Brigham Young University BYU ScholarsArchive
Theses and Dissertations
1958-07-01
The bromination of 1,1,1-Ethanetriacetic acid
John A. Gurney Brigham Young University - Provo
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BYU ScholarsArchive Citation Gurney, John A., "The bromination of 1,1,1-Ethanetriacetic acid" (1958). Theses and Dissertations. 8217. https://scholarsarchive.byu.edu/etd/8217
This Thesis is brought to you for free and open access by BYU ScholarsArchive. It has been accepted for inclusion in Theses and Dissertations by an authorized administrator of BYU ScholarsArchive. For more information, please contact [email protected], [email protected]. TEE BROMINATIONor 1,1,1-ETHANETRIACETIC ACID
An Abstract of a Thesis Submitted to the Department of Chemistry Brigham Young University- Provo, Utah
In Partial Fulfillment of the Requirements for the Degree of Master of Science
John A. Gurney July, 1958 ABSTRACT
Essential to the entire field of Organic Chemistry is the nature of the carbon to carbon bond. Our current concepts and guiding principles concerning it are almost solely constructed from aliphatic compounds, certain simple ring species, and aroma.tic systems. Except for special cases, aliphatic and aromatic types are felt to be mildly strained or free from internal tension while the alicylic small and medium ring compounds are the so-called strained molecules. These strained compounds involve bending back or com- pression of two of the four carbon bonds from an equilibrium position. Distortions of more complex origin occur in the paracyclophanes and hexahelictne, etc. The theory considering strain of two of the four carbon bonds might well be extended to include three bonds. Simple caged compound core types testing three-bond strain. are the tetrahedron, trigonal prism
The tri acid II was very difficult to purify by crystallizing with the techniques of frequent present-day use. Thorpe made no mention of temperature in his accounts, but obtained the acid in good condition. Our work has shown the acid can be easily purified by crystallizing from 50 j hydrochloric acid solution at 65°-70° c. This higher purity product can then be brominated with phosphowus pentabromide 1under special collditions. These are only partially stated by Thorpe. Our work has shown that III can be brominated by making phosphorus pentabromide J.11a.i:!m with slow bromine addition l, . ....__ to a mixture of I+ and phosphorus tribromide. Compoundsnecessary to the acquisition of II and III are e"1'1 isodebydracetate IV, ethyl ~-methyl glutaconate v,·andethy"l ~ . a-cyano ~,~-dimetbylpropane tricarboxylate VI . Discussion of the plausible reasons for method omissions, the synthesis deletions and results of greater interest, reaction achenes . J leading each compound to its successor, and the experimental details of compounds II tbrough VI are presented in the Thesis. Appended is a proposed manuscript for p~blishing in the Journal of the American Chemical Society. THEBROMINATION OF 1,1,1-ETHANETRIACETIC ACID
A Thesis Submitted to the Department of Chemistry Brigham Young University Provo, Utah
In Partial Fulfillment of the Requirements for the Degree of Master of Science
By
John A., Gurney July, 1958 This thesis by John A. Gurney is accepted in its present form by the Department of Chemistry of the Brigham Young University as sat isfying the thesis requirement for the degree of Master of Science.
-ii- ACXNOWI:sDGEMENTS
The writer grateraJ.17 acknowledges the prudent guidance and assistance ot Dr, K. LeBoi Nelson wh6 directed the labors which form the basis of this thesis. Also appreciation is gratetally extended to Ralphena, his wife who patiently and dUigently typed the manuscript, andJfor her suggestions which have been incorporated into the text.
In ~ddition, the use of present Universit7 facilities have come to be cherished bf the currently developing researcher, the author. He wishes to express gratitude for the use of this fine equipment and laboratory space. Further appreciation is extended tor support from the University during part of one summer.
-111- TABLEOF CONTENTS Page
ACKNOWLEDGEMENTS.• • •••• ••• • • • • • • • • • • • • • iii LIST OF TABLES•• • • • • • • • • • • • • • • • • • • • • • • V LIST OF ILLUSTRATIONS.• • • • • • • • • • • • • • • • • • • • vi I. INTRODUCTION.• • • • • •• • • • • • • • • • • • • • • 1 Baeyer strain theory Simple caged-ring systems
II. HISTORICALBACKGROUND. • • • • • • • • • • • • • • • • • 4 Detailed account Later labors III. OURWORK •• • • • ••••• • • • •. •. •. • • • •. 7 Ethyl isodehydracetate,VI Mich•ael condei\sation 1,1,1-ethane triacetic acid, IX Bromination of IX
IV. .REACTIONSCHEMES ••• • • • • • • • • • • • • • • • • • 19 v. EXPERIMENTALDETAILS • • • • • • • • • • • • •• • ••• 26 APPENDIX••••••••• • • • • • • • • • • • • • • • • • • 51 Proposed manuscript for publishing in the Journal of the AmeriMn Chemical Society Elemental Analysis
LITERATURECITED • • • • • • • • • • • • • • • • • • • • • • • 55
-iv- LIST OF TABLES
Table· Page;
l. Yield of Michael Condensation using Diethylmalonate. 12 2. Yield of ,f,{ichael Condensation Ethyl ~-methyl
glutaconate VIII-receiving •••• ., o ••• 0 0 0 0 12
3. Synthetic Results: Ethyl isodehydracetate. e ,. 0 0 26 4. Concentrated Hydrochloric Acid-temperature, volume and generation time •••••• o • •• q. • 28-29
5. Totals of Table 4 ••••• • •••••• o • • o. • 29 6. pH and color changes of ethyl isodehydracetate, • • 32
7. Ethyl isodehydracetate elemental analysis. • • • • • 33 s. Washing and recrystallizing results •• • • • • • • • 36
9 .. Esterification distillation results •• 0 • 0 0 0 0 e 37 10. Elemental analysis of ethyl ~-methyl glutaconate • • 39 11. Distillation of neu.tral diethyl·malQnate condensation product •••••••••• • • 0 • • • 44 12. Distillation of acidic diethyl malonate condensation product •••••••••• eooeoo 45 ~ LIST OF ILLUSTRATIONS
Figure Page
1. Simple caged compound types •• • • • ••• • • • 1 2. Synthesis Pathway ••••••• • • • • • • • • • 8
-vi- I. Introduction
Baezer strain theor;y.-Dr. Adolf von Baeyer, at the end of the :nineteenth . . century was an important force in establishing organic chemistry as the ( ,, fascinating search for ntN QQmpoundsand knowledge. <26> In 1885 he gave added force to the tetra•lent theory of Van1 t Hoff <17> with his \'Spann- ungstheorie/ This tension theory dailt with the change in stability when carbon bonds were pushed back or compressed from an equilibrium position and served as an explanation for the known ring compounds of the day. Although it has been modified in use since that time, it has continued to
stimulate and impell the synthesis of many- so-called strained molecules. This deviation from the optimum angle of 109° 281 between two of the four bonds of carbon; might well be increased to.three bonds with a subsequent possible strain increase. Caged:..RingSystems.-Caged-eompound types testing three-bond strain are 4:·, practically unknown to present day chemistry, These are: the tetra- hedron, trigonal prism
I I LI ___ _ / / / /
Stable. ? Unstable
Weltner <35>has given theoretical consideration to the stability .. -2- of the tetrahedral and cubic systems. From his calculations, he con- cluded that the first structure with the so-called 60° adjacent angles would be stable and the c~bic form would be non-feasible. A Ladenburg type structure su.ch as Farmer pursued <9 >, may also be postulated and expected :aear the border"line between stability and non-existence. The
tetrahedral. '·r system haa, been the object of our interest. Tile ultimate goal of our present e.fferts is to obtain 1,2,3,4- 'te'l.r~:tby'l tric;yclo_,lj.,l,O.O, 2~___.Jbutane, I. This remarkable stru.cture
I. contahis'three kinds or bonds: two carbon types and a carbon-hydrogen bond~ The methyl-to-bridge carbon bond should be essentially normal whiie.\he bridge carbon to carbon bonds should be highly strained. Ap.d above all, the molecule presents multiple s~etry which would lend it to some interesting lDS&sure:mentspossible today, such as spect,ral study, X-ray diffraction, and nuclear Jlllgnetie reson$l'lce. There are three compounds containing this core. They are the acid II, potassit2lll salt III, ,_,,,,. C COaH '-".;e,'1,ti,,H,r C02Et ,.,;,.__ \ I C COaK . ~~0c \ I \ I ~ I \ I N\ I 11\ H02G C02H KOaC C02K Eto2C C02Et II III IV -3- and trietql ester IV of, 4-met!Qrltriqclo [!.1.0.0 ,a-~ butane-1,2,.3- trioarbo~lic acid, and are possible precursors for I. A study' of the preparation of the compoundswas begun. In their synthesis, it was necesaaey that experimental detail be observed and rediscovered clue to .apparent ..method om1ssion and am'biguety. Test1.Jr1Gq of •~od omssicm was soc;tnfoud in the mlting points of 1,1,l-etheme- triacetie a,oid.,-:mt•<4 > "1biguit7 was to1111d1n the bromination of thia samecompoud. <2D In short, our problem was to discover how ke7 com- pounds ..were ob.tained. ·.
Buri.mg the course of our ~vestigJtion, it waa learned tbat Larsen and Woodwardhad :qiadea recent unsuccessful attempt to obtain II. From this and reasons apparen:t; ill the S)'?ltheaia, two ltet compounds, the di- and tri-bromo, e1wrs of Ut,bec&!lleour firJt major .goals. II. Historical Background
At the end of the nineteenth century, the field of organic chemistry was dominated by the busy test tube of the great Baeyer.
