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ik) U n p u b l i s h e d theses s u b m i t t e d for the M a s t e r ' s and Do c t o r ' s d e g r e e s and 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 are o p e n for i n s pe ct ion , but are to be u s e d on l y with duo re g a r d to the r i g h t s of the authors. Bibliographical r e f e r e n c e s m a y be noted, but p a s s a g e s ma y be co pi ed only with the p e r m i s s i o n of the author, and p r o p e r credit mu s t be g i ve n in s u b se qu en t w r i t t e n o r p u b l i s h e d work. E x t e n s i v e c o p y i n g or p u b l i c a t i o n of the t he se s in w h o l e or in part r e q u i r e s also the co nsent of the De a n of the G r a d u a t e S ch oo l of N o r t h w e s t e r n University. Th i s th e s is by has been used by the f o l l o w i n g persons, w h os e s i g n a t u r e s attest their a c c e p t a n c e of the above r e s t r i c ti on s.
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NAME AND ADDRESS
this thesis for use by its s ig nat ur e of each user.
DA T E
CONDENSATIONS INTRODUCING POTENTIAL ISOPEENE UNITS
A DISSERTATION SUBMITTED SfiE THE GRADUATE SCHOOL IN PARTIAL FULFILLMENT OF THE REQUIREMENTS for the degree DOCTOR OF PHILOSOPHY
DEPARTMENT OF CHEMISTRY
BY HILMER ERNEST WINBERG
EVANSTON, ILLINOIS JUNE, 1942
ProQuest Number: 10102143
All rights reserved INFORMATION TO ALL USERS The quality o f this rep rod u ction is d e p e n d e n t u p o n th e quality o f t h e c o p y su b m itted . In th e unlikely e v e n t th at t h e auth or did n o t s e n d a c o m p le t e m anuscript a n d th e re are m issing p a g e s , t h e s e will b e n o te d . Also, if m aterial h a d to b e r e m o v e d , a n o t e will in d ic a te t h e d e le tio n .
uest P roQ uest 10102143 P ublished by P roQ uest LLC (2016). C opyright o f th e Dissertation is h eld by t h e Author. All rights reserved . This work is p r o te c te d a g a in st unau th orized c o p y in g under Title 17, United S tates C o d e Microform Edition © ProQ uest LLC. P roQ uest LLC. 789 East E isenhow er Parkway P.O. Box 1346 Ann Arbor, Ml 48106 - 1346
The writer wishes to express his grateful appreciation to Professor Charles D. Hurd for his supervision, encouragement, and advice throughout this investigation, and to Northwestern University for the University Fellowships which made the work possible.
TABLE OF CONTENTS page I. HISTORICAL................................... 1 Carotenoids* ......................... 1 2 Structure of Vitamin A ..................... Approaches to the Syhthesis of Vitamin A • • 2 Citral in the Synthesis of Vitamin A • • • . 5 P-Methylerotonaldehyde Approach* • • • • • • 6 Methyl Ether of Vitamin A ..................... 10 Use of Acetylene and Vinylacetylene. • • • • 10 Higher Homologs of Vitamin A . * * . * * * * 11 II. PLANS OF APPROACH AND THE RESULTS OBTAINED* . 14 The Plan of Investigation..................... 14 Condensation of Chloroacetone and Various Esters....................................... 15 tf-Chloro-p-hydroxyisovaleronitrile ........ 19 Ethyl X-Chloro-p-hydroxyisovalerate. . . . . 20 Ethyl tf-Chloro-p-methylcrotonate.............20 Ethyl tf-Iodo-p-methylcrotonate ............ 21 (39tf-Dibromoisovaleronitrile................... 23 Reformatzsky Reaction of Ethyl X'-IodorPmethylcrotonate with Benzaldehyde and with Cyclo...................... 24 hexanone. Condensation of p-Ionylideneacetaldehyde with Ethyl ff-lodo-^-methylcrotonate • ...........25 Experiments with tf-Ethynyl-tf-valerolactone . 25 cxf-Benzal- tf-ethynyl- ^-valerolac tone . . . . . 27 &-Acetyl-i?-valerolactone. . ................ 28 III. EXPERIMENTAL. ........................... 31 1. Synthesis of Ethyl tf-Iodo-P-methylcrotonate 31 l-Chloro-3-bromo-2-methyl-2-propanol . . . 31 3-Chloro-2-methyl-1,2-epoxypropane. ... 31 tf-Chloro-/3-hydroxyisovaleronitrile . . . . 32 Ethyl y-Chloro-P-hydroxyisovalerate. . . . 35 Ethyl S-Chloro-P-methylcrotonate ........ 36 Ethyl if-Iodo-P-methylcrotonate.............37 Condensation of Ethyl Bromoacetate with Chloroacetone.............................. 38 Condensation of Ethyl Cyanoacetate with Chloroacetone........................... 39 P-Methylallyl C y a n i d e ...................... 40 p.tf-Dibromoisovaleronitrile........ .. • 41 Attempted Alcoholysis of -Dibromoisovaleronitrile ........................... 41 2. Reformatzsky Condensations of Ethyl tf-Iodop-methylcrotonate .......... • • • Condensation with Benzaldehyde.......... Condensation with Cyclohexanone • • . • • Condensation with f3-ionylideneacetaldehyde
42 42 44 45
3* Investigations with 5'-Ethynyl-6'-valerolactone • 48 Preparation of 4-Benzal-tf-ethynyl-tf-valerolactone............. 49 tf-Acetyl-f-valerolactone.................. • • 50 Attempted Preparation of Ethyl f-Ethynyltf-hydroxyvalerate. • • • 52 Reaction of tf-Ethynyl-^-valerolactone and Methyl Sulfate. .......... •• ........... 54 IV.
