Design of a Neutral Macrocyclic Ionophore: Synthesis and Binding Properties for Nitrate and Bromide Anions

Abstract

A macrocyclic neutral ionophore 8 (X = O) capable of binding weakly coordinating anions such as nitrate and bromide in DMSO solution has been designed by a stepwise, deductive approach. The optimum geometrical arrangement of the hydrogen bond donor sites in the target ionophore was determined by DFT calculations. From these data, a suitable macrocyclic molecular framework was constructed. The 24-membered macrocyclic ionophore was synthesized by standard macrocyclization methods. NMR titrations revealed molecular complexes with defined 1:1 stoichiometries in DMSO for 8 (X = O) with nitrate, hydrogensulfate, acetate, cyanide, iodide, and bromide ions, while dihydrogenphosphate, sulfate, and chloride ions yielded aggregates of higher stoichiometry. The nitrate binding constants of 8 (X = O) are substantial for a neutral ionophore with defined binding sites in pure DMSO solution. Bromide ions, which have a similar ion radius, are bound with an even higher affinity. Chloride is obviously too small, and iodine too large, to form 1:1 complexes. The binding motif of 8 (X = O) was compared with related molecules of similar structure, such as 8 (X = S) and 19. As predicted from calculations, the small structural variations give rise to a complete loss of nitrate and bromide ion binding ability in DMSO. This sensitivity to geometrical changes and the affinity of 8 (X = O) to nitrate and bromide ions, which are poor hydrogen bond acceptors, confirm the predicted complementarity of ionophore binding site and anion geometry. According to DFT and MD calculations the higher affinity of 8 (X = O) to bromide than to nitrate is mainly due to the greater flexibility of the bromide complex and thus to its higher entropy. (© Wiley-VCH Verlag GmbH, 69451 Weinheim, Germany, 2002)