Supramolecular and molecular capsules, cages and containers.

Stemming from early seminal notions of molecular recognition and encapsulation, three-dimensional, cavity-containing capsular compounds and assemblies have attracted intense interest due to the ability to modulate chemical and physical properties of species encapsulated within these confined spaces compared to bulk environments. With such a diverse range of covalent motifs and non-covalent (supramolecular) interactions available to assemble building blocks, an incredibly wide-range of capsular-type architectures have been developed. Furthermore, synthetic tunability of the internal environments gives chemists the opportunity to engineer systems for uses in sensing, sequestration, catalysis and transport of molecules, just to name a few. In this tutorial review, an overview is provided into the design principles, synthesis, characterisation, structural facets and properties of coordination cages, porous organic cages, supramolecular capsules, foldamers and mechanically interlocked molecules. Using seminal and recent examples, the advantages and limitations of each system are explored, highlighting their application in various tasks and functions.

Diastereoselective Self-Assembly of Low-Symmetry Pdn L2n Nanocages through Coordination-Sphere Engineering.

Metal-organic cages (MOCs) are popular host architectures assembled from ligands and metal ions/nodes. Assembling structurally complex, low-symmetry MOCs with anisotropic cavities can be limited by the formation of statistical isomer libraries. We set out to investigate the use of primary coordination-sphere engineering (CSE) to bias isomer selectivity within homo- and heteroleptic Pdn L2n cages. Unexpected differences in selectivities between alternative donor groups led us to recognise the significant impact of the second coordination sphere on isomer stabilities. From this, molecular-level insight into the origins of selectivity between cis and trans diastereoisomers was gained, highlighting the importance of both host-guest and host-solvent interactions, in addition to ligand design. This detailed understanding allows precision engineering of low-symmetry MOC assemblies without wholesale redesign of the ligand framework, and fundamentally provides a theoretical scaffold for the development of stimuli-responsive, shape-shifting MOCs.

Pseudo-heterolepticity in Low-Symmetry Metal-Organic Cages.

Heteroleptic metal-organic cages, formed through integrative self-assembly of ligand mixtures, are highly attractive as reduced symmetry supramolecular hosts. Ensuring high-fidelity, non-statistical self-assembly, however, presents a significant challenge in molecular engineering due to the inherent difficulty in predicting thermodynamic energy landscapes. In this work, two conceptual strategies are described that circumvent this issue, using ligand design strategies to access structurally sophisticated metal-organic hosts. Using these approaches, it was possible to realise cavity environments described by two inequivalent, unsymmetrical ligand frameworks, representing a significant step forward in the construction of highly anisotropic confined spaces.

Multi-functional, Low Symmetry Pd2 L4 Nanocage Libraries*.

Although many impressive metallo-supramolecular architectures have been reported, they tend towards high symmetry structures and avoid extraneous functionality to ensure high fidelity in the self-assembly process. This minimalist approach, however, limits the range of accessible structures and thus their potential applications. Herein is described the synthesis of a family of ditopic ligands wherein the ligand scaffolds are both low symmetry and incorporate exohedral functional moieties. Key to this design is the use of CuI -catalysed azide-alkyne cycloaddition (CuAAC) chemistry, as the triazole is capable of acting as both a coordinating heterocycle and a tether between the ligand framework and functional unit simultaneously. A common precursor was used to generate ligands with various functionalities, allowing control of electronic properties whilst maintaining the core structure of the resultant cis-Pd2 L4 nanocage assemblies. The isostructural nature of the scaffold frameworks enabled formation of combinatorial libraries from the self-assembly of ligand mixtures, generating a statistical mixture of multi-functional, low symmetry architectures.

High-Throughput Computational Evaluation of Low Symmetry Pd2 L4 Cages to Aid in System Design*.

Unsymmetrical ditopic ligands can self-assemble into reduced-symmetry Pd2 L4 metallo-cages with anisotropic cavities, with implications for high specificity and affinity guest-binding. Mixtures of cage isomers can form, however, resulting in undesirable system heterogeneity. It is paramount to be able to design components that preferentially form a single isomer. Previous data suggested that computational methods could predict with reasonable accuracy whether unsymmetrical ligands would preferentially self-assemble into single cage isomers under constraints of geometrical mismatch. We successfully apply a collaborative computational and experimental workflow to mitigate costly trial-and-error synthetic approaches. Our rapid computational workflow constructs unsymmetrical ligands and their Pd2 L4 cage isomers, ranking the likelihood for exclusively forming cis-Pd2 L4 assemblies. From this narrowed search space, we successfully synthesised four new, low-symmetry, cis-Pd2 L4 cages.