Many later well-known names in chemistry came t.o study' with and near him. Thus his influence was felt throughout a large circle. Joycelin F. Thorpe also found himself in the same tradition. He went to Germany for graduate study and., so absorbed the popular technique of the day. <22> This was exemplified by the active research- ing professor working with small quantities, testing properties, evolving new reactions, and reporting in terse concise terms. The large scale preparations, analysis, and routine manipulation were left to the grad- uate student. Thus the teacher knew and often solved the stimulating problems of the laboratory and,though not entirely reported 1ti. the literature, all became aware of the techniques and concepts used. At Sheffield, Thorpe,,with a paid assistant Beesley, developed, through preliminary experiments, a synthetic approach which they thought 1 gave the tricyclobutane derivative,II, melting point 187° c. Thorpe and Beesley announced these results in a preliminary note which was pul,)lished,in 1913. <3> In the end of that year, Thorpe told Beesley that he was not of suf?Ieient 11.A.cademicmind;'/,;:_· ao Beesley said that he was inclined to¥9-rd the wars anyway, and went off to battle. <24> The work was postponed until after the war and accumulation of sufficient material to continueo
1supra P• 3o -5-
Tliorpe also changed positions by going to Imperial College of the University of London in South Kensington. Here Thorpe developed into the Executive Researcher. Soon he was involved with work related to the war and was given more responsibilities at the college. These took him increasingly from the laboratory. Thus much of the work that was done after 191.3 was su:pervised but not actively participated in by Thorpe. The chemistry ot the glutaconic acids was begun in Ge:rmaeyand studi~d quite thoroughly before and after Thorpel's move. Deta&lgg Account.-It was in this situation that the later and more detailed 1 aecoWlt ot the earlier mentioned com.poundsII, III, end IV was obtaine4. <4 > In addition to his own name, Thorpe appended Beesley and Ingeld's namesto this profuse 2 .article as co-authors. He ale~ gave special ac- knowledgement to Mr. A. Wood. This .former student of Thorpe must have done much-of ·the experimental work because Beesle7 was gone and Ingold later hpli~d that he didn 4t remember about the- experimental detail. 3 In this article the melting point of the caged compound II was given as 149° c. anddiffers by .38° c. from the first value of 187° c. reported earlier. Here the matter ~until 1925 when Kohler and Reid at Harvard repeated the synthesis up to and including 1,1,1-ethane triaeetic acid,IX.
<21>· ·i1 though they made no mention of aey further intentions, it might be supposed that the tricycle compound II was their ultimate goal. This the:, never reached. The data they cave indicated their sample o:f IX was impure.
1 Supra p. 3.
2sometwenty seven relating and derivative compounds to the acid II were listed with analytical data. <4 >
3rngold was in a private laboratory doin~ personal research preceeding 1920. <20> -6-
The most recent attempt on the tricyclobutane acid II was the unpublished results ot Larsen and Woodward. <24> They-used the hydrolyzing ,. proeedure:o:r Kohler and Reid to get 1,1,1-ethane triacetic aeid,II, and
improved the acid purity- by using hot acetic acid tor a solvent and cry- stallizing over ice. However, they were Ull8.ble to brominate the acid sufficiently to permit ring closures in the subsequent alkaline dehydro- broni4~tion step. S11mmalj;.-Judgingfrom the above investigators, results, important methods to the area areobscure or unknown today. The men who worked in Thorpe's laboratory at Kensington,. were all·• :able to prep&l"'$the triaeetic acid IX in'tlie samedegree of purit,; <32,10,20> Since then this has apparently not been possible. Therefore the method must have been simple, but not now-,~.
obtainable from the literature by the uninitiated. Farmer, working as an alumni. of Thorpe'·s, knew how to brominate and was able to reproduce earlier accounts of Thorpe's group. <9> · Again men not of this tradition were unable to achieve the desired eri.d. Larsen and Woodward, after they ceased working on this area, ex- pr~ssed disappointment and almost bitterness in the report of their efforts.
The above disparity may be understood on the basis of the strong tradition or the day to include the minimumof experimental detail and perhaps the lack of Thorpefs close research participation in the last published account. III. Our Work
Our work was to fill in between the lines. Thorpe was known for his skillful solution of laboratory manipulation problems and his begin- ning sequences with large scale preps.rations. His preparations often required unusual arrangement of equipment. The present stud)' was no • exception. We were soon aware of this and our work resolved itself into f~ding the lost or remedial technique. The synthesis pathway of Thorpe
<6,15 1 .30>was successfully studied to and including the a.-bromination. of IX. Our synthetic study began with the acid catalyzed condensation of etb.71 acetoaeetate, v.,and ended with the ci-bromination of 1,1,1-ethane- triaeetie aeid 1IX. This sequence presented a variety or reaction types. These were acid-catalyzed aldol condensation, laetone ring fission, Michael condensation, ester and nitrile hy'drolysis, acid bromination, and a-bromina tion
Fig. 2
0 0 0 0 \/\ 11 C ~-C n NaEtO 2: c-c-c-c-OEt H+ > I II > C C-C-OaEt \/ g V VI
C C I I Eto 2C-C-C=C-COaEt --> Et02C-C-C-C-C02Et I C /\ N:C C02Et VII VIII
C 0 C O H20 I II I II > B02C-C-C-C-COaB > Br-C-C-C-C-C-Br H+ I I C C I I C02B C=O I Br IX I
0 BrC 0 BrC fl I I 11 I I --> Br-C-C-C-C
-C-Br -----> Eto2C-C-C-C
-C02Et I I C-Br C-Br I I C=O C02Et I Br XIa = a-dibromo XIIa XIb = a-tribromo IIIb
EthYJ. ~sodeb:Ydracetate9VI.-This reaction was typical. of Thorpe .. It was begun with one kilogram of acetoacetic ester; V, anhydrous hydrogen -9- chloride treatment conducted at or below o0 c. and stored in the dark.
Our first atte•pts at performing this reaction gave consistant yields in the 30-40 j range. At first we didn't get enough acid into the :mix- ture., This was soon overcome by gently pulling the gas into the solu- 1 tion with mild aspirJtion on the system. But the low yields continued. During distillation of the crude ester, a eolQred material was observed in the solvent which collected in a cold trap. Surprizi~gly', this material changed color during the distillatioi. Examination revealed that it gave color changes over a wide pH rangeo Even though the erude ester was washed to a neutral point, t~e distillate contained hy'drocploric acid., This led to the discover,- of ethyl isodehydraeetic acid chloride which was present., The removal of this troublesome by- product
10riginal lit~rature yield was 63 .%.<15> -10-
scale of the preparation used which made washings by us and handling 1 difficult. Dietlql @-methyl glutaeo:nate,VII.-Experiments in this area revealed that the manner of sodium ethoxide preparation was signif'icant. If' this was done in a running water bath as the ring-f'ission reaction directiqns called for, the action slowed to such a rate near the end that all the sodium would not reaeto It was found that if' the mixture was heated to give the reaction between sodium and alcohol that serious side 2 products appeared~ and subsequent ring opening failed to give the de- sired product VII. If cooling was kept at such a level as to give only moderate heat removal, the reaction could be completed with gentle warming near the endo Sodi1111ethoxide prepared in this manner crystalized during the product isolation of VII. Hence another method of preJaration was developed. This method used almost double the amount of alcohol called for. The excess alcohol was then removed by reduced pressure distilla- tion., During all stages of the preparation, the bath temperature was maintained at or below 20° Co This gave literature yields) It was also found that molar or slightly larger amounts of sodium ethoxide gave yield improvement. Very gradual reagent ad.dition 4 gave addi~ tio:nal yieldo The directions specified reaction at room temperature for
1we used 2 kilograms of ethyl acetoaeetate.
2Presumably these were the results of the Guerbet reaction <4l> which gives, among other things, heavier alcohols, unsaturated compounds, and aldehydeso The last item is now known to react with the heterocycle used and may well interfer with the course or the reaction.
4rhe slower the additions were made, the better the yield that resulted. -11-
two hourso Temperatures abo-ve this gave no yield of the desired estero Temperatures below gave less yield~ unreacted VIo This reaction yielded mostly cis=form although both isomers could be formedo An interesting sidelight was observed here. Some cis-isomer 'of'VII that remained on the shelf in a colorless flask for three to four months 1 was found to contain a mixture of both isomerso Also a terpene-odored and unidentified compound was collected in a short fore-fractiono In
general the ring opening reaction was very sensitive to conditions and may well be studied moreo ;Michyl Condensation: Ethyl a-cygo-BoB-dim.ethylpropapetricarbgxylate,vIII.- Following the lead of Kohler and Reid <2D who have shown the need for and water exclusion/care.fu.l reagent drying, maintenance or anhydrous _ conditions was neata.ykept throughout the :x-eactiono If· this was not done, a brown material appeared and a lowered yield resultedo It was not mentioned ,~w th! ;,reagents were combined even though the directions given for the reaction allowed only one way of combining materialso The very insolubility of sodium ethyl cyano· acetate in absolute ethanol was a point which would be obvious to someone who had previously used this sal to Rapid addition of reagents was also advantageous as to ;yield,
the mor~ rapid the bettero Yield improvenent might be accomplished by changes in another direction, that of steric interference avoidanceo The apparent evidence for this was found in the use of dietbylmalonate 2 as the condensing unito The increased grouping of radicals about the double bond apparently decreased the amount of condensation that took placeo If the same relation held with the condensing molecule, then a similar
1This isomerization was also noted by Thorpeo <30> 2see table 1., -12- trend would predict an increased yield with nitrile substitution for the ester groupso
TABLE lo-Yield of Michael Condensation using Dietl:J7)rnalouate
Receiving Molecule· %Yield
C-C=C-C02Et CD • 0 0 0 0 0 0 0 Q O Q O 0. 0 0 90 <28>
c-c=e-co2Et 00eoo••oe1•ooe1000 40 <28> I C c-c=C-CO,aEt OOOOOOOQOOOOOOOO 20 <28> I C • EtD,aC-C-C=C-CO,aEt
Condensing Molecule %Yield
Et02C-C-C02Et 17
EC.,,C-C0 2Et 66 N:C-C-C=N higher?
