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 iN^»*r^7.w^ 
 
 \U 
 
 THE SYNTHESIS OF ALKALOIDS. 
 
 BY ^ 
 
 C. G. L. W«j.i-, B.A.. M.D., 
 Den.onstmtor of Practical Clu'rnistry, McGill University. 
 The synthetical produc^on of alkaloi.is has been a task which 
 numberless chemists have set themselves to perform since the discov- 
 ery ot morphine, ninety years ajro, and although in the matter of 
 actual success in comparison with the an.ount of work that has been 
 done, not much has been accomplished, yet the progress which has 
 been made in the last two decades has been so great, that it is by no 
 means without the range of probability that in the next ten years. 
 many of those alkaloids which are to-day only to be obtained from 
 plants will be the products of the laboratory. 
 
 Problems, such as these, which are of almost insurmountable com- 
 plexity have not only the purely scientific aspect to induce work upon 
 them, but also the enormous commercial importance which is attached 
 to them, and one has only to remember the indigo synthesis of A. v. 
 iJaeyer from a nitro cinnamic acid to understand how a research 
 undertaken to solve a question of constitution will revolutionize an 
 industry wttichhas, for centuries almost, been the exclusive producer 
 ot a necessary^lpi^tic compound. 
 
 In the first pyrt of this century large numbers of plants were 
 investigated and as a result a more than an equivalent nu.nbor of alka- 
 loids wa^ found. It was only when the observers came to investi- 
 gate the constitution, that they realised the enormous difficulties with 
 which tney had to contend. 
 
 The first step whick..^i»ew some light on the subject was theiv 
 behaviour on distillation ; mai.y gave pyridin or a compound allied 
 to It, and It was hence believe^ Ihat they were basic bodies which 
 
 
/ 
 
 2 
 
 contained a pyridin nucleus. Such a definition would shut out 
 sucli very important compounds as cattein and tlieoltrouiin, and it is 
 per]iaj)s Iiest, simply to view them as plant derivatives containin;^ 
 nitrojfen.Jn which the nitrogen is contained in a cyclic atom com- 
 plex. 
 
 As pyridin is the compound from which most of the alkaloids are 
 derived, it may V»e well to speak of it somewhat in detail. 
 
 It consists, accordinif to Korner, wdiose view has been {Generally 
 accepted, of a itonzene rinf; in which a niethin j^roup has Ijeen replaced 
 liy a trivalent nitroifen atom. 
 
 I'iperidin Cj H„ N bears a close relation to jjyridin and following 
 up the researches of Cahours, Hofinann. by the action of bromine on 
 the former compound, converted it into a substanct,' having the em- 
 ])irical formula, Cj H^, NO Brj, which he held to he a l)n)minated 
 pyridin derivative. That there was a close connection between these 
 two sul)stances was shown by the oxidation of piperidin to pyriditi 
 by nu-ans of sulphuric acid. ' 
 
 The full synthesis of piperidin was accomplished l)y Ladenburg by 
 the dry distillation of penta menthylendiamin hydrochloride. The 
 relation between these three substances may be shown by the follow- 
 ing scheme : 
 
 CH 
 
 /> 
 
 CII..-CH.-NH.HCI ^ CHo-ClI., ^ 
 
 lie 
 
 A 
 
 ~CHo-ClI..-NlFIICl 
 
 CIL-CII.,' 
 
 HC 
 
 CH 
 
 CH 
 
 'N 
 
 The nixt syntln'sis which was cHrcted was that of coniin, the alka- 
 loids of conium maeulatum. It was of interest also liecav. e it belongs 
 to the .somewhat restricted group of alkaloids which Contain no oxygen, 
 and Liebig, (Jerhardt, Kekule and Hofmaun submitted it to close 
 investigation without elucidating its constitution. It waA Hofmann 
 who, in LSSl, proved that it was a compound closel|*ifiteted to piperi- 
 din but his conclusions, drawn from experiments >yi^h methyl and 
 dimethyl piperi<lin as to its exact constitution, were unfounded. 
 
