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PART I. THE CLEAVAGE AND REARRANGEMENT OF ALPHA-BROMO-ANILIDES PART II. THE PREPARATION AND PROPERTIES OF ETHER SOLUTIONS OF DIETHYL KETIMINE

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THE PENNSYLVANIA STATE COLLEGE
The Graduate School
Department of Chemistry
X
The Cleavage and Rearrangements of
Some Alpha Bromo Acid Anilides
II The Preparation of Diethylketimine
A THESIS
by
JACOB OSBORN ASHCRAFT Jr.
Submitted in partial fulfillment
for the degree of
DOCTOR of PHILOSOPHY
Jund 1941
Approved
ACKNOWLEDGMENT
The author wishes to express his appreciation
to Dr. T.S. Oakweod and Dr. F.C. Whitmore, under whose
direction this work
was carried out, for
theirmany
helpful suggestions
and criticisms which
have made
this work possible.
In addition,
the author wishes to thankDr. R.
V. McGrew for supplying
numerous chemicals and pieces
of apparatus used in this research.
Table of Contents
Part A
The Alkaline Cleavage and. Rearrangement of Alpha-Bromo-Anilides
I.
Historical Introduction........................ 1
II.
D i s c u s s i o n ................................... ...6
III Description ofColumns .................
LV
13
Experimental.... ............. ............ .. 14
1. Preparation
of Phenylacetyl Chloride ....
14
2. Preparation
of isobutyryl chloride ......
14
3. Preparation
of n-butyryl b r o m i d e ........
15
4. Preparation
of alpha-bromo-phenylacetyl
chloride
........................
15
5. Preparation of alpha-bromo-t-butylacetyl
chloride ..............
15
6. Preparation of alpha-bromo-isobutyryl
c h l o r i d e .......
16
7. Preparation of alpha-bromo-n-butyryl
bromide
................ *.......
16
8. Preparation of alpha-bromo-diethylacetyl
bromide..............................
17
9. Preparation of alpha-bromo-phenylacetanilide ...........................
17
10. Preparation of alpha-bromo-isobutyranilide
••
18
11. Preparation of alpha-bromo-t-buty1acetanilide
.................
19
12. Preparation of alpha-bromo-n- butyranilide
..............
20
13. Preparation of alpha-bromo-diethylacetanilide
............... .
14. Preparation of N-cyclohexyl-t-butylacet
anilide ............................
15. Preparation of alpha-aniiino-phenylacetic acid ........................
16. Preparation o& alpha-anilino-t- butylacetic a c i d ..................... .
17. Preparation of mandelic a.cid
.....
18. Preparation of mandelic anilide ......
19. Preparation of 3-phneyl oxindole .....
20. Reaction of alpha-bromo-phenylacetanilide with 10% NaOH ..............
21. Reaction of alpha-bromo-t-butylacetanilide with 10% NaOH ..............
22. Reaction of alpha-bromo-isobuuyranilide with 10% NaOH ..............
23. Reaction of alpha-bromo-n-butyranilide with 10'% N a O H ..............
24. Reaction of N-cyclohexyl-t-butyranilide vith 10% NaOH
Sum mary
..........
........................................
Part. B
Preparation of* Ether Solutions of Diethyl ketimine
I.
Historical Introduction.......... ........... 33
II.
Discussion
........ ..................... 40
III. Experimental ............. ................... 46
1. Preparation of diethyl acetyl chloride...
46
2. Preparation of diethylacetamide .......... 46
3. Preparation of 3-amino-pentane hydro­
chloride ..........
. 48
4. Preparation of Standard Solutions .......
48
5. Preparation of W-chloro-3-amino-pentane .. 49
6. Reaction of N-chloro-amino-pentane
with sodium methylate
.... .
54
Reaction 1
............................ 64
Reaction 2
................. .........
55
Reaction 3.
......... ....... ...........
58
Reaction 4
................. ......... .
61
Reaction 5... ....... .......... ..........
62
Reaction 6 ...... ................ ....... 65
Summary .................................
67a
PART A
The Cleav age and Re ar rangement
Of A l p h a - B r o m o - A n i l l d e s
wi th
Sodium H y d r o x i d e
HISTORICAL
PART X —
Alpha-bromo-anilides
Kishner,(1) In 1905, found that if alpha- bromoisobutyramide was treated with bromine and potassium
hydroxide, a 54% yield of acetone was obtained along
with 2,2-dibromo-propane and 2-bromo propylele. Alphabromo-cyclobutyl formamide (2 ) likewise gave cyclobutanone,
1
,1 -dibromo-cyclobutanone, and probably some
alpha-beta-unsaturated butyl amine* Later, Mannich and
Zernick(3) found that if alpha-bromo-diethylacetamide
was treated with
10%
sodium hydroxide and boiled, the
primary product was diethyl ketone* The expected hydroxy
amide #as formed in lower yield. Treatment with sodium
in absolute alcohol yielded penatol-3, sodium cyanide,
and sodium, bromide. Boiling water formed the alphabeta-unsaturated amide.
Mossler(4) (1907) undertook
a more complete study of this reaction, extending it to
the alpha»bromo-acidamides of acetic, propiQnic, isobutyric, isovaleric, diethylacetic, and phenylacetic
acids. The acetamide derivative gave no yield of formalde
hyde and sodium cyanide, but all others underwent re­
arrangement to form the aldehyde or ketone and sodium
cyanide. The yields, based upon the cyanide formed were
from
8%
to 97%, better yields being obtained from 20%
alkali than from 4% or 40%. Frey Ion (5) using alpha-bromo*
diisobutylacetamide, has obtained diisobutyl ketone*
Oakwood(1937) prepared the alpha-bromo-acid amides
of t-butylacetic acid,caproic acid and diethylacfetic
acid. Alpha-bromo-t-butyl acetamide gave a 50% yield of
trimethyl acetaldehyde. The alpha-bromocaproamide form­
ed an oil which gave a 2,4-dinitrophenylhydrazone ide®ti&&l
with that from valeraldehyde which had been treated in tie
same manner. The oil is probabl^r a condensation product*
Diphenyl mercury was tried as a base instead of sodium
hydroxide. Tetralin was used as the solvent. Alpha-bromodiethlacetamide with this reagent gave a small amount of
carbonyl oo mpound and HCW*
It seems logical to follow these studies by similar
ones with IT-substituted amides* A survey of the literature
revealed that no such study had been made until that of
0akwood(6). Several accounts are available on similar
reactions in nonagueous solutions, and these will be
mentioned.
tr
Abenius and Widman( 7) in 1888 prepared alpha-broraoacet-o-toluide and found that on treatment with alcoholic
potassium hydroxideN-N'-di-o-tolyl piperazine was formed.
Bischoff( 8 ) in 1891 prepared alpha-bromo-isobujyramide
from ethyl alpha-bromo-isobutyrate and conc. aqueous
ammonia, while alpha-bromo-isobutyranilide was prepared
from alpha-bromo- isobutyryl bromide and iniline. The
following year Bischoff(9) and Hausdorfer report the pre-
a,nparation and reaction of* alpha-bromo-propionilide with al­
coholic potassium hydroxide and Bischoff and Mintz(lO)
describe the preparation of alpha-bromo-n-butyramilide add
its reaction with alcoholic potassium hydroxide. Both of
these reactions led to the formation of Substituted alpha*
gamma-diaci-piperazine according to the following
equation*
8
2 CH3 CHBrCONHCgHg-^KOH — >
§h 3
'NCQHQh2'KBn-2R20
N9 H c r
CH 3 O
In the case of propionanilide, a small yield of alphaethoxy-propionanilide was also obtained.
Tigerstedt (11) in the same year prepared the anilides,
toluides and naphthalides of alpha-bromo-propionic * nbutyric,and iso butyric acids. The derivatives of propioni:
and n-butyric acids on treatment with alcoholic potassium
hydroxide yielded the expected substituted alpha, gamraadiaci- piperazine, but in the case of the isobutyric acid
derivative, no piperazine could be found, theprodpct
being hydroxy and ethoxy anilides.
Bischoff (12) (1897) reported the reaction of aniline
withfalpha-bromo-acid amides and anilides of acetic, pro­
pionic, butyric, isobutyric, and isovaleric acids to yield
the alpha-anilino acid amides and anilides, the reactions
being carried out in neutral solvents. The isobutyric acid
derivatives also yield the ^-anilino acid.
The N-benzyl, o,m,p,tolyl, m-xylyl, o,m,p-nitrophenyl
o,® ,-naphthyl substituted amides of* alpha-bromo-propionic
n-butyric, isobutyric and isovaleric acids have also been
prepared by Bischoff and co wrarrkers, and their reactions
with sodium phenoxide carried out. In the case of the
amides and anilides,the phenoxy substituted amide or
anilide is the only reported product. With the toluides,
naphthalides, and nitnor-anilides, secondary products of
phenol and the aLpha, beta-unsaturated substituted amides
were also obtained. This was most marked in the case of
the iso-butyric derivatives which also formed beta- sub­
stituted products in some cases.
A similar study(14) using N-methyl, phenyl; N-benzyl,
phenyl; and N-diphenyl derivatives showed the normal pro­
duct to be the alpha, beta-uns&turated substituted amide
rather than the alpha-phenoxy derivative.
0akwood(6)
(1937) reported the reaction of aqueous
sodium hydroxide with alpha-broxno-t-butylacetanilide,
t-butylacetdiethylamide, and caproanilide. With alphabromo-t-butylacetanilide he obtained phenylisonitrile
and an acid containing nitrogen. The latter was not
further identified.
Alpha-bromo-t-butylacet-diethyl-
amide was not attacked by the reagent. Alpha-bromocaproanilide gave phenylisonitrile, but after 1-^- hours
of re fluxing 76% of the starting material was recovered.
The reported work on the reaction of bases with alphabromo-acid amides and substituted amides is summarized
by the following series of equations;
Q R
la 2 RCHBRCONHR'-y-KOH (ale)— ? R'-N
lb2 RGHBrCONHE*-^ KOH (ale)
lc
2
N-R V-KBr+H20
? RCHOHCOHHR 1 -+•KBr
RCHBrCONHRVKOHf-BtOH— => RCH(OEt)COHHR^KBr+H^O
a
RCHBrC0NH2-/- KOH (aq. )— * RCHO -^KGN - h KBr
2b
RCHBrCOKHg - h KOH (aq. )— * RCHOHCONHg/-KBr
3
RCHBrCONHR '-h- CgHgNHg
4a
RCHBrCONHR V-lTaOCgHg ---> RCH( OCgHg )CONHR '+NaBr
4b
RCHBrCOMHRVNaOCgHs -- ? R 1’CH CHCONHR V- MaB r+C gHgOH
5a
RCHBrCGHHR VNaOH( a q .) — * RCHOv-RNC ^aJBrf-H20
5b
RCHBrCONHR*^NaOH( aq.)— ? RCHOHCONHR'*-NaBr
2
> RGH( MHCgHg )C0MHR*C6HgMH3Br
\
II
DISCUSSION
A. The rearrangement, and. cleavage of alpha-bromoanilides.
The reactions of the a^-pha-bromo- acid amides and
anilides are of considerable interest in connection
with the general theory of rearrangements. The reaction
as usually written for the amide cleavage is:
RCHBrCOHHg
2 NaOH
> RCHO -*-NaCN -t-NaBr
Very little speculation has been made as to the actual
mechanism of the reaction. Mossier (4) has postulated
that the bromo-amides split out HBr, the H coming from
the NH2 group, and that the resulting unstable inter­
mediate then splits out HCN according to the following
scheme.
g p
EC-C
£r 'NH
H
y0
R-C — C
~b~ RCHO +■HCN
'NH
or, the same thing might occur for the enolic form of
the amide.
H
OH
R-C - C
Br "N
h
H OH
R-C-C
"N
^
RCHO ■+•HCN
'
Although MossL er doesn't mention the matter, it would
seem probable that before the actual cleavage ocoi red
the oxygen would shi£t over to the adjacent carbon atom.
The intermediate in shell a shift might be an ethylene
oxide ring.
Br OH
,0^
R-C - C--RH — r R - C
C HH — > RCHOv-HCN
H
H
Similarly, the alpha-bromo-anilide rearrangement might
be explained by the formation of an intermediate three
membered nitrogen ring which then hydrolyses to the alphaanilino- ac id •
H O
H
p
O
R C - C — > R C— C
Br NC 6 H 5
"N
H
C6 H 5
=* R 9 - C - O H
HH
C6 H 5
Another theory which can be used to explain these re­
actions is that of Whitmore(15) which in general terns
assumes that in an organic reaction involving the removal
of a negative group, this group is removed with its full
octet of electrons leaving a positive fragment thus 5
r
-
H H ..
c ;q ;x: --- v
H H "
H
r
H.
