A Study of Carbamic Acid Esters as Local Anesthetics

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P U R D U E U N IV ER SITY

T H IS I S TO C E R T IF Y T H A T T H E T H E S I S P R E P A R E D U N D E R MY S U P E R V I S I O N

b y ___________________

D a v id A r t h u r S c h l i c h t i n g

ENTnxED

A- STUDY- -OF CARBAMXC -AC IIX ESTERS

____________ AS LOCAL AMESSTHET1RS____________

C O M P L IE S W IT H T H E U N IV E R S IT Y R E G U L A T IO N S O N G R A D U A T IO N T H E S E S

A N D I S A P P R O V E D B Y M E A S F U L F IL L IN G T H IS P A R T O F T H E R E Q U IR E M E N T S

FO R THE DEG REE OF

D o c to r o f P h ilo s o p h y

yê/iuxuohA.

T O T H E L IB R A R IA N :---I S >IV Y T H IS T H E S IS MoMPSV TO B E R E G A R D E D A S C O N F ID E N T IA L .

RNCO

RRCO 2 . RX RNCO 3 * RNHg

+ HOR1

RNHCOgR*

+ Agcsro

RNCO

+ HOR1

RNHCOgRt

+ COClg

RKHCOCi + HOR1

•->

RNHC0C1 RNHCOgR*

K2

♦ AgX

+ HC1 HC1

T he f i r s t m e th o d . I n v o l v i n g th e I n t e r m e d ia t e f o r m a t io n o f a l k y l I s o c y a n a t e s , was c o n s id e r e d t o b e t h e m o s t e f f i c a c i o u s

f o r t h e s e r i e s o f com pounds made* The c h e m is t r y o f o r g a n ic is o c y a n a t e s h a s h e e n r e c e n t l y r e v ie w e d b y S a u n d e rs a n d S lo co m b e i n in

C h e m ic a l R e v ie w s ( 3 2 ) .

an e x c e lle n t a r t i c l e

The m e th o d o f s y n t h e s is u s in g

s o d iu m a z id e i n v o l v e s t h e C u r t l u s R e a c t io n a lt h o u g h t h e H ofm ann o r h o s e e n R e a c t io n s c o u ld a ls o b e u s e d t o m ake t h e is o c y a n a t e s . d e s ir a b le

The C u r t i u s r e a c t i o n was c h o s e n as t h e m o s t

a n d in d e e d h a s p r o v e n v e r y u s e f u l .

A th o r o u g h

d is c u s s io n o f t h e r e a c t i o n h a s b e e n p u b lis h e d r e c e n t l y b y S m ith ( 3 3 ) . A l k y l is o c y a n a t e s in g liq u id s

w ith

a r e s w e e t - s m e llin g , h i g h l y i r r i t a t ­

a p ro n o u n c e d la c r y m a t o r y e f f e c t .

h y g r o s c o p i c i t y m akes th e m d i f f i c u l t p a rt i t in

is

n e c e s s a ry to

a s o lv e n t.

It

is

have b e e n is o la t e d , b e in g m ade. fo rm

s to re

to

s to re .

T h e ir

F o r th e m o s t

th e m u n d e r a n h y d ro u s c o n d i t i o n s

p r e f e r a b l e , h o w e v e r, e s p e c i a l l y i f t o u s e th e m as s o o n as p o s s i b l e

th e y

a fte r

T h e y r e a c t w i t h v a r y in g d e g re e s o f r a p i d i t y t o

s y m m e t r ic a lly s u b s t i t u t e d u r e a s .

is o c y a n a t e s a p p e a r t o

B r a n c h e d - c h a in a l k y l

f o r m u r e a s m o re r a p i d l y

t h a n do t h e

s t r a i g h t c h a in com pounds a n d t h e lo w e r m em bers m o re r a p i d l y t h a n t h e h ig h e r m em bers*

In

t h e p r e p a r a t i o n o f th e i s o ­

c y a n a te s f r o m t h e i r a c i d a z ld e s , i t h ig h b o i l i n g

s o lv e n t

t h e r e a r r a n g e m e n t*

h a s b e e n fo u n d t h a t a

s u c h as t o lu e n e i s

d e s ir a b le t o

R e f lu x in g f o r t h r e e h o u r s i n

caused re a rra n g e m e n t I n

a l l b u t a fe w c a s e s w h i l e

e ffe c t

t o lu e n e th e u se

o f b e n z e n e a s a s o l v e n t g a v e an I n c o m p le t e r e a c t i o n i n same p e r i o d o f t im e .

The p u r i f i c a t i o n

th e

and a n a ly s is o f a lk y l

8* is o c y a n a t e s ,

as such., i s

p r e p a r a tio n o f s u it a b le

som ewhat d i f f i c u l t ; d e r iv a tiv e s

h o w e v e r, t h e

can be r e a d ily

accom p­

lis h e d * The r e a c t i o n o f a l k y l I s o c y a n a te s w i t h d i a l k y l a m in o a lk a n o l s , u s u a l l y i n

an e t h e r e a l s o l u t i o n ,

e v id e n c e d b y a s l i g h t r i s e

In

is

o r d in a r ily

t e m p e r a tu r e o f t h e r e a c t i o n

s o l u t i o n l e s s t h a n o n e h a l f h o u r a f t e r t h e i r m ix in g * t h e o d o r o f t h e I s o c y a n a te h a s d is a p p e a r e d , c a n b e c o n s id e r e d c o m p le te *

fo r

o c c u rre d i n

In

t h a t th e

o r no u n r e a c t e d a c id c h l o r i d e

s id e r e a c t i o n s w i l l o c c u r an d r e s u l t i n

i s o l a b l e m ix t u r e *

th e r e a c t io n

One m u s t b e c e r t a i n

is o c y a n a t e u s e d c o n t a in s l i t t l e

When

a d iffic u ltly

one I n s t a n c e t h e f o l l o w i n g

r e a c tio n s

t h e p r e s e n c e o f RHCO:

RC0C1 + HOCHgCHglf (CHgCHg )2

— »

ROOgCHgCRgNf OSgCH^ )g+HCl

HOCHgCHgNt CHgCHs )g+HCl

— >

HOCHgCHgNf CHgCHs )g" HOI

T h is l a t t e r p r o d u c t was i s o l a t e d a n d t h e p r e s e n c e o f t h e e s t e r was I n d i c a t e d b u t t h e d e s ir e d c a rb a m a te was n o t o b ­ ta in e d . It

h a s b e e n fo u n d t h a t m o s t o f t h e c a rb a m a te s t h a t w e re

made a r e d i s t i l l a b l e *

T h is m e th o d o f p u r i f i c a t i o n ,

p a r t i a l p u r i f i c a t i o n , p r o v e d t o b e e x p e d ie n t i n F o r th e m ost p a r t , h y g r o s c o p ic s o l i d s * be c r y s t a l liz e d

m any c a s e s *

t h e h y d r o c h lo r id e s a r e lo w m e l t i n g , In

some c a s e s h y d r o c h lo r id e s c o u ld n o t

o r i s o l a t e d as s o l i d s *

w e re t h e m o s t d e s i r a b l e a l,

or

in

C itr ic

a c id s a lt s

th e m a j o r i t y o f c a s e s *

In

g e n e r­

e t h y l a c e t a t e o r c o m b in a tio n s o f e t h y l a c e t a t e w i t h

9 a l c o h o l o r o t h e r w e re t h e b e a t s o lv e n t s f o r c r y s t a l l i z a ­ tio n

o f t h e d l a l k y l am in o a l k y l a l k y l c a rb a m a te s a l t s .

