THE SYNTHESIS OF DIVARIN BY CLIFFORD FRED RASSWEILER A. B. University of Denver 1920. THESIS Submitted in Partial Fulfillment of the Requirements for the Degree of MASTER OF SCIENCE IN CHEMISTRY IN THE GRADUATE SCHOOL OF THE UNIVERSITY OF ILLINOIS 1922 UNIVERSITY OF ILLINOIS THE GRADUATE SCHOOL January 19 ^ I HEREBY RECOMMEND THAT THE THESIS PREPARED UNDER MY SUPERVISION BY Clifford Ered H cms we il er ENTITLED THE SYNTHESIS OH D I VAR IN BE ACCEPTED AS FULFILLING THIS PART OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OH SCIENCE Recommendation concurred in* 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/synthesisofdivarOOrass THE SYNTHESIS OP DIVAHIH Clifford F. Rassweiler I wish to take this opportunity to thank Professor Roger Adams for the suggestion of this problem and for the advice ne has given durixig the caur se of the work. TABLE 0 F CONTENTS I INTRODUCTION 1 II HISTORICAL 2 III THEORETICAL 4 A. Preparation of a symmetrical dihydroxy benzene derivative 4 B. Conversion of the preceding into divarin 8 IV EXPERIMENTAL 10 A. Triethyl orcin tricar boxy late 10 B. 3, 5 > Li hydroxy phenyl acetic acid 11 C. 3> 5 , Limethoxy phenyl acetic acid. 12 V CONCLUSIONS 14 VI BIBLIOGRAPHY 13 THE SYNTHESIS OF DIVARIN I INTRODUCTION Divarin is a dihydroxy propyl benzene of the empirical formula C9H12O2, secured by the action of alkalis ana hydriodic acid on certain complex acids extracted from the lichen Evernia illyrica. This research was undertaken with the object of syn- thesizing divarin oy such means as to ijrove the structural f ormula sugg ested by Ilesse. This structure is at present subject to considerable dispute. - 2 - II HISTORICAL Divarin was first definitely identified and cnaracter- 1 3 ized oy 0. Hesse in 1910. although Zopf probably had some of the compound in impure form before that time. Hesse extracted divaricatic acid (C31H34Q7) from the lichen Ever nia illyrica. This divaricatic acid on treatment with alkali and hyair iodic acid yields a dihydroxy phenol of the empirical formula C9K13O3 to which the name divarin is given. Hesse found the melting point of the hydrate to o 0 be 44 and trie anhydrous form 82 . To this compound Hesse assigned the formula 3 > 3 > dihydrocy I, 11 -propyl benzene (I) largely because of its marked resemblance to orcin (II) both in occurrence and properties* CH3CH2 CHs A OH. \J OK CHa A 0i V 0H 1 11 3 Johnson and Hodge have prepared 2,4, dihydroxy I,n- propyl benzene and found its anhydrous form to melt at 82 °- o 0 03 . This melting point agrees with that found by Hesse for anhydrous divarin. The description of the 2,4 compound was too orief , however, to make the identification certain so 4 the work of Johnson and Hodge was repeated by Adolf Som*. - 3 - He found that the anhydrous 2, 4, dihydroxy propyl benzene thus 0 ' Q prepared melted at IP? -10o while tl Lydrated or m melting point of 71 u . He concluded that the compound describe ed by Johnson was a mixture of the two forms and that the 2,4 phenol was not identical with divarin. At present the original structural formula proposed oy Hesse is generally accepted though not definitely proved. Ho attempts to prepare divarin synthetically have seen reported in the literature. Its monomethyl and dimethyl ethers have been prepared however from complex plant pro- fs ducts . -4- III THEORETICAL The chief difficulty to be overcome in this synthesis is in placing the two hydroxyl groups in a symmetrical position with regard to the propyl side chain. The synthesis as taken up in this work divides itself naturally into two parts, first the securing of a benzene derivative with two hydroxyls symme- trically placed with respect to a side chain, and second the conversion of that side chaixi into a propyl group. To accomplish the first step the work of h. Cornelius 6 7 and H. von Pechmann , L. Wolman and K von Peckman and of 8 I). S. Jordan on the preparation of 3> 5 > dihydroxy phenyl ace- tic acid was followed. The starting point was diethyl acetone aicarboxylate (A) prepared 'ey the treatment of citric acid wit a 2 0 per cent fuming sulfuric acid to give one acetone dicarb oxylate wnich v;as esterifiea with etnyi alconol and dry