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The elements of a green catalyst

Making homogeneous catalysis greener is about more than just swapping out precious metals for earth-abundant ones

by Brianna Barbu
February 16, 2024 | A version of this story appeared in Volume 102, Issue 5
An illustration of a person in a lab coat looking at a picket fence. The field is various elements, metals specifically.

Credit: Chris Gash


In brief

Chemists agree that a sustainable future requires reducing reliance on precious metals such as palladium and rhodium. Many of them hold up earth-abundant first-row transition metals as green alternatives to the precious metals used to catalyze cross couplings and other important organic reactions needed to synthesize drug molecules. First-row metals are less costly and less carbon intensive to refine, and they can do a lot of useful chemistry. But making catalytic reactions more sustainable requires thinking about more than just swapping out precious-metal catalysts for earth-abundant ones.

On a summer day about 20 years ago, Paul Chirik returned to his laboratory after a conference with a question on his mind: Why do chemists use expensive rhodium to do hydrogenation reactions? Why don’t they use something more available, such as iron?

Chemists are rightfully proud of the transition-metal catalysts they developed to enable certain organic transformations. For example, rhodium catalyzes asymmetric hydrogenation, ruthenium catalyzes olefin metathesis, and palladium typically catalyzes a whole suite of carbon-carbon and carbon-heteroatom cross-coupling reactions. Each of these reactions is a Nobel Prize–winning accomplishment, but they all use some of the least available elements on earth.

A chemical scheme showing dehydro sitagliptin being converted to sitagliptin by hydrogenation using a cobalt catalyst.
Asymmetric hydrogenation is the final step in the synthesis of sitaglipin, a type 2 diabetes medication sold by Merck & Co. Typically this reaction uses a rhodium catalyst. Paul Chirik and his group developed a cobalt complex that could do the reaction in high yield.

“Why the heck do chemists use these things in the first place? The answer is they work,” says Chirik, a professor at Princeton University. Since the cross-coupling boom of the 1970s, precious-​metal catalysts have transformed the landscape of organic synthesis, medicinal chemistry, and drug discovery.

But the metals carry both a high price tag and a high carbon footprint. According to a 2014 study, the amount of carbon dioxide released from mining and refining 1 kg of palladium metal is about 3,880 kg (PLOS One, DOI: 10.1371/journal.pone.0101298). And that kilogram cost over $30,000 at the beginning of February 2024, according to Business Insider. Meanwhile, just one row up on the periodic table, nickel costs less than $16 per kilogram, and producing it releases just 6.5 kg of CO2.

Chirik realized that his question was an interesting line of scientific inquiry and, potentially, valuable for industry chemists looking to make their syntheses greener and more cost effective. He has spent much of the past 2 decades working on coaxing earth-​abundant metals such as cobalt, iron, and nickel to do reactions that have been dominated by precious metals. And he’s far from the only person doing so.

Entire symposia at scientific conferences are now devoted to reactions with earth-abundant metals. And pharmaceutical companies including Bristol Myers Squibb (BMS), Merck & Co., Pfizer, and AbbVie have research initiatives dedicated to earth-abundant catalysis. These efforts have paid off: there are a growing number of reactions in which first-row transition metals perform on par with, or in some cases better than, precious ones.

But while chemists say they would like to use less precious metal and more earth-abundant elements for cost and sustainability reasons, switching metals is not automatically the greenest choice. “It’s not always going to be beneficial or always going to be the solution,” says Dan Lehnherr, a chemist at Merck.

Many variables affect sustainability. And the overall greenest way to synthesize a molecule requires a holistic view, says Fabrice Gallou, a scientific director at Novartis. “We want to tell people to go through the process of analyzing the fate of everything before concluding” what the most sustainable option is.

The value of precious metals

By the numbers


Year a Nobel Prize was awarded for palladium-catalyzed cross coupling

3,880 kg

Amount of carbon dioxide released to produce 1 kg of palladium metal

6.5 and 1.5 kg

Amount of CO2 released to produce 1 kg of nickel and 1 kg of iron, respectively

10 ppm

Amount of residual precious metal allowed in drugs with doses less than 10 g/day

340 ppm

Amount of residual copper allowed in drugs with doses less than 10 g/day

Sources: Nobel Foundation; PLOS One 2014, DOI: 10.1371/journal.pone.0101298; International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use.

The platinum-group metals—a collection of second- and third-row transition metals that includes platinum, palladium, rhodium, ruthenium, iridium, and osmium—are renowned for their robust catalytic capabilities. As solid-state catalysts, these metals are widely used to refine petroleum, manufacture bulk chemicals, and turn carbon monoxide and other toxic gases into less-harmful products in catalytic converters.