10 PHARMACOLOGY OF LOCAL ANESTHETICS "A l o c a l a n e s t h e t ic tiz e s

th e

is

a d r u g w h ic h t e m p o r a r i l y a n e s th e ­

s e n s o r y n e r v e e n d in g s o r n e r v e t r u n k s w i t h o u t p r o ­

d u c in g p e rm a n e n t dam age #11 ( 3 4 ) kn o w n i n

t h e u s e o f c o l d a nd o f p r e s s u r e t o p r o d u c e a l o c a l ­

i z e d a c t io n # to

The e f f e c t h a s lo n g b e e n

V o n A n re p f o u n d t h a t t h e

th e p r ic k o f a p in a f t e r in je c t io n

was t h e f i r s t

to

n o te t h e

He s a i d t h a t c o c a in e

s k in was i n s e n s i t i v e o f c o c a in e

(2 )*

W o h le r

e f f e c t o f th e d r u g u p o n t h e to n g u e #

"h a s a b i t t e r

ta s te

and has th e p e c u lia r

e f f e c t u p o n t h e n e r v e s o f th e to n g u e o f m a k in g t h e p o i n t o f c o n t a c t e s p e c i a l l y numb a nd a lm o s t d e v o id o f s e n s a t io n # n ( 3 5 ) H o l l e r a c c i d e n t a l l y d is c o v e r e d t h e l o c a l a n e s t h e t ic t h e human c o r n e a a n d a p p lie d t h e t e s t t o was p r o b a b ly t h e f i r s t

to is o la t e

a n im a ls #

th e f r o g

s c ia tic

e f f e c t on A lm s ( 3 5 ) n e rv e and

d e m o n s tr a te th e e f f e c t o f l o c a l a n e s t h e t ic s u p o n i t #

T h e se

e a r l y m e th o d s f o r t e s t i n g l o c a l a n e s t h e t ic s a r e

in

s till

use

t o d a y i n m o d i f i e d fo rm s # A num ber o f f a c t o r s

a r e t h o u g h t t o b e in v o l v e d i n

e f f e c t w h ic h a n e s t h e t ic s h a v e o n th e b o d y . phenom ena p l a y a d o m in a n t r o l e a c t i o n ; i n c lu d e d a r e : o il

in

c o e ffic ie n t,

t i o n , m em brane p e r m e a b i l i t y ,

(3 4 )#

of

s u r fa c e te n s io n ,

d e h y d r a t io n ,

and p a r t i c l e

doubt a g re a t d e a l o f in te r r e la tio n o th e r fa c to r s

P h y s ic o c h e m ic a l

th e p ro p o s e d th e o r ie s

c o l l o i d a l b e h a v io r ,

and w a t e r d i s t r i b u t i o n

th e

a d s o rp ­

o r ie n ta tio n #

e x i s t s b e tw e e n th e s e

No and

M any I m p o r t a n t o b s e r v a t io n s h a v e b e e n

made c o n c e r n in g a n e s t h e t ic d r u g s a n d m any s u c h o b s e r v a t io n s

11. c a n b e fo u n d i n B le te r

t h e c o m p re h e n s iv e r e v ie w b y H i r s c h f e l d e r a n d

(3 5 ).

Among t h e l a r g e n u m b e r o f m e th o d s a v a i l a b l e in g

t h e l o c a l a n e s t h e t ic

e f f e c t o f a g iv e n d r u g a re s

a n d g o l d f i s h n a r c o s i s m e th o d s ; f r o g m u s c le p r e p a r a t i o n s ,

fo r te s t­

s k in ,

fo o t,

t a d p o le

and n e rv e

and f r o g h e a r t p e r f u s i o n m e th o d s ; t h e

n e r v e m u s c le p r e p a r a t i o n and c o r n e a l t e s t s o n d o g s a n d c a t s ; t h e human to n g u e , g u m s, and I n t r a d e r m a l w h e a l m e th o d s ; a n d t h e d o g s u b c u ta n e o u s and g u in e a p i g i n t r a d e r m a l w h e a l m e th o d s . A fe w o f t h e m e th o d s h a v e b e e n u s e d h e r e i n a g e n e ra l id e a a b o u t th e a b i l i t y e f f e c t l o c a l a n e s t h e s ia .

o rd e r to

o b ta in

o f th e s e a lk y lc a r b a m a t e s t o

The l i m i t e d n u m b e r o f t e s t s u t i l ­

iz e d a n d t h e s m a ll n u m b e r o f a n im a ls u s e d c a n o n ly g iv e in d ic a tio n

o f t h e a c t i o n o f t h e d r u g s a n d m u s t n o t be c o n ­

s id e r e d a s c o n c lu s iv e

e v id e n c e o n a n y p o i n t *

The r a b b i t c o r n e a m e th o d was u s e d t o a b ility

an

d e te r m in e t h e

o f t h e d r u g s t o p e n e t r a t e m ucous m embrane t i s s u e

t h e i r p o w e r t o p a r a ly z e n e r v e e n d in g s

(3 6 ).

and

T he r a b b i t * s

e y e la s h e s w e re c l i p p e d o f f and t h e n o r m a l w in k r e f l e x was te s te d .

T he l a t t e r was a c c o m p lis h e d b y l i g h t l y

c o r n e a f r o m b e h in d t h e lo id

s tr ip

a n im a l, u s in g a t h i n ,

s tr o k in g

th e

b e n t, c e llu ­

c o n t a i n i n g a s m a ll b a l l o f b e e s w a x o n t h e p o i n t .

The lo w e r l i d

o f t h e e ye was h e ld o p e n t o

s o l u t i o n t o b e t e s t e d was p la c e d i n w i t h t h e e ye f o r one m in u te .

a n d h e ld i n

c o n ta c t

The d r u g was t h e n e x p r e s s e d .

The r e f l e x was t e s t e d e v e r y t h r e e t o p a r e d w i t h t h e o t h e r , n o r m a l,

it

fo rm a c u p , th e

eye.

f i v e m in u te s a n d com­ The tim e o f o n s e t a n d

12 d u r a t i o n o f a c t i o n w e re n o te d * w ith

.

The r e s u l t s w e re c o m p a re d

a s ta n d a rd (5 7 )* The g u in e a p i g w h e a l t e s t was a n a d a p t a t io n o f t h a t

d e s c r ib e d b y R ose ( 3 8 ) *

T h is m e th o d m e a s u re s t h e p o w e r t o

p a r a ly z e n e r v e e n d in g s w i t h o u t r e g a r d t o tra te

tis s u e *

The h a i r i n

It

w ith o u t i n j u r y

th e

to

to pene­

an a r e a a b o u t tw o in c h e s i n

d ia m e t e r w as c l i p p e d o f f o n o p p o s it e t h e t e s t a n im a l•

a b ility

s id e s o f t h e b a c k o f

was c u t as c lo s e t o s k in *

th e

s k in

as p o s s ib le

A f t e r a t le a s t tw e n ty - fo u r h o u rs

t h e a n im a l was I n j e c t e d w i t h 0 * 2 m l. o f t h e s o l u t i o n t e s t e d and an a r e a a b o u t o n e h a l f i n c h i n lin e d

In in k

a g a in , t o

in s u r e

s k in and b a c k i n t o

t e s t th e

t h e t e s t a r e a and w it h o u t #

made a b o u t t h r e e t o

fiv e

and th e

t h e d e rm is

t h a t th e i n j e c t i o n be in t r a d e r m a l.

n e e d le p o i n t was u s e d t o

The

s h a rp , tw e n ty -fo u r -g a u g e

The s k i n was p in c h e d up b e tw e e n t h e f i n g e r s

n e e d le f o r c e d t h r o u g h t h e

w ith in

d ia m e t e r was o u t ­

a ro u n d t h e w h e a l fo rm e d b y t h e i n j e c t i o n #

i n j e c t i o n was made u s in g a s h o r t , n e e d le *

to be

A

s q u e a l o r absence o f s q u e a l T he r e s u l t s o f s i x p r i c k s

s e c o n d s a p a r t w e re r e c o r d e d a lo n g

w i t h t h e t im e t h a t h a d e la p s e d s in c e t h e i n t r o d u c t i o n o f t h e d ru g *

O b s e r v a tio n s w e re made e v e r y on e t o

t h e r e f l e x was a b o lis h e d , th e n e v e r y f i v e u n til

s e n s it iv it y re tu rn e d .

a s ta n d a rd

tw o m in u te s u n t i l to

t e n m in u te s

The r e s u l t s w e re co m p a re d w i t h

(3 8 ).

T h e f r o g m u s c le n e r v e p r e p a r a t io n m e a s u re s t h e

a b ility

t o p e n e t r a t e t h e n e r v e s h e a th and t o p a r a ly z e t h e n e r v e The i s o la t e d

s c ia tic

(3 6 ).

g a s tr o c n e m iu s m e th o d was c o m p a re d w i t h

13, t h e m e th o d o f R id e r

(3 7 ).

