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 compo- nents. 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 con- trolled 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.