Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Linker-Directed Assembly of Twisted ortho-Phenylene-Based Macrocycles Zacharias J. Kinney and C. Scott Hartley* Department of Chemistry & Biochemistry, Miami University, Oxford, Ohio 45056, United States S Supporting Information *
ABSTRACT: o-Phenylene tetramers have been coassembled with linkers into macrocycles through imine condensation. Variation of linker connectivity and length allows both [1 + 1] and [2 + 2] macrocycles to be obtained, complementing (previously reported) [3 + 3] macrocycles. For the [1 + 1] macrocycles, linker length has a clear effect on o-phenylene geometry and macrocycle stability. For the [2 + 2] macrocycles, both homo- and heterochiral configurations are observed, suggesting limited communication of helix handedness in these systems.
M
In general, the folding state of an o-phenylene is defined by the torsional angles φ about the internal biaryl bonds. These angles can assume four values, φ ≈ ± 55° or φ ≈ ± 125°, that, when combined in sequence, correspond to compact and extended helices, respectively.12 The folding of o-phenylenes is dominated by the φ ≈ ± 55° states, giving geometries analogous to helicenes. o-Phenylene tetramers, as used here, represent the shortest oligomers that can fold. This is shown in the inset in Scheme 1 for model compound M, which was synthesized as a comparison for the macrocycles (see Supporting Information (SI)). Tetramer M should exist as a dynamic mixture of the compact and extended conformers in rapid exchange on the NMR time scale. By analogy with the longer oligomers, we consider the compact φ ≈ ± 55° state to be “folded”. In the context of macrocycles (and other closed architectures), the folding state of the o-phenylene subunits dictates the angle presented by the imines, and thus, there should be a close relationship between folding and overall size. The four dialdehyde linkers, o1,30 o2,31 m1,32 and m2,33 were synthesized according to literature procedures. The acetylene and butadiyne spacers provide torsional flexibility and allow the effect of linker length to be explored. We began by examining the assembly of the ortho-substituted linkers o1 and o2 with oP using our previously optimized conditions22 of 0.1 equiv of trifluoroacetic acid (TFA) at a concentration of 1.5 mM in chloroform at room temperature in the presence of 3 Å molecular sieves. Imine condensations progressed quickly, with complete conversion within 1 h for both systems, as determined by monitoring the reactions by 1H NMR
any oligomers that adopt well-defined secondary structures, or foldamers,1−4 are now known, including many based on aromatic backbones.5−9 The inspiration for much of this work is the hierarchical structure of biomacromolecules; however, the combination of multiple folded subunits within larger architectures remains relatively unexplored. Developing strategies for the synthesis of higherorder structures has therefore become an important goal.3 ortho-Phenylenes represent one of the simplest examples of aromatic foldamers, adopting compact helical conformations stabilized by arene−arene interactions parallel to the helical axis.10−12 The solution-state folding behavior of o-phenylenes has now been thoroughly investigated, demonstrating that enhancement of folding can be achieved via internal (e.g., substitution)13,14 and external (e.g., solvent)15,16 effects. Recently, dynamic covalent chemistry,17−19 long used for the self-assembly of closed species,20 has been used for the assembly of foldamers into macrocycles.21,22 We reported a series of [3 + 3] macrocycles assembled via imine condensation of amino-functionalized o-phenylene tetramer oP with various rod-shaped linkers, as shown in Scheme 1 (top).22 These twisted architectures23−26 exhibit homochiral (PPP/MMM) and heterochiral (PPM/MMP) conformers that are easily distinguishable by NMR spectroscopy. The modular nature of this system suggests that small structural changes could be used to control the assembled macrocycle size and geometry, yielding complex twisted conjugated structures.27 Indeed, the use of linker geometry to control the shape of covalent self-assembled cages has been recently demonstrated by Beuerle28 and has its roots in seminal work on the assembly of inorganic systems.29 Here, we show that by adjusting linker structure a variety of macrocycles of different sizes and shapes can be obtained from oP, as shown in Scheme 1. © XXXX American Chemical Society
Received: April 18, 2018
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DOI: 10.1021/acs.orglett.8b01237 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. Assembly of o-Phenylene-Containing Macrocyclesa
The new macrocycles are labeled as “Tol” or “DPB” to represent the presence of tolane or diphenylbutadiyne linkers, with subscripts “1” or “2” to represent the macrocycle size ([1 + 1] or [2 + 2], respectively). The model of the previously reported [3 + 3] macrocycle is optimized at the PM7 level, with hexyloxy groups truncated to methoxy for clarity. Lower-right inset: Acyclic model compound M, with closed and open geometries optimized at the B97-D/TZV(2d,2p) level (hexyloxy groups truncated to methoxy).
