The Ironworks: a mechanistic foundry for iron-catalysed cross-coupling

Lead Research Organisation: University of Bristol
Department Name: Chemistry


The formation of carbon-carbon bonds lies at the very heart of the production of the molecules that society depends on. Prime examples include pharmaceuticals, agrochemicals and fine chemicals such as the oleds in the screen that you are probably looking at. There are many ways of producing C-C bonds, but exploiting catalysis hugely increases the sustainability of a given transformation as it reduces the amount of energy required and waste produced as well as the number of individual steps necessary in the production. Indeed catalysis is used in the manufacture of around 90% of all chemicals. Transition metals play a special role in catalysis and the platinum group metals (PGMs) such as platinum, rhodium and, in particular palladium, are ubiquitous in many carbon-carbon bond-forming processes, especially in so called catalytic cross-coupling reactions.

However, like all PGMs, due to its toxicity, palladium is subject to FDA and EAEMP regulatory control, currently to less than 5-10 ppm in pharmaceutical products, reducing its attractiveness in larger-scale manufacture. Furthermore, due to low natural abundance, all PGMs are defined as being at "very high risk" on the British Geographical Society's 2011 Risk List of 52 elements or element groups necessary to maintain our economy and lifestyle ( With ever increasing competition from the automotive and consumer electronics sectors the long-term use of PGMs in catalysis is unsustainable.

Therefore there is a major drive to uncover new catalysts based on Earth abundant metals from the first row transition elements: the low toxicity and high availability of iron (fourth most common element in the Earth's crust) make it the ideal candidate to replace palladium. Thus there has been considerable global effort in the use of iron in carbon-carbon bond-formation studies, however the field is about to hit a major impasse: the simplest iron-catalysed cross-coupling reactions have been realised, while many of the more attractive processes, commonly exploited in palladium catalysis, remain elusive. This is because we have at best only a rudimentary grasp of the mechanisms involved in iron catalysis. These mechanisms are far more challenging to study than those based on palladium. Accordingly we propose to launch a detailed mechanistic study exploiting a wide raft of complementary techniques at four different institutions (Bristol, Cardiff, Bath, Princeton) to uncover the detailed nature of the true active catalysts and their modes of catalytic action. Then we intend to use this unique data to deliver iron-based catalysts for highly desirable yet unmet catalytic processes, building them from the bottom up.

Planned Impact

In the short-to-medium term the primary beneficiaries of this research will be process chemists working in, for instance, pharmaceutical, agrochemical and fine chemicals production. The far lower cost (approximately £96 per tonne for iron ore versus over £12,000 per Kg for palladium), toxicity, and environmental impact of extraction (around 6g of Pd are recovered per tonne of mined material from 'palladium-rich' deposits!) of iron compared with palladium makes the use of iron-catalysed processes immediately more attractive for scale-up.

However a more insidious problem is that the chemical manufacture sector's requirement for palladium is subservient to the far greater and rapidly growing needs of the automotive and consumer electronics sectors ( As the need for PGMs in these sectors grows and the supply dwindles, palladium supply to the chemicals manufacturing sector will be hit hard. Therefore, longer term, the development of iron-based alternatives is imperative and will have a huge impact on the sector.

So far, the discussion addresses the replacement of palladium in existent processes. However there are many steps in materials production that are currently not catalytic. For instance, around 22% of reactions used in the production of pharmaceuticals currently rely on palladium-catalysed process, but there is a major drive to increase this number. Providing a timely replacement for palladium will allow new processes to be developed independently of what can be done currently with palladium. However many workers in the manufacturing sector shy away from iron because of the perceived difficulties in studying its mechanisms. By providing a comprehensive approach to the study of iron catalysed C-C bond-formation we will change people's perception in the manufacturing sector, which will impact directly on their willingness to adopt iron-based methodologies. Furthermore, the training elents and outreach that we propose to undertake during the course of the project will inform and equip a new generation of potential researchers in the key skills necessary for them to rise to and take up the challenge of research in base-metal catalysis in the future.


10 25 50
Description Key Outcomes
The isolation and study of a range of catalytically relevant intermediates in kinetically viable oxidation states; delineation of many of their fundamental reactions and in several cases delineating the likely catalytic cycle. In many cases the results were surprising with counterintuitive pathways established. For instance in the case of the Kumada reaction, it appears that the role of any added co-ligand is not to support the active catalyst, as is widely assumed in the literature, but rather to 'shepherd' any low-coordinate species back into the active catalyst manifold and thus prevent population of alternative, less selective catalytic pathways. While several papers have been published, we are currently several major contributions which will be submitted shortly.

Importantly, we have used our understanding to deliver the first genuine example of a (directed) Suzuki biaryl cross-coupling reaction, a key objective in the proposal, and have undertaken significant mechanistic studies on this reaction. The results of this study have been submitted to Nature Catalysis and the manuscript is currently under revision. Here, we exploited a directing group effect to overcome the very significant challenges associated with C-X bond cleavage and this has paved the way for future studies.

Furthermore we have developed time-resolved X-ray absorption spectroscopy, in collaboration with the EPSRC Catalysis Hub and have used this technique to probe the mechanism of the Negishi reaction. The gave highly surprising results: while a strong ligand effect was observed, the ligand was found to be NOT on the iron centre! Instead it appears as if the primary role of the ligand is to coordinate reversibly to the organozinc reagent in order to facilitate transmetallation via the formation of Fe-Zn intermediates. A phosphine-free analogue of one such proposed intermediate has been isolated and structurally characterised. This highly unusual and unexpected result will shortly be submitted to Nature Catalysis.
Exploitation Route The success we have enjoyed both in the mechanistic studies and the preliminary development of new catalytic processes (specifically Co and Fe-catalysed Suzuki biaryl couplings) means that we are poised to be able to deliver a wide range of iron and other first-row metal-catalysed transformations. Accordingly we will shortly be submitting a funding application to deliver generalised first row metal coupling reactions with soft nucleophiles.
Sectors Agriculture, Food and Drink,Chemicals,Manufacturing, including Industrial Biotechology,Pharmaceuticals and Medical Biotechnology