Sustainable Electron-Transfer Processes for the Synthesis and Functionalization of Nitrogen-Containing Compounds

Organic chemistry occupies a central position within the chemical sciences because through its development it grants access to new molecular systems and materials that are vital to the advancement of other sciences and ultimately the wellbeing of society. The ability to create carbon-nitrogen bonds is one of the most important goals in organic synthesis as nitrogen-containing compounds are widespread as therapeutic agents, agrochemicals, organic dyes and materials: as an example, the 20 top-selling drugs all contain C-N bonds.

From this perspective, it is now becoming increasingly important not just to be able to create new and complex molecules but also to identify novel methods that can access them in a more efficient, selective and sustainable way. In fact, factors such as cost, toxicity and waste production in chemical synthesis urgently needs to be addressed. The United Nations General Assembly 68th Session has proclaimed 2015 as the International Year of Light and Light-based Technologies. A key conclusion of this assembly was the recognition about "the importance of raising global awareness about how light-based technologies promote sustainable development and provide solutions to global challenges in energy, education, agriculture and health". The overarching aim of my Fellowship is to address this crucial problem by developing fundamentally new catalytic methods that enable the construction of C-N bonds harnessing visible-light as the source of energy. In this way we will provide unique reactions that will streamline the synthesis of N-containing molecules by enabling easy access to N-radicals.

The project is divided in 4 different but complementary parts aimed at addressing specific challenges relevant to the formation of C-N bonds with applications in chemical synthesis, biology and materials.

1. We will use visible-light to enable novel electron transfer reactions that will generate aminyl and amidyl radicals. Here we will develop divergent methods for the addition of N and H, as well as N and O atoms across alkenes to form cyclic amines and amides. Then, we will use these activation modes for the generation of a broad series of poly functionalised molecules like diamines, amino (di)alcohol, aminothiols, diamino alcohols and thio-aminoalcohols with defined 3D shapes.

2. These visible-light-mediated transformations will be expanded by developing multicomponent reactions. Here we will develop processes where various reaction partners will sequentially react around the key electron transfer manifold to deliver polyfunctionalised N-compounds. Thus we will provide innovative manifolds that will combine high atom-, step-, and time-economy with great possibilities for molecular diversification

3. The development of catalytic protocols that facilitate the formation of stereo defined C-N bonds is of great importance, especially in a therapeutic context in which 3D molecules are acknowledged to have a higher chance of clinical success. We propose to develop a novel strategy based on the use of chiral catalysts to use nitrogen-radicals in asymmetric synthesis. There is no method for carrying out the kind of transformation which is proposed.

4. The controlled functionalization of non-activated C-H bonds is one of the most challenging tasks in current organic chemistry but has the potential to streamline the synthesis of many compounds. Here, we will develop remote functionalizations of unactivated C-H bonds by harnessing the ability of nitrogen-centered radicals to undergo C-H abstraction reactions.

The successful implementation of this research program will deliver novel and sustainable methods that can make the synthesis of nitrogen-containing compounds quicker, greener and more efficient. The development of methods that facilitate the identification as well as the preparation of small molecule drugs, biological probes, agrochemicals and materials will impact the health and wellbeing UK society.

The selective formation of carbon-nitrogen bonds is one of the most important goals in organic chemistry as nitrogen-containing compounds from the structural basis of many pharmaceuticals, agrochemicals, organic dyes and industrial materials. This can be realised by the fact that all of the 20 top selling drugs and agrochemicals contain C-N bonds. As such, this project is expected to generate six types of impact:

(1) Industry Impact: The research described here will impact the pharmaceutical, agrochemical and fine chemical industrial sectors in the UK (and beyond). We will develop innovative activation and reactivity modes for the easy synthesis of many nitrogen-containing molecules that are critical to the development of new drugs, biological probes, agrochemicals and organic materials. The industrial requirements will be addressed by establishing collaborations with industrialists as well as attending workshops. This will ensure that we tackle production-relevant chemical problems and that we orient and tailor our research towards areas which are of great importance to industrial end-users.

(2) Society Impact: The development of methods to form C-N bonds in a faster, easier and more sustainable way will facilitate the identification of more potent therapeutic agents as well as innovative probes for biological studies and herbicides/pesticides thus impacting the health and wellbeing of the society as well as global food production.

(3) Economic Impact: this impact will be generated by taking a proactive approach to IP by closely working with the University of Manchester Intellectual Property Ltd (the University's dedicated business support Department).

(4) People Impact: The high-quality training of the co-workers associated to this project will results in the formation of highly skilled chemists that will embark in high-profile independent academic or industrial position at the end of their contract. I will have a proactive role in nurturing their scientific thinking, good lab practice and communication skills.

(5) Public Impact: This impact will be fostered using the various outreach programs available at the University of Manchester. In this way we will make the public aware of the role and importance of synthetic chemistry in addressing social needs. Face-to-face involvement in schools will be used to provide high quality communication of science to pupils and to encourage their choice of a scientific career.

(6) Academic Impact: This impact will be realised through publication of the results in high-profile journals and communication at national and international conferences to foster collaborations and exchange research ideas.

As carbon-nitrogen bond forming processes are indispensable tools for scientist in all industries in the UK (as well as worldwide), the innovative research programme that I have delineated here is aligned with the needs of UK industry and academia and the EPSRC portfolio (Physical Sciences: "Dial-A-Molecule" Physical Science Grand Chellenge, Catalysis, Chemical Reactions Dynamics and Mechanism, Chemical Biology and Biological Chemistry. Healthcare Technologies: Diagnostics). In particular this Fellowship focuses on two of the three themes identified in the "Dial-A-molecule" Roadmap: "A step change in Molecular Synthesis" and "Catalytic Paradigms for 100% Efficient Synthesis". In fact, our work will target the development of innovative and powerful reactions that are require visible-light as the source of energy thus targeting the themes' general goals of developing "sustainable synthesis for a sustainable future" using "robust reactions that can be relied upon in a wide area of chemical space" and that provide a "step-change in efficiency". The relevance of this project is further demonstrated by the fact that The United Nations General Assembly 68th Session has proclaimed 2015 as the International Year of Light and Light-based Technologies.