The synthesis of amino-hydroxy acids

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THE SYNTHESIS OPo•

H yd r o ly s is

o f Phen ao y 1 C yanid e ...............*

30

E*

R e d u c tio n o fo ^ -O x im in o /^ -fc e to

a c id s * . * *

Summary and C o n c lu s io n s .................. Bi b l i o g r a p h y .

4

32 44

5

FIGURES Page 1*

H y p o t h e t ic a l In te r m e d ia te s i n th e t r a n s i t i o n o f P h e n y la la n in e to E p in e p h r in e *

4

1

INTRODUCTION G e n e ra l Any s tu d y o f th e n u c le a r - s u b s t it u t e d - p h e n y ls e r in e s w o u ld be in c o m p le te w it h o u t r e fe r e n c e to t h e i r im p o r ta n t p o s i t i o n betw een th e am ino a c id s n o r m a lly o c c u r r in g in th e body and e p in e p h r in e .

E s p e c ia lly i s

th is

tr u e

o f th e 3 , 4 - d ih y d r o x y -

p h e n y l- s u b s t it u t e d - a c id , w h ic h has lo n g been s u s p e c te d o f b e in g a p r e c u r s o r o f th e a d re n a l m e d u lla horm one.

Among th e

t h e o r ie s advanced f o r th e c o n v e r s io n o f amino a c id s im p o r ta n t p r o d u c t ,

is

to t h is

th e one b elo w w h ic h i s r e p r e s e n t a t iv e

o f th o s e p r e s e n te d . (6 5 )

-O -H

O-H "■'Yo-

rO -H n 'Y - o- h

h

V,

V,

•O-C-GOOH

.C-C-COOH

-C-C-COOH t T Bf it

f

t

3f H

T y ro s in e

3 * 4 - d ih y d r o x y p h e n y la la n in e ^ -0 -H ^ V y O -H

\y

l

3 , 4 - d ih y d r o x y p h e n y lN - m e th y la la n in e • O-H W o -H

T

-C-C-COOH * i i ? iy - 9 H 3>4 - d ih y d ro x y p h e n y lN-me t h y I s er in e

E p in e p h r in e

2

A ls o th e

th e o r y o f Rosenmund and D o r n s a ft (2 6 ) o u t lin e d

b e lo w , f a r th e b i o l o g i c a l f o r m a t io n o f e p in e p h r in e p o s t u la t e s t h e f o r m a t io n o f f t - ( 3 , 4 - d ih y d r o x y p h e n y l) s e r in e as an i n t e r ­ m e d ia te w h ic h i s a s ta r tin g

o b ta in e d fr o m 3 , 4 - d ih y d r o x y p h e n y la la n in e as

m a t e r ia l.

-O -H

vn^O-H

r \v o -H

rfv w O -H O x id a t i on^ T » -C-C-COOH i »

- CgHggCHgCOGEt t

HOI

0

R. M y e r, T o g e l (4 1 ) r e a c te d "b en zo yl "bromide w i t h monobrom e t h y l a c e ta te i n

th e p re s e n c e o f magnesium t o o b t a in e t h y l

"b e n z o y la e e ta te *

A m o d i f i c a t io n o f th e G rig n a rd

S y n th e s is *

Thus t h e r e were a v a ila b le

numerous m ethods f o r th e p r e p a r a t io n

o f e t h y l b e n z o y la e e ta te *

O f th e s e th e C la is e n C o n d e n s a tio n

app e a re d to p ro m is e th e b e s t r e s u l t s .

A m ethod based on t h i s

r e a c t io n was o b ta in e d fr o m th e Eastm an Kodak Co* ( 3 6 ) . was th e one use d i n

T h is

th e e x p e r im e n ta l w o rk d e s c rib e d l a t e r *

M ethods had been s e le c te d

th u s f a r f o r th e p r e p a r a t io n o f

th e e t h y l e s te r s o f th e k e to a c id s and f o r t h e i r n i t r o s a t i o n . H ow ever, on r e v ie w in g th e r e d u c t io n o f th e s e

- k e to -e < -o x -

im in o - a c id s r a t h e r c o n t r a d ic t o r y r e s u l t s w e re fo u n d . and H a r r in g t o n g lu ta r ic

(2 5 ) r e p o r te d

a c id to

R a n d a ll

th e r e d u c tio n o f o C - o x im in o - ^ - k e to -

th e c o rre s p o n d in g h y d ro x y amino a e id u s in g

p a lla d in iz e d c h a r c o a l and a lc o h o lic HC1 as the s o lv e n t * e v e r , M c llw a in and R ic h a rd s o n (4 3 ), u s in g s o lv e n t ,

How­

the same c a t a l y s t and

c o u ld n o t get th e r e d u c t io n beyond th e k e to s ta g e .

When t h is c? C -a m in o -z^-ke to a e id was is o la t e d to h y d ro g e n a tio n

and a g a in s u b m itte d

th e am ino a c id was is o la t e d .

A d k in s and Reeve

(4 4 ) u s in g Raney n i c k e l on < ^ - c u tim in o - ^ - k e t o b u t y r ie

e s te r

21

c o u ld n o t o b t a in th e h y d ro x y amino a c id * v e r tin g

the o x im in o t o

How ever, by f i r s t

con­

th e e t h y l e th e r and th e n s u b m ittin g

it

t o c a t a l y t i c r e d u c t io n w i t h Haney n i c k e l u s in g a lc o h o lic HG1 as th e s o lv e n t t h e y w e re a b le to o b t a in a c id .

th e d -a m i no

-h y d ro x y

Thus th e o u t lo o k a t t h i s p o i n t was n o t to o p r o m is in g ,

A f t e r r e fe r e n c e t o t h e sm o o th r e d u c t io n o f th e is o n it r o s o a c e t ophenones and p ro p io p h e n o n e s as r e p o r te d b y H a rtu n g and Munch (2 7 ) i t

was d e c id e d

to a tte m p t th e r e d u c t io n i n

th e same manner

u s in g P a lla d iu m c h lo r id e on l o r i t e as the

c a t a ly s t and a b s o lu te

a lc o h o l a t le a s t 2 H i n h y d ro g e n c h lo r id e

as th e s o lv e n t .

T h is

p ro v e d so s u c c e s s f u l t h a t no f u r t h e r changes w ere needed i n

t h is

s te p * These r e s u l t s

e n couraged th e b e l i e f t h a t any in te r m e d ia te

o f the s t r u c t u r e Ar,CO .C,CQ GEt may be s i m i l a r l y h y d ro g e n a te d t o HQH th e c o r re s p o n d in g Ar,CHOH.CH*CQOEt,

p a r e n tly ,

If

th is

th e a v a i l a b i l i t y o f t h e / ^ - k e t o

is

e s te r s

Ar,GO*CHgCOOEt, w o u ld p ro v e th e m o st d i f f i c u l t

t r u e , th e n a p -

o f the

typ e

p ro b le m i n

th is

i n v e s t i g a t io n * The e t h y l e s t e r o f b e n z o ic a c id in

is

r e a d i l y a v a ila b le

th e C la is e n C o n d e n s a tio n , b u t th e e s te rs

cf n u c le a r - s u b s t i­

t u t e d b e n z o ic a c id a re n o t e a s ily o b ta in a b le * was d e c id e d to f i n d f i r s t a m ethod f o r

w h ic h , a f t e r c a r e f u l c o n s id er a t io n , g a t io n is

th e f o l l o w i n g :

T h e r e fo r e , i t

s y n th e s iz in g

e t h y l n u c le a r - s u b s t i t u t e d -b e n zo y la c s ta te s *

f o r use

th e se

The p ro c e d u re

seemed t o m e r it i n v e s t i ­

Ar.CO.OHgGOOBt#

The F r i e d e l - C r a f t s y n th e s is p r o v id e s good y ie ld s a lfc o x y , and h a lo g e n - n u c le a r - s u b s t it u t e d c h lo r id e i n

b o th la b o r a t o r y

of a lk y l,

d e r i v a t iv e s

(45 - 4 6 ) and in d u s t r y

o f phenaoyl (47 - 4 8 )*

F r ie s and P f a f f e n d o r f (4 9 ) d e s c r ib e good m ethods f o r a r a t io n in

o f o - and p - h y d r o x y p h e n a c y l c h lo r id e ,

O rg a n ic S y n th e s is

y ie ld s

(5 0 ) and v a r ie d

to g iv e b e t t e r

(4 2 ) was a v a ila b le ,

T h e r e fo r e , no d i f f i c u l t y was a n t ic ip a t e d i n s t a r t i n g m a t e r ia ls needed f a r t h is

A method g iv e n

s lig h tly

o f 3 ,4 - d ih y d r o x y p h e n a c y l c h lo r id e

o b t a in in g th e

r e a c t io n *

There a re many m ethods o f p r e p a r in g n i t r i l e s ,

b u t fro m th e

p h e n a c y l c h lo r id e t h e r e i s .o n ly one of a n y v a lu e * w o rh o f G a b r e il and ICschenbaeh (5 1 ) and O b re Tg ia c o n s is t s

o f t r e a t in g

( in

d ilu tio n

t o th e f o llo w in g

KCJX ' ■ ---------► A r* C0*CK2CH*XCH

e q u a tio n :

-h K O I.

th e cyanoleetone re m a in s i n s o l u t i o n on

w it h w a te r and th e u n re a c te d m a te r ia ls

by f i l t r a t i o n *

T h is c le a r s o l u t i o n

w i t h c h a r c o a l and f i l t e r e d

is

a r e s e p a ra te d

th e n p e r m itte d

by s u c tio n *

I t is

i c e c o ld

w h ic h fo rm a re f i l t e r e d a lc o h o l and d r ie d .

