This band was assigned to the umbrella vibration in the oxazole ring. We have concluded that these shiftings are due to the intermolecular hydrogen bonding interactions between the carbonyl (O@C) of CZX and ethanol. The CH bending mode at 1473 cm1 in solid phase was observed at 1483 cm1 (calc. 1499 cm1) in solvation phase. Still the dominant nature of this mode is CH bending, but as TED
analysis indicated there is a contribution from the internal vibrations of ethanol. Yet, literature data on the vibrations of ethanol present a medium intensity triplet between 1500–1400 cm1. Although there are several other shiftings observed in the experimental solvation phase spectrum, those shiftings are considered as insignificant.
Theoretical electronic properties The energies of the frontier molecular orbitals of CZX are computed and given in Table 5. For the most stable structure CZX-1, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies were calculated as 6.749 eV and 1.333 eV, respectively. Hence, the HOMO–LUMO energy gap (DELAH) is 5.416 eV. To understand the nature of the skeletal bonds in CZX, we have also created the electrostatic field contour maps which were given in Fig. 6. These contour maps show that HOMO orbital of CZX-1 has bonding nature between the atoms C4AC5AC6, C1AC2AC3, and N7AC8AO9, anti-bonding character between atoms C1AC6, C5ACL12, C3AC4, C1AN7, and C2AO9. On the other hand, LUMO orbital exhibits bonding nature between the atoms C1AC2, C4AC5, and N7AC8; while it has anti-bonding character between the atoms C2AO9AC8, C1AN7, C2AC3, and C5AC6. In solvation phase a slight change in the frontier electrons distribution was computed. For the HOMO orbital the frontier electrons population over 7 N and 15O were calculated denser. For the LUMO orbital we have seen that the frontier electron density on 7 N was lowered while 12CL has some more frontier electron localization. The HOMO–LUMO plots in ethanol solution are given in Fig. S1 (Supp. Information. Fig. S1). We have examined the charge distribution for the skeletal atoms of CZX-1 by using both Merz–Kollman (MK) and Natural Bond Orbital (NBO) analysis. Calculated charge distributions are presented in Table 6. In CZX-1 tautomer the nitrogen (N7) and oxygens (O9, O15) are rich in negative charges, which are beneficial to the bioactivity [25]. As seen Table 6, when CZX is solvated in ethanol, those negatively charged oxygens (O9, O15) have become more negative. We have calculated a loss of charge on N7 which refers to a charge transfer through C8 and O15. The chlorine (CL12) is predicted to have positive charge when in vacuum. When solvated, CL12 becomes negatively charged which may indicate the existence of intermolecular hydrogen bonding interactions between chlorine site and ethanol. Note that, MK charges on CL12 are predicted negative in both media.
Sß. Yurdakul, M. Yurdakul / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 126 (2014) 339–348
Fig. 7. Experimental (a) 1H-, (b)
Nuclear magnetic resonance Results of the experimental 1H and coupled 13C NMR measurements, and our B3LYP/6-311++G(d,p) calculated chemical shifts are collected in Fig. 7 and Table 7. Dimethyl sulfoxide (DMSO) was the solvent used in experiments. NMR calculations are also done in DMSO by employing PCM (polarized continuum model). Calculated 13 C shifts were scaled according to the scaling equation dscal = 0.95dcalc + 0.30 before comparing with the experimental data [26]. We
347
13
C- NMR spectra of CZX.
have not reported any correlation factors for 1H NMR for two reasons. Because a good correlation for proton shifts was not expected, since the protons are located on the periphery of the molecule and are supposed to be more susceptible to solute– solvent effects [27]. Calculated chemical shifts correlate well with the experimental data. The squared correlation factors of 1H and 13 C shifts were found to be 0.9845 and 0.9767, respectively. 13C NMR measurement exhibits a heptet at around 40 ppm which is not included in Table 7. This heptet is the solvent signal of DMSO.
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Table 7 Theoretical and experimental chemical shifts (in ppm) of chlorozoxazone. Atoms
Experimental
Calculated
2C 3C 4C 5C 6C 7C 9C 1H 8H 10H 11H
127.7 154.2 142.0 109.6 110.5 131.6 121.3 7.01 7.19 7.22 7.04
136.359 158.225 149.357 114.080 115.076 142.661 127.023 7.1217 7.2617 7.2788 7.1656
Conclusions The FT-IR and FT-Raman spectra of chlorzoxazone (CZX) were recorded and interpreted by means of B3LYP/6-311++G(d,p) calculated harmonic frequencies followed by total energy distribution (TED) analysis. The geometry of the most stable tautomer of CZX was discussed. Geometrical parameters are predicted very well. The frontier molecular orbitals properties and NBO charges of CZX molecule were also given. It has been found that the CZX molecule has 5.416 eV of HOMO–LUMO energy gap, and common atoms in the molecule such as the nitrogen atom in the oxazole ring, and the oxygens possess richly negative charges. Calculated 1 H and 13C NMR chemical shifts were compared with the experimental data. Calculated chemical shifts correlate well with the experimental data. We have looked forward for how several structural features of CZX were affected when it solvated in ethanol. We have seen that there is a peak in the experimental solvation phase spectrum which was not observed for the solid sample. Hence, we have constructed different models to computationally investigate solvent effects. It has been determined that the vibrational modes of CZX are best represented by a model incorporating both implicit and explicit solvation with two explicit ethanol molecules (i.e., Model D). The experimental solvation phase spectrum has showed that several bands of the CZX were affected by the solvent. The C@O, NAH, and CACL stretching vibrations are such bands. Our PCM DFT (B3LYP) calculations have predicted the vibrational bands of the solvated system very well. Our calculations have shown that the geometrical parameters of CZX were not significantly affected by the solvent in general. The most significant deviations from the gas phase data were determined at the carbonyl site. According to those calculations, the frontier electrons distribution over CZX exhibits small changes in solvation phase. On the other hand, we have seen that the negatively charged oxygens (O9, O15) have become more negative, and the chlorine (CL12) turned to negative from positive when solvated in ethanol.
