Design and Applications of Water-Soluble Coordination Cages

Abstract

Compartmentalization of the aqueous space within a cell is necessary for life. In similar fashion to the nanometer-scale compartments in living systems, synthetic water-soluble coordination cages (WSCCs) can isolate guest molecules and host chemical transformations. Such cages thus show promise in biological, medical, environmental, and industrial domains. This review highlights examples of three-dimensional synthetic WSCCs, offering perspectives so as to enhance their design and applications. Strategies are presented that address key challenges for the preparation of coordination cages that are soluble and stable in water. The peculiarities of guest binding in aqueous media are examined, highlighting amplified binding in water, changing guest properties, and the recognition of specific molecular targets. The properties of WSCC hosts associated with biomedical applications, and their use as vessels to carry out chemical reactions in water, are also presented. These examples sketch a blueprint for the preparation of new metal-organic containers for use in aqueous solution, as well as guidelines for the engineering of new applications in water.

Figure 1

Timeline showing major advances in supramolecular coordination chemistry that have led from (a) the first cage complex to (b–f) early water-soluble complexes in the 1990s, and to (g–i) recent examples of WSCCs synthesized from ligands functionalized with solubilizing functional groups. The name of the group for each work is shown for reference.

Figure 2

Synthesis of the Mg^II-based cage (1) obtained by Saalfrank. The X-ray crystal structure of anionic [Mg₄L₆]^4– (1) is shown.

Figure 3

Synthesis of Fujita’s water-soluble square (4) and the cationic portion of its X-ray crystal structure.

Figure 4

(a) Self-assembly of water-soluble octahedron 6 reported by Fujita. Analogous octahedra can be prepared using different cis-capped metallic corners in place of the [(en)Pd]²⁺ units. (b) The X-ray crystal structure of 6.

Figure 5

(a) The C₂-symmetric catechol ligand 7 combined with trivalent metal ions to yield dinuclear helicates of type 8; the anionic part of the X-ray crystal structure of a gallium(III) helicate (8a) obtained from a modified version of ligand 7 is shown. (b) The similar ligand 9, based on a naphthalene spacer, selectively self-assembles with Ga^III or Fe^III to afford water-soluble tetrahedron 10; the anionic part of the X-ray structure of complex K₅(Et₄N)₇[Fe₄L₆] containing an encapsulated Et₄N⁺ is shown.

Figure 6

(a) Synthesis of capsule 12 built from two 11 ligands and Co^II ions. (b) X-ray structure of 12 showing the four cobalt(II) ions around the periphery.

Figure 7

Reactions of [(en)Pd(NO₃)₂] (2) with rigid oligo(pyridine/pyrimidine) “panels” enable the formation of WSCCs. Examples of these ligands and the X-ray crystal structures of the corresponding cages are shown.

Figure 8

Aqueous subcomponent self-assembly reaction to prepare the tetramethylammonium salt of cage 27; the anionic portion of its X-ray crystal structure is depicted.

Figure 9

(a) Enantioselective formation of ΔΔΔΔ-29 from (S,S)-28; the universal force field (UFF) model of ΔΔΔΔ-29 is shown. (b) Previously reported 4,4′′-diamino-p-terphenyls 30–33 led to water-insoluble cages.

Figure 10

(a) Self-assembly of Co^II ions with 34 led to water-insoluble cube 35. The analogous reaction using 36, equipped with hydroxymethyl groups yielded water-soluble cage 37. (b) View of the X-ray structure of WSCC 37, emphasizing the windows leading to the central cavity, and the decoration of the external surface with hydroxyl groups.

Figure 11

(a) Reaction of Pd^II with ligands 38 and 40, containing a different number of solubilizing chains, led to organic-soluble cage 39(76) and its water-soluble analogue 41, respectively. (b) X-ray structure of the water-soluble cage 41 showing its 12 pendant solubilizing chains.

Figure 12

(a) Self-assembly of Pd^II ions with W-shaped ligands 42 and 43 (bearing four and six solubilizing chains, respectively) yielded 44 and the more water-soluble 45 dual cavity cages. (b) X-ray structure of the water-insoluble cation 44.

