Ei-ichi Negishi: A 50-year dream come true

There is an atmosphere of history, great accomplishment and glamour inside the Grand Hotel during Nobel week. For the Laureates, the Nobel week includes so much more than the banquette on the night of the 10th of December. Their calendars include seminaries, lectures, press conferences, visits to high schools and universities, and of course, lots of interviews. Luckily, I am one of the first out to interview him in Stockholm and we get the chance to have a nice long chat. 

A top student 

I ask him if he has jet lag and he laughs and says he always feels jet lagged. Despite professorial muddle-headed characteristics, he is very expressive and enthusiastic when speaking about his research. A true scientist indeed. He says there had been rumors about him perhaps receiving the Prize this year and he was very happy when he got the announcement.

“This has been a dream of mine for 50 years,” he says and smiles.

His first job was as a research chemist at a Japanese chemical company, Teijin, but he realized he wanted to continue studying and evolving within the field of synthetic organic chemistry. 

We start out by talking about his childhood and formative years. The now 75 year-old professor was born in Changchun China. During World War II the family moved to South Korea and then to Japan. His mother was a housewife and his father worked in the rail – road industry.

Negishi first became interested in science in high school and one of his favorite subjects was mathematics. As a top student in the highly competitive climate in Japan, Negishi continued to study at the University of Tokyo where he graduated with a BSc in 1958. His first job was as a research chemist at a Japanese chemical company, Teijin, but he realized he wanted to continue studying and evolving within the field of synthetic organic chemistry. 

From one Laureate to another 

Negishi’s opportunity to study organic chemistry came when he was chosen as one of only 30 students in all of Japan for a Fulbright scholarship. He was able to go to the United States for graduate studies at the University of Pennsylvania and he received his PhD in 1963. During that time he first met with Professor Herbert C. Brown, a pioneer in synthetic organic chemistry and a 1979 Nobel Laureate. Professor Brown would become a great mentor and dear friend to Negishi.

One of the most important things I learned was actually to handle failure; a very important aspect of being a good scientist.

“He was the best mentor; he taught me almost everything about research. The true way of performing research,” says Negishi and his eyes light up. “One of the most important things I learned was actually to handle failure; a very important aspect of being a good scientist.”

For young scientists today Negishi advises them to have a plan, a dream and an idea, to work hard and keep in mind that the recognition might come, 20 or 30, or even 40 years later. “So the process should be enjoyable and fun.” 

As a post doc in Professor Brown’s group at Purdue University in West Lafayette, Indiana, he started working on organometallic chemistry in 1966. Later he became Professor Brown’s Assistant. In 1972, he moved to Syracuse University where he served as an Assistant Professor and then as an Associate Professor.

Negishi began exploring organotransition metal chemistry for organic synthesis. He initially focused his attention on reductive elimination, and developed the nickel-catalyzed cross-coupling reaction of organoaluminiums, analogous to the Kumada–Corriu reaction of Grignard reagents. This led to the discovery of the corresponding palladium-catalyzed organoaluminium reaction in 1976.

He joined the faculty at Purdue again in 1979, the same year Professor Brown was awarded the Nobel Prize in Chemistry, and has been a researcher there for more than thirty years now. 

A revolutionizing toolkit for chemists 

What Negishi and his fellow Laureates, Professor Heck and Professor Suzuki, have accomplished is nothing less than one of the most widespread and commonly used techniques within chemistry. The trio developed metal-based reactions called palladium-catalyzed cross coupling, a process that knits carbon atoms together so that they form a stable “skeleton” for organic molecules. A carbon skeleton is the chain of carbon atoms that forms the “backbone,” or foundation, of any organic molecule. Because of carbon’s unique ability to form large, diverse and stable compounds, life would not be possible without carbon. However, carbon is stable and carbon atoms do not easily react with one another.

The palladium approach makes carbon atoms bond very easily and very cleanly to each other, and allows for an easy and efficient synthesis of complex organic compounds. When carbon atoms meet on a palladium atom their proximity to one another kick-starts the chemical reaction. Palladium is a catalyst and the technique allows chemists to join molecules at lower temperatures and with less waste than earlier processes.

Professor Heck laid the groundwork for the coupling between carbon atoms by using a catalyzer, or chemical, to promote the process. In 1977 Negishi fine-tuned this using compounds known as organohalides and this was taken a step further by Suzuki who found a practical way to carry out the process using so-called organoborons. They have all lent their names to important chemical reactions.

“One great thing with the technique is the stability and the other great thing is the selectivity, it is very precise,” says Negishi and compares it to previous methods. “The first methods of knitting carbon atoms together were based on different methods of getting the carbon very reactive. For example, Grignard, who received the Nobel Prize in 1912, coupled magnesium to the carbon atom he wanted to become more reactive. These methods worked for building simple molecules but when synthesizing larger more complex molecules there was a problem, since the carbon also reacted with other atoms. There were too many byproducts.”

Negishi’s method is a variant on Grignard’s method but magnesium is switched for zinc, while Suzuki used boron. Common for all methods is that they use palladium as a catalyst. 

Instead of Grignard’s reagent Heck used chemical compounds called olefins. In an olefin the carbon atom is naturally weakly activated and when connected to palladium it becomes even more disposed to react with another carbon atom. Negishi’s method is a variant on Grignard’s method but magnesium is switched for zinc, while Suzuki used boron. Common for all methods is that they use palladium as a catalyst. 

No patents 

The number of applications for the crosscoupling technique is enormous and the technique has clearly revolutionized the field. The three reactions are today used in research worldwide, as well as in the production of, for example, pharmaceuticals and molecules used in the electronics industry. The crosscoupling technique has been useful in everything from fighting colon cancer and HIV to smart plastics, like ultra-thin computer monitors. Cross-coupling reactions are the basis for at least 20% of all chemical reactions in the pharmaceutical industry. The painkiller naproxen is one example and the vital fluorescent marking underpining DNA sequencing another.

The painkiller naproxen is one example and the vital fluorescent marking underpining DNA sequencing another.

“The most characteristic application is just that it can be applied in so many cases. It is one of the most sophisticated tools available to chemists today,” says Negishi.

This is also the reason why neither he nor his fellow Laureates have filed for patents for their techniques. “The applications are so broad and filing for patents would be not just difficult, time consuming and costly, but the technique is also of better use when available for everyone; more people are free to make use of what we have come up with.”

The reactions were first applied industrially in the 1990s and palladium catalyzed cross-couplings are still being refined, optimized and changed. 

The magical power of transition metals 

In 1999 Negishi was named the Inaugural Herbert C. Brown Distinguished Professor of Chemistry at the Purdue University, and he has no intention of stopping doing research just because he has received a Nobel Prize. His research group is focusing on several projects and all of them are to do with, to quote Professor Negishi’s Nobel lecture, “the magical power of transition metals.”

A large number of organic reactions including biochemical processes are promoted by catalysts. Besides traditional Lewis acids and bases and biochemical catalysts, i.e., enzymes, transition metals and their complexes represent one of the most important groups of catalysts.

Actually I am interested in all organic molecules and being able to synthesize them in the best way possible.

“We are focusing on the discovery and development of transition metal-catalyzed organic reactions, their application to those organic transformations which are of interest in the health and energy-related areas, and development of polymer and materials chemistry based on organotransition metal chemistry. Actually I am interested in all organic molecules and being able to synthesize them in the best way possible. Our chemistry will be applicable to a wide range of compounds in the future,” says Negishi and speaks enthusiastically about the need for a safe, renewable energy solution. “This is an unfulfilled job of chemistry and if those problems are reduced other worldwide dilemmas such as food shortage could fall into line.”