A Study on Auto-Catalysis and Product Inhibition: A Nucleophilic Aromatic Substitution Reaction Catalysed within the Cavity of an Octanuclear Coordination Cage.

The ability of an octanuclear cubic coordination cage to catalyse a nucleophilic aromatic substitution reaction on a cavity-bound guest was studied with 2,4-dinitrofluorobenzene (DNFB) as the guest/substrate. It was found that DNFB undergoes a catalysed reaction with hydroxide ions within the cavity of the cubic cage (in aqueous buffer solution, pH 8.6). The rate enhancement of kcat/kuncat was determined to be 22, with cavity binding of the guest being required for catalysis to occur. The product, 2,4-dinitrophenolate (DNP), remained bound within the cavity due to electrostatic stabilisation and exerts two apparently contradictory effects: it initially auto-catalyses the reaction when present at low concentrations, but at higher concentrations inhibits catalysis when a pair of DNP guests block the cavity. When encapsulated, the UV/Vis absorption spectrum of DNP is red-shifted when compared to the spectrum of free DNP in aqueous solution. Further investigations using other aromatic guests determined that a similar red-shift on cavity binding also occurred for 4-nitrophenolate (4NP) at pH 8.6. The red-shift was used to determine the stoichiometry of guest binding of DNP and 4NP within the cage cavity, which was confirmed by structural analysis with X-ray crystallography; and was also used to perform catalytic kinetic studies in the solution-state.

The preservation of sarin and O,O'-diisopropyl fluorophosphate inside coordination cage hosts.

The host-guest chemistry of O,O'-diisopropyl fluorophosphate (DFP), a phosphonofluoridate G-series chemical warfare agent simulant, was investigated in the presence of a number of octanuclear cubic coordination cage hosts. 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 host cage revealed that DFP binds to windows in the cage surface, not in the internal cavity. The phosphorus-fluorine bond is 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 showed a drastically reduced rate of hydrolysis for sarin when bound in the host cage. The ability of these cages to inhibit hydrolysis of these P-F bond containing organophosphorus guests, by encapsulation, may have applications in forensic sample preservation and analysis.

Correction: Disentangling contributions to guest binding inside a coordination cage host: analysis of a set of isomeric guests with differing polarities.

Correction for 'Disentangling contributions to guest binding inside a coordination cage host: analysis of a set of isomeric guests with differing polarities' by Cristina Mozaceanu et al., Dalton Trans., 2022, 51, 15263-15272, https://doi.org/10.1039/D2DT02623F.

Disentangling contributions to guest binding inside a coordination cage host: analysis of a set of isomeric guests with differing polarities.

Binding of a set of three isomeric guests (1,2-, 1,3- and 1,4-dicyanobenzene, abbreviated DCB) inside an octanuclear cubic coordination cage host H (bearing different external substitutents according to solvent used) has been studied in water/dmso (98 : 2) and CD2Cl2. These guests have essentially identical molecular surfaces, volumes and external functional groups to interact with the cage interior surface; but they differ in polarity with dipole moments of ca. 7, 4 and 0 Debye respectively. In CD2Cl2 guest binding is weak but we observe a clear correlation of binding free energy with guest polarity, with 1,4-DCB showing no detectable binding by NMR spectroscopy but 1,2-DCB having -ΔG = 9 kJ mol-1. In water (containing 2% dmso to solubilise the guests) we see the same trend but all binding free energies are much higher due to an additional hydrophobic contribution to binding, with -ΔG varying from 16 kJ mol-1 for 1,4-DCB to 22 kJ mol-1 for 1,4-DCB: again we see an increase associated with guest polarity but the increase in -ΔG per Debye of dipole moment is around half what we observe in CD2Cl2 which we ascribe to the fact the more polar guests will be better solvated in the aqueous solvent. A van't Hoff analysis by variable-temperature NMR showed that the improvement in guest binding in water/dmso is entropy-driven, which suggests that the key factor is not direct electrostatic interactions between a polar guest and the cage surface, but the variation in guest desolvation across the series, with the more polar (and hence more highly solvated) guests having a greater favourable entropy change on desolvation.

Inside or outside the box? Effect of substrate location on coordination-cage based catalysis.

