Ei-ichi Negishi (1935-2021)
The knitting of carbon atoms is fundamental to creating complex molecules for pharmaceuticals or industrial chemistry. In 2010, the architects of three of the most important reactions that make this possible, all using palladium, a rare metal as a catalyst, were awarded the Nobel Prize in Chemistry. One was Japanese chemist Ei-ichi Negishi, whose cross-coupling is estimated to be used in at least a quarter of all reactions in the pharmaceutical industry today. He died at the age of 85.
Carbon atoms are stable and difficult to react. Historically, organic chemists have focused on making carbon more reactive, but this leads to unwanted byproducts and is not effective for larger structures, such as drugs or plastics. Instead, in the 1970s, Negishi developed a reaction in which two intermediate molecules both bind to a metal catalyst, eventually separating and forming a carbon-carbon bond with each other. The catalyst is then reused as the reaction repeats.
Negishi was born in 1935 in Hsinking (now Changchun), the capital of the Japanese puppet state of Manchoukuo, in northeastern China. His father was a railway worker and as a child he lived in Japanese-occupied Harbin, as well as Incheon and Seoul in South Korea, before settling in Japan at the end of World War II. There he excelled as a student. He was admitted to the elite Shonan High School a year earlier and at age 17 he was admitted to the University of Tokyo.
After graduating in 1958, he joined Teijin, a synthetic polymer company, but soon found that his knowledge of organic chemistry was not on par with that of his colleagues. Not having the means to continue his studies in Japan, with the support of the company, he obtained a Fulbright scholarship at the University of Pennsylvania in Philadelphia, where he obtained his doctorate in 1963. He returned to work in Teijin, but his heart now turned career in academia. Unable to find a post in Japan, he returned to the United States in 1966 as a post-doctoral fellow at Purdue University in West Lafayette, Illinois, under Herbert Brown. He narrowly missed his fellow Japanese chemist Akira Suzuki, who had left Brown’s group the year before and with whom he was destined (along with Richard Heck of the University of Delaware at Newark) to share the Nobel Prize.
Negishi thrived, despite the contrast between his calm, conflict-averse personality and that of the eccentric and argumentative Brown. He would later describe his mentor as a “true master of the exploration of chemistry”. After six years, he moved to Syracuse University, New York, where he focused on the problem of the efficient assembly of carbon molecules. Since the mid-twentieth century, transition metals such as copper had been used as catalysts for these reactions, and by the late 1960s palladium had also started to be used. The problem was to find suitable carbon molecules that could be catalyzed.
Between 1976 and 1978, Negishi and his collaborators published a series of articles detailing a new approach. This used an organic zinc compound and a palladium or nickel catalyst to bind to an organic halide (containing a halogen such as chlorine or iodine). As the two molecules bind to the palladium, the halogen and zinc are removed, allowing the two organic molecules to form a new carbon-carbon bond.
Negishi could now manufacture a wide variety of molecules in a simple, economical and energy efficient way. The reaction also limited waste by reusing the palladium and being more focused than previous coupling techniques, thus reducing the amount of side products. Negishi coupling remains one of the most widely used techniques for forming large organic compounds, with a long list of applications in the synthesis of natural products. Its uses range from developing new antibiotics to creating antifungal agents for agriculture, and even building light emitting diodes in computer screens.
In 1979, Negishi returned to Purdue, just in time to see Brown receive the Nobel Prize in chemistry. He stayed for the next 40 years. Here, Negishi was known for his approachable nature. With his door still open, the winner would relentlessly urge his students to surpass themselves. He had a competitive streak – in the lab and at karaoke, in which he could sing over 1,000 tunes. In addition to the Nobel Prize, he was awarded the Order of Culture of Japan in 2010. He did not retire from university life until 2019, at the age of 84.
Palladium-catalyzed cross-coupling reactions revolutionized organic synthesis and reshaped an entire branch of science. However, recognizing the importance of his work, Negishi refused to patent his idea in the hope that it could be used widely. Throughout his career, Negishi has emphasized the importance of work-life balance, believing that there are four key ingredients to happiness: good health; happy environment, including family; pursuit of a dignified career; and at least one long-term hobby. Negishi read everything he could find, from the Bible (although he was not a Christian) to how-to guides and poetry.