Thesis (B.S.) Massachusetts Institute of Technology. Dept. of Chemistry, 1952.MIT copy bound with: An infrared study of acetoacetic ester / John B. Schutt. 1952.by Bruno Martino Vittimberga.B.S

Vittimberga, Bruno Martino

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SYNTHESIS OF SAFRANALBruno Martino VlttlmbergaSubmitted in Partial Fulfillment of theRequirements for the Degree of Bachelor ofScience in Chemistry at the MassachusettsInstitute of.Technology.(1952)C'ertified by - - - -~~f~upervlsor-=- - - - - - - - - - - -- - - - - "" ~ -;..;;' - - - - ~ -~--."" - - - - - - -Head of the Department of ChemistryTABLE of CONTENTSACKNOYlLEG~lENTSINTRODUCTIONTHEORETICAL DISCUSSIONULTRAVIOLET ABSORPTION SPECTRA of the ENOLACETATE of CYCLOCITRALEXPERIMENTAL PARTPREPARATION of SCHIFF BASECYCLIZATION of the BASEPREPARATION of the ENOL ACETATEISOPROPENYL ACETATE lvIETHOD'SODIUM ACETATE, ACETIC A~~YDRIDE ~~THODACETIC ANHYDRIDE, ACETYL CHLORIDE METHODOZONIZATION of the ENOL ACETATELITHIUM ALm~INUM HYDRIDE REDUCTION of theACETATE (I)LITHIUM ALm~I~UM HYDRIDE REDUCTION of theACETATE (II)BASE HYDROLYSIS of the ENOL ACETATEBROMINATION of the ENOL ACETATESUMMARYFOOTNOTES~12499101112121314141417181.AcknowlegmentsThe author wishes to express sincere appreciationto Dr. George Buchi who with great patience has been ofinvaluable assistance in the completion of this thesis.2.INTRODUCTIONWinterstein and Teleczkyl first isolated safranalin 1922 from picrocrocln obtained from the plant SafranAquila. Picrocrocin was purified and hydrollzed with1% sulfuric acid. The hydrolysis products were glucoseand safranal in a 1 to ~. ratio.Many attempts have been made to synthesise safranal,but up to the present time, no satisfactory synthesishas been devised. In the work which has thus far beenreported in the literature, either the yields have beentoo low to be practical, or after isolation of a satisfac-tory intermediate, the desired final product was not forth-coming.In 1936 Kulm and Wendt2 succeeded in convertlng~-cyclocltral into safranal by treatment with Selenous acidin a dehydrogenation reaction. Unfortunately, the yieldsin this reaction were found to be from 1 to 3%. If the con-ditions were so adjusted that all the~-cyclocitral was con-verted to s~franal, the safranal which was formed underwentdecomposition.Of the many other attempts which have been made tosynthesize safranal, only two will be mentioned. Two 'atomsof bromine were added to~ -cyclocitral and by double de-hydrobromination, safranal was to be formed. The intermedi-ate product was isolated in good yield, but the 2 moles of3.hydrogen bromide could not be eliminated to form the finalproduct. 3The other noteworthy attempt made by Karrer andOchsner involved the reaction of' -cyclocitral with N-bromosuccinimide in order to brominate in the allyl position.They then dehydrohalogenated this bromo compound with 001-lidine. The elimination of hydrogen bromide was followedby a rearrangement of the ring double bonds so that safranalwas not obtained.44.THEORETICAL DISCUSSLONIn this thesis, an attempt is made to synthesize sa-franal by methods which have thus far not been attempted.It was first proposed that with citral as the starting ma-terial, a cyclization should be effected. Citra1 was con-densed with a~iline and concentrated sulfuric acid was usedas the cyclizing agent. These reactions were carried outfirst with the 'prescribed amounts of reagents. The yieldsofd..-and~ -cyc locr tral were found to be as expected. v/hendouble or triple quantities of the reagents were used ,theoverall yields were little affected by the increase in thequanti ties of the reactants used; but the ratio of 0( - to~ -cyclocitral was more nearly 1 to 1 rather than theexpected 2/3 to 1/3 ratio of the 0(- to ~ -al.dehydes respec-tively.