The ability to prepare novel heterocyclic compounds efficiently is critical to the success of the pharmaceutical, agrochemical, and fine chemical industries. With the growing healthcare burden and the increasing market for single mirror image drugs, it is essential that new ways to access such compounds are found that meet this need. Current methods to prepare even fairly simple multi-substituted, saturated nitrogen-containing ring systems that are of medicinal relevance are often long-winded and complex, particularly for quaternary substituted compounds where more than one substituent is located on the same carbon atom. This project will use simple chemistry with readily available reagents and a diverse selection of easily accessed starting materials to prepare novel substituted heterocycles, including quaternary substituted compounds. The chemistry uses a simple deprotonation, yet this provides a powerful way to provide a range of different products. In addition it allows the ability to control the absolute configuration to prepare heterocycles that are enriched as a single mirror image. The project will be carried out in collaboration with industry to help steer the choice of targets. The aim will be to generate compounds of pharmaceutical interest that will be made available as scaffolds for drug synthesis. In addition, we aim to uncover principles of mechanism and molecular interaction through collaboration by carrying out calculations and spectroscopy. The research is aligned with the EPSRC Dial-a-Molecule grand challenge and with the priority areas of novel and efficient chemical synthesis, sustainable chemistry, and potentially new physical sciences for biology and healthcare. It also fits with the EPSRC strategy to champion excellence in research, training, and impact as described in the Strategic Plan. This project has particular application to the UK fine chemical industry and hence the pharmaceutical industry and will enhance the EPSRC world-leading investment in partnership with industry.

Being used in the catalytic production of more than half of all the commercial chemicals, oxidation is one of the most significant industrial reactions, second only to polymerisation. Not surprisingly, the U.S. Department of Energy identified selective oxidation of organic chemicals to be the most important research area to impact the future chemical industry. However, it remains "one of the reactions with the greatest potential for improvement", primarily because of the low selectivity encountered in the vast majority of oxidation reactions and the widespread use of stoichiometric, toxic and hazardous oxidants, such as CrO3, H2S2O8, PhIO, HNO3. Using catalysts and environmentally benign oxidants is undoubtedly the most realistic way to address these issues. In this regard, developing iron-catalysed aerobic oxidation is most appealing, due to the unrivalled advantage of abundance, low cost and benign nature of Fe and O2. However, although iron-containing metalloenzymes are capable of selectively oxidizing various substrates with O2 under mild conditions, few man-made iron catalysts are known that can catalyse efficient, selective aerobic oxidation. We recently uncovered a novel class of well-defined iron complexes bearing pyridine bisimidazoline (PyBisulidine) ligands, which allow for highly chemoselective oxygenation of ethers and olefins. Building on this success, this project seeks to develop the next generation of more active iron catalysts for selective oxygenation of more challenging substrates. In particular, we will concentrate on two reactions, depolymerisation of lignin and cleavage of aliphatic C=C double bonds, under aerobic conditions. These reactions, which are vastly different in nature and can thus demonstrate the wide scope of the iron catalysts, are of both fundamental and commercial significance. Lignin is the only natural polymers made of aromatic units and could be used to produce a wide range of platform aromatic compounds. However, this requires the depolymerisation of the lignin ether linkage in the first place. Considering the huge scale of any possible processes toward this end, the catalyst to be used should ideally be based on a cheap metal such as iron. Oxidative cleavage of alkenes into carbonyls is a widely used transformation. However, ozone is most often used in industrial operations, and this comes with the well-known safety issues of explosivity, the cost of special equipment, and the large amount of waste generated. Thus, there has been a strong incentive to develop catalytic methods to replace ozone. Iron-based catalysts are particularly interesting, considering not only the environmental benefit of iron but also the ability of iron oxygenases to oxidize olefins to carbonyl compounds with exquisite selectivity. For both of these reactions, few iron catalysts are known that can make use of O2 as oxidant. The Fe-PyBisulidine complexes are expected to bring about a step change in addressing these challenges. The new catalysts will find applications in other reactions as well. The ether linkage is one of the most ubiquitous bonds found in nature and manmade chemicals, ranging from pharmaceuticals and agrochemicals through household products to lignin and coal. Thus, using the new catalysts and O2, compounds containing an ether bond may be transferred into highly value-added products, and polluting plastics, agrochemicals and detergents may be degraded in air. To further demonstrate the value of the iron catalyst, collaboration with a SME to produce, via acylation of arenes, compounds of direct business interest will be implemented.

