Free radical intermediates play a key role in many chemical and biological processes. Radical detection and quantification is critical for atmospheric and combustion chemistry, reaction mechanisms and kinetics (including catalysis – such as heterogeneous catalysis and a recently developed area of photoredox catalysis), biological chemistry (e.g., monitoring oxidative stress). In medicinal chemistry and pharmaceutical industry, radical chemistry is often used in drug synthesis; radical chemistry is also usually responsible for the degradation of drugs upon storage.
Free radicals are therefore important intermediates and their study is essential for understanding and tuning of many chemical processes. However, they are often very short lived, and cannot be observed directly (particularly in complex real systems). Free radicals are usually detected using spin trapping technique in conjunction with EPR spectroscopy, a method which has been successfully used since 1960s – without any significant recent developments.
We have been working on a novel method for free radical detection, based on radical addition to an alkene possessing a very good radical leaving group in the allylic position. Our preliminary results suggest that the new method offers significant advantages to traditional spin trapping. The new method is very sensitive and provides previously unavailable structural information about the trapped radicals.
In this project, we will use the new method to explore radical reactions in medicinal chemistry. One such area is photoredox catalysis, where organic or inorganic chromophores absorb visible light to initiate free radical reactions, often with exceptional selectivity. These reactions can be used to build new C-C bonds, to activate C-H bonds, for late-stage functionalisation of pharmaceuticals and are being actively adopted by the pharmaceutical industry. An example of a recently-reported photoredox catalysed C-H activation of heterocycles is shown on the inset. These reactions involve radical intermediates which are rarely detected. In this project, we will identify and quantify radical intermediates which will give us unprecedented mechanistic understanding thus enabling rational optimisation of reactions and their scale-up.
Another area of interest is the study of drug stability. The limited lifetime of drugs is usually caused by free radical degradation. While extensive studies of such degradation under harsh conditions (accelerated degradation) are carried out for all new drugs and their formulations, the mechanisms of degradation are rarely studied and the intermediate radicals are not detected. We will use our new traps to obtain quantitative mechanistic understanding of the degradation process (caused by heat treatment and/or UV irradiation) which will provide strategies for improving long-term drug stability.
All research students follow our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills. All research students take the core training package which provides both a grounding in the skills required for their research, and transferable skills to enhance employability opportunities following graduation. Core training is progressive and takes place at appropriate points throughout a student’s higher degree programme, with the majority of training taking place in Year 1. In conjunction with the Core training, students, in consultation with their supervisor(s), select training related to the area of their research.
The project is very interdisciplinary and will involve significant contribution of organic synthesis and spectroscopic characterisation techniques, development of analytical methods (e.g., HPLC with mass spectrometry), kinetic modelling and applications in synthetic and mechanistic chemistry. Training will be provided in all areas, and we expect to establish collaborations with a number of colleagues to facilitate the application of the new technique.
The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/
. This PhD project is available to study full-time or part-time (50%).
This PhD will formally start on 1 October 2019. Induction activities will start on 30 September.