Preparation and Attempted Resolution of Benzoyl-Malic Acid Citation Wisegarver, Burnett Blanchard (1926) Preparation and Attempted Resolution of Benzoyl-Malic Acid. Bachelor's thesis, California Institute of Technology. doi:10.7907/NWAK-8C64. https://resolver.caltech.edu/CaltechTHESIS:06302015-082500873 Abstract The final object of this research was to prepare m-nitrobenzoyl malic acid and to separate it, if possible, into the four stereoisomers predicted by the Huggins' theory of the benzene ring. Inasmuch as the quantity of m-nitro-benzoyl chloride available was limited it was thought better to first prepare i-benzoyl malic acid and then attempt to resolve it. The resolution of m-nitrobenzoyl malic acid could probably be accomplished by a similar method. Item Type: Thesis (Bachelor's thesis) Subject Keywords: Chemical Engineering Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemical Engineering Thesis Availability: Public (worldwide access) Research Advisor(s): Unknown, Unknown Thesis Committee: None, None Defense Date: 1 January 1926 Record Number: CaltechTHESIS:06302015-082500873 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:06302015-082500873 DOI: 10.7907/NWAK-8C64 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 9041 Collection: CaltechTHESIS Deposited By: INVALID USER Deposited On: 30 Jun 2015 15:36 Last Modified: 16 Aug 2023 23:00 Thesis Files Preview PDF - Final Version See Usage Policy. 2MB Repository Staff Only: item control page

The PREPAF.AT ION and ATTEMPTED RESOLUTION Ot BENZOYL-MALIC ACID by Burnett B. w1·s egarver /. . l .' In partial fulfillment of the requirements •' tor the degree ot Bachelor of Science in Chctmica1 Engineering. CALIFORNIA INSTITUTE OF TECimOLOGY pasadena.california 1926 (I) PURPOSE Of The RESEARCH: The final object of this research was to prepare m-nitrobenzoyl malic acid and to separate it,if possible, • into the four stereoiscmers predicted. by the Huggtns'theory of the benzene ring.Inasmuch as the quantity of m-nitro" benzoyl chloride available was limited. 1 t 'Ra& thought better to first prepare i-benzoyl ma.lie acid ani then attempt to resolve it. The resolution of m-nitrobenzoyl ma.lie ao id could probably be aco omp).ished by a aim:l. lar methoi. THEORY: The Huggins• theory of the benzene predicts ortho and meta stereoisomers, e.g. the aooompanting figures represent c om;pounds which are rairror images of each other and \Thie h ahoul:i be (I) stereoiaomers. If a chain containing an asymmetric carbon atom be joined to the benzene ring, as is the case in m-ni trobenzoyl malic a.c id, four t stereoisomers of the resulting compound would be expected. {I) a) M.L.Huggins,Science 55,679-80-(1922) b) ~LA.C.S. 44,1607-I?, (I922) c) Rolfe.Optical Actitivy. (!lacMillan) (2) PREVIOUS WORK: The above isuners have never been found although a (2) number of chemists have done work on different compounds. The preparation of i-benzoyl malic a.cid is described ' (3J by E.E.Shafer,.rr; Its resolution Wd.S not attempted by him. i The resolution of ma.lie acid as described by Dakin (4) was applied. to 1-benzoyl ma.liC acid but it did not give sa.tisfao tory results. It Nas found that by the use of 1 .. . quinine there were ob ta.in ed. two subs tanc ~s of dee ided.ly different habit of crystallization and possessing differ- ent degrees of rotation. Lack of time preventei further investigation. ' A _redetermination of the e.:iuiva.l.ent weight of 1-benzoyl "' . . ma.lie ao id gave results which indicate that the acid crystal~ . . lizes from water with -~HO. Tllis is lost when the compound 2. . 0 is heated at 90 C. for 48 hours, the resulting substance being the anhydrous · a.c :Id. These results do not agree with those obtained by Shater. \ (Z) a) Le Bel,Bulletin Soc.Chem. 38,98 (1882) b) Lewkowitsoh,Trans. Chem. Soc. 53,78/(1888) o) (3) v. ~eyer and Luhn Ber. 28,2795 (1895) a) E.E. Shafer ,Jr.• Seni>ir thesis.Calif. Inet. T:8ch. 1925 . (4) a) Dakin,Jour.Bi ol.Chem. 59, 7 ,(I924) (3) EXPF.IUMENTAL WORK: 2I.I g. (.I5 mole) of redistilled. benzoyl chloride 0 0 :B.P. I92. 5-I93 c. and 20. I g. (. I .6.