Dynamic combinatorial synthesis of a catenane basedon donor–acceptor interactions in waterHo 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, containingboth complementary units in the same ring was synthesized froma dynamic combinatorial library in water. The yield of the watersoluble [2]-catenane is enhanced by increasing either building-block concentrations or ionic strength, or by the addition of anelectron-rich template. NMR spectroscopy demonstrates that thetemplate is intercalated between the 2 electron-deficient naph-thalenediimide units of the catenane.

dynamic combinatorial chemistry � molecular recognition

We report here the spontaneous assembly of a donor–acceptor (D–A) [2]-catenane from a dynamic combina-

torial library (DCL) in water. Unusually, this is a D–A catenanethat contains the electron-deficient and electron-rich aromaticmoieties in the same ring. Owing to their complex topology andthe resulting synthetic challenge, mechanically interlocked mol-ecules such as catenanes have captivated chemists for a long time(1). With advances in the efficient templated synthesis of theseinterlocked structures, applications of these interesting mole-cules have been found in molecular electronic devices, such asswitches, motors, color displays, and molecular memory (2–5).

Conventional catenane synthesis relies on the use of nonco-valent interactions to preorganize precursors in a suitable con-figuration that favors the formation of an interlocked structure,employing an irreversible, kinetically controlled chemical reac-tion as the final catenating step (for recent examples, see 6–9).The recent rise of dynamic covalent chemistry (10) using re-versible chemical reactions under thermodynamic control hasled to an increasing number of catenane syntheses that are eitherdesigned to lead to a particular structure (for recent examples,see 9, 11–19) or result from unpredictable dynamic combinato-rial selection (20, 21). The advantage of either of these dynamicstrategies is the possibility of recycling un-interlocked compo-nents, hence increasing the yield of the desired structure.

Interactions between electron-rich aromatics, such as di-alkoxynaphthalene (DN) and tetrathiafulvalene (TTF), andelectron deficient aromatics, like naphthalenediimide (NDI) andparaquat, have been extensively used in the preparation ofcatenanes (9, 22, 23). The vast majority of these catenaneconstructions rely on kinetically controlled reactions. Someexamples of thermodynamically controlled syntheses of thesestructures include the neutral [2]-catenanes featuring zinc-pyridine coordination (24) and alkene metathesis as the ring-closing reactions (25). More recently, Stoddart and coworkersreported the iodide-catalyzed self-assembly of paraquat-basedcationic D–A [2]- (16) and [3]-catenanes (14) from separate�-donor and �-acceptor rings using thermodynamically con-trolled nucleophilic substitution. Most of the examples of D–Acatenane syntheses depend on a preformed, �-rich crown etherring containing electron-donor units, and the subsequent for-mation of new electron-deficient rings followed by catenation.Hence, the resulting catenanes contain only a �-donor or�-acceptor in each of the individual rings.

Recently, we reported an aqueous disulfide DCL derived fromthe �-accepting NDI that uses an electronically complementaryDN template to amplify a tetramer up to an 80% yield (26).

Because interactions between the �-deficient NDI and �-richDN have been successful in our previous syntheses of neutralD–A [2]-catenanes, it was expected that similar interlockedstructures can be constructed if the electronically complemen-tary aromatic subunits are incorporated into disulfide DCLs.This would allow the formation of macrocycles from bothcomponents through reversible disulfide exchanges (Scheme 1)(27). Here, we present the confirmation of our initial premise inthe form of a new type of D–A [2]-catenane, obtained from anaqueous disulfide DCL containing initially only acyclic compo-nents. In this catenane, both donor and acceptor subunits arepresent in the same ring. We also prove that exerting stimuli onthe equilibrating system, such as changing solvent ionic strengthand template addition, can influence the yield of the [2]-cat-enane, and we demonstrate intercalation of the electron-richtemplate between the electron-deficient NDI units of the cat-enane.

Results and DiscussionDithiol-building block 1, derived from a �-accepting NDI, wasprepared as previously described (26). The cysteine-functional-ized, �-donating counterpart 2 was synthesized in 4 straightfor-ward steps from 1,5-dihydroxynaphthalene (see SI). Incorpora-tion of the amino acid function in the building blocks providesboth water solubility and a thiol group as a handle for reversiblereactions.

