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I. STUDIES ON CYCLIC ALPHA, BETA-UNSATURATED KETONES. II. MISCELLANEOUS STUDIES

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The Pennsylvania State College
The Graduate School
I
Department of Chemistry
I,
Studies on Cyclic alpha,beta-Unsaturated Ketones
II. Miscellaneous Studies
A Thesis
by
George Wesley Pedlow. Jr.
Submitted in partial fulfillment of the
requirements for the degree of
Doctor of Philosophy
August 194-0
Approved:
date
Research Professor of Organic Chemistry
date
Head, Department of Chemistry
ACKNOWLEDGMENT
The author wishes to express his appreciation
to Dean Frank C. Whitmore for suggesting these
problems and for his interest and help throughout
the work.
TABLE OF CONTENTS
STUDIES ON CYCLIC alpha,beta-UNSATURATED KETONES
Part A
THE OXIDATION OF CYCLOHEXENE AND OF
1 -METHYLCYCLOHEXENE
. .. Page
1
Introduction .............................
Historical ....................................
4
Discussion
12
........................ •........
Experimental
......... . •• •............
18
Preparation of Cyclohexene
18
Oxidation of cyclohexene with chromic
anhydride in acetic acid ••••••••••••••••
19
Oxidation of cyclohexene with chromic
anhydride in t-butyl alcohol
............
Preparation of 1,3-cyclohexadiene .........
Preparation of alpha-chloro-cyclohexene
25
25
••• 27
Hydrolysis and oxidation of alpha-chlorocyclohexene
........................
Preparation of 1-methylcyclohexanol ......
Dehydration of 1-methyl cyclohexanol ........
.
Oxidation of 1-methyl c y c l o h e x e n e .......
Summary
27
28
29
30
...........................
Bibliography ••••••••••...............
34
35
Part B
THE ACTION OE GRIGNARD REAGENTS ON
CYCLOHEXENONE AND ISOPHORONE
Page
I n t r o d u c t i o n ......................
37
Historical .....................................
39
.....
Discussion
53
Ez$ e r l m e n t a l ...............................
55
Description of
fractionating c o l u m n s ......
55
Preparation of
starting m a t e r i a l s .........
56
Preparation of
A-oyclohexenone
58
...........
Addition of A^oyclohexenone to methylmagnesium b r o m i d e .......
58
Eractionation of the carbinol from the
methylmagnesium bromide-AS-cyclohexenone..
reaction
.....
59
Dehydration of 1-methyl-A^-cyclohexenol • •..
60
Oxidation of A-l, 5-methylcyclohexadiene ••••
61
A -1 ,5-methyl cyclohexadiene-maleic
anhydride adduct
..................
51
3-Methylcyclohexanone from the methyl­
magnesium bromide-A^-cyclohexenone reaction.62
Addition of A-oyclohexenone to ethylmagnesium bromide
......
63
iii
Fractionation of the carbinol from the ethylmagnesium bromide-A^cyclohexenone reaction.... 64
Dehydration of 1-ethyl-A^cyclohexenol .......
65
3-Ethylcyclohexanone from the ethylmagnesium
bromidiri^-cyclohexenone r e a c t i o n ............... 66
Addition of A-cyclohexenone to isopropylmagnesium chloride .............................
67
Fractionation of carbinols from the isopropylmagnesium chloride- <A^oyclohexenone reaction •• 68
A^Cyclohexenol;
The reduction product from the
i sopropylmagnesium chi or ide- A*-- cyclohexenone
r e a c t i o n .............................
69
The tertiary alcohol from the isopropylmagnesium ohloride-A^-cyclohexenone reaction ....
69
3-Isopropylcyclohexanone from the isopropylmagnesium chloride-A-cyclohexenone reaction •• 69
Addition of A*"-cyclohexenone to t-butylmagnesium c h l o r i d e
.....
70
3-t-Butylcyclohexanone........ ••..................72
Reduction of A^-cyclohexenone with aluminum
i s o p r o p o r i d e .......
Attempted reaction of
73
cyclohexenone with 1,3-
cyclohexediene ....................................
S u m m a r y .............................................
88
Bibliography
82
.....................
i
II. MISCELLANEOUS STUDIES
Part A
THE REDUCING ACTION OP PRIMARY GRIGNAHD
REAGENTS WITH TRIMETHYLACETYL CHLORIDE
Introduction
..............
83
Historical ..........................
84
Discussion
88
...................
Experimental ...............................
Preparation of trimethyljacetyl chloride .....
90
90
Preparation of phosphorus tribromide •••••••••• 90
Preparation of isobutyl bromide
.....
91
Preparation of isobutyl and n-butyl bromides... 91
Preparation of Grignard reagents ..............
91
Addition of trimethylacetylchloride to isopropylmagnesium bromide ............
92
Addition of trimethylacetylchloride to n-butylmagnesium bromide
...........................
94
Addition of trimethylacetylchloride to isobutylmagnesium bromide
.......
95
S u m m a r y ............
98
Bibliography ......................................
99
Part B
THE ACTION OF METHYL AND ETHYL GRIGNARD REAGENTS
ON ETHYL ACETONEDICARBOXYLATE
Introduction ..................................... ..
D i s c u s s i o n ..............
101
Experimental ..................................... ..
Preparation of aoetonedicarboxylic acid •••••• 104
Preparation of ethyl aoetonedicarboxylate •••• 104
Action of methylmagnesium chloride on ethyl
aoetonedicarboxylate ........................ 105
. Action of ethylmagnesium chloride on ethyl
aoetonedicarboxylate
Summary
......
108
...... •. ••....... ...............
111
Bibliography
......................
112
Part G
THE ACTION OF IODINE ON THE SILVER
SALTS OF ORGANIC ACIDS
I n t r o d u c t i o n ..................................... 115
Historical ........
114
D i s c u s s i o n ..........
117
Experimental ••••••................
119
Preparation of silver t r i m e t h y l a c e t a t e
119
Reaction of silver trimethyl^acetate with
iodine •••••........................
Reaction of
the silver salt of Butlerow's
beta-acid with iodine ....................
Summary
119
........
B i b l i o g r a p h y .....................
121
124
i25
I.
STUDIES ON CYCLIC alpha,beta-UNSATURATED KETONES'
Part A.
INTRODUCTION
THE OXIDATION OE CYCHOHEXENE
AND OF 1-METHYLCYCLOHEXENE
This laboratory has for a long time been actively
interested in the study of rearrangements accompanying
the oxidation of olefins.
Outstanding examples(1) are
the formation of methyl-t-butylneopentylacetic acid (II),
and dineopentylacetic acid (IV), by the oxidation of
2,2,4,6,6-pentamethylheptene-3 (I)> and dineopentylethylene (III), respectively:
C
C
C-C-C=C-C-C-C
6
6 c
[0]
--
=>
C
C-6-C
c l
C-C-C-C-COOH
6
c
I
c
II
9
O-C-O-G-O-P-O
a
[o]
9
9
6
i00H 0
c-c-c-c-c-c-c
)
III
IV
In the present work it was hoped that a similar
rearrangement would occur with cyclohexene to give
eyelopentanecarboxylic acid.
obtained was A-cyclohexenone:
However, the product
2
o
I!
0
This reaction solved a very difficult problem previously
attacked in this laboratory, namely the preparation of
cyclic alpha,beta-unsaturated ketones.
o
Previously A-cyclohexenone was obtained only by
difficult syntheses with low yields.
The best method
was probably that of Kotz and G-rethe (2), who obtained
it in 10$ yield by splitting out HBr from alpha-Brcyclohexanone by means of aniline.
Since the second
part of this work involved the preparation of large
amounts of
A
-cyclohexenone, a further study of the
conditions of oxidation of cyclohexene and the methods
of isolation of the ketone was undertaken, with the purpose
of improving the yield.
During this work an American patent on the use of a
solution of chromic anhydride in t-butyl alcohol, as an
oxidizing agent, was issued to Murray and Stevenson (3).
Because of its relation to the oxidizing mixture used in
the present work, a comparison of its action with that of
the chromic anhydride-acetic acid solution was undertaken.
The oxidation of 1-methylcyclchexene was studied to
determine the effect of branching on the course of the
oxidation.
The oxidation of this olefin might give rise
3
to two ketones and an aldehyde, corresponding to the
oxidation of the three alpha-carbon atoms:
CHO
[o l.
=0
*
HISTORICAL
An excellent survey of general oxidation methods,
with references to the literature, is found in an
article by Linstead (4) in the Annual Reports of the
Chemical Society, London 1937.
Discussion of these
methods will therefore be limited to examples directly
related to the present work.
Investigators studying the action of chromic an­
hydride-acetic acid, observed from the first that
cyclic olefins were oxidized in part, to unsaturated
ketones.
The first of these, Semmler and his assistants
(5) found that cedrene and gurjunene were oxidized to
unsaturated ketones whose structures were not determined.
Later, Schroeter (6) obtained a patent on the oxidation
of tetralin to alpha tetralone by means of the same
reagent:
Treibs and Schmidt (7 ) made an extensive study of the
oxidation of a large variety of cyclic olefins with a sol­
ution of chromic anhydride in acetic anhydride.
The olefins and the products obtained are listed below:
=0
alpha-Pmene
verbenone .
verbenol
Carvone
Dipentene
Unidentified
+
Cyclohexene
Cyclohexenol
Isopropylcyclohexenone
Sabinene & Sabinol
if
Tetralin
unsat. ketone
Related alcohol
Tetralone
Cymol
Unsaturated glycol
Terpmeol
— cHi
= CH,
$T
-f-
Camphene
Camphenilone
= 6H;
Camphenilanaldehyde
-0
CtIO
-\r
alpha-Fenchene
Fenchocamphorone
OOH
+
Camplienilanic
acid
+
Fenchenilanaldehyde
COOH
Fenchenilanic
acid
The same workers describe the oxidation of octene-1,
this being the first example of the oxidation of an open
chain olefin by means of the chromic anhydride - acetic
acid mixture.
The products were caprylic acid, an aldehyde
c8h14°2> and an unsaturated alcohol:
0H3(0H2)5CH=CH2
Octene-1
C H 3 (C H 2 )5 C H 2COOH
Caprylic acid
It is interesting to note that the acid formed contains the
same number of carbons as the olefin.
Recent work by Miner (8 ), in this laboratory, furnishes
the only example of the formation of an alpha-,beta-unsatura
ted ketone by the oxidation of open-chain olefins by means
of sodium dichromate-sulfuric acid solution.
H© found that oxidation of 2 ,2 ,4.,6 ,6-pentamethylheptene3 , gave 2,2,4,6,6-M©5-heptene-3one-5 (II), 2 ,2 ,4 ,6 ,6Me5-keptadione-3»5 ( H I ) , and 2 ,2 ,4 ,6 ,6-Me5-heptanol-4one-3 (TV):
. ■
1
■
c
0
c
c — fc— c = 6— - 0 — 6 -— c
6
c
0
0 0
c — 6 — c = 6 -—
0
1
c
c— c
6
11
c o c o c
c — c — 6 — c— S — c — c
5
6
c o c
c
0 — 6 — 6'— 6— 0 — c — 1
c
6h
6
III
17
H© was able to show that II was the intermediate in the
formation of III and 17.
Numerous other products, result­
ing from oxidation at the double bond, were obtained.
These were ketones and acids containing fewer carbons than
the original olefin.
Since they do not seem to be related
to the products obtained by oxidation of an alpha — CH2
group, they will not be presented here.
Willstaetter and Sonnenfeld (9) studied the oxidation
of cyclohexene with oxygen, using an osmium catalyst, and
obtained adipic acid, A-cyclohexenol, 2-OH-cyclohexanone
and A'cyclopentenaldehyde.
Kotz and Richter (10) repeated
this work with essentially the same results except that in
2
**'
addition they found A-cyclohexenone among the products.
Willstaetter and Sonnenfeld indicated the course of the
reaction as follows.:
tHO
C
o
I
Kriegee (11) oxidized cyclohexene with lead tetra­
acetate in acetic acid solution and obtained the acetates
.2
of A-cyclohexenol and cyclohexandiol.
2
Guillemonat (12) obtained the acetate of A-cyclohexenol
by the oxidation of cyclohexene with selenium dioxide in
acetic anhydride.
Zalkind and Markov (13) obtained only adipic acid by
the aqueous sodium dichromate-sulfuric acid oxidation of
cyclohexene.
PREVIOUS METHODS OP PREPARINGCYCLOHEXENONE
The following methods of preparing A-cyclohexenone
have been previously described:
Kotz and G-rethe (2):
Methods 1 to 5 inclusive.
1. The dehydration of 2-OH-eyelohexanone with oxalic acid:
2. The Tschugaeff xanthate method:
3. The splitting out of IiBr from alpha-bromoeyelohexanone
by means of sodium acetate and acetic acid or with aniline.
The latter method, which gave only a 10% yield of
a
1-
cyclohexenone, was the best method which these workers
found:
H Ac
4. Splitting out of HC1 from alpha-chloroeyelohexanone.
This was done in the same manner as with the bromide, but
with even a smaller yield.
5. The decarboxylation of
Al’-dihydrosalicylic acid:
// > c-ooH
2.
Kotz and Richter (10) prepared A-cyclohexenone by
2,
oxidation of A-cyclohexenol with potassium dichromate and
sulfuric acid, and also by heating the chlorohydrin of the
same compound with sodium carbonate and calcium sulfate.
The cyclohexenol was obtained by oxidation of cyclohexene
with oxygen using a colloidal osmium catalyst.
bo-ioo*o.
Courtot and Pierron (14) prepared A Zcyclohexenone by
simultaneous hydrolysis and oxidation of alpha-chlorocyclonexene prepared by the addition of HC1 to 1,3 cyclohexadiene:
11
8.
' fi
ttci
No-ic*z °7|
/ \
lo0—15"C>.
Guillemonat (12) prepared A-cyclohexenone by chromic
acid oxidation of A-cyclohexenol, the acetate of the latter
having been obtained by the selenium dioxide oxidation of
cyclohexene in acetic anhydride:
9.
oAo
SeOfc
A c20
NaOf/
'6<0i
12
DISCUSSION
Treibs and Schmidt (7) obtained mainly A-cyclohexenol
by the oxidation of cyclohexene with chromic anhydride in
acetic anhydride.
In the present work it has been found
that the oxidation is carried a step further when acetic
acid is used as the solvent in place of acetic anhydride,
A 2"-cyclohexenone becoming the chief product of the reaction.
In several runs the average yield of A-cyclohexenone was
35$.
In the one run in which it was isolated, adipic acid
was also obtained in 21$ yield.
In addition there was an
appreciable quantity of high boiling neutrals obtained in
all cases.
These were not identified but appeared to be
phenolic in character:
ft
0 ^ 0
Cyclohexene
A-Cyclohexenone
oooH
■
+ t;
Adipic Acid
The oxidation of 1-methylcyclohexene (I) with chromic
anhydride in acetic acid yielded 20$ of 1-methylcyclohexenone-3 (II) and 2$ of l-methylcyclohexenone-6 (III).
The acidic portion of the products was not worked up:
I
1-methylcyclohexene
II
1-methylcyclohexenone-3
HI
1-methylcyclohexenone-6
13
These results are in direct contrast with those of
Urion (15) who reported the formation of
l-methylcyclo­
hexenone-6 (III) only, by the oxidation of the same olefin
with selenium dioxide.
It should be noted that this ketone
was obtained in the smallest yield in the present work.
Dupont (16) also found that the 6-position was attacked by
autoxidation of 1-methylcyclohexene.
Linstead (4-) made the observation that in the system:
C1 2
C—1 and not C-4.
C - C
3
4-
oxidation favored
This was based on an examination of the
products obtained by the oxidation of such olefins by means
of selenium dioxide and by lead tetracetate.
Dr.Whitmore has suggested a possible mechanism for the
formation of alpha,beta-unsaturated ketones by the oxidation
of olefins.
This involves an initial addition of oxygen at
the end of the double bond with subsequent loss of two
protons.
In the simplest system this can be illustrated as
follows:
1s
H
H
H
-6— C — C—
H
:0: *
This agrees with the formation
H
I?
H
H
C--- *■ - C — G — C - C-+2H*
H
6
0
oftheButlerow’s acids
(1 ) and would appear to be a satisfactory explanation for
the formation of
hexene.
A 2-cyclohexenone by the oxidation of cyclo­
, which contains the system indicated in the mechan­
ism above.
The work of Urion and Linstead also lends support
to the theory.
u
However, with selenium dioxide oxidation the explanation
is probably not so simple.
Concerning the latter, Linstead
(4) says, "It is probable that additive compounds contain­
ing selenium are formed as intermediates, at least in some
reactions.
High boiling residues containing selenium are
often encountered, and in some cases definite compounds
have been isolated."
On the other hand, Riley (17) considers
it possible that selenium dioxide provides the oxygen
directly in a low energy state.
If there is branching at the double bond, in addition
to the product indicated by the first mechanism, a saturated
ketone might be formed.
This would correspond to addition
of an oxygen at the end of the double bond where the branch­
ing occurs, accompanied by a shift of the branched group,
designated R below:
I 5
-C — 6
I
,
~ G — C—
H
1
:0‘
i 5
*
, —> ,
?
i
i -C— C — C — C-C— C— C — C —
1 :0:
1
'
8
1
1
The- oxidation of 1-methylcyclohexene, which contains
such a branched system, gives a ketone I which cannot be
accounted for by the proposed mechanism:
o=
I
III
On the basis of the mechanism in question, products II
and III would be predicted.
i
Actually, I and II were found.
The double bond in compound
I is still in the same position with respect to the methyl
group as it was in the olefin.
The initial addition of
oxygen could, therefore, not have occurred at the end of
the double bond as required by the proposed mechanism.
