Synthesis and Spectroscopy Studies of By-products of Chloroquinaldol

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1 Synthesis and Spectroscopy Studies of By-products of Chloroquinaldol LUCIA PINTILIE 1 *, MIHAELA DEACONU 1, AMALIA STEFANIU 1, CONSTANTIN TANASE 1, MIRON TEODOR CAPROIU 2 1 National Institute for Chemical-Pharmaceutical Research and Development, 112 Vitan Av., 74373, Bucharest, Romania 2 Organic Chemistry Center C.D.Nenitescu, 202 B Splaiul Independentei, , Bucharest, Romania Chlorquinaldol (5,7-dichloro-2-methyl-quinolin-8-ol) presents a significant attention due to its antibacterial activity, antifungal activity, trichomonal and keratoplastic effect and due to the fact it is an important intermediate for the preparation of some biologically active compounds. In the process of the preparation of the chlorquinaldol, by chlorination of 8-hydroxyquinaldine using as chlorinating agent, chlorine gas, have been obtained 5-chloro-8-hydroxyquinaldine and 5,6,7-trichloro-8-hydroxyquinaldine, by-products which contaminate the final compound. This paper presents experimental data regarding the synthesis of byproducts of chlorquinaldol. The quinoline compounds have been analyzed through physico-chemical techniques ( 1 H-NMR, 13 C-NMR, FT IR, UV-Vis). Molecular, topological, conformational characteristics and quantitative structure-activity/property relationships on 3D quinolones optimized structure have been calculated using Spartan 14 Software. For each structure of the analyzed class, the 3D structure used for calculations was generated and its geometry has been optimized by energy minimization, in order to obtain the most stable conformer. NMR and IR spectra of the quinoline compounds have been calculated with Spartan 14 software. After analyzing the experimental and calculated spectra ( 1 H-NMR, 13 C-NMR, IR) the correlation between experimental and calculated data has been observed Keywords: quinoline, hydroxyquinaldine, chlorquinaldol, chlorination, computational studies, spectroscopy studies The quinolines are N-heterocyclic compounds with many applications in pharmaceutical and agrochemical industries [1-4]. One of the quinoline compound, 5,7-Dichloro-2-methyl- 8-hydroxy-quinoline, (chlorquinaldol) has received significant attention in the last years, due of his biological activity(antibacterial activity, antifungal activity, trichomonal and keratoplastic effect) and due to the fact it is an important intermediate for the synthesis of a variety of compounds with biological activity [3,5]. 5,7-Dichloro-2-methyl-8-hydroxy-quinoline (chlorquinaldol) can be prepared (scheme 1) by regioselective conversion of the corresponding N-oxide ( 5,7-dichloro-8- hydroxyquinoline-1-oxide). By coupling reaction of the heterocyclic N-oxide with Grignard reagent (methylmagnesium chloride) have been obtained regioselectively and in good yield the final product [6]. Another method of preparation of the 5,7-Dichloro-2- methyl-8-hydroxy-quinoline is the chlorination of the 8- hydroxyquinaldine with chlorine, in the presence of hydrochloric acid [7,8], in the presence of formic acid [9], in the presence of iodine and chloroform [10]. Fiedler H [11] report the chlorination with tertbutylhypochlorit in carbon tetrachloride of the 8- hydroxyquinaldine or of the 7-chloro-8-hydroxyquinaldine. In the case of the chlorination of the 8-hydroxyquinaldine with chlorine yield by-products: mono- and polychlorinated compounds (scheme 2). Monochlorinated compound : 5-chloro-2-methyl-8- hydroxy-quinoline can be prepared (scheme 3) by regioselective conversion of the corresponding N-oxide(5- chloro-8-hydroxyquinoline-1-oxide).by coupling reaction of the heterocyclic N-oxide with Grignard reagent Scheme 1 * lucia.pintilie@gmail.com REV.CHIM.(Bucharest) 67 No

