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Review
. 2025 Jul 22.
doi: 10.1039/d5sc02081f. Online ahead of print.

Encapsulation of reactive species within metal-organic cages

Soumalya Bhattacharyya  1 , Martin R Black  1 , Ben S Pilgrim  1
Affiliations
Review

Encapsulation of reactive species within metal-organic cages

Soumalya Bhattacharyya et al. Chem Sci. .

Abstract

Reactivity under confinement often differs greatly from reactivity in the bulk. Metal-organic cages (MOCs) are a class of discrete, solution-processable container molecules encompassing well-defined nanospaces, which can be rapidly constructed in modular fashion via self-assembly. Supramolecular chemists have created an extensive library of MOCs and demonstrated their ability to serve as molecular flasks, with cavities tailored to bind guests of interest. In this review, we cover selected examples of the encapsulation and relative stabilisation of reactive species within MOCs, from early reports to the most recent developments. Most reactive species are not inherently unstable; but they persist only as long as they do not encounter a partner with whom they can react. MOCs can prevent or reduce the rate of this deleterious reactivity through acting as a shield and providing a physical barrier between an encapsulated reactive guest and other system components regularly encountered in the bulk environment, including air, water, solvent, light, another molecule of itself, or a co-reactant. Thus, MOCs can extend the lifetime of these short-lived reactive species enhancing their study, or allowing for different reactivity to be explored. Examples have been segregated based on the nature of stabilisation (i.e., with what partner a reaction has been prevented). We believe this analysis will help provide more nuanced understanding of what types of highly reactive species can be tolerated within a dynamic MOC system to enable MOCs to find use in a wider variety of real-world applications.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. Representation of the SCXRD structures of (a) cage 1, and (b) cage 3, alongside cartoon representations and their respective ligands 2 and 4. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey, N = blue, O = red, Pd = turquoise.
Fig. 2
Fig. 2. A selection of common unreactive guest molecules often bound in MOCs, including the gases xenon and carbon dioxide, solvents acetone and acetonitrile, anions hexafluorophosphate and tetrafluoroborate, cations tetramethylammonium and tetraethylphosphonium, steroid epitestosterone, buckminsterfullerene and anthracene, and peptide thermolysin. Colour: C = grey, N = blue, O = red, H = white, F = aquamarine, P = magenta, B = pink, Xe = dark purple. Thermolysin is shown as a cartoon representation.
Fig. 3
Fig. 3. (a) Reversible ligation between a nucleophilic/basic donor atom and a metal centre; when deligated the donor atom can react with electrophiles. (b) Nucleophilic functionality can react with a metal centre, possibly leading to ligand displacement and degradation. (c) More electron-rich donor ligands form stronger interactions both with metal centres and protons. This makes more electron-rich ligands more stable towards base and less stable towards acid. (d) Redox agents can oxidise/reduce metal centres, with changes in coordination number or geometry leading to degradation.
Fig. 4
Fig. 4. (a) Representation of the SCXRD structure of cage 6 constructed from ligand 5. (b) Formation of cationic adduct 7 is promoted by cage 6. (c) Cage 6 binds and stabilises diazonium cation 8 and tropylium cation 11 but does not bind diazonium cations 9 and 10. (d) Cage 6 stabilises iminium ions such as 12 which normally are transient in water. (e) Cage 6 promotes ionisation of Ru complex 13, to cationic complex 14 which binds. 14 reacts with CO to form 15 in the cavity. Disorder, solvent, hydrogen atoms, and counter cations have been omitted for clarity. Colour: C = grey, N = blue, O = red, Ga = burnt pink, P = magenta, Cl = light green, Ru = dark green.
Fig. 5
Fig. 5. Representation of the SCXRD structure of 18 ⊂ 17. Cage 17 is constructed from ligand 16. A fragment of DFP 18 is shown bound on the face of cage 17 with the P–F bond orientated into the cavity (full structure of DFP was not found due to disorder). Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey or black, N = blue, O = red, Co = light blue, P = magenta, F = aquamarine.
