Functionalisable metallo-cages as nano-vessels

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.

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.