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Richard Willsttter and the 1915 Nobel Prize in Chemistry

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Richard Willsttter and the 1915 Nobel Prize in Chemistry Angewandte. Essays International Edition:DOI:10.1002/anie.201505507 1915 Nobel Prize for Chemistry German Edition:DOI:10.1002/ange.201505507 Richard Willstätter and the 1915 Nobel Prize in Chemistry Dirk Trauner* cocaine ·Nobel Prize ·pigments ·Richard Willstätter · total synthesis InOctober of 1915, when World WarI had spiraled from TheNobel Prize must have been abittersweet coda for a“drunken brawl” into afull-blown catastrophe,the Nobel what was otherwise ahorrible year for Richard Willstätter, Prize in Chemistry was awarded to Richard Willstätter aGerman Jewwho had risen to the top echelons of science (Figure 1) “for his researches on plant pigments, especially and civil society.Atthe end of April, his only son Ludwig,by chlorophyll”.[1] Around the same time,itwas announced that all accounts abright and happy child, suddenly fell ill and died of diabetes,possibly diagnosed too late at atime when “an individual human life carried little weight”.[2] At almost the same time,Germany began to launch chemical warfare on amassive scale by releasing chlorine gas in Flanders—and that at the behest of Fritz Haber, aclose friend of Willstätter, with whom he had served as adirector at aKaiser-Wilhelm- Institute in Berlin-Dahlem.[3] In early May,the Lusitania was sunk by aGerman U-boat, all but ensuring that the US would abandon its formal neutrality and enter the war with its vast resources.Meanwhile,the second Battle of Artois (May 9– June 18, 1915) moved the frontline amere two kilometers at the expense of 180000 human lives. Willstätter must have found it difficult to find solace by immersing himself in his work as achemist. His fertile investigations on the structure and function of chlorophyll, amain justification for his Nobel Prize,and his ongoing studies on the synthesis of cocaine and related alkaloids had come to asudden halt for lack of co-workers and chemicals. Most of his students and several of his colleagues had been drafted and some had already fallen. Like most prominent chemists in Germany,hebecame heavily involved in the war effort. At least he could avoid the nastier aspects of chemical warfare,which had ensnared colleagues on both sides of the conflict. Willstätters team in Berlin worked on the improve- Figure 1. Richard Willstätter(1872–1942). ment of gas masks and is credited with the development of the “Dreischichtenfilter”. Consisting of layers of diatomaceous the Braggs,father and son, would receive the Prize in Physics earth and activated carbon soaked with potassium carbonate, “for their services in the analysis of crystal structure by means urotropine,and piperazine,this filter proved effective against of X-rays”and Romain Rolland the Prize in Literature “as lethal electrophiles,such as phosgene and mustard gas.[4] atribute […] to the sympathy and love of truth with whichhe During these dark days,Willstätter must have often has described different types of human beings”. Medicine and reflected on the mostly charmed life that he had led before. Physiology was not acknowledged that year,perhaps reflect- Born in 1872 as ason of Jewish merchants in Karlsruhe and ing an inability to agree on acandidate that would not favor growing up in the shadows of the Grand Dukes beautiful one of the war-faring nations.Understandably,1915, like the palace,Willstätter became an elegant and determined young year before,did not see aNobel Prize for Peace either. man who ultimately decided to study chemistry in Munich— then the epicenter of organic chemistry.Following the requisite examinations,hebegan to pursue graduate studies [*] Prof. Dr.D.Trauner Department of Chemistry and Center for Integrated Protein Science with Alfred Einhorn, with whom he tried to elucidate the Ludwig-Maximilians-Universität München structure of cocaine.With his obvious talent and energy, Butenandtstrasse 5-13, 81377 München (Germany) Richard Willstätter was soon admitted to the inner circle of 11910 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim Angew.Chem. Int. Ed. 2015, 54,11910 –11916 Angewandte Chemie Adolf von Baeyer, the towering figure of organic chemistry in cocaine contained aseven-membered carbocycle.Hearrived Munich and the founder of ahugely influential school that at the correct molecular formula shortly thereafter.Accord- also produced Emil Fischer, Heinrich Wieland, and Moses ing to the scientific standards of his days,the ultimate proof of Gomberg, to name but afew.Baeyer remained alifelong the structure required asynthesis to complement the analysis. mentor and friend of Richard Willstätter and helped him Indeed, Willstätter and his students were able to painstak- launch his independent career at the Ludwig-Maximilians- ingly rebuild cocaine from suberone,which was readily Universität, Munich (LMU). After afew highly productive available from octanedioic acid (suberoic acid, cork acid).