IN MEMORIAM DOI: 10.1002/ejoc.200901130 Discovery of the Michael Reaction Takashi Tokoroyama*[a] Keywords: Michael addition / History of science / Chemical creativity / Reminiscences This essay deals with the details of the discovery of the the Michael addition were observed prior to Michael’s crucial Michael addition reaction, focusing on Arthur Michael, an finding, and the validity of his credit as the discoverer is dis- American chemist, after whom it is named. Michael envis- cussed. At the same time, a general consideration is made on aged the possibility of an addition reaction of sodiomalonate chemical creativity with reference to the individuality in the ester or sodioacetoacetate ester to α,β-unsaturated acid esters career and the personality of A. Michael. and confirmed this by experimentation. Some instances of Introduction At classical school, Michael received private instruction in chemistry, and in his leisure time, he enjoyed performing [1–3] The Michael reaction, addition of stabilized anions chemical experiments in a home laboratory that his father (e.g., enolate) to α,β-unsaturated carbonyl and related com- had set up for him. Toward the end of his teens, he experi- pounds, is a prototype for the conjugate addition reactions enced a great trial: his plan to enter Harvard College was [4,5] of various nucleophiles that now find wide utility in or- foiled by a serious illness. After wavering about his future ganic syntheses (Scheme 1). career following his recovery, Michael decided to study chemistry in Germany. During a family sojourn in Ger- many in the summer of 1871 (the year of the establishment of the German Empire), Michael had the fortune to be ad- mitted to the Chemical Laboratory of Professor August W. Hofmann at the University of Berlin, notwithstanding his Scheme 1. insufficient chemistry background. A year later, Michael moved to the laboratory of Robert W. Bunsen at Heidelberg The reaction is named after the American chemist University, where he received basic training in experimenta- Arthur Michael (1853–1942), who was peculiar in both his tion, and after studying for two years, Michael returned to career and research activity. Details about his career, Berlin to work in the laboratory of Hofmann (1875–1878). achievements, and personality may be gleaned from his me- A first-hand account by an American professor outlines the moirs,[6] biographical articles,[7] and essays on his impetuous behavior of Michael in the Bunsen laboratory, works.[8–10] None of these, however, provides sufficient and it vividly depicts some aspects of Michael’s tempera- background on the chemistry, both specific to Michael’s ment and the nature of his experiments. C. L. Jackson, who work and state of the art at the time, his motives, and the studied with Bunsen and Hofmann at the same time as course of events leading to his crucial findings. Moreover, Michael and who later contributed greatly to education and his role in the discovery and the generalization of the research in organic chemistry at Harvard University in its Michael reaction is not always described correctly. It is the early stage, stated the following in his autobiographical aim of this essay, therefore, to bridge these lacunae and to speech:[11] establish Michael’s crucial role. “My next analysis was copper pyrites, then rhyolite (a rock), chrome ion and triphiline (a mineral phosphate). This last was suggested to me by Arthur Michael, who pro- Stumble in Youth and Studying Abroad posed we should do it together, so we started at the same Arthur Michael (Figure 1) was born in Buffalo, New time. He spoilt his work so often that he had to begin again York, on August 7, 1853 to a well-off real-estate investor.[10] seven times, but worked so fast that he got a good result at the same time that I plodded to the end of my single [a] Osaka City University, analysis.” 3-25-1 Makizuka-dai, Minami-ku, Sakai, Osaka 590-0114, To conclude his studies in Europe, Michael spent an ad- Japan Fax: +81-72-293-2303 ditional year working with Adolphe Wurtz in Paris and De- E-mail: [email protected] mitrij I. Mendeleev in St. Petersburg, and then, in 1880, he Eur. J. Org. Chem. 2010, 2009–2016 © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 2009 IN MEMORIAM T. Tokoroyama van’t Hoff and Joseph Le Bel in 1874 to explain optical isomerism, and the former had extended this idea to ac- count for the isomerism associated with the C–C double bond, that is, geometrical isomerism. However, a number of leading organic chemists at the time were skeptical about the highly imaginative and visual way in which young van’t Hoff made his explanation, and these chemists tried to solve the problem of C–C double bond isomers without a new concept. Therefore, in the early 1880s, when Michael started his research work in the U.S.A., the structural rela- tionship between maleic and fumaric acids, for example, was still in hot dispute.