}mole) o:f' i-ma.J.io ao id (Eastman's) were placed in at 1. balloon flask. The mixture was refluxed. over a water bath until the evolution of HCL became .:iuite slow. Another molal portion of benzoyl . ~ chloride was then added and the mixture ~as heated until no more HOL was evolved.. About Ii hours were required for ~ the completion of the rea.o tion. The resultant liquid wa.s . ~ poured of:f', cooled. and the solid obtained. •ms bro.ken up. ' It was wash~ repeatedly with benzene to remove benzoyl chloride and. benzoio a.c id. The solid \Vas dissolved. in hot water and the solution allo-Red. to crystallize. I2.5 g. 0 I\ 0 • of a substance melting at I26-I28 was obtained.. By recrystallization from hot water a product melting at I37.5 0 was obtaine~. Weight II g. Yield 30.8% on basis of ma.lie a.o id. Shafer found that pure benzoyl malio acid crystallized 0 0 from ·.Jater melted at IIo-IIo. 7 c. and the substance after 0 0 . 0 drying in an oven at 90 for 48 hours melted at I37.5-I38.5 l This yield was rather ema.11 ani difficulty ·R as tou.n:i in obtaining the pure substance so a second preparation was thought advisable. 2d. Preparation: .T:'ae reaction waa carried out as in the Ist preparation except a smaller exoess of benzoyl chloride was used. • . 0 0 The crude product melted at I32-I35 ani after one crystal0 0 lization from hot water, at I28-I30 These resal ts iniica.te • first that the reaction did not go to completion, and. sec oni (4) that hydrolysis takes place in hot water. 3d Preparation: 33.5 g. (.25 mole) of finely ground dry malic acid and 35.I g. (.25 '.; mole) ot benzoyl chloride were mixed and refluxed for! hour by whioh time the evolution of HCL had. becane slow. Another molal portion of benzoyl chloride ;,vas added and the mixture was heated until all the malic acid had d.iaappeare·i . This required. 45 minutes longer. The resultant ~ liqaid. solidified. on cooling. The solid was ground in a mortar wi th benzene.filtere.1.,ani washed. with benzene. Weight of solid 48 grams. On standing the mass became gWIUlzy' but finally dried. This effect is due to the absorption of water by the benzoyl chloride which hydrolyzes to benzoic a.c id. The solid was mixer-! with I50 c .c. of benzene and refluxed for i hour to tree it from benzoio acid. The solid dissolved leaving a gW?mzy' solid on the flask. This gummy substance is malio acid that failed to react. The benzene was poured off and allowed to cool whereupon a solid substance aepa.rated. It was filtered and washed \¥ith benzene.Weight t 0 0 I6. 5 g. M. P. I20-I24 The mother liquor from the above crystallizati on wa.s all owed. to evaporate and more crystals separated. 0 0 0 Weight I8 g. M.P. !30 So£tenei at I09-II8.By recrysta.llizat6on 0 0 of the substances crystals were obtained that melted at 94-96 Weight 29.5 g. 49.5% ytild. Investigation of the mother liquors sho•Ned. that they consisted. ma.inly of benzoic e.oid and small a..~ounta of malic acid . A better way of separating benzoyl ma.lie acid from benzoic acid was desirei so the following procedure was used.: (5) Impure benzoyl malic acid waa dissolved in cold water and lead. acetate was added until the precipitate of lead benzoyl ma.late no longer formed.. Lea:i benzoate is soluble in water. ihe precipitate was filterei an:t washed with hot water. It was then suspenied. in water ani H2 S was bubbled through the solution. The precipitate of lecd sulfide was filterei off and the filtrate was allowed to evaporate spontaneously. 0 0 Crystals of benzoyl rpa.lio acid melting at IIo-III were obtained. It was found that solutions of the acti hydrolyzed 0 (I appreciably even when heated at 7o-se. Consequently all -s olu ti ons of it must be made cold. and allo•Ned to evaporate spontaneously. TREATMENT OF BENZOYL :MALIC ACID WITH CINCHONINE: ~.4 g. (.025 mole) of cinchonine and 6.0 g. (.025 mole) of benzoyl malic acid ·Nere dissolved . in 65 cc of hot methyl /. _ , , ~,¥ f ;/ alcohol. A brown solution resulted. but no crystals formed. <:/ ·. ,. . on '_''(,'·-~:' -l ::-· .·: _ ) .