Cucurbit[7]uril host–guest complexes of the histamineH2-receptor antagonist ranitidine

Abstract

The macrocyclic host cucurbit[7]uril forms very stable complexes with the diprotonated (K_CB[7]¹ = 1.8 × 10⁸ dm³ mol⁻¹), monoprotonated (K_CB[7]² = 1.0 × 10⁷ dm³ mol⁻¹), and neutral (K_CB[7]³ = 1.2 × 10³ dm³ mol⁻¹) forms of the histamine H₂-receptor antagonist ranitidine in aqueous solution. The complexation behaviour was investigated using ¹H NMR and UV–visible spectroscopy as a function of pH and the pK_a values of the guest were observed to increase (ΔpK_a1 = 1.5 and ΔpK_a2 = 1.6) upon host–guest complex formation. The energy-minimized structures of the host–guest complexes with the cationic guests were determined and provide agreement with the NMR results indicating the location of the CB[7] over the central portion of the guest. The inclusion of the monoprotonated form of ranitidine slows the normally rapid (E)–(Z) exchange process and generates a preference for the (Z) isomer. The formation of the CB[7] host–guest complex greatly increases the thermal stability of ranitidine in acidic aqueous solution at 50 °C, but has no effect on its photochemical reactivity.