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.2014.02.156. References [1] R.F. Frye, J. Chromatogr. B Biomed. Appl. 686 (1996) 291–296. [2] D. Lucas, F. Berthou, C. Girre, F. Poitrenaud, J.F. Menez, J. Chromatogr. 622 (1993) 79–86. [3] R. Peter, R. Böcker, P. Beaune, M. Iwasaki, F.P. Guengerich, C.S. Yang, Chem. Res. Toxicol. 3 (1990) 566–573. [4] V. Carriere, T. Goasduff, D. Ratanasavanh, F. Morel, J.C. Gautier, A. Guillouzo, P. Beanue, F. Berthou, Chem. Res. Toxicol. 6 (1993) 852–857. [5] J. March, Advanced Organic Chemistry, Reaction, Mechanism and Structure, 4th ed., John Wiley, New York, 1993. [6] W. Saenger, Principles of Nucleic Acid Structure, Springer, New York, 1994. [7] J. Elks, C.R. Canellin, Dictionary of Drugs: Chemical data, Structures and Bibliographies, Chapman and Hall, New York, 1990. pp 249. [8] S. Budavari, M.J. O’Neil, A. Smith, P.E. Heckelman, Merck Index: an encyclopedia of chemical drugs and biological, Rahway (1989) 340. _ A. Topaçlı, J. Chem. Crystallogr. 27 (1997) 303–306. [9] S. Ide, [10] S. Harikrishnan, T.J. Bhoopathy, IJMMSE 3 (2013) 23–34. [11] C.B. Aakeröy, K.R. Seddon, Chem. Soc. Rev. 22 (1993) 397–407. [12] J.R. Fredericks, A.D. Hamilton, in: J.L. Atwood, J.E.D. Davies, D.D. Mac Nicol, E. Vögtle (Eds.), Comprehensive Supramoleculer Chemistry, Pergamon Press, Oxford, 1996, pp. 161–180. [13] S.L. Childs, K.I. Hardcastle, Cryst. Eng. Comm. 9 (2007) 364–367. [14] S. Miertuš, E. Scrocco, J. Tomasi, Chem. Phys. 55 (1981) 117–129. [15] A.D. Becke, J. Chem. Phys. 98 (1993) 5648–5652. [16] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785–789. [17] M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, J.A. Montgomery, Jr., T.Vreven, K.N. Kudin, J.C. Burant, J.M. Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J.E. Knox, H.P. Hratchian, J.B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W. Ochterski, P.Y. Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, V.G. Zakrzewski, S. Dapprich, A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D. Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A. Nanayakkara, M. Challacombe, P.M.W. Gill, B. Johnson, W. Chen, M.W. Wong, C. Gonzalez, J.A. Pople, Gaussian 03, Revision C.02, Gaussian Inc., Wallingford CT, 2004. [18] R. Dennington II, T. Keith, J. Millam, K. Eppinett, W.L. Hovell, R. Gilliland, GaussView, Version 3.09, Semichem, Shawnee Mission, KS, 2003. [19] P. Pulay, J. Baker, K. Wolinski, 2013 Green Acros Road Suite A, Fayetteville, Arkansas 72703, USA. [20] A.E. Reed, L.A. Curtiss, F. Weinhold, Chem. Rev. 88 (1988) 899–926. [21] U.C. Singh, P.A. Kollmann, J. Comput. Chem. 5 (1984) 129–145. [22] H. Watanabe, N. Hayazawa, Y. Inouye, S. Kawata, J. Phys. Chem. B 109 (2005) 5012–5020. [23] A. Gerega, L. Lapinski, M.J. Nowak, A. Furmanchuk, J. Leszczynski, J. Phys. Chem. A 111 (2007) 4934–4943. [24] M. Piacenza, S. Grimme, J. Comput. Chem. 25 (2004) 83–98. [25] P. Chavatte, S. Yous, C. Marot, N. Baurin, D. Leiseur, J. Med. Chem. 44 (2001) 3223–3230. [26] A.E. Aliev, D. Courtier-Murias, S. Zhou, J. Mol. Struct.-Theochem 893 (2009) 1– 5. [27] B. Os´miałowski, E. Kolehmainen, E. Gawinecki, Magn. Reson. Chem. 39 (2001) 334–340.
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Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy journal homepage: www.elsevier.com/locate/saa
FT-IR, FT-Raman spectra, and DFT computations of the vibrational spectra and molecular geometry of chlorzoxazone q Sß enay Yurdakul a,⇑, Murat Yurdakul b a b
Department of Physics, Faculty of Sciences, Gazi University, Teknikokullar 06500, Ankara, Turkey Department of Mathematics, Faculty of Arts and Sciences, Middle East Technical University, Çankaya 06800, Ankara, Turkey
h i g h l i g h t s
g r a p h i c a l a b s t r a c t
Spectroscopic, structural, and
electronic analysis on chlorzoxazone are reported. DFT calculated data such as IR and NMR are consistent with the experimental data. Spectroscopic data suggest the presence of monomer and dimer forms in the sample. Experimental IR spectrum in ethanol is recorded and compared with solid phase data. Experimental IR data are best represented by a hybrid solvation model in theory.
a r t i c l e
i n f o
Article history: Received 29 November 2013 Received in revised form 21 February 2014 Accepted 23 February 2014 Available online 12 March 2014 Keywords: Chlorzoxazone DFT IR and Raman spectra Tautomers Solvent effects
a b s t r a c t Far-IR, mid-IR, and FT-Raman spectra of the chlorzoxazone (CZX) were recorded. The observed vibrational wavenumbers were analyzed and assigned to different normal modes of vibration of the molecule. Density functional calculations were performed to support wavenumber assignments of the observed bands. The equilibrium geometry and harmonic wavenumbers of CZX were calculated by the DFT B3LYP method. All tautomeric forms and dimer form of CZX were determined and optimized. Additionally, experimental FT-IR spectrum in ethanol solution was recorded and compared with solid phase experimental data for the first time. The combination of the DFT B3LYP with polarized continuum model (PCM) was employed to characterize the solvent effects in ethanol solution. Ó 2014 Elsevier B.V. All rights reserved.
