Northwestern University Manuscript Library Theses U n p u b l i s h e d t h e s e s s u b m i t t e d f o r t h e M a s t e r ’s a n d D o c t o r ’ s d e c r e e s a n d d e p o s i t e d in the N o r t h w e s t e r n U n i v e r s i t y L i b r a r y a r e o p e n f o r i n s p e c t i o n , but a r e to be u s e d o n l y w i t h d u e r e g a r d to the r i g h t s of the a u t h o r s . Bibliographical r e f e r e n c e s m a y be n o t e d , but p a s s a g e s m a y be c o p i e d o n l y w i t h t h e p e r m i s s i o n of t h e a u t h o r s , a n d p r o p e r c r e d i t m u s t be g i v e n in s u b s e q u e n t w r i t t e n or p u b l i s h e d w o r k . Extensive c o p y i n g o r p u b l i c a t i o n of t h e -thesis in w h o l e o r in p a r t r e q u i r e s a l s o t h e c o n s e n t of t h e D e a n o f t h e G r a d u a t e S c h o o l of N o r t h w e s t e r n U n i v e r s i t y . T h i s t h e s i s by. . h a s b e e n u s e d b y the f o l l o w i n g a t t e s t t h e i r a c c e p t a n c e of the its A patrons ....... persons, whose signatures above restrictions. Libr a r y which borrows is e x p e c t e d to s e c u r e NAME AND ADDRESS t h i s t h e s i s f o r u s e by the s i g n a t u r e of e a c h u s e r . DATE NORTHWESTERN UNIVERSITY SOME UNSATURATED COMPOUNDS OP A CONJUGATE NATURE A DISSERTATION SUBMITTED TO THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF THE REQUIREMENTS for the degree DOCTOR OF PHILOSOPHY DEPARTMENT OF CHEMISTRY BY JOHN LEO ABERNETHY EVANSTON, ILLINOIS AUGUST, 1940 ProQuest Number: 10060803 All rights reserved INFORMATION TO ALL USERS The quality o f this re p ro du ction is d e p e n d e n t u p o n t h e quality o f t h e c o p y subm itted. In t h e unlikely e v e n t th a t th e a u th o r did n o t s e n d a c o m p le te m anuscript a n d th e re a re missing p a g e s , th e s e will b e n o te d . Also, if material h a d to b e re m o v e d , a n o te will ind ic a te th e deletion. uest, ProQ uest 10060803 Published by ProQ uest LLC (2016). C opyright of th e Dissertation is held by t h e Author. All rights reserved. This work is p r o te c te d a g a in s t unauthorized cop yin g u n d e r Title 17, United States C o d e Microform Edition © ProQuest LLC. ProQ uest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346 TO LARRY ACKNOWLEDGMENT The writer wishes to express his appreciation of the kind assistance and contributions of Dr* Charles D* Hurd, under whose direction this investigation was conducted* TABLE OF CONTENTS page I. HISTORICAL................................... . . . . Carotene* • • • * • • .......... • • • • • • • • Synthesis of Vitamin A ...................... Alpha and Beta Ionone Peculiarities • • * . . • • yff-Methylcrotonaldehyde Approach ............. Use of Vinylacetylene .................... Methyl Ether of Vitamin A .................. Other Polyene C o m p o u n d s ................... II, THEORETICAL AND DISCUSSION OF R E S U L T S .............. The Plan of Investigation * ..................... Use of ff-Chlorocrotonic Ester. • • • . • • • • • The Chlorination and the Structure of Acetylketene Reduction of Ethyl Chloroacetoacetate . . . . . . Condensation of Acetylketene with Aliphatic Aldehydes • • • • • • ........................... Use of y£-Me thyl glut aconate 1,3,-Diehloro-2-methyl-2-propanol . . . . . . . . Benzal-yJ-methylglutaconate * Ethyl f^Chloro-?#-methylcrotonate................. 1 -Chi or o -3 -br omo-2 -me thyl -2 -propanol • * .......... l-Chloro-3-iodo-2-methyl-2-propanol . . . . . . . Chlorination of Methallyl Chloride. * • • • • • • Use of Levulinic Acid . . * . dT-Ethynyl-^valerolactone. ................... Opening the Lactone R i n g . . . . * • III* EXPERIMENTAL......................................... 1* Investigations with Acetylketene * ............ Attempts at Condensation with Acetaldehyde • Chlorination of Acetylketene * * • • . . • • Ethyl chloroacetoacetate • • • ............ Chloroacetoacetanilide * • • • • • • • . . . Attempt at Iodination......................... Copper Salt of Ethyl Chloroacetoacetate. • • Reduction, of Ethyl Chloroacetoacetate. • • • 2* Investigations with Methallyl Chloride • • • • Chlorination • * . • • * • • * .............. Reaction of Chlorinated Product with Potassium Cyanide......................... Alcoholysis of the Cyano Compound* . • » • • 1.3-Dichloro-2-methyl-2-propano l ............ l-Chloro-3-'bromo-2-methyl^-2-propanol • • • . l-Chloro-3-iodo-2-me thyl-2-propanol.......... 1.3-Dicyano-2-methyl-2-propanol .......... Ethyl j0 -methylglutaconate * • • • • • • • • BenzalTfP-methylglutaconic A c i d .............. 1 1 2 3 6 9 10 11 15 15 16 17 19 20 21 22 24 25 26 27 28 29 30 31 34 34 34 36 37 38 39 39 39 43 43 44 44 45 47 48 49 49 51 Pyrolysis of Benzal- -methylglutaconicAcid* l-Chloro-3-cyano-2-me thyl-2-propanol. • •. Ethyl /^-methyl-^-chlorocrotonat© • • • •• Attempts to Prepare l-Chloro-2-epoxy-2methylpropane* ................. 3* Investigations with Levulinic Acid • • . •• Preparation of ^-Ethynyl-jjT-valerolactone • Reaction of the Lactone with Hydrochloric Acid................ * .................. Attempts to Prepare the N-dlalkylamide. ** Conversion of Ethynyl Group to Acetyl Group Miscellaneous Reactions of the Lactone* •• IV* V. SUMMARY. . ..................................... 52 53 53 54 57 57 57 58 59 60 61 VITA.................................................. 63 HISTORICAL Some Unsaturated Compounds of a Conjugate Nature The carotenoids, and vitamin A in particular, have received considerable study In the past decade, chiefly because of the fact that some of these substances are essential to the well-being of the human body* A carotenoid is a pigment which occurs naturally in many plants and animals* These compounds consist essentially of long chains of carbon atoms which possess an extensive sequence of conjugated double bonds. They lend themselves to a variety of synthetical approaches, at least in theory. The attempted synthesis of these compounds and related substances has opened a wide field of Investigation. i Carotene was first isolated by Wackenrodea? In 1831 and is known to be a mixture of substances of which ^-carotene, 8,3 or provitamin A, is the principal one. It is converted by the animal body into vitamin A, presumably by hydrolysis of ^-carotene. CHS CH3 CH= (=CH-C=CH-CH=) CHS CH3 -Carotene =CH — + 2 Hs 0 CH* — CH3 CH3 CH=CH-C=CH-CH=CH-C=CH-CHs O CH3 CHa CII3 Vitamin A Cl) Gilman, “Organic Chemistry11, Vol.II, John Wiley and Sons, New York, 1938, p. 1139. f2) von Euler, Biochem.Z., 205. 370 fl938). ’ (3) Ahmad and Drummond, J.Soc.Chem.Ind., 185 T (1931). 4 It was Karrer, Morph and Schopp to vitamin A In 1931. who assigned the structure s Kuhn and Morris in 1937 reported the synthesis of the substance in 7.5% purity, starting with ^-ionon©. In the formulas which follow, let C aH ls represent the 2,6,6-trimethyl-l-cyclohexenyl group, I (ch3 )2c c-ch3 1 I CHa CHS S, ' CHS These steps were involved. C qH! 5CH=CH-C OCH3 BrCHgCOOEt ----- 2--- >— C aHi B -CH=CH-C=CHC OOEt jg -ionone o CH3C6 NHMgl -------------------C aH ls-CH=CH-C=CH-C0NHCvH 7 ch3 C 8H 1 b CH=CH-C=CH-CC1=HC7H 7 0H3 .— HaO »— ^QACig pcis — C eH15CH=CH-C=CH-CH=NC7H 7 CH3 (CHs )sC=CHCHO ---------- ---C 8H15CH=CH-C=CH-CHO CHS piperidine + HOAc yj -1onylideneacetaldehyde C qH 15-CH=CH-C=CH-CH=CH-C=CHCHO CHS ch3 Very recently 6 A1 (OCH (CH3 )o L -- 1--- :— vitamin A this work has been questioned by Karrer on the (4) Karrer, Morph and Schopp, Helv.ChimoActa, 14, 1434 (1931) (5) Kuhn and Morris, Ber., 70, 850 (1937). (6) Karrer and Ruegger,.Helv.Chim.Acta, 25, 284 (1940). 3. basis of chromatographic adsorption data. From the structures of the above compounds it may readily be seen that they are essentially ”isoprene units” combined in a conjugate system. It is of value to the synthesis of this type of structure to be able to build up certain of the units of which it is composed. Nearly every type of condensation reaction has been used to achieve this end and some of the more important ones will be considered. Perhaps the earliest real attempt to synthesize vitamin A 7 was that of Karrer, Salomon, Morph and Walker. Indeed, they are the ones who worked out the synthesis of ^ -ionylideneacetic ester which was used by Kuhn and Morris in their synthesis. Starting with yS -ionone, Karrer and collaborators performed a Reformatsky reaction with bromoacetic ester and the corresponding unsaturated ester was readily obtained. C8H15-CH=CH-CQ + BrCH3COOCsH5 + Zn CH3 C qH x s CH=CH-C =CH-C 00Cs H s ch3 Catalytic reduction gave the corresponding saturated ester and reduction with sodium and alcohol converted the ester to the alcohol. Treatment of the alcohol with hydrobromic acid yielded the bromide. ch3 C sHx 5-CH=CH-(jJ=CHC OOCgHs CHS H; Na --- Cs H5OH C 8H17CHsCHa -CH-CHS -CHS OH CH3 c h .. CHg -CHS -CH-Cilg -COOCsH, BBr C 8HX7CHS -CHS -CHCHg CHgBr CII3 (V) Karrer, Salomon, Morph and Walker, Helv.Chim.Acta, 15 878 (1932). 4 An attempt to use the Grignard reagent of the bromide with methyl chloromethyl ether, to lengthen the side chain resulted chiefly in the formation of the hydrocarbon, C qE x 7-CHa-CHS -CH- (CHS )^-Cll-CIIg-CHS -C QH X7, but c oncurrently CH3 ch3 gave rise to a small amount of the ether, C 8H x 7CHgCHsCH-CHs -CHe -CHS -OCH3 . CH3 Another set of reactions performed by Karrer was started by the condensation of allylmagnesium bromide with the ionones. In these reactions one is able to see some of the peculiarities in reaction properties which have made the approach to vitamin A very difficult. Alpha ionone yielded the unsaturated alcohol, which split out water when heated with phenyl isocyanate. ch3 cnz X CHS =CH-CHsMgBr CHs c h - c h = c h - c o c h 3 » — -? ■-T.:, I c h S // c - ch3 CH CHg CH3 / / \ V ch3 C6 Hs M'CO - ch3 ch3 U / \ I CH=CH-C-CHS -CH=CHS CHa - CH=CH-C=CH-CH=CHa - CH3 CH3 When ^ - i onone was subjected to the same reaction with allyl magnesium bromide, little alcohol was formed and the bromide seemed to have added to one of the ethylene bonds, 8 Heilbron changed barium ^ -ionylideneacetate (i) to the (8) Davies, Heilbron, Jones and Lowe, J.Chem,Soc., 584 (1935)* corresponding aldehyde fll) by pyrolysis with barium formate# The aldehyde was subsequently reduced with aluminum isopropoxide to the alcohol fill)# CH3 Compound II was condensed with acetone CHa \ / / \> — - CH=CH-C =CHC 00 CH; x / -- CHS Ba )- on3 ch3 / \ - CH=CH-C=CH-CHO II \/gh3 III ch3 CH s ch3 / \ - CH=CH-C =CH-CIIS OH i I CH3 \ / - ch3 in the presence of piperidine and was then subjected to de hydration. C8H15-CH=CH-C=CH-CHO + CHaCOCHf CH.s C qH x 5 -CH=CH-C =CH-CH-CHS -C 0CH3 CH3 OH Dehydration of the hydroxy ketone was difficult to 9 accomplish but was finally performed oxalic acid# by means of anhydrous Even here the reaction could be carried out with only small amounts of the hydroxy ketone# A Reformat sky reaction was run on the ketone and the resulting ester hydrolyzed to the acid, obtained in the impure state# (9) Heilbron, Jones, Lowe and Wright, J.Chem#Soc#, 561 (1936)# 6 C qH 15-CH=CH-C=OH-CH=OHCOCH3 + BrCHsCOOCsH s + Zn CH3 G qH3.s -CH=CH-C =CH-CH=CH-G =GH-G OOH CHS CH3 This pertains closely to the story in view of the fact that this is the acid of which vitamin A is the related alcohol* The hydroxy ketone was condensed with ethyl hromoacetate and hydrolyzed to yield the ^-hydroxy acid* The barium salt of this acid was pyrolyzed with barium formate but yielded the hydroxy aldehyde instead of the dehydrated analog* (C qHj. 5 -CH=CH-C =GH-CH-CH2 -C =CH-C 00) ^Ba + fHCOOj^Ba ch3 oh ch3 — ** 2 C 8Hxe-CH=GH-C=CH-CH-CHa-C=CH-CHO + 2 BaG0a GH3 OH ch3 It seems reasonable to infer that this hydroxy aldehyde exists in a cyclic hemi-acetal modification (cf* glucose): GH3 C sH 15CH=CH-G=CH-CHCHs -C=CH-CH-OH, which may explain its CHa ---- 0---- ^ resistance to dehydration* io Puson and Christ reported an attempt to prepare vitamin A by condensing one mole of £ -cyclocitral with two moles of ^-methylcrotonaldehyde, followed by the reduction of the theoretically produced aldehyde product with aluminum isopropoxide. CIO) Puson and Christ, Science, 84, 294 (1936). 