Rotaxanes: Recognition of Diarylguanidinium Ions by

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Synthesis of Oxygen-Free [2]Rotaxanes: Recognition of Diarylguanidinium Ions by Tetraazacyclophanes Yu-Hsuan Chang,†,§ Yong-Jay Lee,†,§ Chien-Chen Lai,‡ Yi-Hung Liu,† Shie-Ming Peng,† and Sheng-Hsien Chiu*,† †

Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Road, Taipei, Taiwan 10617, R.O.C. Institute of Molecular Biology, National Chung Hsing University and Department of Medical Genetics, China Medical University Hospital, Taichung, Taiwan, R.O.C.

‡

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ABSTRACT: Simple cyclophanes containing four distant amino N atoms or ether O atoms behave as hosts for the threading of guest diarylguanidinium ions. The recognition system exhibits high synthetic flexibility, allowing unique O-free [2]rotaxanes to be synthesized efficiently (yields of up to 80%) through both “threading-followed-by-stoppering” and “clipping” approaches. have also found that the tetraimino-cyclophane 4 can “clip” around dumbbell-shaped diarylguanidinium ions through a “magic ring”8 process, resulting in facile and highly efficient (yields of up to 80%) syntheses of O-free [2]rotaxanes from two O-free components. The synthesis of the tetraaza-cyclophane 1 is facile and highly effective. Simply by mixing equimolar amounts of isophthalaldehyde (2) and m-xylylenediamine (3) in CHCl3 and then using NaBH4 to reduce the tetra-imino-cyclophane 4, we isolated the tetraaza-cyclophane 1 in 61% yield, without the need to use any particular template (Scheme 1).9 We prepared the corresponding tetraoxo-cyclophane 5 in 19% overall yield through the formation of the dibromide 6 [from excess dibromo-m-xylene (7) and 1,3-benzenedimethanol (8) under basic conditions] and a subsequent 1:1 macrocyclization with the diol 8. We synthesized the threadlike salt 9·TFPB with the expectation that the weakly coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate (TFPB) anion would increase its solubility in less polar organic solvents and enhance the strength of its [N−H···X] hydrogen bonds with the cyclophanes 1 and 5.10 Figure 1 presents the 1H NMR spectrum of an equimolar (20 mM) mixture of the tetraaza-cyclophane 1 and the threadlike salt 9·TFPB in CDCl3. We observed significant upfield shifts of the signals representing the benzylic protons of the host (Ha) and the methyl (H1) and aromatic (H2, H3) signals of the guest, compared with those in their free states, consistent with the encircling of the tetraaza-cyclophane 1 around the guanidinium unit (Figure 1a−c). Under the same conditions, an equimolar mixture of the tetraoxo-cyclophane 5 and the threadlike salt 9· TFPB provided similar upfield shifts for all of the corresponding signals of the host and guest, suggesting that

I

nterlocked molecules, particularly rotaxanes and catenanes, can be useful materials in various applications (e.g., gelation,1 catalysis,2 material transport,3 molecular memory4). Although many different types of interlocked molecules have been synthesized over the past two decades, the number of recognition systems upon which they are based has remained limited.5 Because the properties and potential functions of rotaxanes are strongly related to the nature of their constituent host and guest units, we are always interested in developing new host/guest systems that can form pseudorotaxanes efficiently in solution. Hydrogen bonding has long been applied as a key noncovalent interaction in the assembly of pseudorotaxanes; as such, many of their host and guest units have contained carbonyl or ether O atoms as potential hydrogen bond receptors.6 To the best of our knowledge, only a few examples of O-free or all-hydrocarbon interlocked molecules have appeared previously in the literature,7 but none were assembled based on hydrogen bonding interactions; thus, the construction of interlocked molecules from O-free hosts and guests, which self-assemble mainly through hydrogen bonding, remains a challenging task. Intuitively, a macrocycle featuring only a few widely separated heteroatoms (e.g., ether O or amine N atoms) would probably not be an effective host for threaded hydrogen-bond-donating guests (e.g., guanidinium ions, amides, dialkylammonium ions) because the distant heteroatoms would be unlikely to cooperate in the formation of an efficient guest-binding structure. Nevertheless, aromatic rings can also serve as hydrogen bond acceptors, so we suspected that inserting suitable aromatic bridging units between the heteroatoms might lead to macrocyclic structures capable of accommodating hydrogen-bond-donating guests. Herein, we report that diarylguanidinium ions can be threaded through simple tetraaza- (1) and tetraoxo- (5) cyclophanes to form [2]pseudorotaxane structures stabilized mainly through [N−H···N] and [N−H···O] hydrogen bonds, respectively. We © XXXX American Chemical Society

