Going Soft with Iron: Sustainable Catalysis in Organoboronic Ester Chemistry

Homogeneous iron catalysis holds a great deal of promise to replace environmentally and economically deleterious palladium-catalysed processes, which are routinely used in the development of pharmaceuticals, agrochemicals and numerous other industrial processes. Iron is over 3,000,000 times more abundant in the Earth's crust than palladium, and many iron species have much lower toxicity than their palladium counterparts, presenting iron as a cheaper and often safer alternative as the chemical industry strives towards a greener future.

Despite its numerous advantages, the use of iron in homogeneous catalysis is not routine, owing largely to it's unpredictable reactivity and the specificity in conditions required to perform a particular transformation. As a result, the 'chemist's toolkit' is lacking in robust iron-catalysed transformations that can replicate reactivity seen in other metals, such as palladium and even other Earth-abundant metals including nickel and copper. One such area that is currently underdeveloped is iron-catalysed borylation, particularly the generation of organoboronic esters from sp2 substrates. This can be achieved through numerous methods, including C-H and C-X borylation (X = halide, pseudohalide).

The initial phase of the project will focus on the development of an improved system for iron-catalysed borylation of aryl halides, an attractive prospect which has thus far been limited to 'activated' substrates only, with poor yields demonstrated for simpler systems. The experimental work will begin in the laboratory with optimisation of the reaction conditions, progressing to automated library synthesis and kinetic analysis. Supporting the synthetic work, computational investigations will provide insight into reaction mechanism. Beyond the aforementioned C-X borylation reaction, the project is likely to progress to other iron-catalysed reactions, including alternative methods for the synthesis of organoboron species and their subsequent application (e.g. in Suzuki-Miyaura cross-couplings).

1. PEOPLE: We will train students with skills that are in demand across a spectrum of industries from pharma/biotech to materials, as well as in academia, law and publishing. The enhanced experience they receive - through interactive brainstorming, problem and dragons' den type business sessions - will equip them with confidence in their own abilities and fast-track their leadership skills. 100% Employment of students from the previous CDT in Chemical Synthesis is indicative of the high demand for the skills we provide, but as start-ups and SMEs become increasingly important in the healthcare, medicine and energy sectors, training in IP, entrepreneurship and commercialisation will stimulate our students to explore their own ventures. Automation and machine learning are set to transform the workplace in the next 20 years, and our students will be in the vanguard of those primed to make best use of these shifts in work patterns. Our graduates will have an open and entrepreneurial mindset, willing to seek solution to problems that cross disciplines and require non-traditional approaches to scientific challenges.

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3. SCIENCE: The science emerging from our CDT will continue to be at the highest academic level by international standards, as judged by an outstanding publication record. Incorporating automation, machine learning, and virtual reality into the standard toolkit of chemical synthesis would initiate a fundamental change in the way molecules are made. Automated methods for making limited classes of molecules (eg peptides) have transformed related biological fields, and extending those techniques to allow a wide range of small molecules to be synthesized will stimulate not only chemistry but also related pivotal fields in the bio- and materials sciences. Synthesis of the molecular starting points is often the rate-limiting step in innovation. Removing this hurdle will allow selection of molecules according to optimal function, not ease of synthesis, and will accelerate scientific progress in many sectors.

4. SOCIETY: Health benefits will emerge from the ability of both academia and the pharmaceutical industry to generate drug targets more rapidly and innovatively. Optimisation of processes opens the way for advances in energy efficiency and resource utilization by avoiding non-renewable, environmentally damaging, or economically volatile feedstocks. The societal impact of automation will extend more widely to the freeing of time to allow more creative working and also recreational pastimes. We thus aim to be among the pioneers in a new automation-led working model, and our students will be trained to think through the broader consequences of automation for society as a whole