In this work we compare and contrast the hydrolysis of two different aromatic esters using an octanuclear cubic Co8 coordination cage host as the catalyst. Diacetyl fluorescein (DAF) is too large to bind inside the cage cavity, but in aqueous solution it interacts with the exterior surface of the cage via a hydrophobic interaction with K = 1.5(2) × 104 M-1. This is sufficient to bring it into close proximity to the layer of hydroxide ions which also surrounds the 16+ cage surface even at modest pH values, accelerating the hydrolysis of DAF to fluorescein with kcat/kuncat (the rate acceleration for that fraction of DAF in contact with the cage surface in the equilibrium) ≈50. This is far smaller than many known examples of catalysis inside a cage cavity, but at the exterior surface it is potentially general with no cavity-imposed size/shape limitations for guest binding. In contrast 4-nitrophenyl acetate (4NPA) binds inside the cage cavity with K = 3.5(3) × 103 M-1 and as such is surrounded in solution by the hydroxide ions which accumulate around the cage surface. However its hydrolysis is actually inhibited: either because of a geometrically unfavourable geometry of the bound substrate which makes it inaccessible to surface-bound hydroxide, or because the necessary volume expansion/geometry change associated with formation of a tetrahedral intermediate cannot be accommodated inside the cavity. Any 4NPA that is free in solution as part of the equilibrium undergoes catalysed hydrolysis at the cage exterior surface in the same way as DAF, but the effect is limited by the low affinity of 4NPA for the exterior surface. We conclude that exterior-surface catalysis can be effective and potentially general; and that cavity-binding of guests can result in negative, rather than positive, catalysis.

Interaction of anions with the surface of a coordination cage in aqueous solution probed by their effect on a cage-catalysed Kemp elimination.

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.

Orthogonal binding and displacement of different guest types using a coordination cage host with cavity-based and surface-based binding sites.

The octanuclear Co(ii) cubic coordination cage system H (or HW 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 Hw/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.

One Guest or Two? A Crystallographic and Solution Study of Guest Binding in a Cubic Coordination Cage.

Invited for the cover of this issue is the group of Michael D. Ward at the University of Warwick. The image depicts structures of the host cage containing one guest or two guests. Read the full text of the article at 10.1002/chem.201905499.

A family of diastereomeric dodecanuclear coordination cages based on inversion of chirality of individual triangular cyclic helicate faces.

The dodecanuclear coordination cage [Cd12(Lnaph)12(Lmes)4](BF4)24 consists of a set of four triangular, trinuclear helical panels {Cd3(µ-Lnaph)3}6+ (based on ditopic bridging ligands Lnaph), which are connected by four tritopic ligands Lmes. The result is that the four triangular helical panels and the four Lmes-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 C 3 symmetry; and achiral AACC with S 4 symmetry). This mirrors the known behaviour of many simpler M4L6 tetrahedral cages which can likewise exist as T, C 3 or S 4 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.

One Guest or Two? A Crystallographic and Solution Study of Guest Binding in a Cubic Coordination Cage.

A crystallographic investigation of a series of host-guest complexes in which small-molecule organic guests occupy the central cavity of an approximately cubic M8 L12 coordination cage has revealed some unexpected behaviour. Whilst some guests form 1:1 H⋅G complexes as we have seen before, an extensive family of bicyclic guests-including some substituted coumarins and various saturated analogues-form 1:2 H⋅G2 complexes in the solid state, despite the fact that solution titrations are consistent with 1:1 complex formation, and the combined volume of the pair of guests significantly exceeds the Rebek 55±9 % packing for optimal guest binding, with packing coefficients of up to 87 %. Re-examination of solution titration data for guest binding in two cases showed that, although conventional fluorescence titrations are consistent with 1:1 binding model, alternative forms of analysis-Job plot and an NMR titration-at higher concentrations do provide evidence for 1:2 H⋅G2 complex formation. The observation of guests binding in pairs in some cases opens new possibilities for altered reactivity of bound guests, and also highlights the recently articulated difficulties associated with determining stoichiometry of supramolecular complexes in solution.

Coordination-Cage-Catalysed Hydrolysis of Organophosphates: Cavity- or Surface-Based?

The hydrophobic central cavity of a water-soluble M8 L12 cubic coordination cage can accommodate a range of phospho-diester and phospho-triester guests such as the insecticide "dichlorvos" (2,2-dichlorovinyl dimethyl phosphate) and the chemical warfare agent analogue di(isopropyl) chlorophosphate. The accumulation of hydroxide ions around the cationic cage surface due to ion-pairing in solution generates a high local pH around the cage, resulting in catalysed hydrolysis of the phospho-triester guests. A series of control experiments unexpectedly demonstrates that-in marked contrast to previous cases-it is not necessary for the phospho-triester substrates to be bound inside the cavity for catalysed hydrolysis to occur. This suggests that catalysis can occur on the exterior surface of the cage as well as the interior surface, with the exterior-binding catalysis pathway dominating here because of the small binding constants for these phospho-triester substrates in the cage cavity. These observations suggest that cationic but hydrophobic surfaces could act as quite general catalysts in water by bringing substrates into contact with the surface (via the hydrophobic effect) where there is also a high local concentration of anions (due to ion pairing/electrostatic effects).

Photophysics of Cage/Guest Assemblies: Photoinduced Electron Transfer between a Coordination Cage Containing Osmium(II) Luminophores, and Electron-Deficient Bound Guests in the Central Cavity.

