DOI: 10.1002/chem.201404941
Communication
& Alleno–Acetylenic Macrocycles
Enantiopure Laterally Functionalized Alleno–Acetylenic Macrocycles: Synthesis, Chiroptical Properties, and Self-Assembly in Aqueous Media Manolis D. Tzirakis,[a] Mariza N. Alberti,[a] Haim Weissman,[b] Boris Rybtchinski,[b] and FranÅois Diederich*[a] Abstract: A family of shape-persistent alleno–acetylenic macrocycles (SPAAMs), peripherally decorated with structurally diverse pendant groups, has been synthesized and characterized in enantiomerically pure form. Their electronic circular dichroism (ECD) spectra feature a strong chiroptical response, which is more than two times higher than for open-chain tetrameric analogues. A water-soluble oligo(ethylene glycol)-appended SPAAM undergoes selfassembly in aqueous solution. Morphology studies by cryogenic transmission electron microscopy (cryo-TEM) revealed the formation of aggregates with fibrous fine structures that correspond to tubular, macrocyclic stacks.
Shape-persistent macrocycles (SPMs) have strongly impacted supramolecular chemistry, and a number of well-defined supramolecular assemblies, including three-dimensional nanostructures, discotic liquid crystals, extended tubular channels, receptors for guest encapsulation, and porous organic solids have been reported.[1, 2] At the same time, chiral macrocyclic compounds are becoming increasingly attractive due to their diverse applications in several fields of research, including chiral analysis and separation,[3] chiral recognition and sensing,[4] enantioselective catalysis,[5, 6] and chemical biology.[7, 8] Chiral shape-persistent macrocycles (chiral SPMs) have been introduced,[9] with characteristic examples including 1,1’-binaphthylderived cyclophanes,[9, 10] metallacyclophanes,[11] alleno[12–16] phanes, and alleno–acetylenic macrocycles.[13, 14, 16, 17] A common feature of this last type of chiral SPMs is the optically pure alleno–acetylenic structural motif[18, 19] employed to engineer their macrocyclic backbone. We have shown that enantiomerically pure D4-symmetric tetramers, namely (P)4-()-1 or (M)4-(+)-1 (Figure 1), exhibit exceptionally intense chiroptical [a] Dr. M. D. Tzirakis, Dr. M. N. Alberti, Prof. Dr. F. Diederich Laboratorium fr Organische Chemie, ETH Zurich Vladimir-Prelog-Weg 3, 8093 Zurich (Switzerland) Fax: (+ 41) 44-632-1109 E-mail: [email protected] [b] Dr. H. Weissman, Prof. Dr. B. Rybtchinski Department of Organic Chemistry Weizmann Institute of Science, 76100 Rehovot (Israel) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404941. Chem. Eur. J. 2014, 20, 16070 – 16073
properties (De = 790 m1 cm1 at 253 nm in n-hexane).[17a] We recently described the synthesis of the first enantiopure, laterally-functionalized shape-persistent alleno–acetylenic macrocycle (SPAAM) that is peripherally decorated with eight phenolic rings ((P)4-()-2 and (M)4-(+)-2; Figure 1) to trigger solid-state self-assembly.[20] Indeed, we showed that (P)4-()-2 stacks in pillars in the solid state to form tubular chiral supramolecular channels, filled by solvent molecules, such as n-heptane, and undergoes further self-assembly through lateral, intermolecular hydrogen-bonding interactions into a 3D microporous architecture.[20] We anticipated that (P)4-()- and (M)4-(+)-2 would serve as excellent platforms for additional lateral functionalization aimed at further stabilizing the discotic-type stacking in solution.[20] Here, we report the peripheral decoration of enantiopure SPAAMs (P)4-()- and (M)4-(+)-2 with structurally diverse pendant groups. The effect of the lateral groups on the chiroptical properties of the resulting enantiopure SPAAMs (P)4-()-3–8 and their (M)4-configured enantiomers (Figure 1), and their self-assembly in solution induced by solvophobic effects, electrostatic, and van der Waals interactions are investigated. We also describe the morphological characteristics of the first water-soluble SPAAMs ((P)4-()-8 and (M)4-(+)-8) in solution by cryogenic transmission electron microscopy (cryoTEM). Several studies in the literature show that the incorporation of long alkyl chains around the rigid core of SPMs facilitates their self-organization into two- or three-dimensional assemblies through intermolecular van der Waals interactions.[1, 21] We therefore derivatized (P)4-()-2 with lateral n-dodecyloxy chains by treatment with K2CO3 and 1-bromododecane in DMF at 60 8C, to afford (P)4-()-3 in 48 % yield (see the Supporting Information). In an attempt to further stabilize a discotic-type aggregation in solution, (P)4-()-2 was also derivatized with mesogenic 3,4,5-tris(n-dodecyloxy)benzyl groups by a convergent synthetic route (see Scheme S1 in the Supporting Information). Unlike (P)4-()-2, macrocycles (P)4-()-3 and (P)4-()-4 with peripheral n-dodecyloxy tails are soluble in a wide range of organic solvents, such as n-hexane, toluene, CHCl3, THF, and EtOAc. The efficient incorporation of triflate functional groups (-OTf) afforded (P)4-()-5 (90 % yield), which offers the opportunity for further side group variation through cross-coupling reactions. Synthetic flexibility was also ensured by the preparation of octakis(ethyl ester) (P)4-()-6, which was obtained in good yield (80 %) from Wiliamson etherification of (P)4-()-2 with ethyl bromoacetate (see the Supporting Information). Hy-
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Figure 1. Structures of octakis(tert-butyl)-substituted ((P)4-()-1)[17a] and octakis(phenol)-substituted ((P)4-()-2)[20] SPAAMs employed in our previous studies, as well as the new SPAAMs (P)4-()-3–8 investigated in this work. The (M)4-configured enantiomers have also been prepared; experimental details are given in the Supporting Information.