A DCL was set up by air oxidation of a 5 mM equimolarsolution of 1 and 2 in water at pH 8. The library was equilibratedin a close-capped vial for 5 days and analyzed by reverse-phaseHPLC and LC-MS. At equilibrium, the species containing onlyone kind of building block are the cyclic monomer 3 from thedonor subunit 2 and the cyclic homodimer 4 from the acceptorsubunit 1. Several macrocycles that incorporate both the donorand acceptor subunits are also present, including the het-erodimer 5, the heterotrimer 6, and heterotetramers 7, 8, and 9(Fig. 1).

Macrocycle 7 contains 1 DN and 3 NDI subunits whereas the2 heterotetramers 9 and 8 (retention time �5 and 27 min,respectively) have the same composition, containing 2 of each ofthe donor and acceptor building blocks. Tetramers with otherbuilding-block compositions were not observed. To help distin-guish tetramers 8 and 9 and elucidate their cyclic structures, theywere further analyzed by MS/MS (28–30). Molecular ions ofthese 2 tetramers have different fragmentation behavior: tet-ramer 8 shows fragments from trimeric species (m/z � 1,039.8)and dimeric species (m/z � 930.7, 566.9); whereas tetramer 9 has

Author contributions: H.Y.A.-Y., G.D.P., and J.K.M.S. designed research; H.Y.A.-Y. andG.D.P. performed research; H.Y.A.-Y., G.D.P., and J.K.M.S. analyzed data; and H.Y.A.-Y.,G.D.P., and J.K.M.S. wrote the paper.

The authors declare no conflict of interest.

This article is a PNAS Direct Submission.

1To whom correspondence should be addressed. E-mail: jkms@cam.ac.uk.

This article contains supporting information online at www.pnas.org/cgi/content/full/0809934106/DCSupplemental.

© 2009 by The National Academy of Sciences of the USA

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fragments from dimeric species only (Fig. 2). Fragments largerthan the dimer were also observed for tetramer 7 (m/z � 1,038.6,1,358.7, 1,510.5). Unlike in the case of 7, there were no ho-modimeric fragments observed in the MS/MS of 8 and 9.Because the direct fragmentation of a tetramer to dimer ischaracteristic of an interlocked structure, these observationssuggest that the heterotetramer 9 is a [2]-catenane consisting of2 interlocked heterodimeric donor-acceptor rings [–1–2–], whileheterotetramer 8 is a cyclic tetramer with the cyclic structure[–1–2–1–2–].

The [2]-catenane 9 was isolated from a preparative scale DCLand characterized by 1H NMR and UV–Vis spectroscopies. The1H spectrum of the [2]-catenane 9 in CD3OD (300 K, 500 MHz)consists of broad but assignable signals (see SI). In contrast, the1H spectrum of the heterodimer 5 obtained under the sameconditions shows sharp and well-defined peaks. Two coupleddoublets were observed for the NDI unit of 9, but only onesinglet for the corresponding protons of 5. Upfield shifts of0.53–0.73 and 0.22–0.50 ppm were, respectively, observed for theNDI and DN aromatic protons of 9 compared with those of 5.These observations suggest that the aromatic cores in 9 are incloser proximity than in 5, as one would expect from theinterlocked nature of the former compound.

The 1H spectrum recorded in D2O of 9 (300 K, 500 MHz)consists of sharp peaks with clear splitting patterns observed forthe aromatic signals. Upfield shifts of 0.61–0.77 ppm were

observed for the DN core protons when compared with thespectrum of 9 in CD3OD. These observations suggest that thecatenane adopts an even more compact conformation in the morepolar solvent. Similar behavior was also observed in the 1H spec-trum of 5 (D2O, 300 K, 500 MHz): upfield shifts of 0.11 ppm and0.14–0.39 ppm were observed for the NDI and DN aromaticprotons, respectively, indicating the same kind of closer proximitybetween the donor and acceptor units in D2O versus CD3OD. Inboth solvents, the spectra are easily assignable: the NDI doublets of9 suggest the presence of a well-defined symmetrical conformation,narrowing down the possible conformations for 9 to only I and III(Fig. 3). The larger upfield shift of the NDI protons in 9 whencompared with 5, and the UV–Vis and templating data (see below),allow us to propose the D2 symmetric I as the major conformer of9 in aqueous solution. This is consistent with the expectation of itbeing the most thermodynamically stable conformation, becausethe number of favorable interactions between the donor andacceptor is maximized while the repulsive interactions betweenelectron-rich aromatic cores are minimized (31).

