Theoretical Study of the Regioselectivity of the Interaction of 3-Methyl-4-pyrimidone and 1-Methyl-2-pyrimidone with Lewis Acids

Abstract

A density functional theory (DFT) study is performed to determine the stability of the complexes formed between either the N or O site of 3-methyl-4-pyrimidone and 1-methyl-2-pyrimidone molecules and different ligands. The studied ligands are boron and alkali Lewis acids, namely, B(CH(3))(3), HB(CH(3))(2), H(2)B(CH(3)), BH(3), H(2)BF, HBF(2), BF(3), Li(+), Na(+), and K(+). The acids are divided into two groups according to their hardness. The reactivity predictions, according to the molecular electrostatic potential (MEP) map and the natural bond orbital (NBO) analysis, are in agreement with the calculated relative stabilities. Our findings reveal a strong regioselectivity with borane and its derivatives preferring the nitrogen site in both pyrimidone isomers, while a preference for oxygen is observed for the alkali acids in the 3-methyl-4-pyrimidone molecule. The complexation of 1-methyl-2-pyrimidone with these hard alkali acids does not show any discrimination between the two sites due to the presence of a continuous delocalized density region between the nitrogen and the oxygen atoms. The preference of boron Lewis acids toward the N site is due to the stronger B-N bond as compared to the B-O bond. The influence of fluorine or methyl substitution on the boron atom is discussed through natural orbital analysis (NBO) concentrating on the overlap of the boron empty p-orbital with the F lone pairs and methyl hyperconjugation, respectively. The electrophilicity of the boron acids gives a good overall picture of the interaction capabilities with the Lewis base.

Interactions between temozolomide and guanine and its S and Se-substituted analogues

“…In a number of cases in the literature, the strength of the interaction has been directly related to the MEP of the molecules of interest. The MEP has been particularly useful as an indicator of the sites or regions of molecules to which an approaching electrophile is attracted, and it has also been applied successfully to the study of interactions that involve a certain optimum relative orientation of the reactants, such as a drug and its cellular receptor …”

Regioselectivity of the interaction of temozolomide with borane and boron trifluoride

“…This importance of the latter is perhaps best illustrated by comparison of O17 and N12 as binding sites. O17 represents the area with the most [20] on the interaction of these same molecules with pyrimidones. One can also compare the interactions [19] of TMZ with water.…”

“…Another important scenario involves more general electrophilic interactions with Lewis acids. As an example, our recent DFT study to determine the stability of the complexes formed between the N and O sites of 3-methyl-4-pyrimidone and 1-methyl-2-pyrimidone found their behavior toward Lewis acids especially intriguing [20]. That study pointed out a strong regioselectivity with borane and its derivatives preferring the nitrogen site in both pyrimidone isomers, while a preference for oxygen is observed for alkali acids in 3-methyl-4-pyrimidone.…”

Conceptual DFT study of the chemical reactivity of four natural products with anti-sickling activity

“…The chemical potential (μ), hardness (η), and electrophilicity (ω) were computed to get insight into the global reactivity of A-E molecules. These global descriptors were computed using the following formula [37,38,[46][47][48][49]:…”