Introduction The chlorzoxazone is a centrally acting skeletal muscle relaxant. It acts primarily at the level of spinal cord and subcortical areas of the brain where it inhibits multisynaptic reflex arcs involved in
q Selected paper presented at XIIth International Conference on Molecular spectroscopy, Kraków–Białka Tatrzan´ska, Poland, September 8–12, 2013. ⇑ Corresponding author. Tel.: +90 312 202 12 38; fax: +90 312 212 22 79. E-mail address: [email protected] (S ß . Yurdakul).
http://dx.doi.org/10.1016/j.saa.2014.02.156 1386-1425/Ó 2014 Elsevier B.V. All rights reserved.
producing and maintaining skeletal muscle spasm of variety etiology [1,2]. It was found to be exclusively catalyzed by cytochrome P-4502E1 in human liver microsomes [3]. It was also proposed that chlorzoxazone could be used in vitro and in vivo as a tool to screen for cytochrome P-4502E1 activity and the ability of other drugs or compounds to induce or inhibit cytochrome P-4502E1 in humans [4]. Tautomerism, a particular case of isomerism plays an important role in pharmacology, molecular biology, organic chemistry, biochemistry, and medicinal chemistry. Tautomerization is an important step of many organic reactions [5]. Many biochemical
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processes, including those involving specific interactions with proteins, enzymes, and receptors requires an understanding of tautomerization [6]. Investigations on chlorzoxazone have shown that this molecule exhibits four tautomeric forms (Fig. 1) [7,8]. Based _ and Topaçlı [9] agreed that the amion crystal structure results, Ide no form (I) is predominant tautomer. Harikrishnan and Bhoopathy have investigated the most stable tautomeric form by using vibrational spectroscopy and theoretical methods [10]. There is also growing interest in the construction of supramolecular assemblies with hydrogen bands as the building blocks [11,12]. An example is the cocrystal of chlorzoxazone with carboxylic acid [13]. However, to the best of our knowledge, a complete detailed vibrational study on chlorzoxazone has not been reported yet. Due to the importance of this molecule, the interest in the present manuscript was to carry out analysis of the chlorzoxazone and its tautomeric forms’ energies, geometries and vibrational wavenumbers with the attention focused on the spectroscopic side. The infrared and Raman spectra were used for the comparison with the theoretical spectra. The 1H- and 13C- NMR measurements were performed, and compared with the computed data. Solvent effects draw much attention since years. Shifts in the infrared frequencies and appearance of the new bands are due to the solute–solvent interactions. Besides, supporting experimental results by employing quantum chemical calculations produce good outcome. There are three main approaches in studying solvent effects computationally. Implicit solvation is one of them and known as PCM (polarized continuum model). PCM considers the medium as a dielectric continuum and it is first proposed by Miertuš et al. [14]. Another approach is calculating any given molecular structure in the gas phase with neighboring hydrogen bonded solvent molecules. A third approach is to combine the latter approaches by employing PCM model for a system of several solvent molecules hydrogen bonded to solute molecule. Here in this work, we also report the experimental FT-IR spectrum of CZX in ethanol solution and its interpretation using DFT PCM calculations for the first time. Experimental The pure sample of chlorzoxazone was obtained from Sigma, and used as such without any further purification. Mid-IR
spectrum was recorded in the regions 3800–550 cm1 on Bruker Vertex 80 FT-IR spectrometer with Pike MIRacle ATR apparatus. The resolution of the spectrometer was 2 cm1. Far-IR spectrum was recorded in the region 500–30 cm1 on a Bruker IFS 66 V/S spectrometer. FT-Raman spectrum was obtained on a Bruker FRA 106/S spectrometer using 1064 nm excitation from an Nd:YAG laser. The detector was a Ge-diode cooled to liquid nitrogen temperature. The upper limit for wavenumbers was 3800 cm1 and the lower wavenumbers is around 150 cm1. The 1H- and coupled 13 C NMR measurements were performed by using a Bruker Biospin UltraShield 300 MHz spectrometer at the natural abundance of the nuclei of interest. Dimethyl sulfoxide (DMSO) was the solvent. For liquid sample analysis, a solution of CZX was prepared at 50 mg/mL and the pure solvent spectrum was recorded as reference before sample measurement. Computational methods The calculations were carried out by using density functional theory, with the Becke’s three parameter exchange functional [15] in combination with the correlation functional of Lee, Yang and Parr (LYP) [16]. 6-311++G(d,p) basis set was used. These procedures are implemented in the Gaussian 03 W program package [17]. All calculations submitted via GaussView [18]. Counterpoise correction (CP) is included in calculation of the dimer form. Assignments of the calculated normal modes were made from the corresponding total energy distributions (TEDs). The TEDs were calculated using the Parallel Quantum Solutions software [19]. For the relative DE energies of chlorzoxazone tautomers, QCISD method using cc-pVDZ basis set was also employed. Atomic charges were determined with the Natural Bond Orbital (NBO) [20] and the Merz–Kollman (MK) procedures [21]. The 1H- and 13C-chemical shifts were calculated based on the gauge independent atomic orbital (GIAO) method by using the B3LYP/6-311++G(d,p) level considering the solvent effects. The chemical shifts were derived with respect to the isotropic shielding tensors of the TMS (tetramethylsilane). The structure used was re-optimized according to the same level with considering solvent effects, before the NMR calculations done. The solvent environment was evaluated by using the polarized continuum model (PCM) in all computations for investigating the
Fig. 1. Tautomeric forms of chlorzoxazone.
