It is difficult to find a place on Earth untouched by the palate. The silvery-white metal is a key part of the catalytic converters of the world’s 1.4 billion cars, which carry palladium stains into the atmosphere. Mining and other sources add to this pollution. As a result, traces of palladium are shown in some of the most remote places on Earth, from Antarctica to the top of the Greenland ice sheet.
Palladium is also practically indispensable for the manufacture of drugs. This is because catalysts with palladium atoms in their nucleus have unmatched capacity to help bind carbon-carbon bonds. This type of chemical reaction is key to building organic molecules, especially those used in drugs. “Every pharmaceutical product we produce at one time or another has a palladium-catalyzed step,” says Per-Ola Norrby, a pharmaceutical researcher at pharmaceutical giant AstraZeneca in Gothenburg, Sweden. Palladium-catalyzed reactions are so valuable that in 2010 their discoverers shared a Nobel Prize.
But despite its versatility, chemists are trying to get away from the palladium. Metal is more expensive than gold, and palladium-containing molecules can also be extremely toxic to humans and wildlife. Chemical manufacturers must separate all traces of palladium from their products and carefully dispose of hazardous waste, which is an additional expense.
Thomas Fuchß, a medical chemist at Merck Life Sciences in Darmstadt, Germany, gives the example of a reaction to make 3 kilos of a drug molecule for which the ingredients cost US $ 250,000. Palladium catalyst alone adds $ 100,000; purifying it of the product another $ 30,000.
Finding less toxic alternatives to the metal could help reduce the environmental damage from palladium waste and move the chemical industry toward “greener” reactions, says Tianning Diao, an organometallic chemist at New York University. Researchers hope to change the palladium for more common metals, such as iron and nickel, or invent metal-free catalysts that avoid the problem altogether.
Several times over the past two decades, researchers have reported finding palladium-free catalysts. But in what has become a recurring pattern for the field, every announced discovery turned out to be a mistake.
Then, last year, came an exciting result. An impressive report from January 2021 seemed to put the palladium-free dream within reach1. Researchers in China reported that a “carbon-coupling” reaction, one of the most common carbon-bonding reactions in the pharmaceutical industry, could be catalyzed without palladium or any other metal. If the findings were confirmed, the reaction would change everything we know about how carbon bonds are formed, Norrby says.
The chemists were instantly moved and skeptical. Researchers around the world tried to verify the extraordinary claims in their own laboratories. In two months, three teams published preprints (working papers before the peer review) arguing that palladium contamination was catalyzing the coupling reaction.
These critics would be right (see ‘Carbon Coupling’). The discovery that it was not and the questions about how the mistake was made have dominated the discussion in some circles of analytical and pharmaceutical chemistry. The saga serves as a warning story about how incredibly difficult it is for chemists to keep their reactions and laboratories free of palladium contamination.
Source: Adaptation of the refs. 1 and 7
Warning tales
British chemist Nicholas Leadbeater says that when he saw the new claims, the first thought that crossed his mind was, “Here we go again.” In 2003, Leadbeater followed a palladium-free path to carbon-coupling reactions at King’s College London. His team was trying to catalyze common reactions with a combination of copper compounds and microwave heating. But when they did a metal-free control experiment, the reactions still worked. Understanding this remarkable feat, Leadbeater and his colleagues worked hard to make sure that no palate had slipped into the reaction without being noticed.
The roles of the team were received with great acclaim; Leadbeater was confident that discovery would be the focus of his career. He then moved his research group from the University of Connecticut to Storrs, and it all broke down. “We couldn’t make it work no matter what we tried,” he says.
After months of detective work, Leadbeater found the culprit. A common reagent purchased from a UK chemical supplier had been contaminated with tiny traces of palladium, about 50 parts per billion (ppb), that were not in the same product purchased in the United States. “That was enough to catalyze the reaction,” he says. Leadbeater never retracted his original roles. Instead, the team published an analysis2 that showed that the reaction without metals could produce a small amount of its desired molecule, but that palladium contamination was ultimately responsible for the results reported above.
