- ISOCAMPHOLACTONE BY PHILIP KELSEY PORTER A. B. Grinnell College, 1918 THESIS Submitted in Partial Fulfillment of the Requirements for the Degree of MASTER OF ARTS IN CHEMISTRY IN 1 HE GRADUATE SCHOOL OF THE UNIVERSITY OF ILLINOIS 1921 BE ACCEPTED AS FULFILLING THIS PART OF THE REQUIREMENTS FOR THE DEGREE OF_ Recommendation concurred in* ART' In Charge of Thesis hjead of Department Committee on Final Examination* *Required for doctor’s degree but not for master’s Digitized by the Internet Archive in 2015 https://archive.org/details/isocampholactoneOOport TABLE OP CONTENTS Page IlfBOLUCTIOH 1 THE 0 SET I GAL P^HT 3 Eii.PEHIi-.iGi: TAL PART Preparation of Camphoric Acid 6 Preparation of Camphoric Anhydride 6 Preparation of Alpha and Beta Camphoramidic Acids 6 Preparation of Amino Lauronic acid 7 Preparation of the Anhydride and the i. itroso Leri-fat ive of .amino Lauronic Acid 8 Preparation of Iso-campholactone 10 Preparation of h it ro- iso-campholactone 11 Preparation of Camphoric Imide 11 Attempted Preparation of and Camphoramidic Acids from Camphoric Imide 12 A CEli OviojjjU Gni.u'ii'-i T IL loU C.hvn . IQ LAG 'I Oh A I BllHQDUCTIOii Camphor and its derivatives aiten undergo molecular r car range - Very little is known conoemii re ri - jement , — it is often extremely difficult to 'de whether a rearrangement has t. men place in a given reaction or not The first step in determining whether a rearrangement has t; .ken place is to prove the structure of the compound resulting IroQi - - This : iffj one must use a sort of cumulative evidence, which is obtained from a study of the reactions c lpo oft . fhe study of the derivatives of camphor give many examples of bs . ... - i oso of the amino lauronic acid is treated with sodium hydroxide , laurolene is formed as one of the products." 1 rip - 4 - C 0 , -f- i; / . * Lu ibis reaction, nyl and amino groups leave the molecule as carbon dioxide and nitrogen, . 1 group shifts to form t . ie 1 , 2 , 6 , t rime thyl c onnound . In the same . hon, isocampholactone is formed. As the structure ox this compound has not been j roven , there is a strong possibility that another type of rearrangem t n pi ce. The o eject of this work was to continue the study of the reactions 1 tloyes and Derick, J.ADhe . . .. . 1,- . . . , . . . » ■ os s ible , ossifole structure of the compound, and nature of the rearrangement* is taken place • veiy little progress toward the study of the larger question in » n P- e • However, the series oi reactions wilioil ± '^ L to tiie prepar it ion f isooampholactone have keen studied, and in Most cases, an increase in yields have "been obtained "by — l j g ei one r tne uet.ioes that have "been described, or by Ge -* oc In ... s « TjA0&3TIG.ii 1AAT Three laetones are known which correspond to three hydroxy a °i^ s - - - the tertiary carboxyl of camphoric acid. They are the campho lac tone , the cis-ca ij nololactone, and the iso- \ campholact one . Campholactone was first prepared by fitting x_d Wor L.iger-'- by warming lauronolic acid with dilute mineral acid. It Soyes ■ - Si thio let od . laurolene 1 also beeix prepares oy the distillation of lanronolic acid*^, . shifting of the methyl group to the 1,2,3, trimethyl com- pound may nave occurred either during the formation of lauronolic acid or during its decomposition to form laurolene. The experiment- al woik ui i.oyes ana nurne" snows tnat the shift oi the methyl gr quo tcxw.es place in tne formation of lauronolic acid. This gives the structure of campholactone as being formed by a rearrangement of kke methyl groups giving the 1,2,3 t rime thy 1 compound. Its structure may ue represented ,y the following formula. GHr he; Hw CK^ '31 ft u GH-G- GH 2 -GH, Cis-camphonololactone was first obtained by lioyes and Taveau 4 , who decomposed the nitroso derivative of the anhydride of amino lauronic acid by warming it with a 10?o solution of iiaOE. Bredt^ ^fitting and .'oringer. Aim. 227,-10 TJioyes mid Burke, J.n.G.8. 