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Authors: Thiong'o, George Thuku
Issue Date: 1999
Abstract: Since the time of Louis Pasteur, separation of enantiomers has continued to be not only a difficult task but also a challenge to scientists. Now a days, greater attention is focussed on developing methods for stereoselective and enantioselective synthesis. Nevertheless, the resolution of racemic mixtures into their enantiomers by suitable, economic and rapid methods remains important and desirable. Majority of therapeutics such as anti-inflammatory/analgesic, adrenergic and antihistaminic drugs, agrochemicals and food additives and many other substances are marketed as racemic mixtures. It is an established fact that enantiomers have different biological, physiological and chemical behaviour both in natural biological systems including the human body as well as in the environment. Enantiomerically pure compounds are needed in different areas such as chiral synthesis, mechanistic studies, pharmaceuticals, agrochemical industries, biochemistry and forensic science. Further, regulatory authorities have become aware that efficacy and toxicology of enantiomers may differ from each other and from the racemic mixture and are increasingly asking for data on stereochemistry. Analytical methods capable of discriminating between enantiomers are thus required for a variety of reasons including quality control where the aim is to market only one enantiomer, monitoring chiral synthesis, determination of enantiomeric drugs in body fluids, for pharmacokinetic and metabolic studies, and testing the fate of (i) agrochemicals in the environment. Analytical methods for separating and determining enantiomers includes crystallization, chromatographic techniques such as high performance chromatography, (HPLC), high performance thin layer chromatography (HPTLC), gas-liquid chromatography (GLC), thin layer chromatography (TLC) and capillary electrophoresis (CE). Unlike TLC, these procedures are frequently more complicated and far more expensive than is necessary for routine chemical analysis. TLC involves concurrent processing of multiple samples and standards on the same open layer developed by mobile phase in a variety of modes including simple one-dimensional, multiple, circular and multidimensional. TLC as a procedure is simple, rapid, inexpensive, has a wide variety of both sorbents and solvents as well as low solvent consumption. It is advantageously used for rapid qualitative, quantitative and also preparative tasks. Also availability of various detection techniques and use of automation of all stages: sample application, development units, detection equipment and documentation has increased its efficiency and reproducibility, while special coupled techniques such as TLC/MS and TLC/FT-IR has further increased its usefulness. TLC allows formation of derivatives without resorting to extensive purification and recrystallization. Currently, there are two procedures used for chromatographic resolution of enantiomers. These are classified as direct (involving no chemical derivatization) and indirect (involving chemical derivatization) prior to chromatographic separation. Direct method has several advantages over indirect method for racemization may occur during derivatization reactions and suitable functional groups (ii) must be present for chemical reaction to take place between the chiral selector and the racemate. In the present studies on enantiomeric resolution, direct method has been used. A suitable chiral selector was impregnated by mixing it with the adsorbent during the preparation of TLC plates. Impregnation of thin layer with some suitable organic or inorganic reagent during plate preparations or at the stage before development of the chromatogram improves separation and detection chara cteristics of the same. Amino acids and their derivatives- the dansylamino acids, pharmaceuticals- the p-adrenergic blocking agents and 2-arylpropionic acids, and antibiotics- the cephalosporins were selected for present TLC studies because of their wide application in the fields of chemistry, medicine, forensic science and toxicology etc.,1 and easier availability. The present thesis comprises of six chapters. The first chapter is introductory one dealing with historical developments, theory and mechanism, nature of the adsorbent, advantages and application of TLC, resolution of enantiomers and preamble to the present studies. The literature related to TLC studies of the class of compounds chosen has been cited in subsequent chapters. Second chapter has been divided into two sections. Section A deals with enantiomeric resolution of some DL-amino acids using TLC plates impregnated with an industrial waste namely, (1R,3R,5R)- 2-azabicyclo[3,3,0]octan-3-carboxylic acid as a chiral selector. Enantiomeric separation of DL- arginine, DL-histidine, DL-lysine, DLvaline and DL-Leucine were studied using various solvent comb- (iii) inations of acetonitrile-methanol and water. Effects of temperature, chiral concentration and pH of thin layer on enantioseparation were studied. Detection was by both 0.2% ninhydrin in acetone and iodine. Section B presents studies on enantiomeric resolution of some dansyl- DL-amino acids using TLC plates impregnated with vancomycin as the chiral selector. The dansyl-DL : -leucine, -aspartic, -valine, aamino- n-butyric acid, -«o/Teucine, -ziorvaline, -tryptophan, -phenylalanine, -serine and -threonine were found to resolve under the conditions worked out. Extensive experimental work was carried to work out successful solvent systems. Spots were detected using fixed dual - wavelength (254 nm) uv chamber. Effects of temperature, chiral selector concentration and pH of the thin layer on enantio separation were studied. Third chapter incorporates enantioseparation of 2- arylpropionic acids : (±)-ibuprofen and (±)-flurbiprofen into their enantiomers using 2- dimensional TLC on silica gel G plates impregnated with pure (-) - brucine as a chiral selector. Different combinations of the solvent system acetonitrile - methanol were worked out for the first and the second dimension to get a successful resolution. Effects of temp erature, concentration of chiral selector and pH of the layer were studied. Iodine vapour was used for detection. The Fourth chapter gives a detailed study on enantio-resolution of some p-adrenergic blocking agents: (±)- atenolol, (±)-propranolol and (±)-metoprolol into their enantiomers using TLC plates impregnated with optically pure L-lysine and L-arginine as chiral selectors. In all the cases different combination of acetonitrilemethanol solvent systems were investigated to work out successful
Other Identifiers: Ph.D
Appears in Collections:DOCTORAL THESES (chemistry)

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