Electron Configuration and Hydrogen-Bonding Pattern in Several Thymine and Uracil Analogues Studied by ¹H–¹⁴N NQDR and DFT/QTAIM

Abstract

Some thio- and aza-derivatives of natural nucleobases uracil and thymine: 2-thiouracil, 4-thiouracil, 6-methyl-2-thiouracil, 6-azauracil, and 6-aza-2-thiothymine have been studied experimentally in solid state by (1)H-(14)N NMR-NQR double resonance (NQDR) and theoretically by the Density Functional Theory (DFT)/Quantum Theory of Atoms in Molecules (QTAIM). The (14)N resonance frequencies have been measured at 173 and 295 K and assigned to particular nitrogen sites (-N═ and -NH-). The temperature factor has been found negligible. The changes in the molecular skeletons, electric charge distribution, intermolecular interactions pattern, and molecular aggregations caused by oxygen replacement with sulfur and carbon replacement with nitrogen are discussed in detail. Correlations between all the principal components of the (14)N quadrupole coupling tensor have been found helpful in the search for the experimental (14)N NQR frequencies, their assignment to a particular nitrogen positions and estimation of the strength of the inter- and intramolecular interactions. The variation in the NQR parameters have been mainly related to the variation in the population of π-electron orbital. For thiouracil derivatives a general trend is that the stronger the hydrogen bond is, the lower is the asymmetry parameter, while for thymine and 6-aza-2-thiotymine, the opposite relation holds. Differences in correlations of the principal components of the (14)N quadrupole coupling tensor at the amino and iminonitrogen positions in heterocyclic rings are discussed. The effect of C→H and C→N substitution at the amino nitrogen position and C→N substitution at the iminonitrogen position on the quadrupole coupling tensor is analyzed. This study also demonstrates the advantages of combining NQR and DFT/QTAIM to predict an unsolved crystalline structure of 4-thiouracil.

Towards Understanding Drugs on the Molecular Level to Design Drugs of Desired Profiles

“…A possible explanation of the 14 N NQR spectra is that the sulfamethizole molecules form slightly asymmetric hydrogen bonded pairs, similar to the symmetric pairs formed by the acetazolamide molecules. The NQR parameters obtained by B3LYP/6-311++G(d,p) assuming putative dimeric structure, Fig.1., were in a very good agreement with the experimental data [104]. Studies of isostructurality and annular 50:50 prototropic tautomerism of pentabromobenzimidazoles make another example of the successful prediction of crystalline structure performed by NQR and DFT/QTAIM combined [105].…”

“…An interesting example is the structure of sulfamethizole, known to be able to crystallize in different polymorphic forms [102,103] of which none, even the most stable one, was solved. In a single molecule of sulfamethizole there are four nonequivalent nitrogen positions, but within the NQR experimental resolution five nitrogen positions have been detected [104]. This indicated either two nonequivalent molecules in the unit cell or two polymorphic crystal forms of sulfamethizole.…”

“…A combination of experimental and theoretical techniques has certainly much to offer for the studies of drugs or potential drugs in early phases of drug research. Their capabilities in particular when applied to the known drugs, have been well documented in literature [92,99,101,104,105,148,[156][157][158][159][160][161][184][185][186][187][188][189]. Although in some fields the NMR or NQR are not competitive to IR, UV or XRD the examples of combined studies given above show that both techniques have a potential to elicit structural and physico-chemical information about a molecule of dug, target or the interaction drug-target.…”

“…For the same reason e 2 Qqh -1 is smaller at -NH 2 site in polymorph I in comparison to that in form II. Differences in bonding schemes of the terminal -NH 2 group in the two crystallographic modifications are found to be responsible for a significantly different 14 N NQR parameters, which can be used as a measure of the strength of hydrogen bonds [104].…”

“…Thus the polymorphism of acetazolamide is classified as a packing type or pure combining association type. Interesting results concerning the interaction pattern have been obtained using NMR, NQR and DFT/QTAIM calculations [104]. The marked differences in the 14 N NQR frequencies, quadrupole coupling constants and asymmetry parameters at the nitrogen sites in the thiadiazole ring and -NH 2 on going from phase I to phase II allow distinction of both polymorphs, Table 3.…”