An increase of catalyst basicity and steric i.Di.pedencemay also be of advantage o Experiments with potassium tertiary amyloxide gave sigllifieant yield improvement over sodium ethoxide in Michael condensation reactions by Renfrowo <27> This work was performed ~ s1ief;'icall.7···hindered receptors and is certainly suggestive for trialo Another interesting aspect of this molecule was revealed in decarbox;ylation reaetionso The following sequence has been tentatively suggested to explain experimental observationo -1.3-
C C I I Eto2 c-c-c-c-co2Et 4 > Eto2c-c-c-c-co2Et I <20mm. I C C /\ I +c02 N:C CO,aH O:N VIIIb VIII
0 b,, I E~ c-c-c-c-c=N+ C=C + co2 CompoundXIV easily decarboxylated to the a-unsubstituted nitrile,VIIJ,which surprizingly decomposed at lower pressures to the tentively assigned compound XIV. Such ester decarboxylation has been noted in the literature under various conditions of temperature "11-dcata.lyst. It would seem from Le Chatelier's principle that lowered pressure would favor ester decarboxylation. In general the condensa- tion reaction was easy to perform after experience was gained with sodium ethyl cyanoacetate, but may yet be improved. 1 11 11-ethane triacetic acict,IX.-On the surface this looked like an easy synthesis. The directions <.32>said to mix an equal volume of VIII and concentrated sulfuric acid together and allow to stand for an hour. Then dilute by adding an equal volume of water and boil for two hours. At the end of this time the acid separated on cooling or was extracted with ether. Crystallization was chosen since the extraction recommended seemed awkward for large scale use. It took three or four days of scratching, cooling and seeding to get crystallization. Kohler and Reid's hydrolysis was then tried. It required thirty to forty hours I -14- of reflux with constant boiling hydrochloric acid. They obtained the imide acid XV, melting point 155°-156°C., whicn oo treatment with sodium hydroxide and acidification g$ve IX, m.p. 165°-169° c. C C. I I Eto2c-c-c-c-00 2Et ---> H02 C-C-C-C I I \ C C C=O /\ \ I N:C C02Et C-NH II 0 VIIIa xv C NaOH I > H02c-c-c-c-co2a +H I C I C02H IX In our hands, the hydrochloric acid step yields a mixture of two thirds XV and a third IX. These separated easily but were difficult to purity turthero From these two experiences, a modified procedure was evolvedo Diluted sulfuric acid was used because apparently our reagent wasmore concentrated than that of Thorpe's dayo A .30""40% solution of acid mixed with an equal volume of VIII was boiled until the ester.dissolved. The acid IX then crystallized nicely. It was found that the hydrolysis could be done in a few hours if the alcohol was allowed to escape ..from the flask during gentle boiling. Performance of the concentrated sulfuric acid hydrolysis gave i a surprizing result. Acid anhydride <33>was observed when the reactio~ mixture was crystallized from aqueous solvento A concentrated and cooled -15- solution of l,l,l-ethane triacetic acid,IX,was slowly crystallizing when it was jarred. Almost pure anydride separated in white crystals. This led to discovery of the original method of acid crystallization. Wood, Beesley, Ingold and Farmer: <33,3,20,10 ~ all co-workers of Thorpe, crystallized consistantly from water and hydrochloric acid and obtained the acid IX with a melting point of 1728 Co Kohler and Reid, also from water and acid, got the range 165°-:-169° Co Larsen and material exhibiting W:,odwardprocured from acetic aci.q/the range 1728-17305 8 c. The explanation for all this was found in the anhydride present in aqueous solutiono The anhydride co-crystallized with the acid at room temperature,and particularly below ,250 c., when the system was disturbed 0 The anhydride could be removed after four or five care.f'u.l crystallizations at room temperature. Very good purity could be obtained 1 it the crude acid was dissolved in a minimumof hot water and an equal amount of hydrochloric acid added at 70°-65 8 c. This soon provt1 Bromination 8 1.1.1-ethane triacetic acid brong.d$,!,X;a7di 1 .r The acid supersaturated easilyo The anhydride m~lting about 8 1 97 Co didn t nucleate well until lower temperatures 0 -16- ambiguity. Beesley, Thorpe, and Ingold 1 gave the first detailed accounts in the literature for the bromination of acid IX. <4> This bromination can be effected by adding 317 grams of phosphorus pentabromide to 50 grams of the acid contained in a Geisler flask, and then adding 80 grams of bromine gradually down the condenser tube. No bromine should be added until the contents of the flask, after the addition of the phosphorus penta- bromide, have become completel:y ligyj.d, and it should then be dropped into the nask very slowly, the temperature being kept as far as possible in the neighborhood of 20° c. The operation takes some time, but it is essential to adhere to these conditions, otherwise a product containing the correct amount of bromine will not be obtained. After all the bromine has been added, the mixture may be warmed on the water-bath for half an hour, when it will disappear,o•••o• 1 , It was'P,robably Wood that was the source of these procedures. cf. detailed account p. 5. 2Penta-bromide reacts rapidly with the moisture in the air • • -17- Bromination then proceeded smoothly with the aid of illumination. 1 Liquifaction was obtained by the strong light and gentle warming at the end. Addition of bromine for the a-bromination generated little heat but on treatment as suggested above gave tribrominatioit. 2 Apparently the reaction was performed somewhat as follows: The dried and prepared acid- IX was placed in the Geisler flask and phosphorus tribromide added) ;, Then the amount or bromine, to manufacture the pentabromide, was added very slowly at about 20° c. Theziwhen the mixture was oompletelY liquid, the second addition of bromine for a-bromination was made, also at about 20° c. A bromination was then performed without slow addition which gave undissapated heat at the start. This yielded some unusual results. Long colorless needles appeared which were insoluble at 20° c. More of these appeared when the mixture was warmed as above until the entire mixture was filled with them. Chemical manipulation soon revealed that they were l,l,1-ethane triacetic acid bromide,x. Subsequent a-bromination of these proved difficult and also gave results like Woodwardand Larsen's. Apparently configurational factors were at worlc. An explanation is g1 ven later.4 In short, the bromination reaction can be duplicated. All that was needed was an understanding as to how phqsphorous pentabromide was J made and used. 1Thort>eJD.entioneda well-lighted north window in their laboratory. <30> 2 This was proven by preparation of the trilactone. "No reaction • .:. 4see reaction schemes under Bromination. -18- Conclusions.-Two methods emerge which may well have been commonpractice ' in Thorpe 1s laboratory as well as in others or the day. First, the hot crystallization of acid IX and,aecond, the manner of phosphorous penta- bromide preparation. Their frequent use in that day may explain their omission from published accounts even though they: are or vi ta1. importance to the synthesis sequence. Apparently the small habitual detail was just overlooked. Currently we have prepared the di-and tri-bromo esters XIIa and XIIb by use or these details. Also steric hinderanee has be9n tentively related to the Michael condensation reaction with the possi- bility or yield improvement. This work has proven most challenging and stimulating. IV. Reaction Schemes Introduetion,-Schemes have been worked out or obtained from the litera- ture to aid in attempts to improve and understand what was done. The chemistry or ethyl ~-methyl glutaconate, VII, and the bromination of 1,1,1-ethane triaeetic aeid,IV,bas stimulated much interesting thought for us. General ideas are available for the chemistry of ethyl iso- dehydracetate1 VI, and the Michael condensation reaction., They are all presented here in a general way tor the sake of interpretation and interest. Ethyl isodehydracetate, VI.-This reaction has been of interest in recent years due to the tumor damaging character of some derivatives.< 36 > It may be envisioned as a two-molecule aldol-type condensation with water and alcohol elimination steps. .-, 0 0-Et O C HO C \/ \/ EW,--0 \/ C C C ·c I + I H+ > I II C C-C-OEt C C \ n \ \ C 0 c+ C-OEt /\ /\ \ C 0 C OH 0 H EtO O O C Eto O O C \fl \/ \fl \/ C +C OEt C C OEt --·> I I / -H+ I I I C C-C -- ....> C C-C \/ \ \/\ C 0 C 0 /\ /\ C OH C OH -20- H Eto O O C Eto O O C \Jl. \/ \I ,1 0 C OEt C+ C OEt I I / H+ > I I / C C-C C C-C C 0 ,1'C' 0 ,1' ., I C C H 0 O C Eto O O C ,1\ I \I/\/ C C+ .··OEt C C+ OEt _-E_to_H_> I I / --e> I I/ C C-C C C-C 'I C ' 0 ,1'C O I I C 0 0 0 C ,1\/ C C OEt _-_H+_> I II I C C-C ,1 \ C O I C The effect of time and temperature has been studied by Wiley and Moyero <39> They did not give all the scheme as illustrated but they must have had something J.ike it ..in..mindo Ethyl S-methyl glutaconate,VII.-Roger Adam1s isolation of dicrotallie acid from dicrotallin has in recent years established biological interest in VII. OEt OEt . o o * O 1-0OEt ~I \. \! \I C C-C C C-C I I I I --.