Synthetic Photochemistry of Carbanion Equivalents

The synthetic photochemistry of many lithiated species is unresearched and undiscovered. Previously in the Clayden group, it was realised that lithiated benzamides may undergo an electrocyclic ring-closing to dearomatize an aromatic ring, giving a conjugated lithium enolate. This enolate then underwent a series of photochemical transformations which gave an overall formation of a cycloheptatriene substrate from a chiral or achiral benzyl benzamide, which is a rather striking transformation considering the use of the simplistic reagents. However, this work was halted since the inefficient tungsten lamps irradiated much unwanted heat, which degraded the sensitive lithiated enolate intermediates. Modern LEDs are much more efficient and affordable and do not produce this unwanted heat radiation. As a result, the group has shown this chemistry can be carried out in good yields and high enantioselectivity (where a chiral centre is present).

Now, we want to interrogate this process, the reactivity of intermediates and the mechanistic pathway for the final product formation. Initially this will involve attempting to measure the UV-spectra of the reactive lithium enolates to identify where they absorb in the electromagnetic spectrum. We then will aim to maximise the light intensity reaching the intermediates as well as optimising the light wavelength emitted onto the mixture. We then have the ability to investigate why our benzamide starting materials are potentially unique in their photochemical transformations, by measuring UV-spectra of related (perhaps achiral or with limited conjugation) amides and observing what wavelength they absorb before attempting to force photochemical transformations of these species by using lamps of specific wavelengths. We hope this can vastly widen the scope for these transformations by allowing the photochemical reaction of a multitude of conjugated systems that differ widely from benzamides.

If similar chemistry cannot be initiated from related starting amides, a possible study on molecular orbitals could be carried out using computational methods or visualisation (such as using virtual reality, VR). Since the photochemical transformations are thought to be pericyclic in nature, the related amides could be examined to identify how their molecular orbitals differ for the required overlap when compared to our known reactions. This computational view could provide interesting data about which photochemical excitations are occurring within the lithiated enolates which allows the photochemical transformations.

We would aim to also investigate the possible mechanisms for these transformations by attempting to trap possible intermediates (such as through a radical-trapping pathway) and attempt to rule out possible pericyclic pathways where possible by isolating key intermediates in the photochemical pathway. This would eventually lead us to utilise our chemistry in application to synthetically challenging pharmaceutical molecules, giving potential (and synthetically simple) application in industry. Considering the wide interest currently forming around photochemistry, this process has the potential to simplify many pathways to larger synthetic rings from simple starting materials in one or two steps.

The novelty of this project arises from the lack of current research on the photochemistry of lithiated benzamides and the potential for facile synthesis of complex structures using just commercial LEDs as the initiator.

This project aims to be a collective mix of synthetic lab-based chemistry with technology incorporations (such as photochemistry, flow and VR). Flow chemistry in particular may provide an efficient approach to obtaining a large amount of final product in a short space of time, assuming temperature control on the flow apparatus can be achieved.

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.

2. ECONOMY: Built on the country's long history of scientific ingenuity and creativity, the >£50bn turnover and annual trade surplus of £5 bn makes the British chemical sector one of the most important creators of wealth for the national economy. Our proposal to integrate training in chemical synthesis with emerging fields such as automation/AI/ML will ensure that the UK maintains this position of economic strength in the face of rapidly developing competition. With the field of drug development desperately looking for innovative new directions, we will disseminate, through our proposed extensive industrial stakeholders, smarter and more efficient ways of designing and implementing molecular synthesis using automation, machine learning and virtual reality interfaces. This will give the UK the chance to take a world-leading position in establishing how molecules may be made more rapidly and economically, how compound libraries may be made broader in scope and accessed more efficiently, and how processes may be optimized more quickly and to a higher standard of resilience. Chemical science underpins an estimated 21% of the economy (>£25bn sales; 6 million people), so these innovations have the potential for far-reaching transformative impact.

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