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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 Pd

The high yielding Cu I-mediated click reaction is an effective procedure for the preparation of oligoporphyrinoid conjugates. However, the Cu I catalyst leads to the adventitious and usually undesirable insertion of Cu ions into any non-metalated porphyrinoid centers during reaction. Here we report a "sacrificial rotaxane" strategy for the multifunctionalization of porphyrins with free base corroles without incidental copper insertion. This strategy can be considered a general method for implementing Cu I-mediated click reactions with metal cation sequestration to avoid detrimental effects caused by the presence of copper cations.

With increasing interest in the potential utility of metallo-supramolecular architectures for applications as diverse as catalysis and drug delivery, the ability to develop more complex assemblies is keenly sought after. Despite this, symmetrical ligands have been utilised almost exclusively to simplify the self-assembly process as without a significant driving force a mixture of isomeric products will be obtained. Although a small number of unsymmetrical ligands have been shown to serendipitously form well-defined metallo-supramolecular assemblies, a more systematic study could provide generally applicable information to assist in the design of lower symmetry architectures. Pd2L4 cages are a popular class of metallo-supramolecular assembly; research seeking to introduce added complexity into their structure to further their functionality has resulted in a handful of examples of heteroleptic structures, whilst the use of unsymmetrical ligands remains underexplored. Herein we show that it is possible to design unsymmetrical ligands in which either steric or geometric constraints, or both, can be incorporated into ligand frameworks to ensure exclusive formation of single isomers of three-dimensional Pd2L4 metallo-supramolecular assemblies with high fidelity. In this manner it is possible to access Pd2L4 cage architectures of reduced symmetry, a concept that could allow for the controlled spatial segregation of different functionalities within these systems. The introduction of steric directing groups was also seen to have a profound effect on the cage structures, suggesting that simple ligand modifications could be used to engineer structural properties.

A mechanically interlocked [2]rotaxane is reported incorporating a ditopic ligand moiety as one of the stoppers. Upon complexation with palladium(ii) ions a metallo-[5]rotaxane was formed with a porous Pd2L4 metal-organic cage at the core of the structure. This proof-of-principle system precedes work towards the construction of metal organic polyhedra with switchable mechano-chemical properties.

Unsymmetrical ditopic ligands can self‐assemble into reduced‐symmetry Pd2L4 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 Pd2L4 cage isomers, ranking the likelihood for exclusively forming cis‐Pd2L4 assemblies. From this narrowed search space, we successfully synthesised four new, low‐symmetry, cis‐Pd2L4 cages., Towards the development of sophisticated metal‐organic hosts, low‐symmetry metallo‐supramolecular cages assembled from unsymmetrical ligands are of emerging interest. Designing systems to avoid forming isomeric mixtures, however, is challenging. We report the use of a rapid computational workflow to predict self‐assembly outcomes, informing experimental decisions and optimising synthetic realisation of low‐symmetry, cis‐Pd2L4 cages.

With increasing interest in the potential utility of metallo-supramolecular architectures for applications as diverse as catalysis and drug delivery, the ability to develop more complex assemblies is keenly sought after. Despite this, symmetrical ligands have been utilised almost exclusively to simplify the self-assembly process as without a significant driving foa mixture of isomeric products will be obtained. Although a small number of unsymmetrical ligands have been shown to serendipitously form well-defined metallo-supramolecular assemblies, a more systematic study could provide generally applicable information to assist in the design of lower symmetry architectures. Pd2L4 cages are a popular class of metallo-supramolecular assembly; research seeking to introduce added complexity into their structure to further their functionality has resulted in a handful of examples of heteroleptic structures, whilst the use of unsymmetrical ligands remains underexplored. Herein we show that it is possible to design unsymmetrical ligands in which either steric or geometric constraints, or both, can be incorporated into ligand frameworks to ensure exclusive formation of single isomers of three-dimensional Pd2L4 metallo-supramolecular assemblies with high fidelity. In this manner it is possible to access Pd2L4 cage architectures of reduced symmetry, a concept that could allow for the controlled spatial segregation of different functionalities within these systems. The introduction of steric directing groups was also seen to have a profound effect on the cage structures, suggesting that simple ligand modifications could be used to engineer structural properties., Steric and geometric constraints were used to design unsymmetrical ditopic ligands that form single Pd2L4 cage isomers with high fidelity.