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Sß. Yurdakul, M. Yurdakul / Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 126 (2014) 339–348 Table 1 Calculated total energies Etot (Hartree) and relative DE (kcal/mol) energies of the forms studied. In vacuo
In ethanol
B3LYP/6-311++G(d,p)// B3LYP/6-311++G(d,p)
CZX-1 CZX-2 CZX-3 CZX-4 a
QCISD/cc-pVDZ// B3LYP/6–311++G(d,p)
B3LYP/6-311++G(d,p)// B3LYP/6-311++G(d,p)
QCISD/cc-pVDZ// B3LYP/6-311++G(d,p)
Etot
DE
Etot
DE
Etot
DE
Etot
DE
934.727619054 934.705738360 934.684735170 934.680707790
0.00 13.73 26.91 29.44
932.73353518 932.71469681 932.69606681 932.69220649
0.00 11.82 23.51 25.93
934.73977758 934.71378085 934.69963450 934.69471591
0.00 16.31 25.19 28.28
932.74343838 932.72172162 932.70672750 932.70146733
0.00 13.63 23.04 26.34
DE = EnE1 are the total energy differences between the nth tautomer (n = 2, 3, 4) and the first tautomer.
solvent effects. To investigate the effects of solvation on CZX, the following calculations were carried out: (i) PCM implicit solvation model calculation on the most stable tautomer (Model A), (ii) hybrid (both implicit and explicit solvation model) calculation on 1:1 CZX:Ethanol complex in which an ethanol molecule is bound to chlorine (Model B), (iii) hybrid calculation on 1:1 CZX:Ethanol complex in which an ethanol molecule is bound to ring oxygen (Model C), and (iv) hybrid calculation on 1:2 CZX:Ethanol complex in which two ethanol molecules are bound to chlorine and oxygen (Model D).
Results and discussion Tautomerism of chlorzoxazone The structures and the nomenclature of the studied tautomers were depicted in Fig. 1. To obtain more accurate results which
are comparable with experimental data, the B3LYP/6311++G(d,p) level of computations are used. On the other hand, in view of relative energy differences, we also considered the QCISD method because of its reproducibility of the experimentally measured energy differences [23,24]. The B3LYP/6-311++G(d,p) and QCISD/cc-pVDZ calculated single point energy predictions of four tautomers are compared in Table 1 which shows that CZX-1 has the lowest energy value (934.727619054 and 932.73353518 Hartree, respectively) among four tautomers. The relative abundances of possible CZX tautomers were calculated using Boltzmann Distribution equation. The abundance of the most stable tautomer, CZX-1 equals 100% at 298 K. The remaining species have zero total population and are expected to be of no importance in relation to the experimental spectra. Single point energy predictions are also obtained for ethanol solution. The results have shown that when CZX is solvated in ethanol, CZX-1 stays as the most stable tautomer. Besides, the relative energy difference between CZX-1 and the second most
Table 2 Calculated bond lengthsa and bond anglesa of CZX in various media. Coordinate
Calculated Experimentalb
CL12AC5 N7AC8 N7AC1 O9AC2 O9AC8 O15AC8 C2AC1 C2AC3 C1AC6 C6AC5 C5AC4 C4AC3 CL HAO O HAO C8AN7AC1 C2AO9AC8 O9AC2AC1 O9AC2AC3 C1AC2AC3 N7AC8AO9 N7AC8AO15 O9AC8AO15 N7AC1AC2 N7AC1AC6 C2AC1AC6 C1AC6AC5 CL12AC5AC6 CL12AC5AC4 C6AC5AC4 C5AC4AC3 C2AC3AC4 CL HAO O HAO a b
1.7384 1.3515 1.3866 1.3905 1.3776 1.2036 1.3926 1.3687 1.3716 1.3837 1.3957 1.3796
110.74 107.83 108.44 128.64 123.04 107.54 130.55 122.04 105.44 133.54 121.04 116.24 118.73 118.54 122.84 120.44 116.64
In vacuo 1.7582 1.3845 1.3899 1.3762 1.3919 1.1955 1.3964 1.3772 1.3853 1.3983 1.3933 1.4008
110.57 108.25 109.60 128.06 122.33 106.37 129.38 124.23 105.18 133.41 121.39 116.20 118.29 119.03 122.67 120.29 117.09
All bond lengths are in Angstroms and all bond angles are in degrees. Taken from Ref. [9].
Model A 1.7636 1.3720 1.3903 1.3807 1.3866 1.2052 1.3948 1.3773 1.3857 1.3973 1.3942 1.4007
110.35 108.04 109.14 128.14 122.72 107.02 129.85 123.12 105.44 133.18 121.38 115.84 118.17 118.73 123.10 120.15 116.80
Model B 1.7629 1.3689 1.3909 1.3837 1.3943 1.2036 1.3940 1.3770 1.3857 1.3971 1.3942 1.4006 2.6138 110.59 108.10 108.93 128.27 122.81 106.75 130.39 122.86 105.63 133.00 121.37 115.84 118.19 123.07 120.21 116.71 110.59 175.38
Model C 1.7629 1.3689 1.3909 1.3837 1.3943 1.2036 1.3940 1.3770 1.3857 1.3971 1.3942 1.4006 2.0808 110.59 108.10 108.93 128.27 122.81 106.75 130.39 122.86 105.63 133.00 121.37 115.84 118.19 123.07 120.21 116.71 110.59 175.41
Model D 1.7663 1.3691 1.3906 1.3831 1.3947 1.2033 1.3942 1.3769 1.3856 1.3965 1.3935 1.4007 2.6145 2.0857 110.58 108.11 108.92 128.22 122.86 106.74 130.41 122.85 105.65 133.01 121.34 115.73 118.07 118.64 123.29 120.07 116.71 175.83 175.96
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Fig. 2. Experimental (a) Mid-IR, (b) Far-IR, and (c) Raman spectra of CZX.