 Koenigs, after the conclusion of Hofmaini's investigation came to 
 the view that coiiiin must lie a pro[)yl piperidin. This view found a 
 convincing proof in the work of Hofmann, who, by the distillation of 
 eoniin with zinc dust, discovered a l)ase ^flgfigfrria, wdiich was not as 
 expected, a reduction bnt an t)xida||i«|i,.produet of eoniin, and which 
 stood in tilt' >anie relation to it that jyHdin does to piperidin, and 
 
 t 
 
 7-SP^ 
 

 3 
 
 that it was a liomolofruo of pyridin was shown by its yielding on 
 furthtT <)xi<Iati()ii aiul pyn<liM caihoxyiic acid. » 
 
 From these considerations Ladenburg was induce*! to talve up the 
 synthesis of coiiiin. The difficulties which he encountered, ywinj^f to 
 the uncertainty of a change not occurring in ti)e piopyl group whidi 
 he intr<jduced, cannot be taken up in this placo. He was, however, 
 successful in his endeavours by condensing a picolin with paralde- 
 hyde to jithyl pyridin. This un.saturated compound on reduction 
 gave inactive, normal (i propyl pyi-idin. On combination oi' this l)ase 
 with de.Ktro tartaric acid he was enabled tu separate the inactive com- 
 pound intode.stro and lerorotatory modilieations, the former of which 
 p)-oved in every way to be identical with the natural alkaloid. Some 
 years latei- Engler conden.sed calcium picolinate with calcium propionate 
 and obtaine.1 after the well known ivaction a athyl pyridyl keton 
 and subse(|uent reduction of this to a athyl pipei-yl alkin. which, on 
 continuous reduction, yielded coniin. Thus has coniin been produced 
 in two ways. 
 
 Next in order were three less important alkaloids synthesised 
 whose production was not of interest from a technical point of view, 
 but of great scientific worth. These were trigonellin, the alkaloid of 
 trigonella, f.nnum gnmim by Hant/sch, and arekaidin, and urekolin 
 from the areca nut by Jahns. 
 
 Pipcrin, the original alkaloid of peppei-, was partially synthesised at 
 first by Kiigheimer in 18S2, by the con<lensation of piperinyl chlori.le 
 with piperidin. The ])iperinic acid frc.m which the acid chloride was 
 obtauied was not made until Fittig had, by extremely beautiful work, 
 shown Its constitution, and afterwar.Ls La.lenburg and Scholtz effected 
 its synthesis from proto-catechuic aldehyde. 
 
 The next two compounds are of more than theoretical intei-est, as 
 one plays a large technical nUe and both a.-e of interest from their 
 relation to some important physiological processes. These are caflMn 
 andtheophyllin. These do not, as before mentioned, bel,3ng to the 
 pyridin grcfcp of alkaloids, but tlieir history is closely bound"up with 
 uric acid ai^ urea. Although the aci-l was" discovered l>y Scheele so 
 long ago Of 1776, its connection with catfein was not established till 
 E.nil Fischer began his wonderful researches on the uric acid series, 
 which have yielded splendid results. 
 
 The .iecomposition products of caffein belong to n series of com- 
 pounds which contain the grouping c<''~'>c and which can 
 
 well be supposed to bl torkd by the union of urea with dibasic acids. 
 Oafiem on oxidation with chlg^^j^ields dhnethyl alloxan, which, on 
 
treatment with alkalies, forms dimethyl urea and mesoxalic acid, which 
 contains the grouping above mentioned. 
 
 CH.,N-CO CH.N'H 
 
 \ 
 
 CO 
 
 ob 
 
 + 2H20 = 
 
 CH:,N-CO 
 
 CO 
 
 1 
 
 CH3NH 
 
 Dimethyl urea. 
 
 CO2H 
 
 CO 
 
 I 
 
 CO3H 
 
 Mesoxalic acid. 
 