o ff*

to sta n d

th e n re n d e re d

a c id w i t h d i l u t e h y d r o c h lo r ic a c id and th e c r y s t a ls n itr ile

and m a in ­

o f 50 ° C. f o r ab out one h a lf h o u r ) *

The r e a c t io n p ro c e e d s a c c o rd in g

The p o ta s s iu m s a l t o f

the

(5 2 ) w h ic h

a 5Q^> a lc o h o l s o lu t io n

a t a te m p e ra tu re

Ar*C G *C H gC l +

T h is i s

th e p h e n a c y l h a lid e w it h so d iu m c y a n id e

u n d e r p ro p e r c o n d it io n s ta in in g t h is

th e p re p ­

o f th e

These a re washed w it h

The a u th o rs

r e p o r t y ie ld s up

23

to

60°/o by t h i s m ethod*

ita te

A fe w

changes were in tr o d u c e d

o b t a in in g a p u re p r o d u c t;

th e s e a r e r e p o r te d i n

to f a c i l ­ th e

ex­

p e r im e n t a l p o r t io n * The f i n a l s te p to be s tu d ie d was th e h y d r o ly s is tr ile *

of

th e n i -

Here th e r e was a c h o ic e o f tw o a p p ro a c h e s ; th e n i t r i l e

c o u ld be h y d r o ly z e d t o

th e a c id , o r d i r e c t l y

t o th e e s t e r .

P in n e r (5 4 ) i n 1883 had shown t h a t n i t r i l e s ca n be h y d r o ly z e d to

th e im in o e th e r h y d r o c h lo r id e b y t r e a t i n g i t w it h a lc o h o lic

HC1.

P . P* T . Sah (5 6 ) has shown t h a t the im in o e th e r c o u ld

be changed to

th e o r th o e s t e r by f u r t h e r

tr e a tm e n t i n

a b s o lu te

a lc o h o l and e t h e r i n th e p re s e n c e o f h y d ro g e n c h lo r id e . n a lly H a lle r

F i­

(5 5 ) has shown t h a t b e n z o y l a c e t o - n i t r i l e can be

h y d r o ly z e d to th e im in o e th e r h y d r o c h lo r id e b y t r e a t i n g

i t w ith

a l c o h o l i c HC1 and th e n t o

th e e s te r by w arm ing th e s a l t w it h

d i l u t e h y d r o c h lo r ic a c id .

O th e r w o rk e rs who have succeeded

in

th e h y d r o ly s i s

o f th e n i t r i l e s

by t h i s

P f e i f f e r and M a tt on (5 7 ) and P. P f e i f f e r , and W i l l y A lf u s s p le t e

The la s t

s tru c tu re

or i f

it

S in c e

They showed t h a t

was rem oved fro m th e

b y one c a rb o n atom th e h y d r o ly s is

v e ry w e ll.

on th e p h e n y l r i n g ,

on th e h y d r o ly s i s .

th e r i n g was u n s u b s t it u t e d

n itr ile

Irm a E n g e lh a r d t

g ro u p o f w o rk e rs made a com­

s tu d y o f th e e f f e c t s o f s u b s t i t u t i o n

and c i s - t r a n s if

(5 3 ).

m ethod w e re P.

to

th e e s te r w o rked

th e compounds to be h y d ro ly z e d i n

w e re so c o n s tr u c te d , i t

was j u s t i f i a b l y

h y d r o ly s i s w o u ld ta k e p la c e r a th e r

b e lie v e d t h a t

e a s ily .

and H. S z y d lo w s k y (5 8 ) o b ta in e d good r e s u lt s o f th e a l k y l n i t r i l e s

t h i s s tu d y th is

F i n a l l y 1 . S p e ig e l in

the h y d r o ly s is

u s in g a lc o h o l and s u lp h u r ic a c id .

Thus

24

t h e r e seemed to be s u f f i c i e n t p r e c e d e n t to w a r r a n t th e hope th a t

th e d e s ir e d

e s te r s c o u ld be o b ta in e d d i r e c t l y .

A im f o r r e s e a r c h :

T h is p ro b le m was u n d e rta k e n w it h th r e e

p u rp o s e s i n m in d , v i z . f i r s t , y ^ - k e to f

t o d e te rm in e w h e th e r c ^ - o x im in o -

e s t e r c a n be c o n n e c te d i n t o

- h y d r o x y a c id s o r t h e i r e s t e r s ;

th e c o rre s p o n d in g o^-am ino

second,

f a c t o r y p r o c e d u r e f o r th e s y n th e s is

to

d e v e lo p a s a t i s ­

o f^ -k e to

a c id s o r e s te rs

fro m w h ic h th e o ^ - o x im in Q - /^ - k e to e s te r s may be c o n v e n ie n tly o b ta in e d ; t h i r d ,

t o make a v a ila b le

a s e r ie s o f n u c le a r sub­

s t i t u t e d ^ - p h e n y l s e r in e s f o r p h y s io lo g ic a l cm p h a rm a c o lo g ic a l e x a m in a tio n . M ethod o f A c c o m p lis h in g t h i s e n d : p ro p o s e d , i n s u b s ta n c e ,

(The p ro g ra m as o r i g i n a l l y

re a d s as f o l l o w s :

The e t h y l e s te r o f

b e n z o y la c e tic a c id w i l l f i r s t be p re p a re d by th e C la is e n r e ­ a c t io n .

T h is w i l l th e n be n it r o s a t e d

and re d u c e d .

The p h y s ­

i c a l and c h e m ic a l p r o p e r t ie s o f th e in te r m e d ia te s w i l l be s t u d ie d ,

and f i n a l l y

s e r in e and i t s

t h e e s t e r w i l l be h y d r o ly z e d t o p h e n y l-

p r o p e r t ie s

compared to

th o s e d e s c rib e d by

E rle n m e y e r (30 - 31) and Rosenmund and D orns a f t a c id .

If

th e s e e x p e rim e n ts p ro v e s u c c e s s fu l,

w i l l be p re p a re d b y h y d r o ly s is te rm e d ia te s com pared to te s ts

(£ 6 ) f o r th a t

th e same compound

o f p h e n a c y l c y a n id e and th e i n ­

tho se a b o ve .

If

th e s e w a r r a n t, a t ­

w i l l th e n be made t o p r e p a re th e n u c le a r - s u b s t it u t e d -

a c id s a c c o r d in g t o

th e r e a c t io n s in d ic a t e d .

25

EXPERIMENTAL

G e ne ra l A l l te m p e ra tu re s r e c o r d e d , u n le s s o th e rw is e s p e c if ie d , a re u n c o r r e c te d .

F i n a l te m p e ra tu re s r e p o r t e d , when c o r r e c t e d ,

a re

d e s ig n a te d by " ( c o r . ) ” and w ere d e te rm in e d by A n s c h u tz " s te m im m e rs io n " th e rm o m e te rs * When " a b s o lu te a lc o h o l" was u s e d r

it

was p re p a re d fro m com­

m e r c ia l a b s o lu te a lc o h o l (a b o u t 97$ e t h y l a lc o h o l) .

Ten l i t e r s

o f t h i s was r e f l u x e d a b o u t t w e n t y - f o u r h o u rs w it h th r e e pounds o f f r e s h , u n s la k e d was d i s t i l l e d

lim e , b ro k e n i n t o s m a ll p ie c e s .

o f f and

th e o p e r a tio n s re p e a te d ,

th e second d i s t i l l a t i o n

The a lc o h o l

th e p r o d u c t fro m

b e in g u se d .

A n a ly s e s f o r n it r o g e n w e re c a r r ie d

o u t u s in g

th e K j e l d a h l-

G unning m e th o d . S y n th e s e s P r e p a r a t io n o f e t h y l b e n z o y la c e ta te .

(A c c o rd in g

to C la is e n ’ s

Met h o d ) . C6H5C00Et

+

2Na

C6H5 9:CHCOOEt + Q-Na

+ CHgCQOEt ----- * C6 H59 :CHC00Et O-Na HC1 ----- ► G6H^C.CHg.GOOEt 0

1-

NaOEt

+

+ N aCl

- I I n a 500 cc th r e e - n e c k f l a s k

to w h ic h was a tta c h e d a r e f l u x

c o n d e n s e r, and a m e c h a n ic a l s t i r r e r , was p la c e d 75 g .

{-§- m o le )

o f e t h y l b e n z o a te ( p r e v io u s ly d r ie d f o r 24 h o u rs over a n hydro us

26

c a lc iu m c h l o r id e and d i s t i l l e d o f a b s o lu te e t h y l a c e ta te

a t 197° C .) and 11 g .

( l / 8 m o le )

( d r ie d o v e r a n h yd ro u s c a lc iu m c h lo r id e

f o r 24 h o u rs and r e d i s t i l l e d ,

a t 7 7 -7 9 ° C . )

The s o lu ­

t i o n was h e a te d on a w a te r b a th and th e te m p e ra tu re

m a in ta in e d

b e tw e e n 75 a n d 8 0 ° C, and t o

b o ilin g

i t was added 1 1 .5 g .

so d iu m m e ta l c u t i n t h i n s l i c e s . most a l l th e s o d iu m had r e a c te d g.

T h is was, s t i r r e d

u n t il a l­

(a b o u t two h o u r s ) .

Then 5 .5

( l / l 6 m o le ) m ore o f e t h y l a c e ta te and 5 . 7 g .

so d iu m w e re added and s t i r r i n g A fte r

t h i s a f i n a l 5 .5 g .

( J m ole)

of

c o n tin u e d f o r a b o u t two h o u rs .

