The trifluoromethyl group as a conformational stabilizer and probe: conformational analysis of cinchona alkaloid scaffolds.

Abstract

The introduction of the CF3 group on the C9 atom in quinidine can significantly increase the conformational interconversion barrier of the cinchona alkaloid scaffold. With this modification the conformational behavior of cinchona alkaloids in various solvents can be conveniently investigated via (19)F NMR spectroscopy. Based on the reliable conformational distribution information obtained, the accuracy of both theoretical (PCM) and empirical (Kamlet-Taft) solvation models has been assessed using linear free energy relationship methods. The empirical solvation model was found to provide accurate prediction of solvent effects, while PCM demonstrated a relatively low reliability in the present study. Utilizing similar empirical solvation models along with Karplus-type equations, the conformational behavior of quinidine and 9-epi-quinidine has also been investigated. A model SN2 reaction has been presented to reveal the important role of solvent-induced conformational behavior of cinchona alkaloids in their reactivity.