~-c= ...~H I "\d + H~OThe enol acetate of~ -cyclocitral was then made bythree different methods. First isopropenyl acetate wasused with p-toluene sulfonic acid as a catalyst. Second,sodium acetate and acetic anhydride were used, and last of5.all,acetyl chloride and acetic anhydride were used. Itwas found that the last method gave the poorest yield andthe first method gave the best yield of the acetate. Ineach case the acetate which was formed gave the same in-fra red curve having characteristic bands at 829, 913,1200 and 1360 cm -1~H+~- ACETYLATING AGEW1" );The enol acetate of' -cyc1oci tra1 was also made by thethree methods mentioned above. An acetate was formed whichwas identical with the acetate formed from ~ -cyc1ocitral.60".. .1 <:H + ACETYLAT,NG AGENiAlthough (I) is the formula assigned to the enol ace-tate of~ and' -cyclocitral that was formed, no conclusiveproof has been obtained that this is the structure and not~o~ !:oIA strong band is present in the infra red spectrum ofthis ester at 918 cm-l which could be the sli~ht1y di~placedband of a semi-cyclic double bond similar to that present in~t' -ionone and r -irone series.The enol acetate was then subjected to reduction bylithium aluminum hydride in order to determine whether ornot a""-aldehyde could be isolated in the reduction pro-ducts. The reduction was carried out three times. In thefirst attempt a calculated amount of lithium aluminum hy-dride was used. An unidentified crude product gave a red2,4-dinitrophenylhydrazone melting at 183.8-184.5°. In thesecond attempt, again a calculated amount of lithium alum-inum hydride was used, but·this time a larger quantity ofester was reduced. Two products were isolated from this re-action. These were ~ -cyclocitral and a high boiling yel-10''1 fluid which is at the present time unidentified. Thisyellow compound gave a 2,4-dinitrophenylhydrazone which de-composed at 265-2660• At present, indications are that thiscompound is analdo-ketone but no definite proof has beenobtained at this time. The third time the reduction wasmade, a large excess of 1ithium aluminum hydride was -used ,Again« -cyc1ocitral and the high boiling yellow liquid'wereobtained.An attempt was then made to hydrolize the enol-acetateto the corresponding aldehyde, using potassium carbonate inan alcohol-water solution. The 2,4-dinitrophenylhydrazoneof the products were made. Two derivatives of two different7.compounds were isolated. One was the 2,4-dlnitropheny1-hydrazone of' -cyclocitral. The other was yellow needleswhich melted at 185.8-186.80• The latter compound has notbeen identified but carbon-hydrogen analysis indicate thatit is an isomer of c(- and P -oycloci tral.The enol acetate was then brominated. Assuming (I)to be the structure of the ester, three different bromin-ated products could be obtained. These are:)The brominated prod.uct which was obtained was halved.Half was reacted with sodium acetate and acetic acid, andhalf was reacted with dimethyl aniline. In the first ofthese reactions, one 2,4 dinitrophenylhydrazone was formedfrom the reaction products. In the second reaction, twodifferent 2,4-dinitrophenylhydrazone's were made from theproduct.8.'3.0 1----4----+---t---+--~--+__-_+__-_-__+_-__+-___f--+------J4.23.CJ2700 2'00 2500 24-.00 2300 2200 2/00'1'r7,..