( l / l 6 m o le ) e t h y l a c e ta te and 5 .7 g .

( i m o le ) s o d iu m w e re added and s t i r r i n g

h o u rs a f t e r

( i m ole) o f

c o n tin u e d f o r f i f t e e n

a l l had r e a c te d .

The r e a c t io n m ix tu r e was now c o o le d and poure d th ro u g h a w ir e gauze i n t o

a beaker c o n t a in in g

c o n c e n tr a te d h y d r o c h lo r ic

a c id .

c ra cke d ic e and 500 ce o f

T h is was s t i r r e d

u n t i l th e

r e a c t io n was c o m p le te , when a he a vy o i l s e p a ra te d o u t. o ily

la y e r was s e p a ra te d and th e aqueous la y e r

e x tra c te d w it h

tw o s u c c e s s iv e p o r t io n s o f 150 ce each o f benzene. e x t r a c t s w ere added to th e

The benzene

o i l and the whole n e u t r a liz e d w it h

a s o l u t i o n o f s o d iu m b ic a r b o n a te . a n h y d ro u s so d iu m s u lp h a t e .

The

T h is was th e n d r ie d w it h

I t was th e n p la c e d i n

a d is tillin g

f l a s k and th e benzene removed u n d e r th e re du ce d p re s s u re o f a w a te r pump; fro m

th e r e s id u e a l l d i s t i l l i n g

10 mm. p re s s u re was c o l l e c t e d .

I n t h is

above 140° G. a t

fir s t

r u n th e y ie ld

was n e g l i g i b l e due to d e c o m p o s itio n on d i s t i l l a t i o n .

27

- II In t iiis

case th e e t h y l "benzoate used was made in th e

t o i y , b y r e f l u x i n g b e n z o y l c h lo r id e

w it h e t h y l a lc o h o l u n t i l

h y d ro g e n c h lo r id e no lo n g e r came o f f * d is tille d

and th e f r a c t i o n

la b o r a -

The p r o d u c t was th e n

com ing over a t 197° G. used*

was d r ie d o v e r a n h y d ro u s c a lc iu m c h lo r id e

T h is

and r e d i s t i l l e d .

E t h y l a c e ta te was d r ie d o ve r a n h yd ro u s c a lc iu m c h lo r id e and th a t b o ilin g

7 7 -7 8 ° G* was u s e d .

The same q u a n t it ie s

method as i n

#1 w e re used e x c e p t t h a t a f t e r

and

th e f i n a l amount

o f so d iu m had been added th e te m p e ra tu re was p e r m it te d to s lo w ly and m a in ta in e d a t 95° G. f o r tw e lv e h o u rs * same p ro c e e d u re a s o u t lin e d above was f o llo w e d . th e y i e l d was 61 Gms. c a lc u la t e d

r is e

Then th e In t h i s

case

o r 6 3 .5 °/o o f cru d e e t h y l b e n z o y la c e ta te

on the am ount o f e t h y l b e n zo a te u s e d . - I ll -

The same m ethod and q u a n t it ie s w e re used as i n th a t

th e te m p e ra tu re was p e r m itte d

I except

to r i s e above th e m e ltin g

p o i n t o f s o d iu m b e fo re a ny e t h y l a c e ta te was added. l e n t r e a c t io n to o k p la c e , w h ic h was p e rm itte d no e t h y l a c e ta te was add e d. t r e a t e d as i n s o lid

to c o n tin u e

and

A f t e r c o m p le tio n th e p ro d u c t was

I and I I and d i s t i l l e d .

and th o u g h i t

A v io ­

The d i s t i l l a t e

was a

had a d e f i n i t e o d o r o f b e n z a ld e h y d e ,

th e

m a jo r p o r t i o n p ro ve d t o be b e n z o ic a c id m e ltin g p o in t 121-

122 °.

£8

H itr o s a tio n

o f e t h y l b e n z o y la c e ta t e .

The r e a c t io n p ro ce e d s

as f o l l o w s :

G6H5SCH£ C 00Et 0

+

GH3GHGH 0.11:0

HOI

I n a th r e e - n e c k f la s k : , f i t t e d s u i t a b l e h y d ro g e n c h lo r id e e t h y l b e n z o y la c e ta t e .

*

CgHgfj-g-COOEt 0 H . OH

w it h a r e f l u x condenser and a

tr a p was p la c e d 50 g .

An i n l e t

d r o p p in g f u n n e l w e re a tta c h e d #

+ CHgGHOHGHg

( .2 6 m o le )

f o r h y d ro g e n c h lo r id e ,

The f l a s k was p la c e d on a

c o ld w a te r b a th to p r e v e n t o v e r h e a t in g .

H ydrogen c h lo r id e

was passed in f o r a b o u t tw e n ty m in u te s and th e n 22 g . o f is o p r o p y l n i t r i t e

was drop pe d i n .

The r a p i d i t y

was d e te rm in e d by th e c o lo r and e o n t r o lle d n e v e r became d a rk e r th a n a l i g h t orange# d ro g e n c h lo r id e was c o n tin u e d a f t e r u n t i l th e c o l o r r e tu r n e d q u ir e d tw e n ty t o t h i r t y in a d i s t i l l i n g p re s s u re . Y ie ld

fla s k

to

(J m ole)

o f a d d it io n

so t h a t th e c o lo r The passage o f hy­

th e a d d it io n o f th e n i t r i t e

l i g h t y e llo w #

m in u te s .

and a

T h is u s u a l l y r e ­

The m ix tu r e was th e n p la c e d

and the a lc o h o l removed un d er re d u c e d

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

fro m h o t

to lu e n e .

was 4 8 .9 g . o r 85$ m e ltin g p o in t 1 1 7 .5 to 1 1 8 .5 ° C. ( c o r . )

When th e n i t r o s a t i o n e x p e rim e n t was re p e a te d and th e c o n d i­ t io n s it

and p r o p o r t io n s

gave a y i e l d

o f re a g e n ts u sed , as d e s c rib e d above,

of 51 g . o f is o n it r o s o

in g p o in t 1 1 7 .5 t o 1 1 8 .5 ° G. ( c o r . )

compound o r 8 8 .7 $ m e lt ­

A n a ly s is f o r

n it r o g e n

gave th e s e r e s u l t s : Cl f t i )4W# C a lc u la te d H, 6 .3 3 $ : fo und M, 6 .3 5 $ and 6 .2 9 $ .

29

P re p a r a t io n o f p h e n a c y l c h l o r i d e . n e c k , ro u n d -b o tto m f l a s k , f i t t e d s tir r e r ,

a s e p a r a t o r y f u n n e l,

n e c te d t o a gas a b s o r p t io n

w it h

In a 1 l i t e r ,

th re e -

a s e a le d m e c h a n ic a l

and a r e f l u x co n d e n ser c o n ­

t r a p , w ere p la c e d 102 g ,

m o le ) a n h y d ro u s a llu m in u m c h lo r id e

( 0 .7 7

and 265 cc b e nzen e.

Then

5 3 .1 cc ( 0 .7 0 m o le ) c h lo r a c e t y l c h lo r id e was a llo w e d to d ro p in

d u rin g

th e c o u rs e o f a b o u t one h a l f h o u r.

A f t e r a l l th e

c h l o r a c e t y l c h l o r i d e had been added th e r e a c t io n m ix tu re was r e f lu x e d

o n a w a te r b a th u n t i l e v o lu t io n o f h yd ro g e n c h lo r id e

had c e a s e d .

Then th e m ix tu r e

upon a m ix tu r e o f e q u a l p a r t s h y d r o c h lo r ic a c id .

was a llo w e d to c o o l and p o u re d o f ic e w a te r and c o n c e n tra te d

The o r g a n ic la y e r was th e n s e p a ra te d and

washed w i t h w a te r , and d r ie d w it h a n h yd ro u s c a lc iu m c h lo r id e . The e xce ss benzene was removed by d i s t i l l a t i o n b a th and t h e r e s id u e d i s t i l l e d p ro d u c t d i s t i l l i n g r e d is tille d .

on a w a te r

u n d e r re d u ce d p r e s s u r e .

The

a t 1 2 0 -1 2 5 ° G. a t 4 mm o f p re s s u re was

Y i e l d 8 0 .5 g . o r 7 4?/o: m e lt in g p o in t 57 t o 5 8 ° G.

P r e p a r a t io n o f p h e n a c y l c y a n id e .

The re a c t io n p ro c e e d s

as f o l l o w s : C6H5C0CH2C1 + T h i r t y grams

N a C H -----------------» ( l/5

m o le )

C6 H6C0CHgCN

+ U aCl

c f p h e n a c y l c h lo r id e was d is s o lv e d

i n 90 c c o f a lc o h o l i n a 50 0 cc bea ker a t a te m p e ra tu re o f 4 0 ° C.

I n a s e p a ra te

was d is s o lv e d

in

250 c c beaker 30 grams o f so d iu m c y a n id e

90 cc w a te r .

T h is was added to

s o l u t i o n and s t i r r e d u n t i l a l l d is s o lv e d .

th e above

The te m p e ra tu re

was th e n m a in ta in e d a t 5 0 ° G. f o r a bo ut a h a l f h o u r .

A fte r

th is

coH

w a te r was added u n t i l no more p r e c i p i t a t i o n was

n o t ic e d *

The c r y s t a l s w e re a llo w e d to

t e r e d on a s u c t io n f i l t e r d ilu te to tle

h y d r o c h lo r ic

litm u s .

u n t i l c le a r .

s e ttle

and th e n f i l ­

Then s u f f i c i e n t

a c id was added to make th e s o lu t io n a c id

The c r y s t a l s w h ic h fo rm e d w ere p e r m itte d

and f i l t e r e d

o ff.