[7] years,hereceived acall to the ETH Zurich (1905–1912), As shown in Figure 3, the ketone was first converted into followed by arelatively brief stint at the newly established cycloheptene via aminocycloheptane (1), then into cyclo- institute in Berlin-Dahlem (1912–1916). In 1916, Willstätter heptadiene (via 2)and cycloheptatriene.The latter underwent became Baeyers successor at his Alma Mater,where he addition of hydrogen bromide ( 3), followed by nucleophilic ! remained until his resignation. substitution with dimethylamine and reduction ( 4). A ! Willstätters work as an assistant professor in Munich was transannular aminobromination yielded ammonium salt 5, essentially acontinuation of his graduate studies on cocaine, which was demethylated and underwent elimination to afford the outcome of which he had found unsatisfactory (Figure 2). tropidine.Conversion of tropidine into pseudo-tropine via Cocaine was not only astructural problem that seemed bromide 6,followed by oxidation, gave tropinone,which tractable at the time,but it also was amolecule of great Willstätter had earlier identified as akey intermediate in the medical importance and very much en vogue in the late 19th series.[8] Tropinone was converted into ecgonine by carbox- Century.[6] After Sigmund Freud had unsuccessfully tried to ylation ( 7)and reduction with dissolved metal. Finally, ! launch his career on cocaine as aremedy for morphinism, his Fischer esterification with methanol ( 8)and benzoylation ! colleague at the University of Vienna, Carl Koller,demon- gave racemic cocaine.Overall, the synthesis did not take place strated that the alkaloid was an excellent local analgesic for in the linear fashion shown in Figure 3but occurred in several operations on the eye.Unfortunately,Koller (henceforth interlocking phases.The last missing link was the trans- known as “Coca-Koller”) was forced to abandon his promis- formation of tropidine into pseudo-tropine,which was ing career as aresearcher soon thereafter due to an anti- achieved in 1901. Willstätter was well aware that the whole Semitic incident that resulted in aforbidden duel and his effort amounted to a“total synthesis”. He proudly wrote at subsequent dismissal. the end of his 1901 paper:“Durchdie Umwandlung von By using aseries of Hofmann degradations,Willstätter Tropidin in y-Tropin ist die Synthese der Solanaceen-Alka- was able to trace cocaine to cycloheptatriene carboxylic acid loïde Atropin, Atropamin, und Belladonnin, sowie des Co- and then to suberone,thus establishing the crucial insight that caalkaloïds Tropacocaïn und die Synthese von racemischem Figure 2. The successes of Richard Willstätter. Besides the first synthesis of proline,[5] he is credited with elucidating and synthesizingseveral tropane alkaloids, including cocaine, the first synthesis of cyclooctatetraene, o-quinone, and p-quinone diimine, as well as the elucidation and synthesis of several anthocyanidins. He also contributed substantially to the structural elucidation of chlorophyll, established its magnesium content, and discoveredanenzyme, chlorophyllase, which could cleave the molecule into its components. Angew.Chem. Int.Ed. 2015, 54,11910 –11916 2015 Wiley-VCH Verlag GmbH &Co. KGaA, Weinheim www.angewandte.org 11911 Angewandte. Essays Figure 3. Willstätter’s virtually protecting-group-free 1901 synthesis of racemic cocaine. Cocaïn vollständig geworden.”(“Through conversion of dration ( 9), and twofold Hofmann elimination ( 10 11). ! ! ! tropidine into y-tropine,the syntheses of the Solanaceae Bromination of 11,followed by nucleophilic substitution with alkaloids atropine,atropamine,and belladonnine,aswell as of dimethylamine,which had served him so well in the tropane the Coca alkaloid tropacocaine,and the synthesis of racemic series,then gave the diamine 12,which once again underwent cocaine have become total.”)[7] twofold Hofmann elimination to yield cyclooctatetraene. Unusually for his time,Willstätter was not only interested Lingering doubts about the viability of this simple route and in natural products and associated drugs but also in molecules the identity of cyclooctatetraene were finally laid to rest in that would advance the theory of organic chemistry.In 1947, when Arthur Cope repeated Willstätters experiment aliteral extension of his investigations on highly unsaturated and confirmed his results.[10] In the meantime,Walther Reppe cycloheptenes,heturned to compounds with eight-membered had obtained the same material through the nickel-catalyzed rings.These studies resulted in his seminal synthesis of tetramerization of acetylene.[11] cyclooctatetraene,whose marked difference to benzene he Trying to grasp the essence of benzene and
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