drolysis of (P)4-()-6 with NaOH afforded the highly polar octakis(carboxylic acid) (P)4-()-7, which is insoluble in most organic solvents (i.e., CH3OH, Et2O, CHCl3, CH2Cl2, hexane, and toluene), slightly soluble in THF and CH3CN upon heating, and readily soluble in Me2SO. Finally, by changing the peripheral groups to hydrophilic oligo(ethylene glycol) (OEG) chains, we obtained the first water-soluble SPAAM (P)4-()-8 (vide infra). The incorporation of water-solubilizing OEG chains at the periphery of hydrophobic molecules,[22] including macrocyclic compounds,[23] is a well-established approach for the engineering and design of supramolecular assemblies by spontaneous self-organization in aqueous or other polar media, driven by hydrophobic and van der Waals interactions and, in the presence of lateral arene rings as in (P)4-()-8, by p–p stacking interactions. Water-soluble SPAAM (P)4-()-8 was prepared in 63 % yield by Williamson ether synthesis of (P)4-()-2 with a 3,4,5-tris(tetraethylene glycol)-substituted benzyl bromide (Scheme S2 in the Supporting Information). The corresponding (M)4-configured SPAAMs were obtained in a similar manner, starting from (M)4-(+)-2 (see the Supporting Information). The chiroptical properties of the new enantiopure SPAAMs 3–8 (Figure 2 and Figures S1–S7 in the Supporting Information) were probed by electronic circular dichroism (ECD). The spectra of the enantiomers of 5, 6, and 8 were recorded in MeCN (c = 2.0 106–5.0 106 m), whereas in the case of the enantiomers of 3–4 and 7, n-hexane and Me2SO, respectively, were employed due to the insolubility of these compounds in MeCN. All (P)4-configured tetrameric macrocycles 3–8 exhibit intense positive Cotton effects centered at l = 255–260 nm (De = + 360–520 m1 cm1; Figure 2 and Section 3 in the Supporting Information), which are similar or in most cases even increased with respect to the parent octaphenol macrocycle (P)4-()-2 (l = 254 nm, De = + 375 m1 cm1; MeCN)[20] (Figure 2; for a detailed comparison of ECD spectra including g-factor Chem. Eur. J. 2014, 20, 16070 – 16073
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analyses, see Section 4 in the Supporting Information). Also, consistent with our previous studies,[17, 20] all enantiopure tetrameric SPAAMs 3–8 display a characteristic Cotton effect between 290 and 350 nm, which splits into three maxima due to vibronic coupling with the buta1,3-diynediyl stretch.[17b] A comparison of the ECD spectra of enantiopure 2–8 with the spectrum of the enantiomers of acyclic tetramer 9 featuring MeOCH2 (MOM)-protected phenol rings (in MeCN) revealed very large differences (Section 5 in the Supporting Information).[24] This is illustrated by the superimposition of the spectra of (P)4-()- and (M)4-(+)-6 with those of (P)4-(+)- and (M)4-()-9
Figure 2. ECD spectra of (P)4- and (M)4-configured enantiomers (solid and dashed colored lines, respectively) of SPAAMs 2–8, recorded in MeCN (2, 5, 6, and 8), n-hexane (3 and 4), or Me2SO (7) at 25 8C.
(Figure 3). Compared to the macrocyclic tetramer (see also Figure S16 in the Supporting Information), the Cotton effects of acyclic (P)4-(+)-9 in the higher-energy UV region between 200 and 240 nm are reversed in sign. The strong Cotton effect of the macrocycles around 260 nm is strongly reduced in intensity, whereas the vibronically coupled band extending from about 290 to 340 nm is largely maintained in intensity and shape, but of opposite sign. The ECD spectra of the enantiomers of 9 closely resemble those previously reported for a structurally related acyclic tetramer in which the allene moieties are all garnered with two tert-butyl groups.[24] Previous theoretical investigations suggested that the enhanced chiroptical response in (P)4-()-1 or (M)4-(+)-1 as compared to openchain tetramers should be ascribed to the unique topology of
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Figure 3. ECD spectra of the open-chain tetramers (P)4-(+)-9 (solid black line) and (M)4-()-9 (dashed black line) in comparison with the corresponding spectra recorded for the macrocyclic tetramers (P)4-()-6 (solid grey line) and (M)4-(+)-6 (dashed grey line), respectively. All spectra were recorded in MeCN at 25 8C. Inset: Chemical structure of (P)4-(+)-9; for the sake of simplicity, the structure of (M)4-()-9 is not shown. MOM = methoxymethyl.