> C C-C0 C C-C02Et 2Et \./1 '. \./1 CH CH I I C C HOOEt O OEt \I \I t C C-C 11 C C-C02Et \/1 CH -0 OEt O OEt I \I \I C C C-C EtOH --> II > +.: Ito - C C C02Et \/1·- l c H 0 OEt O OEt I \I \I C C C-C I C C-C02Et. \./ C tTautomer representation used by I *Isolated by Thorpeo <31> Noller C -22- Though studied quite thoroughly in Thorpe's day, this chemistry . has not been studied sine• in spite of current biological interest • . Michl:9:1Condensation,-This reaction, though very useful synthetically, has received only passing :in:terest until recently. The steric aspects l have already been discussed. Increased basicity has been known to increase reaction but often gave unwanted side reactions.< 13 > Hine C I Eto2C-C-C=C-C02Et + N::C-CH-C02Et ---~ C C 0 I _ I I Et0 2C-C-C-C-C02Et <---> Eto2C-C-C-C=C-OEt I I C C /\ /\ N::C C02Et N:C C02Et C I H+ > Eto 2C-C-C-C-C02Et I C /\ N:C C02Et At present this is a growing area of activity since it is a very useful tool. <25> Bromination and stereo specificity.-The special · . and specific conditions for bromination might be explained with special and conformational aspectso Internal as well as external proton bonding possibilities in 1,1,1-ethane- 1supra p. 12. -23- triacetic acid can be observed by use or Fisher:-Taylor:- Hirshfelder models. All of the present information might be explained in terms of two possible internal proton bondings: OH3 I C / L!~H2 f \ C=O C=O C=O I I I OH OH OH IXa IXb Struc\ll,'N XXamay be expected to f'orm readily in· a solveni which interacts little with the carbo:xyl groups. A'more polar i,olvent llb . . ·•· would favor , . structure/which allow• · one or more carboxyl groups to interact with the solvent. The less polarity of solvent tlle more groups that could fold in. At warm temperatures, t.tie acid seaned to be alzllost coapleteq miscible with water. I.fthese carboxylgroups can be:freed, then they might assume.a position up in the space·between t.he methyl gr~up and the methylene carbons very near the a-position hydrogen. As each carboxyl group was oonverted into the acid bromide, an inversion at the a-carbon would allow the group to come up easily into this·new conformation and configuration. \ -24- H 0 H+ OH I II H+ I R~H-C-OH > R-CH=C-OH H OH H 0 Br- I I I n > R-CH-C-OH > R-CH-C + HOH I I Br Br The now activated a-hydrogen could weakly proton-bond with the carboxyls and thus stabilize this somewhat planar arrangement. Even it the bonding was too weak to give much stabilization, the acid bromide · ,_l <-- d ·~ 1 H H I H I c Br I C~/"'-.1 -C .. j·\s,..'., cl- 'C:f'--ifj Br-c?' 'H7,,-- - --0 === C-Br CH3 Xa. groups in this conformation would~ retained by resistance to bond rotation. Either situation could be possible with the last more l.ikel,yq, to give a liquid at room temperature. This would be true especially if the synthesis preferentially g~te the planar arrangement Xa. It was found that several hindered bond rotations were necessary to restore the configuration similar to IXa.. This was much more symmetrical· and could have the same kind of weak a-hydrogen proton bonding assistance. It would take energy getting to the more SJm.etrieai form Xb, sUch·as would be provided by heating. It will be noted that if the non-bonded hydrogens are observed, they lie in close proximity to each other in Xa on the models but not -25- Ib in Xb., Also distanced was noted to be identijal to the internuclear distance in bromine. It may be that form Xa was the form easier to brominate and Xb more dif'ficult since in Xb the distance is less favorable. Supporting evidence may be found in Farmer's work. <9> He attempted to monobromina:te II and when he had three groups converted to acid bromide, he weable to get either two or no a.-bromo groups in place. These ideas are only suggested tentively for passing interest. However they do explain the known facts. V. Experimental Details E;thtl 11odehYdracetate,vI.-This heteroe7cle was prepared in yields ranging from 37 %to 57 ,%. Boiling point ranges on these two were 135-145°/1.5-1 mmtand 140-16.3°/1-2.5 mm. TABLE 3.-Synthe.tic Results 20 Weight in grams Per Cent · b.p. 0 c./mm. nn Run 1. 561 37 135-145°/1.5-l 100 residue 2. 604 39 · 108-125°/-1 to 1.5 1.5122 13.6 residue 1.5140 * 98.9 43.4 ave. 106-125 o/Q~S-0 1.5140 23.2 residue 693 46 165-190°/i2-25 629.6j 48 120-152°/o-o 1.5126 4. 83.2 45.7 residue 152-185°/0-3 mm. 1.5108 776.3 51 ~55,% 140-163°/1-2. 5 DIJll. 5. 55 acid chloride *Side fraction distillation of 1 and 2. Careful distillation gave the.boiling point range 109-121° c./ , . 24 8° C 0.8-0.7 mm.and refractive index= 1.5129 D • • Redistillation at 114-115° C./1.0 mm.gav~ the refractive index 1.5124 f•4° C~ and specific 25° C gravity 1.854 2s~c: <12> A better boiling point was obtained during a 1 . longer and quite slow distillation. The value on the plateau was ½he rate was two and a half drops i;er second. *Pressure decreased as fraction was collected. -27- 118.5° c./o. 7 mmo At this point the ester was very nearly c'Q1orl,ess. The reaction required a somewhat unique equipment arrangement and deserves special mention. A three-liter round-bottomed three- necked flask was fitted with a straight condensor, mechanically driven .IITru-bore'' stirrer, and a fine-pore dispersion fritted disc. An anhy- drous eydrochloric acid generator was connected to the disc with tygon tubing. :Excess hydrochloric ..acid was removed with a water scrubber connected to the condenser by rubber tubing. A mercury bubble counter was placed between the generator and the disc. A calcium chloride drying tube was inserted between the condenser and the scrubber. All connections were then tightly wrapped with heavy rubber bands and painted with tygon. Several aids to dependable and adequate gas generation were developed since treatment periods were up to 10-12 hours~ lo Gentle aspiration on the system with rapid water flow in the scrubber. 2. Keeping t~e concentrated hydroeluoric acid funnel filled to the brim. 3. Filling the generato~ reactor flask with just less than half full of concentrated sul~ic acid. 4o Starting generation before the dispersion disc was introduced into the mixture. 5. Maintaining a r ow of gas that would just break the surface of the mixture. 1 6. Carefully placing the capillary t~be 2 in a vertical position before generation was begun.. 7o Very slow stirring of the mixture. In a typical gas treatment there was an induction period of ½he generation was usually moderately begun and then increased to a maximumas soon as the mixture began a~sorbing gas. 2rn the genetator. -28- about fifteen minutes before absorption took place. Then all that could be generated was taken in by- the mixture. At first moderate generation rates were used until it was found that,small yields were resulting. Then rapid rates were soon achieved by- the previously men- tioned methods and gave yield increase. TABLE4.-Concentrated Hydrochloric A~id--.temperature., 'volume, and gueration 't;ime Temp.<°C> Vol. Run 3 .30 ea32O 8.5 20 ea 30 0.83 5-2° ca 36 l.'O 30 80 2 • .33 ' 30 40 1.25 30 3l5 8.83 30 20 1.0 20 45 2.5 \ 20 40 2.16 20 50 ca2,75 Totals ...... •....•.••.•.• 876 41.15 Run 4 oo to .3o 750 s.2; .30 to 6° 320 4.00 3° to 10° 225 3.5 -2° to 78 280 .3.25 -.3° to 3° 320 3.25 -20 'tCI) -10 155 2.00 .. TABLE 4,-Continued Temp.. < 0c> Vol. Run '4 10 to 30 ca434 4o28 Cont. 3° to 3° 405 6 ..17 O.. 5° to 3° 130 2Q 2° to 4° 225 3.25 4° to 10° 320 1.5 3° to 4° 320 1.17 3° to 4° 228 ,83 Totals •••••••••••••••• o•••o 4212 43.45 Run 5, -7° to -10° 380 s.:; -4 0 to -4 0 375 2.7 0 0 -7 to -8.5 160 2-..0 0 0 -8 to -5 350 1.5 -7°_to -5° 620 5.7 -7° to -6° 600 4.2 -6° to -5° 250 1.; 0 0 -7 to -3 775 5.5 -7° to -3° 200 1,7 Totalso•••••••••••••••••ooo 38:Ul 33 ..1 TABLE5.-Totals or Table 4 Generation Run Moles. Temp.. Range <°C.> Time Rate Effective bath cooling was accomplished by vigorously stirring the water-ice slush and adding spent acids f'rom the generator. It the bath was well packed with freshly cru.shed ice and then covered well with acid, the temperature went down rapidly. The mixture was then soon ready for stirring. Temperatures were maintained by adding enough acid to get the desired temperature level. Ice was replaced and diluted liquid removed as needed. Temperatures to -15° c. could be easily reached but were not handy to maintain. The reaction mixture was then stirred vigorously as the bath reached the desired temperature. 1 While this was being done, the generator was charged and cheeked for operation. Stirring was then reduced to a slow rate, the system closed to contain the gas, and acid treatment begun. Thus tvo kilograms, 15.4 moles, of reagent ethyl acetoaeetate,v, was treated with various amounts of anhydrous hydrochloric acid over a period of two weeks. As can be seen from tables 4 and 5, the more acid, the better the yields were. Not all the concentrated hydrochloric acid was found to react since it was later used for the source of cooling in the ice batho However, the 31.6 moles required for reaction was well approached. The reaction proceeded best and gave the most favorable equalibrit1m at ro9I11temperatures. <.39> The periods of cooling may have been a factor in cutting do~ the yield. 