MINISTRY OF EDUCATION AND TRAINING HANOI NATIONAL UNIVERSITY OF EDUCATION - - LE VAN CO RESEARCH SYNTHESIS, STRUCTURE AND PROPERTIES OF SOME QUINOLINE DERIVATIVES ON THE BASIS OF EUGENOL FROM OCIMUM SANCTUM L OIL SPECIALITY : ORGANIC CHEMISTRY Classification : 62.44.01.14 SUMMARY OF PHD THESIS Advisor: Prof Dr Nguyen Huu Dinh HA NOI, 2014 This thesis was completed in: Departments of Organic Chemistry – Faculties of Chemistry – Hanoi National University of Education Advisor: Prof Dr Nguyen Huu Dinh Reviewer 1: Prof.Dr.Sc Nguyen Dinh Trieu Hanoi University of Science – Vietnam National University Reviewer 2: Prof.Dr.Sc Tran Van Sung Vietnam Academy of Science and Technology Reviewer 2: Assoc.Prof.Dr Dinh Thi Thanh Hai Hanoi University of Pharmacy This thesis will be dotted to the Council to perform thesis at the: Departments of Organic Chemistry – Faculties of Chemistry – Hanoi National University of Education at the time hour October , 2014 This Thesis can be found at the Library of Hanoi National University of Education or Central Library for Science & Technology INTRODUCTION Reasons for selecting topic Chemistry of heterocyclic compounds is a strong growth sector and has created many compounds in practical applications In that field, quinoline heterocyclic plays an important role Many compounds containing a quinoline skeleton is used in various industries such as cosmetics, food, catalysts, dyes and especially in the pharmaceutical industry For example, quinine, cinchonine, chloroquine, pamaquine are used as anti-malarial drugs Several other derivatives of quinoline were applied to cure cancer as camptothecin, antibacterial, antifungal, anti-tuberculosis as bedaquiline Notably, the diarylquinoline currently classified in one of ten new-generation antibiotic alternative for antibiotic resistant bacteria have been Not only that, the kind of quinoline compounds also have many applications in chemical analysis: Ferron, snazoxs, brombenzthiazo used as an indicator of some metals analysis by photometric method Many ligand complexes with quinoline compounds are more substituents have very good optical properties of interest in solar cell manufacturing Recently, the organic synthesis group - Hanoi National University of Education have discovered a new reaction: synthetic quinoline ring from quinone-aci compound prepared from eugenoxyaxetic acid It has opened a research synthesis of new types of quinoline polysubstituted compounds However, this reaction is not stable, performance is low, and the reaction mechanism has not been elucidated The perfect way to create a new quinoline ring and metabolic studies of the products obtained new compounds not only theoretically significant but also the search for promising compounds have high biological activity and the ligand for complex research Therefore, we selected topeak: “Research synthesis, structure and properties of some quinoline derivatives on the basis of eugenol from Ocimum sanctum L Oil” The purpose and tasks of the thesis – Complete method and study mechanism of the quinoline ring synthesis reaction from quinone-aci compound prepared from eugenol in basil oil – Synthesis of some new quinoline polysubstituted compounds – Study the relationship between the structure of the synthetic compound with their spectral properties – Study the possibility of fluorescence of some kind hemixianin quinoline compounds – Exploration of bioactive compounds synthesized Research Methodology ● Synthesis: application of synthetic organic methods of traditional and innovative choice to suit each new object Focus on improving efficiency, reducing the amount of reactants, carefully refined to be clean nature ● Study structure: The structure of the synthetic compounds were identified by IR, 1H NMR, 13 C NMR, 2D NMR and MS spectrum coordination Some compounds was studied further UV-Vis, fluorescence emission spectra and singlecrystal XRD The spectrums were analyzed in detail, the spectral data and the system were arranged to draw comment ● Tested antibacterial activity, antifungal substance with some Gram (+) and Gram (-), yeasts, molds under successive dilution method Tested cytotoxicity of compounds for four cancer cell lines differ Tested the activity of antioxidant compounds In particular, tested the activity against malaria for 7-carboxymethoxy6-hydroxy-3-sulfoquinoline (Q) New contributions of the thesis 4.1 Synthesis – Completing a new method to synthesize quinoline ring from quinone-axi from eugenol in basil oil led to new quinoline compound is 7-carboxymethoxy-6hydroxy-3-sulfoquinoline (Q); Use the single-crystal diffraction method to confirm the structure of Q; Using dynamic 1H NMR methods