34,-182 ^..alker and Henderson? J. Ghem. hoc. 69,-749 floyes and Teveau, am. Ghem. J. 35,-385 ° 3r edt , Ann . 561,-1 -4- later prepared it by the electrolytic reduction of Camphononic acid. The structure of camphononic acid has been shown by Lapworth and tion of camphononic acid, the cis-campholic acid is formed, which upon heating gives the cis-camphonololactone . This lactone has been oxidized back to t c mj . This series of reac- tions show that cis-camphonololactone is formed with no molecular ment , and its structure may be represented by the following Iso campholac tone is the third 3 . known, which retains the tertiary carboxyl of camphoric acid* It was first obtained by the action of nitrous acid on amino lauronic acid. It was later who made a further study of the lactone. The structure of this lactone has not been proven and it is still open to question. The possibility of a more complicated rearrangement in the formation of the lactone Is entirely probable. Isoc iphol 3tone has been oxidized by nitric acid, which form- ed as the principle product , the nitro-iso-campholact'one CJgH^ (UO ,\^ | and also an acid GgH^gO^, mel ... at I. . The titration with standard alkali against t .is acid gave results cor- responding to the molecular weight of 186D and 186.9 for a monobasic Is le , o • Chem. ooc . 79 ,— l^of lent on 1 to consist of ±±o molecular rearrange mu. t . By the reduc- anhydride of amino lauronic acid with sodium hydroxide . This method was repeated by loyes and Taveau® and by fcoyes and Homberger^ cLt , B . 3n oyes and ,-l niveau G.J , ■ t . . - 5 - acid. . . do s a lactone group, was s ing a portion of it in a sealed tube with, an excess of sodium hydroxide. .056$ ms of the acid neutralized 6.57 cc. of L/iC BaOH , the calculated amount for a dibasic acid being 6. 18 cc. The barium salt and the amide were als( ..... The nitro-iso-campholactone was reduced 1 . e amino-iso- campholac t one (inig )\^y0 and also the hydroxylaminoisocampho- 0 lactone, G . 0 Perhaps the most interesting reaction in the study of this compo , is ... jomj si ion of the nitroisocampholactone by ionium hydroxide, and sodium hydroxide to form compc . .... ion atoms .... molecule ’while carbon dioxide is given off. Upon warming the nitre lactone with alcoholic ammonia or on treat- ment with cold concentrated aqueous ammonium hydroxide, the amide is f , wh .. ... . lpiri 1 , ..... ..... i s saponified th .514 BaOH, giving an acid melting .t 75° 0. Upon treating the nitroisocamphol: ctcne directly with .5B BaC , car on dioxide ia given off, and upon acidifying, an acid was / obtained, which was identical with the acid obtained from the amide. Titration o_ . lie i B/lO BaOH gave a molecular weight of 162.$ 163 , ... n 'v _ xide gave 166 . The theoretical molecular weight foi 3 eing 159. a further study of these compounds may throw some light upon the robable structure cl the lactone. . , ■ — u — X O 0 pa xa t X OJL. a- Xx^.-xpl'l 0 1' j b AiO j-U. « JaiUpilO n G UCie. VicxS p 37t. pc-l’C d. ck>^ bOx'dx..ug to me ...1C 1>-1CU C-S u 6SCn u — -} ... 3 , ] ... mother liquor , which gave a decrease in the yield , or 4 p theoreti- cal . xiie v/ o x v xuj.t i ii’ t.ire e circle;, L j. u*. & vuxxSu j — o... oi uO 6G’/v ore , -v . Lai .. ies c i were oxidized at a tine, and the sane results were obtain d. ■X X - * o .ja x . .I uX OX sXC-l.l . O w » Campnonc anhydride was 1 re pared ac «. o x’d ixig to Ixr e i.