Received: March 7, 2018

A

DOI: 10.1021/acs.orglett.8b00757 Org. Lett. XXXX, XXX, XXX−XXX

Letter

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13 (Scheme 2); their association constants for interacting with the threadlike salt 9·TFPB in CHCl3 were 1400 ± 170 and 710 ± 120 M−1, respectively, based on ITC experiments.

Scheme 1. Synthesis of the Cyclophanes 1 and 5 and Structure of the Threadlike Guanidinium Salt 5·TFPB

Scheme 2. Synthesis of the para-Cyclophanes 10 and 13

To unambiguously prove that [2]pseudorotaxanes were formed from the diarylguanidinium ion and the cyclophanes in solution, we synthesized the corresponding [2]rotaxanes. We prepared the threadlike salt 16·TFPB with the expectation that the imine formed through the reaction of its terminal primary amino group with bulky 3,5-di-tert-butylbenzaldehyde (17) would interlock the complexed cyclophanes and allow us to isolate the corresponding [2]rotaxanes after reduction (Scheme 3). Based on 1H NMR spectra, an equimolar (20 mM) mixture of the threadlike salt 16·TFPB, the tetraaza-cyclophane 1, and the aldehyde 17 in CDCl3 reached equilibrium at 323 K after 9 h. Subsequent NaBH4-mediated reduction afforded the [2]rotaxane 18·TFPB incorporating the tetraaza-cyclophane 1 in 55% yield,12 unambiguously confirming the threading of the guanidinium ion into the tetraaza-cyclophane 1 in CDCl3. The Scheme 3. “Threading-Followed-by-Stoppering” Synthesis of [2]Rotaxanes Incorporating Tetraaza- and Tetraoxocyclophanes

Figure 1. 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a) the free tetraaza-cyclophane 1, (b) an equimolar mixture (20 mM) of 1 and 9· TFPB, (c) the free threadlike salt 9·TFPB, (d) an equimolar mixture of 5 and 9·TFPB, and (e) the free tetraoxo-cyclophane 5.

these components could also form a [2]pseudorotaxane. Through 1 H NMR spectroscopic dilution experiments referencing the singlets representing the benzylic protons of the tetraaza-cyclophane 1 (at δ 3.78) and the tetraoxocyclophane 5 (at δ 4.52), we determined association constants of 5700 ± 300 and 1500 ± 60 M−1, respectively, for the interactions of these cyclophanes with the threadlike salt 9· TFPB in CDCl3. Isothermal titration calorimetry (ITC) supported the formation of 1:1 host/guest complexes, affording association constants for the interactions of the threadlike ion 9+ with the cyclophanes 1 and 5 of 10 000 ± 500 and 2500 ± 260 M−1, respectively. We suspected that the higher affinity of the tetraaza-cyclophane 1 to the guanidinium ion 9+, than that of the tetraoxo-cyclophane 5, is largely due to the fact that an [N−H···N] hydrogen bond is more energetically favorable than an [N−H···O] one.11 For comparison, we also prepared the para-tetraza-cyclophane 10 and the para-tetraoxo-cyclophane B

DOI: 10.1021/acs.orglett.8b00757 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters [2]rotaxane 19·TFPB, constructed from the tetraoxo-cyclophane 5 and the guanidinium ion, was isolated in 43% yield under similar conditions. Because the para-cyclophanes 10 and 13 are weaker binders to diarylguanidinium ions than are the macrocycles 1 and 5, the syntheses of their corresponding [2]rotaxanes [20·TFPB (9%) and 21·TFPB (13%), respectively] from the threadlike salt 16·TFPB and the bulky aldehyde 17 were significantly less efficient. Based on our observation that the tetraimino-cyclophane 4 was generated efficiently without a template, and anticipation that imino N atoms could form hydrogen bonds with guanidinium ions,13 we suspected that a guanidinium ion might also form a complex with the tetraimino-cyclophane 4. If so, the dynamic nature of imino bonds should allow the tetraimino-cyclophane 4 to act as a “magic ring” that “clips” around a dumbbell-shaped guest containing a diarylguanidinium center (Scheme 4). Indeed, when we heated a CDCl3

