Dynamic Combinatorial Synthesis of a Catenane Based on Donor–Acceptor

Dynamic combinatorial synthesis of a catenane based SPECIAL FEATURE on donor–acceptor interactions in water

Ho Yu Au-Yeung, G. Dan Pantos¸, and Jeremy K. M. Sanders1

University Chemical Laboratory, University of Cambridge, Lensﬁeld Road, Cambridge CB2 1EW, United Kingdom

Edited by Julius Rebek, Jr., The Scripps Research Institute, La Jolla, CA and accepted December 11, 2008 (received for review October 6, 2008)

A new type of neutral donor–acceptor [2]-catenane, containing Because interactions between the ␲-deficient NDI and ␲-rich both complementary units in the same ring was synthesized from DN have been successful in our previous syntheses of neutral a dynamic combinatorial library in water. The yield of the water D–A [2]-catenanes, it was expected that similar interlocked soluble [2]-catenane is enhanced by increasing either building- structures can be constructed if the electronically complemen- block concentrations or ionic strength, or by the addition of an tary aromatic subunits are incorporated into disulfide DCLs. electron-rich template. NMR spectroscopy demonstrates that the This would allow the formation of macrocycles from both template is intercalated between the 2 electron-deﬁcient naph- components through reversible disulfide exchanges (Scheme 1) thalenediimide units of the catenane. (27). Here, we present the confirmation of our initial premise in the form of a new type of D–A [2]-catenane, obtained from an dynamic combinatorial chemistry ͉ molecular recognition aqueous disulfide DCL containing initially only acyclic components. In this catenane, both donor and acceptor subunits are e report here the spontaneous assembly of a donor– present in the same ring. We also prove that exerting stimuli on Wacceptor (D–A) [2]-catenane from a dynamic combina- the equilibrating system, such as changing solvent ionic strength torial library (DCL) in water. Unusually, this is a D–A catenane and template addition, can influence the yield of the [2]-cat- that contains the electron-deficient and electron-rich aromatic enane, and we demonstrate intercalation of the electron-rich moieties in the same ring. Owing to their complex topology and template between the electron-deficient NDI units of the cat- the resulting synthetic challenge, mechanically interlocked mol- enane. CHEMISTRY ecules such as catenanes have captivated chemists for a long time (1). With advances in the efficient templated synthesis of these Results and Discussion interlocked structures, applications of these interesting mole- Dithiol-building block 1, derived from a ␲-accepting NDI, was cules have been found in molecular electronic devices, such as prepared as previously described (26). The cysteine-functional- switches, motors, color displays, and molecular memory (2–5). ized, ␲-donating counterpart 2 was synthesized in 4 straightfor- Conventional catenane synthesis relies on the use of nonco- ward steps from 1,5-dihydroxynaphthalene (see SI). Incorpora- valent interactions to preorganize precursors in a suitable con- tion of the amino acid function in the building blocks provides figuration that favors the formation of an interlocked structure, both water solubility and a thiol group as a handle for reversible employing an irreversible, kinetically controlled chemical reac- reactions. tion as the final catenating step (for recent examples, see 6–9). A DCL was set up by air oxidation of a 5 