to propose the mechanism for quinoline cyclization reaction not seen in the references – Detect an abnormal nucleophilic reaction of N-metylquinolinium compounds: the replacement of the carboxymethoxy group (OCH2COOH) by ankylamino group (RNH) Through extensive research this reaction, has proposed an unusual reaction mechanism – Detect a reaction which occurs simultaneously with the replacement of the OCH2COOH group by the NHNH2 group and the replacement of Br atom by H atom On the basis of experimental and theoretical proposed the reaction mechanism of this unprecedented reaction 4.2 Study the structures and properties – Have determined the structure of 60 new compounds type of quinoline polysubstituted by using coordinate spectroscopeak methods IR, 1H NMR, 13 C NMR, HSQC, HMBC, NOESY and MS – Provide reliable data on the chemical shift and constant spin-spin interactions of protons and carbons in a few series quinoline polysubstituted compounds – Study UV-Vis and fluorescence emission spectra of 11 compounds kinds of 7alkylamino-1-methylquinolinium-3-sunfonate, sorbents in the visible range and fluorescence with λmax in the range of 505-674 nm – Identified that, Q compound exhibits activity against malaria, but not strong; QNO2 has very weak cytotoxic activity; HzQBr has cytotoxic activity against cell carcinoma; A0 and Q have strong antibacterial activity; HzQBr has weak antibacterial, V5 has average antibacterial and R1 has weak antifungal Layout of the thesis The dissertation consists of 148 typed pages, printed on A4 paper with 26 diagrams, 59 photographs and 45 tables are distributed as follows: Introduction: 03 pages, 25 pages Overview, page 16 Experiments, Results and Discussion page 87, page 02 Conclusion, references 14 pages There is also 126 pages of appendix CONTENTS OF THE THESIS Chapter OVERVIEW Have literature review of domestic and foreign research on the synthesis of homocyclic and heterocyclic compounds from with eugenol, the main constituent of Ocimum sanctum L Oil and preliminary studies on the compounds containing a quinoline ring Especially noticed a ring-closed reduction reaction of quinone-aci derivative creates a quinoline compound (detected by organic synthesis group Hanoi National University of Education ) is a new reaction should continued to refine in order to open up a new direction research of polysubstituted quinoline derivatives Chapter EXPERIMENTAL 2.1 SYNTHESIS Q AND SOME DERIVATIVES FROM Q Scheme Diagram synthetic Q and some derivatives from Q Results synthesis derivatives of Q Table Structure and data synthesis of derivatives from Q Order Notation 10 11 12 13 14 MeQ EsQ HzQ QAc QCHO QCl QBr EsQBr HzQBr QNO2 QNH2 QNHAc MeQBr MeQNO2 15 MeQNHNH2 Yield (%) Me/H H/OH 64,9 H/H H/OMe 65,2 H/H H/NHNH2 62,3 H/H COMe/OH 55,1 H/CHO H/OH 27,0 H/Cl H/OH 62,3 H/Br H/OH 70,1 H/Br H/OMe 65,1 H/Br H/NHNH2 71,9 H/NO2 H/OH 37,0 H/NH2 H/OH 80,1 H/NHCOMe H/OH 50,0 Me/Br H/OH 66,8 Me/NO2 H/OH R1/R2 R3/R4 - Spectrums measurement and analysis 13 IR H C QC BC MS x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x x - - - - 14 14 13 12 2.2 THE REACTION OF QCHO WITH AMINO COMPOUNDS Table Structure and data synthesis of R1-R7 imins Order Notation Yield (%) Y Spectrums measurement and analysis 70,0 79,8 x x R3 PhNH 2,4(NO2)2PhNH Ph 70,0 x x R4 2-MePh 60,4 x x x - x - x R5 4-MePh 74,2 x x x - - - - R6 Naphtyl 73,2 x x x x x x - R7 Xyclohexyl 50,0 x x - - - - - 7 1 R1 R2 H x 13 IR x C - QC - BC - NOESY - MS - x - - - - - - - - 2.3 THE REACTION OF MeQBr WITH ANKYLAMINE Table Structure and data synthesis of S1-S8 compounds Order Notation 10 11 12 13 14 (*) S1a S1b S2a S2b S3a S3b S4a S4b S5a S5b S6a S6b S7a S8b Yield (%) Rf** 72 68 72 74 (*) 65 HOCH2CH2 (*) 64 CH2CH2NH2.HCl (*) 68,4 Xiclo-C6H11 - 0,74 0,70 0,68 0,65 0,67 0,65 0,55 0,50 0,64 0,62 0,18 0,08 0,12 0,61 R Me Me Et Et Pr Pr PhCH2 PhCH2 Spectrums measurement and analysis IR x x x x x x x x x x x x x x 14 H x x x x x x x x x x x x x x 14 13 C x x x x x x x x x x x x X x 14 QC x x x x BC x x x x x x : Internal salt); (**): Thin-layer chromatography in solvent MeOH/CHCl3 (1:1)) MS x x 2.4 THE REACTION OF MeQNO2 WITH ANKYLAMINE Table Structure and data synthesis of T1-T8 compounds Order Notation T1a T1b T2 T3 T4 T5 T6 T7 T8 Yield (%) 50,6 H 70,3 Me 50,2 Et 70,4 Pr 66,8 PhCH2 58,5 HOCH2CH2 CH2CH2NH2.HCl 58,2 Spectrums measurement and analysis R Rf* Xiclo-C6H11 0,8 0,75 0,6 0,62 0,65 0,7 0,55 0,3 0,7 - IR x x x x x x x x x 13 H x x x x x x x x x C x x x x x x x x x QC BC x x x x x x (Rf*: Thin-layer chromatography in solvent MeOH/CHCl3 (1:2)) MS x x x x x x x 2.5 THE SYNTHESIS AND REACTION OF QNHNH2 CARBONYL COMPOUNDS Table Structure and data synthesis of