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  • Review Article
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Strategies for binding multiple guests in metal–organic cages

Nature Reviews Chemistry volume 3, pages 204–222 (2019)Cite this article

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Abstract

The binding of multiple guests by a single entity can lead to new modes of host–guest interactions and thus new applications in, for example, catalysis and sensing. With the aim of developing modular systems that can promote and adapt to allosteric binding events, this Review explores current strategies used to bind multiple guests in the central and peripheral environments of coordination cages. The structural and functional consequences of multi-guest binding are examined, highlighting the methods by which guest configurations involving more than one copy of the same guest, as well as multiple different guests, may be designed. We thus aim to provide new methodological insights and tools into the design of new capsules for multiple guest-specific binding events, towards the development of guest–guest chemistry within synthetic systems.

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Fig. 1: The hydrophobic effect and host–guest fit are general principles in central guest binding.
Fig. 2: Exploiting electrostatics for guest binding.
Fig. 3: Minimizing empty aperture space can maximize host–guest contact, promoting central binding.
Fig. 4: Metal binding sites installed at the centres of ligands, or at the corners of assemblies, can be used to drive the binding of polydentate guests.
Fig. 5: Intermolecular interactions between guest species, as well as between host and guest, stabilize heterotropic guest configurations.
Fig. 6: Dividing the space within a supramolecular capsule generates distinct binding pockets.
Fig. 7: Catenated architectures generate multiple cavities; two guests cause reconstitution of cavities to express unique structures.
Fig. 8: Internal and peripheral binding sites together regulate guest binding.
Fig. 9: New structures and guest reactivity mechanisms emerging from the interaction of multiple guests with coordination cages.

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References

  1. Papin, J. A., Hunter, T., Palsson, B. O. & Subramaniam, S. Reconstruction of cellular signalling networks and analysis of their properties. Nat. Rev. Mol. Cell Biol. 6, 99–111 (2005).

    CAS  PubMed  Google Scholar 

  2. Krauss, G. Biochemistry of Signal Transduction and Regulation (Wiley, 2014).

  3. Monod, J., Wyman, J. & Changeux, J.-P. On the nature of allosteric transitions: a plausible model. J. Mol. Biol. 12, 88–118 (1965).

    CAS  PubMed  Google Scholar 

  4. Motlagh, H. N., Wrabl, J. O., Li, J. & Hilser, V. J. The ensemble nature of allostery. Nature 508, 331–339 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Gale, P. A., Howe, E. N. W. & Wu, X. Anion receptor chemistry. Chem 1, 351–422 (2016).

    CAS  Google Scholar 

  6. Liu, Z., Nalluri, S. K. M. & Stoddart, J. F. Surveying macrocyclic chemistry: from flexible crown ethers to rigid cyclophanes. Chem. Soc. Rev. 46, 2459–2478 (2017).

    CAS  PubMed  Google Scholar 

  7. Barrow, S. J. et al. Cucurbituril-based molecular recognition. Chem. Rev. 115, 12320–12406 (2015).

    CAS  PubMed  Google Scholar 

  8. Kim, K. Mechanically interlocked molecules incorporating cucurbituril and their supramolecular assemblies. Chem. Soc. Rev. 31, 96–107 (2002).

    CAS  PubMed  Google Scholar 

  9. Ogoshi, T., Yamagishi, T.-A. & Nakamoto, Y. Pillar-shaped macrocyclic hosts pillar[n]arenes: new key players for supramolecular chemistry. Chem. Rev. 116, 7937–8002 (2016).

    CAS  PubMed  Google Scholar 

  10. Tozawa, T. et al. Porous organic cages. Nat. Mater. 8, 973 (2009).

    CAS  PubMed  Google Scholar 

  11. Timmerman, P., Verboom, W., van Veggel, F. C. J. M., van Duynhoven, J. P. M. & Reinhoudt, D. N. A. Novel type of stereoisomerism in calix[4]arene-based carceplexes. Angew. Chem. Int. Ed. 33, 2345–2348 (1994).

    Google Scholar 

  12. Atwood, J. L., Koutsantonis, G. A. & Raston, C. L. Purification of C60 and C70 by selective complexation with calixarenes. Nature 368, 229 (1994).

    CAS  Google Scholar 

  13. Piepenbrock, M.-O. M., Lloyd, G. O., Clarke, N. & Steed, J. W. Metal- and anion-binding supramolecular gels. Chem. Rev. 110, 1960–2004 (2010).

    CAS  PubMed  Google Scholar 

  14. Suzaki, Y., Taira, T. & Osakada, K. Physical gels based on supramolecular gelators, including host–guest complexes and pseudorotaxanes. J. Mater. Chem. 21, 930–938 (2011).

    CAS  Google Scholar 

  15. Miyauchi, M., Takashima, Y., Yamaguchi, H. & Harada, A. Chiral supramolecular polymers formed by host−guest interactions. J. Am. Chem. Soc. 127, 2984–2989 (2005).

    CAS  PubMed  Google Scholar 

  16. He, Q., Tu, P. & Sessler, J. L. Supramolecular chemistry of anionic dimers, trimers, tetramers, and clusters. Chem 4, 46–93 (2018).

    CAS  PubMed  Google Scholar 

  17. Rebek, J. Simultaneous encapsulation: molecules held at close range. Angew. Chem. Int. Ed. 44, 2068–2078 (2005).

    CAS  Google Scholar 

  18. Gibb, C. L. D. & Gibb, B. C. Templated assembly of water-soluble nano-capsules: inter-phase sequestration, storage, and separation of hydrocarbon gases. J. Am. Chem. Soc. 128, 16498–16499 (2006).

    CAS  PubMed  Google Scholar 

  19. Ramamurthy, V. Photochemistry within a water-soluble organic capsule. Acc. Chem. Res. 48, 2904–2917 (2015).

    CAS  PubMed  Google Scholar 

  20. Jordan, J. H., Gibb, C. L. D., Wishard, A., Pham, T. & Gibb, B. C. Ion–hydrocarbon and/or ion–ion interactions: direct and reverse hofmeister effects in a synthetic host. J. Am. Chem. Soc. 140, 4092–4099 (2018).