the molecular orbitals involved in the relevant transitions of the macrocycles.[17b] It is reasonable to assume that this is the case also in the present study. It is also fascinating to see that the Cotton effects of enantiopure SPAAMs 3–8 retain high intensity or even show an intensity increase, when compared to 2, despite the large “dilution” of the chirality with increasing achiral peripheral decoration (molecular mass: 2: 1417.76 g mol1; 8: 7088.41 g mol1). Our attempts to obtain the X-ray crystal structures of the enantiomers of SPAAMs 3 and 5–7, which would allow for investigating the potential of these SPAAMs for self-organization in tubular structures in the solid state, as previously reported for 2,[20] were not successful. Also, concentration-dependent 1 H NMR measurements (CDCl3) and ECD spectra (n-hexane or CHCl3 ; see Section 6 in the Supporting Information) did not show any appreciable self-assembly of enantiopure SPAAMs 3– 8 in solution. However, much to our delight, the self-assembly behavior of water-soluble, OEG-appended SPAAM (M)4-(+)-8 could be successfully studied by cryo-TEM in aqueous media. Specifically, cryo-TEM of a sample obtained by ageing a H2O/ THF (70:30) solution of (M)4-(+)-8 (1.0 105) for 4 h showed the presence of vesicles (diameter (100 30) nm), as well as amorphous fibrous aggregates and fibrous lamellae made of 7–50 nm length fibers with a diameter of (2.1 0.3) nm (Figure 4 a; see also Figures S19 and S20 in the Supporting Information). The cryo-TEM of a sample obtained by ageing a H2O/ THF (50:50) solution of (M)4-(+)-8 (3.0 105 m) for 1 h showed only the presence of nanometer-sized amorphous fibrous aggregates made of fibers with diameters in the range of about 2 nm (see Figure S21 in the Supporting Information). Molecular models (MM2)[25] that match the experimental structural data obtained from our cryo-TEM studies involve tubular fibers built from macrocyclic stacks, in which the rigid macrocyclic segments stack on top of each other, presumably by means of hydrophobic and van der Waals interactions (Figure 4 b). Chiral Chem. Eur. J. 2014, 20, 16070 – 16073
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Figure 4. a) Cryo-TEM images of (M)4-(+)-8 showing the presence of vesicles (left; scale bar 200 nm) and fibrous lamellae (right; the inset shows a magnified view of representative fibers; scale bar 50 nm). b) Top and side views of the molecular model (MM2) of the proposed tubular fibers of (M)4-(+)-8. The phenyl-substituted macrocyclic core of (M)4-(+)-8 is represented by a spacefilling model, whereas the aryl rings on the second layer—which are too separated and not dense enough to add sufficiently to the phase contrast of the electron-dense inner sp2/sp1 carbon atoms—are represented by a balland-stick model.
amplification, as a result of the self-assembly, was not observed in solution under the cryo-TEM conditions (H2O/THF 70:30! 50:50) in the concentration range between 1.0 105 and 1.0 104 m (see Figure S22 in the Supporting Information).[26] This result confirms that SPAAM (M)4-(+)-8 tends to stack on top of each other without a helical twist. In summary, we have prepared a family of enantiomerically pure SPAAMs, (P)4-()-3–8 and their corresponding (M)4-configured enantiomers, peripherally decorated with various pendant groups of different nature and size. The ECD spectra of these SPAAMs feature strong chiroptical response, which, in most cases (i.e., for enantiopure SPAAMs 3–7), is higher by a factor of 1.15–1.35 with respect to the parent octakis(phenol)-substituted tetrameric macrocycles (P)4-()-2 or (M)4-(+)-2, and at least two times greater than that of the open-chain tetrameric analogues (P)4-(+)-9 and (M)4-()-9 used as model compounds in the present study. A “dilution” of macrocyclic chirality by the appended achiral substituents does not take place. Cryo-TEM studies of the first water-soluble OEG-appended SPAAM ((M)4(+)-8) revealed the formation of vesicles—the fine structure of which is still under investigation—and also fibrous lamellae and 3D networks with fibrous fine structures that correspond to tubular, macrocyclic stacks. Apart from allowing for finetuning of physicochemical properties, such as size, solubility, polarity, and chiroptical response, the exocyclic functionalization of the allenic substituents promises new approaches to build up chiral supramolecular assemblies in solution and in the solid state. For example, asymmetric SPAAMs could be used to induce macroscopic chirality, leading to optically active liquid-crystalline phases in solution or to chiral patterns on sur-
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Communication faces. Guest encapsulation by the new SPAAMs and their aggregates (in case of (P)4-()-8 and (M)4-(+)-8) and novel second-generation derivatives also remain to be explored. Research along these lines is currently in progress in our laboratory.
