Extensive Analyses on Expanding the Scope of Acid–Aminopyrimidine Synthons for the Design of Molecular Solids

The acid–aminopyrimidine synthon is a well-known robust synthon for cocrystal synthesis that exists both in heterotrimer (HT) and linear heterotetramer (LHT) assemblies. A rational coformer screening methodology was adopted to predict the HT and LHT for the first time. The Cambridge Structural Database (CSD) and a modified site–pair interaction energy difference (ΔEsite-pair), based on molecular electrostatic potential (MESP), were computed to propose a generalization for better predictability. Based on the generalization, four cocrystals of 4-halobenzoic acid (−F, −Cl, −Br, and −I at the para position of benzoic acid) with 2-aminopyrimidine (2-AP) were predicted and obtained using a neat grinding method. Different characterization methods, viz., Fourier transform infrared (FT-IR) spectroscopy, powder X-ray diffraction (XRD), and differential scanning calorimetry (DSC) analysis, were used to confirm the formation of cocrystals. Single-crystal XRD was used for structural confirmations. Geometrical coordinates of cocrystals and their ingredients were optimized using density functional theory (DFT) calculations at the B3LYP-D3/6-311++G(d,p) level for −F-, −Cl-, and −Br-substituted cocrystals and the B3LYP-D3/6-311++G(d,p)/LANL2DZ level for the −I-substituted cocrystal. Extensive computational studies, viz., Frontier molecular orbitals (FMOs), MESP values, natural bond orbitals (NBO), quantum theory of atoms in molecules (QTAIM), and reduced density gradient noncovalent interaction (RDG-NCI) analyses, were done on optimized structures to gain more insights into cocrystals and the effect of halogens on the acid–aminopyrimidine synthon and strength and nature of intermolecular interactions present in the cocrystals. Moreover, the strong and weak intermolecular interactions present in the crystal structure were examined qualitatively and quantitatively using Hirshfeld surface analysis on different parameters, interaction energy calculations, and total energy frameworks.