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Twisted Macrocycles with Folded ortho-Phenylene Subunits Zacharias J. Kinney, and C. Scott Hartley J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 17 Mar 2017 Downloaded from http://pubs.acs.org on March 17, 2017
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Journal of the American Chemical Society
Twisted Macrocycles with Folded ortho-Phenylene Subunits Zacharias J. Kinney and C. Scott Hartley* Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio 45056, United States ABSTRACT: Many foldamers, oligomers that adopt well-defined secondary structures, are now known, including many exhibiting functional behavior. However, examples of foldamer subunits within larger architectures remain rare, despite the importance of higher-order structure in biomacromolecules. Here, we investigate the dynamic covalent assembly of short o-phenylenes, a simple class of aromatic foldamers, into twisted macrocycles. o-Phenylene tetramers have been combined with rod-shaped p-phenylene-, tolane-, and diphenylbutadiyene-based linkers using imine formation. Macrocyclization proceeds efficiently, inducing folding of the o-phenylenes. The resulting [3+3] macrocycles (three o-phenylenes and three linkers) are shape-persistent, triangular structures with twisted cores and internal diameters up to approximately 2 nm. The homochiral D3-symmetric and heterochiral C2-symmetric conformers can be distinguished by NMR spectroscopy. Analysis of the conformational distribution for the p-phenylene-linked macrocycle suggests that the o-phenylene units are largely decoupled, with the less-symmetrical configuration therefore entropically favored. Conformational dynamics were assessed by variable-temperature NMR spectroscopy. Confinement within the macrocyclic architecture slows the inversion of the o-phenylene moieties.
INTRODUCTION Decades of research on foldamers has provided many examples of structural motifs that fold into well-defined secondary structures (e.g., helices).1–5 This control of local conformational behavior has led to a host of functional systems, exhibiting, for example, molecular recognition;6–9 controlled reactivity or catalysis;10,11 self-assembly;12,13 interesting electronic properties;14–17 and biological activity.18–20 There are, however, few examples of higher-order species that incorporate locally folded subunits within larger architectures, particularly for the non-peptidic foldamer classes.21–24 This is a significant limitation given the parallel between foldamers and biomacromolecules: in biology, functionality rarely arises from secondary structures by themselves.22 Thus, understanding abiotic folding within the context of larger chemical structures and systems should enable new approaches to structural complexity, and ultimately new applications. A simple strategy to orient multiple helices in space would be to tether them together in rings so as to restrict their overall conformational freedom. Both folding and the self-assembly of macrocycles are strategies for the generation of structural complexity efficiently; in principle, they could work synergistically to yield increasingly sophisticated architectures. This idea raises questions in two areas: the interplay between folding and synthetic macrocyclization strategies, and the interaction between subunits once linked together (“conformational communication”5). However, while cyclic cross-linking has been used to stabilize single helices,25,26 and some macrocycles are globally folded,27,28 macrocycles incorporating multiple foldamer moieties are rare. An important recent example comes from Huc, who has shown that pairs of aromatic amide foldamers can exhibit homochiral self-sorting when cyclized.29 We are interested in the conformational behavior of orthophenylene oligomers, a fundamental class of linear polyphenylenes and a recent addition to the foldamer family. o-
Phenylenes fold into compact helices in solution because of offset-stacked arene–arene interactions parallel to their helical axes;16,30 there is therefore an interesting conceptual parallel between the folding of o-phenylenes and the folding of peptides into α-helices, even though the two systems are quite different in practice. The o-phenylene structure has been proposed for chiroptical applications,16 can be used to control liquid crystal alignment,31 and is found in a number of related systems.32–36 Here, we show that short o-phenylenes are readily incorporated into macrocycles when combined with rodshaped linkers. By targeting relatively rigid (shape-persistent) macrocycles, the overall structural analysis of the system is simplified; shape-persistence could also ultimately facilitate the integration of foldamer motifs into functional materials.37,38 The thermodynamic driving force for macrocyclization is found to induce better folding of the o-phenylene subunits. The resulting architectures are twisted rings that exist as stereoisomeric conformers in slow exchange. Inversion rates of the folded units within the macrocycles have also been studied.
RESULTS AND DISCUSSION Macrocycle Assembly. The macrocycles were assembled using dynamic covalent chemistry,37 as shown in Scheme 1. We chose diamine 1 as the o-phenylene unit, since tetramers are the shortest that can fold (i.e., the helix has three repeat units per turn). Three different dialdehyde linkers were used, featuring p-phenylene (2), tolane (3), and diphenylbutadiyne (4) structures. These simple, rod-shaped linkers were chosen so as to limit the main elements of conformational freedom of the macrocycles to the o-phenylene moieties. However, the two longer linkers 3 and 4 should be somewhat flexible, both in terms of the bendability of the alkynes and especially because the two arenes (and thus aldehydes/imines) can rotate nearly independently (especially for diphenylbutadiyne39). Assuming that the o-phenylene moieties adopt their folded conformations, we anticipated the formation of [3+3] macro-
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cycles Phen3, Tol3, and DPB3 as the major products (i.e., three equivalents each of 1 and the linkers).40,41 Scheme 1. Assembly of [3+3] macrocycles Phen3, Tol3, and DPB3.