2 synthesized be chlorination the copper(ii) chelate of 8- hydroxyquinaldine with N-chloro-succinimide[19]. For the compound: 5,6,7-Trichloro-8-hydroxyquinaldine, we found only one indication about the preparation. This compound have been synthesized by chlorination of 8- hydroxyquinaldine in N,N-dimethylformamide [22]. This paper presents synthesis and spectroscopy studies of the by-products which results from the chlorination of the 8-hydroxyquinaldine. Scheme 2 (methylmagnesium chloride) have been obtained regioselectively and in good yield the final product [6]. Another method of preparation of the 5-chloro-2-methyl- 8-hydroxy-quinoline is the chlorination of the 8- hydroxyquinaldine with chlorine gas, in the presence of hydrochloric acid [12], in the presence of iodine and hydrochloric acid [13], or chlorination with N-chlorosuccinimide [21]. Talekar and collective [14] reports synthesis of 5-chloro-8-hydroxyquinaldine by heating 5- chloro-7-iodo-8-hydroxyquinaldine in the presence of triethylamine and by hydrolysis and deiodination of 5-chloro- 7-iodo-2-methylquinolin-8-yl-ethanoate in the presence of pyridine/water. 5-Chloro-2-methyl-8-hydroxy-quinoline can be also preparated by condensation of 2-amino-4-chlorophenol with crotonaldehyde, (Skraup, Doebner-Miller synthesis [15,16], condensation with paraldehyde [17,18],or chlorination of 2-amino-4-chlorophenol (Sandmeyer reaction) [20]. 5-Chloro-2-methyl-8-hydroxy-quinoline have been Experimental part Melting points were determined in opened capillary on Melting point apparatus OptiMelt and are uncorrected. 1 H- and 13 C-NMR spectra were recorded in CDCl 3, DMSO-d 6 and trifluoroacetic acid, on two instruments Varian, Varian Gemini 300 BB (operating at 300 MHz for proton and 75 MHz for carbon) and UNITY 400 Plus(operating at 400 MHz for proton and 100 MHz for carbon). Tetramerthylsilane as internal standard was the reference for the chemical shifts. All chemical shifts are given in the delta scale (ppm vs internal TMS). FT IR was recorded on an instrument Bruker Vertex 70 with optical diamond. 5-Chloro-8-hydroxyquinaldine (5-chloro-2-methyl-8- hydroxy-quinoline) 5-Chloro-8-hydroxyquinaldine has been preparated by chlorination of 8-hydroxyquinaldine using as chlorinating agent, chlorine gas. The appropriate amount of chlorine gas was bubbled into a solution obtained by dissolving the 8-hydroxyquinaldine in concentrated hydrochloric acid. The end of the reaction was determined by weighing. The structure of this compound has been confirmated by: 1 H-NMR (fig. 1) (table 1), 13 C-NMR(fig.4) (table 2), FTIR (fig.7) (table 3), UV-Vis (fig. 10). (p.t. o = o C (methanol)) 5,7-Dichloro-8-hydroxyquinaldine (5,7-dichloro-2- methyl-8-hydroxy-quinoline) 5,7-Dichloro-8-hydroxyquinaldine has been preparated by chlorination of 8-hydroxyquinaldine using as chlorinating agent, chlorine gas. The appropriate amount of chlorine gas was bubbled into a solution obtained by dissolving the 8-hydroxyquinaldine in concentrated hydrochloric acid. The end of the reaction was determined by weighing. The structure of this compound has been confirmated by: 1 H-NMR(fig.2) (table 1), 13 C-NMR(fig.5) (table 2), FTIR (fig.8)(table 3), UV-Vis (fig. 10). (p.t. o = o C (acetone)) Scheme REV.CHIM.(Bucharest) 67 No

