Christopher G. P. Taylor

The crystalline sponge method has proven invaluable in the preparation and analysis of supramolecular host/guest complexes if the host can be obtained in a suitable crystalline form, allowing the analysis of guest binding modes inside host cavities which can inform other studies into processes such as catalysis. Here, we report the structures of a set of ten host/guest complexes using an octanuclear coordination cage host with a range of small-molecule neutral organic guests including four aromatic aldehydes and ketones, three cyclic lactams, and three epoxides. In all cases, the cavity-bound guests are anchored by a collection of CH•••O hydrogen-bonding interactions between an O atom on the guest and a convergent set of CH protons at a pocket on the cage interior surface. Depending on guest size and the presence of solvent molecules as additional guests, there may be one or two cavity-bound guests, with small aromatic guests forming π-stacked pairs. Some guests (the lactams) participate in additional NH•••F H-bonding interactions with surface-bound fluoroborate anions, which indicate the type of anion/guest interactions thought to be responsible for solution-phase catalytic reactions of bound guests.

The host-guest chemistry of O,O-diisopropyl fluorophosphate (DFP), a phosphonofluoridate G-series chemical warfare agent simulant, in the presence of a number of octanuclear cubic coordination cages was investigated. The aim was to demonstrate cage-catalysed hydrolysis of DFP at near neutral pH, however, two octanuclear coordination cages, HPEG (containing water solubilising PEG groups) and HW (containing water solubilising hydroxymethyl groups), were actually found to increase the lifetime of DFP in aqueous buffer solution (pH 8.7). Crystallographic analysis of DFP with a structurally related cage revealed that DFP binds to windows in the cage surface, not the internal cavity, with the phosphorus-fluorine bond directed into the cavity rather than towards the external environment, with the cage/DFP association protecting DFP from hydrolysis. Initial studies with the chemical warfare agent (CWA) sarin (GB) with HPEG cage in a buffered solution also drastically reduced the rate of hydrolysis. The ability of these cages to inhibit the hydrolysis of these P-F bond containing organophosphorus guests, by encapsulation, may have applications in forensic sample preservation and analysis.

The cavity is not everything! Catalysed hydrolysis of 4-nitrophenylacetate is inhibitedinsidea cage (left), but hydrolysis of diacetylfluorescein (right) is catalysed by the exterior surface.

An octanuclear M₈L₁₂ coordination cage catalyses the Kemp elimination reaction of 5-nitro-1,2-benzisoxazole (NBI) with hydroxide to give 2-cyano-4-nitrophenolate (CNP) as the product. In contrast to the previously-reported very efficient catalysis of the Kemp elimination reaction of unsubstituted benzisoxazole, which involves the substrate binding inside the cage cavity, the catalysed reaction of NBI with hydroxide is slower and occurs at the external surface of the cage, even though NBI can bind inside the cage cavity. The rate of the catalysed reaction is sensitive to the presence of added anions, which bind to the 16+ cage surface, displacing the hydroxide ions from around the cage which are essential reaction partners in the Kemp elimination. Thus we can observe different binding affinities of anions to the surface of the cationic cage in aqueous solution by the extent to which they displace hydroxide and thereby inhibit the catalysed Kemp elimination and slow down the appearance of CNP. For anions with a −1 charge the observed affinity order for binding to the cage surface is consistent with their ease of desolvation and their ordering in the Hofmeister series. With anions that are significantly basic (fluoride, hydrogen carbonate, carboxylates) the accumulation of the anion around the cage surface accelerates the Kemp elimination compared to the background reaction with hydroxide, which we ascribe to the ability of these anions to participate directly in the Kemp elimination. This work provides valuable mechanistic insights into the role of the cage in co-locating the substrate and the anionic reaction partners in a cage-catalysed reaction.

New synthetic routes are presented to derivatives of a (known) M₈L₁₂ cubic coordination cage in which a range of different substituents are attached at the C⁴ position of the pyridyl rings at either end of the bis(pyrazolyl-pyridine) bridging ligands. The substituents are (i) –CN groups (new ligand L^CN), (ii) –CH₂OCH₂–CCH (containing a terminal alkyne) groups (new ligand L^CC); and (iii) –(CH₂OCH₂)₃CH₂OMe (tri-ethyleneglycol monomethyl ether) groups (new ligand L^PEG). The resulting functionalised ligands combine with M²⁺ ions (particularly Co²⁺, Ni²⁺, Cd²⁺) to give isostructural [M₈L₁₂]¹⁶⁺ cage cores bearing 24 external functional groups; the cages based on L^CN (with M²⁺ = Cd²⁺) and L^CC (with M²⁺ = Ni²⁺) have been crystallographically characterised. The value of these is twofold: (i) exterior nitrile or alkene substituents can provide a basis for further synthetic opportunities via ‘Click’ reactions allowing in principle a diverse range of functionalisation of the cage exterior surface; (ii) the exterior –(CH₂OCH₂)₃CH₂OMe groups substantially increase cage solubility in both water and in organic solvents, allowing binding constants of cavity-binding guests to be measured under an increased range of conditions.

