Fluorine-containing organic molecules are found in a wide range of applications from liquid crystals to blockbuster drugs such as Prozac and Lipitor, but are of particular interest in pharmaceuticals agrochemicals, medical imaging (e.g. fluorodeoxyglucose in 18F-based positron emission tomography) and the next generation of refrigerants (e.g. HFO-1234yf). The unique properties of C-F bonds, which can improve metabolic stability, bioavailability and lipophilicity, mean that around 30% of all agrochemicals and 20% of all pharmaceuticals now contain fluorine. As such, there is a synthetic requirement to develop simple, selective, efficient methods for the introduction of fluorine into organic molecules.
We have recently discovered an entirely new way for transition metal complexes to facilitate the formation of C-F (or C-CF3) bonds. We call this outer-sphere electrophilic fluorination (OSEF) and it occurs rapidly, under mild conditions and with complete regio- and diastereo-selectivity. In previous work we have established the feasibility of a wide range of reactions related to OSEF and the subsequent reactivity of fluorinated organometallic ligands at the metal centre. This has given us access to novel and synthetically interesting bond formation/activation processes that we aim to exploit during this project to prepare highly functional organic molecules of relevance to the pharmaceutical, agrochemical and refrigerant sectors.
By definition, late-stage functionalization of target compounds involves transformations on complex functionalised molecules. This can limit the nature and type of catalysts than can be applied to these systems. We therefore wish to undertake a somewhat unusual approach to the development of new synthetic chemistry for late stage transformations. We will use OSEF, and some of our related work on the functionalization of pyridine derivatives, to develop stepwise, stoichiometric reactions occurring at a metal centre to transform reagents to products within the coordination sphere of the metal. This will all occur in one pot and the final step in the sequence of reactions will liberate the product from the metal and regenerate the initial metal complex, allowing for the process to be repeated.
Underpinning the approach will be the extremely high selectivity of our ruthenium complexes for soft alkyne functional grounds. In previous studies we have demonstrated that Ru(II) complexes will bind selectively to alkynes in functionalised steroids, giving confidence that hard functional groups such as alcohols, amides, amines and esters will be readily tolerated. Furthermore, when one considers the cost of multi-step synthesis, the use of a stoichiometric, but recyclable, ruthenium complex to deliver the final products in high yield is minimal. The ultimate goal will be to take simple building blocks such as terminal alkynes and transform them into high-value fluorinated compounds of use in a range of industrial applications.
The student associated with this project will receive training in synthetic and mechanistic aspects of organometallic chemistry, organic synthesis and catalysis. In particular, they will be required to prepare novel transition metal compounds and study their reactivity towards a range of substrates with a view to the development of novel synthetic protocols. One important facet of the work will be to ensure that the ruthenium complexes bind in a highly selective fashion to the alkyne group of the highly functionalised substrate. The student will therefore use DFT calculations to evaluate the relative binding constants to the different functional groups in complex molecules in order to determine which combination of co-ligands at the metal centre will promote most favourable coordination to the alkyne. This will provide additional training opportunities in computational chemistry that will enhance their skill set and employability after graduation.
All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/
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. This PhD project is available to study full-time or part-time (50%).
This PhD will formally start on 1 October 2020. Induction activities will start on 28 September.