7. CHs xCHa ^ CHO + (CH3 )sC=CH-CHO + (CH3 )sC=CH-CHO \ / ~ CH. CaHls-CH=CH-C=CH-CH=CH-C=CH-CHO CH3 A1 (°GH (GH3 )s> CHs C a H j. s - C H = C H - C = C H - C H = C H - C = C H - C H a OH CH3 ch 3 However, Heilbron and Jones the above report* 11 were not inclined to agree with They pointed out that the physiological test is the fundamental one to determine its structure* their experiments they attempted to Condense In -cyclocitraX with crotonaldehyde and other aldehydes, but were unsuccessful This type of condensation is involved in the formation of the product reported by Fuson and Christ* On the other hand, Heilbron and coworkers 1s have shown that citral condenses readily with ^-methylcrotonaldehyde using sodamide as catalyst. Two stereoisomeric aldehydes, which were called pseudo ionylideneacetaldehyde a and pseudo ionylideneacetaldehyde b. (CHS )2C =CH-CHa -CHS -C“CH3 HC-CH=CH-C=CH-CHO V'-ionylideneacetaldehyde a (c h 3 )3 c =c h -c h 3-c h 2 -c -c h 3 OCH-CH=C~CH=CH-CH ch3 ^-ionylideneacetaldehyde b Condensation of citral with crotonaldehyde in the presence of sodamide gave citrylidenecrotonaldehyde a and an unknown (11) Heilbron and Jones, Chemistry and Industry, 813 (1936). (12) Barraclough, Batty, Heilbron and Jones, J.Chem.Soc., 1549 (1 9 3 9 ). 8. cyclic aldehyde which seemed to contain only three ethylenic linkages• (CH3 )sCH=CH-GHS -CH* -G -CHa HC -CH=GH-CH=OH-OHO Gitrylidenecrotonaldehyde a Cyclization of these compounds was then attempted 13 14 , hut the products obtained were of little value toward the vitamin A problem. 15 13,17,18,19 Bernhauer and coworkers were attempting to approach the problem in a similar manner* Their scheme was to condense citral Cl) with 2,6-dimethyloctatrienal (il). This would be followed by cyclization and then the aldehyde fill) produced would be reduced to the desired vitamin A (IV). They had hoped to obtain the 3,7-dimethy1-2,4,6-octatrienal by condensation of two moles of ^-methylcrotonaldehyde, fCH3 )sC=CH-CHO, but they also were unsuccessful. gQ On the other hand, Kuhn, Bads tuber and Grundmann have succeeded In condensing crotonaldehyde to octatrienal use of piperidinium acetate as the catalyst. by the However, pure crotonaldehyde would not cause the condensation. CHa -CH=CH-CHO + CHa -GH=CH-CHO CHa -CH=CH-CH=CH-CH=CH-CHO (13) Heilbron, Jones and Spinks, J*Chem.Soc., 1554 (1939). ■ (14) Batty, Heilbron and Jones, J.Chem.Soc., 1556 (1939). (15)v Bernhauer and Irrgang, Biochem.Z., 254 . 434 (1932). (16| Bernhauer and Woldan, Biochem.Z., 249. 199 (1932). (17) Bernhauer and Neubauer, Biochem.Z., 251. 173 (1932). (18) Bernhauer and Drobnick, Biochem.Z., 266. 197 (1933). (19) Bernhauer, Irrgang, Adler, Mattauch, Mueller and Neiser, Ann., 525, 43 (1936). (20) Kuhn, Badstuber and Grundmann, Ber., 69^, 98 (1936). / V (CH3 )sC=CH-GH=CH-GH=CH-CHO CHO CHf II CH 3 /CHS > > - CH=GH“G=GH-CH=CH-C=CH-CII0 ch3 ch3 3 3 \/ ~ ch3 III CHa CH5 CH=CH-C=CH-GH=CH-C=CH-GHs OE i \/- ch3 CH? (c h 3 )s c =c h -c h =c h »c =c h -c h o CHa CHs V IV By the use of piperidinium acetate they were able also to condense acetaldehyde and crotonaldehyde to decatetraenal. Benzaldehyde was condensed with crotonaldehyde to yield si citrylideneacetaldehyde. Braun and Rudolph had also prepared citrylideneacetaldehyde with properties, however, which were slightly different. By condensation with malonic acid in the presence of pyridine, followed by decarboxylation, they were able to go from the decatetraenal to the decapentaenoic acid. as Another approach to the synthesis of these compounds was the condensation of y? -iouone with the magnesium derivatives of vinylacetylene. An example is the condensation run on -fi -ionone OMgX C 8H15-CH=CH-COCH3 + X Mg C=C-CH=CHS C 8H 5CH=CH-C-C=aH=CHfl i ch3 (21) von Braun and Rudolph, Ber., 67, 1735 (1934) (22) Tal'kind. Zonis and Blokin, Compt.rend.acad. sci.TJ.R.S.S. ,2. 57 (1935), 10. J&3 Recently, Kipping has reported the synthesis of the methyl ether of vitamin A by a very neat set of reactions. As yet this has not been confirmed. The final step was con densation of ^3 -ionone with an organic lithium compound: LiCHs -CH=GH-G=CH-CHs -OCHs + C eH 5CH=CHCOCH3 — CHS c h =c h -c =c h -c h =c h -c =c h -c h s o c h 3 Methyl ^-methoxyethyl ketone was the starting point for the lithium compound. The tertiary alcohol obtained by reaction of the ketone with allylmagnesium chloride was dehydrated: CHS =CH-CH=C -CHS -CHs -OGH CH« Following this, two atoms of bromine were added to the ends of the conjugate system and the elements of hydrogen bromide were eliminated: BrCHs -CH=CH-CBr-CHsCHs 0CHs ch3 -HBr ■?— BrCHs CH=CHC =CHCHs 0CH3 ch3 Treatment of this monobromide with lithium completed the synthesis• Although these are by no means all of the approaches which have significant bearing on the vitamin A problem, they represent the main types of reactions which are being used. In view of the importance to the development of reactions suitable to the synthesis of the carotenoids, it is appropriate (23) Kipping and Wild, Chemistry and Industry, 58, 802 (1939). 11. to discuss certain other polyene compounds. Synthesis of diphenylpolyenes was carried out to a great extent "by Kuhn and Winterstein An example of this type of condensation is the preparation of diphenyldodecahexaene. 2 C 6 H 5 -CH=CH-CH=CH-CHO + H 3 CCOOH ^ HsCCQ0H — Ap fl csh 5 -ch=ch-ch=ch-gh=ch I Cs H 5 -CH=CH-CH=CH-CH=CH Similar condensations were used to obtain other members of this series. Wittig and Klein ss conducted a series of experiments in which a study was made between color and constitution of polyene compounds. One of these, namely, 1,1,6,6-tetraphenyl- hexatriene, was prepared as follows: CH-CH8 -COOGs H 5 ^ CH-CHS -000Cs H 5 + CsH 5Li 6 5 CH-CH-C(OH) (C6H s)8 ■"M,tm'- 11 CH-CH8 -C(0H) (Cs H 5)s — h""1• (G6H 5 )s C=CH-CH=CH-GH=C (c 6h 5)8 Synthesis of polyenecarboxylic acids was accomplished by 37 Kuhn and Hoffer. 38 Octatrienic acid was prepared from croton aldehyde, acetaldehyde and malonic acid by a series of condensations CH 3 CH=CH-CH 0 + CH 3 CH0 CH 3 CH=CH-CH=CH-CHO gBg CCOOH)^ CH 3 -CH=CH-CH=CH-CH=CH-C 00H By condensing polyene aldehydes with pyruvic aldehyde, (24) Kuhn and Winterstein, Helv.Chim.Acta, 11, 87 (1928). (25) Kuhn and Winterstein, Swiss Patent 134,613, Oct.4,1927; Chem.Abstracts, 24, 1652 (1930). (26) Wittig and Klein, Ber., 6£, 2087 (1936). (27) Kuhn and Hoffer, Ber., 69, 2087 (1930). (28) Kuhn and Hoffer, Ber., 65, 651 (1932). 12 J39 Fischer and Wiedemann polyene acids* obtained the corresponding ^T-keto Oxidation with silver oxide produced the corresponding polyene acids* CH3 (CH=CH)nCHO + CHgCOCOOH CHa (CH=CH)n-CH=CHCOCOOH — *— CHa fCH=CH)n+1COOH 30^31.353 Kuhn and Grundmann prepared polyene 33 and also Kuhn and Michel have oc9co -dibasic acids by an voxalic ester process'1* CsH 5OOC-CH=CH-CH3 + (COOC2H s)2 CSH SOOC-CH=CH-CHS-C OCOOCaH 5 + (CH3CO)sO -- CsH sOOC-CH=CH-CH=C (OCOCH3 )COOCs H s Cs H5 OOC -CHs -CH=CH-CH (OC OCH3 )C OOCSH S It.a,0H> - HOOC -CH=CH-CH=CH-C OOH Polyenes have been 'prepared also with the aid of acetylene. Kuhn and Wallenfels obtained 1,8-diphenyl-3,6-»dihydroxy-l,7- octadiene-4-yne by this process* Cs H js + 2 H e MgBr — BrMgC^CMgBr BrMgCsOMgBr + 2 C6H 5CH=CHOHO (29) (30) (31) (32) (33) (34) C6H 5-GH=CH-GH-C33-0H-GH=CH-G6H S OH OH F* G. Fischer and Wiedemann, Ann*, 515, 251 (1934)* Kuhn and Grundmann, Ber*, 69, 1757 (1936) • Kuhn and Grundmann, Ber*, 69, 1979 (1936). Kuhn and Grundmann, Chem*Abstracts, 34, 1036 (1940). Kuhn and Michel, Ber., 71, 1119 (19381. Kuhn and Wallenfels, Ber., 71, 1889 (1938). 13 Other condensations have been run to prepare polyenes* 35 Kuhn has outlined the preparation of phenyl, carboxyl and methyl polyenes* Kuhn and Grundmann have prepared 1,6- dimethylhexatriene, 1, 8-dime thy lhexatriene and 1,12-dime thyl hexatriene* An interesting article has appeared recently 37 in which a Reformatsky condensation, involving vinylogs of haloacetic esters, was suggested as a possible means of obtaining compounds of the carotenoid type* RCHO + XGHS fCH==CH)n -G OOCsHs — *— RCH-CHS (CH=CH)n ~C00C3H 5 OH RCH=CH (CH=CH)n -C00CgH5 In an actual experiment the V-bromo and -iodocrotonic esters were used with benzaldehyde to obtain the desired unsaturated compounds* One might expect that a Perkin reaction could be run with crotonic anhydride and benzaldehyde to obtain the same product as that in the above reaction* Crotonic anhydride is a vinylog of acetic anhydride* c6 h bcho + c h 3 - c h =c h - c o 63V c s h s c h =c h - c h =c h - co o h 'o CHa-CH=CH-C0 38 In actual practice, Kuhn and Ishikawa (35) (36) (37) (38) obtained vinylcinnamic Kuhn, Angew.Chem*,50, 703 (1937). Kuhn and Grundmann, Ber., 71, 442 (1938)* Fuson, Arnold and Cook, J.Am.Chem.Soc*, 6C), 2273 Kuhn and Ishikawa, Ber., 64, 2347 (1931)* (1938). 