Bull. Hist. Chem. 22 (1998) 2
WHEN PIPERIDINE WAS A STRUCTURAL PROBLEM
Ed r W. W rnh ff, Un v r t f W t rn Ont r
In 8 0 A t f nn n nd n p bl h d h b ph ll t r n r (5). S n p p r n r n l d v l p d th d f r d r d n n , h h t th xt nt f 0% n p pp r rn fr v r h l t r t ll xh t v th l t n, n l d n r (6, nd l xtr t bl b l h l, t nt n f t p t nt l n l l d ( . W th n r d l v l bl t th h l n t r n 8 2 A t C h r n r n r E r p . In f t, p p r n b f th n n d th l t n f n l d b , r t l nt r t n nn t n th rl p p r d n , C , fr p pp r (2 . p l t n n th n t r f pl nt l Wh n r n tr t r l th r n l : W r th r l t n f tr d d n 8 8, th n t t t n f p n th rb n p nd, r, p r d n b pr bl h h t b h d t d, d d th b l n d t h v b n t l r— d f r t th l f d [h r n n n f nn n pr d r . Wh l t r n r d l tt h d t 2] ( ,8 ? n h rd t b l v th t h In r nt th th l tt r v , pl l l ld h v ff r d d f h d r W rth t nn n ll b f lt , t n t nt l b t 88 th t r t n th r dr h hl d r t th tr t r f p p r d n t b b r f nd n 84 th t p p r n l h d. Ir n ll , lth h t f nn pl t b l l nt n d nd h lf h v nt ll ppl d th xh t v l d b h h th d nt f d n l n th l t n pr d r t p p r d n , h n bl t n [ n n n 826 ( ] l l n th b f C, nd t rpr t rr tl th r f th r t n b f r Alb rt t n l f th hl r pl t n t ( 0 . t r n 84 d nb r xpl n d t n 88 . h pr b bl r n W rth h n d h nd ( nd d d d th t th f r th l p ll th r r p t f th rl l d b f t b tt r th pr p rt f th r p h tr f p p r d n r fr th l t r t r , h h l n [n n n t b ] r ntl d v r d n 846 n t bl f r th t ppr h t n t h t ( 2, . Oddl n h, W rth d n nt n f n d r d proof of structure. th b l n p nt f h b v n th h th r p rt d Piperidine became available early in the develop- t ph r b l n p nt f r n l n [ 82°C ( 4 ] nd ment of organic chemistry, at a t h n f l d p l n [ °C ( 2 ] d ff r d d l h pp r ntl h d r n b r known, because it happened to be a n t d t r n d th r t l ph l pr p rt component of the crystalline alkaloid piperine, It th p t t v d nt f t n p l n th t C17H19NO3, which had been isolated as early as 1820- l d th r n h h t A t C h r t r p t 21 from pepper (Piper nigrum) b n Chr t n O r W rth l t n. C h r h d t t d n C p nh n ( , 4 , h t d th n , nd p r n f p l n th n l n , p rh p th th f d t r n n th b f r th r r . t ll
30 Bull. Hist. Chem. 22 (1998)
rivatives. He further surmised that the two alkyl groups attached to the nitrogen atom might be ethyl and ally!. Beyond this in 1853 there was not much more that could be done in investigating piperidine. Hofmann at this time the Professor of Chemis- try at the new Royal College of Chemistry in London. Cahours and Hofmann were already known to each other from having corresponded regularly about chemical matters of common interest (19). On a visit to Paris in 1850 Hofmann took the opportunity to become person- ally acquainted with Cahours (19); the two chemists hit it off well and became good friends. When Cahours visited London for several weeks in 1855 to learn about the state of chemistry there, he stayed with Hofmann, and they began joint investigations which resulted in publications on two topics, neither of which involved nitrogen chemistry (19, 20). They must have discussed piperidine during their time together in London or else in letters, but it was too early for collaboration on a struc- ture for this alkaloid fragment. However, after the struc- tural theory of 1858 had been introduced, the question A t — h C h r 8 - 8 of the structure of the simple piperidine molecule must surely have entered both their minds. Rather puzzlingly, tion of a mixture of piperine, water, and potassium/cal- Cahours never published on piperidine again, even cium hydroxide, followed by addition of more potas- though he did work on the structure of nicotine in 1879- sium hydroxide to the distillate, caused the separation 83. Nor did Hofmann take up the problem until much of an oily base which Cahours distilled