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Macrocycles of higher ortho-phenylenes: assembly and folding.

ABSTRACT: Higher-order structure in abiotic foldamer systems represents an important but largely unrealized goal. As one approach to this challenge, covalent assembly can be used to assemble macrocycles with foldamer subunits in well-defined spatial relationships. Such systems have previously been shown to exhibit self-sorting, new folding motifs, and dynamic stereoisomerism, yet there remain important questions about the interplay between folding and macrocyclization and the effect of structural confinement on folding behavior. Here, we explore the dynamic covalent assembly of extended ortho-phenylenes (hexamer and decamer) with rod-shaped linkers. Characteristic 1H chemical shift differences between cyclic and acyclic systems can be compared with computational conformer libraries to determine the folding states of the macrocycles. We show that the bite angle provides a measure of the fit of an o-phenylene conformer within a shape-persistent macrocycle, affecting both assembly and ultimate folding behavior. For the o-phenylene hexamer, the bite angle and conformer stability work synergistically to direct assembly toward triangular [3 + 3] macrocycles of well-folded oligomers. For the decamer, the energetic accessibility of conformers with small bite angles allows [2 + 2] macrocycles to be formed as the predominant species. In these systems, the o-phenylenes are forced into unusual folding states, preferentially adopting a backbone geometry with distinct helical blocks of opposite handedness. The results show that simple geometric restrictions can be used to direct foldamers toward increasingly complex folds.

SUBMITTER: Kinney ZJ

PROVIDER: S-EPMC6857672 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Macrocycles of higher <i>ortho</i>-phenylenes: assembly and folding.

Kinney Zacharias J ZJ Kirinda Viraj C VC Hartley C Scott CS

Chemical science 20190809 39

Higher-order structure in abiotic foldamer systems represents an important but largely unrealized goal. As one approach to this challenge, covalent assembly can be used to assemble macrocycles with foldamer subunits in well-defined spatial relationships. Such systems have previously been shown to exhibit self-sorting, new folding motifs, and dynamic stereoisomerism, yet there remain important questions about the interplay between folding and macrocyclization and the effect of structural confinem ...[more]

PMID: 31762983

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Project description:The self-assembly of foldamers into macrocycles is a simple approach to non-biological higher-order structure. Previous work on the co-assembly of ortho-phenylene foldamers with rod-shaped linkers has shown that folding and self-assembly affect each other; that is, the combination leads to new emergent behavior, such as access to otherwise unfavorable folding states. To this point this relationship has been passive. Here, we demonstrate control of self-assembly by manipulating the foldamers' conformational energy surfaces. A series of o-phenylene decamers and octamers have been assembled into macrocycles using imine condensation. Product distributions were analyzed by gel-permeation chromatography and molecular geometries extracted from a combination of NMR spectroscopy and computational chemistry. The assembly of o-phenylene decamers functionalized with alkoxy groups or hydrogens gives both [2 + 2] and [3 + 3] macrocycles. The mixture results from a subtle balance of entropic and enthalpic effects in these systems: the smaller [2 + 2] macrocycles are entropically favored but require the oligomer to misfold, whereas a perfectly folded decamer fits well within the larger [3 + 3] macrocycle that is entropically disfavored. Changing the substituents to fluoro groups, however, shifts assembly quantitatively to the [3 + 3] macrocycle products, even though the structural changes are well-removed from the functional groups directly participating in bond formation. The electron-withdrawing groups favor folding in these systems by strengthening arene-arene stacking interactions, increasing the enthalpic penalty to misfolding. The architectural changes are substantial even though the chemical perturbation is small: analogous o-phenylene octamers do not fit within macrocycles when perfectly folded, and quantitatively misfold to give small macrocycles regardless of substitution. Taken together, these results represent both a high level of structural control in structurally complex foldamer systems and the demonstration of large-amplitude structural changes as a consequence of a small structural effects.

Dataset Information

Macrocycles of higher ortho-phenylenes: assembly and folding.

Publications

Macrocycles of higher <i>ortho</i>-phenylenes: assembly and folding.

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