We have prepared the (5-chloro-quinolin-8-yloxy) acetic acid and characterized it by using infrared, Raman and multi-dimensional nuclear magnetic resonance spectroscopies. The density functional theory (DFT) together with the 6-31G* and 6-311++G** basis sets were used to study its structure and vibrational properties. Three stable conformations of the compound were theoretically determined in gas phase and probably these conformations are present in the solid phase. The harmonic vibrational wavenumbers for the optimized geometries were calculated at the same theory levels. For a complete assignment of the observed bands in the vibrational spectra, the DFT calculations were combined with Pulay’s scaled quantum mechanical force field (SQMFF) methodology in order to fit the theoretical wavenumber values to the experimental ones. Besides, the force constants of the three conformers of (5-chloro-quinolin-8-yloxy) acetic acid were calculated and compared with those obtained by us for the 2-(quinolin-8-yloxy) acetic acid. In addition, the characteristics of the electronic delocalization of those structures were performed by using natural bond orbital (NBO), while the corresponding topological properties of electronic charge density are analysed by employing Bader’s atoms in molecules theory (AIM).
Heterocyclic compounds that contain the (quinolin-8- yloxy) moiety exhibit a wide range of biological properties [1-5], such as the 2-(quinolin-8-yloxy) acetohydrazones that have antiamoebic activities [
(5-chloroquinolin-8-yloxy) acetic acid was obtained according to Cho et al. [
A mixture of 5-chloro 8-hydroxyquinoline (3.6 g, 20 mmol), methyl bromoacetate (3.7 g, 24 mmol) and K2CO3 (5.52 g, 40 mmol) in acetone (50 mL) was heated for 3 h under reflux, filtered and concentrated in vacuo. The residue was partitioned between ethyl acetate and brine, and the organic layer was dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by crystallization from isopropyl ether to give (5-chloroquinolin-8-yloxy) acetic acid methyl ester 3584 g (71%) m.p. 102.1˚C - 102.3˚C.
A mixture of ester ((1.26 g, 5 mmol) and LiOH·H2O (352 mg, 8.40 mmol) in 75 mL of THF/CH3OH/H2O (1:1:1, 6) was stirred and heated at reflux for 1 h and concentrated. The aqueous layer was washed with ether and adjusted to pH 3 with 1 N HCl. The precipitate was filtered and dried to give (5-chloroquinolin-8-yloxy) acetic acid (1085 g, 91%) m.p. 219.5˚C - 221˚C.
1H NMR (300 MHz, CDCl3) δ: 4.92 (2H, s, O-CH2); 7.08 (1H, d, J = 8.48, H7), 7.64 (1H, d, J = 8.48, H6); 8,47 (1H, d, J = 8.58, H4); 7.70 (1H, dd, J = 4.18, J = 8.58, H3); 8.94 (1H, d, J = 4.18, H2).
13C NMR (75 MHz, CDCl3) δ: 65.94 (CH2); 110.54 (C7); 121.69 (C5); 123.53 (C3); 126.66 (C4a); 127.07 (C6); 132.64 (C4); 140.55 (C8a); 150.28(C2); 153.54 (C8); 170.34 (CO2H) (Atom numbering according to naphthalene).
The infrared spectrum of the solid substance was recorded in KBr pellets in the wavenumbers range from 4000 to 400 cm−1 with a FT-IR Perkin Elmer spectrometer, provided with a Globar source and a DGTS detector. FT-Raman spectrum of the crystalline solid was recorded on a Bruker RFA 106/S FT-Raman instrument using the 1064 nm excitation line from an Nd: YAG laser in the region of 4000 - 0 cm−1. Two hundred scans were accu mulated at 4 cm−1 resolution using a laser power of 150 mW.
The potential energy curves associated with the internal rotation described by the C21-C18-O17-C10 dihedral angle for CQA were studied at the B3LYP/6-31G* and 6-311++G** theory levels. With both calculations, two conformations stable, named, CI and CII, according to the position of the OH group in relation to the N atom of the ring were obtained. Another plane structure was also considered (CIII) in agreement with the experimental structure of the 8-(carboxymethoxy) quinolinium nitrate monohydrate compound [
Also, in this case, the high values of the dipolar moments for the CI structures could probably explain its stabilities, as was observed in similar molecules [6,23-25].