a
spectroscopy. Imine exchange was quenched after 1 h through the addition of NEt3.22 Analysis of the crude mixtures by gel permeation chromatography (GPC) and MALDI MS indicated that [1 + 1] macrocycles Tol1 and DPB1 were the predominant products. They could be isolated in 73% and 81% yields, respectively, after purification by GPC. Interestingly, when assembly was carried out over longer periods, Tol1 was found to remain as a stable product, whereas DPB1 decomposed into insoluble material after reaching its maximum yield in 1 h, with complete decomposition after 24 h (see SI). That is, whereas Tol1 is the thermodynamic product of its system, DPB1 is only kinetically stable. Despite many attempts, we were unfortunately unable to grow crystals of Tol1 or DPB1 suitable for X-ray diffraction.34 However, one of the very useful properties of o-phenylenes is that their NMR spectra are especially sensitive to their geometries and can be reliably predicted by DFT methods.12 The 1H NMR spectra of M, Tol1, and DPB1 are shown in Figure 1. As the only chemical differences between these compounds are located in the linkers, changes in the five signals corresponding to protons in the o-phenylene moiety should be related to changes in geometry. There are significant differences in chemical shifts between M and Tol1 (highlighted in Figure 1), which are similar to those previously observed for the [3 + 3] macrocycles.22 As noted above, acyclic M should not be particularly well-folded; thus, its spectrum corresponds to a mixture of both open and closed conformers in rapid exchange. The differences with respect to Tol1 are associated with an o-phenylene that is locked in its more compact (φ ≈ 55°) conformation in the ring. This is most easily seen for H(2c) (see Scheme 1 for labels), which moves in and out of the shielding zone of the other
Figure 1. 1H NMR spectra of M and macrocycles Tol1 and DPB1 (CDCl3, 500 MHz). The lines show changes in chemical shifts for analogous protons; the insets show the signals corresponding to the diastereotopic hexyloxy −OCH2R protons.
terminal aromatic ring; however, we note that the changes in the complete set of o-phenylene signals are consistent with increased folding (see SI). Further, the signals for the diastereotopic −CH2O− protons, which show a slight decrease in anisochronicity in Tol1, are indicative of the folded conformation (insets in Figure 1).35 There is also signal broadening in both the 1H and 13C NMR spectra of Tol1, B
DOI: 10.1021/acs.orglett.8b01237 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
possibly indicating greater strain in the products.40 The assembly of Tol2 was screened in different solvents (toluened8, acetone-d6, and DMSO-d6), with the best results obtained in toluene (1:14 aldehyde/imine at equilibrium). Using these revised conditions, macrocycles Tol2 and DPB2 were isolated in 55% and 30% yields, respectively, after purification by semipreparative GPC. The comparatively low yield of DPB2 was due to postassembly decomposition, possibly because of polymerization of the butadiyne moieties (which are expected to be held very close together, as shown below).41 1 H NMR spectra of macrocycles Tol2 and DPB2 are shown in Figure 3. Similar to Tol1, the changes in chemical shifts for
suggesting that rotation of ring 2 is slower in the macrocycle than in the acyclic model.14 Conversely, the chemical shifts for the o-phenylene protons in DPB1 show further changes that are not so easily rationalized on the basis of differences in folding state. To compare the two macrocycles, the geometries of both Tol1 and DPB1 were optimized at the B97-D/TZV(2d,2p) level,36 which is known to provide accurate geometries for o-phenylenes.12 As shown in Figure 2, single stable conformers were identified for the
Figure 2. Optimized geometries (B97-D/TZV(2d,2p)) of Tol1 and DPB1, with overlays of the optimized o-phenylene moiety geometries with that of M.
