SYNTHETIC STUDY OF QUINOLINE CARBOXYLIC ACID DERIVATIVE

• Main Author: ROSALINA (NIM : 20513026), RENY
• Format: Theses
• Language: Indonesia
• Online Access: https://digilib.itb.ac.id/gdl/view/23898
• Institution: Institut Teknologi Bandung

Quinoline is one of heterocyclic aromatic compound derivatives that have wide application in pharmacological as antimalarial, antibacterial, antifungal, and anticancer or materials as catalysts, corrosion inhibitors, preservatives, dyes and luminescense compounds. Quinoline carboxylic acid is a quinoline derivative which has a unique framework. That’s due to the carboxylic group that act as an electron accepting group from quinoline ring conjugation system which make this framework has a good photochemical and photophysical properties, so its widely used as a chromophore of various dyes and fluorophor on a biocompatible fluorescent compound. <br /> <br /> <br /> Source of quinoline compounds can be derived from natural products, one of the plants is Kina which are widely grown in Indonesia and the compounds known as cinchona alkaloids. These compounds are pseudo-enantiomeric quinine-quinidine, cinchonine-cinchonidine. Beside that quinoline compounds also obtained by synthetic method that untill now there are many methods have been developed for quinoline derivative synthesize. So this research aims to explore strategies to obtain quinoline carboxylic acid framework from cinchona alkaloids fragmentation and synthetic method. One of the chincona alkaloid that explored in this research is quinine. Quinine structure consist of quinoline ring and kuinuklidin ring that linked by secondary alcohol group. To obtain quinoline ring from Chincona alkaloid, C-C bond cleavage via alcohol group is required, one of the method is by oxidative cleavage. While the synthesis method was carried out through C-N bond formation reactions followed by cyclization using aromatic amines and &#945;,&#946;-unsaturated carbonyl derivatives which is widely used for the reaction forming a heterocyclic ring. <br /> <br /> <br /> Fragmentation of quinine was carried out by the C-C bond cleavage via oxidation reaction using two oxidizing agent sodium periodate (NaIO4) which is a strong oxidant (E0red=1.601) that selective for aminoalcohol cleavage and potassium permanganate (KMnO4) that also strong oxidant (E0red=1.679). Oxidation with NaIO4 carried out in neutral condition for 7 hours at room temperature with methanol as solvent. The product obtained was characterized by IR, NMR and MS spectroscopy measurements. Based on spectroscopic data, the product of this reaction is quinine-1-N-oxide with 20% yield. Formation of this compound is indicated by the shift of the signal on the NMR spectrum of the product spectrum in comparison with the spectrum of quinine. Singlet peak at &#948;H 5.57 ppm which is the signal of protons at C9 quinine shifted to downfield range &#948;H 6.63 ppm. Also supported by MS spectroscopy data which showed peaks at m/z 341 which is molecular mass of quinine-1-N-oxide. While the oxidation with KMnO4 carried out under acidic conditions for 3 hours at room temperature. The mixture were separated using radial chromatography with chloroform:methanol 10% and Net3. The pure products are characterized by IR, NMR and MS spectroscopy. That are quinine-1-N-oxide and the mixture of epimeric aldehid (R) and (S) kuininal. The formation of epimeric kuininal is indicated by the appearance of two singlet protons signals of the aldehyde group at &#948;H 9.74 and 9.67 ppm and two carbon signals carbonyl group at &#948;C 203.09 and 203.17 ppm. Also supported by the presence of peaks in MS spectroscopy spectrum at m/z 327.17 corresponding to the kuininal molecular mass. From both oxidation reaction that had been done, it couldn’t get fragmentation product to obtain quinoline ring but the products obtained were quinine-1-N-oxide and epimeric aldehyde. <br /> <br /> <br /> Next step was synthetic method of quinoline ring formation which has carboxylate substituents on the C4. To get this molecule target, Doebner-Miller reaction was used with aromatic amine (m-phenylene diamine) and &#945;, &#946;-unsaturated carbonyl derivative (maleic acid anhydride) precursors in two steps, the formation of an amide bond as intermediate followed by cyclization. The product that have been characterized by IR and NMR spectroscopic measurements up to this stage is (2Z, 2'Z) -4.4 '- (benzene-1,3-diildiimino) bis (4-oksobut-2-enoat) with 68% yield which is a product of an 1,2-addition reaction of amine to the carbonyl form an amide bond. Characteristic of amide bond formation in a product are indicated by the amide group proton signal at &#948;H 10.44 ppm and signal of carbonyl amide group on &#948;C 163.22 ppm. This product can be cyclized at a later step to get a quinoline carboxylic acid framework.