Catalytic generation and harnessing of reactive intermediates

Reactive chemical intermediates are short-lived and high-energy molecules. Whilst it is inherently demanding to exploit the high levels of reactivity of these species, the potential benefits are compelling. Great opportunities are afforded to conduct powerful new chemical and biological processes, with applications in medicine and materials development amongst others. The goal of this proposal is to provide new methods to harness reactive intermediates and hence facilitate reactions of immense utility.

We will focus on intermediates called arynes; molecules in which one of the three carbon-carbon (C-C) double bonds in a benzene ring has been replaced with a C-C triple bond. Incorporating this triple bond causes the ring to become highly strained and thus highly reactive. Arynes are extremely useful as they enable rapid generation of complex benzene ring-containing products that are common in pharmaceuticals, agrochemicals, materials and dyes.

Despite recent advances, methods for an ideal scenario whereby arynes are prepared using a catalyst - a small amount of a substance that promotes a reaction but is not consumed and can thus be recycled - are extremely rare and no general procedure exists. As a result, our long term goal will be to develop a general strategy for catalytic aryne synthesis that also exploits abundant chemicals. There are myriad potential benefits, from the development of new chemical reactions for application in healthcare and manufacturing, to the environmental issues of reduced waste production and the use of more plentiful starting materials.

One example of a cheap bulk chemical for this process is phenol (a benzene ring with an oxygen atom attached), with 60,000 commercially available analogues also offering great potential for structural diversification. By attaching an activating group to the oxygen, we will investigate strategies that enable the proximal addition of a catalyst onto the benzene ring. This catalyst can then interact with the adjacent activating group to aid elimination of the two species from the ring, producing an aryne. The catalyst will then be free to add to another activated phenol ring and thus the cycle is established.

We will also look to subsequently exploit the reactivity of arynes in demanding reactions, such as manipulating the ubiquitous carbon-hydrogen (C-H) bond. Breaking a particular C-H bond and replacing that hydrogen with another atom is extremely desirable, as it means valuable compounds can be made directly from cheap hydrocarbon materials. However, this process is very difficult due to the strength of the C-H bond and most progress has been made using metal catalysts that can be expensive and toxic. Here we will utilise the high reactivity of arynes to develop new complementary metal-free methods for selective C-H bond breaking, involving an initial hydrogen ion transfer from the hydrocarbon compound onto the aryne. This novel process results in two oppositely charged molecules, and we propose that via the recombination of these charges, a new C-C bond will be made. Studies into hydrogen ion transfer onto an aryne will commence with systems where the two components are in the same molecule, tied together in close proximity to aid the reaction. As our understanding increases, we will see whether they can be part of different molecules, which is anticipated to be more challenging. Crucially, we have a preliminary result to support this unique concept.

This research area has been chosen because arynes enable rapid construction of useful complex molecules. Developing these new methods will enable chemists to make drug, polymer, dye and agrochemical compounds more efficiently, and maybe even prepare molecules that are currently inaccessible. These advances can benefit wider society through the development of drugs to treat illnesses, herbicides and pesticides to improve global food production and by harnessing more sustainable chemical feedstocks.

Within academia the research described in this proposal will be of fundamental utility to synthetic chemists. These new processes will provide enabling methods for the construction of highly functionalised aromatic and heteroaromatic rings, which are not only central to organic synthesis, but are also key fragments within medicinal agents, polymer materials and natural products. It follows that related disciplines such as medicinal, materials and biological chemistry will be interested in elements of the research. The more mechanistic aspects of the work centre on transition metal catalysis and hydride transfer, which are likely to interest organometallic and computational chemists respectively. Through the engagement of academics in these allied areas, new catalyst systems and applications beyond the scope of this specific research programme will be developed.

Away from academia, the main impact of this research will be realised in the pharmaceutical, agrochemical and fine chemicals sectors. The new routes to heterocycles and functionalised aromatic systems proposed here should enable more efficient access to these important fragments for drug design and the probing of biological systems. Benefits to the manufacturing sector are envisaged due to the catalytic and C-H arylation processes that should allow cheaper and more sustainable hydrocarbon feedstocks to be exploited. Metal-free C-H arylation processes will also be particularly attractive to the industrial sector as a result of reduced costs and toxicity. In addition to the intellectual and economic gains to UK academia and industry, it follows that these benefits will eventually impact upon the health and wellbeing of society in general. For example, applications in the agrochemical arena have potential to impact upon national and global food production, as the development of new herbicides and pesticides should augment current crop output.

Close consultation with industry will ensure that specific synthetic requirements are addressed and will also enable the chemistry to be tailored to areas that are considered to be of fundamental importance to an intended end-user. The applicant has a number of existing links to industry, such as Syngenta, and will look to build upon these whilst also establishing new partnerships. Dissemination of results will occur predominantly through peer-reviewed publication in high quality journals, whilst attendance at conferences with a significant industrial presence, as well as existing links between QMUL and partner institutions, will aid the founding of collaborations. Commercially viable results will be exploited through the QMUL Business Support Office and QM Innovation.

Another important aspect of the fellowship relates to my development as an academic and a leader. Realisation of my personal objectives will result in the foundations of an internationally recognised research profile that presents further high-impacting research avenues on projects outside of this proposal. To this end I have significant experience in the identification and development of research programmes in the areas of catalysis and organic synthesis. It is also my aim to provide a rigorous and stimulating environment in which co-workers (PDRA, Ph.D., Master's students) will be trained as highly skilled scientists, thus impacting upon the futures of UK academia and chemical industry. Furthermore, the students will learn key skills such as critical-thinking and time management that will be directly transferable to non-academic professions. Elsewhere, engagement in public outreach activities offers an invaluable opportunity to impact upon the public perception and understanding of science, as well as encouraging interest amongst young people. To this end the applicant has received media training and created podcasts for the Oxford chemistry website and has experience of coordinating a number of departmental public open days.