Acknowledgements This work was supported by the ERC Advanced Grant No. 246637 (“OPTELOMAC’’). Keywords: alleno–acetylenes · chiral macrocycles · electronic circular dichroism · scanning probe microscopy · self-assembly [1] A. L. Sadowy, R. R. Tykwinski in Modern Supramolecular Chemistry: Strategies for Macrocycle Synthesis (Eds.: F. Diederich, P. J. Stang, R. R. Tykwinski), Wiley-VCH, Weinheim, 2008, Chapter 6, pp. 185 – 231. [2] For selected reviews on SPMs, see: a) C. Grave, A. D. Schlter, Eur. J. Org. Chem. 2002, 3075 – 3098; b) D. Zhao, J. S. Moore, Chem. Commun. 2003, 807 – 818; c) S. Hçger, Chem. Eur. J. 2004, 10, 1320 – 1329; d) W. Zhang, J. S. Moore, Angew. Chem. Int. Ed. 2006, 45, 4416 – 4439; Angew. Chem. 2006, 118, 4524 – 4548; e) M. Iyoda, J. Yamakawa, M. J. Rahman, Angew. Chem. Int. Ed. 2011, 50, 10522 – 10553; Angew. Chem. 2011, 123, 10708 – 10740; f) H. Fu, Y. Liu, H. Zeng, Chem. Commun. 2013, 49, 4127 – 4144. [3] a) G. Li, W. Yu, J. Ni, T. Liu, Y. Liu, E. Sheng, Y. Cui, Angew. Chem. Int. Ed. 2008, 47, 1245 – 1249; Angew. Chem. 2008, 120, 1265 – 1269; b) T. Ema, J. Inclusion Phenom. Macrocyclic Chem. 2012, 74, 41 – 55, and references therein. [4] a) X. X. Zhang, J. S. Bradshaw, R. M. Izatt, Chem. Rev. 1997, 97, 3313 – 3361; also, for selected recent examples, see: b) T. Ema, D. Tanida, T. Sakai, J. Am. Chem. Soc. 2007, 129, 10591 – 10596; c) T. P. Quinn, P. D. Atwood, J. M. Tanski, T. F. Moore, J. F. Folmer-Andersen, J. Org. Chem. 2011, 76, 10020 – 10030; d) T. Ema, K. Okuda, S. Watanabe, T. Yamasaki, T. Minami, N. A. Esipenko, P. Anzenbacher Jr., Org. Lett. 2014, 16, 1302 – 1305; e) K. Sato, Y. Itoh, T. Aida, Chem. Sci. 2014, 5, 136 – 140. [5] R. M. Kellogg, Angew. Chem. Int. Ed. Engl. 1984, 23, 782 – 794; Angew. Chem. 1984, 96, 769 – 781. [6] For selected recent examples, see: a) R. I. Kureshy, T. Roy, N. H. Khan, S. H. R. Abdi, A. Sadhukhan, H. C. Bajaj, J. Catal. 2012, 286, 41 – 50; b) B. Castano, S. Guidone, E. Gallo, F. Ragaini, N. Casati, P. Macchi, M. Sisti, A. Caselli, Dalton Trans. 2013, 42, 2451 – 2462. [7] S. E. Gibson, C. Lecci, Angew. Chem. Int. Ed. 2006, 45, 1364 – 1377; Angew. Chem. 2006, 118, 1392 – 1405. [8] For selected recent examples, see: a) S. K. Reddy Guduru, S. Chamakuri, G. Chandrasekar, S. S. Kitambi, P. Arya, ACS Med. Chem. Lett. 2013, 4, 666 – 670; b) M. Aeluri, C. Pramanik, L. Chetia, N. K. Mallurwar, S. Balasubramanian, G. Chandrasekar, S. S. Kitambi, P. Arya, Org. Lett. 2013, 15, 436 – 439. [9] K. Campbell, R. R. Tykwinski in Carbon-Rich Compounds: From Molecules to Materials (Eds.: M. M. Haley, R. R. Tykwinski), Wiley-VCH, Weinheim, 2006, Chapter 6, pp. 229 – 294. [10] For selected examples, see: a) S. Anderson, U. Neidlein, V. Gramlich, F. Diederich, Angew. Chem. Int. Ed. Engl. 1995, 34, 1596 – 1600; Angew. Chem. 1995, 107, 1722 – 1725; b) A. Bhr, A. S. Droz, M. Pntener, U. Neidlein, S. Anderson, P. Seiler, F. Diederich, Helv. Chim. Acta 1998, 81, 1931 – 1963; c) T. Kawase, T. Nakamura, K. Utsumi, K. Matsumoto, H. Kurata, M. Oda, Chem. Asian J. 2008, 3, 573 – 577; d) C. Coluccini, D. Dondi, M. Caricato, A. Taglietti, M. Boiocchi, D. Pasini, Org. Biomol. Chem. 2010, 8, 1640 – 1649. [11] S. J. Lee, W. Lin, Acc. Chem. Res. 2008, 41, 521 – 537, and references therein.
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[12] a) M. D. Clay, A. G. Fallis, Angew. Chem. Int. Ed. 2005, 44, 4039 – 4042; Angew. Chem. 2005, 117, 4107 – 4110; b) M. Leclre, A. G. Fallis, Angew. Chem. Int. Ed. 2008, 47, 568 – 572; Angew. Chem. 2008, 120, 578 – 582. [13] S. Odermatt, J. L. Alonso-Gmez, P. Seiler, M. M. Cid, F. Diederich, Angew. Chem. Int. Ed. 2005, 44, 5074 – 5078; Angew. Chem. 2005, 117, 5203 – 5207. [14] T. Kawase, Angew. Chem. Int. Ed. 2005, 44, 7334 – 7336; Angew. Chem. 2005, 117, 7500 – 7502. [15] a) J. L. Alonso-Gmez, A. Navarro-Vzquez, M. M. Cid, Chem. Eur. J. 2009, 15, 6495 – 6503; b) I. R. Lahoz, A. Navarro-Vzquez, A. L. LlamasSaiz, J. L. Alonso-Gmez, M. M. Cid, Chem. Eur. J. 2012, 18, 13836 – 13843; c) I. R. Lahoz, A. Navarro-Vzquez, J. L. Alonso-Gmez, M. M. Cid, Eur. J. Org. Chem. 2014, 1915 – 1924; d) S. Castro-Fernndez, I. R. Lahoz, A. L. Llamas-Saiz, J. L. Alonso-Gmez, M. M. Cid, A. Navarro-Vzquez, Org. Lett. 2014, 16, 1136 – 1139. [16] P. Rivera-Fuentes, F. Diederich, Angew. Chem. Int. Ed. 2012, 51, 2818 – 2828; Angew. Chem. 2012, 124, 2872 – 2882. [17] a) J. L. Alonso-Gmez, P. Rivera-Fuentes, N. Harada, N. Berova, F. Diederich, Angew. Chem. Int. Ed. 2009, 48, 5545 – 5548; Angew. Chem. 2009, 121, 5653 – 5656; b) P. Rivera-Fuentes, J. L. Alonso-Gmez, A. G. Petrovic, P. Seiler, F. Santoro, N. Harada, N. Berova, H. S. Rzepa, F. Diederich, Chem. Eur. J. 2010, 16, 9796 – 9807; c) P. Rivera-Fuentes, B. Nieto-Ortega, W. B. Schweizer, J. T. L. Navarrete, J. Casado, F. Diederich, Chem. Eur. J. 2011, 17, 3876 – 3885. [18] a) R. C. Livingston, L. R. Cox, V. Gramlich, F. Diederich, Angew. Chem. Int. Ed. 2001, 40, 2334 – 2337; Angew. Chem. 2001, 113, 2396 – 2399; b) R. Livingston, L. R. Cox, S. Odermatt, F. Diederich, Helv. Chim. Acta 2002, 85, 3052 – 3077. [19] For the first preparation of an optically pure 1,3-diethynylallene (DEA), see: J. L. Alonso-Gmez, P. Schanen, P. Rivera-Fuentes, P. Seiler, F. Diederich, Chem. Eur. J. 2008, 14, 10564 – 10568. [20] M. D. Tzirakis, N. Marion, W. B. Schweizer, F. Diederich, Chem. Commun. 2013, 49, 7605 – 7607. [21] For selected examples, see: a) K. Tahara, S. Furukawa, H. Uji-i, T. Uchino, T. Ichikawa, J. Zhang, W. Mamdouh, M. Sonoda, F. C. De Schryver, S. De Feyter, Y. Tobe, J. Am. Chem. Soc. 2006, 128, 16613 – 16625; b) K. Tahara, S. Lei, J. Adisoejoso, S. De Feyter, Y. Tobe, Chem. Commun. 