The Handed World: From d and l to (R) and (S): discovery of absolute configuration
Creators: name: Rzepa, Henry
Publisher: name: Zenodo
Year: 2020
Subjects: How the absolute configuration of chiral molecules was established

description: The main actor in the prologue to my story is Emil Fischer, who in the 1890s set out on an odyssey to prove by chemical synthesis van't Hoff and Le Bel's famous 1874 hypothesis that for an organic molecule containing <em>n</em> asymmetric carbon atoms (carbons bearing four different substituents in a tetrahedral arrengement), there could be up to 2<sup><em>n</em></sup> three-dimensional stereoisomers. This in turn led to the development of Fischer's famous notation, a map-like projection from three into two dimensions applied to the carbon backbone of the linear forms of glucose and its 15 stereoisomeric forms (2<sup>4</sup> = 16), of which Fischer actually made 12. Historical accounts however rarely note Fischer's remarkable proof in 1914 that if two different substituents on a tetra-substituted asymmetric carbon are transposed by chemical transformations without breaking any of the bonds to that carbon to produce a non-superimposable stereoisomer (a process equivalent to reflection of the three dimensional structure of the molecule in a mirror), the sign of the measured optical rotation (known as [α]<sub>D</sub>) inverts but its numerical value is unchanged. Fischer thus set a formidable challenge; how to link the signed value of [α]<sub>D</sub>measured for an asymmetric molecule with the one or other of its mirror image forms. This became known as the problem of absolute configuration and is encapsulated in his reference molecule for sugars, D-(+)-glyceraldehyde. Here D is the (modern) notation for the absolute configuration of one of the mirror image forms (L being the other) and (+) is the sign of its measured optical rotation at the wavelength of sodium D-line (589nm). Fischer's association of D with (+) was a pure guess. But how to prove this guess was correct? Having thus set the scene, the main act will tell of attempts by three later actors to respond to this challenge. The first notable attempt was by Werner Kuhn in 1936 and the next a most intriguing and largely unheralded effort in 1937 by John Kirkwood, both using the new theories of quantum mechanics which had been introduced well after Fischer's guess. The final denouement in 1951 was by Johannes Bijvoet using experimental crystallography and which finally proved Fischer's guess to be correct. Nowadays, the latter receives most of the credit, but was it an erroneous sign in his (1937) equations that resulted in Kirkwood's theoretical attempt being scuppered? Or was it that chemists (unlike physicists, <em>vis</em> Einstein predicting gravitational waves or Dirac predicting the positron) were not yet ready to trust theoretical over experimental verification? In his 1937 analysis, Kirkwood candidly sets out an important uncertainty in his linkage between the sign of [α]<sub>D</sub> and absolute configuration as being the flexible shape or conformation of the molecules. In this he prepared the stage for players such as Derek Barton in 1948 to formulate a Nobel prize-winning area of chemistry, conformational analysis. Only in 1952, a few months after Bijvoet's work, did Kirkwood report a way of side-stepping the conformational ambiguities of his original choice of molecule with a more rigid system, thus (independently of Bijvoet) verifying Fischer's guess. Bijvoet's assignment of absolute configuration to sugars, and by inference to amino acids, was rapidly accepted and in turn set the stage for two further Nobel-worthy scientific advances to be made at around the same time, the three dimensional helical structures of some proteins and of DNA by respectively Pauling and Watson and Crick. Both discoveries relied on the absolute configurations of amino acids and sugars to infer, <em>inter alia</em>, the right-handed nature of the helical motifs in both proteins and DNA. My epilogue notes that although Fischer's stereochemical notation was a great advance, it applied only to sugars and was also associated with much confusion (such as two quite different meanings of the <em>d</em>/<em>l</em> notations). This problem was soon solved with articles written between 1951-56 by Cahn-Ingold-Prelog (known affectionately as CIP). These changes in nomenclature, along with advances in representing the stereochemistry of molecules using line diagrams with perspective after the 1950s, means that confidently comparing pre-1950s literature with modern CIP notations remains a challenge, especially when writing talks such as this one! You can see one part of this story retold at DOI: 10.14469/hpc/6368 with more detail. The cast Emil Fischer, 1852-1919, John Kirkwood, 1907 - 1959, Johannes Bijvoet, 1892 - 1980, Derek Barton, 1918 - 1998, Linus Pauling, 1901- 1994, Francis Crick, 1916 - 2004 + James Watson, 1928 - present, Robert Cahn, 1899 - 1981 + Christopher Ingold, 1893 - 1970 + Vladimir Prelog, 1906 - 199 (CIP)