The use of autonomous robotic technologies is increasingly common for applications such as manufacturing, warehousing, and driverless vehicles. Automated robots have been used in chemistry research, too, but their widespread application is limited by the cost of the technology, and the need to build a bespoke automated version of each instrument that is required. We have developed a different approach by using mobile 'robotic chemists' that can work within a relatively standard laboratory, replicating the dexterous tasks that are carried out by human researchers. These robots can operate autonomously, 24/7, for extended periods, and they can therefore cover a much larger search space that would usually be possible. Also, the robots are driven by artificial intelligence (AI) and can search highly complex multidimensional experimental spaces, offering the potential to find revolutionary new materials. They can also carry out multiple separate experiments in parallel, if needed, to make optimal use of the available hardware in a highly cost-effective way. Our proposal is to establish a globally unique user facility in Liverpool that covers a broad range of materials research problems, allowing the discovery of useful products such as clean solar fuels catalysts, catalysts for plastics recycling, medicinal materials, and energy materials. This facility will allow researchers from both academic teams and from industry to access this new technology, which would otherwise be unavailable to them. Because the automation approach is modular, it will be possible for users to bring along specific equipment for their experiments to be 'dropped in' temporarily to create new workflows, greatly expanding the possible user base. The scope here is very broad because we have recently developed methods that give these robots have very high placement precision (+/- 0.12 mm): to a large extent, if a human can use the instrument, then so can the robot. We have identified, initially, a group of 25 academic users across 12 universities as 'day one' prospective users, as well as 7 industrial organisations with a specific interest in this technology. The potential user base, however, is far broader than this, and we will solicit applications for access throughout the project and beyond. This will be managed by a Strategic Management Team and an Operational Management Team that involves academics as well as permanent technical, administrative, and business development staff in the Materials Innovation Factory in Liverpool. Our overall objective is to build a sustainable AI-driven robotic facility that will provide a unique competitive advantage for the UK to discover new functional materials on a timescale that would be impossible using more conventional research methodology. In addition to focusing on excellent science, we will also consider diversity and career stage when prioritising access; for example, even a short, one-week visit to this autonomous facility might lead to 100's or even 1000's of new materials with associated property measurements, which might radically transform a PhD project or the change the direction of the research programme for an Early Career Researcher. This facility will therefore build the base of the UK research pyramid, as well as supporting activity that is already internationally leading, and our day-one user base includes researchers at all career stages.

We will train a cohort of students at the interface between the physical and computer sciences to drive the critically needed implementation of digital and automated methods in chemistry and materials. Through such training, each student will develop a common language across the areas of automation, AI, synthesis, characterization and modelling, preparing them to become both leader and team player in this evolving and multifaceted research landscape. The lack of skilled individuals is one of the main obstacles to unlocking the potential of digital materials research. This is demonstrated by the enthusiastic response toward this proposal from our industrial partners, who span sectors and sizes: already 35 are involved and we have already received cash support corresponding to over 27 full studentships. This proposal will deliver the EPRSC strategic priority "Physical and Mathematical Sciences Powerhouse" by training in "discovery research in areas of potential high reward, connecting with industry and other partners to accelerate translation in areas such as catalysis, digital chemistry and materials discovery." The CDT training programme is based on a unique physical and intellectual infrastructure at the University of Liverpool. The Materials Innovation Factory (MIF) was established to deliver the vision of digital materials research in partnership with industry: it now co-locates over 100 industrial scientists from more than 15 companies with over 200 academic researchers. Since 2017, academics and industrial researchers from physical sciences, engineering and computer sciences have co-developed the intellectual environment, infrastructure and expertise to train scientists across these areas. To date, more than 40 PhD projects have been co-designed with and sponsored by our core industrial partners in the areas of organic, inorganic, hybrid, composite and formulated materials. Through this process, we have developed bespoke training in data science, AI, robotics, leadership, and computational methods. Now, this activity must be grown scalably and sustainably to match the rapidly increasing demand from our core partners and beyond. This CDT proposal, developed from our previous experience, allows us to significantly extend into new sectors and to a much larger number of partners, including late adopters of digital technologies. In particular, we can now reach SMEs, which currently have limited options to explore digitalization pathways without substantial initial investment. A distinctive and exciting training environment will be built exploiting the diverse background of the students. Peer learning and group activities within a cross-disciplinary team will accelerate the development of a common language. The ability to use a combination of skills from different individuals with distinct domain expertise to solve complex problems will build the teams capable of driving the necessary change in industry and academia. The professional training will reflect the diversity of career opportunities available to this cohort in industry, academia and non-commercial research organizations. Each component will be bespoke for scientists in the domain of materials research (Entrepreneurship, Chemical Supply Chain, Science Policy, Regulatory Framework). External partners of training will bring different and novel perspectives (corporate, SMEs, start-ups, international academics but also charities, local authorities, consultancy firms). Cohort activities span the entire duration of the training, without formal division between "training" and "research" periods, exploiting the physical infrastructure of MIF and its open access area to foster a strong and vital sense of community. We will embed EDI principles in all aspects of the CDT (e.g. recruitment, student well-being, composition of management, supervisory and advisory teams) to make it a pervasive component of the student experience and professional training.