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Some Reactions of 1-Phenyl-1-Chloro-2-Methylamino-propane i. Reaction With Metals and Hydrogen

Some Reactions of 1-Phenyl-1-Chloro-2-Methylamino-propane i. Reaction With Metals and Hydrogen

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11/13/2012

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[@ONTRIBUTION FROM
THE
DEPaRTMEST
OF
CHEMISTRY,
VILLANOVA
COLLEGE]
SOME
REACTPOKS
OF
P-PHENYL-l-CHLOR0-2-&lETHYLAR!IINO-
PROPANE.
I.
REACTION WITH METALS ANDWITH HYDROGENALEXANDER GERO
Received
July
lY,
1961
1-Phenyl-1-chloro-2-methylaminopropane
I)
PhCHClCHCHB was first pre-
!
KHCH,pared by Emde
(1)
n a study of ephedrine derivatives, continuing earlier studiesby Schmidt
(2)
who had prepared the corresponding 1-phenyl-1-bromo-2-methyl-aminopropane and reduced it to desoxyephedrine, PhCHZCHCH3 with zinc-
I
SHCH3copper and hydrochloric acid. His yield, as reported later by his student Emde,
was
10%.
Emde hydrogenated both
I
and Schmidt's bromine compound cata-lytically
to
desoxyephedrine in yields of
80-90%.
Both authors obtained a hydrocarbon as
a
by-product, which Schmidt identi-fied as propylbenzene, while Emde mites of propenylbenzene PhCH=CHCH3without giving any
proof
of
identity other than the smell of the hydrocarbon.Emde also found a high-molecular base in his hydrogenation mixture. Becausethe analysis and mo!ecular weight of this base corresponded approximately to
a
dimer of desoxyephedrine, Emde named
it
didesoxyephedrine.
He
considered
I1
and
IIP
as possible structures for didesoxyephedrine and
was
able to reject
111
but not to prove
IP.
PhCH-CHCR3 PhCHz
CKCH3NCH8
!
'I
I
"CR,
PhCHCHCH3
111
The introduction of desoxyephedrine as a drug some years
ago has
rekindledinterest in
I.
The present paper is
a
report on attempts to throw some light onthe reasons why Schmidt's and Emde's hydrogenation methods led to such di-1-ergent yields, and on the identity of didesoxyephedrine.
As
a
preliminary, it mas ascertained that the same yield
of
10%
desoxyephed-rine is obtained with
I
when
hydrogenated with zinc-copper and hydrochloricacid
as
Schmidt obtained with the bromine compound. In subsequent experi-ments only
I
was used. The zinc-copper couple was then replaced by zinc alonein one experiment, by alkali-activated aluminum in another. Zinc afforded aboutthe same yield
as
zinc-copper, while aluminum did not react.On the
other
hand, calcium hydride, while without effect in itself, gave yields
1731
 