mM equimolar The recent rise of dynamic covalent chemistry (10) using re- solution of 1 and 2 in water at pH 8. The library was equilibrated versible chemical reactions under thermodynamic control has in a close-capped vial for 5 days and analyzed by reverse-phase led to an increasing number of catenane syntheses that are either HPLC and LC-MS. At equilibrium, the species containing only designed to lead to a particular structure (for recent examples, one kind of building block are the cyclic monomer 3 from the see 9, 11–19) or result from unpredictable dynamic combinato- donor subunit 2 and the cyclic homodimer 4 from the acceptor rial selection (20, 21). The advantage of either of these dynamic subunit 1. Several macrocycles that incorporate both the donor strategies is the possibility of recycling un-interlocked compo- and acceptor subunits are also present, including the het- nents, hence increasing the yield of the desired structure. erodimer 5, the heterotrimer 6, and heterotetramers 7, 8, and 9 Interactions between electron-rich aromatics, such as di- (Fig. 1). alkoxynaphthalene (DN) and tetrathiafulvalene (TTF), and Macrocycle 7 contains 1 DN and 3 NDI subunits whereas the electron deficient aromatics, like naphthalenediimide (NDI) and 2 heterotetramers 9 and 8 (retention time Ϸ5 and 27 min, paraquat, have been extensively used in the preparation of respectively) have the same composition, containing 2 of each of catenanes (9, 22, 23). The vast majority of these catenane the donor and acceptor building blocks. Tetramers with other constructions rely on kinetically controlled reactions. Some building-block compositions were not observed. To help distin- examples of thermodynamically controlled syntheses of these guish tetramers 8 and 9 and elucidate their cyclic structures, they structures include the neutral [2]-catenanes featuring zinc- were further analyzed by MS/MS (28–30). Molecular ions of pyridine coordination (24) and alkene metathesis as the ring- these 2 tetramers have different fragmentation behavior: tet- closing reactions (25). More recently, Stoddart and coworkers ramer 8 shows fragments from trimeric species (m/z ϭ 1,039.8) reported the iodide-catalyzed self-assembly of paraquat-based and dimeric species (m/z ϭ 930.7, 566.9); whereas tetramer 9 has cationic D–A [2]- (16) and [3]-catenanes (14) from separate ␲-donor and ␲-acceptor rings using thermodynamically controlled nucleophilic substitution. Most of the examples of D–A Author contributions: H.Y.A.-Y., G.D.P., and J.K.M.S. designed research; H.Y.A.-Y. and catenane syntheses depend on a preformed, ␲-rich crown ether G.D.P. performed research; H.Y.A.-Y., G.D.P., and J.K.M.S. analyzed data; and H.Y.A.-Y., ring containing electron-donor units, and the subsequent for- G.D.P., and J.K.M.S. wrote the paper. mation of new electron-deficient rings followed by catenation. The authors declare no conﬂict of interest. Hence, the resulting catenanes contain only a ␲-donor or This article is a PNAS Direct Submission. ␲-acceptor in each of the individual rings. 1To whom correspondence should be addressed. E-mail: [email protected]. Recently, we reported an aqueous disulfide DCL derived from This article contains supporting information online at www.pnas.org/cgi/content/full/ the ␲-accepting NDI that uses an electronically complementary 0809934106/DCSupplemental. DN template to amplify a tetramer up to an 80% yield (26). © 2009 by The National Academy of Sciences of the USA