2 However, the colder temperatures gave increased rates of gas absorption, other things being equal. Also it gave a less coiored product. <40> A~ first the treatments were designed to give eight hours ot continuous gas each of the two weeks and short bursts to maintain the 1 This was found to aid a more rapid ed>oling of the mixture inside the flask. 2Further yield improvement may be found in hastening warming back to room temperature after each treatment and perhaps by using a 11ttle longer reaction perioo. -31- acid level in the mixture. Then this was changed to give saturation. This took approximately 12 to 16 hours as would be expected from doubling the preparation size, and then shorter amounts to maintain the acid level. Significant amounts of the hetero,eycle could be detected in the reaction mixture after 12 to 14 days. This was observed through small droplets on the flask walls which reflected a blue light. This was quite striking in appearance. The more that it appeared, the better the yield. A similar color effect was observed during distillation if a small amount of acid was presento After fourteen days, the mixture was washed with 1 to 3.7 , 2 liters of chilled water- and cracked ice in 250 ml. portions. Then the organic phase was washed with 3 portions, 1 liter of 1.0 N. sodium carbonate solution. All the washings were kept chilled below 5o c. by the addition of cracked ice. A typical washing resulted in 20 to 25 liters of solution. Hence a new method was evolved. This was done by taking advantage of the easy low temperature crystallization of eth7l isodehydracetate. About a kilogram of crude ester was isolated by adding cracked ice and ice-water with shaking until it began to crystallize. The crude ester mixed with cracked ice was filtered off and melted 3 by warming in the room. This was recrysta+lized as before, 2If small portions are used, washing could be done with much smaller overall amounts. -32- filtered off and meltedo 1 For this operation, a special siphoning apparatus was fi~ally constructed that allowed the aqueous acid removal to be done in the cooling bath and further reduced the amount of resulting wash solution. The time and difficulty of the procedure was 2 reduced much to our reliefo This crude material was then washed as before with portions of 1.0 No sodium carbonate until the ester was 3 neutral. This was then dried over Na2so4• During one of the earlier distillations,a lavender colored material was detected in the cold trap used to protect the evacuation pump. It changed to an orange color as the distillation proceeded. Examination of this material, also observed on the upper inside wall of the condenser, yielded color changes over the pH range 2-8 0 TABLE6.-pH and color changes of ethyl isodehydracetate pH Color 2 violet 4 orange 6 yellow 8 green This led ultimately to the discovery of the acid chloride, m.po 52°-55° Co It could be partially removed if the sodium carbonate washing was done quite thoroughly. The last traces were then rendered inactive by adding powdered calcium carbonate to the distillation pot. ~.p .. 1° C. M.,po range was very narrow. 2prolonged breathing of crude ester produced a lack Qf blood clottingo Also the ester was absorbed through the skino 3These wash solutions, on acidification, yielded a solid compound, m.p .. 52-55° C. -33- It was fo'ilnd to be essential to add enough carbonate that would give color change to a dark yellow when the pot was heated. This cured the residue problem and the 40 Jgbarrier disappeared. Acid chloride forma- tion see:m.edto be somewhat related to the amount of light the mixture received. Run 5 was shielded better and with apparently less chloride formation. Apparently" quite pure ester was obtainable in this mannero However, elemental analy"sis gave values a little high for carbon and a little low for oxygen. TABIE7 .-Eth.vl iso,,lehydracetate Elemental Analysis <34> Elemental Calculated% Fbund % C 61.2 63.0 H 6.12 6.17 0 32.6 I. 31~3 These values were interpreted on the basis of the ethanolized 1 product isolated by Thorpe. Subsequent use of high purity, b.p. 135°-140° C./1.1 mm. and much less pure 1650-190°/15-25 mm. in the next reaction revealed that there was no difference as to reactivity boiling so long as a very yellow and higJ:/fraction was excluded. This often appeared at the end of the main product fraction. One other item in connection with purity might be mentioned here. Very pure ester 2 was stored in a pyrex glass container and in a few days turned yellow. This color which gradually deepened,, 1n time: could be removed by distillation. 1supra p. 21. 2 Colorless or very nearly so. -34- ~-meth.yl glutaconic acid.-Feist's gave, after air drying, 3 ..8 grams of a yellow solid. Acidification with dilute hydrochloric acid gave heat, effervescence, and a dense waxy- like white precipitate. This was rebrystallized from warm ethanol. This yielded 0.7 grams of recrystillized acid, m.po 115°-135° c. Subsequent recrystallization failed to give significant melting ~oint improvement. This was 90 ,%of a theoretical yield. Large-scale preparation.-On the basis of the above results, a larger scale reaction was set up. Sixteen hundred grams, 40 moles of NaOH was added to 1600 grams of water 1 in a temperature moderating bath. Then 200 grams, 1.02 moles,of ethyl isodehydracetate w,as added contin- 1Near saturation. -35- uously and evenly with rapid stirring over a 40 minute period of time. The temperature was initially 45° c. and maintained at 40 ~. 50 C. throughout. Rapid stirring was niaintained for another 50 minutes. After five and three-quarters hours, a solid layer formed at the surtace, but the color was still significantly orange tinted. The next day the bath was raised to 50° c., stirred, and heated for two and one-t~ird hours. After an hour,. the mix became a little more yellow, then started 1 slowly becoming orange again as the bath cooled slightly. The resulting salt was filtered off using Wha~n 1s No. 54 2 paper and suction. Since it was not possible to entirely remove the aqueous phase, no weight was taken here. The salt was dissolved in a miriimumof water and neutralyzed by adding dilute hydrochloric acid through a dropping funnel. Rapid addition was used until the end point approached. A cooling bath maintained the t~mperature near that of the room. A imrked degree of effervescence resulted just before the end point was re~ched. At this pointJ much slower addition of the hydro- chloric acid was used to give large particle size. Additi.on was continued until the pH began to change. The mixture was then left over night to complete the reaction. The mix was then chilled over ice, the acid filtered off, and the result ait-dried. Small samples were then washed or recrystallized in different ways to get an idea of how to remove the impurities present. It weis also desired to get a rough idea of the relative amounts qf cis- and trans- isomers present. ¼:thyl isodehyAracetate has been known to form in a small amount in basic media. 2A fritted Buchner funnel probably could be easily used here. -36- TABLESo-Washing and recrystallization results Combination Melting Points 0 c. untreated 152-7° washed w:ith \\Skelly Ai; 155-160° recrys. from EtOH, H2 O and CHC13 155-1$9° recrys. from EtoH, H2 O 159-1650 recrys. from abso EtoU 156-7°, 147-149°* recrys. from abs. EtOH 115---1358 small scale prepo * This melting point was taken by heating the block at a slower rateo Ali m.pos except the last one were taken by putting the material in place at 145° Co and then heating slowlyo Feist obtained melting points of the two isomers by repeated crystallization from ether. The trans- melted at 149-150° c. and the cis- at 115-116 8 c. The large scale preparation, due to the longer contact time, gave mostly trans- as would be expected,. The shorter time with small scale gave mostly cis-. An interesting sidelight was observed by accident during the course of the alkali treatment aboveo If ether was added in 1:1 portions 1 to the yellow salt, a bright red-scarlet material resultedo Addition of more ether destroyed the color and gave an amber solution, a yellow precipitate, and an aqueous phase. This material was stable at least for short periods of time 2 in contact with con~entrated sodium hydroxideo The crude acid above was washed with three portions of 1:1 ether-Skelly-A mixture, air dried, and weighedo This yielded 8806 % of theoretical, mopo 175-60° C. lJudged as to relative volumes. 