14. acid, CQH 6CH=C (CH=CHS )-OOOH. Similarly, when -methyl- cratonic anhydride was used the product obtained was 0£-iso- propenylcinnamic aftid, instead of the expected product# Much exploration is still needed in some of the more simple approaches to the polyene series# With these ideas in mind the problem of some of the conjugated compounds was approached. Three principal starting materials were used, namely acetylketene, methallyl chloride and levulinic acid# i i i j J P i 1 \ I . ? T ? (39) Ishikawa and Katoh, Chem#Abstracts, 28, 2697 (1934)# 15. THEORETICAL AND DISCUSSION OP RESULTS The plan of this investigation was to study methods of synthesis of these five compounds: I. II. III. CICHs -CH=CHCOOCsH 5 C3 H 5 OOCCHs -9=CHC OOCbH 6 CHS ClCHaC^JH-COOCaHs CH® IV. V. C=QH CHs-C-CHg-CHs 0 -- CO C®H 5 oocchsch=c -c =ch CH 3 CH 3 Condensation of I with ^-ionone, CHs CH=CHCOCH3 9 would \ / — CHs be expected to give rise to the ester: CHS >*_ / CHS /'t - CH=CH-C=CH-CH=CHCOOCoH I CHs ■'CHs Similarly, condensation of II, III, IV and V with ^ - c y c l o eitral, CH3 CH3 v/ / J--CHO, or with citral, CH3 (CHaJsCaCH-CHs-CHs-CsCH-CHO, GH° followed by cyclization, would give rise to these substances: CHg^ /CHa C00C8H 8 / x - CH=C -C=CH-C OOCsHg \/-CH3 CH» 16. C H ^ ^CHg /\ CH^ ^CHS (JJOOH "” =g -g h =G-C^3H I CH^ /CH;S C=PH or COOCaH s C-CH=C-C=pH I The conjugate unsaturation of these compounds is similar to that of vitamin A and if such compounds could he obtained they would provide independent means of starting towards the synthesis of vitamin A or of related compounds. Although citral and -eyelocitral are the aldehydes listed above it was planned to precede this study by use of simpler aldehydes such as benzaldehyde, then condensation might be expected to work more surely with the desired substances. Condensation of I with -ionone would be anticipated to proceed by the Reformatsky reaction. CHs CH=CH-COCH3 + C lCHa -CH=CH-C OOCsH s Zn — ->► C H ^ /CH3 CH=CH-C =CH-CH=CH-C OOC3H 6 It seemed that I might be made from acetylketene by these steps Cla CHb C0CH=<!0 HOC8 H8 --------------- ►- CHbCOCHC1COC1 ClCHs C0GHaC00Ga H5 C1CH3CHOHCHa C OOCaH s — >- — *- ClCHaCOCHs COCl r e d u c tio n -------------------> - C l C H sC H = C H C O O C sH e Heno© this series of steps was investigated, as a result of which other reactions of acetylketene were studied also# The hromination of acetylketene was performed first by 40 ^ Chick and Wilsmore. The product formed was q -bromoacetoacetyl bromide# Similarly chlorine was found to give if -chloro- 41 acetoacetyl chloride* As the structure of acetylketene (ketene dimer) has been a question for some time, a brief presentation might make the mechanism of chlorination more clearly understood# There is little doubt but that the structure of the dimer is that of acetylketene or a resonance modification of the same, namely, crotono-^-lactone# Opposed to this viewpoint, however, is a recent presentation by Boes©** that vinylaceto^-lactone is the structure. CHa -C-CH a a 0 CO Acetylketene CHa -C=CH t i o-co Crotonoy^-lactone CHa^C-CH® i i* o-co Vinylaceto-^- lactone With vinylaceto-^-lactone addition reactions with alcohols or amines may be explained by assuming reaction at the lactone (40) Chick and Wilsmore, J.Chem.Soc., 61. 3358 (1939)# (41) Hurd and Abernethy, J.Am.Chem.Soc.. 62, 1147 (1940)# (42) Boese, Ind#Eng#Chem#, 32, 20 (1940). 18. position followed by tautomerization, C H a^C -CH g + RNH2 CH2 «C -CHa 0-C0 • OHCOHH^ CHs-C-GHg 0 CONHR Hydrogenation to butyro^-lactone would involve addition at the double bond. Neither of these reactions were critical for purposes of structure proof because they may be explained also from acetylketene or crotono-^-lactone. When the dimer was halogenated, chlorine presumably added to the double bond. If acetylketene were selected as the structure then a subsequent rearrangement would be Involved to explain the formation of chloroacetoacetyl chloride, which was actually produced. Since ethyl acetobromoacetate is known to rearrange to ethyLbromoacetoacetate, CHsCOCHBrCOOGgHs — CHgBrCOCHfcCOOCgHB, such a rearrangement of acetochloroacetyl chloride to chloroacetoacetyl chloride also seems plausible. It may be assumed #hat the C@C1 or COBr groups promote a more rapid rearrange ment than the COOCaH 5 group. The rearrangement Involved from the chlorination of the vinylaceto-^-lactone structure would require less readjustment than with acetylketene. This seems to be the best evidence polymerization and ozonolysis evidence is an accumulation of critical evidence which favors acetylketene and its resonance (43) Hurd and Roe, J.Am.Chem.Soc., 61, 3358 (1939). (44) Hurd and Williams, J.Am.Chem.Soc., 58. 964,968 (1936). 19. isomer as the preferred structure for ketene dimer. Therefore* chlorination may he regarded to take place as follows. CH3 COCH=CO + Cl* — [CHgCOCHClCOCif >> — P- CHaCXCOCHsCOCl During the distillation of chloroacetoacetyl chloride much decomposition took place and crystals of dehydroacetic acid were found as a by-product. This may he explained hy assuming that the addition of chlorine to acetylketene is reversible to a certain extent. The dehydroacetic acid is a dimerization product of the acetylketene. A good yield of ethyl chloroacetoacetate was obtained hy adding alcohol to undistilled chloroacetoacetyl chloride in carbon tetrachloride. CHaClCOCHaCOCl + HOC3 H 5 — *- CHgClGOCHgCOOCaHg The anilide was made in a similar manner. + HC1 It was prepared also from pure chloroacetoacetyl chloride. CH3 C 1COCHaGGOl+2 C QH 6 M S — C H s C l C 0 C H s C01iIHC6 H e + C6 H 6 HH3 C1 Proof of the identity and the enolizability of ethyl chloro acetoacetate was given hy the formation of the copper salt. Reduction of ethyl chloroacetoacetate was carried out in the presence of a platinum catalyst, hut a uniform product was not obtained. The products resulting from the process showed that not only was the ketone group reduced, hut also some of the chlorine was removed. The following processes were considered. mi nnnxr r*n/V!_ CHgClC OCHgCOOCgHg ---wugvxvwugvuw That the first reaction took plade was evidenced hy the production of acetone when the reduced mixture was hydrolyzed* CHaCOOH 8 COOCaH 8 + HOH — »* CHaCOCHa + C 0a + CaH 6QH The second reaction also occurred as shown by hydrolysis of one of the fractions* After acidification it produced iT-chlorocrotonic acid, and this could only happen in case the second reaction had taken place* CHaClCHOHCHaCDOOaH a — a, °.» . CHaClCH=CH-COOCaH a — V CHSC 1 CH=CHC 00 H + CaH sOH No data support the third reaction, other than the tarry residue which it might explain. Since the yield of ^-chlorocrotonic ester was small from this reaction this procedure was abandoned* However, condensation of acetylketene with an aliphatic aldehyde seemed advisable* It was discovered by Hurd and Roe that benzaldehyde would condense with acetylketene when potassium acetate was used as a catalyst* Carbon dioxide was evolved copiously and a 31% yield of benza>lacetone was obtained* By analogy it seemed that acetylketene might be made to condense with acetaldehyde and other aliphatic aldehydes. work then condensation with citral or If this would -eyelocitral would have a definite bearing on the problem. CH=CH-COCHaCOOH CHa f45) Hurd and Roe, J.Am.Chem.Soc* *61, 3358 (1939)* or In a series of experiments various catalysts were employed for the condensation of acetylketene with acetaldehyde• Among those U3ed were pyridine, piperidine, dimethylanaline, piperidinium acetate and potassium carbonate. condensation never occurred. The desired In every Instance a large quantity of dehydroacetic acid tsaaLformed at a more rapid rate than the condensation between acetylketene and acetaldehyde. CH3 -C ^ f t 0 + I CH 00 m _ CH-COCHa CHa-0 — 5*. 8 00 II I CH CHCOCH, s / CO CO The formation of dehydroacetic acid is known to be catalyzed by acids and bases. Aldol was noticed during some of the condensations but this came directly from acetaldehyde. Another approach which seemed promising was to condense y^-cyclocitral with ethyl ^?-methylglutaconate, C8 H8 00CCH 8 C=0HC00Cs H6 t o y i e l d CH 3 CH3 CH3 COOC0 H 5 A - C H = 6 -C^HCO OC 2 H6 I J chs (Jig ^ For this purpose, these reactions were planned starting with methallyl chloride. ( 9Ha H0G1 ■C 6 HaCl 9HaC 1 KCN CHs-C-0H CHaCl 9HsCN CH3 G-OH 6 h3cn CaH B OH aoid ■ 22 CHaCOOCaH s CHa -C-OH C H - C O O C sH„ 3 .° ■_ CHaC CHsCOOC 2 H s bllgC OOC2 H 6 Treatment of methallyl chloride with hypochlorous acid would yield 1, 3-dichl or o-2-me thy 1-2-propanol. Reaction of the dichloro compound with potassium cyanide would give the dicyano compound. Conversion to the ester followed by dehydration would yield the desired product. 46 Dreifus and Ingold have reported that glutaconic acid could he obtained in good yield by a related process, starting with 1 ,3 -dichl or o-2 -propanol. CHgCl CHOH CHaCl kcu 9HSC« CHOH c H -ggj— CHaCtf 0H *- C H B C O O C BH 0 _H CHOH CH-COOO.H8 Q =-*- AhbCOOCbH 6 CH CHaC00CaH o Preparation of l,3-dichloro-2-methyl-2-propanol was accomplished In a reasonably good yield by the reaction of hypochlorous acid on methallyl chloride. Careful fractionation was necessary through a good fractionating column. This reaction 47 has been done previously by Malkemus, although the product was never analyzed before. Difficulty is encountered in this reaction In that methallyl chloride Is insoluble in water. By the use of wDreftn it was hoped that methallyl chloride would be taken into the reaction medium and thus the reactants would be given more Intimate contact with each other, thereby improving the yield. (4:6) Dreifus and Ingold, J.Chem.Soc., 123. 2964 (1923). (47) Malkemus, Ph.D. Dissertation, Northwestern University, June 1939. 