Chemical and spectroscopic studies of chromone derivatives

Abstract

Various chromone derivatives have been used in asthma therapy, and their biological activity is apparently related to certain chemical features which include conformation and acidity. In the present study, substituent effects on conformation and acidity have been explored in chromone systems with potential biological activity. A range of variously substituted symmetrical chromone-2-carboxamides (including a series of N,N-dimethylchromone-2-carboxamides) have been prepared via chromone-2-carboxylic acids, which, in turn, were prepared from the corresponding o-hydroxyacetophenones. The N,N-dimethylchromone-2-carboxamides were prepared by reacting the appropriate chromone-2-carbonyl chlorides with dimethylammonium chloride in pyridine, in an approach which resolved various problems encountered in the preparation of these compounds. Substituent effects on the conformation of chromone-2-carboxamides have been explored using dynamic NMR spectroscopy, and the observed splitting of the N-alkyl signals has been attributed to slow site-exchange of the N-alkyl substituents. Dynamic NMR frequency separations and coalescence temperatures have been used to calculate rotational energy barriers, and substituent effects on these rotational energy barriers have been analysed. The possible implication of ring-opening of chromones in chromone pharmacology has also been examined. A range of 3-(2-hydroxybenzoyl)acrylamides has been prepared via the dimethylamine-mediated ring-opening of N,N-dimethylchromone-2-carboxamides and the E-double-bond configuration of the ring-opened products has been unambiguously established by single crystal analysis of the parent system. The configuration and conformation of the crystal structure of the parent system have been shown, using IR and NMR spectroscopic, and molecular graphics techniques, to be maintained in solution and to characterise the whole series. ¹H and ¹³C NMR spectroscopy have also been used to study the dimethylamine-mediated ring-opening of disodium cromoglycate. The kinetics of the dimethylamine-mediated ring-opening of N,N-dimethylchromone-2-carboxamides have been studied using UV spectroscopy. These reactions have been shown to follow third-order kinetics overall and a mechanism accommodating the observed third-order kinetics has been proposed. Substituent effects have been further investigated by the potentiometric determination of the pKa (pK [subscript a]) values for a series of chromone-2-carboxylic acids. The relationship between acidity and the observed rate constants has been explored and has verified that the observed rate constants are sensitive to the influence of meta-substituents on the stability of the phenoxide ion "leaving group" rather than C-2 electrophilicity.