An investigation of isomeric differences in hydrolytic rates of oxazolidines using computational methods

Abstract

The mechanism of hydrolysis of diastereomeric oxazolidines formed by the reaction of (−)-ephedrine and (+)-pseudoephedrine with formaldehyde was studied using semiempirical and ab-initio methods. (−)-Ephedrine forms a cis-oxazolidine, while (+)-pseudoephedrine forms a trans-oxazolidine. cis-Oxazolidines have been observed to hydrolyze more rapidly than trans-oxazolidines in neutral or basic solution. The structures of all intermediates in the proposed reaction mechanism were optimized using AM1, Hartree–Fock and MP2 levels of theory. Vibrational frequencies were calculated at the Hartree–Fock level of theory in order to obtain zero-point energies. The enthalpy change of each reaction step was calculated from these data. Enthalpy differences between cis- and trans-isomers were noted at the step involving protonation of the oxazolidine ring oxygen. Calculations predict this step to be the most endothermic one at basic pH, and therefore probably it is rate-determining. This step is considerably more endothermic for the trans-oxazolidine than for the cis-isomer. The results of calculations show the O-protonated intermediate formed from the cis-isomer differs in both energy and geometry from the corresponding intermediate obtained from the trans-isomer. Upon O-protonation, the trans-isomer forms a stable O-protonated oxazolidine. However, the cis-isomer undergoes immediate ring-opening to form a syn-cationic imine. The intermediate obtained from the trans-isomer is also higher in energy than the intermediate obtained from the cis-isomer. These results suggest that the relative ease of ring-opening of the cis-isomer compared to that of the trans-isomer explains why the cis-isomer hydrolyzes much faster than the trans-isomer in basic solution.