23 Actually no such, material improvement in yield was noticed* There was a considerable quantity of higher boiling material* It is somewhat difficult to explain this, but in mo 3 t reactions of unsaturated compounds with hypochlorous acid the same seems to be true. Conversion of l,3-dichloro-2-methyl-2-propanol into the corresponding nitrile was accomplished by reaction with potassium cyanide in a mixture of methyl alcohol and water* The product was a very viscous oil. Although distillation was attempted under reduced pressure, it could not be purified in this manner* Crystallization was also attempted, but this also could not be accomplished* Ethyl ^-methylglutaconate was prepared from the dicyano compound by alcoholysis in the presence of acid* distillation, proved to be a light yellow oil* This, on Dehydration of the hydroxy ester evidently took place during distillation. To further insure this dehydration a crystal of Iodine was added during the process* ch3 ch3 ^ 3^5 OOCCHgC —CHgCOQCaHg 1” CgHg OOCCHj^ —G= CH—C 00C j^Hg + H«gO Sh The ease of dehydration of the ^ - h y d r o x y ester is to be expected since the hydroxyl group is midway between two ^-carbonyl groups* The instability is even more Increased by the fact that the hydroxyl group Is tertiary* A high boiling material was obtained, which solidified on standing at room temperature* nitrogen* It was found to contain This compound might be one of several possibilities* It could be partially hydrolyzed nitrile, part ester and part nitrile, part ester and part amide or any of several other combinations# Further study of it was not considered# As usual a considerable quantity of tar remained in the distilling flask, due undoubtedly to various polymers# method of preparing This -methylglutaconic 63 ter was quite successful, although the yield was not as high as anticipated# 43 Previous methods of preparing this ester were considerably more cumbersome and yields were very low# Condensation of ^-methylgluliaconic ester with benzaldehyde took place quite readily in an alcoholic solution of potassium hydroxide# Acidification produced the benzal- -methyl- gluiaconic acid# c 6 h 5cho + chs -coocsh 5 kqh C 6 H sCH=C-COOK C-CHa --- C-CHa chcoocsh 6 (Jhcook c 0h 5 ch=c-cooh O-CH b chcoqh It had been hoped that decarboxylation of this dibasic acid might occur on pyrolysis, to yield the corresponding monobasic acid, C 0 H SCH=CH-C=CHCOOH# CHa In actual experimentation it was found that such was not the case# The method seems to be complicated by side reactions such as polymerization and possibly dehydration to form the inner anhydride# Future study may reveal a satisfactory method for effecting such a decarboxylation# In many condensations in which a conjugation exists between (48) Feist, Ann*, 545* 89 (1906); Bland and Thorpe, J.Chem.Soc#, 1 0 1 , 865, 1557 (1912); Jordan and Thorpe, J#Chem*Soc#, I5T. 388 (1918). 25 a carbonyl and a carbon to carbon double bond there Is a shift of such a double bond and condensation takes place in an alpha position to the carbonyl group* Thus, as mentioned previously, when y^-methylcrotonic anhydride was condensed with benz* aldehyde such a shift took place* In the case of “methyl* glutaconic acid a shift of this sort would make no difference as the same compound would still result* CfiH6 OOCCHg -C =CH-C OOCs H6 ZZ? CS H5 OOCCH=C -CHS -C 00C S H5 CHa CHa Attention was next turned to compound III, namely, ethyl J-chloro^-methylcrotonate* as the starting material* Again methallyl chloride was used Treatment with hypobromous acid produced the bromohydrin in excellent yield* Reaction with potassium cyamide yielded the nitrile and subsequent conversion to the hydroxy ester with final dehydration gave the desired unsaturated ester* ,9He CH3 -C 9HsBr .- P f f i y . I CHS C 1 CHa -C -O H 1 CHS C 1 9H s C 00C s H5 CH3 -C -O H CHS C 1 CHjjCN CHa -C -O H i ° aH s 0H CHS C1 acid flH -CO OCsH s CH3 -C CHS C1 Attempts were made to isolate the intermediate nitrile without success* The hydroxy ester was not Isolated either but by distillation with iodine it yielded the unsaturated ester. Dehydration was undoubtedly facilitated by the fact that a tertiary hydroxyl Is involved as well as a ^-carbonyl. Condensation of this ester with an aldehyde has not been tried yet* Perhaps the best scheme would be to convert it first into tlx© iodo ester and then run the Reformat sky reaction CCHa9=CHC00CaH 6 ., Hal ^ CH 3 ICgaC=CHCOOCsH B CHa 2&.H. sCH0.- v Zn C s H6 CH =CH -9 =GHC OOCgHs CH0 During the distillation of J'-chloro-^-methylcrotonic ester a small amount of higher boiling material was obtained* The substance contained nitrogen and was probably some inter mediate* After standing at room temperature for some time it crystallized* No further attempt was made to study this compound* Treatment of methallyl chloride with hypobromous acid gave a slight amount of low boiling by-product as well as a very small amount of higher boiling material* However, the bromohydrin was readily isolated in the pure state. One of the reasons for this was the substantial difference in boiling points of the plausible by-products* qh + HOBr OHs=C (CH3 )CHaCl + + BrCHg-ggCHsCl Br 3 HBr --- >■ CH3 -(?-CHsC1 CHS Br Brs — ■ »> BrCHs -y-CHSC1 CHS Undoubtedly the low boiling material contained some of the product resulting from addition of hydrogen bromide* The high boiling material might conceivably contain the compound produced by addition of bromine to the double bond* In order to complete the halohydrins of methallyl chloride the iodohydrin was prepared. 27. CHa C H s = C (CH3 )CH S C 1 + HOI — ► ICHa -C-CHaCl The reaction was performed by adding iodine to a mixture of methallyl chloride, ether, water and mercuric oxide* This reaction required vigorous agitation and a long time was involved for completion* The yield was quite low* 49 Braun had used epichlorohydrin (l-chloro-2-epoxypropane) as a starting material to produce ethyl ^3 -chlorocrotonate CHSC1 CH3 CI » CHaCl CHOH I ,0 caH s°H ■ CHS q acid CH3 CI H 0H -Ha 0 I C H jjC N CH II CHaC00CaH s CHC00CaH s By an analogous set of reactions, it would seem that 1-chloro2 -epoxy-2 -methylpropane might be used in a similar process to obtain -chloro- -methylcrotonic ester* CH8 C1 CHaC CH3 CI 0aH6 0<^H CH3 -CN CHfcCl HCH t- C H 3 -C!-QH CH* iHaCN CHa Cl I a C H aC00CaH 5 a°ld CHaCl —IT O CH3 -C-0H CaH s0H * >- C H a -C CHC00CaH a Treatment of methallyl chloride with perbenzoic acid did not give the epoxide* Evidently methallyl chloride is in some way sterically hindered* Another method for obtaining the desired epoxide from methallyl chloride seemed possible* (49) Braun, J*Am.Ghem*Soc*, 52, 3167 (1930)* ^ 28* CHSC1 CHSC1 I H0C1 C H S -C CH-gCl l -EC1 C H 3 -COH ^ CHS -C. 0 xs Ae s C1 CHS When l,3-dichloro-2-methyl-2-propanol was treated with sodium hydroxide, and in another experiment with calcium hydroxide, it gave rise to a low boiling substance which had an aldehyde reaction. The amount of material was small. Further investigation of this material migjht be of value. It is possible that the product was 2-methyl-3-chloropropionaldehyde, CICHw s - C1E C H O • CES Finally, chlorination of methallyl chloride seemed to offer a theoretical possibility for the production of Inter mediates of value to the synthesis of some of these compounds. When isobutylene is chlorinated the chief product allyl chloride. Is meth Since it Is believed that chlorination of isobutylene takes place by substitution It seemed reasonable CHa=C(CHB } 2 + CXB — *- C H s = C (CHa ) C H s C l + HC1 to believe that chlorination of methallyl chloride would take place by a similar process rather than by addition and then splitting out of hydrogen chloride. Eowever, here the reaction has a choice of two active positions* Either a hydrogen of the chloromethyl group or one of the methyl group should be substituted. CHa C (CHa)-CHBCX + CXB ~~<z C H B =C ( C H a ) C H C l 0118*0 (CH b C 1 ) b (50) Vaughan and Rust, J.Am.Chem.Soci, 61. 2X5 (X930 ). + HC1 + HCX In case of the production of - (chloromethyl)allyl chloride, it was hoped that this could then he converted to the nitrile and subsequently to the ester. the ester so produced should yield Upon refluxing, ^^-methylglutaconic ester, by shifting of the double bond into a position conjugate with the carbonyl. CHb=C (CHsC 1 )8 ~°rc » CHe =C (CHa C00CaH 8 )s CHa=C (CHaCN)a — „c. a H°°H > acid CSH S 00C -CHa -C =CH-C OOCsH 8 CHa When the material was chlorinated a mixture of substances was obtained. On treatment with potassium cyanide a nitrile was obtained which was not isolated. Conversion of this Into the ester yielded a small amount of ester which distilled over a wide range of temperature. resulted from the reaction. A large quantity of tar This method was not found to be practicable. A quite independent approach to the synthesis of compounds with the desired type of conjugate unsaturation is the following: Levulinle acid was considered as the source for this process and it was thought that the lactone resulting might then be hydrolyzed, dehydrated and decarboxylated to yield the compounds desired. 30. C H a^C H 3 poOH OH / CHa / V - CH=C -CHa Hp -CaCH CH 3 — ? [i- CH=CH-CE=^-C^JH 0h3 x j — CHa CH® 61 Kreimeier obtained (r-ethynylvalero-Jf-lactone from levulinic acid by treating it with sodium acetylide in liquid ammonia in the presence of a ferric salt. By slight 52 modification according to the method of Hurd and McPhee, in which the ferric salt was eliminated, the time required for reaction was greatly reduced, with no reduction in the yield of product. This simplification was found to be applicable in the case of many ketones. CHgCOCHaCHgC00H + C2 Ha t M am a r CH3 -C -C H s -C H s e 0 0 1 I a Acidification with sulfuric acid caused the resulting acid to lactonize. Ci=PH CHa -C -CHa -C H a -C OONa -2— <?sCH CHa- p- CHg- CHe 0 - ---------- CO OH The condensation of this lactone with benzaldehyde should be a reaction of interest. The final compound, V, desired in the original series was considered to be obtainable from J'-ethynylvalero-^-lactone. Experiments were directed towards opening the lactone ring L in some manner* An example would be conversion of the lactone f5l) Kreimeler, U.S. Patent 2,122,719, July (1938). (52) McPhee, Ph.D. Dissertation, Northwestern University, June, 1940# to the ester followed toy dehydration. C^3H CssCH CHa-C-CHsCH8 0 CO CHa-C-CEa-CHsCOOCaH 6 OH l£a.°.» C£3H CHg -^“CH-CH b -COOCb H 8 The methylene group at the alpha position should be reactive in condensations with aldehydes# It was thought also that treatment of the lactone with concentrated hydrochloric acid might produce a chlorinated unsaturated compound# C sPH CC1=CH^ C H S - C -CHfc " C E g 0 J r z . ■> - CHa-CKJECHeCOOH CO Here again the methylene group would be reactive# Another approach also seemed reasonable# If the levulinic acid could be converted in some way into the H-dialkylamide, then reaction with sodium acetylide would produce an ethynylcarbinol which should readily be dehydrated. p=CH CH3-C-CHa-CH*-COHRs OH C^JH CH3 -6 =CH-CHe -CHa -C OHRa The alkyl groups on the nitrogen atom would prevent formation of a lactone# Again, the product would contain a reactive methylene group# Finally, it would be of interest to convert the ethynyllactone into the acetolactone by treatment with water in the presence of sulfuric acid and mercuric sulfate# tialities of such a keto lactone are obvious# The poten COCH ch 3 -c-chs -chs 0 CO Treatment of Jf-ethynylvaiero-^-lactone with ethyl alcohol in the presence of sulfuric acid yielded a very small amount of another substance and left the remainder of the lactone unchanged* Variations in quantity of sulfuric acid or time of refluxing did not change the results sub stantially* Substitution of hydrogen chloride for sulfuric acid also was not helpful* Ifi/hen the lactone was treated with concentrated hydro chloric acid it polymerized to a rubber-like material of a dark brown color* Perhaps this is not surprising as the product expected (B) would have a structure related to chloroprene (A)• CHa=C-C=CHCH2-C 00H CH b =C-CE=CHb (B) (A) A portion of levulinic acid was refluxed with thionyl chloride and then treated with dimethylamine* Another portion, after similar treatment, was allowed to react with dibutylamine* In each case a small amount of high boiling liquid was obtained, which did not solidify on cooling* results were somewhat confusing* of levulinic acid is suspected (53) Helberger, Ann., 522. 