The use of unsymmetrical components in metallo-supramolecular chemistry allows for low-symmetry architectures with anisotropic cavities toward guest-binding with high specificity and affinity. Unsymmetrical ditopic ligands mixed with Pd(II) have the potential to self-assemble into reduced symmetry Pd2L4 metallo-architectures. Mixtures of isomers can form, however, resulting in potentially undesirable heterogeneity within a system. Therefore 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 a single isomer under constraints of geometrical mismatch. We successfully apply a collaborative computational and experimental workflow to mitigate costly trial-and-error synthetic approaches. Our low-cost computational workflow rapidly constructs new unsymmetrical ligands (and Pd2L4 cage isomers) and ranks their likelihood for forming cis-Pd2L4 assemblies. From this narrowed search space, we successfully synthesised four new low-symmetry, cis-Pd2L4 cages, with cavities of different shapes and sizes.

Mechanically chelating ligands have untapped potential for the engineering of metal ion properties by providing reliable control of the number, nature and geometry of donor atoms, akin to how a protein cavity controls the properties of bound metal ions. 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 behavior 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 behavior of the rotaxane CoII complexes demonstrates that interlocked ligands offer a new strategy to design metal complexes with interesting functionality.

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., Mechanically interlocked ligands enable predictable metal ion coordination, offering a new strategy to engineer their properties. A series of field‐induced CoII single‐ion magnets illustrates this principle. The predictable coordination behaviour of the rotaxane enables remarkably accurate calculation of their zero‐field splittings, which are in agreement with experimental observations, and can be rationalized in terms of metal–ligand bonding.

We demonstrate the first example of bidirectional reversible electronic energy transfer (REET) between the mechanically bonded components of a rotaxane. Our prototypical system was designed such that photoexcitation of a chromophore in the axle results in temporary storage of electronic energy in a quasi-isoenergetic “reservoir” chromophore in the macrocycle. Over time, the emissive state of the axle is repopulated from this reservoir, resulting in long-lived, delayed luminescence. Importantly, we show that cation binding in the cavity formed by the mechanical bond perturbs the axle chromophore energy levels, modulating the REET process, and ultimately providing a luminescence read-out of cation binding. Modulation of REET processes represents an unexplored mechanism in luminescent molecular sensor development., Delayed emission due to reversible electronic energy transfer (REET) between chromophores in the axle and macrocycle components of a rotaxane is demonstrated. The REET process can be modulated by metal ion binding in the cavity of the rotaxane.

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.

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.

Metallo-supramolecular self-assembly tends to be performed with single metal ions and single, highly symmetrical, ligands. This simplifies the self-assembly process as without sufficient bias within the system a mixture of products may be formed. However, with various applications of metallo-supramolecular species having been demonstrated, the ability to generate more intricate architectures is keenly sought after. The use of reduced symmetry ligands is one route to this goal, and allows access to lower-symmetry assemblies. Multiple coordination pockets can also be introduced in this manner, giving rise to assemblies with metal ions in different coordination environments, which can be exploited for the controlled synthesis of mixed-metal species. Herein we discuss the different approaches that have been used to control self-assembly with low symmetry ligands, including the use of mixed-denticity ligands, the incorporation of geometric constraints, charge separation strategies and the use of repulsive or attractive non-covalent interactions between ligands.

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 we have investigated 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. 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.

Summary Catenanes, molecules in which two rings are threaded through one another like links in a chain, can form as two structures related like an object and its mirror image but otherwise identical if the individual rings lack bilateral symmetry. These structures are described as “topologically chiral” because, unlike most chiral molecules, it is not possible to convert one mirror-image form to the other under the rules of mathematical topology. Although intriguing and discussed as early as 1961, to date all methods of accessing molecules containing only this topological stereogenic element require the separation of the mirror-image forms via chiral stationary phase high-performance liquid chromatography, which has limited their investigation to date. Here, we present a simple method that uses a readily available source of chiral information to allow the stereoselective synthesis of topologically chiral catenanes., Graphical Abstract, Highlights • First stereoselective synthesis of a topologically chiral catenane • First absolute stereochemical assignment of a topologically chiral catenane • First example of an auxiliary approach to topologically chiral catenanes, The Bigger Picture Chiral molecules have occupied a special place in chemistry since Pasteur reported the painstaking separation of mirror-image crystals of tartaric acid salts in 1848. In the 21st century, chiral molecules remain a major scientific focus because of their importance in biology and their emerging applications in materials science. However, topologically chiral molecules, such as the catenanes described here, have received little attention because they are hard to make; preparative chiral stationary phase high-performance liquid chromatography allows the separation of their mirror-image forms but only on a very small scale. Here, we demonstrate the synthesis of topologically chiral catenanes by using standard synthetic techniques, marking their transition from “inaccessible curiosities” to valid synthetic targets for investigation in catalysis, sensing, medicinal chemistry, and materials science. Furthermore, this work will inspire efforts to access other neglected classes of chiral interlocked molecules., Catenanes, molecules comprising two rings held together like links in a chain, can exist as two mirror-image forms if the rings lack bilateral symmetry. These “topological enantiomers” are unusual because they cannot be interconverted by stretching or bending chemical bonds. To date, their synthesis has required the separation of mirror-image structures by specialist techniques. We present a simple method to allow the synthesis of topologically chiral catenanes, opening them up to investigation in catalysis, sensing, and materials science.