macrocycles. In both cases, the o-phenylene moieties are wellfolded, with the imine protons directed inward. This orientation places them in the deshielding zones of the opposite imine and the nearby ethynylene groups, consistent with the significant deshielding of their signals in the NMR spectra (∼1 ppm for Tol1, Figure 1). DFT predictions of the NMR properties at the PCM(CHCl3)/WP04/6-31G(d) level37,38 are in excellent agreement with the experimental spectra, suggesting that both computational geometries are realistic (see SI). The π systems of the shortest paths around macrocycles Tol1 and DPB1 comprise 22 and 24 electrons, respectively. We initially considered whether this difference could explain the differences in the NMR spectra (i.e., because of (anti)aromaticity).39 However, the DFT calculations show that, despite full formal conjugation around the rings, the frontier molecular orbitals are localized on either the o-phenylene or linker moieties; thus, effects because of ring currents seem unlikely (see SI). Inspection of the geometries indicated significant differences between the two macrocycles. In Figure 2, the o-phenylene moieties for both macrocycles are compared with the geometry of model M optimized at the same level. For Tol1, the structures are nearly identical (RMSD of 0.05 Å), indicating that the o1 linker is almost perfectly matched with the preferred structure of the folded o-phenylene. Conversely, DPB1 is clearly strained: the butadiynylene unit is noticeably bent and the o-phenylene is pulled well out of alignment with M (RMSD of 0.21 Å). That is, the longer linker distorts the ophenylene from its ideal folded geometry, explaining the perturbations of the chemical shifts and why DPB1 is only kinetically stable. We then turned to macrocyclization with linkers m1 and m2. When the reactions were carried out in chloroform-d, equilibrium was reached within 2 days. Analysis of the crude mixtures by MALDI MS and GPC indicated the formation of [2 + 2] macrocycles Tol2 and DPB2, respectively, as the major products. However, in contrast to the assembly of Tol1 and DPB1, 1H NMR monitoring showed that both reactions could not be driven to high conversion, with 15−20% unreacted aldehyde, despite the use of excess amine and molecular sieves,
Figure 3. 1H NMR spectra of M, Tol2, and DPB2 (CDCl3, 500 MHz).
the protons of the o-phenylene moieties indicate that they are exclusively folded in the macrocycles. However, it is clear that the spectra of both macrocycles are inconsistent with a single, high-symmetry geometry (or rapidly exchanging conformers). In both cases, two imine signals are clearly distinguishable, and doubling of other signals is also apparent. While the behavior of the two macrocycles is similar, the distinct NMR signals are better distinguished for Tol2. Deconvolution of the imine signals (see SI) shows that the two peak areas do not have integer ratios (79:100), suggesting that they correspond to two different species, as opposed to one structure of low symmetry. The simplest explanation is that the o-phenylene moieties are configurationally locked, giving rise to both homochiral and heterochiral configurations that are of D2 and C2h symmetry, respectively, on the NMR time scale (see Scheme 1). This behavior would parallel that of the previously reported [3 + 3] macrocycles for which the assignment of the two configurations was unambiguous.22 Despite their rigidity, there are several rotatable bonds in Tol2 (and DPB2), making identification of the global energy minima challenging. In the NOESY spectrum of Tol2, cross peaks are observed between the imine protons and exclusively linker protons 1b (Figure 3). With this in mind, reasonable geometries for both configurations were obtained at the B97D/TZV(2d,2p) level, shown in Figure 4. The macrocycles are predicted to have oblong shapes with crisscrossed linkers connecting the twisted corners. Both geometries conform to the symmetries observed by NMR spectroscopy: the C
DOI: 10.1021/acs.orglett.8b01237 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters ORCID
Zacharias J. Kinney: 0000-0003-4221-2557 C. Scott Hartley: 0000-0002-5997-6169 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the National Science Foundation (CHE-1608213) for support of this work.
Figure 4. Optimized geometries (B97-D/TZV(2d,2p)) of Tol2 for both homochiral (top) and heterochiral (bottom) configurations.
homochiral geometry is of D2 symmetry, and the heterochiral configuration would be expected to undergo rapid conformational exchange that would give it effective C2h symmetry. They are predicted to be very similar in stability (ΔE = 0.6 kcal/mol in favor of homochiral), consistent with their coexistence on assembly. Comparable geometries were also obtained for DPB2. Thus, the assembly of o-phenylene tetramers and different linkers can be controlled through simple modifications to linker structure, giving an array of shape-persistent macrocycles of various sizes and twisted geometries. While similar structurally well-defined macrocycles are uncommon, the [1 + 1] macrocycles reported here are similar to Cuerva’s “stapled” ophenylene ethynylenes42 and Jeong’s indolocarbazole imine macrocycles,43 and the [2 + 2] macrocycles are reminiscent of Yashima’s spiroborate double helices.44 For Tol1 and DPB1, the relationship between the folded structure and the linker length is apparent by NMR spectroscopy: macrocycle DPB1 is strained, with the o-phenylene distorted from its preferred folded geometry, and is consequently only a kinetic product of assembly. For Tol2 and DPB2, there is little conformational communication4 between the o-phenylenes as both homo- and heterochiral configurations are observed. This behavior is similar to that of the related [3 + 3] macrocycles,22 but very different from that observed by Huc in his foldamer-based macrocycles, which exhibited high degrees of handedness communication,21 or Moore’s BINOL macrocycles with homochiral self-sorting.45 Efforts to control relative configurations in these systems are underway.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01237. Figures and discussion referred to in the text, experimental procedures, NMR spectra, and computational data (PDF) Computational geometries (TXT)
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DOI: 10.1021/acs.orglett.8b01237 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.8b01237 Org. Lett. XXXX, XXX, XXX−XXX
