Cavitand Complexes in Aqueous Solution: Collaborative Experimental and Computational Studies of the Wetting, Assembly, and Function of Nanoscopic Bowls in Water

[Image: see text] Water is the dominant liquid on Earth. Despite this, the main focus of supramolecular chemistry research has been on binding and assembly events in organic solvents. This arose because it is more straightforward to synthesize organic-media-soluble hosts and because of the relative simplicity of organic solvents compared to water. Nature, however, relies on water as a solvent, and spurred by this fact, supramolecular chemists have recently been making forays into the aqueous domain to understand water-mediated non-covalent interactions. These studies can benefit from the substantial understanding of the hydrophobic effect and electrostatic interactions developed by physical chemists. Nearly 20 years ago, the Gibb group first synthesized a class of water-soluble host molecules, the deep-cavity cavitands, that possess non-polar pockets that readily bind non-polar moieties in aqueous solution and are capable of assembling into a wide range of complexes with distinct stoichiometries. As such, these amphipathic host species are ideal platforms for studying the role of negatively curved features on guest complexation and the structural requirements for guided assembly processes driven by the hydrophobic effect. Here we review the collaborative experimental and computational investigations between Gibb and Ashbaugh over the past 10 years exploring questions including the following: How does water wet/solvate the non-polar surfaces of non-polar pockets? How does this wetting control the binding of non-polar guests? How does wetting affect the binding of anionic species? How does the nature and size of a guest size impact the assembly of cavitand hosts into multimeric capsular complexes? What are the conformational motifs of guests packed within the confines of capsular complexes? How might the electrostatic environment engendered by hosts impact the properties and reactivity of internalized guests?