Figure 2. 1H NMR spectra (400 MHz, CDCl3, 298 K) of (a−g) a mixture of the threadlike salt 22·TFPB (10 mM), the dialdehyde 2 (20 mM), and the diamine 3 (20 mM) that had been heated at 323 K for (a) 0, (b) 0.5, (c) 20, (d) 44, (e) 94, (f) 156, and (g) 249 h and (h) the [2]rotaxane 23·TFPB. M and R denote signals representing the macrocycle and the [2]rotaxane, respectively.

Scheme 4. Clipping Synthesis of the O-Free [2]Rotaxanes 23·TFPB and 24·TFPB, Using the “Magic Ring” Approach

We obtained single crystals suitable for X-ray crystallography after liquid diffusion of hexane into CH2Cl2 solutions of the [2]rotaxanes 23·TFPB and 24·TFPB (CCDC 1818807 and 1818806); their solid state structures confirmed the interlocking of their tetraaza-cyclophane components (1 and 10, respectively) around the dumbbell-shaped ion component 22+ (Figure 3). In the solid state structure of the [2]rotaxane 23+,

solution of the dialdehyde 2 (20 mM), the diamine 3 (20 mM), and the dumbbell-shaped salt 22·TFPB (10 mM) at 323 K, we obtained relatively simple 1H NMR spectra (Figure 2). After 0.5 h, a predominant signal appeared as a singlet at δ 4.69 for the benzylic protons (HB, Scheme 1) of the free tetraiminocyclophane 4. After 1 h, a new singlet appeared slightly upfield (δ 4.57); it grew in intensity, as the signal of free 4 at 4.69 ppm was consumed, consistent with “magic ring” synthesis of the [2]rotaxane through “clipping” of the tetraimino-cyclophane 4 around the dumbbell-shaped ion 22+ (Scheme 4). After 150 h, the signal of the benzylic protons of the interlocked tetraiminocyclophane 4 was predominant; the reaction reached equilibrium after 10 days. Subsequent NaBH4-mediated reduction afforded the [2]rotaxane 23·TFPB, incorporating the tetraaza-cyclophane 1, in 80% yield. Similarly, heating a CDCl3 solution of the dialdehyde 2 (20 mM), the diamine 11 (20 mM), and the dumbbell-shaped salt 22·TFPB (10 mM) at 323 K for 3 days, followed by reduction with NaBH4, gave the [2]rotaxane 24·TFPB, incorporating the para-tetraaza-cyclophane 10, in 56% yield.

Figure 3. Ball-and-stick representations of the solid state structures of the [2]rotaxanes (a) 23+ and (b) 24+. Hydrogen bonding geometries, H···N or H···π [Å], and N−H···N or N−H···π [deg]: (a) 2.67, 161.8; (b) 2.09, 149.7; (c) 3.02, 114.9; (d) 2.18, 154.3; (e) 3.02, 138.9; (f) 2.40, 116.3; (g) 2.06, 154.1. C, gray; N, blue; H, purple. Bond coloring: macrocycle, red; dumbbell, blue.

two pairs of [N−H···N] and [N−H···π] hydrogen bonds exist between the four guanidinium NH units and the two opposite amino N atoms and their nearby aromatic rings in the tetraazacyclophane component. Thus, the aromatic rings not only acted as linking units between the amino groups in the tetraazacyclophane 1 but also served as hydrogen bond receptors that helped to stabilize the threaded guest. Possibly because of the C