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

to s e t ­

was d is s o lv e d i n a

m inim um o f w a te r to w h ic h had been added an amount o f sodium c y a n id e e q u a l t o added 1 g .

2 4 .5 g .

th e c r y s t a l s .

o f H o r i t e and f i l t e r e d

th e f i l t r a t e a c id .

th e w e ig h t o f

made a c id

To t h i s was

on a s u c tio n f i l t e r

and

to lit m u s w it h d i l u t e h y d r o c h lo r ic

The c r y s t a l s w e re f i l t e r e d

o f f and d r ie d .

T h is was th e n ta k e n up i n b o i l i n g

W eight

60d jo a lc o h o l 3 g .

o f H o r i t e added and b o ile d f o r a b o u t f i f t e e n m in u te s . was f i l t e r e d

w h ile h o t and set i n

f o r a b o u t two h o u rs . w i t h c o ld d i l u t e

T his

an ic e c h e s t and c o o le d

The c r y s t a l s w ere f i l t e r e d

a lc o h o l and d r ie d .

o f f , washed

Y i e l d 1 7 .5 g . or 6 1 .8 $

M e lt in g p o i n t 79° G. R e p e t it io n o f the e x p e rim e n t ab ove , u s in g

th e c o n d itio n s

and p r o p o r t io n s o f re a g e n ts d e s c rib e d above gave y ie ld s p h e n a c y l c y a n id e , v a r y ir g

of

fro m 55 to 65 p e r c e n t.

R e c r y s t a liz a t io n o f th e p r o d u c t fro m a lc o h o l gave c r y s t a ls m e lt in g 8 0 ° C.

(u n c o r* )

H y d r o ly s i s o f p h e n a c y l c y a n id e .

The r e a c t io n p ro ce e d s

as f o l lo w s : C6H5CQCH2CH

t- GHgGHgOH ( a b s o lu te )

+• HC1

--------------- >

31

-T tr

xx J lf| 1

° 6 H5 C0QH2 C Z o E t

+

H2 °

>C6 H5 C0CH2 C 0 0 E t +

H^Cl

I n a g la s s s to p p e re d s e p a r a to r y f u n n e l was p la c e d 150 cc a b s o lu te a lc o h o l s a tu r a te d w it h h y d ro g e n c h lo r id e * was d is s o lv e d 15 g*

( * 1 m o le ) p h e n a c y l c y a n id e and the s o lu ­

t i o n s e t a s id e f o r f i v e

days i n

w h ic h fo rm e d w e re f i l t e r e d w ere r e d is s o lv e d c h lo r ic

c o o l.

o f f on a s u c t io n f i l t e r .

A c le a r c o lo r le s s l i q u i d

a lc o h o l,

fro m th e m o th e r

was th e n e v a p o ra te d , m inimum o f w a te r ,

The c r y s t a ls

liq u o r

of

These

5 ce o f d i l u t e h y d ro ­

th e s o l u t i o n b r o u g h t to b o i l i n g

low ed t o

s e t t le d

and a l ­

o u t.

The

th e o r i g i n a l h y d r o ly s i s ,

the r e s u l t i n g c r y s t a l s d is s o lv e d i n

a

10 ce o f d i l u t e h y d r o c h lo r ic a c id added

and b r o u g h t to b o i l i n g . liq u id

a c o o l p la c e .

i n a minimum o f w a te r ,

a c id add e d ,

In t h i s

s e t t le d o u t.

In t h i s

The two o i l y

case a ls o a c le a r c o lo r le s s la y e r s w e re com bined and

th e tw o aqueous p o r t io n s e x t r a c te d w i t h e th e r and th e o i l s and e t h e r e a l e x t r a c t s com bined and d r ie d w it h so d iu m s u lp h a t e .

anhydrous

The e th e r was removed by means o f a c u r ­

r e n t o f a i r u n t i l th e o d o r o f e th e r was no lo n g e r o b s e rv e d . The r e s i d u a l

liq u id

s u s p e c te d o f b e in g cru d e e t h y l ben­

z o y la c e ta te w e ig h e d 10 g .

Y ie ld o f c ru d e p r o d u c t 52 p e r c e n t .

A r e p e t i t i o n o f th e above h y d r o ly s is was 25 g . o f phen­ a c y l c y a n id e gave 1 5 .5 . g .

of p ro d u c t (s u s p e c te d o f b e in g

c ru d e e t h y l b e n z o y la c e ta te ) y i e l d

47J&.

32

N i t r o s a t i o n o f e t h y l b e n z o y la c e ta te o b ta in e d fro m th e n itr ile ;

IQ gram s o f th e p r o d u c t o b ta in e d by h y d r o ly s is o f

p h e n a c y l c y a n id e was n it r o s a t e d as a lr e a d y d e s c rib e d u n d e r n i t r o s a t i o n o f e t h y l b e n z o y la c e ta te .

From t h i s was o b ta in e d

7 gram s o f p r o d u c t w h ic h on p u r i f i c a t i o n m e lte d a t 117*5 to 1 1 8 *5 ° G* ( c o r * ) th e

A n a ly s is :

fo r m u la

is

H itr o g e n

c o n te n t c a lc u la t e d on

6*33$: fo u n d jff 6 *3 3$ and 6 .3 1 $ .

T h is p r o d u c t m ixed w L th th e is o n it r o s o compound o b ta in e d by n i t r o s a t i o n o f e t h y l b e n z o y la c e ta te p u rch a se d fr o m E a s t­ man K odak Company showed no s i g n i f i c a n t lo w e r in g o f th e m e lt in g p o i n t .

She m ix tu r e s o fte n e d a t 116° and was com­

p l e t e l y m e lte d a t 1 1 7 ° G* ( u n c o r * } S h is lo o k e d l i k e

s a t i s f a c t o r y e v id e n c e t h a t b o th th e s e

compounds w ere i d e n t i c a l . R e d u c tio n o f p r o p io n a t e : c h lo r id e tille d

oC - i s o n i t r o s o

- p h e n y l / f f -k e t o e t h y l

The c a t a ly s t was p re p a re d .3 g . o f p a lla d iu m

and 3 g . o f M o r it e w e re added t o 100 cc o f d i s ­

w a te r and shaken on a h y d ro g e n a to r.

69 cc o f h y d ro g e n *

T h is was f i l t e r e d

T h is a d so rb e d

on a s u c t io n f i l t e r

and d r ie d * I n a 250 ce r o u n d - b o tto m f l a s k w ere p la c e d 10 g . - is o n itr o s o

- p h e n y l^ - k e to

a lc o h o l, 10 g . h y d ro g e n c h lo r id e above.

( l / 2 2 m o le )

e t h y l p r o p io n a te , 100 cc o f and th e c a t a ly s t d e s c rib e d

T h is was a tta c h e d to th e h y d ro g e n a to r and shaken

u n t i l no f u r t h e r h y d ro g e n was ta k e n up (a b o u t two h o u rs and tw e n ty - fiv e

m in u te s ) .

3350 cc o f h yd ro g e n w ere a b s o rb e d *

T h e o r e t ic a l am ount was 3040 c c .

A f t e r h y d ro g e n a tio n , th e

33

above m ix t u r e was b ro u g h t to b o i l i n g o n a w a te r b a th and s u f f i c i e n t b o i l i n g w a te r added to b r in g th e e t h y l e s te r o f p h e n y ls e r in e i n t o s o l u t i o n and th e m ix tu r e was f i l t e r e d a s u c t io n f i l t e r w h ile h o t#

T h is c le a r s o lu t io n was s e t i n

an ic e c h e s t f o r a b o u t t h r e e h o u rs * c r y s t a l s w ere f i l t e r e d d ilu te

a lc o h o l.

on

The r e s u l t i n g w h ite

o f f and r e o r y s t a l l i z e d fr o m b o ilin g

Y i e l d 8 g* 7 2 $.

R e p e t it io n o f th e above r e d u c t io n gave y ie ld s v a r y in g b e tw e e n 8 8 *4 and 9 3 *6 $ * A n a ly s is :

N it r o g e n c o n t e n t c a lc u la t e d on th e fo rm u la

C11H16N03 ° 1 i s

5 * 73$ :

T h is compound i s c o h o l.

M e lt in g p o in t 162° to 165° C* ( c o r . )

fo u n d N, 5 .7 1 $ and 5 .6 3 $ .

s o lu b le i n w a t e r , n o t so s o lu b le i n a l ­

An aqueous s o l u t i o n i s

o f ammonium h y d ro x y d e .

p r e c ip ita te d

On s t a n d in g ,

a c id in s o lu b le p r e c i p i t a t e ,

on th e a d d it io n

t h i s m ix tu re

g iv e s no

and shows no d is c o l o r a t i o n

(no

p y r a z in e fo rm e d th u s show ing th e absence o f a k e to n e ) . P r e p a r a t io n e th y l e s te r: d is s o lv e d i n

o f p h e n y ls e r in e fro m th e h y d r o c h lo r id e o f th e Ten gram s ( l / 2 4 m ole ) o f th e e t h y l e s te r was

a m inim um o f w a te r .

S u f f i c i e n t 10$ s o l u t i o n

o f s o d iu m h y d ro x id e was added t o r e n d e r i t

b a s ic

to lit m u s .

T h is was th e n warmed a b o u t t e n m in u te s , a f t e r a l l had d i s ­ s o lv e d .