3 Fig. 1 1 H-NMR spectrum of 5-Chloro-8-hydroxyquinaldine 1a- experimental spectrum; 1b-calaculated spectrum Fig.2. 1 H-NMR spectrum of 5,7-Dichloro-8-hydroxyquinaldine 2a- experimental spectrum; 2b-calculated spectrum Fig. 3 1 H-NMR spectrum of 5,6,7-Trichloro-8-hydroxyquinaldine 3a- experimental spectrum; 3b-calculated spectrum Table 1 CALCULATED AND MEASURED 1 H-NMR SPECTRA 5,6,7-Trichloro-8-hydroxyquinaldine (5,6,7- trichloro-2-methyl-8-hydroxy-quinoline) 5,6,7-Trichloro-8-hydroxyquinaldine has been preparated by chlorination of 8-hydroxyquinaldine using as chlorinating agent, chlorine gas. The appropriate amount of chlorine gas was bubbled into a solution obtained by dissolving the 8-hydroxyquinaldine in concentrated hydrochloric acid. The end of the reaction was determined by weighing. The structure of this compound has been confirmated by 1 H-NMR (fig.3)(table 1), 13 C-NMR (fig.6) (table 2), FTIR REV.CHIM.(Bucharest) 67 No

4 Fig C-NMR spectrum of 5-Chloro-8-hydroxyquinaldine 4a- experimental spectrum; 4b-calculated spectrum Fig C-NMR spectrum of 5,7-Dichloro-8-hydroxyquinaldine 5a- experimental spectrum; 5b-calculated spectrum Fig C-NMR spectrum of 5,6,7-Trichloro-8-hydroxyquinaldine 6a- experimental spectrum; 6b-calculated spectrum (fig.9) (table 3) and UV-Vis (fig.10). (p.t. o = o C (methanol)) Computational studies Molecular, topological, conformational characteristics and quantitative structure-activity/property relationships (QSAR/ QSPR) on 3D quinolones optimized structure were calculated using Spartan 14 Software. Results and disscusions Experimental studies for synthesis of: 5-Chloro-8- hydroxyquinaldine (5-chloro-2-methyl-8-hydroxy-quinoline),5,7-Dichloro-8-hydroxyquinaldine (5,7-dichloro-2- methyl-8-hydroxy-quinoline) and 5,6,7-Trichloro-8- hydroxyquinaldine (5,6,7-trichloro-2-methyl-8-hydroxyquinoline) are presented. The quinoline compounds have been analyzed through physico-chemical techniques ( 1 H-NMR, 13 C-NMR, FT IR, UV-VIS). H-NMR spectra have been confirmed the structure of the compounds proposed to be synthetisized by chlorination of the 8-hydroxyquinaldine with chlorine gas in chlorhidic acid. In the case of the monochlorinated compound it was observed the absence of the signal of the proton in 5 position of the quinoline ring (fig. 1a, table 1). In the case of the chlorchinaldol (5, 7-Dichloro-8- hydroxyquinaldine) it was observed the absence of the signals of the protons in 5 and 7 positions of the quinoline ring (fig. 2a, table 1). For the 5,6,7-Trichloro-8-hydroxyquinaldine) it was observed the absence of the signals of the protons in 5, 6 and 7 positions of the quinoline ring (fig. 3a, table 1). Structure of the quinoline compounds synthesized in the study has been also confirmed by C-NMR spectra (fig. 4a, 5a, 6a, table 2). In the figure 6, 8 and 9 are presented the FTIR spectra of the studied compounds: 5-Chloro-8-hydroxyquinaldine, (fig 6a), 5,7-Dichloro-8-hydroxyquinaldine (fig. 8a) and 