DOI: 10.1021/acs.orglett.8b00757 Org. Lett. XXXX, XXX, XXX−XXX

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greater difficulty in aligning the four more distant amino groups in the para-tetraaza-cyclophane 10, only one [N−H···π] and two [N−H···N] hydrogen bonds appeared in the solid state structure of the [2]rotaxane 24+. We suspect that the more preorganized structure and the ability to form more hydrogen bonds simultaneously were the major reasons why the affinity of the tetraaza-cyclophane 1 was significantly higher than that of the para-tetraaza-cyclophane 10 toward guanidinium ions. The [2]rotaxanes 18·TFPB, 20·TFPB, 23·TFPB, and 24· TFPB are rare examples of interlocked molecules containing only C, H, and N atomsbut no O atomsdirectly after interlocking. The ability of the O-free tetraaza-cyclophanes 1 and 10 to recognize O-free diarylguanidinium guests allowed us to synthesize the O-free [2]rotaxanes 18·TFPB and 20·TFPB through a “threading-followed-by-stoppering” approach. The ability of the in situ generated O-free tetraimino-cyclophanes 4 and 12 to encircle diarylguanidinium ions allowed us to realize “clipping” syntheses of the O-free [2]rotaxanes 23·TFPB and 24·TFPB through the “magic ring” approach. We have demonstrated that simple cyclophanes containing four distant amino N atoms or ether O atoms can serve as hosts for the threading of diarylguanidinium ion guests. The recognition system exhibits high synthetic flexibility, with both “threading-followed-by-stoppering” and “clipping” approaches being feasible and efficient means of synthesizing unique O-free [2]rotaxanes. We are now working on the development of molecular switches based on this new host/ guest recognition system.