Equally difficult to explain is the formation of
verbenol (I) and verbenone (II) by the auto-oxidation of
alpha-pinene, observed by Blumann and Zeitschel (18) and
by Wienhaus and Schumm (19), or the formation of myrtenol
(III) and myrtenal (IV) by selenium dioxide oxidation of
the same terpene, Dupont (20):
H
I
m
JY
There are additional examples which cannot be explained
by the proposed mechanism, only one of which will be included
in the present discussion.
The oxidation of tetralin (21),
with a wide variety of reagents, has been observed to give
alpha-tetralone:
o
At the present there appears to be no adequate explanation
for the ketonic products produced by oxidizing agents acting
on an olefin.
An alpha-CHg group is undoubtedly activated in some unex­
plained way and'when more than one is involved, the oxi­
dizing agent used appears to influence the direction of the
oxidation:
-CH = CH — CH2 —
-CH>CH — CO —
For the work described in the second part of this
thesis it was necessary to prepare a considerable quantity
of
-cyclohexenone.
With the purpose of increasing its
yield and ease of isolation, the oxidation of cyclohexene
was studied in some detail.
In all cases the yield was based on the amount of
cyclohexene actually oxidized, since there was always a
large amount recovered.
Changes in temperature, and concen­
trations of reactants and solvent appeared to have little
effect on the yield.
the
At first, the method of isolation of
A z -cyclohexenone consisted in removal of most of the
solvent, acetic acid, by fractionation at reduced pressure.
The residue was continuously extracted with ether to obtain
the ketone.
This method was extremely slow and it was later
found much more satisfactory to neutralize most of the acetic
acid with sodium hydroxide solution, and then ether exbract
the solution in the usual manner to obtain the ketone.
In one run, a solution of chromic anhydride in t-butyl
alcohol was used as the oxidizing agent.
The yield of
A-
cyclohexenone could not be accurately determined because of
17
the difficulty in separating the unreacted cyclohexene
from the t-butyl alcohol.
This method also involved a long
fractionation of the solvent and was abandoned in favor of
the method previously indicated.
The method used by Courtot and Pierron (14) for the
preparation of
A
£
-cyclohexenone was repeated for com­
parison with the oxidation method.
This involved the
addition of HC1 to 1,3-cyclohexadiene to give alpha-chlorocyclohexene, which was then converted to
A 2--cyclohexe­
none by simultaneous hydrolysis and oxidation with sodium
dichromate and sulphuric acid:
The 1,3-cyclohexadiene used in the above synthesis was
prepared by the method of Hofmann and Damm (22).
This in­
volved the addition of bromine to cyclohexene, to give
1,2-dibromo-cyclohexanone, which on treatment with sodium
ethoxide in absolute alcohol gave some of the desired pro­
duct, but mainly alpha-ethoxy-cyclohexene.
The latter was
converted to the former by heating with potassium pyrosulfate:
Dr
0
3<
j
Part I
E]Q?ERIMENT.AIj
Preparation of cyclohexene. The method found in
Organic Syntheses (23) was first used for the preparation
of cyclohexene .
In a 1-liter Claisen flaslc with a 35 cm.
indented side neck was placed a solution of 800g.
(8 moles)
of stock hexalin (cyclohexanol) and 24 cc. of concentrated
sulphuric acid.
The mixture was heated with an oil bath
adjusted at 135-40°C.
causing dehydration of the hexalin.
The distillate, cyclohexene and water, was collected in a
receiver cooled with an ice bath.
The distillation was con­
tinued until the odor of SO2 became apparent, the temper­
ature having been gradually raised to 150°C.
The water was
separated from the distillate and the crude cyclohexene
dried over anhydrous CaClg overnight, then fractionated in
column I.
20
D
Weight
63-S2°C.
1.4408
22.7
739
131
82 °C.
1.4455
1.8
739
3
131
82
1.4458
1.7
739
4
131
82
1.4459
.1.4
739
5
132
82
1.4460
1.6
739
6
132
82
1.4460
460.
Residue '
22.
Cut
Bath Temp.
1
130
2
Boiling Pt.
n
Out § 6, 460 g. (5.6 moles) represents a yield of 70#
Press.
739
19
The method of preparing the cyolohexene was later
modified slightly.
It was found to be more satisfactory
to continually introduce fresh hexalin to the distillation
flask.
This was accomplished by placing a dropping funnel
in one neck of the Claisen flask and regulating the flow
of hexalin so that the level in the flask remained almost
constant.
In this manner 2-3 times as much hexalin could
be dehydrated in one operation.
Oxidation of cyolohexene with chromic anhydride in
acetic acid.
In a 5-liter flask equipped with a mercury
sealed stirrer, reflux condenser, thermometer and dropping
funnel, was placed a solution of 410 g. (5 moles) of
cyolohexene and 1000 g. of acetic acid.
£*03
To this was slowly
in 45‘0 ‘jjf-
added a solution of 750 g. of water and 1500 g. of acetic
A
acid.
The addition of the Cr03 solution was carried out
over a period of 16 hours, the temperature being kept at
25-35°C.
Stirring was continued for 14 hours after the
addition was completed.
The material was then distilled
through column III until the head temperature reached 9S°C.
at 742 mm.
From the distillate, after separation of the
pA
water layer, 181 g. of cyolohexene (n D 1.4455)
recov­
ered.
The residue
from the distillation was fractionated
at ?Qwn- pressure to remove the v/ater and as much of the
acetic acid as possible.
The residue, containing the
chromium salts and high boiling material, became very
vicous toward the end of the fractionation.
A
After coolingjit was diluted with water to make 2.5 liters
of solution, and was then continuously extracted with ether
for five days.
The ether was then stripped and the residue
fractionated in column II:
Cut
Bath Temp.
1
70
2
Boiling Ft.
n20D
Weight
31°C.
1.3770
45.0
25mm.
71
31
1.3751
80.
25
3
70
31
1.3749
35.
25
4
100
31-
1.3802
20.
25
5
105
35-
1.3864
8.3
25
6
110
60-
1.3912
5.4
25
7
115
62-
1.3963
5.1
25
8
115
66-
1.4693
3.9
25
9
115
67
1.4775
9.8
25
10
120
67
1.4783
10.6
25
11
125
67
1.4818
10.2
25
12
128
67
1.4840
13.4
25
13
140
67
1.4851
10.2
25
14
160
67
1.4852
19.6
25
15
172
67
1.4850
17.0
25
16
200
67
1.4810
8.4
25
Residue
Press.
.
30.
Fractions 1-8 were largely acetic acid, the latter four,
containing some of the main product of the oxidation.
Qualitative tests and comparison of physical constants and
derivatives indicated that fractions 9-16 were
A
-cyclo-
hexenone, a yield of 37# based on the cyolohexene actually
oxidized.
The following table includes the constants
previously reported for
A^-oyolohexenone and those of
fraction 15:
B.P.°C.
Kotz and Grethe (2)
Guillemonat (12)
Fraction #15
nTD
D.
63/Hmm. 1.4796/18
67-9/21mm. I.4741/21
67/25mm. I.4850/20
M.P.
Semicarb
0.9868
l6l°C.
0.976
161
0.9962
167-8
Although there is some discrepancy in the above values
the conversion of the material to
.this thesis)
A^-cyclohexenol (Page
and to tribromophenol definitely establish
the identity of the oxidation product.
The conversion to
tribromo-phenol may be indicated by the following equat­
ions :
?»
?H
-ZHKy
This was carried out by the dropwise addition of bromine to
a solution of
A^-cyclohexenone in carbon tetrachloride.
The solution was boiled during the addition of bromine,
which was immediately absorbed^and soon HBr fumes were
evolved, and the odor of phenol became apparent.
Addition
of bromine was continued until the brown fumes of free bro­
mine wereobserved in the vapor of the boiling solvent.
The solvent was then completely distilled off, and the
residue crystallized on cooling.
After crystallizing tv/ice
from dilute alcohol the m.p. was 89? and after subliming it
the m.p. was raised to 92?
It gave no depression in m.p.
with an authentic sample of tribromo-phenol.
The residue from the fractionation of the
A z -cjclo-
hexenone had the characteristic odor of phenolic compounds,
hut attempts to purify it for identification were unsuc­
cessful.
The aqueous solution, containing the chromium salts,
was made alkaline with 30$ NaOH solution and the chromium
hydroxide removed by filtration.
It was found that the use
of a porous cloth filter and the addition of a water paste
of asbestos fiber to the gelatinous chromium hydroxide,
greatly increased the speed of filtration.
The filter cake
of chromium hydroxide was slurried in boiiing water and again
filtered.
The process was repeated a third time with the
wash water kept alkaline at all times.
The combined filt­
rates, about 25 liters, were evaporated to dryness on the
steam bath.
The dry sodium salts were divided into two
equal parts, one half being set aside for later reference
if necessary.
The other half was acidified with cold 50$
sulfuric acid.
One liter of ethyl alcohol was then added
to precipitate the sodium sulfate, which was then filtered
off.
The filtrate was then distilled at atmospheric pres­
sure in column III until the temperature of the vapor reached
11S°C. at 736 mm.
The residue was then diluted with water
and continuously extracted with ether for two days.
The
ether was then distilled off, leaving a solid residue, v/hich;
upon recrystallization from alcohol gave 26g. of white
crystals, m.p. 150-3°
This material was shown to he
adipic acid since it gave no depression in m.p. with an
authentic, sample of adipic acid, m.p. 152-3°C.
From the
mother liquors l6g. more of adipic acid was obtained^a
total of 42g. from 1/2 the sodium salts or 84g. (Q.5& moles)
from the reaction.
reactedncyclohexene.
This is a yield of 21$ based on the
The material balance on the reaction
may be conveniently tabulated as follows:
Cyolohexene
u s e d ----------------- 410g.---- 5*0 moles
Cyolohexene
recovered------------ lSlg.--- 2.2 moles
A -cyclohexenone------------------- 9 9 g .
1.0 mole
Adipic a c i d ------------------------ 8 4 g . ---- 0.6 mole
Residues--------------------------- 5 4 g. ---- 0.5 mole*
Total-------------------------------------- 4.3 moles
Balance
4*3 x 100 / 5.0
86$
*The molecular weight of the residues was assumed to lie
between that of adipic acid and
^-cyclohexenone.
Several additional oxidations were carried out, but
to avoid needless repetition they will not be discussed in
detail since the method was essentially the same as above.
However, since the amount., of material was altered and the
temperature varied^the results will be given in tabular
form with the changes indicated:
Oxidation
I
Cyolohexene used, gms.
II
III
17
410
1066
800
800
1000
1000
1000
1000
Chromic anhydride, gms.
750
900
900
900
Water, gms..
450
450
450
450
1500
2000
2000
2000
25-30
35-45
35-50
35-45
499
508
Acetic acid, gms.
Acetic acid, gms.
Temperature°C.
Cyolohexene recovered, gms . 181
Cyolohexene oxidized, gms.
,730 .
229
286
301
292
Cyclohexenone, weight, gms .
99
130
114
120
Cyclohexenone, $ yield
37
33.5
32.4
The method of isolation of the
35
A z'-cyclohexenone in
the latter two oxidations was simplified.
Instead of slowly-
distilling the acetic acid, it was neutralized to the extent
of about 70$ with 50$ sodium hydroxide solution.
Actually,
the addition of the caustic solution was stopped when the
oxidation mass had a tendency to become gelatinous, vhich
corresponded to about 70$ neutralization.
After the par­
tial neutralization of the acetic acid the solution was
z
extracted with ether in the usual manner to obtain the A cyclohexenone.
The excess acetic acid seemed to be largely
tied up as the chromium salt, since little of it was obtain1
ed by the ether extration. It was also found that the a cyclohexenone could be fractionated at atmospheric pressure
without decomposition.
It boiled at 166°C. at 734 *nm.
pressure, with an index of refraction n
20
D 1.4879*
25
Oxidation of cyolohexene with chromic anhydride in
t-butyl alcohol.
The apparatus used for this oxidation
was the same as that used for the preceding oxidation, in
which acetic.acid was used as the solvent.
The results
will not be discussed in detail since the reaction was quite
unsatisfactory.
It involved the addition of a solution of
500g. of chromic anhydride in 1000 cc. of t-butyl alcohol,
to 600 g. of cyolohexene in 500 cc. of t-butyl alcohol keep­
ing the temperature at 55-6o°C.
During the reaction a dark
precipitate was formed and the mixture became quite viscous.
Removal of the t-butyl alcohol presented a problem since the
mixture was so thick it could not readily be distilled; dil­
ution with water did not help much.
Although some
A z'-cy-
clohexenone was eventually obtained, the calculation of yield
would be meaningless because of the large amount of loss in
handling and because much of the cyolohexene could not be
separated from the t-butyl alcohol.
Preparation of
1,3-cyclohexadiene. The method used
was that of Hofmann and Damm (22).
In the present work no
attempt was made to purify the intermediates except within
reasonable limits.
In a 3-liter flask equipped with stirrer
and dropping funnel was placed 410 g. (5moles) of cyclohexene.
This was cooled in an ice bath and to it was added a
solution of 800 g. (5 moles) of bromine in 14-00 g. of chlo­
roform over a period of 4- hours.
The chloroform was then dis­
tilled off at atmospheric pressure, the last traces being
sucked off in vacUo at the temperature of the steam bath.
This crude dibromo-cyolohexene was then added to a boil­
ing solution of sodium ethoxide, prepared by dissolving
230 g. (10 moles) of sodium in 2500 cc. of absolute ethyl
alcohol.
The addition of the dibromide took 4.5 minutes
and was accompanied by the evolution of considerable heat.
NaBr was split out during the addition.
The mixture was
allowed to stand on the steam bath over night, boiling
gently.
It was then cooled and the HaBr filtered off.
The
filtrate was distilled from an ordinary distilling flask
until no more alcohol came off.
The pressure was then de­
creased to 140 mm. and the portion boiling between 90-9S°G.
was collected.
To this was added the oil layer obtained by
diluting the alcohol distillate with three volumes of water.
This material, containing cyclohexadiene and ethoxycyclohexene, was distilled at atmospheric pressure over 20 g. of
K2s2°7‘fco split out C2H 5OH from the ethoxycyclohexene.
The
decomposition was carried out in column I over a period of
7 hours, regulating the heating to keep the head temperature
at 70-80°C. The distillate was washed tv/ice with water to
remove the alcohol, dried over CaCl2 and then fractionated
in column I over sodium:
27
Cut
Bath
Boiling Pt.
n20D
Weight
Press.
1
114
57-76°C.
1.4316
---
736 mm.
2
118
76-78
1.4461
---
73 6
3
120
76-79
I.4696
---
736
4
121
79
1.4730
22
736
5
119
79
1.4737
206g.
736
Fractions 4-5, 228 g, (2.8 moles) represent a yield of
56fo of 1,3-cyclohexadiene, based on the cyolohexene used.
Preparation of alpha-chloro-cyolohexene.
This prepa­
ration and the following are essentially the same as those
used by Courtot and Fierron (14).
In a 2-liter flaslc, eq­
uipped with a stirrer and tube for addition of dry HC1, was
placed 220 g. (2.7 moles) of cyclohexadiene.
It was cooled
to -5°0. and dry HQ1 (prepared by the addition of concen­
trated H2SO4 to fICl solution) was added until no more seem­
ed to be absorbed.
The weight of the crude chloro-cyclo-
hexene was 295 g.
This was used in the next step without
purification.
Hydrolysis and oxidation of alpha-chloro-cyclohexene.
The crude material from the above preparation was added to
a solution of 46O g. of
in 36OO cc. of water.
The mixture was heated to 60°C. with rapid agitation and
then 730 g. of concentrated H2SO4 was gradually*added,keep­
ing the temperature at 60-65°C.
took' 3.5 hours.
The addition of the acid
After stirring the solution at room temf-
erature for 24 hours it was extracted with ether, the
ether extracts dried oyer anhydrous sodium sulfate, and
the ether then stripped off and the residue fractionated
in column II:
20^
D
Cut
Bath
Boiling Pt.
1
97
27-66°C.
1.4I4O
--
25 mm.
2
111
66-67
1.479S
2.3
25
3
112
67
1.4865
17.8
25
4
112
67
1.4870
28.0
25
5
124
67
1.4872
88.2
25
Residue
57.0
n
Weight
Fractions 3-5 inclusive, 134 g. (1.4 moles) of
Press.
A*"-cyclo­
hexenone, represent an over-all yield of 28$ hased on the
cyolohexene used.
The residue, a very viscous liquid had
a distinct odor of phenol, hut no attempt was made to
identify it.
lower yield of
Because of the many steps involved and the
A
-cyclohexenone, this method is consid­
ered much less satisfactory than the oxidation method for
preparing
A 2--cyclohexenone.
Preparation of 1-methylcyclohexanol.
To the G-rignard
reagent prepared hy bubbling methyl chloride through 73.2 g.
(3 moles) of magnesium in
600 cc. of dry ether, v/as added a
solution of 245 g. (2.5 moles)
e
of Eastman’s Practical cycl-
ohexanone in 300 cc. of dry ether.
hour-s.
The addition required two
The mixture was decomposed in the usual manner with
iced hydrochloric acid; ether extracted, and the ether
solution dried over anydrous K2CO3.
After distilling the ether, the product was fractionated
3ro
0
u
in column I:
Cut
Bath
Boiling Pt.
1
90
60-65°C.
1.441s
8.2
29 mm.
2
88
65-6 8
1.4530
7.1
29
3
90
68-69
1.4580
4.5
29
4
91
69
1.4590
5.8
29
5
91
69
1.4595
. 8.2
29
6
91
69
1.4598
7.8
29
7
92
69.
I.46OO
194.0
29
Weight
Residue
Press.
6.8
Fractions 3-7 inclusive, 220 g. (1.93 moles) represent a
yield of 77$ of 1-methylcyclohexanol based on the cyclohexanone used.
Dehydration of 1-methylcyolohexanol:
hexene.
