Trinity University Digital Commons @ Trinity Chemistry Faculty Research Chemistry Department 9-16-2011 Cucurbit[8]uril Rotaxanes Vijayakumar Ramalingam Trinity University, [email protected] Adam R. Urbach Trinity University, [email protected] Follow this and additional works at: https://digitalcommons.trinity.edu/chem_faculty Part of the Chemistry Commons Repository Citation Ramalingam, V. & Urbach, A. R. (2011). Cucurbit[8]uril rotaxanes. Organic Letters, 13(18), 4898-4901. doi:10.1021/ol201991e This Post-Print is brought to you for free and open access by the Chemistry Department at Digital Commons @ Trinity. It has been accepted for inclusion in Chemistry Faculty Research by an authorized administrator of Digital Commons @ Trinity. For more information, please contact [email protected]. Cucurbit[8]uril Rotaxanes Vijayakumar Ramalingam and Adam R. Urbach* Department of Chemistry, Trinity University, 1 Trinity Place, San Antonio, TX 78212 [email protected] Received Date (will be automatically inserted after manuscript is accepted) ABSTRACT The synthesis of [2]rotaxanes, each comprising a viologen core threaded through a cucurbit[8]uril (Q8, Figure 1) macrocycle and stoppered by tetraphenylmethane groups, and their binding to second guests as inclusion complexes in organic and aqueous media is described. Stoppering was observed to have little effect on binding. Chemical modification of the threaded guest was used to control solubility and binding characteristics, thus demonstrating a novel approach to making artificial receptors with readily modifiable properties. The recent boom in the area of cucurbit[n]uril other macrocyclic compounds (e.g., (Qn) chemistry1 can be attributed to an cyclodextrins, porphyrins, and calixarenes), increasing awareness of the potential of this chemical modification of cucurbiturils is family of macrocycles as receptors for a myriad possible4 but problematic due to their stable and of small molecules with equilibrium association repetitive structures and their limited solubility. constant (Ka) values that span over twelve We have sought to develop methods for orders of magnitude.2 Most remarkably, this altering the properties of Qn receptors without supramolecular chemistry takes place in water, the need for chemically modifying the a medium of great interest for its biological macrocycle itself. This work focuses on Q8 relevance and of great frustration to organic (Figure 1) and takes advantage of its rare ability chemists seeking to mimic biology.3 Qn to bind two guests simultaneously. In their chemistry has already been applied broadly in seminal paper,5 Kim and coworkers showed that areas including catalysis, sensing, polymer Q8 binds to one molecule of methyl viologen chemistry, drug delivery, controlled release, (1), and the resulting Q8•1 complex binds biomolecular recognition, affinity purification, selectively to one molecule of 2,6- enzyme assays, waste remediation, dihydroxynaphthalene (2). Formation of the electrochemistry, photochemistry, and heteroternary complex results in aromatic guest molecular machines.1 stacking face-to-face in the cavity of Q8, the Despite their promise, however, the full formation of a new visible charge-transfer potential of cucurbiturils will not be realized absorbance, and the quenching of naphthalene until further progress is made in the area of fluorescence. Heteroternary Q8•X•Y complexes chemical synthesis. In particular, we need have since enabled the construction of straightforward methods for chemical supramolecular assemblies,6 multivalent derivatization so that useful properties such as receptors,7 supramolecular block copolymers,8 solubility, guest binding, and chemical and aromatic sensors.9 In each of these reactivity (e.g., conjugation, catalysis) can be examples, binding occurs sequentially (Figure modulated and, ideally, optimized. As with 1a), and the properties (solubility, optical, Scheme 1. Rotaxane Synthesis Figure 1. (a) sequential binding in ternary complexation versus (b) binary complexation by a rotaxane; (c) chemical formulas. activity, binding, material) of the first guest, X, The synthesis of rotaxane 10 (Scheme 1) influence the properties of the resulting Q8•X comprised three steps from known reagents. complex, which then acts as a receptor for the The linkers were attached to the core by second guest, Y. The remarkable characteristic coupling 4,4’-dipyridyl (5) with excess alkyl of this system is the reversible joining of X and halide 612 to produce the viologen 7 in 24% Y mediated by Q8. The chief limitation, recovery after column chromatography. however, is the ability of the Q8•X complex to Viologen 7 was mixed with equimolar Q8 in dissociate before binding Y, a problem water to form a water-soluble pseudorotaxane. exacerbated at low concentrations (esp. lower We wanted access to a wide range of stopper -1 than Ka ) and in the many potential applications groups and coupling chemistries, and thus we involving a solid support. Here we present an needed an organic soluble