Organic and Biological Chemistry: Studies on Models for Tetrahydrofolic Acid. II. Additional Observations on the Mechanism for Condensation of Formaldehyde with Tetrahydroquinoxaline Analogs

The condensation of formaldehyde with additional tetrahydroquinoxaline model systems in which the basicity of the exocyclic amino group has been varied through alterations in para substitution has been studied. Supporting evidence for a mechanism involving general base catalysis of attack by the exocyclic amino group on the iminium cation to yield the imidazolidine adduct is derived from these investigations. Experiments with a similar tetrahydroquinoline model indicate the importance of the nitrogen-8 of the tetrahydropyrazine ring on the rate of acid-catalyzed dehydration of the intermediate carbinolamine. The implication of these results as to the mechanism of action of the natural cofactor is discussed.