:'q ©
H H
c
+
x
This positive fragment can then stabilize itself by one
of three ways;
1. It may attach another negative group with a free pair
of electrons:
H
R
H
Y
R
H H
g;.g.-y;
2. It may expel a proton to form a double bond:
8
3*An electron pair
the molecule
may shift from another part
of
and may or may not carry an attached group
with it*
r
H IU
••£ ;
R* H
-----*
E H
R ;d ; c ; R*
® fi
A new positive fragment is formed and may then stabilize
itself as in
1
. and
2
,
Of these theories, the last will most easily explain
all of the products obtained by the reaction of bases on
the alpha-bromo-N-substituted acidamides. The following
equations show the application of this theory.
1
.
• Br- . 0
R .’
C : C\'(>
H
' N.-R'
H
©
..O
R :Q ; C** . -*-;Br;
H
*’NR*
H
R* H or G 6 H 5
This positive fragment can then take up an hydroxyl group
to form the hydroxy amide or anilide which may then under­
go hydrolysis to form the hydroxy acid.
2
a
©
.-O
R ; C I C ‘... -v-.O-'H
H
‘N.-R1 "
H
t »
---^
R
OH
.0
'd : c;.,
H
' N.-R
1
••
H
b
R:
QH . 0
C ; C\.
^ - H 2(E
H
1 N:R*
H
OH
. 0
* R ; Cti­
C * c*
' ‘
-t- RNHg
OH
ll
A second way in which the fragment can be sthbilizedclis
through the expulsion of a proton or other positive group
followed by the formation of a double bond.
3 a,
3a.
b.
H H
.0
R:C'G:C;’
H ®
.NHR1
**. H .. 0
R*C"C!:C;
-t’-NHR1
>
^
H
The pr oton m a y be e x p e l l e d from the n i t r o g e n atom
I nst ead of the ca rbo n a t o m thus?
ti ®
\.0
R ■G :0 •0 '--------- — --- >
H H
‘N H R 1
H # .,0
R -0 *0 •0 ‘
-tH H J-.NR1
H
Two of these f ragm e n t s c o u l d combine to form a s u b s t i t u t e d
d l h e t o — ulDerazlne.
R1
R * •• N .*
5:.G
G::0
••
-.R
0::0 .
C.-r
' N •
H
R1
H &
.0
3 R:0:O:C:'-------- — ---- ^
H H '--NR1
& "
In the case of the anilides,
the n r o t o n m i g h t be
the ortho p o s ition of the ohe n y l group,
e x p elled from
g i v i n g rise to an
o xindo le derivative.
H
H
•.o .
H.-O-
.6 .
0
: NH
' 0
s
NiH
H*
H--C
CH. ,C::0
0 • % '
H
H R
An example
of this tyoe
H'.O
.G .
G’
.:0
C ’ • .p.. ■
h
H R
of r e a c t i o n is foun d in M e l s e n h e i m e r s
p r e p a r a t i o n of b e t a - p h e n y l - o x i n d o l e
from m a n d e l i c
ani lid e
and c o n c e n t r a t e d su lfuri c a c i d as follows:
H
H
.,c .
H: 0 ‘
.c .
' G
:
B.-H
H ■0'''
C
:
••
H-C .
C :H
c *•
H
The p o s i t i v e
h
.G-.-.O
og;
HR
'
fragment m a y also
H--0
•+ A/,O
NH
.
satisf y i t s e l f b y the
of an e l e c t r o n o a i r f r o m a n o t h e r oart of the mole cule .
the e l e c t r o n oa ir a t t a c h e d to the anilino g r o u n
carrie s the groun w i t h it,
an h y d r o x y l gr ouo thus
R —
= C«H=~
usn 5
C .
C"0
o ’’ ' .o ’•
H
H ’R
shift
If
shifts and
the r e s u l t i n g o r o d u c t ma.y a t t a c h
fo r m i n g an anil ino acid.
10
4.
H .Cs H 5
Q
n
'N*
R:H!Cf;^HRl
^
R,g ! °®
H. .Gq H s
'N '
n
R ’C i ClU
j| S>
-.0
H. ,0s H 5
-
i- -OH
•*
T
---- >
n
R •C *• o:^__
jj
• OH
A l t h o u g h the reactio n to form an oxind o l e
the c o r r e s p o n d i n g oroduct,
a beta-alkyl
is p r e d i c t e d ,
oxi ndole, h a s n o t
been I s o l a t e d from an y of the r e a c t i o n s tried.
Th e
same is
true of the u n s a t u r a t e d anilide
All
of the
(rea ction 3 a ) .
other p r o d u c t s have b e e n isolated,
the same reaction.
The course
a l t h o u g h n o t n e c e s s a r i l y f rom
of the r e a c t i o n
is d e p e n d e n t
u o o n the tyre of alkyl chain as well as u n o n t he
oiS the nitrogen.
In the case of a l ^ h a - b r o m o - t - b u t y l a c e t a n i l i d e ,
the yield of a n i l i n o - a c i d is h i g h w h ile in the
b r o m o - i s o b u t y r a n i l i d e , no a n i l i n o - a c i d was
r eco vered from the aq u e o u s solution.
this r e a c t i o n wa~ not made be c a u s e
case
of a l o h a —
obt ained,
p rod uct p r o b a b l y b e i n g the a l o h a — h y d r o x y acid,
(12, 17)
substituent
A more
which, was not
complete
of B i s c h o f f
the
s t u d y of
s investigation
of the p r e p a r a t i o n of a l p h a — a n i l i n o - i s o b u t y r a n i l i d e
and ethyl,
a l o h a - a n i l i n o - i s o b u t y r a t e b y t h e r e a c t i o n of
the a l o h a - b r o m o - a n l l l d e or e s ter wif-- aniline.
In the ca se of
the ester, the principle product was reported as the betaisomer. In the case of the anilide the beta-isomer was re­
potted, but not as the principle product. In view of this
it seemed unwise to spend much time with the alpha-broraoisobutyranilide reaction. Also, the methods for isolation
and identification of the lower alpha-hydroxy acids have
not been well developed, this being a research problem
in itself.
The formation of the piperazine derivative has been
demonstrated by Bassler in these laboratories (18) using
2
bromo-n-butyranilide.
The effect of change in the substituent on the nitrogen
was demonstrated by
0
akwood( 6 )^who found that alpha-bromo-
t-butyl-N-diethyl acetamide was unaffected
by aqueous
alkali after several hours of refluxing, A similar effect
was shown with the reaction of alpha-bromo-N-cyclohexylt-butylacetamide where the starting material was again un­
changed after several hours of boiling.
These experiments when considered with the alpha-bromoamide cleavage indicate the possibility that the group
attached to the nitrogen must possess alpha-beta-unsaturatiaon
before the rearrangement of the nitrogen can occur,However,
the mere presence of a phenyl group,which gives this unsat­
uration, does not insure the formation of anilino-acid. As
yet insufficient reactions have been run to permit the draw­
ing of any conclusions regarding the factors governing the
course of the reaction.
Description of Columns
The columns used in this work were of the
total condensation partial take off type as de­
veloped in this laboratory*
Column I had a packed section 15 mm. in dia­
meter, 50 cm. tall and was packed with 1/8 inch
single turn,glass helices.
Column II
had a packed section 13mm. in dia­
meter, 45 cm. tall, and was packed with 1/8 inch,
single turn,glass helices.
Column III
had a packed section 8 mm. in dia­
meter, 35 cm. tall, and was packed with 3/32 inch,
single turn, glass helices.
14
III EXPERIMENTAL
Alkaline Cleavage and Rearrangement of alph a- br omo anilides
1. Preparation of .Phenvlac etvl Chloride
Phenylacetic acid (1 mole, m.p. 72°, 98% acid by
•titration) was reacted with
2
moles of thionyl chloride.
After standing several days, the reaction mixture was
heated on a steam bath for 3 hours, then the liquid was
decanted from a small amount of solid and distilled from
a 500 cc Claisen flask at 20-24mm. Yield 134 g, 87%, b.p.
98-101, nij201.532.
In preparations where the reaction was only allowed
to stand for one to two days, the yields were somewhat
lower.
A relatively large excess of thionyl chloride
also aided in obtaining a good yield.
2. Preparation .of Isobutyryl Chloride
Thionyl chloride, (230 g,
195 moles, Eastman practi­
cal) was added to 100 g (1.14 moles) of isobutyric acid
( Eastman blue label, redistilled).
The reaction flask
was placed under a reflux condenser attached to a fume
trap and allowed to stand for 18 hours, then was placed
under column 1 and heated for 2.5 hours at 40-50°, then
fractionated. The yield was 79.6 g . , b.p. 90-91, nD2o1.4077,
66%.
3. Preparation. o f n - B u t v r y l Bromide
Phosphorous t£ibromide (204g, 0,75 mole) was mixed with
132 g (1*46 mole) of n-butyric acid (Eastman white label) in
a 500 cc flask attached to a reflux condenser protected from
moisture by a calcium chloride tube. The reaction was heated
for 4 hours, then let stand overnight. The crude product
was distilled giving 101 g, b.p. 124-128 and 20 g, b.p. ISO145. This represents about a 60% yield.
4. Preparation of Alpha-Bromo-Phenylacetyii Chloride
In a 3-neck, 500 cc round bottom flask connected to a
reflux condenser attached to a fume trap, a separatory
funnel, and a mercury sealed air stirrer were placed 161 g
(1.04 moles) of phenyl acetyl chloride and 2 g. of red
phosphorus. To this mixture was added slowly with stirring
180 g (1 . 1 2 males) of bromine (dried over conc.H 2 S 0 4 ) .
The temperature was maintained at from 50-60® during the
addition and for 1 hour afterwards. The mixture was filter­
ed to remove the PBrs, then attached to a column and frac­
tionated under 13mm pressure. Yield 166 g, B.p. 97-130
@13 mm, n^C>D 1.553-1.601. This represented a 70% yield
assuming that the product is about 50% acid chloride and
50% acid bromide. These compounds could not be fraction­
ated apart since they undergo partial decomposition dur­
ing this operation and the loss is too great.
5. Preparation of ATpha-Bromo-t-Butylacetyl Bromide
In a 200 c c , 3-neck flask attached to a mercury sealed!
stirrer, a dropping funnel, and a fume trap were placed
46.5 g, (0.347 mole) of* t-butylacetyl chloride (b.p. 78-79
@ 155 mm., n 20D 1.4220) and 2 g. of red phosphorus. To this
was added dropwise at a rate of about
1
drop per second 72 g
(0.90 moles) of bromine (dry). The reaction was illuminated
with a 150 watt light bulb placed close to the flask. A total
of 5 hours was used for the addition. After standing avernight the product was fractionated through column II, giv­
ing 68.5 g of product, b.p. 104 @ 50 mm., n ^ D 1.5028-1.5036
Yield 77%, based upon the assumption that the product is
alpha-bromo-t-butylacetyl bromide.
6
. P reparation of Alnha-Bromo- Isobutvfcyl Bromide
Diy bromine (98g, 0.61 moles) was added dropwise to a
mixture of 42.4 g of isobutyryl chloride and 2 g of red
phosphorus eontained in a 200 cc, 3-neck, flask attached
to a reflux condenser, a mercury sealed stirrer, and a
separatory funnel, the condenser and separatory funnel
outlets being vented to a water trap. The reaction was
illuminated with a 200 watt light bulb with reflector. No
additional heat was required to maintain a reflux temper­
ature. The bromine was added over a period of 7.5 hours
and the illumination and stirring were continued for 3 hours
more. The product was fractionated through column II, giv­
ing 21.6 g of foreruns and 56.1 g of product b.p. 96° @ 97mm
nSOp 1.5082 Yield 59 %
7. Preparation of Alpha-Bromo-n-Butvryl Bromide
To 130 g.(0.86 moles) of n-butyryl bromide
and 3 cc of
PBr3 , contained in a 3-neck flask attached to a mercury seal-
ed stirrer, a separatory funnel, and a reflux condenser
vented to a water trap, was added dropwise with stirring
200 g of dry bromine. The reaction was illuminated b# a
200 watt light bulb placed close to the flask. The addi­
tion was completed in 3 hours, but the stirring was con­
tinued for another 7 hours. The product was fractionated
through column 11. Yield 183.4 g, 53.2%, b.p. 107-108 @
104 mm. The percentage yield reported is overall from the
n-butyric acid.