    CAS  PubMed  Google Scholar 

  21. Chakrabarty, R., Mukherjee, P. S. & Stang, P. J. Supramolecular coordination: self-assembly of finite two- and three-dimensional ensembles. Chem. Rev. 111, 6810–6918 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Holliday, B. J. & Mirkin, C. A. Strategies for the construction of supramolecular compounds through coordination chemistry. Angew. Chem. Int. Ed. 40, 2022–2043 (2001).

    CAS  Google Scholar 

  23. Saalfrank, R. W., Maid, H. & Scheurer, A. Supramolecular coordination chemistry: the synergistic effect of serendipity and rational design. Angew. Chem. Int. Ed. 47, 8794–8824 (2008).

    CAS  Google Scholar 

  24. Northrop, B. H., Chercka, D. & Stang, P. J. Carbon-rich supramolecular metallacycles and metallacages. Tetrahedron 64, 11495–11503 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Voloshin, Y., Belaya, I. & Krämer, R. The Encapsulation Phenomenon: Synthesis, Reactivity and Applications of Caged Ions and Molecules (Springer International Publishing, 2016).

  26. Garcia-Simon, C. et al. Sponge-like molecular cage for purification of fullerenes. Nature Commun. 5, 5557 (2014).

    CAS  Google Scholar 

  27. Brown, C. J., Toste, F. D., Bergman, R. G. & Raymond, K. N. Supramolecular catalysis in metal–ligand cluster hosts. Chem. Rev. 115, 3012–3035 (2015).

    CAS  PubMed  Google Scholar 

  28. Fujita, M. et al. Molecular paneling coordination. Chem. Commun. 509–518 (2001).

  29. Metherell, A. J., Cullen, W., Williams, N. H. & Ward, M. D. Binding of hydrophobic guests in a coordination cage cavity is driven by liberation of “high-energy” water. Chem. Eur. J. 24, 1554–1560 (2018).

    CAS  PubMed  Google Scholar 

  30. Biedermann, F., Uzunova, V. D., Scherman, O. A., Nau, W. M. & De Simone, A. Release of high-energy water as an essential driving force for the high-affinity binding of cucurbit[n]urils. J. Am. Chem. Soc. 134, 15318–15323 (2012).

    CAS  PubMed  Google Scholar 

  31. Grunwald, E. & Steel, C. Solvent reorganization and thermodynamic enthalpy-entropy compensation. J. Am. Chem. Soc. 117, 5687–5692 (1995).

    CAS  Google Scholar 

  32. Jordan, J. H. & Gibb, B. C. Molecular containers assembled through the hydrophobic effect. Chem. Soc. Rev. 44, 547–585 (2015).

    CAS  PubMed  Google Scholar 

  33. Gibb, C. L. D. & Gibb, B. C. Well-defined, organic nanoenvironments in water: the hydrophobic effect drives a capsular assembly. J. Am. Chem. Soc. 126, 11408–11409 (2004).

    CAS  PubMed  Google Scholar 

  34. Murray, J., Kim, K., Ogoshi, T., Yao, W. & Gibb, B. C. The aqueous supramolecular chemistry of cucurbit[n]urils, pillar[n]arenes and deep-cavity cavitands. Chem. Soc. Rev. 46, 2479–2496 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Hiraoka, S., Harano, K., Nakamura, T., Shiro, M. & Shionoya, M. Induced-fit formation of a tetrameric organic capsule consisting of hexagram-shaped amphiphile molecules. Angew. Chem. Int. Ed. 48, 7006–7009 (2009).

    CAS  Google Scholar 

  36. Hiraoka, S., Nakamura, T., Shiro, M. & Shionoya, M. In-water truly monodisperse aggregation of gear-shaped amphiphiles based on hydrophobic surface engineering. J. Am. Chem. Soc. 132, 13223–13225 (2010).

    CAS  PubMed  Google Scholar 

  37. Diederich, F. Complexation of neutral molecules by cyclophane hosts. Angew. Chem. Int. Ed. 27, 362–386 (1988).

    Google Scholar 

  38. Assaf, K. I. & Nau, W. M. The chaotropic effect as an assembly motif in chemistry. Angew. Chem. Int. Ed. 57, 13968–13981 (2018).

    CAS  Google Scholar 

  39. Lagona, J., Mukhopadhyay, P., Chakrabarti, S. & Isaacs, L. The cucurbit[n]uril family. Angew. Chem. Int. Ed. 44, 4844–4870 (2005).

    CAS  Google Scholar 

  40. Hastings, C. J., Pluth, M. D., Biros, S. M., Bergman, R. G. & Raymond, K. N. Simultaneously bound guests and chiral recognition: a chiral self-assembled supramolecular host encapsulates hydrophobic guests. Tetrahedron 64, 8362–8367 (2008).

    CAS  Google Scholar 

  41. Yoshizawa, M., Tamura, M. & Fujita, M. AND/OR bimolecular recognition. J. Am. Chem. Soc. 126, 6846–6847 (2004).

    CAS  PubMed  Google Scholar 

  42. Yoshizawa, M. et al. Endohedral clusterization of ten water molecules into a “molecular ice” within the hydrophobic pocket of a self-assembled cage. J. Am. Chem. Soc. 127, 2798–2799 (2005).

    CAS  PubMed  Google Scholar 

  43. Leung, D. H., Bergman, R. G. & Raymond, K. N. Enthalpy−entropy compensation reveals solvent reorganization as a driving force for supramolecular encapsulation in water. J. Am. Chem. Soc. 130, 2798–2805 (2008).

    CAS  PubMed  Google Scholar 

  44. Sgarlata, C. et al. External and internal guest binding of a highly charged supramolecular host in water: deconvoluting the very different thermodynamics. J. Am. Chem. Soc. 132, 1005–1009 (2010).