Fig. 6
Fig. 6. Representation of the SCXRD structure of (21)3(22)CO ⊂ 19 constructed from ligand 20. Two Mn tricarbonyls 21 and the one Mn dicarbonyl 22 are shown; the third encapsulated Mn tricarbonyl 21 closest to the camera has been omitted for clarity. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey or black, N = blue, O = red, Pd = turquoise, Mn = purple; other atoms of encapsulated complexes = wheat.
Fig. 7
Fig. 7. Representation of the SCXRD structure of 23 ⊂ 24. Cage 24 is constructed from components 25 and 26. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey or black, N = blue, O = red, Rh = teal, Cd = light orange.
Fig. 8
Fig. 8. Representation of the SCXRD structure of P4 ⊂ 28. Cage 28 is constructed from components 29 and 30. Disorder, solvent, hydrogen atoms, and counter cations have been omitted for clarity. Colour: C = grey, N = blue, O = red, Fe = orange, S = yellow, P = magenta.
Fig. 9
Fig. 9. Representation of the SCXRD structure of 31 ⊂ 3 and light promoted interconversion between 31 ⊂ 3 and 32 ⊂ 3. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey, N = blue, Pd = turquoise, DHP = black.
Fig. 10
Fig. 10. Representation of the structure of C60˙− ⊂ 33. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey, N = blue, O = red, Pd = turquoise, C60 = black. Note the SCXRD was obtained with C60 not the radical anion; the latter is just shown for illustrative purposes.
Fig. 11
Fig. 11. Cartoon representation of cage 35, constructed from components 36 and 37, which binds peptide 38 through the histidines but not peptide 39. Colour: Zn = cool grey, Fe = orange. Peptides are shown by their standard one letter abbreviation for amino acid residues: A = alanine, G = glycine, H = histidine, I = isoleucine, K = lysine, R = arginine, S = serine, V = valine, W = tryptophan, Y = tyrosine. Abz = 2-aminobenzoyl, Dnp = 2,4-dinitrophenyl.
Fig. 12
Fig. 12. Cartoon representation of cage 40 which is constructed from ligand 41, and CLE enzyme 42. Colour: N = blue, O = red, Pd = turquoise.
Fig. 13
Fig. 13. (a) Representation of the SCXRD structure of 45 ⊂ 43, showing the encapsulation of ‘monomeric’ silanetriol 45. (b) Representation of the SCXRD structure of 48 ⊂ 46, showing the encapsulation of silanol dimer 48. (c) Representation of the SCXRD structure of 49 which encapsulates silanol cyclic trimer 50. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey or black, N = blue, O = red, Pd = turquoise, Si = sand.
Fig. 14
Fig. 14. Cartoon representation of cage 52 which is constructed from components 30 and 53. Cage 52 encapsulates cluster 51. Colour: N = blue, O = red, Fe = orange, S = yellow.
Fig. 15
Fig. 15. Representation of the SCXRD structure of 54 ⊂ 19. Complex 55 is also encapsulated. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey or black, N = blue, O = red, Pd = turquoise, Ru = dark green.
Fig. 16
Fig. 16. Representation of the SCXRD structure of 58 ⊂ 56. Cage 56 is constructed from ligand 57. Radical initiator 59 is also encapsulated. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey or black, N = blue, O = red, Pd = turquoise.
Fig. 17
Fig. 17. Representation of the SCXRD structure of 60 ⊂ 3. Spiropyran 61 converts to merocyanine 62 which is encapsulated, but merocyanine 64 is not encapsulated. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey, N = blue, O = red, Pd = turquoise, S = yellow.
Fig. 18
Fig. 18. Representation of the SCXRD structure of cage 65 constructed from ligand 64. Spiropyran 67 converts to merocyanine 68 which is encapsulated. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey, N = blue, O = red, Pd = turquoise, Br = brown.