V1-V13 hydrazons Order Notation 10 11 12 13 V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 R1 R2 H Ph H 3-MePh H 3-OHPh H 4-OHPh H 4-ClPh H 4-NO2Ph H 4-Me2NPh H 4-OH-3-OCH3Ph H 2,4-(OH)2Ph Me Me Me Et Me Ph Me 4-NH2Ph Yield (%) Rf * 64,0 65,2 61,0 61,0 71,6 60,4 67,5 68,0 50,0 71,3 66,7 65,0 63,7 0,84 0,78 0,83 0,83 0,80 0,77 0,82 0,83 0,81 0,80 0,79 0,76 0,82 Spectrums measurement and analysis IR x x x x x x x x x x 10 H x x x x x x x x x x x x x 13 (Rf*: Thin-layer chromatography in solvent MeOH/CHCl3 (1:1)) 13 C x x x x x x x x x x x x x 13 QC BC x x x x x x x MS x x x x x x x x x Chapter RESULTS and DISCUSSION 3.1 Q: 7-CARRBOXYMETHOXY-6-HYDROXY-3-SULFOQUINOLINE 3.1.1 Complete the synthesis method of Q By changing the molar ratio of the reactants, temperature, time of reaction stages and acidulating agent in stage 2, we have found conditions for synthesis reaction Q with high and stability yield Compound Q was checked by IR, NMR and MS spectroscopy, the results consistent with those previously published Result analyzed single-crystal diffraction (Figure 1) also shows that Q has structured in accordance with the expected formula Figure structure of Q determined by single-crystal XRD method 3.1.2 Study mechanisms reaction synthesis Q from A0 Through monitoring reaction progress by 1H NMR method, we propose a mechanism for the transformation from A0 to Q as Scheme Scheme Reaction mechanism to form Q from A0 3.2 SYNTHESIS, STRUCTURE AND PROPERTIES OF SOME DERIVATIVES OF Q From the Q-key, by the methylation reaction, halogenated, nitrated, acylesterified, hydrazide and condensation, have synthesized 14 new quinoline polysubstituted compounds – IR spectra of derivatives of Q contains peaks characterize the main functional groups: OH, NH, CH, C=O, … accordance with structure are listed in tables 3.5 – 3.17 of the thesis – 1H NMR, 13C NMR HSQC, HMBC and MS spectrum are shown in tables 3.5 3.17 of the thesis Spectral data showed that synthetic compounds have been structure accordance with the expected formula - The results analyzed single-crystal diffraction EsQBr compound is shown in figure Figure Structure of EsQBr determined by single-crystal XRD diffraction 3.3 SPECTRA PROPERTIES AND STRUCTURE OF R1-R7 IMINES 3.3.1 Infrared spectrum (IR) Some main absorbtion peak in the IR spectra of the imine R1-R7 are shown in table 3:19 of the thesis 3.3.2 NMR and MS spectrum of R1-R7 10 Based on the chemical shift, constant spin-spin interaction and combined with 2D NMR spectral analysis, we have determined exactly the signal of the proton resonances of S1-S8 compounds, 1H NMR spectral data are listed in table Table Signals on the 1H NMR spectrum of S1-S8,  (ppm), J (Hz) H1 H2 H4 H8 S1a 4,23 s;3H 8,35 s;1H 8,36 s;1H 6,39 s;1H S1b 4,37 s;3H 9,09 s;1H 8,75 s;1H 6,71 s;1H S2a 4,23 s;3H S2b 4,37 s;3H S3a 4,22 s;3H 8,33 s;1H 8,25 s;1H S3b 4,36 s;3H 9,07 s;1H 8,74 s;1H S4a 4,12 s;3H 8,34 d;1H J=1 8,28 s;1H 6,53 s;1H S4b 4,23 s;3H 8,75 s;1H 6,81 s;1H S5a 4,22 s;3H 8,27 s;1H 6,51 s;1H S5b 4,36 s;3H 8,75 s;1H 6,88 s;1H S6a 4,27 s;3H 8,36 s;1H 6,59 s;1H S6b 4,44 s;3H 8,78 s;1H 7,01 3,79 q s;1H J = 6,5 (*) S7a S8b 8,35 8,26 d;1H d;1H J=1 J=1 9,08 8,75 d;1H s;1H J=1 9,05 d;1H J=1 8,34 d;1H J=1 9,09 d;1H J=1 8,46 d;1H J=2 9,13 d;1H J=2 6,46 s;1H 6,78 s;1H H11 2,99 d;3H J=5 3,01 d;3H J=5 2,83 q;2H J=7 3,49 2,74 t;2H J = 7,5 3,40 6,77 d;2H s;1H J=6 6,4 s;1H 4,63 d;2H J=6 4,70 d;2H J=6 3,45 q;2H J = 5,5 3,52 q;2H J = 5,5 3,71 q;2H J=6 3,94 8,34 8,25 5,90 s;3H s, 1H s, 1H s, 1H 2,58 d;2H J=7 4,37 9,06 8,76 6,84 s;3H s, 1H s, 1H s, 1H 3,79 m,1H H12 H13 H11’(**) H12’(**) H13’(**) Others - - 2,39 s;3H - - NH:7,56; NH3+: 7,56 - - - - - NH: 7.86 1,14 3,42 1,26 t;3H m;2H t;3H J=7 J=7 J=7 1,27 t;3H J = 7,5 1,56 0,90 Bị 1,70 0,96 m;2H t;3H che m;2H t;3H J = 7,5 J = 7,5 lấp J = 7,5 J = 7,5 1,70 0,96 q;2H t;3H J = 7,5 J = 7,5 H12/H16/H13’/H17’(**): 7,43 t; 4H; J = 7,5 H13/H14/H15: 7,35 t, 3H; J = 7,5 H14’/H16’(**): 7,39 t; 2H; J = 7,5; H5’(**): 7,26 t; 1H; J = 7,5 H12/H16: 7,47 d; 2H; J = 7,5 H13/H15: 7,36 dd; 2H; J1 = 8;J2 = H14: 7,27 t; 1H; J = 7,5 3,69 t;2H J = 5,5 3,71 t;2H J = 5,5 3,19 t;2H J=6 3,10 dd;2H J1 = 5,5 J2 = 6,5 H14: 1,35 1,63 3,11 s;2H s;2H s; 2H H12e/H16e: 1,97 m;2H; H14e: 1,64d;1H; H14a:1,21 m;1H H13e/H15e: 1,77 m;2H; NH: 7,25 NH: 7,71 NH:7,27 NH: 7,68 NH: 7,79 NH: 8,37 NH: 7,34 NH: 7,50 NH:7,87; NH3+: 8,13 NH: 7,85 NH3+: 8,19 - NH: 7,13 14 H1 (*) H2 H4 H8 H11 H12 H13 H11’(**) H12’(**) H13’(**) H12a/H13a/ H15a/ H16a: 1,47 m;4H Others measured in D2O); (**)H11’ – H17’ the amino protons in salt Table shows, 1H NMR spectrum of the S1a-S7a compounds are similar and different from the spectrum of MeQBr the signal losing at  = 5.21 ppm of proton