pseudorotaxane. approach that overcomes this limitation by Wang and Kaifer showed recently that Qn•guest mechanically linking Q8 to X as a rotaxane.10 complexes can be transferred efficiently to Numerous examples of Qn-based rotaxanes organic solvent by precipitation from water as exist,11 but this paper presents the first example the hexafluorophosphate salt followed by of a Q8 rotaxane. The chief advantage of a Q8 resuspension in polar aprotic solvents.13 rotaxane, versus those of smaller Qn Therefore, we treated the water-soluble homologues, is that a Q8 rotaxane should have pseudorotaxane with excess aqueous KPF6 and the capacity to bind a second guest while not obtained the hexafluorophosphate salt 8 as allowing dissociation of the first guest (Figure precipitate in 75% overall recovery from 7. 1b). The concept of a [2]rotaxane binding a Pseudorotaxane 8 was combined with an excess second guest as an inclusion complex was of stopper group 914 under Huigsen 1,3-dipolar demonstrated by Anderson and coworkers on a cycloaddition conditions in DMF solution to stilbene-threaded -cyclodextrin that binds a obtain crude rotaxane 10 in 45% yield. This cationic cyanine dye. Such a rotaxane molecule mixture also contains 10-15% excess Q8,15 could in principle be modified, via the threaded which was removed as the insoluble material by guest, to affect the binding of the second guest, repeated trituration with acetonitrile, giving thus obviating derivatization of the macrocycle. pure 10 in 25% overall recovery. It is worth Our design (10, 11, Scheme 1) uses a viologen noting that the 1H NMR signals of the glycol core to guide Q8 threading and to promote the linker peaks in 7 shift upfield upon forming selective binding of a second guest. Q8 is large, pseudorotaxane 8 and then return downfield and thus large stopper groups were needed; we upon stoppering (Figure 2), indicating the chose tetraphenylmethane for synthetic positioning of Q8 centrally over the viologen convenience and for its potential to be core in rotaxane 10.16 This result suggests a chemically modified. Oligo(ethylene glycol) steric influence of the stopper groups that forces linkers between the viologen and stopper groups the linker(s) out of the cavity. were installed to allow sufficient space for a Rotaxane 10 is insoluble in water, presumably second guest to access the Q8 cavity. due to the dominating hydrophobicity of the Figure 2. 1H NMR spectra of viologen 7 (bottom), Figure 3. 1H NMR spectral overlay of the titration of viologen pseudorotaxane 8 (middle), and rotaxane 10 (top) in DMSO-D6, 10 with second guest 2 in acetonitrile-D3, showing perturbation showing the influence of Q8 binding (7 to 8) and stoppering (8 of numerous viologen signals. to 10) on the inclusion of the threaded guest. sulfonic acid at room temperature followed by stopper groups. It was, however, soluble in heating in water to obtain the octasulfonated acetonitrile (up to ~0.4 mM) and DMSO (up to rotaxane 11 in 20% recovery after HPLC ~0.9 mM). We saw this as a rare opportunity to purification. Surprisingly, rotaxane 11 was study an unmodified cucurbituril binding in soluble in water up to a concentration of ~15 organic solution. Wang and Kaifer observed mM, 1000-fold higher than Q8 and 10-fold stable complexes of cucurbit[7]uril, but poor higher than the analogous Q8•1 complex. This solubility of the host in organic media precluded result demonstrates that a single chemical the measurement of equilibrium association reaction on the threaded guest was sufficient to constants.13 We titrated rotaxane 10 with the alter the solubility from aqueous insoluble to neutral second guest 2 in DMSO-D6 and highly aqueous soluble. acetonitrile-D3 solutions and looked for Substantial changes in the 1H NMR spectrum changes in the 1H NMR spectra. In DMSO-D6 of 11 in the presence of small amounts of we found no change in the spectrum of 10 upon second guest suggested that binding was much adding ten equivalents of 2.17 In acetonitrile-D3 stronger in aqueous solution than observed for solution, however, we observed a clear upfield rotaxane 10 in acetonitrile-D3. We wanted to perturbation in chemical shift of the inner quantify binding and, importantly, to determine viologen aromatic protons and downfield the influence of the linker and stopper groups. perturbation in chemical shift of several linker The binding of second guests 2, 3, and 4 to protons and the triazole proton of 10 upon Q8•1 is known to result in the quenching of addition of 2 (Figure 3). This observation naphthalene or indole fluorescence,5,9b and thus indicates simultaneous binding of 2 and the it should be possible to use fluorescence viologen core of the threaded axle inside the spectroscopy to monitor the binding of these cavity of Q8. We observed no perturbation of guests to rotaxane 11. Indeed, we observed chemical shift of the stopper signals, indicating quenching of fluorescence upon addition of little if any participation by these groups in the rotaxane 11 or Q8•1 in 5 mM sodium phosphate binding of 2.