www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809934106 PNAS Early Edition ͉ 1of5 Downloaded by guest on September 27, 2021 Scheme 1. Generation of donor-acceptor disulﬁde DCL with ␲-acceptor 1 and ␲-donor 2 in water.

fragments from dimeric species only (Fig. 2). Fragments larger observed for the DN core protons when compared with the than the dimer were also observed for tetramer 7 (m/z ϭ 1,038.6, spectrum of 9 in CD3OD. These observations suggest that the 1,358.7, 1,510.5). Unlike in the case of 7, there were no ho- catenane adopts an even more compact conformation in the more modimeric fragments observed in the MS/MS of 8 and 9. polar solvent. Similar behavior was also observed in the 1H spec- Because the direct fragmentation of a tetramer to dimer is trum of 5 (D2O, 300 K, 500 MHz): upfield shifts of 0.11 ppm and characteristic of an interlocked structure, these observations 0.14–0.39 ppm were observed for the NDI and DN aromatic suggest that the heterotetramer 9 is a [2]-catenane consisting of protons, respectively, indicating the same kind of closer proximity 2 interlocked heterodimeric donor-acceptor rings [–1–2–], while between the donor and acceptor units in D2O versus CD3OD. In heterotetramer 8 is a cyclic tetramer with the cyclic structure both solvents, the spectra are easily assignable: the NDI doublets of [–1–2–1–2–]. 9 suggest the presence of a well-defined symmetrical conformation, The [2]-catenane 9 was isolated from a preparative scale DCL narrowing down the possible conformations for 9 to only I and III and characterized by 1H NMR and UV–Vis spectroscopies. The (Fig. 3). The larger upfield shift of the NDI protons in 9 when 1 H spectrum of the [2]-catenane 9 in CD3OD (300 K, 500 MHz) compared with 5, and the UV–Vis and templating data (see below), consists of broad but assignable signals (see SI). In contrast, the allow us to propose the D2 symmetric I as the major conformer of 1H spectrum of the heterodimer 5 obtained under the same 9 in aqueous solution. This is consistent with the expectation of it conditions shows sharp and well-defined peaks. Two coupled being the most thermodynamically stable conformation, because doublets were observed for the NDI unit of 9, but only one the number of favorable interactions between the donor and singlet for the corresponding protons of 5. Upfield shifts of acceptor is maximized while the repulsive interactions between 0.53–0.73 and 0.22–0.50 ppm were, respectively, observed for the electron-rich aromatic cores are minimized (31). NDI and DN aromatic protons of 9 compared with those of 5. The UV–Vis spectrum of 9 is dominated by broad absorption These observations suggest that the aromatic cores in 9 are in bands at 367 and 383 nm (Fig. 4), corresponding to the NDI Ͻ closer proximity than in 5, as one would expect from the chromophores, and an even broader band 350 nm, likely due interlocked nature of the former compound. to a combination of the 2 chromophores. Red shifts of 6–8 nm 1 and broadening were observed for the NDI absorption maxima, The H spectrum recorded in D2Oof9 (300 K, 500 MHz) consists of sharp peaks with clear splitting patterns observed for supporting a conformation of type I, with the NDI chro- the aromatic signals. Upfield shifts of 0.61–0.77 ppm were mophores in close proximity to each other. The spectrum of uncatenated 5 is strikingly different, displaying only absorbances characteristic for the individual chromophores.

Imposing Stimuli on the DCL. The adaptive ability to respond to external changes due to reversible chemical linkages between building blocks is the main feature of a DCL (27). Addition of a template to a DCL is perhaps the most common way to perturb product distribution of a DCL. Considering that the current building blocks are a ␲-donor and ␲-acceptor, the addition of another ␲-donating or ␲-accepting molecule as template to the DCL may stabilize some of the library members and induce a change in the library distribution. Because the library members in the DCL are anionic due to the carboxylic functionalities, the use of a cationic guest should induce stronger responses than a neutral or anionic one. Therefore, the ␲-rich guest 10, and the ␲-deficient guest 11 were tested as templates for the DCL (Fig. 5). Addition of the electron-rich template 10 to the DCL amplifies the [2]-catenane 9 at the expense of all other Fig. 1. HPLC analysis of a 5 mM DCL of 1 and 2. UV traces were recorded at macrocycles. The amplification factor is approximately 1.5 292 nm (upper trace) and 380 nm (lower trace) where the DN and NDI cores when the library is conducted in water at pH 8 with 5 mM respectively absorb. building block and 2.5 mM template concentration. However,

2of5 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809934106 Au-Yeung et al. Downloaded by guest on September 27, 2021 SPECIAL FEATURE

Fig. 2. Electrospray MS/MS spectra of the molecular ion of the tetrameric [2]-catenane 9 (A); the cyclic tetramer 8 (B); and the cyclic tetramer 7 (C). CHEMISTRY