twice to obtain a later. Cyclic structures were unknown at this time, and colorless basic liquid of strong ammoniacal odor and perhaps Cahours and Hofmann, considering only constant boiling point 106°C (15). Although he did not l arrangements, regarded the question of which simple say so, it was presumably this boiling point, much lower alkyl groups were attached to the secondary nitrogen than that of either aniline or picoline, which first indi- atom as being relatively unimportant. cated to Cahours that he actually had a different base; During the period from 1857 to 1878 several chem- he named the new compound piperidine because of its ists worked on piperine, but they were more interested source (16). in the non—basic part from its hydrolytic cleavage (21). Analysis of the free base and eleven of its crystal- Wertheim continued studying piperidine, and in 1863 line derivatives fixed the formula as C H N [in Cahours' he investigated the nitrosation reaction and its reversal H11terms C10H11Az] Az] which was confirmed by two vapor but got no further before his early death in 1864 (22). density determinations, altogether a very thorough piece In 1871 Karl Kraut in Hannover made several salts from of work for the time (15). Cahours made no mention of the adduct of piperidine and chloroacetic acid but did the fact that his analysis of the chloroplatinate of the not comment on the structure of the base (2 . Ev nt base from piperine differed appreciably from Wertheim's ll v d n f nt r t on Hofmann's part came analysis of [presumably] the same derivative, but he did from a paper appearing in 1871, the first paper of the state that piperidine differs completely in composition twenty one-year old graduate student Julius Brühl, pub- and properties from picoline with which Wertheim had lished from Hofmann's Berlin laboratory (24). In it confused it (17). It is surprising to the modern reader Brühl pointed out that the constitution of piperidine was that no melting points are reported in either Cahours' or still not known, and he prepared some salts in the hope Wertheim's papers; melting points had not yet come into of transforming piperidine into a member of a known general use as criteria of identity or purity (18). Rely- group of compounds, but without success. By now a ing on Hofmann's work on amines, Cahours concluded cyclic structure was beginning to be considered because that piperidine was an imide base [= secondary amine] Brühl remarked on the likelihood that piperidine was since it formed mono- methyl, ethyl, and [iso]amyl de- formed from the entry of a bivalent C 1-1 0 group into
Bull. Hist. Chem. 22 (1998) 31 ammonia (25). Finally in 1879, Hofmann published his group when dimethylpiperidinium hydroxide was dis- first work on the structure of piperidine (26). tilled. When he found by analysis that no alkyl group Although by 1870 five— and six—membered rings had been lost, and the product, C 7 H 15 N, named were becoming generally accepted [ . . benzene (1865), dimethylpiperidine by him, formally contained two pyridine (1869-70), pyrrole (1870)], Hofmann pointed methyl groups added to piperidine, he was puzzled by out that current chemical thinking still supposed that this apparent violation of his own rules for decomposi- piperidine C5H 10NH contained two alkyl groups, one tion of quaternary ammonium salts: It was not possible being unsaturated, such as ethyl and ally' or methyl and to add two methyl groups to the secondary nitrogen atom crotonyl, a view unchanged since Cahours' statement in of piperidine and still have a tertiary amine. As a way 1853 (15). He did not employ his exhaustive methyla- out of this quandary, Hofmann was initially inclined to tion method at first but instead tried to remove one of think "dimethylpiperidine" might be a the [supposed] alkyl groups by the well-known proce- dimethylangelylamine [angelyl = CH 