2Longer was not tried. -37- Attempted esterificationo-Passing mention in the literature <3» to the esterification led us to believe it could be done quite easily. II . Such statements as, Jin the usual manner •••• and vague references as, "the procedure is in the literature., ••• " tended ·to confirm this. But performance of' what was thought to be a good method, helped establish a now deeply and keenly appreciated need for small-scale preparation, even in what seems to be. a well-known chemistry., The attempt was begun by mixing 127.6 grams,Oo88 moles,of ~-methyl glutaconic acid, 160 grams, ¢.48 moles),absolute alcohol, 165 grams, 2ol2 moles,of reagent benzene, and two to teree milliliters of concentrated sulfuric acid in a one-liter round-bottomed flask. A Dean-Stark type water extractor was attached. The mixture was then simultaneously refluxed and extractedo It was intended to extract until practically all the water was rem.ovedG Twenty days with a few stops in between for eqiuipment modification, yielded 520 7 %of the water theoretically expectedo The product was washed with sodium carbonate solution and I then water., It was then dried over anhydrous sodium sulfate and distilled., TABU:9o-Esterification distillation results Fraction Type Weight Transition 34-170°/15-20 Plateau 210-230°/15 Tarry Residue The desired ester 1s boiling point, 167°/68 mmo obviously revealed that the attempt tailed to give the desired product., -38- Ethzl B-meth_yl glutaconate,VIII.-Wiley and Ellert said they obtained 75 %methyl ester <37> :from ethyl isodehydra~tate by using methanolic potassium hydroxide but failed to give experimental detail. Also the methyl ester could be obtained by using cold n:ethyl alcohol and sulfuric acido This procedure was also omittedo After the experience above, . . . Thorpe's sodium ethoxide method.was used and modified 0 This procedure gave 72-75 %yieldso Boiling points ranged from 85-75° Co/10-l mmoto 7405-81° Co/1 mm. In this distillation, it was possible to detect plateaus of each isomer. A plateau at ca 750 Co/1 mm. corresponded to the trans- form and another at ca 800 Co/1 mm. to the cis-o <23> Usually the largest amount was the cis- isomer. l One mole, 2.3 grams, of freshly- trimmed m~tal:U.e I odium was rapidly added in small pieces to 470 grams, 10.,2 moles.,.of absolute ethanol. 1.3-200 C0, the temperatures desired.> Then the excess solvent, 200 grams, was removed by distilllllg at reduced pressure such that the pot temperature stayed below 2O~ C., It was found that if a slight excess of sodium was used; it aided the final product yield 0 1sodium was stored, trimmed and weighed under "Petrolatum." This clear white oil was blotted from the sodium just before additiono 2 WS · . If the reaction/heated a small amount of the Guer~t; reaction occurred. It's products apparently hamper aeriously,later reactionso -39- 1 After the excess solvent was removed, 196 grams, 1 mole,of ethyl isodehydraceta.te was slowly added. Very slow initial addition was felt to be an advantage. The total operation took from 15 to 30 2 minutes., The slower additions apparently gave better yields., After 3 two hours at room temperature <25-300 Co>, the mixture was added to an equal amount of water. The result was chilled with cracked ice addition, and it was extracted f'oUl" time& with two to one ether-Skellysolve A mixtureo The extract was washed twice with ice-cold water TABLE lOo-Eiemental analysis of ethyl j3-methyl glutaconate Element %Calculated ,%Found C H 0 The high oxygen content may have been due to the presence of a trace of solvent or ethanolyzed ethyl isodehydracetateo This reaction in general was qui~ sensitive to alkali concentrations, rate of addition, and careful washingo It seemed to be easily reproduced if care was taken in observing the details:mentionedo lMore alcohol cuts the yield. "} ~Faster additions gave more of the ethanolized product and the coumarin characterized by Thorpeo <3D 3tower temperatures favored reactions in note 2 and higher temperatures increased ethyl acetate .formation., -40- Absolute ethanolo-Commercially available. \\100 'er'A:> ethyl alcohols have a trace of water especially if they have been transferred from bottle to bottle. A slightly modified method of Fieser's <11> compilation was used to remove thiso Magnesium ethanolate was first made by mixing . ~ If 2o5 grams.,. 0103 moles,of reagent magnesium turnings, 30 mlo a~solute 1 ethanol and 025 grams, 0001 moles,of iodine catalyst in a 500 mlo round-bottomed flask. The flask w-p.sfitted with a condenser and a P2 0, drying tubeo The contents were then refluxed gently until a vigorous reaction took placeo Four hundred milliliters, 806 moles,of UoS.Io ~100 %ethyl alcohol •w~re then added by a dropping funnel and Claisen• head arrange- ment which allowed simultaneoue alcohol addition and distillation. Distillation was begun after al;,out 150 mls. were adde4o This arrangement allowed large batch purification, especially if more magnesium compound was used. The success of the operation depended greatly on the exclusion of water. So a vacuum take-off elbow fitted with the P20, drying tube was used in conducting the fraction to a liter flasko This nask was previously washed with anhydrous alcohol to remove traces of water. We 90 obtained 392 grams, 493 mlo of absolute alcohol Nfractive index l.3596r; and boiling point 74-75°/ca 650 mmo Ethyl cyanoaeetateo-The procedure for this preparation was obtained 2 from Organic Synthesise <19> We obtained 72-75 % yield 0 boiling point 94-99°Co/l..6:mrrro In a five-liter round-bottomed flask, 500 grams, lcarbon tetrachloride, suggested by Feiser, w~s also used with some success, however best results se8llled to be obtained when a small amount of Grignard magnesium was addedo 2 77-80 % yield, 94-998 Co/16 mmo .:.41- 5.3 moles of chloroacetic acid in 700 mlo of warm water 1 was cautiously neutralized with 290 grams, 2 0 7 moles, of anhydrous sodium carbonate. After the neutralized solution had cooled, 294 grams, 5.8 moles,sodium cyanide 2 in 750 mlo of water 3 was very rapidly added with cooling under tap water$ When the temperature reached 95° c. the solution was cooled by adding 200 mlo of ice water. The solution was then heated to boiling 4 and held there for five minutes 0 The resulting solution was cooled for an hour and filtered. To this was added with thorough stirring 694 grams, 600 ml., 4o4 moles, of concentrated hydrochloric acido The solution was evaporated at 60-70 c./20-30 mmountil practically no more distillate came over. The sodium chloride removal and esterification was begun by adding 600 ml. of 95 %EtOH to the residue, by filtering off the precipitated salt, and by then removing the alcohol and more water at 50-60° Co and reduced pressure.5 Before distilling the above liquid, the salt was wa,hed with 500 ml. of addit~onal alcohol and washings added to the solution. The procedure of treating with ethanol, acid, heating, and distilling was repeated two more times as follows: <2> JOO ml. ethanol.,.. 4 mlo concentrated sulfuric acid were refluxed two hours. After alcohol removal for the last time, the acid was neutralized with con- 150° c. 295 ,% 3 warmed to 55° c. 4Yellow to light brown solution when properly done. 5 The pot temperature must not exceed 60-70° c. or the yield was substantially reduced by glycolate formation. <19> -42- centrated sodium carbonate solution. The ester was separated off, the aqueous phase extracted with benzene, and the combined products distilledo The product was then stored over (l Drieriteo 1/ Miehe,el Condensation, Eth.vl a-cyan0:{3 ,S-ddmeth:[l propane tricarboXYlate:I' VIIIo- The method here was adapted from the work ot Kohler and Reid <2D with di- methyl glutaconateo We obtained 47-55 %yields, boiling point 179-186° Co/ 23 8° 5 mm., refractive index 104540:0 ° o A dried three-neclra:l5OOmlo round- bottomed flask was fitted witll a dropping funnel, mechanical stirrer, and a straight condensero A PaO, d.1.-yingtube was then connected to the condenser. The ethyl sodium cyanoacetate was then prepared in this assembled system by adding 3.4 grams,D4148 moles,of sodium metal through the condenser to 16 grams,0ol44 moles,of ethyl cyanoacetate dissolved in 25 grams,0..54 moles,of anhydrous ethanol. The drying tube was the~ fitted .to the condenser. Already in place by means of the dropping funnel 35o4 grams,O.177 moles,of diethyl ~-methyl glutaconate w,a.s,N.pidly added.1 and·the mixture heated for five hours. Just before boiling, a bright red color developed which remained throughout the reactiono The reaction 2 mix was then chilled over ice, poured into 74 mlo of 1.0 No hydrochloric acid 3 also over ice, extracted with four portions of ether, 4 washed with a small amount of concentrated sodium bicarbonate solution.and then dried I over anhydrous sodil.Ullsulfate and finally distilled under reduced pressureo The condensation product XIIl boiled at 181° c./22 mm. on the plateau and exhibited a shifted infra· red spectrum., On redistilling lThe more rapid the bettero 2:>ot temperature 81° Co 312.24 ml. concentrated HCl in 6lo7 mlo ice watero 4Product insol,uh,le in ether-skelly A ndxtureo -43- XIII, the 1,1,1-ethane triacetic diethyl ester nitrile.XIII; came OTer at 155-160° Co/1 0 8-1.5 mm. and crystallized on standing. It melted 1 . through the range 34-370 c. This ma~erial XIII gave characteristic absorption for esters and nitril~, U.OUps and corresponded to a !)reduct obtained by Thorpe and others. <29> A third redistillation agaip gave boiling point changes. This change was more striking. The change W$nt from 155-160° c./1.88 mm. to ca.