Functionalisable metallo-cages as nano-vessels

Lead Research Organisation: University of Leeds
Department Name: Sch of Chemistry

Abstract

In this proposal we will be investigating the self-assembly of metallo-supramolecular species and their use as post-construction vessels for chemical space applications. Utilisation of chemical space will ultimately address a variety of important objectives including creation of nano-scale vessels akin to artificial enzymes for performing unusual organic chemistry including catalytic transformations, and organising biologically relevant molecules in an artificial environment. The final area will give important information regarding the fundamental nature of the interactions between biological molecules, which may facilitate modelling studies, and may offer a new route to investigating more complex, higher order, structural motifs. We will be utilising molecular dynamics simulations to better understand the behaviour of guest molecules inside the metallo-cages, and to inform the design of the subsequent generation of functional cages.

Self-assembly involves molecular or ionic components ("building blocks") arranging themselves into more complicated assemblies through reversible interactions between them. Self-assembled systems have well-defined architectures and geometric and interactional design of the building blocks can be used to promote formation of desired assemblies. In this proposal we are targeting discrete hollow cage-like assemblies with significant internal space. In some instances, we will be functionalising the insides of these cages in order to promote functionality such as catalysis, and binding/ordering of guest molecules.

The building blocks that we will be using include the pyramidal-shaped cyclotriveratrylenes (CTVs) which offer hydrophobic binding sites for guest molecules, and we will be developing a new class of folded tetrapodal ligands that can be easily functionalised. Furthermore, CTV derivatives are often chiral and are known to form topologically complicated metallo-supramolecular assemblies. A topologically complicated assembly is one which displays mechanical inter-linking or threading, for example.

Many discrete cages exist in solution and we will be developing their use as nano-scale reaction vessels for performing chemical reactions on guest molecules included inside the cages. A chemical included inside a cage is in a different environment to one outside of a cage in free solvent, and hence will show different chemistry. This is due to both the restricted space inside a cage and the specific interactions between the cage host and chemical guest. We will be designing mixed-ligand cages that allow for different types of interactions with chemical guests, hence an enhanced ability to control spatial orientation, and therefore regio/stereo-chemistry of the guests. For example, the product distribution of 1,3-dipolar coupling reactions could be manipulated or altered through reaction in a confined space. Oxidative reactions using the cages as catalysts will also be investigated.

The novelty of the cage environment will be demonstrated, in solution, by the (NMR) detection and characterisation of interactions between guest molecules, and guest/host molecules. To this end small biologically relevant systems such as complementary deoxydinucleotides sequences will be incorporated and their base-pairing monitored. A DNA tetramer (the i-motif) will be studied to probe the effect of, for example, molecular crowding in the cage. Latterly it will be of interest to note whether the chiral interiors impose any 'order' on the DNA systems, permitting dipole-dipole couplings to be measured and analysed structurally. Such measurements are generally only accessible through the use of ordered media, such as lipids, and provide structural data not otherwise available from solution phase studies.

Planned Impact

Our principal aim is to generate and characterise new molecules which will have wide ranging applications, and to investigate specific applications such as containment of biomolecules and catalysis. This will be underpinned by fundamental investigations of self-assembly processes - both of the cages and their subsequent host-guest chemistry - encompassing X-ray structural, solution NMR and molecular dynamics studies. It will significantly raise the profile of UK research into self-assembled molecular systems and their ultimate functionality which is an internationally competitive and vibrant field. This is an area identified by the UK scientific community as important aspect in the Grand Challenge Directed Assembly of Extended Structures with Targeted Properties and this proposal is thus relevant to the ESPRC signpost for "Control of Self-Assembly".

The detailed research being proposed includes many fields within the chemical sciences and as such, the potential for academic and industrial impact is broad. It includes understanding of self-assembly processes and the development of steric restriction as a tool for organic synthesis; but also has a strong methodological aspect with the development of multi-faceted research approaches to complicated self-assembled systems and their applications. If we are able to show that stereochemical outcome of catalytic reactions can be changed or controlled through steric restriction then this will have significant downstream impact on the organic chemistry academic, and potentially industrial, communities. Base-pair studies will give structural data that is not usually available in solution studies, and are of relevance to a number of areas including the use of these motifs in nano-science. Continued development of the use of steric restriction as a tool will have considerable broader impact in the chemical sciences and associated industries, noting that other systems in the literature have been used for trapping reactive compounds, and studying physico-chemical properties. The systems that we propose considerably extend the scope and ambition of currently known systems, with distinct methods of guest binding allowing for an expansion of known systems and applications.

Dissemination of this research will be through: (i) academic channels such as publication in international journals, presentations at conferences, and through networks such as the grand challenge network; (ii) through links with industrial potential end-users through the Institute of Process Research and Development (iPRD) at The University of Leeds; (iii) through public engagement via a dedicated web-site or other means.