Fig. 19
Fig. 19. Representation of the SCXRD structure of cage 69 constructed from ligand 70. DASA 71 converts to open form 72 which is encapsulated. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey, N = blue, O = red, Pd = turquoise.
Fig. 20
Fig. 20. Representation of the SCXRD structure of cage 73, which selectively encapsulates the cis-form of azobenzene 74. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey, N = blue, O = red, Pt = light grey.
Fig. 21
Fig. 21. Representation of the SCXRD structure of cage 49. Allylic chlorides 75 and 78 are partially encapsulated within 49, protecting them from nucleophilic attack at the internal position and leading to more of terminal alcohol 76 being formed over internal alcohol 77 than in the absence of cage 49. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey, N = blue, O = red, Pd = turquoise, Cl = light green, Ag = silver.
Fig. 22
Fig. 22. Representation of the SCXRD structure of cage 79 ⊂ 19, and selective reactions of terpene 79 to products 80–82. Disorder, solvent, hydrogen atoms, and counter anions have been omitted for clarity. Colour: C = grey or black, N = blue, O = red, Pd = turquoise, Br = brown, reactive alkene carbons = orange.
Fig. 23
Fig. 23. Representation of the SCXRD structure of cage 6 and selective reaction of citronellal 83 to alkene 86 in presence of cage 6. Disorder, solvent, hydrogen atoms, and counter cations have been omitted for clarity. Colour: C = grey, N = blue, O = red, Ga = burnt pink.
None
Soumalya Bhattacharyya
None
Martin R. Black
None
Ben S. Pilgrim
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References

    1. Breiner B. Clegg J. K. Nitschke J. R. Reactivity modulation in container molecules. Chem. Sci. 2011;2:51–56. doi: 10.1039/C0SC00329H. - DOI
    2. Cook T. R. Stang P. J. Recent Developments in the Preparation and Chemistry of Metallacycles and Metallacages via Coordination. Chem. Rev. 2015;115:7001–7045. doi: 10.1021/cr5005666. - DOI - PubMed
    3. Saha S. Regeni I. Clever G. H. Structure relationships between bis-monodentate ligands and coordination driven self-assemblies. Coord. Chem. Rev. 2018;374:1–14. doi: 10.1016/j.ccr.2018.06.010. - DOI
    4. Pan M. Wu K. Zhang J.-H. Su C.-Y. Chiral metal–organic cages/containers (MOCs): From structural and stereochemical design to applications. Coord. Chem. Rev. 2019;378:333–349. doi: 10.1016/j.ccr.2017.10.031. - DOI
    5. Sun Y. Chen C. Stang P. J. Soft Materials with Diverse Suprastructures via the Self-Assembly of Metal–Organic Complexes. Acc. Chem. Res. 2019;52:802–817. doi: 10.1021/acs.accounts.8b00663. - DOI - PMC - PubMed
    6. Pilgrim B. S. Champness N. R. Metal-Organic Frameworks and Metal-Organic Cages – A Perspective. ChemPlusChem. 2020;85:1842–1856. doi: 10.1002/cplu.202000408. - DOI - PubMed
    7. Lewis J. E. M. Molecular engineering of confined space in metal–organic cages. Chem. Commun. 2022;58:13873–13886. doi: 10.1039/D2CC05560K. - DOI - PubMed
    8. Tarzia A. Jelfs K. E. Unlocking the computational design of metal–organic cages. Chem. Commun. 2022;58:3717–3730. doi: 10.1039/D2CC00532H. - DOI - PMC - PubMed