8
.Preparation of Alpha-Bromo-Diethvlacetyl bromide
In a 200 c c , 3-neck flask attached to a dropping fun­
nel, a reflux condenser, and a mercury sealed stirrer,were
placed 67 g (0.5 mole) of diethylacetyl chloride (b.p. 139
@ 730 mm, n^9 1.4235), and 1 cc of phosphorus tribromide.
To this was added slowly (1.5-2 hours) 106 g of dry bromine
The reaction was illuminated for
6
hours with a 200 watt
light bulb,using reflectors. The product was fractionated
through column 3E3E. Yield 96 g, 74%, b.p. 106-107 @ 48mm,
n20D 1.5040-1.5087
9. Preparation of Alpha-Bromo-Phenvlacetanilide
In a 1 liter, 3-neck flask attached to a reflux con­
denser, thermometer, mercury sealed stirrer, and separatory
funnell was placed a solution of 53 g , (0.191 moles) of alphabromo-phenylac etyl bromide(b.p. 130-134, n ^ D 1.6002-1.6012)
in 600 cc of anhydrous ether. The flask was then placed in
an ice salt bath and the contents cooled to 3°C at which
timea solution of 35.8 g (0.385 moles) of redistilled aniline
(b.p.
The
183 at 730 mm)
was ad ded d r o o w l s e with c o ntinuou s
soluti on was f i l t e r e d and the
benzene.
Yield,
36.4. g, m.p.
stirring.
solid e x t r a c t e d with anhy d r o u s
14 3 — 14-4, 47.6%.
A similar r e a c t i o n was run with a l p h a - b r o m o - h a l i d e
fractions, b.p.
105 at 38 mm to 138 at 16 mm,
and with fr ac tion s b.p.
the former,
139 at 15
n^D
n 2 ^D 1.55 0 8 — 1.5889,
1.59 6 0 - 1 . 5 9 6 3 .
With
even t h o u g h the i n d e x of r e f r a c t i o n and the b o i l i n g
points are h i g h for p h e n y l a c e t y l chloride,
phe nyl ace tan ilid e.
W i t h the h i g h e r
nroduct is obt ai ned w h i c h ha s
the o r o d u c t
index fractio ns,
a l o wer m e l t i n g point
which r e q uires several r e c r y s t a l l i z a t i o n s to ourify.
is
a crude
and
The use
of c o m bined fra cti ons h a v i n g i n d i c e s much b e l o w 1.596 y i e l d e d
crude p r o d u c t s which were very diffi c u l t to cr ystallize,
and. the
yields of a l p h a - b r o m o - p h e n y l a c e t a n i l i d e were poor,
b. A l t e r n a t i v e m e t h o d for nre'oaration
To a sus pe ns ion of 30 g.
of m a n d e l i c a n i l i d e in 500 cc of
dry be n z e n e was a d ded in 1 h o u r w i t h constant
solution of 16 g (0.059 moles)
dry benze ne.
The b e n z e n e
sol uti on was d e c a n t e d from the v iscous
The
the w a s hings no longer
s o l u t i o n was then c o n c e n t r a t e d
to about 75 c c . , and a l l o w e d to crystallize.
47%, m.p.
14 4 0 C .
a
of P 3 r 3 d i s s o l v e d in 100 cc of
residue an d w a s h e d with w a t e r u n t i l
showed an acid reaction.
stirring,
Y i e l d 18 g . , or
No d e g r e s s i o n of the m e l t i n g oo int was obtai n e d
b y m i x i n g this n roduct
with that
ob tained b y the first m et hod.
1 0 * P r e p a r a t i o n of A l p h a - B r o m o - I s o b u t y r a n i l i d e
Aloha-bromo-isobutyryl bromide
d i s s o l v e d in 400 cc.
(53.3 g. , 0.33 mole)
was
of a n h y d r o u s ethe r ,and placed, in a 3 - n e c h ,
19
1 l i t e r flask a t t a c h e d to a se carat-ory funnel,
sealed stirrer,
and a the rmometer.
Th e
a mercury
f l a s k was i m m e r s e d
in an ice b a t h d u r i n g the a d d i t i o n of a sol ution of 48 g.
(0.53 mole)
of anili ne in 10 0 cc.
o f anhydrous
t e m p e ratur e was m a i n t a i n e d b e l o w 15°C.
was
c o n c e n t r a t e d to y i e l d 33 g.
crude,
11.
The ethe r
of anilid e,
m.p.
and 83-85° after one r e c r y s t a l l i z a t i o n
The
so lu ti on
77 -83°
(79$ yield).
Pr e p a r a t i o n of A l p h a - B r o m o - t - B u t y l a c e t a n l l l d e
In a 500 cc.,
stirrer,
3-neck flask, a t t a c h e d to a m e r c u r y
a condenser,
solut ion of 38.3
g.
(0.103 moles)
of a l p h a - b r o m o - t - b u t y l ­
of d r y ether.
This m i x t u r e was
co oled In an Ice b a t h to b e t w e e n 0 and 10°.
g.
(0.333 moles)
added with r apid
stirring.
The
solid was
f i l ter ed off,
wate r insolubi e p o r t i o n was added
solid o b t ained b y e v a p o r a t i o n
of tin- ether
One c r y s t a l l i z a t i o n from e t h e r y i e l d e d 33 g.
m e l t i n g from 149-153°C.
Recrystallization
c o n t a i n i n g 1 0 $ acetone gave
from 1 5 3 — 1 5 3 ° C .
A s o l u t i o n of
of a n i l i n e in 135 cc of d r y e ther was
w a s h e d with w a t e r and the
to the
sealed
and a d r o p p i n g fun nel was p l a c e d a
acetyl b romide in 300 cc.
34.5
ether.
31 g.
Th e P e r c e n t a g e
solution.
of p r o d u c t
from l i g r o i n
of p r o d u c t m e l t i n g
yield,
b a s e s uoon the re-
crystallized material was 70,5.
12, Preparation of Alpha-Bromo-n- Butyranilide
Alpha-bromo-n-butyryl bromide, (125g, 0,543 moles)
was dissolved in 500 cc of anhydrous ether and placed in
a 2 liter, 3-neck flask fitted with a mercury sealed stir­
rer, a dropping funnel, and a thermometer. The flask was
placed in an ice bath and cooled to
solution
(101
g,
1.1
mole in
200
10
°, then the aniline
cc of anhydrous ether)
was added in rapid drops, but at such a rate that the
temperature did not rise above 10°. The reaction mixture
was filtered, and the solid extracted with ether. Yield
115 g, 87%, m.p. 97-99 after 2 recrystallizations.
13. Preparation of Alpha-Bromo-Diethvlacetanilide
Alpha-bromo-diethylacetyl bromide, 40 g, 0.15 mole
was dissolved in 400 cc of dry ether in a 1 liter 3-neck
flask attached to a mercury sealed stirrer, a thermometer,
and a dropping funnel. The flask was immersed in an ice
bath and cooled to 5°C when the addition of 22.5 g (0.25
mole)of aniline in 200 cc of dry ether was started. At the
end of this addition, further additions of aniline did
not produce a precipitate. The solid was extracted with
ether and the extracts combined with the original ether
solution and concentrated. The last traces of ether were
removed by vacuum. The oil which remained could not be
crystallized by cooling in an ice isalit bath for 4 hours
nor by leaving it in an ice chest at about lB°for several
days. Attempts to crystallize the material from petroleum
ether likewise failed. The compound contains both nitrogen
and bromine. This anilide has recently been crystallized
by G.C. Bassler by allowing it to remain in the freezing
unit of a refrigerator for several days#
14. Preparation of N-Cyclohexyl-t-Butylacetamide
To a solution of alpha-bromo-t-butylacetyl bromide (14.5g)
dissolved in
of
11.2
200
cc of anhydrous ether, was added a solution
g of cyclohexyl amine in
100
cc of anhydrous ether
The apparatus was the same as for the preparation of alpha:
bromo-anil ides, and the conditions were the same. The pro­
duct was filtered, the solid washed with water, and the
insoluble material combined with that obtained from the
ether solution. Yield, 15 g, 96.7% m.p. 184 after one re­
crystallization from 95% ethanol.
15.Preparation of Alpha-Anilino Phenvlacetic acid
Mandelonitrile (0.75 mole) was prepared according to
the directions given in Organic Synthesis, Collective Vol­
ume L, page 329. This product was mixed with 150 cc of 95%
ethyl alcohol, and 70 g of redistilled aniline , and
heated on a water bath at 97
for 2 hours, then allowed to
stand overnight. On shaking, the oil layer solidified and
was filtered off# Yield 122 g . , 78 % of alpha-anilinObenzyl cyanide based upon benzaldehyde used for the pre­
paration of the mandelonitrile.
Mandelonitrile (100 g . ) was dissolved in 1000 g. of
cold conc. sulfuric acid and allowed to stand for
2
days
after which it was wanned to 50° for 10 minutes, then pour­
ed on to 3500 g. of ice and neutralized with conc. ammonia.
Yield 96 g . 89% of alpha-anilino-phenylacetamide, m.p. 120122
° after recrystallizing from boiling water in which it
is soluble to the extent of about
10
g. per liter.
Of the above product, 20 g. was fefluxed with 200 cc
of
6
N hydrochloric acid until the solution became clear.
Upon neutralizing with ammonia, alpha-anilino-phenylacetic
acid precipitated out, m.p. 182-183°. Yield almost quatitative.
16. Preparation of Alpha-Anilino-t-Butylacetic Acid
Alpha-bromo-t-butylacetic acid was prepared by treat­
ing 58 g, (0.5 moles) of t-butylacetic acid with 104 g,
(0.65 moles) of bromine using 1 cc of phosphorus tribromide as a catalyst. The apparatus used was similar to that
used for the preparation of the alpha-bromo-acid halides.
The reaction mixture was maintained at t>0-70°and was
illuminated by a 200 watt light bulb. The product was dis­
tilled from a Claisen flask at 20 mm. Yield 82.5 g (84.6%)
b.p. 130-131 @ 20 mm. m.p. 70-72°C.
This product was converted to the anilino acid by the
method of Duvillier (47). To a solution of 24 g (0.256
moles) of redistilled aniline in 60 cc of anhydrous ethe-rw
was added 25 g (0.128 moles) of alpha-bromo- t-butylacetic
acid. After standing 12 hours, the ether was removed and
the residue heated for 2 hours at 130°. During this time
the liquid mass slowly solidified. After cooling, the
product was ground with warm water to remove the aniline
hydrobromide? cooled, and filtered. The residue was taken
up in ether, the solution filtered, the ether removed, and
the remaining reddish oil extracted with 2-3 liters of
boiling water (200 cc for each extraction). The product
from these extractions was recrystallized from water.
Yield 7 g or 26.2 %, m.p. 135-137°.
17. Preparation of Mandelic Acid
This method for the preparation of mandelic acid was
worked out by Dr. J.G. aston, Mr. D.M. Jenkins and Mr. J.D.
Newkirk in this laboratory.
In a 3-liter, 3-neck round bottom flask fitted with a
stirrer, a thermometer, and a dropping funnel, was placed
a solution of 234 g, (5.3 moles, 20% excess) of sodium
hydroxide dissolved in 2100 cc of water. After heating the
solution to
6
CP the addition of 300 g (1.59 moles) of di-
chloro-acetophene (prepared by adding the calculated amouifct
of chlorine to acetophene, b.p. 140-144 @ 20-25 mm,
n20D 1.5685 ) was started and regulated so that the temper­
ature did not exceed 65°. When the addition was complete
(about
2
hours) the solution was stirred for an hour, then
cooled and neutralized with 250 cc of 12 N hydrochloric
acid (10% excess). The mandelic acid was recovered by con­
tinuous extraction with ether for 72 hours. The yield after
one recrystallization from benzene was 205 g (m.p. 115-117)
or 85%. Extraction for 24 hours yields only about 70% of
the product, while extraction for longer periods of time
increase the yield only slightly.
18• Preparation of Mandelic Anilide
A mixture of 100 g (0.66 moles) of mandelic acid (m.p.