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REFERENCES

(1) (a) Zhao, Y.-L.; Aprahamian, I.; Trabolsi, A.; Erina, N.; Stoddart, J. F. J. Am. Chem. Soc. 2008, 130, 6348−6350. (b) Hsueh, S.-Y.; Kuo, C.-T.; Lu, T.-W.; Lai, C.-C.; Liu, Y.-H.; Hsu, H.-F.; Peng, S.-M.; Chen, C.-h.; Chiu, S.-H. Angew. Chem., Int. Ed. 2010, 49, 9170−9173. (c) Iwaso, K.; Takashima, Y.; Harada, A. Nat. Chem. 2016, 8, 625− 632. (d) Goujon, A.; Mariani, G.; Lang, T.; Moulin, E.; Rawiso, M.; Buhler, E.; Giuseppone, N. J. Am. Chem. Soc. 2017, 139, 4923−4928. (2) (a) Caputo, C. B.; Zhu, K.; Vukotic, V. N.; Loeb, S. J.; Stephan, D. W. Angew. Chem., Int. Ed. 2013, 52, 960−963. (b) Leigh, D. A.; Marcos, V.; Wilson, M. R. ACS Catal. 2014, 4, 4490−4497. (c) Lee, Y.-J.; Liu, K.-S.; Lai, C.-C.; Liu, Y.-H.; Peng, S.-M.; Cheng, R. P.; Chiu, S.-H. Chem. - Eur. J. 2017, 23, 9756−9760. (3) (a) Sun, Y.-L.; Yang, Y.-W.; Chen, D.-X.; Wang, G.; Zhou, Y.; Wang, C.-Y.; Stoddart, J. F. Small 2013, 9, 3224−3229. (b) Barat, R.; Legigan, T.; Tranoy-Opalinski, I.; Renoux, B.; Péraudeau, E.; Clarhaut, J.; Poinot, P.; Fernandes, A. E.; Aucagne, V.; Leigh, D. A.; Papot, S. Chem. Sci. 2015, 6, 2608−2613. (c) Yu, G.; Wu, D.; Li, Y.; Zhang, Z.; Shao, L.; Zhou, J.; Hu, Q.; Tang, G.; Huang, F. Chem. Sci. 2016, 7, 3017−3024. (4) (a) Molecular Electronics: Science and Technology; Aviram, A., Ratner, M., Eds.; New York Academy of Sciences: New York, 1998. (b) Coskun, A.; Spruell, J. M.; Barin, G.; Dichtel, W. R.; Flood, A. H.; Botros, Y. Y.; Stoddart, J. F. Chem. Soc. Rev. 2012, 41, 4827−4859. (5) (a) Fyfe, M. C. T.; Stoddart, J. F. Adv. Supramol. Chem. 1999, 5, 1−53. (b) Kay, E. R.; Leigh, D. A. Top. Curr. Chem. 2005, 262, 133− 177. (c) Champin, B.; Mobian, P.; Sauvage, J.-P. Chem. Soc. Rev. 2007, 36, 358−366. (d) Bruns, C. J.; Stoddart, J. F. The Nature of the Mechanical Bond: From Molecules to Machines; Wiley: Hoboken, NJ, 2016. (6) (a) Hunter, C. A. Angew. Chem., Int. Ed. 2004, 43, 5310−5324. (b) Schalley, C. A.; Weilandt, T.; Brueggemann, J.; Vögtle, F. Top. Curr. Chem. 2005, 248, 141−200. (c) Kassem, S.; van Leeuwen, T.; Lubbe, A. S.; Wilson, M. R.; Feringa, B. L.; Leigh, D. A. Chem. Soc. Rev. 2017, 46, 2592−2621. (7) (a) Logemann, E.; Schill, G. Chem. Ber. 1978, 111, 2615−2629. (b) Schill, G.; Schweickert, N.; Fritz, H.; Vetter, W. Angew. Chem., Int. Ed. Engl. 1983, 22, 889−891. (c) Sun, J.; Liu, Z.; Liu, W.-G.; Wu, Y.; Wang, Y.; Barnes, J. C.; Hermann, K. R.; Goddard, W. A., III; Wasielewski, M. R.; Stoddart, J. F. J. Am. Chem. Soc. 2017, 139, 12704−12709. (8) (a) Kidd, T. J.; Leigh, D. A.; Wilson, A. J. J. Am. Chem. Soc. 1999, 121, 1599−1600. (b) Kilbinger, A. F. M.; Cantrill, S. J.; Waltman, A. W.; Day, M. W.; Grubbs, R. H. Angew. Chem., Int. Ed. 2003, 42, 3281− 3285. (c) Zheng, H.; Li, Y.; Zhou, C.; Li, Y.; Yang, W.; Zhou, W.; Zuo, Z.; Liu, H. Chem. - Eur. J. 2011, 17, 2160−2167. (9) A better synthetic yield (80%) of 1 was reported when using different solvent systems; see: Rajakumar, P.; Padmanabhan, R. Tetrahedron Lett. 2010, 51, 1059−1063. (10) (a) Strauss, S. H. Chem. Rev. 1993, 93, 927−942. (b) Gaeta, C.; Troisi, F.; Neri, P. Org. Lett. 2010, 12, 2092−2095. (c) Chen, N.-C.; Chuang, C.-J.; Wang, L.-Y.; Lai, C.-C.; Chiu, S.-H. Chem. - Eur. J. 2012, 18, 1896−1900. (11) (a) Nobeli, I.; Price, S. L.; Lommerse, J. P. M.; Taylor, R. J. Comput. Chem. 1997, 18, 2060−2074. (b) Foti, M. C.; DiLabio, G. A.; Ingold, K. U. J. Am. Chem. Soc. 2003, 125, 14642−14647. (c) Iannone, E. Labs on Chip: Principles, Design and Technology; Taylor & Francis Group: USA, 2014. (12) We suspect that the assembly of the imino [2]rotaxanes was disturbed by the formation of [N−H···N] hydrogen bonds from the NH units of the guanidinium ion (and/or cyclophane) to the imino Natom of the dumbbell-shaped component. As evidence, we observed continuous migrations of the 1H NMR spectral signals of the aromatic and methylene protons adjacent to the amino N atom during dilution (from 10 to 1 mM) of a CDCl3 solution of the free amino dumbbell component of 18·TFPB, suggesting the aggregation. (13) Glink, P. T.; Oliva, A. I.; Stoddart, J. F.; White, A. J. P.; Williams, D. J. Angew. Chem., Int. Ed. 2001, 40, 1870−1875.

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00757. Synthetic procedure, characterization data and NMR spectra of new compounds (PDF) Accession Codes

CCDC 1818806−1818807 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Sheng-Hsien Chiu: 0000-0002-0040-1555 Author Contributions §

Y.-H.C. and Y.-J.L. contribute equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Ministry of Science and Technology (Taiwan) (MOST-106-2628-M-002-002) and National Taiwan University (NTU-106R880202) for financial support. D

DOI: 10.1021/acs.orglett.8b00757 Org. Lett. XXXX, XXX, XXX−XXX