1-methylcyclo-
The 1-methylcyclohexanol described in the preced­
ing preparation, 220 g. (1.93 moles) was dehydrated by
heating the material with 0.2 g. of iodine under column I.
The jacket of the column was regulated so that water and
olefin could distil out of the mixture, while retaining
the undehydrated alcohol.
92$ of theory.
The water split out, 32 g. was
The crude 1-methylcyclohexene was dried
over anhydrous KgCO^and then fractionated in column I.
Out
Bath
Boiling Pt.
1
127
9S-105°C.
2
12S
3
n20D
Weight
Press.
1.4476
2 g.
733 mm.
105-107
1.4494
4
733
130
107
1.4496
5
733
4
129
107
1.4498
16
733
5
132
107
1.4500
63
733
6
131
107
1.4501
52'
733
Residue
-
10
Fractions 2-6, 140 g. (I.46 moles) represent a yield of
73$ based on the 1-methylcyclohexanol.
Oxidation of 1-methylcyclohexene.
This oxidation was
carried out in essentially the same manner as the oxidation
of cyolohexene, previously described.
To a solution of
140 g. (1.45 moles) of 1-methybyclohexene in 470 g. of
acetic acid, was added a solution of 230 g. of chromic an­
hydride in 140 g. of water and 470 g. of acetic acid.
The
addition of the oxidizing mixture took nine hours, the tem­
perature being kept between 40-50°C. by controlling the rate
of addition.
The mixture was stirred an additional two
hours^then cooled by the addition of 1 kg. of ice.
It was
then neutralized by the gradual addition of 1100 g. of cold
50# NaOPI solution over a period of 30 minutes with stirring.
The mixture warmed to about 30°C. during the neutralization.
The solution was extracted 8 times with
ether.
500 cc. portions of
As soon as one extraction v/as finished the ether
was distilled off and used over again.
After all of the ether was distilled the residue was
fractionated at atmospheric pressure until the head tem­
perature reached 115°C.
The distillate, after washing with
water to remove any acetic acid, was dried over anhydrous
K2CO3.
This material, 28 g. had an index of refraction
n20p 1.4500, the same as the original olefin, indicating
that 112 g. (1.07 moles) was oxidized.
The residue from
this distillation was fractionated in column I at 14 mm.
pressure:
20
D
Weight
1.3795
10.2
1.3755
6.8
' 23-25
1.3753
4.5
85
25-50
1.3989
0.8
5
86
50-58
1.4290
0.9
6
88
58-67
1.4563
1.3
7
96
67-76
1.4793
1.2
8
98
76
1.4907
3.1
9
97
77
1.4934
4.0
10
97
77
1.4938
4*4
11
98
78
1.4837
6.1
12
101
78
1.4938
6.4
13
108
75-78/ 7 mm.
1.4798
3.4
14
118
85-95/ 7 mm.
1.4803
0.7
Residue
8.6
Gut
Bath
1
50
2
54
3
53
4
Boiling Pt.
20-23°0 .
23
n
32
Fractions £-12, 24 g. (0.22 mole) represent a yield of 20$
of
A
-meth.ylcyclohexenone-3 based on the amount of 1-meth-
ylcyclohexene actually oxidized.
The identity of this ma­
terial was established by comparison of its physical cons­
tants and derivatives with those previously reported.
These
are tabulated below:
B.P./mm
n
20
P
M.P.-S*
M.P. - P.P.*
175-6
Cut # 12
198/73# 1.493#
200-1 D.
Marvel (24)
68-71/3 1.4912
-----
172.5-3
200-2/760 1.493#
-----
---
Rabe (25)
Simonsen (26)
200/760
---
201
---
Vorlander (27)
---
---
199-201 P.
---
*S
Semicarbazone;
P.P.
2,4-dinitrophenylhydrazone.
Fractions 5-7 gave a semicarbazone, m.p. 207-9°C.(P.)
which was different from that of
A 1— methylcyclohexenone
-3, since the mixed m.p. was depressed to 177-#2°«
The
entire material from these suts was therefore converted to
the semicarbazone for purpose of purification.
3.6 g. of
semicarbazone, m.p. 207-9°C.(P.) was obtained.
This was
decomposed to recover the ketone by boiling it with a sol­
ution of 4 g. of oxalic acid in 25 cc. water, and then
steam distilling from this mixture.. The distillate was ex­
tracted with ether, the ether then distilled off and the
residue distilled at 73# hhh. from a small Claisen flask.
Q
The entire quantity boiled at 172-6°C. with an index n P
1.4803.
It was shown to be
^
-methylcyclohexenone-6 by
*
33
comparison of the physical constants and derivatives with
those previously reported.
These are tabulated helow:
MR
M.p.
Oxime °c. Semicarbazone; 0 c
B.P./mm.
n20D
172-6/738
1.4803
61-2
Wallach (28) 178-80/760 I.483I
62-3
207-8 & 211
Urion (15)
62-3
208-10
Guts 5-7
178-9/760
1.4820
207-9 D.
In addition this material formed a dark red 2,4-dinitrophen
ylhydrazone, m.p. 202-3, which has not been reported pre­
viously.
Using the weight of the semicarbazone, 3.6 g.
(0.022 mole)^the yield of
A 1-methylcyclohexenone-6 is 2fo
based on the 1-methylcyclohexene oxidized.
/
SUMMARY
1. The oxidation of cyolohexene with chromic
anhydride yielded 31-3&^ N5$ of
A.2--cyclohexenone.
2. The oxidation of 1-methylcyclohexene yielded
20 fo of
A* -methylcyclohexenone-3
and
2fo
of
A / - m e t h y 1-
cyclohexenone-6.
3. New 2,4-dinitrophenylhydrazones were prepared
for the following:
z
A
M.P.
- c y c l o h e x e n o n e ---------------------1 6 6 - 7
A 1 - m e t h y l c y c l o h e x e n o n e - 6 ------------ 2 0 2 - 3
°C.
BIBLILIOGRAPHY
(1) Whitmore and Co-Workers, I. Jim. Chem. Soo., 56, 1128,
1397, (1934).
(2) Kotz and G-rethe, J. Prakt. Chem. (2), 80, 489 (1909).
(3) Amer. Patent (2,169,368) to Murray and Stevenson
Chemical Abstracts.
(4) Linstead, Annual Reports, Chemical Soc. London 1937*
(5) Seamier, Ber. 40, 3521 (1907).
(6) Schroeter, Ger. Pat. 346948, Zentr. II, 1141 (1922).
(7) Treibs and Schmidt, Ber., 6l, 459 (1928). ,
(8) Miner, PhD. Thesis, The Pennsylvania State College (1940).
(9) Willstaetter and Sonnenfeld, Ber. 46, 2956 (1913).
(10
Kotz and Richter, J. Prakt. Chem. Ill, 373 (1925).
(11
Kriegee, Ann., 461, 263 (1930).
(12
Guillemonat, Ann. Chim., 11, 190 (1939).
(13
Zalkind and Markov, C.A., 31, 3675^ (1934).
(14
Courtot and Pierron, Bull. soc. chim., 45, 286 (1929).
(15
Urion, Compt. rend., 199, 363 (1934).
(16
Dupont, Bull. soc. chim. Belg., 45, 57 (1936), C.A.,
30, 75493 (193 ).
(17
Riley, J.C.S., 901 (1935).
(18
Blumann and Zeitschel, Ber., 46, 1176 (1913).
(19
Wienhaus and Schumm, Ann., 439, 31 (1924).
(20
Dupont, Compt. rend. 196, 1699 (1934); 200, 759 (1935).
36
(21) Schroeter (6 ); Treibs and Schmidt (7).
Hartmann and Seiberth, Helv. Chim. Acta. 15,1390 (1932).
Hook and Susemihl, Ber., 66, 6l (1933).
Nussle and Perkins, Amer. J. Pharm. 107, 29 (1935)•
(22) Hofmann and Damm. Chem. Abstracts, 22, 1249 (1928).
(23) Organic Syntheses, Vol. V. P-33.
(24) Marvel and Levesque, J. Am. Chem. Soc., 60, 280 (193&).
(25) Rabe and Ehrenstein, Ber., 40, 2485 (19
).
(26) Simonsen and Storey, J. Chem. Soc., 95, 2112 (1909)«
(27) Vorlander and Gartner, Ann. 304, 23 (1899)*
(28) Wallach and Eranke, Ann., 329, 373 (19
Wallach, Am., 359, 303 (19
).
)•
I.
STUDIES ON CYCLIC alpha,beta-UNSATURATED KETONES
Part B.
INTRODUCTION
THE ACTION OF GRIGNARD REAGENTS ON
A “CYCLOHEXENONE AND ISOPHORONE
Cyclohexenone, previously obtained only by diffi­
cult syntheses with low yields, was made available in quant­
ity suitable for study by the oxidation of cyolohexene as
described in Part I-A of this thesis.
This, the"
simplest of the alpha,beta unsaturated cyclohexenones,
was well adapted for a study of the relative amounts of 1,
2 and 1,4-addition which might be obtained by the addition
of Grignard reagents.
The results of previous investigators with compounds
containing a highly reactive carbonyl group, indicated that
with the Grignard reagent only 1,2-addition was to be expexted with
A Z-cyclohexenone.
Contrary to expectations,
all of the Grignard reagents used in the present work gave
varying amounts of 1,4-addition along with the 1,2-addition.
During the course of this work, 3,5»5-trimethylcyclohexenone, commonly called isophorone, became commercially
available:
ft
II
3B
•
Because of its relation to
2.
A -cyclohexenone, a study of
its reactivity with Grignard reagents was undertaken.
The
presence of a methyl group in the 3-position, the position
of addition of an alkyl group in event of 1,4-addition, made
isophorone of particular interest for a comparison of the
effect of this group on the relative amounts of 1,4-addition
in the two ketones.
In connection with the identification work, the reduction of
A -cyclohexenone with aluminum isopropoxide was
undertaken.
The corresponding alcohol, A 2"-cyclohexenol
was obtained in 74$ yield:
01*
A j M j ’
O
Ijl
lyj)
Although not directly connected with the preceding work,
an attempt was made to determine whether
A -cyclohexenone
would act as the conjugated carbonyl system in giving a DielsAlder addition of 1,3-cyclohexadiene to the ethylene bond.
There was no appreciable reaction either at room temperature
or at the boiling point of the diene.
HISTOHICMj
In 1903, Kohler (1) studied the action of phenylmagnesium bromide on benzalacetophenone and reported that the
chief product of the reaction was 1,1,3-triphenylpropenol-l,
resulting from normal addition of the Grignard reagent to
the carbonyl group.
Certain anomolous reactions of the com-
t.
pound'caused him to study it further, and the following
year (2) he showed that the compound was not a tertiary
alcohol, but diphenylpropiophenone.
Concerning this unex­
pected reaction he said, "The formation of diphenylpropio­
phenone from benzalacetophenone illustrates a new kind of
reaction of organic magnesium compounds."
Since the publication of this paper there have been
numerous examples of the formation of saturated ketones by
the addition of alpha,beta-unsaturated ketones to Grignard
reagents; in fact, for over thirty years the researches of
Kohler were continued in this field.
The phenomenon of 1,4-addition to conjugated systems
of double linkages has been one of the most widely studied
reactiorffe of unsaturated compounds since Thiele (3) first
drew attention to the peculiarities of such compounds.
Kohler (4) presented positive proof that the formation of
saturated ketones by the addition of alpha,beta unsaturated
ketones to Grignard reagents proceeds through 1,4“addition.
He was able to isolate and identify the intermediate enolic
1,4-addition products in several cases; the action of phenylmagnesium bromide on benzaldesoxybenzoin being one example:
*
(■c6^X-^i^h(c0hs)coc(>hs-
u
* (Ms^CHCOC^Hj +C 6HjCooH
m
JZ
X
The anol I was sufficiently stable for isolation, and
Kohler was able to convert it to the saturated ketone II,
analogous to the products obtained from similar reactions
where the enol form is unstable.
He established the
structure of the enol by its oxidation to III and the de­
composition of the latter to the known compounds IV and V.
Recently Kohler (5) has shown that his earlier proof
of 1,^-addition (6) based on replacement of -MgBr in the
addition product, by benzoylation, is no longer valid.
He
found that the product of this reaction is not the expected
benzoate II, but a diketone I:
rtyCH = C H C O C b tfr
This is analogous to the formation of a new 0-0 linkage by
the action of the sodium enolate of acetoacetic ester and
an alkyl halide:
«
41
oMv
GH3 C = GH-COOE.t
+R.X
*
C
C
=
c
-
C O o £ t
GH3 o t c tf-Cooz-t-
k
Since the present work involves the action of Grignard
reagents on cyclic alpha,beta-unsaturated ketones, further
references to the literature will he limited, for the most
part, to studies involving such ketones.
Grignard (8), the first investigator in this field,
added pulegone to methyl magnesium iodide and obtained a
hydrocarbon, apparently formed by the loss of water from
the expected tertiary alcohol I.
Rupe, Schobel and Abegg
(9) repeated this reaction and, in addition to the 1,2
addition product, found a saturated ketone which they
assumed to have been formed by 3»4-addition of the Grig­
nard reagent to the C-C double bond.
They thought it might
have been a mixture so assigned to it the two possible
structures II and III:
/\
Pulegone
Ctfj
I
II
III
Zelinski (10) obtained a patent on the preparation
of ketones by the action of Grignard reagents such as
benzyl- and alpha-naphthylmagnesiurn bromides on cyclic
alpha,beta-unsaturated ketones.
Examples of the products
mentioned are benzyldihydrocarvone IV, alpha-naphthyldihydrocarvone V, and benzyldihydropulegone VI:
In IV,R
Benzyl-
In V, R
alpha-
NaphthylCarvone
IV and V
R
II
/\
•Pulegone
Benzyl-
VI
Later Rupe and Tomi (11) also obtained benzyldihydro­
carvone IV by the action of benzylmagnesium chloride on
carvone.
Recent work by Doeuvre (12) has shown that pulegone
with isoamymagnesium bromide gives both 1,2- and 1,4addition products in the proportion 2:3 respectively:
bo»YnylM<fBY
—
o
,
i t .
j
I
^
'
M o
Utf&my,
I
Kohler (13) studied the action of phenylmagnesium bromide
on dibenzalmethyloyolohexanone •£, and obtained ultlmatelyf a
IE
saturated ketone^which he was able to show was formed by 1,4
additions
o
V ^ 11*5
({>M<,
^
o
+■
o
<f>icwT j tH k
m
The latter examples, sinoe a semicyclic double bond is
.2,
involved, are not strictly analogous to
^ -cyclohexenone,
where a oyclic double bond is involved.
£he first study of
the action of Grignard reagents on compounds of the latter
type was undertaken by Bamberger and Blangley (14) who found
that toluqulnone and xyloquinone gave quinoles by addition to
the oarbonyl group:
II
ft. oil
ft
I J cf<3
I
cxt f\
of# r\
Toluqulnone
Ctf3“
Xyloquinone
44
A short time later Auwers (15) found that the alpha,betaunsaturated ketones, obtained by condensing chloroform with
phenols, gave only 1,2 addition products with Grignard
reagents:
Kohler (12) stated that 1,4 addition would not be expect­
ed with the simplest compounds of this type unless the reacti­
vity of the carbonyl group were
the alpha position.
diminished by substitution in
Kohler selected carvone to test this theory
Before his work was completed, Bupe and Liechtenhan (16) pub­
lished the results of. their work on the addition of carvone to
methylmagnesium iodide and obtained both a tertiary aloohol and
a saturated ketone.
This was confirmed by fbohler*s work.
^
_
*
Bupe and Liechtenhan assumed that the ketone was formed by 3,4addltlon of the Grignard reagent to the double bond.
Kohler,
because of his previous work with open chain compounds stated
that this was an example of 1,4-addition, and was able to show
by analogy that this was the case.
With diphenyloyclohexenone
I, the products, which were solids, were better adapted for
isolation and study:
*
The products when isolated in the usual manner, consisted of
about 80J& of unsaturated tertiary alcohol II, the remainder a
saturated ketone III*
If the magnesium complex IV were care­
fully decomposed and the ether solution evaporated in a
current of oxygen, the tertiary alcohol II and the enol-peroxide V were obtained.
At the same time Kohler reported that
he found only the 1,2-addition product from the aotion of
2,
phenylmagnesium bromide on 3,5 dimethyl- A
— cyclohexenone.
Auwers (17) studied the aotion of methyl, ethyl and lsopropyl
Grignard reagents on the same ketone and detected only the 1,
2-addition product:
R - Methyl-, Ethyl-, isopropyl-, and Phenyl-*
Sammler, Jonas and Oelsner (18) obtained isoamyldihydrooarvone, II the 1,4-addition product, by the action of isoamylmagnesium iodide on carvone Is
In addition to those previously mentioned, there have been
several additional investigations of the action of Grignard
reagents on cyclic alpha,beta-unsaturated ketones, but in all
oases the tertiary alcohols or their dehydration products were
obtained, with few if any attempts
than that formed by 1,2-addition.
pyl -
to detect any product other
Wallach (19) added 4 isopro­
-cyclohexenone to methylmagnesium iodide and detected
only the 1,2-addition product:
Similar results were obtained by Bupe and Bmnerich (20)
with oarvenone:
Mazurewitsch (21) obtained yields varying from 91.2-99.2
per cent of the tertiary alcohols by the action of allylmagneslum bromide on 3,5-dimethyl- A 2 -Oyclohexenone and the' <sorresponding compounds in which the 5-methyl group was replaced
by ethyl-, propyl-, isopropyl- and isobutyl-groups:
o
alt
a-t=ctiz
B ^ methyl-, ethyl-, propyl-, isopropyl- and isobutyl
Finally, Wallach (22) obtained only the 1,2-addition pro­
duct by the aotion of methylmagnesium iodide on 3-isppropyl—
A
A
-cyclopentenone
o
\i
Considerable work on the addition of Grignard reagents
to benzoquinone and its derivatives has been described.
