Nickel Catalysis

Nickel often has quite different reactivity to palladium (Figure 1). Nickel will react with a wide range of electrophiles, enlarging the scope of possible substrates and introducing opportunities for orthogonal synthesis; it is less prone to undergo B-hydride elimination, allowing the use of alkyl coupling partners. Despite the opportunities promised by this enhanced reactivity, the toxicity of nickel and the familiarity of robust palladium-catalysed methods can hamper the uptake of nickel catalysis in the pharmaceutical industry. The FDA limit for nickel in pharmaceuticals is slightly higher than for palladium (20 ppm versus 10 ppm), despite the slightly higher oral toxicity of nickel. The recycling of palladium can be cost-effective, whereas nickel is too cheap to warrant recycling. The promise of nickel catalysis lies in new reactions and/or new feedstocks, rather than as a direct competitor to palladium; the detailed understanding of mechanism, selectivity, and structure/activity relationships is essential to achieving these aims.

Various aryl electrophiles have been used in cross-coupling (including many phenol derivatives), but alkyl alcohol derivatives are underexplored. Chlorides, bromides, and tosylates have been used but can also be employed in palladium catalysis (with specific ligands); for other alcohol derivatives, most examples are limited to reactions at a benzylic site, while many conditions do not lead to reaction with functional groups such as pivalate. This project will quantify the reactivity of Ni0 with these underexploited substrates, generating information about fundamental reactivity that will lead to new catalytic reactions. In addition, the practical aspects of removing nickel from the product will be considered using robust analytical methods.

Nickel catalysis can enable the cross-coupling of sp3-centres to build the drug molecules of the future, moving away from flat and aromatic systems. However, our mechanistic understanding of these processes is incomplete, and there are concerns about the toxicological implications of nickel. This project will address the challenges of deploying exciting nickel-catalysed procedures in the synthesis of pharmaceuticals by: (i) conducting detailed kinetic studies of the oxidative addition of alkyl halides to Ni0, (ii) studying deleterious B-hydride elimination processes, and (iii) quantifying the levels of nickel present in reaction mixtures after workup and purification.We elucidated - using techniques such as EPR spectroscopy - that all of these reactions lead to NiI products; we proposed a mechanism for the formation of NiI from Ni0 based on mechanistic and kinetic studies, including low temperature NMR spectroscopy. The next stage of our research programme is to quantify the reactivity of other ligands and other substrates, because this works towards a 'users guide' to catalyst selection for different applications based on rate data, decreasing the need for the screening of large numbers of reaction conditions.