Angewandte. Essays

International Edition:DOI:10.1002/anie.201505507 1915 for German Edition:DOI:10.1002/ange.201505507 Richard Willstätter and the 1915 Dirk Trauner* ·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, began to launch on amassive scale by releasing gas in Flanders—and that at the behest of , aclose friend of Willstätter, with whom he had served as adirector at aKaiser-Wilhelm- Institute in Berlin-.[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 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 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”. and reflected on the mostly charmed life that he had led before. 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 — 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

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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 , 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 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 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 , Carl Koller,demon- gave racemic cocaine.Overall, the synthesis did not take place strated that the 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 “-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.

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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 its derivatives, immediately noted (Figure 4).[9] Using the alkaloid pseudo- Willstätter next attempted to synthesize the lower homologue [12] pelletierine,which could be isolated in large quantities from in the (CH=CH)n series,namely cyclobutadiene. For the root bark of pomegranate trees,asan“awesome starting reasons all too clear to the modern reader,this endeavor material” (“herrliches Ausgangsmaterial”), he was able to failed. arrive at cycloocta-1,3,5-triene (11)through reduction, dehy-

Figure 4. Willstätter’s synthesis of cyclooctatetraene from pseudo-pelletierine.

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Less well-known, but equally important are Willstätters underwent addition of aryl Grignard reagent 16.Subsequent investigations of quinones and quinone imines,inparticular acidification and ionization afforded flavylium chloride 17. his correct formulation of o-quinones and their relationship to Global demethylation and conversion into the chloride salt catechols (Figure 2).[13] His studies on purpurogallin, the then gave the anthocyanidin cyanidin. Other members of the oxidative dimerization product of pyrogallol, provided some series,such as pelargonidin, were available through variation important insights but yielded an incorrect structural formula. of the aryl Grignard reagent. In addition, Willstätter and his Willstätter was very fond of his work on tropane alkaloids students clarified the puzzling observation that virtually the and ,which occupied him until the end of his same compound could account for different colors depending career. His most famous and influential work, however, on the pH value of its source (Figure 5b). At low pH values, concerned adifferent topic, which he began to investigate in the flavylium cation predominates,which turns into the so- earnest after his move to Zurich:the plant pigments that called anhydrobase as the pH value nears neutrality.Further surround us in everyday life,inparticular chlorophyll and the deprotonation produces an anionic species that is also beautiful colors of flowers and fruits.[14] These had eluded brightly colored, albeit with abathochromically shifted chemists for decades until Willstätter, with his rigorous absorption spectrum. At even higher pH values,the addition approach toward purification and analysis,entered the field. of ahydroxide ion to the p-quinone methide moiety produced He was able to identify the colorants of geraniums,corn- acolorless chromenol anion that ultimately opens to the flowers,blueberries,roses,pomegranate seeds,grapes,black- corresponding chalcone (not shown). Although these pH currant, etc.asglycosides of certain flavylium ions,such as ranges do not necessarily reflect the physiological reality of pelargonidine,cyanidine,and delphinidine (Figure 2). Eluci- plants,where metal complexes can form with the anthocya- dating the structure and chemistry of these anthocyanins,and nidins,these studies indicated how asingle pigment, such as their glycosides,the anthocyanidins,must have provided no cyanidin, could account for the very different colors of small measure of satisfaction for Willstätter,who was an avid cornflowers,blackberries,blueberries,raspberries,cherries, gardener throughout his life and was partial to red wine. red cabbage,and roses. As before,hecomplemented his structural studies with Already in Munich, Willstätter and his students also began syntheses,inthis case of the aglycons,since selective to work on chlorophyll, whose importance for plant life had glycosylation methods were not available.These systematic been recognized but whose nature had also eluded chem- studies culminated in 1924 with syntheses of anthocyanidins ists.[14] This was mostly due to the fact that “chlorophyll” that are elegant and efficient even by todays standards consisted of closely related lipophilic molecules of fairly large (Figure 5a).[15] Thesynthesis of cyanidinestarted with phloro- molecular weight that were not tractable with the purification glucinol carbaldehyde (13), which underwent acylationand methods of the day,namely crystallization and distillation. Perkin reaction to yield the methoxycoumarin 14.Ester Although Tswett had introduced the principle of chromatog- cleavage and methylation then gave compound 15,which raphy in 1906, it was not widely adopted until well into the

Figure 5. Willstätter’s work on the anthocyanins. a) The 1924 synthesis of cyanidin.b)pH-dependence of its color.