The s o l u t i o n was th e n n e u t r a liz e d w it h c o n c e n tra te d

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

( c o n c e n tra te d a c id was used to p r e v e n t

to o g r e a t in c r e a s e i n th e volume o f l i q u i d ) . fu lly

I t was c a re ­

b r o u g h t to n e u t r a l p o in t w it h ammonium h y d ro x id e and

an e q u a l vo lu m e o f a lc o h o l adde d.

This was th e n c o o le d i n an

34

i c e c h e s t f o r a b o u t one h o u r and th e w h ite c r y s t a l s s e r in e f i l t e r e d

o f f and w ashed w ith 95^ a lc o h o l#

th e n washed w it h h o u rs * e v e r,

o f p h e n y l­

These w ere

e th e r and d r ie d o v e r s u lp h u r ic a c id f o r £4

M e lt in g p o in t 188® to 19£° C wi t h d e c o m p o s itio n #

How­

th e y w e re exposed f o r a b o u t a n h o u r b e fo r e th e n e x t m e lt­

in g p o i n t was ru n *

T h is showed 184° t o 188° C. ( p r o b a b ly due

to a b s o r p t io n o f m o is t u r e ) .

T h is compound had been r e p o r t e d

b y Rosenmund and D o m s a f t ( £ 6 ) as m e ltin g

a t 19£° C. w it h

dec ompos i t io n * The a c id , when c r y s t a l l i z e d

fro m a lc o h o l and w a t e r , fo rm s

w h it e , f l o e c u l e n t , s o f t c r y s t a l s w h ic h a re in s o lu b le i n a lc o ­ h o l and e t h e r , s o lu b le i n

d ilu te

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

P r e p a r a t io n o f th e e t h y l e s t e r o f p h e n y la la n in e fro m p h e n y la la n in e : f la s f c f i t t e d

To £5 c c o f a b s o lu te a lc o h o l i n a tw o -n e c h

w it h a r e f l u x c o n d e n s e r and a h y d ro g e n c h lo r id e

i n l e t was added 10 g . w h ile p a s s in g

o f p h e n y la la n in e and b ro u g h t t o b o ilin g

i n h y d ro g e n c h lo r id e fro m a g e n e r a to r .

From

tim e t o tim e more p h e n y la la n in e was added u n t i l no more w ou ld d is s o lv e #

T h is .was th e n h e a te d f o r a b o u t tw e n ty f i v e m in u te s ,

c o o le d and f i l t e r e d #

A b o u t d o u b le th e volume o f w a te r was

added (50 c c ) and made n e u t r a l w it h ammonium h y d ro x id e and s e t a s id e t o c o o l. liq u id #

The e t h y l e s t e r s e t t le d o u t as an o i l y

T h is was e x tr a c te d w i t h

t i o n was d r ie d w i t h

D ry h yd ro g e n

th e e th e r s o lu t io n and th e e t h y l

as th e h y d r o c h lo r id e .

o f f and w ashed w it h e t h e r . b o ilin g d ilu te

The e t h e r e a l s o lu ­

a n h ydro u s s o d iu m s u lp h a te .

c h lo r id e was p a sse d i n t o e s te r p r e c i p i t a t e d

e th e r#

T h is was f i l t e r e d

They w ere re c r y s t a l l i z e d

a lc o h o l and d r ie d #

fro m

M e ltin g p o in t 1£3 to

35

12 4 ° C.

(c o r.)

The h y d r o c h lo r id e o f th e e t h y l e s te r

of

p h e n y la la n in e m e lts a t 124° C. P r e p a r a t io n

of p - c h lo r o p h e n a c y l c h l o r i d e :

ro u n d - b o tto m , th r e e - n e c k f l a s k f i t t e d ic a l s t ir r e r ,

In a l i t e r ,

w it h a s e a le d n e ch a n -

a d r o p p ir ^ f u n n e l and a r e f l u x

co n de nser to

w h ic h was a tta c h e d a h y d ro g e n c h lo r id e tr a p

was p la c e d 112 g .

(1 m o le ) c h lo rb e n z e n e and 400 cc o f c a rb o n d is u lp h id e * th is

was added 145 g .

c h lo r id e *

To

{ 1 * 1 m o le s ) o f a n h y d ro u s alum inum

Then 112 g« (1 m o le ) o f c h lo r a c e t y l c h lo r id e was

s lo w ly d rop p e d i n a t a r a t e w h ic h d id n o t cause to o v i o l e n t r e f lu x in g : o f th e c a rb o n d is u lp h id e *

A fte r

th e a d d it io n o f

th e c h l o r a c e t y l was c o m p le te d th e m ix tu r e was re f lu x e d u n t i l no more e v o lu t io n o f h y d ro g e n c h lo r id e was n o te d . t u r e was th e n c o o le d and po u re d on a m ix tu re

o f equial p a r t s

o f ic e w a te r and c o n c e n tra te d h y d r o c h lo r ic a c id . la y e r was s e p a ra te d and washed w it h w a te r . d r ie d

o v e r an h yd ro u s

s u lp h id e d i s t i l l e d

The m ix ­

The o rg a n ic

T his was th e n

c a lc iu m c h lo r id e and th e c a rb o n d i ­

o f f under reduced p r e s s u r e .

The r e s id u e

was ta k e n up in b o i l i n g a lc o h o l and r e e r y s t a l l i z ed. was a g a in r e c r y s t a l l i z e d ( 6 6 * 8^) m .p .

fro m b o i l i n g

a lc o h o l.

Y ie ld 125 g .

lO O fl.C .

P r e p a r a t io n o f p - c h lo r o p h e n a c y l c y a n id e : a lc o h o l a t 5 5 ° 0 . was added 15 g .

To 60 ce o f

( .0 8 m ole) p - c h lo r p h e n ­

a c y l c h lo r id e and the m ix tu r e s t i r r e d s o lv e d .

T h is

u n t i l a l l was d i s ­

To t h i s was added 15 g . sodium c y a n id e d is s o lv e d

i n 40 cc warm w a te r .

The m ix tu r e was s t i r r e d

u n til a l l

36

was d is s o lv e d , and p la c e d on a w a te r b a th m a in ta in e d a t 55° C. f o r a b o u t 3 /4 h o u r .

To t h i s

was th e n added c o ld w a te r

u n t i l no more p r e c i p i t a t i o n o c c u r r e d .

The m ix tu re was th e n

s e t a s id e and the s o l i d a llo w e d to s e t t l e

o u t*

was n o t unchanged p - c h lo r o p h e n a c y l c h lo r id e * th e n f i l t e r e d

The m ix tu r e was

on a s u c t io n f i l t e r u n t i l c l e a r .

c h l o r i c a c id was added to th e f i l t r a t e l it m u s .

T h is s o l i d

Then i t

u n til i t

was s e t a s id e t o s e t t l e .

c r y s t a l s w e re f i l t e r e d

o f f aaid d is s o lv e d i n

D i l u t e h y d ro ­ was a c id to

The r e s u l t i n g a minimum o f

w a te r to w h ic h had been added an amount o f so d iu m c y a n id e e q u a l to

th e w e ig h t o f th e c r y s t a l s *

added and th e m ix t u r e was f i l t e r e d c le a r . a c id

on a s u c t io n f i l t e r

and s e t a s id e f o r

70$ a lc o h o l w it h

a b o u t one h o u r.

and d r ie d * 3 g.

The c r y s t a l s w ere r e ­

They w ere p u r i f i e d

o f H o r it e

The s o l u t i o n was c o o le d i n a n ic e

and f i l t e r e d

9 .5 g . 6 6 . 8$ . M e lt in g p o in t

u n t i l c le a r .

and d r ie d .

Y ie ld

1 2 7 -1 2 8 ° G.

R e p e t it io n o f th e e x p e rim e n t gave y ie ld P u re p - c h lo r o p h e n a c y l

by b o ilin g

c h e s t f o r a b o u t two h o u rs

and th e c r y s t a l s w h ic h fo rm e d w ere f i l t e r e d

66$ .

u n til

I t was th e n re n d e re d a c id w it h d i l u t e h y d r o c h lo r ic

moved by f i l t e r a t i o n in

One gram o f H o r it e was

c y a n id e

v a r y in g

fro m 63 to

m e lts a t 1 2 8 °.

H y d r o ly s is o f p- c h lo r o ph en acyl c y a n id e :

I n a g la s s s to p ­

p e re d s e p a r a to r y f u n n e l was p la c e d 100 cc a b s o lu te a lc o h o l s a t u r a t e d w i t h h y d ro g e n c h lo r id e

and 23 g .

{ .1 3 m o le s) o f

p - c h lo r o p h e n a c y l c y a n id e , and a llo w e d to s ta n d a t room tem­ p e ra tu re f o r f i v e filte r e d

days.

and d r i e d .

The c r y s t a l s w h ic h fbrm ed w e re

Y ie ld 7 g .

The m other liq u o r s w ere

37

rem oved u n d e r re d u c e d p r e s s u r e , w e re th e n ta h e n up i n

The r e s id u e and c r y s t a ls

SO oo o f d i l u t e h y d r o c h lo r ic

and warmed f o r a b o u t f i v e An amber c o lo r e d l i q u i d

m in u te s

a c id

and th e n a llo w e d to c o o l.

s e ttle d o u t,

T h is was s e p a ra te d

and th e aqueous la y e r e x tr a c te d w i t h two 25 cc p o r t io n s o f e th e r*

The o i l o b ta in e d above and th e e t h e r e a l e x t r a c t s

w ere com bined and d r ie d

over a n h y d ro u s sodium s u lp h a te .