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 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.

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.

In this issue of Chem, Fujita and co-workers investigate the self-assembly of peptide-based ligands with silver ions. Through selective crystallization they were able to isolate a molecular septafoil knot and a quadruply braided [2]catenane (821 link)—entangled molecules that had, until now, evaded realization.

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

Building on recent progress in the synthesis of functional porphyrins for a range of applications using the Cu-mediated azide–alkyne cycloaddition (CuAAC) reaction, we describe the active template CuAAC synthesis of interlocked triazole functionalised porphyrinoids in excellent yield. By synthesising interlocked analogues of previously studied porphyrin–corrole conjugates, we demonstrate that this approach gives access to rotaxanes in which the detailed electronic properties of the axle component are unchanged but whose steric properties are transformed by the mechanical “picket fence” provided by the threaded rings. Our results suggest that interlocked functionalised porphyrins, readily available using the AT-CuAAC approach, are sterically hindered scaffolds for the development of new catalysts 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.

The need for effective CO

Two simple palladium(II) pyridine-2,6-dicarboxa- mide complexes coordinated to CuAAC derived "click" 1,2,3-triazole ligands are described. Addition of a more basic 4-dimethylaminopyridine (DMAP) ligand to these palladium(II) "click" complexes leads to complete displace- ment of the 1,2,3-triazole ligands by DMAP. The process can be completely reversed by treatment with acid.

There is considerable interest in the development of bifunctional ligand scaffolds for the group 7 metals due to potential biological applications. Building on our recent work in the development of “click” ligands and macrocycles, we show that a CuAAC “click” approach can be exploited for the synthesis of a small family of bioconjugated tridentate pyridyl-1,2,3-triazole macrocycles. These bioconjugated tridentate macrocycles form stable [Re(CO)3]+ complexes, and this could facilitate the development of [M(CO)3]+ (M = Mn, Tc, Re) targeted agents. The parent macrocycle, bioconjugates, and [Re(CO)3]+ complexes were characterized by elemental analysis and HR-ESI-MS, 1H and 13C NMR, and IR spectroscopy, and the molecular structures of the alcohol-functionalized macrocycle and two of the Re(I) complexes were confirmed by X-ray crystallography. The electronic structure of the parent [Re(CO)3]+ macrocycle complex was examined using UV–vis, Raman, and emission spectroscopy and density functional theory calculation...

The synthesis of self-assembled metallosupramolecular architectures has been of steadily growing interest in recent years due to their diverse applications. Appending additional functionality to the ligands of these architectures has been limited as this often involves incorporation of coordinating groups that can potentially disrupt formation of the desired structure. Herein we report the use of the facile, functional group tolerant and high yielding CuAAC ‘click’ reaction to attach a variety of functional moieties to a tripyridyl ligand system. Despite the presence of the potentially coordinating 1,2,3-triazole rings, self-assembly of quadruply-stranded dipalladium(II) cage architectures in the presence of Pd(II) ions was almost universally observed for the functionalised “click” ligands. The only system which did not assemble into the expected cage featured a 2-(1,2,3-triazol-4-yl)pyridine binding pocket which sequestered the Pd(II) ions. Blocking this chelating pocket with an inert [Re(CO)3Cl] moiety restored the ability of the ligand to self-assemble into the desired quadruply-stranded dipalladium(II) cage, generating a heterometallic cage architecture. All ligands and cage architectures have been characterised using 1H, 13C and DOSY NMR, IR, UV-Vis and emission spectroscopies, mass spectrometry and in some cases by X-ray crystallography. Whilst the parent cage system is devoid of useful physical properties and displays a limited range of solubility, the CuAAC methodology provides a facile method to enhance the cage's properties. A variety of fluorescent, redox active and biologically relevant species have been appended to the external surface of these cages. These groups enabled the generation of a series of aqueous soluble, fluorescent and electrochemically active Pd2L4 cages in a modular fashion.

Multicavity [Pd

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.

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.