269 The However, the acid chloride of having a ring structure* (1936). Perhaps this would result in a ring structure for the amide, which would in reality not be an amide at all* CH 3 COCHaCHsCOOH •— CH3 -CCl-CHaCHa I | 0 ----- CO CH3C (HRa )CHaCHa | I 0 ------ CO As further attempts gave similar results this approach was abandoned* The final reaction attempted with the ethynyllactone ! was the reaction with water in the presence of sulfuric acid and mercuric sulfate* reaction* Much heat was evolved during the Attempts are being made to isolate the acid or lactone produced* There is obviously some reaction that takes place, but the product has not been isolated* Further study needs to be made of this reaction* In conclusion it might be said that several interesting approaches have been studied to the original five compounds desired* Side reactions and other pertinent material have been considered* Success has been encountered in many of the reactions and in others the approaches were found not to work* Interesting exploratory experiments have been conducted which may advantageously be studied further* EXPERIMEOTAL I* Investigations with. Acetylketene !• Attempts at Condensation with Acetaldehyde* Acetylketene was carefully distilled at 31 mm* pressure* The portion distilling at 40-42° was used in the following experiments. Acetaldehyde was then purified by fractional distillation at atmospheric pressure, and collected in an Ice-cooled receiver* The portion obtained at 20-23° was used for the condensation reactions. To a mixture of 5 cc* of acetylketene and 8 cc* of acet aldehyde in an ice-cooled flask was added slowly and with constant stirring 2 cc* of pyridine* A somewhat vigorous reaction took place, much heat being evolved* The reaction mixture turned a deep red color and yellow crystals separated from the solution after a few moments standing in the cold* The solution was carefully filtered. The crystals on the filter paper were kept for investigation and the fil trate was allowed to stand overnight In the ice box* More crystals separated and at the end of 24 hours these were separated and the remaining liquid (1*5 cc*) was filtered off and allowed to stand at room temperature for several hours More crystals were obtained and most of the excess of acetaldehyde seemed to have evaporated as only a few drops of oil were left* The solid material was suspected of being dehydroacetic acid* It was crystallized from acetone. A melting point 35* was taken and it was found to melt at 167-168°* value is 106°* The recorded A mixed melting point with known dehydro acetic acid did not substantially lower the melting point* As the concentration of base had been rather large in the previous experiment, three more portions of mixtures of 5 cc* of acetylketene and 8 cc* of acdtaldehyde were treated with small quantities of base* To one mixture was added fine drops of pyridine, to a second was added five drops of dimethylaniline and to a third five drops of piperidine. At the end of 48 hours standing at room temperature, each of the solutions was investigated as before* This time, besides the dehydroacetic acid produced a slight amount of aldol was formed (0*5 cc*)* phenylhydrazone* This was proved by conversion to the A very slight amount of tarry residue remained, from the aldol material* This was not investigated* A mixture of 5 cc* of acetylketene and 8 cc* of acet aldehyde was added to 2 0 cc* of dioxane to which had been added an excess of potassium carbonate in order to keep it saturated* This mixture was placed in an ice bath and stirred for twenty minutes after which it was allowed to stand in the ice box for 48 hours* The solution turned to a deep yellow and the dioxane was removed on a steam bath after this period of time. The resulting light red liquid was subjected to fractional distillation* Only a small fraction came over below 50° at 15 ram* pressure and seemed to be mainly dioxane* The remaining solution, which was not distilled, was cooled and immediately became a mass of crystals* Upon filtration 36 only a few drops of a deep red oily material were obtained# The crystals were identified as dehydroacetic acid# Another set of two experiments was run# Both reaction mixtures contained 5 cc# of acetylketene and 8 cc# of acet aldehyde# To one was added 0#5 g# of piperidine acetate and to the other was added 1.0 g. of piperidine acetate# Both solutions were placed in the ice box for 48 hours, at the end of which time crystals separated from these solutions# Upon fractionation under reduced pressure some aldol and paraldehyde was obtained# The aldol was identified as its phenylhydrazone, while the paraldehyde was decomposed by sulfuric acid upon distillation the resulting acetaldehyde was identified by its dinitrophenylhydrazone# The liquid remaining in the flask, after removal of the lower fractions, was cooled and crystals of dehydroacetic acid separated# About 0*5 cc* of a tarry material was mixed in with the crystals* 2 . Chlorination of Acetylketene* Chlorine was passed into an ice-cold, vigorously stirred solution of 7 cc# of acetylketene in 20 cc# of carbon tetra chloride until there was a 6 g. increase in weight# mixture was slightly yellow in color. The Distillation of the solvent with a steam-bath left an orange colored residue of chloroacetoacetyl chloride, which was vacuum distilled# Extensive decomposition occurred, but 1#5 cc# of the acid chloride was obtained at 93-96° (8 mm*)# orange colored and fumed in moist air# The distillate was A black tar remained in the distilling flask# Upon cooling a few crystals were evident on the sides of the distilling flask# Recrystal lization from, acetone and a melting point determination showed them to be dehydroacetic acid# These physical constants were obtained for the chloro acetoacetyl chloride: d * 0 1*4397; n^° 1*4860; Mol# refrafct., Calc*d. 30.77, Found 30#89. Anal# Subs# 0*3113, 0#3083. nitrate 40*00, 40#00 cc# Vol. of 0#1092 N silver Vol. of 0*05008 N thiocyanate for excess silver nitrate, 7#91, 8 #37 cc# Cl 45#7• Found; Oalcd# for 04 U 4 O3 CI3 ; Cl, 45.2, 45.1. 3# Ethyl Chloroacetoacetate Chloroacetoacetyl chloride was converted to ethyl chloro acetoacetate as follows# Five cc# of acetylketene in 30 cc# of carbon tetrachloride was treated with chlorine until 4#5 g had been absorbed# Then, without distillation, the solution was poured slowly into an excess of absolute alcohol at 0 °# On distillation, 6 cc# of ethyl chloroacetoacetate was collected at 117-119° (17 mm.)# This ester has been made by 54 several other investigators in other ways. A copper salt of ethyl chloroacetoacetate was made to identify the ester. A mixture of 2 g. of ethyl chloroaceto- (54) Lespieau, Compt.rend. 138, 422 (1904); Picha, Doht and Weisl, Monatsh. 27., 1247 (1906); Schlotterbeck, Ber#, 42, 2570 (1909); Alexandrow, Ber#, 46, 1022 (1913). acetate, 7 cc# of ethyl alcohol and 8 cc# of water was stirred vigorously during the addition of 25 cc# of a wateralcohol mixture of the same constituency which had been sat urated with copper acetate# A green solid was precipitated, which upon recrystallization melted at 162-164°# value is 163-165°• The recorded This identified the ester# 4# Chloroacetoacetanilide Chloroacetoacetanilide was obtained by mixing pure chloro acetoacetyl chloride with an equivalent amount of aniline in benzene. The aniline hydrochloride was removed by washing with water# Then the benzene solution was distilled off and the resulting anilide was crystallized from ether# The melting point was 140-141°# Anal# Subs. 0.1152, 0#1242 g.; Vol. 0.06860 N acid, 30.00 cc#, 30#00 cc; vol. 0*04288 N# base, 35.01, 34#10 cc*; Calc *d# for Gx<^ Xo0 ^ G l : N, 6.61; Found: N,6.75, 6.71# A second method of preparing the anilide was devised by addition of undistilled chloroacetoacetyl chloride in carbon tetrachloride# Five cc# of acetylketene in 30 cc# of carbon tetrachloride was treated with chlorine until 4#5 g. had been absorbed# This was added to an equivalent amount of aniline in 5 cc. of carbon tetrachloride# The solution was washed with water to remove the aniline hydrochloride. Evaporation of the carbon tetrachloride produced an oil. On standing in the ice box crystals of anilide were formed# These crystals were separated by filtration, recrystallized from acetone and gave the same melting point as the above compound. 5* Attempt at Iodination or Aoetylkete ne» Iodine (10 g*) in 50 cc* of carbon tetrachloride was added to 5 cc* of acetylketene in 15 cc* of carbon tetra chloride* The solution was stirred vigorously and was kept in an ice-bath* It turned brown and it was difficult to tell whether or not any reaction had taken place* The resulting solution was poured into absolute ethyl alcohol* reacted iodine was in evidence* Much un After filtering the solution, it was subjected to fractional distillation under reduced pressure# Much iodine was obtained and only a small amount of acetylketene (0*5 cc.)