DOI: 10.1002/chem.201404470
Communication
& Macrocycle Synthesis
Heteroaromatic Belts through Fold-in Synthesis: Mechanistic Insights into a Macrocycle-Templated Friedel–Crafts Alkylation Mateusz Kondratowicz, Damian Mys´liwiec, Tadeusz Lis, and Marcin Ste˛pien´*[a] form the belt-like trimethanocyclophane 3B (Scheme 1). The reaction can be performed in the presence of either Lewis or Brønsted acids, such as boron trifluoride (BF3·Et2O) or p-toluenesulfonic acid (p-TsOH). The bridging transformation causes a significant change of molecular topology by simultaneously closing three lateral seven-membered rings[27–30] and the 21membered upper rim of the molecule. Thus, given the presence of a 27-atom circuit in the 0B macrocycle, the formation of 3B can be classified as a fold-in reaction.[24, 26] To the best of our knowledge, the synthesis of 3B is the first example of directly converting an unfunctionalized cyclophane into a complete belt-like structure. The structure of 3B was confirmed by an X-ray crystallographic analysis (Figure 1). The molecular shape of 3B can be
Abstract: Direct alkylation of 9,9’,9’’-triethyl[2.2.2] (2,7)carbazolophane with dimethoxymethane or paraformaldehyde affords a belt-like heteroaromatic structure, which forms as a kinetic product in acid-catalyzed condensations. In a competing, thermodynamically favored process, polymeric structures are formed by a largely regioselective condensation of stereochemically rigid “semibelts”. The relationship between these reactivity routes is rationalized in terms of strain release and differential reversibility of consecutive condensation steps.
p-Conjugated molecules containing well-defined cavities have attracted considerable attention because of their potential utility as receptors,[1–3] containers,[4, 5] chromophores,[6] or components for organic electronics.[7, 8] Synthetic efforts directed at obtaining such systems have led to the development of several structurally distinct families of p-conjugated cavities, including calixarenes,[9–13] nanotube-inspired systems,[14–20] bowl-shaped aromatics,[3, 21–24] and oligoporphyrin belts.[6, 25] In many of these systems, the cavity is made of a strand of aromatic subunits and may show a varying degree of conformational flexibility, dependent on the size of the macrocycle and steric congestion. The relative orientation of subunits Scheme 1. The fold-in synthesis of trimethanocyclophane 3B and the formation of methcan be stabilized, even in very large macrocycles, by anocyclophane 1B (R = Et). introducing an additional set of bridges, leading to a “molecular belt”. This strategy, while highly attractive, is generally difficult to implement synthetically.[15, 17] Here described as a triangular frustum with a height of approximately 4.0 , measured between the two H6 planes consisting, we report on a prototypical carbazole-based system with respectively, of top and bottom carbazole hydrogen atoms. a belt-like structure, synthesized according to the recently reThe carbazole subunits are inclined by approximately 608 relaported fold-in approach.[24, 26] Mechanistic details of this synthetive to the basal H6 plane of the frustum and are curved slightsis are investigated, affording a glimpse of the connections bely outwards. The interior of 3B forms a cavity, which in the tween internal strain, reaction kinetics, and product selectivity crystal is occupied by an ethyl substituent of an adjacent molein the Friedel–Crafts alkylation. cule (base-to-base interaction, Figure 1B). A top-to-top interac9,9’,9’’-Triethyl[2.2.2](2,7)carbazolophane 0B undergoes an tion is also observed, in which the methylene bridges of adjaacid-catalyzed condensation with formaldehyde equivalents cent 3B molecules are meshed together, in a manner resemsuch as dimethoxymethane (DMM) or paraformaldehyde, to bling the Hirth joint. The experimental geometry of 3B is well reproduced by standard DFT calculations. The internal strain [a] M. Kondratowicz, D. Mys´liwiec, Prof. T. Lis, Dr. M. Ste˛pien´ Wydział Chemii, Uniwersytet Wrocławski energy of 3B (R = H), estimated by using DFT relative to the ul. F. Joliot-Curie 14, 50-383 Wrocław (Poland) unbridged 0B precursor, is 10.7 kcal mol 1 (Scheme S2 in the E-mail: [email protected] Supporting Information). This value is thought to reflect the Homepage: http://www.mstepien.edu.pl out-of-plane distortions of carbazole subunits and the Pitzer Supporting information for this article is available on the WWW under strain within seven-membered rings. http://dx.doi.org/10.1002/chem.201404470. Chem. Eur. J. 2014, 20, 1 – 6
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Communication The fold-in synthesis of 3B proceeds in a stepwise manner, beginning with the formation of a singly bridged carbazolophane 1B (Scheme 1), which constitutes a point of divergence for subsequent reactivity. Yields of 1B can be maximized by using a stoichiometric amount of DMM or by shortening the reaction time. However, extended reaction times do not bring the condensation to completion when 1 equivalent of DMM is used, possibly indicating that the formation of 1B is partly reversible. The molecular structure of 1B was determined by an X-ray diffraction analysis (Figure 1) and further confirmed by means of high resolution mass spectrometry, NMR spectroscopy, and GIAO-DFT calculations. In the solid state, 1B adopts a heart-shaped conformation, with the ethyl substituent (9’-Et) of the unbridged carbazole unit located inside the cavity of the macrocycle. In both X-ray and DFT-optimized geometries, out-of-plane distortions of the carbazole subunits are limited to the doubly bridged fragment, and consequently, the calculated strain energy of 1B is only 4.8 kcal mol 1. The orientation of the 3’,3’-unsubstituted carbazole is retained in solution and the cumulative ring current effects of the bridged dicarbazole fragment result in marked shielding of the 9’-Et substituent, with the signal of the CH3 group shifted characteristically to 1.43 ppm. As in the case of 3B, the 1H NMR spectrum of 1B reveals diastereotopic methylene and ethylene signals and remains sharp up to 410 K in [D10]xylene and no signs of belt inversion are observed in the NOESY spectrum. The rigidity of 3B and 1B distinguishes these two compounds from the parent 0B cyclophane, which displays a fully symmetric 1 H NMR spectrum at 300 K, corresponding to complete conformational flexibility. Interestingly, even though the bridging reaction is templated on a cyclophane macrocycle, intermolecular processes efficiently compete with intramolecular bridging even at high dilution, leading to modest isolated yields of 3B. When 0B (0.1 mm in CH2Cl2) was subjected to condensation with paraformaldehyde (10 equiv) catalyzed with p-TsOH (13 mm, 18 h reaction time), a small amount of an initial oligomerization product, 1B2, was isolated in addition to 1B by means of thin-layer chromatography (Scheme 2). The identity of 1B2 was established on the basis of its high resolution mass spectrum and a detailed analysis of one- and two-dimensional NMR data. It was found that the structure of 1B2 consists of two 1B rings connected by an exocyclic CH2 bridge attached to two 3’ positions of the unbridged carbazole moieties. Because of the stereochemical rigidity of the 1B ring, substitution of the 3’ position induces the formation of a chirality plane. Consequently, 1B2 was isolated as a mixture of stereoisomers, an enantiomeric pair (C2 symmetry) and a meso form (Cs symmetry), denoted rac-1B2 and meso-1B2, respectively. The rac and meso isomers could be distinguished by their 1H NMR spectra (Figure 2) because they yield different exocyclic CH2 signals (s3’a, Scheme 2); respectively, a singlet (4.35 ppm) and a diastereotopic AB pair (4.38, 4.34 ppm, 2J 12 Hz, Figure S2 in the Supporting Information). rac-1B2 and meso-1B2 were observed in comparable amounts in crude reaction mixtures, indicating that the formation of the exocyclic bridge is not stereoselective.
Figure 1. X-ray crystal structures of 3B (A, B) and 1B (C, D). Solvent molecules are omitted for clarity. Endo and exo positions in 3B and 1B are defined relative to the interior of the belt (D).
The 1H NMR spectrum of 3B revealed the presence of just one type of symmetrically substituted carbazole (signals at 7.75, 6.58, 3.38, and 0.72 ppm) and was thus consistent with an effective C3v symmetry of the molecule (Figure 2). The methylene and ethylene bridges in 3B are distinctly diastereotopic, yielding, respectively, an AB spin system (4.60 and 3.80 ppm, 2 J = 12.5 Hz), and an AA’BB’ system (3.62 and 2.95 ppm). In both types of bridge, the endo protons (Figure 1) are more strongly shielded than the corresponding exo protons. GIAODFT 1H and 13C chemical shieldings calculated for 3B are in very good agreement with the experimental values (Figures S11–S12 in the Supporting Information). No chemical exchange within the endo–exo pairs could be detected at 400 K in [D10]xylene by using EXSY spectroscopy, indicating that no cage inversion occurs under these conditions. This observation is consistent with DFT calculations predicting a uniquely high energy barrier to inversion (141 kcal mol 1) associated with a distorted, C2-symmetric transition state (Figure S15 in the Supporting Information).
Abstract in Polish: Bezpos´rednie alkilowanie 9,9’,9’’-trietylo[2.2.2](2,7)karbazolofanu za pomoca˛ dimetoksymetanu lub paraformaldehydu prowadzi do powstania heteroaromatycznego „pasa molekularnego,“ ktry tworzy sie˛ jako produkt kinetyczny w katalizowanych kwasem kondensacjach. W konkurencyjnym, preferowanym termodynamicznie procesie powstaja˛ ze znaczna˛ regioselektywnos´cia˛ polimeryczne struktury złoz˙one ze stereochemicznie sztywnych podjednostek zawieraja˛cych pojedynczy mostek metylenowy. Zalez˙nos´ci pomie˛dzy poszczeglnymi ´sciez˙kami reaktywnos´ci uzasadniono zmianami w wewne˛trznych napre˛z˙eniach poszczeglnych produktw i zrz˙nicowanej odwracalnos´ci kolejnych etapw kondensacji.
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Figure 2. 1H NMR spectra (600 MHz, [D]chloroform, 300 K, unless noted otherwise) of compounds 3B ([D8]toluene), 1B, 1B2, and 1Bn (330 K) with signal assignments derived from 2D NMR spectroscopy. Labels are defined in Schemes 1 and 2. Endo and exo positions are defined in Figure 1. The region containing 9b signals is shown only for 1Bn. The original rac/meso isomer ratio in 1B2 (ca. 1:1) was altered during purification.
Scheme 2. Structures of the oligomeric derivatives of 1B. Potential modifications of the 1Bn chain are shown in gray boxes. rac-1B2 is represented by one enantiomer. Stereoisomerism of 1Bn is not indicated. R = Et, Y = OH or Ar, Ar = additional 1B subunit linked through a 3’ or 6 position. s- and u- prefixes denote, respectively, the 3’-substituted and 3’-unsubstituted halves of the 1B ring.
