| dc.description.abstract | The thesis is divided into three chapters. The first chapter is a general introduction on the mechanism of enzyme action and a few model systems. The second chapter deals with the design, synthesis, and kinetic studies on some thiazolium derivatives for mixed acyloin formation. The third chapter consists of studies on a template based on an 8?hydroxyquinoline model system for ampicillin synthesis.
Chapter I – General Introduction
Certain known features for specificity as well as rate acceleration in enzyme catalysis are discussed. Concepts such as proximity effect and intramolecular catalysis, propinquity effect, orbital steering, stereopopulation control, rack and strain theories, covalent catalysis, and general acid–base catalysis are considered. The importance of binding energy in enzyme–substrate complexation and the relevance of hydrophobic association in these processes are also discussed with suitable examples of model systems.
Chapter II – Mixed Acyloin Condensation
This chapter begins with the objectives and approach to the present studies on mixed acyloin formation involving benzaldehyde and acetaldehyde. The important features of thiamine catalysis are reviewed in the introduction. This is followed by the design and synthesis of model systems for achieving specificity and enhanced rates in the formation of mixed acyloin, especially phenylacetyl carbinol, a key intermediate in ephedrine synthesis. Hydrophobic association was invoked as a major criterion for achieving specificity and rate acceleration.
The equilibrium constant and free energy of association of benzaldehyde with 3-(p-phenylethyl)-4-methylthiazolium bromide (1a) was estimated through the linear enhancement of benzaldehyde absorption at 290 nm with graded amounts of the catalyst, and the association energy was found to be about –6.1 kcal/mol.
NMR studies showed that the two rings in catalyst (1a) have perpendicular orientation and the benzaldehyde molecule is sandwiched between them in water. Hydrophobic association of benzaldehyde with terminal aromatic rings determines two main features:
(a) benzaldehyde is more likely to be steered onto the 2?position of the thiazolium ring than acetaldehyde, assisted by the stability of the carbanion formed from benzaldehyde;
(b) hydrophobic association also makes benzaldehyde a better recipient of the active aldehyde at position?2 of thiazole.
As a result, benzoin formation predominates even with moderate molar excess of acetaldehyde. Only with large excess of acetaldehyde are benzoylmethyl carbinol and phenylacetyl carbinol formed. Substituent effects on relative rates of benzoylmethyl carbinol formation were studied, showing that introduction of a p?phenyl group (1a) increases the rate 50?fold compared to (2a), while an additional phenyl group at the ??position (1b) increases the rate 115?fold. A micelle catalyst (2c) increases the rate 757?fold. Specificity in obtaining phenylacetyl carbinol was achieved to some extent by quaternary ammonium groups at the p?position of catalysts (1d, 1e). The chapter concludes with a general discussion on the effect of hydrophobic association and other factors on specificity and rate of mixed acyloin formation.
Chapter III – Templates for Ampicillin Synthesis
This chapter begins with an introduction to important commercial processes for ampicillin synthesis. A short review of studies on the mechanism of action of 8?hydroxyquinoline esters in amide and peptide syntheses is included. 8?Hydroxyquinoline?7?carboxaldehyde is used as a model system in the synthesis of ampicillin from phenylglycine and 6?aminopenicillanic acid, with the aldehyde group in the catalyst serving as a protecting function for the amino group of ??phenylglycine.
The rates of ampicillin formation for various solvent systems and temperatures are discussed. The chapter also reports an attempted synthesis of a complex catalyst (4) with more attachment points for the substrate, 6?aminopenicillanic acid, and methods for introducing a side chain at the 2?position of quinolines. | |