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Table 3 Vibrational modes of CZX and their approximate assignments. Mode
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
Symmetry
00
A A00 A0 A00 A00 A00 A00 A00 A00 A0 A0 A00 A0 A00 A0 A00 A00 A00 A0 A0 A00 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0 A0
Experimental (cm1)
Calculated
IR
Ra
Frequency*
IIR (SRA)
TED (%)
116 m 202 m 237 vs 279 m 343 sh,w 353 s 394 s 417 s 434 w 549 m 592 s 639 sh,m 688 vs 708 s 737 m 751 sh,w 800 vs 842 s 868 w 920 s – 959 vs 1061 m 1102 m 1147 s 1230 sh,w 1255 s 1295 s 1361 m – 1456 sh,m 1473 s 1616 s 1704 sh,m 1764 vs 3053 w 3082 w 3147 w 3472 vw
– 226 w 241 vw 297 w – 362 s 401 s 438 vw – 578 vs 610 vw – 721 s – – 774 vw 824 vw 855 sh 879 s 939 vw – 980 m 1080 w 1118 vw 1178 vw 1239 sh,w 1267 vs 1333 w 1384 w – 1474 m 1492 m 1639 m 1706 vw 1746 w – 3094 w – –
90 (90) 171 (171) 212 (212) 253 (253) 346 (345) 358 (357) 385 (384) 413 (412) 450 (449) 558 (557) 588 (587) 601 (600) 710 (709) 714 (713) 718 (717) 749 (748) 815 (814) 849 (847) 868 (866) 918 (916) 933 (931) 937 (935) 1075 (1073) 1101 (1099) 1154 (1152) 1254 (1252) 1271 (1269) 1294 (1292) 1343 (1341) 1378 (1376) 1485 (1482) 1506 (1503) 1652 (1649) 1659 (1656) 1878 (1875) 3203 (3197) 3210 (3204) 3215 (3209) 3669 (3662)
1.6 (0.2) 2.3 (0.01) 1.7 (1.2) 0.3 (0.7) 0.8 (7.6) 13.6 (1.3) 1.4 (4.8) 12.2 (0.2) 92.7 (0.3) 5.4 (8.0) 17.0 (0.3) 2.1 (0.2) 15.9 (8.6) 0.9 (0.1) 21.8 (13.2) 9.2 (0.1) 38.0 (0.2) 26.9 (0.2) 0.8 (15.5) 62.2 (1.7) 0.7 (0.02) 103.9 (5.1) 26.5 (13.1) 23.8 (1.5) 27.1 (3.9) 6.6 (7.3) 159.4 (36.9) 42.8 (4.2) 18.4 (4.6) 14.2 (20.7) 11.1 (25.8) 214.8 (13.9) 35.1 (9.1) 17.2 (27.3) 1110.0 (39.0) 0.3 (50.9) 0.4 (63.2) 0.1 (168.4) 96.6 (118.4)
UCCCN(22)+UCCNO(19)+UCCCO(17)+UClCCC(17) UClCCC(25)+UCCNO(17)+UCCCO(13)+ UCCHCl(12) dClCC(53) UCCCN(39)+UCCNO(16)+UCCCC(15) mCCl(27)+dCCC(17)+dCCCl(11) UCCNH(30)+UCCCO(26)+UCCCCl(12) dCCCl(26)+mCCl(13)+mCN(10) UCCCC(33)+UCCNH(18)+UCONH(16) UCONH(42)+UCCNH(12) dCCC(27)+mCO(13)+mCCl(12) dCNO(47)+dCCO(22)+dCCN(10) UCCCC(35)+UCCCH(30) mCCl(21)+dCCC(21)+dCCO(14) UCCCC(44)+UCCCH(21) dCCC(19)+dCCN(14) UCCNO(40)+UCONH(30)+UCCOO(11) UCCCH(52)+UCCHO(20)+UCCHCl(18) UCCCH(34)+UCCNH(28)+UCCHCl(26) mCC(34)+dCNO(15)+mCO(13) mCO(66) UCCHH(42)+UCCCN(29)+UCCHO(12) dCCC(23)+mCN(20) mCC(46)+dCCH(24)+mCCl(12) mCN(26)+dCCH(17)+mCO(10)+dCCC(10) dCCH(54)+mCC(24) dCCH(36)+dCNH(24)+mCC(10) mCC(34)+mCO(21)+dCCH(20) mCN(21)+mCC(15)+dCCN(13)+mCO(10) dCCH(34)+mCC(28)+dCNH(24) mCC(48)+dCNH(19) mCC(36)+dCCH(22)+mCN(14) dCCH(44)+mCC(28) mCC(68) mCC(62) mCO(80) mCH(100) mCH(99) mCH(99) mNH(100)
m: stretch, d: bending, C: torsion, vw: very weak, w: weak, m: medium, sh: shoulder, s: strong, vs: very strong. *
Values shown in parenthesis are scaled wavenumbers, scale factor is 0.9982.
Fig. 3. Dimer form of chlorzoxazone.
stable tautomer CZX-2 is larger in ethanol. Hence, CZX-1 is the most abundant tautomer even in the solvation phase. Molecular parameters The optimized bond lengths and bond angles in various media obtained for the most stable tautomer of chlorzoxazone (CZX-1)
using the B3LYP functional with 6-311++G(d,p) basis set are given in Table 2. The optimized geometry is compared with the struc_ and Topaçlı [9]. The tural parameters obtained in the study of Ide conformation of the molecule is planar. Table 2 shows that some bond lengths (O9AC2 and O15AC8) in vacuum are shorter than the experimental values. Some others; like CL12AC5, N7AC8, or O9AC8, are overestimated. These
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Fig. 4. Experimental mid-IR spectrum of CZX in ethanol.
It has been seen that when passed from gas phase to solvation phase the bond lengths of the most stable tautomer CZX-1 have not been changed significantly. The biggest differences were determined in N7AC8 (|D| 0.015 Å) and in O15AC8 (|D| 0.010 Å). Considering solvent effects in implicit or in mixed fashion has not been created much difference. Solvent effects were determined clearer on bond angles, though mostly the differences between the gas phase and solvation phase are small. Significant changes were determined in N7AC8AO15 and in O9AC8AO15. Vibrational analysis
Fig. 5. Optimized geometries of considered CZX:EtOH complexes in ethanol; (a) Model B, (b) Model C, and (c) Model D.
deviations are because of the fact that experimental data belong to the solid phase of the molecule while the calculations referred to a structure in the gas phase. N7AC1, C2AC1, and C5AC4 bond lengths are predicted very well. On the benzene ring, the valence angles between non-hydrogen atoms are in the range of 116– 123°, referring to a significant ring distortion.