The many possibilities for reaction always result in the for­
mation of a complex mixture of products.
With the Grignard
reagent, mono- and di- 1,2- and 1,4-addition products, hydroquinone, bimolecular reduction products and others are
possible products of the reaction.
With xyloquinone and
methylmagnesium iodide, Bamberger and Blangey (23) of. ref
(14), obtained substances corresponding to most of these:
I, II and IV result from 1,2-addition, III and V from 1,4addition and VII, from reduction.
48
Smith and Crawford (84) gave a complete review of
literature on this subjeot up until 1928,
the
These workers, to
avoid side reactions involving the hydrogen atoms present in
benzoquinone, used duroquinone, tetramethylbenzoquinone, in
their studies*
With phenylmagnesium bromide, the products
which were identified^ accounted for only about
starting material, the remainder being a
ture.
of the
complex oily mix­
The results were similar to those of Bamberger and
ELangey above:
Worrall and Cohen (85) studied the action of diphenylmagnesium bromide on benzoquinone and obtained chiefly dibi­
phenyl, the condensation product of the Grignard reagent;
and hydroquinone, the reduction product of benzoquinone*
With polynuclear ketones both 1,2 and 1 ,4-addition has
been observed*
Allen and Overbaugh (26) obtained 4-substi-
tuted benzanthrones II by the aotion of phenyl, benzyl,
oyclohexyl
n-heptylmagnesium halides on benzanthrone I,
but with t-butylmagnesium chloride a carbinol III, was
obtained:
49
OU cCc-i+i)3
R — Phenyl-, benzyl-, cyclohexyl-, and n-heptyl.
Later the same workers (27) obtained similar results wLth
phenylbenzanthrone:
oh c,Ccib)3
R - Ethyl-, n-butyl-, n-hexyl-, benzyl-, phenyl-,
oyolohexyl-, beta styryl- and beta phenylethyl-.
They do not claim to have excluded the possibility of
simultaneous 1,2- and 1,4-addltion, since the yields in all
cases were low, a large amount of tarry material being for­
med, which m a y have Included the missing products.
Recently Allen and Gilman (28) have shown that najithacenequinone I adds phenylmagnesium bromide in the 1,4position.
The product XI, a tetrahydroaromatio derivative,
was isolated:
o » .UFT
I
*
50
A search of the literature reveals that
A*"-oyolohexe-
none reacts with some reagents giving 1 ,4-addition products,
with others, giving the expected reactions of a ketone modi­
fied in some cases by the presence of the double bond.
Until the present work the action of Grignard reagents on
this oompound has not been studied.
reactions of
A
The following are the
-oyclohexenone whioh have been previously
described:
Kotz and Grethe (29) found that
with 1 mol of hydroxylamine.
^
-cyclohexenone reacted
EC1 to give a normal oxime
which on heating with aoetio anhydride and subsequent treat­
ment with sodium hydroxide gave aniline.
iNltj.OH-<hci
With 2 mols of the hydroxylamine. KOI, one mol is added to
the C to C double bond of the normal oxime.
This compound,
on oxidation with merourlc oxide is converted to the dioxime
of 1 ,3-cyclohexanedione; on reduction with sodium in alcohol,
1,3-diaminocyelohexane is obtained.
EHOH-
In dry ether HOI added 1,4 to give 3-ohlorooyclohexanone
Hu
"=C
E -t, 0
An attempt to produce 6-carboxy-
A
-cyclohexenone by the
addition of carbon dioxide to a mixture of metallic sodium
and
A z-cyclohexenone was unsuccessful.
Ethyl oxalate in the presence of sodium ethoxide condensed
with
C-5.
A 2--cyclohexenone the condensation taking place on
This was shown by the following reactions:
(lOOEt^
CO o£f
COCOOE+
l\fa o £ - t
A -w
s
j
coo&t
PCOO&
too Ci
tH jO lf
C60E+
A r
A■CH3
6lf3
(I 1>cooEf
KOIH ^
V'
On condensing
A^-oyclohexenone with benzaldehyde an oily
2.
material was produced which was thought to be 6- b e n z a l - A -cyclohexenone.
%
Kotz and Richter (30), treated cyclohexenone with ROCl
and obtained 2-Cl-3-0H-cyelohexanone, which, on treating with
acetic anhydride, was dehydrated
to 2-C1—
— cyclohexenone
On catalytic redaction it was converted to cyclohexenone:
o
o
An attempt to make its oxide by the addition of HgOgin
methyl alcohol caused It to resinify.
Treibs (31), found that
^-cyclohexenone absorbed
oxygen very slowly in alkaline solution.
Guillemonat
(32) determined the Ramen spectrum of A
-cyclohexenone^ which indicated the presence of conjugated
double bonds.
Kotz and Grethe
(29) found that
A^-cyclohexenone added
one mole of bromine giving 2 ,5-Br2-oyclohexanone,
illy lost 2HBr giving phenol:
which read
53
DISCUSSION
Early in his work on the addition of Grignard reagents
to alpha,beta-unsaturated ketones, Eohler (4) stated that he
believed the simpler eyclie alpha,beta-unsaturated ketones,
beoause of their highly reactive carbonyl group, would give
only 1 ,2-addition unless the reactivity of
the group were
diminished by substitution in the alpha-positlon.
His own
work and that of other investigators appeared to verify this.
Consequently,
-cyclohexenone would be predicted to give
only 1 ,2-additlon with Grignard reagents.
Contrary to expectations, the present work has shown that
1,4-addition is obtained with all of the Grignard reagents used.
With methyl, ethyl and isopropyl Grignard reagents, 1,2-addit­
ion was obtained.
Reduotlon was observed only with the iso­
propyl Grignard reagent.
The various products of the reaction
are illustrated as follows:
o if
The results with the individual Grignard reagents are
tabulated in the following table:
Grignard
Rnagent
1,2addition
1,4addition
CHsMgBr ----- 38 35 --CHgCHgMgBr -
52 % ---
(CH^gCHMgCl- 10
(GH3)3<3MgCl
?
Reduction
14.6 35 ---
0
----
---
0
---- -
24
—
44 fo---
---
70 $ ---
Complex
Products
13 35
12 35 --0
----
It will be noted that the relative amounts of 1,2- and
1 ,4 -addition vary considerably with the reagent.
With iso­
propyl and t-butyl Grignard reagents the amount, of 1,4-addition
exceeds that of 1 ,2-addition, in fact, with the latter the
amount of 1 ,2-addition was so small that there is seme ques­
tion as to its presence.
That t-butylmagnesium chloride
favors 1 ,4 -addition has reoently been shown by the work of
Stevens (33), who found that with crotonic aldehyde, this re­
agent gave much better yields of the 1 ,4-addition product than
any of the other reagents except t-amylmagnesium ohloride which
gave slightly better yields.
With ethylidene aoetone the re­
sults were similar but not as pronounced.
Lack of sufficient time prevented the positive identi­
fication of the products of the action of Grignard reagents
on isopHorone However, tertiary alcohols were obtained with
both methyl and ethyl Grignard reagents in 83 and 80 $
yields respectively.
There was no indication of the forma­
tion of a saturated ketone by 1,4-addition of these rea­
gents.
The formation of the tertiary alcohols was undoubted-
ly the result of 1,2-addition of the Grignard reagents on
the carbonyl group of the isophorone:
o
u
ft oH-
With the isopropyl Grignard reagent, a saturated
ketone was formed in *T,6<£yield.
This can be aodounted for
only by the assumption that 1,4-addition occurred during
the reaction:
o
li
o
ll
The carbinol portion of the products from this reaction
were hot thoroughly examined and no definite conclusions
as to its composition were reached.
It is probable that
it is largely the tertiary alcohol from 1,2-addition with,
perhaps, some of the reduction product.
The results of the work with the isophorone are,
however, sufficiently clear to indicate that the methyl
group in the 3-position hinders 1,4-addition in some man­
ner, since with
A^-cyclohexenone, all of the Grignard
reagents added 1,4*
EXPERIMENTAL
DESCRIPTION OF FRACTIONATING COLUMNS
During this work, four fractionating columns of the
adiahatic, variable take-off type were used.
These will
be referred to as columns I, II and III.
Column I
Inside diameter----------------------- 1.2 cm.
H.E.T.P.
------------------------- 5.0 cm.
Length------------------------------Theoretical Plates-------------
75 cm.
15
Packed with 3/16 inch glass helices.
Column II
Inside diameter
0.7 cm.
H.E.T.P. ----------------------------- 3.1 cm.
Length------------------------------- 43*0 cm.
Theoretical Plates------------------- 14.0
Packed with 3/16 inch fine drawn glass triangles
Column III
Inside diameter
—
H.E.T.P.
Length
Theoretical Plates -----------------Packed with 3/16 inch glass helices.
1*7 cm.
6.3 cm.
1°°
16
om*
EXPERIMENTAL
PREPARATION OP STARTING MATERIALS
Introduction.
The reagent common to many of the
reactions in this and the following problems, is the
Grignard rea&ent.
Por the sake of economy of space,
the preparation of a representative Grignard reagent,
ethylmagnesium bromide, will be described in detail.
The preparation of the additional reagents used, involve
essentially the same procedure.
Preparation of alkyl bromides.
The ethyl, isopropyl
and n-butyl bromides used in this work were prepared by
the aotion of a sulfuric acid-hydrobromic acid mixture on
the corresponding alcohol.
The method is described in
detail in Organic Syntheses, Collective Vol. I, P-30.
constants of the bromides obtained by this method are:
Bromide
Boiling Point
Ethyl
-____
Isopropyl
—————
n-Butyl
Isobutyl
36°/730 mm.
58/736 mm.
n
-----
20
D
1.4240
1.4250
100/728
1.4395
90/738
1.4363
The methyl bromide used in this work was obtained
from the Dow Chemical Co.
The
Preparation of ethylmagnesium bromide.
Into a
three liter, three necked flask equipped with a mercury
sealed stirrer, dropping funnel and reflux condenser was
placed 121 g.
(5 moles) of magnesium turnings.
was added 5 c.c. of a solution of545 g.
To this
(5 moles) of
ethyl bromide dissolved in 400 c.c. of anhydrous ether.
The reaction started almost immediately as evidenced by
refluxing in the condenser.
After the initial reaction
had proceeded for five minutes, 600 c.c. of dry ether was
added to the mixture, and the ether-halide solution added
dropwise over a period of about three hours.
The mixture
was rapidly agitated during the addition.
This procedure is applicable to the preparation of
all Grignard reagents used in
this work.
PART H
EXPERIMENTAL
Preparation of—
^
-Cyclohexenone.
The preparation of
2.
^
— cyclohexenone has been thoroughly described in Part I
of this thesis, P — 19 , it is, therefore, unnecessary to re­
peat it in this section.
However, for convenience the phy­
sical constants are tabulated below:
B.P. 166 <3 734 mm.
Addition of
^
n20D 1.4879.
D S00.9962
-cyclohexenone to methylmapaiesiuni bromide.
The Grignard reagent prepared by bubbling methyl bromide
through 2 4 .3g.
(1 mole) of magnesium in 300 co. of dry ether
was cooled to -5°C. and to it was added a
(0.5 mole) of
solution of 48 g.
-oyclohexenone in 300 cc. of dry ether,
with rapid stirring.
The temperature was kept below 0°C.
during the addition, which required 1.5 hours.
After standing
at room temperature for 12 hours it was decomposed by pouring
into a mixture of 1 kg. ioe and 250 jg. NH^Ol.
It was then
ether extracted and the ethei/solution dried over anhydrous
KgCOg.
The ether was s t r i p p e d” through a 50 om. Vigreux
column and the residue remaining was then treated with 300 oc.
of saturated NaHS03 solution causing the formation, in a few
minutes, of a white, solid bisulfite addition product.
The
addition product was separated by filtration through a Buchner
funnel, the filter cake washed thoroughly with ether and the
filtrate extracted with ether to remove the non-ketone portion
of the products.
After drying the ether solution over K 2C03
the ether was stripped off as before.
A small sample of this
residue was again treated with the NaHS03 .solution with no
more addition product being formed.
Without further treat­
ment it was fractionated.
ffraotdonation of the oarblnol from the methylTnQflnaginm bromlde :?■ A
— cyclohexenone reaction.
tionated
in column II.
This material was frac­
About 0.5 g. of K2CO3 was added to
inhibit dehydration of the oarbinol.
20n
D
Cut
Bath Temp.
1
118
60-63°C.
1.4661
1.7 g.
20 mm.
2
123
63-64
1.4732
5.0
20
3
125
64
1.4737
5.3
20
4
128
64
1.4740
6.7
20
5
132
64-65
1.4750
4.3
20
6
130
65-75
1.4823
1.3
20
7
131
75-80
1.4848
2.0
20
8
136
1.4868
2.3
20
Residue
8.5
Boiling Pt
80
n
Weight
Press.
Cuts 2-5 inclusive, show active unsaturation, indicated by
the ease with which they absorb bromine in carbon tetrachloride
and decolorize cold dilute potassium permanganate solution.
Attempts to prepare a phenylurethane result only in dehydra­
tion of the material by the phenyl isocyanate even at room
temperature. The method of preparation of this compound in­
dicates that it is probably 1 -methyl— ^ — -oyclohexenol
resulting from normal addition of the Grignard reagent on the
oarbonyl group of
-oyolohexenone.
The reactions of this
material described later and the calculation of molecular refraction confirm this.
Density!
D 20
The density was determined on cut #3 .
4.501 x .9982 / 4.724
Moleoular Refraction observed:
The yield based on the
0.9512.
33.13, calculated: 3 3 .3 9 .
A 2"-oyolohexenone is 38 %
Cuts 6-8 inclusive are unsaturated but appear to be of
a complex nature and could not be identified.
The residue
was of a resinous nature and probably resulted from conden­
sation of the
AS-oyolohexenone.
Calculated as
such the
yield is 18 %.
£
Dehydration of 1-methvl-— ^ ^-ovolohexenol.
Fractions
2-5 inclusive, from the preceding fractionation were combin­
ed and 15 g. of this material was dehydrated by distilling
it at atmospheric pressure in the presence of 0.1 g. of anhy­
drous CUSO4 .
theory.
The water split out was 2.3 g. or 95 ^ of
The oil layer, 10 g., was dried over anhydrous 1^ 003,
then fractionated in column II:
Cut
Bath
Boiling Pt.
n 20D
Weight 1
Press.
1
131
105.5-106.5°C.
1.4784
1.1
738 m m
2
133
106.5-106.8
1.4793
1.5
738
3
134
106.8-107.0
1.4798
2.3
738
4
132
107.0-107.1
1.4806
2.4
738
5
136
107.1-107.3
1.4811
0.8
738
Residue
1.4
That this material is
A
“1,5-meth.ylcycloh.exadiene, is in­
dicated by the following facts: 1) its oxidation to succinic
acid, 2) its reaction with maleic anhydride giving a cryst­
alline product, indicating the presence of conjugated double
bonds*
Oxidation of_ A » l , 5 -methylovolohexadlene*
6 g. of KMn(>4 in 120 cc. of water 2 g. of
In a solution of
out #3 of the
preceding fractionation, was refluxed for 20 minutes.
M11O2
The
was then removed by filtration and the filtrate evapo­
rated to dryness on the steam bath*
Thfe residue was
then
dissolved in 10 00 • of water and acidified with concentrated
HC1 solution, then extracted 10 times with ether.
After dis­
tilling off the ether, 0*6 g. of crystalline residue remained,
which after 3 crystallizations from water, melted at 188-9°G.
and gave no depression with an authentic sample of sucoinic
acid*
There was no indication of pyruvic acid in the
tion produots.
oxida­
As there was considerable evolution of C0g dur­
ing the acidification, it seems probable that any pyruvic aoid
formed was oxidized further to carbonic acid*
A - 1 .5-methvlevclohexadiene - maleic anhydride adduct.
To a solution of 1 g. of maleic anhydride in 3 oc. of thiophene free benzene was added 1 g. of
diene.
A
-1,5-methylcyclohexa-
A yellow color was immediately produced and the temper­
ature rose from 28-56°C.
in about 15 minutes.
The solution
was then poured on a watch glass and the benzene slowly evapo­
rated*
Upon standing over night the residue partially
62
crystallized; the crystals,-were sucked dry on a sintered glass
funnel'and then recrystallized four times from an ether-petroleum ether mixture giving a constant m.p. of 65-6°C. That
this was not unchanged maleic anhydride, was shown by mixing
the two with the immediate formation of an oil at room tem­
perature.
5-methylovolohexanone from the methYTmaflnftatum bromide - A 2mPTolohexenone reaction.
ribed
The NaHSOg - addition produot desc­
on P-J"? was decomposed, to recover the ketone, by add­
ing it to a solution of 100 g. of N a 2C03 in 300 oo. of water
and steam distilling from this mixture.
The distillate cont­
aining the ketone was ether extracted, the ether solution
dried over anhydrous K2CO3 , and after distilling the ether, the
material was fractionated in column I:
Cut
Bath
Bolling Pt.
nSOD
Weight
Press.
1
199
163°C.
1.4456
1.8
730 m m
2
203
163
1.4459
2.1
730
3
207
163
1.4459
2.3
730
4
210
163
1.4459
1.8
730
Residue
2.3
All cuts appeared to be saturated since they absorbed bromine
in carbon tetrachloride only very slowly,
orize aqueous KMn04 solution.
readily:
and did not decol­
Derivatives were formed very
Semicarbazone, m.p. 157-8°C., 2,4 dinitrophenyl-
hydrazone, m.p. 157-8°C. The oonstants for this material are
in agreement with those of Signaigo and Cramer (34) who give
63
the following data for inactive 3-methylcyolohexanones b.p.
