Stabilities of uracil and pyridone-based carbanions: a systematic study in the gas phase and solution and implications for the mechanism of orotidine-5′-monophosphate decarboxylase

Abstract

The stabilities of the C6-centered carbanions derived from 1,3-dimethyluracil, N-methyl-2-pyridone, and N-methyl-4-pyridone were systematically investigated in the gas phase and in DMSO and water solutions. The stabilities of the carbanions in the gas phase and DMSO were directly measured through their reactions with carbon acids with known proton affinity or pKa values. The stabilities of the carbanions in DMSO were also probed through their kinetic isotope effects of protonation over deuteriation using acids with different acidity. The stabilities of the carbanions in water were determined through the rates of hydrogen-deuterium exchange reactions of the corresponding conjugate acids. The carbanions derived from the two pyridones were found to have the same stability, whereas the carbanion derived from 1,3-dimethyluracil was more stable. The order of the stability of the carbanions showed no correlation with the decarboxylation rates of their corresponding carboxylic acids. The implications of the results for the mechanism of orotidine-5′-monophosphate decarboxylase (ODCase) are discussed.

Anionic derivatives of uracil: fragmentation and reactivity

“…1 outlines the formation of deprotonated uracil-5-carboxylic acid from the solution containing uracil-5-carboxylic acid by ESI. Our previous work 35 and that of others 49,50 often involve molecules whose most acidic site is on the carboxylic acid group itself. Here, the N 1 site is the most acidic, yielding parent anions that are predominantly deprotonated there.…”

Convenient synthesis of N1-substituted orotic acid derivatives

“…1–12 We are interested in understanding the effect of hydrogen bonds to the pyrimidine moiety on the rate of decarboxylation. This investigation requires N1-substituted orotic acid derivatives (structure 1 in Scheme I) as substrates.…”

Improved synthesis of N1-substituted orotic acid derivatives

“…1–12 Part of the mechanistic investigation requires N1-substituted orotic acid derivatives (structure 1 in Scheme I) as substrates. Direct alkylation of orotic acid, unfortunately, produces a mixture of disubstituted and N3-substituted orotic acid derivatives because N3 is the more reactive site.…”