The stabilities of the CII and CIII structures of CQA, in relation to the CI structure, were investigated by using the natural atomic charges [26-29] and the results are given in
The stability of the three structures of CQA was also investigated by means of NBO calculations [10-12]. The second order perturbation energies E(2) (donor ® acceptor) that involve the most important delocalization all conformers of CQA are given in Tables S5, S6. The contributions of the stabilization energies for the DETs®s* charge transfers are similar to those obtained for the 2-(quinolin-8-yloxy)-acetic acid compound [
Here, the delocalizations DETLP®s* for the CII structure has lower values than the DETs®s* delocalizations, and the calculated total energy values favours to the CI and CIII conformers, which structures are the most stable in the gas phase. Thus, the total energy values clearly show the higher stability of the CI conformer however, by using the 6-311++G** basis set, the CII and CIII conformers have the same ones approximately total energy values.
Furthermore, the three structures of CQA were analysed by means of Bader’s charge electron density topological analysis [
The Figures 2, 3 show the registered infrared and Raman spectra for the compound in solid phase. In this study, in accordance with the NBO and AIM results, the three structures for the compound in gas phase were considered. The CQA’s structures have C1 symmetries and 66 normal vibration modes, all active in the infrared and Raman spectra. Probably, the three species are present in the solid phase because the comparison of each vibrational spectrum with the corresponding experimental one is very different among them, as observed in
infrared spectra (from B3LYP/6-31G* level for the CI, CII and CIII conformers) by using average wavenumbers and intensities with the corresponding experimental one demonstrate a good correlation, as observed in
Thus, the resulting IR spectrum reproduces rather well some bands of the experimental spectrum, especially in the 2000 - 400 cm−1 region. The assignment of the experimental bands to the expected normal vibration modes were made on the basis of the PED in terms of symmetry coordinates and taking into account the corresponding assignment of related molecules [6,30-34]. Tables 2, S8-S10 show the experimental and calculated frequentcies, potential energy distribution based on the 6-31G* basis set, and assignment for the CI, CII and CIII structures of CQA. In a similar way as observed in the molecular packing of the 2-(2’-furyl)-1H-imidazole [
Here, the B3LYP/6-31G* calculations were considered because the used scale factors are defined for this basis set. The SQM force fields for this compound can be obtained upon request. Below we discuss the assignment of the most important groups.
4.4.1.1. OH Modes The weak bands in the IR spectra at 3569, 3432 and 3149 cm−1, in accordance to the values reported for similar molecules [30,33,34], can be assigned to the O-H stretching vibrations of the three conformers, as observed in
4.4.1.2. CH Modes The C-H stretching modes can be clearly assigned, for their positions, to the group of bands in the 3125 - 3025 cm−1 region of the IR and Raman spectra. The in-plane deformation modes of the phenyl ring, in similar compounds are observed between 1267 and 1042 cm−1 [
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deformations of C-H group for the three conformers of CQA are assigned to the IR and Raman bands located between 981 and 806 cm−1.
4.4.1.3. CH2 Modes The group of bands in the 3006 - 2923 cm−1 region of the Raman spectra are assigned to the antisymmetric and symmetric stretching modes of this group in agreement to similar compounds [26,32]. The scissoring modes for the three conformers of CQA can be assigned to the shoulder in the IR spectrum and to the weak Raman band respectively at 1423 and 1431 cm−1. The shoulder in the IR spectrum and the weak Raman band at 1423 cm−1 and the band of medium intensity at 1386 cm−1 are assigned to the wagging modes of this group, as predicted by calculation, while the strong bands and the shoulder at 1280, 1254 and 1251 cm−1 are assigned to the rocking modes. The twisting mode for all CQA conformers are associated with the shoulders in the IR spectrum at 954 and 948 cm−1 as was observed in the 2-(quinolin-8-yloxy)-acetic acid [