168.6-168.9° (corr.), n
1*4463, Semloarbazone m.p. 182*
f a c t i o n s 1-4 inclusive, 8 g.; M m
(.072 mole) represent a
yield of 14.4 ft of 3-methylcyclohexanone, the result of 1 ,
4-addition of the Grignard reagent to the
A 2"-cyclohexe­
none •
Addition of
A -cyclohexenone to ethylmagnftslum bromide.
The Grignard reagent was prepared by the addition of 109 g.
(1 mole) of ethyl bromide (B.P. 37.5 @ 732 mm., n20D 1.4235)
to 24.3 g.
(l mole) of magnesium in 300 cc. of dry ether over
a period of 2.5 hours.
It was then cooled to -5°C. and to
it was added a solution of 48 g.
xenone
(0.5 mole) of
A^-cyclohe-
in 200 cc. of dry ether over a period of 2 hours
keeping the temperature below 0°C. during the addition.
After standing 9 hours at room temperature it was decomposed
by pouring on 1 kg. of crushed ice and 250 g. of MH4 CI, then
ether extraoted, the ether solution dried over anhydrous
K2C03 , and the ether "stripped” off through a 50 cm. Vigreux
column.
The residue was then shaken with 300 co. of saturat­
ed NaHS03 solution, with the foxmation of the addition com­
pound, crystallizing in shiny white plates. It was filtered,
the filter cake and filtrate extracted with ether and the
ether again "stripped" off.
Another treatment with 200 cc.
of saturated NaHS03 gave an additional crop of crystals.
After filtering and ether extracting as before;the ether sol­
ution was dried over K 2CO3 , the ether removed, and the residue
(a gwiftii sample gave no precipitate with NaHS03 solution)
fractionated, with about 0.5 g. of K 2C03 added to inhibit de­
hydration of any carbinol present.
Fractionation of the carbinol portion from the ethylmagnesium bromide-—
cyclohexenone reaction.
Column II, Pressure 20 mm.
Cut
Bath
Jacket
Boiling Pt.
n20D
Weight
R.R.
1
90
71
25-68°0.
1.4610
00.6
8:1
2
110
82
68-74
1.4749
0.8
8:1
3
110
81
74
1.4770
4.0
8:1
4
■ 112
82
74
1.4772
5.1
8:1
5
111
82
74
1.4768
7.6
8:1
6
113
83
74
1.4765
10.1
8:1
7
119
85
74-75
1.4759
6.3
8:1
8
124
86
75-76
1.4752
3.0
8:1
Residue
6.3
As in the reaction with MeMgBr the resinous residue appeared
to be condensation products of the starting material.
ated as such the yield is 13 %•
Calcul­
Cuti 3-7 inclusive, were
fairly uniform as indicated by boiling point and refractive
index.
Tests on cut #5 indicate that it is unsaturated since
it quickly added bromine in carbon tetrachloride and decolor­
ized oold dilute Kmn04 solution.
product,
A^-cyclohexenol
This is not the reduction
(B.P. 74*6*^ 25 mm., n
20
D 1.4861)
is shown by the fact that attempts to prepare a phenylurethane
result in dehydration of the material even at room temperature,
whereas the reduotion product is not dehydrated even with
strong heating, but gives an easily crystallized phenylure­
thane.
Its method of preparation and ease with whioh it
is dehydrated indioate that it is 1-ethyl-
cyclohexe-
nol resulting from normal addition of the Grignard reagent
to the carbonyl group of the
Density:
D 20
14.11 x .9985
14.92
/^-cyclohexenone.
0.9439
Molecular Refraction observed: 37.76; calculated: 38.01.
Dehydration of 1-ethvl — A^-evclohexenol.
Cuts 3-7 inc
luslve, from the preceding fractionation were combined, and
25.2 g. (0.2 mole) of this material was dehydrated by distil
ling it at atmospheric pressure in the presence of 0.2 g.
of anhydrous copper sulfate. 3.5 g. of water, 97 % of the
theory, was obtained.
The oil layer was dried over anhydrous
KgCOs and then fractionated over 0.5 g. of KgCOg in column
II at 728 mm. Pressure.
Cut
Bath
Jacket
Head
n20D
Weight
r .b
1
166
130
120-134
1.4648
1.2
9:1
2
169
135
134-136
1.4785
2.8
9:1
3
172
138
136-137
1.4869
2.6
10:1
4
170
138
137
1.4908
4.0
10:1
5
172
139
137-138
1.4992
4.3
10:1
Residue
3.5
.
It was evident, from the wide range in B.P. and index of re
fraotion, that the above material was very impure.
Since
its odor was similar to that of ethyl benzene, it seemed
66
possible that some of tbis m a y have been formed by dehydro­
genation of the expected diene.
However, attempts to obtain
benzoic acid by oxidation of outs 1,3 & 5 with KM11O4 solut­
ion,
in all oasesjgave only small
amounts of suooinic aoldj
with some oil which could not be identified.
The succinic
acid was identified by means of a mixed M.P. with an authen­
tic sample with which it gave no depression.
All fractions
from the preceding fractionation reacted with maleic anhy­
dride in thiophene free benzene, with the evolution of heat
and the formation of a yellow color.
However, in no case
was it possible to obtain a crystalline product after evapor­
ation of the benzene, only a mixture of oil and a rubber like
material being produced.
The formation of suooinic acid as
an oxidation product and the reaction with maleic anhydride
(showing conjugated double bonds) indicate that at least a
part of the material is the expected dehydration product,A1 ,5-ethylcyclohexadiene.
3-ethylcycloheyanone from the ETMgBr—
one reaction.
— ovclohexen-
The NaHS03 addition product described on P-&3
was decomposed to recover the ketone by adding it to a solut
ion of 100 g. of Na2C05 in 300 cc. of water and steam distil
ling from this mixture.
The distillate containing the ketone
was ether extracted, the ether solution dried over anhydrous
K 2C03 and after distilling off the ether, the material was
fractionated in
column II at 18 mm.
67
20«
D
Cut
Bath
Jacket
Head
n
1
111
84
73-76
1.4523
1.2
9:1
2
113
82
76
1.4518
3.4
9:1
3
112
82
76
1.4518
2.9
9:1
4
113
83
76
1.4518
3.8
9:1
5
115
84
76
1.4518
3.9
9:1
Residue
2.3
Weight
R.R
This material was apparently saturated, since it absorbed
bromine in carbon tetrachloride only very slowly and did
not decolorize dilute KM11O4 solution.
Derivatives of out
#3 were prepared and these are compared below, along with
the physical constants, with those of 3-ethyl cyclohexenone
prepared by Braun, Mannes and Beuter,
(35).
B.M. & R.
Cut #3
B . P . -------------------------------- 192-4
190 ® 732 mm.
n20D --------------------------------
1.4518
1.4543
Se m i c a r b a z o n e ------- — ---- ------- - 184
182-3
p-nltrophenylhydrazone — — — ------
129-30
130
2,4 dinitrophenylhydrazone -------- —
Guts 1-5 inclusive, 15.2 g.
146-7
(0.12 mole) represent a yield of
24 ft of 3-ethyl cyclohexenone resulting from 1,4-addition of
the Grignard reagent to
■Addition of
A ^ -cyclohexenone•
A^-cvolohexenone to lsopropylmagneslum
The Grignard reagent was prepared by the addition
of 78 g.
(1 mole) of isopropyl
of dry ether, to 24.3 g.
chloride, dissolved in 100 cc.
(1 mole) of magnesium in 300 0 0 . of
dry ether, over a period of three hours.
To this reagent,
oooled to -5°C., was added a solution of 48 g. (0.5
of
mole)
^ - oyolohexenone in 200 cc. of dry ether over a period
of 2 hours keeping the temperature below 0°G. during the
addition.
After standing 12 hours at room temperature it
was decomposed by pouring on 1 kg. of crushed ice and 250 g.
of NH^Cl, then ether extracted, the ether solution "stripped”
off, and the residue shaken with 300 oc. of saturated NaHS03
solution, preoipitating the addition product.
This was fil­
tered off, the filtrate and filter cake ether extracted, the
ether again stripped off and the residue again treated with
NaHSOg solution as before.
After the second treatment with
NaHS03 the residue after "stripping" off the ether gave no
further precipitate when a small sample was treated with
NaHS03 solution.
The residue was then fractionated, after
adding 0.5 g. of K2CO3 to inhibit dehydration of carbinols
which might be present.
Fractionation of carblnol portion from the isopropylr
magnesium chlorideColumn:
II
Pressure:
-oyolohexenone reaction.
13 mm.
Weight
R.R.
Cut
Bath
Jacket
Head
n20D
1
104
80
64-65
1.4852
2.6
10:1
2
107
82
65-66
1.4858
3.1
10:1
3
107
89
66-67
1.4853
2.2
10:1
4
108
90
67-72
1.4821
2.3
10:1
5
114
92
72
1.4788
2.7
10:1
20
D
Cut
Bath
Jaoket
Head
6
115
98
72-73
1.4785
1.8
10:1
7
118
101
73-74
1.4780
2.1
10:1
Besidue
7.5
n
Weight
R.R
The residue was calculated as condensation products in 15.5#
yield.
—
rPyplPfrgzeflfll?
propyl MgOl-
Tbe_reduction product from the iso-
^- o y o l o h e x e n one reaction.
Cuts # 1-3 inclusive, were shown to be
reduotion product of
Af'-cyclohexenone•
A^-oyclohexenol, the
This was proved by
the preparation of a phenylurethane, M.P. 105-6, which gave
no depression in M.P. with an authentic sample of the same M.P.
The yield of reduction product, cuts 1-3, 7.9 g. (0.06 mole)
was 12 #•
The tertiary alcohol from the isopropvl MgClhexenone reaction.
A^-oyoio-
Cuts 5-7 were probably 1-isopropyl— A 1-—
oyolohexenol, but insufficient material made positive identi­
fication impossible.
They were unsaturated, as shown by the
ease with which they added bromine in carbon tetrachloride,
and decolorized KMnO^. solution.
Attempts to prepare a pheny­
lurethane resulted in their dehydration, and the formation of
diphenylurea.
Calculated as 1-iaopropyl - /A2-cyolohexenol the
yield id 6.6 g. (0.05 mole) or 10
-
5-isopropvlcvoloheyanone from the isppropyl MgCl-—
oyolohexenone reaction*
The NaHSO^ addition compound describ­
ed on P — 62 was decomposed to recover the ketone by adding it
to a solution of 100 g. NagCO^ in 300 co. of water qnfl
steam distilling from this mixture.
The distillate was
then extracted with ether and the ether solution dried
over anhydrous K 2003 and the ether "stripped" off and the
residue fractionated in column XX at 736 mm, pressure.
Cut
Bath
Jacket
Head
n20D
1
258
221
204*5
1.4562
3.8
8 :1
2
262
218
205
1.4563
7.8
8 :1
3
261
215
205
1.4563
8 .2
8 :1
4
263
215
205
1.4563
6.3
8 :1
5
268
215
205
1.4563
4* 9
8 :1
Residue
1 .8
Weight
R.R
This material decolorized bromide in carbon tetrachloride
very slowly and did not decolorize dilute KMnO^ solution.
Its odor was similar to that of the 3-me- and 3-ethylcyclohexanones.
Derivatives of cut # 3 were prepared;
Semicarbazone M.P. 189-90, and 2,4 dinitrophenylhydrazone,
M.P. 139 -4 0 .
Crossley and Pratt, (3 6 ) prepared 3-isopro-
pylcyclohexanone, b.p# 208°C., Semicarbazone m.p. 186-7•
The material obtained in the present work is undoubtedly
identical with that of Crossley and Pratt.
The yield, cuts
1-5, 31 g. (0 .2 2 mole) is 44 9&.
Addition of A-oyolohexenone to t-butylmagnesium chloride.
The Grignard reagent was prepared by the addition of 92 g.
(1 mole) of t-butyl chloride, B.P. 50°C., n2®D 1.3645-dis­
solved in 100 oc. of dry ether, to 24.3 g. (1 mole) of mag-
nesium in 200 co. of ether, over a period of 4 hours.
It
was then cooled to -5°C. and to it was added a solution of
U& g» (0.5 mole) of
^-oyolohexenone in 300 cc. of dry
ether, keeping the temperature below 0°C. during the addi­
tion, whioh required 2 hours.
After standing at room tem­
perature for 10 hours it was decomposed by pouring it on
1 kg. of crushed ice and 250 g. of HH^Cl, then ether extra­
cted, the ether solution dried over anhydrous K 2CO3 011,1 ‘bile
ether "stripped" off through a 50 cm. Vigreux column.
A
small sample treated with saturated NaHSO-j solution quickly
gave a white precipitate, but it was so finely divided
(almost gelatinous) that filtration was practically impos­
sible.
So, instead of treating the entire amount it was
fractionated as it was over anhydrous K2CO3 in column II
at 20 mm. pressure.
Cut
Bath
Jacket
Head
n20D
Weight
R.B.
1
110
72
63-65
1.4821
1.5
10:1
2
114
74
65-67
1.4863
1.4
10:1
3
118
74
67-68
1.0688
1.3
10:1
4
123
83
68-77
1.4762
1.0
10:1
5
128
99
77-94
1.4707
1.1
10:1
6
130
103
94-96
1.4675
2.9
10:1
7
132
104
96-98
1.4621
1.0
10:1
8
132
104
98
1.4617
4.3
10:1
9
134
105
98
1.4615
8.0
10:1
10
136
105
98
1.4614
10.6
10:1
72
Cut
Bath
Jacket
Head
n 20D
Weight
R.R.
11
135
105
98
1.4615
11.0
1051
12
138
105
98
1.4615
6.1
10 si
13
142
107
98
1.4616
0.8
10:1
Residue
6.8
The residue calculated as condensation products is a yield
of 14
Cuts 1-3 were identified as unchanged
^^-oyolo-
hexenone, by means of the 2,4 dlnitrophenylhydrazone, m.p*
165-6, which gave no depression in m.p. with an authentic
sample,
fractions 4 and 5 which would be expected to oon-
tain the reduction product,
A*"-cyclohexenol, if formed in
the reaotion, were dehydrated when treated with phenylisocyanate; in an attempt to prepare the known phenylurethan of
the reduction product.
They m a y oontaln some of the terti­
ary alcohol from the 1,2 addition of the Grignard reagent to
the oarbonyl group, but lack of material prevented any furth­
er work on the intermediate outs.
3-t-butyloyolfthftTftnnne«■
Cuts 6-13 inolusive from the
preceding fractionation, absorbed bromine in carbon tetrach­
loride only very slowly and they did not decolorize dilute
KMn04 solution indicating that the material was saturated.
The odor of
this material was very similar to that of the
previously described
ketones obtained from the correspond­
ing reactions of methyl, ethyl and isopropyl Grignard reag­
ents with
A^-cyclohexenone •
It f o m s a semi oar bazone, m.p.
207-8°D. and a 2,4 dlnitrophenylhydrazone, m.p. 158-9°
By
analogy with the preceding reactions it seems certain that
this material is 3—t-butyloyclohexanone, a compound whioh has
not been previously described in the literature.
cuts 6-13, 50.7 g.
(0.35 mole) is 70 %>.
Density on Cut # 11
0.9177, B.P. ® 736 mm., 220®C.
Molecular Refraction observed:
Reduotlon of
poxide.
A
46.09, calculated: 46.29.
-oyolohexenone with aluminum isopro-
A mixture of 28.8 g.
none and 31.2 g.
The yield,
(0.3 mole) of
z^'-oyolohexe-
(0.2 mole) of aluminum isopropoxlde and
100 co. of isopropyl alcohol were refluxed under column P-2,
with gradual removal of acetone over a period of 6 hours.
At this time the head temperature had risen to the boiling
point of isopropyl alcohol and remained there even when pla­
ced under total reflux.
The excess isopropyl alcohol was re­
moved under vacuum, the viscous residue then decomposed with
cold 20 Jfo sulfurio acid.
The oil layer was separated and
the aqueous layer extracted with ether.
The ether solution
was dried over anhydrous KgCOg, the ether then "stripped" off
and the residue fractionated in column I, at 25 mm. prei
Cut
Bath
Jacket
Head
n 20D
Weight
R:R.
1
123
78
40-67
1.4321
2.3
10:1
2
132
84
67-72
1.4712
0.2
10:1
3
138
92
72-73
1.4858
4.2
10:1
4
142
88
73-74
1.4861
4.7
10:1
5
155
87
74
1.4861
5.3
10:1
6
167
87
74
1.4861
5.1
10:1
Cut
Bath
Jacket
7
182
87
Head
n 20D
Weight
74
1.4860
2.6
v.
Residue
H.B.
10 Si
5.6
30.0
A 1 cc. sample of fraction 5 was converted to the phenylurethan, by treatment with an equal volume of phenyl iso­
cyanate and warmed for 10 minutes on the steam bath.
After
cooling, the product quickly crystallized and was then recrystallized from petroleum ether, giving a m.p. 105-6°0.
Guillemonat
urethan of
(32a) reported 107 as the m.p. of the phenylA^-cyclohexenol for which he gave also b.p.
67/16 mm., and n 20D 1.4860.
Fractions 3-7, 21.9 g. (0.22
mole) represent a yield of 74 % of
on the
A^-oydok e x e n o l based
A 2"-oyolohexenone reduced.
Attempted reaction of
ovclohexadlene.
A -oyolohexenone with 1.5-
A solution of 30 g. of
A^-cydohexenone
in 60 g. of 1,3-cyclohexadiene was allowed to stand at room
temperature for three days.
This treatment which is usually
sufficient for a Diels-Alder reaction resulted inno visible
change in the solution (positive reactions are usually aooompanied by a yellow color) and the index of
the solution had
changed only slightly, n20D 1.4765-1.4768.
The solution was
then refluxed on the steam bath for 22 hours oausing some
yellow
ooloration and the index changed to 1.4779.
