The Persistence\nof Hydrogen Bonds in Pyrimidinones:\nFrom Solution to Crystal

Pyrimidinone scaffolds are present in a wide array of\nmolecules\nwith synthetic and pharmacological utility. The inherent properties\nof these compounds may be attributed to intermolecular interactions\nanalogous to the interactions that molecules tend to establish with\nactive sites. Pyrimidinones and their fused derivatives have garnered\nsignificant interest due to their structural features, which resemble\nnitrogenous bases, the foundational building blocks of DNA and RNA.\nSimilarly, pyrimidinones are predisposed to forming N–H···O\nhydrogen bonds akin to nitrogenous bases. Given this context, this\nstudy explored the supramolecular features and the predisposition\nto form hydrogen bonds in a series of 18 substituted 4-(trihalomethyl)-2(1<i>H</i>)-pyrimidinones. The formation of hydrogen bonds was observed\nin solution via nuclear magnetic resonance (NMR) spectroscopy experiments,\nand subsequently confirmed in the crystalline solid state. Hence,\nthe 18 compounds were crystallized through crystallization assays\nby slow solvent evaporation, followed by single-crystal X-ray diffraction\n(SC-XRD). The supramolecular cluster demarcation was employed to evaluate\nall intermolecular interactions, and all crystalline structures exhibited\nrobust hydrogen bonds, with an average energy of approximately −21.64\nkcal mol<sup>–1</sup> (∼19% of the total stabilization\nenergy of the supramolecular clusters), irrespective of the substituents\nat positions 4, 5, or 6 of the pyrimidinone core. To elucidate the\nnature of these hydrogen bonds, an analysis based on the quantum theory\nof atoms in molecules (QTAIM) revealed that the predominant intermolecular\ninteractions are N–H···O (average of −16.55\nkcal mol<sup>–1</sup>) and C–H···O (average\nof −6.48 kcal mol<sup>–1</sup>). Through proposing crystallization\nmechanisms based on molecular stabilization energy data and contact\nareas between molecules and employing the supramolecular cluster and\nretrocrystallization concepts, it was determined that altering the\nhalogen (F/Cl) at position 4 of the pyrimidinone nucleus modifies\nthe crystallization mechanism pathway. Notably, the hydrogen bonds\npresent in the initial proposed steps were confirmed by <sup>1</sup>H NMR experiments using concentration-dependent techniques.