1732
ALEXANDER
GEE0
Zn-Cu-Pd
+
HCl..
..............................
AI-Pd
+
IpG1..
...................................
Hn-Pd
+
CHaCOOHb..
...........................
CaH2-Pd
+
HC1..
................................
of
desoxyephedrine comparable to those
of
Emde Then used
in
conjunction withpalladium, in acidic solution. Since a metal hydride in acidic solution
is
a
source
of
molecular hydrogen
(3):
E-
+
H30+
Hz
+
NzO
the calcium hydride experiment amounts to a duplkathn
of
Emde’s catalytichydrogenation,From these results it
is
plain that two difierent mechanisms must be
at
work,depending on whether hydrogen froni zinc and acid or catalytically-excitedmolecular hydrogen
is
used as a hydrogenating agent. In the first case replace-ment
of
chlorine by hydrogen
is
a
minor reaction, in the latter the principal one.Next, the several metal-and-acid reductions mere repeated
in
the presence ofpalladium catalyst
in
order to decide whether the faster rate
of
the reaction
26
44
80-90
88
TABLE
I
REDUCTIOS
F
l-?HESrL-l-CHLoRO-2-METHYLA~IIn”B
’~IELD~
B
REDUCING
AGENT
Desoxyephedrine
(%)
j
Hydrocarbon
(71)
I
I
77
74
42
46
36
tracetrace
0
Yields do not add
up to
100%
because some
I
is inevitab!y hydrolyzed
to
a
mixture
*
Yield reported by Emde
(1).
For
all other results see experimental part
of
the present
of
ephedrine and pseudoephedrine.paper.
2H
3
z
is
responsible for the bad yields
of
the reaction
R--@I
+
2H
4
R-H
+
HCI.
If
so,
then in the presence
of
the catalyst which reverses thereaction
2H
4
z,
the same high yields should be obtained as with molecularhydrogen and palladium catalyst. Furthermore, the by-product hydrocarbonwas isolated in every case and its quantity determined. The results
of
the aboveexperiments are summarized in Table
I.
It
is
immediately apparent that the most important competitive reaction inthe hydrogenation with metal and acid is
not
the conversion
of
atomic to
mo-
lecular hydrogen but the conversion
of
I
to
a
hydrocarbon, which cannot besuppressed even by increasing the concentration of atomic hydrogen
by
thecatalyst. The identity
of
the hydrocarbon was not established at this point.
As
will be reported below, propenylbenzene
was
identified as the primary productof the reaction, in conformity with Emde’s report; whether, and to what extent,it
is
further hydrogenated to propylbenzene as reported
by
Schmidt, is irrelevantto the reactions
of
I.
 
1
PHEXYL-~-CHLORO-~-METHYLAMIIITOPROPANE
1733
The results summarized in Table
I
may be expressed by the schemePhCHzCWCH3
I
"CH3
/
PhCHC
1
C
H
C
H8
/'
PhCH=CHGRapath
1
being the main reaction with hydrogen and palladium as the hydrogenat-ing agent, and path
2
with metal and acid.Obviously the presence
of
a metal has something
to
do with the predominanceof path
2.
In order to obtain further information on its mode
of
action,
I
was
reacted with zinc alone, without solrent and without acid.
The
reaction is al-most instantaneous, strongly exothermic, and results in
a
good
yield
of
propenyl-benzene, without any identifiable side reactions.This confirms the r61e
of
the metal, and we may interpret the findings re-ported above by the assumption that the zinc donates tx70 electrons to the polarC-Cl and C--N bonds
of
I,
allowing the ions C1- and CK3NH- to break away,and leaving the biradical PhCHCHCH3 behind which is propenylbensene whenthe orbitals
of
the two odd electrons overlap
to
form a
T
electron pair. Hydrogen,on the other hand, is not metallic enough to break the slightly polar C--N bondbut
it
can break the C-C1 bond which in I-a substituted benzyl chloride-is
very
highly polar. Consequently a monoradical
PhCH
CHCHa
"CH3
IVis formed, which quickly combines either with a hydrogen atom to form desoxy-ephedrine,
or,
to a lesser extent, with another radical IV to
form
11.
To test this hypothesis,
I
was reacted with copper, an element even lessmetallic than hydrogen.
It
might be reasonably expected
to
yield the mono-radical
IV
which, in the absence
of
atomic hydrogen, can only dimerize. Theexpectation was confirmed and the product obtained showed the propertiesEmde reports for didesoxyephedrine. This may be considered as evidence forstructure
I1
for desoxyephedrine which Emde had suggested without being ableto prove
it.
Further studies, concerning the behaviour of
I
as
a
nitrogen mustard, will bereported later.
-1
EXPERIMENTAL
1
-Phenyl-I-chloro-2-methylaminopropane
ydrochloride
(V)
was
prepared
fro=
ephedrinehydrochloride
(Merclr)
and thionyl chloride, following the directions given
by
Emde
(1).

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