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

The mechanism of hydrolysis of diastereomeric oxazolidines formed by the re action of (-)-ephedrine and (+)-pseudoephedrine with formaldehyde was studi ed using semiempirical and ab-initio methods. (-)-Ephedrine forms a cis-oxa zolidine, while (+)-pseudoephedrine forms a trans-oxazolidine. cis-Oxazolid ines have been observed to hydrolyze more rapidly than trans-oxazolidines i n neutral or basic solution. The structures of all intermediates in the pro posed reaction mechanism were optimized using AM I, Hartree-Fock and MP2 le vels of theory. Vibrational frequencies were calculated at the Hartree-Fock level of theory in order to obtain zero-point energies. The enthalpy chang e of each reaction step was calculated from these data. Enthalpy difference s between cis- and trans-isomers were noted at the step involving protonati on of the oxazolidine ring oxygen. Calculations predict this step to be the most endothermic one at basic pH, and therefore probably it is rate-determ ining. 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 geometr y from the corresponding intermediate obtained from the trans-isomer. Upon O-protonation, the trans-isomer forms a stable O-protonated oxazolidine. Ho wever, the cis-isomer undergoes immediate ring-opening to form a syn-cation ic imine. The intermediate obtained from the trans-isomer is also higher in energy than the intermediate obtained from the cis-isomer. These results s uggest 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 faste r than the trans-isomer in basic solution. (C) 2001 Elsevier Science B.V. A ll rights reserved.