Rotaxanes as Cages to Control DNA Binding, Cytotoxicity, and Cellular Uptake of a Small Molecule*.

The efficacy of many drugs can be limited by undesirable properties, such as poor aqueous solubility, low bioavailability, and "off-target" interactions. To combat this, various drug carriers have been investigated to enhance the pharmacological profile of therapeutic agents. In this work, we demonstrate the use of mechanical protection to "cage" a DNA-targeting metallodrug within a photodegradable rotaxane. More specifically, we report the synthesis of rotaxanes incorporating as a stoppering unit a known G-quadruplex DNA binder, namely a PtII -salphen complex. This compound cannot interact with DNA when it is part of the mechanically interlocked assembly. The second rotaxane stopper can be cleaved by either light or an esterase, releasing the PtII -salphen complex. This system shows enhanced cell permeability and limited cytotoxicity within osteosarcoma cells compared to the free drug. Light activation leads to a dramatic increase in cytotoxicity, arising from the translocation of PtII -salphen to the nucleus and its binding to DNA.

Rotaxane CoII Complexes as Field-Induced Single-Ion Magnets.

Mechanically chelating ligands have untapped potential for the engineering of metal ion properties. Here we demonstrate this principle in the context of CoII -based single-ion magnets. Using multi-frequency EPR, susceptibility and magnetization measurements we found that these complexes show some of the highest zero field splittings reported for five-coordinate CoII complexes to date. The predictable coordination behaviour of the interlocked ligands allowed the magnetic properties of their CoII complexes to be evaluated computationally a priori and our combined experimental and theoretical approach enabled us to rationalize the observed trends. The predictable magnetic behaviour of the rotaxane CoII complexes demonstrates that interlocked ligands offer a new strategy to design metal complexes with interesting functionality.

Synthetic strategies towards mechanically interlocked oligomers and polymers.

Mechanically interlocked molecules have fascinated chemists for decades. Initially a tantalising synthetic challenge, interlocked molecules have continued to capture the imagination for their aesthetics and, increasingly, for their potential as molecular machines and use in materials applications. Whilst preliminary statistical attempts to prepare these molecules were exceedingly inefficient, a raft of template-directed strategies have now been realised, providing a vast toolbox from which chemists can access interlocked structures in excellent yields. For many envisaged applications it is desirable to move away from small, discrete interlocked molecules and turn to oligomers and polymers instead, either due to the need for multiple mechanical bonds within the desired material, or to exploit an extended scaffold for the organisation and arrangement of individual mechanically interlocked units. In this tutorial-style review we outline the synthetic strategies that have been employed for the synthesis of mechanically interlocked oligomers and polymers, including oligo-/polymerisation of (pseudo)interlocked precursors, metal-organic self-assembly, the use of orthogonal template motifs, iterative approaches and grafting onto polymer backbones.

Rotaxane-Based Transition Metal Complexes: Effect of the Mechanical Bond on Structure and Electronic Properties.

Early work by Sauvage revealed that mechanical bonding alters the stability and redox properties of their original catenane metal complexes. However, despite the importance of controlling metal ion properties for a range of applications, these effects have received relatively little attention since. Here we present a series of tri-, tetra-, and pentadentate rotaxane-based ligands and a detailed study of their metal binding behavior and, where possible, compare their redox and electronic properties with their noninterlocked counterparts. The rotaxane ligands form complexes with most of the metal ions investigated, and X-ray diffraction revealed that in some cases the mechanical bond enforces unusual coordination numbers and distorted arrangements as a result of the exclusion of exogenous ligands driven by the sterically crowded binding sites. In contrast, only the noninterlocked equivalent of the pentadentate rotaxane CuII complex could be formed selectively, and this exhibited compromised redox stability compared to its interlocked counterpart. Frozen-solution EPR data demonstrate the formation of an interesting biomimetic state for the tetradentate CuII rotaxane, as well as the formation of stable NiI species and the unusual coexistence of high- and low-spin CoII in the pentadentate framework. Our results demonstrate that readily available mechanically chelating rotaxanes give rise to complexes the noninterlocked equivalent of which are inaccessible, and that the mechanical bond augments the redox behavior of the bound metal ion in a manner analogous to the carefully tuned amino acid framework in metalloproteins.