As solution-phase catalysts, these elements are also crucial to making drugs. Three of the most common transition-metal-catalyzed reactions used in pharmaceutical manufacturing—​Suzuki-Miyaura cross coupling, Miyaura borylation, and Buchwald-Hartwig amination—all typically use palladium, according to Steven Wisniewski and Eric Simmons, coleads of BMS’s base-metal initiative.

Such famous named reactions have been around for a long time. Akira Suzuki and Norio Miyaura published their namesake coupling reaction in 1979, only a handful of years after Richard F. Heck and Ei-ichi Negishi published the reactions that would earn Suzuki, Heck, and Negishi Nobel honors in 2010 for their contributions to forging carbon-carbon bonds with palladium catalysts. The Buchwald-Hartwig reaction arrived on the scene in the 1990s. Geoffrey Wilkinson first reported his hydrogenation catalyst, the rhodium complex that motivated Chirik at the beginning of his career, in 1965.

After decades of research, chemists have become very good at controlling these reactions. They’ve developed strategies that are reproducible, work with a variety of functional groups, and can stitch together the types of organic molecules that are useful as drug candidates. When people think of C–C bond formation, they usually associate it with palladium, says Carin Seechurn, a catalysis specialist at Sinocompound, which makes and supplies metal catalysts to companies and researchers around the world.

Crucially, chemists have developed a deep understanding of how precious-metal catalysts work­—and how to troubleshoot them when they don’t perform as expected, Wisniewski says. “We have to understand how the reaction can fail in order to ensure success on [commercial] scale.”

Chemists typically use 1–5 mol % catalyst when they’re evaluating a reaction for a pharmaceutical synthesis, according to Wisniewski. But precious metals can often mediate reactions in much lower concentrations, which is illustrated by the multiple “metal free” reactions reported in the literature that turned out to be contaminated by a trace amount of palladium or another metal.

“For a long time, our approach has been, ‘Let’s stick with palladium; we know how it functions,’ ” Gallou says. His Novartis group has focused mainly on reducing cross-coupling reactions’ cost and environmental impact by cutting the amount of palladium used. But he says recent developments in first-row transition-metal chemistry have prompted him to consider those metals more seriously.

Great catalysts with bad histories

Catalysis is one of the 12 principles of green chemistry originally developed by Paul Anastas and John Warner and now championed by the American Chemical Society’s Green Chemistry Institute (GCI). ACS publishes C&EN but is not involved in editorial decisions.

A long row of translucent, orange storage containers with yellow labels, each containing three shelves of vials.
Credit: Eric Simmons/Bristol Myers Squibb
Pharmaceutical companies such as Bristol Myers Squibb maintain large collections of catalysts and ligands for screening.

It’s far more sustainable to use a catalyst than a stoichiometric reagent that will produce a stoichiometric amount of waste. A related principle, atom economy, states that the amount of material put into a reaction should be as close as possible to the amount of product that comes out. Those ideas are the basis of process mass intensity, a metric that companies use to assess the efficiency and sustainability of their processes.

Many companies use additional metrics, such as life-cycle assessment (LCA), to determine a process’s environmental, health, and safety impacts. It’s in these factors that a metal catalyst’s greenness comes into play.

LCA accounts for the full environmental impact of a product, says Isamir Martínez, manager of the GCI Pharmaceutical Roundtable, an alliance of drug companies devoted to developing and sharing green chemistry best practices. The metric includes everything from the raw materials used in manufacturing to how the product is disposed of at the end of its life. LCA also considers how each stage of making and distributing the product fares in terms of carbon emissions, energy use, water use, and other criteria.

A proper LCA illuminates a synthetic route’s environmental footprint well before the materials involved even arrive at a manufacturing plant, says Michael Luescher, a process chemist at Novartis who works with Gallou on sustainable process design.

If you are dependent on one specific metal to make a product and facing supply issues with it, it can have a real impact on people’s lives.
Dan Bailey, associate scientific fellow in sustainability, Takeda Pharmaceutical

“You can have a great catalyst with a very bad history,” says Volker Hessel, a professor of sustainable chemical engineering at the University of Adelaide. Hessel was one of the authors of a paper last year analyzing the environmental impacts throughout the life cycle of each component in the original Suzuki-Miyaura and Heck cross-coupling reactions (Green Chem. 2023, DOI: 10.1039​/D3GC01896B). The palladium catalysts dominated every environmental impact category the researchers examined, including global warming, air and water pollution, and toxicity. Much of that impact came from the emissions and pollution associated with mining palladium and manufacturing the catalysts.

