Reactions of pyrimidine nucleosides with aqueous alkalies: kinetics and mechanisms

Kinetics for the reactions of various cytosine and uracil nucleosides and their alkyl derivatives with aqueous sodium hydroxide have been studied by liquid chromatography. Blocking of the glycosyl hydroxyl groups with alkyl groups and changes in the glycon moiety configuration have been observed to exert only moderate effects on the rate of deamination of cytosine nucleosides. Methylation of the 4-amino group retards deamination considerably, while a methyl substituent at C5 is rate accelerating and at C6 only moderately rate retarding. These findings have been accounted for by a mechanism involving a rate limiting bimolecular displacement of the 4-amino group by a hydroxide ion. Analogous comparisons with uracil nucleosides suggest that the decomposition of uridine is initiated by an intermolecular attack of hydroxide ion on the C5 atom of the base moiety. In contrast, beta-D-arabino- and beta-D-lyxo-furanosyl derivatives appear to be cleaved via an intramolecular nucleophilic attack of the ionized 2'-hydroxyl group.