    CAS  PubMed  Google Scholar 

  45. Han, M. et al. Light-triggered guest uptake and release by a photochromic coordination cage. Angew. Chem. Int. Ed. 52, 1319–1323 (2013).

    CAS  Google Scholar 

  46. Kang, J. & Rebek, Jr, J. Entropically driven binding in a self-assembling molecular capsule. Nature 382, 239 (1996).

    CAS  PubMed  Google Scholar 

  47. Sun, W.-Y., Kusukawa, T. & Fujita, M. Electrochemically driven clathration/declathration of ferrocene and its derivatives by a nanometer-sized coordination cage. J. Am. Chem. Soc. 124, 11570–11571 (2002).

    CAS  PubMed  Google Scholar 

  48. Kusukawa, T. & Fujita, M. Self-assembled M6L4-type coordination nanocage with 2,2‘-bipyridine ancillary ligands. facile crystallization and X-ray analysis of shape-selective enclathration of neutral guests in the cage. J. Am. Chem. Soc. 124, 13576–13582 (2002).

    CAS  PubMed  Google Scholar 

  49. Nakabayashi, K. et al. Cavity-induced spin−spin interaction between organic radicals within a self-assembled coordination cage. J. Am. Chem. Soc. 126, 16694–16695 (2004).

    CAS  PubMed  Google Scholar 

  50. Yoshizawa, M. et al. Discrete stacking of large aromatic molecules within organic-pillared coordination cages. Angew. Chem. Int. Ed. 44, 1810–1813 (2005).

    CAS  Google Scholar 

  51. Yamauchi, Y., Yoshizawa, M., Akita, M. & Fujita, M. Discrete stack of an odd number of polarized aromatic compounds revealing the importance of net versus local dipoles. Proc. Natl Acad. Sci. USA 106, 10435–10437 (2009).

    PubMed  Google Scholar 

  52. Samanta, D., Mukherjee, S., Patil, Y. P. & Mukherjee, P. S. Self-assembled Pd6 open cage with triimidazole walls and the use of its confined nanospace for catalytic Knoevenagel- and Diels–Alder reactions in aqueous medium. Chem. Eur. J. 18, 12322–12329 (2012).

    CAS  PubMed  Google Scholar 

  53. Samanta, D. et al. Reversible photoswitching of encapsulated azobenzenes in water. Proc. Natl Acad. Sci. USA 115, 9379–9384 (2018).

    CAS  PubMed  Google Scholar 

  54. Mecozzi, S. & Rebek, J. J. The 55% solution: a formula for molecular recognition in the liquid state. Chem. Eur. J. 4, 1016–1022 (1998).

    CAS  Google Scholar 

  55. Fang, Y., Murase, T., Sato, S. & Fujita, M. Noncovalent tailoring of the binding pocket of self-assembled cages by remote bulky ancillary groups. J. Am. Chem. Soc. 135, 613–615 (2013).

    CAS  PubMed  Google Scholar 

  56. Mahata, K., Frischmann, P. D. & Würthner, F. Giant electroactive M4L6 tetrahedral host self-assembled with Fe(II) vertices and perylene bisimide dye edges. J. Am. Chem. Soc. 135, 15656–15661 (2013).

    CAS  PubMed  Google Scholar 

  57. Meng, W. et al. A self-assembled M8L6 cubic cage that selectively encapsulates large aromatic guests. Angew. Chem. Int. Ed. 50, 3479–3483 (2011).

    CAS  Google Scholar 

  58. Rizzuto, F. J., Wood, D. M., Ronson, T. K. & Nitschke, J. R. Tuning the redox properties of fullerene clusters within a metal–organic capsule. J. Am. Chem. Soc. 139, 11008–11011 (2017).

    CAS  PubMed  Google Scholar 

  59. Clegg, J. K., Li, F., Jolliffe, K. A., Meehan, G. V. & Lindoy, L. F. An expanded neutral M4L6 cage that encapsulates four tetrahydrofuran molecules. Chem. Commun. 47, 6042–6044 (2011).

    CAS  Google Scholar 

  60. Szalóki, G., Croué, V., Allain, M., Goeb, S. & Sallé, M. Neutral versus polycationic coordination cages: a comparison regarding neutral guest inclusion. Chem. Commun. 52, 10012–10015 (2016).

    Google Scholar 

  61. Bilbeisi, R. A., Ronson, T. K. & Nitschke, J. R. A. Self-assembled [FeII 12L12] capsule with an icosahedral framework. Angew. Chem. Int. Ed. 52, 9027–9030 (2013).

    CAS  Google Scholar 

  62. Wise, M. D. et al. Large, heterometallic coordination cages based on ditopic metallo-ligands with 3-pyridyl donor groups. Chem. Sci. 6, 1004–1010 (2015).

    CAS  PubMed  Google Scholar 

  63. Liu, Y., Sengupta, A., Raghavachari, K. & Flood, A. H. Anion binding in solution: beyond the electrostatic regime. Chem 3, 411–427 (2018).

    Google Scholar 

  64. August, D. P., Nichol, G. S. & Lusby, P. J. Maximizing coordination capsule–guest polar interactions in apolar solvents reveals significant binding. Angew. Chem. Int. Ed. 55, 15022–15026 (2016).

    CAS  Google Scholar 

  65. Szalóki, G. et al. Controlling the host–guest interaction mode through a redox stimulus. Angew. Chem. Int. Ed. 56, 16272–16276 (2017).

    Google Scholar 

  66. Colomban, C. et al. Reversible C60 ejection from a metallocage through the redox-dependent binding of a competitive guest. Chem. Eur. J. 23, 3016–3022 (2017).

    CAS  PubMed  Google Scholar 

  67. Croué, V., Goeb, S., Szalóki, G., Allain, M. & Sallé, M. Reversible guest uptake/release by redox-controlled assembly/disassembly of a coordination cage. Angew. Chem. Int. Ed. 55, 1746–1750 (2016).

