Biomedical
Intramolecular Interactions in Derivatives of Uracil Tautomers
Paweł A. Wieczorkiewicz,
Tadeusz M. Krygowski,
Halina Szatylowicz
Peer Reviewed
Abstract
The influence of solvents on intramolecular interactions in 5- or 6-substituted nitro and amino derivatives of six tautomeric forms of uracil was investigated. For this purpose, the density functional theory (B97-D3/aug-cc-pVDZ) calculations were performed in ten environments (1 > ε > 109) using the polarizable continuum model (PCM) of solvation. The substituents were characterized by electronic (charge of the substituent active region, cSAR) and geometric parameters. Intramolecular interactions between non-covalently bonded atoms were investigated using the theory of atoms in molecules (AIM) and the non-covalent interaction index (NCI) method, which allowed discussion of possible interactions between the substituents and N/NH endocyclic as well as =O/−OH exocyclic groups. The nitro group was more electron-withdrawing in the 5 than in the 6 position, while the opposite effect was observed in the case of electron donation of the amino group. These properties of both groups were enhanced in polar solvents; the enhancement depended on the ortho interactions. Substitution or solvation did not change tautomeric preferences of uracil significantly. However, the formation of a strong NO∙∙∙HO intramolecular hydrogen bond in the 5-NO2 derivative stabilized the dienol tautomer from +17.9 (unsubstituted) to +5.4 kcal/mol (substituted, energy relative to the most stable diketo tautomer).
Key Questions and Answers
1. How do solvents influence the intramolecular interactions in substituted nitro and amino derivatives of uracil?
The study shows that solvents, particularly polar ones, enhance the electron-withdrawing and donating properties of the nitro and amino groups, respectively. This modification in the properties of the substituents affects their interactions, with solvent polarity playing a key role in strengthening the intramolecular interactions.
2. What role does the polarizable continuum model (PCM) play in analyzing solvation effects in this study?
The PCM model is used to simulate the effect of solvent environments on the uracil derivatives. It helps quantify how different solvents impact the electronic and geometric parameters of the substituents and intramolecular interactions.
3. How does the electron-withdrawing effect of the nitro group differ between the 5- and 6-position?
The nitro group exhibits a stronger electron-withdrawing effect when positioned at the 5-position compared to the 6-position, which influences the electron density distribution of the uracil ring.
4. What is the significance of the NO-HO intramolecular hydrogen bond in stabilizing the dienol tautomer of uracil derivatives?
The NO-HO intramolecular hydrogen bond in the 5-NO2 derivative stabilizes the dienol tautomer, reducing its energy relative to the most stable diketo tautomer, thus enhancing the stability of this tautomer in polar solvents.
5. Does substitution or solvation significantly alter the tautomeric preferences of uracil?
Substitution or solvation does not significantly change the tautomeric preferences of uracil. The tautomeric distribution remains mostly unaffected, with solvation primarily affecting the intramolecular interactions.