H7a, the resonance signals of H2, H4, H8 shift in the downfield than the spectrum of MeQBr because of the effect +C of RNH group (replaced OCH2COOH group) Also, in the 7-7.9 ppm appears a triplet with 1H of intensity attributed to NH proton (RCH2NH group) For S1a-S4a compounds, beside of the resonance signal of 7-ankylamino molecule (denoted Q-NHR), there appears signals of amino RNH3+ ion with QNHR/RNH3+ intensity ratio is equal to 1:1 Therefore, we believe that these compounds exist in the form of amino salt [RNH-Q-O]- [H3N-R]+ For S6a and S7a, two amino function amine is used, on the spectrum have not appeared resonance signal of an amine molecule to create salt, but an NH2 group remaining molecules will create internal salt On the 13C NMR spectra of each compounds in the S1-S8 series, we found enough resonance signals of the carbon atoms not equivalent, in accordance with their structural formula The difference from 13C NMR spectrum of MeQBr is not appearing the resonance signal in 160-180 ppm of C7b (COOH group); not appears the signal in 60-70ppm of C7a (OCH2 group) On the HMBC spectrum of each compounds have still interaction peak between C7 and H11, interaction peak between C6 and C8 (j and i example in Figure 4) that confirmed the amino group RNH replaced OCH2COOH group in 7th position 15 Figure Part of HMBC spectrum of S6b Combined results analysis HSQC, HMBC spectrum, the signals on the 13 C NMR spectrum of S1-S8 has been attributed as in table Table The chemical shift on the spectrum 13C NMR of S1-S8 S1a S1b S2a S2b S3a S3b S4a S4b S5a S5b S6a S6b S7a(*) S8b C1 45,6 44,4 43,8 44,5 43,8 44,4 43,8 44,4 43,80 44,5 44,0 45,1 44,4 44,5 C2 131,3 141,3 131,4 141,4 131,6 141,4 131,8 141,7 131,3 141,5 C3 135,1 136,3 135,0 136,2 135,0 136,2 135,1 136,5 135,1 136,3 135,7 136,7 134,2 136,2 C4 128,0 136,4 128,1 136,5 128,2 136,5 C5 97,1 C6 157,5 145,9 157,5 145,8 157,4 145,8 157,5 145,9 157,7 145,8 C7 152,6 148,5 151,4 147,5 151,5 147,7 151,3 147,4 151,8 147,9 151,3 147,5 C8 86,2 C9 135,5 138,6 135,5 138,6 135,5 138,6 135,3 138,2 135,4 138,5 135,7 138,3 134,2 138,6 C10 125,7 121,6 125,6 121,6 125,5 121,6 C11 29,1 29,7 36,7 37,3 43,6 44,1 C12 - - 13,7 13,2 21,4 20,8 C16 - - - - - - C14 - - - - - C13 - - - - 11,5 11,4 C15 - - - - - - Ci - - - - - 105,0 90,2 97,2 86,26 105,4 90,3 97,3 86,4 105,5 90,4 - 141,6 130,6 141,5 136,6 128,0 136,5 128,9 136,5 130,0 136,5 97,5 87,2 105,6 91,1 97,1 86,5 105,4 90,77 98,1 105,4 100,8 105,8 - 146,1 156,1 145,7 87,0 91,1 146,5 87,2 90,6 121,7 125,7 121,6 125,6 121,8 125,1 121,5 45,6 44,7 45,2 72,5 45,1 42,4 59,1 58,9 37,7 37,1 29,6 - - - - - - - - - 40,5 - - - - 25,2 - - - - 138,3 137,5 - - - - - - 127,2 45,7 128,5 127,3 128,5 127,6 50,99 31,3 25,1 24,5 (**) 24,5 34,2 - 40,5 42,4 - - - - - - - (**) - 12,6 - 20,4 134,0 - - - - - - - C11’ C12’ 16 S1a (**) S1b S2a S2b S3a S3b - - - - 10,8 (**) - - - - - - (**) C13’ C17’ - - - - - - (**) - - - - - - (**) - - - - - - C14’ C16’ C15’ (*) measured in D2O; (**) S4a 128,8 128,5 127,2 S4b S5a S5b S6a S6b S7a(*) S8b - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - C11’ – C17’: carbon atoms in the amino salt The difference spectrum of S1b-S8b compounds compared to 13 C NMR spectrum of S1a-S8a are: losing signals of the carbon atoms in the ankylamino ion (RNH3+); signals of C6 of the S1a-S8a series appear in the 156-158 ppm proved C6 linked with O- group, remaining S1b-S8b series, those signals appear at 145,5 – 146,1 ppm proved the C6 linked with OH group For S6 and S7, two amino functions amine is used, on the 13C NMR spectrum of S6a and S6b have 11 signals corresponding to 11 carbon atoms; S7a has 13 signals However, in the spectrum of S7a and S6a the signals of C6 resonance at 156,1 ppm (similar to S1a-S5a), while spectrum of S6b has signal of C6 at 146,1 ppm (similar to S1b-S5b and S8b) Thus it can be stated, S7a and S6a form internal salt between the OH group at position th and 2nd NH2 function group of ankyldiamine molecule, and whereas S6b form internal salt with a molecule of acid (there hydrochloric acid is in solvent crystallization) 3.4.4 MS spectrum of a number of S series We have recorded mass spectrum of the S5b and S4b compounds The results of the spectral analysis of compounds are received the molecular weight is equal to molecular weight calculated by the assuming formula with the molecular ion peak has high intensity (Table 9) Table The results analysis MS spectrum of S4b and S5b S4b S5b Molecular Formular /M C17H15BrN2O4S 422/424 C12H13BrN2O5S 376/378 Main peaks, m:z / intensity (%) 445/100, 447/98: [M+Na+]; 423/47, 425/46: [M+H+] 421/94, 423/100: M-H+] 399/95, 401/100: [M+Na+]; 377/28, 379/32: [M+H+] 375/92, 377/100: [M-H+] 