    Google Scholar 

  68. Chifotides, H. T., Giles, I. D. & Dunbar, K. R. Supramolecular architectures with π-acidic 3,6-Bis(2-pyridyl)-1,2,4,5-tetrazine cavities: role of anion−π interactions in the remarkable stability of Fe(II) metallacycles in solution. J. Am. Chem. Soc. 135, 3039–3055 (2013).

    CAS  PubMed  Google Scholar 

  69. Chepelin, O. et al. Luminescent, enantiopure, phenylatopyridine iridium-based coordination capsules. J. Am. Chem. Soc. 134, 19334–19337 (2012).

    CAS  PubMed  Google Scholar 

  70. Cookson, N. J. et al. Encapsulation of sodium alkyl sulfates by the cyclotriveratrylene-based, [Pd6L8]12+stella octangula cage. Dalton Trans. 43, 5657–5661 (2014).

    CAS  PubMed  Google Scholar 

  71. Taylor, C. G. P., Piper, J. R. & Ward, M. D. Binding of chemical warfare agent simulants as guests in a coordination cage: contributions to binding and a fluorescence-based response. Chem. Commun. 52, 6225–6228 (2016).

    CAS  Google Scholar 

  72. Ronson, T. K., Meng, W. & Nitschke, J. R. Design principles for the optimization of guest binding in aromatic-paneled FeII 4L6 cages. J. Am. Chem. Soc. 139, 9698–9707 (2017).

    CAS  PubMed  Google Scholar 

  73. Ramsay, W. J. et al. Designed enclosure enables guest binding within the 4200 Å3 cavity of a self-assembled cube. Angew. Chem. Int. Ed. 54, 5636–5640 (2015).

    CAS  Google Scholar 

  74. Yoshizawa, M. & Klosterman, J. K. Molecular architectures of multi-anthracene assemblies. Chem. Soc. Rev. 43, 1885–1898 (2014).

    CAS  PubMed  Google Scholar 

  75. Kusaba, S., Yamashina, M., Akita, M., Kikuchi, T. & Yoshizawa, M. Hydrophilic oligo(lactic acid)s captured by a hydrophobic polyaromatic cavity in water. Angew. Chem. Int. Ed. 57, 3706–3710 (2018).

    CAS  Google Scholar 

  76. Yoshizawa, M. & Yamashina, M. Coordination-driven nanostructures with polyaromatic shells. Chem. Lett. 46, 163–171 (2017).

    CAS  Google Scholar 

  77. Kishi, N. et al. Wide-ranging host capability of a PdII-Linked M2L4 molecular capsule with an anthracene shell. Chem. Eur. J. 19, 6313–6320 (2013).

    CAS  PubMed  Google Scholar 

  78. Kishi, N., Li, Z., Yoza, K., Akita, M. & Yoshizawa, M. An M2L4 molecular capsule with an anthracene shell: encapsulation of large guests up to 1 nm. J. Am. Chem. Soc. 133, 11438–11441 (2011).

    CAS  PubMed  Google Scholar 

  79. Matsuno, S. et al. Exact mass analysis of sulfur clusters upon encapsulation by a polyaromatic capsular matrix. Nat. Commun. 8, 749 (2017).

    PubMed  PubMed Central  Google Scholar 

  80. O’Sullivan, M. C. et al. Vernier templating and synthesis of a 12-porphyrin nano-ring. Nature 469, 72–75 (2011).

    PubMed  Google Scholar 

  81. Liu, P. et al. Synthesis of five-porphyrin nanorings by using ferrocene and corannulene templates. Angew. Chem. Int. Ed. 55, 8358–8362 (2016).

    CAS  Google Scholar 

  82. Rickhaus, M. et al. Single-acetylene linked porphyrin nanorings. J. Am. Chem. Soc. 139, 16502–16505 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  83. Anderson, S., Anderson, H. L., Bashall, A., McPartlin, M. & Sanders, J. K. M. Assembly and crystal structure of a photoactive array of five porphyrins. Angew. Chem. Int. Ed. 34, 1096–1099 (1995).

    CAS  Google Scholar 

  84. Liu, S. et al. Caterpillar track complexes in template-directed synthesis and correlated molecular motion. Angew. Chem. Int. Ed. 54, 5355–5359 (2015).

    CAS  Google Scholar 

  85. Otte, M. et al. Encapsulated cobalt–porphyrin as a catalyst for size-selective radical-type cyclopropanation reactions. Chem. Eur. J. 20, 4880–4884 (2014).

    CAS  PubMed  Google Scholar 

  86. Otte, M. et al. Encapsulation of metalloporphyrins in a self-assembled cubic M8L6 cage: a new molecular flask for cobalt–porphyrin-catalysed radical-type reactions. Chem. Eur. J. 19, 10170–10178 (2013).

    CAS  PubMed  Google Scholar 

  87. Resendiz, M. J. E., Noveron, J. C., Disteldorf, H., Fischer, S. & Stang, P. J. A. Self-assembled supramolecular optical sensor for Ni(II), Cd(II), and Cr(III). Org. Lett. 6, 651–653 (2004).

    CAS  PubMed  Google Scholar 

  88. Amouri, H. et al. Host–guest interactions: design strategy and structure of an unusual cobalt cage that encapsulates a tetrafluoroborate anion. Angew. Chem. Int. Ed. 44, 4543–4546 (2005).

    CAS  Google Scholar 

  89. Amouri, H. et al. Supramolecular cobalt cages and coordination polymers templated by anion guests: self-assembly, structures, and magnetic properties. Chem. Eur. J. 13, 5401–5407 (2007).

    CAS  PubMed  Google Scholar 

  90. Desmarets, C., Policar, C., Chamoreau, L.-M. & Amouri, H. Design, self-assembly, and molecular structures of 3D Copper(II) capsules templated by BF4 – guest anions. Eur. J. Inorg. Chem. 2009, 4396–4400 (2009).

    Google Scholar 

  91. Liao, P. et al. Two-component control of guest binding in a self-assembled cage molecule. Chem. Commun. 46, 4932–4934 (2010).