A heterometallic octanuclear coordination cage [Os4Zn4(Lnap)12]X16 (denoted Os•Zn; X = perchlorate or chloride) has been prepared (Lnap is a bis-bidentate bridging ligand containing two pyrazolyl-pyridine chelating units separated by a 1,5-naphthalenediyl spacer group). The {Os(NN)3}2+ units located at four of the eight vertices of the cube have a long-lived, phosphorescent 3MLCT excited state which is a stronger electron donor than [Ru(bipy)3]2+. The chloride form of Os•Zn is water-soluble and binds in its central cavity the hydrophobic electron-accepting organic guests 1,2,4,5-tetracyanobenzene, 1,4-naphthoquinone and 1-nitronaphthalene, with binding constants in the range 103-104 M-1, resulting in quenching of the phosphorescence arising from the Os(II) units. A crystal structure of an isostructural Co8 cage containing one molecule of 1,2,4,5-tetracyanobenzene as a guest inside the cavity has been determined. Ultrafast transient absorption measurements show formation of a charge-separated Os(III)/guest•- state arising from cage-to-guest photoinduced electron transfer; this state is formed within 13-21 ps, and decays on a time scale of ca. 200 ps. In the presence of a competing guest with a large binding constant (cycloundecanone) which displaces each electron-accepting quencher from the cage cavity, the charge-separated state is no longer observed. Further, a combination of mononuclear {Os(NN)3}2+ model complexes with the same electron-accepting species showed no evidence for formation of charge-separated Os(III)/guest•- states. These two control experiments indicate that the {Os(NN)3}2+ chromophores need to be assembled into the cage structure to bind the electron-accepting guests, and for PET to occur. These results help to pave the way for use of photoactive coordination cages as hosts for photoredox catalysis reactions on bound guests.

Catalysis in a Cationic Coordination Cage Using a Cavity-Bound Guest and Surface-Bound Anions: Inhibition, Activation, and Autocatalysis.

The Kemp elimination (reaction of benzisoxazole with base to give 2-cyanophenolate) is catalyzed in the cavity of a cubic M8L12 coordination cage because of a combination of (i) benzisoxazole binding in the cage cavity driven by the hydrophobic effect, and (ii) accumulation of hydroxide ions around the 16+ cage surface driven by ion-pairing. Here we show how reaction of the cavity-bound guest is modified by the presence of other anions which can also accumulate around the cage surface and displace hydroxide, inhibiting catalysis of the cage-based reaction. Addition of chloride or fluoride inhibits the reaction with hydroxide to the extent that a new autocatalytic pathway becomes apparent, resulting in a sigmoidal reaction profile. In this pathway the product 2-cyanophenolate itself accumulates around the cationic cage surface, acting as the base for the next reaction cycle. The affinity of different anions for the cage surface is therefore 2-cyanophenolate (generating autocatalysis) > chloride > fluoride (which both inhibit the reaction with hydroxide but cannot deprotonate the benzisoxazole guest) > hydroxide (default reaction pathway). The presence of this autocatalytic pathway demonstrates that a reaction of a cavity-bound guest can be induced with different anions around the cage surface in a controllable way; this was confirmed by adding different phenolates to the reaction, which accelerate the Kemp elimination to different extents depending on their basicity. This represents a significant step toward the goal of using the cage as a catalyst for bimolecular reactions between a cavity-bound guest and anions accumulated around the surface.

A Quantitative Study of the Effects of Guest Flexibility on Binding Inside a Coordination Cage Host.

We have performed a systematic investigation of the effects of guest flexibility on their ability to bind in the cavity of a coordination cage host in water, using two sets of isomeric aliphatic ketones that differ only in the branching patterns of their alkyl chains. Apart from the expected increase in binding strength for C9 over C7 ketones associated with their greater hydrophobic surface area, within each isomeric set there is a clear inverse correlation between binding free energy and guest flexibility, associated with loss of conformational entropy. This can be parameterized by the number of rotatable C-C bonds in the guest, with each additional rotatable bond resulting in a penalty of around 2 kJ mol-1 in the binding free energy, in good agreement with values obtained from protein/ligand binding studies. We used the binding data for the new flexible guests to improve the scoring function that we had previously developed that allowed us to predict binding constants of relatively rigid guests in the cage cavity using the molecular docking programme GOLD (Genetic Optimisation of Ligand Docking). This improved scoring function resulted in a significant improvement in the ability of GOLD to predict binding constants for flexible guests, without any detriment to its ability to predict binding for more rigid guests.

Photoinduced energy- and electron-transfer from a photoactive coordination cage to bound guests.

In a coordination cage which contains an array of twelve naphthyl chromophores surrounding a central cavity, photoinduced energy or electron-transfer can occur from the chromophore array to the bound guest in supramolecular host/guest complexes.

Binding of chemical warfare agent simulants as guests in a coordination cage: contributions to binding and a fluorescence-based response.

Cubic coordination cages act as competent hosts for several alkyl phosphonates used as chemical warfare agent simulants; a range of cage/guest structures have been determined, contributions to guest binding analysed, and a fluorescent response to guest binding demonstrated.