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20th century,when Willstätters student picked German intellectuals to deny responsibility that was typical of up and refined the method.[16] Willstätters crucial insight was the propaganda in the early phase of the war. Other signees that chlorophyll could be cleaved into alipid side chain included Emil Fischer,Fritz Haber, Ernst Haeckel, Wilhelm (phytol) and chlorin-type tetrapyrroles that were amenable to Ostwald, , Max Reinhart, Wilhelm Rçntgen, and crystallization and purification. This enabled the determina- Wilhelm Wundt.[21] tion of the molecular formula and proved that magnesium was In addition to this,Willstätter found it difficult to regain an integral part of the molecule and not acontamination. His traction as ascientist after the war.Hemust have felt, at meticulous studies ultimately enabled the full structure times,that his best days as aresearcher were over. In 1917, elucidation by in 1940, which Willstätter himself acertain Robert Robinson published aone-step synthesis of and his students could not complete.[17] In addition, Will- tropinone,Willstätters signature molecule.This study made stätters investigations established that chlorophylls,with Willstätters efforts look abit outdated.[22,23] It did not help small variations,occurred across all photosynthetic plants and that Willstätter himself seems to have developed ideas along algae,thus making it likely that they were central to photo- similar lines.Hewas always gracious toward Robinson but, as synthesis.The mechanistic role of the chlorophylls was ahighly competitive man, he could not help noting in his ultimately clarified through crystallization and structure autobiography that because of the war and the incompetence elucidation of the photosynthetic center by Deisenhofer, of one of his co-workers “… the long planned condensation of Michel, and Huber in the early 1980s.[18] As such, three Nobel succinic dialdehyde with acetone dicarboxylic acid never took Prizes in Chemistry are associated with both chlorophyll and place.[..]Atthevery same time (my German Patent was filed Munich. in January of 1917 and the work was disclosed publically in In the course of his investigations on chlorophyll and front of the Bavarian Academy in July of 1917), we carried out photosynthesis,Willstätter isolated the chlorophyl- the synthesis of tropinone carboxylic ester from our Dahlem lase,which could cleave the pigments into atetrapyrrole succinyl diacetic ester [that is,diethyl 3,6-dioxooctanedioate, carboxylic acid and phytol under very mild conditions.This see Figure 6].”[24] Willstätter returned to succinic dialdehyde sparked his interest in and enzymatic ,which afew years later when he combined it with methylamine and occupied the later phase of his career. Unfortunately,his the monomethyl ester of acetone dicarboxylic acid to make studies on this subject were not as fruitful as the previous ones racemic cocaine and its diastereomers,which he then resolved on alkaloids and pigments,which provided aconsiderable and tested for biological activity.This four-step synthesis, amount of frustration to aman accustomed to ahigh level of repeated and optimized by Casale in 1987,[25] could have success. found practical applications if cocaine were not so cheaply In 1924, at the age of 52 and in good health, Richard available from Coca shrubs. Willstätter announced his resignation from the most presti- Even more frustrating must have been Willstätters gious chair in chemistry in Germany.Much has been attempts to clarify the structure of proteins and enzymes speculated about his motivations,and the rising anti-Semitism and understand the nature of enzymatic catalysis.His in Munich in the early 1920s is usually cited as the major approach toward structure elucidation—to purify and crys- cause.[1,19] It is true that parts of the faculty at the Ludwig- tallize—was unfortunately not successful with the proteins he Maximilians-Universität were deeply anti-Semitic,but they chose.Ithad served him well with the alkaloids,the were far from the majority and certainly not the dominant anthocyanins and anthocyanidins,and even the chlorophylls, voice in the Department of Chemistry,where colleagues such but it was afailure once he turned toward enzymes that were as Heinrich Wieland or Kazimierz Fajans set the tone.Atthe familiar to him, such as chlorphyllase.Hedid make significant student level, Willstätter had regularly to deal with anti- advances in protein purification using on silica gel Semitic manifestations,such as the degrading posters cited in and metal salts,but his samples stubbornly refused to undergo his autobiography.[19] It cannot have eluded him that one of his crystallization. That he had simply picked the wrong target brightest students,Richard Kuhn, whom he graduated summa became clear when Sumner published his work on crystalline cum laude in 1922, sympathized with the nationalist move- Jack bean urease in 1926, abreakthrough result that earned ment. It should be noted, however, that Willstätters resig- Sumner the Nobel Prize in 1946 (Figure 6d).[26] nation came at atime when the Nazi party numbered around Willstätter can hardly be blamed for structures that turned 20000 and was seen as more of afringe movement. That it out to be wrong or were unlikely on theoretical grounds would come to power through democratic elections nine years (Figure 6a). His formula for purpurogallin[27] and his futile later and establish adictatorship immediately thereafter was attempts to synthesize cyclobutadiene[12] simply reflect the foreseen by few. poor understanding of in his days.Erich Hückels It can be argued that the rising anti-Semitism, within the ideas were not formulated until the early 1930s and resonated university and beyond, was only one of the factors that drove little with synthetic chemists until the 1950s.[28] Richard Willstätter into early retirement.[20] Like Emil Willstätter seems to have struggled with more contempo- Fischer,who had committed suicide in 1919, he was deeply rary ideas regarding chemical structure and bonding.His distressed by World WarIand the private losses he suffered clinging to the formula of flavylium salts with a“tetravalent during that time.Hewas clearly loyal to the monarchy and he oxygen” (Figure 6b), which he still used in his 1942 autobiog- was offended by the idea that the war was caused solely by raphy,indicates that the octet rule and G. N. Lewis ideas German militarism and aggressiveness.Accordingly,he never took firm hold in his mind. It may also reflect the fact signed the “Manifesto of the 93”, amisfired attempt by that he saw “tetravalent oxygen” as his first original discovery