115-117) and 62 g (o . 6 6 moles) of aniline was heated for
30 minutes at 180-190°. The crude product was recrystallized
from 50% ethyl alcohol, yielding 124 g of product, m.p. 14^“
146 crude, 145-146 recrystallized, 82%.
19. Preparation of 3-Phenvl-Oxindole
Mandelic anilide, (15 g . , m.p. 145-146) was dissolved
in 75 cc of sold conc. sulfuric acid and allowed to stand
4 hours at room temperature. The solution was then slowly
poured onto 400 cc of cracked ice with continuous stirring.
The pink solid was filtered, washed well with water, then
recrystallized from 95% ethanol. Yield 4 g, 29% m.p. 182183.
20• Reaction of Alpha-Bromo-Phenylacetanilide with aqueous
NaOH
a)
A preliminary reaction was carried out using 11.5 g of
the anilide and 150 cc of 10% NaOH. The reactants were re­
fluxed for 30 minutes, then the mixture-was cooled and fil­
tered, yielding 9.1 g of alkali insoluble product. From
the alkaline filtrate was obtained an acidification, a
small amount of acid insoluble product(0.4 g) which burn­
ed, leaving a small residue.
An attempted recrystallization of the alkali insoluble
products from benzene resulted in small fractions having
relatively wide melting ranges..
25
A n attempted separation of this product by chromato­
graphic absorption from benzene solution, using activated
alumina resulted in
11
small fractions, none of which had
good melting points. The bulk of the material remained on
the alumina and could not be extracted by benzene, benzenealcohol mixtures, ethyl alcohol, mor ethyl acetate,
b)
On the basis of the previous experiment, lOg of anilide
was boiled with 50 cc of 10% NaOH under a reflux condenser
for 30 minutes,then allowed to cool. The alkaline liquid
was decanted from the yellow, alkali insoluble residue (I)
and acidified. The precipitate which formed (0.5g., II) ^
was filtered, and the acid solution extracted with ether.
The ether extract yielded 0.4 g. of solid, III.
Residue I was dissolved in warm alcohol and fractionary
precipitated by adding water. All fractions except
6
were
precipitated as oils, which after being worked onjai porous
plate, solidified. The results are summarized in the
following tables:
Fraction
Weight
Melting
g
105-115
1
1.2
2
1.3
95-101
3
0.8
82-88
4
1.1
72-80
5
1.0
68-95
6
0.7
142-146
7
0.3
95-105
8
0.2
102-134
Fractions 1-5 were redissolved in alcohol as before
and precipitated in three fractions by the addition of
water* Fraction 1 was then
redissolved in a fresh sam­
ple of alcohol and reprecipitated by water. The mother
liquor from this precipitation was then used to dissolve
fraction
2
, adding slightly more alsohol if necessary to
bring about solution. The process was repeated for fraction
3, This entire procedure was then repeated for twelve
crystallizations when fraction
1
had attained a melting
point of 145-146 and fraction 3, 143-146, A mixed meltingnpoint with these two fractions was 75, showing that e^eem
though their melting point ranges are close, they are not
the same substance. A
6
mixed melting point with fraction 3 and
showed no depression, m.p, 143-146, and is therefore
mandelic anilide as will be shown. Fraction 1 has not
been identified. Fraction 1 after this recrystallization
weighed 1 g, and fraction 3 weighed 0.5 g. The mother
liquors on evaporating to dryness left an impure solid
which was not further studied.
Fraction
6
was recrystallized from alcohol., forming
plates, m.p. 148-149. Elementary analysis showed nitrogen,
but only a very faint trace of halogen which might have
been due to imcomplete removal of HCN. It was thought that
this product might be mandelic anilide, therefore a sample
of mandelic anilide was prepared as described earlier, and
a mixed melting point taken, m.p. 145-146 . No depression
Residue II redissolved in dilute sodium hydroxide and
reprdcipitated by adding dilute acid, m.p, 172-185, On re­
crystallization from 50% ethyl alcohol, the melting point
was raised to 181-183. The reported values for alj)haanilino-phenylacetic acid were 164-168, 173-175 and 183.
3
-phenyl oxindole, aa other possible product was also re­
ported as melting at 182-183.
The unknown was found to reduce alkaline permanganate
solution slowly, to dissolve in cold conc. sulfuric acid,
a cold conc. sulfuric acid solution, on grinding with potas­
sium permanganate gave d dark brown color, a white preci­
pitate was formed on heating with Fehlings solution, and a
pink color formed with ammoniacal silver nitrate, but no
reduction. These properties are reported for 3-phenyloxindole with the exception that the oxindole reduces ammon­
iacal silver nitrate. A sample of the oxindole was prepared
as described earlier. A mixed melting point showed a depre­
ion of
20
°, therefore the unknown was not the oxindole.
Alpha-anilino-phenylacetic acid was then prepared, and a
mixed melting point showed no depression.
Precipitate III from the ether extraction of the acid­
ified reaction liquid was recrystallized from benzene, m.p.
116-118, mixed m.p. with mandelic acid 116-118. The pro­
duct appears to be mandelic acid. In order to prove this,
0.2 g
was reacted with 0,13 g of aniline at 180-190?
The product was washed with 10% HC1, dried on a porcelain
plate, and recrystallixed from henzene, m.p, 142-146 -^fter
two recrystallizations, mixed melting point with SSmdelic
anilide prepared as described earlier, 145-146. Precipitate
III concluded to be mandelic acid,
c)
A third reaction was carried out with alpha-bromo-
phenylacetanilide in order to abtain better figures on the
yields of these products. The reaction was carried out as
above, using 30g. of anilide and 150 cc of 10% sodium
hydroxide. The alkaline solution yielded 2 g of alphaanilino-phenylacetie acid and
1.2
g. of crude mandelic acid.
The alkali insoluble residue was then extracted with cold
10%
sodium hydroxide until no more precipitate was obtain­
ed from the extracts on acidifying. Approximately 0.5 g.
was obtained in this manner, thus making the total yield
of anilino acid 2.5 g, crude.
The residue from the alkali extraction was then extrac­
ted with several portions of 25% ethyl alcohol by heating
on the steam bath. On cooling, a precipitate formed. By
this method, 4.9 g. of mandelic anilide (m.p. 144-146)
were obtained. Further crystallization of the residue from
this extraction was not attempted. The yields found are
summarized belowj
alpha-anilino-phenylacetic acid....1 0 %
mandelic acid
7.6%
mandelic anilide
21%
total
38.6%
21. Reaction of Alpha-BromO-t-Butylacetanilide with aqueous
NaOH
a)
This reaction was carried out by placing 6.7 g . of
alpha-bromo-t-bu£ylacetanilide (0.026 moles) in a
200
cc
3-neck flask with 40 cc of 10% sodium hydroxide. The flask
was fitted with a mercury sealed stirrer, a dropping fun­
nel, and an outlet tube attached to a dondenser for dis­
tillation. The reaction flask was heated at such a rate
that slow distillation occurred, water being added to
maintain the volume. The distillate smelled strongly of
phenyl isocyanide and also gave a qualitative test for an
aldehyde or ketone using a solution of 2,4-dinitrophenylhydrazine. The distillation was continued until 75 cc of
distillate had been obtained and no further odor of phenylisonitrile could be detected. The test for the ketonic
substance was also negative. (To the distillate was added
5 cc of 12 IT hydrochloric acid and the mixture allowed to
stand 1.5 hours for conversion of the phenyl isonitrile to
aniline hydrochloride). At the end of this time no odor of
isonitrile was noticeable. The acid solution was steam
distilled and the distillate treated with 2,4-dinitrophenyl
hydrazine reagent which, gave a yellow precipitate having a
m.p. of 117-118° after recrystallization from ethanol. This
is not the derivative of trimethylacetaldehyde as expected.
The distillation residue was made alkaline and again dis­
tilled, the distillate being caught in dilute hydrochloric
acid. The yi eld of aniline aydrochloride was 0.12 g.
The alkaline solution from the original reaction was
filtered,.giving a small amount of alkali insoluble pro­
duct. The filtrate was acidified, yielding 4 g of dry pre­
cipitate having a melting point of 136-138 with decomposi­
tion. Its neutral equivalent was found to be 213.
Theo­
retical for alpha-anilino-t-butylacetic acid is 207. m.p.
alpha-anilino-t-butylacetic acid 135-137, mixed melting
point 136-138. The two products were identical.
Yield, anilino-acid, 4 g
alkali insol.0.9 g
78%
17% if hydroxy anilide
The other reaction products consist of a ketonic compound,
phenyl isonitrile, and a trace of a waxy solid obtained by
ether extraction of the reaction liquid after removal of ti
the anilino-acid.
b)
(©
A second raction was carried out in the same manner as
just described except that the alkali was slowly added in
the hope that the lower concentration of base might per­
mit/a better recovery of the aldehyde or ketone.The results
were the same as described for the first reaction.
22
Reaction of Alnha-Bromo-isobutvranilide with Aqueous
NaOH
a)
Alpha-bromo-isobutyranilide (6.1 g, 0.025 moles) was
mixed with 40 cc of 10% sodium hydroxide in a 200 cc,3neck flask attached to a mercury sealed stirrer, a dropp­
ing funnel,and an outlet tube to a condenser for distill­
ation. The flfeesk was heated to boiling and stirred. Water
was added to maintain the volume. The distillate smelled
strongly of phenylisocyanide. No precipitated was formed
with a 2,4- dinitrophenylhydrazine solution, thus showing
no ketonic products in the distillate. After 180 cc of
distillate had been collected, no odor of isonitrile was
noticeable.
On acidifying the alkaline reaction mixture, a
small amount of sodium silicate was precipitated, but no
anilino-acid.
The acidified solution gave a positive
ferric chloride test, indicating the presence of an alphahydroxy acid.
b)
A second reaction was carried out as above, collect­
ing the distillate in dilute hydrochloric acid.A strong
odor of isonitrile was present as before, but no test
was obtained for an aldehyde or ketone with 2,4-dinitrophenyl-hydrazine. The distillate, on evaporating to dry­
ness gave 1.5 g of residue, presumable aniline hydrochlor­
ide formed from the phenylisonitrile and aniline from
hydrolysis of the anilide. This represents 53% of the theo
retical aniline obtainable from the reaction. About 0.1 g
of alkali insoluble material was also obtained, but no ani
lino-acid could be found, and no alpha-hydroxy acid could
be recovered.
23. Reaction of Al-pha-Bromo-n-butvranilide with Aqueous
NaQH
Alpha-bromo-n-butyranilide (10 g, 0.0413 moles) was
32
mixed with 40 cc of* 10% sodium hydroxide in a 200 cc 3-neck
flask fitted as described before. The mixture was heated to
boiling and water added as necessary to maintain the vol­
ume. The distillate possessed a strong odor of phenyl
isocyanide, and the distillate, when evaporated to dry­
ness after acidifying with hydrochloric acid, yielded
1
.8 g
of solid. A slight 2,4-dinitrophenylhydrazene test was ob­
tained from the first few cc of distillate.
The alkaL ine reaction mixture was filtered and the fil­
trate neutralized with HC1, forming 5.2 g of crude alphaanilino-n-butyric acid which after re crystallization melted
at 143-144°. Yi&fed 77%
24. Reaction of N-Cyclohexyl-Alpha-Bromo-t-Butylac etamide
The reaction was carried out as described above, using
10 g of N-cyclohexyl-alpha-bromo-t-butylacetamide and 40 cc
of
10%
sodium hydroxide. No apparent change was observed
in the reaction flask, no odor o£ an isonitrile was present.
The solid remaining from the reaction melted at 133-184°
after one crystallization from 95%alcohol. This is the same
as for the unreacted material. There was apparently no
reaction.
The alkaline solution, when acidified, precipitated a
small amount of sodium silicate, but there was no organic
material.
32a
Summary
1 . A l p h a — b r o m o - p h e n y l a c e t a n i l i d e has been p r e p a r e d and
t r e a t e d wi th 10 $ aqueous
sodium h y d r o x i d e to p r o d u c e
a l o h a - a n 11 ino— p h e n y l a c e t i c acid,
acid,
m a n d e l i c anilide, m a n d e l i c
an d u n i d e n t i f i e d products.
3. A l p h a - b r o m o - t - b u t y l a c e t a n l l l d e h a s b e e n p r e p a r e d an d
treated
with 10 $ a q u e o u s
sodium h y d r o x i d e
to give
a l o h a — a n i l i n o - t — b u t y l a c e t i c a c i d in good yield.
