Week 13 Mega Chemist Challenge Solution

This weeks solution was Howard E. Zimmerman; congratulations to Mr Mears. [The folk musician was of course Bob Dylan, aka Robert Zimmerman. Have a fitting Bowie track to play as background music whilst you read].

Zimmerman sadly died earlier this year, less than two years after his retirement from the University of Wisconsin – Madison, where he had been the Hilldale and A. C. Cope Professor of Chemistry since 1990. Following the Second World War in which he served as a tank gunner, Zimmerman completed undergraduate (1950) and postgraduate studies (1953) in chemistry at Yale University, Connecticut. Zimmerman then moved to Harvard as a post-doctoral researcher under the supervision of the preeminent R.B. Woodward. Following his time at Harvard with Woodward, Zimmerman moved to the Northwestern University as an Assistant Professor, before moving to the University of Wisconsin where he remained for the following 40 years, until his retirement in 2010. Zimmerman’s son caught the chemistry bug off his father and Steven C. Zimmerman‘s is currently the Head of Chemistry at the University of Illinois.

Zimmerman was a internationally leading physical organic chemist and was renowned in the fields of quantum chemistry and molecular orbital theory. Zimmerman was also a leading pioneer in the field of photochemistry, for which he received the inaugural Northeast ACS Award for Photochemistry in 1971. Zimmerman has had an astounding academic career, and the ‘Z group’ have published nearly 300 papers over the years, though Zimmerman’s most cited paper was published early in his career in whilst he was working as Assistant Professor at Northwestern. This 1957 paper is now most definitely considered a ‘classic’, and is a paper ALL organic chemists should read (DOI: 10.1021/ja01565a041). It was written with Majorie D. Traxler and was the seminal paper introducing the now widely cited Zimmerman-Traxler transition state model.

The Zimmerman-Traxler model is probably most recognised for its application to determining the stereochemistry of metal mediated aldol reactions that proceed via a 6-membered transition state, though Zimmerman’s seminal work was actually reported as the “Stereochemistry of the Ivanov and Reformatsky reactions” (scheme 1). The parallels between all three reactions are clear in the respect that they can be generalised as the nucleophilic addition of metal-enolates and carbonyl groups (primarily ketones and aldehydes).

Zimmerman proposed that the Ivanov reaction should result in the formation, as retrospectively we would assume automatically, of two possible diastereoisomers. Despite a lack of literature precedent at the time supporting this assumption [1], Zimmerman began investigating the Ivanov condensation of benzaldehyde with phenylacetic acid, and after what sounded like a laborious sequence of recrystalisations, identified two compounds with distinct melting points.  A switch to what would now be most peoples first port of call, column chromatography, eased the pain and allowed the isolation of two diastereoisomers of 2,3-diphenyl-3-hydroxypropionic acid and 2 in 91% overall yield, and in a ratio of ~3:1.

Without access to 2-D NMR (the application of NMR to liquids and solids was only reported 10 years earlier) or facile x-ray crystallography, Zimmerman and Traxler set about derivitising their products to known compounds to determine the stereochemistry of the major and minor isomers (scheme 2). Fisher esterification and conversion to the respective hydrazides followed by Curtius rearrangement gave oxazolidones and 4. Comparing melting points of the synthesised compounds with authentic samples determined the major diastereoisomer as the threo compound (syn) and the minor as the erythro (anti). Zimmerman, on the basis that reaction was a result of sigma-bond formation through orbital overlap of the electron rich p-orbital of the enolate and the electron deficient p-orbital of benzaldehyde, and that it was likely that co-ordination of the carbonyl oxygen by magnesium would occur intramolecularly, suggested transition states that may account for the observed selectivity.

You can see that of three chair transition states 5a-c and three alternate transition states 6a-c (suggestions please – Zimmerman’s TS doesn’t really seem to fit any of the traditional conformations to me and my drawing is definitely more boat-like than his) only 5a does not result in significant phenyl-phenyl interactions at any stage of the bond-forming process. This was cited as the reason for the observed selectivity, and considering the continued citation of this paper today, it seems most of the organic chemistry world is in agreement. This now seemingly obvious model for determining stereochemistry was at its time absolutely groundbreaking, and the fact that it is now applied far and beyond the Ivanov and Reformatsky reactions is a true indictment of its significance.

[1] No isolated examples with product distribution had been reported at the time.


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