Prolonged condensations performed in the presence of an excess of a formaldehyde equivalent led to the formation of a polymeric product, 1Bn. A representative 1H NMR spectrum of 1Bn, synthesized from 0B under moderate dilution (6.6 mm in CH2Cl2, 10 equiv paraformaldehyde, 2 equiv p-TsOH, 4 h) is shown in Figure 2. In spite of severe broadening, the spectrum displays striking similarities to the spectra of 1B and 1B2. Aromatic and aliphatic signals cover similar ranges of chemical shifts and, most significantly, a broad peak is present at the unusual shift of approximately 1.5 ppm, indicating that 1Bn is actually composed of 1B subunits. Further support for this structural proposal was provided by the NOESY and 1H-13C HSQC spectra of 1Bn, which enabled the identification of the key structural features of the 1B ring (Figures S4–S5 in the Supporting Information). The above synthesis yields a polymer Chem. Eur. J. 2014, 20, 1 – 6
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with the weight-average molecular weight (Mw) of approximately 4.3–5.4 kDa, estimated by using diffusion-ordered NMR spectroscopy (DOSY, Figure S6 in the Supporting Information).[31] Because of the high molecular weight of the monomer unit, the above Mw value corresponds to a relatively low average chain length of approximately 6.4–8.0 units. This estimate agrees with the MALDI-TOF spectrum of 1Bn, which revealed oligomer lengths of up to n = 18 subunits. The NMR data are consistent with the formulation of 1Bn as a cyclophane-based[32] oligomer, in which 1B units are linked through the 3’ positions, to form a methylene-carbazole[33–35] backbone (Scheme 2). The presence of a stereogenic plane in the 1B unit leads to stereoisomerism in the 1Bn chain, and the two diastereomers of 1B2 can serve as models of the respective racemo and meso dyads in 1Bn. The extreme broadening 3
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Communication of the 1H NMR spectrum of 1Bn is indicative of low stereoregularity, which is expected in view of the non-stereoselective formation of 1B2. The end groups in 1Bn could not be reliably determined by NMR spectroscopy, however, MALDI spectra indicate that the chains might be terminated with either unsubstituted 3’ positions or with 3’-CH2OH groups. At the microscopic level, the structure of 1Bn can depart from the proposed linear 3’,3’-linked motif in several ways (Scheme 2). Positions 6 on the bridged dicarbazole fragment of 1B are potentially susceptible to electrophilic attack, thus providing an alternative route to oligomerization. The resolution of the NMR spectra of 1Bn is insufficient to detect small contributions of 6-substitution; however, the dominance of 3’-alkylation is indicated by specific spectral features, including (a) the significant intensity of the 6-H peak (6.5 ppm), (b) the s1’-C shift in 1Bn (109.7–110.7 ppm) corresponding with s1’-C in 1B2 (110.2 ppm) rather than with u1’-C (109.0 ppm), and (c) the close similarity between 13C shifts of the remaining carbazole positions observed in the HSQC spectra of 1B2 and 1Bn. Freshly prepared 1Bn displays a characteristic blue color in solution (lmax 630 nm), which, in analogy to simple methylene-carbazole polymers,[34, 35] can be attributed to a small contribution of oxidized s3’a bridges (Scheme 2). Because of their carbocationic character, such oxidized bridges can undergo further condensation, leading to oligomer branching,[35] though in the case of 1Bn, the process may be hindered sterically. The solubility of solid samples of 1Bn was observed to decrease over time, indicating that the material is indeed capable of spontaneous cross-linking. The progress of the bridging reaction was monitored spectroscopically for two different initial concentrations of 0B (Figure 3). For [0B]0 = 0.1 mm, the molar fraction of 1B reached
solubility of the polymer. For [0B]0 = 0.01 mm, the above reactivity pattern was retained but the overall conversion rate was slower. However, higher dilution improved the maximum observed fraction of 3B to approximately 0.14. The observed difference between typical isolated yields of 3B (ca. 3 %) and the above NMR estimates is believed to be largely due to purification losses. The mechanistic picture emerging from the above experiment is outlined in Scheme 3. The use of a large excess of
Scheme 3. Proposed mechanism for the bridging reaction between 0B and an excess of the formaldehyde equivalent. Y = CH2OH or CH2OMe. 2B 2BY 0.
DMM effectively drives the formation of 1B to completion, as all subsequent products contain at least one endocyclic methylene bridge. Alkylated species, such as 0B-Y, 1B-Yx, and 2B-Yy (Y = CH2OH, CH2OMe; y > 0), which are the expected intermediates in the bridge-forming reactions, were not identified among the major reaction products. Their effective absence in processed reaction mixtures is thought to indicate that, for the studied [0B]0 range, the second C C bond is formed more rapidly than the first one[36] in the course of both inter- and intramolecular bridging. In contrast to 1B, which is the key intermediate en route to 3B, the expected doubly bridged species 2B was not observed among the major products at any stage of the condensation. Because of the steric hindrance at the unsubstituted 6’ positions (Scheme 3), 2B is unlikely to undergo faster substitution than 1B, so the apparent absence of 2B is not thought to result from its rapid consumption in subsequent bridging but rather indicates its less efficient (and likely reversible) formation. In partial support of the latter assumption, the strain energy calculated for 2B (11.3 kcal mol 1, R = H) is higher than the value obtained for 3B. A potentially efficient route to 3B may therefore involve a double alkylation of 1B to an appropriately substituted 1B-Y2, followed by two sequential bridging steps, leading, respectively, to 2B-Y and 3B. Although fast equilibration is expected to occur in the first of these steps, the reversal of the ultimate ring closure is slow enough to provide isolable quantities of 3B. The observed conversion of 3B into 1Bn during prolonged condensations indicates that
Figure 3. Reaction between 0B and DMM, monitored with 1H NMR spectroscopy. Molar fractions (x) were obtained by integration of 1H NMR spectra recorded for quenched aliquots of the reaction mixture. Initial conditions: dichloromethane solvent, [DMM]0 = 10 mm, [BF3·Et2O]0 = 10 mm.
