Studies on models for tetrahydrofolic acid. II. Additional observations on the mechanism for condensation of formaldehyde with tetrahydroquinoxaline analogs

Abstract

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.

Tetrahydrofolate and tetrahydromethanopterin compared: functionally distinct carriers in C1 metabolism

“…As discussed above, the rate constant for ring closure is enhanced in model compounds in which the para substituent renders N"! more basic [145]. Extending this reasoning to H % MPT and H % folate, ring (re-)closure will be more favoured for H % MPT than for H % folate ; hence the steady-state level of the cationic imine will be lower for H % MPT, and the overall reduction will be thermodynamically less favourable on H % MPT than on H % folate, as is found.…”

“…Replacement of the electron-withdrawing carbonyl by a methyl group increased the rate of condensation of the model compound with formaldehyde ; this was attributed to an increase in the rate constant for ring closure from the cationic imine intermediate, due in turn to greater basicity (electron density) at N"! in the methyl-substituted compound [145]. That study was carried out before H % MPT had been discovered, but can now be seen as a model for differences between H % folate and H % MPT.…”

“…of the arylamine is crucial in tuning the reactivity of N"! [145]. Replacement of the electron-withdrawing carbonyl by a methyl group increased the rate of condensation of the model compound with formaldehyde ; this was attributed to an increase in the rate constant for ring closure from the cationic imine intermediate, due in turn to greater basicity (electron density) at N"!…”

“…Under ecological conditions of 1-10 Pa H # , the energy yield is only about 15-35 kJ:mol −" ( [82], pp. [142][143][144][145][146][147]. This is insufficient for synthesis of 1 mol of ATP per methane molecule produced [75,77].…”

Preparation of aminals in water

“…Even the hindered 2,6-dichloro-benzaldehyde gave the corresponding aminal 3i in a good yield of 88% (entry 9). In cases where the melting points of the benzaldehydes where higher than room temperature, the mixtures were heated to 80 8C in order to melt the aldehydes and ensure the formation of an emulsion containing both reactants (entries 6,8,9,16). When the benzaldehydes were not melted, yields where significantly lower.…”