addition of the electron-deficient template 11 under the same building-block concentrations of 2 mM, there is hardly any 9 condition leads to the disappearance of 9, and the redistribu- detected while the amount of this compound increases from 5 tion of the library material (Fig. 5). These results also support mM to 10 mM. Solubility limitations prevented the exploration the conclusion that conformation I is most probable in water of higher concentrations. for 9, because it has the right donor–acceptor–acceptor–donor Interactions between the hydrophobic surfaces of NDI and sequence for intercalating the electron rich 10, but not 11, DN should be stronger in a solvent of higher ionic strength, and more hydrophobic surface should be buried in the compact between the 2 NDI cores. [2]-catenane 9 than in the donor-acceptor dimer 5, providing Apart from introducing a template molecule, changing the another way to manipulate the DCL equilibrium position (32, concentration of the DCL solution can also alter the library 33). A new set of DCLs was prepared at 5 mM in the presence distribution. Toward this end, DCLs of equimolar mixtures of 1 of NaNO3 (Fig. 5). Indeed the salt has a significant impact on the and 2 at different total concentrations were prepared. As amount of 9 in the DCL, with the largest amplification of expected, at higher concentrations, higher oligomers are favored approximately 6-fold observed at 1 M NaNO3 (similar results over lower oligomers so the proportion of the monomeric 3 have been obtained using NaCl, KNO3,Na2SO4, and K2SO4, see decreases while that of the tetrameric 9 increases. At total SI). Amplification of 9 is largely at the expense of 5, which was reduced by approximately 4 times while the proportion of monomer 3 also decreases, by a factor of approximately 1.5.

Binding of 10 to the [2]-catenane 9. Upon titrating 10 (up to 3 equiv.) to a sample of 9, significant upfield shifts were ob-

Fig. 4. UV-Vis absorption proﬁle of the [2]-catenane 9 (orange) and the Fig. 3. Three possible conformers of 9. heterodimer 5 (blue) in D2O.

Au-Yeung et al. PNAS Early Edition ͉ 3of5 Downloaded by guest on September 27, 2021 Fig. 5. HPLC analysis ofa5mMDCLmixture in the absence of template (A); the presence of 2.5 mM 10 (B); 2.5 mM 11 (C); 0.01 M NaNO3 (D); 0.1 M NaNO3 (E); and 1 M NaNO3 (F). UV traces shown were recorded at 292 nm.

served for all of the aromatic protons of the catenane: 0.60 and 0.62 ppm shifts were found for the 2 NDI signals, while 0.47, 0.83, and Ͼ0.63 ppm shifts were observed for the DN protons (Fig. 6). Downfield shifts of approximately 0.3 ppm of the aromatic proton signals from the guest were also observed with increasing number of equivalents of 10 as the proportion of the bound guest decreases; this again is consistent with intercalation of the guest between aromatic rings of the host. An association constant of 7,700 Ϯ 1,300 M–1 was estimated by 1 monitoring the NDI resonances. Less precise association Fig. 6. Partial H NMR spectra (D2O, 300 K, 500 MHz) of the [2]-catenane 9 in the presence of 0 (A); 0.2 (B); 0.4 (C); 0.6 (D); 0.8 (E); 1.0 (F); 2.0 (G); and 3.0 constants, but with the same order of magnitude, can be equiv. of 10 (H). Signals from NDI and DN core of 9 and the DN core of 10 are calculated by monitoring the DN signals of 9. The estimated highlighted with red, green, and blue, respectively. binding strength between 9 and 10 is consistent with the modest amplification observed for 9 at5mM. On the binding of 10 to the host 9, the protons of one of the Conclusions methylene groups become diastereotopic (Fig. 7), indicative of In summary, we have identified an unusual donor-acceptor the chiral environment (34). Evidence of the geometrical [2]-catenane from an aqueous DCL. The use of only acyclic relationship between 9 and 10 comes from nOe experiments components allows the first construction of a [2]-catenane that carried out on a sample of 10 and 9 in 3:1 molar ratio. contains both donor and acceptor units in the same ring. The Irradiation of the NDI protons shows close contacts with both yield of the [2]-catenane depends on the library conditions: the DN protons on the catenane and of the guest (Fig. 8). In contrast, irradiation of the DN protons of either 9 or 10 shows cross magnetization due to nOe only with the NDI protons of 9. These findings not only confirm the binding of 10 to 9, but also confirm the presence of conformation I in the complexed catenane as the aromatic plane of 10 is only in close proximity with the NDI moieties of 9 (molecular modeling at semiem- pirical levels supports this model, see SI). In contrast, no nOe was observed between protons of the complementary aromatic units in uncomplexed 9, suggesting the presence of a larger cavity due to the flexible linkages of the compound. Addition of 11 to an aqueous sample of 9 induces shifts in aromatic signals of both the guest and the catenane, but no nOe was observed between the aromatic protons of 9 and 11, indicating Fig. 7. Resonance of one of the methylene groups of the side chain of 10 a different binding mode to that of 10 to the catenane. when complexed by (A) 1.25 and (B) 0.33 equiv. of 9.