T he l a t t e r m e th o d was a d o p te d

b e c a u s e c o n s id e r a b le tra u m a was b e l i e v e d t o t h e n e r v e a n d m u s c le w e re I s o l a t e d tio n , th ir d

as I n

b e c a u s e d w hen

th e

fo rm e r p re p a ra ­

The f r o g w as d e c a p it a t e d a n d p i t h e d f o r a b o u t o n e o f an In c h ,

T he s c i a t i c

n e r v e s w e re e x p o s e d b y

r e m o v a l o f t h e v i s c e r a a n d t h e a n im a l w as p la c e d o n a t i l t e d b o a rd # to r a is e

A s m a ll g la s s r o d was p la c e d u n d e r t h e It

a n d t h u s f o r m tw o c u p - l l k e

s id e o f t h e c o r d . s c ia tic

T w e n ty t o

th ir ty

s a lin e

o rd e r to

a llo w r e ­

n o r m a l r e f l e x e s o f b o t h n e r v e s w e re n o t e d

and th e d ru g th e n a p p lie d t o t h e o t h e r n e rv e #

a n d m a in t a in e d

m in u te s w e re a llo w e d t o

e la p s e f r o m t h e t im e o f d e c a p i t a t i o n i n c o v e ry fro m s h o c k ,

d e p r e s s io n s o n e i t h e r

The u p p e r d e p r e s s io n , c o n t a i n i n g o n e

n e r v e , w as b a th e d w i t h f r o g

as a c o n t r o l.

s p i n a l c o lu m n

t h e lo w e r d e p r e s s io n c o n t a i n i n g

The t im e o f a b o lis h m e n t o f b o t h m o to r a n d

s e n s o r y r e f l e x e s was n o t e d as w e l l as t h e t im e o f r e c o v e r y #

14. EXPERIMENTAL

1*

The S y n t h e s is o f 5«* p l e t h y l am i n o p r o p y l B u t y l e a r b am at e . A*

p e n t a n o y lf t a h lo r ld e was made a c c o r d in g t o

o f ^ O rg a n ic S y n th e s e s ”

(3 9 ).

t h r e e - n e c k f à l s k was f i t t e d p in g f u n n e l w i t h

8 2 . 0 Gm.

A tw o h u n d re d and f i f t y w i t h a s e a le d s t i r r e r ,

a c a lc iu m c h l o r i d e

d e n s e r c o n ta in in g

a d r y in g t u b e .

tu b e ,

In

a n d 6 0 .0 Gm.

a d ro p ­

and a r e f l u x

r e c e n tly d i s t i l l e d

The f l a s k was h e a te d t o

80 - 9 0 ° C*

The g a s e v o lv e d was a llo w e d t o

c a p e fr o m t h e c o n d e n s e r u n d e r a h o o d .

t h e n was f i t t e d

w ith

tw o g la s s

r e c e i v e r e q u ip p e d w i t h

s to p p e rs ,

a d r y in g t u b e .

es­

A f t e r a d d i t i o n w as

c o m p le te d , h e a t in g was c o n t in u e d f o r a h a l f h o u r .

105 -

con­

( 0 . 5 8 m o le ) o f p e n t s n o ic a c id was a d d e d o v e r

th e p e r io d o f an h o u r.

tille d

cc*

t h e f l à s k was p la c e d

( 0.6 m o le ) o f t h i o n y l c h l o r i d e

o v e r a tw o d e g re e r a n g e .

t h e m e th o d

The f l a s k

a c o n d e n s e r and

The p r o d u c t was d i s ­

and 61 Gm. ( 0 .5 1 m o le ) o f p e n t ano y l c h l o r i d e , b . p . 1 1 5 ° , was o b t a in e d .

R e d is tilla tio n

( 0 . 4 8 m o le ) o f a c id c h l o r i d e , b . p .

g a v e 5 8 .3 Gm.

118 - 1 2 8 ° .

The y i e l d

was 83j£ o f t h e t h e o r e t i c a l b a s e d o n p e n t a n o ic a c i d . B.

A c t i v a t e d S o d iu m A s id e was made a s d e s c r ib e d i n

^ O r g a n ic R e a c t io n s ”

(4 0 ).

A 2 5 .0 Gm. ( 0 .3 8 m o le ) p o r t i o n o f

c o m m e r c ia l s o d iu m a z id e was m o is te n e d w i t h 0.6 c c . h y d r a z in e h y d r a t e a n d m ix e d i n t i m a t e l y i n s t a n d in g f o r

a m o rta r.

o f 85% A fte r

s ix t e e n h o u r s , t h e m ix t u r e was d is s o lv e d i n

50 c c . o f h o t w a t e r and th e n p r e c i p i t a t e d b y t h e a d d i t i o n

15 o f one l i t e r

o f c o ld a c e to n e »

s ta n d f o r o n e h o u r# w ith

ly .

The p r e c i p i t a t e

tw o 5 0 c c * p o r t i o n s

The r e s u l t i n g

The m ix t u r e was a llo w e d t o

o f c o ld a c e to n e and s u c k e d d r y .

c a k e was c o m m in u te d a n d a llo w e d t o

d r y th o r o u g h »

T he p r o d u c t w e ig h e d 2 1 * 0 Gm» (0 # 3 2 m o le ) g i v i n g

o f 85%»

A l l o f th e

jC»

th e y ie ld s

r a n g in g f r o m 78 » 96%*

T he p r e p a r a t i o n o f b u t y l is o c y a n a t e was c a r r i e d o u t

u n d e r a h o o d b y p l a c i n g 1 4 * 5 Gm. s o d iu m a z id e i n t o fitte d

a y ie ld

s o d iu m a z id e u s e d s u b s e q u e n t ly was p r e ­

p a r e d as d e s c r ib e d h e re #

w ith

The f l a s k

( 0 * 2 2 m o le ) o f a c t i v a t e d

a t h r e e h u n d re d -c c »

a r e flu x

fro m th e to p i n t o

r o u n d - b o t to m f l a s k

c o n d e n s e r h a v in g a th e rm o m e te r s u s p e n d e d

th e f l a s k

and a d r y in g tu b e a t t h e o u t l e t *

a ls o c o n t a in e d a d r o p p in g f u n n e l w i t h

tu b e and a m e r c u r y - s e a le d s t i r r e r * w ith

w as th e n rem oved# w a sh e d

a d r y in g

The s a l t was c o v e r e d

50 c c * o f t o lu e n e w h ic h h a d b e e n d r i e d b y s t a n d in g o v e r

s o d iu m f o r

s e v e ra l h o u rs ,

th e n d i s t i l l e d .

N e x t, 2 4 * 0 Gm.

( 0*20 m o le ) o f p e n t a n o y l c h l o r i d e was a d d e d s l o w l y , w i t h s tir r in g ,

t h e a d d i t i o n b e in g r e g u la t e d

a tu r e d id n o t r i s e .

so t h a t t h e te m p e r­

T h is r e q u ir e d a b o u t f o r t y - f i v e

The m ix t u r e w as r e f l u x e d f o r t h r e e h o u r s , th e n c o o le d a n d f i l t e r e d , su ch *

o d o r,

D.

c o l o r , h a d an u n p le a s a n t ,

and was a la c r y m a t o r ( 4 1 ) *

The s y n t h e s is o f 3 - d i e t h y la m in o p r o p y l b u t y lc a r b a m a t e

was a t t e m p t e d . c o o le d t o

th e c o n te n ts

and t h e t o lu e n e s o l u t i o n u s e d a s

The p r o d u c t w as b ro w n i n

ir r ita tin g

m in u te s *

To 50 c c * o f th e a b o ve t o lu e n e

s o lu tio n ,

5 - 1 0 ° , was a d d e d 2 6 .2 Gm. ( 0 * 2 0 m o le ) o f 3 -

d ie t h y la m in o - 1- p r o p a n o l I n

20

cc.

o f c o ld ,

d r y t o lu e n e .

16. T h e s o l u t i o n w as k e p t c o ld f o r o n e h o u r d u r i n g w h ic h tim e c r y s ta lliz a tio n o v e r n ig h t.

o c c u rre d .

The m ix t u r e was a llo w e d t o

The p r o d u c t was f i l t e r e d ,

and p a r t i a l l y

d e c o l o r iz e d w i t h n o r i t e .

fro m a v a r i e t y o f s o lv e n ts f a i l e d . m onium s a l t s w i t h m e th y l i o d i d e g iv e

a c r y s ta lliz a b le

a b le c i t r i c s fu l.

tio n

s o lid .

a c id and p i c r i c

D is tilla tio n

w a x - lik e

d is s o lv e d i n

s ta n d

a lc o h o l

R e c r y s ta lliz a tio n

A tt e m p t s t o m ake am­

and b e n z y l c h lo r id e

d id n o t

A tte m p ts t o make c r y s t a l l ! z a c id s a l t s

w e re a ls o u n s u c c e s ­

o f t h e r e m a in in g c r u d e b a s e g a v e a y e llo w ,

s o lid , b .p .

1 6 2 - 1 6 0 ° / 1 - 2mm.

A tte m p te d p u r i f i c a ­

o f t h i s p r o d u c t was u n s u c c e s s f u l. E.

A r e p e titio n

o f t h i s w o rk on a s m a lle r s c a le f a i l e d

to p ro d u c e a p u re p r o d u c t. F.