a maximum of approximately 0.44 after 3 min of reaction time, and then declined in the course of subsequent condensation steps. 3B and 1Bn formed concurrently, in an approximate molar ratio of 1:7, until the complete consumption of 1B. The molar fraction of 3B reached approximately 0.11 after 7 min, and then slowly decreased, so that the compound was no longer detectable after 2 h. Simultaneously, 1Bn underwent further polycondensation, which was inferred from the decreasing &
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Communication opening of endocyclic methylene bridges is both kinetically feasible and thermodynamically favored. The above analysis shows that the bridging reaction occurs under a mixture of thermodynamic and kinetic control, which is a typical feature of many arene–aldehyde condensations.[9, 12, 37, 38] Complete equilibration in such reactions is usually preferred, because it provides dynamic covalent chemistry conditions[37] and enables efficient macrocycle formation at relatively high reactant concentrations. However, equilibrium conditions yield products with the smallest internal strain, so that only strain-free cyclic structures can compete with polymer formation. In the present case, the competition between the differently strained products 1Bn and 3B, occurs remarkably at both the kinetic and thermodynamic levels. Consequently, the optimum conditions for the synthesis of 3B combine high dilution (to limit the kinetically competing polymerization) with short reaction times (to suppress the thermodynamically driven loss of 3B). In summary, we have shown that direct alkylation of carbazolophanes with formaldehyde equivalents can provide access to belt-like heteroaromatic structures and topologically nontrivial polymers. Our work indicates that moderately strained cyclization products that are not normally observed in reversible reactions can have a transient existence before the equilibrium is reached. Performing the Friedel–Crafts alkylation on a macrocyclic template provides an unexpected insight into the kinetic and thermodynamic features of the bridging reaction, which can be valuable in subsequent development of this chemistry. We hope that further refinements of the proposed approach may provide a practical method of synthesizing functional molecules and macromolecules with complex multicyclic topologies.
[5] B. W. Purse, J. Rebek, Proc. Natl. Acad. Sci. USA 2005, 102, 10777 – 10782. [6] N. Aratani, D. Kim, A. Osuka, Acc. Chem. Res. 2009, 42, 1922 – 1934. [7] A. V. Zabula, A. S. Filatov, S. N. Spisak, A. Y. Rogachev, M. A. Petrukhina, Science 2011, 333, 1008 – 1011. [8] S. T. Schneebeli, M. Frasconi, Z. Liu, Y. Wu, D. M. Gardner, N. L. Strutt, C. Cheng, R. Carmieli, M. R. Wasielewski, J. F. Stoddart, Angew. Chem. 2013, 125, 13338 – 13342; Angew. Chem. Int. Ed. 2013, 52, 13100 – 13104. [9] C. D. Gutsche, Calixarenes: An Introduction, Royal Society Of Chemistry, Cambridge, 2008. [10] A. Szumna, Chem. Soc. Rev. 2010, 39, 4274 – 4285. [11] T. Ogoshi, S. Kanai, S. Fujinami, T. Yamagishi, Y. Nakamoto, J. Am. Chem. Soc. 2008, 130, 5022 – 5023. [12] S. T. Schneebeli, C. Cheng, K. J. Hartlieb, N. L. Strutt, A. A. Sarjeant, C. L. Stern, J. F. Stoddart, Chem. Eur. J. 2013, 19, 3860 – 3868. [13] P. A. Gale, J. L. Sessler, V. Krl, V. Lynch, J. Am. Chem. Soc. 1996, 118, 5140 – 5141. [14] R. Herges, in Modern Cyclophane Chemistry (Eds.: R. Gleiter, H. Hopf), Wiley-VCH, Weinheim, 2005, pp. 337 – 358. [15] R. Gleiter, B. Esser, S. C. Kornmayer, Acc. Chem. Res. 2009, 42, 1108 – 1116. [16] L. T. Scott, E. A. Jackson, Q. Zhang, B. D. Steinberg, M. Bancu, B. Li, J. Am. Chem. Soc. 2012, 134, 107 – 110. [17] D. Eisenberg, R. Shenhar, M. Rabinovitz, Chem. Soc. Rev. 2010, 39, 2879 – 2890. [18] R. Jasti, C. R. Bertozzi, Chem. Phys. Lett. 2010, 494, 1 – 7. [19] H. Omachi, Y. Segawa, K. Itami, Acc. Chem. Res. 2012, 45, 1378 – 1389. [20] S. Yamago, E. Kayahara, T. Iwamoto, Chem. Rec. 2014, 14, 84 – 100. [21] V. M. Tsefrikas, L. T. Scott, Chem. Rev. 2006, 106, 4868 – 4884. [22] Y.-T. Wu, J. S. Siegel, Chem. Rev. 2006, 106, 4843 – 4867. [23] S. Higashibayashi, H. Sakurai, Chem. Lett. 2011, 40, 122 – 128. [24] M. Ste˛pien´, Synlett 2013, 1316 – 1321. [25] M. Hoffmann, C. J. Wilson, B. Odell, H. L. Anderson, Angew. Chem. 2007, 119, 3183 – 3186; Angew. Chem. Int. Ed. 2007, 46, 3122 – 3125. [26] D. Mys´liwiec, M. Ste˛pien´, Angew. Chem. 2013, 125, 1757 – 1761; Angew. Chem. Int. Ed. 2013, 52, 1713 – 1717. [27] I. Tabushi, Z. Yoshida, F. Imishiro, Tetrahedron 1975, 31, 1833 – 1836. [28] F. Imashiro, Z. Yoshida, I. Tabushi, Bull. Chem. Soc. Jpn. 1976, 49, 529 – 532. [29] A. Tsuge, H. Nago, S. Mataka, M. Tashiro, J. Chem. Soc. Perkin Trans. 1 1992, 1179 – 1185. [30] F. R. Heirtzler, H. Hopf, P. G. Jones, P. Bubenitschek, V. Lehne, J. Org. Chem. 1993, 58, 2781 – 2784. [31] W. Li, H. Chung, C. Daeffler, J. A. Johnson, R. H. Grubbs, Macromolecules 2012, 45, 9595 – 9603. [32] Y. Morisaki, Y. Chujo, Prog. Polym. Sci. 2008, 33, 346 – 364. [33] P. Bruck, J. Org. Chem. 1970, 35, 2222 – 2227. [34] P. Bruck, A. Ledwith, A. C. White, J. Chem. Soc. B 1970, 205 – 208. [35] S. V. Lowen, J. Buschek, R. Mastantuono, D. A. Holden, G. J. Kovacs, R. O. Loutfy, Macromolecules 1990, 23, 3242 – 3249. [36] A. R. Cruz, M. C. G. Hernandez, M. T. Guzmn-Gutirrez, M. G. Zolotukhin, S. Fomine, S. L. Morales, H. Kricheldorf, E. S. Wilks, J. Crdenas, M. Salmn, Macromolecules 2012, 45, 6774 – 6780. [37] M. Holler, N. Allenbach, J. Sonet, J.-F. Nierengarten, Chem. Commun. 2012, 48, 2576 – 2578. [38] J. S. Lindsey, Acc. Chem. Res. 2010, 43, 300 – 311.