 Dlmetliyl alloxKii. 
 
 There i.s also t'oimed at the same time mono-methyl urea. In both 
 these \v(! have i;roupings which are present in caffein and the question 
 tirises: In wliicli way are they joined together in the alkaloid ? This 
 has been found by other decomposition products, €.(/., cholestrophan 
 
 , ,,,,,,. ^N(CII,)-CO ^N(CH,)-CH., 
 
 and methyl hydantom, CO^ | CO^ | 
 
 •^ ^CH,) -CO ^ NH-CO 
 
 both of which contain the ring system previously men- <^^^~9 
 tioned. N— C 
 
 The breaking up cf caffein into mono methyl urea and dimethyl 
 alloxan is a pi-oof also of the fact that of the ten hydrogen atoms, nine 
 are contained in the molecule as methyl groups, the tenth being pecu- 
 liar in being replaceable by chlorine, bromine, hydroxyl, or amido 
 groups. Further, the addition of two atoms of bromine clearly shows 
 an unsaturated carbon bond. Fischer from these considerations sug- 
 
 ge.sted the formula 
 
 CH,X-CH 
 
 I I 
 
 CO C— NCH3 
 
 for caffein. Thirteen years after this it fell to Fischer and Ach's 
 lot to synthesise this compound from the consideration of the investi- 
 gation of Mulder on the reaction between the dimethyl urea and 
 malonic chloride 
 
 CH,- NH CI CO CH, X - CO 
 
 I ! II 
 
 CO I CH.. =- CO CH.. 
 
 I I ' II" 
 
 CH:, NH CI CO CH, N — CO 
 
 by which was obtained dimethyl barbituric acid ; from this he obtained 
 by mean.* of nitrous acid, dimethyl violuric acid which gav6 on reduc- 
 tion dimethyl uramil. A. v. Baeyer had at the same time submitted 
 the unsubstituted compound uramil to the action of cyanic acid, 
 expecting to obtain uric acid by the reaction, and had obtained not 
 that body but a pseudo uric acid, in which the second ring system was 
 not closed. On treating dimethyl uramil with melted oxalic acid 
 Fischer and Ach split off the molecule of water and produced di- 
 methyl urie acid. By the action of phospliQm| penta chloride on this 
 compound, they obtained a substance w^^ was also obtained on 
 treating theopyllin, a second alktylaflfct in tea extract with the same 
 
 ,. 't- 
 
reajjfent. Now theophyllin has a methyl jL?roup less than caffein, and, 
 
 as both on oxidation, yield tliructhvl alloxan no^ >('0 
 
 •^ "^ ^N(CH.,)-(;() 
 
 it is clear that the third methyl group does not belong to tl^j- alloxan 
 ring ; so that theo}»hyllin must l)e representtnl l»y formuln \'T., in whieli 
 chlorine is replaced bj' a methyl group. 
 
 Theophyllin can he changed to caffein liy the action of methyl iodid 
 on its silver salt. This is one of the ]ii't;ttiest exainpli-s of a com- 
 pound being synthesised by purely scientific considerations, '{'he fol- 
 lowing formulae show the relation between tlu; different compounds 
 which led up to it : 
 
 CH..-N-CO 
 
 CO CIINII., •> 
 
 CH;,-N-CO 
 III. Diinetliyl uramil. 
 
 CHn-N-CO CH,N-CO 
 
 II ^ I 
 
 CO CH., 
 
 I I 
 
 CO C : NOII 
 
 I I 
 CH,N-Co 
 
 II. nimcthyl violiiric Acid. 
 
 > CO 'C: NOII > 
 
 CH3-N-CO 
 I. Dimethyl alloxan. 
 