A th ir d

a tte m p t on a la r g e r

s c a le was m ore s u c ­

c e s s fu l.

p e n t a n o y l c h l o r i d e w as made as i n

1 2 3 .0 Gm.

( 1 . 0 3 m o le ) o f t h i o n y l c h l o r i d e

( 0 . 9 8 m o le ) o f p e n t a n o ic a c i d ,

p a r t A u s in g

a n d 1 0 0 .0 Gm.

fr o m w h ic h 8 0 . 0 Gm.

( 0 .6 6 m o le )

o f p e n t a n o y l c h l o r i d e b o i l i n g b e tw e e n 116 - 1 2 8 ° was o b ­ ta in e d .

The y i e l d w as 6 9 ^ o f t h e t h e o r e t i c a l b a s e d o n

p e n t a n o ic

a c id .

a c tiv a te d

s o d iu m a z id e and 100 c c . o f t o lu e n e was t r e a t e d

w i t h 4 6 .0 Gm. C above. T h is

A m ix t u r e o f 2 7 .8 Gm.

( 0 . 3 8 m o le ) o f p e n t a n o y l c h l o r i d e

On r e f l u x i n g

t h e m ix t u r e r e t a i n e d i t s

s o l u t i o n was c o o le d and f i l t e r e d .

t i o n was t r e a t e d w i t h 6 0 .0 Gm. tille d n ig h t.

( 0 . 4 3 m o le ) o f

p a rt

w h it e

c o lo r .

The t o lu e n e

s o lu ­

( 0 .3 7 m o le ) o f r e c e n t l y d i s ­

3 - d i e t h y l a m i n o - l« p r o p a n o l a nd a llo w e d t o No c r y s t a l l i z a t i o n

as i n

c o u ld b e in d u c e d .

s ta n d o v e r­

D r y h y d ro g e n

17, c h l o r i d e g a s was p a s s e d I n t o a tu re .

S in c e an o i l

s ta r te d to

c o o le d a n d t h e g a s p a s s e d i n lin e

m ass p r e c i p i t a t e d #

filte r e d ,

th e s o lu t io n

sucked d r y .

s e p a ra te ,

a t 10 -

A p o r tio n

w a sh e d w i t h p e t r o le u m The r e s u l t i n g

a t ro o m te m p e r * t h e m ix t u r e was

2 0 °,

A w h it e

o f th is

c r y s ta l*

p r o d u c t was

e th e r ( b ,p .

30 * 6 0 ° )

and

p r o d u c t m e lt e d b e tw e e n 55 * 9 1 ° ,

R e p e a te d p r e c i p i t a t i o n g a v e no s h a r p ly m e l t i n g p r o d u c t . F r a c tio n a l c r y s t a l liz a t io n

was c a r r i e d o u t u s in g a m ix t u r e

o f b e n z e n e and a c e to n e as a s o l v e n t .

F o u r f r a c t i o n s w e re

o b t a in e d , t h e l a s t tw o b e in g d i f f i c u l t l y th e

c r y s ta lliz a b le

o ils ,

s e c o n d one b e in g a c r u d e p r o d u c t m e l t i n g b e tw e e n 55 *

96° and th e f i r s t

o n e b e in g a w h it e m ic r o c r y s t a l l i n e

m e l t i n g b e tw e e n 100 * 1 1 0 ° •

F u rth e r p u r if ic a t io n

w h it e c r y s t a l s g a v e a p r o d u c t , m ,p# 110 - 1 1 5 ° ,

p ro d u c t

o f th e T h is p r o ­

d u c t was a n a ly z e d f o r n i t r o g e n u s in g t h e H e n g a r a p p a r a tu s f o r t h e K j e l d a h l m e th o d * in

th is

w ay e x c e p t f o r p i p e r i d in o n i t r o g e n f o r w h ic h t h e

Dumas m e th o d was u s e d . N g C ls K , 1 0 . 5 1 . 2*

A l l o t h e r p r o d u c t s w e re a n a ly z e d

A n a ly s is

- c a l c u l a t e d f o r C igH gyO g

F o u n d jN , 1 0 . 2 8 , 1 0 . 2 3 .

The S y n t h e s is o f 2 * D i e t h y l am ino e t h y l B u t y lc a r b am at e A.

P e n ta n o y l c h lo r id e , b . p .

p a r e d as i n

E x p e r im e n t I

t h io n y l c h lo r id e The y i e l d

- A u s in g 4 3 .6 Gm.

a n d 3 1 .6 Gm.

was 3 2 *6 Gm.

1 2 5 .5 - 1 2 6 . 5 ° , was p r e ­

( 0 .3 1 m o le ) o f p e n t a n o ic

a c id .

( 0 . 2 7 m o le ) r e p r e s e n t in g 87% o f t h e

t h e o r e t i c a l y i e l d b a s e d on p e n t a n o ic B.

( 0 , 3 7 m o le ) o f

a c id *

B u t y l is o c y a n a t e was p r e p a r e d a s i n

E x p e r im e n t I

* C

18* u s in g

2 6 .0 Geu

t o lu e n e

( 0 . 4 0 m o le ) o f s o d iu m a s id e i n

75 c c . o f d r y

a n d 3 2 ,6 GSn. ( 0 . 2 7 m o le ) o f p e n t a n o y l c h l o r i d e .

v ig o r o u s r e a c t i o n o c c u r r e d a f t e r a d d i t i o n o f t h e w as c o m p le t e . ly

A f t e r th e r e a c t io n

a p p l ie d u n t i l t h e r e f l u x i n g

t o lu e n e 5

c o lo r .

t e m p e r a tu r e w as a t t a i n e d *

th e fo llo w in g

s o l u t i o n was a d d e d 9 . 4

Gm.

The s o l u t i o n

To h a l f o f t h e

( 0 .0 8 m o le ) o f 2 -

d i e t h y l a m in o e t h a n o l a t ro om te m p e r a t u r e . to be u n n e c e s s a ry .

th e

s te p .

2 - B i e t h y 1 am in o e t h y l b u t y lc a r b a m a t e .

a b o ve t o lu e n e

The

t h e s o l u t i o n b e c o m in g

T h is was c o o le d and f i l t e r e d ,

s o l u t i o n b e in g u s e d i n

.

a c id c h l o r i d e

s u b s id e d , h e a t was c a u t i o u s ­

m i x t u r e was r e f l u x e d f o r t h r e e h o u r s , l i g h t b ro w n i n

A

C o o lin g was fo u n d

s to o d f o r t h i r t y

w h ic h t im e n o o d o r o f t h e is o c y a n a t e r e m a in e d .

h o u rs a t

T o lu e n e was

re m o v e d u n d e r r e d u c e d p r e s s u r e a n d th e p r o d u c t was d i s t i l l e d g iv in g fo r

a c o l o r l e s s , v is c o u s l i q u i d ,

a y ie ld

b .p .

1 2 4 .5 - 1 2 6 . 5 ° / 2 mm.

o f 1 2 . 7 Gm* ( 0 .0 6 m o le ) o r 2 2 # o f t h e t h e o r e t i c a l

y i e l d based on p e n ta n o y l c h lo r id e * A b o u t f o u r g ra m s o f t h e p e t r o le u m

e th e r ( b .p .

added a s o lu t io n

eum e t h e r .

6 0 °)

was fo rm e d .

To t h i s

in

was

p e t r o le u m

e th e r

The s o lv e n t w as d e c a n te d and

w as w a s h e d s i x t im e s w i t h e t h e r a n d p e t r o l ­

The h y g r o s c o p ic p r e c i p i t a t e

fr o m a m ix t u r e o f e t h y l a c e t a t e t im e s .

a n d c o o le d .

o f d r y h y d ro g e n c h l o r i d e

and a p r e c i p i t a t e th e p r e c ip it a t e

30 -

a b o ve p r o d u c t was d is s o lv e d i n

was r e c r y s t a l l ! z e d

and p e t r o le u m e t h e r s e v e r a l

The h y g r o s c o p ic n e e d le s t h u s fo r m e d w e re d r i e d f o r

tw o d a y s i n

an A b d e r h a ld e n d r y in g p i s t o l *

ed a t 9 1 .5 - 9 4 .5 ° .

A n a ly s is -

The p r o d u c t m e l t ­

c a l c u l a t e d f o r C^^HggO gNgCls

19. H, 1 1 . 0 8 .

Se

P o u n d :K , 1 1 . 1 3 , 1 1 . 4 8 .

