Revealing the Hidden Costs of Organization in Host–Guest Chemistry Using Chloride-Binding Foldamers and Their Solvent Dependence

Preorganization is a key concept in supramolecular chemistry. Preorganized receptors enhance binding by minimizing the organization costs associated with adopting the conformation needed to orient the binding sites toward the guest. Conversely, poorly organized receptors show affinities below what is possible based on the potential of their specific binding interactions. Despite the fact that the organization energy is paid each time like a tax, its value has never been measured directly, though many compounds have been developed to measure its effects. We present a method to quantify the hidden costs of receptor organization by independently measuring the contribution it makes to chloride complexation by a flexible foldameric receptor. This method uses folding energy to approximate organization energy and relies on measurement of the coil-helix equilibrium as a function of solvent. We also rely on the finding, established with rigid receptors, that affinity is inversely related to the solvent dielectric and expect the same for the foldamer's helically organized state. Increasing solvent polarity across nine dichloromethane-acetonitrile mixtures we see an unusual V-shape in affinity (decrease then increase). Quantitatively, this shape arises from weakened hydrogen-bonding interactions with solvent polarity followed by solvent-driven folding into an organized helix. We confirm that dielectric screening impacts the stability of host-guest complexes of flexible foldamers just like rigid receptors. These results experimentally verify the canonical model of binding (affinity depends on the sum of organization and noncovalent interactions). The picture of how solvent impacts complex stability and conformational organization thereby helps lay the groundwork for de novo receptor design.