The octanuclear Co(II) cubic coordination cage system H (or H^W if it bears external water-solubilising substituents) has two types of binding site for guests. These are (i) the partially-enclosed central cavity where neutral hydrophobic organic species can bind, and (ii) the six 'portals' in the centres of each of the faces of the cubic cage where anions bind via formation of a network of CH⋯X hydrogen bonds between the anion and CH units on the positively-charged cage surface, as demonstrated by a set of crystal structures. The near-orthogonality of these guest binding modes provides the basis for an unusual dual-probe fluorescence displacement assay in which either a cavity-bound fluorophore (4-methyl-7-amino-coumarin, MAC; λ_em = 440 nm), or a surface-bound anionic fluorophore (fluorescein, FLU; λ_em = 515 nm), is displaced and has its emission ‘switched on’ according to whether the analyte under investigation is cavity-binding, surface binding, or a combination of both. A completely orthogonal system is demonstrated based using a H^w/MAC/FLU combination: addition of the anionic analyte ascorbate displaced solely FLU from the cage surface, increasing the 515 nm (green) emission component, whereas addition of a neutral hydrophobic guest such as cyclooctanone displaced solely MAC from the cage central cavity, increasing the 440 nm (blue) emission component. Addition of chloride results in some release of both components, and an intermediate colour change, as chloride is a rare example of a guest that shows both surface-binding and cavity-binding behaviour. Thus we have a colourimetric response based on differing contributions from blue and green emission components in which the specific colour change signals the binding mode of the analyte. Addition of a fixed red emission component from the complex [Ru(bipy)₃]²⁺ (Ru) provides a baseline colour shift of the overall colour of the luminescence closer to neutral, meaning that different types of guest binding result in different colour changes which are easily distinguishable by eye.

The dodecanuclear coordination cage [Cd₁₂(L^naph)₁₂(L^mes)₄](BF₄)₂₄ consists of a set of four triangular, trinuclear helical panels {Cd₃(μ-L^naph)₃}⁶⁺ (based on ditopic bridging ligands L^naph), which are connected by four tritopic ligands L^mes. The result is that the four triangular helical panels and the four L^mes-capped triangular faces of the cuboctahedral core form two alternating subsets of the eight triangular faces of the cuboctahedron. Crystallographic investigations revealed that the triangular helicate faces can have ‘clockwise’ (C) or ‘anticlockwise’ (A) helicity, and that the helicity of each face can vary independently of the others as they are mechanically separated. This generates a set of three diastereoisomers in which all four cyclic helicate faces in the cuboctahedron have the same chirality (AAAA/CCCC enantiomers with T symmetry; AAAC/CCCA enantiomers with C₃ symmetry; and achiral AACC with S₄ symmetry). This mirrors the known behaviour of many simpler M₄L₆ tetrahedral cages which can likewise exist as T, C₃ or S₄ isomers according to the sense of tris-chelate chirality around each individual metal centre: but here it is translated onto a much larger scale by the four chiral units being entire trinuclear helicate faces rather than single metal centres. ¹H NMR spectroscopy confirms the presence of the three diastereoisomers with their different molecular symmetries in a ratio slightly different from what is expected on purely statistical grounds; and ¹H NMR measurements on a non-equilibrium sample (enriched by manual crystal-picking before preparing the solution) showed that the distribution does not change over several weeks in solution, indicating the kinetic inertness of the cage assemblies.

Coordination cages are well-known to act as molecular containers that can bind small-molecule guests in their cavity. Such cavity binding is associated with interactions of the guests with the surrounding set of surfaces that define the cavity; a guest that is a good fit for the cavity will have many favourable interactions with the interior surfaces of the host. As cages have exterior as well as interior surfaces, possibilities also exist for ‘guests’ that are not well-bound in the cavity to interact with the exterior surface of the cage where spatial constraints are fewer. In this paper, we report a combined solid-state and solution study using an octanuclear cubic M₈L₁₂ coordination cage which illustrates the occurrence of both types of interaction. Firstly, crystallographic studies show that a range of guests bind inside the cavity (either singly or in stacked pairs) and/or interact with the cage exterior surface, depending on their size. Secondly, fluorescence titrations in aqueous solution show how some flexible aromatic disulfides show two separate types of interaction with the cage, having different spectroscopic consequences; we ascribe this to separate interactions with the exterior surface and the interior surface of the host cage with the former having a higher binding constant. Overall, it is clear that the idea of host/guest interactions in molecular containers needs to take more account of external surface interactions as well as the obvious cavity-based binding.

The aldol condensation of indane-1,3-dione (ID) to give ‘bindone’ in water is catalysed by an M₈L₁₂ cubic coordination cage (H^w). The absolute rate of reaction is slow under weakly acidic conditions (pH 3–4), but in the absence of a catalyst it is undetectable. In water, the binding constant of ID in the cavity of H^w is ca. 2.4 (±1.2) × 10³ M⁻¹, giving a ∆G for the binding of −19.3 (±1.2) kJ mol⁻¹. The crystal structure of the complex revealed the presence of two molecules of the guest ID stacked inside the cavity, giving a packing coefficient of 74% as well as another molecule hydrogen-bonded to the cage’s exterior surface. We suggest that the catalysis occurs due to the stabilisation of the enolate anion of ID by the 16+ surface of the cage, which also attracts molecules of neutral ID to the surface because of its hydrophobicity. The cage, therefore, brings together neutral ID and its enolate anion via two different interactions to catalyse the reaction, which—as the control experiments show—occurs at the exterior surface of the cage and not inside the cage cavity.