Figure 13

(a) The self-assembly of Pd^II ions with 46 afforded water-insoluble capsule 47. (b) Water-soluble analogues were obtained using functionalized ligands 48(80) or 49(81) instead of 46.

Figure 14

(a) Cationic ligand 50 selectively self-assembles with Pd^II ions under different conditions to yield water-soluble capsule 51 or tube 52. (b) The combination of the elongated cationic ligand 53 with Pd^II affords expanded water-soluble capsule 54. The X-ray structures of the products are depicted.

Figure 15

Examples of WSCCs based on palladium(II) ions and pyridinium ligands. (a) Synthesis of Mukherjee’s “molecular dice” (56) and (b) Sun’s nanocapsule 58. X-ray structures of the cages are depicted.

Figure 16

Preparation of water-insoluble cube 60 and reversible anion exchange to obtain water-soluble cube 61, the direct synthesis of which is not possible. Adapted with permission from ref (88). Copyright 2017 Wiley-VCH.

Figure 17

[Ga₄L₆]^12– tetrahedron Ga-10 and its less-labile congeners [M₄L₆]^8– (M = Ge^IV, Ti^IV, Si^IV), built using tetravalent metal ions.^,

Figure 18

(a) Assembly of tetrahedral Ti₄L₆ cage 62, the vertices of which bound Co^II or Ln^III ions. (b) X-ray structures of the ΔΔΔΔ and ΛΛΛΛ enantiomers of 62. Inset: photo of cage crystals in DMF/H₂O solution. Adapted with permission from ref (97). Copyright 2017 American Chemical Society.

Figure 19

(a) Crystal structures of zirconium tetrahedra 64–67. Color code: Zr, turquoise; O, red; N, blue; C, black. Yellow balls represent the cage inner void. (b) Scheme for the postassembly modification (PAM) of cage 65 containing up to six functionalized sites per cage. Adapted with permission from ref (101). Copyright 2018 American Chemical Society.

Figure 20

(a) Self-assembly of subcomponents 68–72 with metal(II)-ions (M = Co^II, Ni^II, Zn^II, and Cd^II) yielded cages M-73–77. Kinetically stable WSCC assemblies were obtained in the cases noted.

Figure 21

(a) Self-assembly of water-soluble Zn^II-helicates and Cd^II-tetrahedra from tritopic amines TREN (78) and TRPN (79) and C₂-symmetric subcomponents 72 and 80–82. Cationic portions of the X-ray structures of (b) helicate Zn-84, (c) tetrahedron Cd-88, (d) helicate Zn-85, and (e) tetrahedron Cd-90. Adapted with permission from ref (89). Copyright 2019 Royal Society of Chemistry.

Figure 22

Stability of cubes M-73 in water noting their decomposition conditions. (a) Half-lives (t_1/2), (b) ionic radii (IR, Å), and (c) ligand-exchange rates for water (k_H2O, s^–1) for the different metal ions are shown for comparison. ^†Fe-76 is low-spin, but k_H2O for high-spin Fe^II is given as reference. Adapted with permission from ref (89). Copyright 2019 Royal Society of Chemistry.

Figure 23

Reaction of 5 with Pt^II-complex 91 yielded a kinetic mixture of oligomers containing the target cage Pt-6. Addition and subsequent removal of a template led to the clean formation of the kinetically robust product Pt-6.

Figure 24

(a) Ligand 92 assembles with Co^II to afford cobalt(II) tetrahedron 93, which is transformed into the more robust cobalt(III) tetrahedron 94 through oxidation. (b) X-ray crystal structure of a cobalt(III) cage (94a) obtained from a derivative of ligand 92; peripheral groups are omitted.

Figure 25

(a) Conditions for the selective preparation of tetrahedron 96 and prism 97 and their interconversion. The cationic parts of the crystal structures of (b) 96 and (c) 97.

