Understanding Mechanism and Selectivity in Oxidative Addition to Nickel(0) for Catalytic Cross Coupling

The use of palladium-catalysed cross-coupling reactions has allowed certain classes of molecules to be constructed in a rapid and efficient manner, by combining two substrate molecules that bear appropriate chemical groups. The impact of this technology was recognised in 2010 by the award of the Nobel Prize in Chemistry to three researchers who were instrumental in the development of this chemistry: Richard Heck, Ei-ichi Negishi, and Akira Suzuki. Nickel is capable of mediating many of the same reactions, and is currently approximately one thousand times cheaper than palladium, but exhibits a somewhat different reactivity profile. Nickel can interact with a wider range of chemical groups, including common carbon-oxygen bonds, and can therefore mediate a wider range of reactions; this then provides challenges in terms of selectivity in functionalised molecules. The current generation of nickel catalysts is typically much less efficient than state-of-the-art palladium catalysts. Larger quantities of nickel are typically required to carry out cross-coupling reactions, and so the spent catalyst and ligand must then be separated from the final products. This has practical implications for the production of pharmaceuticals, for example. For nickel to become a competitive, low-cost alternative to palladium, or for its different reactivity profile to be utilised in industry, the required levels of nickel must be decreased. If this could be done, it would provide industry and academia with a means by which to prepare new molecules and/or a more cost-effective route to current target molecules.

One way by which the efficiency of nickel catalysts might be improved is by altering the groups (ligands) that are attached to the nickel atoms that perform the catalysis. While a number of researchers have investigated this, the typical approach is by 'trial-and-error' in which a range of nickel complexes is prepared with different ligands and each complex is tested in turn. In some cases, catalysts are prepared in the reaction vessel during the reaction itself; the consistent parts, such as a metal salt and a ligand precursor, are combined with the substrates and it is assumed that a certain catalyst complex is formed during the reaction. However, it is often not clear why the performance of complexes differ, as only a single measure is taken at a single time point (conversion and/or isolated yield), and it is not trivial to determine what the chemical structure of the active catalyst is.

The proposed course of research aims to prepare a set of well-defined model complexes, of known structure and purity, determined using state-of-the-art techniques in organometallic chemistry. These compounds will then be used to study a single, isolated step of the overall catalytic cycle known as oxidative addition; this is where the first substrate reacts with the catalyst. This study will comprise a number of components: the products of this single step will be prepared and characterised, giving insight into their structure; the rate at which this step happens will be measured with different reactants, in order to explore how the substrate structure affects the rate of this step; the selectivity for reaction with different chemical groups will be explored, so that it can be understood where on a given molecule reaction will occur; and the overall catalytic activity of the complexes will be explored in industrially-relevant test reactions. Together, these studies will provide a detailed understanding of a key step in nickel catalysis that can be used as the foundation for further studies on the effect of substrate and catalyst structure on reactivity, and in the design of new and more efficient catalytic reactions. In doing so, this will also aid the PI, Dr David Nelson, in establishing a research group at the University of Strathclyde.

The research detailed in this proposal is all directed towards the longer-term goal of developing new and improved methods for the synthesis of molecules. Cross-coupling reactions can be carried out with a number of motifs, rendering the scope of this chemistry broad and exciting. It is the approach that has been selected that makes this proposal unique amongst those seeking support for nickel catalysis, and rare and valuable amongst those in the field of catalysis. Ultimately, new and better ways to synthesise target molecules can render difficult-to-access targets more accessible and uneconomical processes more economical. It is through the development of these processes and the training and development of the researchers who work with and study them that impact can be achieved. Four key impact outcomes have been identified.

People: The training of a postdoctoral research associate (PDRA) is a key component of the research programme; someone with skills and experience in synthetic chemistry and catalysis is required, who will also get the opportunity to acquire new skills and experience in synthesis and mechanistic studies. The continued success of the UK chemical industry hinges inexorably on the availability of a workforce of skilled, creative and driven chemists. The PDRA employed on this research project will gain experience and skills useful in organic and organometallic synthesis, and the rational study of catalytic reactions. Training and development, in the form of this research project, will equip the PDRA well to embark on a productive career in industry or as an independent researcher in academia.

Knowledge: A key long-term goal of David Nelson's research is to render nickel-catalysed cross-coupling reactions a routine option for industrial processes. However, even in the shorter term, access to new processes and more efficient processes can enable new chemistry in industry, or improve existing routes. Catalysis makes an enormous contribution to the UK chemical industry, which in turn is responsible for a sizeable proportion of the UK GDP. The provision of catalytic methodology to industry is arguably the most significant means of generating impact through this research.

Society: In supplying industry with state-of-the-art catalytic processes, this research will facilitate access to a wide range of materials that modern society relies upon. These include advanced organic electronics, pharmaceuticals, and fine chemicals. While this research does not generate this impact directly and immediately, the longer term efforts in this area will contribute to this outcome.
In addition, David Nelson is keen to ensure that the (often taxpayer-funded) research that takes place in his research laboratories is as accessible to the general public as possible. For each peer-reviewed manuscript that is published, a lay summary will be made available to the general public via the research group website. This will generate impact through engagement of the general public, and potentially media outlets (including specialist publications/blogs), especially if significant breakthroughs are made.

Economy: The desire within industry and academia for new and more active catalysts renders the commercialisation of new species potentially very lucrative. There is the potential to generate significant impact through the commercialisation of promising new nickel complexes; not only does this provide a potential source of income to contribute towards the funding of future research, but it improves the accessibility and availability of these complexes.