A STUDY OF THE STRUCTURE OF SOME CYCLIC AMIDES
AND RELATED TETRAZOLES

By
RICHARD 3LERDA BURKE

A THESIS
Subm itted to the >chool of G raduate Studies of M ichigan
State College of A g ricu ltu re and Applied Science
in p a r tia l fulfillm en t of the re q u ire m e n ts
fo r the d eg ree of

DOCTOR OF PHILOSOPHY

D ep artm en t of C h em istry
1952

ProQuest Number: 10008220

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To My M other And F a th e r

ACKNOWLEDGMENT

The au th o r w ishes to e x p re s s
h is g ratitu d e to D octor R obert M.
Herhst* who gave valuable guidance
during th is in v estig atio n .

TABLE OF CONTENTS

P age
INTRODUCTION . . . . . . ........................................
HISTORICAL

1

. . ......................................

3

DISCUSSION................................................................
EXPERIM ENTAL
P re p a ra tio n of Compounds fo r
P re lim in a r y E xperim ent*

21
..............

63

.............................

63

P re lim in a ry E x p erim en ts lo r
C o n v ersio a of L actam to S aturated
E s te r
.................................

67

R eaction of N itro n s Acid with
€~C aprolactam and A ttem pted Conv e rs io n of A ll P ro d u c ts to C aproic
..........................
A cid

73

P re p a ra tio n s of Ethyl c~Carboethoxy arninoc a p r oate ..............................................

SO

C onversion of Ethyl c-C arhoethoxyam in o eap ro ate to Ethyl C aproate and
O th er P ro d u c ts ..............

.

82

N itro u s A cid T re a tm e n t of
I • C ap ro lactam

.

85

P re p a ra tio n of €~Iodocaproic Acid

....................

88

R eduction of e~Iodoc*proic Acid
to Ethyl C ap ro ate
...............................................

90

V

Page
P re p a r a tio n of 3- Methyl*S - E thyicyclo 91

....................

P re p a ra tio n of 3- M ethyl-5 -E th y lcy clo hexanone O x i m e .................................. .................................

94

The B eckm ann R e arra n g em e n t of
3 -M ethyl- 5- Ethylcyclohexanone O x i m e ................

96

P re lim in a r y Solubility Studies of Dialkyl
S ubstituted e - C ap ro lactam M ixtures ....................

98

Method fo r S ep aratio n of Iso m eric L actam s
R esulting F ro m the B eckm ann R e arra n g em e n t
©f 3-M ethyl- 5 -Ethylcyclohex&none Oxime . . . . . . .

103

C onversion of the L actam of 3 - E thyl-5 M ethyl - 6 - A m inohexanoic Acid to Ethyl
3 - Ethyl - 5 -M ethylhexanoate and O th er
P ro d u c ts
.......................................................

107

C onversion of the L actam of 3,5-D im eth y l-6 A m inoheptanoic Acid to Ethyl 3,5-D im eth y lheptanoate and O ther P ro d u c ts
...........................

114

P re p a ra tio n of Ethyl Isobutyl Ketone...................

117

P re p a ra tio n of Ethyl 3 - E th y l-5Methylhexanoate
..........................

121

P re p a ra tio n of thyl 3 ,5 -D im ethylheptanoate . .........................................

125

P re p a ra tio n of 3 Ethyl- 5 - M ethylhexanoic
A cid
..........................

129

P re p a ra tio n of 3 ,5 -D im ethylheptanoic Acid

.....

130

P re p a ra tio n of 7 -M « th y l-9 -E th y l-1,5P en ta m eth y len e tetran o le ..................................................

131

vi

P age
P re p a ra tio n of 7 - E th y l-9 -M e th y l-1*5F e n ta m e th y le n e te tra z o le
........................* ....................

135

SU M M A R Y ......................................

137

REFERENCES

139

....................

LIST OF TABLES
TABLE
I.
II,

III.

IV,

V.

VI.

VII.

VIII.

P age
C om posite R esu lts fro m T able i n

..........................

The B eckm ann R earran g em en t of
Cyclohex&none Oxime Using Sulfuric
A cid of V ario u s C oncentrations

. . . . .

36

65

N itrogen A nalysis Used to Indicate
E ffectiv en ess of V arious M ethods
of D egradation of * -A m iao cap ro ie
A cid D eriv ativ es . .................. • . . . ..........................

71

F u rth e r A nalysis of Solutions R esulting
fro m the D egradation of e - A m inocaproic
Acid Derivative® . . . . . . . . ..............

72

N itro g en A nalysis of V arious Solution©
O btained F ro m the D egradation of
e-C ap ro laetam w ith N itrous A cid . . . . . . . . .

75

A pproxim ate Solubility of M ixtures
of M ethyl Ethyl S ubstituted
€ - C ap ro lactarn s . . . . . . . . . . . . . . . . . . . . .

100

A pproxim ate S olubility of a D istilled
M ixture of M ethyl Ethyl S ubstituted
e~ G aprolactam s , . . ..........................................
A pproxim ate Solubility of the Low est
M elting M ixture of M ethyl Ethyl
Substituted C“ C ap ro lactam s Rem aining
A fter Isolation of Some P u re L actam A . . . .

100

102

INTRODUCTION
The w ork d e s c rib e d in th is th e s is was undertaken p rim a rily
to Inv estig ate the n a tu re of the cy clic am id es fo rm e d by B eckm ann
re a rra n g e m e n t of u n sy m m etric ally su b stitu te d cyeloheseanone ox­
im e s.

The s tr u c tu re s of the cy clic am id es could be stu d ied by

d eg rad ativ e p ro c e d u re s involving ring opening, rem o v al of the
n itro g e n and fo rm a tio n of b ran ch ed chain fa tty e s te r s .

The a p ­

p ro p ria te fa tty e a te r s could be sy n th e sise d by m ethods th a t would
le a d unequivocally to the d e a ire d e s te r s .

The e s te r s obtained by

sy n th e sis and by d eg rad atio n of the cy clic am id es could be co m ­
p a re d by p h y sic al co n stan ts and p re p a ra tio n of d e riv a tiv e s.

The

id en tificatio n of the e s te r s obtained by d egradation of the cy clic
am id es would e s ta b lis h the s tru c tu re s of the cyclic am id es.
The seco n d ary objective of th is in v estig atio n w as to e s ­
ta b lis h the s tru c tu re s of c e r ta in dialkyl su b stitu ted 1 ,5 -p en tame thylene te tr a a o le s .

A n u m b er of dialkyl su b stitu te d p en ta-

m ethylene tetra& oles have been d e sc rib e d <J).

The m ethod of

sy n th e sis u se d in th e ir p re p a ra tio n did not p e rm it rig o ro u s d e ­
te rm in a tio n of the position of the substituent® due to the p o ssib ility

2

of the fo rm a tio n of is o m e ric s tr u c tu re s .

The cy clic am id es,

w hose s tr u c tu re s could he e sta b lish e d by the g en e ra l m ethods
d e s c rib e d above could be co n v erted into dialkyl su b stitu te d 1,5p e n ta m e th y le n e te tra e o le s,

The s tr u c tu re s of the tetr& soles so

fo rm e d would be known fro m the m ethod of p re p a ra tio n and they
would th e re fo re s e rv e a s re fe re n c e com pounds fo r the c la r if ic a ­
tion of the s tru c tu re of s im ila r te tra z o le s p re p a re d by o th e r
m ethods.

HISTORICAL
The p re p a ra tio n of oxim e s fro m ketones m ay le a d to the
fo rm a tio n of e ith e r the syn o r the an ti is o m e r o r a m ix tu re of
b o th is o m e rs .

K etones m ay fo rm only one oxim e due to en erg y

d iffe re n c e s o r s te ric re q u ire m e n ts of the oxime a; n e v e rth e le s s,
fa ilu re of a ttem p ts to s e p a ra te the is o m e rs does not defin itely
indicate th a t only one Iso m e r h as been fo rm ed (2).

In the B eck­

m ann re a rra n g e m e n t of ketoxim es one fa c t Is c le a r - - th a t the
s tr u c tu re of the am ide fo rm ed depends on the configuration of
the oxim e undergoing re a rra n g e m e n t

(3 ,

4 ).

the hydroxy group m ig ra te s to the nitrogen.

The group tra n s to
If the oxim e is a

m ix tu re of the two is o m e rs then the two iso m e ric am id es w ill
be fo rm ed .

It is a lso p o ssib le th a t two iso m e ric am id es could

be obtained fro m a single oxime is o m e r if the conditions of the
re a rra n g e m e n t w ere d ra s tic enough to cau se the iso m e riz a tio n
of the oxim e.
A n u m b er of oxime® of cylic ketones have been se p a ra te d
into the is o m e ric syn and anti fo rm s (5, 6, 7).

The B eckm ann

re a rra n g e m e n t of a p a ir of s te re o is o m e ric m onocyclic ketoxim es
h as n e v e r b een in v estig ated .

In m o st in stan ce s no attem p t to

4

s e p a ra te is o m e rs w as m ade p r io r to subjecting the cy clic k etoxim e s to the re a rra n g e m e n t.

In the p rev io u s in v estig atio n s of the

B eckm ann re a rra n g e m e n t of u a sy m m e tric a l cy clic k etoxim es a ll
a tte m p ts to s e p a ra te is o m e rs have been m ade w ith the lactam s*
w hich w ere the p ro d u cts of the re a rra n g e m e n t.
The p rev io u s in v estig atio n s of the Beckm ann r e a r r a n g e ­
m en t of su b stitu te d cy clic k etoxim es ca n be c la s sifie d as follow s;
(!) R e a rra n g e m e n ts of sy m m e tric a lly su b stitu ted cy clic k etoxim es
w here only one la c ta m Is p o ssib le .

(2) R e arran g em en ts of on*

sy m m e tric a lly su b stitu te d cy clic k etoxim es w hich s te ric a liy fav o r
only one oxim e configuration and th e re fo re fav o r the fo rm atio n
of only one la c ta m ,

Substitution in the £-p o sitio n u su ally fa v o rs

the fo rm a tio n of a single ketoxim e.

(3) R earran g e m eats of u a-

sym m e tric ally su b stitu ted cyclic k etoxim es w hich fo rm both p o s­
sib le la c ta m s.

In th is group the ketone has an equal chance of

form ing both oxim e co n fig u ratio n s and thus both re a rra n g e m e n t
pro d u cts a r e obtained.
The f i r s t group m ay be d isp o sed of quickly since the s tr u c ­
tu re of the p ro d u ct is n e v e r in doubt.

It should be noted th at a

few w o rk e rs have in v estig ated oxim es th a t fa ll in th is group in
connection w ith o th e r in v estig atio n s (8, 9* 10).

The re a rra n g e m e n t

s
of 3,5-dim ethylcyclohexanone oxim e (10) is an exam ple fro m th is
group and m ay be re p re s e n te d a s shown in P la te 1, F ig u re 1.
The second group contains by f a r the la r g e s t n u m b er of
su b stitu te d cy clic ketoxim es th a t have been su b jected to r e a r ­
rangem en t.

The fo rm a tio n and the Beckm ann re a rra n g e m e n t of

the oxim es in th e se c a se s m ay be re p re s e n te d as taking the
c o u rse shown in P la te !» F ig u re 2.
R e a rra n g e m e n ts of th is type have been c a r r ie d out with
eyclopentanones (1 1-15, lb* 17) and w ith cyclohexanones (8, 10,
11, 13-29)*

The s te ric re q u ire m e n ts of the su b stitu en t in the

2-p o sitio n cau se the hydroxyl group to assu m e a p o sitio n an ti o r
tr a n s w ith re s p e c t to the su b stitu en t.

The s tru c tu re of the l a c ­

ta m s re su ltin g fro m the re a rra n g e m e n t of 2 - su b stitu ted cyclic
k etoxim es is in a c c o rd w ith the tr a n s configuration of th e se ox­
im e s.

A few exceptions should be noted.

W allach (8) h as su c ­

ceed ed in se p aratin g two iso m e ric la cta m s re su ltin g fro m the
B eckm ann re a rra n g e m e n t of 2,4,4-trim ethyleyelohexanone oxim e;
how ever, he did not prove the s tru c tu re s of the two p ro d u cts.
Httckel and Doll (5) have se p a ra te d the syn and an ti fo rm s of
2-cyclohexylc yclohexanone oxim e.

W allach and O st (18) in the

re a rra n g e m e n t of th is sam e oxime have n e v e rth e le ss found only

6
PLAT.E 1

<*3
JZ&v
CHrx-CH "Nm-GH,
3 i
CHg

i
^, GHg

^9-CEL
CH^CH
GHo

3

>

* i

r
^ ^ , G= 0

CHg

N
noh

Figure 1

C
H ^ C ?H 2
?E2
R- CH

^

-CH-

^

R- CH

“2
O

O r f f S j®2
*.
9^8
.CHj,

?

^2
R- CH___

C=0

“*
H

H

X0H
Figure 2

one la c ta m w hich they p ro v ed to he 7-cyclohexyl- 2 -ketohexam ethylenim ine by oxidation to 6 -cy clo h ex y l-6 -k eto h ex an o ic acid.
It should he noted th a t S h ech ter and K irk (12) in a study of the
v e ry s im ila r Schm idt re a c tio n of 2 - su b stitu te d cy clic ketones
have found th a t the p ro d u cts a r e the sam e a s would be expected
fro m the B eckm ann re a rra n g e m e n t of the oxim es of th e se ketones
The Schm idt re a c tio n w ith 2 -chlorocyclohexanone, however* gave
a low y ield of the unexpected la c ta m , 3*ehlero~2«ketohexaineth*
yienim ine.

The fav o red p ro d u ct w as n o t iso la te d but the fo rm a*

tion of adipam ide in d icated th a t the re a rra n g e m e n t also o c c u rre d
in the ex p ected direction*
The com pounds stu d ied in th is in v estig atio n a r e unsym*
m e tric a lly su b stitu te d cyclohexanone oxim es and p ro p e rly belong
in the th ird group.

The B eckm ann re a rra n g e m e n t of a n u m b er

of oxim es of th is type h as been studied (8, 10, 16, 17, 30*32).
W allach (8) h as succeed ed In iso latin g the two la c ta m s re su ltin g
fro m the re a rra n g e m e n t of 3- m ethylcyclohexanone oxim e and the
two la c ta m s re su ltin g fro m the re a rra n g e m e n t of 3 ,5 ,5 -trim e th ytcyclohexanone oxim e.

Only in the f i r s t c a se did he prove the

s tr u c tu re s of the p ro d u cts.

All o th e r in v e stig a to rs of the B eck­

m ann re a rra n g e m e n t of u n sy m m etric al oxime s of th is type have

8

fa ile d la e s ta b lis h the s tru c tu re of the la c ta m o r m ix tu re of la c ­
tam® obtained*
I t should be noted th a t a few sim p le b icy clic k eto x im es
have been re a rra n g e d (14, 24, 33, 34). but in no c a se w as it
unequivocally e sta b lish e d w h eth er a sin g le p ro d u ct o r m ix tu re of
p ro d u c ts re su lte d .
The s tr u c tu re s of the la c ta m s have been p ro v ed by a
v a rie ty of m eth o d s.

In m any c a s e s the m ethod of p ro o f is sp e ­

c ific fo r one com pound o r a group of s im ila r com pounds.

If the

su b je c t w ere co v ered in d eta il the im p o rtan ce of the d ifferen t
m ethods would be lo s t in the m a s s of inform ation.
of proof ca n be divided g e n e ra lly a s follow s:

The m ethods

(1) sy n th e sis of

the la c ta m by an o th er m ethod o r h y d ro ly sis of the la c ta m to a
known am ino acid, (2) h y d ro ly sis of the la c ta m to the am ino acid
and red u ctio n of the am ino acid to the sa tu ra te d acid by hydriodic
ac id , (3) oxidation of the la c ta m to known com pounds - - the ox id a­
tio n m ay be p re c e d e d by a p re lim in a ry tre a tm e n t of the la cta m
such a s h y d ro ly sis to the am ino acid and rea c tio n of the la tte r
w ith n itro u s acid , (4) an unusual proof th at cannot be c la ss ifie d
in the foregoing.
be d isc u sse d .

R ep resen tativ e exam ples of each m ethod w ill

9
T h ere a r e m any in sta n c e s in the lite r a tu r e w here la cta m s
have b een sy n th e siz ed by heating the a p p ro p ria te am ino ac id s.
M oat of th e se la c ta m s have not been p re p a re d by the Beckm ann
re a rra n g e m e n t * H ildebrand and B o g ert (11) have d e s c rib e d the
only in stan ce w here the la c ta m w as sy n th e sise d sp e cifica lly to
p rove the s tr u c tu re of a p ro d u ct re suiting fro m the B eckm ann
re a rra n g e m e n t.

They have sy n th e sise d 6 -p ro p y l-2 -k eto p e n ta-

m ethyleitim ine fro m Z -p ro p y lp ip erid iae by benzoylation, oxidation
w ith p o ta ssiu m p erm an g an ate to the benzoyl d eriv ativ e of the
am ino acid, h y d ro ly sis w ith co n cen trated h y d ro ch lo ric ac id to
the am ino acid and heating the la tte r to fo rm the la c ta m ring.
S h ech ter and K irk (12), In th e ir study of the Schm idt reactio n ,
have p ro v ed the s tru c tu re of 3 -c h lo ro - Z -ketohexam ethylenim ine
by h y d ro ly sis follow ed by benzoylation to fo rm the known 2ch lo ro ~6-bcnzoylam inohexanoic acid.

O ther ex am p les in th is

group involve sim p le h y d ro ly sis to am ino acid s whose s tr u c ­
tu r e s had p re v io u sly been proved.
The second m ethod u sed to prove the s tru c tu re s of la c ­
ta m s is b ased on the in v estig atio n of Kwisda (35).

The am ino

a c id p re p a re d by h y d ro ly sis of the la c ta m is h eated to about
200° C. in a se ale d tube fo r ap p ro x im ately tw enty-four h o u rs

10

w ith c o n e tn tfa te d by d r iodic acid.

It ap p aren tly is n e c e s s a ry to

use hydriodic a c id of a c e rta in m inim um co n cen tratio n in o rd e r
to effect s a tis fa c to ry red u ctio n (35, 36).

Some useful m odifications

of th is p ro c e d u re have b een m ade by M ieseh er and B ille ts r (37).
H ildebrand and B o g ert (11), a s w ell a s S hechter and K irk (1.2),
have u sed th is m ethod to prove the s tr u c tu re s of som e la c ta m s
p re p a re d fro m 2 -su b stitu te d cy clic k eto n es.

None of th ese w o rk­

e r s have iso la te d the sa tu ra te d acid s; but, they have m ade the
p-phenylphenacyl d e riv a tiv e s fro m the p u rifie d re s id u e s fro m the
re a c tio n m ix tu re s.

T hese d e riv a tiv e s w ere then co m p ared w ith

the known com pounds.
O xidation e ith e r alone (10, 14, 16, Id) o r in com bination
w ith o th e r tre a tm e n ts (8, 15, 27) has been u sed ex tensively to
prove the s tru c tu re of la c ta m s re su ltin g fro m the B eckm ann r e ­
a rra n g e m e n t of cy clic k eto x im es.

Wallach and O st (18) studied

the re a rra n g e m e n t of 2 -c yclohexylcyelohexanone oxim e.

T h eir

proof of s tr u c tu re can be sch em atically re p re s e n te d a s shown
in P la te 2.
The 7~cyclohexyl -2 -keto h ex am eth y len im in e, HI, th a t they
obtained a s p ro d u ct fro m the Beckm ann re a rra n g e m e n t w as h y ­
d ro ly se d to the am ino acid , V, w hich was oxidised to the keto

11

PLATS 2

CHp

T

.OE2

-> °H*

1

^H-CH^

CH
1

/OIL,

Uiig—CHg

OH
II

OX,

j

CEU
53H-CO(GH2)4COOH
GH2-GH2
17

v

v

p
H-GH^

H
III

p
_C-0

12

acid* IV*

The k«lo acid , IV* w as a lso obtained by oxidation of

tb s s ta rtin g ketone* 2-cyclohexylcyclohexanone, I*

The s tru c tu re

of tbs keto ac id . XV* w as f u rth e r e sta b lish e d by re a rra n g e m e n t
of Its oxim e and h y d ro ly sis of the re su ltin g am ide to cyclohexyl*
am ine and adipic acid.
Ungnade and M cL aren (IQ) in fav o rab le c a s e s have u se d
an oxidation w ith hypoiodite to prove the s tr u c tu re s of c e rta in
lactam s*

T hey studied the re a rra n g e m e n t of a n u m b er of mono**

di* and tri-m e th y l su b stitu te d cyclohexanone oxim es.

A m a jo rity

of th e se m ethyl su b stitu te d cyclohexanone oxim es contained a
m ethyl group in the 2*position.

The fo rm atio n of the oxim e s and

th e ir re a rra n g e m e n t thus fav o red the fo rm atio n of ?*m ethyl
su b stitu te d 2 *ketohexam ethylenim ines a s has a lre a d y b een dis*
cu ssed .

T hese la c ta m s w ere then hydrolysed to the 6-am ino*

heptanoic a c id s and the s tru c tu re s of the am ino acids esta b lish e d
by tre a tm e n t w ith hypoiodite and iso latio n of the iodoform .

The

adipie acid s re su ltin g fro m the hypoiodite oxidation w ere also
id entified in som e c a s e s .

The y ield of iodoform n e v e r exceeded

elev en p e rc e n t of the theoretical*

In one case they attem p ted to

im p ro v e the y ield of iodoform by f i r s t converting the am ino acid
to the keto ac id by tre a tm e n t w ith n itro u s acid and oxidation of

13
the p ro d u ct w ith ch ro m ic acid.

T re a tm e n t of the re su ltin g keto

ac id w ith hypoiodite s till le d to a low o v e r-a ll y ield of iodoform*
W allach (8) h as p ro v ed the s tru c tu re of the two iso m e ric
la c ta m s re su ltin g fro m the re a rra n g e m e n t of 3 ~m e thy 1c y clohsx anone oxim e by an oxidative degradation.

His w ork w ith th is

oxim e m ay be sc h em a tica lly re p re s e n te d as shown in P la te 3.
He s e p a ra te d the two iso m e ric la c ta m s re p re s e n te d by
F o rm u la s 1 and II.

The s tru c tu re of 6- m ethyl -2 -ketohexam e th -

ylenim ine, X, w as e s ta b lish e d by h y d ro ly sis to the am ino acid
hy d ro ch lo rid e, III.