3—CH=C(CH 3)— dure of heating with the strongest hydrochloric acid for CH2—]. Although this idea was close to the truth, he days in a sealed tube, even up to 300°C, but no alkyl rejected it on the basis of the following experiment: halide was split off (26). Nor did dry distillation of the When the dry hydrochloride salt of "dimethylpiperidine" hydrochloride salt give an alkyl halide. Reaction of pi- was heated, methyl chloride was evolved. The residue peridine with bromine in a sealed tube at 200-220°C from this pyrolysis on treatment with alkali yielded a afforded a crystalline product of dehydrogenation, C5H3NOBr2, soluble in hot hydrochloric acid and in so- dium hydroxide solution, which Hofmann was tempted to consider a pyridine derivative. However, because he was unable to obtain the same crystalline product from the reaction of bromine with pyridine [instead a dibromopyridine, m.p. 109-110°C, now known to be the 3,5-dibromo—isomer, was isolated], he did not insist on the crystalline product being a pyridine compound (26). Hofmann was not the only chemist concerned with the structure of piperidine. Fortuitously in the same year, 1879, the young Wilhelm Koenigs at Munich announced in the r ht that he had been able to oxidize piperi- dine directly to pyridine, albeit in low yield, with con- centrated sulfuric acid at . 300°C (27). The pyridine was identified by odor and C,H and Pt analyses of its chloroplatinate salt. He felt confident that the forma- tion of pyridine was structurally meaningful and not an artifact of cyclization, probably because he also found that ethylallylamine gave no trace of pyridine when heated with sulfuric acid (27). Therefore Koenigs pro- posed the reduced pyridine [ . ., cyclic pentamethylenimine] structure for piperidine. Almost two years later in 1881 Hofmann finally reported on the application of his exhaustive methyla- tion method to piperidine, first in a preliminary notice August Wilhelm Hofmann 1818 1892 (28) followed shortly by the full description (29). While the method had been announced 30 years previously (1), liquid base which he reported to have the same boiling this was the first application to a compound of unknown point 107° C as the known monomethylpiperidine and structure. Hofmann was well aware of Koenigs' oxida- to form the same crystalline chloroplatinate derivative tion of piperidine to pyridine, but he was skeptical of as methylpiperidine. Hence, whatever the structure of the significance of the result because of the low yield the C5—portion of piperidine might be, Hofmann believed and brutal conditions; he was still thinking in terms of a [mistakenly as it turned out] it to be unchanged by the dialkylamine and was expecting removal of an alkyl exhaustive methylation to "dimethylpiperidine." 32 Bull. Hist. Chem. 22 (1998)
Hofmann's solution to the problem was to suggest Hofmann continued work on the dehydrogenation and that during methylation the second methyl group intro- found that N—acetylpiperidine would react exothermi- duced had become attached to a carbon atom of piperi- cally at room temperature with two molecular equiva- dine. In proposing this he was unfortunately misled by lents of bromine to form dibromopyridine [3,5—isomer], his own earlier work in which he and Ernst Mylius had monobromopyridine [presumably the 3—isomer], and found that trimethylanilinium iodide did undergo ther- pyridine (33). Hofmann now accepted the cyclic x— mal change above 220°C to N,N—dimethyltoluidine ring structure for piperidine, but he still did not under- [ortho from its b.p.], overall a true case of methyl mov- stand the exhaustive methylation results. ing from N to C (30). Finally in 1883 Albert Ladenburg, who had been After another methylation of the "dimethyl- working on the reaction of piperidine hydrochloride with piperidine" and distillation of the quaternary hydrox- methanol, had