3.4.5 UV-Vis spectrum and fluorescence spectroscopy of a number of S series The UV-Vis spectrum of MeQBr different from the spectrum of the S1-S3 and S5, it has separate peaks so popular and separated from the spectra of other 17 compounds, while in the spectrum of the remaining compounds, absorption peaks in the visible range mixed together but still filling enough to realize two distinct spectral peak tips, in addition have some shoulder spectral The value λmax and intensity of the absorption peaks are listed in table 10 In this table, we add value λmax in UV-Vis spectrum of S2a and S2b measured in the solid state for comparison purposes Table 10 Absorption peaks on UV-Vis spectrum of S1-S3 and S5, λmax (nm)/ logε Notation MeQBr S1a S1b Peak I 241/ 0.9975 254/ 1.0411 254/ 1.0386 253/ 0.8539 * 245 254/ 1.0464 * 240/ 255/ 0.9447 255/ 1.1373 254/ 0.9277 255/ 0.6208 Peak II 294/ 0.8363 284/ 0.7198 284/ 0.7189 286/ 0.6673 S2a * 305 284/ 0.7541 S2b * 305/ 284/ 0.6756 S3a 284/ 0.8160 S3b 284/ 0.6677 S5a 283/ 0.4524 S5b (*) measured in the solid state Peak III 366/ 0.2855 413/ 0,6573 414/ 0,6593 414/ 0,5406 * 385 415/ 0,6965 * 370/ 417/ 0,6370 415/ 0,7651 414/ 0,6221 413/ 0,4167 Peak IV 420/ 0.1659 430/ 0.6641 429/ 0.6667 430/ 0.5510 * 450 430/ 0.7077 * 440/ 430/ 0.6435 431/ 0.7773 429/ 0.6182 427/ 0.4261 The results shows, the first, S1-S3 and S5 compounds are strong absorption in the visible region rather than MeQBr only absorbs in the ultraviolet region; the second, λmax values of peak III and peak IV of S1A-S3a and S5a are similar to corresponding S1b-S3b and S5b λmax values, fluorescence intensity I and width of absorption peaks of a number of a number of S series are listed in Table 11 Table 11 Fluorescence maxima of research compounds Compounds λmax (nm) I (au) Compounds λmax (nm) I (au) width (nm) MeQBr 644; 685 878; 1033 S4a 543 43872 78,1 S1a 594; 674 6574; 3014 S1b 514 30880 91,4 S2a 600; 674 3508; 2023 S2b 522 13356 56,8 S3a 589; 674 7194; 3508 S3b 505 5053 71,6 S5a 587; 674 4748; 2178 S5b 516 20397 62,1 S6a 596; 674 2550; 1343 S6b 532 2529 70,8 18 From the data of table 11, we drawn following comments: the fluorescence of the S1a, S2a; S3a; S5a and S6a compounds are similar; the fluorescence of S1b-S6b are similar too, but also different from MeQBr and S4a That MeQBr is not the type of hemixianine and S4a has addition benzene core Coloring matters Xianin used in biotechnology CY2, Cy3, Cy3B, Cy3.5 and Cy5 have λmax of fluorescence respectively 506; 570; 572; 594 and 670 nm The S4a, S1b, S2b and S5b compounds have λmax of fluorescence similar to the foregoing, there are strong fluorescence intensities and spectral widths so small would certainly be useful for the purpose of using them in the classification area 3.5 SPECTRA PROPERTIES AND STRUCTURE OF T1-T8 3.5.1 Infrared spectra of T1-T8 IR spectrum of T1-T8 compounds are similarities: not appear absorption peak so characteristic vibrations of C=O bond in 1700 -1750 cm-1, and in 30003500 cm-1 appear two amino absorption peak of the average intensity (Table 3.33 of the thesis) 3.5.2 NMR spectrum of T1-T8 H NMR spectrum of the T1-T8 compounds are similarities, they differ only in part amine (RNH) and different from the spectrum of MeQNO2: appears only true signals with the expected structural formula, this means lost the signal at  = 5,1 ppm with equal intensity 2H (H7a) of precursor MeQNO2, resonance signals of H2, H4, H8 shift upfield than MeQNO2 because of the effect +C of RNH group (replaced OCH2COOH group, Table 12) Table 12 Resonance Signals on 1H NMR of T1-T8,  (ppm), J (Hz) H1 T1a T1b T2 H2 4,17 s;3H 8,52 s;1H 4,34 s;3H 4,34 s;3H 9,03 s;1H 8,91 s;1H H4 8,48 d;1H J =1,5 8,42 s;1H 8,43 s;1H H8 H11 H12 H16 H13 H15 H14 Others 6,76 s;1H - - - - - - NH4+: 7,10 s - - - - - - - 3,02 s;3H - - - - - NH: 7,9 7,07 s;1H 6,65 s;1H 19 8,86 s;1H 3,46 1,26 q; 2H t; 3H J = 7,5 J = 7,5 3,40 1,70 t; 2H m; 2H J = 7,5 J = 7,5 T3 4,32 s;3H 8,42 s;1H 6,69 s;1H T4 8,85 4,32 8,42 d; 1H s; 3H s;1H J=1 6,69 s;1H T5 4,19 s;3H 8,79 s;1H 8,44 s;1H 6,70 s;1H 3,67 s; 2H T6 4,32 s;3H 8,90 d;1H J=1 8,43 s;1H 6,81 s;1H 3,51 t; 2H J=6 T8 4,33 s;3H 8,86 s;1H 8,40 s;1H 6,75 s;1H - - - - NH: 7,75 - - - - NH: 7,75 7,54 d; 2H J = 7,5 7,34 t; 2H J = 7,5 7,27 t; 1H NH: 8,32 J = 7,5 3,70 t; 2H J=6 H12e, H16e: 1,96 m; 2H 3,77 H12a/H13a/H15a/H16a:1,46m;4H m;1H H13e/H15e: 1,75 m; 2H H14e: 1,64 d;1H; H14a:1,22 m; 1H NH: 7,65 NH: 7,30 On the 13C NMR spectra of T1-T8, we found enough resonance signals of the carbon atoms are not equivalent in accordance with the formula Difference spectrum of QNO2: Not appear the resonance signal at 160-180 ppm of C7b and signal at 60-70ppm of C7a (OCH2COOH group) Other