* The remaining substance was a black tarry product, form which nothing could be obtained* 6 * Copper salt of Ethyl Chloroacetoacetate* A saturated solution of copper acetate was prepared* To a vigorously stirred mixture of ethyl chloroacetoacetate (2 g*) and water (30 cc*) was added a 5 cc* portion of the sat urated copper acetate solution over a period of 30 minutes# The green solid material which settled out was removed by filtration and recrystallized from acetone. A melting point was taken and found to be 162-164° (recorded value 163-165°)• 7* Reduction of Ethyl Chloroacetoacetate* 65 A* Preparation of Platinum Catalyst* A 1*5 g* strip of platinum was dissolved In aqua regia (50 cc*) and the solution resulting, after heating six hours (55) Adams, Voorhees and Shriner, ^Organic Syntheses”, Vol* VIII, John Wiley and Sons, New York (1928), p*92* with addition of concentrated hydrochloric acid, was evaporated to dryness. To the resulting solid, 25 g. of C.P. sodium nitrate and 10 cc* of distilled water was added* The sub stances were mixed and evaporated to dryness In a bunsen flame while stirring with a glass rod* The temperature was raised to 350-370° in about ten minutes. Fusion took place, brown oxides of nitrogen were evolved and a precipitate of brown platinum oxide gradually separated. At this stage foaming took place, so the mixture was stirred vigorously and covered with a watch glass* An additional flame was applied at the top of the casserole* At the end of fifteen minutes the temperature reached 400°, the evolution of gases decreased and at the end of twenty minutes it had reached approximately 500°* at this temperature for fifteen minutes* Then It was held The mixture was allowed to cool and ifcas washed with 30 cc* of water and filtered on a Gooch filter using hardened filter paper* The platinum oxide resulting was then dried in the air and was then ready for use* The next step was calibration of the hydrogenator. acid was used as the standard. A blank was run first. Maleic The tank was filled with hydrogen until a pressure of 40 lbs. was reached. Seventy-five cc*-C75 cc.) of absolute alcohol and 0*1 g* of platinum oxide were placed in the bottle, which was then evacuated to about 17 mm. pressure and then hydrogen was admitted. The pressure of the tank was taken and the bottle was shaken for six hours* At the end of thi3 time the pressure 41* had decreased about three pounds, or approximately 0*5 pounds per hour. The same procedure was then used for calibration* anhydride Maleic (0*05 mole, 5*8 g*), previously crystallized from alcohol, was added to the alcohol-platinum oxide mixture* The bottle containing these substances was again evacuated and filled with hydrogen, under a pressure of approximately forty pounds* The bottle was shaken for about an hour and a reduction in pressure of 5*8 pounds was noticed* When the correction from the blank was used the value obtained for the calibration was 106 pounds per mole* '4 B* Reduction A 15 g.-portion of ethyl chloroacetoacetate was dissolved in 75 cc* of absolute alcohol and 0*1 g* of platinum oxide was added to the mixture in the reduction bottle* The bottle was evacuated, filled with hydrogen at a pressure of 40 lbs, and shaken for a period of one and one-half hours* Over the period of the first hour about 12 lbs. pressure decrease was noticed and after another half hour only 1 lb* more decrease in pressure was noticed* The ethyl alcohol was removed on the steam bath and the remaining hydrogenated product was subjected to fractionation under 25 mm* pressure* About 6 cc* distilled at 112-117°. There was a slight forerun and a small amount of material that boiled higher. Also, there was about 6 g. of tarry residue remaining in the distilling flask* A portion (2 g*) of the material which distilled at 42 112-117° -was hydrolyzed with dilute sodium hydroxide* It was placed in 1 0 cc. of water and then 1 0 cc. of dilute sodium hydroxide was added. It was refluxed for about 0.5 hour. The solution turned a deep orange color during this process. It was then acidified with dilute sulfuric acid until it was just acid to litmus and then 3 cc. excess of acid was added. The resulting solution was extracted with four 275-cc. portions of ether. The ether solution obtained was dried over anhydrous sodium sulfate and the ether was slowly removed on a steam bath. About 0.5 cc. of an oil remained in the distilling flask. After standing for three days in the ice box only a very few crystals were formed which on recrystallization from acetone melted at 80-83°. crotonic acid* This corresponded to ^f-chloro- An attempt was made to crystallize the remaining oil from petroleum ether but only the oily substance remained. It was readily decomposed by heat. Another portion (2 g.) of the material distilling at 112-117° was hydrolyzed after which it was acidified with excess sulfuric acid and refluxed for fifteen minutes. The solution was distilled, the distillate being obtained in an ice cooled receiver* A portion of the distillate was treated with 2,4-dinitrophenylhydrazine reagent. A precipitate of the 2 ,4 -dinitrophenylhydrazone of acetone was obtained as evidenced by its melting point. II* Investigations with Methallvl Chloride# 1* Chlorination of Methallyl Chloride Methallyl chloride (190 g*), which had "been purified by distillation, was placed in a flask surrounded by an ice bath* Chlorine was bubbled slowly through the solution over a period of about 3*5 hours until the solution had gained In weight about 54 g. in weight, or about 0*7 mole of chlorine had been used per mole of methallyl chloride* Constant stirring during the addition of the chlorine was necessary to prevent localization of more highly chlorinated products* The hydrogen chloride evolved was passed into a sodium hydroxide solution# The chlorinated product was then fractionated and the following fractions were obtained# Temperature °C. Below 130 130-135 135-142 High©** Fraction, g. 18 86 12 The Remainder (50 cc#) Analysis for chlorine was undertaken on the portion distilling at 130-135°* Anal* Subs* 0.1251, 0*1253 g.; wt* silver chloride, 0*1447, 0#1448 g#; Calc'd. for C4 H 6 C1S , 56.73; Found, 57#4, 57.1# Chlorination of methallyl chloride was attempted in which one mole of chlorine was used per mole of methallyl chloride. This decreased the quantity of material distilling at 130-135° and Increased the amount of the more highly chlorinated product# 44. 2* Reaction of Chlorinated Product •with Pot as alum Cyanide. The fraction obtained at 130-135° was treated with potassium cyanide. A mixture of 86 g. and 150 cc* of methyl alcohol was placed in a round-bottom flask fitted with a mercury-sealed stirrer* a reflux condenser and a separatory funnel* The solution was refluxed on a water bath during the addition of a solution of 86 g* of potassium cyanide in 150 cc. of water* The addition took approximately thirty minutes, during which time the reaction mixture was constantly stirred. Refluxing and stirring was continued for a period of forty hours* At the end of this time the solution was cooled and filtered to remove any unreacted potassium cyanide and the potassium chloride produced during the reaction. The alcohol and water were removed from the dark brown solution under reduced pressure. The brown oil, along with solid inorganic material, was extracted with three 100 cc*portions of methyl alcohol* Removal of the alcohol under reduced pressure yielded a viscous brown oil, which did not solidify on standing in the ice box for two days. Attempts to crystallize the material by use of a bath of solid carbon dioxide and acetone only resulted in a viscous brown oil* Distillation was attempted under reduced pressure. very small amount of material distilled and the remainder became a tarry substance* 3. Alcoholysis of the Cyano Compound. A portion of the cyano compound was made by starting A with 55 g. of dichloro compound as prepared above* The b r o m removal of water and alcohol and extraction with three 1 0 0 cc* portions of absolute alcohol, was refluxed with 50 g* of concentrated sulfuric acid for a period of eighteen hours* Then 100 cc* of the alcohol was removed by fraction ation under atmospheric pressure* The remainder of the alcohol was removed under reduced pressure* The resulting brown sludge was extracted with five 2 0 0 cc. portions of ether The ether solution was dried over anhydrous sodium sulfate and then the ether was removed on the steam bath. About 60 cc* of a brown oily liquid resulted. Fractionation was attempted on this liquid under 18 mm* pressure* About 10 cc. was obtained at 95-145°. the material polymerized in the flask* The rest of The portion which distilled had a very pleasant odor* 4* 1.5-Diehloro-2-me thyl-2-propanol. Hypochlorous acid was obtained by the method of Coleman S3 and Johnston. To a solution of 25 g. of mercuric chloride in 500 cc* of water in a 5 liter flask, 800 g. of crushed ice was added* A cold solution of 180 g* of sodium hydroxide in 500 cc* of water was added and a rapid stream of chlorine was passed into the solution, which was kept below 5°. The addition of chlorine was continued in this way until the yellow precipitate of mercuric oxide just disappeared. (56) Coleman and Johnston, "Organic Syntheses”, Vol.V, John Wiley and Sons, New York (1925), p.57. Then 600 cc* of cold 1*5 N nitric acid was added slowly with stirring* To the above solution was added slowly, 135 g* (1*5 moles) of methallyl chloride, while the temperature was kept below 5°* At the end of fifteen minutes the methallyl chloride had been added and the mixture was stoppered and placed in a mechanical shaker* It was allowed to shake vigorously for a period of one and one-half hours* At the end of this time the heavy liquid was separated by means of a separatory funnel* The aqueous solution was extracted with two 500 cc* portions of ether and this was added to the heavy liquid obtained. The ether solution was then dried over anhydrous sodium sulfate and the resulting solution was fractionated* After removal of ether, distillation was carried out under reduced pressure* Temperature, °C. Below 71 71-74 74-80 Above 80 Fraction 52 cc* 71 g. 23 g* Remainder The portion which distilled at 71-74° was the chlorohydrin* About & 30% yield was obtained* Anal. Subs., 0*272 g., 0.2779 g. ; vol. 0.1092 N silver nitrate, 40.00, 40.00 cc.; vol. 0.05008 N thiocyanate, 10.07, 8.79 cc.; Calcfd*; Cl, 56.73; found, 57.4, 57.1. An attempt was made to improve the yield by adding "Dreft” (a mixture of sodium sulfate and sodium f,lorol!r sulfate) to the hypochlorous acid solution* A 20 g. portion of"Draft” was added and a run was made similar to the above. This 47* aided the solution of methallyl chloride in water considerably* However, the yield was not substantially improved* 5* l-Chloro-5-bromo-2-methyl- 2 -propanol* A 95-g. portion of methallyl chloride was added to 500 cc* of water in a 1-liter round bottom flask* A solution of bromine in potassium bromide was prepared by adding 160 g* of bromine to a solution of 50 g* of potassium bromide in 200 cc* of water* The methallyl chloride-water mixture was vigorously stirred for a period of 500 minutes, during which time the bromine in potassium bromide solution was added slowly by means of a dropping funnel* At the end of this time the solution was allowed to cool, the bromohydrin layer was re moved by means of a separatory funnel and the aqueous layer was extracted with a 100 - g c * portion of ether* The ether layer was added to the bromohydrin and the material was dried over anhydrous sodium carbonate for a period of eight hours* The ether was removed and the remaining colorless liquid was distilled under reduced pressure* The slight forerun obtained below 82° at 17 mm. had lachramatory properties* The portion obtained at 82-84° was the desired bromohydrin (65# yield). Temperature,°C♦ Below 82 82-84 Above 84 Fraction 10 cc. 123 g. 3 cc* Anal. Subs., 0.1108, 0.1116 g.; vol. 0.0692 N silver nitrate, 30.00, 30.00 cc*; vol. 0*0733 N. thiocyanate, 12*02, 11.91 cc.; Calcfd for C4 H 8 0BrCl: per g*; found, 0.0107, 0.0108. total halogen, 0.01066 eq. 48. ao 1.5171; so a^o 1*7578. Mol. Refr., Calc'd. : 54.82. Found: 32.38. 