Fract­
ionation of the material resulted in almost quantitative re­
covery of both of the reactants,
The residue from the re­
action, 4.5 g. was of a rubbery nature and could not be
75
Identified.
It m a y have been a polymer of the diene, slnoe
Hofma nn and Damm. (37) have shown that l,3-oyclohexadi0ne
readily polymerizes.
There was no evidence of the format­
ion of a true Diels-Alder adduot of the two compounds.
Addition of isophorone to methylmagnesiinn br™n~ide.
To the G-rignard reagent, cooled to 5°C«> prepared by bubb­
ling methyl bromide through 48.6 g. (2 moles) of magnesium
in 900 cc. of ether, 'was added a solution of 207 g. (1*5 mdes)
of isophorone in 200 cc. of ether over a period of three
hours, keeping the temperature below 0°C. during the addit­
ion.
The Grignard complex was decomposed by pouring it on
200 g. of ammonium chloride and 1.5 mg. of ice.
The solution
was extracted with ether in the usual manner; the ether sol­
ution dried over anhydrous K 2CO3 and the ether then "stripped"
off.
Upon cooling, the product crystallized and was separat­
ed by filtration, through a sintered glass funnel.
Addition­
al crops of crystals were obtained by cooling the mother liq­
uor in a salt-ice bath.
duct was 192 g.
The total weight of crystalline pro­
The melting point was 35-7°C. and this was
raised to 37-8°0 . by repeated crystallization from petroleum
ether.
Qualitative tests indicated that this was an un­
saturated tertiary alcohol.
It absorbed bromine and decol­
orized potassium permanganate solution.
Attempts to prepare
a phenyl urethan resulted in dehydration of the material.
Its method of preparation and the characteristics of the
compound indicate that it is 3i3»5»5-tetramethylhexenol.
The yield based on the isophorone is 83
-cyclo-
76
Cut
Bath
Boiling Pt.
n20D
Weight
Press.
1
85
45-57
1.4792
2.5
6 mm.
2
88
57-58
1.4763
1.8
6 mm.
3
92
58-59
1.4768
3.1
6 mm.
4
93
59
1.4773
4.2
6 mm.
5
96
59
1.4775
2.8
6 mm.
6
99
60
1.4774
3.1
6 mm.
Besidue
12.6
Fractions 2-6 were Identified as isophorone as shown
by the semicarbayone m.p. 193-5, which gave no depression
with an authentic sample.
There was no indication of the
presence of a saturated ketone in the residue.
■Addition of isophorone to ethylmagnesium bromide.
To the Grignard reagent, cooled to -5°C., prepared from
48.6 g.
(2 moles) of magnesium, 218 g. (2 moles) ethyl bro­
mide, and 900 c.c. of ether, was added a solution of 207 g.
(1.5
moles) of isophorone in 200 c.c. of ether, over a
period of three hours, keeping the temperature below 0°C.
during the addition.
The Grignard complex was decomposed
by pouring it on 200 g. of ammonium chloride and 1.5 Mg. of
ice.
The
solution was extracted with ether in the usual man­
ner; the ether solution dried over anhydrous KgCOg a&d the
ether then "stripped** off.
Upon cooling, the product gradua­
lly crystallized and was repeatedly filtered off in a sinter­
ed glass funnel.
Additional crops of crystalline product were
obtained by cooling the mother liquor in a salt-ice mixture.
The tot a?, weight of crystalline product was 301 g.
ing point was 44-7°C.
and
The melt­
this^ after:several reorystalliza-
tions from petroleum ether^was raised to 49-50°C. Qualitative
tests on this material indicated that it was an unsaturated
tertiary alcohol*
It absorbed bromine and decolorized pot­
assium permanganate solution.
Attempts to prepare a phenyl-
urethan resulted in its dehydration.
Its method of prepara­
tion and these tests indicate that it is l-ethyl-3,5,5-trimethyl— ^ 7-— cyclohexenol.
The yield based on the isopho­
rone is 80 %
The mother liquor from the reaction was fractionated
in Column II:
20
D
Weight
Press.
Cut
Bath
Boiling Pt.
n
1
80
50-53
1.4768
1.8
3
88
53-53
1.4770
3.4
4 mm.
3
93
53-54
1.4773
4.5
4 mm.
4
93
54
1.4776
3.1
4 mm.
5
96
54
1.4773
1.8
4 mm.
6
105
54
1.4773
1.0
4 mm.
Residue
4 mm.
14.9
Fractions 1-6 were identified as isophorone by means of
the semicarbazone m*p. 194-5, which gave no depression with
an authentic sample*
A careful examination of the residue
gave no indication of a saturated ketone*
Addition of isophorone to isopronylmagnesium bromide,..
To the Grignard reagent prepared from 48.6 g.
(2 moles) of
isopropyl bromide and 900 cc. of ether, was added a solution
of 207 g.
(1.5 moles) of isophorone in 200 c.c. of ether,
over a period of three hours, keeping the temperature below
0°C. during the addition.
The Grignard complex was decompos­
ed and ether extracted in the same manner as in the preceding
reaction. The products after removal of ether were fractionated in column I:
Cut
Bath
Boiling Pt.
n20D
Weight
Press.
1
131
70-90
1.4645
6.0
20 mm.
2
136
90-92
1.4698
5.8
20 mm.
5
138
92-93
1.4728
19.6
20 mm.
4
137
93
1.4738
20.2
20 mm.
5
140
93
1.4740
19.8
20 mm.
6
140
93
1.4742
19.9
20 mm.
7
140
93
1.4744
19.1
20 mm.
8
139
93
1.4744
16.0
20 mm.
9
141
93-94
1.4745
16.6
20 mm.
10
143
94-95
1.4742
16.7
20 mm.
11
145
95-96
1.4738
8.6
20 mm.
12
148
96-97
1.4728
8.2
20 mm.
13
150
97-101
1.4715
7.3
20 mm.
14
150
101-114
1.4698
6.2
20 mm,
15
162
114-115
1.466-6
3.2
20 mm.
16
164
115
1.4657
8.8
20 mm.
17
168
115
1.4656
8.6
20 mm.
79
Fractions 15-17 were saturated, as indicated by the
faot that they did not absorb bromine in carbon tetrachloride,
nor did they decolorize potassium permanganate solution.
They formed derivatives very slowly:
2,4-dinitrophenyl-
hydrazone, m.p. 154-5°C., and semicarbajpme, m.p. 199-200°C.
(D).
This material is probably 3-isopropyl-3,5 ,5-trimethyl-
oyclohexanone resulting from 1 , 4 -addition of the Grignard
reagent to the isophorone.
These cuts, 20.6 g.
(0.11 mole)
represent a yield of 7.6 fo based on the isophorone.
The
remaining products from this reaction were not worked up.
4
SUMMARY
q_
1.
A -Oyolohexenone gave 1,4-addition products with
methyl, ethyl, isopropyl, and t-butyl Grignard reagents in
14.6, 24, 44 and 70 $ yields respectively.
2.
^ - C y o l o h e x e n o n e gave 1 ,2-addition products with
methyl, ethyl, and isopropyl Grignard reagents in 38, 52
and 10 fo yields respectively.
3. Isopropylmagnesium bromide reduced A-oycloxenene
to A^oyolohexenol in 12 a
Jo yield.
4. Methyl and ethyl Grignard reagents gave only
1,2-addition products with isophorone , in 83 and 80 ft
yields respectively.
5. Isopropyl Grignard reagent, with isophorone, gave
the 1 ,4 -addition product in 7.6
yield.
The oarbinol
portion of the products from this reaction were not
examined•
BIBLIOGRAPHY
1 ) Kohler, Am. Chem. J. 29,352
(1903).
2 ) Kohler, ibid, 31,642 (1904).
3)
Thiele, Ann., 306,87 (1899).
4)
Kohler, Am. Chem. J. 36,181
Kohler and Mydans
(1906); 37,369 (1907).
J. Am. Chem. Soc. 54,4667 (1932).
Kohler, Tishler and Potter, ibid, 57,2517
(1935).
5) Kohler and Tishler, ibid, 54,1594 (1932).
6 ) Kohler and Johnstin, Am. Chem. J. 31,642 (1904).
8 ) Grignard, Ann. chim. phys.
24,463 (1901).
9) Rupe, Sohobel and Abegg, Ber 45,1536 (1912).
10) ZelinsfcL, Ger. Patent 202,720, Zen$r. II, 1837
(1908).
11) Rupe and Tomi, Ber., 47,3064 (1914).
12) Doeuvre, Bull. soc. chim., 6 , 1067 (1939).
13) Kohler^ Am. Chem. J . , 37, 369 (1907).
14} Bamberger and Blaggey, Ber. 36, 1625 (1903).
15) Auwers and Keil, Ber., 36, 1861 (1903).
16) Rupe and Liechtenham, Ber., 39, 1119 (1906).
17) Auwers, Ber., 43, 3087 (1910).
L8 ) Semmler, Jonas and Oelsner, Ber., 50, 1838 (1917).
19) Wallach, Ann. 359, 283 (1908).
20) Rupe and Emmerich, Ber., 41, 1752 (1908).
31) Mazurewitsch, J. Russ. Phys. Chem. Soc. 43, 980 (1911)
Zentr. II, 1922 (1911).
22) Wallach, Ann., 414, 222 (1918).
23) Bamberger and Blangey,
Smith and Crawford, J. Am. Chem. Soc. 50, 869
Worroll and Cohen, ibid, 58, 533 (1936).
Allen and Overbaugh, ibid, 57, 740 (1935).
Allen and Overbaugh,
ibid, 57, 1322
(1928).
(1935).
Allen and Gilman, ibid, 58, 937 (1936).
Kotz and Grethe, J. prakt. chem., 80, 489 (1909).
Kotz and Richter, ibid, 111, 373 (1925).
Treibs, Ber., 63 B, 2423 (1931).
a. Gulllemonat, Compt. rend. 205, 67 (1937).
b. Gulllemonat, Ann. chim., 11, 143 (1939).
Stevens, J. Am. Chem. Soo.
Signaigo and Cramer,
57, 1112
(1935).
ibid, 55, 3326
(1933).
Braun, Mannes and Reuter, Ber., 66 B, 1499 (1933).
Crossley and Pratt, J. Chem. Soc. 107, 175 (1915).
Hofmann and Damm, Chem. Abs.
22, 1249 (1928).
85
H . MISCELLANEOUS STUDIES
Part A
INTRODUCTION
THE REDUCING ACTION OF PRIMARY GRIGNARD
REAGENTS WITH TRIMETHYLACETYL CHLORIDE
The study of the reducing aotion of Grignard
reagents on acyl chlorides has been attacked from
many angles in this laboratory.
In the present work, the preparation of a series
of secondary oarblnols, for use in subsequent rearrange­
ment &R studies, involved the addition of trimethylacetyl
chloride to ethyl-, propyl-, isopropyl-, butyl-, iso­
butyl-, amyl-, and isoamylmagnesium bromides.
This
work offers a new approach to the study of the reducing
action of Grignard reagents, namely the effect of
structure of primary Grignard reagents on the reduction
of trimethylacetyl chloride.
m
HISTORICAL
A complete survey of the literature until 1929 on
the reducing action of Grignard reagents with acy^halides has been reported in the theses of Wheeler (1 ), M^yer
(2 ) and Whitaker (5).
In order to avoid repetition, the
present survey will contain only a
description, of the
later work in this field.
Recently Whitaker (3) made a very detailed study of
the reducing aotion of Grignard reagents with acylchlorides.
His investigation was divided into five parts:
1* Mechanism:
RC0C1
i
RCOR*
II
^
RCHO
III -- 4 RCHOHR*
rch2oh
nr
v
R' - alkyl group in R*MgX
The primary aloohol IV is obtained by direct reduction
of the acyl chloride I through the intermediate aldehyde III
The latter can also react with the Grignard reagent to form
the secondary alcohol V, which can also be formed by reduct­
ion of the intermediate ketone II.
Later work by Meyer (2 )
lends support to this mechanism, slnoe, by the addition of
several Grignard reagents to an excess of trimethylacetyl
chloride, the proposed intermediates were actually isolated
along with the final products*
His work is summarized in
the following table:
Trimethylacetates
RMgBr
$R*CH0
#R»C0R
;2R"-
R lCHCMe5
Ethyl
2*0
5.5
15.0
56.0
n-propyl
2.1
10.2
10.4
21.6
n-butyl
4.0
3.5
10.0
42.0
n-amyl
2.3
3.2
30
0
R = alkyl group of HMgX, R* = t-butyl-, R" n neopentyl2.
Effeot of struoture of
the acyl chloride.
this work, t-butylmagnesium chloride was the Grignard re­
agent used in all cases:
Acid chloride
RGHgOH
RCHOHR*
Neopentylaoetyl
15.5
67
Lauroyl
13*7
72
Etg -acetyl
20
63
Et-n-Bu-acetyl
29*6
64
Me-t-bu-neopentylacetyl
Et3-aoetyl, Lewis
(4)
(n-bu)3-acetyl, Lewis (4 )
2 0 (and aldehyde)
0
90
27
88
0
These results confirm the observations of Greenwood,
Whitmore and Crooks (5), who stated that the order of red
uction
of
aoid chlorides to primary alcohols by t-butyl
MgCl was tertiary > secondary > primary.
For
86
halogen In the Grignard reagent.
In this
work trimethylacetyl chloride was added to isobutylmago.esium chloride, bromide and iodide, with the following results:
,
f> neopentyl ale.
n
Grignard reagent
#t-butyl-isobutyl
oarbinol
Isobutyl MgCl
61.5
26
Isobutyl % B r *
61
26
Isobutyl Mgl
____
74 (crude)
’These results were obtained in the present work.
With the chloride and bromide the results were almost
identical.
With the iodide the yield of primary alcohol.was
!
somewhat higher, but the products were difficult to purify.
4. Effeot of structure of Grignard reagent.
Whitaker
studied the relative reducing action of t-butyl- and tamylmagnesium chlorides on a number of acyl chlorides:
Acyl Chloride
Lauroyl —
Primary alcohol
with t-butMgCl
— — —
Etg-aoetyl —
—
Primary alcohol
with t-amylMgCl
13*7
—
54.8
20
—
74.5
Et-n-but-acetyl —
29.6----- ---
74.5
Me-t-but-neopentyl-
2 0 (and aldehyde)
1 9 (and aldehyde)
Me 3-aoetyl
95
96
---
These results indicate that the formation of primary
alcohol is greatly favored by the use of the t-amyl- in­
stead of t-butylmagnesium chloride.
5 . Effeot of order of addition of reactants,.
Crooks
y
(6 ) studied the produots of the addition of butryl and isobutyryl ohlorides to t-butylmagnesium chloride.
**or
com-
4
parison Whitaker added the reactants in the reverse order,
that is, Grignard reagent to acyl chloride:
Compounds added
Butyryl chloride,!
RCHgOH
9 ft
RCHOHR*
RCOR1
71
0
Isobutyryl chloride,II
20
63
0
t-ButylMgCl to I
11.6
36.8
21
t-ButylMgCl to II
18.8
45
17.7
The alcohols were isolated as esters of the corresponding
acyl
ohloride, in the last two reactions.
The reverse add­
ition studied by Whitaker, did not appreciably affect the
yields of primary alcohols.
However, the yield of second­
ary alcohols was decreased, accompanied by the appearance
of ketones.
Wagner,
(7) studied the effect of magnesium in the
Grignard reagent and found that the yields, with filtered
reagent and with reagent containing excess magnesium, were
essentially the same.
In addition, he studied the effect
of the halogen in the acyl halide using diethylaoetyl halides.
With the chloride and bromide the results were essentially
the same; with the iodide no definite conclusions were reach­
ed sin9e the products were difficult to purify, and the re­
action was complicated by side reactions.
DISCUSSION
In the present work trimethylacetyl chloride was
added to an excess of isopropyl-, butyl- and isobutylmagnesium bromides*
The products in each case were neopen-
tyl alcohol I and a secondary alcohol II varying with the
reagent:
I
II
KUgBr
(CH3 )3CC0C1
----- i
(GH3)3CCH20H-t-(CH3 )3CCH0HR
R = isopropyl-, butyl-, and isobutyl-*
The yields of products in eaoh case are indicated in
the following table in which the results of Meyer (2) are
included for comparison:
Grignard tfeagent
ft I
3b II
0
69
PropylMgBr
20
76
Isopr opylMgBr
23
53
n-ButylMgBr
28
72
IsobutylMgBr
61
26
n-AmylMgBr
20
75
IsoamylMgBr
15
71
EthylMgBr
The reduction of trimethylacetyl chloride to neopentyl
alcohol by each of the Grignard reagents except ethyl is in
sharp contrast to the failure to reduce t-butylacetyl
chloride to neopentylcarbinol even by a tertiary Grig­
nard reagent (5).
The obvious explanation that the re­
duction depends on the attachment of a tertiary group
directly to the C0C1 group is unsound since n- and isobutyryl chlorides are reduced to the primary alcohols in
20 and 9 # yields by t-butylmagnesium chloride (5)•
e xperimental
PREPARATION OP STARTING MATERIALS
Preparation of trimethylacetyl chloride.
In a 2-litter
flask, equipped witli a reflux oondenser, dropping funnel and
a tube leading to $ water trap for absorption of HC1 and S02
gases, was placed 510 g. (5 moles) of trimethylaoetic acid,
b.p. 158°C./ 725 mm., m.p. 34°C.
To this was added, in 50
cc. portions, 655 g. (5.5 moles) of thionyl chloride (East­
man Kodak) over a two hour period.
The reaction started
slowly at room temperature and was allowed to continue for
eight hours without external heating.
It was then heated to
the reflux temperature for 1/2 hour and then fractionated in
column I. 528 g. of trimethylacetyl chloride, b.p. 58/150
mm., n ^ D 1.4125, was obtained, a yield of 84.4
Preparation of phosphorus tribromide.