CONDENSATIONS INTRODUCING POTENTIAL ISOPRENE UNITS HISTORICAL The carotenoids are a class of polyene pigments which, like the terpenes, may be regarded as constructed of "isoprene units 11 because the most widely distributed members of the class possess molecular formulas in which carbon is some multiple of five.
They occur widely distributed in
both plant and animal structures, and are essentially long chains of carbon atoms arranged in a sequence of conjugated double bonds.
The carotenoids have received considerable
attention not only because of their widespread occurrence in nature as the products of the living cell, but also because several of them have been recognized as progenitors of vitamin A. Carotene, the first to be discovered, is the most abundant in nature and the best known member of the class. 1
It was first isolated by Wackenroder
in 1831 from the root
of the cultivated carrot, and is now known to be a mixture of isomers of which
,6 -carotene is the dominant form.
has been shown to be a provitamin A 5
it is transformed in
the animal body into vitamin A, probably by hydrolysis. CH 3
CH^ y CH 3
, CH 3
+ 2H20 I®-Carotene (1) Gilman, "Organic Chemistry", Vol. II, John Wiley and Sons, New York, 1938, p. 1139.
C E \ / CH3
-ch=ch-c=chch=ch-c=chch2 oh ~ch3 vitamin A The problem of the synthesis of vitamin A will be discussed since the reactions involved include most of the synthetical approaches to the introduction of isoprene units in a conjugated sequence and, as yet, it may be considered unsolved*
carotenoid has been synthesized although the methods have led 2
and to related compounds
containing isoprene units not in a conjugated sequence, such 4
and perhydrovitamin A*
In 1931 Karrer
and his co-workers assigned a structure 6
to vitamin A which was definitely proven in 1933
synthesis of perhydrovitamin A, shown to be identical with the product obtained by hydrogenation of natural vitamin A concen trates.
This structure elucidation led to numerous attempts
to synthesize the pure vitamin, one of the first of which was 8
that of Karrer, Salomon, Morf and Walker* the cases,
As in a majority of
^-ionone was chosen as the starting point for the
following series of reactions, in which C 9Hi 5 represents the 2
,6 ,6 -trimethyl-l-cyclohexenyl group,
(2) (3) (4) (5) (6 ) (7) (8 )
Karrer, Helfenstein and Widmer, Helv.Chim.Acta, 11. 1201 (1928) Karrer, Benz and Stoll, ibid., 16, 297 (1933) Karrer and Helfenstein, ibid., 14. 78 (1931) Fischer and Ldwenberg, Ann., 475. 183 (1929) Karrer and Morf, Helv.Chim.Acta, 16, 625 (1933) Karrer, Morf and Schdpp, ibid., 14, 1434 (1931) Karrer, Salomon, Morf and Walker, ibid., 1^., 878 (1932)
/ CX ce 2 x cce 2
jC-CH3 un 3 CHS
C 9 H 1 BCH=CHC0CHs
BrCH2 CpOCaH 5 >
c 9 H 1 5 CH=CH-C=CHC00C3 H 5
|?-ionone Ma C 9E 1 7 CE 2 CE 2 CECE2 C00C2 E 5
o 2 Jl5 Un
C 9 H 1 7 CH 2 CH2 CHCH2 CH2Br
C 9 H 1 7 CH2 CH2 CHCE2 CH2 0H
C 9E 1 7 CH2 CE2 CECE2 CE2MgBr
CHS c 9 h 1 7 ce 2 ch2 chch2 ch 2 ch2 och3
CH 3 + (C 9E 1 7 CE 2 CH2 CHCH2 CE 2 ) 2