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Figure 6. Willstätter shortcomings and “failures”. a) His formula of purpurogallin and his attempt to synthesize cyclobutadiene reflect the poor understanding of aromaticity in the early 1900s. b) His formula of pelargonidine with “tetravalent oxygen”. c) Robinson’s celebrated one-step synthesis of tropinone, which Willstätter claims to have “thoughtof” as well, and his 1917 patent on cocaine. d) Sumner’s crystallization of Jack bean urease paved the way for modern protein and enzymology.The photograph is taken from Sumner’s original paper.[26] and that he felt abit cheated by his mentor , following the Kristallnacht in 1938. As aconsequence of lucky who took the credit for this concept. On the other hand, circumstances—he was in his beloved garden when the Willstätter himself was not shy of claiming his co-workers Gestapo showed up—he avoided detection and imprisonment results and moving aggressively into fields established by in Dachau. After an unsuccessful attempt to flee to Switzer- other researchers.This was particularly true for local anes- land via Lake Bodensee,hewas finally able to leave the Reich thetics,which Willstätters teacher Alfred Einhorn had with the help of his loyal students,although not without pioneered on the basis of certain (erroneous) ideas about leaving behind most of his possessions.[30] Settling in Muralto the structure of cocaine.Atatime when scientists considered on the shores of Lago Maggiore,hefound the time and energy fields (“Arbeitsgebiete”) as their fiefdoms and expressly to complete his autobiography.This book, simply entitled reserved the right to methodically reap the fruits of their “Aus meinem Leben” (“From My Life”), is one of the most discoveries,[29] this did not earn him universal admiration. beautifully written scientific autobiographies and should Another aspect that may have contributed to Richard appeal to everyone interested in the history of science and Willstätters decision to step down so early was the fact that the 20th Century.[31] It discusses Willstätters discoveries,his he could afford it economically.Hewas apopular and highly family life,his friendship with Adolf von Baeyer and Fritz paid consultant for the German and Swiss chemical industry Haber, and the circumstances of his emigration in much (e.g. for Bayer,Bçhringer,Merck, and Sandoz) and, as greater detail than can be provided here.Although it has the aholder of several lucrative patents,aman of considerable usual shortcomings of an autobiography,itremains the best wealth. He received several prestigious calls,such as an offer and most easily accessible source on his life and his times. to return to Berlin (as Emil Fischers successor), head the Richard Willstätter died in August of 1942, aged 70, at Siemens research laboratories,move to the newly established atime when victory over the Nazis was by no means assured Rockefeller Institute in Madrid (at the invitation of (the battle of Stalingrad took place in the winter thereafter). Ramón yCajal) or the University of Chicago,all of which Several of his discoveries,such as the anthocyanidins,cyclo- he declined. He preferred life as agentleman of leisure in octatetraene,the ortho-quinones,and the structure of cocaine, Munich, running asmall research program with his co-worker now belong to the canon of organic chemistry and will forever Margarete Rohdewald by telephone.After his resignation, he be associated with his name.Although he was at times too built avilla in amodern style in the most fashionable ambitious,hewill always remain amodel of ascientist who neighborhood (Thomas Mann lived nearby), which housed successfully operated in vastly different fields.His students his vast library and art collection. This,ofcourse,made him and postdoctoral colleagues were equally diverse:they aprime target for the Nazis,who harassed and humiliated him include Rudolf Pummerer (born as an Austrian and natural- after they came to power in 1933 and tried to arrest him ized as aGerman), Riko Majima (Japanese), Kazimierz

