A semi-flexible tetrahydrazone macrocycle for binding of pyrophosphate and smaller anions

Macrocyclization has proven to be a useful design strategy in the development of efficient anion receptors. In addition to ring size, the overall preorganization by structural rigidity is of key importance. To explore this in the context of developing an efficient pyrophosphate receptor, three macrocycles featuring a 26-membered interior ring size and similar H-bonding motifs have been synthesized and their anion binding ability investigated. Computational studies and NMR data showed different degrees of preorganization as a result of differences in flexibility. The interaction of the three macrocycles with chloride, dihydrogenphosphate, and dihydrogen pyrophosphate was investigated in solution by NMR and UV-Vis spectroscopy, and in the solid state by X-ray crystallography. The tetrahydrazone based macrocycle featuring intermediate flexibility exhibited the best affinity for all three anions investigated. Our results suggest that in addition to the proper preorganization of binding groups in a macrocycle a certain degree of flexibility is also required for an optimal affinity with the target guest.