the insight to see clearly what had hap- ide, Hofmann was again surprised to obtain trimethy- pened when dimethylpiperidinium hydroxide was lamine and a liquid hydrocarbon C5H8 , but he did not heated: one of the ring bonds to nitrogen had been bro- comment on the apparent return of the methyl group ken, and "dimethylpiperidine" was really from carbon to nitrogen. The liquid hydrocarbon, b.p. CH2=CH—H2—CH2--N(CH 2. rth r th l t n nd d 42°C, which he named piperylene, afforded a crystal- p t n pr d d tr th l n nd p p r l n line tetrabromide, m.p. 114.5°C. He considered sev- h h d nb r f r l t d C 2=C —C 2— eral possible structures for C =C 2 ( 4 . M h l t r t piperylene, but a straight chain f nd th t p p r l n pentadiene was not one of them. r ll th nj t d
In fairness to Hofmann, the two p nt d n C 2 =C unexpected results forced him C =C —C (35), but to reconsider what result to ex- d nb r h d n r n t pect if piperidine actually did p t th . have the cyclic In th b nt t pentamethylenimine structure. r 88 8 d nb r He concluded that upon loss of d f rth r d v r th t trimethylamine, the carbon r v d n l n r n d bt chain would reclose to give b t th tr t r f p p r cyclopentene (31)! He realized d n . r t h n d t that this was obviously not the l t ll nt f p p r case because cyclopentene, al- d n fr th d th n l though not yet known, would r d t n f p r d n ( 6 nd give a dibromo derivative. At l t r pr v d th pr d r t the end of this publication (29) v l t pl t r d Hofmann was left without a t n f p r d n nd b tt r structure that would explain to ld f p p r d n ( . his satisfaction all of the experi- Alb rt d nb r 842 n ll , dr d t ll t n f , — mental results. p nt th l n d n Even a year later, after Hofmann's co—worker Carl d h dr hl r d pr v d d d r t nth f p p r Schotten exhaustively methylated N—benzylpiperidine d n fr n n l pr r r ( 8 . and obtained N,N—dimethylbenzylamine plus A n t d rl r, f nn j r t bl n bl piperylene, i.e. the same outcome as with piperidine it- t nd r t nd n th tr r f th d r d t n f self, the true course of the exhaustive methylation reac- th t rn r h dr x d f p p r d n h nv tion still did not become apparent to them (32). Schotten t n th t th p p r d n tr t r h d rv v d th r was also able to convert piperidine directly to t n n h n d. Wh l h h d n d r d th p b l dibromopyridine by the action of bromine on dry pip- t th t l p p r d n ht h v b n p n d n eridine hydrochloride at a much lower temperature h t n th t rn r n h dr x d , t d d n t (180°C) than for Koenigs' sulfuric acid reaction, but he r t h th t r n ht h v b n r l d d r did not comment on any possible significance of this n th pr p r t n nd p r l f th h dr hl r d observation for the cyclic structure of piperidine. lt f "d th lp p r d n " (2 d nb r d d r l Bull. Hist. Chem. 22 (1998) 33
ize this possibility. Only later in 1891 did Georg Merling von Pfeffer und die Anwesenheit von Piperidin in carefully demonstrate that "dimethylpiperidine" did demselben," Chem. Zentralbl., 1889, 60-1, 481-482. cyclize on treatment with hydrogen chloride, not to N- 7. Piperidine itself actually occurs in traces in pepper, but methylpiperidine, but to the isomeric N,a- it was not detected until late in the nineteenth century dimethylpyrrolidine, b.p. 96-97°C (39). The two com- (Ref. 6b). 8. J. Liebig, J.C. Poggendorff, and F. Wöhler, pounds can be distinguished by boiling point (10° dif- Handwörterbuch der reinen und angewandten Chemie, ference) and by melting points of derivatives to which F. Vieweg und Sohn, Braunschweig, 1842 (fascicle Hofmann's laboratory had evidently devoted insufficient 1840), Vol. I, pp. 697-699. care. 9. (a) O. Unverdorben, "Über das Verhalten der organischen The problems in Hofmann's laboratory over the Körper in höheren Temperaturen," Poggendorff's Ann. struggle to visualize the changes occurring during the Phys., 1826, 8, 397-410; (b) J. Fritsche, "Über das stepwise exhaustive methylation of piperidine and the Anilin, ein neues Zersetzungsproduct des Indigo," Ann. two—year lag before the correct explanation was forth- Chem. Pharm., 1840, 36, 84-90. coming from another laboratory reveal in a striking 10. F. Rochleder and T. Wertheim, "Constitution der manner the difficulty chemists had in adjusting their organischen Basen," Ann. Chem. Pharm., 1845, 54, 254- 256. thinking to include the consequences of cyclic structures. 