Multifacial Recognition in Binary and Ternary Cocrystals from 5-Halouracil and Aminoazine Derivatives

Abstract

A systematic analysis using single crystal X-ray diffraction was performed to explore the role exerted by potential intercomponent proton-transfer reactions in the supramolecular structures of A–B cocrystals formed by 5-haloderivatives of uracil (A), coupled with 2-aminoadenine simulants (aminoazines, B). Twelve new heterodimers were synthesized in different stoichiometries and cocrystallized by solvent cogrinding followed by solution crystallization. In the binary cocrystals, uracil or 1-methyluracil with halide modification at the 5 position (F, Cl, Br, I) was coupled with amino-aromatic N-heterocycles (melamine, 2,4,6-triaminopyrimidine, 2,6-diaminopyridine) as a multivalent site for pyrimidine nucleobase recognition. The crystallographic analysis showed that, next to the expected neutral three-point hydrogen bonds (TPI), ionized TPI, favored by A → B proton transfer, can be used for WC multifacial recognition. Noteworthy, the formation of the charged TPI, which depends on the acid/base properties of the components, always takes place between the more acidic site of the 5-halonucleobases (N3 atom) and the more basic site (imino N atom) of 2,4,6-triaminopyrimidine or 2,6-diaminopyridine, and melamine recognition unit results in being insufficiently basic to accept a proton. The general ability of pyrimidine nucleobases to provide electron donating groups to halogen bonding has been confirmed in seven cocrystals containing the 5-chloro, 5-bromo, or 5-iododerivatives coupled with melamine or 2,4,6-triaminopyrimidine. Considerations of the relative acidities of coformers A and of the relative basicities of coformers B allowed us to design and characterize by single-crystal X-ray diffraction the first ternary pyrimidine nucleobase-containing cocrystal based on the JANUS-WEDGE concept: the nucleobase–Janus–nucleobase (1:1:1) triad showing a 2,4,6-triamino pyrimidine molecule wedged via neutral and ionized TPI between the 5-fluorouracil/1-methyluracil pair in reverse WC fashion.