hand, the HMBC spectrum of each compounds have interaction peak between C7 and H11 This proves that OCH2COOH group was replaced by RNH group at 7th position Combining analysis and 13C NMR HMBC spectrum have attributed the chemical shift of the carbon atoms in the T1-T8 molecule (Table 13) Table 13 The chemical shift of C in 13C NMR spectrum of T1-T8, δ (ppm) C1 C2 C3 C4 C5 C6 C7 C8 C9 C10 C11 C12 C16 C13 C15 C14 T1a 44,0 136,0 134,1 125,4 126,5 157,94 154,41 90,6 133,4 121,4 - T1b 44,3 139,9 136,8 129,7 130,9 146,62 150,9 94,5 135,2 116,9 - T2 44,62 138,67 136,59 128,97 129,50 148,45 150,34 90,24 135,59 117,59 29,64 - T3 44,56 138,11 136,56 128,44 129,24 149,39 149,49 89,92 135,38 117,87 40,09 13,33 - T4 44,62 138,16 136,52 128,48 129,78 149,30 149,73 90,02 135,40 117,86 44,09 20,91 11,43 - T5 44,56 138,00 137,56 128,56 129,13 149,71 150,20 90,65 134,94 118,28 45,76 127,70 128,56 127,33 T6 44,64 138,59 136,67 128,79 129,48 148,71 149,75 90,63 135,37 117,66 45,16 58,88 - T8 44,60 138,18 136,56 128,35 129,38 149,21 148,38 90,11 135,31 117,73 50,63 31,24 25,03 24,32 20 Ci T1a - T1b - T2 - T3 - T4 - T5 136,78 T6 - T8 - 3.4.3 MS spectrum of T1-T8 We have recorded ESI MS spectrum of T1, T2 and T4 compounds The main peaks in the spectrum show that their molecular weight equal to the molecular weight by calculated as expected (Table 14) Table 14 Kết phân tích phổ MS T1, T2 T4 NHR T1 C10H9N3O6S 299 C11H11N3O6S 313 C13H15N3O6S 341 298/100: [M-H+]; 299/11: 13C; 300/5,7: 34S; 282/10: [M-H+-O]312/100: [M-H+]; 313/13: 13C; 314/6: 34S; 297/10: [M-H+-CH3]340/100: [M-H+]; 331/15: 13C; 342/7: 34S; 325/10: [M-H+-CH3]- NHCH3 T4 Main peaks, m/z / (%) NH2 T2 Molecular formula /M NHC3H7 3.5 QNHNH2 HYDRAZINE and V1-V13 HYDRAZONES 3.5.1 MeQNHNH2: 7-hydrazinyl-6-hydroxy-1-methylquinolinium-3-sunfonate When heating a mixture of MeQBr and hydrazine excess in hours, we obtained a yellow solid brown, dark gradually when exposed in air On Thin-layer chromatography of the products have different spots close together We denote this product is Qhh IR and NMR spectrum of Qhh proved OCH2COOH group linked to the aromatic group that has been replaced by NHNH2 group Simultaneously Br atom in position is replaced by H atom as scheme Scheme Replacement reaction mechanism OCH2COOH group lead to NHNH2 group 21 On Scheme above, the first reaction is similar with the replacement reaction OCH2COOH group by ankylamine according to mechanism such as in the section 3.4.1, mechanism of the second reaction is suggested such as scheme following Scheme Replacement reaction mechanism Br by H when MeQBr reacts with hydrazine 3.5.2 Structure and spectrum properties of the V1-V13 hydrazones a Infrared spectrum of V1-V13 hydrazones The IR spectrum of V1-V13 are similar to each other: no absorption peak characteristic C=O bond in 1700 -1750 cm-1 which appear absorbtion peaks in 1625-1630 cm-1 attributed to C=N quinoline ring (Table 3.39 of the thesis) b NMR spectrum of V1-V13 hydrazones The 1H NMR and 13C NMR spectrum of the studied hydrazones have signals of many groups of protons and carbon atoms Combined with analysis of HMBC spectrum, we have attributed the exact signals on 1H NMR spectrum of the hydrazones as in Table 15 Table 15 Signals on the 1H NMR spectrum of V1-V13 Structure V1 H1 H2 H4 9,13 4,48 8,91 d;1H s;1H s;1H J=1,5 H5 H8 Hi; H11 7,56 s;1H 7,75 s;1H 8,57 s;1H H12 H16 7,84 dd;2H J1 = J2 = H13 H15 7,47 m;3H H14 Others NH: 11,22 OH6:11,91 22 V2 9,13 4,49 d;1H s;1H J=1 8,92 s;1H 7,56 s;1H 7,73 s;1H 8,54 s;1H V3 4,47 9,13 s;1H s;1H 8,91 s;1H 7,55 s;1H 7,69 s;1H 8,47 s;1H 7,21 d;2H J=2 V4 4,44 9,08 s;1H s;1H 8,86 7,65 7,51 s s;1H s;1H 8,46 s;1H 7,66 d;2H J = 8,5 6,86 d J = 8,5 V5 9,14 4,49 d;1H s;1H J=1 8,93 s;1H 7,57 s;1H 7,75 s;1H 8,55 s;1H 7,85 d;2H J = 8,5 7,53 d J = 8,5 - NH: 11,26 OH6: 11,89 V6 4,52 9,17 s;1H s;1H 8,96 s;1H 7,59 s;1H 7,84 s;1H 8,63 s;1H 8,29 d;2H J = 8,5 8,07 d J = 8,5 - NH: 11,50 OH6:11,96 V7 4,43 9,07 s;1H s;1H 8,83 s;1H 7,52 s;1H 7,63 s;1H 8,46 s;1H 7,67 d;2H J=9 6,88 d J=6 - NH: 11,03 OH6: 11,85 H14a: 3,01 - NH: 9,60 OH6: 11,1 H13a: 3,89 OH14: 9,55 7,60 s;1H 7,64 d;1H J = 7,5 - 6,84 NH: 11,17 dd,1H OH6: 11,91 J1= 7,5 OH13:9,7 J2= 1,5 NH: 11,04 OH6: 11,85 OH14: 9,90 7,18 dd;1H J1 = 8,5 J2 = - 6,86 d;1H J = 8,5 6,36 s;1H 6,37 s;1H - NH: 11,04 OH6: 11,85 OH12:11,1 OH14:11,8 - - - NH: 9,1 Hk:2,06 s;3H - - - V8 8,85 s;1H 7,51 s;1H 7,70 s;1H 8,45 s;1H V9 4,44 9,06 s;1H s;1H 8,84 s;1H 7,51 s;1H 7,65 s;1H 8,75 s;1H - 7,67 d;J=8 V10 4,39 9,12 s;1H s;1H 8,90 s;1H 7,53 s;1H 7,47 s;1H 2,12 s;3H - - V11 4,38 9,11 s;1H s;1H 8,88 s;1H 7,52 s;1H 7,47 s;1H V12 9,16 4,49 d;1H s;1H J=1 8,96 s;1H 7,60 s;1H V13 4,44 9,10 s;1H s;1H 8,89 s;1H 7,59 s;1H 2,40 1,15 q,2H