In the last step of the series the main product resulted from bimolecular condensation and only a small amount of the desired ether was formed* One of the closer approaches to the synthesis of vitamin A 9
was that of Heilbron
and his associates who prepared
ideneacetaldehyde by distilling under low pressure a mixture of barium
fl-ionylideneacetate with barium formate* CH 3 ce3 (C9 H 1 5 CH=CH-C=CHCOO)2Ba + (EC00)2Ba — C 9H 1 5 CE=CHC=CHCE0 + 2 BaC0 3
Reduction of the aldehyde by the action of aluminum isopropoxide gave the corresponding alcohol, a lower homolog of vitamin A which was found to be devoid of vitamin A activity. By the Reformatzsky reaction,
was condensed with ethyl bromoacetate*
Dehydration of the
?h3 C 9H 1 5 CE=CE-C=CECEO + BrCE2 C00C2 E 5 + Zn
CE 3 C 9 H 1 5 CH=CH-C=CHCH-CH2 OE I COOC2 E 5 (9) Davies,Eeilbron,Jones and Lowe, J *Chem.Soc*,1935,584*
hydroxy ester under mild conditions was not possible, and distillation of the barium salt of the corresponding hydroxy acid with barium formate caused a cleavage of the carbon chain, resulting in the formation of
The next step in the series was the condensation of the aldehyde with acetone in the presence of piperidine* GH 3 C 9 Hi 5 CH=CHC=CHCH0 + CH 3 COCH3 ch 3 C 9H i&CH=CHC=CHCHCH2 C0CH 3 OH Dehydration of the hydroxy ketone proved difficult but was 10
accomplished by means of anhydrous oxalic acid*
P-^3 G9H 1 5 CH=CHC=CIiCHCH2 C0CH3 OH
C 9Hi 5 ch=ch- 6 =chch=ciicoch3
The resulting ketone was condensed with ethyl bromoacetate yielding the difficultly distillable unsaturated ester* CH 3 C 9 H leCH=CHC=CHCH=GHC0 CH 3 + BrCH2 C00C2 H 5 + Zn
CH 3 CHs C 9 H i5 ch=chc=chch=chc=chcooc2 h 5 The ester was hydrolyzed but the resulting acid could not be obtained pure since on attempted recrystallization it was partly converted into an alkali insoluble material* The hydroxy ketone was then condensed with ethyl bromo acetate and hydrolyzed to the hydroxy acid*
On pyrolysis of
the barium salt of the acid with barium formate the hydroxy
(10) Heilbron, Jones, Lowe and Wright, J.Chem.Soc•,1936, 561
5. aldehyde was obtained, ch 3 ch 3 (C9H 1 5 CH=CHC=CHCHCH3 C=CHC00)2Ba + (HC00)2Ba OH CH 3 ch 3 2 C 9 H l5 CH=CHC=CHCHCH2 (i=CHCHO + 2 BaC0 3 OH n It has been suggested that the lack of dehydration during the pyrolysis may be due to the existence of the hydroxy aldehyde in the cyclic hemiacetal modification: CH 3
c 9H 15 CH=CHC=CHCHCH2 C=CHCH0 H 1
This series of reactions Indicate the peculiarities often encountered in the synthesis of conjugated systems related to vitamin A. More recently Heilbron and his co-workers have turned their attention to condensations with citral, believing that this method offers a simpler approach than synthesis of vitamin A.
/?-ionone to the
Citral was found to condense readily
with crotonaldehyde or ^-methylcrotonaldehyde using sodamide 12 ,13 as the catalyst. Two products were obtained with croton aldehyde, one the expected citrylidenecrotonaldehyde and the other an isomeric aldehyde which, on the basis of spectroscopic data and microhydrogenation, was shown to be cyclic and to have only three ethylenic linkages.