Tbe Attempted Synthesis of 3-Piperldino-l.2-Proeanediol Bi s(Butylcarbamate) T h e r e m a in in g t o lu e n e

s o l u t i o n o f b u t y l is o c y a n a t e

f r o m E x p e r im e n t 2 «• B w as t r e a t e d w i t h 6 . 4 o f 3 » p ip e r id in o ~ l,2 * p r o p a n e d io l.

Gm. ( 0 . 0 4 m o le )

A fte r t h ir t y

h o u rs th e

t o lu e n e was re m o v e d i n

v a c u o and t h e p r o d u c t w as d is s o lv e d

in

d e c o lo r iz e d w i t h n o r i t e .

e th e r and p a r t i a l l y

The e t h e r e a l

s o l u t i o n was c o o le d a n d a s o l u t i o n o f d r y h y d ro g e n c h l o r i d e in

e t h e r w as a d d e d .

An o i l y

p r o d u c t s e p a r a te d .

The e th e r

was d e c a n te d a n d t h e r e s id u e w as w a sh ed s e v e r a l t im e s w i t h e th e r g iv in g tio n

m oved.

e x tra c te d

D is tilla tio n

and d r ie d ,

F u rth e r p u r i f i c a ­

The s a l t was n e u t r a l i z e d

and th e

o f th e r e s u lt in g

s o lv e n t was r e ­

o i l gave a p ro d u c t

162 - 1 7 6 ° / 2 mm. w h ic h c o u ld n o t b e r e e r y s t a l l ! z e d as

th e b a s e . o f th is 4.

c r y s ta lliz e d o i l .

o f th e h y d r o c h lo r id e f a i l e d .

w ith b a se ,

b .p .

a p a r tia lly

An a tt e m p t t o

d is tilla te

r e c r y s t a l l ! ze th e h y d r o c h l o r i d e

a ls o f a i l e d .

The S y n t h e s is o f 2 -D 1 e t h y l am ino e t h y l P e n t y l c a rb a m a te A.

H e x a n o y l c h l o r i d e w as made fr o m 5 4 .6 Gm.

o f t h io n y l c h lo r id e a c id g i v i n g

4 7 .8 Gm.

1 7 mm. and b . p .

and 4 4 .1 Gm.

( 0 . 3 8 m o le ) o f h e x a n o ic

( 0 . 3 5 m o le ) o f p r o d u c t , b . p .

1 5 2 ° /7 5 0 mm.

( 0 . 4 6 m o le )

61 - 6 2 ° /

T he y i e l d b a s e d o n h e x a n o ic

a c i d was 9 3 . 5 # . B.

P e n t y l is o c y a n a t e was s y n t h e s iz e d fr o m 2 4 .0 Gm.

( 0 . 3 6 m o le ) o f a c t i v a t e d

so d iu m a z id e i n

50 c c . o f d r y t o lu e n e

20e a n d 4 7 » 0 Gm.

( 0 . 3 5 m o le ) o f h e x a n o y l c h l o r i d e .

w as s t a r t e d b y h e a t in g t h e m ix t u r e p le te .

a f t e r a d d i t i o n was com*»

C o o lin g was n e c e s s a r y t o p r e v e n t t o o

r e a c tio n .

t h e is o c y a n a t e f r o m t o lu e n e b y d i s t i l l a t i o n a n d was u n s u c c e s s f u l*

d ir e c tly . s till

v ig o r o u s a

The r e a c t i o n c o n t in u e d f o r a n h o u r a f t e r w h ic h

t im e t h e m i x t u r e was r e f l u x e d f o r tw o h o u r s .

tw ic e

The r e a c t i o n

It

The t o lu e n e

S e p a r a t io n o f was a tt e m p te d

s o l u t i o n was u s e d

h a d a p le a s a n t arom a w hen g r e a t l y d i l u t e d

and

r e t a i n e d a t y p i c a l la c r y m a t o r y e f f e c t # 2*»D ie t h y l am i n o e t h y l p e n t y l c a rb a m a te w as made b y

tr e a tin g Gm.

h a l f o f t h e t o lu e n e

s o l u t i o n fr o m a b o ve w i t h 1 1 * 9

( 0 . 1 0 m o le ) o f 2 - d i e t h y l am ino e t h a n o l a t a b o u t 4 0 ° f o r

t w e lv e h o u r s .

A tte n q p ts t o p u r i f y

t h e h y d r o c h l o r i d e , made

fro m a p o r t io n o f th e r e a c t io n p r o d u c t, f a i l e d .

T o lu e n e was

re m o v e d f r o m t h e r e m a in d e r o f t h e r e a c t i o n p r o d u c t a nd t h e o i l was d i s t i l l e d

g i v i n g 9 . 0 Gm. o f a p r o d u c t , b . p .

1 6 0 .5 ° /2 -

R e d is tilla tio n

b .p .

3 mm.

1 5 7 .5 - 1 5 9 . 5 ° / 2 -

3 mm.

157 -

g a v e 7 .1 Gm. o f m a t e r i a l ,

The t o t a l y i e l d was 1 5 * 7 Gm.

( 0 .0 6 8 m o le ) w h ic h was 68 ^ o f t h e t h e o r e t i c a l b a s e d on 2 d ie t h y l a m in o e t h a n o l . N, 1 2 .1 6 . 5*

A n a ly s is - c a l c u l a t e d f o r ^ i 2 B2 6 0 2N2 8

F o u n d ;# , 1 2 * 0 6 , 1 1 * 7 5 .

T h e S y n t h e s is o f 3- D le t h y la x n ln o p r o p y l P e n t y l c a rb a m a te One h a l f o f t h e t o lu e n e

s o l u t i o n f r o m E x p e r im e n t 4 - B

was r e a c t e d f o r t w e lv e h o u r s w i t h 1 3 * 1 Gm. 3 - d i e t h y l a m in o - 1 - p r op a n o l a t 4 0 ° . c o o le d i n

( 0 . 1 0 m o le ) o f

H a lf o f t h is

s o l u t i o n was

an i c e b a t h a n d th e h y d r o c h lo r id e fo r m e d .

c r y s ta lliz a tio n

o f th is

Re­

h y d r o c h lo r id e was e v e n m o re d i f f i c u l t

21e

th a n t h e p r e v io u s o n e * re c o v e re d .

O n ly t h e c r u d e h y d r o c h l o r i d e was

An a t t e m p t t o make a c r y s t a l l i z a b le c i t r i c

s a lt f a ile d .

T he c r u d e p r o d u c t e q u iv a le n t t o

f r e e h a s e was r e c o v e r e d . p r o d u c t w as d i s t i l l e d ,

1 0 . 4 Gm. o f

The r e m a in in g h a l f o f t h e r e a c t i o n

a f t e r re m o v a l o f th e s o l v e n t , g i v i n g

1 0 . 7 Gm. o f a p r o d u c t b + p . 1 6 0 • 1 6 6 ° / 1 mm. gave a p r o d u c t b . p .

a c id

1 6 6 ** 1 6 7 . 5 ° / 2 mm.

R e d is tilla tio n

The y i e l d ,

c a lc u la te d

o n th e f r e e b a s e , was 2 1 * 6 Gm. ( 0 . 0 9 m o le ) o r 90% .

The c i t r i c

a c id s a l t was p r e p a r e d , m#p* 6 6 .5 * 6 7 . 5 ° • c u la t e d f o r C^gHggO gRg:N, 6 . 4 2 . 6.

A n a ly s is -

c a l­

F o u n d ;R , 6 . 4 9 , 5 . 9 3 .

The S y n t h e s is o f 2- P i e t h y l am ino e t h y l H e x y lc a r b am at e A.

H e p ta n o y l c h l o r i d e was s y n t h e s iz e d f r o m 1 0 0 .0 Gm.

( 0 .7 6 m o le ) o f h e p t a n o ic a c id w h ic h was r e a c t e d w i t h 1 0 7 .0 Gm. ( 0 . 9 m o le ) o f t h i o n y l c h l o r i d e .

The y i e l d was 7 0 .0 Gm.

( 0 . 4 7 m o le ) o f h e p t a n o y l c h l o r i d e , b . p .

171 - 1 7 2 ° /7 4 5 ram.

o r 62% o f t h e t h e o r e t i c a l b a s e d o n h e p t a n o ic B.

H e x y l is o c y a n a t e , made fr o m 4 0 .0 Gm.

o f a c tiv a te d

s o d iu m a z id e a n d 7 0 .0 Gm.

h e p t a n o y l c h l o r i d e , was o b t a in e d i n m a t e r i a l w as r e c t i f i e d b .p .

g iv in g

( 0 .4 7 m o le ) o f

a y ie ld

3 3 .5 Gm.

( 0 .6 2 m o le )

o f 53%.