An illustration of a person in a lab coat reaching into a cabinet. Inside the cabinet are various elements. The upper shelf is pristine, while the lower shelf is dusty with cobwebs.
Credit: Chris Gash

Many catalyst metals, including the platinum-group metals, are considered “critical minerals” in the US, according to the US Department of Energy. That means they are essential to the nation’s economic security and have vulnerable supply chains. In the case of platinum-group elements, their use in catalytic converters makes them essential to the economy. And because over 80% of platinum-group metals come from Russia and South Africa, according to the US Geological Survey, supply is contingent on the economic and political happenings in those two countries.

When cross coupling was invented in the 1970s, “nobody foresaw that palladium would become critical,” Hessel says. But that criticality, and the price fluctuations that come with it, is something chemists must contend with now.

“If you are dependent on one specific metal to make a product and facing supply issues with it, it can have a real impact on people’s lives,” says Dan Bailey, an associate scientific fellow in sustainability at Takeda Pharmaceutical. Precious metals do extremely valuable chemistry, “but because of these sustainability issues, and especially because of the cost and supply constraint issues, they’re things that we think twice about using,” he says.

Naturally, the first place to look for alternatives is one row up on the periodic table—to nickel instead of palladium, cobalt instead of rhodium, and so on.

That’s not to say that first-row metals all have squeaky-clean histories. Mining in general is hard on the environment, and cobalt mining is known to be associated with human rights violations. Cobalt and nickel are also critical minerals because of their use in lithium-ion battery cathodes. Copper is listed as near critical because of its importance in electrification and solar technology.

But catalysis makes up just a tiny sliver of most metals’ commercial use, so other industries are responsible for the brunt of their environmental impact. For example, just 1% of all nickel is used for catalytic purposes, according to Clare Richardson of the Nickel Institute, and that figure includes both heterogeneous (solid phase) and homogeneous (solution phase) catalysts. Most nickel found in a pharmaceutical plant is in the stainless-steel process equipment, not in catalysts.

Chemists do need to think more about the elemental footprints of their processes, Chirik says, but he points out that his laptop contains enough cobalt to hydrogenate a year’s supply of a drug for one person.

More metals, more trade-offs

Developing a synthetic route involves evaluating multiple ways of making a target drug or other molecule, including what catalysts to use in each step. The pros and cons of each synthetic step must be weighed in terms of yield, cost, safety, and sustainability, Lehnherr says. “You want to think three steps ahead or even further” to determine what has the best chance of being useful if the drug makes it to commercialization.

Two piles of powder on pieces of white weighting paper on a dark-colored benchtop. The pile on the left is orange and much smaller than the pile on the right, which is yellow.
Credit: Lipshutz lab
Relative amounts of palladium (left) and nickel (right) salts used as catalysts in a Suzuki-Miyaura cross coupling, showing that the Pd-catalyzed reaction requires much lower amounts of metal.

The GCI Pharmaceutical Roundtable has reagent guides to advise chemists about sustainable conditions for many important organic reactions. Many of the guides discuss earth-abundant catalysts and recommend using them wherever feasible, though Martínez acknowledges that such alternatives don’t yet exist for every situation.

The tricky thing about first-row metals is that they don’t always react by the predictable two-electron-transfer mechanisms that are the basis of the well-known precious-metal-catalyzed reactions, Chirik says. First-row metals also like to do one-electron transfers, and this tendency is more pronounced the further left on the periodic table an element sits. It takes additional reaction design effort to convince first-row metals to behave like their second-row siblings when it comes to selectivity and yield.


Ligands play a major role in directing a metal complex’s reactivity, and a huge number have been developed for precious-​​metal-catalyzed reactions. Chemical suppliers’ websites offer a dizzying array of phosphine ligands, many with amusing names paying homage to the people who designed them. But most of those ligands are optimized for palladium. When chemists screen first-row metals for a reaction, they often must dress the metal in hand-me-down ligands that may not fit quite right.

Developing new ligands tailored to the needs of first-row metals is an ongoing area of research. One strategy, which Chirik and his group work on, is using redox-active ligands that provide an electron reservoir to get metals that prefer to do one-electron chemistry to participate in two-electron chemistry.

A chemical scheme showing an amination reaction with a copper catalyst and N-aryl picolinamide ligand, linking together uracil and an aryl iodide to make a precursor to dasabuvir.
A copper-catalyzed amination reaction is used in the early stages of the synthesis of AbbVie’s dasabuvir, an antiviral used to treat hepatitis C.