<16-120° c./1.0 mm. Acid hydrolysis ~f all three products yielded 1,1,1-ethane triacetic acid,IXo However the third product gave a lowered yield and melting point of 165-170° c. and may well pave contained compound XIV. For a higher yield in the next step and solution of the de- carboxylation problem, the ethereal extract can be prepared for hydr~lysis.i After acidification, the ether was boiled off and b:3ated at 100° c. under reduced pressure for a short time. -The result was then hydrolyzed with sulfuric acid and recrystallized from concentrated hydrochloric acid. Michy] condensation with dieth.yJMlonate, ethyl a.-<,w·t>avlltt>,:_ 3 1.1.1-ethlU ~tate •:This exploratory reaction was set up and carried out in much the same way as the one just aboveo In the nask was placed 67. 7 grams, 0.423 moles diethyl· malonate4 and 110 grams, 2.39 moles, absolute ethanolo .To this was added 9.7 grams,o.422 moies, sodium in small freshly trimmed pieces. Then a CaC12 drying tube was fitted to the condenser. Next 84 grams, 0,42 moles, of ethyl ~-methyl- glutaconate was rapidly added from the dropping funnel, and the whole mixture was heated for 7 hours on the water bath. Tm result was added 1 cf., P• 13. 2 From work by Ingold. <20> 3This compound has not been previously synthesized or named. ' 4n~O ~ 1.4131. -44- to 700 ml. of dilute sulfuric acid. 1 An organic phase separated and the aqueous phase was extra~ted with 200 ml. of ether in 50-ml. portions. These combined ethereal extracts and organic phase were evaporated down on the water bath to then be esterified. The residual oil was then refluxed with 100 ml. absolute alcohol and 10 mlo concentrated sulfuric acid for six and one-half hours. During this time, some long'thin needles separated from the reddish mixtureo The entire reaction mixture was treated with cracked ice until cloudiness persisted. This was extracted with a little ether. The phase separation was quite easy. The combiiled organic phase and ether extracts were then washed with 125 ml. of 1.6 molar sodium carbonate solution. The organic phase was then washed with three small portions of water o The neutral ester was dried over anhydrous sodium sulfate and distilled under reduced pressure. TABIE11.-Distillation of neutral diethyl- malonate condensation product Fraction Type Weight Temperature 0 c/mm.;* n~o Unreacted reagents 35.5 1i5-1bS 0 c./o 1.4440 Transition 2.0 105-135° c./o ------Condensation 18.2 160-176°/.5 to -1.5 L.4660 product Transition 3.7 170-184°/.5 to -.5 1.4718 Final frae. 6.9 184- °/.5- 1.4718 * Negative values due to imperfect manometer. ,. -45- Approximately 52 %of the diethyl -1.onate was recovered. The condensation product fraction was 12 %of theory. Further material was obtained from the sodium carbonate wash solution mentioned earlier by neutralizing ~ith dilute sulfuric acid. Distillation revealed some unesterified material. TABIE12.-Distillation of acidic diethyl m.alonate condensation product 20 Fraction Type Weight Temperature oo/mm.* nn Unreacted reagents 30.5 22-26° o./-155 1.3560 14.0 30-35°0./160-105 1.3693 Transition 2.6 30-65°0./105 to -.5 1.3733 3.7 104-114°0./-,.5 104340 Decarboxylation 2.3 115~135°0./0 to -.1 1.4714 Condensation 4.6 1.35-150°0./o 1.4571 product Residue 1.9 150- 0 c./o thick dark liSuid * Same imperfect manometer. The pressure change through the last three fractions was ~hought to indicate a decarboxylation taking place such as was observed with Thorpe and Wood's acid cyano-ester. Assuming that the two fracti.ens before the residue were due to this, there was an additional 4.9 % 1 condensation indicated 0 This would give the 17 % mentioned. earlier. 1,1,1-ethane triacetic acid IX.-Hydrolysis of the Michl.el condensation product was carried out three ways. Our method was felt to be the best. The cyano ester IV can be hydrolyzed in yields of 80-90 %. Experiments with Thorpe and Wood•s procedure led us to believe the original sulfuric acid used contained more water than current reagent. 1supra Po 12. -46- Kohler and Reid's procedure was also felt to be unsatisfactory. Hence the following reagent, 30-40 %sulfuric acid, was tried •. Almost one and a half volumes of acid to cyano-ester r:v were mixed and very gently boiled until solution took place. Alcohol escaped and the reaction went rapidly to completion if the flask was left exposed to the atmos- phereo After solution 1 the mixture was then refluxed for two hourso The triacetic acid IX readily separated on cooling. This could then be readily purified by 11Norite' 4 treatment in water solution. The water solution was then concentrated by evaporation and treatment as follows: an equal amount of concentrated hydrochloric acid was added. At 70° Co crystallization was induced by scratching the walls of the containero Crystallization continued to 65° Co and pure white crystals, m.p. 17204-17502° were filtered from the mother liquor. Air drying gave the melting point range 17300-17508° c. Thorpe and Wood <32> hydrolyzed by mixing equal volumes of cyano ester and concentrated sulfuric acid, ailowing 1 to stand one hour, then mixing an equal volume of water and boiling for two hours. When the sulfuric acid was added, much heat developed and gas evolvedo After water was added and the mixture heated for two hours, it was found difficult to induce crystallization. Three to four days of cooling, scratching, stirring, and seedingwere required to get crystallizationo As expected, the crystallization ratewas very- slow. Three products were isolated from this mixture, the tri-acid IX, anhydride, and a double anhydrideo 2 The acid could be grown in colorless branching l 1At this point, unhydrolyzed ''imido~ acid was present. 2 Both anhydrides were mentioned by Thorpe and Woodo -47- needles, ftii)~bttial ~hapes, or cubes depending on temperature, purity, and rate of crystal growth. The acid anhydride crystals grew in long soft white needles radiating from one seed nuclei, m.p. 97-99° c. The double anhydride was a white chalky powder, m.p. 185° C. Both anhydrides could be converted to the .acid with boiling water. The triacid IX above was colored and could be purified to white- ness through several ''Norite" treatments. The melting point 172-174° Co was obtained from water and concentrated hydrochloric acid at room temperatures after three to four ceystallizations. Kohler and Reid~s procedure-was then performed with cons1.ant boiling hydrochloric acid .. Fourteen grams, 0.045 moles, cyano ester 1 was suspended in 60 mlo, 22 ..2 grams, 0 0 61 moles, concentrated hydro- chloric acid.. Concentrated acid was replaced as the mixture was heated on the steam bath for about forty hours. Two products resulted .. Approximately two-thirds of the crystallized solid, m.p. 151-153° c. 2 separated on cooling. On standing, a second crop m.p. 161-165° c.3 resulted. These two products, being colored, were difficult to purify further. Moreover, boiling water was found to partially convert the imide acid to the triacetic acid IX. Ic~ bath, room temperature and 70° c. crystallizations with water and hydrochloric acid were eventually tried in the course of purifying the triaoid .. Each higher temperature gave a better grade of purity ... Acid melting point 172-174° c .. was dissolved in 50 %HCl acid and crystallized at ice-bath 137 .%anhydrous HCl. 2~ImidoMacid m.p. 155-156° c. 3Kohler and Reid obtained 165-169° c. for their Na.OHhydrolyzed triacetic acid IX. -48- temperfl,tures. • range of 169-174.5° c.1 resulted. Apparently anhydride was invariably formed during dissolving which was done by warming the acid in water and co-crystallized at the lower temperatures. Eth.yl 1.1,1-ethane tribromo triacetate,XII 0 -Several preliminary experi- ments were performed. From these, two different results were obtained. The equipment assembly used was constructed from a 50 ml. erlyn:meyer flask equiped with a rubber stopper taken from a blood receptor kit and thin enough to admit a syringe needle and a small condenser. The condenser was fitted with a P2o, drying tube. Liquid reagents were transferred with a syringe and needle throughout the experiments. The results, like Thorpe's were obtained by adding O.5O grams, 2.45 x 10-3 moles, of triaeetic acid, m.p. 173-174.5° c. and a arystal of iodine to the dried flask. The equipment was then assembled. To this was addedO.999 grams, <.350 m1.2>,7.35 x 10-3 moles, of phosphorus tribromide. Then0.515 grams, <.165 m1.3>,7.35 x 10- 3 moles, of bromine was slowly added to give a yellow mixture. A little heat was fvolved at this point. A red area developed about the iodine and then action ceased. The mixture was then strongly irradiated with a 200 watt tungsten lamp. Soon the entire mixture reacted giving off hydrogen bromide and resulted in the liquified mss. Then .0857 grams, <.0275 ml.>,1.27 x 10-3 moles, of additional bromine was added, again with a good brisk reaction. 4 Weighing revealed that bromination was not 1The highest upper value obtainable was 174.5° c. without hot crystallization. · 150 2sp. grav. 2.a52 • 3sp. grav. 3.119 20• 4A little slower than with acetic acid.