HC1. This is the method descrioed 'ey Wi list fitter and Pfannemstiei . Two methods for condensing the dietnyl acetone dicar- boxy late into a dinjalroxy benzene derivative nave seen des- cribed and ooth were tried. The first method is tn.au of e 13. S. Jerdan in which magnesium powder is used as trie condens- ing agent with ethyl chloroacetate as a catalyst. The product secured by this condensation is diethyl hydrogen ore in tricarboxylate (B). This reaction ran very smoothly and littae -5- COOCaHs (B) difficulty was encountered in the purification, out the yield was too low to warrant its use in this problem. The second method was first used by Cornelius and von , 8 Pechman in IS06 and later L .ed by I). 1. Jordan. It con- sists in the use of about 1 per cent of Ha as a condensing agent and the compound formed in this case is triethyl ore in tricar coxy late (C)’ CK3CCOC3EB /'N C00C3H5 ho on COOC3H5 (c) This reaction, according bo von Pechman can oe explained as foiiows. (A) COOC3H5 COOCsKb 1 1 Cha haC I C = 0 I CKa COOC3H5 COOCsHb I I C h 1 ^ c = 0 I Ha- C-ii ’OC ah 6 COOC3H5 COOC 2 K 6 I CHa C / \ HC C-COOCaHji -» II I ho-C C-O-H \f „ (Cl ^COOCahs - 6 - Along with, the triethyl orcin tricarboxylate (C) a con- siderable quantity of by-products are formed which can be best separated from C by washing its ether solution with di- lute sodium caroonate and acidifying the sodium carbonate solution. Most of the by-products precipitated by this acid- ification appear to be partially hydrolyzed products from C. / In some cases a small quantity of a compound that agrees in 10 melting point with Jordan's lactone can be isolated from this precipitate. Jerdan’s lactone is the principal product when this condensation is carried out in benzene solution. It was found advisable to proceed with the next step without purifying the triethyl orcin tricarboxylate. first because both the washing with sodium carbonate and the crystal- lization result in the loss of considerable pure product, and second, since the next step is complete Hydrolysis the partial- ly hydrolyzed compounds which are present as oy-pooducts yield the same compound as the pure triethyl orcin tricarboxylate . Both unchanged diethyl acetone dicaroo^ylate and Jerdan’s lactone, drop out in the course of the next few steps. If the hycLroijrsis is carried out carefully a rather large number of partially hydrolyzed products may oe secured from 8 the triethyl orcin tricarboxylate . When subjected to vigorous hydrolysis however the compound loses not only tnree molecules of alconoi but also two molecules of carbon dioxide, giving 2, 5 > dihydro xy acetic acid. (D) This is what 'would be ex- pected from the usual instability Ox' carboxj^l groups attqcned to a polyhydroxy phenol. Trie original method of von Pechioan involving fusion with 50 per cent KOH was found most satis- factory for this hydrolysis though it would seem, at first thought, entirely too vigorous a treatment for trie synthesis of so delicate a compound as dihydroxy phenyl acetic acid. The original method devised by von Pecinnan for purifying the hydroxy acetic acid (D) involving an ether extraction and purification thru the lead salt was not practicable for this problem where relatively large quantities of the compound we re desired. Wot only is the process too involved for large quan- tities but the hydroxy phenyl acetic acid is so soluble in water that even 7 or 3 extractions fail to give anything aike a quantitative separation. Enough of the compound was puri- fied 03 unis method however to identify it as 5> dihydroxy phenyl acetic acid. It was desirable to convert the hyaroxy acid into some compound less water soluble in order to make its isolation easier . xhe natural derivative was of course trie dimethcxy ellier wnich. had trie added advantage of being more staole than o;ie free hydroxy acid. Its preparation was made easy 03 regu- lating file amount of alkali used in the hydrolysis in such a way that the methylation could be carried out by simply adding dimethyl sulfate to the cruae saponification mixture. x)ie 1 ree acid was desired, so the methyl ester of the di- me thoxy phenyl acetic acid, produced during the