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Fajans (Polish), Arthur Stoll (Swiss), Lµzló Zechmeister [4] D. Martinez, Der Gaskrieg 1914 – 1918: Entwicklung, Herstel- (Hungarian), Richard Kuhn (Austrian), and Roger Adams lung und Einsatz chemischer Kampfstoffe,Bernard &Graefe, (American). With his rigorous scientific style and his uncanny Bonn, 1996. [5] R. Willstätter, Ber.Dtsch. Chem. Ges. 1900, 33,1160. ability to pick important scientific problems,heremains [6] H. Markel, The Anatomy of Addiction, Sigmund Freud, William ahuge inspiration for his successors.His legacy looms large in Halsted and the Miracle Drug Cocaine,Pantheon Books,New Zurich and Munich, which has largely recovered from the York, 2011. disasters that befell Richard Willstätter and his contempo- [7] R. Willstätter, Chem. Ber. 1901, 34,3163. raries and has regained much of its former beauty (Figure 7). [8] R. Willstätter, Chem. Ber. 1896, 29,392. Every spring, when the English Garden in the center of the [9] R. Willstätter,E.Waser, Chem. Ber. 1911, 44,3423. city turns green, and every fall when newly synthesized [10] A. C. Cope,G.Overberger, J. Am. Chem. Soc. 1947, 69,976. [11] W. Reppe,O.Schlichting, K. Klager,T.Toepel, Justus Liebigs anthocyanins account for red and orange colors,one should Ann. Chem. 1948, 560,1. pause for amoment to think of this great man. [12] R. Willstätter,W.von Schmadel, Chem. Ber. 1905, 38,1992. [13] R. Willstätter,R.Pfannenstiel, Chem. Ber. 1904, 37,4744. [14] Richard Willstätter—Nobel Lecture:OnPlant Pigments“. http://Nobelprize.org.Nobel Media AB 2014. http://www. nobelprize.org/nobel_prizes/chemistry/laureates/1915/ willstatter-lecture.html. [15] R. Willstätter,L.Zechmeister, W. Kindler, Chem. Ber. 1924, 57, 1938. [16] R. Kuhn, E. Lederer,W.Kindler, Chem. Ber. 1933, 66,488. [17] Hans Fischer—Nobel Lecture:OnHaemin and the Relation- ships between Haemin and Chlorophyll“. http://Nobelprize.org. Nobel Media AB 2014. http://www.nobelprize.org/nobel_prizes/ chemistry/laureates/1930/fischer-lecture.html. [18] a) —NobelLecture:“ThePhotosynthetic ReactionCentre from the Purple Bacterium Rhodopseudomo- nas Viridis”. Nobelprize.org.Nobel Media AB 2014. http://www. nobelprize.org/nobel_prizes/chemistry/laureates/1988/ deisenhofer-lecture.html;b)—Nobel Lecture: “A StructuralBasis of Light Energy and ElectronTransfer in Biology”.Nobelprize.org.Nobel Media AB 