Macrocycles of Higher Ortho-Phenylenes: Assembly and Folding

Abstract

<p>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 <i>ortho</i>-phenylenes (hexamer and decamer) with rod-shaped linkers. Characteristic <sup>1</sup>H 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 <i>o</i>-phenylene conformer within a shape-persistent macrocycle, affecting both assembly and ultimate folding behavior. For the <i>o</i>-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 <i>o</i>-phenylenes are forced into unusual folding states, preferentially adopting a backbone geometry with distinct helical blocks of opposite handedness. The results show that simple restrictions can be used to direct foldamers toward increasingly complex geometries.</p>

Folding-Controlled Assembly of Ortho-Phenylene-Based Macrocycles

“…To understand their fit within macrocycles, the relative energies ∆E of different folding states and their associated β can be computationally predicted for all possible conformers. The resulting plots are shown in Figure 2 for (unsubstituted) octa(o-phenylene) and (previously reported 28 ) deca(o-phenylene), which are of greatest relevance to this study.…”

“…23,24 It is less common to construct rings from multiple discrete foldamer subunits, but there are examples: Huc has demonstrated homochiral self-sorting of folded segments within macrocycles, 25 and structurally intricate, foldamer-based coordination complexes have been reported by Sawada and Fujita. 26,27 Recent work from our group [28][29][30] has focused on the self-assembly of foldamer monomers into macrocycles via dynamic covalent chemistry, 31,32 as shown in Figure 1a. In particular, we are interested in how folding affects self-assembly and vice versa: Confinement within a cyclic structure imposes conformational constraints on the foldamer subunits, affecting their geometries; at the same time, the (dynamic) geometric preferences of the foldamer ultimately dictate the size and shape of the product that is obtained.…”

“…The interplay between these effects leads to new emergent behavior, such as new folding patterns and complex dynamics. 22,28,29 Our chosen foldamer system is the o-phenylenes, a simple class of helical aromatic foldamers. [33][34][35] In solution, o-phenylenes fold into helical geometries (Figure 1b) driven by arene-arene stacking between every third repeat unit.…”

“…36,37 Previous work has shown that amino-terminated o-phenylene tetramers, hexamers, and decamers can be assembled with dialdehyde linkers to give [2+2] and [3+3] macrocycles (Figure 1a). 28,29,38 For a particular length of o-phenylene, the size of the product macrocycle and the folding state are related via the foldamer's bite angle β, the angle made by the terminal connection points (β = arccos( v 1 • v 2 ), Figure 1b). 28 That is, only certain bite angles fit within certain macrocycle sizes.…”

“…28,29,38 For a particular length of o-phenylene, the size of the product macrocycle and the folding state are related via the foldamer's bite angle β, the angle made by the terminal connection points (β = arccos( v 1 • v 2 ), Figure 1b). 28 That is, only certain bite angles fit within certain macrocycle sizes.…”