No matter what metal is used, however, a complicated ligand that requires multiple steps to make is going to add to the cost and the environmental footprint of a reaction when the process is scaled up. As Chirik explains, putting expensive tires on a cheap car makes it an expensive car.

The ideal scenario for most chemistry would be to use an inexpensive metal and inexpensive ligands. “Hopefully, we can get around the tyranny of the fancy-pants ligand,” says Julian West, an assistant professor at Rice University. His group works on reactions catalyzed by one of the least expensive metals: iron.

First-row metals usually require a larger amount of catalyst to drive a reaction to completion compared with precious metals, which means using a larger amount of ligand. Conversely, using less of the catalyst may cause the yield to fall, which means more impurities and waste to remove later, Lehnherr says.

“The yield and purity become increasingly important as you move to later stages of the synthesis,” says Shashank Shekhar, the head of AbbVie’s Center of Catalysis. A low yield on a late step in a synthesis is a huge deal-breaker no matter what the catalyst is made of, because by that point, the intermediate is just too valuable to lose, he says.

But it’s also not affordable to use large amounts of very expensive catalysts to ensure the yield is high. If a precious-metal catalyst is necessary, chemists should try to use it in a tiny amount, Lehnherr says.

You want to think three steps ahead or even further.
Dan Lehnherr, principal scientist in process R&D enabling technologies, Merck & Co.

Bruce Lipshutz, a professor at the University of California, Santa Barbara, is a strong advocate of using tiny amounts of catalyst. He says the combination of using water as a solvent and very small quantities of well-known palladium catalysts is by far the greenest way to do cross coupling. He adds that the research community has pushed the idea of exchanging palladium for nickel or other supposedly green metals too hard, to the detriment of other environmentally friendly options.

Lipshutz, Gallou, and Luescher recently published a study, which has not yet been peer-reviewed, on the preprint server ChemRxiv, comparing LCAs of two purportedly greener alternatives to a Suzuki-Miyaura reaction. One used 1 mol % of a nickel catalyst in 2-methyltetrahydrofuran, which many consider a relatively green solvent, and another used less than one-twentieth of that amount of a palladium catalyst in an aqueous micellar process (ChemRxiv 2024, DOI: 10.26434/chemrxiv-2024-tc9hm).

The authors determined that the palladium-catalyzed aqueous process was far greener, even though it used a “less green” metal, because it was done in water. The amount and cost of the catalyst turned out to be relatively insignificant. Gallou says the takeaway is that the best course of action is to use the smallest amount possible of the most effective catalyst in the greenest-possible solvent, ideally water.

Lipshutz says the comparison is also evidence that precious metals don’t need to be replaced but rather used more judiciously. “The technology is already in place to use low levels of palladium in water essentially forever.”

Getting the metal out

The identity of the metal catalyst matters in pharmaceuticals because drugs need to contain as little residual metal as possible, Takeda’s Bailey says. Drug companies are in the business of making products that heal people, not harm them. And many metals are toxic to humans.

A 2016 study compared the solubility and toxicity of common salts of seven catalytic metals: iron, nickel, copper, rhodium, palladium, platinum, and gold. The study found that the toxicity of a metal salt depends on many variables, including its form, oxidation state, and the ligands attached to it. And some nickel- and copper-based compounds are just as toxic as—and in some cases more toxic than—the analogous precious-metal compounds (Angew. Chem., Int. Ed. 2016, DOI: 10.1002/anie.201603777).

Erfan Oftadeh, a second-year graduate student in Bruce Lipshutz’s lab, entering a sample into an inductively coupled plasma mass spectrometer for elemental analysis.
Credit: Lipshutz lab
Inductively coupled plasma mass spectrometry is commonly used to measure the amount of residual metal in a sample—for example, to determine if an active pharmaceutical ingredient meets purity standards.

That conclusion is reflected in safety regulations: several nickel-based compounds, including common catalyst precursors such as nickel chloride and bis(cyclooctadiene)nickel, have been classified as restricted substances under Registration, Evaluation, Authorisation, and Restriction of Chemicals regulations in the European Union because of concerns about their toxicity and potential to cause cancer. The EU has also recommended some cobalt salts for restriction for similar reasons.

A chemical scheme showing a Suzuki-Miyaura cross-coupling reaction to make pictilisib, using nickel nitrate as the precatalyst and triphenylphosphine as the ligand.
Scientists at Genentech found that a Suzuki-Miyaura cross-coupling reaction had a higher yield and easier purification when they used a nickel catalyst rather than a palladium one in the final stages of the synthesis of pictilisib, a kinase inhibitor they were evaluating to treat cancer.