    9. Tateishi T. Yoshimura M. Tokuda S. Matsuda F. Fujita D. Furukawa S. Coordination/metal–organic cages inside out. Coord. Chem. Rev. 2022;467:214612. doi: 10.1016/j.ccr.2022.214612. - DOI
    10. Cox C. J. T. Hale J. Molinska P. Lewis J. E. M. Supramolecular and molecular capsules, cages and containers. Chem. Soc. Rev. 2024;53:10380–10408. doi: 10.1039/D4CS00761A. - DOI - PubMed
    1. Yoshizawa M. Klosterman J. K. Fujita M. Functional Molecular Flasks: New Properties and Reactions within Discrete, Self-Assembled Hosts. Angew. Chem., Int. Ed. 2009;48:3418–3438. doi: 10.1002/anie.200805340. - DOI - PubMed
    2. Smulders M. M. J. Zarra S. Nitschke J. R. Quantitative Understanding of Guest Binding Enables the Design of Complex Host–Guest Behavior. J. Am. Chem. Soc. 2013;135:7039–7046. doi: 10.1021/ja402084x. - DOI - PubMed
    3. Löffler S. Lübben J. Krause L. Stalke D. Dittrich B. Clever G. H. Triggered Exchange of Anionic for Neutral Guests inside a Cationic Coordination Cage. J. Am. Chem. Soc. 2015;137:1060–1063. doi: 10.1021/ja5130379. - DOI - PubMed
    4. 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. 2016;55:15022–15026. doi: 10.1002/anie.201608229. - DOI - PubMed
    5. Rizzuto F. J. von Krbek L. K. S. Nitschke J. R. Strategies for binding multiple guests in metal–organic cages. Nat. Rev. Chem. 2019;3:204–222. doi: 10.1038/s41570-019-0085-3. - DOI
    6. Grommet A. B. Feller M. Klajn R. Chemical reactivity under nanoconfinement. Nat. Nanotechnol. 2020;15:256–271. doi: 10.1038/s41565-020-0652-2. - DOI - PubMed
    7. Percástegui E. G. Guest-Induced Transformations in Metal-Organic Cages. Eur. J. Inorg. Chem. 2021;2021:4425–4438. doi: 10.1002/ejic.202100657. - DOI
    8. Lewis J. E. M. Developing sophisticated microenvironments in metal-organic cages. Trends Chem. 2023;5:717–719. doi: 10.1016/j.trechm.2023.06.003. - DOI
    9. Speakman N. M. A. Heard A. W. Nitschke J. R. A CuI6L4 Cage Dynamically Reconfigures to Form Suit[4]anes and Selectively Bind Fluorinated Steroids. J. Am. Chem. Soc. 2024;146:10234–10239. doi: 10.1021/jacs.4c00257. - DOI - PMC - PubMed
    1. Olenyuk B. Whiteford J. A. Fechtenkötter A. Stang P. J. Self-assembly of nanoscale cuboctahedra by coordination chemistry. Nature. 1999;398:796–799. doi: 10.1038/19740. - DOI - PubMed
    2. Takeda N. Umemoto K. Yamaguchi K. Fujita M. A nanometre-sized hexahedral coordination capsule assembled from 24 components. Nature. 1999;398:794–796. doi: 10.1038/19734. - DOI
    3. Debata N. B. Tripathy D. Chand D. K. Self-assembled coordination complexes from various palladium(II) components and bidentate or polydentate ligands. Coord. Chem. Rev. 2012;256:1831–1945. doi: 10.1016/j.ccr.2012.04.001. - DOI
    4. Tsujimoto Y. Kojima T. Hiraoka S. Rate-determining step in the self-assembly process of supramolecular coordination capsules. Chem. Sci. 2014;5:4167–4172. doi: 10.1039/C4SC01652A. - DOI
    5. Kieffer M. Pilgrim B. S. Ronson T. K. Roberts D. A. Aleksanyan M. Nitschke J. R. Perfluorinated Ligands Induce Meridional Metal Stereochemistry to Generate M8L12, M10L15, and M12L18 Prisms. J. Am. Chem. Soc. 2016;138:6813–6821. doi: 10.1021/jacs.6b02445. - DOI - PubMed
