A Greener Future through Sustainable Catalysis

Catalysis has had a transformative impact on the chemical industry and society at large. The process has been indispensable in producing everything from fuels to pharmaceuticals. The linchpin to most of these compounds is typically precious-metal catalysts. But these metals come with a high price tag and a high carbon footprint.

As chemists strive for a more sustainable future, they are looking to earth-abundant and especially biochemically common transition metals such as copper and iron as green alternatives. Earth-abundant metals are plentiful, so they are less costly and less carbon intensive to refine, and biochemically common metals tend to be less toxic. And nature already cleverly uses them to do extraordinary chemistry.

"Metals such as iron, copper, manganese, calcium and potassium are critical for natural catalytic process," said Isaac Garcia Bosch, associate professor of chemistry. "For example, our liver uses iron catalysis to process pharmaceuticals, and trees use manganese catalysis during photosynthesis to transform water into the oxygen that we breathe."

A broad group of enzymes containing metal ions are known as metalloenzymes, which play a vital role in many essential metabolic processes. They enable efficient and reversible reactions under mild conditions — a goal synthetic chemists strive to meet. But recreating the powerful functions of metalloenzymes in the lab is a daunting task, said Garcia Bosch. Due to their structural complexity, the specific active sites, reaction mechanisms and intermediates of many of these enzymes, especially copper ones, are still not well known. This is where synthetic inorganic chemists like Garcia Bosch can help by synthesizing model copper compounds as analogues of the enzymes' active sites.

"Model systems are very, very helpful in terms of determining the structure and the kind of intermediates that are formed for some of these metalloenzymes," Garcia Bosch said. "But we're also trying to take the next step, which is: can we use these copper compounds to do useful synthetic organic chemistry."

Garcia Bosch's lab is developing copper (Cu) complexes that can do selective carbon-hydrogen (C-H) hydroxylation reactions. C-H bonds are quite strong, so doing a selective hydroxylation and putting an oxygen on a specific C bond opens up an organic chemists' options for making a wide variety of useful compounds. He said building metal complexes that can oxidize selectively and at a particular position is very challenging, especially since his lab is using hydrogen peroxide (H2O2) as the oxidant. Because solutions of H2O2 are stable, it is more practical to use, plus it's a stronger oxidant than oxygen. One of the main challenges of this approach is that H2O2's reactivity with metals can lead to the formation of Fenton oxidants, which can oxidize most bonds, leading to non-selective oxidations. Nature, including metalloenzymes like lytic polysaccharide monooxygenases, has evolved to bypass these issues.

"To control the reactivity, our lab uses directing groups to direct what C-H bond we want to oxidize," he said. "Our work has been focusing a lot on this approach because it is becoming more apparent that that's what metalloenzymes do — a substrate coordinates to the active site of the metalloenzyme before the oxidant is introduced."

In research published over the last few years, Garcia Bosch and collaborators developed a synthetic protocol for the functionalization of ketones (and aldehydes) using directing groups, copper and H2O2. The reaction resulted in remarkable C-H hydroxylation yields with unprecedented selectivities. While the lab used the directing group approach to do sp3 hydroxylations, the team recently published several papers doing sp2 C-H hydroxylation reactions. They also have shown that they can change the identity of the hydroxylation product by changing the directing group that's used.

Garcia Bosch said that things that were impossible five years ago, like selective hydroxylations using copper and hydrogen peroxide, are now not only possible but his lab has developed a simple protocol to make it happen easily and inexpensively. Typically in copper chemistry, chemists need to work in an environment — like a glovebox — free of water and oxygen, but with Garcia Bosch's protocol using directing groups, the Cu(I) and Cu(II) precursors used are stable in air so a glovebox isn't necessary.

And now, people from outside the field are using Garcia Bosch's protocols to do these types of Cu (II)-mediated organic syntheses.

"People are using our protocols to do selective hydroxylations to synthesize complex molecules, and that makes me very proud," he said.

Garcia Bosch also is looking to cooper-containing enzymes for new ways to promote useful oxidations of hydrocarbons. He's particularly inspired by particulate methane monooxygenase (pMMO), a membrane-bound enzyme that catalyzes the oxidation of methane to methanol in methanotropic bacteria.