International regulations strictly limit the levels of impurities allowed in medications. The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use limits most platinum-group metals to 10 ppm for drugs with a dose of less than 10 g/day. The limit is 22 ppm for nickel, just 5 ppm for cobalt, and 340 ppm for copper.

Those regulations mean it’s a myth that chemists can use as much of a first-row metal as needed to get the job done simply because it’s cheap, Bailey says. Using a lot of metal will require removing a lot later in the process.

Gallou says the chemical identity of the metal doesn’t usually affect how easy it is to remove. Purification depends mostly on the drug molecule.

Ideally, crystallization, which must happen anyway, will be sufficient to remove residual metal and other stuff that shouldn’t be in the final product. But sometimes chemists have to resort to extraction or precipitation to remove unwanted chemical species. And those approaches require carefully considering the solubility of the metal and ligand. Nickel is more water soluble than palladium, for example, so it may be easier to wash out.

Every additional purification step adds time, cost, and waste to the process and lowers the yield, Gallou points out. So he says the best approach, once again, is to use the least amount of metal possible.

Cooperative and complementary

Another way to make a synthesis process greener and more cost effective is to make it shorter. “You start doing new reactions, now molecular space starts to expand,” Chirik says. And that’s where he and many other researchers working on first-row metals believe that these elements can really shine. “There’s no question that they can do unique things,” he says.

A chemical scheme showing a cross-coupling reaction using an iron catalyst.
Paul Chirik’s group is one of many academic labs working on expanding first-row metal catalysis to do things that precious metals struggle with, including cross-coupling reactions between sp2 and sp3 carbons. Iron catalysts are particularly attractive because the metal is particularly low cost and abundant, and it has a low carbon footprint.

For one, Chirik says, first-row metals can be better at cross coupling with sp3 carbons because those elements are slower to do β-hydride elimination, which is what tends to doom palladium catalysts in those reactions. Coupling with sp3 partners is extremely valuable to drug developers, who want to be able to construct a greater variety of 3D molecular geometries.

In a 2021 paper, scientists at BMS reported that a nickel catalyst could mediate an sp2–sp3 bond-forming reaction in just one step. That reaction requires two steps with a palladium catalyst (J. Org. Chem. 2021, DOI: 10.1021/acs.joc.1c01073). Chirik’s group has also published studies in collaboration with BMS on sp2–sp3 couplings using iron and cobalt.

Bailey says iron would be the gold standard for safety and availability if more work were put into developing it as a catalyst. It’s much less toxic than other metals used as catalysts. Producing it releases only 1.5 kg of CO2 per kilogram of metal. And “it’s dirt cheap and available everywhere,” West says.

But iron has a downside: a particularly strong proclivity for one-electron chemistry. That’s why West’s research focuses on trying to use one-electron mechanisms to develop new reactions that are entirely different from what precious metals do.

When you get down to it, green chemistry is just good chemistry.
Julian West, assistant professor of chemistry, Rice University

Nature is an expert at capitalizing on first-row metals’ uniqueness, West says. He and other scientists working on first-row transition-metal chemistry take inspiration from metal cofactors in biological systems. Those cofactors make complex molecules using first-row metals, and they often do it through one-electron mechanisms. West believes that chemists are reaching an inflection point where mechanistic knowledge of first-row metals is becoming good enough to start unlocking more of their catalytic potential.

“Our ultimate goal is to make high-quality drugs that will be safe for humans,” Shekhar says. “So we will not compromise on that. But we look at opportunities where we can do it more responsibly, and nonprecious metal plays a big role in doing that.”


Most pharmaceutical chemists say precious metals aren’t going away anytime soon. But researchers see an expanded role for earth-abundant metals as they continue to learn about these elements’ reactivity and usefulness. Companies are investing in research into ways to use base metals while they refine strategies that make precious-metal-catalyzed reactions greener.

Earth-abundant metal catalysts are part of the sustainability-conscious synthetic chemistry toolbox. But they share that toolbox with other ways of doing reactions, such as biocatalysis and photocatalysis, and with process interventions such as doing reactions in flow systems, reducing catalyst loadings, and using greener solvents. Expanding that tool kit is why collaborations between academia and industry, and partnerships such as the GCI Pharmaceutical Roundtable, are so valuable, Bailey says.

“When you get down to it, green chemistry is just good chemistry,” and companies want to use good chemistry, West says. In the 20th century, the biggest question in synthetic chemistry evolved from “Can we make this molecule?” to “Can we make this molecule efficiently?” West says the equivalent challenge for the 21st century is to make that molecule sustainably.


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