The am ino acid hyd ro ch lo rid e was then tre a te d

w ith sodium n itr ite and gave an u n sa tu ra te d acid th at was r e ­
m oved by ste a m d istilla tio n and a resid u e containing a hydroxy
ac id , IV.

The resid u e was oxidised w ith ch ro m ic acid and gave

a s p ro d u cts a d icarb o x y lic acid and 5-ketohexanoic acid, V, w hich
w as c h a ra c te ris e d a s the se m ic a rb a so n e .
The 4~methyl*2 -ketohexam ethylenim ine, II, was hydro ly sed
to its am ino acid h y d ro ch lo rid e, VI,

The am ino acid h y d ro ch lo rid e,

VI, w as then ox id ised w ith alk alin e p erm an g an ate to the known
3-m ethy lad ip ic acid, VII.
W allach e t al. (27) e sta b lish e d the stru c tu re of the l a c ­
ta m re su ltin g fro m the B eckm ann re a rra n g e m e n t of 2 ,2 ,5 - tr i-

14

FIATS 3

J3t2
0%
yH-CHg

R

.H
(HO)'"' 'OH

I

- ° H8-CH2v_
and
.0=0

CHj,

f 5
^OHg-CH
(3T
T3Hjo
| 2
CHg
.CzO

H
II

CHp-CH?

®3

HC1

CHg-SH

->

C1H •HgNCHgCH {CH2 ) gCOOH

Cp O

CH.

III

T

H

HKOB

HgCrO.

CH&
I

CHgOO(GHg)^COOH £ - = ----- — BDCHgGH{CHg) ^30GH

r

17
{Continued)

15
PLATE

3 (Continued)

CHrr

I
^ 3 -C H

CH3

CH2

CHg

|

|

CKr,

HC1

I

> ClH'HjgET(CHg) gCKJHgCOOH

__ C=0

71
II

/

HOOC (CHJ

22

GH,
l 3
GHCH COOH

VII

2

KMnO.
KOH

16
m ethylcyclohexanone oxim e.

T h e ir p ro c e d u re m ay be sc h e m a t­

ic a lly re p re s e n te d a s shown in P la te 4.
They is o la te d the la c ta m , 4 ,7 ,7 -trim e th y l- 2 -k eto h ex am ethy len im in e, II, a s p ro d u ct of the B eckm ann re a rra n g e m e n t
of the oxim e, I.

The la c ta m was co n v erted to the u n sa tu ra ted

acid , HZ, by heating under p r e s s u r e w ith co n cen trated su lfu ric
acid .

The u n sa tu ra te d acid , III, was then oxidised w ith p o ta s ­

siu m p erm an g an ate to the known p ro d u cts 3-m eth y lg lu ta rie acid,
V, and aceto n e, IV,
Von B rau n and Heymons (19) have proved the s tru c tu re
of the 7-m eth y l -2 -ketohexam ethylenim ine re su ltin g fro m the r e ­
a rra n g e m e n t of 2 - m ethylcyclohexanone oxim e.

The s tru c tu re of

th is la c ta m h as sin ce b een e sta b lish e d by m o re conventional
m ethods (10, 11, 12) but the unusual m ethod of von B rau n and
Heym ons d e se rv e # m ention here*

T h e ir m ethod of proof m ay

be re p re s e n te d a s shown in P la te 5.
T hey had e s ta b lish e d th at lactam # of s tru c tu re , I, w ith
no alkyl su b stitu tio n in the 3-p o sitio n , would fo rm a d ic h lo ro la e ta m , II, when tre a te d with e x c e ss phosphorus p en tach lo rid e.
T his c h lo rin a ted la c ta m , XX, could then be co n v erted into the
hy d ro ch lo rid e of the 2 ,2 -d ich lo ro -6 -am in o h ex an o ic acid , III.

If

17
PIATS 4

f s

j*8 Y2

f2
x-CHs

^.CH-CH

/C H -

(C H g lg C -^

C=0

¥

H

X0H

II
I

I
GHgCOCHg - ( —

IV

heat
press*
fa
I

ox.

I

S2S04
fs
|

HOOCCHgCHCEgOOOH <-------------- (CHgJgC-CHCHgCKJHgCOOH
KllnD4

T

III

18
FIATS S

^OH-CHj,
OH*. 2 ^>CH2
CHg

^PHg-CH
<^2
Y G1>2

^

^,0=0

CH

^,0=0
H
II

CIH

(OHg)4C-C00H
III

^ ^ C H -R
I*
I
CH*
^-C=0
2^ I p
H

PCI
— b

CHg 2 ^ C - C l
P
I
CH*
0=0
H

IT

Cl
I
CIH*H^S {CH2)40-C00H
R
VI
(Continued)

19

FIATS 5 (Continued)

CH2 ~CH2
CH2
'OHg

CHo-CHp
CHg

PC15

J3=S>

CH3 -CH.-

CHg-CH

¥

H

..0=0
H

V II

/
C%

,

C l2

Cm-HgNCHfCHg) ^C-COOH

IX

(Cl) 2

V III

20
the la c ta m tre a te d in th is way w ere su b stitu ted in the 3-p o sitio n
w ith an alkyl g roup, as re p re s e n te d by F o rm u la IV, then the
c o rre sp o n d in g m onochlorinated p ro d u cts V and VI would be
fo rm e d .

The Beckm ann re a rra n g e m e n t of 2-m ethylcyclohexanone

online can le a d to the 3-m eth y l su b stitu ted la c ta m o r the 7 -m eth y l
su b stitu te d la c ta m re p re s e n te d by F o rm u la VII.

Von B rau n and

H eym ons found th a t the la cta m fo rm e d by the re a rra n g e m e n t of
th is oxlm e could be tra n sfo rm e d into a d lch lo ro lactam and a
d ich lo ro am ino ac id h y d roch lo rid e.

T h e ir p ro d u ct was th e r e ­

fo re 7 -m e th y l- 2 -ketohexam ethylenzm ine, VII, and it was tr a n s ­
fo rm e d by rea c tio n with phosphorus p en tach lo rid e into the d ich lo ro la c ta m , VIII, w hich was fu rth e r tra n sfo rm e d into the d i­
c h lo ro am ino acid h y d ro ch lo rid e, IX.
The m ethod of proof of stru c tu re of the la c ta m s d e sc rib e d
in th is th e s is is s till som ew hat d ifferen t than the p rev io u s m ethods
used; how ever, it w ill be evident in the following d isc u ssio n th a t
the m ethod u se s w ell-know n re a c tio n s and can be applied to a
wide v a rie ty of la c ta m s .

DISCUSSION
A study h as been m ade ©f the s tru c tu re s of the la c ta m s
re su ltin g fro m the Beckm ann re a rra n g e m e n t of 3 -m eth y l-S ethylcyclohexanone oxim e.

T his oxim e was not available fro m

c o m m e rc ia l so u rc e s and its p re p a ra tio n re q u ire d the sy n th esis
of the in te rm e d ia te ketone.

In view of the ea se of p re p a ra tio n

and the a v a ila b ility of the sta rtin g m a te ria ls , the m odified
K noevenogel technique of H om ing, D eaekas, and F ie ld (38, 39,
40) w as u sed to sy n th esize 3-m e th y l**5-e th y l- A -cyclohexenone.
The p re p a ra tio n of the u n sa tu ra te d ketone m ay be sch em atically
re p re s e n te d as shown in P la te 6.
On® m ole of propionaldehyd® , 1, and two m oles of ethyl
a c e to a c sta te , II, in the p re se n c e of diethylam ine, condense to
fo rm the b is e s te r , HI.

T re a tm e n t of Compound III w ith alk ali

and h ea t effects the cy clizatio n to 3-m eth y l* 5 -e th y l-4 ,6 -d ic a rb o 2
ethoxy- A - cyclohe xenon®, IV, and the fu rth e r saponification and
d ecarb o x y latio n of IV to fo rm
V.

.2

3

m eth y l- 5 -e th y l- A -cyclohexenone,

The u n sa tu ra te d ketone, V, was cataly tic ally reduced to 3-

m ethyl-5 -eth y lcy clo h ex an o n e by e sse n tia lly the m ethod of Henze,
W ilson, and Towniey (41).

22

PLATS 6

CHgCHgCHD

+

2 CHgCOCHgCOOCHgCHg

I

II

(CHgGHg)^H
oooch2gh3

CH.
CH*xCHo-CH
I
CHgpHpOOC-CHS

X-CH„
11
^CH

a lk .
<--------heat

CHgCHgOOCCHCOCHg
/
CH3CH GH
\

CHgCHgOOOCHCOCHg

nr

in
\ aaJl k .

Vheat
CH^3H -<pA
I

3H»

1 '

NC-CH3
II
,CH

23

2
The u n sa tu ra te d ketone. 3~methyl*5*ethyl~ A -cy clo h cx enone, is a s y m m e tric and e x is ts a s two optical Is o m e rs .

Tike

red u ctio n of e a c h o p tical is o m e r m ay le a d to the e ls o r tra n s
a rra n g e m e n t of the m ethyl group w ith r e s p e c t to the ethyl group.
The 3-m ethyl~5 -cthylcyclohexsxion©, th e re fo re , m ay e x is t a s fo u r
Is o m e rs , one el# ra c e m a te and one tra n s ra e e m a te .

No attem p t

h as b een m ade in th is in v estig atio n to d eterm in e if a ll the p o s ­
sib le is o m e rs a r e fo rm ed , n o r to se p a ra te the is o m e rs th a t a re
fo rm e d .

The re la te d 3, S~dim ethylcyelohexaaone, w hich m ay e x ist

only a s e ls - tr a n s is o m e rs , has b een p re p a re d by the m ethod
ju s t d e s c rib e d and h as been found to have the c is configuration
(42. 43).

T h e re fo re , the 3-m e th y l- S-ethylcyclohexsnone, u sed

In th is in v estig atio n , p robably is the c is ra c e m a te .
The 3 -m eth y l- 5-ethyleyclohexanone w as co n v erted into its
oxixne by tre a tm e n t w ith an aqueous solution of h y droxylam ine.
The liq u id oxim e boiled o v er a n a rro w te m p e ra tu re ran g e and
due to the p o ssib ility of m any is o m e rs fra c tio n a l d istilla tio n was
not c o n sid e re d fe a sib le .

E ach iso m e ric ketone m ay le ad to a

aya and an an ti fo rm of the oxim e.

T h ere a r e fo u r p o ssib le

is o m e ric ketones and thus th e re a re eight p o ssib le iso m e ric
3-m eth y l-5 -eth y lcy clo h ex an o n e oxim e s.

Using the te rm s c is

24

and tr a n s to d esig n ate con fig u ratio n al re la tio n sh ip s of the alkyl
gro u p s in the cy clic ketones and sy a and an ti to designate g eo ­
m e tric is o m e ris m of the oatime group, th e re would thus be fo u r
oxim e ra c e m a te s , the c l s - sy a oxim e, the c is -a n ti oxim e, and
s im ila rly , the tr a n s - syn and t r a n s *an ti oxim e.

It has a lre a d y

b een noted th a t the alk y l groups su b stitu ted on the ketone p ro b ­
able have the c■><W
is
III ' configuration.

If th is be tru e then onlyw the

c i s - syn and the c i s - anti ra c e m a te s of the oxim e would be fo rm ed .
F o r the p u rp o se s of th is in vestigation the oxime was co n sid ered
to c o n s is t sim p ly of the syn and an ti fo rm s ,

No attem p t w as

m ade to se p a ra te the syn and an ti fo rm s of the oxim e sin ce the
conditions of re a rra n g e m e n t probably would have b een d ra s tic
enough to effect isom eriasation.
The th e o ry of the Beckm ann re a rra n g e m e n t h as been d is ­
c u sse d adequately elsew h ere <3, 4, 44-52).

C oncentrated s u l­

fu ric a c id w as u sed in th is in v estig atio n to effect the Beckm ann
re a rra n g e m e n ts .

T h ere a re indications in the lite r a tu r e (53-55)

th a t a high te m p e ra tu re of re a rra n g e m e n t w ith th is agent is not
d e s ira b le and c e rta in ly the avoidance of high te m p e ra tu re e lim ­
in a tes c o n sid erab le decom position of the p ro d u ct by the hot c o n ­
c e n tra te d acid .

A p re lim in a ry in v estig atio n of the B eckm ann

25

re a rra n g e m e n t of cyclohexanone oxim e d e m o n stra te d th a t the
m ethod of M arvel and Eck (16) co aid he m odified to avoid v e ry
v io len t re a c tio n w ith its accom panying high tem p eratu re*

The

su lfu ric ac id w as h eated to the te m p e ra tu re n e c e s s a ry f o r re a r*
ran g em en t and the so lid cyclohexanone oxim e w as then added
p o rtio n w lse so th a t the te m p e ra tu re of the re a c tio n did n o t e x ­
ce ed 130* C.

It should be noted in p assin g th a t the te m p e ra tu re

c o n tro l w as c o n sid erab ly e a s ie r w ith the 3-raeth y l~ 5 -eth y lcy clo hexanone oxim e since the re a rra n g e m e n t w as not a s ex o th erm ic
in th is c a se .
H ildebrand and B o g ert (II) have d em o n strate d th at in the
c a se of the re a rra n g e m e n t of cyclohexanone oxim es with su lfu ric
ac id m o re co n c en trated ac id le ad s to su b stan tially b e tte r yields
of la c ta m .

A p re lim in a ry in v estig atio n of the B eckm ann re a r*

ran g em en t of cyclohexanoite oxim e using la r g e r am ounts of s t a r t ­
ing m a te ria ls and the m odified m ethod of re a rra n g e m e n t ju s t
d e s c rib e d h as su b stan tia te d the claim of th e se in v e stig a to rs.

It

w as found in th e p re s e n t in v estig atio n th at su lfu ric ac id of co n ­
c e n tra tio n g r e a te r th an ninety p e rc e n t gave su b stan tia lly b e tte r
y ield s of € -e a p ro la e ta m than lo w er co n cen tratio n s.

H ow ever,

fo r su lfu ric ac id co n cen tratio n s of 90 to 97 p e rc e n t the yields

26
w ere ap p ro x im ately the sam e.

The co m m e rc ia l co n cen trated

s u lfu ric ac id w as th e re fo re u sed f o r la te r re a rra n g e m e n ts b e ­
cau se of the convenience.
The B eckm ann re a rra n g e m en! of 3 -m eth y l - 5 -eth y lcy clo hexanone oxim e m ay le a d to the two s tru c tu ra lly iso m e ric l a c ­
ta m s.

The c o u rse of the re a rra n g e m e n t m ay be re p re se n te d

a s shown In P la te T.
If F o rm u la VI is d esig n ated a s rep re se n tin g the syn fo rm
of the oxime* then F o rm u la VIII would re p re s e n t the an ti fo rm
of the oxim e.

T here a r e fo u r Iso m eric oxim es th a t can be r e p ­

re s e n te d by F o rm u la VI, a c is ra c e m a te w ith the alkyl groups
a rra n g e d in a c is configuration w ith re s p e c t to each other* and
a tr a n s ra c e m a te w ith the alkyl g roups a rra n g e d In a tra n s con­
fig u ra tio n w ith re s p e c t to each o th e r.

All iso m e ric oxim es re p ­

re s e n te d by F o rm u la VI* on re a rra n g e m e n t le ad to d ifferen t is o ­
m e ric lactam s* w hich m ay be re p re s e n te d by F o rm u la VII.
S im ila r c o n sid e ra tio n s apply to the iso m e ric oxim es and the is o ­
m e ric la c ta m s re p re se n te d resp e ctiv e ly by F o rm u las VIII and IX.
The la c ta m s re p re s e n te d by F o rm u la VII a r e s tru c tu ra lly is o ­
m e ric w ith the la c ta m s re p re s e n te d by F o rm u la IX.

T h ere a re

eig h t p o ssib le is o m e ric oxim es and each iso m e ric oxim e on

PLATE 7

CiyJHg
^CHg
CHg-CH

^CHg-CH
'CH-CHgCHg

'
CH2V ^ 0H2
S
N

C ttj-C H

->

CH_

I
CH2 ^ m^
9

'
C=°

H

OH
V II
VT

.CH.

CH^-CH

SvCH-CH2CH3

r-

.CHg-CH
CH^jCHg-GH
^CHg

28
re a rra n g e m e n t would le ad to a d iffe re n t iso m e ric la c ta m .

T here*

fore* th e re a r e eig h t p o ssib le is o m e ric la c ta m s th a t could r e s u lt
fro m the Beckm ann re a rra n g e m e n t of 3 ~ m ethyl-5-ethylcyclohexanone oxim e.

If the alkyl groups a r e a ssu m ed to h a re the c is

configuration, f o r the reaso n sta te d p rev io u sly , then the Beck*
m aim re a rra n g e m e n t of th is oxim e m ix tu re could lead to the
two s tru c tu ra lly iso m e ric la c ta m s re p re s e n te d by F o rm u la s
VII and IX, e a c h of w hich Is a ra c e m a te .
3-M ethyl-5*ethylcyclohexanone oxim e h as been re a rra n g e d
and the p ro d u c t p u rified by d istilla tio n .

The p ro d u ct boiled o v er

a n a rro w te m p e ra tu re range and fra c tio n a l d istilla tio n was not
c o n sid e re d fe a s ib le .

The p ro d u ct so lid ified on cooling to room

te m p e ra tu re and w as p u rified fu rth e r by re e ry sta llia a tio n .

Melt*

Ing points of the v a rio u s c ro p s of c ry s ta ls fro m the c r y s ta llis a ­
tion m ed ia in d icated th a t a t le a s t two is o m e ric la c ta m s had r e ­
su lted fro m the re a rra n g e m e n t of the oxim e.

One p u re is o m e r

m elting a t 105.@ to 106,2* C. could be Iso lated fro m the m ix tu re
by a p ro c e s s of fra c tio n a l c ry s ta llis a tio n using "hexane*' a s the
so lv en t.

A ll the rem ain in g m ix tu re s of varying content of is o ­

m e ric la c ta m s m elted w ithin the te m p e ra tu re range of 75 to
106.2* C.

A nother p u re is o m e r m elting a t 100.3 to 101.3* C.

29

could be iso la te d by e x tra c tio n of the lour m eltin g m ix tu re s w ith
cold eth y l a c e ta te follow ed by extensive r e c r y s ta lli nation fro m
"hexane*1 of the re sid u e s le ft fro m the ev ap o ratio n of the ethyl
a c e ta te e x tra c ts .

M ixtures of the two p u re is o m e rs se em e d to

in d icate th a t only th e se two is o m e rs w ere p re s e n t and th a t th e ir
e u tectic m ix tu re m elted a t ap p ro x im ately 75* C.
The developm ent of a sa tisfa c to ry m ethod fo r proving th e
s tr u c tu re s of the la c ta m s re su ltin g fro m the Beckm ann re a rra n g e *
m e a t of 3 -m e th y l*5*ethylcyclohexanone oxim e was undertaken using
the p a re n t compound* e -c a p r ©lactam.

The d e s ire d r e s u lt w as to

o btain sa tu ra te d a c id s o r e s te r s fro m the la c ta m s sin ce the
dialkyl su b stitu te d sa tu ra te d ac id s o r e s te r s could be unequivo­
c a lly sy n th esized w ith a co m p arativ ely few w ell-know n re a c tio n s.
Some p re lim in a ry a tte m p ts to red u ce e -c a p ro la c ta m to cap ro ic
ac id w ith co n c en trated hydriodic acid , following in g e n e ra l the
p ro c e d u re of K wisda (35) showed little p ro m ise .

T his m ethod

su ffe rs som ew hat in th a t n o rm ally only sm a ll q u an tities of m a ­
te r ia l m ay be red u ced a t one tim e and the aqueous solutions
used develop c o n sid erab le p r e s s u r e a t the high te m p e ra tu re
needed fo r red uction (35, 36).

30
It is w ell known th at n itro u s acid r e a c ts w ith alip h atic
a m in es to give p ro d u c ts devoid of n itro g en .

W hitmore and Lang*

lo is (ST) have in v estig ated the re a c tio n of n itro u s ac id w ith bu~
ty lam ln e.

The n itro u s acid in th e ir study w as g e n e ra ted by

tre a tm e n t of sodium n itrite w ith h y d ro ch lo ric acid.

They found

th a t the m a jo r p ro d u cts re su ltin g fro m the n itro u s acid tre a t*
m ent of butylam ine w ere straig h t* ch ain b u tan es, butyl alcohols
and butyl c h lo rid e s.

If n itro u s ac id re a c te d analogously w ith

€ *am inocaproic acid , w hich could be obtained by h y d ro ly sis of
e -c a p ro la c ta m , then the p ro d u cts would be u a sa tu ra te d cap ro ic
a c id s, hydroxy ca p ro ic ac id s and chloro cap ro ic a c id s.

The

re a c tio n could be re p re s e n te d a® shown in P la te 8 .
H elferic h and M alkom es (§&} have in v estig ated the reac*
tion of sodium n itr ite w ith c -am in o cap ro ic ac id h y d ro ch lo rid e,
re su ltin g fro m the h y d ro ly sis of e« cap ro lactam .

They obtained

ap p ro x im ately a tw enty p e rc e n t yield of hexenoic acid as m ain
p ro d u ct.

A sm a ll quantity of a lactone w as iso la te d by fu rth e r

tre a tm e n t of the resid u e fro m the d istilla tio n of the hexenoic
ac id but no o th e r p ro d u cts w ere identified,

The p o ssib le p ro d u cts

of th e ir re a c tio n have been re p re se n te d p rev io u sly by F o rm u la s
XII through XVII.

The p re se n c e of two re a c tio n c e n te rs in th ese

31

PLATE 8

' CHg=CH(GHg) gCOOH
X II

CH3CH=CH {CHg) ^COOH
X III

IX>(CH2 )^300H

w\

XIV

OH

HgNtCHgJgPOOH
CH^CH (CHg) ^COOH
XV

X
C1(CH2 ) 5C00H
XVI

Cl
I
CH^CH(CEg) gCOOH
XVII

32

eom po o ad i le a d s to difficulty in th e ir iso latio n .

F o r exam ple,

the C -h y d ro x y cap ro ic acid , re p re se n te d b y F o rm u la XIV, m ay
undergo the changes on attem p ted iso latio n shown in P la te 9.
The C -h y d ro x y cap ro ic acid, un d er the influence of h eat,
m ay cy cliae to the lacto n e, XVIII <59, 60), o r m ay p o ly m e rise
to a long ch ain p o ly e ste r, XIX <61, 62),

The o th e r p o ssib le

hydroxy and ch lo ro su b stitu ted cap ro ic a c id s, re p re se n te d by
F o rm u la s XV through XVII, could p o ssib ly undergo s im ila r
changes.