The e th e r was rem oved by a s tr e a m o f a i r and th e r e s id u e p la c e d i n a n i c e c h e s t f o r a b o u t one h o u r and f i l t e r e d . The f i l t r a t e

w e ig h e d 15 g* r e p r e s e n t in g a y i e l d

o f 5Q.fo o f

th e c ru d e e s t e r . The same q u a n t i t i e s ceed!

o f a l l m a t e r ia ls w ere used i n

a suc­

e x p e rim e n t and th e m ix t u r e was re f lu x e d s lo w ly f o r

a b o u t two h o u rs w h ile p a s s in g i n h y d ro g e n c h lp r id e ,

The

re m a in d e r o f the p ro e e e d u re was th e same.

in

The y i e l d

t h is

ca se was 66* 6jS o f th e c ru d e e s t e r , n i t r o s a t i o n o f th e e t h y l e s t e r o f p - c h lo r o b e n z o y la c e t a t e : The n i t r o s a t i o n

o f t h is

e s te r was c a r r ie d o u t a f t e r th e man­

n e r a lr e a d y d e s c rib e d f o r th e n i t r o s a t i o n o f e t h y l b e n z o y l­ a c e ta te , From th e c ru d e e t h y l p - c h lo r o b e n z o y la c e ta te ,

o b ta in e d

fro m h y d r o ly s i s o f th e c y a n id e , y ie ld s o f 57 fo and 6 2 , 5fo w e re o b ta in e d *

The p r o d u c t , a f t e r r e c r y s t a l l i z a t i o n

h o t t o lu e n e m e lte d a t 135 t o 136° C, ( c o r . ) U it r o g e n c o n te n t c a lc u la t e d is

5 , 49$ :

fo u n d N, 5 ,4 5 fo.

fro m

A n a ly s is :

f o r th e fo rm u la C ^ H ^ Q ^ n C l

38

R e d u c tio n o f e t h y l oC- o x im in o - ^ - p - c h lo r o p h e n y l- f t -k e to p ro _ p io n a t e :

The c a t a l y s t used was th e same as t h a t d e s c rib e d p r e ­

v io u s ly in

th e r e d u c t io n o f at - i s o n i t r o s o ^ - p h e n y l ^ -k e to e t h y l

p r o p io n a t e .

I n a 250 cc ro u n d -b o tto m f l a s k was p la c e d 5 g .

( l/5 1 a o le )

o f e t h y l ^ - o x i m i n o - / ^ - p - c h lo r o p h e n y l- ^ - k e t o p r o -

p io n a t e , 5Q cc o f 9 &fo a lc o h o l, 5 g . o f h y d ro g e n c h lo r id e and th e c a t a l y s t m e n tio n e d ab ove . g e n a to r and s h a k e n .

T h is was a tta c h e d to a h y d ro ­

820 cc h y d ro g e n were absorbed r a p i d l y ,

th e n t h e a b s o r p t io n s to p p e d c o m p le te ly , so 50 cc o f a lc o h o l and 25 cc o f w a te r w ere added and s h a k irg t i o n was s t i l l

p r a c tic a lly

n e g lig ib le

c o n tin u e d .

so .1 g . o f p a lla d iu m

c h lo r id e was added and h y d r p g e n a tio n re sum e d . d id n o t p ro d u c e r e s u l t s f l a s k w h ile

s h a k in g .

A b s o rp ­

When t h i s

a ^ e t o f steam was d ir e c t e d a t th e

A b s o r p tio n speeded u p u n t i l 560 cc o f

h y d ro g e n were ta k e n u p , a f t e r w h ic h a b s o r p tio n s to p p e d com­ p le te ly .

T o t a l h y d ro g e n ta k e n u p was 1380 c c .

The t h e o r e t ­

i c a l am ount o f h y d ro g e n needed f o r r e d u c t io n t o th e amino a lc o h o l i s

1318 c c .

The f l a s k was th e n d is c o n n e c te d and

th e m ix t u r e b r o u g h t t o added to b r in g n e e d e d ).

b o ilin g

and s u f f i c i e n t b o i l i n g w a te r

th e compound in t o

s o lu t io n

The c a t a l y s t was f i l t e r e d

t i o n on a s u c t io n f i l t e r .

(v e ry l i t t l e

was

o f f fro m th e h o t s o lu ­

T h is c 3 e a r l i q u i d

was p la c e d in

an ic e c h e s t f o r t w e n t y - f o u r h o u rs and th e c r y s t a l s f i l t e r e d o f f and d r ie d .

The s u p e r n a ta n t l i q u i d was th e n p e r m itte d

t o e v a p o ra te s p o n ta n e o u s ly i n

a vacuum d e s c ic a to r under r e ­

duced p re s s u re and th e re s id u e was c r y s t a l l i z e d m inim um o f b o i l i n g

a lc o h o l.

fro m a

These c r y s t a l s w ere added to

39

th o s e o b ta in e d above and th e w h o le r e c r y s t a l l i z e d in g a l c o h o l. and d r ie d

They w ere washed w i t h a l i t t l e

fro m b o i l ­

io e o o ld a lc o h o l

o v e r s u lp h u r ic a c id i n a d e s c ic a t o r f o r 24 h o u rs *

Y ie ld 4 .2 g* 7 7 $ . R e p e t it io n o f th e e x p e rim e n t u s in g 7 g .

( l / 3 6 m o le ) e t h y l

- o x im in o - / ^ ~ ] c e t o - ^ - p - c h lo r o p h e n y lp r o p io n a t e

i n 175 cc o f

a lo o h o l and 20 g * o f h y d ro g e n c h lo r id e and th e c a t a l y s t p r e ­ v io u s ly d e s c r ib e d a b so rb e d 2080 cc o f h y d ro g e n . am ount o f h y d ro g e n needed f o r th e r e d u c t io n t o cohol is

1848 ©a*

p o in t 16&-17Q0 0*

T h e o r e t ic a l th e am ino a l ­

The y i e l d was 6 *3 g . o r 8 2 *5 $ . (c o r*)*

.A n a ly s is :

c u la te d f o r th e fo r m u la

M e lt in g

n it r o g e n c o n te n t c a l ­ is

5 *0 2 $ :

Found H* 5*19 fo

and 5 .3 j£ . One h a l f g ra m o f th e h y d r o c h lo r id e o f e t h y l / ^ - p - c h l o r o p h e n y l^ - h y d r o x y c^-am ino p r o p io n a te was t r e a t e d w i t h ammon­ iu m h y d r o x id e f i l t e r e d

and th e p r e c i p i t a t e washed on th e

f i l t e r u n t i l th e w a s h in g s gave no t e s t f o r c h lo r id e s w i t h s ilv e r n it r a t e . t o s o d iu m f u s i o n .

The p r e c i p i t a t e was th e n d r ie d

and s u b je c te d

I t gave a p o s it io n t e s t f o r c h lo r id e s .

One g ram was d is s o lv e d i n w a te r and p o ta s s iu m pe rm a n g a n a te added and b o ile d u n t i l no f u r t h e r r e a c t io n to o k p la c e * s o l u t i o n was e x t r a c t e d w it h e t h e r .

The e th e r la y e r was ex­

t r a c t e d w i t h a s o l u t i o n o f so d iu m h y d r o x id e . ifie d

T h is was a c id ­

and th e p r e c i p i t a t e washed w it h c o ld w a te r .

p o r t i o n was added to fe rv e s c e n c e

( fre e

a s o lu tio n

a c id ) .

( p - c h lo r o b e n z o ic

a c id ) .

A s m a ll

o f sodium b ic a r b o n a te .

The re m a in d e r was d r ie d I n

uum d e s c ic a t o r o v e r n i g h t .

E f­

a vac­

M e ltin g p o in t 228 t o 2 2 9 ° C.

T h is m e lt in g p o i n t and th e s l i g h t l y

h ig h n it r o g e n c o n te n t s u g g e s ts a s l i g h t lo s s o f c h lo r in e h y d ro g e n a tio n *

T h is

96891

in

40

One h a l f gram added to ammonium h y d ro x id e gave no y e llo w c o lo r o r a c id in s o lu b le p r e c i p i t a t e ,

(no f r e e k e t o n e ) .

P r e p a r a t io n o f 3 . 4- d ih y d r o x y p h e n a c y l c h l o r i d e ; cc th r e e - n e c k , ro u n d - b o tto m f l a s k f i t t e d ic a l s t ir r e r , gen c h lo r id e

a r e flu x

4 2 .5 g .

(0*45 m o le ) o f m o n o c h lo r a c e tic to sta n d

added 200 cc o f benzene a n d 44 g* The m ix tu r e was r e f lu x e d

400 cc o f b o i l i n g w a te r . t i o n f l a s k and c o o le d .

s m a ll p o r t io n s T h is was r e f lu x e d

over n i g h t .

To t h i s was

( 0 .4 mole ) o f c a t e c h o l. The b e n ze n was

and th e r e s id u e t r e a t e d w i t h

T h is was r a p i d l y f i l t e r e d

on a s u c ­

A f t e r c o o lin g , t h e c r y s t a l s w e re se p ­

a r a te d on a s u c t io n f i l t e r

and washed w it h a m inim um o f c o ld

The r e s u l t i n g n e a r ly w h ite

c r y s t a ls w e re t h e n ta k e n

a m inim um o f b o i l i n g w a te r and b o ile d w i t h 5 g. N o r it e

f o r f i f t e e n m in u te s .

T h is was f i l t e r e d

lo w e d to r e c r y s t a l l i z e i n c r y s t a l s w e re f i l t e r e d Y i e l d 35 g . liq u id

a c id .

f b r f i f t e e n h o u rs .

th e n re c o v e re d by d i s t i l l a t i o n

up i n

( 0 .4 m o le ) o f p h o sp h oru s

To t h i s was added c a r e f u l l y i n

f o r two h o u rs and p e r m itte d

w a te r .

w it h a s e a le d mechan­

c o n d e n s e r t o w h ic h was a tta c h e d a h y d r o ­

t r a p was p la c e d 8 3 .3 g .

p e n t a c h lo r id e .

