Some Derivatives of Sulfamide

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PURDUE UNIVERSITY

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

b y ___________

Benjam in E l b e r t S a n d e rs

E N T IT L E D

SOM DERIVATIVES OF SULFAMIDE

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

AND IS A P P R O V E D BY 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 DEGREE O F

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SOME DERIVATIVES OF SULFAMIDE A T h esis Subm itted t o th e F a cu lty of Purdue U n iv e r s ity by Benjamin E lb e r t Sanders In P a r t ia l F u lfillm e n t o f th e Requirements f o r th e D egree of D octor o f P hilosop hy A ugust, 1949

ProQuest Number: 27712239

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ACKNOWIEDGMSNT The w r it e r w ish es t o e x p r e ss h is s in c e r e a p p r e c ia tio n to D r. Ed. F . D egering and Dean Glenn L. Jenkins f o r t h e ir i n t e r e s t and v a lu a b le a s s is t a n c e in d ir e c t in g t h is work. The w r ite r a l s o w ish es to exp ress h is g r a titu d e to h is la b o r a to r y "bench" m ates, George O 'D ell and L e s lie B o a tr ig h t, f o r t h e ir tim e ly a d v ic e and c o o p e r a tio n . Acknowledgment i s a ls o made to th e American Chemical S o c ie ty and th e V eterans A d m in istra tio n f o r t h e ir f in a n c ia l support o f t h is r e se a r c h .

TABLE OF CONTENTS

Page INTRODUCTION............................................................................................................

1

DISCUSSION................................................................................................................

2

EXPERIMENTAL.................................................................................................................12 P r e p a r a tio n o f carb o m eth o x y su lfam id e

.............................................. 12

P r e p a r a tio n o f c a rb e th o x y su lfa m i d e .

.....................................13

P r e p a r a tio n o f N, N* d ic a rb e th o x y s u lfa m id e

................................ 15

P r e p a r a tio n o f N, N1 d ic a rb o p ro p o x y s u lfa m id e ..........................

16

A ttem pted p r e p a r a ti o n o f N, Nf d i b u ty l , N, N1 d i c a r b e t b o x y s u l f a m d e ..........................

17

A ttem pted p r e p a r a tio n o f N, N* d ip h e n y l, N, Nf d i c a r b e th o x y s u lf a m id e ........................................

18

A ttem pted p r e p a r a tio n o f N,N,N* ,N ' t e tr a c a r b e th o x y s u lf a m id e . . . ..................

19

P r e p a r a tio n o f sym. d ip h e n y ls u lfa m ide

. . . . . . . .

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

P r e p a r a tio n o f 2 -d ie th y la m in o e th y le n e d ia m in e . . . . . . .

23

P r e p a r a tio n o f d i e t h y la m in o a c e to n i tr i le . . . . . . . . .

26

P r e p a r a tio n o f e th y l N -p h e n y lc a rb am a te ......................

27

A ttem pted p r e p a r a tio n o f e th y le n e s u l f a m i d e . ..........................

27

P r e p a r a tio n o f e th y le n e im in e

............................................................. 29

P r e p a r a tio n o f N -c a rb e th o x y , N* d im e th y ls u lfa m y l e th y le n e d i amine .................................30 P r e p a r a tio n o f d i e t h y l s u l f amyl c h l o r i d e ..........................

31

A ttem pted p r e p a r a tio n o f N ,N -d im eth y l, NT- (3 - d ie th y la m in o p ro p y l) su lfa m id e . . . . . . . . . .

32

P r e p a r a tio n o f 1 ,2 b is -(N ,N -d im e th y l su lfaray lam in o ) e th a n e . . . . . . . . . . .

32

P r e p a r a tio n o f p y ro c a rb o n ic e s t e r ......................

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

54

TABLE OF CONTENTS - C o a t'd . Page SUMMARY........................

56

BIBLIOGRAPHY.................................................................................................................37 ABSTRACT.................................................................................................................... HTA

i

SOME DERIVATIVES OF SULFAMIDE INTRODUCTION The p rep a ra tio n o f v a r io u s d e r iv a t iv e s o f su lfam id e o f f e r s an extrem ely in t e r e s t in g f i e l d f o r p o s s ib le m ed icin a l u s e .

L i t t l e has

been rep o rted on th e p h y s io lo g ic a l a c tio n o f su lfam id e d e r iv a t iv e s . Aeschlim an (1) rep orted t h a t t e t r a e t h y l su lfam id e in sm a ll d oses has a s l i g h t a n a le p tic a c t io n . a c tiv ity (2 ).

I t was found n o t t o have any a n tith y r o id

R ussian in v e s t ig a t o r s (3 ) found th e t h ia z o le d e r iv a tiv e

o f sulfam ide t o be e f f e c t i v e a g a in s t sta p h y lo c o c c i i n v i t r o . The carbamates th em selves have been found t o have p h ysio­ l o g i c a l a c t i v i t y as l o c a l a n e s t h e t ic s , s e d a t iv e s , h y p n o tic s and a v a r ie t y o f oth er a c t i o n s .

I t was thought d e s ir a b le t o combine th e

a c t i v i t y o f a known compound w ith one which has not been thoroughly in v e s t ig a te d , nam ely, su lfa m id e.

A co n sid er a b le number o f d e r iv a t iv e s

o f su lfam id e have been r e c e n t ly rep orted in c lu d in g th e r e a c tio n products w ith k e to n e s, a ld eh y d es, and a c id s ( 4 , 5 , 6 , 7 , 8 , 9 ) .

However,

most o f th e se compounds have n ot been com p letely checked fo r t h e ir pharm acological a c t io n .

2

DISCUSSION Even though su lfam id e was f i r s t c h a r a c te r iz e d in. 1838 by B egnau lt ( 1 0 ) , i t has been o n ly in th e p a st few y ea rs t h a t any a p p r e c ia b le work on su lfam id e has been r e p o r te d .

P reviou s work on

th e p rep aration o f su lfam id e d e r iv a t iv e s has been la r g e ly n e g le c te d because o f t h e d i f f i c u l t y o f o b ta in in g th e s t a r t in g m a t e r ia l.

S in ce

Anderson and D egering (6 ) have found th a t a cy la te d compounds were r e a d ily o b ta in a b le from th e r e a c t io n o f su lfa m id e w ith a c id anhydrides c a ta ly z ed by s u lf u r ic a c id , i t was thought f e a s i b l e th a t th e ch lo ro ­ form âtes m ight r e a c t under s im ila r c o n d itio n s . S c h if f (11) rep orted th a t eth y lch lo ro fo rm a te r e a c te d w ith urea to form e th y l a llo p h a n a te .

I t was found, however, th a t t h e ir

y ie ld s were n e g l i g i b l e . The u se o f s u lf u r ic a c id a s a c a ta ly s t f o r t h e r e a c t io n o f chloroform âtes w ith su lfam id e was u n s u c c e s s fu l.

S in ce su lfam id e i s

s e n s i t i v e to a c id s , b a s e s , and h e a t, th e u se o f proton a c c ep to r s such as pinene and p y r id in e were t r i e d , b ut w ith no s u c c e s s .

The a d d itio n

compound o f e t h y l chloroform ate and p y rid in e f i r s t d escrib ed by Hopkins (12) and l a t e r by Engleman (13) was in v e s t ig a t e d .

I t was

b e lie v e d th a t on g e n tly warming t h i s complex in th e presen ce o f su lfa m id e, th e d e s ir e d carbethozysulfam ide would be form ed.

A lthough

urea r e a c te d i n t h i s manner, sulfam id e d id n ot appear to be changed. Mono- and d ip otassiu m s a l t s o f su lfam id e were d escrib ed by F ran k lin and S ta ffo r d ( 1 4 ) .

They prepared th e se s a l t s in liq u id

ammonia, but exp erien ced some d i f f i c u l t y in o b ta in in g th e pure monoo r dip otassiu m s a l t s o f sulfam ide» An attem pt was made to prepare th e di potassium su lfam id e and

3

th e n r e a c t i t w ith th e c h lo r o fo r m t e , la r g e l y th e m onocarbethoxysulfam ide.

The product ob tain ed was The y i e l d s were poor s in c e th e

s o l u b i l i t y o f th e s a l t i s so lim it e d . S in c e th e s a l t s o f su lfa m id e are so in s o lu b le , a thorough sea rch was made f o r an in e r t s o lv e n t .

A c t u a lly , even eth a n o l was

t r ie d in one in s ta n c e a t low tem peratu res. found t o be v e r y s a t i s f a c t o r y .

However, no s o lv e n t was

Nitrom ethane was to o a c id , co n v ertin g

th e sodium s a l t to th e f r e e su lfa m id e .