3. A l o h a - b r o m o - i — b u t y r a n i l i d e ha s b e e n p r e p a r e d an d treat ed
w i t h 1 0 $ ao u e o u s
sodium hydrox ide .
a c l d was formed.
was not
The product,
No a l o h a - a n i l i n o -
w h i c h was
water
soluble,
isolated.
4. A l p h a — b r o m o — n— b u t y r a n i l i d e lias b e e n urepared
t r e a t e d with 10$ a queous
sodium hydr ox ide.
an d
A g o o d yi eld
of al'o a— a n i l i n o - n - b u t y r i c a c i d was obtained.
5. A l p h a - b r o m o - N - c y c l o h e x y l — t— b u t y l a c e t a m i d e ha s b e e n
p r e p a r e d an d t r e a t e d w i t h a q u e o u s 10 $ sodium h y d r o x i d e
for several hours.
No r e a c t i o n occurred.
1
PART B
The P r e p a r a t i o n
of
D i e t h y l Ketiraine Solutions
I HISTORICAL REVIEW
The literature on the imines can be conveniently
divided into three classes;
1
( aliphatic,
2
) aromatic, 3 )
and cyclic. Thorpe (19) suggested that the term imine be
C\
used for the compounds of the structure C-NH and that com­
pounds having the structure CrHH be called aldimines and
ketimines. The compounds having the latter structure are
readily hydrolized to the corresponding aldehydes or
ketones and ammonia by dil. mineral acids.
This review will cover only aldiww« and ketimines.The
.✓
literature on the aldimines is sparse and much of it is in­
conclusive.
The first published account of the preparation of an
aliphatic imine seems to be that of Mixter(20), who in 1877
prepared the silver nitrate salts of ethylidene imine and
isovaleraldimine by adding the aldehyde to silver nitrate
solution containing an equi^olecular amount of ammonia.
The precipitated compounds are given the formula
(CH3 CH-HH) 4 .2 Ag]Sr0 3
and
(C4HgCH =NH)gAgNOg
Lieberman and Goldschmidt(21),Goldschmidt(22), and
Reychler(23) obtained similar results. The composition
of the silver nitrate complex depends upon the method of
preparation.
Bethal and Choay(24) in 1892 report the formation of
chloral and isochloraldimide by dehydration of chloral
ammonia with chloral anhydride.
Equation 1
CClgCHO
.o h
CCI'3^n
q CHC’
.
NNH2
NH3
>
»
c c i 3 c h XnH2
c c i 3c h -=k h
h 2o
Delepine(25) has also reported chloralimine and claims
that it exists as the trimer rather than as the monomer
altho the molecular weight depends upon the solvent used.
Delepin (26) and Aschan (27) report the preparation of
ethylidene imine by dehydration of acetaldehyde ammonia
in vacuo over conc. sulfuric acid. The products obtained
were reported as either dimers or trimers.
Strain (28) attempted the preparation of a series of
imines from ethylidene imine to hexaldimine by the reac­
tion of aldehydes with liquid ammonia followed by dehy­
dration of the aldehyde ammonia formed using calcium amide.
In most cases it appears that his aldehyde ammonias were
not dehydrated to the imine or that the hydro-amide was
formed.Ethylidene imine seems to have been obtained satis­
factorily as the trimer and converted to the monomer by
heating to 260° then cooling the vapors rapidly.
Berg,by the reaction of KOH or !TaOCH3 with N-chloroamines, has obtained several solutions which have the
properties to be expected from imines, but has failed to
isolate any of these compounds.
No references have been found to the preparation of
aliphatic ketimines.
The literature concerning the aromatic imines is much
more complete than that on the aliphatic analogs. Grignard
and Escourrou (30) in 1925 prepared phenylacetaldimine by
the hydrogenation of benzyl nitrile at 200°C and 220 mm
pressure using Pt 2 0 s as the catalyst. Benzylidene imine was
prepared by hydrogenation with nickel as the catalyst at
150° and 50 mm. The use of higher pressures increases the
yield of the amine.
Strain (31) has prepared benzylidene imine from hydrobenzamide, (C0 H 5 CIO 3 N 2 9
in liquid ammonia using ammonium
nitride,chloride, or bromide as a catalyst.
Equation 2
C6H 5CH*
N
C 6 H 5 CH(
NH3 (liq) -------- 3 CgHgCHs- NH
CgHgCH^
This compound was found to revert to hydrobenzamide when
dissolved in solvents other than ammonia or when distilled
under vacuum, On treatment with potassium amide the imine
forms the potassium salt.
Hydrolysis of beta-phenylethyl-
idene imine with 5% KOH yielded the aldehyde.Reduction
using sodium in ethyl alcohol yielded the amine.
Moureau and Mignonac (32) have prepa.red a series of
aromatic and aromatic-aliphatic ketimines by the action of
36
G-rignard r e a g e n t s
(bromides)
upon n i t r i d e s to give a d d i t i o n
complexe s w h ich are d e c o m p o s e d wi th ice and a m m o n i u m ch loride
o
at 150 C.
E q u a t i o n 3.
RG=N
+
R 1M g B r
RC*NMgBr +
Hs°
---- >
----^
The yields vary from 60— 92/£>.
were basic,
colorless,
^^NlIgBr
R R 1C=NH
The
+ MgOHBr
comp oun ds
thus p r e p a r e d
oil y l i q u i d s or l o w m e l t i n g solids
and have h i g h In d i c e s of refraction.
could be d i s t i l l e d in vacuum.
All of t heir p r o d u c t s
Th= acyl d e r i v a t i v e s of the
imines w e r e obtai n e d if the a d d i t i o n c o m pound was treat ed
with a r o m a t i c or al iph atic a c i d chlorides,
E q u a t i o n 4.
R C ^ N M gBr
+
^ R R 1C = N O O R
RG0Cl
i nst ead of b e i n g d e c o m p o s e d
4
MgBrCl
w i t h ice and g p m o n i u m chlo rid e
C u l b e r t s o n and c o - w o r k e r s
(33)
h a v e u s e d the above
m e t h o d in the o r e o a r a t i o n of h y d r o x y o h e n y l an d furf ury lohe nyl ket imi nes .
Cam-obell
(34)
used benzyl magnesium
chloride an d b e n z y l n i t r i l e . l n the o r e o a r a t i o n of p h e n y l benzyl ketimine
and r eports this comoourid to d e c o m o o s e
to
a y e l l o w g u m on
exposure to air, to form d e s o x y b e n z o i n
with
water,
to react
with N a O C l or N a O B r to form N - h a l o - d e r i v a —
;
37
tives.
The
c h l o r o - c o m p o u n d is the more stable, but b o t h are
r ead ily decomposed.
W i t h p h e n y l - b e n z y l ketim ine ,
aqu eo us
potas s i u m hydro x i d e or oduces b e n z i l i c acid.
H o u b e n and F ischer
(35)
re;oort the synt hes is of k etimines
and ket o n e s thr ough the c o ndensation of v a r i o u s aromatic
compo und s with nitrilec.
E q u ation 5
cci3
0H 3 CsH 5
OCI 3 CN — ?’p_Ch 3 c3 h /
° i N H 'H C 1
This is k n o w n as the H o u b e n — Fi s c h e r synthesis.
ensation of n i t riles wi th phenol,
methyl
ethers in ethyl
ether u s i n g
■
The co nd­
me thyl p h e n o l s an d ohenylzinc ch loride and h y d r o ­
chloric ac id as the cond e n s i n g agent has b e e n reoorted.
Ferric
chlorid® and a l u m i n u m chlori de have als o be en used.
The yields vary from 31-95$.
T h c h y d r o l y s i s of these
com pounds to ketones was car r i e d out in y i e l d s from 20- 5 0 $
The condensation of* benzene trichoromethyl cyanide (36)
if aarried out in the cold with zinc chloride-hydrochloric acid gives small yields of ketimine along with phenyltrichloromethyl ketone. The use of aluminum chloride in
benzene (37) has been found in some cases of condensation
of trichloromethyl cyanide with alkylbenzenes and phenols.
The di-and tri-chloro ketimines obtained are comparatively
stable to water and dilute alkali.
Bresson and Culbertson (38) unsuccessfully attempted
to prepare ketimines from benzonitrile and phenols,cresols,
catechol, pyrogallol and carvaotol using zinc chloride or
aluminum chloride in anhydrous ether.
Positive results
were obtained with quinol, and meta-hydroxy-phenyl methyl
ether.
Beta-bromonaphthalene has been condensed with betacyanonaphthalene to give the ketimine. Alpha-beta naphthoketimines have basn prepared by the same method (39).
Mignonac (40) reports the preparation of aromatic and
mixed aliphatic-aromatic ketimines by reaction of the cor­
responding ketones with ammonia over thorium oxide at 300400°.
Equation
6
CHS
THOg
300-400°'
c6 h 5
cS HH
/
£6*5
Complex condensation products were not formed
Strain (41) reporsts the preparation of benzyl-methyl
ketimine in 3 % yield by the reaction of Benzyl-methyl
ketone with liquid ammonia at 180°. The use of aluminum
chloride increased the yield to 30%. Benzophenone keti­
mine was prepared in
20%
yield by the same reaction.
Equation 7
(C 6 H 5 )2C - C H N 0 2 V- H 2 ----^
(C 6H 5 )2CHCH -KH
Kohler and Drake (42) found that diphenylacetaldimine
could be prepared quantitatively by the reduction of betadiphenyl nitroethylene. Other nitro compounds tried did
not yield the ketimine. Mignonac (43) catalytically hydro­
genated a series of aromatic and mixed aromatic and aro­
matic-aliphatic oximes
to the corresponding
imine. The
products were distilled under pressure which was reduced.
Hellerman and Sanders(44) ha.ve prepared diphenyl ketimine
by the reaction of the corresponding amine with hypobromite
followed by splitting out of HBr with sodium ethylate in
alcohol.
Equation
8
(C 6H 5 )2CHNC1
N a O C 2H 5 — > (C 6H 5 )2C =NH ^ N a C l ^ N a O C 2H 5
Wagner (45) has prepared cyclobutanone,pentanone-3, heptanone-3, and cyclohexanone in yields varying from 25% to
50% by the reaction of sodium methylate on the corres­
ponding N-chloro-amines followed by hydrolysis.
II DISCUSSION
A literature survey of the reported work on imines has
shown that
very little is know about the aliphatic aldi-
mines and ketimines. The work of Delepine, Behai and Choay
and of Aschan, in which aldehyde ammonias of acetaldehyde -.
and of chloral were dehydrated, yielded trimers of the cor­
responding imines. The structure of these trimers was the
subject of some controversy, and is still uncertain. Dele­
pine reported the fonration of the monomer from the trimer
of ethylidine imine by heating to 260°C and rapidly con­
densing the vapors. However, other reports showed that th«se
compounds also lost ammonia and formed substituted pyridines
on heating.(31)
Strain treated aldehydes with liquid ammonia and de­
hydrating agents, but obtained no products which were iden­
tified as imines. Instead he apparently obtained hydroamidte
or aldehyde ammonias which formed substituted pyridines.
i-C3H7CH^.
i-C3H7C H I^ -^-3 H20
F
i-C3 H 7 CH/'
/
i-C3H7CH0-^2NH3 ---7
H
C
CH 3
(CH 3 C H 2 C H = F H ) 3 -- 7
H
\\
c
11
c
C CH3
I
\
*
2 FH3 V-H2
C C2H5
N
(Jsrignard and Escourrou hydrogenated nitriles at reduced
pressure to form a few aromatic imines, while Kohler and
Drake hydrogenated alpha-beta-uns&turated nitro compounds
and obtained the corresponding imines in a few cases. These
reactions are few in number.
The most used method was that of Moureau and Mignonac
in which nitriles were reacted with Grignard reagents and
the complexes decomposed by ice and ammonium chloride at
- 15° C
RC =l\r */* R ’MgBr —
MH+C1
RR'C-NMgBr *
ICE
-15°C
RR'C=NH
The studies of Berg and Hellerman and Sanders, in
which N-chloroamines were treated with bases such as
potassium hydroxide and sodium methylate, resulted in the
preparation of diphenyl ketimine and of solutions thought
to contain the imines.
(C 0 H 5 )2 CKNH 2 -t- Br 2
(CgHg)gCHNHBr -h NaOCH 3
y
(C6 H5 )2CHNHBr
(CgHg) 2 C* NH-/- RaBr ^-CH3 0H
Wagner (45) , in applying this reaction to the syn­
thesis of ketones obtained cyclobutanone, pentanone-3,
heptanone-3 and cyclohexanone, and diethyl ketone in yields
varying from 25% to 80%.