The la rg e p ercen tag e of unidentified p ro d u ct of H el-

fe r ic h and M alkom es <56) was p resu m a b ly p o ly m er re su ltin g
fro m the tra n sfo rm a tio n s ju s t d escrib ed ,

^ a lla c h (15, 16) has

in v e stig a ted the re a c tio n of n itro u s ac id w ith € -am in o ca p ro ic
a c id s.

H is w ork d em o n strate d th at u n sa tu ra ted cap ro ic acid s

and hydroxy c a p ro ic acids w ere am ong the p ro d u cts of the r e ­
action.

The re a c tio n of n itro u s acid w ith c -c a p ro la c ta m o r the

am ino ac id and its d e riv a tiv e s was chosen fo r fu rth e r develop­
m ent sin ce i t p ro m ise d to yield a f a ir am ount of u n sa tu ra te d
acid w hich could be tra n sfo rm e d e a sily to cap ro ic acid.
A sem iq u an titativ e in v estig atio n of the reac tio n of n itro u s
acid w ith C -am inocaproic acid and v ario u s of its d e riv a tiv e s was
undertaken.

The pu rp o se of the in v estig atio n was to d eterm in e

33
PLATE 9

^ g -C H o

HD(CHg)^COOH

CH2

|® 2

GEL

C^O

XVIII

HO (CHg) g C O ^ (CH2 ) g O o L o (CH2 ) gCOOH

mr

34

w hich p ro c e d u re rem o v ed the m o st o rg an ic ally bound n itro g en .
It wee f e lt th a t an a ly sis of the v ario u s solutions f o r n itro g e n
by the K jeldahl p ro c e d u re would roughly indicate the am ount of
o rg a n ic a lly hound n itro g en th a t rem a in ed in the solutions a fte r
the n itro u s ac id tre a tm e n t.

K ornbium and Iffland (63) have d em ­

o n stra te d th a t alip h atic am in es do not r e a c t w ith n itro u s ac id a t
a pH lo w er than 3.

The v ario u s ex p erim en ts in th is p re lim in a ry

in v estig atio n w ere th e re fo re c a r r ie d out in acetic ac id solutions
o r In m in e ra l ac id solutions b u ffered w ith p o tassiu m a c e ta te .
One exception to th is w ill be noted la te r .
used w ere a s follow s.

In b rie f the p ro c e d u re s

A ll w ere c a r r ie d out below 5° C.

Method

A c o n s iste d of the tre a tm e n t of c -e a p ro la c ta m d isso lv ed in fifty
p e rc e n t a c e tic acid w ith sodium n itr ite .
w as e x tra c te d w ith an o rg an ic solvent.

The re a c tio n m ix tu re
The resid u e le ft on

ev ap o ratio n of the solvent w as tr e a te d fu rth e r w ith co n cen trated
p o ta ssiu m hydroxide to decom pose the n itro so com pound if fo rm ed ,
a s w ill he explained la te r .

The aqueous alk alin e solution w as

m ade ac id to Congo re d and e x tra c te d again w ith e th e r.

M ethod

B co n siste d of th e tre a tm e n t w ith sodium n itrite of e -cap ro la cta ro
d isso lv ed in tw enty p e rc e n t su lfu ric acid.

T his m ethod w as the

one exception noted p rev io u sly w here the m in e ra l acid solution

35

w as n o t b u ffered .

The re sid u e le ft fro m the ev ap o ratio n of the

solvent e x tra c ts w as tre a te d a s In Method A to decom pose the
n itro s o com pound If fo rm e d and then acid ified to Congo re d and
e x tra c te d w ith ether*

M ethod C c o n siste d of the tre a tm e n t with

sodium n itr ite of € -am in o cap ro ic acid h y d rochloride d isso lv ed
In w a te r and b u ffered w ith p o ta ssiu m a c eta te.

Method D co n siste d

of the tre a tm e n t w ith sodium n itrite of e-am in o cap ro ic acid die*
solved in fifty p e rc e n t acetic acid*

Method E co n siste d of the

tre a tm e n t w ith sodium n itr ite of ethyl £ -am inocaproat© hydro*
ch lo rid e d isso lv ed in w ate r and bu ffered w ith p o tassiu m a c e ta te .
Method F co n siste d of the tre a tm e n t w ith sodium n itr ite of ethyl
€ -am in o cap ro ate d isso lv ed in fifty p e rc e n t acetic acid .

The r e ­

actio n m ix tu re s obtained In m ethods C to F w ere m ade ac id to
Congo re d and e x tra c te d w ith e th e r.

A liquots of a ll solutions

w ere an aly sed fo r n itro g e n by the K jeldahl m ethod.
p o slte re s u lts a r e su m m a rise d in Table I.

The com*

Com plete re s u lts

a r e given in T able HI.
Method B, w hich was the tre a tm e n t w ith sodium n itrite
of e -c a p ro la c ta m d isso lv ed in tw enty p e rc e n t su lfu ric acid , and
M ethod D, w hich w as the tre a tm e n t w ith sodium n itr ite of e - a r a lno cap ro ic acid d isso lv ed in fifty p e rc e n t acetic acid, ap p aren tly

36
TABLE I
COMPOSITE RESULTS FROM TABLE III
M ethod

P e r c e n t of O rig in al O rg an ically Bound N itrogen
R em aining in All Solutions

A

58.8

B

18.5

C

30.7

D

18.5

E

37.0

F

23.1

a r e m o at effectiv e f o r the rem o v al of o rg an ically hound n itr o ­
gen.
We m u st d ig re ss b rie fly h e re to explain the b a s is fo r
the tre a tm e n t of € -c a p ro la c ta m w ith sodium n itr ite .

The a n ­

tic ip a te d c o u rse of the re a c tio n m ay be re p re s e n te d a s shown
in P la te 10.
The € -c a p ro la c ta m . XX, is co n v erted into the n itro so
derivative# XXI, w hich under the influence of p o tassiu m hydroxide
m ay decom pose to the diaa&o compound, XXII, o r m ay decom pose

37

PULTS 10

^CHg-CHg
CBg

CHg

CH-

^0=0
H

CBg

"CHg

0Ho

^C =0
NO

XX

XXI

u n sa tu ra te d cap ro ic a c id s
and
hydroxy c a p ro ic a c id s

> <r

N2CH(CH2^
X X II

COOK

to ttnsatu ra te d c a p ro ic acid s and hydroxy c a p ro ic ac id s p r e s u m ­
ab ly th ro u g h the dlaao com pound.

The n itro s o d e riv a tiv e s of

som e la c ta m s have been p re p a re d and found to be un stab le (64,
65).

D ecom position of th e se n itro s o d e riv a tiv e s le ad s to the un-

sta b le dlaao com pound (65) o r d ire c tly to p ro d u cts th a t m ight
b e exp ected fro m the n itro u s ac id tre a tm e n t of the fre e am ino
a c id s (64, 66).

It w as found in th is in v estig atio n th at the n itro so

d eriv a tiv e of £ -c a p ro la c ta m p resu m a b ly decom posed a s It was
form ed* sin ce the fu rth e r tre a tm e n t of the re sid u e fro m the
e v ap o ratio n of the e th e r e x tra c ts of the o rig in al n itro u s acid
re a c tio n d id not sig n ifican tly im prove the rem o v al of o rg an ic ally
bound nitrogen*
The fin a l e th e r e x tra c ts re su ltin g fro m the n itro u s acid
tre a tm e n ts of M ethods B and D w ere an aly sed fu rth e r fo r un­
sa tu ra te d a c id s, to ta l acid s and the w eights of the re sid u e s le ft
on ev ap o ratio n of the solvent.

The Hanus m ethod w as u sed to r

the d e te rm in a tio n of the u n sa tu ra te d acid s and the re s u lts w ere
in te rp re te d a s indicating how w ell the re a c tio n had p ro ceed ed
in the d e s ire d d irec tio n .

The to tal acid content and th e w eights

of the re sid u e s w ere in te rp re te d a s indicating the o v e r-a ll yield
of a ll p ro d u cts.

A nalysis indicated th a t both m ethods gave

39

ap p ro x im a tely ten p e rc e n t of the u n sa tu ra ted ac id th e o re tic a lly
p o ssib le .

The am ount of u n sa tu ra te d acid w as the im p o rta n t

fa c t sin c e the u n sa tu ra te d acid could be e a s ily red u ced to the
sa tu ra te d acid*

M ethod D gave the la r g e s t o v e r-a ll yield of

m a te ria l b a se d on both the to ta l acid a n a ly sis and the w eight of
the re sid u e re su ltin g fro m ev ap o ratio n of the solvent.

Though

Method D g iv es the la r g e s t o v e rfa ll y ield of m a te ria l. It m u st
be re m e m b e re d th a t the s ta rtin g m a te ria l w as £ - azninocaproic
a c id w hich re q u ire d an e x tra ste p in p re p a ra tio n plus the added
disadvantage of the tedious p ro ced u re fo r iso latio n of am ino ac id s.
F u rth e r w ork w as in itiated using e sse n tia lly the n itro u s acid
tre a tm e n t of c*caprolaet& m as d e sc rib e d in Method 3 .
It can be sa id with reaso n ab le c e rta in ty <15, lb . 37, 38, 44,
46-70) th at the p ro d u cts re su ltin g fro m te e n itro u s ac id tre a tm e n t
of € - azninocaproic acid and its v ario u s d e riv a tiv e s a re u n sa tu ra ted
a c id s, la c to n e s, hydroxy acid s and ch lo ro acids <57, 47), if h y d ro ch lo ric acid w ere u sed to g en e ra te the n itro u s acid. An attem p t was
m ade to c o n v e rt a ll th e se p ro d u cts to cap ro ic acid w ithout is o ­
la tio n of the in te rm ed ia te p ro d u cts.

€ - C aprolactam w as tre a te d

w ith n itro u s acid by Method B a s d e sc rib e d p rev io u sly .

The

m ix tu re of p ro d u cts w as tre a te d w ith hydrogen and platinum

40

oxide c a ta ly s t to hydrogenate the u n sa tu ra ted acid s p re s e n t.

At

th is p o in t the p ro d u ct p robably c o n siste d of cap ro ic ac id and the
hydroxy ac id , XXJH, lacto n e, XXIV, and ch lo ro acid, XXV, r e p ­
re s e n te d by the fo rm u la s shown in P la te 11, F ig u re I.
It is also p o ssib le th a t the hydroxy acid, XXVI, the la c ­
tone, XXVII, and the ch lo ro acid , XXVIII, a s re p re se n te d by the
fo rm u la s shown in P la te 11, F ig u re 2, would also be p re se n t.
A n u m b er of in v e stig a to rs (71, 72, 75) have shown th a t
ethyl € -hy d ro x y cap ro ate can be co n v erted into ethyl e -b ro m o c a p ro a te by tre a tm e n t w ith phosphorus trib ro m id e (72, 73), o r
by tre a tm e n t w ith co n cen trated hydrobrom ic acid (71).

F u rth e r,

P a p a and Schwenk and co-w orker® (74, 75) have developed a
p ro c e d u re f o r reducing halogen containing com pounds with Raney
n ickel alloy.

Using the m ethod of Brown and P a rtrid g e (7!), the

m ix tu re of acid s resu ltin g fro m the hydrogenation w as tre a te d
w ith a solution of c o n c en trated hydrobrom ic and su lfu ric acid s
to co n v ert the hydroxy acid and lactone to the 6 -h ro m o cap ro ic
acid .

The acid s re su ltin g fro m the hydrobrom ic acid tre a tm e n t

w ere then tre a te d w ith Raney n ick el alloy and alk ali to c o n v e rt
the e -b ro m o c a p ro ic acid to cap ro ic acid.
p ro c e d u re w ere v e ry u n sa tisfa c to ry .

The re s u lts of th is

The quantity of cap ro ic

41

PLATS 11

HD(CHg)gC°OH

^ CH2“0H2v_

m u

I 8
^-0*0

T Z

0Ho

Cl(CHo )«£00H
XXIV
XXV

F ig u re 1

OK
GH^CH (CHg) gCOOH
XXVI

2
Cl

CBfe-CH

|

"N*0

CH3QH(CH2 ) 3C00H

XXVII

xxrai
F ig u r e 2

12
C=0

42

a c id iso la te d w as n o t m o rs th an could be expected fro m hyd ro g­
en atio n of the u n sa tu ra te d acid s o rig in a lly p re s e n t.

No o th e r

p ro d u c ts w ere iso la te d and attem p ts to find o th e r p ro d u cts w ere
u n su c cessfu l.

F u rth e r w ork was designed to elim in ate an e x c e s ­

siv e n u m b er of re a c tio n s b efo re iso latio n of the p ro d u cts so th at
th e effe c tiv e n e ss of the individual ste p s could be d eterm in ed .
It w as fe lt th a t lo s s of p ro d u ct due to p o ly m erizatio n
could be avoided if the carboxyl group w ere e ste rifle d .

Con­

sid e ra tio n of o th e r s tra ig h t-c h a in com pounds th at could be p r e ­
p a re d fro m c -c a p ro la c ta m and th a t m ight undergo reac tio n s
s im ila r to th o se d e s c rib e d p rev io u sly fo r the n itro u s ac id t r e a t ­
m en t of c -c a p ro la c ta m led to an in v estig atio n of the reac tio n s
of ethy l e -carb o eth o x y am in o cap ro ate.

The p re p a ra tio n of ethyl

€ -c a rb o e thoxyam inocaproate (76, 77) fro m c -c a p ro la c ta m m ay be
sc h e m a tic a lly re p re s e n te d as shown in P la te 12.
6 - C ap ro lactam , XXIX, w as hydrolyzed to the am ino acid
h y d ro ch lo rid e, XXX, which was e ste rifle d to give ethyl € -a m in o cap ro ate h y d ro ch lo rid e, XXXI.

The crude e s te r h y d ro ch lo ride,

XXXI, on re a c tio n w ith ethyl ch lo ro fo rm ate gave ethyl € -c a rb o ethoxy am in o cap ro ate, XXXII.

The n itro sa tio n and decom position

PLATE 12

GHg

_ 0=0

HgNtCHgJgCOOH
XXX

XXIX

CHgCHgOOCNH (CHg) ^C500CHgCH^
XXXII

OICOOCHLCH< --------------- — — ClH»HgR (CHg) gCOOCHgCHg
XXXI

44

of ethyl c -earb o eth o x y am ln o cap ro ate m ay be re p re se n te d as
shown In P la te 13.
The u reth an e * XXXII, was tre a te d w ith n itro u s acid to
give the n ltro s o compound (68, 77, 78), XXXIII.

D ecom position

of th e n ltro s o compound (68*70, 79), XXXin, w ith p o tassiu m
carb o n ate in m ethyl alcohol le d to a m ix tu re of p ro d u cts.

The

boiling p o in ts of the v ario u s fra c tio n s in d icated th a t the p ro d u cts
p ro b ab ly w ere p red o m in ately the u n satu rated e s te r , XXXIV, ethyl
€ -m eth o x y cap ro ate, XXXV, and ethyl € -h y d ro x y cap ro ate, XXXVI.
The y ield of u n sa tu ra ted e s te r was ap p ro x im ately te n p e rc e n t
which w as not any b e tte r than could be expected fro m the d ire c t
tre a tm e n t of € -c a p ro la c ta m w ith n itro u s acid.

T his line of a p ­

p ro a c h w as th e re fo re discontinued since It re q u ire d s e v e ra l
e x tra re a c tio n s and offered no im provem ent in yield of u n satu ­
ra te d e s te r .

It was noted th a t co m p arativ ely little re sid u e was

le ft fro m the d istilla tio n of the p ro d u cts.

T his Indicated th at

e s te rific a tio n a t som e stag e would elim in ate co n sid erab le p o ly ­
m e ris a tio n on d istilla tio n .
None of the p re lim in a ry in v estig atio n s of the re a c tio n of
n itro u s ac id w ith c -am in o cap ro ic acid o r one of its d e riv a tiv e s
im prov ed on the yield of hexenoic acid fro m € -c ap ro la cta m as

t

45
PLATS 13

CHjjCHgOOCNHtCHg)gCOOCHgCH^
XXXII

m iu

CHg=CH (CHg) gCOOOHgC*Hg

xrav

CH O ^JgC O O G H gC H g

3

XXXV

HD (GHg J gCOGCHgCHjj
XXXVI

46
re p o rte d by H elferic h and M&lkomes (96),

It was fe lt th a t th e ir

p ro c e d u re coupled w ith a hydrogenation and e s te rific a tio n would
le a d to a m axim um y ield of ethyl ca p ro a te and elim in ate lo se
of m a te ria l by polym er!nation.

The suggested p ro ced u re was

found to be s a tis fa c to ry and was adopted fo r the proof of s tr u c ­
tu re of the la c ta m s.

The p ro ced u re and re s u lts using € -c a p ro -

la c ta m m ay be re p re s e n te d as shown In P la te 14.
c -C Aprolactam, XXXVU, was hydrolysed with the c a lc u ­
la te d am ount of h y d ro ch lo ric ac id to give € -am in o cap ro ic ac id
h y d ro ch lo rid e, XXXVH1.

T re atm en t of the am ino acid h y d ro ­

ch lo rid e w ith a co n cen trated solution of sodium n itrite gave a
m ix tu re , XXXIX, of the u n sa tu ra ted acid, the hydroxy acid and
the ch lo ro acid.

C atalytic hydrogenation of the m ix tu re, XXXIX,

using p latinum oxide c a ta ly s t gave a m ix tu re , XL, of cap ro ic
acid , € -hydro x y cap ro ic acid and c -c h lo ro c a p ro ic acid.

E s te r ­

ificatio n of the acid s using ethyl alcohol and su lfu ric acid gave
ethyl c a p ro a te , XLI, identified by re fra c tiv e index; ethyl c -h y d ro x y eap ro ate, XLH, identified by co n v ersio n to the known h y d rasid e;
and ethyl € -c h lo ro c a p ro a te , X 1III, identified by re fra c tiv e index.
F u rth e r evidence fo r the stru c tu re of the hydroxy e s te r w as
obtained by co n v ersio n to e-io d o cap ro ic acid, which had

47

PLATE 14

JSHg-CHp
CHg

CH^CHlCHgJgCOOH

\JHg

I

| *

OK

c=o

hyd.
> C1H*H^J (CHg) gCOOH

b o (c h 2)5cooh

^01 (CHg)gpOOH

?
H

XXXIX

X X X 7II

H(CH2 )^COOCHgOH3
X LI
H(CKg)gCOOH
HD (CH g) gCOOCHgCHjj ^

XLII
CKOHgJ^OOOOHgOHg
ZLIII

CHgCHgOH

H2304

b d (c h .

) 5c o o h

CKCHgljCOOE
XL

48

p re v io u sly b t e a p re p a re d Irons an authenic sam p le of ethyl
€ -h y d ro x y c a p ro a te .
E thyl e -h y d ro x y cap ro ate p re p a re d by the m ethod of
Robinson and Sm ith (80) w as co n v erted into the new £ -io d o cap roic
a c id by tre a tm e n t w ith phosphorus and iodine (81-83), follow ed by
h y d ro ly sis.

The c-io d o cap ro ic ac id h as been reduced w ith sin e

and h y d ro ch lo ric acid (82, 84, 88) and e s te rifie d to give ethyl*
c a p ro a te , id en tified by re fra c tiv e index.

It is w ell known th a t

eh io ro o r b ro m o su b stitu ted aliphatic com pounds can be con­
v e rte d into iodo su b stitu ted com pounds w ith co m p arativ e ea se ;
and, th is has a lre a d y been acco m p lish ed w ith a b ro m o ac id (36).
If it w ere n e c e s s a ry to co n v ert the hydroxy e s te r and the eh io ro
e s t e r to cap ro ic acid , the co n v ersio n to the iodo acid , follow ed
b y red u ctio n , se e m s to offer the b e s t ro u te.

A n u m b er of iodo

a c id s and e s te r s co m p arab le to e - iodocaproic acid have b een
p re p a re d p rev io u sly (30, 86-88).

N e v e rth e le ss, the ethyl e a te r

of e -io d o c ap ro ic ac id could not be iso late d in a p u re sta te (39).
The sam e m ethod used to co n v ert e -c a p ro la c ta m to ethyl
ca p ro a te was applied to the p u re la cta m s resu ltin g fro m the
B eckm ann re a rra n g e m e n t of 3-m ethyl-S-ethylcyclohexatnone oxim e.
A p re lim in a ry ex p erim en t using a m ix tu re of th ese la cta m s

49

d e m o n stra te d th a t the o v e r-a ll y ield of p ro d u cts was co m p arab le
to th a t obtained w ith ( - c a p r o la c ta m .

The re fra c tiv e index of the

lo w e r boiling fra c tio n , which should have contained the s a tu ra te d
e s te r s , in d icated th a t red u ctio n of the u n sa tu ra te d e s te r s was not
com plete o r had not taken p lace.

In the co n v ersio n s of the p u re

la c ta m s to th e ir resp e c tiv e sa tu ra te d e s te r s it was n e c e s s a ry to
Iso late the u n sa tu ra te d e s te r s and c a ta ly tic a lly hydrogenate them
u sin g p latin u m oxide c a ta ly s t and acetic a c id solvent.

The p u re

la c ta m is o m e r m elting a t 109.8 to 106.2° C ., which w ill be d e s ­
ignated a s L actam A, w as co n v erted into the sa tu ra te d e s te r .
The s a tu ra te d e s te r w as identified as ethyl 3-e th y l**5-m eth y lhexanoate by its re fra c tiv e index and m elting points of the p toluidide and S-benssylthiur onium s a lt.

The d e riv a tiv e s showed

no d e p re s s io n of m elting point on m ix tu re w ith the sam e d e riv ­
ativ es obtained fro m ethyl 3-e th y l- 5 -m ethylhexanoate th a t had
b een p re p a re d by an unequivocal sy n th e sis.

M elting point d e ­

p re s s io n s w ere o b se rv e d on m ix tu re of the d e riv a tiv e s w ith the
co rresp o n d in g d e riv a tiv e s p re p a re d fro m the iso m e ric e s te r ,
ethyl 3,5-diraethylheptanoate.

