The properties of inclusion complexes of 1,4-di-R-bicyclo[2.2.2]octanes (R = H (1), Me (2), Cl (3), Br (4), OH (5), Me,OH (6)) with cyclodextrins (Cdx) have been studied by various NMR-techniques, microcalorimetry and molecular mechanics and dynamics computations. Compounds 2, 3 and, possibly, 4 (but not the other compounds) gave dynamically stable 1 ∶ 2 guest–host complexes with α-Cdx, but did not show any indication of a 1 ∶ 1 complex. Microcalorimetry of 5 in water indicates a moderately
strong 1 ∶ 1 complex with β-Cdx but at best very weak complexes with α- or γ-Cdx. The unsymmetrically substituted compound 6 behaved similarly to 5. The behavior depends on the subtle interplay of size, polarity, hydrophobicity, type of solvent and temperature. The origin of the unusually high barrier for formation of the 1 ∶ 2 complex is proposed to be unsynchronized entropy and enthalpy development, originating in the requirement for strong preorganization in the formation of the complex. A slow exchange between dissolved and dispersed 2 was observed and characterized in the solution in the same temperature range.