Acknowledgements Financial support from the National Science Center (Grants N N204 199340 and 2012/07/E/ST5/00781) is kindly acknowledged. Quantum chemical calculations were performed in the Wrocław Center for Networking and Supercomputing. Keywords: cyclophanes · electrophilic substitution · fused ring systems · nitrogen heterocycles · polymers [1] [2] [3] [4]
E. M. Prez, N. Martn, Chem. Soc. Rev. 2008, 37, 1512 – 1519. S. K. Kim, J. L. Sessler, Chem. Soc. Rev. 2010, 39, 3784 – 3809. A. Sygula, Eur. J. Org. Chem. 2011, 1611 – 1625. A. Jasat, J. C. Sherman, Chem. Rev. 1999, 99, 931 – 968.
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Received: July 18, 2014 Published online on && &&, 0000
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COMMUNICATION & Macrocycle Synthesis
Belts and chains: A simple Friedel– Crafts alkylation is sufficient to transform a flexible cyclophane molecule into a rigid molecular belt. The competition between different alkylation modes, governed by a mixture of kinetic and thermodynamic effects, leads to the formation of a unique polymer consisting of singly bridged semi-belts.
M. Kondratowicz, D. Mys´liwiec, T. Lis, M. Ste˛pien´* && – && Heteroaromatic Belts through Fold-in Synthesis: Mechanistic Insights into a Macrocycle-Templated Friedel–Crafts Alkylation
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& Macrocycle Synthesis
Heteroaromatic Belts through Fold-in Synthesis: Mechanistic Insights into a Macrocycle-Templated Friedel–Crafts Alkylation Mateusz Kondratowicz, Damian Mys´liwiec, Tadeusz Lis, and Marcin Ste˛pien´*[a] form the belt-like trimethanocyclophane 3B (Scheme 1). The reaction can be performed in the presence of either Lewis or Brønsted acids, such as boron trifluoride (BF3·Et2O) or p-toluenesulfonic acid (p-TsOH). The bridging transformation causes a significant change of molecular topology by simultaneously closing three lateral seven-membered rings[27–30] and the 21membered upper rim of the molecule. Thus, given the presence of a 27-atom circuit in the 0B macrocycle, the formation of 3B can be classified as a fold-in reaction.[24, 26] To the best of our knowledge, the synthesis of 3B is the first example of directly converting an unfunctionalized cyclophane into a complete belt-like structure. The structure of 3B was confirmed by an X-ray crystallographic analysis (Figure 1). The molecular shape of 3B can be
Abstract: Direct alkylation of 9,9’,9’’-triethyl[2.2.2] (2,7)carbazolophane with dimethoxymethane or paraformaldehyde affords a belt-like heteroaromatic structure, which forms as a kinetic product in acid-catalyzed condensations. In a competing, thermodynamically favored process, polymeric structures are formed by a largely regioselective condensation of stereochemically rigid “semibelts”. The relationship between these reactivity routes is rationalized in terms of strain release and differential reversibility of consecutive condensation steps.