6 . 1 -Chi oro-3-iodo-2 -me thyl -2 -pr opanol♦ Methallyl chloride (45 g.) was diluted with 150 cc. of ether. To this solution was added 8 cc. of water and 55 g. of yellow mercuric oxide. The resulting mixture was vigorously I stirred in a 500 cc. erlenmeyer flask during the addition of 124 g. of iodine. Addition was concluded at the end of thirty minutes and the resulting mixture was stirred for a period of five hours. At the end of this time the solution was filtered to remove the solid suspended matter. Then the solution was shaken in a separatory funnel with sodium thiosulfate solution to remove the excess iodine. The ether layer was separated and dried over anhydrous magnesium sulfate. The ether was removed under reduced pressure and the iodohydrin was fractionated. About 18 g. of the iodohydrin was obtained at 101-103° at 18 mm. The product became an orange color on distillation, evidently due to slight decomposition. The iodohydrin was shaken with a thiosulfate solution, dried directly over anhydrous sodium sulfate for five minutes, and an attempt made to distil the compound at 7 mm. pressure without decomposition. again; n^ An orange colored solution resulted 1.5460—1*5475. Anal. Subs., 0.1758 g.; vol. 0.0692 silver nitrate, 30.00 cc.; vol. 0.0733 N thiocyanate 7.63 cc.; Calcfd. for C*Ka0ClI, total halogen 0.008528 eq. per g., Found, 0.00861 eq. per g* ^ • 3^»5-Dlcyano-2-me thyl-2 -propanol ♦ A 25-g. portion of l,3-dichloro-2-methyl-2-propanol was added to 1 00 cc* of methyl alcohol in a round bottom flask fitted with a reflux condenser and a dropping funnel. The solution was refluxed on a water bath during the addition of 20 g. of potassium cyanide In 30 cc* of water. The potassium cyanide was added dropwise over a period of thirty minutes* Then the solution was refluxed for a period of forty eight hours* A dark brown solution resulted* At the end of this period the solution was cooled and the solid material, potassium chloride and unreacted potassium cyanide, was rempved by filtration. Then the methyl alcohol and water was removed under reduced pressure and the brown sludge fcas extracted with three 250 cc. portions of ether. The ether was removed on the steam bath and the brown oil, dicyano compound, was subjected to fractionation under reduced pressure. Attempts to isolate the nitrile had to be abandoned as decomposition and polymerization took place. 8 . Ethyl yff-methy1 glutaconate» A similar portion of material as used above was employed in obtaining the dicyano compound. The nitrile, after re moval of ether on the steam bath was used directly to prepare the ester. The brown oil was dissolved in 300 cc. of absolute alcohol and it was then saturated with dry hydrogen chloride and allowed to stand at room temperature for ten hours. was followed by refluxing for twelve hours. This The resulting solution was allowed to cool, after which the ammonium salts 50 were removed by filtration. The alcohol was removed under reduced pressure and the resulting brown oil was extracted with two 150 cc. portions of ether and the ethereal solution was dried over anhydrous sodium sulfate. Removal of the ether on the steam bath was followed by distillation under reduced pressure, after first adding a crystal of iodine. About 9 cc. of ethyl ligfrt yellow oil. /^-methylglutaconate was obtained as a It distilled at 129-153° at 18 mm. pressure 58 (recorded value 131° at 19 mm. ). A higher boiling material was obtained at 133-152°, about 3 cc., which solidified to a considerable extent on being cooled to room temperature. Tar remained in the flask. Treatment of this higher boiling material with sodium hydroxide resulted in ammonia being given off. It was not investigated further. Another method for obtaining the ester was by treatment with concentrated sulfuric acid instead of dry hydrogen chloride. The results were about the same with the exception that there seemed to be somewhat more tarry material in the flask on distillation. Absolute ethyl alcohol (300 cc.) was added to the dark brown 1 ,3-dicyano-2 -methyl-2 -propanol (20 g.). To this was added 15 cc. of concentrated sulfuric acid. The resulting solution was refluxed for a period of fifteen hours, cooled, the ammonium salts removed by filtration and the ethyl alcohol removed on a steam bath. The resulting oil (58) Auwers and Ottens, Ber., 5*7, 441 (1929). was poured onto crushed ice, extracted with ether and dried over anhydrous sodium sulfate* Treatment was the same as above from this point on, similar results were obtained* 9* Benzal^-methvlglutaconic acid* Condensation of ^-methylglutaconic ester with benz- aldehyde was carried out as follows* A mixture of 5 g* of I potassium hydroxide in 2 0 0 cc* of methyl alcohol was added to a mixture of 10 g* of ethyl g* of benzaldehyde* /2-methylglutaconate and 4*8 Slight warming of the solution was noticed and it was allowed to stand for forty eight hours, during which time the solution became a deep orange color* At the end of this time the mixture was evaporated to about one-fourth of its original volume under reduced pressure and the resulting brown solution was set in the ice box for two days* A few crystals were noticed and on evaporation to 25 cc* and cooling in an acetone-solid carbon dioxide bath a considerable quantity of crystals of potassium b e n z a l ^ methy 1 glutaconate were formed. These crystals were removed by filtration, the solution further evaporated to obtain more crystals and the combined crystals were washed with 25 cc* of ether* The light brown crystalline mass was acidified with excess of dilute hydrochloric acid* The water was removed under reduced pressure on the steam bath and the resulting material was extracted with three 50 cc* portions of acetone* On evaporation of the combined acetone solutions and re crystallization from acetone, about 3 g. of benzal-^methyl- 52. glutaconic acid was obtained. This material softened at about 170°. It turned brown and decomposed to a tarry substance at 175—200°. Analysis was accomplished by determination of an equivalent weight. Anal. Subs.* 0.4752, 0.5102 g.; vol. 0.1021 N sodium hydroxide, 40.41, 43.64; eq.wt. calc'd., 116.05, found 115.1, 114.5. 10. Pyrolysis of Benzal^-me thylglutaconic Acid. Pyrolysis of benzal-^-methylglulaconic acid was under taken over various time ranges. 200°. The acid decomposes at 175- Therefore the pyrolyses were carried out at 175-180°. A 1.5 g.-portion of the acid was used in each case. The following pyrolysis were run Duration, min. Products 5 1.0 g. original acid, 10 20 1 . 0 g. original acid, 0.2 g. original acid, 30 tar tar tar Tar At the end of each pyrolysis the product was fractionally recrystallized from acetone and then from ether. The tarry substance in each case was dissolved in benzene, and then in petroleum ether in an attempt to obtain a solid material other than benzal^-methylglutaconic acid. The material was dissolved In acetone and crystallization attempted in a solid carbon dioxide-acetone bath. obtained. No solid residue could be No further attempts were made to obtain a crystalline product. The tarry residues were combined and distillation under reduced pressure was attempted. Decomposition took place and 53* only a few drops were obtained* Pyrolysis of a large portion f5 g.) of benzalglutaconic acid was accomplished by heating at 175-180° for thirty minutes* This larger portion was subjected to the same treatment as the smaller portions* Still no solid product could be obtained by the pyrolysis* 11* 1 -Chi or o -5 -cyano -2 -me thy 1 -2 -pr opanol * A 43 g* portion of l-chloro-3-bromo-2-methyl-2-propanol was added to a solution of 350 cc* of methyl alcohol and 35 cc* of water* To the mixture was added 32 g* of potassium cyanide and the resulting material was refluxed with vigorous stirring, on a water bath for a period of 24 hours* At the end of this time the dark brown solution was cooled and then filtered to remove potassium bromide and any unreacted potassium cyanide* The water and methyl alcohol were then removed under reduced pressure on a water bath and the remaining brown oil was subjected to fractionation under reduced pressure* material would not distill* The A slight amount of material came over at 140-143° at 18 mm* and solidified in the condenser* Isolation was not practicable* 12* Ethyl ^-methyl-jf^chlorocrotonate* Another portion of the nitrile was prepared in a similar manner* The dark oil remaining after removal of methyl alcohol and water was subjected to extraction with absolute ethyl alcohol* Three 100-cc* portions of alcohol were used for the extraction of the nitrile* Then the solution was filtered and saturated with, dry hydrogen chloride over a period of eight hours* At the end of this time the solution was filtered to remove ammonium salts and subsequently was re fluxed on a water bath for a period of ten hours* After being cooled, the mixture was filtered to remove further ammonium salts and then the alcohol was removed under reduced pressure* The dark oily material remaining in the flask was fractionated at 18 mm* pressure, after first adding a crystal of Iodine for the purpose of dehydration* About 20 g* was obtained at 92-97° at 18 mm. Temperature,°C* 81-92 92-97 97-142 142-144 Fraction, cc* 2 20 3 4 Preliminary analysis has shown this ester to be slightly low In chlorine content* The material obtained at 142-144° solidified on standing 24 hours at room temperature* showed this material to contain nitrogen* Analysis It turned light brown after several days exposure to the air* 13* Attempts to Prepare l-Chloro-2-epoxy-2-ðylpropane* A. Means of Bases * Fifteen grams of l,3-dichloro-2-methyl-2-propanol was dissolved in 150 cc* of dry ether in a 250 cc* flask* To this was added 5 g* of finely powdered sodium hydroxide and the solution was refluxed for eighteen hours* The reflux condenser was fitted with a calcium chloride drying tube* The resulting, somewhat