5,6,7- Trichloro-8-hydroxyquinaldine (fig. 9a). In table 3 are presented some characteristic bands of studied molecules. The introduction of chlorine atom in the 8-hydroxy quinalidine ring was has been also proved in by UV spectrum (fig.10). UV absorption spectra study was carried out using solutions with concentration of 10 m g/ml in methanol. Interpretation of the UV absorption spectrum of 5-Chloro- 8-hydroxyquinaldine (ClHQ) has been made in comparison with that of the 8-hydroxyquinaldine (2-methyl-8-hydroxyquinoline)(8HQ). The presence of the quinoline nucleus determines in methanol the appearance of electronic transitions in the field of nm. The introduction of chlorine atom in 5 position produces a batocroma displacement of the entire spectrum. REV.CHIM.(Bucharest) 67 No

5 Table 2 CALCULATED AND MEASURED 13 C-NMR SPECTRA Fig. 7. FTIR spectrum of 5-Chloro-8-hydroxyquinaldine 7a- experimental spectrum ; 7b-calculated spectrum Fig.8. FT-IR spectrum of 5,7-Dichloro-8-hydroxyquinaldine 8a- experimental spectrum; 8b-calculated spectrum Fig.9 FT-IR spectrum of 5,6,7-Trichloro-8-hydroxyquinaldine 9a- experimental spectrum; 9b-calculated spectrum The introduction of the second chlorine atom in the 7 position of quinoline nucleus produces also a batocroma displacement of the entire spectrum. Interpretation of the UV absorption spectrum of 5,7-Dichloro-8-hydroxy- quinaldine (chlorquinaldol) (DiClHQ) has been made in comparison with that of 5-Chloro-8-hydroxyquinaldine (ClHQ). REV.CHIM.(Bucharest) 67 No

6 Table 3 CALCULATED AND MEASURED IR SPECTRA The introduction of the third chlorine atom in the 6 position of quinoline nucleus produces also a batocroma displacement of the entire spectrum. Interpretation of the UV absorption spectrum of 5,6,7-trichloro-8-hydroxy-quinaldine (5,6,7TriClHQ). Has been made in comparison with that of chlorchinaldol. Fig. 10. Claculated and measured UV-Vis aborption spectra Table 4 CALCULATED UV-Vis SPECTRA Computational studies In addition, a study of the molecular and structural characteristics and properties has been achieved using Spartan 14 software. A computational study to compare molecular properties, QSAR properties and mechanics calculations for quinoline compunds, has been conducted using Spartan 14 Software. For each structure of the analyzed class, the 3D structure used for calculations was generated and its geometry has been optimized by energy minimization, in order to obtain the most stable conformer (table 5). For these conformers, the most important topological and conformational characteristics has been calculated: weight, energy of solvation, dipole moment, energy of the frontier molecular energies (fig. 11), HOMO-LUMO gap (table 5). The HOMO-LUMO gap is related to kinetic stability or chemical reactivity. The higher value of HOMO-LUMO gap, for all three quinolines of the study, refers to chemically stable molecules [23]. We have been calculated the important structural parameters: bond lenght (table 6), dihedral angles (the value of all dihedral angles is zero, it indicates that the all atoms are placed in the same plane). H-NMR (fig. 1b. 2b. 3b), C-NMR (fig. 4b, 5b, 6b), IR (fig. 7b, 8b, 9b) and UV (fig.10b) spectra of the quinoline compounds have been calculated with Spartan 14 software. After analyzing the experimental and calculated spectra REV.CHIM.(Bucharest) 67 No