p-Conjugated molecules containing well-defined cavities have attracted considerable attention because of their potential utility as receptors,[1–3] containers,[4, 5] chromophores,[6] or components for organic electronics.[7, 8] Synthetic efforts directed at obtaining such systems have led to the development of several structurally distinct families of p-conjugated cavities, including calixarenes,[9–13] nanotube-inspired systems,[14–20] bowl-shaped aromatics,[3, 21–24] and oligoporphyrin belts.[6, 25] In many of these systems, the cavity is made of a strand of aromatic subunits and may show a varying degree of conformational flexibility, dependent on the size of the macrocycle and steric congestion. The relative orientation of subunits Scheme 1. The fold-in synthesis of trimethanocyclophane 3B and the formation of methcan be stabilized, even in very large macrocycles, by anocyclophane 1B (R = Et). introducing an additional set of bridges, leading to a “molecular belt”. This strategy, while highly attractive, is generally difficult to implement synthetically.[15, 17] Here described as a triangular frustum with a height of approximately 4.0 , measured between the two H6 planes consisting, we report on a prototypical carbazole-based system with respectively, of top and bottom carbazole hydrogen atoms. a belt-like structure, synthesized according to the recently reThe carbazole subunits are inclined by approximately 608 relaported fold-in approach.[24, 26] Mechanistic details of this synthetive to the basal H6 plane of the frustum and are curved slightsis are investigated, affording a glimpse of the connections bely outwards. The interior of 3B forms a cavity, which in the tween internal strain, reaction kinetics, and product selectivity crystal is occupied by an ethyl substituent of an adjacent molein the Friedel–Crafts alkylation. cule (base-to-base interaction, Figure 1B). A top-to-top interac9,9’,9’’-Triethyl[2.2.2](2,7)carbazolophane 0B undergoes an tion is also observed, in which the methylene bridges of adjaacid-catalyzed condensation with formaldehyde equivalents cent 3B molecules are meshed together, in a manner resemsuch as dimethoxymethane (DMM) or paraformaldehyde, to bling the Hirth joint. The experimental geometry of 3B is well reproduced by standard DFT calculations. The internal strain [a] M. Kondratowicz, D. Mys´liwiec, Prof. T. Lis, Dr. M. Ste˛pien´ Wydział Chemii, Uniwersytet Wrocławski energy of 3B (R = H), estimated by using DFT relative to the ul. F. Joliot-Curie 14, 50-383 Wrocław (Poland) unbridged 0B precursor, is 10.7 kcal mol 1 (Scheme S2 in the E-mail: [email protected] Supporting Information). This value is thought to reflect the Homepage: http://www.mstepien.edu.pl out-of-plane distortions of carbazole subunits and the Pitzer Supporting information for this article is available on the WWW under strain within seven-membered rings. http://dx.doi.org/10.1002/chem.201404470. Chem. Eur. J. 2014, 20, 1 – 6
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Communication The fold-in synthesis of 3B proceeds in a stepwise manner, beginning with the formation of a singly bridged carbazolophane 1B (Scheme 1), which constitutes a point of divergence for subsequent reactivity. Yields of 1B can be maximized by using a stoichiometric amount of DMM or by shortening the reaction time. However, extended reaction times do not bring the condensation to completion when 1 equivalent of DMM is used, possibly indicating that the formation of 1B is partly reversible. The molecular structure of 1B was determined by an X-ray diffraction analysis (Figure 1) and further confirmed by means of high resolution mass spectrometry, NMR spectroscopy, and GIAO-DFT calculations. In the solid state, 1B adopts a heart-shaped conformation, with the ethyl substituent (9’-Et) of the unbridged carbazole unit located inside the cavity of the macrocycle. In both X-ray and DFT-optimized geometries, out-of-plane distortions of the carbazole subunits are limited to the doubly bridged fragment, and consequently, the calculated strain energy of 1B is only 4.8 kcal mol 1. The orientation of the 3’,3’-unsubstituted carbazole is retained in solution and the cumulative ring current effects of the bridged dicarbazole fragment result in marked shielding of the 9’-Et substituent, with the signal of the CH3 group shifted characteristically to 1.43 ppm. As in the case of 3B, the 1H NMR spectrum of 1B reveals diastereotopic methylene and ethylene signals and remains sharp up to 410 K in [D10]xylene and no signs of belt inversion are observed in the NOESY spectrum. The rigidity of 3B and 1B distinguishes these two compounds from the parent 0B cyclophane, which displays a fully symmetric 1 H NMR spectrum at 300 K, corresponding to complete conformational flexibility. Interestingly, even though the bridging reaction is templated on a cyclophane macrocycle, intermolecular processes efficiently compete with intramolecular bridging even at high dilution, leading to modest isolated yields of 3B. When 0B (0.1 mm in CH2Cl2) was subjected to condensation with paraformaldehyde (10 equiv) catalyzed with p-TsOH (13 mm, 18 h reaction time), a small amount of an initial oligomerization product, 1B2, was isolated in addition to 1B by means of thin-layer chromatography (Scheme 2). The identity of 1B2 was established on the basis of its high resolution mass spectrum and a detailed analysis of one- and two-dimensional NMR data. It was found that the structure of 1B2 consists of two 1B rings connected by an exocyclic CH2 bridge attached to two 3’ positions of the unbridged carbazole moieties. Because of the stereochemical rigidity of the 1B ring, substitution of the 3’ position induces the formation of a chirality plane. Consequently, 1B2 was isolated as a mixture of stereoisomers, an enantiomeric pair (C2 symmetry) and a meso form (Cs symmetry), denoted rac-1B2 and meso-1B2, respectively. The rac and meso isomers could be distinguished by their 1H NMR spectra (Figure 2) because they yield different exocyclic CH2 signals (s3’a, Scheme 2); respectively, a singlet (4.35 ppm) and a diastereotopic AB pair (4.38, 4.34 ppm, 2J 12 Hz, Figure S2 in the Supporting Information). rac-1B2 and meso-1B2 were observed in comparable amounts in crude reaction mixtures, indicating that the formation of the exocyclic bridge is not stereoselective.
Figure 1. X-ray crystal structures of 3B (A, B) and 1B (C, D). Solvent molecules are omitted for clarity. Endo and exo positions in 3B and 1B are defined relative to the interior of the belt (D).
The 1H NMR spectrum of 3B revealed the presence of just one type of symmetrically substituted carbazole (signals at 7.75, 6.58, 3.38, and 0.72 ppm) and was thus consistent with an effective C3v symmetry of the molecule (Figure 2). The methylene and ethylene bridges in 3B are distinctly diastereotopic, yielding, respectively, an AB spin system (4.60 and 3.80 ppm, 2 J = 12.5 Hz), and an AA’BB’ system (3.62 and 2.95 ppm). In both types of bridge, the endo protons (Figure 1) are more strongly shielded than the corresponding exo protons. GIAODFT 1H and 13C chemical shieldings calculated for 3B are in very good agreement with the experimental values (Figures S11–S12 in the Supporting Information). No chemical exchange within the endo–exo pairs could be detected at 400 K in [D10]xylene by using EXSY spectroscopy, indicating that no cage inversion occurs under these conditions. This observation is consistent with DFT calculations predicting a uniquely high energy barrier to inversion (141 kcal mol 1) associated with a distorted, C2-symmetric transition state (Figure S15 in the Supporting Information).
