A STUDY of C A M P H 0 R 0 X I M E . 0000000 A THESIS Submitteu to the Exarn!X'lin:g" O'i<>mlr\iP~eye of the Faculty ' I ._I ' C. ( l l CC t. (. l VG f' "' "'l {ll( ( ( ( l( "" .. l f' University 'or "ih'nrresuta for the Degree of D 0 C T 0 R of P H I L 0 S 0 P H Y by Paul Maurice Glasoe, ili. s. I 0000000 Minneapoli Minn. May 19, 1902. HISTORICAL PART. The pec~liar ouors of many blossoms, j~ices of fruits and saps of trees, especially of the Coniferae and varieties of Citrus, are due to a series of volatile or etherial oils, known by the general name of terpenes. The I '-9 I oils are obtained either by distillation with steam or bY pressure. The close relation existing between the para- benzole compounds, cymol, tJ:iyip91P carvul, carvacrol, an- " ' ' thol, eugenol,etc., anu the ter~~ne~ and ca~phor deriva- l ..c • < t '"e '' tiveu, establishes to a great extent their formulas . Thus terpentine eoes directly into cymol when heated with io- dine and yields various benzole derivatives upon oxydation. That they are unsaturated compounds may be seen from the ease Nith which they form addition p!'oducts with bromine and halogen . hydride . From a stuay of the chemical and physical 1roperties of the terpen~s, they may be divided into three classes: 1) tnose ',1ith t·No double bo.. ds , which are able to u.nite with four univa ent atoms or radicles, anu upon oxidation yielu acids of the fatty seriea; 2) those with one double bond, capable of uniting with t ~o atoms of a univalent substance and on oxidation pass into camphor; 3) those which have no double bonds, but form nitrosites with ni- trous aciu. Representing cymol as para-iEopropyl-mcthyl benL.ole, H en .: . !' ;-. \. .. " ~ the f i :r~t class, to ,i;hich belo1{e' ~iti · ene, dipen ene, iso- terpene, terpinolene and sylvestrene, may be .cepn:isen\.ed b - t'o1•mula I, of which seven varieties are pod::>ible, four active and three inactive; the secor.d class, with one un- saturated linkage hy formula II, of which there are three isomer~ possiole, two with t o ass•metric narbon atoms ar.u one with three . H I. II. ( 3) To the second class belong australene, pinene, and tere- benthene. The third class with isoprupyl and methyl in the para position must be either or H H 1.. C HC Hl. By audition of hydrogen the t c ~re nes become hydro- terpenes, which give rise to a large number of alcohols and ketones, classecl under the general name of camphors. Th e camphors differ from the terpenes in that they a.~e all solid while only one solid terpene is known . Borneo cam- been recogni~ed as alicylic alcohols, forming esters with organic acids, xanthogenates with bisulphide of carbon and passing into camphene and menthene on removal of a mole- cule of water. Treating borneol with nitric acid camphor is produceu, q0 H ~O . This, which is distinguished from the rest of the camphor group as Japan camphor, wa s proven to ( 4) be a ketone by its similar behavior to acetone, which may beshown as follows: c!> H'° o + H~ =:. c3 H&' o c,0 n,c. o +H 2 - c,0 E,g o acetone pseudopropyl ale. camphor borneol C,,o IIIo .,.0 +0 = cto :IllD I 0 +H.,,._, 0. c3 Hs-Cl = c3 Hi--t- HCl C10 H1~Cl2=q0 H,..,e+ 2 HCl allylene cymol Ordinar~r or Japan ca.mphor occurs in three varieties in nature, two optically active and one inactive. Then there is a substance isomeric with camphor which has been named fenchone, apparently identical with it in chemical and physical properties, but which must be cliff1...1·ent in strucLire inasmuch as it yields different products upon treatment with dehydrating or reuuc1ng agents . The dif- ference may be represented as follows: Borneol ( + 2.Tl Camphor - ;>-/2.0 _ .-,. ... p-cymo 1 Fenchyl alcohol +&ti_ 1''enchone -=::...21..:i..Q ~ m-c ymol Japan camphor is founu in the camphor t1·ce (Laur- us camphora); is obtained by distillation with steam and purified by sublimation. It has a melting point of 175°C, ( 5) boils at 204°; [°"] =44.22 in alcohol. Artificially it can• J:) be p:cepared by oxydizing borneol with r itric acid and cam- phene with chromic acid. It has a specific gravity of .985. Yields pure cymol when distilled slowly with phos- phoric anhyQride, and on boiling with iodine it forms car- vacrol. 