[15] In 1886, Michael proposed his own concept of alloisomerism,[10,16] which reduced the indi- viduality of the isomeric compounds to merely differences in energy content and withholding the structural implica- tion – the prefix “allo-” was assigned to the more-stable isomer, and thus fumaric acid was allomaleic acid. In this way, one could be, Michael contended, free from the spell of the uncertain and unreliable concept, and the method might be adaptable to the putative presence of more than two double-bond isomers and to contingent isomerism in Figure 1. Arthur Michael around 1886. Photo courtesy of the Digi- the case of methylene compounds like itaconic acid. In fact, tal Collections and Archives, Tufts University. he allegedly reported cases in which more than two isomers were found especially in cinnamic acid derivatives,[17] returned to America. He became an assistant in the chemi- though these were proved later to embrace polymorphic [18] cal laboratory at Tufts College and then, after a short compounds. In any case, Michael strived persistently to period, was promoted to a professor of chemistry. He de- maintain his stand on stereoisomerism, even after other voted himself to teaching and training his students as well chemists came to accept the new theory. as to his own research, successfully overcoming the disad- vantages of working at a small institution. Michael made great use of his ample knowledge and experience he ob- Towards the Crucial Experiments tained in Europe, and even used his own money to cover research expenditures. In 1887, Michael first reported on In the mid-1880s, Michael noticed a paper by M. Conrad [19] the reaction that bears his name. and M. Guthzeit that reported the formation of a cyclo- propane derivative by the reaction of diethyl 2,3-dibrom- propionate with diethyl sodiomalonate. The formulation Evolving Research Activity was based on an analogy with the case of W. H. Per- kin Jr.,[20] who assigned the diethyl cyclopropan-1,1-dicar- Michael’s early work, which began after his return to boxylate structure to the product obtained by the reaction Hofmann’s laboratory, seemed to be focused on various of 1,2-dibromethane with sodiomalonyl ester. At that time, separate problems in preparative and structural organic the cyclopropane structure was not yet generally accepted, chemistry. Among his noteworthy achievements was the as R. Fittig had coincidently conducted the same reaction first synthesis of natural phenol glucosides (helicine, salicin, as Perkin with a different aim and had assigned a vinyl methylarbutin, etc.),[12] work that began during his stay in malonate formula for the product.[21] Michael considered Paris. Chloroacetoglucose, the first of its kind, had been that the debate might be ended by his concept of alloiso- prepared by a French chemist,[13] and Michael treated it merism.[16a] Thus, he treated 2-bromacrylic acid ester with with potassium phenolate. The improvement of this method sodiomalonic acid ester and indeed found that the product led to the Koenigs–Knorr synthesis (use of more reactive was identical to that reported by Conrad and Guthzeit.[22] acetobromo sugars), known as an important standard Although Michael thought the product was the allo isomer method for glycosidation.[14] Another series of work at that of 2c, he would not be convinced of its formation via the time was on the constitution of coniine, a simple piperidine direct substitution of the vinylic bromine atom in 3 with a alkaloid, which was discontinued on the elucidation of its malonate residue. Considering carefully the reason why structure by the Hofmann group in 1885. both reactions starting from 2,3-dibrompropionate and 2- Around the mid-1880s, Michael’s interest in his research bromacrylate afforded the same product, he came to the gradually shifted to general and theoretical problems in or- realization that it might concern an addition reaction, pro- ganic chemistry. One of these foci was the problem associ- vided that in the Conrad–Guthzeit case the latter com- ated with geometrical isomerism.[10] The concept of the tet- pound formed from the former, initially by elimination. rahedral carbon atom was introduced by Jacobus H. Then, the two-way addition A and B was, Michael rea- 2010 www.eurjoc.org © 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Eur. J. Org. Chem. 2010, 2009–2016 Discovery of the Michael Reaction soned, possible (Scheme 2), and A would be preferred, as journals Liebigs Annalen and Chemische Berichte were the negative organic residue should add to the β-position merged with other European chemistry journals to form of the double bond by analogy of the addition reaction with EurJOC and its sister journal EurJIC.