1977

Nozaki Coupling

Hitosi Nozaki (b. 1922), Yoshito Kishi (b. 1937), Tamejiro Hiyama (b. 1946)

The Nozaki coupling reaction illustrates two key points in modern organometallic chemistry. One is that metal-catalyzed couplings are extremely useful, and the other is that figuring out just what’s going on in a metal-catalyzed coupling can be extremely difficult.

The original Nozaki coupling reaction, reported in 1977 by Japanese chemists Tamejiro Hiyama and Hitosi Nozaki, was sort of a chromium variation of the magnesium-based Grignard reaction. Unlike the classic magnesium reagents, these were very selective toward reacting with aldehydes, and the chemistry was later extended to other sorts of functional groups that could form organochromium reagents. But as other chemists tried out these transformations, they discovered that sometimes these couplings would work, and sometimes they wouldn’t, even on the same starting materials.

This was frustrating, because the reagents had potential to solve some very delicate synthetic problems. Japanese chemist Yoshito Kishi’s group was involved at this time in trying to synthesize palytoxin, and these sorts of mild carbon-carbon-bond-forming reactions were just what they needed. But they ran into the same reproducibility issues, which were especially horrifying when applied to precious intermediates that had taken months to make.

Both the Kishi and Nozaki groups eventually found the problem: different batches of chromium chloride were giving the different results. And the difference between those batches? Tiny amounts of nickel. Ironically, the cleanest and most expensive sources of chromium chloride gave the worst results, since they were least likely to have the essential nickel contamination. Deliberately spiking these with a couple of hundredths of a percent of nickel chloride, though, made them fly right every time. What’s known as the Nozaki-Hiyama-Kishi (NHK) reaction is still a valuable tool for bond formation, now that it’s been tamed.

Spheres of pure nickel—the metal that caused all the difficulty in the Nozaki coupling procedure.