Complexation of an anionic meta-cyclophane with histamine and analogous bioactive amines in aqueous media

Molecular recognition of an anionic meta-cyclophane towards bioactive amines and related compounds has been studied by ¹H NMR titration: the meta-cyclophane, which is functionalised by pendant CH₂CO₂^- arms, is 2,9,18,25-tetraoxo-4,7,20,23-tetrakis(carboxymethyl)-1,4,7,10,17,20,23,26-octaaza[10.10]metacyclophane; the bioactive guests studied are histamine, tryptamine, tyramine, phenethylamine, imidazole, histidine, phenylalanine and 4-aminobenzoic acid. Complex formation of a para-cyclophane isomer has also been studied for comparison. The meta-cyclophane forms a complex with histamine with a formation constant of 63M^-1, while the complexes with the other amines have a smaller constant in the range of 1-24M^-1; the compounds other than the amines have no interaction with the host. The major binding force for the complex formation is electrostatic interaction between the CH₂CO₂^- arm of the hosts and the CH₂CH₂NH₃⁺ arm of the guests. The aromatic group of a guest amine molecule is encapsulated into the cavity of a host molecule, and the deepness of the encapsulation is increased with the hydrophobicity in the order histamine < tyramine ~ phenethylamine < tryptamine. In addition to hydrophobic interaction, the meta-cyclophane is supposed to have a dipolar interaction with a guest molecule. The combined effect of the three types of interactions stabilises the histamine complex of the meta-cyclophane.