Even n itr o b e n z e n e , d ioxan e,

and liq u id s u lf u r d io x id e were n o t s a t i s f a c t o r y as s o lv e n t s . A stu d y was made o f th e r e a c t io n s o f s u lf u r y l c h lo r id e . g r e a t q u a n tity o f work has been rep orted on th e s e r e a c t io n s . la c k o f agreem ent in much o f th e e a r l i e r work.

A

There i s

T his i s probably due

to th e f a c t t h a t th e ch em icals used were fr e q u e n tly n o t p u r ifie d and tr a c e im p u r itie s change th e e n t ir e course o f th e r e a c t io n .

Even w ith

th e g r e a t e s t o f c a re in u s in g t h i s r e a g e n t, i t i s fr e q u e n tly alm ost im p o ssib le t o o b ta in rep ro d u cib le r e s u l t s . An e x c e lle n t example o f c o n tr o v e r s ia l l it e r a t u r e i s the r e a c tio n o f s u l f u r y l c h lo r id e w ith a n i li n e .

In 1910 Wohl and

Koch (1 5 ) rep o rted dip h en yl su lfam id e in good y i e l d when s u lf u r y l c h lo r id e i s added to a n ilin e in c o ld e th e r e a l s o lu t i o n .

They a ls o

rep orted th a t azobenzene i s reco v ered but gave no mechanism.

E lle r

and Klemm, (1 6 ) in 1932 rep orted th a t th e y obtain ed m ixtures o f th e mono-, d i - , and t r ic h lo r in a t e d a n i li n e h yd rochloride u sin g e th e r e a l s o lu t io n a t room tem perature.

A number o f a ttem p ts were made t o

prepare sym m etrical dip h en yl su lfa m id e.

Even though the e t h e r , th e

a n i li n e , and th e s u lf u r y l c h lo r id e were c a r e f u lly p u r ifie d , th e b e s t y i e l d was on ly about 2 g . in a s in g le experim en t.

On th e b a s is o f

s t a r t in g m a te r ia ls t h i s i s l e s s than 10 per c e n t y i e l d .

Attem pts t o

prepare i t by low ering th e tem perature were even l e s s s u c c e s s f u l. E v id e n tly Meybeck (17) must have encountered d i f f i c u l t y w ith t h i s r e a c t io n s in c e he prepared th e sodium s a l t o f a c e t a n i l id e , and th e n r e a c te d t h i s product w ith s u lf u r y l c h lo r id e . adding a n i l i n e he rep orted th e d e s ir e d p rod u ct.

F in a lly , a f t e r T his procedure i s n ot

v e r y s a t i s f a c t o r y f o r i t i s lo n g and in v o lv e d , and, i n the hands o f th e in e x p e r ie n c e d , i t i s n o t alw ays r e p r o d u c ib le . S in c e i t i s p o s s ib le t o prepare diphenylurea from a n ilin e h yd roch lorid e and u r e a , i t was thought th a t d ip henyl su lfam id e m ight be prepared i n s im ila r f a s h io n .

This attem p t, however, was f r u i t l e s s .

R ecen tly d ip h en ylsu lfam id e has been prepared in 84 per c e n t y i e l d by h e a tin g a n i li n e and su lfam id e to g e th e r ( 5 ) . In th e p a s t few years Kharasch and Brown (1 8 ,1 9 ,2 0 ) have done a g r e a t d e a l to c l a r i f y th e r e a c t io n s o f s u lf u r y l c h lo r id e .

Because

o f th e extrem e com p lexity o f th e s u b j e c t th e re i s s t i l l much t o c o n s id e r .

Much o f t h e e a r l i e r u se o f s u lfu r y l c h lo r id e was a s a

c h lo r in a tin g a g e n t. p h e n o ls.

I t r e a c ts v e r y r e a d ily w ith arom atic amines and

Arom atic hydrocarbons r e q u ir e th e u se o f c a t a l y s t , but some

re a g en ts c o n ta in enough im p u r itie s t o s e r v e as a c a t a l y s t .

S u lfu r ,

io d in e , s u lfu r m onochloride, and aluminum c h lo r id e a l l se r v e as c a t a ly s t f o r c h lo r in a tin g w ith s u lf u r y l c h lo r id e .

The c h lo r in a tio n o f a lip h a t ic

compounds i n th e p resen ce o f minute tr a c e s o f p ero x id es has been thoroughly in v e s t ig a t e d ( 1 8 ,1 9 ,2 0 ) .

P eroxid es a ls o c a ta ly z e con version

o f to lu e n e t o b en zyl c h lo r id e ( 2 1 ) .

Ordinary l i g h t has a ls o been found

t o c a ta ly z e a number o f r e a c t io n s .

I t was th e ch lo ro su lf© n a tio n and

a c y la tio n r e a c tio n s which were most p e r tin e n t t o t h i s i n v e s t ig a t io n .

5

S u lfu r y l c h lo r id e r e a c t s w ith urea to form a v a r ie t y o f p roducts depending on th e c o n d itio n s ( 2 2 ) . t r i u r e t have been r e p o r te d .

Cyanic a c id , b iu r e t , and

S u lfu r y l c h lo r id e w ith th e sodium s a l t

o f a lip h a t i c amides g iv e s th e iso c y a n a te ( 2 5 ) .

Ephraim (24) rep o rts

th a t e th y l a llo p h a n a te was o b ta in ed by h ea tin g urethan w ith s u lf u r y l c h lo r id e .

I t was shown th a t w ith th e sodium s a l t o f urethan and

s u lf u r y l c h lo r id e , N ,N *dicarbethoxysulfam ide was o b tain ed .

However,

t h i s must not have been a v e r y good s y n th e s is f o r in the same a r t i c l e he r e p o r ts th a t he was n o t alw ays a b le to reproduce h i s own work. S e v e r a l attem p ts were made to r e p e a t Ephraim* s p rep a ra tio n but none were s u c c e s s f u l. Baumgarten (2 5 ) reported the form ation o f an a d d itio n product o f s u lf u r y l c h lo r id e and p y rid in e in co ld e th e r e a l s o lu t io n .

He was

n o t a b le to i s o l a t e i t s in c e i t i s e x c e e d in g ly u n s ta b le , sm e lls s tr o n g ly o f s u lf u r d io x id e , and q u ic k ly darkens i f th e tem perature i s r a is e d . S in c e t h i s a d d it io n compound i s formed in a c o ld s o lu t io n , i t was proposed th a t t h i s m ight be an e f f e c t i v e way o f preparing sym m etrical earbalkoxy d e r iv a t iv e s o f su lfa m id e.

Urethan was d is ­

s o lv e d in benzene and molar q u a n titie s o f p y rid in e was added.

The

s o lu tio n was c o o le d by i c e and s u lf u r y l c h lo r id e was added v e r y s lo w ly . The a d d itio n compound formed and as th e s o lu tio n warmed up over 16-20 hours th e d e sir e d earbalkoxy su lfam id e was prepared.

This r e a c tio n

could probably be extended to s e v e r a l c la s s e s o f compounds which have n ot been prepared b e fo r e . The e x te n sio n o f t h i s r e a c t io n to th e s u b s titu te d carbamates n eeds fu r th e r i n v e s t i g a t i o n .

I n th e ca se o f e th y l N-methylcarbamate

6

more than tw o -th ir d s o f th e carbamate was recovered unchanged.

I t may

be th a t the s u lf u r y l c h lo r id e -p y r id in e compound decomposed b e fo re th e exchange r e a c tio n could take p la c e . I t was thought th a t an in t e r e s t in g r e a c tio n would be th e r e a c t io n o f 2-d iethylam inoeth ylcarbam ate w ith s u lf u r y l c h lo r id e ,

The

p rep aration o f th e carbamate through th e fo llo w in g s e r i e s o f r e a c tio n s appeared t o be th e s im p le st method ( 2 6 ) . ( E t ) 2-H-CH3CH30H + C0C12 -> +

(E t ) 2-NH(C1)CH3CH20C0C1

—

(E t ) 3MH{ Cl) CHgCHgOCOCl + m g -> ( B t ) 3-N-CH2CH20C0MH2 + HOI -*•

(E t) 2-NCH2CH2000NH2

(E t ) 2-NH(Cl)OH2CBfeOCOI%

Commercial S -d ieth ylam in oeth an ol (Carbide and Carbon) was u s e d .

I t was

r e d i s t i l l e d and i t s r e f r a c t iv e in d e x was v e r y c lo s e t o th e l it e r a t u r e v a lu e .

H eiln er (26) rep orted th e m eltin g p o in t to be 153*-155*C. f o r

th e 2-diethylam inoeth ylcarbam ate h y d ro ch lo rid e.