Figure 26

(a) Schematic representation of the template-controlled syntheses of WSCCs 98 and 99. (b) X-ray structure of tetrahedron 99 with CBr₄ in its cavity. (a) Adapted with permission from ref (121). Copyright 2000 American Chemical Society.

Figure 27

(a) Template-induced self-assembly of monoend-capped tube 103 and dimeric open tube 104. (b) Crystal structure of 104 with two equivalents of biphenylcarboxylate included. (a) Reproduced with permission from ref (122). Copyright 2003 Wiley-VCH.

Figure 28

Equilibrium between catenane 105 and monomeric ring 106 shifts to either side depending on the polarity of the solvent employed.

Figure 29

Self-assembly of ligand 107 with Co^II ions results in an equilibrium between three assemblies 118, 109 and 110 in D₂O. The X-ray crystal structures of each assembly are shown.

Figure 30

Crystal structures of coordination cages containing water clusters in the central cavity. (a) Fujita’s Pd^II₆L₄ octahedron 6c(149) and the (b) Co^II₈L₁₂ cube 35 made by Ward.

Figure 31

Initial WSCCs as examples of binding of hydrophobic neutral organic molecules. (a) Fujita octahedra can bind up to four identical guests or two different ones. Cages reported by (b) Harrison^, and (c) Raymond also bind hydrophobic molecules in water.

Figure 32

Contrasting binding ability of two isostructural Fe^II₄L₆ tetrahedra. (a) Cage 111 binds only small inorganic anions in acetonitrile but not larger anions or neutral organic molecules. (b) Analogous cage 27 binds a wide variety of neutral organic molecules, some gases, and P₄ in water.⁻ (c–g) X-ray crystal structures of selected host–guest complexes of each cage are depicted.

Figure 33

(a) Subcomponent self-assembly of cage 113 and its crystal structure. Guest molecules for 113. In D₂O (b) all molecules shown were encapsulated (outer blue box) in 113, whereas in CD₃CN (c) only a subset (inner red box) were bound.

Figure 34

Binding of biologically relevant guests was only observed in aqueous solution using the water-soluble cube 61 obtained upon anion exchange from the MeCN-soluble cube 60.

Figure 35

Guests used to compare binding between hosts 35 and 37 in acetonitrile and water, respectively. The highest binding association was observed between host 37 and 2-hydroxyquinoline (amide tautomer) in water.

Figure 36

(a) Ketone guests for 37 in water. The plot of binding free energy vs number of C atoms for guest series A, and the X-ray crystal structure of the cycloundecanone⊂37 complex are shown. (b) The three guests used in the pH-swing experiment and their binding constants within cage 37 as a function of protonation state, together with a diagram showing which host–guest species predominates as a function of pH.

Figure 37

Cage 27 as a protective environment for guests. (a) Crystal structure of P₄⊂27. (b) Extraction of P₄ from 27 by n-heptane was not possible, whereas replacing P₄ with benzene results in phosphorus release into the organic phase. (b) Reproduced with permission from ref (165). Copyright 2009 American Association for the Advancement of Science. (c) Schematic representation of a cage-controlled Diels–Alder reaction: encapsulation of furan by 27 prevented its reaction with maleimide. Addition of benzene released furan, triggering reaction.

Figure 38

Stabilization of otherwise unfavorable guest configurations by cage 6 in aqueous media. (a) Ruthenium(II) complex 117 exists in equilibrium among four isomers; cage 6 stabilizes the 117a form upon encapsulation. (b) Chemical structures of the lactone (118a) and the quinone (118b) forms of phenolphthalein, along with a cartoon representation of the cavity-directed stabilization of the ordinarily unstable lactone dianion. (b) Adapted with permission from ref (179). Copyright 2015 American Chemical Society.

Figure 39

(a) Self-assembly of barrel 120 from ligand 119 and cis-[(tmeda)Pd(NO₃)₂]; the X-ray structure of 120 is shown. (b) Encapsulation of 121-MC and 122-MC into the cavity of 120 led to stable green and pink aqueous solutions of the host–guest complexes. (b) Adapted with permission from ref (183). Copyright 2018 American Chemical Society.