Likewise, with f3 -methy1-
(11) Abernethy, Ph.D. Dissertation, Northwestern University, August, 1940, p.6 . (12) Heilbron and Jones, Chem. and Ind., 55, 813 (1936) (13) Barraclough, Batty, Heilbron ggd Jones, J.Chem.Soc., 1939. 1549
crotonaldehyde two isomeric aldehydes, pseudo-ionylideneacetaldehydes a and b, were formed hut, in this case, neither were cyclic structures. (CH3 )gC=CHCH2 CH2 C=CHCH0
+ (CHS )2 C=CHCH0
citral CHS CHs (CHs)2C=CHCH2 CH 2 C=CHCH=CHC=CHCH0 pseudo-ionylideneacetaldehyde 14
of the semicarbazones of the two pseudo-
ionylideneacetaldehydes with phosphoric acid gave hexahydronaphthaldehyde derivatives, the products suggesting that the two forms were derived from cis and trans citral.
since di-cyclization occurred, the results were of little interest in the problem of vitamin A synthesis. 15
Zalkind, Zonis and Blokhin
the magnesium derivative of vinylacetylene to give the tertiary alcohol. C 9Hi 5 CH=CHC0CH3 + XMgC=CCH=CH2
CHS C 9H 1 5 CH=CHC-C=CCH=CH2 OH
Reduction produced the saturated carbinol whose constitution was established by oxidation to tetrahydroionone and butyric acid.
Biological tests with the unsaturated alcohol showed
that it was not a vitamin. 16 ,17 Several workers have investigated the condensation
(14) Batty, Heilbron and Jones, J.Chem.Soc., 1939. 1556 (15) Zalkind,Zonis and Blokhin, Compt.rend.Acad.Sci.U.R.S.S., 2, 57 (1935); C.A.,-22, 5819 (1935) (16) Beanhauer, Irrgang, Adler, Mattauch, Mttller, and Reiser, Ann ^95 43 Tl936'i (17) Fisher~and Hultzsch, Ber., 6 8 , 1726 (1935)
7. I I !of ^-methylcrotonaldehyde in the hopes of obtaining 3,7-diimethyl-2 .4,6 -octatrienal# (CH3 )2 C=CHCH0 + (CHs )sC=CHCH0
?Hs (CH3 )2 C=CHCH=CHC=CHCH0
;However, efforts to obtain the pure octatrienal were unsuc cessful, the products were invariably complex mixtures pro duced by further condensations.
These investigators hoped
,to condense the octatrienal with citral, cyclize the result ing aldehyde and then reduce it to vitamin A. CHs CH3 (CH3 )2 C=CHCH2 CH 2 C=CHCHO + (CH3 )2 C=CHCH=CHC=CHCH0 citral QK3 CH3 (ch3 )2 c=chch2 ch2 (C=CHCH=CH)2 C=CHCHO
c 9h 1 5 ch=chc=chch=ch§=chcho CIi3 CHs C 9 H 1 5 ch=chc=chch=chc=chch2 oh vitamin A Fuson and Christ 1 8 utilized a similar scheme in their condensation of one mdfe of
/5-cyclocitral with two moles of
j?-methylcrotonaldehyde followed by reduction of the aldehydic product with aluminum isopropoxide. C 9H 1 5 CH0 + (CH3 )2 C=CHCH0 + CCH3)2 C =CIiCHO j^-cyclocitral c 9 h 1 5 ch=chc=chch=ch6 =chcko qii3 ch3 C 9 Hi5 CH=CHC=CHCH=CH6=CHCH2 0H vitamin A The resulting reaction mixture gave a blue color with antimony trichloride in chloroform and an ultra-violet absorption spectrum with a maximum in the vicinity of 328
,Heilbron and Jones 12 have pointed out that in all of their (18) Fuson and Christ, Science, 84, 294 (1936)
8. condensations of citral, crotonaldehyde and
aldehyde considerable quantities of complex materials giving a blue color with antimony trichloride were obtained. was especially true with /3-methylcrotonaldehyde.
it is to be expected that the products of such reactions would have an absorption maximum in the neighborhood of 328 m ^ , and in view of these facts, the authors believe that bio logical tests alone would determine the presence of vitamin A in the mixture of Fuson and Christ. 19,20
In 1937 Kuhn and Morris
reported the synthesis of
impure vitamin A by condensing (3 -methylcrotonaldehyde with ^-ionylideneacetaldehyde. C 9H 1 5 CH=CHCOCH3 f3-ionone Q-CH3 C 6 H4KHMgI
The following steps were involved.
BrCHaC0 0 C3 H 5
?h 3 C 9Hi5 CH=CHC=CHCOKHC 7H 7
CHs C 9 Hi 5 ch=chc=chcci=nc 7 h 7 h8 0
CHS c 9h 1 5 ch=chc=chcooc2 h 5
CHs ^ c 9h 15 ch=chc=chch=hc7 h.
CH 3 (CH3 )aC=CHCH0 c 9h 1 5 ch=ch-c=chcho Piperidine + HOAc (3-ionylideneacetaldehyde