PDRA/PhD student working on this project will benefit from an outstanding training environment. They will significantly expand their research and technical skills in areas of direct interest to pharmaceutical, fine chemicals, and petrochemical industries such as organic synthesis, catalysis, coordination chemistry, crystallography, and in the theory and practise of NMR spectroscopy and in its application to supramolecular and host-guest chemistry (PhD). They will also benefit from working in an interdisciplinary team, as well as developing generic skills of importance to any employers including research management, data analysis, effective time management, independent working, development of supervision skills, presentation and other dissemination skills and public engagement. Training will be both on-the-job and through University offered courses.

The project has a strong element of fundamental research which therefore may not have an immediate societal impact beyond what is described above. However, in achieving the goals we have set, we will be developing, for example, new reaction vessels which may lead to cleaner and more efficient chemistries which could benefit material science and pharmaceutical science (drug development) both of these have consequences for the public at large.

Publications

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Description In this proposal we investigated the self-assembly of metallo-supramolecular species and their use as post-construction vessels for chemical space applications. Self-assembly involves molecular or ionic components ("building blocks") arranging themselves into more complicated assemblies through reversible interactions between them. Self-assembled systems have well-defined architectures and geometric and interactional design of the building blocks can be used to promote formation of desired assemblies. In this work we investigated discrete hollow cage-like assemblies with significant internal space. The building block ligands (L) that were used were the pyramidal-shaped cyclotriveratrylenes (CTVs) which offer hydrophobic binding sites for guest molecules and can be easily functionalised with metal-binding groups. Furthermore, CTV derivatives are often chiral and are known to form topologically complicated metallo-supramolecular assemblies. A topologically complicated assembly is one which displays mechanical inter-linking or threading, for example. We also developed a new class of folded tetrapodal ligands, however these did not form the desired cage-like structures, rather formed coordination polymers that did not exhibit any unusual properties.
Host-guest chemistry is the main chemical space application that was investigated. Solution NMR studies focussed on [Pd6L8]12+ stella octangula cages (resembles a spiked octahedron) and [Pd3L2]6+ trigonal bipyramidal cages (termed metallo-cryptophanes) where both their self-assembly and their abilities to bind surfactant guests were fully investigated. Different L ligands were investigated. Stella octangula cages bind surfactant (soap-like) anions in a 1:2 host:guest ratio with rapid exchange between bound and free surfactant, with highest binding constants for the smallest octyl sulphate anion. Molecular dynamics modelling studies were also undertaken. Self-assembly studies of metallo-cryptophanes which use a Pd building block which is protected by a chelate ligand showed very different behaviour in terms of assembly and dynamics, according to the L ligand and the chelating ligand, which established fundamental self-assembly behaviour critical for the design, and chemical space applications of future cages.
The proposed designs for heteroleptic cubic cages composed of two different ligand types (including where one ligand could be imparted with additional functionality for catalysis or other applications) did not eventuate mainly due to difficulties with ligand synthesis, solubility issues and inconclusive cage self-assembly studies from a series of metal-containing building units using CTV ligands with tridentate chelate groups. A number of different trinuclear complexes of these tridentate ligand appended CTV's were successfully made with different metals including Pd, Pt, Ru. While solution chacaterisation indicated some complexations of these species with linker ligands were occurring, the mass spectra did not correspond to expected species and crystals could not be obtained for structure determination. A new series of new [{Re(CO)3Br}3L2] metallo-cryptophane cages were successfully synthesised. These have two CTV ligands linked together by the luminescent rhenium-based units, and several crystal structures have been obtained. Trinuclear [{Re(CO)3Br}3L] complexes have also been synthesised and characterised in solution and in the solid state by X-ray crystallography. For these complexes we established collaboration with Dr Mike Coogan of University of Lancashire for luminescence studies of these and other trinuclear complexes (submitted for publication), with some preliminary luminescence work also performed on the Re-cages. All of these Re complexes have potential as luminescent compounds (signally, sensors, imaging) or for photocatalysis.
A series of Cu(I), Cu(II) and mixed Cu(I/II) coordination polymers have been synthesised, and characterised by crystallography, spectroscopy, elemental and thermal analysis. These show a remarkable range of framework topologies and structural types. For example, two vet unusual chemical topologies were found in a Cu(I/II) [Cu5.5L5(CN)6]+ 3D coordination polymer is formed which has a 3,4-connected framework of cyanide-linked giant hexagonal prisms, and in [Cu3(H2O)3L4]6+ which has a structure composed of metallo-cryptophanes linked through their metal-vertices to form a 2D network with hierarchical pore-space - small enclosed cryptophane spaces and very large (ca. 3nm width) lattice pore-space. This pore space can take up fullerene-C60 from solution. A variety of other structural types were also found. This work demonstrates that tris-ligand-functionalised CTV-type molecular hosts are excellent building blocks for coordination polymers (aka metal-organic frameworks), with both common and unusual topologies resulting. Their use promotes the formation of cage and capsule-embedded frameworks, with potential as heterogeneous hosts for a range of applications from molecular separations to gas storage, and potentially catalysis exploiting pendant binding sites on metals and redox processes of mixed oxidation state materials.
In related results, a series of new [Agn(dabco)m]+ (dabco = diazabicyclo[2.2.2]octane) coordination polymers were synthesised and characterised including and isostructural series with a zeolitic framework (same topology as the zeolite MTN). These showed a surface up-take of guest iodine however also showed surface pore collapse (shown by Transmission Electron Microscopy) inhibiting high levels of uptake.
A particularly exciting and unanticipated outcome of this research work was the discovery of a hitherto unknown and unclassified example of mechanical entanglement of chemical species. In the solid state a [Cu6L6] metallacyclic complexes forms what we have dubbed a Borromean chain-mail arrangement. A Borromean ring is where three cyclic entities are entangled and inseparable but do not have any chain-links between them. Chemical Borromean rings and networks have been reported before but this example is unique in that an infinite arrangement Borromean arrangement of rings is formed in 2D whereby each ring is part of six different Borromean ring association. The material was characterised by crystallography and Scanning Electron Microscopy as the crystals grew in an unusual hollow straw morphology.
Exploitation Route Work will have strong academic impact through publications and conference presentations. Results have been published in particularly high impact journals including Nature Chemistry and Chemical Science. The Borromean chainmail has garnered considerable interest and, as a completely new chemical topology, will have significant impact in chemistry and potentially mathematics. Some of the recently discovered coordination polymer and coordination cage materials may have catalytic function which may have down stream application in the fine chemical or pharmaceutical sector. The luminescent Re-complexes and cages (currently unpublished) have potential application in the area of chemical sensors, or as photocatalysts.
Sectors Chemicals