The compound w hich

was ob tain ed had a m eltin g p o in t o f 194*-195*C.

A n a ly sis o f t h i s

compound d id not a g r e e w ith th e c a lc u la te d v a lu e s f o r th e carbamate h y d ro ch lo rid e. An e x p la n a tio n o f t h i s d i f f i c u l t y may be g iv e n . th r e e p r in c ip a l ways o f preparin g th e d iethylam ino eth a n o l:

There are 1) from

d ieth ylam in e and e th y le n e oxid e (2 7 ), 2) from dieth ylam in e and e th y le n e ehloroh ydrin ( 2 8 ) , 3) and f i n a l l y , from d ie th y l s u l f a t e and eth an olam in e.

The l a s t i s a French p a te n t (29) a ssig n e d to th e

company which made t h e a lc o h o l u sed .

The r e f r a c t iv e in d ic e s and b o ilin g

p o in ts o f 2 -eth ylam in oeth an ol and 2 -d ieth y la m in o eth a n o l are so c lo s e t h a t se p a r a tio n o f a m ixture b o ilin g o n ly a few d egrees ap art was im p o ssib le w ith th e fr a c t io n a tin g equipment th a t was a v a ila b le . I t was thought th a t th e r e a c tio n o f N ,N -d ie th y le th y le n e diam ine w ith s u lf u r y l c h lo r id e or d im eth ylsu lfam yl c h lo r id e would

7

y i e l d in t e r e s t in g compounds, d i lu t e s o l u t i o n s .

The r e a c tio n s were c a r r ie d ou t i n c o ld

I t was hoped t h a t th e fo llo w in g would be th e

r e a ctio n #

(E t) gNCHgCHgNHg + CISOgOl -» (E t) gNCHgCHgNESO2NHCH2GH2K[(E t) 2( 2HC1 ) The r e a c t io n o f s u lf u r y l c h lo r id e w ith th e t e r t ia r y amine group o f th e m o lecu le t o form an a d d itio n product was deemed h ig h ly probable# I n th e ev en t o f i t s form ation th e d e s ir a b le a c tio n would be f o r i t t o s h i f t , a s th e s o lu t io n g r a d u a lly warmed up, t o th e primary amino group.

In th e case o f N ,N -d ie th y le th y le n e diam ine and N ,N -d le th y l-

propylene diam ine w ith s u lf u r y l c h lo r id e , b oth g iv e an orange—-colored v isc o u s o i l .

I t was im p o ssib le to c r y s t a l l i z e th e m a te r ia l, and

when th e y were s u b je c te d t o d i s t i l l a t i o n s a t 2 mm. p r e ssu r e , th e re was d ecom p osition .

Even when d i s t i l l e d a t 0 .0 0 5 mm. p ressu re

decom p osition occurred#

A sim p le e x p la n a tio n would be d i f f i c u l t to

fin d s in c e th e r e a r e so many ways i n w hich th e r e a c tio n could proceed# E thyleneim ine in th e p a s t te n years has been in v e s t ig a te d c o n sid er a b ly ( 5 0 ,5 1 ,3 2 ,3 3 ) .

I t i s an extrem ely a c t iv e compound and

i t has even been t e s t e d l a t e l y f o r i t s v ir u c id a l a c tio n ( 3 4 ) .

I t is

known to dim erize and polym erize r e a d ily even in th e p resen ce o f carbon d io x id e .

However, eth ylen eim in e and i t s dimer w ere prepared

i n v e r y poor y i e l d s .

The r e a c tio n o f d im eth ylsu lfam yl c h lo r id e w ith

eth y len eim in e g iv e s an o i l y v is c o u s product w hich d e fie d i d e n t i f i c a t i o n . The d i a lk y l s u l f amyl h a lid e s a r e very in t e r e s t in g compounds. They are o i l y liq u id s and a r e p r a c t ic a lly in s o lu b le in co ld w a te r . They have been th e sou rce o f th e la r g e s t number o f sulfam id e d e r iv a t iv e s ( 4 , 7 ) .

The r e a c tio n o f dim eth ylsu lfam yl c h lo r id e w ith

e th y le n e diam ine gave l,2 -b is-(N ,N -d im e th y lsu lfa m y la m in o )e th a n e .

8

Me2NSO2Cl +HeNCH2CH2NHe -> ItogNSOglJHOH^CB^mOgNlltog ♦ HClîIHgCHgCHgNHgHDl So r e a c tio n v a s observed in th e c a se o f d im eth ylsu lfam yl c h lo r id e and urethan i n an i n e r t so lv e n t* D im ethylsulfam yl c h lo r id e r e a cte d w ith e th y l N -( 2 -a m in o e th y l) carbamate to g iv e th e ex p ected product • r e s u lt e d in d ecom p osition .

Attem pted d i s t i l l a t i o n a t 1 mm.

S h is product d i s t i l s a t 0 .0 0 5 mm. p ressu re

a t approxim ately 100*0. C y c lic compounds o f su lfam id e have been d e sid e r a ta o f a number o f in v e s t ig a t o r s ( 5 , 7 , 9 , 3 5 ) .

The c y c liz in g o f m alonyl

c h lo r id e and i t s d e r iv a t iv e s w ith su lfam id e has been th e p r in c ip a l o b j e c t iv e .

Paquin (5 ) r e c e n t ly rep orted th e c y c liz a t io n o f s u b s titu te d

su lfam id e w ith m alonyl c h lo r id e and phosphorous o x y c h lo r id e . Glenn (9 ) has in v e s t ig a te d th e r e a c tio n s o f pentanedione and o th e r k eton es w ith s u lfa m id e s. M ixing a s o lu t io n o f phosgene in chloroform w ith e th y le n e diamine r e s u lt s in th e form ation o f e th y le n e urea ( 3 6 ). ^N*(H) •HC1 H2N-C0-HE2 + C1-C0~C1-*0=CX .0=0 N H The r e a c tio n o f carbon d i s u lf i d e w ith eth ylen ed iam in e a ls o y i e l d s th e e th y le n e th io u rea ( 3 7 ) . The r e a c t io n o f s u lf u r y l c h lo r id e w ith eth ylen ed iam in e o ffe r e d a good chance f o r su c c e ss i f th e previou s r e a c tio n s were i n d i c a t i v e . A number o f h ig h d i lu t i o n r e a c tio n s were c a r r ie d out w ith s u lf u r y l c h lo r id e and eth y len ed ia m in e.

A ll v a r ia t io n s o f procedure appeared

t o make no change in th e product o b ta in ed .

A w h ite c r y s t a l li n e

m a te r ia l which decomposed w e ll above 300*0. was re co v e r e d .

Attem pts

a t p u r if ic a t io n appeared n o t to change the range o f th e d ecom p osition .

9

A m ixture o f lon g ch ain compounds presum ably r e su lte d * A number o f d if f e r e n t azamaIonat e s have r e c e n t ly been rep orted ( 3 8 ,3 9 ) . NaHMC(0)0C3H5) + G1C00C3%

-»

HN(C00C3H5)S

These compounds are b ein g t e s t e d f o r t h e ir pharm acological a c t i v i t y . P relim in ary t e s t i n g shows th a t th ey have some prom ise a s fu n g ic id a l a g e n ts .

The p o s s i b i l i t y o f th e fo llo w in g r e a c tio n o ccu rrin g would

g iv e r i s e to an in t e r e s t in g s e r i e s o f compounds. ÏM(C00C3H5)3 + CISOgCl

(%G300G)3N-S03-N(COOCgHs)2 0°C. + CbHsN-HCI

A n a ly sis o f th e compound ob tain ed showed 9 .0 5 c o n tra ste d to 7 .3 p er cen t c a lc u la t e d .

p er c e n t N p r e s e n t, as

No oth er s tr u c tu r e th a t might

p o s s ib ly be p r e se n t has been found to f i t t h is d a ta . E th yl pyro carbonate was f i r s t d escrib ed by Boehm and Mehta ( 4 0 ) .

They d e sc r ib e i t s p rep aration by th e r e a c t io n o f e t h y l

chloroform ate on th e a lk a lo id s , em etine or q u in in e .

The a lk a lo id

w ith e x c e ss chloroformât© was d is s o lv e d in chloroform and shaken w ith d ilu t e potassium hyd roxid e.

