The HAT trick that chemists use to make chemical synthesis greener

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Making new chemical compounds, like new drugs, is not as easy as putting together one of those models with coloured balls and sticks that you might have seen in a beginning chemistry class. No, it’s usually a complicated process with many steps and a lot of chemicals, some of which are dangerous to people and the environment.

HAT stands for “hydrogen atom transfer.” This is a method that is used in chemical synthesis. It could be a powerful and flexible chemical tool, but technical problems have made it hard to use. Now, chemists at the University of Utah, Scripps Research, and other places have used a technique from the chemistry of energy storage to make HAT with fewer chemicals and for less money.

Samer Gnaim, who works at Scripps Research and is the first author of a study about the researchers’ findings, says that HAT has the potential to change in very useful ways. “These chemical problems can be solved by introducing a fundamentally new idea. This will make HAT a useful tool for the vast majority of organic chemicals in both industry and academia.”

Nature has written about the study.

“This is a classic example of why we need multidisciplinary centres that bring together organic chemists, electrochemists, and computer scientists to solve big problems in organic synthesis,” says Minteer, a distinguished professor of chemistry.

The benefits and problems of HAT

HAT is a process in which a hydrogen atom is moved from one molecule to another. It can be used to use unsaturated carbon-carbon bonds, which are the most common useful chemical bond in organic chemistry, to make a wide range of new bonds, such as carbon-carbon, carbon-oxygen, and carbon-nitrogen bonds. All of these are important steps in making molecules with many parts. “Functionalization” is the process of making new bonds from a carbon-carbon double bond.

Gnaim says, “The functionalization of such bonds is an attractive way to build molecules and get molecular complexity quickly.”

But as helpful as HAT is, it also has some problems. To make an active catalyst, a compound that helps the reaction go forward, oxidants and reductants are added to the simple process of moving a hydrogen atom. Large amounts of oxidants and reductants are needed, which makes it hard to use HAT on a large scale and almost impossible to use it for chemical processes in industry.

Lessons from how energy is stored

While chemists have been trying to figure out how to make HAT better, energy storage researchers have been working on a way to help. With the help of a cobalt hydride catalyst, positively charged protons must be turned into hydrogen molecules in order to store energy as hydrogen. It is the same kind of catalyst that is needed for the HAT process.

But in the energy storage field, protons and electrons have been used instead of oxidants and reductants to make cobalt hydride catalysts. This is a completely different chemical process that leads to the same end product.

So, Gnaim and his colleagues tested how well the electrochemical process worked in a wide range of organic chemistry reactions to see how it stacked up against traditional HAT chemistry. The results were a big boost. They found that using electrochemistry to make cobalt hydride catalysts was both more environmentally friendly and more efficient. It also made the process more precise and easy to control.

How we can move forward

There were also other benefits to the electrochemical process. It could be done in small or large batches, didn’t require removing all air and water from the process, and didn’t require expensive oxidants and reductants.

“Chemists are always looking for ways to make chemicals react in new ways, so they can find new transformations that can make it easier to find new drugs,” Gnaim says. “In our case, we can get to new molecular patterns by using substances that are cheap and good for the environment and relying on classic HAT reactions and new transformations.”

Further information: Phil Baran, Cobalt-electrocatalytic HAT for functionalization of unsaturated C–C bonds, Nature (2022). DOI: 10.1038/s41586-022-04595-3. www.nature.com/articles/s41586-022-04595-3

Journal information: Nature

Source: University of Utah