X-ray data showed that proposed β-lactam structure was right

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By today’s standards, penicillin is a pretty small molecule. But when Dorothy Crowfoot Hodgkin determined the antibiotic’s structure in 1945, it was the largest molecule yet to have its structure solved by X-ray crystallography.

That X-ray structure helped settle the debate over the structure of penicillin. After scientists figured out in 1943 that penicillin contains a sulfur atom, they had two main hypotheses of its structure. One hypothesis, advocated primarily by British organic chemist and future Nobelist Robert Robinson, thought the structure consisted of two five-membered rings connected by a single bond, the thiazolidine-oxazolone structure. The other side, led by Edward P. Abraham and Ernst B. Chain at the University of Oxford and Robert Burns Woodward at Harvard, was convinced that the structure consisted of a four-membered β-lactam ring fused to a five-membered ring.

The chemical evidence, much of it based on degradation, thermochemical, and spectroscopic studies, supported the β-lactam structure, but Robinson’s prominence and persuasiveness kept the controversy going. The crystal structure drove the point home. In May 1945, Hodgkin’s X-ray diffraction data showed that the β-lactam model was right. Even with the X-ray data, however, Robinson remained unconvinced.

The X-ray crystal structure of penicillin definitively showed that the β-lactam model, as shown in this model Hodgkin built, was correct.

The X-ray crystal structure of penicillin definitively showed that the β-lactam model, as shown in this model Hodgkin built, was correct.
Science Museum, London

Hodgkin and her colleagues grew crystals of sodium, potassium, and rubidium benzylpenicillin, the form then known as penicillin G in the U.S. and penicillin II in the U.K. The electron density maps didn’t form an isomorphous series, which made solving the structure more difficult. Hodgkin needed to draw projections of the different structures to the same scale and then rotate them until many of the peaks coincided.

Because the wartime work on penicillin was considered secret, the structure was not published until December 1945 and even then in tentative language. The unambiguous structure declaration was finally published four years later in “The Chemistry of Penicillin,” a behemoth 1,000-plus-page monograph featuring sometimes contradictory chapters written by many of the people involved in the wartime penicillin efforts of the U.S. and the U.K.

The X-ray structure of penicillin was “a considerable achievement,” Chain said in his Nobel Lecture in 1946.

“For the first time the structure of a whole molecule has been calculated from X-ray data, and it is the more remarkable that this should have been possible in the case of a substance having the complexity of the penicillin molecule,” he said. Hodgkin’s Nobel, honoring her structural work on not just penicillin but also the even more structurally complex vitamin B-12, came years later, in 1964.—Celia Arnaud

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