The experimental FT-IR and FT-Raman spectra are presented in Fig. 2. The experimental frequencies are also gathered in Table 3, together with the TED (%) values. Theoretical data were calculated at B3LYP/6-311++G(d,p) level and a uniform scaling factor 0.9982 was applied [22]. Calculations achieved a good agreement with the experimental spectrum. The experimental FT-IR spectrum is dominated by a single tautomer as expected, and it would be interpreted accordingly. The FT-IR spectrum of CZX investigated exhibits several broad and intense absorption bands in the range 550–1750 cm1. This absorption is due to the NAH and CAN bending, and C@O stretching vibrations of the oxazole and carbonyl groups. On the other hand, Raman spectrum presents only narrow bands because highly polar bonds like C@O give weak (virtually nonexistent) scattering. Hence, the Raman spectrum of CZX is unaffected. In the FTIR spectrum the band observed at 202 (Ra 226, calc. 171) cm1 is a medium band which is due to the CACL bending of benzene ring. The strong band at 353 (Ra 362, calc. 357) cm1 is the butterfly motion of benzoxazole skeleton. At 417 (Ra 438, calc. 412) cm1 wavenumber a strong band is observed and assigned as a mix of deformation in benzene ring and the NH bending of oxazole. A C@O bending mode is observed at 592 (Ra 610, calc. 587) cm1 as a strong band. A very strong band at 688 (Ra 721, calc. 709) cm1 is assigned to CACL stretch and ring deformation vibrations. Skeletal CH and NH bendings are observed at 842 (Ra 855, calc. 847) cm1 as a strong band. Another CH bending is observed at 1147 (Ra 1178, calc. 1152) cm1, again as a strong band. The medium band at 1102 (Ra 1118, calc. 1099) cm1 is due to the
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Table 4 Vibrational modes of CZX in various media and approximate assignments in ethanol solution. a
Experimental (cm1)
Calculated
(cm1)
Solid
EtOH soln.
Model A
Model B
Model C
Model D
% TEDb
592 s 688 vs 737 m 800 vs 842 s 868 w 920 s 959 vs 1061 m 1102 m 1147 s 1255 s 1295 s 1361 m 1456 sh,m 1473 s 1616 s 1704 sh,m 1764 vs 3472 vw
558 m 590 m 708 m 756 m 801 m 845 m 865 w 918 m 944 m 1064 w 1105 w 1149 m 1256 s 1295 m 1364 w 1451 sh,w 1483 s 1623 m 1694 sh,w 1776 vs 3499 w
555 (12.8) 587 (35.8) 706 (36.1) 750 (13.4) 813 (62.6) 862 (39.8) 868 (1.7) 921 (50.7) 936 (245.3) 1071 (38.8) 1109 (27.5) 1156 (63.6) 1265 (253.1) 1293 (91.2) 1376 (30.9) 1478 (28.4) 1497 (351.9) 1649 (87.2) 1654 (13.1) 1800 (1890.1) 3640 (178.3)
554 (12.1) 589 (33.7) 706 (35.4) 750 (13.1) 813 (61.2) 862 (38.6) 869 (1.7) 918 (63.4) 936 (234.1) 1069 (33.2) 1111 (22.8) 1157 (62.4) 1265 (233.8) 1293 (91.3) 1380 (31.9) 1479 (41.4) 1498 (335.1) 1649 (81.1) 1654 (13.1) 1802 (1897.6) 3638 (181.4)
554 (8.1) 591 (38.0) 708 (43.2) 749 (13.5) 813 (62.6) 862 (36.1) 870 (7.8) 910 (139.6) 933 (177.4) 1071 (40.4) 1111 (24.4) 1157 (59.6) 1264 (288.5) 1293 (88.7) 1375 (31.7) 1478 (26.4) 1498 (351.9) 1649 (87.7) 1655 (14.2) 1810 (1852.6) 3634 (186.8)
554 (9.1) 592 (36.8) 707 (44.5) 749 (13.4) 816 (62.1) 863 (37.9) 870 (6.6) 910 (143.7) 934 (175.9) 1071 (36.7) 1111 (23.0) 1158 (58.7) 1265 (261.7) 1293 (86.3) 1380 (34.2) 1479 (39.9) 1499 (335.6) 1649 (85.5) 1656 (14.1) 1811 (1853.5) 3637 (191.4)
45 d(CCC) + 12 m(CLC) 63 d(CCO) + 10 d(CCC) 22 m(CLC) + 19 d(CCO) + 13 m(CC) + 12 d(CCN) 87 C(OONC) 87 C(HCCO) 79 C(HCCC) 54 m(CC) + 23 d(CCN) 23 d(CCN) + 19 d(CCO) + 16 m(NC) 22 d(CCO) + 15 m(CC) + 12 d(CCC) 29 m(CC) + 14 d(HCC) 22 d(HCC) + 20 m(NC) + 13 d(CCN) + 13 m(CC) 44 d(HCC) + 11 m(NC) + 11 d(CCC) 16 d(HCC) + 14 m(NC) + 11 m(CC) 29 m(NC) + 16 m(CC) + 12 d(HCC) 34 m(CC) + 28 d(HNC) 16 d(HCC) + 12 d(CCC) + 11 m(NC) + 10 m(CC) 47 d(HCC) + 29 m(CC) 38 m(CC) + 13 d(CCN) + 13 d(CCC) 66 m(CC) 79 m(OC) + 13 m(NC) 100 m(NH)
m: stretch, d: bending, C: torsion, vw: very weak, w: weak, m: medium, sh: shoulder, s: strong, vs: very strong. a b
Calculated wavenumbers are belong to form B and they are scaled by 0.9982. Given assignments are for Model D.
Table 5 Energiesa (in eV) of HOMO and LUMO for the structures studied.
a
Structure
HOMO
LUMO
DELAH
CZX-1 CZX-2 CZX-3 CZX-4 Model Model Model Model
6.749 6.763 7.601 6.895 6.652 6.695 6.716 6.758
1.333 1.190 3.149 3.373 1.147 1.179 1.189 1.218
5.416 5.573 4.452 3.522 5.505 5.516 5.526 5.540
A B C D
Calculated at the B3LYP/6-311++G(d,p) level with the option pop = reg.
