Dynamic Refolding of Ion-Pair Catalysts in Response to Different Anions

Four distinct folding patterns are identified in two foldamer-type urea-thiourea catalysts bearing a basic dimethylamino unit by a combination of X-ray crystallography, solution NMR studies, and computational studies (DFT). These patterns are characterized by different intramolecular hydrogen bonding schemes that arise largely from different thiourea conformers. The free base forms of the catalysts are characterized by folds where the intramolecular hydrogen bonds between the urea and the thiourea units remain intact. In contrast, the catalytically relevant salt forms of the catalyst, where the catalyst forms an ion pair with the substrate or substrate analogues, appear in two entirely different folding patterns. With larger anions that mimic the dialkyl malonate substrates, the catalysts maintain their native fold both in the solid state and in solution, but with smaller halide anions (fluoride, chloride, and bromide), the catalysts fold around the halide anion (anion receptor fold), and the intramolecular hydrogen bonds are disrupted. Titration of catalyst hexafluoroacetylacetonate salt with tetra-n-butylammonium chloride results in dynamic refolding of the catalyst from the native fold to the anion receptor fold.