L actam A was thus identified as

4 -ethyl - 6 - m ethyl - 2 -ketohexam ethylenim ine and the tra n sfo rm a tio n

so
to the s a tu ra te d e s te r m ay be re p re s e n te d b rie fly a s shown in
P la te 15, F ig u re 1*
Two of the h ig h e r boiling fra c tio n s resu ltin g fro m the con­
v e rs io n of L actam A to the sa tu ra te d e s te r w ere id en tified a s a
eh io ro e s te r and a hydroxy e s te r by an a ly sis of th e ir re sp e c tiv e
S -bennylthiuronium sa lts .

By analogy to the re s u lts obtained

w ith th e £ -c a p ro la c ta m the p osition of the su b stitu en ts w as p ro b ­
ably ep silo n ; how ever, no attem p t has b een m ade to definitely
e s ta b lis h th is conclusion.
The p u re iso m e ric la cta m m elting at 100.3 to 101.3° € .,
w hich w ill be designated a s L actam B, w as co n v erted into the
sa tu ra te d e s te r in a s im ila r m anner.

The sa tu ra te d e s te r was

identified a s ethyl 3 ,5 -dim ethylheptanoate by its re fra c tiv e index
and m elting points of the p -to lu id id e and S-benaylthiuronium sa lt.
The d e riv a tiv e s showed no d e p re ssio n of m elting point on m ix tu re
w ith the sam e d eriv a tiv es p re p a re d fro m ethyl 3 ,5-dim ethyl heptanoate th a t h ad b een p re p a re d by an unequivocal sy n th esis.
M elting point d e p re ssio n s o r in c re a s e s w ere o b serv ed on m ix ­
tu re of the d e riv a tiv e s with the co rresp o n d in g d e riv a tiv e s p r e ­
p a re d fro m the iso m e ric e s te r , ethyl 3 - ethyl - 5 - me thylhexanoato.
L actam B was thus identified as 4 -m e th y l-6 -e th y l-2-k etohexa-

51

PLATE 15

CHgCHg
c h s -c h '3H2^ c h 2
'
'

r

f3

T*™ 5
> OHgCHCHgCHmgCOOCHgCBg
XLV

XLIV

F ig u re 1

gh 3

,^3H2-CH
CH*CHg-CH
CH2
I
I
CHg
.C=0

>

0H3 CHg
I
I
CHgCHgCHGHgCHCHgCOOCHgCHg
XLYII

H
XLYI

F ig u r e 2

52

m ethyleA im ine and the tra n sfo rm a tio n to the sa tu ra te d e a te r m ay
he b rie fly re p re s e n te d as shown in P la te 15, F ig u re 2.
The two new is o m e ric e s te r s , ethyl 3-e th y l- 5 -m eth y lhexanoate and ethyl 3,5 -dim ethylhexanoate, have been sy n th esized
and c h a ra c te riz e d fo r co m p ariso n w ith the sa tu ra te d e s te r s th a t
have b een p re p a re d fro m the iso m e ric L actam s A and B.

The

sy n th e sis of ethyl 3 - e thyl - 5 - me thylhe xanoate re q u ire d the p r e p ­
a ra tio n o f ethyl isobutyl ketone a s an in te rm ed ia te.
h as b een sy n th esized by two m ethods.

This ketone

The f i r s t m ethod co n siste d

of p a ssin g a m ix tu re of propionic acid and iso v a le ric acid o v er
th o riu m oxide c a ta ly st a t 4500 C. (89).

The re a c tio n m ay be

re p re s e n te d as shown in P la te 16.
The propionic acid , XLVXH, condenses with iso v a le ric
acid, XLIX, to fo rm the d e s ire d ketone, ethyl isobutyl ketone,
L.

The side p ro d u ct, diethyl ketone, LI, is fo rm ed by the con­

densatio n of two m olecules of propionic acid, XLVIII.

The side

p roduct, diisobutyl ketone, LII, is fo rm ed by condensation of two
m o lecu les of iso v a le ric acid, XLIX.

A fo rty -o n e p e rc e n t yield

of the ethyl isobutyl ketone, L, w as obtained using a fo u r-to -o n e
m ole ra tio of propionic acid to iso v a le ric acid.

When the ra tio

of propionic acid to iso v a le ric acid was d e c re a se d to two to

53

PLATE 16

CHgCHgCOGH
XLVTII

<2%
CHgCHDEgCOOH
XLIX
ThO.

CHgCHgCOCHgCH (CHg) g
L

+
CHgCHgOOCHgCH^
LI

(CH3 ) gCHCHgCOCHgGE (CHg) g
L II

54
on® the yield of ethyl isobutyl ketone d e c re a se d to eighteen p e r ­
cen t.
The second m ethod u sed to sy nthesize ethyl isobutyl
ketone w as p a tte rn e d a fte r the g en e ra l m ethod of C ason (90-95),
The re a c tio n s involved in th is p ro ced u re m ay be re p re s e n te d as
shown in P la te 17.
Ethyl b ro m id e, LHI, was co n v erted Into ethyl m agnesium
b ro m id e, L1V, by the usual G rignard p ro ced u re.

The ethyl m ag­

n esiu m b ro m id e, L1V, was co n v erted into diethyl cadm ium , LV,
by tre a tm e n t w ith anhydrous cadm ium c h lo rid e .

The diethyl

cadm ium , LV, w as p re p a re d un d er an atm o sp h ere of n itrogen.
Iso v a le ry l chloride* LVII, p re p a re d fro m iso v a le ric acid, LVI,
b y tre a tm e n t w ith thionyl chloride* w as condensed w ith the d i­
ethyl cadm ium , LV, under an atm o sp h ere of n itro g en to fo rm
ethyl isobutyl ketone* LVIIL
w as fo rty - s in p e rc e n t.

The yield of ketone by th is m ethod

A co m p ariso n of the two p ro c e d u re s u sed

fo r the p re p a ra tio n of ethyl isobutyl ketone d em o n strated th a t
the diethyl cadm ium m ethod gave the b e tte r yield.

However*

the sim p lic ity of the cataly tic m ethod f a r outweighs the sm a ll
disadvan tag e in yield and the cataly tic m ethod w as co n sid ered
to be the b e tte r of the two p ro c e d u re s .

55

PLATE 17

Mg
CHgCHgBr — — >
L III

CcLClg
CSHgCHgMgBr --------- >

(CHgCHgJgOd

LIV

LV

SOClg

(CH3) gCHCHgCOOH --------- > (GH^gOHCH^COCl
LVI

(CHrjGHgJgCd
LV

—|—

LV II

(CH35gCHOHgCOCl ---------- > CHgCHgCOCHgCHfCHg)#,
LV II

LV II I

56
The ethyl isobutyl ketone, p re p a re d by the two m ethods
d e s c rib e d p rev io u sly , w as tra n sfo rm e d Into ethyl 3-e th y l-5 m ethylhexanoate by a Ref o r m a t sky rea c tio n follow ed by d e h y d ra ­
tion an d hydrogenation.

The re a c tio n s m ay be re p re s e n te d a s

shown in P la te IS.
The R efo rm atsk y re a c tio n as m odified by N atelson and
G o ttfried (96) w as used to p re p a re the m ix tu re, LXI, of u n sa tu ­
ra te d a c id s.

thy! isobutyl ketone, LV1II, and ethyl b ro m o a c e -

ta te , LDC, d isso lv ed in an ap p ro x im ately fifty p e rc e n t m ix tu re
of benaene and to lu e n e, w ere condensed by reac tio n w ith nine to
fo rm the hydroxy e s te r LX.

The hydroxy e s te r , LX, w as not

iso la te d but was dehydrated in solution by re a c tio n with p h o s­
p h o ru s pentoxide (97) to fo rm the m ix tu re, LXl, of u n sa tu ra ted
e s te r s ,

An attem p ted dehydration of the hydroxy e s te r with

a c e tic anhydride w as not su c cessfu l and p robably le d to the
acety l d eriv a tiv e of the hydroxy e s te r .

The m ix tu re, LXI, of

u n sa tu ra te d e s te r s was cataly tic ally hydrogenated a t low p r e s s u r e
of hydrogen using platinum oxide c a ta ly st and acetic acid solvent
to fo rm ethyl 3 -ethyl -5 -m ethylhexanoate, LXII.

Low p r e s s u r e

hydrogenation of the m ix tu re of u n sa tu ra ted e s te r s using platinum
oxide c a ta ly s t and ethyl alcohol solvent was not su c cessfu l (9 3).

57

PLATE 18

OH^CEgCOOHgCE (GE3 ) 2

-f~

BrCHgC00CHgCH3

L V III

LIX

CHgCHs
(CH5 ) gCKJHgC-CHgCOOCHgOHg
OH
LX

CH2CH3
(CHg)gCHOHgC^GHCOOCHgCHg
red.
and

OHgC^
( ^ 3 ) 2CHDH=C-CHgCOOCHgCHg
LXI

CH3

CHgCHg

|

I

» CHgCHGHgOHOHgCOOOTgC^
LX II

58
P a r tia l red u ctio n of the m ix tu re of u n sa tu ra te d e s te r s could be
e ffe c te d u sin g high p r e s s u r e hydrogenation a t 60° C. w ith Raney
n ic k el c a ta ly s t and ethyl alcohol so lv en t (98, 99).
The sy n th e sis of the is o m e ric ethyl 3 ,S-dim e thylheptanoate
m ade n e c e s s a r y the p re p a ra tio n of 4 - m ethyl - 2 •hexanone a s an
in te rm e d ia te .

The re a c tio n s used fo r the p re p a ra tio n of the

ketone m ay be re p re s e n te d a s shown in P la te 19'.
E thyl ac eto a ce tate, LXIV, w as alk y lated w ith seco n d ary
butyl b ro m id e (100), LX1II, using sodium eth y late a s the con­
densing agent.

The cru d e keto e s te r , h X V , fo rm e d by the

alkylatio n w as saponified w ith sodium hydroxide and the fre e
ac id decarboacylated to give 4- m ethyl - Z-hex&none» LXYI.
Ethyl 3 ,5 -dim e thylheptanoate w as p re p a re d fro m the 4m e th y l- 2 -hexanone by e s se n tia lly the sam e p ro c e d u re u se d fo r
the p re p a ra tio n of ethyl 3 -eth y l - 5 - me thylhexanoate.
The two new e s te r s , ethyl 3 -e th y l- 5 - m e thylhexanoate and
ethyl 3 ,5 -dim ethylheptanoate w ere c h a ra c te ris e d by a n a ly sis,
p h y sic a l co n stan ts, and an aly sis of th e ir re sp e c tiv e p -to lu id id es
and S-benasyl th iu ro n iu m s a lts .

E ach e s te r w as co n v erted into

the re sp e c tiv e p a re n t acid by sap o n ificatio n and acid ificatio n and
the acid s w ere c h a ra c te ris e d by a n a ly sis and p h y sical co n stan ts.

59

PIATE 19

Br

I
CHgCHgCHCHg

-f_

CHgCOCHgCOOCHgCHg

x x lii

ixnr
HaOCHgCHjj

CHg

CHgCOCHgCKJHgCHg <--------LXVT

CHgCHgCHCHg

CH^COCHCOOCHgC^
LXV

60
II hast f u rth e r b een d e m o n stra te d In th is in v estig atio n
th a t the two new is o m e ric L actam s A and B, p re p a re d by the
B eckm ann re a rra n g e m e n t of 3• m eth y l- 5 -ethylcyclohexanone online,
ca n b e tra n s fo rm e d into the re sp e c tiv e su b stitu te d 1,5-p en ta m eth ylenetetraasole by tre a tm e n t w ith phosphorus p en tach lo rid e fol*
low ed by re a c tio n w ith a solution of hydr azoic acid d isso lv ed In
benzene (101)*

The fo rm atio n of the te tr azo les m ay be r e p r e ­

se n ted a s shown in P la te 20,
The two te tra s o le s , LXV1I and LX V in, have b een c h a ra c ­
te r is e d by a n a ly sis.
H arvU l, R o b erts, and H e rb st (1) have d e s c rib e d a m ethyl
ethyl p en tam eth y len etetran o le w hich had been obtained by the
in te ra c tio n of 3-m ethyl - 5 -ethylcyclohexanone oxim e w ith sodium
asid e and chloroeulfonic acid.

The m ethod of fo rm a tio n which

involved an expansion of the cyclohexanone ring s im ila r to th a t
en co u n tered in the Beckm ann re a rra n g e m e n t could have le d to
two iso m e ric te tra n o le s tru c tu re s .

T hese au th o rs a r b itr a r ily

assig n e d a ten tativ e s tru c tu re , LXVIII. to th e ir compound.

The

tetrassole of H arv ill. R o b erts, and H erb st (1) has been co m p ared
w ith th e se te tra a o le s of known s tru c tu re by m eltin g points and
m ixed m elting po in ts.

It has thus been shown th at the tetrassole

PLATE 20

CHgCHg
CHg-CH
CHg-CH

CH2

CHp

,.C=0

H
H

CHjjCHg
^3H8-CH
CHg-CH
^CBg
CHg

, C^

''" B
I
N

1

N
I
H

LACTAM A

LOTI

j®3
CHg-CH,
CHgCHg-CH

,CHg-CH
'C H 2

CHg

0=0
H

0HgCH2 -CH

CHg

CHg

^

H =

LA.CTAM B
LX7III

62
p r e p a r e d b y H a rv ill, R o b erts, and H e rb st (1) is ? -e th y i-9 -m e th y l t ,5 -pen taro e th y le n etet ra a o le , LXVH, and does not have the s tr u c ­
tu r e , L X V in, w hich had been a r b itr a r ily assig n e d to i t p rev io u sly .

EXPERIMENTAL * 2
P re p a ra tio n of Compounds f o r
P re lim in a ry E x p erim en ts
€ -C a n ro la c ta m

€ - C apr o lactam was p re p a re d e s se n tia lly a s d e sc rib e d by
M arvel and E'ck (56) In O rganic S yntheses.

H ow ever, the m ethod

of re a rra n g e m e n t of the cyclohexanone oxizne was changed.

U s­

ing the sa m e p ro p o rtio n s of su lfu ric acid to oxim e, the to tal
am ount of su lfu ric acid w as placed in a b e a k e r of ap p ro p riate
sine and w as h eated to the te m p e ra tu re n e c e s s a ry fo r r e a r r a n g e ­
m ent, 305* C.

The so lid oxim e w as added p o rtio n w ise by m eans

of a sp atu la so th a t the te m p e ra tu re w as m aintained betw een 105
and 130* € .

A fter all the oxime had b een added the m ix tu re w as

cooled to 10° C. and double its weight of ice was added a ll at

1 A ll m elting points in th is th e sis a re c o rre c te d .
Z

All K jeldahl an aly ses fo r n itro g en w ere com pleted in
th is la b o ra to ry . Ail o th e r an aly ses w ere com pleted by M icroT ech L a b o ra to rie s , Skoki®, Illinois.

64
once.

The p ro d u c t w as Iso lated a s a lre a d y d e s c rib e d (56) and

re c ry s ta llin e d fro m hexane.
H ildebrand and B o g art (11) have found th at in the r e a r ­
ran g em en t of 2-alkyleyclohexanone oxim es b e tte r y ield s w ere ob­
ta in ed w ith su lfu ric acid m ore co n c en trated than 85 p e rc e n t.
T h e ir re s u lts have been su b stan tiated h e re by an in v estig atio n
of the re a rra n g e m e n t of 25 g. of cyclohexanohe oxim e effected
w ith su lfu ric ac id of v ario u s co n c en tratio n s.
th is in v estig atio n a r e su m m a rise d in Table XI.

The r e s u lts of
The p ro d u ct was

not iso la te d by d istilla tio n a s p rev io u sly d e sc rib e d (56) b u t w as
iso la te d by re c ry s ta llia a tio n of the so lid resid u e rem ain in g a f te r
ev ap o ratio n of the e x tra c ts .
The r e s u lts indicate th at the m ore co n cen trated su lfu ric
ac id gives the b e tte r yield.

T h ere w as little d ifferen ce betw een

the yields given by the 90, 95, and 97.1 p e rc e n t acid.

The co m ­

m e rc ia l co n c en trated su lfu ric acid was th e re fo re u sed fo r the
re a rra n g e m e n t of cyclohexanone oxim e and the 3 ,5 -alk y lated
cyclohexanone oxim e s.

65
TABLE II
THE BECKMANN REARRANGEMENT OF CYCLOHEXANONE
OXIME USING SULFURIC ACID OF VARIOUS
CONCEN TRATIONS
P ercen t
V °4

ssgsaaargiaatsassaga:
Wt. of
F irs t
Crop

Wt. of
Second
Crop

T otal
Wt. of
P ro d u ct

P e rc e n t
Yield

97 A

16.3 g.

2.6 g.

18.9 g.

75.6

95

16.5 g.

2.9 g.

19.4 g.

77.6

90

16.1 g.

3.4 g.

19.5 g.

77.9

85

15.0 g.

1*3 g.

16.3 g.

65.2

80

13.9 g.

2.8 g.

16.T g.

66.8

e-Amin® cap ro ic A cid H ydrochloride
€ - Am inoc aproic acid hyd ro ch lo rid e w as p re p a re d by the
m ethod of E ck (102) 4a O rganic S yntheses.
£ - A m inocaproic Acid
€ - A m inocaproic acid w as p re p a re d fro m e-ca p ro lactair,
by h y d ro ly sis w ith su lfu ric acid and n eu tra liza tio n w ith an equiv­
a len t am ount of b ariu m hydroxide.
202* C. (u n co rrected ).
C.)

The p ro d u ct m elted a t 200 to

(R eported m elting point [102], 201 to 203*

66
Ethyl € - A m inocaproate H ydrochloride

E thyl

am ino cap ro ate h y d ro ch lo rid e w as p re p a re d by

the m ethod of M arvel e t al. (103).

C ry sta llisa tio n fro m ethyl

alcohol«diethyl e th e r solution gave hydroscopic c ry s ta ls m elting
a t 38.3 to 61.8* C. (re p o rte d m elting point, 54 to 58* C. [103]).
Ethyl c - Am inoc ap ro ate
Ethyl c -am in o cap ro atc was p re p a re d by the m ethod of
M arvel «e4nM
tMob afOll-r^
l. (103).
*
y

The M
p ro d u ct b o iled a t 123-125° C ./2 3 m m .

(The re p o rte d boiling points a r e 122* C ./2 8 m m . [103J; 90-92*
C ./4 m m . [103]; 105* C ./1 6 m m . [7?].)

67
P re lim in a ry E x p erim en ts fo r C onversion of
L actam to Saturated E s te r
M ethod A

F iv e g ra m s , 0*044 m ole, of c -c a p ro la c ta m w as d isso lv ed
in 20 m l. of 50 p e rc e n t acetic acid and w as cooled below 5* C.
T h re e g ra m s , 0,044 m ole, of sodium n itr ite w as added to the
m ix tu re In th re e p o rtio n s in fifteen m in u tes.

The re a c tio n m ix ­

tu re w as p laced overnight In a r e f r ig e r a to r a t 5 to 10* C.
The m ix tu re w as m ade acid to Congo re d with 1:1 h y d ro ­
c h lo ric ac id and e x tra c te d w ith five 20 m l. p o rtio n s of e th e r.
The rem ain in g aqueous solution w ill be d esig n ated a s Solution I.
The e th e r w as ev ap o rated and the m ix tu re n e u tra lise d w ith 40
p e rc e n t p o ta ssiu m hydroxide in an ic e-b ath .

Ten m illilite r s of

40 p e rc e n t p o ta ssiu m hydroxide was added and the re a c tio n a l ­
low ed to sta n d fo r th irty m in u tes.

The m ix tu re w as cooled,

m ade acid to Congo re d w ith 1:1 h y d ro ch lo ric acid and w as e x ­
tra c te d w ith five 20 m l, p o rtio n s of e th e r.

The rem ain in g aq u e­

ous solution w ill be d esignated a s Solution 12,

The e th e r e x tra c ts

w ill be d esig n ated as Solution 111.
A liquots of Solutions Z, 12, and 112 w ere analysed fo r n i­
tro g e n by the K jeldahl m ethod.

68
M e th o d

B

F iv e g ra m s of € -e a p ro la c ta m w as d isso lv ed in 20 m l. of
20 p e rc e n t su lfu ric ac id and was tre a te d with 3 | . f 0.044 m o le,
of sodium n itr ite a s d e sc rib e d in M ethod A.

The re a c tio n mix*

tu r e , in th is e a se , was a lre a d y acid to Congo re d and th e re fo re
no h y d ro c h lo ric ac id w as added.

Solutions I, II, and HI w ere

obtained in a m an n er id en tical to Method A and w ere analy sed .
Method C
Six and six -te n th s g ra m s, 0.044 m ole, of € *am inocaproic
acid h y d ro ch lo rid e w as d isso lv ed in 20 m l. of w a te r and w as buf*
f e re d w ith 4.3 g., 0.044 m ole, of p o tassiu m a c e ta te .

The solution

w as co oled below S* C. and 3 g., 0*044 m ole, of sodium n itrite
w as added in th re e p o rtio n s in fifteen m in u tes.

The re a c tio n

m ix tu re was p la c e d overnight in a r e f rig e ra to r at 5 to 10° C.
The m ix tu re was m ade acid to Congo red w ith Is! h y d ro ­
ch lo ric ac id and e x tra c te d with five 20 m l. p o rtio n s of e th e r.
The rem ain in g aqueous solution w ill be d esig n ated a s Solution
I.

The e th e r e x tra c ts w ill be desig n ated a s Solution III.
A liquots of Solutions 1 and III w ere an aly sed fo r n itro g en

by the KJeldmhl m ethod.

69
M ethod D

F iv e and e ig h t-ten th s g ra m s , 0.044 m ole, of e -am m o c ap raic
ac id w as d isso lv ed in £0 m l. of 50 p e rc e n t ac etic acid and was
tr e a te d w ith 3 g., 0.044 m ole, of sodium n itrite a s d e sc rib e d in
M ethod C.

Solutions

I

and

III

w ere obtained in a m an n er id en tical

to M ethod C and w ere s im ila rly analysed.
M ethod £
Seven and e ig h t-ten th s g ra m s , 0.044 mol®, of ethyl e - a m inocaproat® h y d rochloride w as d isso lv ed in £0 m l. of w ater and
the solution was buffered w ith 4.3 g,„ 0,044 m ole, of p o tassiu m
a c e ta te .

This solution was tre a te d w ith 3 g., 0.044 m ole, of

sodium n itr ite a s d e sc rib e d in Method C.

