Publications
44 results found
Lewis JEM, 2022, Molecular engineering of confined space in metal-organic cages, CHEMICAL COMMUNICATIONS, Vol: 58, Pages: 13873-13886, ISSN: 1359-7345
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- Citations: 1
Lewis JEM, 2022, Pseudo-heterolepticity in Low-Symmetry Metal-Organic Cages, ANGEWANDTE CHEMIE-INTERNATIONAL EDITION, Vol: 61, ISSN: 1433-7851
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- Citations: 1
Perez NH, Sherin PS, Posligua V, et al., 2022, Emerging properties from mechanical tethering within a post-synthetically functionalised catenane scaffold, Chemical Science, Vol: 13, Pages: 11368-11375, ISSN: 2041-6520
Maintaining close spatial proximity of functional moieties within molecular systems can result in fascinating emergent properties. Whilst much work has been done on covalent tethering of functional units for myriad applications, investigations into mechanically linked systems are relatively rare. Formation of the mechanical bond is usually the final step in the synthesis of interlocked molecules, placing limits on the throughput of functionalised architectures. Herein we present the synthesis of a bis-azide [2]catenane scaffold that can be post-synthetically modified using CuAAC ‘click’ chemistry. In this manner we have been able to access functionalised catenanes from a common precursor and study the properties of electrochemically active, emissive and photodimerisable units within the mechanically interlocked system in comparison to non-interlocked analogues. Our data demonstrates that the greater (co-)conformational flexibility that can be obtained with mechanically interlocked systems compared to traditional covalent tethers paves the way for developing new functional molecules with exciting properties.
Tarzia A, Lewis JEM, Jelfs KE, 2021, High‐throughput computational evaluation of low symmetry Pd <sub>2</sub> L <sub>4</sub> Cages to Aid in System Design**, Angewandte Chemie, Vol: 133, Pages: 21047-21055, ISSN: 0044-8249
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.
Tarzia A, Lewis J, Jelfs KE, 2021, High‐throughput computational evaluation of low symmetry Pd2L4 cages to aid in system design, Angewandte Chemie International Edition, Vol: 60, Pages: 20879-20887, ISSN: 1433-7851
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 Pd 2 L 4 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 Pd 2 L 4 cage isomers) and ranks their likelihood for forming cis -Pd 2 L 4 assemblies. From this narrowed search space, we successfully synthesised four new low-symmetry, cis -Pd 2 L 4 cages, with cavities of different shapes and sizes.
Martin Diaz A, Lewis J, 2021, Structural flexibility in metal-organic cages, Frontiers in Chemistry, Vol: 9, ISSN: 2296-2646
Metal-organic cages (MOCs) have emerged as a diverse class of molecular hosts with potential utility across a vast spectrum of applications. With advances in single-crystal X-ray diffraction and economic methods of computational structure optimisation, cavity sizes can be readily determined. In combination with a chemist’s intuition, educated guesses about the likelihood of particular guests being bound within these porous structures can be made. Whilst practically very useful, simple rules-of-thumb, such as Rebek’s 55% rule, fail to take into account structural flexibility inherent to MOCs that can allow hosts to significantly adapt their internal cavity. An often unappreciated facet of MOC structures is that, even though relatively rigid building blocks may be employed, conformational freedom can enable large structural changes. If it could be exploited, this flexibility might lead to behavior analogous to the induced-fit of substrates within the active sites of enzymes. To this end, in-roads have already been made to prepare MOCs incorporating ligands with large degrees of conformational freedom. Whilst this may make the constitution of MOCs harder to predict, it has the potential to lead to highly sophisticated and functional synthetic hosts.
Cirulli M, Salvadori E, Zhang Z-H, et al., 2021, Rotaxane Co-II complexes as field-induced single-ion magnets, Angewandte Chemie International Edition, Vol: 60, Pages: 16051-16058, ISSN: 1433-7851
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.
Yu S, Kupryakov A, Lewis JEM, et al., 2021, Damming an electronic energy reservoir: ion-regulated electronic energy shuttling in a [2]rotaxane, CHEMICAL SCIENCE, Vol: 12, Pages: 9196-9200, ISSN: 2041-6520
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- Citations: 2
Kench T, Summers PA, Kuimova MK, et al., 2021, Rotaxanes as Cages to Control DNA Binding, Cytotoxicity, and Cellular Uptake of a Small Molecule**, Angewandte Chemie, Vol: 133, Pages: 11023-11029, ISSN: 0044-8249
Kench T, Summers PA, Kuimova MK, et al., 2021, Rotaxanes as cages to control DNA binding, cytotoxicity, and cellular uptake of a small molecule, Angewandte Chemie International Edition, Vol: 60, Pages: 1-1, ISSN: 1433-7851
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.
Lewis JEM, 2021, Multi-functional, low symmetry Pd2L4 nanocage libraries**, Chemistry: A European Journal, Vol: 27, Pages: 4454-4460, ISSN: 0947-6539
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-Pd2L4 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.
Perez NH, Lewis JEM, 2020, Synthetic strategies towards mechanically interlocked oligomers and polymers, Organic and Biomolecular Chemistry, Vol: 18, Pages: 6757-6780, ISSN: 1477-0520
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.