11. T. Wertheim, "Über das Piperin," Ann. Chem. Pharm., A similar and even more difficult situation would be 1849, 70, 58-73. experienced somewhat later when three-dimensional 12. T. Anderson, "Über Picolin: eine neue Basis aus dem cyclic structures were encountered in terpene and alka- Steinkohlen—Theerbl," Ann. Chem. Pharm., 1846, 60, loid investigations. 86-103. 13. No one who has ever smelled aniline and alpha—picoline ACKNOWLEDGMENT could confuse the two or mistake piperidine for either; Wertheim was evidently not personally familiar with The author would like to thank Professor Alan Rocke either of the known bases. for commenting on a preliminary draft of this manu- 14. A. W. Hofmann, "Chemische Untersuchung der script. organischen Basen im Steinkohlen—Theeröl," Ann. Chem. Pharm., 1843, 47, 37-87, esp. p. 50. REFERENCES AND NOTES 15. A. Cahours, "Recherches sur un nouvel alcali dérivé de la pipérine," Ann. Chim. (Paris), 1853, [3] 38, 76-103. 1. (a) A. W. Hofmann, "Beiträge zur Kenntniss der 16. Technically, Cahours was not the first to isolate piperi- flüchtigen organischen Basen," Ann. Chem. Pharm., dine and claim it as a new base. Unbeknown to Cahours, 1850, 74, 117-177; (b) A. W. Hofmann,"Übergang der Thomas Anderson in Édinburgh had isolated the same flüchtigen Basen in eine Reihe nichtflüchtige Alkaloide," base by treating piperine with nitric acid. However, Ann. Chem. Pharm., 1851, 78, 253-286; (c) A. W. Anderson did no further work beyond determination of Hofmann, continuation of (b), Ann. Chem. Pharm., 1851, its formula. (a) T. Anderson, "Vorläufiger Bericht über 79, 11-39. die Wirkung der Salpetersäure auf organische Alkalien," 2. A. Cahours, "Recherches sur un nouvel alcali dérivé de Ann. Chem. Pharm., 1850, 75, 80-83; (b) T. Anderson, la pipérine," C. R. Hebd. Séances Acad. Sci., Ser. C, 1852, "Réclamation de priorité élevée a l'occasion d'une Note 34, 481-484. récente de M. Cahours, sur une base volatile obtenue de 3. H. C. Oersted, "Über das Piperin, ein neues la pipérine," C. R. Hebd. Séances Acad. Sci., Ser. C, Pflanzenalkaloid," J. Chem. Phys., Nürnberg, 1820, 29, 1852, 34, 564-565; (c) A. Cahours, "Réponse a une 80-82. réclamation de priorité élevée par M. Anderson, a 4. This is the same Oersted who later discovered electro- l'occasion d'un Mémoire de M. Cahours, sur un nouvel magnetic radiation. His father was an apothecary, and alcali dérivé de la pipérine," C. R. Hebd. Séances Acad. at the age of 11, H.C.O. began serving as his father's Sci., Ser. C, 1852, 34, 696-698. assistant in the pharmacy. In 1797 H.C.O. received his 17. "Elle [la pipéridine] diffère en outre complètement, par pharmaceutical degree from the University of sa composition et ses propriétés, de la picoline, avec Copenhagen. laquelle MM. Rochleder et Wertheim l'avaient 5. J. Pelletier, "Examen chimique du poivre (Piper confondue, en se basant uniquement sur ces caractères nigrum)," Ann. Chim. (Paris), 1821, 16, 337-35I. exterieurs." (Ref. 15, pp. 101-102). 6. (a) P. Cazeneuve and O. Caillol, "Extraction et dosage 18. (a) W. V. Farrar, "Melting Points," Educ. Chem., 1970, de la pipérine dans les poivres," Bull. Soc. Chim. Fr., 7, 16-17; (b) J. Jacques, "Eugène Chevreul (1786-1889) 1877, [2] 27, 290-291; (b) W. Johnstone, "Die Analyse et les points de fusion comme critères de pureté", C. R. Hebd. Séances Acad. Sci., Ser. C, 1996, 322 Ilb, 843-845. 4 ll. t. Ch . 22 ( 8