Self-templated synthesis of amide catenanes and formation of a catenane coordination polymer.

A self-templation strategy was used to synthesise isophthalamide [2]catenanes of various sizes in up to 51% yield without the need for metal ions as templates or mediators of covalent bond formation. Using this strategy a bis-monodentate catenane was prepared incorporating exohedral pyridine units. Upon complexation of this ligand with AgOTf a one-dimensional coordination polymer was obtained in the solid state in which both macrocycles of the catenane are involved in binding to the metal nodes, resulting in a rare example of a coordination assembly in which mechanical bonds are incorporated into the structure backbone.

Efficient Multicomponent Active Template Synthesis of Catenanes.

We describe a simple and high yielding active template synthesis of [2]catenanes. In addition to mechanical bond formation using a single premacrocycle bearing an azide and alkyne moiety, our method is also suitable for the co-macrocyclization of readily available bis-alkyne and bis-azide comonomers and even short alkyne/azide components which oligomerize prior to mechanical bond formation.

Metal ions in the synthesis of interlocked molecules and materials.

The use of metal ions to template the synthesis of catenanes by Sauvage and co-workers was a pivotal moment in the development of the field of interlocked molecules. In this Review Article we shall examine the different roles metal-ligand interactions play in modern syntheses of interlocked molecules and materials, with a particular focus on seminal contributions and the advantages and disadvantages of employing metal ligand interactions.

Multicavity [PdnL4]2n+ Cages with Controlled Segregated Binding of Different Guests.

Multicavity [Pdn(L)4]2n+ metallosupramolecular cages based on long backboned ligands are an attractive approach to increasing molecular size without loss of the binding specificity conferred by small cavity [Pd2(L)4]4+ assemblies. We herein report the synthesis of two double cavity polypyridyl [Pd3(L)4]6+ cages that bind cisplatin [Pt(NH3)2Cl2] within their internal cavities and interact with triflate (TfO-) on their exohedral faces. We also report the first example of a triple cavity [Pd4(L)4]8+ cage. This cage differs in that the central cavity is phenyl-linked rather than having the pyridyl core as in the peripheral cavities. The difference in cavity character results in selective guest binding of cisplatin in the peripheral cavities, with triflate binding within the central cavity and on the exohedral faces of the peripheral palladium(II) ions. All the cavities could be simultaneously filled by introducing both cisplatin and triflate concurrently, providing the first example of a discrete metallosupramolecular architecture with segregated guest binding in different designed internal cavities. The ligands and cages were characterized by NMR spectroscopy, mass spectrometry, elemental analysis, and, in one case, X-ray crystallography.

Solid-State Gas Adsorption Studies with Discrete Palladium(II) [Pd2 (L)4 ]4+ Cages.

The need for effective CO2 capture systems remains high, and due to their tunability, metallosupramolecular architectures are an attractive option for gas sorption. While the use of extended metal organic frameworks for gas adsorption has been extensively explored, the exploitation of discrete metallocage architectures to bind gases remains in its infancy. Herein the solid state gas adsorption properties of a series of [Pd2 (L)4 ]4+ lantern shaped coordination cages (L = variants of 2,6-bis(pyridin-3-ylethynyl)pyridine), which had solvent accessible internal cavities suitable for gas binding, have been investigated. The cages showed little interaction with dinitrogen gas but were able to take up CO2 . The best performing cage reversibly sorbed 1.4 mol CO2 per mol cage at 298 K, and 2.3 mol CO2 per mol cage at 258 K (1 bar). The enthalpy of binding was calculated to be 25-35 kJ mol-1 , across the number of equivalents bound, while DFT calculations on the CO2 binding in the cage gave ΔE for the cage-CO2 interaction of 23-28 kJ mol-1 , across the same range. DFT modelling suggested that the binding mode is a hydrogen bond between the carbonyl oxygen of CO2 and the internally directed hydrogen atoms of the cage.

Stepwise, Protecting Group Free Synthesis of [4]Rotaxanes.

Despite significant advances in the last three decades towards high yielding syntheses of rotaxanes, the preparation of systems constructed from more than two components remains a challenge. Herein we build upon our previous report of an active template copper-catalyzed azide-alkyne cycloaddition (CuAAC) rotaxane synthesis with a diyne in which, following the formation of the first mechanical bond, the steric bulk of the macrocycle tempers the reactivity of the second alkyne unit. We have now extended this approach to the use of 1,3,5-triethynylbenzene in order to successively prepare [2]-, [3]- and [4]rotaxanes without the need for protecting group chemistry. Whilst the first two iterations proceeded in good yield, the steric shielding that affords this selectivity also significantly reduces the efficacy of the active template (AT)-CuAAC reaction of the third alkyne towards the preparation of [4]rotaxanes, resulting in severely diminished yields.