Solutions

I

and

III

w ere obtained in a m an n er id en tical to Method C and w ere s im ­
ila rly analyzed.
M ethod F
One and o n e-h alf g ra m s, 0.011 m ole, of ethyl c -am in o ca p ro a te w as d isso lv ed in 4.S m l. of 50 p e rc e n t acetic acid and
w as cooled below 5* C.

S eventy-three hundredths g ra m s, 0 .0 H

m ole, of sodium n itrite was added to the m ix tu re in th re e p o rtio n s

70
in liv e m in u tes.

O n e-to -o n e h y d ro ch lo ric acid was added until

the solu tio n te s te d p o sitiv e to starch * io d id e p a p e r.

The reac tio n

m ix tu re w as s e t o v ern ig h t in a r e f r ig e r a to r a t 5 to 10* C.
The m ix tu re w as tre a te d fu rth e r a s d e sc rib e d in Method
C and gave s im ila r Solutions I and III which w ere an aly sed as
b efo re.
The re s u lts of n itro g en an aly ses on Solutions I, IX, and
III obtained in the ex p e rim en ts ju s t d e s c rib e d a r e su m m a rise d
in T able XXX.
The re s u lts indicate th a t M ethods B and D a r e m o st e f­
fectiv e f o r rem oving n itro g en fro m the re sp e c tiv e am ino acid
d e riv a tiv e s .
A liquots of Solutions XII fro m M ethods B and D w ere f u r ­
th e r te s te d fo r u n sa tu ra ted acid by the Hanus method; to ta l acid
by titra tio n of an alcoholic solution w ith sta n d ard sodium h y ­
droxide using a phenolphthaiein in d icato r and, fo r the am ount of
re sid u e le ft a fte r ev ap o ratio n of solvent.

The to ta l acid fo r So­

lution III of M ethod D was d eterm in ed by the d ifferen ce betw een
a d ire c t titra tio n of an aliquot and titra tio n of the acetic acid
se p a ra te d fro m an aliquot by aaeo tro p ic d istilla tio n w ith b en aen e.
The re s u lts a re su m m a rise d in T able IV.

71
TABLE i n

NITROGEN ANALYSIS USED TO INDICATE EFFECTIVENESS
O F VARIOUS METHODS OF DEGRADATION OF
* - AMINOC APROIC ACID DERIV ATIVES

Method

P e r c e n t of O rg an ically Bound N itrogen
Rem aining in Solution
Total

Solution I

Solution II

Solution III

A

36,2

S3.8

8.8

58.8

B

8.3

4.2

6.0

1 6.5

C

28.!

-

2.6

30.7

D

14.4

-

4,1

18.5

E

30.3

m

6.5

37.0

F

16.5

m

6.6

23.1

M ethods B and D both gave ap p ro x im ately ten p e rc e n t of
the u n sa tu ra te d acid th e o re tic a lly p o ssib le.

The am ount of un­

sa tu ra te d acid is the im p o rta n t co n sid eratio n since the u n s a t­
u ra te d acid m ay be red u ced e a sily to the sa tu ra te d acid.

Method

D gives the la rg e s t yield of m a te ria l b ased on the valu es fo r
to tal acid and resid u e weight* but it m u st be re m e m b e re d th a t
the sta rtin g m a te ria l w as

-am in o cap ro ic acid w hich re q u ire d

72
TABLE XV
FURTHER ANALYSIS OF SOLUTIONS RESULTING FROM THE
DEGRADATION O F C-AMINOCAFROIC ACID DERIVATIVES
C om parative V alues fo r O n e-fifth Aliquots
M ethod

Un s a t­
u ra te d
Acid

T otal
A cids

B

0.895
m .e .

3.66
m .e.

D

9.S35
m .e.

32.34
m .e.

A cetic
Acid
*H
r

23.36
m .e.

T otal
C aproic
Acids

Weight of
Residue

3.66
m .e.

0.598
g-

6.90
m .e.

0.862

* R esidue rem ain in g a f te r a z eo trep ic d istilla tio n of the
ac etic acid w ith benzene and evaporation of the benzene by
h eatin g on a ste am bath.

an e x tra step in p re p a ra tio n plu s the added disadvantage of the
tedious p ro ced u re fo r iso latio n of am ino ac id s.

73
R eaction of N itro u s Ac Id w ith € * C aprolactam and
A ttem pted C onversion of Ail P ro d u c ts
to C aproic Acid
F ifty gram s* 0.442 mole* of £-c a p ro la c ta m w as d isso lv ed
in 300 m l. of 20 p e rc e n t su lfu ric ac id and the solution was cooled
to S’ C*

F o rty * six g ra m s , 0,663 mole* of sodium n itr ite d is ­

solved in 100 m l. of w a te r was added to the s ti r r e d su lfu ric
acid m ix tu re .

The te m p e ra tu re w as kept below 7* C.

A fter

com plete addition of the sodium n itrite solution the reac tio n
m ix tu re w as s tir r e d fo r eight h o u rs w ith the te m p e ra tu re m a in ­
tain ed below 7* C. w ith an ic e-b ath .

The m ix tu re was k ep t in

a r e f r ig e r a to r overnight.
The following day the m ix tu re w as s tir r e d fo u r h o u rs
lo n g er w ith the te m p e ra tu re below 7* Q. and then was n e u tr a l­
ise d w ith 40 p e rc e n t sodium hydroxide w ith the te m p e ra tu re kept
below 15* C.

The p re c ip ita te of sodium sulfate was filte re d

and w ashed w ith ch lo ro fo rm .

The aqueous la y e r w as e x tra c te d

w ith seven 70 m i. p o rtio n s of ch lo ro fo rm .

The aqueous solution

rem ain in g a fte r ch lo ro fo rm e x tra c tio n w ill be d esignated as So­
lution I.

The com bined org an ic la y e rs w ere d rie d o v er anhydrous

sodium su lfate.

The sodium sulfate was filte re d and the filtra te

74

d ilu ted to 500 m l, w ith ch lo ro fo rm .

T his ch lo ro fo rm solution

w ill ho d esig n ate d a s Solution II.
T itra tio n of a 10 m l. aliquot of Solution II w ith sta n d a rd
a lk a li in d icated 151 m .e . of total acid in the ch lo ro fo rm e x tra c t.
(The th e o re tic a l to ta l acid w as 442 m .e.)
The ch lo ro fo rm w as rem oved by d istilla tio n and *QG m l.
of 40 p e rc e n t sodium hydroxide was added to the resid u e w ith
s tir r in g and cooling.

The m ix tu re w as s tir r e d fo r fo u r h o u rs

a t room tem perature* cooled and m ade stro n g ly acid to Congo
re d w ith 60 p e rc e n t su lfu ric acid.

The te m p e ra tu re w as kept

below 25® C. during the n e u tra lisa tio n by cooling in a n ic e-b ath .
The m ix tu re w as e x tra c te d w ith s ix 70 m l. p o rtio n s of c h lo ro ­
fo rm ,

The aqueous solution left a fte r ch lo ro fo rm e x tra c tio n w ill

be d esig n ated a s Solution III.

The com bined organic la y e rs w ere

d rie d o v e r anhydrous sodium sulfate.

The sodium sulfate was

filte re d and the filtra te diluted to 500 m l, with ch lo ro fo rm .

T his

ch lo ro fo rm solution w ill be desig n ated as Solution IV.
A liquots of solution® I. II* III* and IV w ere analysed fo r
n itro g e n by the K jeldahl m ethod (Table V).

75
TABLE V
NITROGEN ANALYSIS OF VARIOUS SOLUTIONS OBTAINED
FROM THE DEGRADATION OF €-CAPROLACTAM
WITH NITROUS ACID
Solution

P e rc e n t ot O riginal O rg an ically Bound N itrogen
R em aining In Solution

I

5.5

n

9.5

in

i.i*

IV

6.8*

* The p e rc e n t of n itro g en obtained by an a ly sis of s o ­
lu tio n s III and IV should add up to the p e rc e n t of n itro g en o b ­
tain ed by a n a ly sis of solution II if no o rg an ic ally bound n itr o ­
gen is rem o v ed by the sodium hydroxide tre a tm e n t. The re s u lts
indicate th a t the tre a tm e n t with sodium hydroxide is of doubtful
value.

76

R eduction o£ the Uns a t u ra te d A cids

The solvent waa rem o v ed fro m the second ch lo ro fo rm
e x tr a c t by d istilla tio n through a V igreux colum n.

The resid u e

w as d isso lv e d in 100 m l. of ethyl alcohol and hydrogenated on
the low p r e s s u r e F a r r h y d ro g en ato r a t an in itia l hydrogen
p r e s s u r e of SO I h s ./s q , in. in the p re se n c e of platinum oxide
c a ta ly st.

The o b se rv e d hydrogen p r e s s u r e drop of 6.9 lb s.

w as eq u iv alen t to the fo rm a tio n of 9.5 g. of cap ro ic acid fro m
hexenoic ac id s.
The platinum was filte re d , the solution w as m ade a lk a ­
line to litm u s and the ethyl alcohol w as rem oved by steam d is ­
tilla tio n .

The aqueous re sid u e was m ade stro n g ly acid to Congo

r e d and e x tra c te d w ith six 80 m l. p o rtio n s of ch lo ro fo rm .

Total

a c id content w as d eterm in ed by titra tio n of an aliquot and w as
equivalent to 110 m .e.
The rem ain in g ch lo ro fo rm solution was d rie d o v er an ­
hydrous sodium su lfate.

A fter filtra tio n and rem oval of the

solvent by d istilla tio n through the V igreux colum n on a steam
b ath a re sid u e of 41 g. rem ain ed .

F o rm a tio n of B rom o A cid s <63-65)

The re sid u e fro m the la s t step w as added to a m ix ­
tu re of 170 m i. of 4$ p e rc e n t hydrobrom ic acid and 41 m l,
of 97.1 p e rc e n t su lfu ric acid.

The m ix tu re was allow ed to

sta n d fo r two h o u rs a t room te m p e ra tu re and then was h eated
fo r th re e h o u rs on a steam bath.

The cooled re a c tio n m ix ­

tu re w as pou red into 350 m l. of w ate r, and was sa tu ra te d
w ith sodium sulfate and e x tra c te d w ith six 30 m l. p o rtio n s
of e th e r.

T otal acid, d eterm in ed by titra tio n of an aliquot,

w as HO m .e .
A fter drying the e th e re a l solution and rem oving the
solven t by d istilla tio n as p rev io u sly d escrib ed , 37 g. of r e ­
sidual m a te ria l rem ain ed .
A ttem pted Reduction ofJ w i a o
S ubstituted Cap ro ic Acids with
Raney N ickel <66, 67)
T.UPL

'li _j.r —

Li— - —

*iJ~

• i.WMWMMnnm

The re sid u e fro m the p rev io u s step w as d isso lv ed in
100 m l. of a solution of 113 g. of sodium hydroxide in 450
m l. of w ate r.

N inety g ra m s of Raney nickel alloy was added

portionw ise to the s tir r e d solution.

The rem aining sodium

76
hydroxide solution was added o v er a one h o u r p erio d .

The

m ix tu re w as h eated one and o n e-h alf h o u rs a t 90 to 100* G.
A fte r cooling and filte rin g to rem ove the n ick el, the solution
w as m ade stro n g ly acid to Congo re d w ith 60 p e rc e n t su lfu ric
acid .
The acidic m ix tu re w as steam d is tille d until 600 m l.
erf d is tilla te w as co llected .

The d istilla te was s a tu ra te d w ith

sodium su lfate, e x tra c te d with six SO m l. p o rtio n s of e th e r
and the com bined e th e re a l e x tra c ts w ere d rie d o v e r anhydrous
sodium su lfate.

The sodium sulfate w as filte re d off and the

solven t w as rem oved by d istilla tio n fro m a ste a m bath.

F ra c ­

tionation of the re sid u e gave 6.9 g. of p ro d u ct boiling a t 109
to 110* C ./2 0 m m ., n^

30

1.4134; and 2.9 g. of m a te ria l b o il-

ing a t 109 to 112* G ./19 m m ., n^
tive index f o r cap ro ic acid, n^

1 ft

31 5
‘ 1.4140 (re p o rte d r e f r a c 1.41877,

1.4143? f I OS];

re p o rte d boiling point fo r cap ro ic acid , 107.3* C ./S 6 m m .

[ns]).
If both fra c tio n s w ere co n sid ered to be cap ro ic acid
then th e ir com bined weight would re p re s e n t a 19.1 p e rc e n t
yield of the th e o re tic a l am ount.

T his p ercen tag e yield was

not sig n ifican tly g r e a te r than could be expected by iso latio n

79
of the c a p ro ic a c id obtained by hydrogenation of the hexenoic
a c id .

The re a c tio n s follow ing the hydrogenation step w ere ap

p a re n tly not v e ry effective.

80
P re p a ra tio n ©f Ethyl e-C arb o eth o x y arn in o cap ro ate

CH3-CH2OOC-NH-(CH2)5-COO-CH2 -C H 3
F ifty g ra m a , 0,442 m ole of e -c a p ro la c ta m w as h y d ro ly sed
b y refloating fo r one hour w ith a m ix tu re of 36.8 m l. of co n cen ­
tr a te d h y d ro ch lo ric acid (37,3 p ercen t) and 70 m l. of w a te r.

The

w a te r w as rem oved by d istilla tio n on a ste am bath under red u ced
p re ssu re .

The w hite c ry sta llin e resid u e was d isso lv ed in 70 m l.

of w ater*

One hundred and six ty m illilite r s of ethyl alcohol and

120 ml* of benaene w ere added and the m ix tu re refluxed fo rty th re e h o u rs through a B a rr e tt m odification of the D ean-S tark
tr a p , a t w hich tim e no m o re w a te r co llected in the tra p .

The

solvent was rem oved by d istilla tio n and le ft a g ra y solid re sid u e .
The cru d e e s te r hydrochloride w as d isso lv ed in 150 m l.
of w a te r and 100 m l. of e th e r was added.

A solution of 17.7 g.,

0.442 m ote, of sodium hydroxide d isso lv ed in 50 m l. of w ater
w as added slow ly w ith the te m p e ra tu re m ain tain ed below 5* C.
until the m ix tu re had tu rn ed b asic to litm u s.
42.3

F o rty -e ig h t g ra m s,

m l., 0.442 m ole, of ethyl chi o r ©formate w as added slowly

w ith the te m p e ra tu re kept below 12® C.

When ap p ro x im ately

th re e q u a rte rs of the ethyl ch lcro fo rm ate had been added the

81
m ix tu re b ecam e a c id ic .

A solution of 30.5 g., 0.442 m ole, of

p o ta ssiu m ca rb o n ate d isso lv ed in 50 m l. of w ate r was now added
to g e th e r w ith the ethyl ch lo ro fo rm ate solution so th a t they both
w ere co m p letely added a t the sam e tim e.
s tir r e d th irty m in u tes.

The m ix tu re was

The e th e r la y e r w as se p a ra te d and the

aqueous la y e r e x tra c te d w ith two 50 m i. p o rtio n s of e th e r.

The

e th e r so lutions w ere d rie d by shaking w ith two s e p a ra te p o rtio n s
of anhydrous p o tassiu m carb o n ate.

The solvent w as rem oved by

d istilla tio n on a steam b ath under reduced p r e s s u r e .

F ra c tio n -

ation of the resid u e gave 75.5 g. of p ro d u ct (73.7 p e rc e n t of the
th e o re tic a l amount) boiling a t I S3 to 189* C . / 17 m m . (re p o rte d
boiling point [77] is 135* C ./2 0 ' xnvn*).

b2
C o n v ersio n of Ethyl £ -C arb oethoxyam inocaproate
to Ethyl C aproate and O ther P ro d u c ts
N it ro ta tio n (68. 78)

A 500 nal., th re e -n e c k e d fla sk was equipped w ith a th e r ­
m o m e te r and a dropping funnel w ith an attach m en t to allow a d ­
ditio n of re a g e n ts to the bottom of the flask .

T w en ty -th ree

g ra m s . 0*1 m ole, of ethyl £ -carb o eth ex y am in o cap ro ate d isso lv ed
in 40 m l. of diethyl e th e r and 32,5 g M 0*45 m ole, of sodium
n itr ite d isso lv e d in 60 m l, of w a te r w ere p laced in the fla sk .
The m ix tu re w as cooled to ID® C. and m aintained below th is
te m p e ra tu re throughout the reac tio n .

A solution of cold 35 p e r ­

cen t n itric acid (60 g ., 0.33 mole) was added slow ly in sev en tyfive m in u tes.
an ic e -b a th .

The m ix tu re was allow ed to stand th re e h o u rs in
The e th e r la y e r had now tu rn ed b lu e -g re e n .

The

e th e r la y e r w as se p a ra te d and w ashed w ith ten 10 m l. p o rtio n s
of ic e -c o ld w a te r.

The la s t w ash solution s till te ste d ac id to

Congo re d p a p e r.

The e th e r solution w as d ried o v er anhydrous

sodium su lfate, filte re d , and the solvent w as rem oved under
red u ced p r e s s u r e on a w ater bath h eated no h ig h er than 40° C.
The lig h t orange liquid resid u e weighed 21.3 g.

63
D ecom position (68*70. 79)

The re sid u e fro m the la s t step w as added slow ly to a
m ix tu re of IE ml* of m ethyl alcohol (p rev io u sly d rie d o v er a n ­
h y drous p o ta ssiu m carbonate) and 0.05 g. of finely pow dered
anhydrous p o ta ssiu m carb o n ate.

The reac tio n m ix tu re becam e

hot and w as cooled in an ic e -b a th during the addition and until
the com pletion of the reac tio n .
th re e h o u rs.

V igorous bubbling took p lace fo r

The m ix tu re was allow ed to stand overnight a t

room te m p e ra tu re .

The next day the solution had tu rn ed y e l­

low and bubbling had ce ase d .

The m ix tu re w as refluxed one hour

on a ste a m bath, cooled, filte re d , and diluted with 100 m l. of
ethyl alcohol.

This solution was hydrogenated a t 50 lb s. h y d ro ­

gen p r e s s u r e w ith 0. t g, of platinum oxide c a ta ly st.
p r e s s u r e drop was o b serv ed in fifty m in u tes.

A 2.6 lb*

The platinum w as

f ilte re d off and the solvent was rem oved by d istilla tio n on a hot
w ate r b ath .

The resid u a l liquid was d istille d under red u ced p r e s ­

s u re and the following fra c tio n s w ere collected:
1.4 g*

66-99* C ./1 6 m m .

3.7

99.5-110° C ./1 6 mm.

III

7,1 ae*

110-165° C ./1 6 m m .

IV

1.9 g-

190-19&* C ./1 6 m m .

I
11

U4

Two g ra m a of b lack re sid u e was le ft in the d istilla tio n
fla sk .
C o n sid eratio n of the p o ssib le p ro d u cts th at m ight be
fo rm e d by the decom position of the n itro so com pound le a d s
to the te n tativ e identification of the fra c tio n s as follow s:

F ra c ­

tion I is p ro b ab ly p red o m in ately ethyl cap ro ate; F ra c tio n EE is
p ro b ab ly a m ix tu re of ethyl £ -rnethoxycap ro ate and ethyl c -h y ­
droxy ca p ro a te (re p o rte d boiling point of ethyl € - m ethoxyc ap ro a te ,
94-95* C ./1 5 m m , [72]; re p o rte d boiling point of ethyl € -h y d ro *y ca p ro a te, 135* C ./1 5 m m . [80]); F ra c tio n HI is p ro b ab ly p r e ­
dom inately ethyl £ -hydroxycaproate; F ra c tio n IV m ight be 5carbethoxyam yl-6-hydroxyhexanoate (re p o rte d boiling point of
5-carb eth o x y am y l- 6 -hydroxyhexanoate, 191* C ./U 5 m m . [80]),
#
U F ra c tio n 1 w ere a ll ethyl ca p ro a te then th is fra c tio n
would re p re s e n t a te n p e rc e n t co n v ersio n to the d e s ire d p roduct.
This p erce n tag e yield is ap p ro x im ately the sam e a s obtained
w ith o th e r procedures*
No fu rth e r in v estig atio n of th is rea c tio n was m ade since
the yield of sa tu ra te d e s te r was no b e tte r than obtained w ith
o th e r s im p le r m ethods.

as
N itro u s Acid T reatm en t of € -Caprol& ctam
T w enty-five g ra m s, 9.22 m ole, of € -caprol& ctam was
h y d ro ly sed w ith the calcu lated am ount of h y d ro ch lo ric acid a s
p re v io u sly d e s c rib e d (58).

The solvent was rem o v ed by d is til­

la tio n un d er red u ced p r e s s u r e on a ste am bath.

T w en ty -th ree

g ra m s . 0.33 m ole, of sodium n itrite in 40 m l. of w ate r was
added slow ly to the white solid re sid u e during one hour.
vigorous ex o th erm ic reac tio n took p lace.

A

The te m p e ra tu re w as

kept below 90* C* by in te rm itte n t cooling in an ic e -b a th .

The

solution w as allow ed to stand th re e h o u rs a t room tem p eratu re*
m ade stro n g ly acid to Congo red w ith 20 p e rc e n t su lfu ric acid
and h ea ted on a steam bath fo r one h our.

The m ix tu re w as

cooled and e x tra c te d with five 50 m i. p o rtio n s of ch lo ro fo rm .
The com bined ch lo ro fo rm e x tra c ts w ere d rie d o v er anhydrous
sodium su lfate, filte re d , and the solvent was d istille d through a
V igreux colum n leaving 33 g, of re sid u e .

The re sid u e was e s -

te rifle d by refluxftng overnight with 100 m l. of absolute alcohol
and 10 m l. of co n cen trated su lfu ric acid.

The m ix tu re w as

cooled and n e u tra lis e d with a co n cen trated solution of sodium
carb o n ate; it was filte re d and e x tra c te d f i r s t with one 100 m l.
p o rtio n of ben&ene follow ed by th re e 50 m l. p o rtio n s of benzene.

86

The com bined benzene e x tra c ts w ere w ashed tw ice w ith 25 ml*
©I cold s a tu ra te d sodium ch lo rid e solution.

The solvent w as

rem o v ed by d istilla tio n through a V igreux Colum n.

F ractio n s*

tion thro u g h a C laisen fla sk w ith a one foot V igreux side a rm
gave the follow ing fra c tio n s:
t

1.8 g.

59-60* C ./1 3 m m .

11

7,0 g.

58-67* C ,/ i m m .

1X1

1.4 g.

67-89* C ,/ l m m .

XV

8,6 g.

89-92* C ./ l m m .

V

0.2 g.