2010, 46, 8507 – 8525; c) Z. He, X. Xu, X. Zheng, T. Ming, Q. Miao, Chem. Sci. 2013, 4, 4525 – 4531; d) K. Tahara, J. Adisoejoso, K. Inukai, S. Lei, A. Noguchi, B. Li, W. Vanderlinden, S. De Feyter, Y. Tobe, Chem. Commun. 2014, 50, 2831 – 2833, and references therein. [22] a) E. Krieg, B. Rybtchinski, Chem. Eur. J. 2011, 17, 9016 – 9026; b) H.-J. Kim, T. Kim, M. Lee, Acc. Chem. Res. 2011, 44, 72 – 82. [23] For selected examples, see: a) S. Lahiri, J. L. Thompson, J. S. Moore, J. Am. Chem. Soc. 2000, 122, 11315 – 11319; b) D. Zhao, J. S. Moore, J. Org. Chem. 2002, 67, 3548 – 3554; c) S. H. Seo, T. V. Jones, H. Seyler, J. O. Peters, T. H. Kim, J. Y. Chang, G. N. Tew, J. Am. Chem. Soc. 2006, 128, 9264 – 9265. [24] P. Rivera-Fuentes, J. L. Alonso-Gmez, A. G. Petrovic, F. Santoro, N. Harada, N. Berova, F. Diederich, Angew. Chem. Int. Ed. 2010, 49, 2247 – 2250; Angew. Chem. 2010, 122, 2296 – 2300. [25] The geometry of the central aryl-substituted alleno–acetylenic macrocyclic fragment used in our molecular models, was based on the D4-symmetric structure that was previously predicted by theoretical calculations (see ref. [17a]) and further confirmed by the solid-state X-ray structure of (P)4/(M)4–1 (see ref. [17b]). In the present study, both 1H and 13C NMR studies corroborate that (P)4-()-8 and (M)4-(+)-8 adopt a similar D4-symmetric structure in solution. [26] A. R. A. Palmans, E. W. Meijer, Angew. Chem. Int. Ed. 2007, 46, 8948 – 8968; Angew. Chem. 2007, 119, 9106 – 9126.
Received: August 20, 2014 Published online on October 24, 2014
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& Alleno–Acetylenic Macrocycles
Enantiopure Laterally Functionalized Alleno–Acetylenic Macrocycles: Synthesis, Chiroptical Properties, and Self-Assembly in Aqueous Media Manolis D. Tzirakis,[a] Mariza N. Alberti,[a] Haim Weissman,[b] Boris Rybtchinski,[b] and FranÅois Diederich*[a] Abstract: A family of shape-persistent alleno–acetylenic macrocycles (SPAAMs), peripherally decorated with structurally diverse pendant groups, has been synthesized and characterized in enantiomerically pure form. Their electronic circular dichroism (ECD) spectra feature a strong chiroptical response, which is more than two times higher than for open-chain tetrameric analogues. A water-soluble oligo(ethylene glycol)-appended SPAAM undergoes selfassembly in aqueous solution. Morphology studies by cryogenic transmission electron microscopy (cryo-TEM) revealed the formation of aggregates with fibrous fine structures that correspond to tubular, macrocyclic stacks.
Shape-persistent macrocycles (SPMs) have strongly impacted supramolecular chemistry, and a number of well-defined supramolecular assemblies, including three-dimensional nanostructures, discotic liquid crystals, extended tubular channels, receptors for guest encapsulation, and porous organic solids have been reported.[1, 2] At the same time, chiral macrocyclic compounds are becoming increasingly attractive due to their diverse applications in several fields of research, including chiral analysis and separation,[3] chiral recognition and sensing,[4] enantioselective catalysis,[5, 6] and chemical biology.[7, 8] Chiral shape-persistent macrocycles (chiral SPMs) have been introduced,[9] with characteristic examples including 1,1’-binaphthylderived cyclophanes,[9, 10] metallacyclophanes,[11] alleno[12–16] phanes, and alleno–acetylenic macrocycles.[13, 14, 16, 17] A common feature of this last type of chiral SPMs is the optically pure alleno–acetylenic structural motif[18, 19] employed to engineer their macrocyclic backbone. We have shown that enantiomerically pure D4-symmetric tetramers, namely (P)4-()-1 or (M)4-(+)-1 (Figure 1), exhibit exceptionally intense chiroptical [a] Dr. M. D. Tzirakis, Dr. M. N. Alberti, Prof. Dr. F. Diederich Laboratorium fr Organische Chemie, ETH Zurich Vladimir-Prelog-Weg 3, 8093 Zurich (Switzerland) Fax: (+ 41) 44-632-1109 E-mail: [email protected] [b] Dr. H. Weissman, Prof. Dr. B. Rybtchinski Department of Organic Chemistry Weizmann Institute of Science, 76100 Rehovot (Israel) Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404941. Chem. Eur. J. 2014, 20, 16070 – 16073
properties (De = 790 m1 cm1 at 253 nm in n-hexane).[17a] We recently described the synthesis of the first enantiopure, laterally-functionalized shape-persistent alleno–acetylenic macrocycle (SPAAM) that is peripherally decorated with eight phenolic rings ((P)4-()-2 and (M)4-(+)-2; Figure 1) to trigger solid-state self-assembly.[20] Indeed, we showed that (P)4-()-2 stacks in pillars in the solid state to form tubular chiral supramolecular channels, filled by solvent molecules, such as n-heptane, and undergoes further self-assembly through lateral, intermolecular hydrogen-bonding interactions into a 3D microporous architecture.[20] We anticipated that (P)4-()- and (M)4-(+)-2 would serve as excellent platforms for additional lateral functionalization aimed at further stabilizing the discotic-type stacking in solution.