Chemists still rely on rare, expensive metals like platinum and palladium to split apart the H2 molecule. In contrast, hydrogenases use cheap, abundant iron or nickel as their catalytic sites while achieving rates that rival precious metals. Platinum is the catalyst of choice for splitting H2 to generate electricity in fuel cells, while palladium is often the go-to metal in chemical manufacturing for adding hydrogen atoms across a double bond in unsaturated organic molecules. |
In this study published in Nature Communications, we show how a hydrogenase enzyme can replace nanoparticles of palladium to open up a new era of precision catalysis for chemical manufacturing under mild, environmentally-friendly conditions.
This piece of research started in a moment of curiosity: how could we exploit hydrogenase in new ways? We had already shown that hydrogenases and H2 could be used for cleaner recycling of biological cofactors, which are helper molecules needed in biotechnology for chemical manufacturing. Now, we started to wonder whether we could exploit hydrogenases for reactions that go beyond their native roles in biology. |
Jack Rowbotham, a postdoctoral researcher in my group at the time, set about screening dozens of reactions in tiny flasks to see if we could find interesting hits. There was great excitement in the group when Jack brought back an NMR spectrum which indicated that one of the starting molecules he had screened, a nitro-containing chemical, had been transformed in the presence of hydrogenase and H2. The reduction of nitro groups is crucial in the manufacturing of so many pharmaceuticals that we were aware immediately that this might be significant.
Jack was working with two other postdoctoral researchers, Sarah Cleary and Tim Sudmeier, on a biotechnology project led by Holly Reeve and myself. They set about following up this finding. Soon after, Jack confirmed that putting hydrogenase onto a carbon-based support gave a wonderful catalyst for reducing nitro groups all the way to important amine compounds.
Had we hit upon a new method for amine synthesis? Researchers are always looking for new ways to synthesise amines more cleanly because amines are so ubiquitous across the chemical industries: from pharmaceutical molecules and agricultural chemicals to other building blocks for chemical manufacturing. Tim and Sarah oversaw a Masters project carried out by Georgia Stonadge to see whether the reactivity we had observed worked on a wider range of nitro-containing molecules – and it did!
Tim and postgraduate student Tara Lurshay then brought in electrochemical analysis. ‘Electrochemistry helped to explain the mechanism,’ Tim comments, ‘showing how we could use electrochemical reduction potentials to predict why aromatic, but not aliphatic, nitro compounds could be reduced by this catalyst.’ ‘Using electrochemistry to understand our redox-type catalyst led us to predict that we might be able to extend to aliphatic (hydrocarbon chain) nitro compounds if we switched to a different hydrogenase,’ Tara says, ‘and it was exciting to find that we were correct.’ |
By now the project that Holly and I had been leading was drawing to a successful end, with Holly and Sarah moving to C-suite roles in the biotech spin-out company HydRegen and Jack moving on to a Fellowship at the University of Manchester. Our preliminary findings were, however, too promising to abandon.
Daria Sokolova joined my group as a postdoctoral researcher at this point, and brought her synthetic organic chemistry background to further develop our hydrogenase-on-carbon catalyst. She demonstrated that the reaction worked on a wide range of aromatic nitro compounds. |
Daria also showed that the carbon support is critical in allowing accumulation of electrons for the 6-electron reduction of the nitro group right through to the amine functional group, and that the reaction proceeds via an initial 4-electron reduction to a hydroxylamine intermediate.
'We were really pleased to find that functional groups like halides, which are easily lost from nitro-compounds during reduction by a palladium-on-carbon catalyst, were fully retained using the hydrogenase on carbon catalyst', says Daria. 'We were encouraged to find that the catalyst could be recovered by a simple filtration and re-used many times, and that, incredibly, over the course of this experiment, a single hydrogenase molecule acts on more than 1.5 million molecules of nitro-containing substrate.' |
We quickly spoke to technology transfer experts at Oxford University Innovation, who helped us to file a patent application, and simultaneously we wrote up the work for publication.
Developing this catalyst has been a long journey, with many important contributions from different researchers along the way. Like all research, our study takes inspiration from earlier work, and I remain indebted to my own postdoctoral advisor Fraser Armstrong for passing on his enthusiasm for hydrogenases and his insight into how to ‘harvest’ electrons from enzyme reactions.
Hydrogenases remain intriguing, inspirational enzymes, and I’m quite sure we will find many more ways to exploit and learn from these fascinating biocatalysts in the future.
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