They suggested th a t la r g e h e t e r o c y c lic

r in g s w ith t e r t ia r y n itr o g e n were n e c e ssa r y fo r th e f o r m t lo n . +

—

+

—

2R3N(C1)C00C3H5 + K0H-» RSNH(C1) + H5C2-00( 0 ) 0-C( 0 ) -0C2H5 + KOI Any method u s in g em etine a t # 3 .5 0 a gram i s h ard ly p r a c t i c a l. D ie t h y la n ilin e and qu in in e were both t r ie d s e v e r a l tim e s, but w ith o u t su ccess. The prep aration o f pyrocarbonic e s t e r was thought t o be p o s s ib le through a much sim p ler procedure. KOC(0)OC3H5 + ClC(0)0C3H5-> EgC30C( 0 ) - 0 - 0 ( 0 ) 002Hs + KOI

10

Ttxe p rep a ra tio n o f potassium e th y l carbonate i s d e sc r ib e d a s prepared from potassium hydroxide and e t h y l carbonate ( 4 1 ) . F au rh olt (42) m entions th e p rep a ra tio n from p otassium e th o x id e and carbon d io x id e . The a d d itio n o f potassium hydroxide t o e t h y l carbonate, fo llo w e d by th e a d d itio n o f e t h y l chloroform ate f a i l e d t o y i e l d any pyrocarbonic e s t e r .

This was n o t e f f e c t i v e , probably because o f th e

form ation o f e th y l carb on ate.

P otassium e th y l carbonate was prepared

from potassium e th o x id e and carbon d io x id e .

E th y l chloroform a t e was

added t o th e potassiu m e th y l carbonate to form e t h y l pyrocarbonate in 50 p er c e n t y i e l d . The pyrocarbonic e s t e r s a re extrem ely r e a c t iv e compounds. They r e a c t w ith v io le n c e in the co ld s o lu t io n w ith hydrazine hydrate to form th e bicarbam ic e s t e r .

E th ylen e diamine and pyrocarbonic

e s t e r g iv e e x c e lle n t y i e l d s o f th e d i carbam ate. E th y l pyrocarbonate i s a l iq u id , in s o lu b le in w ater, which b o l ls a t 85®C. a t 12 mm. p ressu re and which decomposes when h eated in th e p resen ce o f a c id or a l k a l i .

I t a l s o decomposes above 100°C.

I t r e a c ts so r e a d ily w ith am in o a lco h o ls, p h e n o ls, and v a r io u s oth er compounds, th a t i t seemed p o s s ib le th a t i t would r e a c t e a s i l y w ith su lfa m id e.

However, when i t was h eated w ith su lfam id e

on a steam b a th , no carbethoxysulfam ide was d e te c te d . S in ce o n ly two groups o f in v e s t ig a t o r s (4 0 ,4 3 ,4 4 ) have rep orted work on th e pyrocarb on ates, t h e ir e x te n s io n in to common usage i s u n lim ite d .

Shamshurin (43) g iv e s a p rep a ra tio n o f t r i phenyl

c a r b in o l from phenyl magnesium bromide and pyrocarbonic e s t e r . C herbullez and Landolt (45) rep orted d e t e c t in g a tr a c e o f

n

su lfam id e when th ey h eated su lfa m ic a c id and urea to g eth er* H2N-S03H + H2NC0MH2 ■* H3N-S03HHg. + H2N-S02NH2 + C03 T his r e a c tio n was in v e s t ig a te d in t h i s la b o r a to r y .

I t would b e an

in e x p e n siv e and sim ple way to prepare a compound now s y n th e siz e d in few gram q u a n titie s when u se d . ments c a r r ie d ou t h e r e .

No su lfam id e was d e te c te d in e x p e r i­

However, su lfam id e i s n o t s t a b le when h eated above

i t s m e ltin g p o in t , so i f th e r e a c tio n proceeds as p o s tu la te d , i t would probably be decomposed b e fo re i s o l a t i o n .

12

E X B B R im m , P rep aration o f carboms th o x y s u lf amide *

ïh e su lfa m id e was

prepared by t h e method o f D egering and Gross ( 4 6 ) .

A sample o f 4 , 4 g ,

(0 ,0 4 5 m ole) o f dry su lfam id e i s d is s o lv e d in 100 m l, o f a b so lu te a lc o h o l ( d i s t i l l e d from magnesium m ethyls t e ) in a f la s k f i t t e d w ith r e f lu x con d en ser. m e t a llic sodium.

To t h i s f la s k i s added 1 ,2 g . ( 0 .0 5 m ole) o f The monosodium s a l t o f sulfam ide p r e c ip it a t e s

during th e r e flu x ln g o f th e a lc o h o lic s o lu t i o n .

This s a l t i s th en

f i l t e r e d w ith s u c tio n and h eated over a steam p la te u n t i l th e odor o f a lc o h o l no lo n g e r can be d e t e c t e d .

This i s th en added from a s o l i d -

a d d itio n f la s k t o 50 m l. o f r e d i s t i l l e d m ethyl chloroforma t e (E . K, Co.) in a 200 m l. th ree-n eck ed f l a s k .

I t i s added over a p erio d o f about

th r e e hours w ith s t i r r i n g , and th e tem perature i s m aintained a t th a t o f r e flu x ln g ch loroform ate.

I t i s h eated f o r an a d d itio n a l two

hours a f t e r a l l th e sodium s a l t o f su lfam id e i s added.

I t i s allow ed

to stan d o v ern ig h t and 1 .4 g . o f c r y s t a l li n e su b sta n ce s e t t l e d o u t. There a r e s e v e r a l grams o f th e amorphous sodium s a l t o f su lfa m id e . The c r y s t a l li n e m a te r ia l i s washed w ith petroleum e th e r , and iso p r o p y l e th e r .

I t i s re c r y s t a l li z e d from e th y l a c e ta t e and th e m e ltin g p o in t

i s 1 2 4 °-1 2 5 °C.

The y i e l d on th e b a s is o f su lfam id e u sed was about

23%.

P rep aration o f th e sodium s a l t o f sulfam id e and i t s r e a c t io n w ith e th y l c h lo r o f orm ate.

Commercial 200 p roof e th a n o l i s d r ie d by

means o f magnesium m eth ylate and l a t e r d i s t i l l e d .

Four grams o f

13

su lfa m id e (0 ,0 4 1 mole) i s added t o 100 m l. o f th e h o t a l c o h o l.

One

gram (0 .0 4 3 m ole) o f m e t a llic sodium i s added through th e con d en ser. The sodium s a l t p r e c ip it a t e s alm ost im m ed iately.

The s o lu t i o n i s f i l t e r e d

w ith s u c tio n and th e w h ite powder d ried in a vacuum d e s ic c a t o r . F i f t y m l. o f e th y l chloroforma t e i s added to a 200 m l. th r e e -n e c k e d , round-bottom ed f la s k f i t t e d w ith a s t i r r e r , con d en ser, and a s o lid - a d d it io n f l a s k .

The sodium s a l t o f su lfam id e i s added

from t h i s a d d itio n f l a s k t o th e r e f lu x ln g e t h y l ch loroform ate over a p e r io d o f fo u r h o u rs.

About 1 g . o f w h ite product i s ob ta in ed and a

dark y e llo w product i s ob tain ed i n la r g e r am ounts.

The dark y e llo w

product appears to be a sodium s a l t , w hich i s in s o lu b le in a lc o h o l and e th e r .

The l i g h t c r y s t a l li n e m a te r ia l i s very s o lu b le in a lc o h o l,

w a te r , and s l i g h t l y s o lu b le in e t h e r .

I t i s d is s o lv e d in e t h e r , then

l a t e r r e c r y s t a l li z e d from chloroform .

The carbethoxysulfam ide m elted

a t 134°-135®C.

T his r e p r ese n ts o n ly about 16% y i e l d .

A n a l, c a lc d . f o r CgHeN20 4S : Found:

H, 16*67,

N, 17.13

Attempted p rep aration o f carbom ethoxysulfam ide.

Four grams

(0 ,0 4 2 mole) o f su lfam id e was added to 250 m l, o f a b so lu te e th a n o l. The s o lu t io n was heated t o b o ilin g and 0 .9 5 g . o f sodium was added over a th r e e hour p e r io d .

The s o lu t io n was f i l t e r e d and th e sodium

s a l t was added t o 200 m l, o f liq u id s u lfu r d io x id e cooled by a d r y -ic e condenser.

M ethyl chloroform a t e (0 .0 4 2 mole) was added t o t h i s

s o lu tio n w h ile a c t i v e ly s t i r r i n g f o r an a d d it io n a l four h ou rs.

The

s u lfu r d io x id e was a llow ed to d i s t i l l o f f and th e w h ite s o l i d was removed from th e f l a s k . rem aining.