    CAS  Google Scholar 

  92. Sato, H. et al. Positive heterotropic cooperativity for selective guest binding via electronic communications through a fused zinc porphyrin array. J. Am. Chem. Soc. 127, 13086–13087 (2005).

    CAS  PubMed  Google Scholar 

  93. Nakamura, T., Kaneko, Y., Nishibori, E. & Nabeshima, T. Molecular recognition by multiple metal coordination inside wavy-stacked macrocycles. Nat. Commun. 8, 129 (2017).

    PubMed  PubMed Central  Google Scholar 

  94. Scarso, A., Onagi, H. & Rebek, J. Mechanically regulated rotation of a guest in a nanoscale host. J. Am. Chem. Soc. 126, 12728–12729 (2004).

    CAS  PubMed  Google Scholar 

  95. Kang, J. & Rebek, Jr, J. Acceleration of a Diels–Alder reaction by a self-assembled molecular capsule. Nature 385, 50–52 (1997).

    CAS  PubMed  Google Scholar 

  96. Kang, J., Hilmersson, G., Santamaría, J. & Rebek, J. Diels−Alder reactions through reversible encapsulation. J. Am. Chem. Soc. 120, 3650–3656 (1998).

    CAS  Google Scholar 

  97. Yoshizawa, M., Tamura, M. & Fujita, M. Diels-Alder in aqueous molecular hosts: unusual regioselectivity and efficient catalysis. Science 312, 251–254 (2006).

    CAS  PubMed  Google Scholar 

  98. Sawada, T., Yoshizawa, M., Sato, S. & Fujita, M. Minimal nucleotide duplex formation in water through enclathration in self-assembled hosts. Nat. Chem. 1, 53–56 (2009).

    CAS  PubMed  Google Scholar 

  99. Sawada, T. & Fujita, M. A. Single Watson−Crick G·C base pair in water: aqueous hydrogen bonds in hydrophobic cavities. J. Am. Chem. Soc. 132, 7194–7201 (2010).

    CAS  PubMed  Google Scholar 

  100. Yamashina, M. et al. Preparation of highly fluorescent host–guest complexes with tunable color upon encapsulation. J. Am. Chem. Soc. 137, 9266–9269 (2015).

    CAS  PubMed  Google Scholar 

  101. Leenders, S. H. A. M. et al. Selective co-encapsulation inside an M6L4 cage. Chem. Eur. J. 22, 15468–15474 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Kim, H.-J. et al. Selective inclusion of a hetero-guest pair in a molecular host: formation of stable charge-transfer complexes in cucurbit[8]uril. Angew. Chem. Int. Ed. 40, 1526–1529 (2001).

    CAS  Google Scholar 

  103. Clever, G. H., Kawamura, W., Tashiro, S., Shiro, M. & Shionoya, M. Stacked platinum complexes of the magnus’ salt type inside a coordination cage. Angew. Chem. Int. Ed. 51, 2606–2609 (2012).

    CAS  Google Scholar 

  104. Vasdev, R. A. S., Preston, D. & Crowley, J. D. Multicavity metallosupramolecular architectures. Chem. Asian J. 12, 2513–2523 (2017).

    CAS  PubMed  Google Scholar 

  105. Baxter, P. N. W., Lehn, J.-M., Kneisel, B. O., Baum, G. & Fenske, D. The designed self-assembly of multicomponent and multicompartmental cylindrical nanoarchitectures. Chem. Eur. J. 5, 113–120 (1999).

    CAS  Google Scholar 

  106. Crowley, J. D., Goshe, A. J. & Bosnich, B. Molecular recognition. Self-assembly of molecular trigonal prisms and their host-guest adducts. Chem. Commun. 2824–2825 (2003).

  107. Crowley, J. D., Steele, I. M. & Bosnich, B. Molecular recognition – allosterism generated by weak host–guest interactions in molecular rectangles. Eur. J. Inorg. Chem. 2005, 3907–3917 (2005).

    Google Scholar 

  108. Lewis, J. E. M., Gavey, E. L., Cameron, S. A. & Crowley, J. D. Stimuli-responsive Pd2L4 metallosupramolecular cages: towards targeted cisplatin drug delivery. Chem. Sci. 3, 778–784 (2012).

    CAS  Google Scholar 

  109. Preston, D., Lewis, J. E. M. & Crowley, J. D. Multicavity [PdnL4]2n+cages with controlled segregated binding of different guests. J. Am. Chem. Soc. 139, 2379–2386 (2017).

    CAS  PubMed  Google Scholar 

  110. Yazaki, K. et al. Polyaromatic molecular peanuts. Nat. Commun. 8, 15914 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Chang, S.-Y., Jang, H.-Y. & Jeong, K.-S. Self-assembled metallocycles with two interactive binding domains. Chem. Eur. J. 10, 4358–4366 (2004).

    CAS  PubMed  Google Scholar 

  112. Fujita, M., Fujita, N., Ogura, K. & Yamaguchi, K. Spontaneous assembly of ten components into two interlocked, identical coordination cages. Nature 400, 52–55 (1999).

    CAS  Google Scholar 

  113. Yamauchi, Y., Yoshizawa, M. & Fujita, M. Engineering stacks of aromatic rings by the interpenetration of self-assembled coordination cages. J. Am. Chem. Soc. 130, 5832–5833 (2008).

    CAS  PubMed  Google Scholar 

  114. Han, M., Engelhard, D. M. & Clever, G. H. Self-assembled coordination cages based on banana-shaped ligands. Chem. Soc. Rev. 43, 1848–1860 (2014).

    CAS  PubMed  Google Scholar 

  115. Löffler, S. et al. Influence of size, shape, heteroatom content and dispersive contributions on guest binding in a coordination cage. Chem. Commun. 53, 11933–11936 (2017).

