Molecular Recognition of Hydrophilic Molecules in Water by Combining the Hydrophobic Effect with Hydrogen Bonding

During the last half a century, great
achievements have been made
in molecular recognition in parallel with the invention of numerous
synthetic receptors. However, the selective recognition of hydrophilic
molecules in water remains a generally accepted challenge in supramolecular
chemistry but is commonplace in nature. In an earlier Communication
[Huang et al. J. Am. Chem.
Soc. 2016, 138, 14550], we reported a pair of endo-functionalized
molecular tubes that surprisingly prefer highly hydrophilic molecules
over hydrophobic molecules of a similar size and shape. The hydrophobic
effect and hydrogen bonding were proposed to be responsible, but their
exact roles were not fully elucidated. In this Article, we present
a thorough study on the binding behavior of these molecular tubes
toward 44 hydrophilic molecules in water. Principal component analysis
reveals that the binding strength is weakly correlated to the hydrophobicity,
volume, surface area, and dipole moment of guests. Furthermore, molecular
dynamics simulations show the hydrophobic effect through releasing
the poorly hydrogen-bonded cavity water contributes to the binding
of all the hydrophilic molecules, while hydrogen bonding differentiates
these molecules and is thus the key to achieve a high selectivity
toward certain hydrophilic molecules over other molecules with a similar
size and shape. Therefore, a good guest for these molecular tubes
should meet the following criteria: the hydrogen-bonding sites should
be complementary, and the molecular volume should be large enough
to expel all the cavity water but not too large to cause steric hindrance.
This rule of thumb may also be used to design a selective receptor
for certain hydrophilic molecules. Following these guidelines, a “best-fit”
guest was found for the syn-configured molecular
tube with a binding constant as high as 106 M–1.