Figure 40

(a) Self-assembly of barrel 124 and the unusual stabilization of the open forms of DASA molecules 125 and 126; the X-ray crystal structure of 124 is depicted. (b) Photoswitching behavior of DASA molecules in organic solvents or water in the presence and absence of 124.

Figure 41

(a) Self-assembly of heterometallic cage 128 from ruthenium(II)-ligand 127 and palladium(II). (b) The X-ray structure of 128, and (c) the aromatic and photosensitive guests bound by 128 are shown. (d) Preresolved ligands Δ/Λ-127 assemble with Pd^II to yield WSCCs Δ/Λ-128, which crystallized in the presence of S- or R-BINOL. The crystal structures of Δ/Λ-128 showing S-/R-BINOL guests residing in the window pockets. (e) Chiral guests tested for enantioselective resolution.

Figure 42

(a) X-ray crystal structure of AMMVN⊂Pt-41 and diagram of encapsulated radical initiators. (b) Addition of the confined initiator (red) to an organic solution of monomers induces the spontaneous release of the initiator from the capsule and the polymerization initiates by light or thermal stimuli. (b) Adapted with permission from ref (77). Copyright 2014 Springer Nature.

Figure 43

(a) Selective sucrose recognition by Pt-41 in water and (b) the X-ray crystal structure of sucrose⊂Pt-41. (c) Hierarchy of binding affinity of artificial and natural sweeteners by Pt-41. Reproduced with permission from ref (136). Copyright 2019 American Chemical Society.

Figure 44

Preferential binding of lactic acid tetramer by 41. The X-ray crystal structure and specific host–guest interactions are shown. Reproduced with permission from ref (136). Copyright 2019 American Chemical Society.

Figure 45

(a) Coiling of 133 and threading of 134 into Pt-41 in water, showing the X-ray and computationally optimized structures of 133⊂Pt-41 and 134⊂Pt-41 complexes, respectively. (b) Formation of pseudorotaxane complex 135⊂(Pt-41)₂. Reproduced with permission from ref (136). Copyright 2019 American Chemical Society.

Figure 46

(a) Fluorescent guests 136–138 for Pt-41 and the X-ray crystal structure of 136⊂Pt-41 with the cage represented as transparent spheres and the included BODIPY in green. (b) Schematic representation of the formation of 136•139⊂Pt-41 and 136•141⊂Pt-41 along with the fluorescence spectra (H₂O, λ_ex = 495 nm, rt) of 136•139⊂Pt-41, 136•140⊂Pt-41, 136•141⊂Pt-41, and 136⊂Pt-41. (b) Adapted with permission from ref (194). Copyright 2015 American Chemical Society.

Figure 47

Water-soluble triangular prisms 142–147 prepared through the use of different bipyridyl pillars.

Figure 48

(a) Prism 142 encapsulates tetraazaporphyrin 148, preserving its red emission. (b) Electrostatic interactions in discrete stack 144; the D–A heterocomplex (149•150)⊂144 is shown along with its X-ray crystal structure. (c) Formation of triple-decker cluster (151•Ag^I•151•Ag^I•151)⊂146; the X-ray crystal structure is shown. Structural formulas of pillared cages shown in (a, b, and c) are reproduced with permission from refs (196), (197), and (198), respectively. Copyrights 2009 and 2010, American Chemical Society, and 2012 Wiley-VCH.

Figure 49

Crystal structures of (a) the (152•153)⊂142 inclusion complex, highlighting H-bonds between nucleotides, and (b) the (154)₂⊂143 duplex formed in a taller cage.

Figure 50

Cation binding within cage 10. (a) Cage 10 exhibits a preference for the inclusion of Et₄N⁺ over the smaller Me₄N⁺ and larger Pr₄N⁺. (b) Stabilization of iminium ions generated in water from pyrrolidine and various ketones. (c) Examples of amines and phosphines that bind within 10 upon protonation.