The

( 0 .2 5 m o le ) o f p r o d u c t ,

1 6 1 - 1 6 2 ° /7 4 5 ram* C.

2 - D i e t h y l am ino e t h y l h e x y lc a r b am at e .

( 0 .0 6 3 m o le ) p o r t i o n

a m in o e th a n o 1 .

A 7 . 4 Gm.

o f t h e a b o ve p r o d u c t was r e a c t e d w i t h

an e t h e r e a l s o l u t i o n o f 8 . 0 Gm.

days.

a c id .

( 0 .0 6 3 m o le ) o f 2 - d i e t h y l -

The s o l u t i o n was a llo w e d t o

s ta n d f o r tw o

E t h e r was re m o ve d a nd t h e o i l was d i s t i l l e d

g iv in g

22 7 . 8 Gm.

( 0 .0 3 2 m o le ) o f a p r o d u c t , b . p .

1 3 6 . 5 ° / 2 mm.

The

y i e l d was 51% o f t h e t h e o r e t i c a l b a s e d o n h e x y l is o c y a n a t e . A n a ly s is -

c a l c u l a t e d f o r C ^ H g g O g N g jN , 1 1 .4 7 »

1 1 .4 3 , 1 1 .1 3 .

T he c i t r i c

F o u n d :N ,

a c id s a l t , m .p . 1 0 1 .5 -

1 0 2 .5 ° ,

was p r e p a r e d b y a d d i t i o n o f a s a t u r a t e d s o l u t i o n o f c i t r i c a c id ,

d is s o l v e d i n

a 5 :1 e th e r - a lc o h o l m ix tu r e ,

e a l s o lu t io n o f th e f r e e b a s e .

The p r e c i p i t a t e

w a sh e d w i t h e t h e r a n d r e c r y s t a l l i z e d

to

an e t h e r ­

fo rm e d was

fr o m an e t h y l a c e t a t e -

m e th a n o l s o l u t i o n . 7.

The S y n t h e s is o f 3- D l e t h y l a m in o p ro p y 1 H e x y lc a rb a m a t e To 8 . 0 Gm.

( 0 . 0 6 3 m o le ) o f h e x y l is o c y a n a t e f r o m

E x p e r im e n t 7 * B a n d 20 c c .

o f a n h y d ro u s e t h e r w as a d d e d

8 . 3 Gm. ( 0 .0 6 3 m o le ) o f 5 » d ie t h y la m ln o - l- p r o p a n o l . t h e is o c y a n a t e o d o r h a d d is a p p e a r e d , t h e r e s i d u a l o i l was d i s t i l l e d o f a p ro d u c t, b .p . th e t h e o r e t ic a l.

The y i e l d

A second d i s t i l l a t i o n

m o le ) o f a c o l o r l e s s o i l ,

b .p *

( 0 .0 3 9 m o le ) was 62% o f

g a v e 6.8 Gm.

154 - 1 5 6 ° / 2 mm.

c a l c u l a t e d f o r O i^ H g o O g N g :# , 1 0 .8 5 . 8.

e t h e r was re m o ve d a n d

g i v i n g 1 0 .0 Gm.

1 5 4 - 1 7 0 ° / 2 mm.

A fte r

( 0 .0 2 6

A n a ly s is -

F o u n d ;H , 1 0 . 8 1 , 1 0 . 6 9 .

The A tte m p te d S y n t h e s is o f 2- D i e t h y l a m in o p r o p y l H e x y lc a rb a m a te An e t h e r e a l s o l u t i o n c o n t a in in g 2 . 8 Gm.

o f h e x y l is o c y a n a t e

and 2 .9 Gm.

a m in o - l- p r o p a n o l, b . p .

( 0 .0 2 1 m o le )

( 0 .0 2 2 m o le ) o f 2 - d i e t h y l -

1 54 - 1 5 6 ° /7 5 0 mm.

( H e ilb r o n , b .p .

166 - 1 6 9 ° /7 4 9 mm# ) was p r e p a r e d an d a llo w e d t o

s ta n d f o r

tw o d a y s a f t e r w h ic h t im e th e e t h e r a n d e x c e s s a lc o h o l w e re

.

23» re m o v e d u s in g h e a t a n d r e d u c e d p r e s s u r e # filte r e d

t h r o u g h s i n t e r e d g la s s

an d s o l i d i f i e d

T h i s p r o d u c t w as r e c r y s t a l i i ze d f r o m 9 5 $ a c e to n e g i v i n g

1 0 .8 4 .

F o u r a d d itio n a l r e c r y s t a lliz a t io n s d u c t m e ltin g a t 6 9 *5 t h e v a lu e 1 1 * 7 8 $ N.

7 2 .5 ° .

o n s ta n d in g #

75$ a lc o h o l,

a p r o d u c t , m#p* 6 7 , 5 -

c a lc u la te d f o r

in

The r e s id u e was

7 2 .5 ° •

th e n fro m A n a ly s is •*

F o u n d :R , 1 1 * 8 7 , 1 1 * 6 9 . f r o m a c e to n e g a v e a p r o ­

A n a ly s is o f t h i s

p ro d u c t gave

The t h e o r e t i c a l p e r c e n t o f n i t r o g e n

t h e c o r r e s p o n d in g N ,N f « d ih e x y l u r e a ,

c a lc u la te d f o r

C1 3 H28 0 N2> 1 s 9*

The A tte m p te d S y n t h e s is o f 3- P i p e r l d l n o - l . 2- F r o p a n e d io l B i s ( H e x y lc a r b am at e ) A 1 4 * 0 Gm.

added to

( 0 .1 1 m o le ) p o r t i o n o f h e x y l I s o c y a n a te was

an e t h e r s o l u t i o n c o n t a i n i n g 9 . 5 Gm.

o f 3 - p ip e r id in o - l,2 - p r o p a n e d io l* a llo w e d t o

A tte m p ts to

and as t h e c i t r i c s u c c e s s f u l* 130 t o

c r y s ta lliz e

a c id s a l t s w e re n o t

o f th e c ru d e base o v e r a ra n g e o f

2 mm. g a v e 6 * 2 Gm. o f a l i g h t y e l l o w o i l

i i ze d f r o m p e t r o le u m a t 7 4 *5 - 7 5 .5 ° .

d u c t o f th e

E th e r

t h i s m a t e r i a l as t h e b a s e

a c id and h y d r o c h lo r ic

D is tilla tio n

1 6 0 ° /1 -

1 0 .1 6 .

s o l u t i o n was

g ra m s o f an o ra n g e v is c o u s o i l r e ­

w h ic h c r y s t a l l i z e d o n s t a n d in g .

in g

T he r e s u l t a n t

r e a c t f o r tw o d a y s a t ro o m t e m p e r a t u r e .

was re m o v e d and f i f t e e n m a in e d *

( 0 .0 6 m o le )

T h is m a t e r i a l w as r e e r y s t a l ­

e t h e r s i x t im e s g i v i n g A n a ly s is

- c a l c u l a t e d f o r C22 H4 3 O4 M3 :

F o u n d :N , 1 2 * 2 7 , 1 2 * 3 1 . a b o ve r e a c t i o n i s

a p r o d u c t m e lt­

A p o s s ib le r e a c t io n p r o ­

N , î P - d i h e x y l u r e a w h ic h , w hen

24 c a l c u l a t e d f o r C^^HggONg, g iv e s 1 2 . 2 7 $ N* 10.

The S y n t h e s is 2* p i e t h y l am i no e t h y l Hep t y l c a rb a m a te A#

O c ta n o y l c h l o r i d e ;

To 2 9 .5 Gm.

t h i o n y l c h l o r i d e was a d d e d 3 3 .0 Gm. a c id o v e r a p e r i o d o f an h o u r . f o r an h o u r fo llo w in g

( 0 .2 5 m o le ) o f

( 0 .2 3 m o le ) o f o c t a n o ic

The s o l u t i o n was r e f l u x e d

a d d i t i o n o f t h e a c id .

E xcess t h io n y l

c h l o r i d e was re m o v e d and t h e p r o d u c t d i s t i l l e d . was 3 2 .3 Gm.

The y i e l d

( 0 . 2 0 m o le ) o f o c t a n o y l c h l o r i d e , b . p .

1 5 m m ., o r 8 7 $ o f t h e t h e o r e t i c a l b a s e d on o c t a n o ic B.