There was l i t t l e odor o f chloroform ate

S in c e th e carbom ethoxysulfam ide, p r e v io u s ly prepared, was

14

s o lu b le in m ethyl a c e t a t e , th e s o l i d was h eated w ith t h i s s o lv e n t* The w h ite c r y s t a ls th a t f e l l o u t o f s o lu t io n m elted a t 89 * 0 . Approxim ately 60 p er c e n t o f t h e su lfam id e was r e co v e r e d . o r ig in a l s o li d gave a p r a c t i c a ll y n e u tr a l s o lu t i o n .

The

No carbomethoxy­

su lfam id e was d e te c te d in th e in f u s i b l e m a te r ia l remaining* Attem pted p r e p a r a tio n o f carb eth oxysu lfam id e, u sin g eth a n o l as a s o lv e n t*

The sodium s a l t of su lfam id e (0*082 mole) was added t o

200 ml* o f eth a n o l (d r ie d over calcium h y d r id e ).

To t h i s su sp en sion

was added 9 g . o f e th y l ch loroform ate, w h ile keeping th e s o lu t io n c o o le d t o 0 * 0 .

The s o lu t io n was s t i r r e d f o r a t o t a l o f 12 hours

s in c e i t i s an u n sta b le su sp e n sio n . d e te c ta b le a t t h i s tim e . carb on ate.

No odor o f chloroform a t e was

However, th e re was a str o n g odor o f e t h y l

An alm ost q u a n tita tiv e re co v e r y o f sulfam id e was made. Attem pted p rep aration o f carbethoxysulfam ide u sin g n i t r o ­

benzene as s o lv e n t *

T h irty m is. o f e th y l chloroform ate ( r e d i s t i l l e d )

was added t o 125 m is . o f n itro b en zen e ( r e d i s t i l l e d ) in a 3 -n eck , round-bottom f l a s k .

To t h i s s o lu t io n 7 .4 g . (0 .0 5 4 mole) o f mono­

sodium s a l t o f sulfam id e was added over a p erio d o f 24 h o u r s. f la s k was h eated between 60*-85®C. throughout t h is p e r io d .

The

Attem pts

a t id e n t if y in g t h is r e s in o u s m a te r ia l, which was s o lu b le in w ater, were u n s u c c e s s fu l. A second experim ent was attem pted, u sin g th e same c o n d itio n s e x c ep t f o r low er tem peratu re, 40®-50®C« y ie ld in g a l i g h t y e llo w , amorphous m ass.

This a ls o r e s u lt e d in No d e f i n i t e m e ltin g p o in t

could be o b tain ed from th e product f a l l i n g o u t o f a sa tu r a te d aqueous s o lu t io n .

15

P rep aration o f N,N* d i carbethoxysulfam ide from s u l f u r y l c h lo rid e » u reth an e, and p y rid in e»

To a 1 l i t e r , th r ee -n e c k e d , round-

bottomed f l a s k , f i t t e d w ith a s t i r r e r , con d en ser, and dropping fu n n e l, i s added 500 ml# o f benzene (d r ie d ov er sodium and d i s t i l l e d ) .

To

th e benzene i n th e f l a s k , 15 g . (0 .1 6 9 mole) o f urethan ( r e c r y s t a l li z e d from benzene and d r ie d in vacuum d e s ic c a to r ) and 1 3 «4 g . (0 .1 6 9 mole) o f p y r id in e i s added.

Over a p e r io d o f th r e e h ours, 1 1 .4 g . (0 .0 8 5

m ole) o f s u lf u r y l c h lo r id e i s added, w h ile th e tem perature i s k ep t around 0 * 0 .

The f la s k i s allow ed t o warm up t o 30*0. and th e s o lu t io n

i s s t i r r e d v ig o r o u s ly f o r 14 h o u rs.

Prom th e benzene s o lu t io n 36*1 g .

o f w h it e , amorphous s o l i d i s o b ta in e d .

I t i s washed s e v e r a l tim es

w ith 10 m l. p o r tio n s o f d ilu t e h y d ro ch lo ric a c id and f i l t e r e d .

The

p r e c ip it a t e i s washed w ith c o ld w a ter t o remove any h y d ro ch lo ric a c id rem aining.

I t i s extrem ely d i f f i c u l t t o g e t r id o f t h e l a s t tr a c e s

o f p y r id in e .

The p r e c ip it a t e i s r e c r y s t a l li z e d from 95 per c e n t

e th a n o l forming r a th e r t h ic k , g la s s y c r y s t a l s .

I t i s r e c r y s t a l li z e d

from a lc o h o l f i v e tim e s, p la c ed i n an Abderhalden p i s t o l and d r ie d a t 10 mm. p ressu re f o r s e v e r a l h ou rs, a t th e tem perature o f re flu x in g to lu e n e .

The m eltin g p o in t i s 163*-164®C. (u n c o r r e c te d ).

A 90%

y i e l d was o b ta in ed . A n a l, c a lc d . f o r CgB^gNgOgS: Found:

C, 3 0 .1 ; 3 0 .1 .

0 , 30*1; H, 5 ,0 ; N, 1 1 .7 .

H, 5 .2 ; 5 .2 .

N, 1 1 .6 2 .

Attem pted p rep a ra tio n o f N,H* d i carb eth oxysu lfam id e.

A

sample o f 6 .5 g . (0 .0 6 7 m ole) sulfam ide (m .p. 9 2 .5 ° -9 3 * 0 .) was added to 400 m l. o f liq u id ammonia i n a 1 l i t e r , th ree-n eck ed f l a s k .

A

sm a ll amount o f Fe (N0g ) 3 .9H2o ( 0 .1 g .) was added t o t h i s s o lu t io n and th e m ixture was s t ir r e d f o r about 10 m in u tes.

Over a p eriod o f

16

two h ou rs, 4 .9 g . (0 .1 2 6 m ole) o f potassium was added. was con tin u ed f o r two and o n e -h a lf a d d it io n a l h o u rs. allo w ed to evap orate o v e r n ig h t.

The s t i r r i n g The ammonia was

The ammonia rem aining in th e f la s k

was p u lle d o f f by u se o f a w ater pump w ith fo u r c o n s e c u tiv e t r a p s , two empty, one f i l l e d w ith D r i e r i t e , and t h e l a s t f i l l e d w ith o i l .

The

f l a s k was heated s l i g h t l y f o r s e v e r a l hours and n itr o g e n was passed through th e system f o r an hour.

T his compound, su p p osed ly the

d ip otassiu m s a l t o f su lfa m id e, was added t o 100 m l. o f e th y l ch loro­ forma t e a s a s o lv e n t and r e a c t a n t .

The s a l t was p u lv e r iz e d and added

t o th e e th y l chloroform ate over a p e r io d o f two h ou rs.

I t was o n ly

s l i g h t l y s o lu b le in th e c h lo r o f orm ate, but i t was b e lie v e d t h i s d i f ­ f i c u l t y m ight be overcome t o some e x te n t by means o f a c t i v e s t i r r i n g and h e a tin g a t th e b o ilin g p o in t o f th e ch loroform ate. The r e a c tio n m ixture was s t i r r e d f o r a p eriod o f 12 hours near the b o ilin g p o in t o f th e ch loroform ate.

A sm all amount o f w h ite

c r y s t a ls and about 10 g . o f l i g h t brown m a te r ia l were r eco v ered . l i g h t c r y s t a ls were d is s o lv e d in a b so lu te e th a n o l.

The

The darker

m a te r ia l was washed w ith eth a n o l and th e w ashings added t o th e f i r s t a lc o h o l s o lu t io n .

I d e n t if ic a t io n o f th e a lc o h o l- s o lu b le p o r tio n

showed i t to be m ainly m onocarbethoxysulf amide w ith tr a c e s o f th e d icarb eth oxy d e r iv a t iv e .

The m eltin g p o in t was 130e-131®G.

P rep aration o f N.H1 dicarb opropoxysulfam ide.

There i s added

to 400 m l. o f anhydrous e th e r 2 0 .6 g . ( 0 .2 mole) o f propylcarbam ate, and r e d i s t i l l e d d ried p y r id in e ( 0 .2 mole) in a th ree-n eck ed f l a s k . S u lf u r y l c h lo r id e ( 0 .1 mole) p r e v io u sly d i s t i l l e d and d ilu te d w ith 100 m l. o f e th e r i s added over a 3 hour p erio d t o th e s o lu t io n . D uring t h i s tim e th e s o lu t io n i s cooled to 0 *0. and s t ir r e d

17

v ig o r o u s ly .

The s t i r r i n g i s c o n tin u e d f o r an a d d i t i o n a l tw e n ty - f o u r

h o u rs w h ile a llo w in g th e s o l u t i o n t o r i s e to 30*0. cru d e p ro d u c t i s o b ta in e d .

