Pharmaceuticals, fine chemicals, and agrochemicals are produced industrially using a wide range of chemical reactions. These processes need to become more efficient, less expensive, and more sustainable. The Pieber group at the Institute of Science and Technology Austria (ISTA) has now taken a step in this direction. In Nature Catalysis , researchers present today a new nickel catalyst that can be activated with visible light to efficiently make a broad array of chemical bonds.
Behind a glass wall in the Pieber Lab at the Institute of Science and Technology Austria (ISTA) , blue LED lamps shine light onto small reaction vessels. The light is not simply illumination: it supplies the energy that fuels a nickel catalyst to drive chemical reactions.
In a new study published in Nature Catalysis , the research group led by Bartholomäus Pieber shows that a carefully designed nickel catalyst can make light-driven chemical synthesis both more versatile and more efficient.
Pieber and his team members Aleksander Bena, Trisha Banik, Christos Giannoudis, Florian Ortis, Haralds Baunis, and Gayathri Palissery (all ISTA), in collaboration with Daniel Bím of the University of Chemistry and Technology in Prague, developed a new catalytic system that selectively and efficiently joins chemical building blocks using very small amounts of nickel.
Turning on nickel with light
Drugs don’t grow on trees—they are produced through multistep chemical processes. This requires a wide range of different reactions. One of the most widely used strategies for building these molecules is cross-coupling chemistry, in which two molecular building blocks are joined by a new chemical bond with the help of a metal catalyst.
A catalyst is a substance that enables or speeds up a chemical reaction without being consumed itself. Often, they are single metal atoms connected to organic molecules called ligands. These influence how the metal behaves and can be designed to fine-tune its catalytic properties.
In many important cross-coupling reactions, the catalyst is based on a palladium atom. The importance of this was recognized with the 2010 Nobel Prize in Chemistry awarded to Richard Heck, Ei-ichi Negishi, and Akira Suzuki for their development of palladium-catalyzed cross-coupling reactions in organic synthesis. These reactions have become influential for making complex molecules, including pharmaceuticals. Palladium catalysts are highly efficient, but the noble metal is also scarce and expensive, which is a significant drawback.
About 10 years ago, the first studies showed that the combination of a nickel catalyst with a second catalyst that converts visible light into “chemical energy” could be used instead of palladium. This has the potential to make these reactions cheaper and more sustainable. But there is a catch: nickel catalysts are less efficient and do not enable the same breadth of reactions as palladium catalysts.
“In our lab, we try to understand why contemporary nickel catalysis systems have limitations, and based on that understanding, we design, make, and study alternative candidates and methods,” Pieber explains.
The group took an important step in 2020 by demonstrating that the limitations of nickel catalysis can be addressed. The researchers found that nickel catalysts can be destroyed when using challenging building blocks and showed that this can be avoided by carefully controlling the reaction conditions. The approach worked, but the reactions were very slow and required high amounts of nickel catalysts.
“Of course, that was still far from an efficient method,” Pieber says. “But it was an important proof-of-concept, and over the past few years, our understanding of these catalytic reactions has continued to improve.”
Bena, a PhD student, used this growing understanding to design possible structures for more efficient, robust nickel catalysts that can be directly activated with visible light and tested his ideas in the lab. This ultimately led the team to a new ligand that helps nickel overcome some of the remaining limitations of light-driven catalysis.
“I like the challenge of solving a chemical puzzle. You develop an idea, test it experimentally, and learn something from each result,” Bena says. His persistence ultimately led to a new catalyst system that is broadly applicable and requires substantially less nickel.
A small task force formed within the Pieber group—consisting of Banik, Giannoudis, Ortis, Baunis, and Palissery—to study the general applicability of the new catalyst. The team demonstrated the versatility of their method by making more than 150 products, ranging from simple building blocks to complex molecules and derivatives of drugs such as fluoxetine, one of the most common and widely prescribed antidepressants.
A little nickel goes a long way
The breakthrough is based on a tailor-made ligand that boosts the catalytic activity of the nickel atom upon initiation with visible light. This enables the new catalyst to make bonds between carbon, nitrogen, oxygen, sulfur or phosphorus atoms thereby fusing two molecules into a bigger and more complex structure.
“The most striking result was that we can make challenging bonds efficiently with a very small amount of the nickel catalyst,” says Bena.
The researchers were able to reduce the catalyst loading to 100 parts per million, or 0.01 mol%. Put simply, this means that in this experiment only one nickel catalyst molecule produces up to 10,000 molecules of product.
Their work therefore demonstrates how understanding the fundamental reactivity of nickel-based molecules can help turn an abundant metal into a more powerful catalyst.
“These low catalyst loadings are typically only achieved with catalysts based on palladium. Being able to do this with a nickel catalyst is really exciting.” Pieber explains. “The combination of low catalyst loading and high generality across many building blocks could make the approach particularly interesting for pharmaceutical and fine-chemical synthesis.”
Nature Catalysis
Experimental study
Not applicable
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