cloudy, solution was then rapidly filtered to remove the sodium chloride• It was then fractionated* A slight forerun of 1 cc* distilled below 124°* About 3 cc* of the material distilled at 124-128° and this was thought to be the desired product* aldehyde test* However, it gave an It had a slight lachrymatory odor and turned a dark yellow on standing at room temperature for several days* The liquid remaining in the flask was a dark yellow color and would not distill under atmospheric pressure without poly merization and decomposition* A similar process to the above was used with the exception that calcium hydroxide was substituted mole for mole for sodium hydroxide* The results were approximately the same, although only 1*5 cc* of material was obtained at 124-128°* ! B* Bjr Means of Perbenzoic Acid* 59 Perbenzoic acid was made by the method of Tiffeneau* In a 520 cc* flask 5*2 g* of sodium was dissolved in 100 cc* of absolute methyl alcohol, with moderate cooling* The resulting solution of sodium methoxide was cooled to -5°. solution of 50 g* A (0* 2 1 mole) of benzoyl peroxide, recrystal lized from acetone, in 2 0 0 cc* of chloroform was prepared, cooled to 0 °, and added immediately to the sodium methoxide solution with shaking and cooling at such a rate that the temperature did not rise above 0°. The mixture was kept four minutes in an ice-salt bath with continuous shaking. It (5 9 ) Tiffeneau, Organic Svntheses, Vol. VIII, John Wiley and Sons, New York (1928), p.30* 56. turned milky and was extracted with 500 co. of water which contained plenty of chopped ice* The chloroform layer then was separated and the aqueous layer extracted with two 1 0 0 -cc* portions of cold chloroform to remove methyl benzoate* The aqueous solution contained the sodium salt of perbenzoic acid. sedition It was liberated by 225 cc* of cold 1 IT sulfuric acid and removed from solution by extracting 3 times with 1 0 0 —cc* portions of cold | chloroform* The united chloroform layer was washed twice with two 50-cc* portions of water and was then dried over anhydrous sodium sulfate* To the resulting perbenzoic acid solution was added 30 g. of methallyl chloride and the mixture was shaken vigor ously for one hour* At the end of this time the mixture was allowed to stand at room temperature for five days* After this period of time it was assumed that any reaction taking place was completed* The solution was wa&hed with 100 cc* of 5# sodium hydroxide to remove the benzoic acid and was then dried over anhydrous sodium sulfate for one hour* The mixture was fractionally distilled. After the chloroform was removed a large portion (25 cc.) came over at 72-75°, which was methallyl chloride* A small portion (2 cc*) distilled at 1 0 0 -1 1 0 ° and a solid residue remained distilling flask* in the III# Investigations with Levullnic Acid* !• Preparation of jf-Ethvnylvalero-^-lactone* Ammonia was distilled and condensed into a 500 cc* round "bottom flask fitted with a mercury-sealed stirrer, and an outlet tube, until about 175 cc* of liquid was obtained* The flask was surrounded by an acetone-solid carbon dioxide bath. To tliis was added, with vigorous stirring, 16.5 g. of sodium* Acetylene was passed into the resulting solution until the deep blue turned to the light grey of sodium acetylide. Forty grams of levulinic acid was slowly added to the mixture over a period of fifteen minutes* At the end of this time the solution was stirred vigorously for three hours and then the ammonia was allowed to evaporate at room temp erature* The solid mass was then acidified with an excess of sulfuric acid and the solution obtained was warmed on the steam bath for fifteen minutes. An oily layer separated and this was then extracted with 200 cc. of ether. The aqueous layer was then extracted with two 1 0 0 -cc. portions of ether and the combined ether solutions dried over anhydrous sodium sulfate. B£ distillation the ether was removed and the remaining red oil was distilled under reduced pressure* About 30 g. of the lactone was obtained at 99-100° at 13 mm. pres sure. 2. Polymerization of the Lactone with Hydrochloric Acid* The 6 -ethynylvalero-^f-lactone was shaken for various periods of time with a solution of concentrated hydrochloric acid, it was thought that addition of hydrogen chloride would take place across the triple bond. In each Instance 5 g. of lactone was shaken with 40 cc* of concentrated hydrochloric acid* Time Shaken,hr* ^•5 Product Rubber-like tar and 2 cc* of original lactone Rubber-like tar and 2 cc. of original lactone Rubber-like tar and 1 cc. of original lactone Very elastic brown tar* I«0 5*0 24*0 The lactone was seemingly converted to a material which was either a rubber-like tar or in some instances more of a resinous substance* In each case the solution was carefully neutralized withsLightly less than the theoretical amount of sodium hydroxide and the solution was subsequently extracted with 150 cc. of ether in two portions. The ethereal solution was dried over anhydrous sodium sulfate and the ether removed on the steam bath* pressure* The solution was then distilled under reduced In every instance a small amount of material boiling high©** than the lactone was obtained. It was not sufficient to allow Investigation. Attempts to Prepare the R-dialkylamide* Levulinic acid (10 g*) was slowly added to a solution of an equivalent amount of thionyl chloride in 30 cc. of benzene and the mixture was refluxed, on the steam hath for a period of thirty minutes. At the end of this time a slight excess of dihutylamine was slowly added and the solution was cooled. 59 * r University U-.rri-v It was extracted with water to remove the amine hydrochloride and then with diluted acid to remove the excess amine* Finally it was washed again with water and dried over an hydrous sodium sulfate* Removal of the benzene on the steam bath resulted in an orange colored oil which would not solidify* Distillation was undertaken * An oil was obtained which boiled at 143-146° at 18 mm* pressure* About 2 g* was obtained* Reaction with diethylamine was undertaken in a similar manner* A similar reaction was found to take place but the amount of nitrogen containing oil was much less* 4* Conversion of Ethynyl G-roup to Acetyl Group* so The method of Scheibler and Fischer was used to convert the y-ethynylvalero-^-lactone to the corresponding acetyl derivative* To a mixture of 6 cc* of concentrated sulfuric acid 30 cc* of water was added 1*2 g* of mercuric oxide* After the mercuric oxide was dissolved 12*4 g* of the lactone was slowly added with constant shaking* very warm during this addition* The solution became As soon as the lactone had been completely added the mixture was refluxed for a period of one hour* At the end of this time the solution was cooled. A solid material separated, which seemed to be an inorganic salt* Attempts to isolate the reaction product have been hindered by the fact that the ketone also has an acidic group* (60) Scheibler and Fischer, Ber., 55, 2903 (1922)* 5* Misce 1laneous Reactions of the Lactone* Experiments were performed in which the tf-ethynyl-d1,- valerolactone was subjected to various attempts to open the lactone ring and then remove the elements of water by removal of the hydroxyl on the tertiary carbon and hydrogen on the adjacent carbon* The lactone was refluxed with ethyl alcohol and sulfuric acid in an attempt to convert it to the ester* The equilibrium was in favor of the lactone and this attempt was futile* Pyrolysis of the lactone produced tar and the original lactone* 61 SUMMARY Certain compounds of a conjugate nature, or of a poten tially conjugate nature have been studied with the syntheses of compounds of the carotenoid type in view. Attention was focused on five principal compounds, namely, ethyl crotonate, ethyl ^-methylglutaconate, J^chloro- Jf^ethynylvalero-/- lactone and ethyl 4-ethynyl-3-pentenoate. Acetylketene, methallyl chloride and levulinic acid were used as starting materials. Chlorination of acetylketene yielded chloroacetoacetyl chloride. Reaction of chloroacetoacetyl chloride with ethyl alcohol produced ethyl chloroacetoacetate. Reduction of this ester produced a mixture of compounds of which ethyl acetoacetate and ethyl ^-hydroxy-J-chlorobutyrate were the principal ones. The mechanism of chlorination and the structure of acetylketene Is discussed. Attempted condensation of acetyl ketene with acetaldehyde by means of various catalysts resulted in the dimerization of acetylketene to dehydroacetlc acid. Methallyl chloride was converted into the chlorohydrin, the bromohydrin and the iodohydrin. mately 30#, 65# and 1 0 # respectively. The yields were approxi Prom the chlorohydrin was obtained 1 ,3 -dicyano-2 -methyl-2-propanol. Alcoholysis of this nitrile, followed by dehydration, produced ethyl onate• Ethyl ^ - m e t h y 1 glutaconate was condensed with benzaldehyde to yield benzol-#-methylglutaconic acid. acid caused polymerization. Pyrolysis of this Isolation of the monocarboxylic acid from the pyrolyzed product could not be accomplished. Treatment of l-chloro-3bromo-2-methyl-2-propanol with a molar quantity of potassium cyanide produced l-chloro-3 cyano-2-methyl-2-propanol. This was converted to the ester by alcoholysis and subsequent dehydration produced ethyl ehloro-^-me thylcrot onate • Conversion of levulinic acid into J^ethynylvalero-^- lactone was accomplished by a much simplified process in which the acid was reacted with sodium acetylide in liquid ammonia. The lactone so produced was treated with water in the presence of sulfuric acid and mercuric sulfate to yield an unidentified product. Attempts to open the lactone ring, followed by removal of the tertiary hydroxyl group have not i || been effective so far. VITA John Leo Abernethy Born: March 6 , 1915 at San Jose, California* Education: Grammar School, Spokane, Washington, 1921-23 Canoga Park Grammar Schools, Canoga Park, California,1923-27 Canoga Park High School, Canoga Park, California, 1927-31 University of California at Los Angeles, A*B. 1936, 1931-36 Northwestern University, M.S.,1938, 1936-40 Positions: Assistant in Chemistry, Northwestern University, 1937-40 Societies: Alpha Chi Sigma American Association for the Advancement of Science American Chemical Society Phi Lambda Upsilon Sigma XI Publications: "The Chlorination and the Structure of Acetylketene", J.Am.Chem.Soc.,62, 1147 (1940), with Professor Charles D. Hurd. BIBLIOGRAPHY 1. Gilman, Organic Chemistry", Vol. II, John Wiley and Sons, New York, 1938, p.1139. 2. von Euler, Biochem.Z.,203, 370 (1938). 3. 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