2014. http://www. nobelprize.org/nobel_prizes/chemistry/laureates/1988/huber- lecture.html;c)HartmutMichel—Nobel Lecture:“ThePhoto- syntheticReaction Centre from the Purple Bacterium Rhodop- seudomonas Viridis”. Nobelprize.org.Nobel Media AB 2014. http://www.nobelprize.org/nobel_prizes/chemistry/laureates/ 1988/michel-lecture.html. [19] R. Willstätter, Ausmeinem Leben, 2nd ed.,Verlag Chemie, Weinheim, 1973,p.338 ff. [20] F. Litten, Studien zur Geschichteder Mathematik und der Naturwissenschaften,Heft 32;München (Institut für Geschichte der Naturwissenschaften) 1999,VII, 88. Figure 7. The colors of Richard Willstätter.Top:The English Garden in [21] J. von Ungern-Sternberg,W.von Ungern-Sternberg. Menschen the center of Munich in May with chlorophyll (and carotene) in full und Strukturen. Historisch-sozialwissenschaftliche Studien, display.Bottom:The same in October,with anthocyanins dominating Bd. 21, 2.,erw.Aufl.,Peter Lang, 2013. the scene. [22] R. Robinson, J. Chem. Soc. 1917, 111,762. [23] A. J. Humphrey,D.OHagan, Nat. Prod. Rep. 2001, 18,494. [24] R. Willstätter, Ausmeinem Leben, 2nd ed.,Verlag Chemie, Weinheim, 1973,p.448 f. Acknowledgements [25] J. F. Casale, Forensic Sci. Int. 1987, 33,275. [26] J. B. Sumner, J. Biol. Chem. 1926, 69,435. Ithank Prof.Wolfgang Steglich, Prof.Heinz Langhals,Dr. [27] R. Willstätter,H.Hess, Justus Liebigs Ann. Chem. 1923, 430,269. David Barber,Dr. Oliver Thorn-Seshold, and Dr.Henry [28] E. Hückel, Z. Phys. 1931, 76,204. Toombs-Ruane for critical reading and valuable suggestions. [29] O. Diels,K.Alder, Justus Liebigs Ann. Chem. 1928, 460,98. [30] HeinrichWieland: Naturforscher, Nobelpreisträger und Will- stätters Uhr (Eds.: S. Wieland, A.-B.Hertkorn, F. Dunkel), Howtocite: Angew.Chem. Int. Ed. 2015, 54,11910–11916 Wiley-VCH, Weinheim, 2008. Angew.Chem. 2015, 127,12078–12085 [31] R. Willstätter, Ausmeinem Leben, 2nd ed.,Verlag Chemie, Weinheim, 1973.English version:R.Willstätter, From My Life, [1] TheNobel Prize in Chemistry 1915“. http://Nobelprize.org. W. A. Benjamin,New York, 1965. Nobel Media AB 2014. http://www.nobelprize.org/nobel_prizes/ chemistry/laureates/1915/. [2] R. Willstätter, Ausmeinem Leben, 2nd ed.,Verlag Chemie, Weinheim, 1973,p.232. [3] D. Stolzenberg, Fritz Haber: Chemiker, Nobelpreisträger, Received:June 15, 2015 Deutscher, Jude,Wiley-VCH, Weinheim, 1994. Published online: August 20, 2015

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