Abstract
<jats:p> Molecular self-assembly and aggregation are ubiquitous phenomena in supramolecular and host-guest chemistry, particularly in aqueous media. Aggregation of host molecules affects guest binding and spectroscopic properties of the system. Porous organic cryptophane (Cry) cages are the gold standard for xenon capture in hyperpolarized <jats:sup>129</jats:sup> Xe NMR biosensors (XBS). Despite the Cry structure being hydrophobic and aromatic, both of which promote aggregation, the XBS field has so far mostly considered monomeric (isolated) Xe@cage systems where two-site Xe exchange occurs only between the cage and the solvent environments. With this in mind, I have performed large-scale molecular dynamics simulations of water-soluble Cry cages and free Xe atoms in aqueous conditions to study Cry aggregation and Xe-aggregate interactions at the molecular level. The simulations predict aggregation that depends strongly on the number of hydrophilic groups on the cages, with cages having fewer such groups aggregating more. Aromatic π-π interactions between the cages are found to play an important role in the aggregation. Analysis of Xe interactions with the largest observed Cry aggregate revealed hitherto unreported solvent-exposed and buried Xe binding sites with Xe residence times of more than a hundred nanoseconds. These findings suggest that aggregation of cryptophanes and other porous organic cages should be considered in their host-guest chemistry and applications. In particular, the validity of the commonly assumed two-site Xe exchange model in the XBS field should be carefully assessed in the presence of aggregation. </jats:p>