19. J. Volhard and E. Fischer, "August Wilhelm von 31. "Auch konnte man wohl erwarten, daB sich bei der Hofmann: Ein Lebensbild," Ber. Dtsch. Chem. Ges., Abscheidung von (trimethylirtem) Ammoniak aus dem 1902, 35 Sonderheft, 60-62. ringförmig construirten Piperidin die Kohlenstoffkette 20. (a) A. Cahours and A. W. Hofmann, "Recherches sur de wieder schliessen werde, so dass ein Kohlenwasserstoff nouvelles bases phosphorées," C. R. Hebd. Séances [cyclopentene structure drawn out] austräte." (Ref. 29, Acad. Sci., Ser. C, 1855, 41, 831-834; (b) A. Cahours p. 668). and A. W. Hofmann, "Recherches sur une nouvelle classe 32. C. Schotten, "Beitrag zur Kenntniss des Piperidins," Ber. d'alcools," Ann. Chim, (Paris), 1857, 50, 432-462, also Dtsch. Chem. Ges., 1882, 15, 421-427. Ann. Chem. Pharm., 1857, 102, 285-311; (c) A. Cahours 33. A. W. Hofmann [and F. Mylius], "Noch einige and A. W. Hofmann, "Recherches sur les bases Beobachtungen über Piperidin und Pyridin," Ber. Dtsch. phosphorées," Ann. Chim. (Paris), 1857, 51, 5-47, also Chem. Ges., 1883, 16, 586-591. Ann. Chem Pharm., 1857, 104, 1-39. 34. A. Ladenburg, "Über die Einwirkung von Methylalkohol 21. (a) C. H. L. von Babo and C. Keller, "Über die auf salzsäures Piperidin," Ber. Dtsch. chem. Ges., 1883, Piperinsäure, ein Zersetzungsprodukt des Piperins," J. 16, 2057-2059. Prakt. Chem., 1857, 72, 53-72; (b) A. Strecker, "Über 35. (a) J. Thiele, "Zur Kenntniss des Piperylens und die Spaltung des Piperins mit Kali," Ann. Chem. Pharm., Tropilidens," Ann. Chem. Pharm., 1901, 319, 226-230; 1858, 105, 317-320; (c) A. Strecker, "Über die Spaltung (b) C. Harries and F. Drivel, "Zur Kenntniss der des Piperinsäure durch Kalihydrat,"Ann. Chem. Pharm., Konstitution des Dimethylpiperidins und des 1861, 118, 280-290; (d) G. C. Foster, "On Piperic and Piperylens," Ann. Chem. Pharm., 1915, 410, 54-70; (c) Hydropiperic acids," J. Chem. Soc., 1862, 15, 17-24. K. v. Auwers, "Spektrochemische Notizen," Ber. Dtsch. 22. T. Wertheim, "Beiträge zur Kenntniss des Piperidins," Chem. Ges., 1916, 49, 827-834. Ann. Chem. Pharm., 1863, 127, 75-93. 36. A. Ladenburg, "Synthese des Piperidins," Ber. Dtsch. 23. K. Kraut, "Über die Éinwirkung von Mono- Chem. Ges., 1884, 17, 156. chloroessigsäure auf Piperidin," Ann. Chem. Pharm., 37. A. Ladenburg [and H. Stöhr], "Synthese des Piperidins 1871, 157, 66-71. und seiner Homologen," Ber. Dtsch. Chem. Ges., 1884, 24. J. W. Brühl, "Über einige Derivate des Piperidins," Ber 17, 388-391. Dtsch. Chem. Ges., 1871, 4, 738-741. 38. A. Ladenburg [and W. Laun], "Piperidin aus 25. "...da dem Anscheine nach wenigstens das Piperidin Pentamethylendiamine," Ber. Dtsch. Chem. Ges., 1885, selbst durch den Eintritt einer zweiwerthigem Gruppe 18, 3100-3102.
(C 11, 0) in das Ammoniakmolecul entstanden ist." (Ref. 39. G. Merling, "Verhalten des Dimethylpiperidins und 24). verwandter Basen gegen Chlorwasserstoff,"Ann. Chem. 26. A. W. Hofmann, [G. Körner, and C. Schotten], "Zur Pharm., 1891, 264, 310-351. Kenntniss des Piperidins und Pyridins," Ber. Dtsch. Chem. Ges., 1879, 12, 984-990. ABOUT THE AUTHOR 27. W. Koenigs, "Überführung von Piperidin in Pyridin," Ber. Dtsch. Chem. Ges., 1879, 12, 2341-2344. Ed r W rnh ff ( h. ., W n n, th W. S. hn n, 28. A. W. Hofmann [and C. Schotten], "Über die Einwirkung p td t r l r th . . . rt n nd G. . M l , der Wärme auf die Ammoniumbasen," Ber. Dtsch. Chem. r f r E r t f Ch tr t th Un v r t f Ges., 1881, 14, 494-496. W t rn Ont r , nd n, Ont r , C n d , 6A , 29. A. W. Hofmann [and C. Schotten], "Einwirkung der h b n pr f n nd pr t n r n h tr n Wärme auf die Ammoniumbasen," Ber. Dtsch. Chem. th . U.S. nd C n d f r l t f ft r . n Ges., 1881, 14, 659-669. r r h th r t f r n h tr n th l t r 30. A. W. Hofmann [and E. Mylius], "Synthese aromatischer Monoamine durch Atomwanderung im Molecule," Ber. t r f th n n t nth nt r . Dtsch. Chem. Ges., 1872, 5, 704-719.