KINETICS AND MECHANISMS OF RACEMIZATION - 5-SUBSTITUTED HYDANTOINS (=IMIDAZOLIDINE-2,4-DIONES) AS MODELS OF CHIRAL DRUGS

A chiral center in a drug molecule increases the complexity of synthet ic, metabolic, pharmacological, and clinical studies, an additional pr oblem being a possible lack of configurational stability. Here, we rep ort detailed kinetic and mechanistic studies on the deuteration and ra cemization of seven 5-monosubstituted hydantoins (= imidazolidine-2,4- diones) used as model compounds. Using H-1-NMR and chiral RP-HPLC, rat es of reaction and thermodynamic parameters of activation were determi ned for the reactions of deuteration and racemization. Energies of dep rotonation were obtained by molecular-orbital calculations performed a t the AM1 level. Ir is demonstrated that the deuteration and racemizat ion of 5-monosubstituted hydantoins follow general-base catalysis. The identical (within experimental errors) activation energies of deutera tion and racemization indicate that the two reactions share a common r eaction mechanism. The fact that the pseudo-first-order rate constants of deuteration are about half of those of racemization suggests that deuteration occurs with inversion of configuration. Very large differe nces in reaction rates were observed between the seven compounds, indi cating the marked influence of substituents on chiral stability. These results, together with the small isotope effects observed, and the co mparison between experimental activation energies and calculated energ ies of deprotonation, suggest a S(E)2 push-pull mechanism for the race mization of 5-monosubstituted hydantoins.