t;3H J=7,5 J=7,5 7,98 dd;2H 7,74 J1 = 8,5 s;1H J2 = - 7,27 t;1H J=8 7,43 d;1H J=2 4,46 9,08 s;1H s;1H 7,53 s;1H 7,37 7,25 NH: 11,20 t;1H d;1H OH6: 11,89 J = 7,5 J = 7,5 H13a: 2,38 - 7,70 d;2H J = 8,5 7,48 m;3H 6,61 d J = 8,5 - NH: 9,11 OH6: 11,91 Hk:2,04 s;3H NH: 9,42 OH6: 12,0 Hk:2,46 s;3H NH: 9,30 OH6: 11,95 NH2: 5,68 Hk:2,35 s;3H On 13C NMR spectrum of V1-V13, we have found enough resonance signals of the carbon atoms are not equivalent in accordance with the expected formula Combined with HMBC spectrum identified the chemical shift of the carbon atoms of V1-V13 as in Table 16 Table 16 The chemical shift of C on 13C NMR spectrum of V1-V13, δ (ppm) C1 C2 C3 C4 V1 V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 44,1 44,1 44,1 44,1 44,2 44,3 43,9 43,9 43,9 44,0 44,1 44,1 44,0 141,3 141,3 141,3 141,0 141,4 141,8 140,8 141,0 140,8 141,1 141,2 141,6 141,0 137,3 137,3 137,2 136,9 137,4 138,2 136,9 136,9 136,9 137,2 137,1 137,7 137,0 137,8 137,8 137,8 137,5 137,8 140,8 137,3 137,5 137,3 137,7 137,8 138,1 137,6 23 C5 C6 C7 C8 C9 C10 C11 C12 C16 C14 C13 C15 Ci 109,3 147,0 143,2 94,3 136,6 124,6 134,4 Others - 127,1 127,2 128,9 146,3 109,3 147,0 143,3 94,2 136,6 124,2 134,3 128,8 130,6 124,6 138,1 127,7 146,5 C13a: 20,9 109,3 147,0 143,3 94,1 136,6 124,6 135,6 118,4 113,1 117,2 157,7 129,9 146,5 - 109,0 146,9 143,4 93,5 136,8 124,4 125,4 128,9 109,3 147,1 143,1 94,5 136,5 124,7 133,3 109,7 147,5 142,7 95,4 137,8 125,0 136,2 124,1 108,9 147,2 143,4 93,3 136,7 124,4 109,0 147,0 143,4 93,7 136,8 124,4 125,9 109,6 128,7 128,5 121,7 159,4 134,2 147,1 147,0 149,0 115,8 127,8 148,1 128,9 115,6 146,9 144,8 143,2 146,8 C13a: C14a 55,6 108,1 147,0 143,2 93,0 136,8 124,4 128,7 160,7 112,0 158,3 102,4 108,9 145,6 - 109,0 146,9 143,6 93,5 136,6 124,3 25,3 156,1 Ck: 17,0 109,1 146,9 143,7 93,1 136,7 124,3 31,7 9,44 159,6 Ck: 15,7 109,3 147,1 143,1 94,9 136,4 124,7 137,6 108,8 147,1 143,3 93,7 136,7 124,6 124,5 126,3 127,7 129,4 150,5 129,4 113,3 151,9 153,1 Ck: Ck: 13,4 13,0 c MS spectrum of V1-V13 hydrazones We have record mass spectrometry of some hydrazones, spectral analysis of the compounds received the molecular weight equal to molecular weight calculated by the expected formula (Table 17) Table 17 Results of the MS spectral analysis of hydrazones Formula / M V1 V2 V4 V5 V6 V7 V8 V10 V12 C17H15N3O4S 357 C18H17N3O4S 371 C17H15N3O5S 373 C17H14N3O4SCl 391/393 C17H14N4O6S 402 C19H20N4O4S 400 C18H17N3O6S 403 C13H15N3O4S 309 C18H17N3O4S 371 Main peaks, m:z / intensity (%) 380/100: [M+Na ]; 358/48: [M+H+]; 381/20: 13C; 737/18: [2M+Na+] 356/100: [M-H+]; 357/20: 13C; 713/17: [2M-H+] 394/93: [M+Na+];372/31: [M+H+]; 357/18: [M+Na+–CH3]; 370/100: [M-H+]; 371/23: 13C; 356/25: [M+H+–CH3] 396/100: [M+Na+]; 374/34: [M+H+]; 769/23: [2M+Na+] 372/100: [M-H+]; 373/22: 13C; 745/8: [2M-H+] + 414/74: [M+Na+]; 392/45: [M+H+]; 805/15: [2M+Na+] 401/100: [M-H+]; 402/21: 13C; 385/36: [M-H+–O] 401/100: [M+H+]; 402/28: 13C; 423/27: [M+Na+] 399/100: [M-H+]; 400/24; 401/20; 799/9: [2M-H+] 426/70: [M+Na+]; 427/18; 13C 402/100: [M-H+]; 403/22: 13C; 805/8: [2M-H+]; 332/100: [M+Na+]; 310/47: [M+H+]; 333/16: 13C 308/100: [M-H+]; 309/16: 13C; 252/7: [M+Na+–SO3] 394/38: [M+Na+]; 372/13: [M+H+]; 370/100: [M-H+]; 371/25: 13C 3.6 BIOLOGICAL ACTIVITY TESTS – Of the 32 polysubstituted quinoline compounds, A0 and Q have strong antibacterial activity; HzQBr has weak antibacterial; V5 has average antibacterial and R1 has antifungal likely weak 24 – The results testing antioxidant activity of 08 samples hydrazone showed that they have not antioxidant activity – Of the 04 sample testing cell toxicity, QNO2 has cytotoxic activity against four cancer cell lines at weak; HzQBr has cytotoxic activity against cell carcinoma – We only test activity against malaria for 7-carboxymethoxy-6-hydroxy-3sulfoquinoline (Q) The results show that Q has activity against the malaria parasite but not strong 25 CONCLUSION In this thesis, we have achieved some results: Completed a new way to quinoline ring derived from eugenol, the main constituent of Ocimum sanctum L Oil, forms 7-carboxymethoxy-6-hydroxy-3sulfoquinoline (Q), the "key" to open the direction synthesis of the new polysubstitution quinoline compounds, especially: i) Crystallized Q in the form of large crystals suitable for X-ray diffraction single-crystal; ii) Use of single-crystal X-ray diffraction to determine the complete structure of Q; iii) Use the 1H NMR method, given the reaction mechanism has not met quinoline in references From the Q key, by using the methylation, halogenated, nitrated, acylation, esterified, hydrazinlation and condensation synthesized 24 polysubstitution quinoline compounds that are not in the reference Detected