The present work has resulted in the preparation of
ether solutions -which contained a basic substance possess­
ing the properties to be expected from the ketimine. The
reaction by which the substance would be formed consists
of the removal of HC1 from one molecule of the F-chloroamine as follows:
1. (C 2 H 5 )2CHNHC1 -r-NaOCH3
(C 2 H 5 )2 C=NH ^-NaC 1 -t~CHQGH
There is also the possibility that instead of* splitting
out HClj NaCl might be split out from the two reactants ,
forming an hydroxylamine derivative.
2 . (C 2H 5 )2 C H W H G l v - N a O C H 3
(C 2H 5 ) g C H m O C H g H B T a C l
A survey of the literature shows no work in which hydroxyl­
amine derivatives of this type have been by this method
prepared.
The evidence which has been found in this work and
which seems to favor reaction
1
is summarized below:
1.The solution reacted with water to form a base and
diethyl ketone.
(C2 H 5 )2 C-NH-PH20 — y (C2 H 5 )2 C = 0 -A-KH3
2
.Hydrogenation of the ether solutions containing the
reaction product yielded 3-amino-pentane.
(C2 H 5 )2 C = N H ^ H 2
y (C2 H 5 £CHMH 2
3.Dry hydrogen chloride gas, when passed into an ether
solution of the product precipitated a gummy semi­
solid, presumably the hydrochloride.
(c2h5 )2c=]N!h-/-hci —
y (c2h 5 )2g=nh.hci
4.The abover hydrochloride precipitate, when washed re­
peatedly with dry ether, then hydrolyzed by water,
formed diethyl ketone.
(C2H5 )2C^NH-*fICl "rH2° ~ ^ (C2H5 >2C~0 ^ :
n H4 c :l
5.Distilling the ether from these solutions, using
vacuum, gave an ether distillate which was basic
and which gave the 2,4-dinitrophenylhydrazone of*
diethyl ketone. Two possible interpretations of
this are:
a.The inline is volatile, distilling with the
ether, then hydrolizing to the ketone and amonia
when water is added..To account for such volatil­
ity, it would appear that the inline was present
as the monomer.
b.The inline might react with the methanol,formed
in the sodium methylate reaction, to yield diethyl
ketone and methyl amine.
(c2h 5 ) c -nh
+-
hoch3
(CgHg^c-o
-i'
ch3nh2
An attempt to isolate methyl amine as its benzoyl
derivative failed, indicating that reaction did
not occur to any large extent.
Fractionation of a concentrate,b.p. 58-90, n2<^D
1.3908 (maximum), resulted in a high boiling resi­
due, n2C^D 1.4960, which was insoluble in water,
soluble in dilute (1 0 %) hydrochloric acid and re­
precipitated by alkali, and did not give a 2,4dinitrophenylhyarazone as did the original concen­
trate. This substance might possibly be a substi­
tuted pyriding (2 ,4 ,6 -triethyl-
3
,5 -dimethyl-pyri­
dine). This compound is not known and insufficient
material was available for its identification.The
formation of substituted pyridines from aldehyde
ammonias and possibly from imines, was reported
by Strain(31).
g 2h 5
3CC2H5)2C-NH-
C
/ ^
CH3-C
G-CH3
//
i
-tG2H5-G
C-C2H5
'v //
N
2
nh 3 k: 2 H 6
7. The isolation of methanol as a product of the reaction
is likewise in accord with the formation of the imine
by reaction
1
,
There is no apparent reason to eliminated the forma­
tion of the hydroxylamine derivative by reaction 2, Sev­
eral compounds of this type have been prepared by var­
ious workers (47-61)* The methods used for their prepa­
ration are illustrated in the following equations:
^o c 2h 5
C=0
x NHONa
/OC2H5
C-0
-rC2H 5 O N a
x NHOH
OG 2 H 5
C>0
\
Y-CH 3 I
HHONa
/OC2 H 5
G^O
~ h CH 3 I
s HHOCH 3
/OC2 H 5
C^O
-/-HCl(conc)
NHOGH 3
O C 2H 5
C^O
y-HClCconc)
NN(CH3 ) och 3
■T
C 0 H 5 OH
/OC 2 H 5
C-0
v-Nal
\ NHOCH 3
.OC2 H 5
CaO
-v-HI
>N(CH3)0CH3
HC1
nh 2 och3+ co 2 ^ c 2 h 5ci
HG1
CH 3 NH0C%v-C0 2 -rC2 H5Cl
These products can be further alkylated by the use
of alkyl iodides until quaternary ammonium compound is
formed. They are low boiling, N-isopa?opy 1-0-ethy 1-hydroxy 1amine boiling at 78°G.
They form hydrochloride salts,
iff*
chloroplatinates, and picrates. These derivatives are solids
except for a few of the hydrochloride salts. Their reducing
action is quite variable. Most of those known will reduce
Tollens reagent, while only about half of these will reduce
Fehlings solution, even when hot.
Although no hydroxylamine derivatives has been isolated,
such a compound might have contaminated the various frac­
tions obtained. Their separation would not be an easy matter
due to the instability of the imine on heating and to its
reactivity. The hydrogen chloride treatment would have pre­
cipitated both of these compounds. Such a mixture could have
accounted for the oily character of the precipitate. The
titration for chlorine in these-hydrochloride precipitates
does not agree with this since the values obtained were
too high for the imine hydrochloride, and the theoretical
values for the hydroxylamine derivative are even lower.
Calculated (C2 H 5 )2 C=-NHHC1
Found
Found
(C 2 H 5 )2 CHNIIOCH3
29.2% Chlorine
23%
chlorine
33.5% and 34.2%
46
III EXPERIMENTAL
B. Preparation of Diethylketimine
solutions
X . Preparation of Diethvlacetyl Chloride
In a 2-liter round bottom flask, attached to a reflux
condenser vented to a fume trap through a calcium chloride
tube, was placed 464 g*(4 moles) of diethylacetic acid,
(Commercial product, not distilled). To this was added 615 g
( 5 moles) of thionyl chloride(Eastman Kodak Practical),
The mixture was allowed to stand at room tempera.ture for a
week, then refluxed for
8
hours on a steam bath and frac­
tionated through column I. The product (451 g , , 83% of
theoretical) boiled at 137.5 to 140, and had an index of
refraction ( n ^ D ) 1.4240. In addition to this there were ob­
tained 40 g. of higher boiling product and 23 g. of residue*
The yields varied from 73-85%, the lowest being obtained
when the reaction mixture was allowed to stand overnight, and
the highest when the reactants were allowed to stand for
about a week before heating.
II.Preparation of Diethylacetamide
In a 2-liter, 3 neck flask attached to a mercury sealed
stirrer, an inlet tube, and an outlet tube closed by a mer­
cury trap was placed a solution of 270g ( 2 moles) of di­
ethylacetyl chloride (b.p. 137-138) dissolved in 1 liter
of anhydrous ether (stored over sodium). Into this flask
through a tube extending about
2
inches above the surface
of the liquid, was passed a stream of ammonia which had been
dried by passing through a drying train consisting of a
tower filled with lump calcium oxide, a tower filled with
soda-lime, and two
6
ounce bottles filled with flake sodium
hydroxide. The flow of ammonia was adjusted so that a
slight pressure was maintained in the reaction flask. At
the end of 4^- hours no more ammonia was being absorbed.
The mixture was then filtered and the solid extracted sev­
eral times by refluxing with ether. The total yield of amide
(m.p. of crude
109°C, recrystallized 112°C) was
88
g. or
38% of the theoretical. The crude product possessed a
pleasant sweet odor.
The yields in these preparations (maximum 43%) was very
unsatisfactory.
A 0.25 mole run was made using benzene as the solvent
and keeping the other factors the same as before except for
the tempera.ture, which was maintained at 10°C. The yield
was only
21
% of thetheoretical.
In all preparations the total weight of residue from
the extractions was greater than the theoretical for ammon­
ium chloride and the concentrates from the ether extract­
ions were thick, viscous liquids which yielded no more
amide after being subjected to a vacuum for several hours,
then being placed in the ice box for several days. This
reaction is being investigated by Mr. Albert Pahland.
48
III* Preparation of 3-Amino-Pentane Hydrochloride
In a 2-liter,3-neck flask was placed 1680 cc of* a
10% sodium hydroxide solution. After cooling to 0° C
in an ice salt bath, 160 g
(1
mole) of bromine was
added with constant stirring. After the addition was
complete, (about 30 min.) the solution was stirred for
20 min.,then 115 g (lmole) of diethylacetamide (crude
from the above preparation) was added.
When this had
completely dissolved, the ice bath was removed and the
solution allowed to come to room temperature (lhour).
It was then heated to boiling over a period of about
1.5 hours and finally distilled into 200 cc of
6N
HC1.
After a total of 400 cc had been collected, the dis­
tillate was only faintly basic. The yield was 110 g
or 91% of the theoretical.
The product melted at 212-
215°C, m.p. pure product is 216°C«
IV• Preparation of Standard Solutions
1. Calcium Hypochlorite
To 400 cc of water at 0°C
was added 75 g. of
H.T.H. (High Test Hypochlorite, 70%, Mathiason
Alkali). The mixture was shaken thoroughly, allowed
to remain in a cold place for about
20
min., then
filtered giving a clear yellow solution. The strength
of this solution was determined by titration with
standard arsenite solution.
1 cc. hypochlorite 26.15 cc
0.1032 N arsenite
Normality hypochlorite 26.15 x 0.1032
Moles OG1 per liter
2.69/2
2.69
1.35
2. Sodium Thiosulfate
An approximately 0.1 N solution was prepared from
analytical reagent sodium thiosulfate and standarized
against a standard solution of potassium dichromate,
N
0.08705.
3. Silver Nitrate
This solution was made up volumetrically to 1.0000
normal from Bakers c.p. silver nitrate. Titration against analytical grade sodium chloride gave 0.1008 N.
4. Ammonium Thiocyanate
An approximately 0.1 N solution was prepared from
analytical reagent ammonium thiocyanate and standard­
ized against the above standard silver nitrate.N 0.0997
Prep_aration.jQf_J^Chloro-3-Amino-Pentane
A.
In a 3-neck, 500 ccround bottom flask was placed a
mixture of 127.5 cc (0.186 mo}.e ) of calcium hypochlo­
rite solution and
200
cc of anhydrous ethyl ether.
Anhydrous ether was used to avoid contamination of the
product with ethyl alcohol. The solution was surrounded
by an ice bath and stirred for 5 min. ,then 20 g. of ice
was added and a solution of 27 g (0,218 mole) of 3amino-pentane hydrochloride in 80 cc of water (made just
alkaline to litmus) was dropped in over a period of* 15
minutes. After stirring for 5 minutes the ether layer
was separated and the water solution extracted twice
w i t h 100 cc portions of aihydrous ether. The ether
solution and washings were combined and dried over cal­
cium chloride in the refrigerator. After standing about
4 hours, a fine needle like precipitate had settled out.
Without separating this', the solution was titrated for
active chlorine and showed 0,168 moles. The calculations
and procedures for this determination and for the ni­
trogen determination follow. They are essentially those
of Colman (46).
1. Determination of active halogen
A 1 cc sample of the ether solution of the chloroamine was pipetted into a solution of
iodine in
10
cc of water and
1
2
g of sodium
cc of contentrated
hydrochloric acid contained in a ground glass stop­
pered flask. After standing for about 10 minutes the
liberated iodine was titrated with standard sodium
thiosulfate solution. Duplicate determinations were made.
Liberated l£ required 10.11 cc of 0.08705 F Fa 2 S 2 0 3
Total volume of ether solution
380 cc
FaoSoOo eouivalent to ether solution 3 8 0 x 1 0 . 1 1
d ^ *
*
3,842 cc
RNHC1 + 2 HI — >RHH 2 + HC1 +I 2
^ a 2S2^3
3-2 * ^ 2 ^ —^ ^ a 2 ^ 2 ^ >4 “f‘ ^
From -these equations) 1 equivalent of sodium thiosul­
fate is equal to 0.5 mole of chloramine) therefore the
yield of chloramine was: 380 x 10.11 x .08705 x 0.5
0.168 moles.
milliequivalents RHHC1 per cc
10.11 x 0.8705
2
0.4423
2. Determination of nitrogen
A lcc sample was pipetted into 10 cc of concentra­
ted hydrochloric acid and let stand in a glass stopper­
ed bottle for several minutes. The sample was then trans­
ferred to a
200
cc. round bottom flask and carefully
neutralized with constant cooling. When almost neutral
an excess of sodium hydroxide was added and the flask
immediately attached to a condenser for distillation.
