It is of interest to consider the possible causes of these structure-activity relationships. Small molecule crystallographic studies of pure phenothiazines show that the aromatic rings of neighboring phenothiazines can form various stacked conformations that are probably energetically favorable . However, CDs lack aromatic groups, so such interactions are not available to stabilize the present hostguest systems. It has also been argued, based on crystallographic data, that the aromatic protons of phenothiazines can donate hydrogen bonds to, e.g., nitro oxgyens . Here, in principle, these protons could donate hydrogen bonds to the hydroxyl oxygens of the CDs. However, aromatic hydrogens are not very good hydrogen bond donors, so any such interaction is likely weak and, in the aqueous environments studied here, would likely be outcompeted by strong hydrogen bonds from water molecules. All of the phenothiazine drugs studied here possess an amine side chain that is expected to be fully protonated at the experimental pH, and we expect that the ammonium groups spend most of their time at locations where they remain well hydrated --i.e., outside the hydrophobic binding cavities of the CDs --because of the high free energy cost of stripping water from charged groups. Thus, the ammonium groups could, in principle, form stabilizing interactions with the hydroxyl groups of the CDs, since these are at the wellhydrated portals of the host molecules . However, if ammonium-hydroxyl interactions contributed much to binding, we would expect the drugs to bind H26DM-βCD with less affinity than native βCD, because 14 of the hydroxyls in H26DM-βCD have been converted to ethers in H26DM-βCD, and ether oxygen atoms are considerably worse hydrogen bond acceptors than hydroxyl oxygens( ), but we find instead that H26DM-βCD binds the drugs at least as well as βCD does. Thus, we doubt that ammonium-hydroxyl interactions contribute much to stability. That said, it remains possible that the 3-hydroxyls, which remain in H26DM-βCD, do form stabilizing interactions with the ammonium groups of the phenothiazine drugs.