Designing Macrocycles to Adopt Persistent, Isoenergetic Conformations

Targeting molecules that exist as an ensemble of preorganized conformations represents a compromise between the pursuit of flexible molecules of undefined structure and rigid molecules biased toward a single conformation. Here, condensation of two self-reactive monomers quantitatively produces macrocyclic dimers that adopt persistent and structurally well-defined conformers observable using 1H NMR spectroscopy under ambient conditions. Conformers result from hindered bonds with rotational barriers of ∼18 kcal/mol. At elevated temperatures (∼75 °C), the barrier is overcome and a single species is observed by 1H NMR spectroscopy. When a single monomer is used, three conformers are obtained. When two monomers are used, ten conformers are obtained. Because these conformers exist as enantiomeric pairs, a chiral environment doubles the number of conformers accessed. Computation (CREST) identifies persistent conformations and corroborates the observation that these conformations are of similar energy.