The UV–Vis spectrum of 9 is dominated by broad absorptionbands at 367 and 383 nm (Fig. 4), corresponding to the NDIchromophores, and an even broader band �350 nm, likely dueto a combination of the 2 chromophores. Red shifts of 6–8 nmand broadening were observed for the NDI absorption maxima,supporting a conformation of type I, with the NDI chro-mophores in close proximity to each other. The spectrum ofuncatenated 5 is strikingly different, displaying only absorbancescharacteristic for the individual chromophores.

Imposing Stimuli on the DCL. The adaptive ability to respond toexternal changes due to reversible chemical linkages betweenbuilding blocks is the main feature of a DCL (27). Addition ofa template to a DCL is perhaps the most common way toperturb product distribution of a DCL. Considering that thecurrent building blocks are a �-donor and �-acceptor, theaddition of another �-donating or �-accepting molecule astemplate to the DCL may stabilize some of the librarymembers and induce a change in the library distribution.Because the library members in the DCL are anionic due to thecarboxylic functionalities, the use of a cationic guest shouldinduce stronger responses than a neutral or anionic one.Therefore, the �-rich guest 10, and the �-deficient guest 11were tested as templates for the DCL (Fig. 5).

Addition of the electron-rich template 10 to the DCLamplifies the [2]-catenane 9 at the expense of all othermacrocycles. The amplification factor is approximately 1.5when the library is conducted in water at pH 8 with 5 mMbuilding block and 2.5 mM template concentration. However,

Fig. 1. HPLC analysis of a 5 mM DCL of 1 and 2. UV traces were recorded at292 nm (upper trace) and 380 nm (lower trace) where the DN and NDI coresrespectively absorb.

Scheme 1. Generation of donor-acceptor disulfide DCL with �-acceptor 1 and �-donor 2 in water.

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addition of the electron-deficient template 11 under the samecondition leads to the disappearance of 9, and the redistribu-tion of the library material (Fig. 5). These results also supportthe conclusion that conformation I is most probable in waterfor 9, because it has the right donor–acceptor–acceptor–donorsequence for intercalating the electron rich 10, but not 11,between the 2 NDI cores.

Apart from introducing a template molecule, changing theconcentration of the DCL solution can also alter the librarydistribution. Toward this end, DCLs of equimolar mixtures of 1and 2 at different total concentrations were prepared. Asexpected, at higher concentrations, higher oligomers are favoredover lower oligomers so the proportion of the monomeric 3decreases while that of the tetrameric 9 increases. At total

building-block concentrations of 2 mM, there is hardly any 9detected while the amount of this compound increases from 5mM to 10 mM. Solubility limitations prevented the explorationof higher concentrations.

Interactions between the hydrophobic surfaces of NDI andDN should be stronger in a solvent of higher ionic strength, andmore hydrophobic surface should be buried in the compact[2]-catenane 9 than in the donor-acceptor dimer 5, providinganother way to manipulate the DCL equilibrium position (32,33). A new set of DCLs was prepared at 5 mM in the presenceof NaNO3 (Fig. 5). Indeed the salt has a significant impact on theamount of 9 in the DCL, with the largest amplification ofapproximately 6-fold observed at 1 M NaNO3 (similar resultshave been obtained using NaCl, KNO3, Na2SO4, and K2SO4, seeSI). Amplification of 9 is largely at the expense of 5, which wasreduced by approximately 4 times while the proportion ofmonomer 3 also decreases, by a factor of approximately 1.5.

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

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).

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

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served for all of the aromatic protons of the catenane: 0.60 and0.62 ppm shifts were found for the 2 NDI signals, while 0.47,0.83, and �0.63 ppm shifts were observed for the DN protons(Fig. 6). Downfield shifts of approximately 0.3 ppm of thearomatic proton signals from the guest were also observed withincreasing number of equivalents of 10 as the proportion of thebound guest decreases; this again is consistent with intercala-tion of the guest between aromatic rings of the host. Anassociation constant of 7,700 � 1,300 M–1 was estimated bymonitoring the NDI resonances. Less precise associationconstants, but with the same order of magnitude, can becalculated by monitoring the DN signals of 9. The estimatedbinding strength between 9 and 10 is consistent with themodest amplification observed for 9 at 5 mM.