4of5 ͉ www.pnas.org͞cgi͞doi͞10.1073͞pnas.0809934106 Au-Yeung et al. Downloaded by guest on September 27, 2021 intercalated between 2 electron-deficient moieties of the [2]- catenane, creating a supramolecular assembly featuring 5 alter- SPECIAL FEATURE nating ␲-donor and ␲-acceptor units. By appropriate modification of the cationic template, it is expected that supramolecular assemblies with more complex topology could be efficiently constructed using this dynamic combinatorial approach. Materials and Methods Chemicals were purchased from commercial suppliers and used as received. Water and MeOH for LC-MS were purchased from Romil or Rathburn. HPLC/LC-MS was performed on HP 1050 or Agilent 1100 LC/MSD trap XCT systems coupled to a diode array detector and the data processed using ChemStation software. Mass spectra (negative mode) were acquired in ultra scan mode using drying temperature of 325 °C, nebulizer pressure of 55 psi, drying gas flow of 10 L/min, capillary voltage of 4,000 V, an ICC target of 200,000 ions, and target mass of 1,000. Analytical separations were achieved by injecting 5 ␮L (for 5 mM DCL, scaled accordingly for DCL at different concentrations) of DCL solution onto a Symmetry C8 reverse phase column (150 ϫ 4.6 cm, 3 ␮m particle size) with an isocratic elution of 58% MeOH in water (with 0.1% formic acid) at room temperature and a flow rate of 1 mL/min. Preparative separation was performed on a Symme- tryPrep C18 column (300 ϫ 7.8 mm, 7 ␮m particle size). Elution was performed using the same solvent system at 30 °C at a flow rate of 3 mL/min. UV–Vis spectra were recorded using Cary 400 UV Spectrometer at room temperature. 1H and 13C NMR spectra were recorded on Bruker DPX-400 or Advance 500 TCI Cryo Spectrometers and internally referenced to solvent residue. Fig. 8. 1D NOE spectra (D2O, 300 K, 500 MHz, mixing time ϭ 1.2 s) of A typical analytical DCL was prepared on a 1-ml scale by dissolving an complexed 9 in the presence of 3 equiv. of 10 (top 3) and the reference

equimolar mixture of 1 and 2 in 10 mM aqueous NaOH, followed by titration CHEMISTRY spectrum (bottom). Irradiation (marked with an arrow) of DN signal of 9 (A); with 100 mM aqueous NaOH to pH 8, to the desired concentration. Where DN signal of 10 (B); and NDI signal of 9 (C). Signals from NDI and DN core of 9 appropriate, alkali metal salts, guests 10 or 11, were added in solid form. The and the NDI core of 10 are shaded with red, green, and blue in the reference DCL was stirred in a close-capped vial at room temperature until being spectrum, respectively. analyzed. Preparative DCL was prepared in the same manner on a 10-ml scale. For further experimental details, see SI.

changing the concentration or ionic strength, the addition of an ACKNOWLEDGMENTS. We thank the Croucher Foundation, Pembroke College, external template increases the yield of the interlocked com- and the Engineering and Physical Sciences Research Council for ﬁnancial support, pound. It is also found that a cationic, electron-rich molecule is and Dr. Ana Belenguer for maintaining the chromatography laboratory.

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