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Kinetics and Mechanisms of Racemization: 5‐Substituted Hydantoins (= Imidazolidine‐2,4‐diones) as Models of Chiral Drugs
Author(s) -
Reist Marianne,
Carrupt PierreAlain,
Testa Bernard,
Lehmann Søren,
Hansen Jan Jørn
Publication year - 1996
Publication title -
helvetica chimica acta
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.74
H-Index - 82
eISSN - 1522-2675
pISSN - 0018-019X
DOI - 10.1002/hlca.19960790319
Subject(s) - racemization , chemistry , deprotonation , kinetic isotope effect , imidazolidine , computational chemistry , reaction rate constant , reaction mechanism , molecule , catalysis , stereochemistry , medicinal chemistry , kinetics , organic chemistry , deuterium , ion , physics , quantum mechanics
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 hydantions (= imidazolidine‐2,4‐diones) used as model compounds. Using 1 H‐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. It 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.