Características Cristalinas de 4-(Trihalometil)Pirimidinonas: Resiliência de Ligações de Hidrogênio Independentemente dos substituintes

Abstract

The pyrimidinone scaffold is present in a wide range of molecules with synthetic applications and pharmacological properties. The inherent properties may be related to intermolecular interactions, which are analogous to the interactions that molecules tend to create with active sites. Pyrimidinones and their fused derivatives receive great attention due to their intrinsic structural features, which resemble nitrogenous bases, building blocks of DNA and RNA. Furthermore, willingly like nucleobases, pyrimidinones also tend to form hydrogen bonds. In this context, the objective of this work seeks to explore the crystalline features present in a series of substituted 4- (trihalomethyl)-2(1H)-pyrimidinones. For this, 18 compounds were used which were previously crystallized through crystallization assays using the slow solvent evaporation methodology, and after all diffracted. The supramolecular cluster demarcation was employed to assess intermolecular interactions. It was found that all crystal structures herein show strong hydrogen bonds, around ~21.5 kcal mol-1 (~19%, on average, of the stabilization energy of the supramolecular cluster), regardless of the substituents at the positions 4, 5 or 6 of the pyrimidinone core. Seeking to understand the nature of these hydrogen bonds, an analysis using the Quantum Theory of Atoms in Molecules (QTAIM) was used and it was verified that the main intermolecular interactions that occur in this group are predominantly NH⋯O (average of ~15.8 kcal mol-1) and CH⋯O (average of ~5.6 kcal mol-1). Through proposals of crystallization mechanisms, based on molecular energy stabilization data and contact areas between molecules, using the supramolecular cluster and retrocrystallization as fundamentals, it was established that the change of halogen (F/Cl) in position 4 of the pyrimidinone core, modifies the proposed pathways of crystallization mechanisms. Categorically, the hydrogen bonds present in the first proposed crystallization steps were confirmed by Concentration-Dependent 1H Nuclear Magnetic Resonance (CD-NMR) techniques.