Twisting the night away

In today’s issue of Nature, Tani & Stoltz reported the first chemical synthesis, isolation, and full characterization of 2-quinuclidonium tetrafluoroborate: at first glance, you might think that this molecule would be easy to synthesize, as it’s quite small. But the amide bond is highly twisted (it is an ‘anti-Bredt’ amide: it violates Bredt’s rule), which makes this molecule very susceptible to amide hydrolysis. Harry Wasserman wrote the accompanying News & Views article, in which he says:

Amides are surprisingly robust compared with structurally related derivatives, and it is believed that this linkage gains stability from electron ‘delocalization’ … In circumstances where such coplanarity cannot be achieved without distortion of the structure, as would be the case with 2-quinuclidone (Fig. 1b), stabilization of the amide bond by electron delocalization is inhibited. Such twisted amides demonstrate unusually reactive chemical behaviour compared with typical amide bonds.

He then continues:

In 1941, during his studies on the synthesis of quinine, the young Harvard investigator (and eventual Nobel prizewinner) Robert B. Woodward thought deeply about the reactivity expected of this type of distorted amide. As one of his first graduate students, I was given the problem of synthesizing 2-quinuclidone. Originally, this research was largely of academic interest, but a few years later the expected chemical behaviour of twisted amides became an important issue in the determination of the structure of penicillin.

Stoltz said that he first learned about this molecule when he was house-sitting for Wasserman during graduate school. A few years later, EJ Corey mentioned the molecule to Stoltz (who was doing post-doctoral research in Corey’s laboratory), calling it a “classic unsolved problem in synthesis.”

If you’re interested in learning more about this molecule, you can download the CIF file from the Cambridge Crystallographic Data Centre and take a closer look at this highly-strained amide bond…


Joshua Finkelstein (Associate Editor, Nature)