F i f t y grams o f

A f te r w ashing w ith d i l u t e h y d ro c h lo ric

a c i d , 25 g . o f c o m p a ra tiv e ly p u re p ro d u c t i s o b ta in e d , which i s a b o u t 94 p e r c e n t o f t h e o r e t i c a l y i e l d .

The compound i s found to be v e ry

s l i g h t l y s o lu b le in w a te r , in s o lu b le i n benzene and e t h e r .

I t was

re c r y s t a l l i z e d from d i l u t e a lc o h o l and m elted a t 135*0. A n al, c a lc d . f o r C8H16N206S: Found:

C, 5 5 .3 8 , 3 5 .5 5 .

C, 3 5 .8 2 .

N, 1 0 .4 5 .

H, 1 0 .7 4 , 1 0 .9 2 .

A ttem pted p r e p a r a tio n o f H, N -d in s th y l-N ' - c a rb e th o z y s u lf a m id e .

To a s o lu tio n o f 300 m is. o f a b s o lu te e th e r was added 4 .8 g .

(0*054 m ole) o f e th y lc a rb a m a te in a 1 l i t e r io u n d -b o tto m f l a s k .

The

s o lu t i o n was s t i r r e d and cooled w ith ic e w a te r as 8 g . o f d im eth y l s u l f amyl c h lo r id e was dropped i n over a two h o u r p e r io d .

W hile t h e

s o lu t i o n was s t i r r e d , one drop o f p y r id in e was added and s t i r r i n g was c o n tin u e d f o r a n o th e r t e n h o u rs .

The two r e a c ta n t s were re c o v e re d

unchanged. A nother a tte m p t was made u s in g m olar q u a n t i t i e s o f p y r id in e and g r a d u a lly warming th e c o o le d s o lu tio n up to 50*0.

Again t h e two

r e a c t a n t s were re c o v e re d l a r g e l y unchanged.

A m inute q u a n ti ty o f a

m a t e r i a l m e ltin g a t 70®-71*C. was o b ta in e d .

The amount was n o t s u f ­

f ic ie n t f o r c h a ra c te riz a tio n . A ttem pted p r e p a r a tio n o f N, Kf d i b u ty l , H, NT d i c a rb e th o x y ­ s u l f ami d e . H9C4—NHCOOEt + CISOgOl

i âi SS —^

K9C4—N (COOSt )SOgN— (GOO Et ;

C5H5N-KCI

+

18

E th y l N -b u ty lc a rb a m ate was p r e v io u s ly p re p a re d from b u t y l amine and e th y l c h lo ro fo rm a te .

T here was added to 350 m l. o f d r ie d

t o l u e n e , 29 g . o f e th y l N -b u ty lc a rb a m a te ( 0 .2 m o le ), and 0 .2 mole o f p y r id i n e .

S u l f u r y l c h lo r id e ( 0 .1 m ole) was th e n added dropw ise t o the

ic e co ld s o lu t i o n w h ile s t i r r i n g v ig o ro u s ly .

The s o lu tio n was s t i r r e d

f o r a t o t a l o f 12 h o u rs w h ile a llo w in g th e s o lu t i o n t o warm up t o room te m p e ra tu re .

A f te r rem oval o f s o lv e n t, and n e u t r a l i z i n g an d d i s t i l l i n g

th e p y r i d i n e , a b o u t 60$ o f carbam ate was re c o v e re d unchanged.

Ho

su lfa m id e d e r i v a ti v e was d e te c te d . The r e a c t i o n o f e th y l N -m ethylcarbam ate a n d s u l f u r y l c h lo r id e was c a r r i e d out a l s o .

I n t h i s c a se , th e m a jo r ity o f t h e c a r b a r a te was

re c o v e re d unchanged to o . A ttem pted p r e p a r a tio n o f N, H* d ip h e n y l, N N* d i c a rb e th o x y ­ s u l f ami d e .

Ten grams (0 .6 7 m ole) o f e t h y l , H -phenyl carbam ate and

5 .3 g . o f p y rid in e were added t o 450 m is . o f d r ie d benzene i n a 1 l i t e r , t h r e e - n e eked, round-bottom ed f l a s k .

The f l a s k was c o o le d w ith

ic e w a te r and k e p t below 1 0 °0 . w h ile ad d in g 4 .5 9 g . o f s u l f u r y l c h lo r id e w ith in n i n e t y m in u tes.

The s o lu t i o n was s t i r r e d v ig o ro u s ly

f o r o v e r t e n h o u rs w h ile a llo w in g t h e s o lu t i o n te m p e ra tu re t o r i s e t o t h a t o f t h e room. F o u rte e n grams o f a w h ite s o l i d p ro d u c t w as o b ta in e d a t th e c o m p le tio n o f t h e r e a c t i o n .

I t was fo u n d t o be s o lu b le in e th a n o l ,

w a te r, m eth a n o l, and a number o f o th e r s o lv e n ts .

The l a s t t r a c e s o f

p y r id in e were removed by w ash in g w ith d i l u t e h y d ro c h lo ric a c i d . A f te r r e c r y s t a l l i z a t i o n a m e ltin g p o in t of 171°C. w as o b ta in e d . However, t h i s p ro d u c t was n o t s u b m itte d f o r a n a l y s i s and was n o t sa v e d , f o r l a t e r p r e p a r a tio n s were p la n n e d .

19

F iv e o th e r a tte m p ts fo llo w in g a v e iy s i m i l a r p ro c e d u re f a i l e d t o y i e l d any s o l i d m a t e r i a l t h a t c o u ld be i d e n t i f i e d , o t h e r th a n th e s t a r t i n g m a t e r i a ls .

A p l a u s i b l e e x p la n a tio n o f t h e i n a b i l i t y t o

r e p e a t t h e f i r s t work cannot be g iv e n . A ttem pted p r e p a r a ti o n o f H, NT d ip h e n y l N, N* d ic a r b e th o x y s u lf a m id e .

E th y l, N -phenylcarbam ate (41 g . , 0 .2 5 m o le ), p r e v io u s ly

p r e p a r e d , was added to 300 m l. o f b e n z en e . added to t h i s h e a te d s o l u t i o n .

P o ta ssiu m (10 g .) was

A f t e r a l l t h e p o ta s s iu m ta d r e a c te d

w ith th e carb am ate, s u l f u r y l c h lo r id e (0 .1 2 5 m ole) was added t o the warm s o lu t i o n d ro p w ise . th e a d d i t i o n .

The s u s p e n s io n was s t i r r e d v ig o ro u s ly d u rin g

The s o lv e n t was removed b u t no c r y s t a l s a p p e a re d .

An

a tte m p t was made to d i s t i l th e l i g h t brown l i q u i d , f i r s t a t 1 mm. p r e s s u r e , and f i n a l l y a t 0*005 mm. p r e s s u r e a t 45*0.

The r e s u l t i n g

p ro d u c t s o l i d i f i e d a f t e r s e v e r a l days and i t was s u b je c te d to s u b lim a tio n a t 0*005 mm. p r e s s u r e .

The sublim ed p ro d u c t was

i d e n t i f i e d a s e th y l N -p h e n y lc a rb am a te . A ttem pted p r e p a r a tio n o f N, H, Nf , N1 te t r a c a r b e t h o x y s u lf a m id e . H(KT-C00C2H5)2 + CISOgCl -» (HqC200G)2NS02N(C00C2H5 )3 + CgH ^.H C l A zam alonie e s t e r was p re p a re d a c c o rd in g t o th e m ethod o f Tompkins and D e g e rin g (3 8 ).

Eed i s t i l l e d azam alonie e s t e r (3 5 .4 g . ,

0 .2 2 m ole) was added to 500 m l. o f r e d i s t i l l e d b e n z en e .

To t h i s

ro u n d-bottom ed f l a s k was added 1 7 .4 g . (0 .2 2 m ole) o f d r ie d p y r id i n e , and i t was c o o le d w ith i c e .

S u lf u r y l c h lo r id e (1 4 .9 g . , 0 .1 1 m ole)

was added o v e r a two h o u r p e r io d .

S t i r r i n g was c o n tin u e d f o r a n o th e r

12 h o u rs , w h ile a llo w in g th e s o lu t i o n t o warm up t o room te m p e ra tu re .

20

About 41 g . o f y e llo w c o lo re d m a t e r i a l was re c o v e re d a f t e r filte rin g . T h is p ro d u c t was s o lu b le in w a te r , a n d m ost o r g a n ic s o lv e n t s . I t was r e c r y s t a l l i z e d from c h lo ro fo rm s e v e r a l t i m e s . sublim ed tw ice a t 0 .0 0 5 mm. p r e s s u r e . p u r i f i e d pro d i e t i s 109°C.