methylation, was saponified with KOH and the free acid liberated with HC 1 . rs — o— Up to this point none of the by-products formed in the sodium condensation had been removed. It was at first thougnt advis- able to separate them at this point oy taking advantage of the solubility of the dimethoxy phenyl acetic acid in dilute sodium carbonate. Jerdan’s lactone would be changed to trimethoxy phloroglucinol at this point and be insoluble* Experience showed however that this was not necessary as these impurities were eliminated during crystallization. The compound was easii; isolated by salting it out from the strongly acidified me thy la- ri on mixture ana recrys tallizing it. Its neutral equivalent checked the theoretical. The 5> dimethoxy phenyl acetic acid thus prepared becomes the starting point for the second part of the problem, namely the changing of the side chain into a propyl group. In order to introduce another carbon into the siae chain advantage is 1 1 taken of the work of Clibbins and Kiernstein on the formation of chloroket ones from acid chlorides and diazo methane. The acid chloride is prepared by the action of thienyl chloride on the dimethoxy phenyl acetic acid. This acid chloride in dry ether solution is then treated with a molecular quantity of diazo methane also in dry ether solution. The product thus formed is 5 > dimethoxy phenyl cnloroacetone . (E) Glia COCKs Cl * - 9 ' The difficulty encountered at this point is due to the ease with which small Quantities oi alcohol present in the diazo methane solution react with the acid chloride to give the ester. Thus if the diazo methane is prepared by the method of von Pechman, by adding KOH in absolute methyl alcohol to nitroso methyl urethane in ether and distilling off the ether solution of diazo methane, enough alcohol is carried over to prevent the formation of even a trace of the chloroketone. If absolute butyl alcohol is substituted for the methyl aiconoi and a stream of nitrogen -used to carry over the diazo methane, a small quantity of the chloroketone can be isolated, but the butyl ester is the principal product. The method of Staudiiiger 13 and Kaupfer used in the original work of Clibbins and Niernstein is probably the most/ desirable for the preparation of diazo methane for this reaction. The chloroketone is then reduced to the dimethoxy phenyl 13 propane the metnod of Clemnenson using zinc amalgam and hydrochloric acid. Divarin itself is secured by hydrolyzing the methyl groups with hydriodic acid to give the >, 5, dihydroxy phenyl propane. - 10 - IV EXPERIMENTAL A. Triethyl Ore in Tricar boxy late. 150 g. of diethyl acetone dicarboxylate are placed in a flask equipped with a reflux condenser and an efficient mecnan-' ical stirrer. This is heated to 140 J on an oil oath and 1*5 g. of finely chipped sodium is added slowly. The material is kept at 140 with continuous stirring for 1 1/2 nours at the end of which time amother 1*5 g« of sodium is added. The 0 temperature is kept at 140 and the stirring continued until a rather heavy yellow flocculeht precipitate separates out. This occurs at trie end of about another 1 l/2 hours. Addi- tional heating is not harmful. The mat ar lax is poured into a beaker and solidifies on standing. The crude product (about 145 g. ) is centifuged or pressed free from adhering liquid, digested with a little cola dilute sulfuric acid and dissolved in ether. The ether solution is washed with a xittie dilute sodium car oonate solution. Care must be exercised at this point as the triethyl orcin tricarooxylate is quite soluble in sodium carbonate solution. The washing should oe stopped as soon as tne wash water is no longer colored green. Trie ether solution is dried with calcium chloride axid the ether evaporated. Trie trimethyl compound may be recrystallized from petroleum ether or dilute alcohol. iHe petroleum ether product has a slight cream color while that from alcohol is pure white. Considerable difficulty is experienced with alco- - 11 - hoi however due to the tendency of the material to separate as an oil* One crystallization from alcohol yielas the triethyl | 0 ! ore in tricarboxylate as matted white needles melting < 13. 