Long-Lived Fluxional Barbaralyl Cations

The covalent bonds that hold atoms together to make molecules are, by and large, flexible linkages that are prone to stretching and bending. This flexibility imparts a degree of responsiveness to molecules' three-dimensional shape that is key in determining their physical properties and mediating their interactions with other molecules. For example, the molecular recognition of a pharmaceutical within the binding site of a protein can induce organisation in one, or even both, of the binding partners. A mutually favourable spatial arrangement (conformation) is stabilised.

In certain cases, the structural dynamics of molecules can be extended beyond changes in their conformation to include changes in their constitution (i.e., changes in their atomic skeleton). Processes termed 'dynamic covalent' reactions rely upon chemical transformations that are reversible in nature, allowing specific covalent bonds to be broken and formed freely under the same set of conditions. In this way, molecular fragments come together and break apart over and over again, reversibly forming different compounds of varying shapes and sizes.

This research project seeks to explore constitutional dynamics in a rather unique class of compounds. The 'barbaralyl cations' that will be developed are built around a core of nine carbon atoms in a cage-like arrangement. Each carbon atom is connected to two or three similar neighbours. As a result of this particular composition and the type of covalent bonds that make up the core, the carbon atoms are able to reversibly trade bonds with one another, switching positions with their neighbours. As one bond breaks, another is made and the outcome is that the barbaralyl cation core is 'fluxional'. When different groups are appended to this fluxional core, the molecule as a whole develops the property of being able to change its shape dramatically, not just in terms of its conformation, but also in terms of its constitution. It becomes a 'shapeshifting molecule'. Unlike the vast majority of dynamic covalent processes, this rearrangement occurs entirely within single molecules, meaning that the rate at which it occurs is not dependent on the presence of other reactants and their concentration. The linkages at the centre of the molecule interchange, causing the positions and orientations of the functional groups around the exterior to be switched and giving rise to hundreds (or even thousands!) of different structural permutations.

Importantly, the shapeshifting molecules developed during this research will not require onerous preparation, but rather they will be made using relatively straightforward methods, overcoming one of the major impediments associated with the handful of related shapeshifting molecules that have been studied in the past. Ultimately, constitutional dynamics of this kind, occurring within a single molecule, will offer a new means through which to search for structures with mutually stabilising binding interactions with conceivably any target of interest. Applications, therefore, may lie in the improved design of molecular components for sensing medicinally relevant species.

The groundwork laid by this research project will lead to the development of anion binding and saccharide sensing derivatives of BBCs. These goals are aligned with the EPSRC's Complexity Science and Synthetic Supramolecular Chemistry research areas, which fall under the Manufacturing the Future and Physical Sciences Themes. Both of these target species (anions and saccharides) present unmet challenges in terms of their selective molecular recognition and are of significant contemporary interest on account of their roles in biochemistry. In the medium term (3-5 years), therefore, the impact of this research will extend to the chemists and biochemists that are engaged in studying the molecular recognition of anions and saccharides. They will benefit from (i) access to an additional family of hosts on which to base their research, and, in a more general sense, (ii) the insight that is gained into which host geometries are optimal in order to complex specific targets. Publication of the results of this EPSRC First Grant in open access journals will ensure that there is no barrier to prevent other researchers from engaging with the research. A budget of £500 has been requested in order to cover publishers' open access fees. In addition, preprint versions of each manuscript will be uploaded to Durham University's publically accessible 'Research Online' repository within one month of their publication, from which they can be downloaded without charge.

Although the primary objectives of this research proposal are rooted in fundamental concepts, with sufficient development they may lead to industrial applications. In the longer term (>5 years), this research may contribute to developments in medicinal chemistry. A common problem that is faced when designing host or guest molecules of unknown or flexible structure (as can be the case when targeting certain enzymes, for example) is finding a first approximation of a complementary binding partner. The unique, large scale constitutional dynamics of shapeshifting molecules may lend them to application as a tool to experimentally explore the three-dimensional structure of such targets.

The skills acquired by the PDRA as a direct result of participating in this research project will prepare him/her for employment in the chemical industry. Training in organic synthesis and homogeneous catalysis are important prerequisites to embarking upon a career in industries ranging from drug discovery and fine chemical synthesis up to the production of commodity chemicals and polymers. Exposure to a wide range of analytical techniques (NMR and UV spectroscopy, mass spectrometry, HPLC, X-ray diffraction, isothermal titration calorimetry, and cyclic voltammetry) to fully characterise the BBCs will serve as good preparation for employment as an analytical chemist. By gaining experience in working with DFT calculations, the PDRA will increase his/her employability in the chemical industry, where computation is exploited with increasing frequency. The PDRA will also benefit from a rigorous training in data management, literature searching, and presentation skills, which would be applicable in industries beyond the chemical industry, such as in pharmacology, education, science writing, and patent law.