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Some unsaturated compounds of a conjugate nature

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its
A
patrons
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AND
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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
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TO
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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-&ethylpropane*
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. Ahmad and Drummond, J.Soc.Chem.Ind., 185T (1931).
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5. Kuhn and Morris, Ber., 70, 850 (1937).
6 . Karrer and Ruegger, Helv.Chim.Acta, 23, 284 (1940).
7. Karrer, Salamon, Morph and Walker, Helv.Chim.Acta. 15,
878 (1932).
8 . Davies, Hellbron, Jones and Lowe, J.Chem.Soc., 584 (1935).
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Chem.Abstracts, 24, 1652 (1930).
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27. Kuhn and Hoffer, Ber., 69, 2087 (1930).
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29. P. G. Fisfiher and Wiedemann, Ann., 515, 251 (1934).
30. Kuhn and Grundmann, Ber., 69. 1757 (1936)•
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32. Kuhn and Grundmann, Chem.Abstracts, 34, 1036 (1940).
33. Kuhn and Michel, Ber., 71, 1119 (1938)•
34* Kuhn and Wallenfels, Ber., 71, 1889 (1938).
35. Kuhn, Angew.Chem.,50, 703 (1937).
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37. Fuson, Arnold and Cook, J.Am.Chem.Soc..60, 2273 (1938).
38. Kuhn and Ishikawa, Ber., 64,2347 (193k) •
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40. Chick and Wilsmore, J.Chem.Soc.,61, 3358 (1939).
41o Hurd and Abernethy, J .A m .Chem.Soc., 62, 1147 (1940).
42. Boese, Ind.Eng.Chem.,52, 20 (1940).
43. Hurd and Roe, J.Am.Chem.Soc., 61, 3358 (1939).
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45. Hurd and Roe, J.Am.Chem.Soc.,^!^ 3358 (1939).
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46. Dreifus and Ingold, J.Chem.Soc., 123, 2964 (1923).
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June,(1939).
Ann., 345, 89 (1906); Bland and Thorpe, J.Chem. etc.
49. Braun, J.Am.Chem.Soc., 52, 3167 (1930).
50. Vaughan and Rust, J.Am.CKem.Soc. ,61, 215 (1939).
51. Kreimeier, U.S.Patent 2,122,719, July (1938).
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June, 1940.
53. Helberger, Ann., 522. 269 (1936).
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Weisl, Monatsh.,27, 1247 (1906); Schlotterbeck, Ber.,
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VIII, John Wiley and Sons, New York (1928), p.92.
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