Design and Synthesis of New Macrocyclic Cyclophanes Using 1,3-Dioxane Units as Bridges: A Molecular “Rocking Chair” Mirela Balog,†,‡ Ion Grosu,*,†,‡ Ge´rard Ple´,*,‡ Yvan Ramondenc,‡ Eric Condamine,‡ and Richard A. Varga§ Organic Chemistry Department and CSOFSTM and National Laboratory of X-ray Diffractometry, “Babes-Bolyai” University, 11 Arany Janos str., RO-3400 Cluj-Napoca, Romania, and Universite´ de Rouen, IRCOF, UMR 6014, Faculte´ des Sciences, 76821 Mont Saint-Aignan, Cedex, France
[email protected] Received September 24, 2003
The design, synthesis and structural analysis of architecturally new cyclophanes (monomers, dimers, and trimers) are reported. Variable temperature NMR experiments reveal a regular, tandem dynamic in the cyclophane 2a that enables its description as a “molecular rocking chair”. The NMR and X-ray structure investigations show important intra- and intermolecular aromatic π-stacking interactions. Introduction Inspired by the intricate machinery of F0F1-ATP synthase1 that indicated the possibility of constructing devices at a molecular scale for the conversion of energy into work, a plethora of “molecular motors”2 and other “molecular devices” or “tools”3 such as compasses,3a,b gyroscopes,3a,b brakes,3c ratchets,3d turnstiles,3e shuttles,3f saddles,3g and mousetraps,3h have been reported. A vast majority of the molecular engines pertain to the rotaxane family, but [n]catenands, cryptands, and cyclophanes with a peculiar structure are also used in the design of molecular devices. Cyclophanes are bridged aromatic compounds and attractive synthetic targets as a result of their intriguing chemical, physicochemical, and biological properties.4 * To whom correspondence should be addressed. Phone: 40-2-64593833. Fax: 40-2-64-590818. † Organic Chemistry Department and CSOFSTM, “Babes-Bolyai” University. ‡ Universite ´ de Rouen. § National Laboratory of X-ray Diffractometry “Babes-Bolyai” University. (1) (a) Boyer, P. D. Angew. Chem. 1998, 110, 2424-2307; Angew. Chem., Int. Ed. 1998, 37, 2296-2307. (b) Walker, J. E. Angew. Chem. 1998, 110, 2438-2450; Angew. Chem., Int. Ed. 1998, 37, 2308-2319. (2) (a) Schalley, C. A.; Beizai, K.; Vo¨gtle, F. Acc. Chem. Res. 2001, 34, 465-476. (b) Balzani, V.; Credi, A.; Raymo F. M.; Stoddart, J. F. Angew. Chem., Int. Ed. 2000, 39, 3348-3391. (c) Kelly, T. R.; Silva, R. A.; De Silva, H.; Jasmin, S.; Zhao, Y. J. Am. Chem. Soc. 2000, 122, 6935-6949. (d) Balzani, V.; Go´mez-Lo´pez, M.; Stoddart, J. F. Acc. Chem. Res. 1998, 31, 405-414. (3) (a) Dominguez, Z.; Dang, H.; Strouse, M. J.; Garcia-Garibay, A. J. Am. Chem. Soc. 2002, 124, 2398-2399. (b) Dominguez, Z.; Dang, H.; Strouse, M. J.; Garcia-Garibay, A. J. Am. Chem. Soc. 2002, 124, 7719-7727. (c) Kelly, T. R.; Bowyer, M. C.; Bhaskar, K. V.; Bebbington, D.; Garcia, A.; Lang, F.; Kim, M. H.; Jette, M. P. J. Am. Chem. Soc. 1994, 116, 3657-3658. (d) Kelly, T. R.; Sestelo, J. P.; Tellitu, M. P. J. Org. Chem. 1998, 63, 3655-3665. (e) Bedard, T. C.; Moore, J. S. J. Am. Chem. Soc. 1995, 117, 10662-10671. (f) Cao, J.; Fyfe, M. C. T.; Stoddart, J. F.; Cousins G. R. L.; Glink, P. T. J. Org. Chem. 2000, 65, 1937-1946. (g) Christensen, C. A.; Batsanov, A. S.; Bryce, M. R.; Howard, J. A. K. J. Org. Chem. 2001, 66, 3313-3320. (h) Julian, R. R.; May, J. A.; Stoltz, B. M.; Beauchamp, J. L. Angew. Chem., Int. Ed. 2003, 42, 1012-1015.