The outlet was connected to an adapter below the sur­
face of 20 cc of standard sulfuric acid. The amine liber­
ated by the reactions:
RNHCIL+ HC1 --- ^
RMH 2 HC1+ Cl 2
RNHg.HCl+NaOH-^- RNHg-/- NaCl -f- H20
was distilled into the standard acid and the excess ti­
trated wsing methyl red as an indicator. This required
17.90 cc of standard sodium hydroxide) 1 cc of which is
equivalent to 0.8440 cc of 0.0875W sulfuric acid. The
volume of acid neutralized by the sample is therefore
17.90 x 0.8440
20
or 4.9 cc. The milliequivalents of ni­
trogen per cc. of sample are then 4.9 x 0.0875 or 0.429.
The ratio of active chlorine to nitrogen for this sample
-
is 0*4423/0.429 or 1.032. This value is within experiment­
al error.
The percentage yield in this preparation,based upon
the active halogen in the product and the quantity of
hypochlorite used is (0.168/0.186) x
B.
100
or 90.6%.
A second method for the preparation of this compound
was tried in which the hypochlorite was added to the
amine hydrochloride solution instead of adding the amine
hydrochloride solution to the hypochlorite solution as
above. This method should leave the amine hydrochloride
always in large excess, and might give still better ratios
of chlorine to nitrogen.
In the apparatus described above were mixed 200cc of
ether and a solution of 37.2 g (0.3 moles) of 3-aminopentane hydrochloride in 70 cc of water. After cooling to
0
about 2 C, a cooled solution of calcium hypochlorite
(0.275 moles) was added over a period pf about one hour
with stirring. The layers were separated, the water solu­
tion washed twice with ether, and the ether solutions
combined and dried over anhydrous sodium sulfate in the
ice box. The analysis was run after the solution had stood
for about three hours. The total volume of ether solution
was 370 cc. This solution contained 0.609 m.eq. of active
chlorine per cc. and 0.541 m.eq. of nitrogen per cc.,
giving a ratio of chlorine to nitrogen of 1.128. Assuming
that the total halogen is accounted for by mono- and- dichloro-amines, the yields of these can be calculated as
follows:
ra.eq. of dichloro-amine 0.609 - 0.541
0.068
m.ei|. of mono-chloramine 0.541 - 0.068
Total mono-chloro-amine 370 x 0.473
0.473
0.175 moles
Percent monochioro-amine (0.175/0.275) x 100 63.7
Total dichloro-amine 370 x 0.068
0.028 moles
Percent dichloro-amine (0.068/0.275) x 100
24.7%
Prom the above results it appears that the first
method gives a better product. The reason for this is not
apparent, but it agrees with the results obtained by
Coleman (46) who prepared several similar compounds by
this method.
In all subsequent preparations method A was used and
the products had chlorine-nitrogen ratios from
1.00
to
1.045. The ether solutions were dried over stock anhydrous
calcium chloride for from
1
to
2
hours, then decanted onto
freshly dried calcium chloride. If this latter drying agent became noticeably wet, the solution was again decanted
onto fresh drying agent. The solutions when thus dried pre­
cipitate the amine hydrochloride very slowly. In spite of
thisjthe solutions were used as soon as possible after be­
ing prepared, usually not more than a few hours afterwards.
Whenever the solutions were stored, they were kept in the
refrigerator. If any precipitate had formed, it was fil­
tered before using the solution.
A small recovery of amine hydrochloride could be
obtained by making the aqueous solutions from these pre-
54
. arations alkaline and steam distilling into dilute
hydrochloric acid.
V I •The reaction of* jN~-Chloro-3—Amino—Pentane with Sodium
Me thylate
An 0.05 mole preparation of* N-chloro-3-aminopentane was made by procedure r,A n using a large excess
of* amine hydrochloride. The ether from this preparation
was placed in a 3-neck round bottom flask attached to a
reflux condenser and a stirrer. The reflux condenser
was vented to the air through a soda-1 ime tube to keep
moisture out of the reaction. To this solution was add­
ed 3.2 g of sodium methylate (0.5g excess), and the mix­
ture stirred overnight. Since the reaction still showed
active halogen, another gram of sodium methylate was
added and the reaction stirred till the test for active
halogen was negative (21 hours). The reaction mixture was
then filtered with vacuum and the filtrate placed under
column II which had previously been dried by passing dry
air through it while the jacket was heated to 60°C for
1 hour. The stream of dry air was continued while the
column cooled to room temperature. The ether was fraction­
ated off leaving a light brown residue which was trans­
ferred to a clean dry distilling J^L&sk (25 cc capacity).
The material was distilled into a receiver protected
from moisture by a soda-lime tube. The following frac­
tions were obtained:
55
1.
0.9 g.
32-40
.
0.4 g-
40-80
2
3.
1.2
g.
80-100
4.
0.7 g.
100-150
5.
0.4 g.
150
All fractions were tested with a solution of 2,4dinitrophenyl-hydrazine in a mixture of
2
parts of
2N HC1 and 1 part of 95% ethyl alcohol.Fractions 3,4
and 5 gave positive tests, hut 3 was very weak.Frac­
tions 4 and 5 were converted to the 2,4-dinitrophenylhydrazone .derivative. Fraction 4 gave an orange pre­
cipitate which melted from 145-150, and which after one
crystallization from alcohol melted at 152-154°C. A
mixed melting point with an authentic sample,m.p.154Tne/TcJ
155, of the derivative from diethyl ketone from 152-154.
Fraction 5 gave a darker, orange brown, derivative
which melted from 151-153°C, and when mixed with the
derivative of diethyl ketone gave no depression.
These results suggest that the product might be the
desired diethylketimine which is hydrolized to diethyl
ketone by the reagent.lt was therefore thought advisable
to prepare more of this compound and study it further.
Sodium methoxide (18 g. ,0.33 mole) was added to 300cc
of a chloramine solution (containing 0.183 mole of
chloramine) in a 3-neck flask and allowed to stir over­
night. After over 24 hours the solution was titrated for
active halogen, and. at intervals after that other titra­
tions were made to follow the reaction. When the rate of
decrease became very slow, another 5 g of sodium methylate
were added and the reaction followed again until the re­
action again became too slow, then another
6
g of sodium
were added. After a total of 187 hours, all active halogen
had reacted. The reaction mixture was filtered as rapidly
as possible through a Buchner funnel under vacuum and
stored in the refrigerator for
column
1
2
days, then placed under
, which had been dried as described before, for
the removal of the ether. The ether distillate had a
strong odor of amoiiia, but titration showed it to contain
only 0.0036 equivalents of base.
The residue from the above distillation was trans­
ferred to a small distillation setup for further distill­
ation.
The following fractions were obtained.
cut
wt.
"d 2 0
b.p.
bath t.
1
4.9
1.3518
42-51
75-80
2
0.-5
1.3502
51-62
80-98
3
3.2
1.3478
62-75
98-120
4
0.7
1.3482
75
120-140
A precipitate began to form in the distilling flask
after cut 1, and after cut 3 the distillation was inter­
rupted to remove the precipitate by filtration. Upon
starting the distillation again, the precipitate formed
so rapidly ■that after cup 4 had been taken, the residue
was a pasty mass.
Fraction 1 is largely ether although the boiling point
is high.
Fraction 2 is an intermediate cut probably containing
ether, methyl alcohol, and traces of diethyl ketone or
diethyl ketimine. Methyl alcohol is to be expected as a pro­
duct of the sodium methylate reaction.
Fraction 3 gave a 2 ,4-dinitrophenylhydrazone which melt­
ed at 154-156°C and did not depress the melting point of
that derivative for diethyl ketone,
A n 0.1080 g sample was
titrated for basicity, and assuming this was due to basic
nitrogen, it represents 0.68% nitrogen. Asodium fusion gavea
only a faint test for nitrogen. The refraction index and
boiling point (n2°D
1.3478, b.p. 75 max) were too low for
diethyl ketone ( n ^ D
1.3905, b.p. 102.7). The fraction
was probably a mixture of methonol,diethyl ketone, and poss­
ibly a small amount of diethyl ketimine.
Fraction 4 gave a 2,4-dinitrophenylhydrazone melting at
153-155 and which gave no depression with that of diethyl
ketone, but the boiling point and refraction index were too
low for this compound.
The lack of basicity in these products suggested the
possibility that in the filtering and transfer, moisture
from the air might have caused hydrolysis of the ketimine,
or that possible the methyl alcohol caused alcoholysis
during the distillation. The methyl amine formed by this
reaction would have been lost in removing the ether or in
the final distillation*
(C2 H 5 )2 C-NH
-T- CH 3 OH
(G2H5)2CcO y-CH3 KH 2
This last reaction might pessibly occur late in the
distillation when the methanol is concentrated in the pot
and the temperature is rising.
Reaction 3
A n ether solution containing 0.155 equivalents of active
chlorine was .reacted with 16.8 g (0.310 moles) of sodium
raethylate as described previously. After 24 hours all active
chlorine had disappeared. This product was then filtered
with nitrogen pressure. The stirrer was replaced by a fil­
ter unit as shown in the diagram.
The receiver was a clean, dry distilling flask protected
from moisture by a drying tube. Titration showed one cc.
of this filtrate to be equivalent to 4.42 cc. of 0.0875 N
acid. The ether was removed under a vacuum of 200 mm and
caught in a tra.p immersed in a dry ice ether bath. The
distilling flask was heated by a bath maintained at 25-
30 C. Throughout, "this pperation the product, was carefully
protected from moisture and all apparatus used was thorough­
ly dried. A 10 cc. sample of the fether distillate was ti­
trated for basicity, and from this the ether solution was
calculated to contain 0.0156 equivalents of base. A 2 cc.
sample of this distillate gave the 2,4-dinitrophenylhydrazone of diethyl ketone.
The residue in the distilling flask required 11.14 cc.
of 0.0875 N acid to neutralize a 0.2 cc. sample, and gave
a 2,4-dinitrophenylhydrazone of diethyl ketone. Hydrogena­
tion of this residue was carried out by dissolving a 3 cc.
sample in
100
cc of anhydrous ether contained in a bottle
for the laboratory hydrogenator. To this was added about
0.2 g of raney nickel. The system was swept out with hydro­
gen, then placed under 39 lbs. of hydrogen pressure. After
about
12
hours there was no evidence of hydrogenation; so
the product was removed, filtered from the old catalyst,
about
0.2
g of new catalyst added, and the hydrogenation
again started at 40 lbs. After 2 days the pressure remain­
ed constant and the reaction was assumed to be complete.
The ether solution was shaken thoroughly with 20 cc. of
10% HGl. The water solution was evaporated on a steam
bath leaving
1.2
g of crude product which after recrys­
tallization from absolute alcohol melted at 205—210 and
gave no depression when mixed with 3— amino—pentane hydro­
chloride.
The ether solution after being washed with acid was
treated with 2,4-dinitrophenylh;, draz ine reagent and gave
a precipitate of* the derivative of diethylketone.
In order to prove that the 3-amino-petane hydro­
chloride was not present in the product before hydrogena­
tion, another sample of this material was dissolved in
anhydrous ether and washed with 10% HC1 as was the hydro­
genated product.
On evaporation of this only a
residue
of ammonium chloride remained. The amine salt was therefore
formed from the hydrogenation product. Since ammonium
chloride is formed from the unhydrogenated material, it
seems quite probable that the reaction product from the
N-chloro-amine is the desired ketimine which hydrogenated
to the amine,hydrolized to the ketone and ammonium chlor­
ide.
A sample of the crude ketimine product was placed in
a small all glass distilling apparatus and distilled from
an oil bath.
...
bath
dist.
temp.
temp.
20
. . .
fraction
nD
97
52
1
1.3552
107
63
2
1.3413
125
107
3
1.4019
A small residue of solid remained in the distilling
flask.
Fraction 3 gave a qualitative test for nitrogen and
also the
2
,4 -dinitro-phenylhydrazone test, the derivative
checking with that of diethylketone.
Two samples of fraction 3 were weighed out and ti­
61
trated with acid. Sample 1 gave a neutral equivalent of
183.5 and sample 2, 185.5.