H e p ty l Is o c y a n a te ;

m o le ) o f a c t i v a t e d was r e a c t e d w i t h

3 2 *3 Gm. ( 0 .2 0 m o le ) o f o c t a n o y l c h l o r i d e .

h e a te d f o r n i n e t y m in u te s .

s t a r t e d a v ig o r o u s

The m ix t u r e was t h e n

A fte r f i l t r a t i o n

v a c u o and t h e p r o d u c t d i s t i l l e d

( 0.12 m o le ) o f a c o l o r l e s s ,

lim p id ,

w h ic h b o i l e d a t 8 3 * 5

i n g p o i n t a t 745 mm. was 1 9 7 ° . c h l o r i d e was 61%.

g i v i n g 1 7 . 5 Gm.

8 4 . 5 ° / 1 5 mm.

The b o i l ­

The y i e l d b a s e d o n o c t a n o y l

A second d i s t i l l a t i o n

c a l c u l a t e d f o r CgH^gON:N, 9 . 9 2 .

t h e s o lv e n t was

s w e e t* * s m e llin g , la c r y m a ­

o f a p o r tio n o f t h is

m a t e r i a l g a v e a p r o d u c t , b . p . 8 3 . 5 ° / 1 5 mm.

0.

( 0 .2 6

s o d iu m a z id e a n d 50 c c . o f d r y t o lu e n e

r e a c t i o n w h ic h l a s t e d f o r an h o u r .

to ry liq u id

a c id .

A m ix t u r e o f 1 7 . 0 ©tn.

S l i g h t h e a t in g o f t h e r e s u l t a n t m ix t u r e

re m o v e d i n

9 0 •» 9 5 ° /

A n a ly s is -

F o u n d ;H , 9 .6 5 *

2**Di e t h y l am ino e t h y l hep t y l c a rb a m a te ;

( 0 . 1 0 m o le ) o f h e p t y l is o c y a n a t e i n was a d d e d 1 4 .0 Gm.

To 1 4 . 2 Gm.

25 c c . o f d r y t o lu e n e

( 0 . 1 2 m o le ) o f 2 - d i e t h y l ami no e t h a n o l.

D r y h y d ro g e n c h l o r i d e

g a s was l a t e r p a s s e d i n t o

h a l f o f th e

25e t o lu e n e

s o lu tio n

and. t h e p r o d u c t a llo w e d t o

s ta n d o v e r n ig h t •

M o re HG1 was I n t r o d u c e d b u t no m o re p r e c i p i t a t i o n o c c u r r e d . The p r e c i p i t a t e f o r m t w ic e

was c o l l e c t e d

and r e c r y s t a l l i z e d

a n d f r o m a c e to n e f o u r tim e s #

m e lt e d a t 150 -

1 3 3 °♦

The h y d r o c h lo r id e

The r e m a in in g t o lu e n e

f r e e b a s e w as f r a c t i o n a t e d

A se c o n d d i s t i l l a t i o n

b o i l i n g p o i n t o f 156 - 1 5 7 ° /1 mm.

In

m o le ) o f p r o d u c t w e re o b t a in e d f o r

a y ie ld o f

a ll,

t h e o r e t i c a l b a s e d o n h e p t y l is o c y a n a t e .

D,

o f th e

A n a ly s is

a c id - c a lc u la t­

F o u n d :N , 6 . 2 0 , 5 . 8 1 .

A p o r t i o n o f t h e h e p t y l is o c y a n a t e fr o m p a r t B was

h e a te d w i t h

a n ilin e

a n d w a te r f o r

d u c t was e x t r a c t e d w i t h p e tr o le u m r e c r y s ta lliz e d A n a ly s is 11.

gave a

8 . 5 Gm. ( 0 .0 3 3

The c i t r i c

1 0 0 .5 - 1 0 1 . 5 ° , was p r e p a r e d .

e d f o r C ggE ggO gN g:#, 6 . 2 2 .

s o lu tio n o f th e

and 6 . 4 Gm. o f a p r o d u c t , b . p .

1 8 2 . 5 ° / 2 m m ., w e re o b t a in e d .

s a l t , m .p .

fr o m c h l o r o ­

a fe w m in u t e s . e th e r ( b .p .

g i v i n g w h it e n e e d le s , m .p . 67 -

c a l c u l a t e d f o r C ^H g g O M g :N , 1 1 . 9 5 .

The p r o ­

30 - 6 0 ° )

and

0 8 .5 ° . P o u n d ;N , 1 1 * 5 4 .

The S y n t h e s is o f 5~ D i e t h y l a m in o p r o p y l Hep t y l c a r b am at e To 2 .5 8 Gm. ( 0 .1 8 0 m o le ) o f h e p t y l is o c y a n a t e f r o m

E x p e r im e n t 1 0 - B was a d d e d 1 .3 3 Gm. ( 0 .0 1 1 m o le ) o f 3 d i e t h y l a m in o - 1 - p r o p ano 1 .

The s o l u t i o n becam e warm i n

m in u te s and s t a r t e d t o

co o l in

p r o d u c t was a llo w e d t o

s ta n d o v e r n i g h t .

ta te (b .p .

w h ic h fo rm e d was f i l t e r e d , 30 - 6 0 ° )

a b o u t f i f t e e n m in u t e s .

86 °

.

The

The w h it e p r e c i p i ­

w a sh ed w i t h p e t r o le u m

and d r i e d , g i v i n g 2 * 5 5 Gm.

p r o d u c t , m .p . 8 2 -

a fe w

e th e r

( 0 .0 0 9 m o le ) o f

The y i e l d w as 93% o f t h e t h e o r e t i c a l

26 b a s e d o n S ^ d ie t h y la n iin o « * lwp r o p a n o l•

R e c ry s t a l l i z a t i o n

e t h e r g a v e w h i t e p l a t e l e t s , m *p * 9 1 * 5 w 9 5 ° • c a l c u l a t e d f o r C15 H 52 0 2 Ng :N , 1 0 * 2 9 . T he c i t r i c 12.

a c id s a l t , m .p .

fr o m

A n a ly s is *

F o u n d :N , 1 0 . 3 1 , 1 0 . 6 5 .

7 7 .5 " 6 0 . 5 ° , was p r e p a r e d *

The S y n t h e s is o f 2 - D l e t h y l a m in o e t h y l O c ty lc a r b a m a te A*

H o n a n o y l c h l o r i d e was p r e p a r e d i n

u s in g 2 5 * 0 Gm.

t h e u s u a l w ay

( 0 . 1 6 m o le ) o f n o n a n o ic a c i d and 2 4 .0 Gm.

( 0 . 2 0 m o le ) o f t h i o n y l c h l o r i d e . m o le ) o f n o n ano y 1 c h l o r i d e , b . p .

A y ie ld

o f 2 2 * 2 Gm.

( 0 .1 4

96 - 9 8 ° / 1 4 mm. was o b t a in e d

w h ic h was 8 7 .5 % o f t h e t h e o r e t i c a l b a s e d o n th e a c i d , 2 5 .0 Gm. tille d

A

sa m p le o f c o m m e r c ia l a c id c h l o r i d e was a ls o d i s ­

g iv in g

2 4 .0 Gm. o f d i s t i l l a t e

a t th e

same b o i l i n g

p o in t. B.

O c t y l is o c y a n a t e was p r e p a r e d fr o m 4 6 .0 Gm. ( 0 . 3 0

m o le ) o f n o n a n o y l c h l o r i d e s o d iu m a z id e .

and 2 2 .8 Gm.

F r a c t i o n a t i o n o f t h e r e a c t i o n m ix t u r e g a v e

2 6 .1 Gm, ( 0 . 1 7 m o le ) o f p r o d u c t b o i l i n g C.

( 0 .3 5 m o le ) o f

a t 79 - 8 4 ° .

2 - D i e t h y l am ino e t h y l o c t y lc a r b a m a t e :

A 6 . 0 Gm.

( 0 .0 3 9 m o le ) p o r t i o n o f th e a b o ve p r o d u c t w as a d d e d t o s o lu tio n in

o f 4 . 7 Gm.

( 0 . 0 4 m o le ) o f 2 - d i e t h y l am ino e t h a n o l

15 c c . o f d r y e t h e r .

A fte r

s t a n d in g f o r 24 h o u r s th e

s o l v e n t and e x c e s s a l c o h o l w e re re m o v e d i n 9 . 6 Gm.

( 0 .0 5 5 m o le ) o f p r o d u c t f o r

th e t h e o r e t ic a l. to

vacuo g iv in g

a y i e l d o f 90% b a s e d o n

The h y d r o c h lo r id e o f t h e p r o d u c t p r o v e d

b e a m orp h o u s and p u r i f i c a t i o n

The c i t r i c

a

of it

was n o t a t t e m p t e d .

a c id s a l t was made b y a d d in g a s a t u r a t e d

s o lu tio n

27. o f c itr ic

a c id i n

e t h e r , w h ic h c o n t a in e d 5% e t h a n o l ,

e th e r e a l s o lu t io n o f th e p r o d u c t. w ashed, and r e c r y s t a lliz e d

fiv e

t im e s fr o m a s o l u t i o n o f

13.