    Google Scholar 

  116. Lu, Y. et al. Molecular borromean rings based on dihalogenated ligands. Chem 3, 110–121 (2017).

    CAS  Google Scholar 

  117. Sun, Q.-F., Murase, T., Sato, S. & Fujita, M. A. Sphere-in-sphere complex by orthogonal self-assembly. Angew. Chem. Int. Ed. 50, 10318–10321 (2011).

    CAS  Google Scholar 

  118. Bhat, I. A., Samanta, D. & Mukherjee, P. S. A. Pd24 pregnant molecular nanoball: self-templated stellation by precise mapping of coordination sites. J. Am. Chem. Soc. 137, 9497–9502 (2015).

    CAS  PubMed  Google Scholar 

  119. Byrne, K. et al. Ultra-large supramolecular coordination cages composed of endohedral Archimedean and Platonic bodies. Nat. Commun. 8, 15268 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Löffler, S. et al. Triggered exchange of anionic for neutral guests inside a cationic coordination cage. J. Am. Chem. Soc. 137, 1060–1063 (2015).

    PubMed  Google Scholar 

  121. Mirtschin, S., Slabon-Turski, A., Scopelliti, R., Velders, A. H. & Severin, K. A. Coordination cage with an adaptable cavity size. J. Am. Chem. Soc. 132, 14004–14005 (2010).

    CAS  PubMed  Google Scholar 

  122. Gan, Q., Ronson, T. K., Vosburg, D. A., Thoburn, J. D. & Nitschke, J. R. Cooperative loading and release behavior of a metal–organic receptor. J. Am. Chem. Soc. 137, 1770–1773 (2015).

    CAS  PubMed  Google Scholar 

  123. Rizzuto, F. J. & Nitschke, J. R. Stereochemical plasticity modulates cooperative binding in a CoII 12L6 cuboctahedron. Nat. Chem. 9, 903–908 (2017).

    CAS  PubMed  Google Scholar 

  124. Ramsay, W. J., Ronson, T. K., Clegg, J. K. & Nitschke, J. R. Bidirectional regulation of halide binding in a heterometallic supramolecular cube. Angew. Chem. Int. Ed. 52, 13439–13443 (2013).

    CAS  Google Scholar 

  125. Ramsay, W. J. & Nitschke, J. R. Two distinct allosteric active sites regulate guest binding within a Fe8Mo12 16+cubic receptor. J. Am. Chem. Soc. 136, 7038–7043 (2014).

    CAS  PubMed  Google Scholar 

  126. von Krbek, L. K. S., Roberts, D. A., Pilgrim, B. S., Schalley, C. A. & Nitschke, J. R. Multivalent crown-ether receptors enable allosteric regulation of anion exchange in an Fe4L6 tetrahedron. Angew. Chem. Int. Ed. 57, 14121–14124 (2018).

    Google Scholar 

  127. Sgarlata, C. & Raymond, K. N. Untangling the diverse interior and multiple exterior guest interactions of a supramolecular host by the simultaneous analysis of complementary observables. Anal. Chem. 88, 6923–6929 (2016).

    CAS  PubMed  Google Scholar 

  128. Davis, A. V. & Raymond, K. N. The big squeeze: guest exchange in an M4L6 supramolecular host. J. Am. Chem. Soc. 127, 7912–7919 (2005).

    CAS  PubMed  Google Scholar 

  129. Davis, A. V. et al. Guest exchange dynamics in an M4L6 tetrahedral host. J. Am. Chem. Soc. 128, 1324–1333 (2006).

    CAS  PubMed  Google Scholar 

  130. Rizzuto, F. J., Wu, W. Y., Ronson, T. K. & Nitschke, J. R. Peripheral templation generates an MII 6L4 guest-binding capsule. Angew. Chem. Int. Ed. 128, 8090–8094 (2016).

    Google Scholar 

  131. Fujita, M. et al. Self-assembly of ten molecules into nanometre-sized organic host frameworks. Nature 378, 469–471 (1995).

    CAS  Google Scholar 

  132. Rizzuto, F. J., Kieffer, M. & Nitschke, J. R. Quantified structural speciation in self-sorted CoII 6L4 cage systems. Chem. Sci. 9, 1925–1930 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  133. Bai, X. et al. Peripheral templation-modulated interconversion between an A4L6 tetrahedral anion cage and A2L3 triple helicate with guest capture/release. Angew. Chem. Int. Ed. 57, 1851–1855 (2018).

    CAS  Google Scholar 

  134. Hiraoka, S. et al. Isostructural coordination capsules for a series of 10 different d5–d10 transition-metal ions. Angew. Chem. Int. Ed. 45, 6488–6491 (2006).

    CAS  Google Scholar 

  135. Riddell, I. A. et al. Cation- and anion-exchanges induce multiple distinct rearrangements within metallosupramolecular architectures. J. Am. Chem. Soc. 136, 9491–9498 (2014).

    CAS  PubMed  Google Scholar 

  136. Riddell, I. A. et al. Anion-induced reconstitution of a self-assembling system to express a chloride-binding Co10L15 pentagonal prism. Nat. Chem. 4, 751–756 (2012).

    CAS  PubMed  Google Scholar 

  137. Haynes, C. J. E. et al. Blockable Zn10L15 ion channels through subcomponent self-assembly. Angew. Chem. Int. Ed. 56, 15388–15392 (2017).

    CAS  Google Scholar 

  138. Klein, C. et al. A new structural motif for an enantiomerically pure metallosupramolecular Pd4L8 aggregate by anion templating. Angew. Chem. Int. Ed. 53, 3739–3742 (2014).

    CAS  Google Scholar 

  139. Tashiro, S. et al. PdII-directed dynamic assembly of a dodecapyridine ligand into end-capped and open tubes: the importance of kinetic control in self-assembly. Angew. Chem. Int. Ed. 42, 3267–3270 (2003).

    CAS  Google Scholar 

  140. Yoshizawa, M., Klosterman, J. K. & Fujita, M. Functional molecular flasks: new properties and reactions within discrete, self-assembled hosts. Angew. Chem. Int. Ed. 48, 3418–3438 (2009).

