Glacial acetic acid catalyzed a novel stereospecific epimerization of chinchona alkaloids at C - 9. In the presence of water, acetic acid also catalyzed the known toxine rearrangement and oxidation to the corresponding 9- keto derivatives. Addition of acetic anhydride to acetic acid diminished oxidation and epimerization at C-9, and the main products were the results of hydramine fission. Only propionic acid but not other acids, effected similar but not identical transformations. Addition of small quantities of H 2 O 2 or exclusion of oxygen produced quantitative oxidation and rearrangement products, respectively. The catalysis by aqueous solutions of acetic acid, involves C-9-OH in the formation of a three-membered ring intermediate. On the other hand,with anhydrous acetic acid, the acetoxyl at G-9 participates in construction of a five-membered ring intermediate. In both cases the reaction appears to be intramolecular. Support for the proposed mechanisms was provided by the isolation of a quarternary salt derived from quinidine, the structure of which was also characterized by X-ray diffraction analysis. Aqueous acetic acid catalyzed the rearrangement of this salt to its corresponding toxine only . and neither oxidation nor epimerization could be observed under conditions employed for the natural alkaloids.

Two epimeric aldehydes [(R)- and (S)-quinidinals] and the corresponding acids[(R)- and (S)-norhydroquinidinoic acids] were prepared by the oxidation of quinidine. The alpha-alpha interactions of the carbonyl group and the aromatic moiety, as reflected in the NMR spectra, were compared with those of quinidine. NMR spectroscopic analyses made it possible to assign both the stable conformation and their configuration at C-3 to these molecules. The free hydroxyl group at C-9 must be present for the chemical shift values to be concentration dependent. These findings provide more information on association in the parent molecules.

NMR analyses of quinidine and other cinchona alkaloids and their monoprotonated salts in deuterium oxide and in deuterochloroform revealed that the molecules assume new conformations in polar and nonpolar media, affecting the protonation site and hydrophilic-lipophilic characteristics. The ion-pair feature of the salts is lost and the molecules assume a neutral feature when they are transferred from an aqueous to a lipoid phase. Hydrophobic bonds-between the molecules and their environment and within the molecule itself may affect the binding of cinchona alkaloids to membranes in biological fluids.