Structural and quantitative analysis of intermolecular solid-state interactions in cocrystals obtained from nucleobases and methylxanthines with gallic acid

Cocrystallization experiments of nucleobases (NB) and methylxantines (MX) with gallic acid (GA) yielded a total of five multicomponent solids, i.e., (GA)(TPL) (I), (GA)(CAF).0.5H(2)O (II), (GA)(TBR).2H(2)O (III), (GA)(HGUA)Cl.H2O (IV) and (H(-1)GA)(HCYT) (V), where TPL = theophylline, CAF = caffeine, TBR = theobromine, GUA = guanine and CYT = cytosine. The products were prepared by the slurry method and characterized by single-crystal and powder X-ray diffraction analysis, IR spectroscopy, Hirshfeld surface analysis and PIXEL calculations to assess the intermolecular interaction energies and related parameters. In accordance with the pK(a)-rule, TPL, CAF and TBR provided cocrystals. The reaction of GA with GUA (in this case in the presence of HCl) and CYT gave a cocrystal salt and a salt, respectively. In the crystal structures of I-III, homo- and/or heterodimeric hydrogen bonding motifs based on moderate to strong N-HmiddotmiddotmiddotO and O-HmiddotmiddotmiddotO interactions were observed, constituting the most significant contributions to the solid-state stabilization. In IV and V, charge-assisted hydrogen bonds formed among GUAH(+) and Cl- (IV) or HCYT+ and gallate (V) were identified. All five crystal structures exhibit heterosynthons with O-H(GA)middotmiddotmiddotOC(NB/MX) and/or COOH(GA)middotmiddotmiddotN(NB/MX) hydrogen bonds and pi-pi interactions, through which the molecular components are linked in the three-dimensional space. Comparative structural analysis of compounds I-V and a total of 93 other previously reported cocrystals and salts, revealed that GA is an excellent reagent for the generation of multicomponent molecular crystals, which is related to its property of adopting different molecular conformations (concerning the mutual OH group orientations) and carrying a large number of hydrogen bond donor and acceptor sites. The intermolecular interaction energies established by PIXEL calculations afforded results consistent with the experimental crystal structures@2023 Elsevier B.V. All rights reserved.