I n a 500

u n t i l c le a r and a l ­

an ic e c h e s t o ver n i g h t .

o f f o n a s u c t io n f i l t e r

The

and d r ie d .

(4 6 $ ) m .p . d e c o m p o s itio n to a r e d d is h b ro w n

a t 170° C. ( r e p o r te d m e ltin g p o i n t was d e c o m p o s itio n

a t 1 7 3 ° C.

(2 5 ).

R e p e t it io n

c£ th e above e x p e rim e n t gave y i e l d s v a r y in g

b etw een 5 0 .6 $ and 5 4 ^.

41

P r e p a r a t io n o f 3 14 - d ih y d ro x y p h e n a c y l c y a n id e : was a n t i c i p a t e d i n c h lo r id e

D iffic u lty

th e c o n v e rs io n o f th e 3 , 4 - d ih y d r o x y p h e n a c y l

to th e c y a n id e due to

d ih y d r o x y compound i s

th e ease w it h w h ic h t h e 3 , 4 -

o x id iz e d I n a lk a lin e medium#

th e c o n v e rs io n was a tte m p te d

in

the u s u a l m anner*

H ow ever, As was

e x p e c te d o n ly a d a rk t a r r y mass was o b ta in e d w h ic h g a ve v e ry p o o r y i e l d o f d a r k b ro w n c r y s t a l s when b o ile d w i t h H o r it e * T h is d id n o t p ro m is e t o be

c f a n y v a lu e *

I t was th e n a tte m p te d t o p r e v e n t o x id a t io n o f 1 g* o f sodium s u lp h it e t o p h e n a e y l c h lo r id e u se d *

each 15 g *

by t h e a d d it io n

o f 3 , 4 - d ih y d r o x y -

These e x p e rim e n ts y ie ld e d brow n

c r y s t a l s , w h ic h on b o i l i n g w it h M o r it e , y ie ld e d

l i g h t y e llo w

c r y s t a l s w h ic h w e re r e o r y s t a l i i zed fro m b o ilin g : w a te r and d r ie d *

When a s m a ll p o r t io n

o f th e above c r y s t a l s was d i s ­

s o lv e d i n w a te r and a s o lu t io n o f f e r r i c a deep

g re e n

c o lo r d e ve lo p e d i n d i c a t i n g th e p re s e n c e o f th e

f r e e p h e n o l g ro u p s * je c t e d

c h lo r id e ad d e d ,

One h a l f gram o f t h e c r y s t a l s w e re s u b ­

to sodium f u s io n and checked w i t h s i l v e r n i t r a t e

a c id s o lu t io n *

The p r e c i p i t a t e p ro ve d to be s i l v e r

and a s tr o n g o d o r o f h y d ro g e n s u lp h id e was o b s e rv e d . c o u ld n o t be a c c o u n te d f o r ,

o f w a te r. w h ile

s u lp h id e T h is

so th e method was g iv e n up*

I t was th e n d e c id e d to a tte m p t th e a d d i t i o n o f h yd ro g e n #

in

to p r e v e n t a x id a t io # b y

I n a 250 cc f l a s k was p la c e d 100 cc

T h is was h e a te d t o b o ilin g - and h y d ro g e n p a sse d i n

th e s o l u t i o n c o o le d t o 4 0 ° C*

To t h i s was added 15 g *

( f 08 m o le ) o f 3 , 4- d ih y d r o x y p h e n a c y l c h lo r id e s o d iu m c y a n id e *

and 15 g . o f

I t was s to p p e re d Im m e d ia te ly and the s to p p e r

42

s e a le d w it h p a r a f f i n *

T h is was p e r m itte d

te m p e r a tu re f o r one hour*,

to s ta n d a t room

The s to p p e r was removed and th e

s o l u t i o n re n d e re d a c id w i t h d i l u t e h y d r o c h lo r ic a c id . was th e n p la c e d i n an i c e

It

c h e s t o v e r n ig h t and f i l t e r e d .

The c r y s t a l s w e re b o ile d w it h 2 g . o f M a r it a and f i l t e r e d 5 *5 g . , 40jS y i e l d o f l i g h t y e llo w

c r y s t a l s w e re o b ta in e d *

M .P. was 2 1 8 -2 1 8 ° 0* w it h d e c o m p o s itio n *

A n a ly s is .:

gen c o n te n t c a lc u la t e d f o r th e fo r m u la

is

n itr o ­

7*99 fo»

Found n . 7 *7 8 $ . T h is n it r o g e n c o n te n t was a l i t t l e a t p u r i f i c a t i o n w ere t r i e d *

lo w so f a r t h e r a tte m p ts

The m a t e r ia l was p u r i f i e d

by

b o i l i n g w i t h M o r ite s e v e r a l tim e s u n t i l a w h it e f l o c c u l e n t c r y s t a l s were o b ta in e d .

T h is was d r ie d f o r

h o u rs i n a vacuum d e s c ic a t o r * w it h d e c o m p o s itio n .

M e ltin g

tw e n t y - f o u r

P o in t 2 2 0 -2 2 3 ° C*

T h is f i n a l p r o d u c t was 3 * 4 - d ih y d r o x y -

p h a a a c y l c y a n id e . O th e r a tte m p ts a t o b t a in in g lo w ii^ :

V a rio u s s o lv e n ts

th e c y a n id e in c lu d e

tr ie d

f o r th e c o n v e rs io n w e re ,

e th y le n e g l y c o l , b e n z e n e , p y r id in e th e s e p ro v e d s u c c e s s f u l; f i n a l l y

and a c e to n e .

to th e d ib e n z y l

th e d is o d iu m s a l t o f 3 ,4 - d ih y d r o x y p h e n a c y l

c h lo r id e w it h b e n z y l io d id e *

T h is a ls o p ro v e d u n s u c c e s s fu l

b u t r e s u l t s w e re s u f f i c i e n t l y p ro m is in g s tu d y *

Hone o f

an a tte m p t was made t o

c o n v e r t th e 3 ,4 - d ih y d r o x y p h e n a c y l c h lo r id e e th e r by t r e a t i n g

the f o l -

to w a r ra n t f u r t h e r

42

P r e p a r a t io n o f p -m e th o xyp h e na cy 1 c y a n id e :

E ig h t grams

(* 0 4 7 m o le ) o f p -m e th o x y p h e n a c y l c h lo r id e was t r e a t e d

as

p r e v io u s ly d e s c rib e d u n d e r th e p r e p a r a t io n o f p h e n a c y l c y a n id e *

Y ie ld was 5 *4 grams o r 71 fo o f p-me th o x y p h e n a c y l

c y a n id e *

M e ltin g

P o in t 128$ C*

t e n t c a lc u la t e d f o r

A n a ly s is ::

the fo r m u la C^QH^OgH i s

K i t no gen con­ 8$ *

Pound n i t r o ­

g e n , 7 *9 1 $ and 7*84$♦ P r e p a r a t io n o f p-b ro m p h e n a c y l c y a n id e :

T h i r t y gram s o f

p -b ro m p h e n a o y l b ro m id e (* 0 6 7 ) m o le was t r e a t e d as p r e v i o u s ly d e s c rib e d u n d e r th e p r e p a r a tio n o f p h e n a c y l c y a n id e * was 3 2 *6 grams o f th e c ru d e c y a n id e * was l o s t i n h o t t o lu e n e . o f th is

an a tt e m p t to p u r i f y i t

Most

cf th is

Y ie ld

compound

by r e c r y s t a l l a t i o n fr o m

T here was no o p p o r t u n it y

to o b t a in an a n a ly s is

p r o d u c t ; a s m a ll p o r t io n re c o v e re d m e lte d a t 2 4 3 -2 4 4 °

w it h d e c o m p o s itio n *

44

SUMMARY 1*

The s y n t h e s is o f p h e n a c y l c y a n id e and i t s

tu t e d d e r i v a t iv e s

n u c le a r s u b s t i ­

fro m th e c o r re s p o n d in g p h e n a c y l c h lo r id e s

has been s t u d ie d . 2*

The c o n v e r s io n o f t h e p h e n a c y l c y a n id e i n t o

s p o n g in g , ^ - a r y l - / ^ - I c e to p r o p io n ic 3*

e s te r s i s

th e c o r r e -

d e s c r ib e d .

T h e ^ - fc e to e s te r s m y be c o n v e rte d i n good y i e l d t o

th e

c o rre s p o n d in g e s t e r o f ^ - a r y l- y ^ - I c e t o - c K - o x im in o p r o p io n ic a c id . 4#

These © t - o x im in o - ^ - ic e to e s te r s have been h y d ro g e n a te d to

th e c o r re s p o n d in g p h e n y ls e r in e d e r i v a t iv e s * 5*

I n th e g e n e r a l p r o c e d u r e : A r.C O -C H g C l— > Ar.CO -C H Gn —» lr*CO -G Hg-G O O Et —* Ar.CO-C-COGEt —> I r . CHOH-CH-COOEt S oh

ra 2

The y i e l d s a t a l l s ta g e s a re s a t i s f a c t o r y and e n co u ra g e th e b e lie f th a t

th e m ethod i s

a v a ila b le

o f ^ -h y d ro x y -o C .-a m e n o a c iid s ♦

f o r g e n e r a l s y n th e s is

45

BIBLIOGRAPHY (1 )

Embden, E . and B a ld e s , 1 . : B io ch e m . Z . , 5 5 , 2 0 1 , ( 1 9 1 3 ) .