Figure 51

(a) The organometallic intermediates 186–189 are stabilized in water within 10. (b) Structural formula of Ru^II complexes 190–193 that are partially encapsulated.

Figure 52

Binding of guanidinium to the faces of 27. A space-filling representation is shown of the crystal structure of host 27, as viewed perpendicular to a face capped by one guanidinium ion (194, depicted in blue).

Figure 53

Self-assembly of the urea-functionalized anion hosts constructed from (a) nickel(II) and (b) zinc(II). Representative X-ray structures of the host–guest complexes are depicted.

Figure 54

Subcomponent self-assembly of cages 200 and 201. The X-ray crystal structure of 200 is shown along with the hydrogen bonding between the central SO₄^2– and the urea functions.

Figure 55

Schematic representation of the encapsulation of trifluoroborates by capsule 51 in water.

Figure 56

(a) Schematic representation of the cage isomers X^–⊂T-205 and X^–⊂C₃-205 obtained by aqueous self-assembly in the presence of template anions. Adapted with permission from ref (218). Copyright 2017 American Chemical Society. (b) X-ray structure of the OTf^–⊂T-205 complex. (c) X-ray crystal structure of ReO₄^–⊂205. (d) Selective extraction of ReO₄^– from water into an organic phase in the presence of competing anions. (e) Liquid–liquid extraction of ReO₄^– from an organic phase into water. Adapted with permission from ref (219). Copyright 2018 Wiley-VCH.

Figure 57

(a) Self-assembly reaction to form fluorescent tetrahedron 208; an MM3-optimized molecular model of the cage is depicted. (b) While neutral molecules and nucleobases were not encapsulated, their anionic congeners, including nucleotides, were bound in fast exchange; affinity constants were measured from NMR titration experiments.

Figure 58

Helicate Ga-210 transforms into tetrahedron Ga-211 following the addition of Me₄N⁺.

Figure 59

Guest-induced Pd₁₈L₆–Pd₂₄L₈ cage–cage conversion. X-ray structures of 212 and (215)₄⊂213 complexes as well as structural formulas of the ligand and guests are shown.

Figure 60

Cage–Bowl conversion driven by encapsulation of hydrolyzed guest 222. X-ray structures of 218 and 222⊂219 are shown.

Figure 61

(a) Synthesis of hexaruthenium prism 223 for transporting M(acac)₂ (M = Pd^II, Pt^II) complexes into cells. Reproduced with permission from ref (240). Copyright 2008 Wiley-VCH. (b) Crystal structure of the platinum containing adduct 226⊂223. (c) A pyrenyl-floxuridine derivative encapsulated within 223.

Figure 62

Structural formula of hexa- (223) and octa-ruthenium (229) cages encapsulating porphyrin 228. Fluorescence microscopy of HeLa cells incubated with [228⊂229]⁸⁺: (A) white light and (B) fluorescence. Reproduced with permission from ref (242). Copyright 2012 American Chemical Society.

Figure 63

(a) Scheme of click reaction to obtain 232. (b) Chemical structure of 5-fluorouracil (231) and the release of 231 from control (square) and cage 232. Adapted with permission from ref (243). Copyright 2011 Wiley-VCH.

Figure 64

Representation of the release of cisplatin upon reduction of (233)₄⊂Pt-6 by ascorbic acid.

Figure 65

(a) Synthesis of WSCC 238 and encapsulation of coronene; the X-ray structure of the (coronene)₂⊂238 complex is shown. (b) Micrographs reveal that perylene does not enter the cell on its own (no fluorescence) but that blue emission corresponding to perylene was observed from the cytoplasm of HeLa cells after the incubation with an aqueous solution of perylene⊂238. (b) Adapted with permission from ref (247). Copyright 2015 American Chemical Society.

Figure 66

(a) Synthesis of barrel 239. The crystal structure of 239 and structural formula of cucurmin guest 241 are shown. (b) Plot showing the decrease in cancer cell growth when treated with 241⊂239 as compared to 239 alone. (b) Reproduced with permission from ref (248). Copyright 2017 American Chemical Society.

