A Semiflexible 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 the ring
size, the overall preorganization due to structural rigidity is key.
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 has been investigated. Computational studies
and nuclear magnetic resonance (NMR) data showed different degrees
of preorganization as a result of differences in flexibility. The
interaction of the three macrocycles with chloride, dihydrogen phosphate,
and dihydrogen pyrophosphate was investigated in solution by NMR and
ultraviolet–visible 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.