Mechanically interlocked molecules have a long and rich history as ligands thanks to the key role coordination chemistry has played in the development of high yielding passive template syntheses of rotaxanes and catenanes. In this Feature Article, we highlight the effect of the mechanical bond on the properties of metal ions bound within the sterically hindered environment of the macrocycle cavity, and discuss the emerging applications of interlocked ligands in catalysis, sensing and supramolecular materials.

There is considerable interest in exploiting metallosupramolecular cages as drug delivery vectors. Recently, we developed a [Pd2L4]4+ cage capable of binding two molecules of cisplatin. Unfortunately, this first generation cage was rapidly decomposed by common biologically relevant nucleophiles. In an effort to improve the kinetic stability of these cage architectures here we report the synthesis of two amino substituted tripyridyl 2,6-bis(pyridin-3-ylethynyl)pyridine (tripy) ligands (with amino groups either in the 2-(2A-tripy) or 3-(3A-tripy) positions of the terminal pyridines) and their respective [Pd2(Ltripy)4]4+ cages. These systems have been characterised by 1H, 13C and DOSY NMR spectroscopies, high resolution electrospray mass spectrometry, elemental analysis and, in one case, by X-ray crystallography. It was established, using model palladium(II) N-heterocyclic carbene (NHC) probe complexes, that the amino substituted compounds were stronger donor ligands than the parent system (2A-tripy > 3A-tripy > tripy). Competition experiments with a range of nucleophiles showed that these substitutions lead to more kinetically robust cage architectures, with [Pd2(2A-tripy)4]4+ proving the most stable. Biological testing on the three ligands and cages against A549 and MDA-MB-231 cell lines showed that only [Pd2(2A-tripy)4]4+ exhibited any appreciable cytotoxicity, with a modest IC50 of 36.4 ± 1.9 μM against the MDA-MB-231 cell line. Unfortunately, the increase in kinetic stability of the [Pd2(Ltripy)4]4+ cages was accompanied by loss of cisplatin-binding ability.

A one-pot, multi-component CuAAC reaction was exploited for the safe generation of an exo alcohol-functionalised pyridyl-1,2,3-triazole ‘click’ macrocycle in good yield. The macrocycle was characterised by elemental analysis, HR-ES-MS, 1H and 13C NMR spectrometry, and the molecular structure was confirmed by X-ray crystallography. Efforts to use the ‘click’ macrocycle in both passive and active metal template syntheses of [2]rotaxanes were unsuccessful, and this appears to be connected to the coordinating ability of the 1,2,3-triazole units in the macrocycle. The coordination chemistry of the macrocycle with Cu(I) and Ag(I) was examined. It has been demonstrated using HR-ES-MS, 1H NMR spectrometry and X-ray crystallography that the macrocycle can form both discrete and polymeric coordination compounds with Cu(I) and Ag(I) and in all cases the 1,2,3-triazolyl units of the macrocycle are coordinated to the metal ions.

Metallosupramolecular cages are an emerging, but as of yet relativity unexplored, drug delivery vector. Herein we show that discrete dipalladium(II) molecular cages of the formula [Pd2L4](X)4 can be quantatively self-assembled from a simple tripyridyl ligand (2,6-bis(pyridin-3-ylethynyl)pyridine) and [Pd(CH3CN)4](X)2 (X = BF4− or SbF6−). The cages have been fully characterised using 1H, 13C and DOSY NMR spectroscopy, elemental analysis, IR spectroscopy, and high resolution electrospray mass spectrometry (HR-ESMS). Additionally, the molecular structure of the [Pd2L4](SbF6)4 cage was confirmed unequivocally using X-ray diffraction. These [Pd2L4](X)4 cages are stimuli-responsive and can be reversibly disassembled/reassembled upon the addition/removal of suitable competing ligands. The central cavities of the [Pd2L4](X)4 cages are lined with four hydrogen bond accepting pyridine units which enable the encapsulation of two cisplatin molecules within the metallosupramolecular architecture through hydrogen bonding interactions between the cage and the amine ligands of the cisplatin guest. The structure of the [Pd2L4⊃(cisplatin)2](BF4)4 host–guest adduct has been confirmed by 1H NMR spectroscopy, HR-ESMS and X-ray crystallography. Additionally we have demonstrated that the cage–cisplatin host–guest adduct can be quantatively disassembled upon the addition of a competing ligand, releasing the cisplatin guest. This is the first crystallographically characterised example of a discrete metallosupramolecular cage encapsulating an FDA-approved inorganic drug molecule. This host–guest chemistry could open the way to relatively unexplored methods of drug delivery, which circumvent the malicious side effects and drug resistance associated with cisplatin and other anticancer therapeutics.