The same problem arose in 2008, when an article by Robert Franzén at Tampere University of Technology in Finland and his colleagues reported an iron-catalyzed version of another carbon-coupling reaction. A research team led by Robin Bedford at the University of Bristol, UK, found that palladium contaminants were responsible and published a “warning story” about the risks of false positives3. The document of the Finnish team was withdrawn. Norrby says that even his team’s successful development of a nickel-catalyzed reaction was initially affected by palladium contamination that hindered progress4.
The chemistry literature is full of palladium-related controversies like these, the researchers say: some have been definitively denied, while the suspicion lingers on others. “This has become a minefield,” says Leadbeater.
Ghost catalysis
Medicinal compounds are usually large and complex molecules, so chemists have to synthesize them piece by piece. Carbon coupling reactions bind these fragments together. But the energy needed to make and break bonds in coupling partners can make these reactions slow, if not impossible, without a catalyst, Diao says. Palladium catalysts are especially good at overcoming these energy barriers because the metal’s unique electronic structure makes it a versatile manufacturer for a wide variety of molecular fragments, he says.
But palladium compounds are so widely used that metal reaches everywhere. Even scratches on rotating magnetic bars, which are commonly used to mix liquids in chemistry labs, can trap enough palladium to cause some reactions, according to a 2019 study by Valentine Ananikov at the Academy. of Russian Sciences in Moscow5. This “ghost catalysis” can make it look like a reaction is going on without a catalyst, says Ananikov. “Great care must be taken, because the palladium can penetrate through contaminated laboratory material as well as through impurities in chemicals and solvents,” he says.
Dirty magnetic stirrers can trap traces of metals, which can catalyze chemical reactions. Credit: Pentsak, EO, et al./ACS Catal.
Experienced chemists to prevent unwanted palladium follow strict protocols to limit its spread. Gergely Tolnai and Zoltán Novák, synthetic organic chemists at Eötvös Loránd University in Budapest, restrict the use of palladium to a designated quadrant of the research laboratory. The Tolnai equipment also labels its spatulas for exclusive use with particular metals to prevent any possible cross-contamination. At the Bedford Laboratory, researchers are banned from sharing glass objects and use new agitation rods when palladium contamination is a concern. They even treat commercial reagents, marketed as ultrapure, to remove any persistent palladium. Investigators are also analyzing the final reaction mixture for contamination, in case an unknown agent introduced impurities along the way.
“We’re a little superstitious about anything related to palladium,” Tolnai says.
Spatulas labeled for use exclusively with certain metals, to avoid contamination. Credit: Gergely L. Tolnai
Three years of precautions
Chinese chemists who reported a palladium-free reaction in 2021 claimed that their carbon-coupling catalyst contained no metals – just an organic molecule with nitrogen-containing structures called amines. The problem was that they used palladium to make their amine catalyst.
The team, led by Hua-Jian Xu at Hefei University of Technology and Hai-Zhu Yu at Anhui University in Hefei, knew that the palate hanging from this synthesis could contaminate his later experiments. So they did their best to make sure that didn’t happen.
First, the researchers purified their palladium amine catalyst by a kind of chromatography, based on the principle that molecules with different polarities (a property related to the distribution of electric charge) move through of a silica gel at different speeds. This was aimed at separating the catalyst from any excess metal complex.
They then mixed the purified amine catalyst with a removal complex that was supposed to bind and remove any remaining traces of palladium.
Finally, they immersed a sample of the amine catalyst in a solution of nitric acid to chew the compound into fragments. This would release any residual palladium atoms bound to organic complexes. These acid-digested parts could be analyzed by mass spectrometry to look for any signs that indicate the presence of palladium as a function of mass and load. The technique is the gold standard for detecting metal pollution, say other researchers.
These experiments showed less than 1 ppb of palladium, and any other potentially reactive metal, in the catalyst or reaction mixture. Even when the researchers deliberately added palladium to their reactions, the product would not form without the amine catalyst, Xu …