Special attention has been given in recent years to the synthesis of chiral derivatives of the parent [2.2]paracyclophane, to their applications in stereoselective reactions,5 and to the design and synthesis of cyclophanes with different cavities as molecular “hosts”.6 (4) (a) Weber, E. Cyclophanes. In Topics in Current Chemistry; Springer-Verlag: Berlin, Germany, 1994; Vol. 172. (b) Vo¨gtle, F. Cyclophane Chemistry: Synthesis, Structures and Reactions; John Wiley and Sons: Chichester, UK, 1993. (c) Diederich, F. Cyclophanes; Royal Society of Chemistry: Cambridge, UK, 1991. (d) Keehn, P. M.; Rosenfeld, S. M. Cyclophanes; Academic Press: New York, 1983; Vols. 1 and 2. (e) Boekelheide, V. Synthesis and Properties of [2n]Cyclophanes. In Topics in Current Chemistry; Springer-Verlag: New York, 1983. (f) Smith, B. H. Bridged Aromatic Compounds; Academic Press: New York, 1964. (5) (a) Gibson, S. E.; Knight, J. D. Org. Biomol. Chem. 2003, 1, 1256-1269. (b) Rozenberg, V. I.; Danilova, T. I.; Sergeeva, E. V.; Shouklov, I. A.; Starikova, Z. A.; Hopt, H.; Ku¨hlein, K. Eur. J. Org. Chem. 2003, 432-440. (c) Islas-Gonzales, G.; Bois-Choussy, M.; Zhu J. Org. Biomol. Chem. 2003, 1, 30-32. (d) Wu, X.-W.; Yuan, K.; Sun, W.; Zhang M.-J.; Hou, X.-L. Tetrahedron: Asymmetry 2003, 14, 107112. (e) Braddock, D. C.; MacGilp, I. D.; Perry, B. G. J. Org. Chem. 2002, 67, 8679-8681. (f) Cipiciani, A.; Fringuelli, F.; Piermatti, O.; Pizzo, F.; Ruzziconi, R. J. Org. Chem. 2002, 67, 2665-2670. (g) Taticchi, A.; Minuti, L.; Marrocchi, A.; Lanari, D.; Gacs-Baitz, E. Tetrahedron: Asymmetry 2002, 13, 1331-1335. (h) Sergeeva, E. V.; Rozenberg, V. I.; Antonov, D. Y.; Vorontsov E. V.; Starikova, Z. A.; Hopt, H.; Tetrahedron: Asymmetry 2002, 13, 1121-1123. (i) Minuti, L.; Taticchi, A.; Rosini, C.; Lanari, D.; Marrocchi, A.; Superchi, S. Tetrahedron: Asymmetry 2002, 13, 1257-1263. (6) (a) Tae, J.; Yang, Y.-K. Org. Lett. 2003, 5, 741-744. (b) Smith, B. B.; Hill, D. E.; Cropp, T. A.; Walsh, R. D.; Cartrette, D.; Hipps, S.; Shachter, A. M.; Pennington, W. T.; Kwochka, W. R. J. Org. Chem. 2002, 67, 5333-5337. (c) Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Org. Lett. 2002, 4, 11-14. (d) Nielsen, K. A.; Jeppesen, J. O.; Levillain, E.; Thorup, N.; Becher, J. Org. Lett. 2002, 4, 4189-4192. (e) Park, K. K.; Lim, H.; Kim, S.-H.; Bae D. H. J. Chem. Soc., Perkin Trans. 1 2002, 310-314. (f) Rajakumar, P.; Murali, V.; Tetrahedron Lett. 2002, 43, 7695-7698. (g) Srinivasan, M.; Sankararaman, S.; Hopf, H.; Dix, I.; Jones, P. G. J. Org. Chem. 2001, 66, 4299-4303. (h) Yamato, T.; Fujita, K.; Tsuzuki, H. J. Chem. Soc., Perkin Trans. 1 2001, 2089-2097. (i) Benniston, A. C.; Clegg, W.; Harriman, A.; Harrington, R. W.; Li, P.; Sams, C. Tetrahedron Lett. 2003, 44, 2665-2667. (j) Srinivasan, M.; Sankararaman, S.; Hopf, H.; Varghese, B. Eur. J. Org. Chem. 2003, 660-665. (k) Bauer, H.; Stier, F.; Petry, C.; Knorr, A.; Stadler, C.; Staab, H. A. Eur. J. Org. Chem. 2001, 3255-3278. (l) Prautzsch, V.; Ibach, S.; Vo¨gtle, F. J. Inclusion Phenom. Macrocyclic Chem. 1999, 33, 427-457.