[20] Here, we report the peripheral decoration of enantiopure SPAAMs (P)4-()- and (M)4-(+)-2 with structurally diverse pendant groups. The effect of the lateral groups on the chiroptical properties of the resulting enantiopure SPAAMs (P)4-()-3–8 and their (M)4-configured enantiomers (Figure 1), and their self-assembly in solution induced by solvophobic effects, electrostatic, and van der Waals interactions are investigated. We also describe the morphological characteristics of the first water-soluble SPAAMs ((P)4-()-8 and (M)4-(+)-8) in solution by cryogenic transmission electron microscopy (cryoTEM). Several studies in the literature show that the incorporation of long alkyl chains around the rigid core of SPMs facilitates their self-organization into two- or three-dimensional assemblies through intermolecular van der Waals interactions.[1, 21] We therefore derivatized (P)4-()-2 with lateral n-dodecyloxy chains by treatment with K2CO3 and 1-bromododecane in DMF at 60 8C, to afford (P)4-()-3 in 48 % yield (see the Supporting Information). In an attempt to further stabilize a discotic-type aggregation in solution, (P)4-()-2 was also derivatized with mesogenic 3,4,5-tris(n-dodecyloxy)benzyl groups by a convergent synthetic route (see Scheme S1 in the Supporting Information). Unlike (P)4-()-2, macrocycles (P)4-()-3 and (P)4-()-4 with peripheral n-dodecyloxy tails are soluble in a wide range of organic solvents, such as n-hexane, toluene, CHCl3, THF, and EtOAc. The efficient incorporation of triflate functional groups (-OTf) afforded (P)4-()-5 (90 % yield), which offers the opportunity for further side group variation through cross-coupling reactions. Synthetic flexibility was also ensured by the preparation of octakis(ethyl ester) (P)4-()-6, which was obtained in good yield (80 %) from Wiliamson etherification of (P)4-()-2 with ethyl bromoacetate (see the Supporting Information). Hy-
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Figure 1. Structures of octakis(tert-butyl)-substituted ((P)4-()-1)[17a] and octakis(phenol)-substituted ((P)4-()-2)[20] SPAAMs employed in our previous studies, as well as the new SPAAMs (P)4-()-3–8 investigated in this work. The (M)4-configured enantiomers have also been prepared; experimental details are given in the Supporting Information.
drolysis of (P)4-()-6 with NaOH afforded the highly polar octakis(carboxylic acid) (P)4-()-7, which is insoluble in most organic solvents (i.e., CH3OH, Et2O, CHCl3, CH2Cl2, hexane, and toluene), slightly soluble in THF and CH3CN upon heating, and readily soluble in Me2SO. Finally, by changing the peripheral groups to hydrophilic oligo(ethylene glycol) (OEG) chains, we obtained the first water-soluble SPAAM (P)4-()-8 (vide infra). The incorporation of water-solubilizing OEG chains at the periphery of hydrophobic molecules,[22] including macrocyclic compounds,[23] is a well-established approach for the engineering and design of supramolecular assemblies by spontaneous self-organization in aqueous or other polar media, driven by hydrophobic and van der Waals interactions and, in the presence of lateral arene rings as in (P)4-()-8, by p–p stacking interactions. Water-soluble SPAAM (P)4-()-8 was prepared in 63 % yield by Williamson ether synthesis of (P)4-()-2 with a 3,4,5-tris(tetraethylene glycol)-substituted benzyl bromide (Scheme S2 in the Supporting Information). The corresponding (M)4-configured SPAAMs were obtained in a similar manner, starting from (M)4-(+)-2 (see the Supporting Information). The chiroptical properties of the new enantiopure SPAAMs 3–8 (Figure 2 and Figures S1–S7 in the Supporting Information) were probed by electronic circular dichroism (ECD). The spectra of the enantiomers of 5, 6, and 8 were recorded in MeCN (c = 2.0 106–5.0 106 m), whereas in the case of the enantiomers of 3–4 and 7, n-hexane and Me2SO, respectively, were employed due to the insolubility of these compounds in MeCN. All (P)4-configured tetrameric macrocycles 3–8 exhibit intense positive Cotton effects centered at l = 255–260 nm (De = + 360–520 m1 cm1; Figure 2 and Section 3 in the Supporting Information), which are similar or in most cases even increased with respect to the parent octaphenol macrocycle (P)4-()-2 (l = 254 nm, De = + 375 m1 cm1; MeCN)[20] (Figure 2; for a detailed comparison of ECD spectra including g-factor Chem. Eur. J. 2014, 20, 16070 – 16073
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analyses, see Section 4 in the Supporting Information). Also, consistent with our previous studies,[17, 20] all enantiopure tetrameric SPAAMs 3–8 display a characteristic Cotton effect between 290 and 350 nm, which splits into three maxima due to vibronic coupling with the buta1,3-diynediyl stretch.[17b] A comparison of the ECD spectra of enantiopure 2–8 with the spectrum of the enantiomers of acyclic tetramer 9 featuring MeOCH2 (MOM)-protected phenol rings (in MeCN) revealed very large differences (Section 5 in the Supporting Information).[24] This is illustrated by the superimposition of the spectra of (P)4-()- and (M)4-(+)-6 with those of (P)4-(+)- and (M)4-()-9
Figure 2. ECD spectra of (P)4- and (M)4-configured enantiomers (solid and dashed colored lines, respectively) of SPAAMs 2–8, recorded in MeCN (2, 5, 6, and 8), n-hexane (3 and 4), or Me2SO (7) at 25 8C.