We present an operationally simple approach to 2,2?-bipyridine macrocycles. Our method uses simple starting materials to produce these previously hard to access rotaxane precursors in remarkable yields (typically >65%) across a range of scales (0.1–5 mmol). All of the macrocycles reported are efficiently converted (>90%) to rotaxanes under AT-CuAAC conditions. With the requisite macrocycles finally available in sufficient quantities, we further demonstrate their long term utility through the first gram-scale synthesis of an AT-CuAAC [2]rotaxane and extend this powerful methodology to produce novel Sauvage-type molecular shuttles.

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.

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.

There is emerging interest in the anti-proliferative effects of metallosupramolecular systems due to the different size and shape of these metallo-architectures compared to traditional small molecule drugs. Palladium(II)-containing systems are the most abundant class of metallosupramolecular complexes, yet their biological activity has hardly been examined. Here a small series of [Pd2(L)4](BF4)4 quadruply-stranded, dipalladium(II) architectures were screened for their cytotoxic effects against three cancer cell lines and one non-malignant line. The helicates exhibited a range of cytotoxic properties, with the most cytotoxic complex [Pd2(hextrz)4](BF4)4 possessing low micromolar IC50 values against all of the cell lines tested, while the other helicates displayed moderate or no cytotoxicity. Against the MDA-MB-231 cell line, which is resistant to platinum-based drugs, [Pd2(hextrz)4](BF4)4 was 7-fold more active than cisplatin. Preliminary mechanistic studies indicate that the [Pd2(hextrz)4](BF4)4 helicate does not induce cell death in the same way as clinically used metal complexes such as cisplatin. Rather than interacting with DNA, the helicate appears to disrupt the cell membrane. These studies represent the first biological characterisation of quadruply-stranded helicate architectures, and provide insight into the design requirements for the development of biologically active and stable palladium(II)-containing metallosupramolecular architectures.

A series of [Pd2L4]4+(X− )4 metallosupramolecular architectures have been synthesised where X− = , , OTf− , OMs− or OTs− and L = 2,6-bis(pyridin-3-ylethynyl)pyridine. These systems have been characterised by NMR, IR and UV–vis spectroscopies, mass spectrometry, elemental analysis and, in several cases, by X-ray crystallography. Using these solution- and solid-state methods, we have investigated the exohedral and endohedral interactions of various anions with these cationic assemblies.

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.

Herein we describe a CuAAC "click" methodology for exo-functionalisation of Pd2L4 metallosupramolecular architectures. The potentially coordinating 1,2,3-triazole does not affect formation of the desired discrete complexes, nor does this external functional decoration affect the cisplatin-binding ability of the interior cavity of the assembly.

The syntheses of the 4-n-propyl and 4-phenyl substituted fac-Re(CO)(3) complexes of the tridentate "click" ligand (2,6-bis(4-substituted-1,2,3-triazol-1-ylmethyl)pyridine) are described. The complexes were obtained by refluxing methanol solutions of [Re(CO)(5)Cl], AgPF(6) and either the 4-propyl or 4-phenyl substituted ligand for 16 h. The ligands and the two rhenium(I) complexes were characterised by elemental analysis, HR-ESMS, ATR-IR, (1)H and (13)C NMR spectroscopy and the molecular structures of both complexes were confirmed by X-ray crystallography. The electronic structure of the fac-Re(CO)(3) "click" complexes was probed using UV-Vis, Raman and emission spectroscopy, cyclic voltammetry and DFT calculations. Altering the electronic nature of the ligand's substituent, from aromatic to alkyl, had little effect on the absorption/emission maxima and electrochemical properties of the complexes indicating that the 1,2,3-triazole unit may insulate the metal centre from the electronic modification at the ligands' periphery. Both Re(I) complexes were found to be weakly emitting with short excited state lifetimes. The electrochemistry of the complexes is defined by quasi-reversible Re oxidation and irreversible triazole-based ligand reduction processes.

A series of copper(ii) complexes of the ligand 2,6-bis(pyridin-3-ylethynyl)pyridine have been synthesised and characterised by 1H and DOSY NMR, IR and UV-Vis spectroscopies, mass spectrometry, elemental analysis and single crystal X-ray diffraction. In solution these systems display almost identical spectroscopic properties, however the solid state structures are shown to vary widely, depending upon the choice of anion. The tetrafluoroborate salt was revealed to be a discrete Cu2L4 cage-like helicate. The tosylate salt, whilst of the same Cu2L4 stoichiometry, was shown to be a coordination polymer. Finally the nitrate salt structure was observed to be a discrete Cu2L2 metallocycle.