10.1021/jo0353987 CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/22/2004
J. Org. Chem. 2004, 69, 1337-1345
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Many properties that are characteristic to macrocyclic cyclophanes, both in solution and in the solid state, are correlated with the intramolecular or intermolecular interactions between the aromatic rings.4 The importance of aromatic π-π stacking interactions, in general, stems from the contribution of these forces to the tertiary and quaternary structure of proteins,7 to the “host-guest” binding in macrocyclic compounds, and to the recognition processes.8 Many recent studies9 have investigated the nature of the forces involved in the interactions between aromatic rings and the factors that influence the magnitude of these interactions. Aromatic interactions are apparent in NMR or X-ray investigations in macrocyclic cyclophanes. We report herein the design, synthesis, and NMR and single crystal X-ray diffraction based analysis of a series of unprecedented cyclophanes, which have embedded in their molecules 1,3-dioxane rings to bridge the benzene rings. Our efforts to obtain new macrocyclic cyclophanes started with careful observations on the stereochemistry of several bis(1,3-dioxane-2-yl)benzene derivatives, previously reported from our laboratories.10 We recognized that these molecules possess the pre-organization element that would facilitate their inclusion in macrocyclic molecular architectures. The 1,3-dioxane derivatives of 1,4-diacetylbenzene (Chart 1, I)10c exhibit an interesting anancomeric structure; the aromatic group prefers the axial orientation and the orthogonal rotamer relative to both heterocycles. The structure of I is in agreement with the axial preference of the aromatic group of about 2.42 kcal/mol measured in 2-methyl-2-phenyl-1,3-dioxane.11 These compounds are easily obtained by acetalization of 1,4-diacetylbenzene with 1,3-propanediols. If they exhibit appropriate groups at the positions 5′ and 5′′ of the heterocycles (R in Chart (7) (a) Burley, S. K.; Petsko G. A. Science 1985, 229, 23-28. (b) Burley, S. K.; Petsko G. A. Adv. Protein Chem. 1988, 39, 125-189. (c) Brandl, M.; Weiss, M. S.; Jabs, A.; Su¨hnel, J.; Hilgenfeld, R. J. Mol. Biol. 2001, 307, 357-377. (8) (a) Fyfe, M. C. T.; Stoddart, J. F. Acc. Chem. Res. 1997, 30, 393401. (b) Kim, K. S.; Tarakeshwar, P.; Lee, J. Y. Chem. Rev. 2000, 100, 4145-4186. (c) Brutschy, B. Chem. Rev. 2000, 100, 3891-3920. (d) Mahoney, J. M.; Shukla, R.; Marshall, R. A.; Beatty, A. M.; Zajicek, J.; Smith B. D. J. Org. Chem. 2002, 67, 1436-1440. (e) KorybutDaszkiewicz, B.; Wieckowska, A.; Bilewicz, R.; Domagala, S.; Woz´niak, K. J. Am. Chem. Soc. 2001, 123, 9356-9366. (f) Kishikawa, K.; Tsubokura, S.; Kohmoto, S.; Yamamoto, M.; Yamaguchi, K. J. Org. Chem. 1999, 64, 7568-7578. (9) (a) Jennings, W. B.; Farrell, B. M.; Malone, J. F. Acc. Chem. Res. 2001, 34, 885-894. (b) Chessari, G.; Hunter, C. A.; Low, C. M. R.; Packer, M. J.; Vinter, J. G.; Zonta, C. Chem. Eur. J. 2002, 8, 28602867. (c) Ribas, J.; Cubero, E.; Luque, F. J.; Orozco, M. J. Org. Chem. 2002, 67, 7057-7065. (d) Carver, F. J.; Hunter, C. A.; Livingstone, D. J.; McCabe, J. F.; Seward, E. M. Chem. Eur. J. 2002, 8, 2847-2859. (e) Cozzi, F.; Annunziata, R.; Benaglia, M.; Cinquini, M.; Raimondi, L.; Baldridge, K. K.; Siegel, J. S. Org. Biomol. Chem. 2003, 1, 157162. (f) Rashkin, M. J.; Walters, M. L. J. Am. Chem. Soc. 2002, 124, 1860-1861. (g) Kim, C.-Y.; Chandra, P. P.; Jain, A.; Christianson, D. W. J. Am. Chem. Soc. 2001, 123, 9620-9627. (h) Acharya, P.; Plashkevych, O.; Morita, C.; Yamada, S.; Chattopadhyaya, J. J. Org. Chem. 2003, 68, 1529-1538. (i) Nakamura, K.; Houk, K. N. Org. Lett. 1999, 1, 2049-2051. (j) Martin, C. B.; Mulla, H. R.; Willis, P. G.; Cammers-Goodwin, A. J. Org. Chem. 1999, 64, 7802-7806. (10) (a) Grosu, I.; Mager, S.; Ple´, G.; Ple´, N.; Toscano, A.; Mesaros, E.; Martinez, R. Liebigs Ann./Recl. 1997, 2371-2377. (b) Grosu, I.; Mager, S.; Toupet, L.; Ple´, G.; Mesaros, E.; Mihis, A. Acta Chem. Scand. 1998, 52, 366-371. (c) Grosu, I.; Muntean, L.; Toupet, L.; Ple´, G.; Pop, M.; Balog, M.; Mager, S.; Bogdan, E. Monatsh. Chem., 2002, 133, 631641. (11) Anteunis, M. J. O.; Tavernier D.; Borremans, F. Heterocycles 1976, 4, 293-361.