the abnormal nucleophilic reaction in N-methylquinolini compounds: replaced the carboxymethoxy group (OCH2COOH) by alkylamino group (RNH) Due extensively investigated on this response, has proposed an unusual reaction mechanisms and synthesized 23 new 7-alkylaminoquinoline compounds Proceeded the reaction of 5-bromo-7-carboxymethoxy-6-hydroxy-3-sulfonate1-methylquinolinium with hydrazine, obtained product which carboxymethoxy group (OCH2COOH) has been substituted by hydrazinyl group (NHNH2), and Br atom is replaced by H atom On the basis of experiment and theory proposed the mechanism of this unprecedented reaction From obtained hydrazine derivatives, have been synthesized 13 new compounds of kind xetohydrazon and andohydrazon containing quinoline skeleton The structure of 60 new compounds mentioned in the conclusions 1-4 were determined by spectroscopic methods IR, 1H NMR, 13C NMR, 2D NMR, MS 26 and UV-Vis By using HSQC, HMBC and NOESY spectrum have been attributed to each signal on H and 13 C NMR spectrum of obtained polysubstitution quinolines Studied UV-Vis and fluorescence emission spectra of 11 compounds type 7alkylamino-1-methylquinolinium-3-sulfonate proved they are structurally similar to the type hemixianin color, they are absorbed in the visible range and are fluorescence with λmax in the range 505-674 nm The λmax of fluorescence studies with similar hemixianin being used in biochemical research, with strong fluorescence intensity and spectrum width so small very promising applications is continuing to study i) Tested antimalarial activity of 7-carboxymethoxy-6-hydroxy-3-sulfoquinoline (Q), results show that Q exhibits activity against malaria, but not strong ii) Tested the cytotoxic activity of 04 samples synthesized in 04 cancer cell lines The results showed that 01 samples have cytotoxic activity against four cancer cell lines at weak level (IC50 = 60-76 g/ml), and 01 samples with cytotoxic activity with carcinoma cells with IC50 values = 49.3 g/ml iii) Tested antioxidant activity of 08 samples compounds synthesized The results show that they are not active antioxidant iv) Tested activity against microorganisms tested 32 samples of the 10 bacterial strains, yeast and filamentous fungi The results showed that 02 samples have strong antibacterial activity (IC50 = 12.5 g/ml), 01 samples have weak antibacterial activity (IC50 = 84 g/ml) and 01 samples were resistant fungal weak level (IC50 = 83.7 g/ml) 27 LIST OF PROJECTS ANNOUNCEMENT Nguyen Huu Dinh, Tran Thi Thu Trang, Le Van Co, Nguyen Thi Kim Thoa, Nguyen Thi Men (2011), “Synthesis and structure of some new compounds kind of quinoline polysubstituted”, Journal of Chemistry, vol 49 (2ABC), p.138-143 Nguyen Huu Dinh, Le Van Co, Nguyen Manh Tuan, Le Thi Hong Hai and Luc Van Meervelt (2012), “New route to novel polysubstituted quinolines starting with eugenol, the main constituent of ocimum sanctum l oil”, Heterocycles, Vol 85 (3), pp 627 – 637 Nguyen Huu Dinh, Vu Thi Len, Le Van Co (2012), “Analyzing ESI MS of a series of polysubstituted quinolines”, Journal of Chemical Analysis, Physics and Biology, vol 17 (3), p 61-66 Nguyen Huu Dinh, Le Van Co, Hoang Thi Tuyet Lan, Nguyen Thi Huong (2012), “Abnormal nucleophilic reaction in N-metylquinoline polysubstituted”, Journal of Chemistry, vol 50 (4A), p 39-42 Le Van Co, Tran Thi Thu Trang, Nguyen Minh Hai, Nguyen Huu Dinh (2012), “Synthesis of 7-(carboxymethoxy)-9-hydroxy-3-sunfoquinolin-5-cacbandehide on the basis of eugenol from Ocimum sanctum L Oil”, Journal of Chemistry, vol 50 (4A), p 469-472 Nguyen Huu Dinh, Le Van Co and Hoang Thi Tuyet Lan (2012), Analysing 13C NMR of several polysubstituted quinolines, Journal of Science of HNUE, 2012, Vol 57 (8), p 3-8 Le Van Co, Nguyen Dang Dat and Nguyen Huu Dinh (2012), Sinthesis of several aromatic aldazines, Journal of Science of HNUE, Vol 57, No 8, pp 16-21 (2012) Nguyen Huu Dinh, Le Van Co, La Thi Trang, Bui Thi Yen Hang (2013), Abnormal nucleophilic reaction in N-metylquinoline polysubstituted, Journal of Chemistry, vol 51 (6ABC), p 151-155 28 ... 7-carboxymethoxy6-hydroxy-3-sulfoquinoline (Q) New contributions of the thesis 4.1 Synthesis – Completing a new method to synthesize quinoline ring from quinone-axi from eugenol in basil oil led to new quinoline compound... properties of some quinoline derivatives on the basis of eugenol from Ocimum sanctum L Oil” The purpose and tasks of the thesis – Complete method and study mechanism of the quinoline ring synthesis... derived from eugenol, the main constituent of Ocimum sanctum L Oil, forms 7-carboxymethoxy-6-hydroxy-3sulfoquinoline (Q), the "key" to open the direction synthesis of the new polysubstitution quinoline