92* C ./ l m m . and above

and fo u r g ra m s of re sid u e rem ain ed in the d istilla tio n flask .
F ra c tio n l s n ^
e s te r .

20 5
‘ 1*4230, w as probably the u n sa tu ra te d

In a s im ila r ex p erim en t a low p r e s s u r e red u ctio n w as

effected b efo re the c a lo rificatio n step ,

fa th is Instance the f i r s t

fra c tio n fro m the d istilla tio n boiled a t 57*58* C ./I3 mm*, n t
d
1.4072, and w as identified as ethyl c a p ro a te , n^

20

20

1.4076 (108).

F ra c tio n s 11* 111* IV. and V w ere reco m b in ed and r e f r a c ­
tio n ated through a one foot ta ll, eig h t m illim e te r d ia m e te r V igreux
colum n w ith d istilla tio n head and cow type vacuum ta k e-o ff using
a 10:1 reflu x ra tio to give the following fra c tio n s :

87

A

2.3 g.

36-72* C ./ l m m .

B

1.1 g.

72-91* C ./ l m m .

C

4.3 g.

91-95* C ./ l m m .

Frag*ISHLA. a ,

20 S
* 1.4*79. gave a p o sitiv e B . i l . f i a te s t

fo r halogen and w as identified a s ethyl £ -e h lo ro ca p ro a te; re p o rte d
ig

boiling point 106“ C ./1 4 m m . and n .
1.4398 (73).
a
20, Z
F r a c tion B , n .
1.4377, w as ap p a re n tly a m ix tu re of
the com pounds obtained In fra c tio n s A and C and thus was not
f u rth e r in v estig ated ,
F ra c tio n C, n„
"n" ~
a

20

1.4360, w as id en tified a s ethyl £ -h y d ro x -

ycapro& te; re p o rte d boiling points 134° C ./1 S m m , (80), 104-6°
C ./4 m m . (62). 135-140* C ./1 6 m m . (104); a

1.4381 (62).

F a r t of th is fra c tio n w as co n v erted to e -io d o cap ro ic acid by the
m ethod d e s c rib e d in the e x p e rim en ta l sectio n .

The e -io d o c ap ro ic

acid , so fo rm ed , m elted a t 42,9-44° C. and showed no d e p re ssio n
of m elting point on m ixing w ith an authentic sam ple.

In a s im ­

i l a r e x p e rim en t the hy d raaid e (109) was p re p a re d fro m the f r a c ­
tion boiling at 93-99* C ./3 m m .

The hydr&side m elte d a t 114.8-

116.3° G. and the high boiling fra c tio n was thus identified as
ethyl £ -hyd ro x y cap ro ate; re p o rte d m elting point of hydranide,
! 14-U S* C. (61, 62).

38

P re p a ra tio n of £ -Iodocaproic Acid (81, 82, S3)

I * <CH2)g - COOH
O a t and o n e * q u a rte r g ra m s , 0,04 m ole, of re d p h o sp h o rus,
15.4 g.» 0,046 m ole, of ethyl c-h y d ro x y cap ro ate (p re p a re d by the
m ethod of Robinson and Sm ith [80] in 33 p e rc e n t yield, boiling
point 149-154* C ./1 9 m m .), and 15.3 g., 0,06 m ole, of iodine
w ere m ixed and reflu x ed on a steam b ath fo r five h o u rs .

The

m ix tu re w as cooled, 100 m l. of e th e r w as added and the p h o s­
pho ru s w as filte re d off.

The e th e r solution was w ashed w ith

fo u r 20 m l. p o rtio n s of 10 p e rc e n t sodium b isu lfite, once w ith
w a te r and d rie d o v er calcium ch lo rid e.

The calciu m ch lo rid e

w as filte re d and the e th e r was ev ap o rated by p assin g a s tre a m
of d ry a i r o v er the su rface of the solution,
The re sid u e was s tir r e d a t room te m p e ra tu re fo r fo u r
h o u rs w ith 100 m l, of 10 p e rc e n t sodium hydroxide.

The an*

sapoxiified la y e r wa® se p a ra te d and the aqueous la y e r m ade
stro n g ly acid to Congo re d w ith dilute su lfu ric acid,
c ip ita ted on the addition of the acid.
a r e f r ig e r a to r overnight and filte re d .

"olid p r e ­

The m ix tu re w as s e t in
The c ry s ta ls w ere s u s ­

pended in 100 m l. of w ate r and s tir r e d to d issolve the sodium

89
su lfa te ,

n i t r a t i o n gave 10 g. of cru d e m a te ria l (43 p e rc e n t of

the th e o re tic a l am ount).
A s m a ll am ount of the cru d e m a te ria l w as reerystaX Uned
fro m ethyl alcohol - w a te r and m elted a t 42.5-44* C.
Anal:

C a lc ’d fo r

I, 32.4.

Found:

I, 52.4, 52.7

90
R e d u c tio n

e - I o d o c a p r o ic A c id
C aproate (32, 84, 85)
of

to

Ethyl

Two and fo u r-te n th s g ra m s , 0.01 m ole, of £ -io d o cap ro ic
a c id w as p la c e d in an eig h t inch te s t tube equipped w ith a con­
d e n s e r,

The ac id was p a rtia lly d isso lv ed in 15 m l, of ethyl

alcohol.

To th is m ix tu re was added 2.6 g ., 0.04 m ole, of 30

m e sh zinc w hich had been p rev io u sly cleaned by w ashing su c ­
c e ssiv e ly w ith dilute acid , w a te r, and alcohol.

Five m l. of

co n c en trated h y d ro ch lo ric ac id w as added fro m a d ro p p er to th is
m ix tu re o v er a fifteen m inute p erio d .

The m ix tu re w as refiu x ed

fo r tw enty m inutes and allow ed to stand fo u r h o u rs.

Five m l.

m o re of co n c en trated h y d ro ch lo ric ac id was added and the m ix tu re
reflu x ed f o r th irty m inutes a t which tim e the zinc had a ll re a c te d .
The reac tio n m ix tu re was steam d istille d and the d is tilla te e x ­
tra c te d w ith th re e 10 m l, p o rtio n s of e th e r.

The e th e r w as

ev ap o rated on a - steam bath and 20 m l. of benzene was added
to the m ix tu re to aid in the evaporation of the alcohol and w a te r.
D istilla tio n of the re sid u e gave 0,55 m l, of p ro d u ct, n .
a
(re p o rte d [106] re fra c tiv e index of ethyl ca p ro a te is n ^

20
20

1.4080
1,4076).

T his r e p re s e n ts a 43 p e rc e n t y ield of the th e o re tic a l am ount.

91
P re p a r a tio n of 3 - Methyl - 5 - 5'thylcyclohe xanone (38*41)

CH*

/

\

C H ,- CH
3 |

,

CH,

CH - C H ,—CH ,
2
3

CH,
\

I
c

/

2

o

One hundred and sev en ty -fo u r g ra m s , 3 m o les, of fre s h ly
d is tille d propionaldehyde <b. 47.2 - 49*5® C ./7 3 ! m m .) and 780
g ,, 6 mole®, of fre s h ly d istille d ethyl aeeto acetate (b. 170 - 173“
C ./7 3 ! m m .) w ere p laced in a 3 lite r , th ree -n e ck ed , ro u n d -b o t­
tom fla sk equipped with m echanical s t i r r e r , th e rm o m e te r, and
dropping funnel.

The m ixture was cooled to - 5 “ C. by m eans

of an ic e - s a lt bath.

F ifteen m illilite r s of diethyl am ine was

then added in sm a ll portion® o v er a two hour p erio d so th at
the te m p e ra tu re n ev e r ro se above +5* C.

The m ixture was

s tir r e d fo r tw enty-four h o u rs in an ic e -b a th and s tir r e d an o th er
tw enty-fo u r h o u rs a t room te m p e ra tu re .
Two p re p a ra tio n s using the quantities above w ere com bined
fo r the next p h a se s of the reactio n .

Saponification and d e c a r­

boxylation w ere acco m p lish ed by boiling th irty m inutes w ith 999
g, of sodium hydroxide d isso lv ed in 6 lite r s of w ate r.

The

92
m ix tu re w as ste a m d is tille d until 14 lit e r s oaf d istilla te w as c o l­
lected*

The o rg an ic la y e r w as se p a ra te d and the aqueous la y e r

ag ain d is tille d until the d is tilla te becam e clear*
w as re p e a te d tw ice more*

T his o p eratio n

The final w ater solution w as e x tra c te d

w ith th re e 100 m l. p o rtio n s of e th e r.

The com bined organic

la y e r s w ere d rie d o v er calciu m ch lo rid e, filte re d , and d istille d
to rem ove solvent.
F ra c tio n a tio n of the re sid u e gave 29 S g. of 3-m eth y l-5*
2
eth y l- A - cyelohexeacuie (36 p e rc e n t of the th e o re tic a l amount)
boiling a t 102 - 1!2* C ./ l 1 m m .
Z

Sixty g ra m s of 3 -m eth y l- 5 - ethyl - A ~cycl ohexenone # 0.1
g. of platinum oxide, and 60 m l. of ethyl alcohol w ere p laced
in a h eav y -w alled g la ss bottle and hydrogenated on the low p r e s ­
su re F a r r h ydrogenator.

The in itial p r e s s u r e was 50 lb s .

The

m ix tu re ab so rb e d the calcu lated am ount of hydrogen (36 lb . drop
in p re s s u re ) during th irty m inutes to th re e h o u rs in d iffe re n t
e x p e rim en ts.
The p ro d u cts of five runs w ere then com bined, the p la t­
inum filte re d , and the solvent was rem oved by d istilla tio n .
F ra c tio n a tio n of the resid u e gave 232 g. of p ro d u ct boiling a t
89,5-94° C ./1 7 m m . (re p o rte d boiling point 200-291,5° C. [11;

93

204-205* C ./7 4 7 m m . [41]).

Hed istilla tio n of the fo re ru n and

re sid u e gave an additional 26 g. of p ro d u ct.

The to ta l yield

w as 258 g. and re p re s e n te d an 85.5 p e rc e n t y ield f o r the hy­
d rogen atio n p h ase.

94

P re p a r a tio n of 3* Methyl* 5-E thylcyclahexanone Oxime

CH3— CH

CH— CH2— CH3

\

C
II
N

(HO--)

/

\

OH

Two hundred and fifty -e ig h t g ra m s , 1.84 moles* of 3m e th y l-5«©thylcyclohexaaone d isso lv ed in I lite r of isopropyl
alcohol was m ixed with 399.5 g., 2.76 m o les, of hydroxylam ine
h y d ro ch lo rid e, 148 g., 3,68 m oles, of sodium hydroxide and 500
g ., 3.6-i m o tes, of sodium a c e ta te trih y d ra te d isso lv ed in 1.5
lit e r s of w ate r.

The m ix tu re w as h eated th irty m inutes on the

ste am h ath and allow ed to stan d overnight.

The following day

the m ix tu re w as again h eated fo r th irty m inutes on a steam hath
and allow ed to stand overnight.

The isopropyl alcohol la y e r w as

se p a ra te d and the w ate r la y e r e x tra c te d w ith th re e 150 m l. p o r ­
tions of e th e r.

The com bined e x tra c ts w ere w ashed w ith 100

m l. of sa tu ra te d s a lt solution, d rie d o v er sodium sulfate and the
solvent was rem oved through a V igreux column.

93
The resid u e contained w a te r and was th e re fo re fu rth e r
d rie d by adding benzene and rem oving the w ate r by azeo tro p ic
d istilla tio n .

F ra c tio n a tio n of the resid u e gave 240 g. of a v is ­

cous p ro d u ct (84 p e rc e n t of th e o re tic a l amount) boiling a t 129.5134* C ./1 5 m m , (re p o rte d boiling point 127-128* C . / l l m m .
tm .

96

The Beckm ann R earran g em en t of 3-M ethyl-5
Sthylcyclohexanone Qxime

/ c\
i2 n

CH,— CM
'S j

GH — CH,—CH­
|
2
3

CH,

GH,

H N ---------- CO
and

/ CH2
/

\

CH,—CH
3 |

CH
| — CH.—
E CH,

CH,

CH

\

I

O C1--------- ■ NH

Two hundred and fo rty g ram a of su lfu ric ac id (96.5 p e r ­
cent) w as p la ced is* a b e a k e r equipped with a s tirre r* th e rm o m ­
e te r and dropping funnel*

The su lfu ric acid w as h eated to 110*

C. and the te m p e ra tu re w as m aintained betw een 110 and US* G.
by the slow addition of 120 g. of 3-m ethyl - 5 -ethylcyclohexanone
oxim e fro m the dropping funnel.

A fter the com plete addition

of the oxim e, w hich re q u ire d one and o n e-h alf h o u rs, the r e a c ­
tion m ix tu re was h eated f o r fifteen m inutes betw een 110 and
115* C.

97
Two of the above rea c tio n m ix tu re s w ere com bined, cooled
to 10* C. and p o u red onto ice su fficien t to dilute to 2 lite r s .
The m ix tu re was e x tra c te d w ith fiv e 250 ml* p o rtio n s of c h lo ro ­
fo rm , w ashed th re e tim e s w ith 50 ml* of 10 p e rc e n t sodium c a r ­
bonate and d rie d o v er anhydrous sodium su lfate and anhydrous
m ag n esiu m su lfate.

The solvent w as rem oved by d istilla tio n .

D istilla tio n of the resid u e fro m a C laisen fla sk gave 179.5 g.
of slig h tly yellow p ro d u ct (74. k p e rc e n t of the th e o re tic a l amount)
boiling a t 179 - 171.5* C ./1 7 -1 8 m m .
cooling to room te m p e ra tu re .

The p ro d u ct so lid ified on

98

P re lim in a ry Solubility Studies of Dialkyl Substituted
€ -C ap ro la cta m M ixtures

The ap p ro x im ate so lu b ilitie s of v ario u s m ix tu re s of the
la c ta m o b tain ed by Beckm ann re a rra n g e m e n t of 3-m e th y l-5ethylcyclohexanone oxim e w ere d eterm in ed in a n u m b er of s o l­
ven ts in an attem p t to find a su itab le solvent fo r iso latio n of
the p u re iso m e ric la c ta m s.
I.

la a p re lim in a ry B eckm ann re a rra n g e m e n t of 3 -m ethyl -

5-ethylcyclohexanone oxim e a la cta m m ix tu re c ry s ta lliz e d on
pouring the reac tio n m ix tu re onto ice.

T his la c ta m m ix tu re

w as recry stallissed fro m w ate r to give the following fra c tio n s ;
1
ii
iii

m .p. 75-84* C*
m .p. 70-78.5* C.
m*p. 86-^3* C.

The ac id f iltr a te rem aining a fte r filtra tio n of the o rig in al
la c ta m c r y s ta ls w as e x tra c te d w ith ch lo ro fo rm .

The ch lo ro fo rm

e x tra c ts w ere w ashed w ith sodium carb o n ate solution and d rie d
o v er anhydrous sodium su lfate.

The resid u e rem ain in g on ev ap ­

o ratio n of the ch lo ro fo rm w as re c ry s ta llis e d fro m 1‘h e x a n eM to
give the following fra c tio n s;

99
iv

m .p .

76*78* G.

v

m .p.

90-92* C.

Tli® so lu b ilities of fra c tio n s i, ii, ill, iv, and v w ere d e ­
te rm in e d by d isso lv in g a known w eight of so lid In a known v o l­
um e of so lv en t and allow ing c ry s ta llis a tio n to o cc u r a t the
d esig n ated te m p e ra tu re .

C ry sta llisa tio n was allow ed to p ro cee d

o v ern ig h t f o r the so lubility d eterm in atio n s a t room te m p e ra tu re
and fo r one h o u r fo r the d eterm in atio n s a t ic e -b a th te m p e ra tu re .
The c r y s ta llis e d solid w as then filte re d and d rie d .

The d iffe r­

ence betw een the w eight of the c ry s ta llis e d so lid and the w eight
of the so lid o rig in ally tak en w as used to e stim a te the solubility.
The r e s u lts a re su m m arised in T able VI.
2.

S o lubilities w ere d eterm in ed on a la c ta m m ix tu re

boiling a t IT S -176.3° 0 , / I S m m . w hich was obtained by r e a r ­
ran g em en t of 3 - m ethyl - 5 - e thylcyclohexanone oxim e.

All the

p ro d u ct in th is ca se was iso la te d by ch lo ro fo rm ex tra ctio n f o l­
low ed by d istilla tio n .

The so lu b ilities a re re c o rd e d in Table

VII and w ere d eterm in ed in a m an n er id en tical to the m ethods
ju s t d e sc rib e d .

100
T A B L E VI

APPROXIM ATE SOLUBILITY OF MIXTURES O F METHYL
ETHYL SUBSTITUTED e-CAPROLACTAM S
■hi

■■

Solvent

L actam
F ra c tio n

W ater

V

W ater

Solubility in G ram s p e r 100
M illilite rs of Solvent
Room
T em p e ra tu re

Ice-b ath
T e m p e ra tu re

1.4 g.

1.4 g.

1

1 .6

1 .6

E thyl a c e ta te

i

V ,8 .

33.

g.

Sthyl ac e ta te

ili

v .s .

11.

g.

g.

g.

TABLE VII
APPROXIMATE SOLUBILITY OF A DISTILLED MIXTURE OF
METHYL ETHYL SUBSTITUTED e-CAPROLACTAMS

Solvent

Solubility in G ram s p e r 100 M illilite rs of
Solvent
Room T em p e ra tu re

Ic e -b a th T em p e ra tu re

W ater

2.6 g.

2.3 g.

Cfchyl ac e ta te

v*&.

H exane

7.4 g.

29.

g.

5,b g.

101
3.

F ra c tio n a l c ry s ta llis a tio n of the la c ta m m ix ture d e ­

s c rib e d In (1.1 using hexane as the solvent, gave p u re L actam
A, m .p . 105.8-106.2® C.» and s e v e ra l m ix tu re s of lo w er m e lt­
ing point.

The so lu b ility of the lo w est m elting lactam m ix tu re,

m .p. 73-79-5® C., obtained fro m the fra c tio n a l c ry s ta llis a tio n
w as d e te rm in e d in v ario u s so lv en ts.

The re s u lts a re re c o rd e d

in T able VUL
Subsequently it was found th a t se p aratio n could be a c ­
com plish ed m o re conveniently by e x tra c tio n of the o rig in al la c ­
ta m m ix tu re w ith cold ethyl ac eta te and re c ry s ta llis a tio n of the
v ario u s re s id u e s and e x tra c tiv e s fro m hexane.

102
TA B L E VIII

APPROXIM ATE SOLUBILITY OF THE LOWEST MELTING
MIXTURE OF METHYL ETHYL SUBSTITUTED
6-CAPROLACTAMS REMAINING AFTER
ISOLATION OF SOME PURE
LACTAM A
Solubility in G ram s p e r 100
M illilite rs of Solvent
Solvent
Room
T em p e ra tu re
A ceto n itrile

v.».

H eptane

22 g-

Ice-b ath
T em p e ra tu re
33 g.
m

eth y len e dichloride

45 g.

Ethyl b ro m id e

41 g.

103
M ethod fo r

o f Is o m e r ic L a c ta m s R esu ltin g F ro m

the Beckm ann R earran g em en t of 3-M eth y l-5thylc yclohexanone Oxime
The d istille d m ix tu re of la c ta m s re su ltin g fro m the r e ­
a rra n g e m e n t of 3-m e th y l-5-ethylcyclohexanone oxim e w as d is ­
solved In half its w eight of ethyl acetate and tr a n s f e r r e d to a
b e a k e r.

The m ix tu re was cooled in an ic e -b a th to c ry s ta llis e

the la c ta m s .

This p re lim in a ry o p eratio n was p erfo rm e d to give

the solid a c ry s ta llin e c h a ra c te r b e tte r suited f o r the subsequent
o p eratio n s.

T his o p eration was not n e c e s s a ry when se p aratin g

m ix tu re s th a t w ere alre ad y in a s a tisfa c to ry fo rm , such a s m ix ­
tu r e s of la c ta m s re su ltin g fro m fra c tio n a l c ry s ta llis a tio n s .
The m ix tu re of la c ta m s w as e x tra c te d w ith se v e ra l p o r ­
tions of ethyl ac eta te cooled to 0* G.

The solid w as s tir r e d

in te rm itte n tly with the solvent fo r five m inutes and then filte re d
by suction.
The m elting points of the re sid u e s and the e x tra c tiv e s w ere
used as the c r ite r i a of the p ro g re s s of the sep aratio n .

The am ount

of solvent fo r each ex tractio n was adjusted so th a t a fte r all e x ­
tra c tio n s . approxim ately o n e -th ird of the weight of the o rig in al
m a te ria l rem ain ed .

The resid u e at th is point m elted o v er a

104

co n sid e ra b le ran g e but did n o t m e lt co m p letely until the te m p e r­
a tu re had r is e n to a t le a s t 90* C.

T his w as found s a tisfa c to ry

f o r p u rific a tio n by r e c r y sta lliaatio n .
F o u r to sin recry stalli& atio n s of the re sid u e fro m ' ’h ex ­
a n e " {from petroleum ) gave iso m e r A, m .p. 105.8 - 106.Z* C.
A nal.:

C alc'd fo r C ^H ^O N :
Founds

C. 69.64; H» 11.04; N, 9.0.

C, 69.65; H, 11.00; N, 8.9 (Kjeldahl).
/ GHZ

/
C H .—CH
3 |
CH*

\2

\

CH — CH,— CH ,
|
2
3
CH,

I

2

HN------------CO
The ethyl ac eta te solutions fro m the e x tra c tio n s w ere
ev ap o rated to d ry n e ss and if n e c e s s a ry re ex tra cte d w ith ethyl
a c e ta te so th a t the e x tra c tiv e obtained by evaporation of the
solvent m elte d above 73° C.

In a few c a s e s the e x tra c tiv e was

r e c r y s ta llis e d once fro m 1h e x a n e 11 in o r d e r to obtain th e d e s ire d
m elting point.
The ap p ro p riate e x tra c tiv e s w ere com bined and r e c r y s ta llin ed a t le a s t twelve tim e s fro m "h e x a n e 1* to give is o m e r B.
m .p. 100*3-101.3* C.

105

Anal.:

C a lc ’d fo r C .H ^ O N :
Found:

C, 59.64; H, 11.04; N, 9.02.