- --' 1 standing for several days. The solution was evaporatei further a.n:i a brown glass-like substance remained., It showed no crystalline structure when dry. Al.l attempts to crystallize it from other solvents failei. Attempts to prepare the neutral cinchonine salt reaultei in -t he formation of a similar non-crystalline gum. TREATJICENT OF BENZOYL M.ALI C AC ID WI TH l3RUCINE: 2.3 g. (.005 mole) of' brucine and I.2 g. (.005 mole) of benzoyl malic acid were dissolved in 30 cc of hot 95% alcohol. The solution uae allowed to ata.ni overnight uncorked. (6) A few crystals formed but the li ~uid was too viscous for crystallization to continue. More alcohol was added and the mixture was stirred.. The crystals formed. by this treatment were dissolved in 50 ca of hot water and the solution was all~Ned to stand. Circular nodules formed. They consisted. of exceeiingly fine crysta.J.s which were arrangsi about a cente.r . 0 0 Y.Y. I?3-I75. The habit of crystallization and. the melting point indicate that the substance is mainly bruoine. 2d TREATJ.{ENT OF BENZOYL l!ALIC ACID WITH BRUCINE: !.3 g. of brucine and. I.2 g. of benzoyl ma.lie acid were dissolved in 30 co of hot 95% alcohol am stoppered.. Nodular crystals formed after standing for several days. They were o e washed with ale ohol. M. P. I?I-1?2. The mother liquor was allO'Ned. . to stand longer. Fine crystals a.ppearei which were sep· 0 'O ara ted. and. \Vashei with a.le ohol. M.P. I38-I43. The mother l iq- .. uor from the second crystallization was al.lowed to evaporate slO'Nly. Plate like prisms resembling those of benzoyl ma.lie 0 ac :ld orya•llized out. M:.P. Ioa-IIO. The Ist t wo crops of crystals obtained were almost inso~uble in water. Solutions made by filtering hot extracts of them were optically inactive. TREATMENT- OF BENZOYL MAI.IC ACID WITH Q.UDUNE : I.89 g. (.005 mole) of quinine an:i I.I9 g. (.005 mole) of benzoyl malic acid were dissolved. in about 30 co of hot absolute alcohol. The solution was filtered. and allowed to stan~ until compact nodules separated out. The a oluti on was then pour~ off. The nodules were washed with alcohol and diss9.~ved (7) in absolute alcohol. Small neeile-like crystals appeared. 0 The recrystallized product decanposed at I50. This is called quinine benzoyl ma.late A. The mother liquor from the Ist ~ ~ crystallization waa allo•Ned. to evaporate slowly. Naiules formed at f'irst but a new type o-r crystal appeared. The liquid ~ was pourei off in omer to separate the two ld.ni of crystals . The 2d. type was neeile like in s true ture. Thit• ie ': called 0 quinine benzoyl malate B. Crystals of it turned brown at 125 0 0 ani melt~ a.t I28-I29. ROTATION OF Q,UININE BENZOYL MAL.ATES A AND B : Solution #I was made by dissolving .I006 g. of quinine ~ benzoyl ma.late A in 50 cc of butyl alcohol; solution #2 by dissolving .o5I6 g. Of quinine benzoyl mala.te B in 25 cc of b~tyl alcohol. Attempts to polarize the solutions using a sodium flame were unau ocessful because the intensity of the light was too sma.11. The results -below were obtaintli by using a mercury arc giving the line )...== 5461 1. Reading # I 2 0 Water 3 Avg. 4 0 0 +.926 0 " Butyl Ale. +.87 -t.86 +. 86 • Sol. #I -i-. 23 #2 .. +-. 24 +. 23 e Sol. +.863 0 0 o c o . 0 +.233 .. 0 + .33 +.30 +.30 +-.32 +.315 Probable error Spec. Rot. [<>eJ 1.0 0 +.93 +.93 +.92 0 Obs.Rot. 0 - .545 -128. - Ioe. 4.ofo 0 Specific rotation of quinine (in 97% alcohol) - 145.2 ~ Specific rotation of anhyd. quinine " - I?0.5 • . (8) The results obtainei in the treatment of benzoyl malic acid with cinchonine and brucine might iniicate that the substance thought to be the acid was the anhydride. For this reason the following determinations were maie:Sta.niardizati on of Ba(OH) 2 ' Sample #I Sample #2 Weight of <malic acid .4040 g. .4002 g. Titration- 48.88 cc 48.42 cc " .06 cc .03 00 Volume used 48.82 co 48.39 cc Final Read. Initial Normality .I3I3 N. I3I3 N. Titration of Benzoyl Malic Acid Crystallizei from Water:Sample #I Sample #2 • 75II g. .7508 g • Weight of Acid Titration- Final Read.Ba.<,06H)2 46. 