Cyclam(OH)₄ as an adaptable co-former for co-crystals with carboxylic acids and phenols

Abstract

While (macro)cyclic amines are widely used as co-formers in the design of supramolecular hydrogen-bonded crystalline networks, organic hydroxylamines remain almost unexplored in this context. Here, co-crystallization of the tetra-N-hydroxylated cyclam with several organic hydrogen-bond donors (pharmaceutically relevant carboxylic acids, hydroquinone) was investigated for the first time. The results demonstrate co-former-dependent control over crystal packing, proton transfer, supramolecular organization, macrocyclic conformation, and tautomerization leading to either closed H-bonded subunits or novel three-dimensional self-catenated H-bonded networks. In specific cases, the dynamic nature of crystal formation gives rise to conformational polymorphs. Remarkably, a very rare tautomerization of the hydroxylamine unit to the N-oxide form was observed in the co-crystal of cyclam(OH)4 with hydroquinone. Comparison of the observed H-bonding parameters and patterns with those of the known co-crystals of unsubstituted cyclam highlights the pronounced advantage of the hydroxylated scaffold in engineering supramolecular hydrogen-bonded motifs.