The theoretical value for
diethyl ketimine is 85. Prom this data this fraction con­
tains about 46% of the ketimine, assuming all basicity is
due to the ketimine.
Reaction 4
An ether solution containing 0.378 moles of N-chloro3-amino-petane was treated with 0.666 moles of sodium
methylate as before.
The time of reaction was 13 hours.
The ether was removed under vacuum as described for the
previous experiment.
The ether distillate contained 0.0179
equivalents of base and gave a test for ketone.
The residue after the removal of the ether was dis­
tilled giving the following fractions:
dist.
temp.
Fraction
wt.
n
nD 2°
1
50
1.0
1.3543
2
61
2.3
1.3516
3
66
2.3
1.3460
4
85
2.3
1.3478
5
90
7.2
1•3908
attempt was made to refractionate this pi
through column.
3. The fractionation table follows:
bath
temp.
column
temp.
head
temp.
127
45
39
127
48
48
fraction
1
2n
rtQ
1.3582 @17°C
62
131
47
53
2
131
52
64
3
132
60
50
4
1.3280
The column was shut down. before starting again, fract:
from previous distillation was added.
99
58
62
120
60
58
135
108
75
150
111
84
152
123
93
165
124
89
214
135
65
275
200
5
1.3312
6
135
7
1.3928 @17°C
8
1.4402 @17°C
Residue
1.4960 @17°C
Fraction 1 was largely ether.
Fractions 2 and 3 were mixtures with steadily rising •
boiling points , the value given being the maximum.
Fraction 4 was identified as methyl alcohol from its
constants and its 3 ,5-dinitrobenzoate . A comparison of
these follows:
boiling
point
nD
melting point
3 ,5-dinitrobenzoate
fraction 4
64 (:3 730mm
1.3280 @ :
20
methanol
64.65
1.3292 @ 17.4
107-107.5
107
Reaction 5
A n ether solution containing 0.273 moles of IT-chloro3-amino-pentane was reacted with 0.55 moles of sodium
methylate which had been pulverized by placing it in a
stout walled glass bottle one third filled with glass beads
and containing about 75 cc. of anhydrous ether. The bottle
was shaken vigorously until the sodium methylate appeared
to be completely pulverized. This suspension was then trans­
ferred to the reaction flask, using more anhydrous ether if
necessary. The transfer was made with a stream of nitrogen
passing through the reaction flask. When the reaction was
complete, the stirrer was removed and the apparatus shown
below was set in place. Nitrogen was also run through the
flask during this operation.
Li
After the solid had settled to the bottom, the filter tube
E, which was surrounded by filter paper, was adjusted so
that it was about
centimeter above the solid. Bottle C
was filled with about 400 cc of anhydrous ether. With pinch
clamps 1,2, and 3 open, the nitrogen pressure was regulated
so as to force a slow stream of liquid into the receiver B,
When the clear solution had been transferred, the filter
tube was raised, clamps 4 and 5 opened, and clamp 2 closed.
When about, half of the ether had been transferred from C to
A, clamps 2,4, and 5 were closed and the solution in A allow­
ed to settle before the filter tube was again lowered into
the solution and the process repeated. Two washings were con­
sidered sufficient. When the ether wash solutions were run
into B, a small amount of precipitate formed which proved
to be sodium methylate.
A sample of this imine solution containing 0.082 equiva­
lents of base was hydrogenated as described previously using
0.7 g of Raney nickel. The hydrogenation was complete in
about 24 hours. The ether solution was filtered and the fil­
trate washed three times with small quantities of 10% HC1
which extracted 7.2 g of material, of which 6.7 g was sol­
uble in absolute alcohol, and on recrystallization melted at
212-215. A mixed meltirg point with 3-amino-pentane hydro­
chloride showed no depression.
In order to show that this amine hydrochloride was form­
ed from the hydrogenation product, a sample of unhydrogen­
ated ether solution was worked up in an identical manner.
From 60 cc. of solution 1.8 g of solid was obtained which
was insoluble in absolute alcohol.
Since attempts at the distillation of these ether sol­
utions had proven unsuccessful, an attempt was ma.de to pre­
cipitate the imine as the hydrochloride salt. For this
purpose hydrogen chloride was generated from concentrated
sulfuric acid and sodium chloride-hydrochloric acid mixture.
65
The gas was passed through a drying train consisting of a
sulfuric acid wash bottle, a sulfuric acid tower, and a
bottle filled with glass wool to catch any spray. A slight
pressure was maintained on the system by means of a mercury
trap. The product of this reaction was a tan semi-solid
which could not be crystallized. This solid contained 33.5%
chlorine and
8.66
% nitrogen. The chlorine value is too high
and the nitrogen too low for the imine hydrochloride, (theo­
retical 29.38% chlorine and 11.52% nitrogen),but the values
are those which would be expected from a mixture of the
imine salt and sodium, chloride formed from Sodium methylate,
shown to be present in these ether solutions. Such a mixture
would be expected since the presence of sodium methylate has
been demonstrated in the ether solution. Based upon the
chlorine determination the mixture would consist of- 87% imiiee
and 13% sodium chloride.
Reaction
6
An ether solution containing 0.138 moles of N-chloro3-amino-pentane was reacted with 0.37 moles of sodium methyl­
ate as described for reaction 5. The reaction was complete if*
about 12 hours. The ether solution from the reaction was
filtered as described, and placed under column
only momentary contact with the atmosphere.
1
allowing
The cQiQlumn had
previously been dried out as described earlier. The column
was connected through a fraction cutter to a 300 cc trap
*
immersed in a dry ice-ether bath. To this was attached a seo
cond trap,followed by a pressure regulator and the water
pump. All volatile products were distillied off and the pro­
ducts tested for basicity.
Fraction
Volume
cc. 0.1120 N acid
per cc. solution
1
300
0.50
2
225
0.90
3
75
1.5
4
13
11.18
5
3 to 5
6.77 cc for 0.1046 g.
of sample
Fractions 4 and 5 were fractionated from column 3 which
had been carefully dried. After the ether and methanol had
been removed, a good reflux could not be maintained in the
column. A fraction was obtained which contained nitrogen,
gave a 2,4-dinitro-phenylhydrazone derivative of diethyl
ketone, was insoluble in water, but soluble in dil. hydro­
chloric acid, did not reduce Fehlings solution in cold or
hot, gave a weak reaction with Schiffs reagent, did not re­
duce Tollens reagent, but did give a slow reduction
of al­
coholic silver nitrate, a good mirror being deposited on
standing several days.
The residue from this fractionation was a viscous, yel­
low oil, 0.1383 g. of which neutralized 5.53 cc of 0.1120
N acid. Assuming the basicity to be due to nitrogen, this
would show the compound to contain 6.27% nitrogen.
The ether distillate (fraction 2) containing 0.0227
equivalents of base was reacted with dry hydrogen chloride
as before. The product was a white gummy solid which re­
acted with 2,4-dinitrophenylhydrazine slowly. Analysis for
chlorine by the Volhard method gave 34.2%
Summary
N — chl o r o — 3— a m ino— pen t a n e has "been p r e p a r e d and
t rea ted with
so di um m e t h y l a t e 'in a n h y d r o u s ether.
A l t h o u g h the p r o d u c t oould not he i s o l a t e d from t h e
e t h e r solution,
the foll o w i n g facts in dicate that
d iet hyl ket inline was fo rmed in the reaction,
1. T r e a t m e n t of the ether solution with wa.ter
gives a b asic
soluti on and forms diethyl
ketone.
2_. H y d r o g e n a t i o n of the ether so lution yields
3-amino -pe nta ne.
3. The
e ther sol ution re act s wit h d r y h y d r ogen
chloride to form an ether in soluble,
visc ous oil.
4. The h y d r o g e n chl ori de p r e c i p i t a t e reacts with
water to form di e t h y l ketone.
5. A t t e m p t e d d i s t i l l a t i o n of the o i lly residu e after
r e m o v i n g the ether b y va c uum yie lds a h i g h boiling,
h i g h l y r e f r a c t i v e r esidue w h i c h is aci d soluble,
but no long e r h y d r o l y s e s to d i e t & y l ketone.
is
6.
It
oossi b l e a s u b s t ituted pyridine.
The n r o d u c t is volatile,
and is oarti a l l y carried
over w h e n the ether is r e m o v e d b y vacuum.
7. !.■e t h a n o l ha s b e e n i s o l a t e d as a pro duc t of the
sodium m e t h y l a t e
reaction.
Bibliography
1.
Kishner, IT.
2.
Kishner, IT. ibid-* (1905) 1,1220
3.
Mannich & Zennik - ibid. (1908) 1, 1831
4.
Mossier - Monats. 29
5.
Freylon - Ann de Chem.Phys.
6
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7.
8
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9.
Chem.
Cent.
(1905) 1,1219
69 (1907)
(8 ) 20
73 (1910)
Oakwood - Ph.D.Thesis - Pennsylvania State college (1937)
Abenius & Widman - J. Pr. Chem. (2) 38
Bischoff - Ber.- 24
296 (1888)
1044 (1891)
Bischoff & Hausdorfer * Ber. 25 2300 (1892)
10. Bischoff & ttjintz.- Ber. 25
11. Tigerstedt, A. - Ber. 25
2317 (1892)
2919 (1892)
12. Bischoff - Ber. 30
2312,2315 (1897)
13. Bischoff - Ber. 34
1835 (1901)
14. Bischoff - Ber. 3 ±
2125 (1901)
15. Whitmore - J. Am. Chem.Soc. 54
3274 (1932)
16. Meisenheimer - Ber. 57B 289-97 (1924)
17. Bischoff - Ber. 35_, 2326, (1892)
18. Bassler - Unpublished work
19. Thorpe - Proc. Chem. Soc. 95. 309; C.A._4, 32174 (1910)
20. Mixter - J. Fortsch. Chem. (1877) 432
21. Lieberman & Goldschmidt - Ber. 10 2179 (1877)
22. Goldschmidt - Ber. 11
23. Reychler - Ber.17
1198 (1878)
44 (1884)
24. Behai & Choay - Ann. de Chem. (6 ) 26, 11 (1892)
25. Delepine - Bull. Soc. Chem. (3) 19, 171 (1898)
26. Delepine - ibid.
(3) 19, 15 (1898)
Ann. de Chem. (7) 16, 103 (1899)
27. Aschan - Ber. 48. 878
(1915)
r
28. Strain - J. Am. Chem. Soc. 54, 1221 (1934)
29. Berg - Ann., de Chim.
(7), Z_, 315, (1894)-
30. Grignard and Escourrou-Compt. rend.180,1883 (1925);C.A.19,30867
31. Strain - J. Am, Chem. Soc. 49, 1560 (1927)
32. Moureau and Mignonac -Compt.rend.156,1801 (1912);C.A. 7 3114^
Ann.Chem.(9) 14, 322 (1920);C.A.15 14957
Compt.rend.170,1353 (1920):C.A. 16,15823
Ann. de Chem (9) 14, 322 (1920)
33. Vittmer,Culbertson - Proc.Iowa Acad.Sci.36 266,(1929)
C.A. 25, 1231 (1931)
Culbertson, Davis -Proc. Iowa Acad. Sci. 39, 177 (1932)
C.A. 28, 6710 (1934)
34.
Campbell - J. Am.
35.
Houben, Fischer -J .
Chem. Soc. 59, 2058 (1937)
Pract. Chem. 123 89 (1925;C.A.23 833^(1929)
36. Houben & Fischer - J. Pract.Chem.123 313 (1929);C.A. 24,1106^
37.
Houben & Fischer - Ber. 63B, 2455, (1930); C.A. 25, 935
Ber. 64B, 2645 (1931); C.A. 26,12685 (1932)
38. Bresson, Culbertson - Proc. Iowa A c a d . S c i . 36,266 (1929)
C.A. 25,1230,(1931)
39. Chichibabin & Roryagin -C.A. 8,912
40. Mignonac - Compt. rend. 169,237 (1912);C.A. 14, 2794
41. Strain - J. Am. Chem. Soc. 52, 820 (1930)
42. Kohler & Drake - J.Am. Chem. Soc. 45, 128 (1923)
43. Mignonac - Compt. rend. 170, 936 (1920); C.A. 14, 21665
44. Hellerman & Sanders - J. Am. Chem. Soc. 49, 1742 (1927)
45. Wagner - Unpublished Work
46. Coleman - J. Am. Chem. Soc. 55, 3001 (1933)
47. Duvillier - Ann de Chem. (5) 21, 445 (1880)
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