Cheap and sustainable cross-coupling photocatalyst

Organic chemists are continually seeking improvements to C-C coupling reactions, owing to the fundamental nature of the carbon-carbon bond within chemistry. Specifically, coupling reactions between a carbon atom with a double bond [C(sp²)] and single bonds [C(sp³)] have become increasingly important, as this bond type is prevalent in pharmaceutical products, amongst others.

To create these C(sp²)-C(sp³) bonds photocatalytically, one can use a combination of an iridium catalyst, a nickel catalyst, and blue light, which works perfectly well. ‘But iridium is five times more expensive than platinum or palladium, and legitimate questions can be raised about its mining and refining when it comes to environmental and ethical concerns’, says Benjamin Martin, Continuous Manufacturing Network Leader at Novartis. To address these concerns, Martin and colleagues at Novartis collaborated with the research group of Timothy Noël at the University of Amsterdam to investigate a relatively overlooked photocatalyst that could replace iridium: graphitic carbon nitride (gCN).

Greener chemistry

The collaboration between them began in 2022, Martin recalls. ‘In Europe, there are not many people of Tim’s calibre working in photocatalysis who also have a deep understanding of the underlying chemical engineering aspects.’ Previously, Noël had completed a postdoc at MIT, where Novartis sponsored a ten-year programme to investigate flow chemistry. ‘That is how I came to know his name.’ Like many companies, Novartis is increasingly gravitating towards greener chemistry, in which catalysis plays a significant role. ‘Photocatalysis can be a particularly mild method, because it allows you to explore single-electron catalysis in an accessible way’, Martin explains. ‘That is something we as a company wish to apply to chemical development and, ultimately, to manufacturing as well.’

Because a large, focused company such as Novartis cannot simply conduct large-scale, fundamental trial-and-error research into a new methodology, Martin sought out an academic partner. ‘We came across the idea of working with graphitic carbon nitride in the literature’, says Martin. ‘It struck me as rather ambitious, but if it were to work, we could use it to pursue powerful chemistry in a sustainable manner. Tim had already published other work on graphitic nitrides, so it was a perfect marriage between one partner with the need and one partner with the right research capacity.’

Abundance

The researchers began by searching for the optimal conditions for coupling an aryl halide and an aliphatic carboxylic acid using gCN and nickel catalysts. The team had to prevent the formation of esters through competing C-O bonds — the natural result of incomplete loss of carbon dioxide during the desired reaction. ‘Although it all appears to proceed smoothly in the publication, it was not a straightforward start’, says Martin. ‘There were three or four months during which little progress was made, until the team finally achieved a breakthrough, enabling them to investigate a whole range of substrates. It opened up an abundance of possibilities.’

‘The exciting thing is that we can implement Tim’s methodology directly into our own projects’, Martin continues. ‘We are already conducting photochemistry on a large scale, and these new techniques will certainly be applicable there, though it will naturally take some time before they reach the manufacturing stage.’

The researchers also examined the environmental impact of this new methodology. Martin: ‘At Novartis, we assess green chemistry on the basis of total carbon dioxide emissions — we call that TCR. Some ideas initially sound green but turn out not to be. That is why we wanted to quantify the impact of our new gCN method and compare it with the previous iridium method.’

In terms of solvents and reagents, the TCRs are very comparable, but when you consider the impact of the photocatalyst, it is 491 kgCO₂eq/kg for iridium and just 1 kgCO₂eq/kg for gCN. ‘In doing so, we halve the total footprint simply by replacing the catalyst. These are therefore not empty words, but real, quantifiable improvements. All of these findings strongly encourage us to continue our collaboration with the Noël group.’

Lukas, F. et al. (2024) Ang. Chem. Int. Ed. e202405902, DOI: 10.1002/anie.202405902