Abstract in Polish: Bezpos´rednie alkilowanie 9,9’,9’’-trietylo[2.2.2](2,7)karbazolofanu za pomoca˛ dimetoksymetanu lub paraformaldehydu prowadzi do powstania heteroaromatycznego „pasa molekularnego,“ ktry tworzy sie˛ jako produkt kinetyczny w katalizowanych kwasem kondensacjach. W konkurencyjnym, preferowanym termodynamicznie procesie powstaja˛ ze znaczna˛ regioselektywnos´cia˛ polimeryczne struktury złoz˙one ze stereochemicznie sztywnych podjednostek zawieraja˛cych pojedynczy mostek metylenowy. Zalez˙nos´ci pomie˛dzy poszczeglnymi ´sciez˙kami reaktywnos´ci uzasadniono zmianami w wewne˛trznych napre˛z˙eniach poszczeglnych produktw i zrz˙nicowanej odwracalnos´ci kolejnych etapw kondensacji.
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Communication
Figure 2. 1H NMR spectra (600 MHz, [D]chloroform, 300 K, unless noted otherwise) of compounds 3B ([D8]toluene), 1B, 1B2, and 1Bn (330 K) with signal assignments derived from 2D NMR spectroscopy. Labels are defined in Schemes 1 and 2. Endo and exo positions are defined in Figure 1. The region containing 9b signals is shown only for 1Bn. The original rac/meso isomer ratio in 1B2 (ca. 1:1) was altered during purification.
Scheme 2. Structures of the oligomeric derivatives of 1B. Potential modifications of the 1Bn chain are shown in gray boxes. rac-1B2 is represented by one enantiomer. Stereoisomerism of 1Bn is not indicated. R = Et, Y = OH or Ar, Ar = additional 1B subunit linked through a 3’ or 6 position. s- and u- prefixes denote, respectively, the 3’-substituted and 3’-unsubstituted halves of the 1B ring.
Prolonged condensations performed in the presence of an excess of a formaldehyde equivalent led to the formation of a polymeric product, 1Bn. A representative 1H NMR spectrum of 1Bn, synthesized from 0B under moderate dilution (6.6 mm in CH2Cl2, 10 equiv paraformaldehyde, 2 equiv p-TsOH, 4 h) is shown in Figure 2. In spite of severe broadening, the spectrum displays striking similarities to the spectra of 1B and 1B2. Aromatic and aliphatic signals cover similar ranges of chemical shifts and, most significantly, a broad peak is present at the unusual shift of approximately 1.5 ppm, indicating that 1Bn is actually composed of 1B subunits. Further support for this structural proposal was provided by the NOESY and 1H-13C HSQC spectra of 1Bn, which enabled the identification of the key structural features of the 1B ring (Figures S4–S5 in the Supporting Information). The above synthesis yields a polymer Chem. Eur. J. 2014, 20, 1 – 6
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with the weight-average molecular weight (Mw) of approximately 4.3–5.4 kDa, estimated by using diffusion-ordered NMR spectroscopy (DOSY, Figure S6 in the Supporting Information).[31] Because of the high molecular weight of the monomer unit, the above Mw value corresponds to a relatively low average chain length of approximately 6.4–8.0 units. This estimate agrees with the MALDI-TOF spectrum of 1Bn, which revealed oligomer lengths of up to n = 18 subunits. The NMR data are consistent with the formulation of 1Bn as a cyclophane-based[32] oligomer, in which 1B units are linked through the 3’ positions, to form a methylene-carbazole[33–35] backbone (Scheme 2). The presence of a stereogenic plane in the 1B unit leads to stereoisomerism in the 1Bn chain, and the two diastereomers of 1B2 can serve as models of the respective racemo and meso dyads in 1Bn. The extreme broadening 3
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Communication of the 1H NMR spectrum of 1Bn is indicative of low stereoregularity, which is expected in view of the non-stereoselective formation of 1B2. The end groups in 1Bn could not be reliably determined by NMR spectroscopy, however, MALDI spectra indicate that the chains might be terminated with either unsubstituted 3’ positions or with 3’-CH2OH groups. At the microscopic level, the structure of 1Bn can depart from the proposed linear 3’,3’-linked motif in several ways (Scheme 2). Positions 6 on the bridged dicarbazole fragment of 1B are potentially susceptible to electrophilic attack, thus providing an alternative route to oligomerization. The resolution of the NMR spectra of 1Bn is insufficient to detect small contributions of 6-substitution; however, the dominance of 3’-alkylation is indicated by specific spectral features, including (a) the significant intensity of the 6-H peak (6.5 ppm), (b) the s1’-C shift in 1Bn (109.7–110.7 ppm) corresponding with s1’-C in 1B2 (110.2 ppm) rather than with u1’-C (109.0 ppm), and (c) the close similarity between 13C shifts of the remaining carbazole positions observed in the HSQC spectra of 1B2 and 1Bn. Freshly prepared 1Bn displays a characteristic blue color in solution (lmax 630 nm), which, in analogy to simple methylene-carbazole polymers,[34, 35] can be attributed to a small contribution of oxidized s3’a bridges (Scheme 2). Because of their carbocationic character, such oxidized bridges can undergo further condensation, leading to oligomer branching,[35] though in the case of 1Bn, the process may be hindered sterically. The solubility of solid samples of 1Bn was observed to decrease over time, indicating that the material is indeed capable of spontaneous cross-linking. The progress of the bridging reaction was monitored spectroscopically for two different initial concentrations of 0B (Figure 3). For [0B]0 = 0.1 mm, the molar fraction of 1B reached
solubility of the polymer. For [0B]0 = 0.01 mm, the above reactivity pattern was retained but the overall conversion rate was slower. However, higher dilution improved the maximum observed fraction of 3B to approximately 0.14. The observed difference between typical isolated yields of 3B (ca. 3 %) and the above NMR estimates is believed to be largely due to purification losses. The mechanistic picture emerging from the above experiment is outlined in Scheme 3. The use of a large excess of
Scheme 3. Proposed mechanism for the bridging reaction between 0B and an excess of the formaldehyde equivalent. Y = CH2OH or CH2OMe. 2B 2BY 0.