In a 5-liter
flask, equipped v/ith stirrer, reflux condenser and dropping
funnel, was placed 280 g. of red phosphorus and 2-liters of
carbon tetrachloride.
To this, vdth rapid stirring, was
added 1920 g. (12 moles) of bromine, over a period of 12
hours, keeping the carbon tetrachloride barely refluxing.
The mixture, was then distilled from an ordinary distilla­
tion flask, and the portion boiling l68-72°C./735 nnn. was
collected.
1690 g. (7 moles) of PBr^ was obtained, a yie}d
of 77 # based on the bromine used.
Preparation of Isobutyl bromide.
The directions found
in Organic Syntheses (8) were followed for this preparation#
In a 5-liter flask! equipped with stirrer! dropping funnel
and reflux condenser, was placed 1036 g. (14 moles) of
stock isobuuyl alcohol (duPont).
To it was slowly added
1390 g. (5.12 moles, 10 ft excess) of phosphorus tribomide
over a period of 5 hours, the temperature being kept below
0°C. during the addition. It was then allowed to warm to
room temperature and then stand over night.
It was distil­
led at 200 mm. pressure, the portion boiling at 45-56°C.
collected.
The distillate was cooled to 0°C. and washed
three times with concentrated sulfuric acid, then with lOjfc
KgCOg solution and dried over anhydrous KgCOg for 24 hours.
Practionation of this material in oolumn I, gave 820 g. of
isobutyl bromide, B.P. 89.5/740 mm., tf20D 1.4362, a yield of
42.8
based on the alcohol used.
Preparation of isopropyl and n-butvl bromides.
The pre­
paration of these alkyl bromides was the same as that given
on P- 5 6 •
The physical constants and yields were as follows:
Isopropyl bromide, B.P. 59°G./738 mm., n 2®D 1.4255 , 82.5
yield.
n-Butyl bromide, B.P. 99-109/724 mm. n 20D 1.4400, 84.0 $ yield
of Grignard reagents. The same method as
that described on P-5/ was followed. The amounts of materials
and yields will be indicated under the reactions, as they are
Preparation
described.
REACTIONS
Addition of trimethylacetyl ohloride to isonropvlmagneslum bromide.
To the filtered Grignard reagent, prep­
ared from 121*5 g. (5 moles) of
magnesium turnings, 615 g.
(5 moles) of isopropyl bromide and 2150 co. of dry ether,
was added 181*5 g*
(1*5 moles) of trimethylacetyl ohloride
over a period of three hours.
by pouring it on ice.
The complex was decomposed
The ether solution was separated and
the aqueous layer extracted with ether.
The ether was dis­
tilled off and the residue fractionated in column I:
Cut
Bath
Boiling Pt.
n 20D
Weight
Press.
743 mm
1
140
35-36°C.
2
145
36-43
1.3574
0.9
743
3
145
43-56
1.3633
0.9
743
4
148
56-80
1.3720
1.9
743
5
156
80-82
1.3763
2.7
743
6
160
82-85
1.3777
0.9
743
7
163
85-99
1.3840
2.3
743
8
165
99-111
1.4970
2.5
743
9
117
73
Solid
6.6
150
10
121
73
Solid
8.8
150
11
123
73
Solid
10.5
150
12
124
75
Solid
2.1
150
13
128
81
1.4108
3.0
150
14
132
96
1.4212
3.0
150
Ether
Cut
Bath
Boiling Ft.
15
137
98°C.
16
138
17
n
20D
ts
Weight
Press
1.4277
6.4
150
100
1.4285
4.0
150
135
100
1.4290
7.6
150
18
135
100
1.4292
10.2
150
19
135
100
1.4293
11.7
150
20
137
100
1.4293
11.1
150
21
136
100
1.4293
11.0
150
22
138
100
1.4293
11.7
150
23
150
100
1.4293
11.4
150
24
154
100
1.4293
12.2
150
25
158
100
1.4295
6.7
150
Besldue
8.2
f a c t i o n s 4-6 contained isopropyl aloohol, as identi­
fied by means of the phenylurethan, m.p. 89-90, which gave
no depression on mixing with an authentic specimen.
The
formation of this alcohol was probably due to the action of
atmospheric oxygen on some of the Grignard reagent.
f a c t i o n s 8-12, 30.5 g. (0.34 mole) were identified as
neopentyl alcohol formed in 23
yield.
Fractions 8 and 12
gave a phenylurethan, m.p. 113-114°C. which gave no depress­
ion with an authentic sample prepared from neopentyl alcohol.
Fractions 15-25, 105.1 g. 10.8. mole) were identified
as isopropyl-t-butylcarbinol, a yield of 53 % based on the
trimethylacetyl chloride.
Fractions 15 and
25 gave a
phen­
ylurethan, m.p. 86-86.5, which gave no depression in m.p. with
an authentic sample.
Enactions 1-3, 7, 13, and 14 were impure, Intermediate
outs.
Mfll-t.lon of trimethylacetyl chloride to n-hutyi magnesium
bromide. To the filtered Grignard reagent, prepared from
121.5 g.
(5 moles) of magnesium turnings, 680 g. (5 moles)
of n-butyl bromide and 2050 oc. of ether, was added 181.5 g.
(1.5 moles) of trimethylacetyl chloride, over a period of
1.5 hours.
The products were worked up in the same manner
9
as with
the isopropylmagnesium bromide reaction, and were
fractionated in column I:
Bolling Pt.
n
20«
D
Weight
Press.
Cut
Bath
1
125
34-35°C.
Ether
2
133
35-70°C.
1.3636
2.5
739
3
165
70-100
1.3980
1.4
739
4
167
100-106.5
1.3991
1.6
739
5
166
106.5-107
1.3993
2.8
739
6
168
107-110
1.4005
2.8
739
7
172
110-111
1.4029
2.7
739
8
170°C
111-112°C.
1.4032
4.1
150
9
177
112-113
1.4025
11.0
150
10
187
113-115
1.4014
5.7
150
739 m m
Pressure reduced to 150 mm.
11
150
78
1.4009
10.7
150
12
154
76-120
1.4070
5.3
150
13
157
1.4303
9.8
150
120-121.5
95
Cut
Bath
Boiling Pt.
n
20_
O
Weight
Press
1.4313
10.0
150
14
154
15
160
122
1.4317
11.1
150
16
157
122
1.4317
11.1
150
17
158
122
1.4317
11.6
150
18
177
122
1.4317
91.0
150
19
180
122
1.4318
12.1
150
121*5-122
Besidue
Traotlons 6-12, 30 g.
8.9
(0.42 mole) solidified upon
ing and were identified as neopentyl aleohol representing a
yield of 28
based on
the trimethylacetyl chloride.
Tractions 6 and 12 gave a phenylurethan, m.p. 113-114°C.
and gave no depression in m.p. on mixing with an authentic
sample prepared from neopentyl alcohol.
Tractions 14-20, 156.7 g. (1.1 moles) were identified
as n-butyl-t-butylcarbinol, a yield of 72
trimethylacetyl chloride.
based on the
Tractions 14 aid' 20 gave a phenyl­
urethan, m.p. 64.5 - 65.5°C., which gave no depression in
m.p. with an authentic sample prepared from n-butyl-t-butyloarblnol.
Tractions 1-5, and 13 were impure, intermediate fractions •
Arid it ion of tr^mftthvlacetyl chloride to isobutylmagneslum bromide.
To the filtered Grignard reagent, prepared from
181.5 g. (5 moles) of magnesium turnings, 680 g. (5 moles) of
isobutyl bromide, and 2050 oc. of ether, was added 181.5 g.
(1.5 moles) of trimethylacetyl chloride, over a period of
^
96
1.5 hours*
The products were
worked up in the same manner
as in the preceding reactions, and were fractionated in column
I:
Cut
Bath
Boiling Pt.
n
20
D
Weight
Press.
1
127°C •
34-35°C.
2
131
35-52
1.3572
1.8
735
3
132
52-61
1.3699
1.3
735
4
148
61-92
1.3876
2.4
735
5
150
92-96
1.3933
1.7
735
6
150
96-97
1.3939
1.7
735
7
152
97-98
1.3943
2.1
735
8
152
98-105
1.3952
2.2
735
9
153
105-109
1.4010
1.4
735
10
152
109
1.4024
11.6
735
11
156°0.. 109-109.5°^
1.4031
4.5
735
12
160
Solid
10.7
735
13
171
Solid
10.5
735
14
173
110-110.5
Solid
11.1
735
15
188
110.5-111
Solid
10.1
735
16
193
111
Solid
12.1
735
17
195
111
Solid
5.6
735
109.5-110
110
Ether
735 m m
Pressure reduced to 150 mm.
Solid
3.7
150
76-100
1.4131
1.1
150
160
100-109
1.4212
2.2
150
160
109-110
1.4270
7.4
150
18
160
76
19
154
20
21
Cut
Bath
Boiling Pt.
n 2GD
Weight
Press.
22
158
110-111
1.4293
4.8
150
23
159
111-111.5
1.4299
4.5
150
24
158
111.5
1.4301
10.2
150
25
165
111.5
1.4301
9.7
150
26
177
111.5
1.4301
10.4
150
27
206
111.5
1.4301
10.6
150
Besidue
5.8
Eractions 5-8 contained isobutyl alcohol, identified
by the phenylurethan, m.p. and mixed m.p. 83-84°c.
fractions 9-18, 81.4 g. (0.91 mole) were neopentyl
alcohol, m.p. and mixed m.p. of phenylurethan, 115-114°C.
The yield is 61 % based on the trimethylacetyl chloride.
Erections 21-27, 55.4 g.
(0.38 mole) were identified
as isobutyl-t-butyloarbinol, a yield of 26
trimethylacetyl chloride.
based on the
Erections 21 and 27 gave a phenyl­
urethan, m.p. 112-112.5°C. and alpha-naphthylurethan, m.p.
103.5-104.5.
These derivatives gave no depression in m.p.
with authentic samples prepared from isobutyl-t-butylcarbinol.
f a c t i o n s 1-4, 19 and 20, were impure, intermediate
fractions.
SUMMARY
1.
The reducing action of Grignard reagents with acyl
ohlorides has been studied further by the addition of
trimethylacetyl chloride to isopropyl-, n-butyl, and isobutylmagnesium bromides.
2* Neopentyl alcohol was obtained with all of the
Grignard reagents used*
Isobutylmagnesium bromide gave
the largest yield (61 $>) of this reduction product*
99
BIBLIOGRAPHY
(1) Wheeler, M.S. Thesis, The Penna.State College, 1937.
(2) Meyer, M.S. Thesis, Ibid (1939).
(3) Whitaker, PhD. Thesis, Ibid (1939).
(4) Lewis, M.S. Thesis, Ibid (1939).
(5) Whitmore and Co-workers, J.A.C.S., 60, 2029, 2458,
2462 (1939).
(6) Crooks, PhD. Thesis, The Penna. State College,
(7) Wagner, M.S. Thesis, ibid,
(1939).
(8) Organic Syntheses, Vol 13, P-20.
(1939).
II. MISCELLANEOUS REACTIONS
Part B
THE ACTION OP METHYL AND ETHYL GRIGNARD REAGENTS
ON ETHYL ACETONEDICARBOXYLATE
INTRODUCTION
Tlie purpose of this work was the preparation of 2 ,4 ,
6-trimethylheptanetriol-2 ,4,6 by the action of an excess
of methylmagnesium chloride on ethyl acetonedioarboxylatet
O
CH3MgCl
C2H5OOC-CH2C-CH3-COOC2H5
* -6-6-6-C-C-C-C6h OH OH1
It was found that, instead of the expected product,
acetone and its condensation products were the chief pro­
ducts of the reaction. The action of ethylmagnesium
bromide on the ester was then studied for the purpose of
gaining some insight into the mechanism of the reaction.
DISCUSSION
As has been stated, the primary purpose of this work
was the preparation of 2,4,6-trimethylheptanetriol-2,4,6
by the addition of ethyl aeetonedioarboxylate to an excess
of methylmagnesium chloride*
The absence of any detectable
amount of this compound among the products made it seem
advisable to discontinue the problem.
Consequently, no
definite conclusions were reached oonoerning the course of
the reaction*
However, it was shown that the main: products of the
reaction of the ester with methylmagnesium
chloride were
acetone and acetone condensation products.
Of the latter,
only mesityl oxide was identified*
The other high boiling
products, although not identified, form ketone derivatives
and appear to be condensation products derived from acetone.
It was hoped that the products from the action of ethylmagnesium bromide on ethyl acetonedicarboxylate would give
some insight into the mechanism of the reaction.
With the
exception of ethyl alcohol, the liquid products from this
reaotion were of a complex nature and were not identified*
All attempts to detect methyl ethyl ketone or aoetone
among the products were unsuccessful.
Quite unexpected,
was the formation of a solid organic compound containing
magnesium* Its analysis and properties indicate that it is
102
a ohelate ring compound containing two molecules of the
ester combined with one atom of magnesium*
Its structure
may be indicated as followst
C2H 5OOC-CH2C — 0 V
HC,f
02H 50-0 = - 0 -'
/O —
'0
C-CH2COOC2H 5
> H
c-o-c2h 5
It is undoubtedly identical with the compound prepared by
Fechmann (l), who obtained it by adding magnesium chloride
to a saturated solution of the mono-potassium salt of ethyl
aeetonedicarboxylate.
Fechmann did not investigate the
properties of the material, so his preparation was repeated
and the compound was found to be identical with that obtain­
ed from the Grignard reaction.
The formation of magnesium compounds by the aotion of
Grignard reagents on keto-esters has been reported by Grig­
nard (2).
B y the action of methylmagnesium iodide on ethyl
acetoacetate, he obtained, in addition to methane, a compound
containing two molecules of the ester combined with one atom
of magnesium.
Grignard assigned the following structure to
the compound:
CH3C-CH-COOC2H5
CHgG-CH-COOCgHg
In the light of present knowledge, it would seem preferable
to use the chelate ring formula, that is:
It is probable that the magnesium compound was
also
formed in the reaction of methylmagnesium chloride with
ethyl aeetonedicarboxylate, in the present work.
However,
in this case, acid was used to decompose the magnesium
complex and this would be sufficient to decompose the
ohelate compound as well.
With the ethylmagnesium
bromide reaotion, ammonium chloride was used in place of
the acid, and the ohelate compound was not affected.
EXPERIMENTAL
a t 'U
Preparation of cuMlM aoetonedicarboxvlataL
.
In a 5-
liter flask, equipped with a stirrer, was placed 3000 g.
of fuming sulfurio acid (20# S03 ), which was then cooled
to -5°C.
To it was then added 700 g.(3.64 moles) of pow­
dered citrio acid with constant stirring.
One third was
added during a period of 1*5 hours with the temperature
below 0°0»
The remainder was added over a period of two
hours, with the temperature below 10°C. Stirring was con­
tinued for one hour until the acid had completely dissolv­
ed.
The salt-ice bath was then replaced with ice water and
the
solution allowed to warn slowly to 30°C. It was then
oooled to 0°C. and 800 g. of ice was added keeping the tem­
perature below 10°C.; 1600 g. more of ice was then added
allowing the temperature to rise to 30°C.
It was again
oooled to 0°0 . oausing the separation of crystalline mater­
ial.
The liquid was removed by filtering
the mass through
a Buchner funnel, using an asbestos filter cloth.
After
sucking the crystals as dry as possible, they were reorystallized from 300 cc. of ethyl acetate, yielding 350 g . (2.3 moles)
of acetonedicarboxylic acid.
Based on the citric acid, the
yield is 60 #.
Preparation of ethyl a c e t o n e d l c a r b o x y l & f e In a
solution of 145 g. of dry HC1 in 700 g. of absolute alcohol,
was plaoed 350 g. of aoetonedicarboxylio sold*
The mixture
was heated to 45°C.until all of the acid had dissolved, and
was then allowed to stand at room temperature for 12 hours*
Moisture was kept from the
flask by connecting it to a
Gilm an trap containing sulfuric acid*
It was then poured
into 1400 cc* of ice water causing the separation of two
layers.
The oil layer was separated and the aqueous layer
extracted with benzene*
The extraots were combined with
the oil layer and washed with 400 cc. of 10 fo solution of
sodium carbonate and then with 400 cc. of 10 # sulfurio acid
solution.
After the benzene was
wae fractionated in
distilled off the product
column I, yielding 184 g. (0.92 moles)
of ethyl aeetonedicarboxylate, b.p. 150/20 mm., n
20
D 1.4403,
a yield of 38 # based on the citric acid.
Action of methylmagnesium ghlnpiae on ethyl aoetonedloarboxvlate.
To the Grignard reagent prepared by passing
methyl chloride into a mixture of 219 g. (9 moles) of mag­
nesium and 4
180 g.
liters of dry ether, was added a solution of
(0.9 mole) of ethyl aeetonedicarboxylate in one liter
of ether, over a period of 45 minutes.
During the addition
an orange solid separated from solution and a large amount
of gas was evolved.
After standing three days, the solid
changed to a deep red color.
The complex was decomposed by
pouring it on ice, the ether layer separated and the gelati­
nous material containing the magnesium salts was extracted
with ether.
The aqueous layer was then acidified with HC1
106
to decompose the magnesium compounds, and was again extracted
with ether*
The two ether solutions were fractionated sep­
arately and will be designated as the untreated and acid trea­
ted products, respectively.
The untreated portion was
fractionated in column I:
Cut
Bath
Boiling Ft.
ns0D
Weight
Press.
----
738 m m
1.3569
1.0
738
50-55
1.3640
1.8
738
135
55-58
1.3637
2.2
738
5
138
58-60
1.3622
1.5
738
6
140
60-63
1.3611
1.7
738
7
143
63-75
1.3640
2.4
738
8
170
75-78
1.4370
2.0
738
1
121°C
33-36°C.