· -49- complete. Excess bromine was added and the mixture irradiated until all action stopped. The temperature between:the light and flask finally went to 84° c. The reaction mixture was cooled and poured into three volumes of well chilled ancydrous ethanol. The large amount of heat produced was removed with a dry-ice cooling bath. The result was then dissolved in d17 benzene which precipitated a small amount of solid :material. The esterified product above was proven1to 'be the tribromo- ester XII by conversion to the trilactone. The other result was accomplished by the same assembly and methods. The only change was the addition of; a. running water bath which had been fitted with a constatlt-leveling device. - To 9Q07 grams, 0.444 moles, of triacetic acid, 173-176° c. was added 36.09 grams, <12.67 ml.>,c.133 moles, of phosphorus tribromide. Then 6.76 ml., <21.27 grQ.S), 6.1.332 moles., ot bromine was syringed into the mixture.; Slow hydrogen bromide evolution began. This s9on subsided· indieatug that local heating was the cause of reaction. Then very slowly at first ,gas. evolution began at the point of irradiation.: ;Jl'he mixture was then irradiated and kept at or below 20° C. for· a week. During this time, a slow gas evolution was noted and long colorless needles of tri.Saeid bromide XI ~gan separating. Heating to 408 c. · produced-additional acid bromide crystals with more rapid gas evolution. Reaction was then completed by heating at 40o c. for about two heurs with complete crystallization at room temperatu±-e. The final bromine was then slowly add,ed, but little action took place. Approximately half the material would then react on heating to 708 c. Cooling again gave colorless crystals, this time in plates, but the color of the bromine failed to be absorbed from the mixture. -50- 1.1.1-ethane triacet:p trilaetone.-The tribrominated ester XII was dissolved in an equal amount of·reagent benzene and an equal amount of pyridine added. The yellow color of the ester disappeared immediately and a white precipitate began appearing. Warming completed the pre- cipitation. Trilactone m.p. 205-207° c. < 5> appeared. This could be recrystallized from ethyl acetate. Ethfl 1.1.1-etane triacetateo-This ester was made by adding the acid bromide crystals XI to well-cooled absolute ethanol in atlr,-icebath. After addition was finished, the reaction was completed,iby gently warming with the hand. Excess heat was removed by momentary cooling in the bath mentioned • . The compounJ ide!ti ty was tentatively assigned by it's lack of action with pyridine and potassium carbonate solutions4 Appendix I 0 Proposed Manuscript for Publishing in the Journal of' the American Chemical Society @ontribution from the Department of Chemistry, Brigham Young University, Provo, Uta~ Bromination of 1,1,1-Ethane Triacetic Acid-- A Preliminary Note K. LeRoi Nelson and John A. Gurney-1 1 . Submitted to the Graduate School of Brigham Young University in partial :fulfillment of requirements leading to the Master of Science Degree. Method omis!i~ns vital to the synthesis of compounds leading to 4-methyl g..1.0.0 - Jtrioyclobutane-l,2 1.3-tricarboJcy"late have been revealed by a recent reinvestigation. They are the recrystallization and bromination of l,l,l-ethane triacetic acid. Beesley, Thorpe and Ingold 2 reported the successful synthesis 2R.M. Beesley, J.F. Thorpe, C.K. Ingold, lo .Qblm.§a,;., JJ.2, 591<1920>. 2-4 of 4-methyl 1..1..0.0 trioyclobutane-l,2,.3-tricarboxylate,I 9 thirty eight years ago. A reinvestigation of this remarkable synthesis has revealed method omissions vital to acquiring the compounds leading to I. These methods, apparently then current in the laboratory of Thorpe, involved the preparations or 1,1,1-ethane triacetic acid II and tri- ethyl tribromo-l,l,1-ethane triacetate III. The tri acid II was very difficult to purify by cr,ystallizing with the techniques of frequent present-day use. Thorpe nade no -52- mention or temperature in his aecOWtts,but obtained the acid in good condition. Our work has shown the acid can be easily purified by ccystallizing .from 50 ·,I; hydrochloric acid solution ·at 65-70 1 C. This higher purity product can then be bromina~d wi:th phosphorus pents.bromide -. Y1 ' ' ' . . -~~.' . ,.,. ····-:.··~·.:.~"--:~~-~--:-·- . '·.: ,. :,', - under special conditions. Thes(il are only pa1'tialljlsta.W;;~.:Thorfe~f •\ "I Our work has shown that III can be brominated by making phosphorus pentabromide J.a i!m with slow bromine addition to a. mixture of II and phosphorus tribromide. Further work toward I is now in progress. Experimental Detail i,1,1-ethanetriacetic acid,II.-Equal volumes or pure or crwie ethyl ~-cyano-~ 1~-dimeteyi propane tricarboxylate4 and 30-40 J sulfuric acid ¼:ohler and Reid, "-11;·"1:m.~. §as,., It,']., 28060.925>. c. K. Ingold, ir,. ~. ~., Jail, 1148<1922>. Thie ester was ~-~pared by the Micheal condensation between eteyl f3-methyl glU;te.conatem'.( The crude acid separated on cooling and could be partially purified by dissolving in hot water and treating with ''Norite."' The acid can then be easily purified byadding concentrated hydrochloric acid to a concentrated5 solution of the acid at 95° Co and scratching 5s01ution evaporated by boiling at room pressureo the side of the container at 70° Co Acid II obtained in 80-90 % yield melted over the range 17300-175.8° Co r. , -53- Eth:yl.. tribromo-1 11.l-e:l;liSe triaeetate 9II;J;.-In a small flask fitted 3 with a condenser and P2o, drying tube o.;o grams,<~_.45 x 10-' moles>, of II, a crystal of iodine, and.Q.350ml., <7.35 x 10-3 moles>, of phosphorus tribro¢ide was slowly added at room temperature. Stro~ ' . . irradiation with a 200 watt ~ungsten lamp aided the nNL~tion to the necessary liquifactiono 6 To this was added Qi028 mlo, 6 ' R.M.Beesley, J.F. Thorpe a:nd CoKo,Ingold,~. ill• or additional bromine. The mixture was irradiated until all action had 7 . . ceased. The reaction mixture was cooled and poured into three volumes 7It was also necessary to heat to 84° c. to absorb the bromine color. of well-chilled absolute ethanol. T~e identity of the product III was 8 prove~ by the easy preparation of the trilactone m.p. 205-207° c. 1.1.1-ethane ~rilaetone.-An equal volume or III, reagent benzene, and pyridine wer•. all mixed and gently warmed on a steam plate. White trilactone separated from t~ mixture and can be recrystallized from ethyl acetate •. Appendix II.-Elemental Analysis of Compmmds<34> Ethyl isodehydracetic acid chloride, C8&,o4ci.- Element Calculated FOUllQ C 47.6 H 3.46 0 31.6 Cl 17.3 Diet!r£1 ~-methtl gl]ltaeonate.VII.-• C10H1604 0 60.8 H 8.,0 0 31.2 Tgorpe's Ooumarin.- Before dehydration.- C20H240s 0 61.3 H 6.13 0 32.6 After dehydrationo- H 5.89 0 29.9 Tri-eth:yl a-cyano-6,8-dimethy;lpropane-tricarboxylate VIII, C1 ,H2iO,N9 - C 57.5 H 7.36 0 30.7 N 4o47 -54- Diethyl 1,1,1-ethane triacetate ester nitrile XIV,- C1aH19 04N Element Calculated Found C 59.7 H 7.88 0 26.5 N 5.88 1,1,1-ethane triacetic acid IX,- C8H1 206 C 47.0 H 5.91 0 47.0 LITERATURECITED 1. Adams, R., Van Duuren, B.L., l,. Am•~. 22£•, 22, 2371<1953>. 2. Arnold, R.T., :t.• Org. fil!!m., 12,, 1256<1950>. 3. Beesley, R.M., Thorpe, J.F., ~.Chem..~.,~, 346<1913>. 4. Beesley, R.M., Thorpe, J.F., Ingold C.K., l,. ~. Soc., ID, 610, 618<1920>. 5. Il2!.g., 619. 6. Blande, Thorpe, J.F., ibi~., 101, 1;65<1912>. 7. Breslow, D.s., Hauser, C.R., :I_. Am•Chem. Soc.,~, 2385<1940>. 8. Connor, R., McClellan, W.R., l,. Org• .Q!'.um!.,J., 574<1939>. 9. Farmer, E.H.~ :I.•~. Soc., 12J, 3337<1923>. 10. Farmer, E.H., Ross, J., ibid., 127., 2361, 2367<1925>. 11. Fieser, L.F., •Experiments in Organic Chemistry: 3rd ed., D.C. Heath and Co., Boston,· 1955, p. 286. 12. Feis~, !Im•, fil, 78<1906>. 13. Goss, Ingold,C.K., Thorpe, J.F., :t.• Chem• .§g£., ill, 337(1923>. 14. Ibid., 338. 15. Ibid., 348. 16. Hine, J., "Physical Organic Chemistry ,1' McGraw-Hill Book Co., inc., Ne~ York, 1956, P• 222. 17. Hoff, J.H. van't, lmJl. ~• chim.i[2)g,l, 295<1875>. 18. Hurd, c.n., Blunclc, F.H., :t.• Am•Chem. ~-, §Q, 2419<1938>. 19. Ing;I.is? J .K.R., Org. §m. 24. Larsen, H.o., Woodward;Ph.D. dissertation, Dept. of Chemistery Harvard University 1950. 25; Oda, R., Shono, T., :!,. ~. ~. ~, :m,1680<1957>. 26. Perkin., W.H., :!,. ~. Soc., m, 1520<192.3>. 27. Renfrow jr., W.B. , :!,. .4:m.Chem. Soc., ~, 144<1944>. 28. Royals, E.E. ~Advanced Organic Chemistry/ 1954, p. 792. 29. Thorpe, J. F., :!,. Chem. Soc., ill., 681<1918>. 30. Ibid., 682, 685. 31. Thorpe, J.F., Jordon, L.A.,~., lQZ, 387<1917>. 32. Thorpe, J.F., ,Wood, Ao,~. 103, 1583<1913>. 3.3. Ibid., 1584.' .34. Drs. Weiler and Strauss, 164 Banbury Road, Oxford, England. 35. Waltner, w., :[. !11!•Chem. Soc., 2.2, 4224<1953>. : 36. 'Wiley; R.H., ,:L. !11!•~. §oc., 11;., 4931<1945> 37. Wiley, R.H., Ellert, H.G., .:r.Org. Chem.,~, 330<1957>. 38. Wiley, R.H., Ellert, H.G., :!,. Am.Chem. Soc., 'J!l, 2266<1957>. 39. wi1ey, R.H., Moyer, A.N., ibid., 11;., 5706<1954>. 40. Young, D.w.s.,Atkins, N.M., u.s. patent 2,739,156 Mar. 20, 1956 ·tg..A,.,50, 15593 g.<19568. 41. Balle, J ., Compt. ~., m, 1628<1951>W,.!., iJi., 1578d