CAN and CAO stretchings in oxazole ring. 1361 (Ra 1384, calc. 1341) is mostly due to the ring deformations. The medium intensity shoulder at 1456 (Ra 1474, calc. 1482) cm1 is a similar band which is also contributed by CC stretching and CH bending vibrations. A CC stretching mode of benzene is observed at 1616 (Ra 1639, calc. 1649) cm1. The most important band of such a structure, the C@O stretch, is observed at 1764 (Ra 1746, calc. 1875) cm1 with a very strong intensity. The very strong band at 237 (Ra 241, calc. 212) cm1 is due to the CACL bending vibration. A medium band at 279 (Ra 297, calc. 253) cm1 is the ring puckering of oxazole. Another medium band is observed at 737 (Ra not observed, calc. 717) cm1, and it is contributed by the deformation of benzene and oxazole rings. The out of plane CH bending is observed at 800 (Ra 824, calc. 814) cm1 as a very strong band. Another CH bending mode is observed at 1473 (Ra 1492, calc. 1503) cm1 as a strong band. Two bands at 920 (Ra 939, calc. 916) cm1 and 959 (Ra 980, calc. 935) cm1 are assigned to the stretching vibrations of CAO and CAN. The mode at 1061 (Ra 1080, calc. 1073) cm1 is observed at medium intensity and assigned to deformation of benzene ring together with the CACL stretching vibration. Two strong bands at 1255 (Ra 1267, calc. 1269) cm1 and 1295 (Ra 1333, calc. 1292) cm1 are both ring stretching modes. The NH stretching mode of CZX is observed at 3472 (Ra not observed, calc. 3662) cm1.
Fig. 6. (a) HOMO and (b) LUMO of CZX.
The IR spectrum of CZX exhibits a broad contour in the 1800–3300 cm1 range. We may conclude that this contour is due to the overtones and combination bands of CZX fundamentals. On the other hand, it is known that CZX can be found as hydrogen bonded homomolecular dimers. Also, anti-parallel centrosymmetric dimers of CZX can be observed in cocrystal structures. And for the cocrystal structures, there are repulsive
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Table 6 MK and NBO charges (in e) of CZX-1 in vacuo and in ethanol. No.
Atom
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
C C C C C C N C O H H Cl H H O
In vacuo
Model A
Model B
Model C
Model D
MK
NBO
MK
NBO
MK
NBO
MK
NBO
MK
NBO
0.27259 0.36733 0.38129 0.04962 0.07135 0.25066 0.67310 0.84653 0.40340 0.22771 0.14709 0.07650 0.19462 0.40822 0.55817
0.12924 0.27909 0.21436 0.22965 0.03632 0.25463 0.61416 0.90249 0.50286 0.23054 0.22629 0.00854 0.22986 0.42375 0.57782
0.19967 0.38325 0.38098 0.04743 0.08759 0.20259 0.58855 0.83156 0.40884 0.23598 0.15745 0.09968 0.20908 0.43083 0.63213
0.13450 0.27792 0.21526 0.23249 0.03771 0.24772 0.59597 0.91032 0.51065 0.24013 0.23394 0.00735 0.24416 0.44506 0.63887
0.22774 0.34172 0.36218 0.04292 0.05025 0.21022 0.61787 0.88554 0.41672 0.23640 0.14350 0.10438 0.20370 0.42999 0.64730
0.13514 0.27998 0.21452 0.23137 0.03732 0.24645 0.59546 0.91049 0.51041 0.24055 0.23481 0.01374 0.24540 0.44556 0.63750
0.30098 0.24072 0.35554 0.05468 0.02956 0.25842 0.59387 0.74882 0.27918 0.24045 0.15137 0.10864 0.21387 0.43156 0.59664
0.13541 0.27934 0.21433 0.23015 0.03660 0.24563 0.59351 0.91405 0.53450 0.24147 0.23470 0.00511 0.24500 0.44675 0.63058
0.27676 0.18862 0.29065 0.06325 0.00574 0.25861 0.55137 0.75118 0.27384 0.22625 0.14352 0.11115 0.21378 0.41774 0.59774
0.13613 0.28135 0.21357 0.22907 0.03578 0.24413 0.59313 0.91417 0.53406 0.24190 0.23555 0.01195 0.24619 0.44717 0.62942
CAH CLAC interactions in the packing motif [12]. Hence, the broad contour observed in CZX spectrum is the absorption of dimeric structures superimposed on the overtones and combinations of the monomeric form. A possible dimeric form of CZX (Fig. 3) which is stabilized by intermolecular hydrogen bonding was also computed. Complete lists of the vibrational frequencies of CZX dimer is given in Table S1 (Supp. Information. Table S1). We have looked forward for how CZX’s vibrational modes were affected when it solvated in ethanol. When the experimental solvation phase spectrum (see Fig. 4) was compared with the solid phase experimental data, we have spotted a peak at 558 cm1 which was not observed for the solid sample. Hence, we have concluded that CZX might have been established hydrogen bonded complexes with ethanol. Considered complexes are plotted in Fig. 5. Experimental and theoretical vibrational data of the solvated CZX are given in Table 4. We have gathered the most suitable results from Model D (see Fig. 5c). Hence, the basis of our conclusions is Model D. The band observed at 558 cm1 is calculated at 554 cm1 as a medium band and assigned as a mix of CLC bending and ring deformation of benzene. O@C stretching band was observed at 1764 cm1 in very strong intensity. This band is shifted to 1776 cm1 and it is observed in very strong intensity again. The calculated wavenumber for this band is 1811 cm1 and the intensity of the calculated band matches with our experimental results. NAH stretching band is also affected by the presence of solvent. It was observed at 3472 cm1 as a very weak band for the solid sample. When solvated, it is shifted to 3499 cm1 and the band shape is superimposed by the broad band of ethanol. The very strong CACL stretching band at 688 cm1 is shifted to 708 cm1 (calc. 707 cm1). This shift might have been occurred most probably due to the intermolecular hydrogen bonding interactions between the chlorine site of CZX and ethanol. Another significant shift is observed for the ring bending vibration of oxazole of 959 cm1. This band is detected at 944 cm1 (calc. 934 cm1) in medium intensity when in solvation phase. Similarly the band at 737 cm1 is shifted to 756 cm1 (calc. 749 cm1) in solution. This band was assigned to the umbrella vibration in the oxazole ring. We have concluded that these shiftings are due to the intermolecular hydrogen bonding interactions between the carbonyl (O@C) of CZX and ethanol. The CH bending mode at 1473 cm1 in solid phase was observed at 1483 cm1 (calc. 1499 cm1) in solvation phase. Still the dominant nature of this mode is CH bending, but as TED
analysis indicated there is a contribution from the internal vibrations of ethanol. Yet, literature data on the vibrations of ethanol present a medium intensity triplet between 1500–1400 cm1. Although there are several other shiftings observed in the experimental solvation phase spectrum, those shiftings are considered as insignificant.