On the binding of 10 to the host 9, the protons of one of themethylene groups become diastereotopic (Fig. 7), indicative ofthe chiral environment (34). Evidence of the geometricalrelationship between 9 and 10 comes from nOe experimentscarried out on a sample of 10 and 9 in 3:1 molar ratio.Irradiation of the NDI protons shows close contacts with boththe DN protons on the catenane and of the guest (Fig. 8). Incontrast, irradiation of the DN protons of either 9 or 10 showscross magnetization due to nOe only with the NDI protons of9. These findings not only confirm the binding of 10 to 9, butalso confirm the presence of conformation I in the complexedcatenane as the aromatic plane of 10 is only in close proximitywith the NDI moieties of 9 (molecular modeling at semiem-pirical levels supports this model, see SI). In contrast, no nOewas observed between protons of the complementary aromaticunits in uncomplexed 9, suggesting the presence of a largercavity due to the f lexible linkages of the compound. Additionof 11 to an aqueous sample of 9 induces shifts in aromaticsignals of both the guest and the catenane, but no nOe wasobserved between the aromatic protons of 9 and 11, indicatinga different binding mode to that of 10 to the catenane.

ConclusionsIn summary, we have identified an unusual donor-acceptor[2]-catenane from an aqueous DCL. The use of only acycliccomponents allows the first construction of a [2]-catenane thatcontains both donor and acceptor units in the same ring. Theyield of the [2]-catenane depends on the library conditions:

Fig. 5. HPLC analysis of a 5 mM DCL mixture 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.

Fig. 6. Partial 1H NMR spectra (D2O, 300 K, 500 MHz) of the [2]-catenane 9in the presence of 0 (A); 0.2 (B); 0.4 (C); 0.6 (D); 0.8 (E); 1.0 (F); 2.0 (G); and 3.0equiv. of 10 (H). Signals from NDI and DN core of 9 and the DN core of 10 arehighlighted with red, green, and blue, respectively.

Fig. 7. Resonance of one of the methylene groups of the side chain of 10when complexed by (A) 1.25 and (B) 0.33 equiv. of 9.

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changing the concentration or ionic strength, the addition of anexternal template increases the yield of the interlocked com-pound. It is also found that a cationic, electron-rich molecule is

intercalated between 2 electron-deficient moieties of the [2]-catenane, creating a supramolecular assembly featuring 5 alter-nating �-donor and �-acceptor units.

By appropriate modification of the cationic template, it isexpected that supramolecular assemblies with more complextopology could be efficiently constructed using this dynamiccombinatorial approach.

Materials and MethodsChemicals 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 XCTsystems coupled to a diode array detector and the data processed usingChemStation software. Mass spectra (negative mode) were acquired inultra scan mode using drying temperature of 325 °C, nebulizer pressure of55 psi, drying gas flow of 10 L/min, capillary voltage of 4,000 V, an ICC targetof 200,000 ions, and target mass of 1,000. Analytical separations wereachieved by injecting 5 �L (for 5 mM DCL, scaled accordingly for DCL atdifferent concentrations) of DCL solution onto a Symmetry C8 reverse phasecolumn (150 � 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 flowrate of 1 mL/min. Preparative separation was performed on a Symme-tryPrep C18 column (300 � 7.8 mm, 7 �m particle size). Elution was per-formed 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 roomtemperature. 1H and 13C NMR spectra were recorded on Bruker DPX-400 orAdvance 500 TCI Cryo Spectrometers and internally referenced to solventresidue.

A typical analytical DCL was prepared on a 1-ml scale by dissolving anequimolar mixture of 1 and 2 in 10 mM aqueous NaOH, followed by titrationwith 100 mM aqueous NaOH to pH 8, to the desired concentration. Whereappropriate, alkali metal salts, guests 10 or 11, were added in solid form. TheDCL was stirred in a close-capped vial at room temperature until beinganalyzed. Preparative DCL was prepared in the same manner on a 10-ml scale.For further experimental details, see SI.

ACKNOWLEDGMENTS. We thank the Croucher Foundation, Pembroke College,and the Engineering and Physical Sciences Research Council for financial support,and Dr. Ana Belenguer for maintaining the chromatography laboratory.

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Fig. 8. 1D NOE spectra (D2O, 300 K, 500 MHz, mixing time � 1.2 s) ofcomplexed 9 in the presence of 3 equiv. of 10 (top 3) and the referencespectrum (bottom). Irradiation (marked with an arrow) of DN signal of 9 (A);DN signal of 10 (B); and NDI signal of 9 (C). Signals from NDI and DN core of 9and the NDI core of 10 are shaded with red, green, and blue in the referencespectrum, respectively.

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