The synthesis and binding properties of nano-scale hydrophobic pockets

Computational investigations into the conformational preferences of previously reported host are presented. Single point calculations, in conjunction with NMR evidence, indicate that the open conformation is considerably more stable than the closed form. The thermodynamic binding parameters for nano-scale host encapsulating a range of halogenated guests are reported. Association constants for guests as small as bromobenzene, to as large as 3[(1R)-endo]-(+)-bromocamphor, were determined in both deuterated chloroform and toluene-d8. The unavailability of large guests prevented determining the optimal guest to cavity volume ratio for this rigid host. In contrast however examining a range of small guests indicated that in the less competitive toluene, binding only occurred with guests that filled greater than 33% of the cavity. As anticipated all halogenated guests were noted to bind halogen atom down, indicating that the formation of C–H⋯X–R hydrogen bonds is a major contributor to complex stability. Three related hosts with more open cavities were synthesized to evaluate the effects of preorganization of the cavity walls on guest binding. Binding studies with the best guest for , 1-iodoadamantane, demonstrated that cavity wall integrity and rigidity is essential for strong binding. These results are set in context of how de Novo active-site syntheses may provide access to new catalysts with tailored properties and/or substrate selectivities. Important considerations relating to this task, and possible ways in which the field may develop in accomplishing this goal, are also briefly discussed.