«FIG. I - ULTRAV/oL£T ABSoRPTION SPECTRA:ENOL ACETATE of CYCLOC'TRAL9.EXPERIMENTAL PARTPreparation of and CyclocitralPreparation of the Schiff-~ase:Fifty grams (0.53 moles) of reagent grade aniline and50 mI. of reagent ether were placed in a lOOOml. three-neck flask. One neck of the flask was closed with a corkstopper. At the other small neck of the flask was placed aseparatory funnel from which 77g. (0.51 moles) of redistilledcitral, b.p. 126-127° (at 29mm.) were added over a period ofone hour. The reaction was stirred vigorously by a stirringmotor attached to a stirring shaft which passed through thecenter neck of the flask. The reaction was carried out at-10 to ~20. After the citral addition was complete, themixture was stirred at this temperature for another hour. Atthe end of the reaction time, the solution was allowed tocome to room temperature. It was then placed in a separatoryfunnel and the water which was formed in the reectlon (about9 mI.) was then separated. This preparation was used im-mediately in the followln cycllzatlon.Cyclizati~n of the Base:The same apparatus was used in this ste~ as was used inthe preparation of the base. Five hundred millileters ofconcentrated sulfuric acid and 20g. of ice were placed inthe 1000ml. reaction flash. The acid was then cooled to -20to -25°, and while the acid was vigorously stirred, the ethersolution of the base was added at this .temperature over the10.period of one hour. Stirring of the solution was continuedfor another hour at this temperature. A thick,red reactionmixture was formed. This mixture was poured into a twoliter long-neck flask containing a quantity of ice. Waterwas then added to the mixture until the volume was approxi-mately 1 3/4liters, and the mixture was steam distilled.One liter of distillate was collected. The distillate wassaturated with sodium chloride and was then extracted withreagent ether. Tbe ether solution was first washed with asolution of sodium carbonate and then with water thoroughlyand dried with sodium sulfate. Tbe ether was then distilledoff on a steam bath and the yellow residue was distilled inan Sn Vigreaux column adapted to vaCUQm distillation in anattempt to separate thed.- and p -oycLocItraJS.Yield: 68%.25The 0( -cyc1ocitra1 was colorless, 11 D • 1.4730. The~ -cyclocitral was slightly yel10w'~B5 = 1.4880.Preparation of the ~nol AcetateIsopropenyl Acetate MethodA large exeess of isopropenyl acetate was added to aquantity off -cyclocitra1 and a catalytic amount of p-toluene sulfonic acid was added. The resulting solution wasplaced in an S" Vigreaux type distilla'tion column and theacetone which was formed in the reaction was distilled offat atmospheric pressure. After the acetone was completelyremoved, the remaining solution was distilled in an efficientcolumn. A greenish-yellow main fraction was obtained, b.p.11.118-120.9°(at 12mm.)Yield: 84%, n~5 • 1.4990Anal. Oalcd. for 012H1802: C, 74.19:H, 9.34. Found: 0,74.37; H, 9.41.The preparation was repeated usingO(.-eyclocitral inplace off' -cycloci tral. The same ester was obtained.Sodium Acetate, Acetic Anhydride MethodFOrty grams (0.26 moles) of cyclocitral (n~O = 1.4819)were placed in a 300 mI. side arm f'Lask, One hundred andfifty millileters of acetic anhydride and 20 g. (0.30 moles)of sodium acetate were added and the mixture was then re-fluxed for 48 hours under a nitrogen atmosphere. After thistime, the mixture was poured into a three neck flask contain-ing water and was sti~red for one hour in order to hydrolyzethe excess acetic anhydride. The solution was then extract-ed with ether which was then dried overnight with sodiumsulfate. While the ether was being evaporated fromthe solution, acetic acid separated out. The mixturewas then placed in a separatory funnel and the water layercontaining the bulk of the acetic acid .was separated out.The remaining solution which was a reddish-brown oil was dis-tilled in an efficient fractionating column. The mainfraction which was obtained was greenish yellow, b.p. 119.4-1200 (12mm). n~5 = 1.4990Anal. Caled. for 012H1802: 0, 74.19; H, 9.34. Found: 0,74. 17; H, 9. 