(Figure 3). Compared to the macrocyclic tetramer (see also Figure S16 in the Supporting Information), the Cotton effects of acyclic (P)4-(+)-9 in the higher-energy UV region between 200 and 240 nm are reversed in sign. The strong Cotton effect of the macrocycles around 260 nm is strongly reduced in intensity, whereas the vibronically coupled band extending from about 290 to 340 nm is largely maintained in intensity and shape, but of opposite sign. The ECD spectra of the enantiomers of 9 closely resemble those previously reported for a structurally related acyclic tetramer in which the allene moieties are all garnered with two tert-butyl groups.[24] Previous theoretical investigations suggested that the enhanced chiroptical response in (P)4-()-1 or (M)4-(+)-1 as compared to openchain tetramers should be ascribed to the unique topology of
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Figure 3. ECD spectra of the open-chain tetramers (P)4-(+)-9 (solid black line) and (M)4-()-9 (dashed black line) in comparison with the corresponding spectra recorded for the macrocyclic tetramers (P)4-()-6 (solid grey line) and (M)4-(+)-6 (dashed grey line), respectively. All spectra were recorded in MeCN at 25 8C. Inset: Chemical structure of (P)4-(+)-9; for the sake of simplicity, the structure of (M)4-()-9 is not shown. MOM = methoxymethyl.
the molecular orbitals involved in the relevant transitions of the macrocycles.[17b] It is reasonable to assume that this is the case also in the present study. It is also fascinating to see that the Cotton effects of enantiopure SPAAMs 3–8 retain high intensity or even show an intensity increase, when compared to 2, despite the large “dilution” of the chirality with increasing achiral peripheral decoration (molecular mass: 2: 1417.76 g mol1; 8: 7088.41 g mol1). Our attempts to obtain the X-ray crystal structures of the enantiomers of SPAAMs 3 and 5–7, which would allow for investigating the potential of these SPAAMs for self-organization in tubular structures in the solid state, as previously reported for 2,[20] were not successful. Also, concentration-dependent 1 H NMR measurements (CDCl3) and ECD spectra (n-hexane or CHCl3 ; see Section 6 in the Supporting Information) did not show any appreciable self-assembly of enantiopure SPAAMs 3– 8 in solution. However, much to our delight, the self-assembly behavior of water-soluble, OEG-appended SPAAM (M)4-(+)-8 could be successfully studied by cryo-TEM in aqueous media. Specifically, cryo-TEM of a sample obtained by ageing a H2O/ THF (70:30) solution of (M)4-(+)-8 (1.0 105) for 4 h showed the presence of vesicles (diameter (100 30) nm), as well as amorphous fibrous aggregates and fibrous lamellae made of 7–50 nm length fibers with a diameter of (2.1 0.3) nm (Figure 4 a; see also Figures S19 and S20 in the Supporting Information). The cryo-TEM of a sample obtained by ageing a H2O/ THF (50:50) solution of (M)4-(+)-8 (3.0 105 m) for 1 h showed only the presence of nanometer-sized amorphous fibrous aggregates made of fibers with diameters in the range of about 2 nm (see Figure S21 in the Supporting Information). Molecular models (MM2)[25] that match the experimental structural data obtained from our cryo-TEM studies involve tubular fibers built from macrocyclic stacks, in which the rigid macrocyclic segments stack on top of each other, presumably by means of hydrophobic and van der Waals interactions (Figure 4 b). Chiral Chem. Eur. J. 2014, 20, 16070 – 16073
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Figure 4. a) Cryo-TEM images of (M)4-(+)-8 showing the presence of vesicles (left; scale bar 200 nm) and fibrous lamellae (right; the inset shows a magnified view of representative fibers; scale bar 50 nm). b) Top and side views of the molecular model (MM2) of the proposed tubular fibers of (M)4-(+)-8. The phenyl-substituted macrocyclic core of (M)4-(+)-8 is represented by a spacefilling model, whereas the aryl rings on the second layer—which are too separated and not dense enough to add sufficiently to the phase contrast of the electron-dense inner sp2/sp1 carbon atoms—are represented by a balland-stick model.
amplification, as a result of the self-assembly, was not observed in solution under the cryo-TEM conditions (H2O/THF 70:30! 50:50) in the concentration range between 1.0 105 and 1.0 104 m (see Figure S22 in the Supporting Information).[26] This result confirms that SPAAM (M)4-(+)-8 tends to stack on top of each other without a helical twist. In summary, we have prepared a family of enantiomerically pure SPAAMs, (P)4-()-3–8 and their corresponding (M)4-configured enantiomers, peripherally decorated with various pendant groups of different nature and size. The ECD spectra of these SPAAMs feature strong chiroptical response, which, in most cases (i.e., for enantiopure SPAAMs 3–7), is higher by a factor of 1.15–1.35 with respect to the parent octakis(phenol)-substituted tetrameric macrocycles (P)4-()-2 or (M)4-(+)-2, and at least two times greater than that of the open-chain tetrameric analogues (P)4-(+)-9 and (M)4-()-9 used as model compounds in the present study. A “dilution” of macrocyclic chirality by the appended achiral substituents does not take place. Cryo-TEM studies of the first water-soluble OEG-appended SPAAM ((M)4(+)-8) revealed the formation of vesicles—the fine structure of which is still under investigation—and also fibrous lamellae and 3D networks with fibrous fine structures that correspond to tubular, macrocyclic stacks. Apart from allowing for finetuning of physicochemical properties, such as size, solubility, polarity, and chiroptical response, the exocyclic functionalization of the allenic substituents promises new approaches to build up chiral supramolecular assemblies in solution and in the solid state. For example, asymmetric SPAAMs could be used to induce macroscopic chirality, leading to optically active liquid-crystalline phases in solution or to chiral patterns on sur-
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Communication faces. Guest encapsulation by the new SPAAMs and their aggregates (in case of (P)4-()-8 and (M)4-(+)-8) and novel second-generation derivatives also remain to be explored. Research along these lines is currently in progress in our laboratory.
