Self-Assembled Multi-Component Catenanes: The Effect of Multivalency and Cooperativity on Structure and Stability

Abstract

Using dynamic combinatorial chemistry, mixtures of dipeptide monomers were combined to probe how the structural elements of a family of self-assembled [2]-catenanes affect their equilibrium stability versus competing non-catenated structures. Of particular interest were experiments to target the effects of CH-π interactions, inter-ring hydrogen bonds, and β-turn types on [2]-catenane energetics. The non-variant core of the [2]-catenane was shown only to adopt type II' and type VIII turns at the β-2 and β-4 positions, respectively. Monomers were designed to delineate how these factors contribute to [2]-catenane equilibrium speciation/stability. Dipeptide turn adaptation studies, including three-component dynamic self-assembly experiments, suggested that stability losses are localized to the mutated sites, and that the turn types for the core β-2 and β-4 positions, type II' and type VIII, respectively, cannot be modified. Mutagenesis studies on the core Aib residue involved in a seemingly key CH-π-CH sandwich reported on how CH-π interactions and inter-ring hydrogen bonds affect stability. The interacting methyl group of Aib could be replaced with a range of alkyl and aryl substituents with monotonic affects on stability, though polar heteroatoms were disproportionately destabilizing. The importance of a key cross-ring H-bond was also probed by examining an Aib for l-Pro variant. Inductive affects and the effect of CH donor multiplicity on the core proline-π interaction also demonstrated that electronegative substituents and the number of CH donors can enhance the effectiveness of a CH-π interaction. These data were interpreted using a cooperative binding model wherein multiple non-covalent interactions create a web of interdependent interactions. In some cases, changes to a component of the web lead to compensating effects in the linked interactions, while in others, the perturbations create a cascade of destabilizing interactions that lead to disproportionate losses in stability.