Figure 67

Cage 242, assembled from 243 and Pd^II ions, forms the heteroternary complex 245 with CB[8] and prodrug 244 for the delivery of doxorubicin. Adapted with permission from ref (249). Copyright 2016 American Chemical Society.

Figure 68

Self-assembly of cages 246 and 251 and schematic representation of the stimuli-responsive release of guests from the hydrophobic cavity of 251 by 252. Chemical structures of compounds used are shown. Adapted with permission from ref (250). Copyright 2017 American Chemical Society.

Figure 69

(a) Self-assembly of zirconium(IV) cages 254 and 255 from carboxylate molecular rotors 256 and 257. (b) Cell imaging of 254 (top) and 255 (bottom) in HeLa cells. Adapted with permission from ref (252). Copyright 2020 Wiley-VCH.

Figure 70

(a) Chemical structure of ^99mTcO₄^–⊂258/259 complexes. (b) X-ray crystal structure of ReO₄^–⊂259. (c) Comparison of ^99mTcO₄^– uptake in mice (left) vs ^99mTcO₄^–⊂259 (right). (c) Reproduced with permission from ref (253). Copyright 2018 American Chemical Society.

Figure 71

(a) Selective testosterone binding by Pt-41 and X-ray structure of TES⊂Pt-41. (b) Schematic representation of nanogram-scale fluorescent detection of TES with one drop of 137⊂Pt-41 solution on a Petri dish. (c) Fluorescence spectra and pictures of a H₂O solution of 137⊂Pt-41 before and after addition of TES. Adapted with permission from refs (136) and (254). Copyright 2019 American Chemical Society. Copyright 2019 American Association for the Advancement of Science.

Figure 72

Aqueous self-assembly of ubiquitin-containing spheres 260a–c. Reproduced with permission from ref (256). Copyright 2012 Springer Nature.

Figure 73

(a) Self-assembly of 263 from porphyrin 264. (b) Trypsin treatment of peptides 265 and 266 in the presence and absence of 263. Red arrows indicate the cleavage positions of peptides: Abz, 2-aminobenzoic acid; Dnp, 2,4-dinitrophenyl.

Figure 74

Self-assembly of cages 267a–d with (b) the crystal structure of complex 267a shown. (c) Illustration of the end-stacking binding of cage 267 to two G-quadruplexes. (c) Reproduced with permission from ref (265). Copyright 2016 Royal Society of Chemistry.

Figure 75

(a) Schematic representation of the fluorescence quenching of DNA structures upon binding with cage 269. (b) Molecular structure of cage 269. (c) Quenching efficiency based on the ratio of 269 to the DNA. Adapted with permission from ref (267). Copyright 2019 American Chemical Society.

Figure 76

Examples of pericyclic reactions mediated by Fujita’s Pd^II and Pt^II octahedral cages. (a) [2 + 2] Photodimerization of acenaphthylenes. (b) [2 + 2] Cross-photoaddition of acenaphthylene and 5-ethoxy-1,4-naphthoquinone. (c) Asymmetric [2 + 2] cross-photoaddition of fluoranthenes and N-cyclohexylmaleimide. Diels–Alder reactions of N-cyclohexylmaleimide with (d) 9-hydroxymethylanthracene to give a 1,4-adduct and with normally unreactive (e) triphenylene and (f) 2,3-diethylnaphthalene. The X-ray structure of Diels–Alder adduct 280⊂6a is shown.

Figure 77

Regio- and stereoselective light-mediated 1,4-radical addition within 6. The crystal structure of 286•285⊂6c is shown.

Figure 78

(a) Schematic representation showing WSCCs as photosensitizers for reactions. (b) Example showing demethylenation of 288via photoinduced guest-to-host electron transfer in cage 6a under UV radiation.

Figure 79

Regio- and stereoselective reactions mediated by Δ-128. (a) Photoinduced biaryl coupling of 289 to give 290. (b) Photodimerization of 291.

Figure 80

Organometallic transformation of dinuclear ruthenium complex 293 encapsulated in 6a. The complex undergoes photosubstitution of a CO ligand by an alkyne, followed by rearrangement upon extraction from the cage.

