The First Century of Ketenes (1905–2005): The Birth of a Versatile Family of Reactive Intermediates

An explosive history: Diphenylketene was isolated and identified by Staudinger (see photo) in 1905, as the first example of this class of highly reactive compounds. Others had previously generated these species, but missed the opportunity to claim their discovery. This Essay provides an enlightening view of the history behind these useful reagents. A carbanion intermediate was suggested by Clarke and Lapworth in 1907 to occur in the benzoin condensation,4a and the conversion of 1 or triphenylmethyl chloride with sodium into triphenylmethylsodium was demonstrated in 1914 by Schlenk and Marcus, who studied the ion pairing of the intermediate by measuring the conductivity.4b The name carbanion was coined by Wallis and Adams in 1933.4c These findings combined with an emerging understanding of the theory of organic chemistry incorporating reaction kinetics and stereochemical and structural studies created what came to be known as physical organic chemistry. After decades of work, argument, and controversy the pivotal role of reactive intermediates was well recognized by 1940, marked by the text "Physical Organic Chemistry" by Hammett.6 As pointed out by Leffler in 19561a reactive intermediates in reactions were assumed "which have not been isolable for direct experimental study" but whose existence could be inferred by comparison to observable species "of the same type as the hypothetical intermediate" and which "have a great variety of degrees of stability, depending upon their structures. The extrapolation to the properties of the hypothetical intermediate is therefore a continuous one." Now with vastly improved methodology many formerly hypothetical intermediates have been observed directly, and even isolated. There are still hold-outs which are too short-lived for observation, or whose preparation has eluded the synthetic skills of the investigators, and these provide a continuing challenge. In 1903 a young instructor (Unterrichts-Assistent) Hermann Staudinger joined the laboratory of Thiele at the Kaiser-Wilhelms-Universität of Strassburg (Strasbourg in French) in the Alsace.7a Strasbourg occupies a strategic position on the Rhine River on the border between Germany and France and over the centuries has been part of one or the other, depending on the political and military situation. After the Franco-Prussian war of 1870–1871 it had become part of the new Germany, and the University was endowed with an imposing chemical laboratory (Figure 1), which still stands.7b The University is now a prominent center of chemistry in France, the Université Louis Pasteur. Chemical laboratory at the University of Strasbourg, around 1960. Courtesy of Professor Jean-Marie Lehn. Hermann Staudinger (1881–1965). Courtesy of the GDCh (Gesellschaft Deutscher Chemiker (German Chemical Society)). Ludwig Wolff (1857–1919). Courtesy of the GDCh. Why is Staudinger and not Wedekind or Wolff credited with the discovery of ketenes? Recognition of priority for discoveries is of intense interest to scientists, but there is no apparent record of dispute between Staudinger, Wedekind, and Wolff. Staudinger was a highly prolific investigator, and with more than 50 papers and a book on ketenes12a following his 1905 work in rapid order, his position as the founder of ketene studies has not been challenged. The nature of chemical discovery has been discussed by Berson,12b and Staudinger's clear recognition of what he had discovered and extensive further study established him as the founder of the field. Wedekind had correctly identified the structure of the ketene as an unisolated reactive intermediate,10a but was not firm in his conviction and missed his opportunity. Staudinger's further career in the tumultuous development of polymer chemistry, as well as his complex personal life and sometimes outspoken political views, have generated much comment.12c–12e Wolff has the honor of two well-known named reactions, the Wolff-rearrangement and the Wolff–Kishner reaction, and can be satisfied that every student of organic chemistry still sees his name. Ironically Berson's comments on the need to recognize a discovery were directed at Fittig, Thiele's predecessor and Wolff's supervisor at Strassburg, who had discovered the rearrangement of pinacol with acid, but did not recognize what had occurred, and so the reaction is known as the pinacol rearrangement, an example of the broader class of Wagner–Meerwein rearrangement. As noted above Schröter was the first to formulate the ketene intermediate in the Wolff rearrangement,11c and by Berson's criterion Wolff does not deserve credit for the ketene discovery.12b N. T. M. Wilsmore (1868–1940). Courtesy of Dr. Andrea Stella. The Ketene Song There is a new substance discovered In a room that's just over the way. —The inventor's assistant recovered, Though it was a near squeak, doctors say—. But though it is ages & ages E'er the world saw as much as a grain, Later on you will hear, say the sages, Of keten again. It has quite a good constitution —C twice and H twice and an O—: And even in weakest dilution Of its presence you will very soon know. For the smell of that simple creation Will grasp at your nose & remain And hours after you'll sneeze in iration At ketene again. It's a simple enough preparation. You stick in acetic a wire Which gives the required dehydration When raised to a red heat or high'r. Then out comes a torrent of gases Bearing liquid along in their train: When this you have trapped ere it passes, You've keten again When the O.L. in slumber reposes And room No 7 is asleep Dr. Wilsmore, as usual, proposes To let loose the winds on the deep. And the sleepers, awakened, grab vainly After beakers that scatter like rain, While A and B rage quite insanely At ketene again. S. (A & B were two small research labs, and O. L. refers to the Organic Lab.) Staudinger and Klever shortly thereafter reported the preparation of ketene by the zinc debromination of bromoacetyl bromide.13c There was a brisk dispute between Staudinger and Wilsmore as to the priority for this discovery as well as to the purity of Wilsmore's sample of ketene and whether it had the formula CH2CO or HCCOH, another possibility noted by Wilsmore. This was resolved in favor Wilsmore and the ketene structure.13d,13e The development of ketene chemistry has been bedeviled with controversy, most prominently with the structure of ketene dimer 20 [Eq. (10)], originally suggested by Wilsmore in 190814a to have the acetylketene structure CH3COCHCO. This debate lasted for more than 40 years, and elicited the comment from one worker in the field "The extraordinary chemical behavior of the ketene dimers has lent exceptional interest to that class of substances, and the controversy which has raged for decades over the structures of the compounds is without parallel in the study of small molecules."14b This was finally settled definitively by chemical investigations,14c electron diffraction,14d and X-ray diffraction.14e The continual dispute regarding the chemistry of ketenes may be attributed to their extraordinary reactivity and unique structures. Hurd (Figure 5) was active in the discussion of the structure of diketene, and carried out many studies in ketene chemistry.15 He modified Wilsmore's procedure for ketene preparation by pyrolysis of acetone with the widely used apparatus known as the "Hurd lamp" (Figure 6).15e This method was also used for the industrial preparation of ketene for conversion into acetic anhydride. Charles D. Hurd (1899–1997). Courtesy of Northwestern University. Hurd lamp for ketene preparation (reproduced from Ref. [15 e] with the permission of the American Chemical Society). Horst Pracejus (1927–1987). Courtesy of Professor Matthias Beller, Universität Rostock. Among the distinctive characteristics of ketenes are their propensity for dimerization and their sensitivity towards hydration, but a notable exception is di-tert-butylketene (271 ). This ketene, which was prepared in the laboratory of Newman (Figure 8) at Ohio State University in 1960,19a is protected by its bulky substituents. Another exception is trimethylsilylketene (28), discovered by Shchukovskaya, Pal'chik, and Lazarev in 1965 in Leniningrad (now St. Petersburg; Russia) (Figures 9 and 10).19b,19c Neither of these ketenes is known to dimerize,19a,19b and both are much less reactive towards water than CH2CO. The stabilization by the trimethylsilyl group in 28 is due to the β-silicon effect and the general tendency of ketenes to be stabilized by electropositive groups through electron donation from ketenyl CM σ bonds to the in-plane carbonyl π orbital.19d The first acylketene was EtO2CCEtCO, also discovered by Staudinger in 1909,19e which was only stable at −80 °C, while the crowded example 29, first prepared in 1978 in Leningrad, appeared to be stable indefinitely as a neat liquid.19f Melvin Newman (1908–1993). Courtesy of Professor J. D. Roberts. Lidiya L. Shchukovskaya (1926–2002). Courtesy of Dr. Valerij Nikolaev, St. Petersburg State University. Adrian N. Lazarev (1928–1993). Courtesy of Dr. Valerij Nikolaev, St. Petersburg State University. William T. Brady (*1933). Courtesy of Professor Brady. Lee Irvin Smith (1891–1973). Courtesy of the University of Minnesota. Derek H. R. Barton (1918–1998). Courtesy of Professor Harold Hart, Michigan State University. Rolf Huisgen (*1920). Courtesy of the Universität München. Takahisa Machiguchi (*1940). Courtesy of Professor Machiguchi. Ketene chemistry in its first 100 years has been a microcosm of organic chemistry as a whole, with useful contributions in synthesis, theory, mechanisms, and practical applications. The major types of ketenes and their typical reactions as described above are now being increasingly applied in new and ingenious ways. Ketenes have always attracted many of the most talented individuals in chemistry, including many Nobel prize winners.23 Ketenes have found many industrial applications, ranging from the seemingly mundane manufacture of acetic acid and acetic anhydride, to the widespread use of ketene dimers from fatty acids as coatings for paper,24a the sophisticated application of the Süs photochemical Wolff rearrangement24b for the manufacture of the integrated circuits used in computer chips,24c,24d and the use of ketenes in the preparation of drug candidates. The unique structural features of ketenes and their high reactivity ensure the vitality of these species in their second century.