44.12.Acetic Anhydride,Acetyl Chloride MethodThirty grams (0.20 moles) of~-cyclocitral were placedin a 250 m~ side arm flask. One hundred millileters of a-cetic anhydride and 20 mI. of acetyl chloride were addedand the mixture was refluxed under a nitrogen atmosphere fortwo days. After this time, the excess acetlc anhydride andacetyl chloride were evaporated off under vacuum and theproduct was distilled in an efficient column. The productwas greenish-yellow n~5 = 1.4981.Anal. Oa1cd. for 012H1202': 0, 74.19; H, 9.34. round: 0,74.05;ti, 9. 39.Ozonization of the Enol AcetateOne gram of enol acetate was disolved in ethyl acetate.The solution was cooled to -806 and ozonated in a commermia1ozonator for about 30 minutes. After this time, the ozoni-zation was stopped and the water in the water trap was testedfor formaldehyde by addition of an alcohol solution of me-thane. Traces of a white flocculent precipitate were formed,but th~s was not in sufficient quantity for analysis ormelting point determination. The ethyl acetate in the ozonatedsolution was evaporated off j room temperature under yacuum.The ozonide residue which remained was then destroyed by boil-ing with water, and this solution was then extracted with1igroin. The ligroin was then tested for formaldehyde withmethane. After 24 hours, a slight white precipitate was ob-13.tained, but the quanti~y was not enough for analysis.LIthium Aluminum Hydride Reduction (IlTen grams, (0.05 moles) of the enol acetate were dis-olved in reagent grade ether and the solution was placed ina 500 mI. three neck flask. A stirring motor was attachedto a stirring shaft which passed throu6h the center neck ofthe flask. An efficient condensor was placed through thesecond neck and a separatory funnel containing an etherslurry of an excess of lithium aluminum hydride (0.05 moles)was placei at the third neck of the flask. The three neckflask was then cooled to -12 to -130 with a methanol- dryice bath. While the ether-enol acetate solution was undervigorous agitation the lithium alu_inurnhydride slurry wasadded over the period of 15 minmtes. The solution was thenstirred for another 2 hours, and 45 minutes at this temper-ature. After this time, the mixture was poured into a con-centrated solution of amonium chloride, and extractedwith ether. The ether solution was tben dried and the etherwas distilled off after which the residue was distilled ina Holtsmann distillation column. 0( -cyclocitral and a highboiling yellow compound b.p. 115-1190 (lOmm) were obtainedas products. The 2,4 dinitrophenylhydrazone of the highboiling yellow liqUid was a dark red powder when crystallizedfrom methanol-chloroform solution.This liquid is believed to be an aIda-ketone having thesame imperical formula as the enol acetate.Anal. Caled. for C12"1862: a, 74.19; H, 9.34. Found:C,74.21;H, 9.44.14.Lithium Aluminum Hydride Reduction (II)This reaction was carried out in the same ap~aratus aswas the previous lithium aluminum hydride reduction. Thistime, 5g. (0.03 moles) of the enol acetate were reacted witha calculated amount of lithium aluminmm hydride (0.025 moles).The reduction was carried out at -40 to -440• The productsobtained were the same as those obtained in reduction I.Base Hydrolvsis of Enol AcetateTwenty grams (0.10 moles) of enol acetate were placedin a 500 mI. glass stoppered erlenmeyer flask. A concentratedwater-methanol solution of potassium carbonate was then addedand the mixture was stirred overnight with a. magnetic stirrer.After this time, the reaction mixture was diluted with waterand extracted with petroleum ether. The ether was dried anddistilled off on a steam bath, and the product was distilledin a Hickman distillation flask. 2,4-dinltrophenylhydrazonewere made from the products. Two different products were i-solated. One was the orange derivative of ~ -cyclocitral,m.p. 172.2-172.40• Th~ther product was yellow needles frommethanol-chloroform, m.p. 185.8-186.8°. The analysis forthis compound was~Found: C~ 77.83; H, 10.49Bromination of the Enol AcetateA carbon tetrachloride solution of 5g.