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This paper describes a comprehensive NMR analysis of the inclusion complexation of neutral 2,6-disubstituted naphthalene and para-disubstituted benzene derivatives by cyclophanes. The major attractive host-guest interactions in these complexes are --stacking and edge-to-face aromatic-aromatic interactions. Individual studies investigate relative binding strength as a function of (i) the electronic properties of the guests, (ii) the nature of the solvent, and (iii) the nature of the cyclophane hosts. For these investigations, two new tetraoxa[n. 1 . . 1 jcyclophanes with eight methoxy groups ortho to the aryl ether linkages were synthesized. A comparison between different cyclophanes shows that functional groups attached to the aromatic rings increase binding strength if they deepen the cavity without perturbing the apolar character of the binding site.Electron donor-acceptor (EDA) interactions control the relative stability of cyclophane-arene inclusion complexes in CD3OD and (CD3)2SO. Generally, electron-deficient guests form the most stable complexes with the electron-rich cyclophanes. Deviations from the EDA model in these solvents are best explained by unfavorable complexation-induced changes in the solvation of the guest functional groups. In water, such solvation effects may dominate, thus masking contributions of EDA interactions to the relative complexation strength. Electronic host-guest complementarity determines the relative association strength in water only if guest functionalities retain their favorable solvation in the complexes formed. In binary aqueous solvent mixtures, overall complexation strength increases with the amount of water added and follows a linear free energy relationship with the empirical solvent polarity parameter £T(30).

Calix[4]-, [6]-, and [8]-arenes have been converted into a series of alkyl acetates which show significant phase-transfer activity and selectivity towards alkali metal picrates; the X-ray crystal structures of t w o members of the series, (lb) and (2d), have been determined.

The synthesis and biochemical evaluation of a series of indole oxadiazole 5-HT3 antagonists are described. The key pharmacophoric elements have been defined as a basic nitrogen, a linking group capable of H-bonding interactions, and an aromatic moiety. The steric limitations of the aromatic binding site have been determined by substitution about the indole ring. Variation of the heterocyclic linking group has shown that while two hydrogen-bonding interactions are possible, only one is essential for high affinity. The environment of the basic nitrogen has been investigated and shown to be optimal when constrained within an azabicyclic system. These results have been incorporated into a proposed binding model for the 5-HT3 antagonist binding site, in which the optimum distance between the aromatic binding site and the basic amine is 8.4-8.9 A and the steric limitations are defined by van der Waals difference mapping.

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