Wong K, Hoyas Perez N, White A, et al., 2020, Self-assembly of a porous metallo-[5]rotaxane, Chemical Communications, Vol: 72, Pages: 10453-10456, ISSN: 1359-7345
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.
Huynh TN, Lewis JEM, Payne DT, et al., 2020, Rotaxanation as a sequestering template to preclude incidental metal insertion in complex oligochromophores, CHEMICAL COMMUNICATIONS, Vol: 56, Pages: 7447-7450, ISSN: 1359-7345
Lewis J, Crowley J, 2020, Metallo‐supramolecular self‐assembly with reduced symmetry ligands, ChemPlusChem, Vol: 85, Pages: 815-827, ISSN: 2192-6506
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 metallosupramolecular 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, allowing 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 mixeddenticity ligands, the incorporation of geometric constraints, charge separation strategies and the use of repulsive or attractive non‐covalent interactions between ligands.
Lewis JEM, 2020, Knotting to See Here, CHEM, Vol: 6, Pages: 14-15, ISSN: 2451-9294
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- Citations: 1
Lewis JEM, Tarzia A, White AJP, et al., 2019, Conformational control of Pd2L4 assemblies with unsymmetrical ligands, Chemical Science, Vol: 11, Pages: 677-683, ISSN: 2041-6520
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.
Denis M, Lewis J, Modicom F, et al., 2019, An auxiliary approach for the stereoselective synthesis of topologically Chiral catenanes, Chem, Vol: 5, Pages: 1512-1520, ISSN: 2451-9294
Catenanes, molecules in which two rings are threaded through one another like links in a chain, can form as two structures related as object and mirror image but otherwise identical if the individual rings lack bilateral symmetry. These structuresare described as “topologically chiral” as, unlike most chiral molecules,it is not possible to convert onemirror-image formto the other undertherules of mathematical topology. Although intriguing, and discussed as early as 1961, to date all methods to access molecules containing only this topological stereogenic element requiretheseparation ofthe mirror imageforms using chiral stationary phase high performance liquid chromatography (PCSP-HPLC)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.
Lewis JEM, 2019, Self-templated synthesis of amide catenanes and formation of a catenane coordination polymer, Organic & Biomolecular Chemistry, Vol: 17, Pages: 2442-2447, ISSN: 1477-0520
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.
Cirulli M, Kaur A, Lewis JEM, et al., 2019, Rotaxane-based transition metal complexes: Effect of the mechanical bond on structure and electronic properties, Journal of the American Chemical Society, Vol: 141, Pages: 879-889, ISSN: 0002-7863
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.
Lewis JEM, Modicom F, Goldup SM, 2018, Efficient multicomponent active template synthesis of catenanes, Journal of the American Chemical Society, Vol: 140, Pages: 4787-4791, ISSN: 1520-5126
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.
Ngo TH, Labuta J, Lim GN, et al., 2017, Porphyrinoid rotaxanes: building a mechanical picket fence, CHEMICAL SCIENCE, Vol: 8, Pages: 6679-6685, ISSN: 2041-6520
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- Citations: 19
Preston D, White KF, Lewis JEM, et al., 2017, Solid-State Gas Adsorption Studies with Discrete Palladium(II) [Pd-2(L)(4)](4+) Cages, CHEMISTRY-A EUROPEAN JOURNAL, Vol: 23, Pages: 10559-10567, ISSN: 0947-6539
Lewis JEM, Beer PD, Loeb SJ, et al., 2017, Metal ions in the synthesis of interlocked molecules and materials, CHEMICAL SOCIETY REVIEWS, Vol: 46, Pages: 2577-2591, ISSN: 0306-0012
Preston D, Lewis JEM, Crowley JD, 2017, Multicavity [PdnL4](2n+) cages with controlled segregated binding of different guests, Journal of the American Chemical Society, Vol: 139, Pages: 2379-2386, ISSN: 1520-5126
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.
Lewis JEM, Galli M, Goldup SM, 2017, Properties and emerging applications of mechanically interlocked ligands, CHEMICAL COMMUNICATIONS, Vol: 53, Pages: 298-312, ISSN: 1359-7345
Lewis JEM, Winn J, Goldup SM, 2017, Stepwise, Protecting Group Free Synthesis of [4]Rotaxanes, MOLECULES, Vol: 22, ISSN: 1420-3049
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- Citations: 9
Lewis JEM, Winn J, Cera L, et al., 2016, Iterative synthesis of oligo[n]rotaxanes in excellent yield, Journal of the American Chemical Society, Vol: 138, Pages: 16329-16336, ISSN: 1520-5126
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.
Lewis JEM, Bordoli RJ, Denis M, et al., 2016, Correction: High yielding synthesis of 2,2'-bipyridine macrocycles, versatile intermediates in the synthesis of rotaxanes., Chem Sci, Vol: 7, ISSN: 2041-6520
[This corrects the article DOI: 10.1039/C6SC00011H.].
Preston D, McNeill SM, Lewis JEM, et al., 2016, Enhanced kinetic stability of [Pd2L4](4+) cages through ligand substitution, Dalton Transactions, Vol: 45, Pages: 8050-8060, ISSN: 1477-9234
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.
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