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CHART 1. Structure of 1,3-Dioxane Derivatives of 1,4-Diacetylbenzene (I)
1), these derivatives can be versatile substrates in the synthesis of macrocyclic cyclophanes. The cyclization processes are predicted to be more favorable than the open chain reactions as a result of the discussed restriction in a “productive” conformation. Also worth noting is that the steric constraint and the semiflexible behavior of the target cyclophanes may determine concerted movements of parts of the molecules similar with those observed at “macro” scale during the work of common (household) devices. Results and Discussion The synthesis of the new macrocyclic cyclophanes (24) was performed by reacting the cis,cis isomer of compound 1 with isomeric phthaloyl dichlorides (Scheme 1), using DMAP as the base and acetonitrile as the solvent, by a typical procedure for the synthesis of macrocyclic esters.3g,12 The different macrocycles (monomers, dimers, and trimers; Chart 2, Table 1) were separated by flash chromatography. The attempts to obtain similar macrocycles in the reaction of terephthaloyl dichloride with the other two stereoisomers (trans,trans and trans,cis) of compound 1 failed. This result is most likely due to the two hydroxymethyl groups in these two isomers being too far apart to be stitched together with a terephthaloyl moiety and to the steric hindrance that would be produced in the cyclophanes by the equatorial methyl group(s) of the 1,3-dioxane rings [positions 5′ (5′′)]. The yield of 2a (monomer) was very good, with only traces of dimer 2b and trimer 2c formed, whereas the syntheses of 3 and 4 proceeded with the formation of important amounts of dimer (3b, 4b) and trimer (3c, 4c) macrocycles (see Table 1). It is remarkable the increase of the ratio of the monomer to the other two macrocycles and of the overall yields (see Table 1) when going from ortho- to meta- and finally to terephthaloyl dichloride. These trends correlate well with the “fit” of the hydroxymethyl groups in 1 with the acid chloride groups in the other reactant. The distance between the functional groups in terephthaloyl dichloride appears to be (12) (a) Godbert, N.; Batsanov, A. S.; Bryce, M. R.; Howard, J. A. K. J. Org. Chem. 2001, 66, 713-719. (b) Ranganathan, D.; Haridas, V.; Karle, I. L. Tetrahedron 1999, 55, 6643-6656. (c) Mertens, I. J. A.; Jenneskens, L. W.; Vlietstra, E. J.; van der Kerk-van Hoof, A. C.; Zwikker, J. W.; Smeets, W. J. J.; Spek, A. L. J. Chem. Soc., Chem. Commun. 1995, 1621-1622. (d) Wang, T.; Bradshaw, J. S.; Huszthy, P.; Kou, X.; Dalley, N. K.; Izatt, R. M. J. Heterocyclic Chem 1993, 31, 1-10.
A Molecular “Rocking Chair” SCHEME 1
CHART 2.
Structural Formulas of Cyclophanes 2-4: (a) Monomers, (b) Dimers, and (c) Trimers
the “optimum” (albeit with some conformational reorganization, vide infra) for reacting with both alcohol groups in 1 and thus favoring the monomer, on the expense of the other cyclic terms, and of the intermolecular processes. Compound 2a was isolated cleanly by chromatography as a single product, whereas the dimer 2b and the trimer 2c could only be isolated each as mixtures of three components: the macrocycle and complexes with one and, respectively, two molecules of DMAP. These macrocycles
and their complexes with DMAP were identified by MALDI-TOF spectra. The structural investigations revealed significant differences among monomers, dimers, and trimers and among the different isomers (ortho, meta, and para) of the series. Structure of 2a. A Molecular “Rocking Chair”. The synthesis of 2a occurs with the modification of the conformation of the 1,3-dioxane rings. One of the 1,3dioxane rings (named Ar-ax) keeps the axial orientation J. Org. Chem, Vol. 69, No. 4, 2004 1339
Balog et al. SCHEME 2
TABLE 1. Data Concerning the Synthesis of Compounds 2-4 compound
position of ester groups
n
macrocycle
yields (%)
2a 2ba 2ca 3a 3b 3c 4a 4b 4c
para para para meta meta meta ortho ortho ortho
1 2 3 1 2 3 1 2 3
monomer dimer trimer monomer dimer trimer monomer dimer trimer
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