*e xic u &s described b.y Loye .,1 _ . ger quantities, as 5QC acio. , were used at Ox^e ti e , < .nd is sjc i s .. — oox ... file yields varied iron 66 to 93 c /o theoretical , with an average of 9 0 yo . ... ... . i on — 0 . | ..... j . 03 ii . ... Acic . • the alpha and beta campho rami die acids were prepared according s de s crib y 1 . . i 5 of camphoric anhydride were treated with 6c cc. co... cent rated a. .non run hy dro — Lde , 1 . cc * wa fc . .. — .. pressure bottle • dhe bottle was wrapped in a towel , and shaken for ten minutes, after which it was placed In a 3ol .... h, an _ dually heated , shaking ' it occasionally . A pi ic llj 1 . \ After cooling somewhat, the cent exits in the bottle were poured into a 3eaker, jooI Ly s po constant stirring. I L€ . . id crystallized; out ux.d was filter- Loyes , .A*C.*L 16,-501, 502 2ivoyes ud faveau, .a. 5. J-, 52,-285 . * ’ * • ' * .... -7- I .. y recryg .lizat a small of warm water and ammonia. The filtrate i'r. • m the alpha salt contained the salt of the beta acid. To this, 30 go. of sodium hydroxide (3 cc. = 1 gram.) were added, with stirring, and the sodium salt of the beta acid was precipitated. The filtrate from this solution ,• and the mother liquors from the purification of the alpha salt were carefully neutralized with hydrochloric acid. 30 ] s constantly stirred, and the acid added very slowly until the mixed acids be- gin to separate out as a crystalline product. The addition of a small amount of some mixed acids from a previous preparation may preTi nt the precipitation of the acids, as a gummy product. The acids were filtered , and then dissolved in a little more than the theoretical amount of ammonium hydroxide and the separation repeat- ed. To obtain the free amidic acids, the ammonium or sodium salt was dissolved in water, and concentrated hydrochloric acid was added, using the same precautions, to insure a crystalline product . The yields varied from 55 to 65' /U by weight of the alpha salt, and from Os to 68 $ of the beta salt. Precipitation of the acids from the salts gave yields varying from 75-78$ of the alp la ci , md from 50-55$ of the beta acid. The yields of acids based upon the amount of camphoric anhydride used, gave from 45-50$ ight of e al] acid, c 35-45; of the beta acid. Preparati on of „n,iino fauronic ^cid . Amino lauronic acid was prepared according to the method as 1 described by hoyes # 199 grams (1 mole) of the alpha acid were - 1 - hoyes, . A . C . J . 16,-506 J - 8 - dissolved in a liter of a 10$ solution of IJ'aOH. 51 go. or 160 g. of bromine were dissolved in 1100 cc. of a 10$ solution of II a OH, ana this solution of hypobromite ac.de d to the solution of the alpha c acid. The solution was ieai . water bath to about 75 for os. After cooling, a little sodium sulfite was added, and the solution was strongly acidified with HOI. The solution was then porated, and the amino acid separated out as the hydro- Ohio ride , and may be purified by a re- lizati i r. The yield was about 100$ theoretical. Preparation of t..e .niliydride a^o the nit, oso Derivative of nmiiiQ rauronic ^cid . The anhydride of amino lauronic acid has been prepared by the following methods; by distilling the hydrochloride of amino lauron- ic acid with an excess of lime^; by heating the free amidic acid to 300° in an oil bath ; by heating the hydrochloride with acetic a anhydride^; and, by heating the hydrochloride with acetic anhydride 4 : and fused sodium acetate . From all of these methods, the nitroso derivative was obtained by dissolving the anhydride in dilute EG1 and adding sodium nitrite. All of these methods were tried, with varying yields of nitroso, However, it was thought best to unite these two reaction, and not is olal pur ydride , was done as fai as possible. Dive and two tenths grams of the free acid were heated in a •< oo<~ 1 metal ba i at 300° fox one lour. The at lydride formed was dissolved in ether and the ether distilled off. The impure anhy- dride was then dissolved in dilute HC1, and so .1 uni nitrite added. 