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isolate and fully characterize a small amount (7%) of the larger [4+4] macrocycle Phen4.
OHex NH
O O 2: Terephthalaldehyde 3 4
H N HexO 1
TFA, CHCl3, 3 Å MS HexO
OHex
N N
N
N N
HexO
N
HexO
OHex
OHex
Phen3 (45%): Tol3 (51%): DPB3 (47%):
Assembly was carried out by mixing one of the linkers 2–4 (1 eq), 1 (1.1 eq), and TFA (0.1 eq) in chloroform. The progress of the reactions was easily monitored by 1H NMR spectroscopy, or the reaction mixtures could be quenched with NEt3 for analysis by GPC (discussed further below). We began with the synthesis of p-phenylene-based macrocycles using 2 (i.e., targeting Phen3). A brief concentration-dependence study (see Supporting Information) showed that at concentrations of 2 ≥25 mM some products precipitate out of solution as the reaction progresses. GPC analysis of the remaining soluble products indicated a mixture of oligomers. At 10 mM, no precipitate was observed and the GPC chromatogram showed a major product, but with significant amounts of higher molecular weight species. Lowering the concentration further to 1.5 mM, 1H NMR, GPC, and MALDI MS analyses of the reaction mixture indicated assembly into one predominant product, as shown in Figure 1 (top) and in the Supporting Information (the reaction was complete after ~4 d, as determined by NMR monitoring): The MALDI spectrum of the crude product was dominated by a set of peaks corresponding to the [3+3] macrocycle Phen3, with the [4+4] macrocycle Phen4 as the only other observable species. The GPC trace indicated a single major product with only a small shoulder at shorter retention time. The 1H NMR spectrum showed only signals that were later assigned to the (easily distinguished) macrocycles Phen3 and Phen4. The major product could be isolated in 45% yield by semi-preparative GPC and was confirmed to be Phen3 by NMR analysis and mass spectrometry.42 It was also possible to
Figure 1. MALDI mass spectra (left) and GPC traces (right) of crude reaction mixtures for the assembly of macrocycles Phen3 (from 2), Tol3 (from 3), and DPB3 (from 4). Starting concentrations were 1.5 mM in linker.
Taken together, these experiments suggest that the assembly of the [3+3] macrocycle Phen3 is very efficient, although further mechanistic study will be required to conclusively establish that it is the equilibrium product. Very similar results were obtained when the longer linkers 3 and 4 were used, with analysis of the crude mixtures indicating effective assembly of the [3+3] macrocycles, as shown in Figure 1. Compounds Tol3 and DPB3 were isolated in 51% and 47% yields, respectively. When the diphenylbutadiyne linker 4 was used, we could not detect any evidence of the higher molecular weight [4+4] macrocycle by either GPC or NMR spectroscopy (although a small peak is detectable in the MALDI spectrum). Presumably, the added flexibility of this linker relieves some strain that destabilizes the macrocycles with the p-phenylene and tolane linkers. Di Stefano has shown that imines can undergo exchange in the presence of catalytic amounts of primary amines, even in the absence of acid catalysts.43,44 A concern then is whether neutralizing the TFA catalyst with NEt3 actually quenches imine reactivity before analysis or isolation. Two key pieces of evidence indicate that in this system assembly is stopped. First, GPC analysis after quenching was always consistent with corresponding (unquenched) 1H NMR monitoring experiments. Second, we explicitly tested the system using the isolated Phen4 (see Supporting Information). If allowed to exchange, this macrocycle should convert to the favored [3+3] macrocycle Phen3 (see above). To simulate the quenched reaction mixtures, purified Phen4 was treated with 0.1 eq of 1 and triethylamine, then concentrated. Only unreacted Phen4 was observed by 1H NMR (the two macrocycles are easily distinguished); thus, no significant disassembly occurs. Only when stoichiometric amounts of amine were used did we begin to see evidence for decomposition at extended reaction times. Presumably, amine-catalyzed exchange does not occur on the timescale of our experiments because we are operating at concentrations orders of magnitude lower than those used in Di Stefano’s studies.
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Structural Analysis. Simple o-phenylene tetramers should not be particularly well-folded in isolation.31,45 The folding state is defined by the torsional angle of the central biaryl bond,30 with possible conformations shown in Figure 2(a). By analogy with longer o-phenylenes, the compact folded state is the “A” conformer (there is also an analogous, enantiomeric conformer “A′”), which is stabilized by a single arene–arene interaction. No such interaction is possible for the extended misfolded “B” state (or its enantiomer “B′”), but its strength (