{0.03 moles) ofenol acetate were placed in a 500ml. three-neck flask. Astirring motor and shaft was placed at the center neck of15.or tbe flask. At another neck was placed a drying tubeoontaln1ng anhydrous oalcium chlor1de and at the third neokwas pla..oeda ee~e.re.tory runnel OOlltl\11~"ns 4.88- (0.03 moles)of brom1ne in oarbon tetraohlor1do solution. The reaotionflank waeoooled to _20° and the bro$lne sQlut10n was thenaddod over a period or 20 minutes. The reaotion m1xture wascontlnuQlly st1rred tbroughout the bromlnat1on. The stirr1ngwas oontinUed. tor 15 more minutes nt this tempera.ture aftertho bromiDe had been llcdded. After the reCiotlon was oomplete,the ca.rbon tetraohlorlie wa~ evaporated orr undervaouum atroom temperature. The res1due was distilled 1~ Hiokman dis-tillat10n flask. A reddish produot was obtainod. This pro-duct was separated into two halves. One half was plaoed 1na 50mi. round bottom flask, and anexoeS9 or dimethyl an1line~~d i~e~ wa, ~'{Luxedwan added. The mlxture was allowed. to sit overn1ght~ undervaouum. This m1xturewaa then poured into a bewter oontaln-tng oold water a.nd extraetEtdvlth ether. Tho ether wtla washedwith oold 3Hhydroohlo!'1c 6l01d. The ether was then (11etl11edotr and a 2,4 d1n1trophenylhydrazone or the produot was made.One derivative was obtained.The ot.her ha.lf of the bromlnated produot waa plaoed ina 50 ml. round bottomrlaak. Sodllum aoetate a.nd aoetic aoldwere added and the mixture wan allowed to sit for three dayn.After this time. 1t was heated on a steam bath for 2 hours.The mixture was then poured 1nto a beaker oontain1ng ooldvater and qxtraoted wlthether. The ether solution was washedw1th a solution ot sod1um oarbonato and then w1th water eater16.which it was steam distilled. Five hundred millileters ofdistillate were collected. This was extracted with ether andthe ether wasdrled. The ether was then distilled off andthe residue was distilled in a Hickman distilling flask. Ayellow'product was obtained with a wide boiling range. Two2,4 dinitrophenylhrdrazones were obtained from this com-pound.Summaryofo{- and @ -cvc toct tral were made by cycl.t zat.Lon;citrA1 andthe enol acetates of these compounds were made using threedifferent methods of acetilation. Both et - and p -cycloci tralsgave the same enol acetate by all three methods. The enol a-cetate was brominated and the brominated product was reactedwith sodium acetate and aeetic aoid and also with dimethylaniline. Two products were isolated from the first of thesereactions, and one product was obtained from the other reaction.The 2,4-dinitrophenylhydrazones of these compounds did notmelt in the range of the corresponding safranal derivative.Although safranal has not been obtained by this prescribedsynthesis, an intermediate has been obtained which upon bro-m1nat1on and subsequent hydrolysis or dehydrohalogenation mayresult in the formation of the desired final product. Theproblem that remains now is to determine the structure of allthe unknown compounds formed in this attempted synthesis.Once this has been done, it can be determined whether or notsafranal can be synthesized by this method.18.FOOTNOTES1. E. -Winterstein and J. Te1eczy, He1v. Chim. Acta., 2,376-3811T92~Chern. Aba., 16, 2503(1922).2. R. Ku1m and G. Wendt, Chern. Abs., 2Q., 5959 (1936) •Ber., ~b, 1549-1555(1936).3. R. Ku1m and G.Wendt, Chern. Abs. ,}Q, 5959(1936).4. P. Karrer and P. Ochsner, He1v. Chim. Acta., ~,2092( 1947) ••

Synthesis of safranal

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Synthesis of safranal

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