Amide cyclodextrin that recognises monophosphate anions in harmony with water molecules

Abstract

Anion recognition in water by synthetic host molecules is a popular and challenging topic. It has been considered difficult because the water molecules compete for the recognition units. In this study, we have successfully created a novel macrocycle that achieves precise recognition through multipoint hydrogen bonding in harmony with water molecules. Specifically, an N-methylpyridinium amide β-cyclodextrin (β-CD) derivative 1(OTf)₇ was synthesized, whose amide groups are directly attached to each pyranose ring. The pyridinium amide CD encapsulated a monophosphate anion in water, but it did not show interactions with sulfonates or carboxylates, thus a remarkable selectivity was demonstrated. Two monophosphates with different substituents, phenyl phosphate (PhOPO₃²⁻) and adamantyl phosphate (AdOPO₃²⁻), exhibited interesting contrasting pictures in the inclusion process, which were revealed by a combination of NOESY experiments, ITC measurements, and MD simulations. PhOPO₃²⁻ was positioned slightly “upper” (closer to the pyridinium amide side) in 1⁷⁺ with the oxygen atom of the phosphate ester R–O–P involved in the hydrogen bonds with the amide N–H, and configurational entropy plays a key role in the inclusion. Meanwhile, AdOPO₃²⁻ was positioned “lower” (closer to the methoxy rim of CD) with the terminal –PO₃²⁻ forming hydrogen bonds with the amides, and the hydrophobic effect is a major contributing driving force of the inclusion. The molecular design presented herein to achieve the precise recognition in water and clarification of the detailed mechanisms including the hydration phenomenon greatly contribute to the development of functional molecules that work in aqueous environments.