 CHr,N-Co 
 
 11 ^ 
 
 CO CH NH CONH., — ^ 
 
 II ' ^ 
 CH,,N-CO 
 
 IV. Dimethyl pseudo uric acid lyanate. 
 
 CH,N-CO 
 
 CO C-NII — -"^ 
 
 I I \C11 ^ 
 CH:,N-C-N^ 
 
 VI. Chlortheophylliii. 
 
 Pautiai, Synthesis 
 
 CJI.N-CO 
 
 CO C-NH — > 
 
 I II >C0 
 CH:iN-C-Nn 
 
 V. Dimethyl uric arid. 
 
 Cll,N-CH 
 
 ' I I! 
 
 CO C-XCII, 
 
 i i '>cii 
 
 CH,N-C-N^^ 
 VII. CalJein. 
 
 Atropin — The sj-nthesis of atropin has not been a complete one, 
 yet much successful work has been done in this direction since Liebig 
 determined that its formula was C,. H,,, NO... Ladenburg, after Kraut 
 and Lossen had split it into two of its couiponents, tropin and atropaic 
 acid, combined these two to forni the alkaloid. Investiiiutinii- the 
 
 latter product, he found it had the formula C,,!!, CH^ ' jind 
 
 ^CO OH 
 
 determined it thus to be (it phenyl hydraerylie acid, and the first 
 synthesis of this acid, starting from aeetophenon, was due to these 
 observers working in conjunction with Kiiglieimer. They treated 
 phenyl methyl ketone with phosphorus penta chloride, obtaining the 
 ketone chloride, this treated with alcohol and potassium c\'anide the 
 
 compound C„H7— C<.^ — OH which on saponification after the well- 
 
 u 
 
 known method with l>lipife.^water yields a saturated acid, atrolactic 
 acid, the athyl ester of which^lilh strong sulphuric acid, splits off 
 
6 
 
 ftthyl alcohol, ffiving the unsaturatt'd atropaic acid. By tientimnt 
 of tliis witli hypochloroUH acid, tlu'chloi-iiiatt-d acid is obtained, which 
 oil ticatmciit with uoscent hydrogen gives tropaic acid. The aci«i 
 part of uti-opin having V)een syntliesised, Ladenhing, (jn the ground 
 of some cleavage ])roducts of tropin, hns suggested the formula I, 
 which has Ihhm changed liy Merling, with the couMut of many 
 chemists, to forunda II. 
 
 CH 
 
 CH., 
 
 nc 
 
 HC 
 
 CIJ.. 
 
 CH- CH.,-("[I.. OH 
 
 U.,c{^ii OH 
 
 n, CN 
 
 on.. 
 
 CH., 
 
 \ CH:, 
 
 I. 
 
 Although neither of these compounds has as yet been completely 
 synthesised, yet, tropin has been built up again froni one of its decom- 
 position products which, according to Merling's fornuda, nuist be 
 diliy<lro benzyl dimethylannn. This latter is a derivation of tropidin 
 methyl ammonium hydrate, which is, in its turn, derived from tropin 
 by dehydration. \ow Mt-rling showed that the mon(icycliccompoun<l, 
 the <«■ methyl tropin, condtined with two molecules of hydrochloric 
 ivcid to hydrochlor ^*' methyl tropin hydrochloride, which, with .sodium 
 hydrate, gave the Itase hydiochlor <>! methyl tropidin. This changed 
 to ti'opidin methyl annnonium chloride, which broke up by distillation 
 into tropidin and methyl chloride. The tranyformation of tropidin 
 into tropin was previously accomplished by Ladenburg. 
 
 The ne.\t alkaloid, which is of gicat ijiipoi-tance medically, iscocain. 
 This compound liears a close relation sti'uctui'ally with the foregoing 
 as VVMl.statter showed, and also with the alkaloid o tro])in found in 
 Javanese coca leaves. 
 