    CAS  Google Scholar 

  141. Zarra, S., Wood, D. M., Roberts, D. A. & Nitschke, J. R. Molecular containers in complex chemical systems. Chem. Soc. Rev. 44, 419–432 (2015).

    CAS  PubMed  Google Scholar 

  142. Nishioka, Y., Yamaguchi, T., Yoshizawa, M. & Fujita, M. Unusual [2 + 4] and [2 + 2] cycloadditions of arenes in the confined cavity of self-assembled cages. J. Am. Chem. Soc. 129, 7000–7001 (2007).

    CAS  PubMed  Google Scholar 

  143. Yoshizawa, M., Takeyama, Y., Kusukawa, T. & Fujita, M. Cavity-directed, highly stereoselective [2+2] photodimerization of olefins within self-assembled coordination cages. Angew. Chem. Int. Ed. 41, 1347–1349 (2002).

    CAS  Google Scholar 

  144. Takaoka, K., Kawano, M., Ozeki, T. & Fujita, M. Crystallographic observation of an olefin photodimerization reaction that takes place via thermal molecular tumbling within a self-assembled host. Chem. Commun. 1625–1627 (2006).

  145. Nishioka, Y., Yamaguchi, T., Kawano, M. & Fujita, M. Asymmetric [2 + 2] olefin cross photoaddition in a self-assembled host with remote chiral auxiliaries. J. Am. Chem. Soc. 130, 8160–8161 (2008).

    CAS  PubMed  Google Scholar 

  146. Yoshizawa, M., Miyagi, S., Kawano, M., Ishiguro, K. & Fujita, M. Alkane oxidation via photochemical excitation of a self-assembled molecular cage. J. Am. Chem. Soc. 126, 9172–9173 (2004).

    CAS  PubMed  Google Scholar 

  147. Yoshizawa, M., Kusukawa, T., Fujita, M. & Yamaguchi, K. Ship-in-a-bottle synthesis of otherwise labile cyclic trimers of siloxanes in a self-assembled coordination cage. J. Am. Chem. Soc. 122, 6311–6312 (2000).

    CAS  Google Scholar 

  148. Kawano, M., Kobayashi, Y., Ozeki, T. & Fujita, M. Direct crystallographic observation of a coordinatively unsaturated transition-metal complex in situ generated within a self-assembled cage. J. Am. Chem. Soc. 128, 6558–6559 (2006).

    CAS  PubMed  Google Scholar 

  149. Hart-Cooper, W. M. et al. The effect of host structure on the selectivity and mechanism of supramolecular catalysis of Prins cyclizations. Chem. Sci. 6, 1383–1393 (2015).

    CAS  PubMed  Google Scholar 

  150. Wang, Z. J., Brown, C. J., Bergman, R. G., Raymond, K. N. & Toste, F. D. Hydroalkoxylation catalyzed by a gold(I) complex encapsulated in a supramolecular host. J. Am. Chem. Soc. 133, 7358–7360 (2011).

    CAS  PubMed  Google Scholar 

  151. Fiedler, D., Bergman, R. G. & Raymond, K. N. Stabilization of reactive organometallic intermediates inside a self-assembled nanoscale host. Angew. Chem. Int. Ed. 45, 745–748 (2006).

    CAS  Google Scholar 

  152. Levin, M. D. et al. Scope and mechanism of cooperativity at the intersection of organometallic and supramolecular catalysis. J. Am. Chem. Soc. 138, 9682–9693 (2016).

    CAS  PubMed  Google Scholar 

  153. Hastings, C. J., Pluth, M. D., Bergman, R. G. & Raymond, K. N. Enzymelike catalysis of the nazarov cyclization by supramolecular encapsulation. J. Am. Chem. Soc. 132, 6938–6940 (2010).

    CAS  PubMed  Google Scholar 

  154. Fiedler, D., Bergman, R. G. & Raymond, K. N. Supramolecular catalysis of a unimolecular transformation: aza-cope rearrangement within a self-assembled host. Angew. Chem. Int. Ed. 43, 6748–6751 (2004).

    CAS  Google Scholar 

  155. Zhao, C., Toste, F. D., Raymond, K. N. & Bergman, R. G. Nucleophilic substitution catalyzed by a supramolecular cavity proceeds with retention of absolute stereochemistry. J. Am. Chem. Soc. 136, 14409–14412 (2014).

    CAS  PubMed  Google Scholar 

  156. Wang, Q.-Q. et al. Self-assembled nanospheres with multiple endohedral binding sites pre-organize catalysts and substrates for highly efficient reactions. Nat. Chem. 8, 225–230 (2016).

    CAS  PubMed  Google Scholar 

  157. Gramage-Doria, R. et al. Gold(I) catalysis at extreme concentrations inside self-assembled nanospheres. Angew. Chem. Int. Ed. 53, 13380–13384 (2014).

    CAS  Google Scholar 

  158. Leenders, S. H. A. M., Dürr, M., Ivanovic´-Burmazovic´, I. & Reek, J. N. H. Gold functionalized platinum M12L24-nanospheres and their application in cyclization reactions. Adv. Synth. Catal. 358, 1509–1518 (2016).

    CAS  Google Scholar 

  159. Ueda, Y., Ito, H., Fujita, D. & Fujita, M. Permeable self-assembled molecular containers for catalyst isolation enabling two-step cascade reactions. J. Am. Chem. Soc. 139, 6090–6093 (2017).

    CAS  PubMed  Google Scholar 

  160. Suzuki, K., Sato, S. & Fujita, M. Template synthesis of precisely monodisperse silica nanoparticles within self-assembled organometallic spheres. Nat. Chem. 2, 25 (2009).

    PubMed  Google Scholar 

  161. Murase, T., Nishijima, Y. & Fujita, M. Cage-catalyzed knoevenagel condensation under neutral conditions in water. J. Am. Chem. Soc. 134, 162–164 (2012).