 
Description Work published in Nature Chemistry on new chemical topology (Borromean chain-mail) garnered significant social media interesting including nonacademic, industrial attention. This paper is currently ranked in the top 8% of all research outputs scored by Altmetrics.
Impact Types Societal

 
Title Data for CEJ Ir-cages 2017 
Description Data depository for publication "Homochiral self-sorted and emissive Ir(III) metallo-cryptophanes", V. E. Pritchard, D. Rota Martir, S. Oldknow, S. Kai, S. Hiraoka, N. J. Cookson, E. Zysman-Colman, M. J. Hardie, Chem. Eur. J. 2017, 23, 6290-6294 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact NA 
URL http://archive.researchdata.leeds.ac.uk/136/
 
Title Data for Organomet 2016 
Description Data depository for publication "Tris-rhenium fac-tricarbonyl polypyridine-functionalised cyclotriguaiacylene ligands with rich and varied emission", F. L. Thorp-Greenwood, V. E. Pritchard, M. P. Coogan, M. J. Hardie, Organometallics, 2016, 35, 1632-1642 
Type Of Material Database/Collection of data 
Year Produced 2016 
Provided To Others? Yes  
Impact NA 
URL http://archive.researchdata.leeds.ac.uk/48/
 
Title Data for Supramol Chem 2018 
Description Data depository for "Metallo-cryptophane cages from cis-linked and trans-linked strategies", N. J. Cookson, J. M. Fowler, D. P. Martin, J. Fisher, J. J. Henkelis, T. K. Ronson, F. L. Thorp-Greenwood, C. E. Willans, M. J. Hardie, Supramol. Chem., 2018, 30, 255-266 
Type Of Material Database/Collection of data 
Year Produced 2017 
Provided To Others? Yes  
Impact NA 
URL http://archive.researchdata.leeds.ac.uk
 
Description Eli Zysman-Colman 
Organisation University of St Andrews
Department School of Chemistry St Andrews
Country United Kingdom 
Sector Academic/University 
PI Contribution Synthesis of a series of iridium-complexes and iridium-based supramolecular cages
Collaborator Contribution Measurement of photophysical properties of the cages
Impact Publications: "Homochiral self-sorted and emissive Ir(III) metallo-cryptophanes", V. E. Pritchard, D. Rota Martir, S. Oldknow, S. Kai, S. Hiraoka, N. J. Cookson, E. Zysman-Colman, M. J. Hardie, Chem. Eur. J. 2017 DOI:10.1002/chem.201701348 "Multimetallic and mixed environment iridium(III) complexes: A modular approach to luminescence tuning using a host platform", V. E. Pritchard, D. Rota Martir, E. Zysman-Colman, M. J. Hardie, Chem. Eur. J., accepted. 2017 DOI:10.1002/chem.201700237 "Structure-switching M3L2 Ir(III) coordination cages with photo-isomerising azo-aromatic groups", S. Oldknow, D. Rota Martir, V. E. Pritchard, M. A. Blitz, C. W. G. Fishwick, E. Zysman-Colman, M. J. Hardie, Chem. Sci. 2018, 9, 8150-8159. DOI:10.1039/c8sc03499k Unsuccessful funding application to EPSRC
Start Year 2015
 
Description Mike Coogan 
Organisation Lancaster University
Department Department of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution Synthesised a number of Re-based complexes with luminescent properties
Collaborator Contribution Dr Mike Coogan oversaw luminescence measurements both during a site visit by Leeds team members and afterwards, and interpretation of results
Impact Publication currently in submission: "Tris-rhenium fac-tricarbonyl polypyridine-functionalised cyclotriguaiacylene ligands with rich and varied emission", F. L. Thorp-Greenwood, V. E. Pritchard, M. P. Coogan, M. J. Hardie, Organometallics, submitted.
Start Year 2014