Figure 81

Cavity-promoted C−H activation by WSCCs. (a) C−H activation of aldehydes, where R is a short alkyl group, by an encapsulated Ir^III host−guest complex. (b) C−H activation of a terminal alkyne, where R = ⁿBu or ⁱBu, by an encapsulated Pd^II complex. In both, the cavities of the WSCCs exhibited shape selectivity for their substrates.

Figure 82

Site-selective electrophilic addition reactions of diterpenoids within 6a. The crystal structure of 300⊂6a is shown.

Figure 83

(a) Hydrolysis of twisted amides in the cavity of 6a. (b) X-ray structure of (301)₂⊂6c with cutout of the dimer composed of two inequivalent amides, which are twisted by 34° and 30° around their C–N–C(O)–C bonds.

Figure 84

Catalytic acceleration of the aza-Cope rearrangement of allyl enammonium ions, promoted by constrictive binding effects within 10.^,

Figure 85

Examples of catalysis via enhancement of substrate basicity through encapsulation within 10. (a) Hydrolysis of orthoformates in basic solution.^, (b) Nazarov cyclization, which also benefits from conformational restriction.

Figure 86

(a) Cyclization of monoterpene (±)-citronellal (307) catalyzed by 10 gives alkene 308a as the major product, whereas diol 309 is obtained for the acid catalyzed reaction in bulk solution. (b) Structure of water-soluble enantiopure tetrahedron 310 used as an enantioselective catalyst, showing the X-ray structure of ΔΔΔΔ-310.

Figure 87

(a) Aza-Prins reaction catalyzed by 10 to give a different product to the one observed in bulk solution as a result of stabilization of a more spherical transition state in the cage cavity. (b) Three-component Aza-Darzens reaction catalyzed by 10.

Figure 88

(a) Stereoretentive solvolysis reaction catalyzed by cages 10 and 310. (b) Proposed intermediate showing a transient carbocation interacting with one of the six naphthalene walls through cation−π interactions (X = leaving group).

Figure 89

Knoevenagel condensation of an aromatic aldehyde with Meldrum’s acid in cage 6 showing the structure of the cage-stabilized anionic intermediates formed during the reaction, which then undergo dehydration in the hydrophobic cavity.

Figure 90

(a) Self-assembly of tetrahedron 320 from ligand 321 and cis-[(cyhex)Pt(NO₃)₂]; the X-ray structure of 320 is shown. (b) Michael addition of aromatic nitroalkene guests with indole promoted by cage 320.

Figure 91

(a) Catalytic reaction cycle for the Kemp elimination catalyzed by cage 37. (b) Autocatalysis of this reaction occurs in cage 35 in the presence of chloride. (c) X-ray structure of 325⊂37. (d) Structure of phosphoester guests bound by the chloride salt of cage 35 and X-ray structure of the BF₄^– salt crystallized with dichlorvos 327, showing both the internally and externally interacting guests. In both structural representations the guests are shown in space-filling mode, and the tetrafluoroborate anions that occupy the cage windows are shown with the frontmost anion omitted for clarity in both cases.

Figure 92

Selective monohydrogenation of 330 using cage 332 and an encapsulated rhodium catalyst.

Figure 93

(a) Structure of porphyrin-based cage 334 and encapsulated porphyrin catalysts. (b) Size-selective cyclopropanation catalyzed by 333⊂334 controlled by the pore size of the cage. Adapted with permission from ref (362). Copyright 2014 Wiley-VCH.

Figure 94

One-pot multicatalytic relay system, in which all steps take place in water at room temperature at pH 4.0.

Figure 95

Tandem enzymatic and transition-metal catalysis sequences mediated by 10. (a) Esterase- or lipase-mediated acetate hydrolysis followed by Me₃PAu⁺⊂10-catalyzed hydroalkoxylation. (b) Ru^II-mediated olefin isomerization of allyl alcohol to give propanal followed by reduction to propanol via ADH.