    CAS  PubMed  Google Scholar 

  162. Cullen, W., Misuraca, M. C., Hunter, C. A., Williams, N. H. & Ward, M. D. Highly efficient catalysis of the Kemp elimination in the cavity of a cubic coordination cage. Nat. Chem. 8, 231–236 (2016).

    CAS  PubMed  Google Scholar 

  163. Cullen, W. et al. Catalysis in a cationic coordination cage using a cavity-bound guest and surface-bound anions: inhibition, activation, and autocatalysis. J. Am. Chem. Soc. 140, 2821–2828 (2018).

    CAS  PubMed  Google Scholar 

  164. Pluth, M. D., Bergman, R. G. & Raymond, K. N. Acid catalysis in basic solution: a supramolecular host promotes orthoformate hydrolysis. Science 316, 85–88 (2007).

    CAS  PubMed  Google Scholar 

  165. Wood, D. M. et al. Guest-induced transformation of a porphyrin-edged FeII 4L6 capsule into a CuIFeII 2L4 fullerene receptor. Angew. Chem. Int. Ed. 54, 3988–3992 (2015).

    CAS  Google Scholar 

  166. Wang, S., Sawada, T., Ohara, K., Yamaguchi, K. & Fujita, M. Capsule–capsule conversion by guest encapsulation. Angew. Chem. Int. Ed. 55, 2063–2066 (2016).

    CAS  Google Scholar 

  167. Sekiya, R., Fukuda, M. & Kuroda, R. Anion-directed formation and degradation of an interlocked metallohelicate. J. Am. Chem. Soc. 134, 10987–10997 (2012).

    CAS  PubMed  Google Scholar 

  168. Sekiya, R. Kuroda, Pd2+∙∙∙O3SR– interaction encourages anion encapsulation of a quadruply-stranded Pd complex to achieve chirality or high solubility. Chem. Commun. 47, 12346–12348 (2011).

    CAS  Google Scholar 

  169. Zhang, T., Zhou, L.-P., Guo, X.-Q., Cai, L.-X. & Sun, Q.-F. Adaptive self-assembly and induced-fit transformations of anion-binding metal-organic macrocycles. Nat. Commun. 8, 15898 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Lee, H. et al. Selective synthesis of ruthenium(II) metalla[2]catenane via solvent and guest-dependent self-assembly. J. Am. Chem. Soc. 137, 4674–4677 (2015).

    CAS  PubMed  Google Scholar 

  171. Vilar, R., Mingos, D. M. P., White, A. J. P. & Williams, D. J. Anion control in the self-assembly of a cage coordination complex. Angew. Chem. Int. Ed. 37, 1258–1261 (1998).

    CAS  Google Scholar 

  172. Paul, R. L., Bell, Z. R., Jeffery, J. C., McCleverty, J. A. & Ward, M. D. Anion-templated self-assembly of tetrahedral cage complexes of cobalt(II) with bridging ligands containing two bidentate pyrazolyl-pyridine binding sites. Proc. Natl Acad. Sci. USA 99, 4883–4888 (2002).

    CAS  PubMed  Google Scholar 

  173. Custelcean, R. et al. Urea-functionalized M4L6 cage receptors: anion-templated self-assembly and selective guest exchange in aqueous solutions. J. Am. Chem. Soc. 134, 8525–8534 (2012).

    CAS  PubMed  Google Scholar 

  174. Paul, L. E. H., Therrien, B. & Furrer, J. The complex-in-a-complex cation [Pt(acac)2⊂(p-cym)6Ru6(tpt)2(dhnq)3]6+: its stability towards biological ligands. Inorganica Chim. Acta 469, 1–10 (2018).

    CAS  Google Scholar 

  175. Ahmad, N., Younus, H. A., Chughtai, A. H. & Verpoort, F. Metal–organic molecular cages: applications of biochemical implications. Chem. Soc. Rev. 44, 9–25 (2015).

    CAS  PubMed  Google Scholar 

  176. Gupta, G., Oggu, G. S., Nagesh, N., Bokara, K. K. & Therrien, B. Anticancer activity of large metalla-assemblies built from half-sandwich complexes. CrystEngComm 18, 4952–4957 (2016).

    CAS  Google Scholar 

  177. Casini, A., Woods, B. & Wenzel, M. The promise of self-assembled 3D supramolecular coordination complexes for biomedical applications. Inorg. Chem. 56, 14715–14729 (2017).

    CAS  PubMed  Google Scholar 

  178. Schmidt, A. et al. Evaluation of new palladium cages as potential delivery systems for the anticancer drug cisplatin. Chem. Eur. J 22, 2253–2256 (2016).

    CAS  PubMed  Google Scholar 

  179. Kaiser, F. et al. Self-assembled palladium and platinum coordination cages: photophysical studies and anticancer activity. Eur. J. Inorg. Chem. 2016, 5189–5196 (2016).

    CAS  Google Scholar 

  180. Zheng, Y.-R., Suntharalingam, K., Johnstone, T. C. & Lippard, S. J. Encapsulation of Pt(iv) prodrugs within a Pt(ii) cage for drug delivery. Chem. Sci. 6, 1189–1193 (2015).

    CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the European Research Council (695009) and the UK Engineering and Physical Sciences Research Council (EPSRC, EP/P027067/1). F.J.R. acknowledges Cambridge Australia Scholarships for PhD funding, and L.K.S.v.K. acknowledges the Alexander von Humboldt Foundation for a Feodor Lynen Research Fellowship.

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Nature Reviews Chemistry thanks M. Ward and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Department of Chemistry, University of Cambridge, Cambridge, UK

    Felix J. Rizzuto, Larissa K. S. von Krbek & Jonathan R. Nitschke

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F.J.R. and L.K.S.v.K. researched the data for the article and discussed the content. All authors contributed to the writing of the Review and editing of the manuscript before submission.

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Rizzuto, F.J., von Krbek, L.K.S. & Nitschke, J.R. Strategies for binding multiple guests in metal–organic cages. Nat Rev Chem 3, 204–222 (2019). https://doi.org/10.1038/s41570-019-0085-3

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