Acknowledgements This work was supported by the ERC Advanced Grant No. 246637 (“OPTELOMAC’’). Keywords: alleno–acetylenes · chiral macrocycles · electronic circular dichroism · scanning probe microscopy · self-assembly [1] A. L. Sadowy, R. R. Tykwinski in Modern Supramolecular Chemistry: Strategies for Macrocycle Synthesis (Eds.: F. Diederich, P. J. Stang, R. R. Tykwinski), Wiley-VCH, Weinheim, 2008, Chapter 6, pp. 185 – 231. [2] For selected reviews on SPMs, see: a) C. Grave, A. D. Schlter, Eur. J. Org. Chem. 2002, 3075 – 3098; b) D. Zhao, J. S. Moore, Chem. Commun. 2003, 807 – 818; c) S. Hçger, Chem. Eur. J. 2004, 10, 1320 – 1329; d) W. Zhang, J. S. Moore, Angew. Chem. Int. Ed. 2006, 45, 4416 – 4439; Angew. Chem. 2006, 118, 4524 – 4548; e) M. Iyoda, J. Yamakawa, M. J. Rahman, Angew. Chem. Int. Ed. 2011, 50, 10522 – 10553; Angew. Chem. 2011, 123, 10708 – 10740; f) H. Fu, Y. Liu, H. Zeng, Chem. Commun. 2013, 49, 4127 – 4144. [3] a) G. Li, W. Yu, J. Ni, T. Liu, Y. Liu, E. Sheng, Y. Cui, Angew. Chem. Int. Ed. 2008, 47, 1245 – 1249; Angew. Chem. 2008, 120, 1265 – 1269; b) T. Ema, J. Inclusion Phenom. Macrocyclic Chem. 2012, 74, 41 – 55, and references therein. [4] a) X. X. Zhang, J. S. Bradshaw, R. M. Izatt, Chem. Rev. 1997, 97, 3313 – 3361; also, for selected recent examples, see: b) T. Ema, D. Tanida, T. Sakai, J. Am. Chem. Soc. 2007, 129, 10591 – 10596; c) T. P. Quinn, P. D. Atwood, J. M. Tanski, T. F. Moore, J. F. Folmer-Andersen, J. Org. Chem. 2011, 76, 10020 – 10030; d) T. Ema, K. Okuda, S. Watanabe, T. Yamasaki, T. Minami, N. A. Esipenko, P. Anzenbacher Jr., Org. Lett. 2014, 16, 1302 – 1305; e) K. Sato, Y. Itoh, T. Aida, Chem. Sci. 2014, 5, 136 – 140. [5] R. M. Kellogg, Angew. Chem. Int. Ed. Engl. 1984, 23, 782 – 794; Angew. Chem. 1984, 96, 769 – 781. [6] For selected recent examples, see: a) R. I. Kureshy, T. Roy, N. H. Khan, S. H. R. Abdi, A. Sadhukhan, H. C. Bajaj, J. Catal. 2012, 286, 41 – 50; b) B. Castano, S. Guidone, E. Gallo, F. Ragaini, N. Casati, P. Macchi, M. Sisti, A. Caselli, Dalton Trans. 2013, 42, 2451 – 2462. [7] S. E. Gibson, C. Lecci, Angew. Chem. Int. Ed. 2006, 45, 1364 – 1377; Angew. Chem. 2006, 118, 1392 – 1405. [8] For selected recent examples, see: a) S. K. Reddy Guduru, S. Chamakuri, G. Chandrasekar, S. S. Kitambi, P. Arya, ACS Med. Chem. Lett. 2013, 4, 666 – 670; b) M. Aeluri, C. Pramanik, L. Chetia, N. K. Mallurwar, S. Balasubramanian, G. Chandrasekar, S. S. Kitambi, P. Arya, Org. Lett. 2013, 15, 436 – 439. [9] K. Campbell, R. R. Tykwinski in Carbon-Rich Compounds: From Molecules to Materials (Eds.: M. M. Haley, R. R. Tykwinski), Wiley-VCH, Weinheim, 2006, Chapter 6, pp. 229 – 294. [10] For selected examples, see: a) S. Anderson, U. Neidlein, V. Gramlich, F. Diederich, Angew. Chem. Int. Ed. Engl. 1995, 34, 1596 – 1600; Angew. Chem. 1995, 107, 1722 – 1725; b) A. Bhr, A. S. Droz, M. Pntener, U. Neidlein, S. Anderson, P. Seiler, F. Diederich, Helv. Chim. Acta 1998, 81, 1931 – 1963; c) T. Kawase, T. Nakamura, K. Utsumi, K. Matsumoto, H. Kurata, M. Oda, Chem. Asian J. 2008, 3, 573 – 577; d) C. Coluccini, D. Dondi, M. Caricato, A. Taglietti, M. Boiocchi, D. Pasini, Org. Biomol. Chem. 2010, 8, 1640 – 1649. [11] S. J. Lee, W. Lin, Acc. Chem. Res. 2008, 41, 521 – 537, and references therein.
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Received: August 20, 2014 Published online on October 24, 2014
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