Tyramine as a Prolific\nCoformer in Crystal Engineering:\nInsights from Classical Crystal Structure Analysis and Electron Density\nStudies

Prolific coformers are compounds that readily form multicomponent\ncrystals with diverse partners, playing a crucial role in crystal\nengineering by enabling the creation of new solids with enhanced physicochemical\nproperties. In this study, we investigated tyramine as a potentially\nattractive cocrystallization component, given its reported ability\nin the Cambridge Structural Database (CSD) to interact with over 60\ndiverse building blocks. We conducted classical crystal structure\nand charge density analyses, along with Hirshfeld surface studies,\non three distinct tyramine organic salts with L-pyroglutamic\nacid, D-mandelic acid, and <i>p</i>-aminohippuric\nacid. This work aimed to determine whether and why tyramine can be\nconsidered a prolific coformer. Tyramine cations were evaluated in\nterms of similarities and differences in intermolecular interactions\nacross these salts. Additionally, we examined the conformation of\nthe aliphatic chain and Δp<i>K</i><sub>a</sub> values\nfor all tyramine salts in the CSD to identify the most significant\nfactors influencing cocrystallization with tyramine. Our findings\nsuggest that proton transfer is a crucial factor in the formation\nof stable multicomponent materials with tyramine. Furthermore, the\nselection of coformers for cocrystallization with tyramine should\nprioritize repeatable synthons, particularly those containing carboxylic\ngroups.