C. 69.58; H. 11.00; N. 9.10.

/ \
CH ,

CH,— CH
3 |

,

CH — CH — CH,
2
3

CH,

CH ,

OC —

NH

\

|

2

A# an exam ple, 179.5 g, of d istille d la c ta m s w ere d is ­
solved in 100 m l of ethyl ac eta te and cooled in an ic e -h a th to
c ry s ta llin e .

T his m ix tu re w as e x tra c te d w ith 350 m l. of cold

ethyl a c e ta te to leave 101.5 g. of resid u e m .p. 70-83.5* C.
T his re sid u e was fu rth e r e x tra c te d w ith 150 m l. of cold ethyl
ac e ta te to leav e 54.5 g. of resid u e m .p. 82-96.0° G.

Four re -

c ry s ta llis a tio n s of th is resid u e fro m ’'hexane ’1 gave 25.5 g. of
is o m e r A, m .p. 105.8-106.2* C.
The ethyl acetate solutions fro m above w ere ev ap o rated
to d ry n e ss and the resid u a l m a te ria l e x tra c te d again indepen­
dently w ith cold ethyl a c e ta te .

The ethyl acetate solutions fro m

th e se second ex tra ctio n s w ere ev ap o rated to d ry n ess and the
e x tra c tiv e s r e c r y sta llise d once fro m " h e x a n e ."

By s im ila r

tre a tm e n t of the e x tra c tiv e s fro m the second e x tra c tio n s, m o re
c r y s ta ls w ere obtained.

The com bined c ry s ta ls weighed 59.6 g.

106

and had an ap p ro x im ate m elting point of 75 to 87* C.

T his

m a te r ia l w as re e ry s fa llie e d twelve tim e s fro m " h e x a n e " to
give 9.1 g. of is o m e r B, m .p. 100.3-101.3* C.

107

C onversion of the L actam of 3 - E th y l-5-M ethyl-6 A m inohexanoic Acid to Ethyl 3 - E th y l-5 M ethylhexanoate and O th er
P ro d u c ts
The m ethod as d e sc rib e d h e re w as e s s e n tia lly the sam e
a s a lre a d y d e sc rib e d in th is th e s is fo r the n itro u s ac id t r e a t ­
m ent of e -c a p ro ia c ta m .
Twenty g ra m s, 0.13 m ole, of the la c ta m of 3 -eth y l-S m e th y l-6 • am lnohexanoic acid , is o m e r A, w as h ydrolysed by r e fluxing f o r one h o u r w ith the ca lcu late d am ount of h y d ro ch lo ric
a d d (11 m l. of co n cen trated h y d ro ch lo ric acid diluted to 36 m l.
w ith w ate r).

A fter evaporation of the solvent under vacuum on

a ste a m bath, th e re rem a in ed a c o lo rle ss viscous oil.

A so ­

lution of 13,4 g „ 0.19 m ole, of sodium n itrite d isso lv ed in 32
m l. of w a te r w as added to the o il o v e r th irty m in u tes.

A v ig ­

o ro u s ex o th erm ic reac tio n took p lace w ith co n sid erab le foam ing.
A fter the sodium n itrite solution had been added the solution
w as m ade acid to Congo re d by addition of dilute h y d ro ch lo ric
a c id (one volum e of co n cen trated hy d ro ch lo ric acid to one v o l­
um e of w ater).

The o rg an ic upper la y e r tu rn ed g reen .

The

re a c tio n m ix tu re w as h eated f o r one h o u r on a steam bath.

The

m ix tu re was cooled, e x tra c te d w ith ch lo ro fo rm and the ch lo ro fo rm

10S

e x tra c ts w ere d rie d o v er anhydrous sodium su lfate.
fo rm w as rem oved by d istilla tio n on a steam bath.

The c h lo ro ­
The re sid u e

w as d isso lv ed in 100 m l. of absolute ethyl alcohol and was h y ­
d ro g en ated oij a low p r e s s u r e B u r g e s s - P a r r h y d rogenator using
0.1 g. of platinum oxide c a ta ly st.
su re drop w as o b serv ed .

Only a 0.5 lb. hydrogen p r e s ­

B ased on ex p erien ces in the d e g ra d a ­

tion of £ -e a p ro la e ta m a p r e s s u r e drop of about Z lb s. was a n ­
tic ip a te d a t this point.
The platinum was filte re d and the m ix tu re of acid s was
e s te rifle d b y refloating th e ir alcoholic solution f o r tw elve h o u rs
a fte r addition of 5 m l. of co n cen trated su lfu ric acid.

The m ix ­

tu re w as cooled In an ic e -b a th and w as n e u tra lis e d w ith a con­
c e n tra te d solution of sodium carb o n ate.

The sodium sulfate

w as f ilte re d and the f iltra te w as diluted w ith ch lo ro fo rm until
two la y e rs fo rm e d and the aqueous la y e r w as e x tra c te d w ith
c h lo ro fo rm .

The ch lo ro fo rm e x tra c ts w ere w ashed tw ice w ith

cold sa tu ra te d sodium ch lo rid e solution and w ere d rie d o v e r a n ­
hydrous sodium su lfate.

The solvent was rem oved by d is tilla ­

tion under vacuum on a steam bath.

F ra ctio n a tio n of the resid u a

through a on® foot V igreux colum n of & m m . d ia m e te r gave the
follow ing fra c tio n s;

109

X

0.4 g.

below 44* C ./0 .7 m m .

XI

2.5 g.

51* C . / l . 4 m m . - 59* C . / l . 9 m m

III

1.0 g.

59-67.5* C . / l . 9 m m .

IV

2.6 g.

87.5-97,5* C . / l . 9 m m .

V

1.1 g.

97.5-108* C ./2 m m .

VI

2.1 g.

108-113* C ./2 m m .

The re sid u e le ft in the d istilla tio n H ash w eighed 2.7 g.
F ra c tio n I was fo re ru n and was not fu rth e r investigated.
F ra c tio n XI, n ^

25

1.4288, w hich should be the sa tu ra te d

fa tty e s te r , gave p o sitiv e brom ine and B aey er te s ts fo r u n sat u ra tio n .

Two and th re e -te n th s g ra m s of F ra c tio n XI w as d is ­

solved in § m l. of acetic ac id and w as hydrogenated on the low
p r e s s u r e h y d ro g en ato r using platinum oxide cataly st.

T here

w as o b se rv e d a 0.5 lb . hydrogen p r e s s u r e drop in one hour.
The platin u m was filte re d and the solvent w as rem oved by d is ­
tilla tio n .

D istillatio n of the re sid u e through a s m a ll C laisen

flask w ith V igreux side a rm gave 0.1 g. of fo re ru n , and 1.6 g.
of ethyl 5 -ethy 1- 5 - m ©thylhexaaoate boiling a t 50-58* C ./ l m m .,
**d

^<1

20

1*4218,

25

1,4198, see p re p a ra tio n of ethyl

3-ethyl - 5 - m ethylhexanoate).
Anal.:

Saponification equivalent Calc d fo r C l l H2 E °2 !
Found:

166.1.

Kit>-3

no
The S-benxyl thiuronium s a lt (107) w as p re p a re d , and
veeryitftliiiBttd fro m aqueous alcohol, m .p . 148,6*148.8* C .| no
d e p re s s io n of the m elting point w as o b serv ed when m ined with
an authentic sam ple (see p re p a ra tio n of ethyl 3-ethyl* 5 -m eth y lhexanoate)s a d e p re ssio n of the m elting point w as o b serv ed when
m ined w ith the S-benny! thiuronium s a lt of the Iso m e ric 3,5dim ethyiheptanoiG acid (see p re p a ra tio n of ethyl 3,5-d im eth y lheptanoate).
Anal.s

C a lc'd fo r C
Found?

N, 8.6.

N, S.4 (K jeldahl).

The p -to lu id id e was p re p a re d (10a, 109) by in te ra ctio n
of the e s te r w ith the m agnesium b rom ide d eriv ativ e of p -to lu id in e
and w as re c ry s ta llia e d fro m aqueous alcohol, m.p.- 56.8-57.8* C.;
no d e p re s sio n of the m elting point was o b serv ed when m ixed w ith
an authentic sam ple (see p re p a ra tio n of ethyl 3- e th y l-5-m e th y lhexanoate); a la rg e m elting point d ep ressio n was o b serv ed when
m ixed w ith the p -to lu id id e of the iso m e ric ethyl 3 ,5-dim ethyl heptanoate (see p re p a ra tio n of ethyl 3,5-dim ethylheptanoate).
Anal.:

Calc*d fo r C 16h 25ON:
Found:

N. 5.7.

N, 3.6 (Kjeldahl).

Ill
F ra c tio n III w as ap p aren tly a m ix tu re of the com pounds
obtained in F ra c tio n s II and IV and was not f u rth e r in v estig ated.
F ra c tio n IV gave a stro n g B e ilstein te s t fo r halogen and
a p o sitiv e sodium fusion te s t fo r halogen*

By analogy to the

r e s u lts obtained by deg rad atio n of € -cap ro la c ta m th is fra c tio n
w as te n tativ ely identified a s co n sistin g p red o m in ately of ethyl
3 -ethyl-5~ m ethyl - 6 -cM orohexanoate.

The position of the ch lo rin e

w as n o t rig o ro u sly estab lish ed .
The p o ta ssiu m s a lt of the acid obtained by acid h y d ro ly sis
of the e s te r follow ed by n e u tra lisa tio n w ith p o ta ssiu m hydroxide
w as co n v erted into the S -beaayl thiuronium sa lt by in te ra ctio n
w ith S -benayl thiuronium ch lo rid e (1071.

The S-benayl th iu ro -

nlum s a lt obtained in th is m an n er was re c ry sta llin e d fro m ethyl
a c e ta te and m elted a t 153-154.5® C.
Anal.s

C a lc ’d fo r C ^ H ^ O ^ R jS C ls
Found;

N* 7*8* S, 8.9s Cl, 9,9.

N, 7.5 (Kjeldahl); S, 8.9* 9.0; Cl, 9.7, 9.9.

The p o tassiu m s a lt of the acid obtained by saponification
of the e s te r w ith alcoholic p o tassiu m hydroxide was co n v erted
Into the S-bennyl thiuronium s a lt which was recryst& U ised fro m
e&tyl a c e ta te , m .p. 146-147.5* G.

The S-bea»yl thiuronium s a lt

p re p a re d in the sam e m an n er fro m F ra c tio n V m elted at

112

146-147.5* C.

C o m p ariso n of the m elting po in ts of the two S-

b eazy l th iu ro n iu m s a lts p re p a re d fro m F ra c tio n IV indicated
a p p a re n tly th a t saponification of the e s te r le d to som e h y d ro ly ­
s is of th e ch lo ro su b stitu en t.
F ra c tio n V gave a p o sitiv e B e ilste in te s t f o r halogen
and w as probably a m ix tu re of the com pounds obtained in F r a c ­
tio n s IV and VI.

The S-benzyl thiuronium s a lt was p re p a re d ,

m .p, 146-147.5* C.
Anal.s

Calc*d fo r C ^ H ^ O ^ S C l :
C a lc'd fo r C t? HE8G3HaS:
Found;

N, 7.8.
N, 8.2.

N, 8.0 (Kjeld&M).

F ra c tio n VI gave a slig h t B e ilstein te s t f o r halogen.

By

analogy to the re s u lts obtained by d egradation of c -c a p ro la c ta m
th is fra c tio n w as ten tativ ely identified a s co n sistin g p red o m in ately
of ethyl 3-e th y l- 5 -m ethyl - 6-hydroxyhexanoate.

The p osition of

the hydroxyl group was not rig o ro u sly established*
The p o tassiu m s a lt of the acid obtained by saponification
of the e s te r w ith alcoholic p o tassiu m hydroxide was co n v erted
Into the $ -benzyl thiuronium s a lt which was re c ry s ta lliz e d fro m
ethyl a c e ta te , m .p. 128,8-129.4° C.

113
A n al.:

C n lc'd fo » C 17H2g0 3N2S:
Found:

N, 8.2; S, 9 .4 .

N, 8.4 (K jaldahl); S, 9 .4 . 9.6.

114

C onversion of the L actam of 3,5-D im eth y l-6 Am inoheptanoic Ac 14 to Ethyl 3,5Dime thylheptano&te and
O ther P ro d u c ts
T en f r a m e of the la cta m of 3,5-d im eth y l-6 -am inoheptanoic
a c id w as d eg rad ed in an analogous m an n er to th at d e s c rib e d fo r
the is o m e ric la c ta m of 3 -ethyl - 5 - m ethyl - 6 - am inohexanoic acid*
A fter h y d ro ly sis with the calcu lated am ount of h y d ro ch lo ric acid
and ev ap o ratio n of the solvent th e re rem ain ed a c o lo rle s s v is ­
cous oil.

A fter tre a tm e n t of th is oil w ith 6.7 g., 0.1 m ole, of

sodium n itr ite d isso lv ed in 16 ml* of w ater the cru d e product
was hydrogenated and e s te rifle d a s a lre a d y described*

On d is ­

tilla tio n of the m ix tu re of e s te r s the following fra c tio n s w ere
obtained:
I

0* 1 g.

fo re ru n

11

2*0 g.

66.5-69.5* C ./2 .9 m m .

III

0*2 g*

69.3-69* C ./3 m m .

IV

L 2 g*

89-109* C ./3 m m .

V

2.3 g.

109-122* G ./3 m m .

and 1.7 g. of b lack resid u e rem ain ed in the d istilla tio n fla sk .
F ra c tio n II*
n,
<2

29

——-— —

te s ts fo r u n satu ratio n .

1.4244, gave positive brom ine and B aey cr
One and seven-tenth® g ra m s of F ra c tio n

115

II w as d isso lv ed in 5 m l. of a c e tic ac id and was hydrogenated
on the low p r e s s u r e hy d ro g en ato r using platinum oxide c a ta ly st.
T h e re w as o b se rv e d a 0.1 lb. p r e s s u r e drop*

The platinum w as

f ilte re d and the solvent w as rem oved by d istilla tio n .

D istillatio n

of the re sid u e through a sm all C laisen flask w ith V igreux side
a rm gave 1.2 g. of ethyl 3,5-dim ethylheptanoaie boiling a t 5054* C . / l m m .t

1.4191 ( n ^ ° 1.4218, n ^ ^ 1.4199, see p r e p ­

a ra tio n of ethyl 3,5-dim ethyl hep tana ate).
Anal.s

Saponification equivalent C a lc ’d fo r c a H2 2 ° 2 :
Founds

IS6-3-

164,5*

The S-beitsyl thiuronium s a lt $10?) w as p re p a re d and r e c ry s ta llla e d fro m aqueous alcohol, m .p. 139.6-140.6® C.j no d e ­
p re s s io n of the m elting point w as o b serv ed when m ixed w ith an
authentic sam ple (see p re p a ra tio n of ethyl 3,5-dim ethylheptanoate);
when m ixed w ith the S-benayl thiuronium s a lt of the iso m e ric 3eth y l- 5 -m ethylhexanoic acid (see p re p a ra tio n of ethyl 3 -eth y l-5 m ethylhexanoate) a d ep ressio n of the m elting point of the h ig h er
m elting iso m e r was observed.
A nal.:

C a lc ’d fo r C^H ^gO ^N ^S:
Found:

N, 8.5 (Kjeldahl)*

N, 8.6.

116

The p -to lu id id e was p re p a re d (108, 109) by in te ra ctio n
of the e a te r w ith the m agnesium b ro m id e d eriv ativ e of p -to lu id ine
and w as r e c ry s ta lliz e d fro m aqueous alcohol, m .p, 62.3-64.3* G.;
no d e p re s s io n of the m elting point was o b serv ed when m ixed w ith
an authentic sam ple (see p re p a ra tio n of ethyl 3 ,5 -dim ethylheptanoate); a la rg e m elting point d e p re ssio n was o b serv ed when
m ixed w ith the p -toluidide of the h o m e ric ethyl 3 -e th y l-5m e thylhexanoate (see p re p a ra tio n of ethyl 3 -e th y l-5-m eth y lh exanoate).
A nal.:

C alc’d f o r
Found:

N, 5.7.

N, 5.7 (Kjeldahl).

F ra c tio n III w as an in te rm ed ia te fra c tio n and was not
f u rth e r in v estig ated .
F ra c tio n s IV and V gave stro n g B elistein te s ts fo r halogen
and by analogy to the degradation of the la c ta m of 3- e th y l- 5m e th y l- 6 -am inohexanoic acid probably co n siste d of the analogous

ch loro and hydroxy e s te r s .
investig ated .

T hese fra c tio n s w ere not fu rth e r

117

P re p a ra tio n of Ethyl Isobutyl Ketone

CH3~CH2 -CO -CH 2-C H -(C H 3)2
M ethod At

C ataly ticaliy o y e r T horium Oxide (89)

The ap p aratu s and m ethod fo r p re p a rin g ethyl isobutyl
ketone w as e s se n tia lly the sam e a s d e sc rib e d fo r the p re p a ra tio n
of m ethyl benzyl ketone in O rganic Syntheses (89).
T h re e hundred and fo u r g ra m s, 4 m o les, of p ra c tic a l
g rad e propionic acid and 104 g., 1 m ole, of tech n ical g rad e is o ­
v a le ric acid w ere m ixed and added fro m a dropping funnel a t a
ra te of six teen d ro p s p e r m inute to a hot tube containing th o riu m
oxide d ep o sited on p e a -sin e p orous p late.

The te m p e ra tu re of

the tube w as m aintained betw een 400 and 450* C.

Sim ultaneously

a slow s tr e a m of carb o n dioxide o r n itro g en w as p a s se d through
the tube to keep the g a se s in m otion.
ra n through in tw elve h o u rs.

The e n tire solution was

A fter all the solution had been

added, 10 m l. of propionic acid was used to rin se out the funnel
and it was p a sse d through the reactio n tube to fa c ilita te the r e ­
m oval of the product.

The hot g ases w ere condensed in a long

tube fille d w ith g la ss beads and the condensate co llected in an
E rle n m e y e r fla sk of ap p ro p riate sia e.

m
The condensate c o n siste d of two la y e rs .

Both la y e rs

w ere tr e a te d w ith a 300 g. m ix tu re of ice and w ate r and w ere
re n d e re d alk alin e to litm u s w ith a slig h t e x c e ss of 50 p e rc e n t
sodium hydroxide solution.

The oil was se p a ra te d and the aqueous

la y e r e x tra c te d w ith two 50 m l. p o rtio n s of henaene.

The ex ­

tr a c ts w ere com bined w ith the oil and d rie d o v e r anhydrous s o ­
dium su lfate,

The solvent was rem oved by d istilla tio n .

F ra c ­

tionation of the resid u e gave 44.3 g. of p ro d u ct (41 p e rc e n t of
the th e o re tic a l am ount b a se d on iso v a le ric acid) boiling a t 132
- 133° C. (re p o rte d boiling point. 135® C. [l!0 ]j 136-137* C.
f 111]).

Notes

When the ethyl isobutyl ketone w as p re p a re d

using a tw o -to -o n e ra tio of propionic ac id to is o v a le ric acid,
the p erce n tag e yield w as reduced to 18 p erce n t.
Method Bs

Cadm ium Dialkyl Method (90-95)

A five lite r , th re e -n e c k e d flask was fitte d w ith a H ersh b e rg s t i r r e r , co n d en ser, and Y -tube.

The co n d en ser was fitte d

w ith a drying tube fille d w ith soda lim e.
tttbe w as u sed fo r introduction of n itrogen.

One opening of the YThe o th e r opening

of the Y -tube was used fo r the addition of reag e n ts.

119

A solution of ethyl m agnesium b ro m id e w as p re p a re d in
the flask b y the u su al m ethod using 218 g ., 2 m o le s, of E astm an
p r a c tic a l g rad e ethyl b ro m id e, 49 g.» 2 m o les, of m agnesium
tu rn in g s and one l i t e r of diethyl e th e r d rie d o v e r sodium .
One hundred and e ig h ty -th re e g ra m s, I m ole, of anhydrous
cadm ium ch lo rid e, d rie d a t 110* € . overnight, w as added to the
G rig n a rd reag e n t o v e r fo rty -fiv e m inutes u n d er a n itro g en a t ­
m o sp h ere.

The reactio n m ix tu re w as cooled in an ic e -b a th

during the addition.

The m ix tu re w as refluxed fo r one h o u r a t

w hich tim e the te s t fo r G rig n ard reag e n t with M ic h ie r’s ketone
w as neg ativ e.

The re a c tio n m ix tu re a t th is point w as thick w ith

so lid and s tirr in g was difficult and rem ain ed so up to the hy­
d ro ly sis step .

The e th e r was d istille d off and rep la ced w ith an

equal volum e of benaene.
One hundred and tw enty g ra m s, 1 m ole, of iso vale ry l
ch lo rid e p rev io u sly p re p a re d fro m iso v a le ric acid and thionyl
ch lo rid e by the usual p ro ced u re (112) (b. 154 - 115* C „ p r e ­
p a re d in 30 p e rc e n t yield) w as introduced into the re a c tio n
m ix tu re fro m a dropping funnel during fo rty -fiv e m inutes w ith
no ex tern a! cooling.

The m ix tu re was reflu x ed fo r one and

o n e-h alf h o u rs and then allow ed to stand overnight.

120

H y d ro ly sis w as acco m p lish ed by pouring onto 1.5 lite r s
of dilute su lfu ric acid (one p a rt co n c en trated su lfu ric acid to
th re e p a r ts of w ater).

The organic la y e r w as se p a ra te d and the

aqueous la y e r e x tra c te d with two 190 m i. p o rtio n s of benzene.
The solvent w as rem oved by d istilla tio n .

F ra ctio n a tio n of the

re sid u e gave 53 g. of the p roduct, b.p. 132-133* G. (46.5 p e r ­
c e n t of th e th e o re tic a l am ount b a se d on is ovale ry l ch lo rid e).

121

P re p a ra tio n of Ethyl 3 - E thyl- 5 - Me thylhexanoate (96, 113)

I

CEL

CH3 *G H -C H ^C H - CH2 - COOCH2GH3
T W rty-nine and th re e -te n th s g ram a , 0,6 m ole, of 30 m esh
»iac (B a k e r’s C .F .) p rev io u sly cleaned by the p ro ced u re of F ie s e r
and Johnson (114) w as p laced in a two lite r , th re e -n e c k e d fla sk
fitte d w ith a s t i r r e r , dropping funnel and co n d en ser.

A drying

tube fille d w ith calcium ch lo rid e was fitte d to the top of the co n­
d e n se r.