A w h ite ,

p r o d u c t , m .p . 9 4 - 9 6 ° , w as o b t a in e d .

c a lc u la te d f o r

an

The s a l t was s e p a r a t e d ,

e t h y l a c e t a t e c o n t a i n i n g 1% m e th a n o l. lin e

to

6 .0 3 .

c r y s ta l­

A n a ly s is w

F o u n d :B , 6 . 0 7 , 6 . 1 6 .

The S y n t h e s is o f 3- D I e t h y l a m in o p r o p y l O c ty lc a r b a m a te À s o l u t i o n o f 5 * 2 Gm. ( 0 * 0 4 m o le ) o f 3 - d i e t h y l a m i n o - 1 -

p ro p a n o l i n

e t h e r w as added t o

6 . 0 Gm. ( 0 .0 3 9 m o le ) o f

o c t y l is o c y a n a t e fr o m E x p e r im e n t 12 - B . a llo w e d t o

The m a t e r i a l s w e re

r e a c t f o r 24 h o u r s a f t e r w h ic h tim e t h e

e x c e s s a lc o h o l w e re re m o v e d . w e ig h e d 1 0 .4 Gm.

e t h e r an d

The r e s i d u a l c r u d e p r o d u c t

( 0 .0 3 6 m o le ) e q u iv a le n t t o

o f t h e t h e o r e t i c a l b a s e d o n t h e is o c y a n a t e .

a y ie ld

o f 92%

The c i t r i c

s a l t was p r e p a r e d a n d p u r i f i e d b y r e c r y s t a l 1 1 z in g s i x f r o m an e t h y l ac e t a t e - m e th a n o l s o l u t i o n . 8 0 .5 -

8 2 .5 ° •

It

a c id

tim e s

m e lt e d a t

A n a l y s is - c a l c u l a t e d f o r C g g H ^O g M g iN , 5 . 8 5 .

F o u n d ;N , 5 . 9 2 , 5 . 6 8 . 14.

T h e S y n t h e s is o f 2 - D im e t h y l am ino e t h y l O c ty lc a r b a m a te T h is was p r e p a r e d fr o m 3 . 7 Gm. ( 0 .0 4 1 m o le ) o f 2 - d i -

m e th y la m in o e th a n o l i n

e t h e r t o w h ic h w e re ad d e d 6.0 Gm.

( 0 .0 3 9 m o le ) o f o c t y l is o c y a n a t e . e ig h t h o u rs th e g iv in g

8 .9

Gm.

s t a n d in g f o r f o r t y -

s o lv e n t and e x c e s s a l c o h o l w e re re m o v e d ( 0 .0 3 6 m o le ) o f c r u d e p r o d u c t f o r a y i e l d

92% b a s e d o n t h e is o c y a n a t e . d is s o lv e d i n

A fte r

of

A p o r t i o n o f t h e p r o d u c t was

e t h e r and t h e a d d i t i o n o f a s o l u t i o n o f h y d r o g e n

28, c h lo r id e I n

e t h e r c a u s e d t h e f o r m a t io n o f a p r e c i p i t a t e .

T he p r e c i p i t a t e fro m

was w a sh e d w e l l a n d t h e n r e c r y s t a l l i z e d

e th y l a c e ta te f i v e

t im e s g i v i n g

in g p o in t o f 95 - 9 7 ° , N g C lîN , 9 . 9 8 . 15.

a p r o d u c t w i t h a m e lt ­

A n a ly s is » c a l c u l a t e d f o r C^gHggOg

P o u n d ;N , 9 . 8 4 ,

1 0 .2 8 .

The A t t e m p t e d S y n t h e s is o f g*» F i p e r id in o - l . 2 - P r o p a n e d io l M o n o o c ty lc a rb a m a te A b e n z e n e s o l u t i o n o f 7 .8 Gm.

is o c y a n a t e

a n d 8 . 0 Gm.

( 0 . 0 5 m o le ) o f o c t y l

( 0 . 0 6 m o le ) o f 3 - p i p e r i d i n o - 1 , 2 -

p r o p a n e d io l w as a llo w e d t o

s ta n d u n t i l t h e o d o r o f is o c y a ­

n a te h a d d is a p p e a r e d ( 1 1 ) .

B enzene a n d u n r e a c t e d s t a r t i n g

m a t e r i a l s w e re re m o v e d u s in g h e a t and vacuum a nd 1 4 * 5 Gm. ( 0 . 0 5 m o le ) o f c r u d e p r o d u c t was o b t a in e d .

The y i e l d ,

b a s e d o n t h e is o c y a n a t e , w as 60% o f t h e t h e o r e t i c a l . a t t e m p t s t o make a c r y s t a l l i z a b l e

h y d r o c h lo r id e f a i l e d .

The f r e e b a s e w as r e c o v e r e d b y n e u t r a l i z i n g c a rb o n a te , th e b .p .

e th e r. 155 -

e x tr a c tin g w ith

b .p .

w i t h 5% s o d iu m

and e v a p o r a t in g

g iv in g

a p ro d u c t,

1 6 5 ° / 3 mm. a n d a s e c o n d d i s t i l l a t i o n

6 0 °,

and t w ic e

p r o d u c t, m e ltin g

g a ve a b . p .

T h is l a t t e r p r o d u c t s o l i d i f i e d

a n d was t h e n r e c r y s t a l l i z e d 30 -

d r y in g ,

T h is r e s id u e was d i s t i l l e d

o f 159 - 1 6 4 ° / 3 mm. in g

e th e r,

th r ic e

fro m l i g r o i n , b . p .

7 7 .5 ° .

e th e r,

90 - 1 0 0 °.

The

a sa m p le

o f 3 - p l p e r i d l n o - 1 , 2 - p r o p a n e d i o l , m .p . 8 0 . 5 - 8 2 . 5 ° m e l t i n g p o i n t o f th e m ix t u r e was 72 -

o n s ta n d ­

f r o m p e t r o le u m

a t 8 2 - 8 3 * 5 ° , w as m ix e d w i t h

w as w a t e r s o lu b le w h i l e

Two

a nd t h e

The a lc o h o l

t h e p r o d u c t was w a t e r i n s o l u b l e .

29* A n a ly s is 10* 7 1 ,

c a l c u l a t e d f o r C17 H 340 3N2 :N , 8 * 9 9 .

F o u n d :N , 1 0 * 5 5 ,

The c o r r e s p o n d in g u r e a , N ,N f " d l o c t y l u r e a , c o n t a in s

9 .8 5 # N . 16.

The S y n t h e s l s o f 2 * D l e t h y l am ino e t h y l N o n y lc a r b am at e A*

D e c a n o y l C h lo r id e :

t h io n y l c h lo r id e

F ro m 7 *2 Gm.

( 0 * 0 5 8 m o le ) o f

and 9 * 6 Gm. ( 0 .0 5 6 m o le ) o f d e c a n o lc a c id ,

1 0 * 1 Gm* ( 0 . 0 5 3 m o le ) o f d e c a n o y l c h l o r i d e w e re o b t a in e d * The y i e l d , b a s e d o n d e c a n o ic a c id w as 9 5 # o f t h e t h e o r e t i c a l * B.

N o n y l Is o c y a n a te :

s o d iu m a z id e i n

To 5 * 2 Gm. ( 0 . 0 8 m o le ) o f

15 c c * o f t o lu e n e w as a d d e d 1 0 *0 G&u ( 0 * 0 5 3

m o le ) o f d e c a n o y l c h l o r i d e * t h e p r o d u c t was f i l t e r e d , d is tille d ,

b .p *

116 - 1 1 6 * 5 ° /1 5 mm*

C io H i 9 O N:N, 8 . 2 8 *

f o r th re e h o u rs ,

t o lu e n e re m o v e d and t h e p r o d u c t

o r 5 3 # y i e l d was o b t a in e d *

3 *9 Gm.

A fte r r e flu x in g

A 4 * 8 Gm* ( 0 .0 2 8 m o le )

A n a ly s is -

F o u n d :IT , 7 . 8 6 ,

c a lc u la te d f o r

7 .8 5 .

( 0 .0 2 3 m o le ) o f p r o d u c t , b . p .

R e d !s t i l l a t i o n

1 2 5 . 5 ° / 2 1 mm*

gave

A n a ly s is

o f t h i s p r o d u c t g a v e 7 .3 4 # N.