1 Berthelot as early as 1858 had discovereuthat cam- phor would yield with alcoholic potash the compo md C10H18'0, or borneol, and from that time on numerous attempts have been made to express the structural formula of camphor and 1- allied comp01mds. Kachler in 1872 gave the following: camphor borneol camphoric acid camphorplioron KeKule' made a more exhaustive stud of camphor and terpenes than any of the previous investigators.Although formulas ha.d been proposed by Victor Meyer, Kaehler and others he held that the difficulties in the way of deter- ·Jahresb~ri cht e, 1858-441. =Jahre berichte, 1873-929. ( 6) inine the structure of cc.mrn:')r had increased rather than decreased, and that to meet with success one had to col- lect d3ta from which to derive a formula and then make new experiments on camphor derivatives and varieties. In de- veloping his formula he had the followine facts in mind: that camphor is essentially of an indifferent nature; that it cha~ges into the alcoholic body borneol; the building of of a monobas1c campholer.ic acid through the influence of alkalie&; thechange through oxydation into the dibas·ic camphoric acid. He also reasoned that ~oing so easily into cymol .i.t il.kel~' containea. both methyl and isopropyl groups. T:hese consiueration~ led him to p!"'opose these formulas fol" camphor ana. its irrunediate derivatives: C3 H7 C3H7 F HP(~J!s PfG JOE HcyooH PC 00 T q C (H ~ C H3 Campholenic Camphoric acid acid This considers carr.phur a ketone havinrr a CO group ( 7 ) connected on both sides t o a carbon chain . It ~ho~~ its relation to cymol by a six atom carbon ring . After the discovery of Dale and Glaustone's law a r,reat deal of work was done on organic comrounds do it was found that the physical arrangement of the molecules exerted a dcfinit influence upon the molecular refractive constant. Thus Kanonnikoff investigated ethylcamphor and from its refractive constant concluded that it did not , possass a double linking as expressed b the Kekule for- I. mula. Brdhl conf1rmeu this view by usinG the theoretical n"=-1 F formula (rl'-2)d, while Kanonnikoff use the old Gladstone and Dale formula and came to the same conclusions. To con­ -tJ.;~ form t o t his view he suggeste writineK k l{ form la eith- / er C ~ 1 H7 C3 H1 or !~¢:~ :~I:~ C H~ C H~ Ber hel o ~ and R1ban s t ccc~ded i n converting pinene into crunphor, and this reaction may be represented by the following changes: Berichte, 21-457. ( 8) C3 H. C~ H.., HC0'H + HCl= HCl+ HC H2' H C H-. Pinene Pinene h H,., 0 C H ~ c l 3 Camphene Camphor Later in a very extensive s t ..idy of camphoric acid 1 I and its esters, Ertlhlcompared the Kekule and diagonal for- r mulas. The Kekule formula for camphoric acid may be writ- ten thus: HOOC-CH-CHz-Cr=<(- COOH which wo 1ld be oc-methyl- 6 H7 C H~ J-isoproryl~~Phydromuconicacid, but the researches of von Baeyer have p1·oven that Ll°'13 hydromuconi c acid has the for- mula: HOOC-CH2-Cr CH=CH-COOH. The diagonal formula on 2 (3 oC the other hand woulu be, C3 H1 CH--r--COOH JH:-9--cooH C H !> - 1) Beric1te-14-6373 ( 9 } or a derivative of tetramethylene dicarboxylic acid. The problem was therefore to show whether camphoric acid is a subs ti tute.d hydromuconic acid or a deriva~1ve of tetra- methylene dicarboxylic acid. Menschutkin') showed that the fo.i·rnation of esters takes place most rapidly in the primary acids, and slow- est in the tertiary, and that camphoric acid possess the properties of a tertiary acid. It was shown also b~· Victor Meyer, Auwers, Bischoff, that the difficulty of ~orming anhydridos of the acids ofthe succinic t pe increases in proportion to the number of alkyl radicles which have been substituted for hydrogen. Reasoning from this it is not surprising that such a tetra substituted compound- ethy- lene-methyl-isopropyl-succinic acid shoulu show it to a laree extent. Brfilll makes the follo ine conclusion: The entire chemical behavior of camphoric acid toward oxydiz- ing and' reducing agents, toward halogen hydride and brom- ine; further its weak tendency to form acids amt its re- 8istance toward the formation of an anhydride, go to prove that it is not a derivative of4«t:.hydromuconic acid, while 1) Berichte, 14-2631; 1881. (10) it bespeaks most plainlr the succinic structure. Viewed side by side it can be seeu that of the hydromuconic acid derivative there can be only three isomeric forms,one dex- tro rotatory, one laevo- and one inactive, while in reali- ty there are four known for a certainty, and two more have been suspected by Wreden and others.