Theoretical electronic properties The energies of the frontier molecular orbitals of CZX are computed and given in Table 5. For the most stable structure CZX-1, the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energies were calculated as 6.749 eV and 1.333 eV, respectively. Hence, the HOMO–LUMO energy gap (DELAH) is 5.416 eV. To understand the nature of the skeletal bonds in CZX, we have also created the electrostatic field contour maps which were given in Fig. 6. These contour maps show that HOMO orbital of CZX-1 has bonding nature between the atoms C4AC5AC6, C1AC2AC3, and N7AC8AO9, anti-bonding character between atoms C1AC6, C5ACL12, C3AC4, C1AN7, and C2AO9. On the other hand, LUMO orbital exhibits bonding nature between the atoms C1AC2, C4AC5, and N7AC8; while it has anti-bonding character between the atoms C2AO9AC8, C1AN7, C2AC3, and C5AC6. In solvation phase a slight change in the frontier electrons distribution was computed. For the HOMO orbital the frontier electrons population over 7 N and 15O were calculated denser. For the LUMO orbital we have seen that the frontier electron density on 7 N was lowered while 12CL has some more frontier electron localization. The HOMO–LUMO plots in ethanol solution are given in Fig. S1 (Supp. Information. Fig. S1). We have examined the charge distribution for the skeletal atoms of CZX-1 by using both Merz–Kollman (MK) and Natural Bond Orbital (NBO) analysis. Calculated charge distributions are presented in Table 6. In CZX-1 tautomer the nitrogen (N7) and oxygens (O9, O15) are rich in negative charges, which are beneficial to the bioactivity [25]. As seen Table 6, when CZX is solvated in ethanol, those negatively charged oxygens (O9, O15) have become more negative. We have calculated a loss of charge on N7 which refers to a charge transfer through C8 and O15. The chlorine (CL12) is predicted to have positive charge when in vacuum. When solvated, CL12 becomes negatively charged which may indicate the existence of intermolecular hydrogen bonding interactions between chlorine site and ethanol. Note that, MK charges on CL12 are predicted negative in both media.
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Fig. 7. Experimental (a) 1H-, (b)
Nuclear magnetic resonance Results of the experimental 1H and coupled 13C NMR measurements, and our B3LYP/6-311++G(d,p) calculated chemical shifts are collected in Fig. 7 and Table 7. Dimethyl sulfoxide (DMSO) was the solvent used in experiments. NMR calculations are also done in DMSO by employing PCM (polarized continuum model). Calculated 13 C shifts were scaled according to the scaling equation dscal = 0.95dcalc + 0.30 before comparing with the experimental data [26]. We
347
13
C- NMR spectra of CZX.
have not reported any correlation factors for 1H NMR for two reasons. Because a good correlation for proton shifts was not expected, since the protons are located on the periphery of the molecule and are supposed to be more susceptible to solute– solvent effects [27]. Calculated chemical shifts correlate well with the experimental data. The squared correlation factors of 1H and 13 C shifts were found to be 0.9845 and 0.9767, respectively. 13C NMR measurement exhibits a heptet at around 40 ppm which is not included in Table 7. This heptet is the solvent signal of DMSO.
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Table 7 Theoretical and experimental chemical shifts (in ppm) of chlorozoxazone. Atoms
Experimental
Calculated
2C 3C 4C 5C 6C 7C 9C 1H 8H 10H 11H
127.7 154.2 142.0 109.6 110.5 131.6 121.3 7.01 7.19 7.22 7.04
136.359 158.225 149.357 114.080 115.076 142.661 127.023 7.1217 7.2617 7.2788 7.1656
Conclusions The FT-IR and FT-Raman spectra of chlorzoxazone (CZX) were recorded and interpreted by means of B3LYP/6-311++G(d,p) calculated harmonic frequencies followed by total energy distribution (TED) analysis. The geometry of the most stable tautomer of CZX was discussed. Geometrical parameters are predicted very well. The frontier molecular orbitals properties and NBO charges of CZX molecule were also given. It has been found that the CZX molecule has 5.416 eV of HOMO–LUMO energy gap, and common atoms in the molecule such as the nitrogen atom in the oxazole ring, and the oxygens possess richly negative charges. Calculated 1 H and 13C NMR chemical shifts were compared with the experimental data. Calculated chemical shifts correlate well with the experimental data. We have looked forward for how several structural features of CZX were affected when it solvated in ethanol. We have seen that there is a peak in the experimental solvation phase spectrum which was not observed for the solid sample. Hence, we have constructed different models to computationally investigate solvent effects. It has been determined that the vibrational modes of CZX are best represented by a model incorporating both implicit and explicit solvation with two explicit ethanol molecules (i.e., Model D). The experimental solvation phase spectrum has showed that several bands of the CZX were affected by the solvent. The C@O, NAH, and CACL stretching vibrations are such bands. Our PCM DFT (B3LYP) calculations have predicted the vibrational bands of the solvated system very well. Our calculations have shown that the geometrical parameters of CZX were not significantly affected by the solvent in general. The most significant deviations from the gas phase data were determined at the carbonyl site. According to those calculations, the frontier electrons distribution over CZX exhibits small changes in solvation phase. On the other hand, we have seen that the negatively charged oxygens (O9, O15) have become more negative, and the chlorine (CL12) turned to negative from positive when solvated in ethanol.
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