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.

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Photofoldamers are sequence-defined receptors capable of switching guest binding on and off. When two foldamer strands wrap around the guest into 2:1 double helical complexes, cooperativity emerges, and with it comes the possibility to switch cooperativity with light and other stimuli. We use lessons from nonswitchable sequence isomers of aryl-triazole foldamers to guide how to vary the sequence location of azobenzenes from the end (F END ) to the interior (F IN ) and report their impact on the cooperative formation of 2:1 complexes with Cl − . This sequence change produces a 125-fold increase from anti-cooperative (α = 0.008) for F END to non-cooperative with F IN (α = 1.0). Density functional theory (DFT) studies show greater H-bonding and a more relaxed double helix for F IN . The solvent and guest complement the synthetic designs. Use of acetonitrile to enhance solvophobicity further enhances cooperativity in F IN (α = 126) but lowers the difference in cooperativity between sequences. Surprisingly, the impact of the sequence on cooperativity is inverted when the guest size is increased from Cl − (3.4 Å) to BF 4 − (4.1 Å). While photoconversion of interior azobenzenes was poor, the cis−cis isomer forms 1:1 complexes around chloride consistent with switching cooperativity. The effect of the guest, solvent, and light on the double-helix cooperativity depends on the sequence.