Iterative Synthesis of Oligo[n]rotaxanes in Excellent Yield.

We present an operationally simple iterative coupling strategy for the synthesis of oligomeric homo- and hetero[n]rotaxanes with precise control over the position of each macrocycle. The exceptional yield of the AT-CuAAC reaction, combined with optimized conditions that allow the rapid synthesis of the target oligomers, opens the door to the study of precision-engineered oligomeric interlocked molecules.

Luminescent Cages: Pendant Emissive Units on [Pd2L4](4+) "Click" Cages.

The photophysics of a family of exo-functionalized [Pd2L4](4+) metallo-supramolecular cage architectures constructed from a tripyridyl 1,2,3-triazole backbone are reported. Several spectroscopic techniques are employed including both electronic (steady-state and transient absorption and emission) and vibrational (resonant and nonresonant Raman) methods. These experimental results are interpreted alongside simulated results from density functional theory calculations of the system's vibrational and electronic properties. The ligands and cages are shown to be essentially insulated from the exo-functionalization. They exhibit electronic transitions in the UV region and excited-state properties that are little affected by formation of the cage. Upon functionalization, characteristic Raman bands, electronic transitions, and emission bands associated with, and confined to, the substituent are observed.

A Stimuli-Responsive Rotaxane-Gold Catalyst: Regulation of Activity and Diastereoselectivity.

A rotaxane-based Au catalyst was developed and the effect of the mechanical bond on its behavior was studied. Unlike the non-interlocked thread, the rotaxane requires a catalytically innocent cofactor, the identity of which significantly influences both the yield and diastereoselectivity of the reaction. Under optimized conditions, Au(I) (the catalyst), Ag(I) (to abstract the Cl(-) ligand), and Cu(I) (the cofactor) combine to produce a catalyst with excellent activity and selectivity.

[Fe2L3]4⁺ cylinders derived from bis(bidentate) 2-pyridyl-1,2,3-triazole "click" ligands: synthesis, structures and exploration of biological activity.

A series of metallosupramolecular [Fe2L3](BF4)4 "click" cylinders have been synthesized in excellent yields (90%-95%) from [Fe(H2O)6](BF4)2 and bis(bidentate) pyridyl-1,2,3-triazole ligands. All complexes were characterized by elemental analysis, IR, UV-vis, ¹H-, ¹³C- and DOSY-NMR spectroscopies and, in four cases, the structures confirmed by X-ray crystallography. Molecular modeling indicated that some of these "click" complexes were of similar size and shape to related biologically active pyridylimine-based iron(II) helicates and suggested that the "click" complexes may bind both duplex and triplex DNA. Cell-based agarose diffusion assays showed that the metallosupramolecular [Fe2L3](BF4)4 "click" cylinders display no antifungal activity against S. cerevisiae. This observed lack of antifungal activity appears to be due to the poor stability of the "click" complexes in DMSO and biological media.

Molecular engineering of confined space in metal-organic cages.

Metal-organic cages (MOCs) have become an intensely studied class of abiotic host molecules. This is due to the ability to generate a myriad of polyhedral architectures from relatively simple, and minimal numbers of, components in high yield and under thermodynamic control. The encapsulation of molecular guests within the nanoscale, confined cavities of these cages frequently draws comparisons with enzymatic binding sites. In this regard, the ostensible ease with which chemical modifications can be made to these internal cavities adds to their attractiveness, as they can be readily tailored with a high degree of precision. In this Feature Article, the ways in which the cavities of MOCs can be engineered at the molecular level will be looked at. The discussion will be divided across three key parameters: size, shape and functionality. Most concepts will be exemplified with a focus on the Pd2L4 class of assemblies due to their relative structural simplicity and the wealth of studies reported in the literature. The core principles discussed will, however, be generalisable to other classes of MOCs, and abiotic host systems as a whole. Gaining increasing mastery over the fine tuning of MOC cavity properties, whilst retaining facile, high-fidelity self-assembly processes, will lead to ever more precise engineering of the cavities of artificial host systems with complex and highly specific functionality.