 Cocain, on saponification, splits up into ecgonin benzoic aci<l and 
 methyl alcohol. From this decomposition one may infei- that ecgonin 
 contains an acid and a hydi-oxyl group, of whi(;h the latter one is 
 benzoylated and the former methylated in cocain. Ecgonin is very 
 similar to tropin, and Einhorn has been able from the former body to 
 prepare the latter. By dehydration ecgonin yields an hydro ecgonin 
 which gives off carbon dioxide air on siii||^le treatment yielding 
 tropidin. The i-elation between tropin^nlvecgonin, according to the 
 newer formuho, may he easily seen by tJoinparing the two formula'. 
 
Ch, 
 
 CH2 
 
 CHa 
 
 ceo OH 
 
 CK» 
 
 Ecgoiiin on trciitmciit with Ijonzoic aiiliy<lri<l<' uinl inctfiyl i<Mli(U' 
 j^ivcs cocaiii. Takiii;,' into accuuiit tlir previous work on tropin one 
 may say that the synthesis of cocain is far advanced tuwanls coiu- 
 pletion. 
 
 Piloearpin has also enjifrosscd the attention of many oliscrvers. Ac 
 cordiiifj; to Hardy and Cahnels it consists of a pyridin nucleus 
 comhined with a betain group in the fi position. 
 
 Piloearpin, on hoiling' with watci-, i)reaks up into triinethylaniin and 
 an acid of the formula C„N,,X(>,. The InXrium salt of this acid on 
 • listillation yields C,H,,X(), which oti oxidation gives (i p_^ ridyl 
 methyl keton hydrate, which can lie prepared synthetically. The 
 tirst named of these compouTids is from these considei-ations a fi 
 pyridyl, a lactic acid, and from the splitting of jnlocarpin into this 
 acid and trimethylamin it may he assumed to liave the formula 
 
 HC 
 
 HC 
 
 / 
 
 CH 
 
 \ 
 
 CHs 
 / . 
 
 OH 
 CO OH 
 
 <^ 
 
 CH 
 
 CH3 
 
 C NrCHs) 
 
 I I 
 
 CO I 
 
 u 
 
 ji pyridyl a lact ic acid . 
 
 CH 
 
 HC C — 
 
 " i 
 
 HC ^H 
 
 N 
 
 Pilocarpi!!. 
 
 Hardy and Cahnels endeavoured to synthesiso piloearpin from its 
 decomposition products. By treating (i pyridyl a lactic acid v;ith 
 pliosphorus dibromide and heating tlte liromo acid so olitained with 
 dimethylamin, pilocarpidin was ol)tained, Thi.s when heated in methyl 
 alcohol .solution with methyl iodide and potash gave pilocarpinic acid. 
 This on oxidation and dehydration with permanganate of silver yields 
 piloearpin. According to| Hei'/ig and Meyer piloearpin contains but 
 one group attached to nrtw^en, but owing to th(^ extremely unsuit- 
 able state in which the vnrious'*6«mpoiUKlsj|re obtained, it is too early 
 
8 
 
 to form a definite opinion as to which is the precise constitutional 
 formula. 
 
 The work of Schmidt and Freund has done much to clear up the con- 
 stitution of hydrastin, the alkaloid of hydrastis canadensis, and we 
 may be said now to liave a fully formed idea of its constitution. The 
 work which led up to the views of its formula would require a some- 
 what leiiothy statement, which cannot be given here. One of its 
 decomposition products (hydrastinin) has beei shown to have the 
 formula 
 
 HaC 
 
 oc 
 
 CH 
 
 CHO 
 
 OC 
 
 CH 
 
 .. NHCHs 
 
 This has been pre])ared synthetically, but the transformation into 
 hydrastin has not been effected. Neither has the formation of opianic 
 acid been coiupleted, so that these two steps are lacking to the pre- 
 paratio) . .' i original alkaloid itself. 
 
 I m. mention that much of the data given here are to be 
 
 found ii. u,dmirable work of Scholtz " Die Kunstliche Aufbau der 
 Alkaloide," and those wishing to pursue the subject further will find 
 in it references to the oi-iginal papers, which contain fuller accounts 
 of the work done in this interesting field. 
 
 ^t^ 
 

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