5? cc 46.43 cc .IO cc .02 cc 46.47 cc t6.4I cc I23.I 123.2 123.15 Shafer's value Initial II Volume used " " Equivalent Weight ~ • At!g. Equiv • Weight ~vas 12~. (9) Titration of the Substance obtained by Heating Benzoyl 0 llalic Acid for 48 Hours at 90 c. Shafer' a Prep. -Sample # I :Sa.mple #2 My Prep. #I Weight • 73I7 g. • 6005 g • • 6005 g. 47.40 cc 26.41 co 38.70 00 38.63 co " .02 co .55 cc .!3 cc .03 cc Volume used 47.38 cc 25.86 00 38.57 cc 38.60 co Equiv. Weight II7.5 II8.0 II8.7 II8.5 Final Rec::ding Initial ' .4002 G. #2 Average n n II7.75 Shafer•s Value II8.6 II6.5 Check on the Normal! ty of Ba(OR)z. made a.t eni of ti trati one: - Weight of oxalic Acid Final Reading Ba(OH)~ Sample #2 • 3000 g. • 3003 g. 36.57 cc 36.44 co • " .04 co .o5 cc Volume used n 36.53 co 36.39 cc Normality " .1303 N. .1309 N. Avg. " " .1306 N. Avg. " -!st. Deter • Initial • Sample # I Difference • I3I3 N• .54% ( IO) CONCLUSIONS : The best methoi for the prepara.ti on of benzoyl ma.lie acid i s the foll owing : - Finely ground dry ma.lie acid ani benzoyl chloride are mixed in molal proportions and refluxed ever a water bath unti l the evolution of HCL becomes slow; thismrequires abaut "' 45 minutes. Another molal portion of benzoyl chloride is then added and the mixture is heated until no more HCL is evolved; this requires about 30 minutes. The liquid obtainei is then poured out into a mortar and. the solid forme:i on cooling is ground up· with benzene. '.Ihe residue may be treate:i in the following ways:0 a) Dissolve tha solid in water at · 50 c. and filter off the crystals formai on cooling. They consist largely of benzoio acid. Allow tha filtrate to evaporate spontaneously a.Di recrystallize th& p:toiuct obtained fran o old water. Another crystallization may be necessary to give a . 0 0 proiunt melting at !Io-III c. 0 b) Dissolve the solid in water at 50 c. ani aid t the quantity of lead acetate crystals necessary to precipa.tate the acid as lead benzoyl ma.late. Filter off the precipitate ani wash it ~i th hot water, Suspeni it in water and pass in H2 S for a considerable time. Filter off the precipitate of Pb8 an1. allow the filtrate to evaporate spontaneously. This methoi furnishes very pure crystals of benzoyl malic acid but the reaction between lea:i benzoyl ma.late and H2 S takes considerable time and agi tation to complete. especially if iarge quantities of the lead salt are involved. (II) Cinchonine failed to form a crystalline salt with benzoyl ma.lie acid. Attempts were made to form both the acid and neutral salt. Treatment of benzoyl malic acid with brucine !'ailed to prcduce a sa.l t. • The treatment of benzoyl ma.lie acid with quinine seems to iniicate that a compound is forme1 between the two substances. Shortage of time prevented the purification and further investigation of the salt. The titration of benzaoyl malic acid and the substance de~ribed by Shafer aa t;bhe anhydride le;;¥is to some new conclusions, The difference in equivalent weight between the two substances is 4.5. 'lhis represents a difference of 9 in their molecular weigh~. The molecular weight obtained. for the heatei substance is 238 which is that of the CC>Jilpound;H H -C- C OOl-1 0 CO·O - ~~ cooH - H or benzoyl ma.lie acid. The conclusion reached is that the substance crystallizing fran water is .. • a hydrate containing tH 2 0 per molecule of acid ani that the 0 canpou.nd obtainsi by heating the hydrate at 90 C. is the acid i tse1f. This research wae carried out under the direction of' Prof. H.J'.Lucas whose kind assistance I wish to acknowle1.ge here. (12) SUWARY: I) Benz oyl ma.lie a.o id was prepare:! and. then purifie;i by two methois a) By treatment ot the leai salt with H~ s. b) By crystalliaation from water. - 2) The resolution of benzoyl malic acid. was attempted • by the use of cinohonine,bruoine ani quinine. The first two alkaloids gave negative results but favorable evidence was obtainei by the use of quinine. ~ 3) A r~etermination of the equiTalen~ weight of the a.c id crystallizing .frcm water and the c om.pouni obtainei by heating leads to different results from those obtainei by Shafer. I