F i n a l l y , i t was

The m e ltin g p o i n t o f t h i s

The m e ltin g p o in t o f a z am a lo n ie e s t e r i s

49*-50*0. and p y r id in e h y d ro c h lo rid e m e lts a t 82*0.

A s a tis fa c to ry

e x p la n a tio n o f t h e p ro d u c t o b ta in e d cannot be g iv e n a t t h i s tim e . A n a l, c a lc d . f o r Found:

:

7 .5 .

H, 8 .9 5 , 9 .0 5 .

A ttem pted p r e p a r a tio n o f e t h y l a llo p h a n a te . u re a was d is s o lv e d in 125 m is . o f w a te r.

One mole o f

C a lc u la te d am ounts o f sodium

h y d ro x id e w ere added a t th e same tim e e th y l e h lo ro fo rm a te was added d ro p w ise .

The f l a s k was a g i t a t e d d u rin g th e a d d i t i o n o f e th y l

c h lo r e fo r m a te .

The s o l u t i o n was n e u tr a li z e d w ith a c e t i c a c i d an ho u r

a f t e r th e c o m p le tio n o f t h e a d d i t i o n . u n d e r re d u c e d p r e s s u r e .

The w a te r was removed by h e a tin g

The s o li d re m a in in g i n t h e f l a s k was found

t o be m ain ly u n re a c te d u r e a and s a l t , b u t no e th y l a llo p h a n a te was d e te c te d . A ttem pted p r e p a r a tio n o f Tü-chloros u l f o n y l a c e t a n i l i de.

A

s l i g h t m o d if ic a tio n o f t h e s a th o d o f Meybeck (17) was u s e d i n t h i s a tte m p t.

To a f l a s k c o n ta in in g to lu e n e was added 9 .2 g . ( 0 .4 m ole)

o f sodium . sodium .

The f l a s k was h e a te d and a g i t a t e d to form f i n e l y d iv id e d

Then 56 g . ( 0 .4 m ole) o f a c e t a n i l i d e i n 350 m l. o f benzene

was added t o th e to lu e n e s u s p e n s io n o v e r a f o u r hour p e r io d w h ile h e a tin g up t o th e b o i l i n g p o i n t .

The r e a c t i o n m ix tu re was s t i r r e d

21

v ig o r o u s ly d u rin g t h i s p e rio d and f o r 14 a d d i t i o n a l h o u rs.

F ifty -

f o u r gram s o f s u l f u r y l c h lo r id e ( 0 .4 m ole) i n 300 m l. o f benzene m s added t o th e a c t i v e l y s t i r r e d s o lu t i o n o f th e sodium s a l t o f a c e ta n ilid e .

The r e a c t i o n g r a d u a lly to o k on an orange c o lo r .

r i n g was c o n tin u e d f o r t e n more h o u rs.

S tir­

The s o l u t i o n was washed w ith

s e v e r a l p o r tio n s of c o ld w a te r t o remove sodium c h lo r id e .

A fte r

f i l t r a t i o n and rem oval o f s o lv e n t, i t was found t h a t t h e p ro d u c t was m ain ly p - c h l o r o a c e t a n i l i de. is o la te d .

Mo c h lo r o s u li ti n y l - a c e ta n il i d e was

S e v e r a l f u r t h e r a tte m p ts w ere a ls o u n s u c c e s s fu l. P r e p a r a tio n o f sym. d ip h e n y ls u lfa m id e .

i s e s s e n t i a l l y t h a t o f Wohl (4 7 ).

The p ro c e d u re u s e d

A d d itio n i s made o f 84 m l,

(0 .9 2 m ole) o f r e d is t i l l e d a n i l i n e to 300 m l. o f anhydrous e t h e r . The f l a s k i s co o led by ic e c o ld f r e e z in g m ix tu re .

S u l f u r y l c h lo r id e

(1 6 .4 m l.) i n 75 m l. o f e t h e r i s added slo w ly and w ith v ig o ro u s s t i r r i n g o v e r a f o u r h o u r p e r io d . h o u rs .

The s o lu t i o n i s s t i r r e d f o r a n o th e r two

The a n i l i n e h y d ro c h lo rid e i s removed by f i l t r a t i o n .

D ilu te

h y d r o c h lo r ic a c id i s added t o th e s o l u t i o n t o remove a n y a n i l i n e s t i l l p re s e n t.

The e th e r i s e v a p o ra te d and c a lc u la te d amounts o f sodium

h y d ro x id e i s added and t h e s o lu t i o n i s h e a te d on t h e h o t p l a t e . r e d o i l s e p a r a te s out from th e aqueous l a y e r .

Wohl was a b le to

c r y s t a l l i z e an o i l and i d e n t i f i e d i t a s azo b en zen e. d id n o t c r y s t a l l i z e in th e s e e x p e rim e n ts.

However, th e o i l

D ip h en y l su lfa m id e f e l l o u t

o f s o lu t i o n upon ad d in g d i l u t e h y d r o c h lo r ic a c id . from c h lo ro fo rm and m e lts a t 111°C.

A

I t is re c ry s ta lliz e d

T h is i s n o t a v e r y p r a c t i c a l

m ethod f o r l e s s th a n 2 g. o f p ro d u c t i s o b ta in e d .

22

A ttem pted p r e p a r a ti o n o f sym. dLp h e n y l s u lfa m id e . hydro c h lo r i c a c id was added t o 8 g . o f r e d i s t i l l e d a n i l i n e .

C o n c e n tra te d I t was

th e n h e a te d o v e r a steam p l a t e t o rem ove e x c e ss h y d r o c h lo r ic a c i d .

The

a n i l i n e h y d ro c h lo rid e was t h e n added t o 250 m is . o f a b s o lu t e e th a n o l. Four gram s o f s u lfa m id e was a l s o added to th e s o lu tio n an d r e f lu x e d f o r 24 h o u r s .

None o f th e d e s ir e d d ip h e n y ls u lfa m id e was d e te c te d , b u t

some su lfa m id e re c o v e re d .

P r e p a r a tio n o f N, N* d i e t h y la m in o e th a n o l.

The m ethod f o l ­

lowed i s a m o d if ic a tio n o f S h r in e r (2 7 ).

(Et)g-NH + H g C ^ C H g

-> MeOH

Etg-NCHgCHgOH

E th y le n e o x id e , 50 g . (1 .1 4 m oles) i s h e a te d i n a f l a s k and p a sse d th ro u g h an e l e c t r i c f u r n a c e , h e a te d betw een 4 5 o-50°C .

The

e th y le n e i s th e n p a sse d i n t o th e b o tto m o f a long tu b e th ro u g h a p o ro u s gas d i f f u s e r i n to 60 g . o f d ie th y la m in e a n d 60 g. o f m e th a n o l. t e s t tu b e i s c o n n e cte d to a r e f l u x c o n d e n se r.

The

The tu b e is h e a te d by

a w a te r b a th and t h e te m p e ra tu re i s m a in ta in e d betw een 4 5 o-60°C . th e e th y le n e o x id e was added o v e r a p e rio d o f 3 h o u rs.

A ll

A f te r rem oval

o f th e m eth a n o l, 47 m l. o f p ro d u c t d i s t i l l i n g a t 1 5 9 °-1 6 0 eC. was c o l ­ l e c t e d , w hich r e p r e s e n t s a b o u t 44% o f th e t h e o r e t i c a l y i e l d . B ie th y la m in o e th a n o l was a ls o p re p a re d from e th y l e nec h lo r o h y d rin (28) i n 70% y i e l d . P r e p a r a tio n o f die t h y l amino e t h y lb r omi de hydro b ro m id e. E s s e n t i a l l y th e method d e s c rib e d i n th e l i t e r a t u r e in t h is s y n th e s is .

(48) i s fo llo w e d

S l i g h t l y l e s s th a n 4 m oles o f 2 -d ie th y la m in o e th a n o l

25

i s added, th ro u g h a d ro p p in g f u n n e l, c o n s tr u c te d from a c o n d e n se r, w ith c a p i l l a r y and sto p c o c k s e a le d on.

Cold w a te r i s p a s se d th ro u g h

th e condenser w ith a c i r c u l a t i n g pump.

The die th y la m in o e th a n o l i s

dropped i n o v e r a 15 h o u r p e r io d i n t o a 3 l i t e r , ro und-bottom ed f l a s k c o n ta in in g 13 m oles o f 48% hydrobrom ic a c i d .

The s o l u t i o n i s s t i r r e d

w ith a g l a s s p addle s t i r r e r w h ile k e e p in g c o o l w ith i c e w a te r.