    6. Bhattacharyya S. Ali S. R. Venkateswarulu M. Howlader P. Zangrando E. De M. Mukherjee P. S. Self-Assembled Pd12 Coordination Cage as Photoregulated Oxidase-Like Nanozyme. J. Am. Chem. Soc. 2020;142:18981–18989. doi: 10.1021/jacs.0c09567. - DOI - PubMed
    1. Seidel S. R. Stang P. J. High-Symmetry Coordination Cages via Self-Assembly. Acc. Chem. Res. 2002;35:972–983. doi: 10.1021/ar010142d. - DOI - PubMed
    2. Chakrabarty R. Mukherjee P. S. Stang P. J. Supramolecular Coordination: Self-Assembly of Finite Two- and Three-Dimensional Ensembles. Chem. Rev. 2011;111:6810–6918. doi: 10.1021/cr200077m. - DOI - PMC - PubMed
    3. Smulders M. M. J. Jiménez A. Nitschke J. R. Integrative Self-Sorting Synthesis of a Fe8Pt6L24 Cubic Cage. Angew. Chem., Int. Ed. 2012;51:6681–6685. doi: 10.1002/anie.201202050. - DOI - PubMed
    4. Ramsay W. J. Szczypiński F. T. Weissman H. Ronson T. K. Smulders M. M. J. Rybtchinski B. Nitschke J. R. Designed Enclosure Enables Guest Binding Within the 4200 Å3 Cavity of a Self-Assembled Cube. Angew. Chem., Int. Ed. 2015;54:5636–5640. doi: 10.1002/anie.201501892. - DOI - PubMed
    5. Howlader P. Das P. Zangrando E. Mukherjee P. S. Urea-Functionalized Self-Assembled Molecular Prism for Heterogeneous Catalysis in Water. J. Am. Chem. Soc. 2016;138:1668–1676. doi: 10.1021/jacs.5b12237. - DOI - PubMed
    6. Oldacre A. N. Friedman A. E. Cook T. R. A Self-Assembled Cofacial Cobalt Porphyrin Prism for Oxygen Reduction Catalysis. J. Am. Chem. Soc. 2017;139:1424–1427. doi: 10.1021/jacs.6b12404. - DOI - PubMed
    7. Wu Z. Zhou K. Ivanov A. V. Yusobov M. Verpoort F. The simplest and fascinating metal–organic polyhedra: Tetrahedra. Coord. Chem. Rev. 2017;353:180–200. doi: 10.1016/j.ccr.2017.10.008. - DOI
    8. Komine S. Takahashi S. Kojima T. Sato H. Hiraoka S. Self-Assembly Processes of Octahedron-Shaped Pd6L4 Cages. J. Am. Chem. Soc. 2019;141:3178–3186. doi: 10.1021/jacs.8b12890. - DOI - PubMed
    9. Tang J.-H. Ni R. He Y.-Q. Vanderlinden R. T. Li Y. Shi B. Li Z.-Y. Wang H. Li X. Sun Y. Zhong Y.-W. Stang P. J. Metal–Organic Pt(II) Hexagonal-Prism Macrocycles and Their Photophysical Properties. Inorg. Chem. 2019;58:13376–13381. doi: 10.1021/acs.inorgchem.9b02267. - DOI - PMC - PubMed
    10. Black M. R. Bhattacharyya S. Argent S. P. Pilgrim B. S. Structural Transformations of Metal–Organic Cages through Tetrazine-Alkene Reactivity. J. Am. Chem. Soc. 2024;146:28233–28241. - PMC - PubMed
    1. Tominaga M. Suzuki K. Kawano M. Kusukawa T. Ozeki T. Sakamoto S. Yamaguchi K. Fujita M. Finite, Spherical Coordination Networks that Self-Organize from 36 Small Components. Angew. Chem., Int. Ed. 2004;43:5621–5625. doi: 10.1002/anie.200461422. - DOI - PubMed
    2. Preston D. Inglis A. R. Garden A. L. Kruger P. E. A symmetry interaction approach to [M2L2]4+ metallocycles and their self-catenation. Chem. Commun. 2019;55:13271–13274. doi: 10.1039/C9CC07130J. - DOI - PubMed

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