2
124
36-50
3
132
4
Ether
Pressure reduced to
125 mm.
9
133
60-75
1.4110
0.4
125
10
140
75-76
1.4385
2.5
125
11
158
76
1.4404
2.7
125
12
170
76
1.4385
2.1
125
Pressure reduced to 22 mm.
13
120°C
45-52°C.
1.4472
1.6
22
14
160
52-75
1.4445
1.0
22
Pressure reduced to 5 m m •
15
160
58-75
1.4708
1.9
5
16
170
75-100
1.4648
1.2
5
«
107
Cut
17
Bath
Boiling Ft*
190
100°C.
n 20D
Weight
1.4695
Residue
Press.
8.0
5
18.0
f a c t i o n s 3-6 were acetone, as shown by m.p.
and
mixed m.p. of the 8,4-dinitrophenylhydrazone, 185-6°C.
Fractions 10-18 were mesityl oxidb, as shown by m.p.
and mixed m.p. of the 8,4-dinitrophenylhydrazone, 198-199°C,
The remainder of the fractions were not identified.
The acid treated portion of the product was fraction­
ated in column I:
Cut
Bath
Boiling P t .
35°C
n 20D
Weight
Press.
736 m m
1
1S8°C.
8
138
35-65
1.3697
1.3
736
3
148
65-71
1.3702
1.0
736
4
146
71-71. 5
1.3680
2.2
736
5
149
71
1.3669
2.4
736
6
168
71
1.3670
1.3
736
7
185°C.
72°C
1.3747
2.4
736
8
195
1.3753
1.6
736
72-75
Ether
Pressure reduced to 125 mm.
..
9
133
80
1.4027
0.5
125
10
148
90
1.4375
2.2
125
11
159
93
1.4417
2.3
125
18
170
120
1.4511
2.3
125
Pressure reduced to 18
mm.
*
Cut
Bath
Boiling Pt.
n20D
Weight
Press
13
145
78-85°C.
1.4600
1.5
18
14
159
85-100
1.4682
2.5
18
15
165
100-123
1.4701
1.7
18
Pressure reduoed to 4 mm.
16
165
82-100
1.4903
2.7
4
17
200
100-112
1.5139
4.8
4
18
210
112-125
1.5063
3.7
4
Fractions 3-8 were identified as acetone as shown by
m.p. and
mixed m.p. of the 2,4-dinitrophenylhydrazone, m.p.
125-6°C.
Fraction 18 formed a red 2,4-dinitrophenylhyarazone,
m.p. 175-6, and a semicarbazone, m.p. 173-4.
This material
may be identical with isoxylitone (an acetone condensation
product) reported by Khoevenagel and Blach (3).
They give
the following constants:
B.p. 129-30 at 11 mm., n 2®D 1.5196, Semicarbazone, m.p. 175.
A number of the remaining cuts reacted with 2,4-dinitrophenylhydrazine, but none of the products was obtained
in crystalline form.
Action of ftthYlmagnesium bromide on ethyl acetonedlcarboxylate.
The Grignard reagent prepared from 109 g. (1 mole)
of ethyl bromide 24.3 g. (1 mole) of magnesium and 400 oo. of
dry ether, was added to a solution of 50.5 g. (0.15 mole) of
ethyl aeetonedicarboxylate in 200 cc. of ether.
reagent was added 45 cc.
The Grignard
(0.15 mole) at a time, until 0.75
109
mole had been added.
After each addition it was stirred
until the Gilman test for Grignard reagent was negative.
The
total
time of addition and stirring was 4.5 days.
A
large amount of gas was evolved, and as in the case with the
methylmagnesium chloride, an orange solid preoipated and
then gradually turned red.
The complex was decomposed in
a solution of 800 g. of HH^Cl, 20 cc. MH4 OH, 500 cc. water
and 500 g. of ice.
The aqueous layer contained a white
solid, which upon shaking, was transferred to the ether
layer.
The solid was filtered off, and after repeated cry­
stallization from methanol melted at 113-115°C. In methanol
solution it reacted with 2,4-dinitrophenylhydrazine upon
the addition of a drop of HC1 solution, forming a solid
derivative, m.p. 84-85.
This was shown to be identical with
the same derivative of the original ester, with whioh it
gave no depression on mixed m.p.
Following the directions
of Pechmann (l), magnesium chloride was added to a saturated
solution of the mono-potassium salt of ethyl acetonedicarboxylate and the product was found to be identical with the
compound obtained from the Grignard reaction.
shown by mixed m.p.,
Analysis!
This was
which was not depressed.
Mg. Calculated for MgfCgH^jj^g
- 5.7
found:
5.5
The ether extract from this reaction was concentrated
by evaporation in vacuo, the ether and other low boiling
material being collected in dry ice traps.
The latter was
then fractionated in column II:
Out
Bath
Bolling Ft.
Weight
Press.
1
105
35
1.2
728 mm
2
110
35-72
0.7
728
3
114
72-76
0.8
778
4
115
76-77
1.6
728
5
116
3.0
728
77
Fractions 3-5 contained ethyl alcohol as shown by
m.p. and mixed m.p. of the 3,5-dinitrobenzoate, 92-3°C.
A careful search of these fractions failed to reveal any
acetone or methyl ethyl ketone.
The high boiling material from
the reaction was
fractionated in column II, giving 10 outs, 7 g. b.p. 47/
200 mm. to 122/7 mm., n^^D 1.4404-1.4686, and 9 g. of
residue.
None of these outs was identified.
SUMMARY
1 , The products from the reaction of methylmagne­
sium chloride and ethyl acetonedioarboxylate were a com­
plex mixture, of which acetone and mesityl oxide were
the only compounds Identified.
Other high boiling
products appear to be acetone condensation products.
2 . The reaction of ethylmagnesium bromide with
ethyl aeetonedicarboxylate yields a solid produot con­
taining two molecules of the ester combined with one
atom of magnesium.
compound.
It is undoubtedly a chelate ring
Of the liquid products from this reaction
only ethyl alcohol was identified.
BIBLIOGRAPHY
(1) Fechmann, Bar., 24, 4100 (1891).
(2) Grignard, Compt. rend., 134, 842 (1902)
(3) Organic Syntheses, Collective Tol I, P-232
If. MISCELLANEOUS STUDIES
Part C
INTRODUCTION
THE ACTION OP IODINE ON THE SILVER
SALTS OP ORGANIC ACIDS
In 1892 Simonini (l) found that, upon heating the
silver salt of an organic aoid with iodine, an ester of
the acid was formed.
The alcohol portion of the ether
was formed by loss of oarbon dioxide from one half of
the silver salt.
In the simplest form this can be il­
lustrated as follows:
2 RCOOAg
* I2
R°00R
-* c°2
+-
BA^ 1
The purpose of the present work was the application
of this reaction to the degradation of aliphatic acids
of high molecular weight, whose identification has for
a long time been a difficult problem in this laboratory.
Two tertiary acids trimethylacetic and methyl-t-butylneopentylacetic which were readily available, were
selected for study.
114
HISTORICAL
In 1892 Simonini (l) found that methyl acetate
oarbon dioxide were formed when silver acetate was heated
with iodine*
Since that time, analogous reactions have
been observed with the silver salts of a number of add­
itional acids, although with some of the more complex acids,
products other than an ester were obtained.
The reactions
which have been described previously are the following:
Ref.Silver Salt_______ Product._______ Yield if available
(l)
Silver acetate
Methyl acetate
50 S&
(1)
Silver oaproate
Amyl caproate
70 $
(2)
Silver stearate
Heptadecyl stearate
55
(3)
Silver caproate
Amyl caproate
71
$»
(3 ) Silver phenylacetate
Benzyl phenylacetate 68 #
(3 ) Ag triphenylacetate
Triphenylmethyl
Quantitative
triphenylacetate
(3) Silver suooinate
Maleic acid
(3) Silver adipate
Valeriolactone
(3) Silver phthalate
Phthalic anhydride
(3) Silver mandelate
Benzaldehyde
(3) Silver benzilate
Diphenyl ketone
(3) Silver lactate
Acetaldehyde
(3) Silver Glycolate
Formaldehyde
(3) Silver Grotonate
Highly unsaturated acids.
60 %
Several mechanisms have been suggested for the react­
ion which is now called Simonini*s reaction.
Simonini (1)
observed that silver salts of organic acids react with
iodine in the cold, in equivalent amounts, splitting out
one mol of
silver iodide from two mols of the salt and
one mol of iodine.
If it were then heated carbon dioxide,
silver iodide and an ester were formed.
Simonini succeed­
ed in isolating the intermediate compound and was able to
study its reactions,
iie suggested the following formula
for the intermediate:
y OCOR
I — COR
^OAg
Wieland and Fischer (3) suggest that the compound has
a coordination number of 2, and they prefer the following
formula:
,'OCOR
OCOR
They at first believed that the mechanism of the decom­
position of the above complex to give Agl, C02 and the ester,
involved the intermediate formation of free radicals.
But,
since the typical color of triphenylmethyl was not observed,
when the complex from silver triphenylacetate and iodine was
decomposed by heat, they concluded that the complex, alone,
was involved.
In no cases did they find hydrocarbons among
the products of the reactions.
They found that the com­
plexes from many of the silver salts and iodine, upon
decomposition, evolve only a small amount of C02 and the
a d d was largely regenerated, hydrogen being withdrawn
from a part of the substances
2(BHC002 )2AgI
2RHC00H
(RC00)2AgI
Birkenbach, Goubeau and Berninger (4) studied the
reaction of the complex, from silver acetate and iodine,
with oyclohexene.
They added iodine to an ether suspen­
sion of silver acetate at 80°C», filtered off the Agl,
qnd then added cyclohexene to the solution, obtaining:
CHg ICHg)gCHICHOAc .
They believed that
intermediate in the reaction.
CH3C00I
was an
DISCUSSION
Previous workers investigating the action of silver salts
of saturated aliphatic acids with iodine have obtained, in
all cases, an ester of the acids as one of the products.
The alcohol portion of the esters obtained, contained one
less carbon atom than the acid.
In no cases were olefins
obtained.
In the present work, in which the silver salts of
tertiary aliphatic acids were used for the first time;
it
has been found that the action of iodine produces olefins,
no esters being isolated.
The action of iodine on
silver tumethylacetate yield­
ed 3.2 ^ of isobutylene and 31 fo carbon dioxide, with 59 >
of the acid being recovered.
The action of iodine on the silver salt of methyl-tbutylneopentylacetio acid resulted in the formation of un­
identified olefinio material.
This probably corresponds to
the olefins which would be obtained by the dehydration of
methylneopentyl-t-butyl carbinol.
Methyl-t-butylneopentylacetic acid was recovered in
70.5 fo yield from the reaction.
In addition to the olefin,
32 °J» of carbon dioxide was produced.
This problem was not brought to completion.
The lack
of sufficient data would; therefore., make a discussion of the
results almost meaningless.
However, it is probable that
the olefins obtained correspond to the dehydration product
of the alcohol containing one less carbon than the original
acid.
m
119
EXPERIMENTAL
Preparation of silver trimethylacetate.
To 1 liter of
water at 40°C. was added 31 g. (0*3 mole) of trimethylacetio
acid.
To this was then added sufficient dilute ammonium
hydroxide solution to dissolve the acid and make the solution
neutral to litmus paper.
The solution WfcS cooled to 0°C.
by adding ioe, and when all
of 51 g.
the ice
(0.3 mole) of AgNOg in
was added.
The silver salt
Buchner funnel, washed with
500
had melted, a solution
cc. of water (at0°C.)
was then filtered off in a
500 cc.
of ice water and then
dried at 75°0. for 48 hours.
Analytical:
0.247 g. sample was ignited to 0.126 g. silver.
0.126 x 100
£ Ag 0.247
- 51.0 fo. Calo’d ; 51.6 %.
Reaction of silver trimethylacetate
with iodine.
In
a 2-necked 3-liter flask equipped with a mercury sealed
stirrer, reflux condenser and tube leading to a
ting bottle was placed one liter of dry benzene.
gas collec­
To this
was added 50.0 g. of silver trimethylacetate and the mixture
refluxed with stirring for one hour.
was
100 cc. of the benzene
distilled off to remove any water present.
The first
10-15 cc. were cloudy with water, the remainder being quite
clear.
g.
The mixture was cooled to room temperature and 30.5
(0.24 mole) of dry iodine (sublimed from P 2O5 ) was added
with stirring.
The iodine was decolorized as fast as it
went into solution and formed a yellow precipitate with the
m
120
silver salt.
This mixture was heated, with stirring, until
at reflux temperature a large amount of gas was evolved.
After about 20 minutes the evolution of gas had oeased.
Some of the gas was
the mercury seal.
lost due to a leak which developed in
Continuing the
heating for 4 hours pro­
duced no noticeable increase in the amount of gas.
The gas
was then analyzed in an Orsatt apparatus, the CQg being oolleoted in 20 % NaOH and the isobutylene in 63 % HgSC^.
An
average of two analyses showed that the gas (3300; oo. at
26°C. and 735 mm. pressure) was 56.5 % COg and 59 % iso­
butylene.
The yields were then calculated using the perfeot
gas equation.
i
j
isobutylene - n - F Y
RT
Yield
-
- 735 x 5.5 x 0*059 - 0,0077 moles.
760 x 0.082 x 299
.,0077 x_ipp
0.24
oarbonjiioxlde , ,
7 ?5 ,
Yield
-
0.074 y^lOQ
_
g #2 $» isobutylene
0.074 mole.
- 31 $ Carbon dioxide
The benzene layer containing Agl was filtered to re­
move the Agl.
The filtrate was colored with iodine and this
was removed by shaking the solution with mercury and
filtering.
then
The benzene was "stripped" off in column I, and
the residue fractionated in column II:
Cut
Bath
Boiling P t .
1
185
103-152
2.1
732
2
188
152-158
1.3
732
3
193
158-160
3.8
732
4
194
160
6*4
732
5
192
l6l
3.2
732
6
196
161
1.0
732
Weight
Press.
Residue 4.6
Fractions 3-6 inclusive, were solid, melting at
34-5°0. and gave no depression in m.p. with an authentic
sample of trimethylacetic acid.
These cuts 14.4 g. rep­
resent a recovery of 59 % of the acid.
There was no
indication of the presence of an ester in any of the
fractions or in the residue, which was quite tarry.
Reaction of the silver salt of Butlerow's betaacid *with iodine. *For convenience, methyl-t-butylneopentyl acetic acid will be referred to as Butlerow*s
beta-acid.
The silver salt of this acid was prepared in
the same manner as the silver trimethylacetate P-(/9*
From 70 g. (0.35 mole) of the acid, 84 g. (0.27 moles) of
the silver salt was obtained, a yield of 77 %.
The
reaction of the silver salt with iodine, was carried out
in the same manner as that previously described on P-!/^ .
A suspension of 83 g. (0.27 mole) of the silver salt of
122
Butlerow’s beta-acid in one liter of benzene was refluxed
for two hours and then 100 cc. of benzene distilled off to
remove any water from the mixture.
After cooling the
mixture to 15°C., 34*3 g. (0.27 mole) of dry iodine was
added.
This was decolorized as with the silver trimethyl­
acetate reaction previously described.
Upon refluxing,
gas was steadily evolved over <a period of about two hours.
Heating an additional hour produced no more gas.
The
solution, at the end of this time was colored a deep
purple with free iodine.
4200 cc. of gas at 29°C. and
735 n m u , was collected and analyzed.
tions showed 51.0 and 51.5 % C02 .
Check determina­
After the CO2 was re­
moved less than 1 % dissolved in concentrated sulfuric
acid.
Yield of C02 :
= 0.086 mole
Yield _ .086 x 100
0.27
_
32 % carbon dioxide
The benzene layer from this reaction was filtered to
remove the suspended silver iodide, which was then dried
in an over at 85 for 3 days.
The weight of the dry Agl
was 62 grams, which is 98 $ of theory.
The benzene layer
was colored with free iodine, which was removed by shaking
the solution with mercury and then filtering.
The benzene
m
123
layer was then extracted with two 500 cc. portions of 5 #
NaOH solution to remove the dissolved beta-acid.
The
basic extract was acidified with dilute sulfuric acid to
precipitate the beta-acid, which was then filtered off,
dried and weighed.
Weight of acid:
38.0 g.
Recovery:
70.5%*
The M.P. of the recovered acid was 126-8°C.
The benzene layer after extraction with NaOH solution was
"stripped11 of benzene in column I and then fractionated
in column II at 100 mm.
Cut
Bath
Jacket
Head
Weight
R.R.
1
120
80
30-82
1.0
10:1
b2
140
90
82-85
3.8
10:1
3
160
93
85-88
5.0
10:1
U
170
95
88-89
2.3
10:1
Residue 1.3
Cuts 2-4 inclusive add bromine very readily indicating
unsaturation.
Although nothing further has been done to
identify this material, it seems likely that these frac­
tions contain the olefin or olefins corresponding to the
dehydration of methylneopentyl-ter-butylcarbinol.
'
124
•SUMMARY
1. The action of iodine on silver trimethylacetate,
produces 3.2 # isobutylene, 31
carbon dioxide, and
59 i<> trimethylacetic acid.
2. The action of iodine on the silver salt of
methyl-t-butylneopentylacetic acid produces 32 % carbon
dioxide, 70.5 $ of the acid, and an unidentified olCfin
or mixture of olefins.
BIBLIOGRAPHY
(1) Simonini, Monotsh.,
13, 320 (1892); 14, 81
(1892).
(2) Heiduschka and Ripper, Ber., 56, 1736 (1923)
(3) Wieland and Fischer, Ann. 4 4 6 , 49 (1926)
(4 ) Birckenbach, Goubeau and Berninger, Ber., 65 B, 1339
(1932).
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