A m ix tu re of ST g ., 0.5 m ole, of ethyl isobutyl ketone,

S3.5 g.» 0.5 m ole, of ethyl b ro m o acetate (E astm an white la b el),
200 m l. of benaen® and 170 m l. of toluene (96) both d rie d o v er
sodium was added o v er a p erio d of one hour.

H eat w as applied

a t the beginning of the addition to in su re th a t the re a c tio n had
s ta rte d .

Continued vigorous in te ra c tio n was reg u lated by the

ra te of addition of the reag e n t m ix tu re.

The m ixture w as fin ally

reflu x ed fo r fo u r h o u rs, cooled and h y d ro ly sed by pouring into
409 m l. of 10 p e rc e n t su lfu ric acid.

The org an ic la y e r w as

se p a ra te d and the aqueous la y e r w as e x tra c te d w ith th re e 50 m l.
p o rtio n s of hennene.

The com bined organic la y e rs w ere w ashed

122
su c c e s siv e ly w ith 50 m l. of cold 5 p e rc e n t su lfu ric acid. 50 m l.
of co ld 10 p e rc e n t sodium carb o n ate. 50 m l. of cold w a te r and
d rie d o v e r anhydrous sodium su lfate.
The sodium sulfate w as f ilte re d and the filtr a te reflu x ed
I
fo u r Hours w ith $5 g., 0.6 m ole, of phosphorus pentoxide (97).
The m ix tu re w as cooled and the solution decanted.

The resid u e

w as rin s e d w ith benaene and the bensene decanted and com bined
w ith the f i r s t solution.

The solvent w as rem oved by d istilla tio n .

D istillatio n of the re sid u e gave 39.7 g. of u n sa tu ra ted e s te r (43,2
p e rc e n t of the th e o re tic a l amount) boiling at 103-106° C ./1 9 -2 0 m m .
Tw enty-nine and eig h t-ten th s g ra m s of the u n satu rated
e s te r w as hydrogenated

Z

on the P a r r low p r e s s u r e h y drogenator

1

In the R eform atsky reac tio n dehydration was not e f­
fected using acetic anhydride a s the dehydrating agent.
2

The in te rm ed ia te u n sa tu ra ted e s te r s in the p re p a ra tio n
of ethyl 3 -ethyl - 5 - m e thylhexanoate could not be hydrogenated in
ethyl alcohol by low p r e s s u r e hydrogenation w ith platinum oxide
c a ta ly st. P a r tia l hydrogenation w as effected using 1,360 p .s .i.
of hydrogen, 60° C. te m p e ra tu re , ethyl alcohol solvent and R a­
ney nick el as c a ta ly st (99). Cope and Hancock (96) have u sed
high p r e s s u r e , high te m p e ra tu re hydrogenation fo r reduction of
a s im ila r u n sa tu ra ted e s te r . It is in te re stin g to note th a t the
u n sa tu ra ted e s te r s obtained in p re p a ra tio n of ethyl 3,5-d im eth y lhexanoate by the sam e m ethod could be hydrogenation in fo u r
h o u rs using low hydrogen p r e s s u r e , ethyl alcohol a s solvent,
and platinum oxide c a ta ly st.

123

• » equal volum e of ac etic ac id a s solvent and 0.2 g. of
platinu m oxide a s c a ta ly s t.

The platinum w as filte re d off and

the so lv en t rem oved by d istilla tio n .

D istilla tio n of the resid u e

th ro u g h a sm a ll C laisea fla sk w ith V igreux side a rm gave 26.4
g. of p ro d u ct (33 p e rc e n t of the th e o re tic a l amount) boiling a t
85-87* C ./1 7 m m .
R ed istillatio n of the p ro d u ct through a sm a ll diam eter*
one foot tall* h eated V igreux colum n gave 20.7 g. of p ro d u ct
boiling a t 62.0-64.0° C ./4 .2 mm.* « * ^ 1.4218. a ** 1.4198*
u
a
d4

20

0.867*
A nal.:

C a lc'd f o r

C, 70.9; H, 11.9; sap o n ifica­

tio n equivalent, 186.3; MR, 54.53.
Found:

C, 70.7; H* 12.0; saponification equivalent,

183.3; MR* 54.58.
Six and th re e -te n th s g ra m s of m a te ria l boiling a t 6 4.0-65.0® C ./
4.2 m m , was also obtained by fu rth e r d istilla tio n and was not
fu rth e r in v estig ated .
The S-benxyl thiuronium s a lt (107) of 3-e th y l-5 -m ethyl hexanoic acid was p re p a re d and r© cry stallised fro m aqueous
alcohol* m .p. 148,6-149.1* C.

M ixtures of th is s a lt w ith the

S-benxyl thiuronium s a lt of the iso m e ric 3 ,5 -dim ethylheptanoic

124

a c id (stit p re p a ra tio n of ethyl 3,5~dlzne thylheptanoa t«) showed
m elting points in te rm ed ia te betw een the m elting points of the
two p u re s a lts .
Anal.:

C a lc 'd fo r C ^ H ^ O jN ^ S :
Found:

N, 8.6.

N, 8,4 (Kjeldahl).

The p-toluidide was p re p a re d (108, 109) by in te ra ctio n
of the e s te r w ith the m agnesium bro m id e d eriv ativ e of p-to lu id ine
and w as re c ry s ta llin e d fro m aqueous alcohol, m .p. 52.8-60.3* C.
M ixtures of th is d eriv ativ e w ith the p~toluidide of 3,5 -d im eth y lheptanoic acid (see p re p a ra tio n of ethyl 3,5-dim ethylheptanoate)
showed m eltin g point d ep ressio n s a t le a s t ten d eg ree s below the
lo w er m eltin g iso m e r.
Anal.:

C a ic'd fo r C ^ H ^ O N s
Found:

N, 5.7.

N, 5.5 (Kjeldahl).

125
P re p a ra tio n of Ethyl 3 ,5 -D im ethylheptanoate (96, H i)

CH3 - CH2 - CH-CH2 - CH- CH2 - COOCH2CH3
4 - M ethyl - 2 *Heacanonc

T his in te rm ed ia te was p re p a re d by alkylation of ethyl
aceto& cetate w ith secondary butyl bro m id e and ketonic h y d ro ly sis
of the alkylation pro d u ct following the p ro ced u re of M arvel and
H ager (100).

The pro d u ct w as obtained in 24.4 p e rc e n t yield,

b.p. 138-140.5* C ./749 m m . (re p o rte d b.p. 139*142° C. flOOl),
Eihvl
3nW
.5
.... lifi—
n«i**ii-D
w
»*n—
*«im
*>***«■<ethylheptanoate
' ihmiihimtm
T his com pound was p re p a re d by e sse n tia lly the sam e pro*
ced u re u sed fo r the sy n th esis of the iso m e ric eth y l 3-© thyl-5m e thylhexanoate.
The H eform atsky re a c tio n was c a rr ie d out with 39.3 g .,
0.6 m ole, of nine, 5? g ., 0.3 m ole, of 4-m e th y l- 2 -hexanone, 83.5
g., 0.3 m ole of ethyl b ro m o a c e ta te , 200 m l. of benzene and 170
m l. of toluene.

126

The hydroxy e a te r waa d eh y d rated w ith phosphorus p en toxide as p rev io u sly d e sc rib e d .

D istillatio n of the re su ltin g mix*

tu re of u n sa tu ra te d e s te r s gave the follow ing fra c tio n s:
I

14.2 g.

fo re ru n

II

20.7 g.

98*102° C ./l® m m .

Ill

8.1 g ..

100.5-108° C ./1 6 m m .

F ra c tio n 1 was not fu rth e r investigated.
F ra c tio n 11 w as hydrogenated as a lre a d y d e sc rib e d using
a c e tic ac id solvent and platinum oxide c a ta ly st.

The platinum

w as f ilte re d and the solvent rem oved by d istilla tio n .

D istilla ­

tion of the re sid u e gave the following fra c tio n s:
A

10.1 g.

86-91.5° C ./1 5 m m .

B

8.1 g.

89-94.0® C ./1 7 m m .

F ra c tio n HI w as tre a te d id en tically to F ra c tio n II and
gave on d istillatio n :
C

4.8 g,

87*90.5° C ./ U m m .

p -T o lu id id e s w ere p re p a re d (I OS, 189) of F ra c tio n s A,
B, and C and a ll m elted a t 64 *65® C.

M elting points of m ix­

tu r e s of the v ario u s toluididess showed no d ep ressio n .
A B

F ra c tio n s

and C w ere th e re fo re com bined and re fra c tio n a te d to give

127

17,8 g. of ethyl 3,5-dim ethylheptanoate hailing a t 59.5-61.0* C j
2,6 m m ,,
A nal.:

20 1.4218, i»d25 1.4198, d j 20 0.867.

C a lc 'd f o r Gn H2 2 °2 :

C ’ 70-9: H-

sap o n ifica­

tio n equivalent, 186.3j MR, 54.53.
Found:

C, 70.7: H, 12.0; saponification equivalent,

185.3; ME, 54.58.
The S-benzyl thiuronium s a lt (107) of 3,5-dim ethylheptanoic ac id w as p re p a re d and re c ry s ta llix e d fro m aqueous a lc o ­
hol, m .p. 141.2-141.7* C.

M ixtures of th is s a lt w ith the 5-benzyl

thiuron iu m s a lt of the iso m e ric 3-ethyl - 5*m ethylhexanoic acid
(see p re p a ra tio n of ethyl 3-ethyl -5 -m ethylhaxanoate) showed
m elting points in term ed iate betw een the m elting point® of the two
p u re s a lts .
Anal.:

Cale*d f o r C 17H28° 2N2S:
Found:

N* 8

N, 8.7 (K jeldahl).

The p -to lu id id e was p re p a re d (108, 109) by in te ra ctio n
of the e s te r w ith the m agnesium brom ide d eriv ativ e of p -to lu id ine
and w as re c ry sta lliz e d fro m aqueous alcohol, m .p, 65.8-66.8* C,
Mixture® of this d eriv ative w ith the p-toluidide of 3-e th y l-5m ethylhexanoic acid (see p re p a ra tio n of ethyl 3-e th y l-5-m eth y l­
hexanoate) showed m elting point d e p re ssio n s a t le a s t ten d eg rees
below the lo w er m elting iso m e r.

A n al.:

C a lc'd f o r Cj^HLgON:
Found:

N,

N, 5.4 (K jeldah l).

129
P re p a ra tio n of 3 - Ethyl - 5 - Me thylhexanoic Acid

ch3

lZ

CH3 - CH- CH2 ~CH- CHZ -COOH
F ive gram® of ethyl 3-«th yl-5-roe thylhexanoate w as saponif led by r«flttxi»g fo r two and o n e-h alf hour a with a solution of
3 g. of p o tassiu m hydroxide d isso lv ed in 30 m l. of w ate r and
10 m l. of alcohol.

The re a c tio n m ix tu re w as cooled and was

m ade acid to Congo re d by addition of dilute h y d ro ch lo ric acid.
The m ix tu re w as e x tra c te d w ith e th e r and the e th e r e x tra c ts
w ere d rie d o v er anhydrous sodium su lfate.

The sodium sulfate

w as filte re d and the solvent w as rem oved by d istillatio n .

F ra c ­

tionation of the resid u e through a sm a ll C laisen fla sk w ith
V igreox sid e a rm gave 0.6 g. of fo re ru n boiling below 86° € . /
0.6 m m ., and 3.0 g. of pro d u ct boiling a t 86-90® C ./0 .6 m m .,
« 20 1.4321. a 25 1.4301. d . 20 0.907.
d

d

A nal.;

a

C a lc 'd fo r

C, 68.31; H, U .47; n e u tra li­

sa tio n equivalent, 158,2s H R, 45.30.
Found:

C, 68.07, 68,00; H, 11.51, 11.43; n e u tra lis a ­

tion equivalent, 156*2; MR, 45.25.

130
Preparation of 3 ,5 -Dime thylheptanoic Acid
CH*
| 3

CH*
! 3

CH3~CH2 -CH -CH 2 ~GH-CH2~COOH
Five g ra m s of ethyl 3 ,5 ~di m ethylheptanoate w as saponified
w ith a solution of 3 g. of p o tassiu m hydroxide d isso lv ed in 30 ml.
of w ate r and 10 m l. of alcohol.

The cru d e m a te ria l w as iso late d

a s p rev io u sly d e sc rib e d fo r the p re p a ra tio n of 3 -eth y l-5 -m eth y lhexanoic acid and on fractio n atio n gave 0.6 g. of fo re ru n boiling
below S7® C./O.T m m ., and 3.0 g, of p ro d u ct boiling a t 87-90®
C ./0 .7 m m , , n 20 1.4319, n 25 1.4300, d 20 0.906.
a

A nal.:

d

C a lc ’d fo r

4

C, 68.31; H, 11.47; n e u tra li­

satio n equivalent, 158.2; ME, 45.30.
Found;

C, 68.20* 68.00; H, 11.43, 11.53; n e u tra li­

sa tio n equivalent, 156,4; MR, 45.26.

131

P re p a ra tio n of 7 -M e th y l-9 -E th y l-1,5 -P .n ta o n .th y l.n e te tra K o le
( 101)

/
CH,—CH
3

y CHz

(

\ CH — CH.—CH.
,

|2

CH,

2

3

CH.
, 2

G --------- - N

II

N

\

I

N

N

S

A 250 m l, th ree -n e ck ed flask was equipped with a s t i r r e r
and co n d en ser,

A sm a ll E rlen m e y er flask was attach ed to the

th ird opening by m eans of la rg e d ia m e te r ru b b er tubing slipped
o v er the opening.

The ap p aratu s w as d rie d in a hot room and

p ro te c te d fro m m o istu re by a calcium ch lo rid e tube attach ed to
the top of the co n d en ser.

Five g ra m s, 0.032 m ole, of the lac*

tarn of 3 ,5 -dim ethyl *6-am inoheptanoic acid and 45 m l, of b en aene w ere p laced in the flask and s tir r e d to effect solution.
Seven and o n e-h alf g ra m s, 0.037 m ole, of phosphorus p entachloride
w as w eighed quickly into the E rlen m e y er fla sk and attach ed to the
ap p a ra tu s.

The phosphorus pentachloride was added to the r e a c ­

tion fla sk in sm a ll p o rtio n s.

D uring th is addition the m ixture

132

w as k ep t a t room te m p e ra tu re by o ccasio n al cooling in an ic e b ath.

The re a c tio n m ix tu re wae s tir r e d until the phosphorus

jw ntach lo rid e had gone into solution.
The E rle n m e y e r H ash and ru b b e r tubing attach m en t w as
then re p la c e d w ith a dropping funnel and SO m l. of a 10 p e rc e n t
solution of hydrassoic acid in bennene was added to the re a c tio n
m ix tu re during one-half hour.

B ering the addition of hydrassoic

ac id the m ix tu re becam e w arm and som e hydrogen ch lo rid e was
evolved.

The rea c tio n was kept a t room te m p e ra tu re by in te r ­

m itten tly cooling It with an ice -bath,

rh e m ix tu re was refluxed

th re e h o u rs during w hich o p eration m uch hydrogen chloride was
evolved.

It was allow ed to stand overnight and then refluxed

th re e h o u rs lo n g er until hydrogen ch lo rid e evolution had ceased .
D uring the refluxing p erio d solid p re c ip ita te d fro m the reac tio n
m ix tu re.
The re a c tio n m ix tu re was cooled to 10° € .

A solid th at

se p a ra te d w as filte re d off and re c ry s ta llia e d fro m w ate r to give
1.0 g, of c o lo rle s s c ry s ta ls m elting at 91.S-95.8* C.

T his m a ­

te r ia l w hich p resu m a b ly was a m ix tu re of la cta m and te tra a o le
w as n o t f u rth e r investigated.

133

The benzene m o th e r liq u o r wa« evap orated to d r y n e ss
u n d er vacuum on the ste a m hath.
o re d v isco u s oil.

The re sid u e was a d ark c o l­

The o il w as p o u red onto ic e and allow ed to

c r y s ta llis e in the r e f rig e ra to r .

The w a te r was decanted and the

se m iso lid m a ss e x tra c te d th re e tim e s with boiling " h e x a n e ."
On cooling the "hexane ’ solution deposited 0.9 g. of product
m elting a t 76-77.5* C.

The p ro d u ct re c ry s ta llis e d fro m hexane

m e lte d at 793-80.5® C«
A nal,;

Calc*d f o r
Found:

C, 59.97; H, 8.95; N, 31.09.

C, 60.00. 59.97; H, 8.90, 9.10; N, 31.13.

31.20,
M ixture m elting points of th is te tra s o le w ith the iso m e ric
7 -e th y l- 9 -m eth y l-1 ,5 -pentam efchylenetetraxole (see following p re p ­
aratio n ) showed m elting points in te rm ed ia te betw een the m elting
points of the two p u re te tra s o le s.
H arv ill, R oberts, and H erb st (1) d escrib ed a m ethyl ethyl
pentam ethylenetetraasole w hich had been obtained by the in te r ­
action of 3 - m e thyl - 5 - e thylc y clohe xanone oxim e with sodium asid e
and chlorosulfonic acid.

T h eir compound could have been e ith e r

of the iso m e ric te tra z o le s d e sc rib e d in th is and the following
p re p a ra tio n .

An authentic sam ple obtained fro m the above au th ors

134

m e lte d a t 85.1-86.6* C.

A m ix tu re m elting point d eterm in atio n

w ith th e te tra z o le d e sc rib e d in th is p re p a ra tio n showed a d e p re s ­
sion of the h ig h e r m elting te tra a o le .

T h e re fo re , th e ir te tra a o le

w as n o t 7-m e th y l- 9 - e th y l- 1#5 -p en tam eth y len etetraao le.

135

P re p a ra tio n of 7 - Cthyl - 9 - M ethyl -1 ,5 - P en t am ethylenet* t r anole
( 101)

3

2

3
CH 2

I

CH
'2

C

N

N

N

F ive gram s* 0.032 m ole, of the lactam of 3-©thyl~5~
m ethyl - 6 -am inohexanoic acM dissolved in 45 m l. of benzene
w as tre a te d w ith 7.5 g,, 0.37 m ole, of phosphorus pentachloride
and 50 m l. of a 10 p e rc e n t solution of hydrazoic acid in benzene
as p rev io u sly d e sc rib e d fo r the iso m e ric la c ta m of 3,5-d im eth y l6 -am inoheptanoic acid.
A solid th a t se p a ra te d on cooling the reactio n m ixture
to 10® C. w as filte re d off and re c ry s ta llia e d fro m w ater to give
0.4 g. of c o lo rle s s c ry s ta ls m elting at 37.6-09.1 ® C.

This m a ­

te r ia l w hich p resu m ab ly was teir& aole containing a slig h t am ount
of la c ta m was not fu rth e r investigated.

136
The p ro d u ct w as iso la te d a s p rev io u sly d e sc rib e d fo r the
p re p a ra tio n of 7*me thyl - 9 - ethyl -1 ,5 -pentam e thyl e ne te t r a zol e .

Re­

c r y s ta ll! nation fro m hexane gave 0 .1 g. of product, m .p. 37.208.2* C.
Anal.:

C alc d fo r
Found:

C, 59.97; H, 8.95; N, 31.09.

C, 59.92, 59.96; H, 8.95, 9.14; N, 31.30,

31.28.
M ixture m elting points of th is te tra a o le w ith the iso m e ric
7 -m e th y l- 9 - e th y l- 1, 3-pentam e th y le n etetr ancle (see p rev io u s p r e p ­
aratio n ) showed m elting points in te rm ed ia te betw een the m elting
points of the two p u re tetraasoles.
A sam p le of the m ethyl ethyl pent& m ethylenetetranole
p re p a re d by H arv ill, R oberts, and H e rb st (1) (see p rev io u s p re p ­
aration ) m elted a t 85,1-86.6® C.

A m ixed m elting point d e te r ­

m ination w ith the te tra x o le d e sc rib e d in th is p re p a ra tio n showed
no d e p re ssio n ,

T h erefo re , th e ir te tra a o le was 7-e th y l- 9 -m ethyl -

1,5 -pentam ethylenetetrassole.

SUMMARY

1.

A study has been m ade of the degradation of e - c a p -

ro la c ta m to ethyl ca p ro a te.

The o th e r m ain pro d u cts fro m the

d eg rad atio n have been identified a s ethyl € -ch lo ro cap ro ate and
ethyl € -h y d ro x y cap ro ate.
2.

The Beckm ann re a rra n g e m e n t of 3 - m ethyl - 5 -ethyl -

cyclohexanone oxim e has been shown to give a m ix tu re of the
two s tru c tu ra lly iso m e ric la c ta m s .

The la c ta m s have been se p ­

a ra te d by solvent ex tra ctio n and fra c tio n a l c ry sta llisa tio n and
th e ir s tr u c tu re s have b een esta b lish e d by co n v ersio n to ethyl
3 -eth y l - 5 - me thylhexanoate o r to ethyl 3,5- diroethylheptanoate.
3.

The new esters* ethyl 3-ethyl-5~m ethylhexanoate and

ethyl 3,5-d im ethylheptanoate, have been unequivocally synthe­
siz e d by a Ref o r m atsk y reactio n and have been c h a ra c te riz e d
by p h y sical co n stan ts and p re p a ra tio n of d e riv a tiv e s.
4.

The two iso m e ric la c ta m s, p re p a re d by the Beckm ann

re a rra n g e m e n t of 3-m ethyl-5-ethylcyclohexanone oxime* have b een
co n v erted into th e ir resp e c tiv e m ethyl ethyl 1,5-pen tam eth y len e-

13*
te tr a z o le s .

The p o sitio n of the alkyl su b stitu en ts in 7-m e th y l-

9-e th y l- t »5-psnt& m ethylenetetrazole and in 7 -e th y l- 9 - m eth y l1.S -pent& m ethylenetetrazole has now been estab lish ed .

The

m ethyl ethyl 1 ,5 -p en tam eth y len etetrazo le p re p a re d by H arv ill,
R o b e rts, and H e rb st (1), whose s tru c tu re had not been e s ta b ­
lish e d , h as been shown to be 7-eth y l~ 9 -m eth y l- 1 ,5 -pcntam ethy le n etc tra n o le by co m p ariso n w ith the two new te tra z o le s of
known s tru c tu re .
5.

A b rie f in v estig atio n has been m ade of the n itro sa tio n

and decom position of the n itro so com pound of ethyl C -c a rb o ethoxy am in o cap ro ate.
6.

The new e -io d o c ap ro ic acid has been p re p a re d and

c h a ra c te riz e d by a n a ly sis.

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