"It's a really cool transformation because this metalloenzyme can transform methane to methanol at room temperature using oxygen. This is probably one of the most challenging organic transformations and it has a lot of application in industry. We would like to take the methane that comes from extracting oil, for example, and take it to methanol, a liquid that we can use for organic synthesis."

To mimic nature's catalysis, Garcia Bosch is developing copper complexes as oxidation catalysts to tackle some of these challenging transformations, such as the functionalization of C-H and C=C bonds, under mild conditions using cheap and non-toxic reagents. Like some of their natural counterparts, the catalysts contain a redox-active ligand with tunable H-bonding donors, which allows for control of the reactivity of the intermediate species that are formed during these transformations. The long-range goal is to discover new synthetic routes to compounds that could be useful as pharmaceuticals, polymers, and other industrially useful chemical compounds.

Strength in Sustainability

Garcia Bosch's arrival at Carnegie Mellon two years ago adds to the Department of Chemistry's faculty strengths in the fields of metalloproteins and green chemistry, including two Presidential Green Chemistry Challenge Award winners who have for years been looking to nature for inspiration in the lab.

Terry Collinsy, the Teresa Heinz Professor of Green Chemistry and director of the Institute for Green Science at Carnegie Mellon, has dedicated his career to developing methods to remove synthetic chemicals from water. Inspired by the way peroxidase enzymes work in the human liver to destroy hazardous compounds, Collins invented TAML (tetraamido-macrocyclic ligand) catalysts.

"We had to make the iron center of our catalysts do the same kind of chemistry as the iron center of the peroxidase enzymes," said Collins, who successfully did so and has continued to develop TAMLs for environmentally sustainable and efficient use over the last three decades.

TAMLs catalytically activate hydrogen peroxide to eliminate micro-pollutants and pathogens from water. By mimicking oxidative metabolism, TAMLs' oxidation processes can be used for cleaning, water treatment and the removal of recalcitrant toxic chemicals like endocrine disrupting chemicals, active pharmaceutical ingredients, pesticides, and more. These discoveries are underpinning new technologies for treating diverse wastewaters and enabling other products, such as cleaning products for mold remediation.

The U.S. Environmental Protection recognized Collins' work with the Presidential Green Chemistry Challenge Award in 1999. Ten years later, the EPA again honored a Carnegie Mellon chemist with the award. Krzysztof Matyjaszewski, J.C. Warner University Professor of Natural Sciences, was recognized for his development of an environmentally low-impact form of Atom Transfer Radical Polymerization (ATRP) — a widely used method for the preparation of functional polymers.

ATRP, which was developed by Matyjaszewski, relies on a specialized copper catalyst to synthesize well-defined polymers with precisely controlled molecular architectures. The process is used in industry to create polymers that are employed as components of everything from coatings and surfactants to applications in medicine and electronics. The success of ATRP in creating such a range of commercial products has motivated Matyjaszewski to develop more efficient, environmentally friendly and scalable ways that minimize ATRP's environmental impact.

In the early stages of ATRP development, high levels of copper catalyst were required to maintain the process. To lessen to amount of copper catalyst needed, Matyjaszewski's group introduced an approach that incorporates environmentally benign reducing agents, like vitamin C and sugars, to regenerate the active form of the catalys — lessening the amount of copper catalyst needed for the reactions. They've also used external stimuli, including electrical current, light, mechanical forces and ultrasound, to regenerate the copper catalyst. These techniques, which reduce the level of copper to a few parts per million, have allowed for not only for needing to use less catalyst, but also for increasing the oxygen tolerance of the polymerization and developing systems to conduct ATRP in open air. Together, these advances offer a promising approach for creating specialized polymers in greener and more practical ways.

Catalysts will play a pivotal role in achieving a greener future. Carnegie Mellon chemists are tackling some of the grandest challenges in catalysis science through bio-inspired design and cost-saving, greener reaction pathways. Together these advancements are promising steps toward more sustainable catalysis for a better tomorrow.