DMM effectively drives the formation of 1B to completion, as all subsequent products contain at least one endocyclic methylene bridge. Alkylated species, such as 0B-Y, 1B-Yx, and 2B-Yy (Y = CH2OH, CH2OMe; y > 0), which are the expected intermediates in the bridge-forming reactions, were not identified among the major reaction products. Their effective absence in processed reaction mixtures is thought to indicate that, for the studied [0B]0 range, the second C C bond is formed more rapidly than the first one[36] in the course of both inter- and intramolecular bridging. In contrast to 1B, which is the key intermediate en route to 3B, the expected doubly bridged species 2B was not observed among the major products at any stage of the condensation. Because of the steric hindrance at the unsubstituted 6’ positions (Scheme 3), 2B is unlikely to undergo faster substitution than 1B, so the apparent absence of 2B is not thought to result from its rapid consumption in subsequent bridging but rather indicates its less efficient (and likely reversible) formation. In partial support of the latter assumption, the strain energy calculated for 2B (11.3 kcal mol 1, R = H) is higher than the value obtained for 3B. A potentially efficient route to 3B may therefore involve a double alkylation of 1B to an appropriately substituted 1B-Y2, followed by two sequential bridging steps, leading, respectively, to 2B-Y and 3B. Although fast equilibration is expected to occur in the first of these steps, the reversal of the ultimate ring closure is slow enough to provide isolable quantities of 3B. The observed conversion of 3B into 1Bn during prolonged condensations indicates that
Figure 3. Reaction between 0B and DMM, monitored with 1H NMR spectroscopy. Molar fractions (x) were obtained by integration of 1H NMR spectra recorded for quenched aliquots of the reaction mixture. Initial conditions: dichloromethane solvent, [DMM]0 = 10 mm, [BF3·Et2O]0 = 10 mm.
a maximum of approximately 0.44 after 3 min of reaction time, and then declined in the course of subsequent condensation steps. 3B and 1Bn formed concurrently, in an approximate molar ratio of 1:7, until the complete consumption of 1B. The molar fraction of 3B reached approximately 0.11 after 7 min, and then slowly decreased, so that the compound was no longer detectable after 2 h. Simultaneously, 1Bn underwent further polycondensation, which was inferred from the decreasing &
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Communication opening of endocyclic methylene bridges is both kinetically feasible and thermodynamically favored. The above analysis shows that the bridging reaction occurs under a mixture of thermodynamic and kinetic control, which is a typical feature of many arene–aldehyde condensations.[9, 12, 37, 38] Complete equilibration in such reactions is usually preferred, because it provides dynamic covalent chemistry conditions[37] and enables efficient macrocycle formation at relatively high reactant concentrations. However, equilibrium conditions yield products with the smallest internal strain, so that only strain-free cyclic structures can compete with polymer formation. In the present case, the competition between the differently strained products 1Bn and 3B, occurs remarkably at both the kinetic and thermodynamic levels. Consequently, the optimum conditions for the synthesis of 3B combine high dilution (to limit the kinetically competing polymerization) with short reaction times (to suppress the thermodynamically driven loss of 3B). In summary, we have shown that direct alkylation of carbazolophanes with formaldehyde equivalents can provide access to belt-like heteroaromatic structures and topologically nontrivial polymers. Our work indicates that moderately strained cyclization products that are not normally observed in reversible reactions can have a transient existence before the equilibrium is reached. Performing the Friedel–Crafts alkylation on a macrocyclic template provides an unexpected insight into the kinetic and thermodynamic features of the bridging reaction, which can be valuable in subsequent development of this chemistry. We hope that further refinements of the proposed approach may provide a practical method of synthesizing functional molecules and macromolecules with complex multicyclic topologies.
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Acknowledgements Financial support from the National Science Center (Grants N N204 199340 and 2012/07/E/ST5/00781) is kindly acknowledged. Quantum chemical calculations were performed in the Wrocław Center for Networking and Supercomputing. Keywords: cyclophanes · electrophilic substitution · fused ring systems · nitrogen heterocycles · polymers [1] [2] [3] [4]
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Received: July 18, 2014 Published online on && &&, 0000
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COMMUNICATION & Macrocycle Synthesis
Belts and chains: A simple Friedel– Crafts alkylation is sufficient to transform a flexible cyclophane molecule into a rigid molecular belt. The competition between different alkylation modes, governed by a mixture of kinetic and thermodynamic effects, leads to the formation of a unique polymer consisting of singly bridged semi-belts.
M. Kondratowicz, D. Mys´liwiec, T. Lis, M. Ste˛pien´* && – && Heteroaromatic Belts through Fold-in Synthesis: Mechanistic Insights into a Macrocycle-Templated Friedel–Crafts Alkylation
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