4.4.1.4. COO Modes The C=O stretching mode, for the CI conformer of CQA is calculated at 1792 cm−1, it is at lower wavenumber than the other conformers (1823 and 1814 cm−1, CII and CIII conformers, respectively). On the other hand, for the benzoic acid the C=O stretching mode is predicted between 1786 and 1608 cm−1 while the C-O stretching mode are assigned between 1359 and 1334 cm−1 [33,34]. Hence, the IR bands of the media intensities and the strong IR band at 1892, 1854 and 1696 cm−1 are clearly assigned to the C=O stretching modes, as predicted by the calculations while the the Raman and IR bands respectively at 1219 and 1107 cm−1 are assigned to the C-O stretching mode corresponding to the three conformers of CQA. In the 4-hidroxybenzoic acid dimer [
4.4.1.5. Skeletal Modes Here, the skeletal stretching modes in the three CQA’s conformers are predicted strongly mixed among them (Tables S8-S10). In agreement to the values reported for similar molecules [30-34] and our theoretical results, the IR bands of the media intensities at 1626, 1608 and 1585 cm−1 are mainly associated to a C=C stretchings. Also, the IR bands at 1368, 1324, 1202, 1133, 1107, 1042, 913 and 830 cm−1, and the shoulders in the same spectrum at 1395, 1238 and 836 cm−1 are associated to the C-C stretching modes, as observed in
The calculated forces constants for the three CQA’s conformers are given in
Units are mdyn·Å−1 for stretching and stretching/stretching interaction and mdyn·Å·rad−2 for angle deformations; aThis work; bAnhydrous from Ref [
are higher in CQA, with exeption of the f(C-O) force constant. An explanation can be probably due to that the chloro atom increase the topological properties of the RCPs in the CI conformer and as conesquence decrease the O-H distance increasing the C-O distance in this conformer in relation to the 2-(quinolin-8-yloxy) acetic acid [
The frontier molecular HOMO and LUMO orbitals were calculated for 2-(quinolin-8-yloxy) acetic acid and compared with the corresponding values for the (5-chloroquinolin-8-yloxy) acetic acid [
Tables 4, 5 show a comparison between the experimental and calculated chemical shifts for the 1H and 13C nuclei, respectively. The calculated chemical shifts for the H nuclei show a reasonable agreement in relation to experimental values with observed RMSD values between 0.578 and 0.174 ppm, while the chemical shifts for the carbon nuclei show higher RMSD values (7.325 and 0.254 ppm). The calculated 1H chemical and 13C shifts show a good concordance for the three conformers when the 6-311++G** basis set is used. Thus,
The (5-chloro-quinolin-8-yloxy) acetic acid was synthesized and characterized by infrared, Raman and NMR spectroscopic techniques. The presence of CI, CII and CIII conformers was detected in both spectra, and a complete assignment of the vibrational modes was accomplished. The B3LYP/6-31G* and B3LYP/6-311++G** calculations suggest the existence of three conformers for CQA in the gas phase and, probably, the three are present in the solid state. An SQM/B3LYP/6-31G* force field was obtained for the three structures of CQA after adjusting the force constants obtained theoretically to minimize the difference between the observed and calculated wavenumbers. Also, the principal force constants for the stretching and deformation modes of CQA were determined. The NBO and AIM analysis confirm the O-H and N-H bonds in the three conformers of CQA while the HOMO-LUMO study shows that the Cl atom increases the reactivity of CQA, as compared with 2-(quinolin-8-yloxy) acetic acid.
This work was supported with grants from CIUNT (Consejo de Investigaciones, Universidad Nacional de Tucumán) and CONICET (Consejo Nacional de Investigaciones Científicas y Técnicas, R. Argentina). The authors thank Prof. Tom Sundius for his permission to use MOLVIB and the Dr. Jorge Güida for the Raman spectrum.
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Abbreviations:n, stretching; b, deformation in the plane; g, deformation out of plane; wag, wagging; t , torsion; bR, deformation ring; tR, torsion ring; r, rocking; twis, twisting; a, angular deformation; d, deformation; a, antisymmetric; s, symmetric; A1, Ring 1; A2, Ring 2.
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aThis work; bDFT B3LYP/6-31G*; cFrom scaled quantum mechanics force field; dUnits are km∙mol−1; eRaman activities in Å4 (amu)−1.
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aThis work; bDFT B3LYP/6-31G*; cFrom scaled quantum mechanics force field; dUnits are km∙mol−1; eRaman activities in Å4 (amu) −1.
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aThis work; bDFT B3LYP/6-31G*; cFrom scaled quantum mechanics force field; dUnits are km·mol−1; eRaman activities in Å4 (amu) −1.
aThis work, bFrom Ref [