Cycloalkane and Alicyclic Heterocycle Complexation by New Switchable Resorcin[4] arene-Based Container Molecules: NMR and ITC Binding Studies

The synthesis and structural characterization of novel, molecular basket-type bridged cavitands is reported. The resorcin[4] arene-based container molecules feature well-defined cavities that bind a wide variety of cycloalkanes and alicyclic heterocycles. Association constants (K-a) of the 1: 1 inclusion complexes were determined by both H-1 NMR and isothermal titration calorimetry (ITC). The obtained Ka values in mesitylene ranged from 1.7 x 10(2)m(-1) for cycloheptane up to 1.7 x 10(7) m(-1) for morpholine. Host-guest complexation by the molecular baskets is generally driven by dispersion interactions, C similar to H center dot center dot center dot pi interactions of the guests with the aromatic walls of the cavity, and optimal cavity filling. Correlations between NMR-based structural data and binding affinities support that the complexed heterocyclic guests undergo additional polar C-O center dot center dot center dot C=O, N-H center dot center dot pi, and S center dot center dot center dot pi interac-tions. The first crystal structure of a cavitand-based molecular basket is reported, providing precise information on the geometry and volume of the inner cavity in the solid state. Molecular dynamic (MD) simulations provided information on the size and conformational preorganization of the cavity in the presence of encapsulated guests. The strongest binding of heterocyclic guests, engaging in polar interactions with the host, was observed at a cavity filling volume of 63 +/- 9%.