(2)

K o ta k e , Y . , M o a a i, Y . and M o r i, Y . : Z , P h y s io l. Chem ., 1 8 2 . 1 9 5 , ( 1 9 2 2 ) .

(3)

H h p h o ld , P. C. and R a p e r, H. S . : B io ch e m . J . , 1 9 , 8 4 , ( 1 9 2 l) .

(4 )

O nslow , M. W. and R o b in s o n , M. E . : B io ch e m . J . , 1 9 . 4 2 0 , ( 1 9 2 5 ) .

(5)

R a p e r, H. S . : B ioch e m . J . , 2 1 , 8 9 ,

(6)

(1 9 2 7 ) .

Guggenheim , M .: Z . P h y s io l. Chem ., 8 8 . 2 7 6 ,

(1 9 1 2 ).

(7 )

M ille r , E. R .: J . B i o l . Chem., 4 4 , 4 8 1 ,

(8)

R a p e r, H. S . and Speakman, H. B . : B ioch e m . J . , 2 0 , 6 9 , ( 1 9 2 6 ) .

(9 )

Durham , E . M .: P ro e . R o y. Soc. o f L o n d o n , 7 4, 3 1 0 ,

(1 9 2 0 ).

(10)

E va n s, W. C. and R a p e r, H. S .: B ioch e m . J . , 3 1 , 2 1 5 5 , (1 9 3 7 ) .

(11)

H a a k in H e a rd , R. D . and R a p e r, H. 3 . : B ioch e m . J . , 2 7, 3 7, (1 9 3 3 ) .

( 12)

R a p e r, H. S . : B ioch e m . J . , 2 6 , 2 0 0 0 , ( 1 9 3 2 ) .

(13)

A lo o c k , R. S . : B io ch e m . 3 . , 2 8 , 1 1 74 ,

(1 4 )

Medes , G ., B io ch e m . J . , 26_, 917,

(1 9 0 5 )

(1 9 3 4 ) . (1 9 3 2 ) .

(1 5 )

H is , W .: A r c h . P a th . u . P h a rm ., 2 2 , 25 3 ,

(16)

A cke rm an , D . : Z. B i o l . , 59, 17,

(1 7 )

H e u h e rg , C* and G o ttschaLfc* B iochem * Z * , 146, 16 4, (1 9 E 4 )*

(1 9 1 2 ) .

(1 8 8 7 ) ,

46

B in g , R, J * : A m e ric a n J . P h y s i o l . ,

132, 4 9 7 -5 0 3 ,

B in g , R* J . and Z ucker , M. S . : J . Am er. Med. A s s o c ., 1 1 8 , 89 9,

( 1 9 4 1 ),

(1 9 4 2 ).

M ason, M. F . , R o b in s o n , G, S. and B la lo c k , A . : J . E x p e r im e n ta l M e d ic in e , 72^ 289, (1 9 4 0 ) . D e v in e , J * : B io c h e m *, J . , 3 4 , 2 1 -3 1 ,

(1 9 4 0 ).

Edmunds, C. W. and S m ith , R. 0 . : J . L a b . C l i n . M e d ., 1 7 , 3 9 9 -4 0 4 ,

(1 9 3 2 ).

ORG. SYNTHESIS, John W ile y & Sons, I n c . , New Y o r k , N. Y . V o l. 15'," 1X935 ) , P . 1 7 . Pechmann, H. Y . : B e r., 24, 860,

(1 8 9 1 ).

H a r r in g t o n , c . and R a n d a ll, s * B iochem . J . , 2 5 , 1 91 7, ( 1 9 3 1 ) . : Rosenmund, K . W* and D o rn s a f t , B e r . , 52., 1 7 43, ( 1 9 1 9 ) .

H .:

H a rtu n g , W. H. and M unch, J . G .: J . Am. Chem. S o c ., 5 1 , 2 2 6 2 , ( 1 9 2 9 ) . C la is e n , L . : B e r . , 3 8 , 7 09,

(1 9 0 5 ).

C la is e n , L , a n d Low man, 0 . : B e r ., 20, 653, (1 8 8 7 ). E rle n m e y e r, 1 . : A n n ., 2 8 4 , 3 6 ,

(1 8 9 4 ).

E rle n m e y e r, E . and F r u s tu c k , E . : A n n ., 2 7 1 , 155, ( 1 8 9 2 ) . F is c h e r , E. and B u lo w , R . : B e r . , 1 8 , 2131, ( 1 8 8 5 ) . C la is e n , L . : A n n ., 2 9 1 , 6 7 , James, J . t A n n ., 226 , 2 2 0 ,

(1 8 9 6 ). ( 1 8 8 4 ).

M ic h a e l, A . and B row ne, G, M«: B e r . 1 9 , 1 3 9 3 , (1 8 8 6 ) .

47

(36 )

H a rtm a n , W. W. (Eastm an Kodak C o * ), P e r s o n a l C o m m u n ica tio n , J u ly 2 5 , 1 94 1,

(37)

C la is e n , L , : A n n ,, £ 9 1 , 7 0 ,

(1 8 9 6 ).

C la is e n , L . : B e r . , £ 0 , 656,

(1 8 8 7 ).

(38) (39)

B uoixner, E . and C u r tiu s , T h . : B e r . , 1 8 , 2373, ( 1 8 9 5 ) .

(40)

M a rg u e iy , A . : B u l l e t i n de l a Soe • C him . de F ra n ce * ( 3 ) , 3 3 , 5 4 9 .

(41 )

M e ye r, R . and Tog e l , K . : A n n ., 3 4 7 , 7 7 , ( 1 9 0 6 ) .

(42)

L e v in , N . : P h .D . T h e s is , THE SYNTHESIS AND REDUCTION OF ARYLGLQXYLOHXDRQXAMJXt. H A IL E S , U n iv e r s i ty " o f Mm? y 'la n d ', i m

r —





r



~

(43)

M c llw a in , H» and R ic h a rd s o n , G. M .: B ioch e m . J . , 33^, 4 4 , ( 1 9 3 9 ) ,

(44)

A d k in s , H, and R eeve, E , : J . Am, Chem. S o c ., 6Q , 1328,

(45) (46) (47)

(1 9 3 8 ).

F r i e d e l , C . , and C r a f ts * J . M . : A n n . c h im . p h y s ., ( 6 ) , 1 , 5 0 7 , Tut in , F , : J . Chem. S o c ., 97., 2 5 0 0 , B r i t t o n , E . C .: News E d i t i o n ,

A . C. S .,

(1 8 8 4 ).

(1 9 1 0 ). IS , 2 5 1 ,

(1 9 4 1 ).

(48)

G ro g g in s , P . H . ; U n it P ro c e s s e s i n O rg a n ic S y n th e s is , M eGraw-Hi 11 Book C o ., New Y o r k , 2nd e d . , (193 8 J, p p . 6 3 4 -9 1 .

(49)

F r ie s , K . and P f a f f e n d o r f , W .: B e r,, 4 3, 214, (1 9 1 0 ).

(50)

O rg . S y n th e s e s , John W ile y and Sons, I n c . , New Y o r k , N .Y . V o l. X IX , ( 1 9 3 9 ) , p . 2 4 .

(51 )

G a b r ie l, B e r.,

(52)

O b re 'g ia , A . : v A n n ., 266, 326, ( 1 8 9 1 ) .

S. and E schenbaeh, G .: 3 0 , 1127, (18 9 7 ) .

48

(5 3 )

P f e i f f e r , P. E n g e lh a r d t, I . and A lf u s s , W .: A n n ., 4 6 7 , 1 5 8 -1 9 0 , ( 1 9 2 8 ) .

(5 4 )

P in n e r , A . : B e r., !£ ,

(5 5 ) (5 6 )

1 6 44,

(1 8 8 3 ).

H a lle r , H .: B u i. de l a S oc« Chim . de F ra n c e , Sah, P. P. T . : J* Am. Chem. S o c . , 5 0 , 5 1 6 ,

(5 7 )

P f e i f f e r , P . and M a tto n , K * : B e r . , 4 4 , 7 1 3 , (1 9 1 1 J*.

(5 8 )

S p ie g e l, 1 . and S z y d lo w s h y , H . : B e r . , 5 1 , 2 9 6 -2 9 8 , (1 9 1 8 ).

(5 9 )

S c h u lz e , E, and B a r h i e r i , J . : B e r ., 14, 1785, (1 8 8 1 ).

(6 0 )

L ie b ig , J . A n n . , . 57, 1 2 7 ,

(6 1 )

( 2 ) , 43, 25.

(1 9 2 8 ).

(1 8 4 6 ).

H a rtu n g , W. H * : C h e m ic a l R e v ie w s ,

3 8 9 -4 5 8 ,

(1 9 3 1 ).

(6 2 )

B a r g e r, G .; Some A p p lic a t io n s o f O rg a n ic C h e m is try to B io lo g y and" Medic The". MeG-ra w -H i I I ! Bo ok C o . , In c . , Kew Y o rh , IF. Y . (1 9 3 0 )*

(6 3 )

T a i n t e r , M. L . : A r c h , i n t e r n , p harm acodynam i. 4 6 , 192, ( 1 9 3 3 ) .

(6 4 )

T a in t e r , M, L . Q ,u a rt. J . and Year Booh o f Pharm. S3, 5 8 4 ,

(6 5 )

(1 9 3 0 )*

S c h m id t, C. L . A . : C h e m is try o f The Amino A c id s and P r o t e in s , C. C. Thomas, B a l t o . , ( 1 9 3 8 ) .