1 Doyes, 16,-507 %loyes and lave au , • 32,-287 SBredt , 3. 35,-1251 ■ . . * . t . , * ..... -9- .638 grama of the iiitroao derivative were obit , or 12$ by weight from the amount of amino lauronic acid taken. rive and two tenths grams of the hydrochloride with 10 cc . of acetic anhydride and 2 grams of f sed sodium acetate were heated 2 hours over a very small flame . The anhydride was obtained by extrac ith her. It was then dissolved in dilute HC1, and sodium nitrite added. 2.066 grams of the nitroso derivative were obtained, or 40$ yield by weight . Five and two tenths grams of the hydrochloride and 11 grams of lime were heated in a Wood’s metal bath for one and one -half hours at a temperature of 280°. The mass rac . ic . fch not water, filtered, acidified with [Cl, cc dI , and sodium nitrite . ad 3d. 2.226 grams of the nitroso derivative were obtained, or a yield of 43$ by weight. It was founc however, that by distilling a mixture of the h .ro chloride and calcium carbonate instead of lime, better yields than those from the other method were obtained. Twenty grams of the hydrochloride and 40 grams of calcium cai ... ..... mixec , < ... .. t. ... mass heated, quite strongly with a free fl me. The anhydride formed, was distilled over into a flask cooled by ice water, or it sublimed in the neck of the retort. The heating was continued for about one-half Lour, oi - all of ... anhyc had distilled, or sub- limec . on cooling, the anhy ide 3 ...ass in the retort were extracted throe times with hot water, fcered, 1 te an- hydride being soluble in water. The filtrate was acidified with i-.'j.L ex rid coomed. 6c ... .. ..... .0 added witn constant st_ . , - 10 - to insure the precipitation oi the nitroso as a crystalline product. It was sometis.es necessary to inoculate the solution with some , t o prevej of i inmy md less pure compound . The nitroso derivative was purified by 0 0 crystallizing once from alcohol. It melts at 158-139 J. Ihe yields varied from 10.5 grams so one high yield of 15.8 g. which was an average yield of 11.5 grams or 66,. theoretical from amino 1 3 n. Preparation or Iso-camphoiactone . iso-cam - pared by the method as c . . hoyes and Taveau using a log solution of baOh, anc also by the method as described by boyes and Potter 2 in their preparation of . is — c phono lol Lone , - - , - — - I ... • modification made in their method was the fact that after distilling off the laurolene , the solution was made acid, and steam distilled directly without extracting the acids and lactones with ether. Due to t e fact .hat the cis-camj lonolol . . . . was also prepared , perhaps by the use of the stronger, sodium hydroxide, and the higher . i] -- ;ure Cc nod by the heat of reaction, and being somewhat vola- tile ... .-v am, a mixture of the two 1 .so tw.es were obtained. These separated by refluxi g the lactones with a 5p solution of LaGH for 3C . s , 1 i€ . .. -c lolactone , of the isocampholaot one . Ihe solution was cooled to zero degrees and acidified, separati: '.he isocsmpholactone and the ..._ Lroxj acid corresponding to the cis-camphonololactone . These were ex- . oy e s - . , l. *.G ..I*. 32 , — ! 