7 Table 5 ANALYZED STRUCTURE Fig. 11. Frontier molecular orbitals for quinoline compounds Table 6 SELECTED BOND LENGTHS (H-NMR, C-NMR, IR, UV) the correlation between experimental and calculated data has been observed (table 1-4). Conclusions In conclusion, we have synthesized the by-products of chlorquinaldol : 5-Chloro-8-hydroxyquinaldine and 5,6,7- REV.CHIM.(Bucharest) 67 No

8 Trichloro-8-hydroxyquinaldine.The quinoline compounds have been analyzed through physico-chemical techniques ( 1 H-NMR, 13 C-NMR, FT IR, UV-Vis). Molecular, topological and conformational characteristics on 3D quinolines optimized structure have been calculated using Spartan 14 Software. For each structure of the analyzed class, the 3D structure used for calculations was generated and its geometry has been optimized by energy minimization, in order to obtain the most stable conformer. NMR, IR and UV spectra of the quinoline compounds have been calculated with Spartan 14 software. The correlation between experimental and calculated data has been observed after analyzing the experimental and calculated spectra ( 1 H-NMR, 13 C-NMR, IR, UV). References 1. H.GERSON, R. PARMEGIANI and P.K. GODFREY, Antimicrobial Agents and Chemotherapy, 1, (5),1972,p R.MUSIOL, J. JAMPILEK, J.E. NYCZ, M. PESKO, J. CARROLL, K. KRALOVA, M. VEJSOVA, J.O MAHONY, A. COFFEY, A. MROZEK and J. POLANSKI, 15, 2010, p G. MALECKI, J.E. NYCZ, E.RYRYCH, L, PONIKIEWSKI, M. NOWAK, J. KUSZ, J. PIKIES, Journal of Molecular Structure, 969, 2010, p R.MUSIOL, J. JAMPILEK, V. BUCHTA, L. SILVA, H. NIEDBALA, B. PODESZWA, A. PALKA, K. MAJERZ-MANIECKA, B. OLEKSIN and J. POLANSKI, Bioorganic & Medicinal Chemistry, 14, 2006, p W. CIESLIK, R. MUSIOL, J. E. NYCZ, J. JAMPILEK, M. VEJSOVA, M. WOLFF, B. MACHURA, J. POLANSKI, Bioorganic Medicinal Chemistry, 20, 2012, p O.V. LARIONOV, D. STEPHENS, A. MFUH and G. CHAVEZ, Organic Letters, 16, 2014, p *** Ansalt Parthenon, Patent Specification CH245365, M.G. VAIDYA and J.G. CANNON, Journal of Medicinal and Pharmaceutical Chemistry, 5, 1962, p *** A.G. GEIGY, Patent Specification CH229982, ***Rutgerswerke und Teerverwertung Aktingesell Schaft, Patent Specification FR , H.FIEDLER, J. Prakt. Chem. 13, 1961, p K. RUHL, L. RAPPEN, Patent Specification DE , K. RUHL, L. RAPPEN, Patent Specification DE , R.S. TALEKAR, G.S. CHEN, S.-Y. LAI, J.-W. CHERN, Journal of Organic Chemistry,70,2005, p E.J. NYCZ, M. SZALA, G.J. MALECKI, M. NOWAK, J. KUSZ, Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy,117,2014, p M. SZALA, E.J. NYCZ, G.J. MALECKI, Journal of Molecular Structure, 1071, 2014, p M. WEIZMAN, E. BOGRACHOV, Journal of American Chemical Society, 69, (5), 1947, p ZI-GUO JIAO, HONG-QIU HE, CHENG-CHU ZENG, JIAN-JUN TAN, LI-MING HU AND CUN-XIN WANG, Molecules, 15,(3), 2010, p R.PRASAD, H.L.D. COFFER, Q. FERNANDO AND H. FREISER, Journal of Organic Chemistry, 30,1965, p R.G. BEIMER, Q. FERNANDO, Analytical Chemistry, 41, 1969, p G. Mc NEIL, Journal of Heterocyclic Chemistry,9(3), 1972, p J.P. BOURQUIN, R. GRIOT and E. SCHENKER, Archiv der Pharmazie und Berichte der Deutschen Pharmazeutischen Gesellschaft, 295, 1962, p S. SARVESWARI, A. SRIKANTH, N. ARUL MURUGAN, V. VIJAYAKUMAR, J.P. JASINSKI, H.C. BEAUCHESNE, E.E. JARVIS, Spectrochimica Acta- Part A: Molecular and Biomolecular Spectroscopy,136, 2015, p Manuscript received: REV.CHIM.(Bucharest) 67 No