3, 5,Dihydr xy nyl Acetic Acid. 20 g. of the crude sodium condensation product, pressea free from liquid, is added to 40 g. of potassium hydroxide dis- solved in an equal weight of water. This mixture is heated in a nickel crucible as strongly as frothing will permit for about 15-20 minutes or until a drop on the end of ^ glass rod solidi- fies on cooling. Most of the alcohol comes off during the first 5 minutes heating as is indicated by the inf lapmability of the gas during this period. 40 cc. of water are adaea before the material has cooled enough to solidify* The solu- tion thus prepared is used for trie preparation of 3> 5 > dimethoxy phenyl acetic acid which is described later. If the pure dihydroxy acid is desired decompose the fusion product with dilute sulfuric acid and extract repeatedly with ether. The residue from the last portions of ether is almost pure dihydroxy phenyl acetic acid. The residue secured by evaporating the ether is dissolved in a considerable quantity of water, digested from 1 to 3 hours with an excess 01 lead carbonate, and filtered boiling hot. On cooling the filtrate the lead salt separates out in white needles. Yield, from puri- fied triethyl ore in tricar boxy late, about 40 per cent. - 12 - C. 3 , 3 ,Dimethoxy Phenyl Acetic Acid. The material from 7 of the preceding fusions (i.e. from 130 g. of diethyl acetone dicarboxylate ) is combined and placed in a 2 liter flask equipped with a stirrer and a reflux con- denser. 295 g. of dimethyl sulfate is added in small par-cions with vigorous stirring. The addition should require about an hour and the heat of reaction is sufficient to xeep tne temper- ature at about 7 Q J - So"*. At the end of 2 hours stirring 70 g* additional dimethyl sulfate with 30 g* of potassium hydroxide in an equal weignt of water is added slowly. The mixture is stirred for another 2-3 hours at the end of wnicn time a i^er resembling whipped gelatin forms on top of the solution. 200 cc. of 30 per cent potassium nydroxiue is added and the r. 0 mixture stirred on a water bath at about 03 for 3 hours by the end of which time the water insoluble layer has disappeared. A rather heavy precipitate of salt has formed however. The saponified mixture is cooled and, without filtering, aciuified with hydrochloric acid. A rather heavy flocculent precipitate comes down with the salt and continues to increase as more acid is added until a considerable excess of hydrochloric has been added. The precipitate is filtered, sucked dry, and trie dimeth- oxy acid extracted from the salt with ether. The test yield is secured by extracting the dry salt several times and then dis- solving it in water and extracting the balance of the acid from the solution. The ether residues are re crystallized first from benzene and then from a rather large volume of petroleum ether. • W \ 1 -13- Yield about 20 per cent of the theory based on the diethyl acetone dicarboxylate . If very pure material is desired it can be secured by recrystallising from hot water. Crystallizes o o from water in long white needles melting at 100.5-101.5 » -14— V CONCLUSIONS 1. 5 1 dimethoxy phenyl acetic acid can be prepared in yields sufficiently large t o warrant its use as a starting point for the synthesis of symme- trical dihydroxy benzene derivatives. It is superior for this purpose to the dihydroxy phenyl acetic acid. 2. The work is being continued with every indi- cation that a successful conclusion will be reached. -13- VI BIBLIOGRAPHY 1. Oswald Hesse J. prakt . Che in. Si . 22-96* 2. Zopf 5* Johnson and Hodge 4. Adolf Sonn 5* F. W. Semmler H. Thoms 6. Cornelius and von Pechman 7* Wolman ana von Pecnman Ann. Chem. 1£Q, 335* Flechtenstoffe, 1907, C. 251. J. Am. Chem. Sac., 7 )5 . 1014-23* Ber. 14, 773~4- (1921) Ber. 41, 2556. Ber. J&, 3449* Ber. H, 1447 ( 1886 ) Ber. 11, 2014 (1698) J. Chem. Soc., 21, 808 (1899) 8. D. S. Jerdan 9. Willst&tter and Pfannenst ieAnn. 422 . 5 (1921) 10. I). 8. Jerdan 11. Clibcens and Jiernstein 12. Staudinger and Kupfer. 13. Clemmensen J. Chem. Soc., 21, 1106 (1897) J. Chem. 80c., 107 . 1491-2 (1913) Ber. 41, 50 1 (1912) Orig. Com. 8th Intern. Congr. Appl. Chem. 1, 68-76. Ber. 42, 31-63 Ber. 47 . 681-7.