Expanding the Supramolecular Toolkit: Computed Molecular and Crystal Properties for Supporting the Crystal Engineering of Higher-Order Molecular Ionic Cocrystals

Over the past 2 decades, significant progress has been made in developing a robust supramolecular toolkit for the crystal engineering of simple binary cocrystals. By contrast, crystal engineering of higher-order molecular ionic cocrystals (ICCs) is not well established. Her; we report the results of the most extensive survey of the molecular and crystal properties of ICCs reported to date and use the resulting data to propose a set of guiding principles to aid the crystallization of molecular ICCs sustained by charge-assisted hydrogen bonding interactions. Using a data set comprising a total of 94 ICC crystal structures, this work reveals that molecular ICCs are favored within a narrow range of the property landscape. Specifically, most of the ICCs in the data set are crystallized using molecules with significantly different polar surface areas. The data also highlight the importance of choosing molecules with a similar number of conformational degrees of freedom when targeting higher-order cocrystals. Molecular ICCs comprising conjugate acid-base fragments are more likely to be observed in crystallization screens when the difference in the ionization constants of the acid-base pair lie within the "gray" zone of the salt-cocrystal continuum. This work also reveals the hierarchy in the supramolecular heterosynthons of molecular ICCs. Finally, periodic dispersion-corrected density functional theory calculations on a limited subset of crystal structures reveals that most of the ICCs surveyed are driven to form on the basis of favorable energetics as indicated by a mean stabilization energy of -5 kJ mol(-1).