8h ^ . Pott ■. . . . •> • b . , — ^ ' - 11 - traoted with ether, and the other distilled off under diminished pressure so as to keep the temperature low. The hydroxy as id was tnen dissolved ixx a i^o .assrum carGOxxate solution, and ^..o iso— oampholao tone was purified by distillation under diminished pressure The boiling point of the is ooampholactone was 121-122° at 25 O O mm. pressure, and the ... . oi -32 . about 20$ by we.. . . mount of x.itroso derivative taken. irrupt rat i Oxx or i itro-J-aoca.-i^olactoxie . Nitro-isocampholactone was prepared according to the method as icr: Noyes . . 2.031 grams of the isocampho- lactoxie axid 5 cc . of nitric acid (sp. gr. 1.27) were refluxed in a 5s so. flask . 56 hours over a steam bath, until the oily layer of lactone disappeared, a little concent rated acid being added from time to time. Upon cooling and dilution with water, the nitro- is ooampholactone crystallized out. 1.2 grams of the nitro lactone were obtained , m 121-122, yield of 46 fo theoretical. -reparation p__ Jam:.horic Imide . ms of ^-camphoramidic acid and IGOcc. of concentrated . 31 and 25 co . of wg fl ours The solution coolec and who imide filtered c The im- p imide by dissolving it in 2ou cc. of a 5$ solution of laOH, axid r e p r e c ip) i t a t in g it by passing a strong current of OOg hro olution. iel .. ... 72$ theoretical. It melts at 245° . The filtrate from the camphoric imide gave a precipitate oi camphoric acid 'when acidified with HOI . An attempt was made to inn >f ; acid od. 1 Noyes and iiomberger, J.A.G.a. 31,-280 . ti - 12 - However , no imide wa obtained, but c . .. .. ric cic pre- 3o , is of both, the D( and P-camphor- ami arc a c i 0 . s uO campho x i o a c i 0 . * . a a 0 b c e d oy bet x'lmxi . x*e a — mounl ion c in the it ion. 1.0012 grams of fr(-c mphoi Lc . 2 cc. of 03 3 HC1 , and .5 cc.of ws 1 3 re re on a water bath for £4 hours. The solution was t _en slowly evaporated to dryness on a water bath, and the residue extracted with water to dissolve the ammonium chloride formed by the rol ,. the solution was diluted to .. cc* fr< Jh ire samples of 2C cc. each were pipetted off, and an excess of sodium carbonate added to each sample. Air was pass- ed through the solution for three hours, drawing the ammonia into standard acid, nd he excess acid titrated with st li. She two samples were equivalent io 14.9 and 15.005 cc. of .0924 3 acid respectively , or the total volume of 50 cc. of solution was equivalent to 37.53 cc. of aci . This being equivalent to .18478 grams of amrnoi e 68.64$ of the acid is hydro- lysed to camphoric acid. Five grams of the ^*camphoramidic o.cid 7/e re treated in like man 1 a s K- id. The tw< mj 3 20cc. each we re e 3 nt to 14.11 cc. and 14.28 cc. of .0924 3 acid respectively, or the total volume of 50 cc. was equivalent to 35.5 cc. of acid. This bei equivalent to .1775 grams of ammonium chloride , shows that 13.2$ the (3-acid is hydrolyse . A second determination was made in the same manner , and 14.4$ of^-acid was fc me :o be hydrolysed. attempted a rep- ration of ft hnd ^Ouu. hora.nii ic -xcids from Camphoric -imide . Twenty five grams of the imide were dissolved in 80 cc. of -13- 15% KaOH and the solution was heated on a water "bath for one and one-half hours. On cooling and adding a crystal of some /3-salt, the sodium salt separated and filtered off. salt was dissolv- j; , e/5-acid _ ... cipitated bj HG1. THe yield is about 14-15 grams of /5-acid. She alkaline mother liquor was acidi- fied with HC1 , in hopes of obtaining some impure (K~ac id , but none was obtained. The possibility of a further hydrolysis to camphor- ic acid will be studied later. xLOKL'i 0 w jjHj jjGriiijiitjii. x xhe writer wishes to express his thanks to Doctor william n. Doyes for the many valuable suggestions in connection with this investigation.