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Kinetics and mechanisms of racemization: 5-substituted hydantoins (=imidazolidine-2,4-diones) as models of chiral drugs

Reist, Marianne
Testa, Bernard
Lehmann, S.
Hansen, J. J.
Published in Helvetica Chimica Acta. 1996, vol. 79, no. 3, p. 767-778
Abstract A chiral center in a drug molecule increases the complexity of synthetic, metabolic, pharmacological, and clinical studies, an additional problem being a possible lack of configurational stability. Here, we report detailed kinetic and mechanistic studies on the deuteration and racemization of seven 5-monosubstituted hydantoins (= imidazolidine-2,4-diones) used as model compounds. Using H-1-NMR and chiral RP-HPLC, rates of reaction and thermodynamic parameters of activation were determined for the reactions of deuteration and racemization. Energies of deprotonation were obtained by molecular-orbital calculations performed at the AM1 level. Ir is demonstrated that the deuteration and racemization of 5-monosubstituted hydantoins follow general-base catalysis. The identical (within experimental errors) activation energies of deuteration and racemization indicate that the two reactions share a common reaction 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 differences in reaction rates were observed between the seven compounds, indicating the marked influence of substituents on chiral stability. These results, together with the small isotope effects observed, and the comparison between experimental activation energies and calculated energies of deprotonation, suggest a S(E)2 push-pull mechanism for the racemization of 5-monosubstituted hydantoins
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REIST, Marianne et al. Kinetics and mechanisms of racemization: 5-substituted hydantoins (=imidazolidine-2,4-diones) as models of chiral drugs. In: Helvetica Chimica Acta, 1996, vol. 79, n° 3, p. 767-778.

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Deposited on : 2010-08-06

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