The

3 l i t e r f l a s k i s th e n co nnected to a f r a c t i o n a t i n g column ( g la s s h e l i c e s ) and 460 m l. a re c o l l e c t e d and d is c a r d e d . d im in ish e d and l i q u i d i s r e f l u x e d f o r one h o u r.

R ate o f h e a tin g i s S u c c e s s iv e ly ,

f r a c t i o n s w ere ta k e n o f f an d d is c a r d e d , fo llo w e d by r e f lu x i n g u n t i l 1 ,5 6 0 m l. a re c o ll e c t e d i n a l l . and po u red i n to two b e a k e r s .

The d a rk c o lo r e d r e s id u e i s d iv id e d

A f te r the l i q u i d c o o ls t o a b o u t 7 0 °C .,

400 m l. o f a c e to n e a re added to e a c h b e a k e r and s t i r r e d w e l l . l i q u i d i s a llo w e d t o s ta n d f o r 15 h o u rs i n i c e .

The

The m a t e r i a l i s th e n

f i l t e r e d and washed w ith a c e to n e u n t i l i t becomes c o l o r l e s s . o b ta in e d 530 g . o f d ieth y la m in o e th y lb ro m i de hydro brom ide.

There i s

Between

50-60 % o f t h e o r e t i c a l y i e l d i s o b ta in a b le i f a l l t h e f i l t r a t e s a r e worked u p . P r e p a r a tio n o f 2 d ie th y la m in o e th y la m in e .

L iq u id ammonia i s

p a s se d i n t o 750 m is . o f 90% e th a n o l u n t i l th e w e ig h t g a in i s b e t t e r th a n 100 g .

T h is i s r e p e a te d in a second f l a s k a n d t h e a lc o h o lic

ammonia i s added t o 200 g . d i e t hylam ino e th y l brom ide hydro brom ide (0 .7 6 m ole) i n a 2 l i t e r f l a s k .

The f la s k s a re s to p p e re d and s e t

a s id e w ith p e r io d ic s h a k in g f o r 6 d a y s.

At t h e and o f t h i s p e r i o d th e

d ieth y la m in o e th y la m in e s o lu tio n i s t r a n s f e r r e d t o a la r g e e v a p o ra tin g d is h and s t i r r e d p e r i o d i c a l l y w h ile i t i s e v a p o ra te d t o a r a t h e r

24

c r y s ta llin e m a te ria l.

T h is i s t r a n s f e r r e d t o a b e a k e r and a b o u t 100 g„

o f sodium h y d ro x id e i n 125 m is . o f w a te r i s a d d e d .

The s o l u t i o n

s e p a r a te s i n to an u p p er l a y e r o f brown o i l and low er l a y e r w hich c o n ta in s a c o n s id e ra b le amount o f u n d is s o lv e d sodium b ro m id e. A p p roxim ately 50 m is . o f w a te r i s added to d is s o lv e t h e s a l t . E x t r a c ti o n i s made w ith f o u r p o r tio n s o f b e n z e n e . d r ie d o v e r p o ta s s iu m c a rb o n a te o v e r n ig h t. a tm o sp h e ric p r e s s u r e t h e n e x t d a y .

The e x t r a c t s a re

The benzene i s removed a t

The d ie th y la m in o e th y la m in e i s

r e p o r te d t o b o i l a t 7 9 °-8 2 0C. a t 85 mm. p r e s s u r e .

The f r a c t i o n

b o i l i n g i n t h i s ran g e amounted t o aro u n d 13 g . w hich i s o n ly a b o u t 15% o f t h e o r e t i c a l y i e l d .

A nother i n v e s t i g a t o r r e p o r te d y i e l d s above

20% (4 9 ). A ttem pted p r e p a r a ti o n o f die th ylam inoe t h y l c a rb a m a te .

One

mole o f 2 d ieth y la m in o e th a n o l and 67 g . (0 .6 7 m ole) o f u re th a n were added t o a 500 m is. ro u n d-bottom ed f l a s k .

A sm a ll amount o f anhydrous

hydrogen c h lo rid e was p a sse d i n f o r a few se co n d s. th e n h e a te d w h ile s t i r r i n g s im u lta n e o u s ly .

The s o l u t i o n was

The taupe r a t u r e o f t h e

s o lu t i o n was m a in ta in e d aro u n d 90*0. f o r a p e r io d o f e ig h t h o u r s .

At

th e end o f t h i s p e r io d , t h e c o lo r l e s s s o l u t i o n had a c q u ir e d a d ark brown c o lo r .

A f te r m aking i t a lk a lin e w ith sodium c a rb o n a te th e

c o n te n ts o f th e f l a s k d i s t i l l e d o v e r f i r s t un d er a tm o sp h e ric p r e s s u r e and th e n u n d e r vacuum.

The l a s t f r a c t i o n d i s t i l l e d gave some d i f ­

f i c u l t y becau se o f te n d e n c y t o s o l i d i f y . d r ie d on a porous p l a t e m alte d a t 48°C.

T h is l a s t f r a c t i o n when D ie th y l a m in o e th y l carbam ate

i s r e p o r te d t o m elt a t 43 ° C ., and e th y l carbam ate i t s e l f m e lts a t 4 9 °C.

S in c e most o f th e d ieth y la m in o e th a n o l was re c o v e re d unchanged.

25

l i t t l e o f exchange r e a c t i o n must have ta k e n p la c e .

However, a

d e r i v a ti v e o f t h e 48°C. p ro d u c t was made by d i s s o l v in g i t i n e t h e r an d p y r id in e and a d d in g s u l f u r y l c h lo r id e .

The p r o d u c t o b ta in e d a f t e r

f i l t e r i n g , w ashing w ith d i l u t e h y d ro c h lo ric a c id and w a te r, was found t o m elt a t 161*0.

H, H* d ic a rb e th o x y su lfam id e m e lts a t 1656-1 6 4 °C .,

w hich confirm s t h a t th e u re th a n was unchanged. A ttem pted p r e p a r a tio n o f d ie th y la m in o e t h y l ca rb a m a te . was p re p a re d e s s e n t i a l l y by t h e method o f He l i n e r (2 6 ).

T h is

F our hundred

grams o f e t h e r was added to a th re e -n e c k e d f l a s k , fo llo w e d by 100 g . (1 m ole) o f l i q u i d phosgene.

Then one hundred and se v e n te e n grains

(1 m ole) o f 2- d i e t h y l amino e th a n o l (C. and 0 .) was d is s o lv e d i n 350 g . o f e t h e r and dropped in o v e r a f iv e h o u r p e rio d .

The f l a s k was c o o le d

by an i c e b a th and a d ry ic e condenser was a tt a c h e d .

The s o lu t i o n was

s t i r r e d f o r an a d d it io n a l two h ours and th e n th e e t h e r was removed by f i l t r a t i o n .

The s o l i d was washed w ith f r e s h e th e r to remove any

e x c e s s phosgene and a lc o h o l. The d i e t h y l amino e th y lc h lo r o form ate h y d ro c h lo rid e was th e n re su sp e n d e d i n e th e r i n a f l a s k .

E ig h ty m i l l i l i t e r s o f l i q u i d ammonia

was c o ll e c t e d and allow ed t o p a s s i n t o t h e two l i t e r f l a s k w h ile s t i r ­ r i n g th e s o lu t i o n v ig o ro u s ly .

T h is a d d it io n r e q u ir e d about fo u r h o u r s .

The p r e c i p i t a t e g r a d u a lly d is s o lv e d and a more c r y s t a l l i n e m a t e r i a l s e p a r a te d o u t.

A f te r f i l t e r i n g o f f th e ammonium c h lo r i d e , anhydrous

hydrogen c h lo r id e i n e th e r was added to th e e t h e r e a l s o l u t i o n , presum ably c o n ta in in g th e carb am ate.

Im m ediately p r e c i p i t a t i o n to o k p l a c e , and

hydrogen c h lo r id e was added a s lo n g a s any p r e c i p i t a t i o n o c c u rr e d . H e iln e r r e p o r te d a y i e l d o f 60% o f a compound m e ltin g a t 154*0.

The

compound p re p a re d i n t h i s la b o r a to r y , when r e c r y s t a l l i z e d from a b s o lu te e th a n o l, m elte d a t 196®-197°C. ( d e c .) .

26

The r e s u l t s o f a second p r e p a r a tio n w ere e s s e n t i a l l y the same a s t h e firs t. A n al, c a lc d . f o r C7H17lîg02C l: Pound:

C, 4 6 .2 .

H, 8 . 6 .

C, 4 2 .6 .

H, 8 . 6 .

N, 1 4 .2 .

N, 8 . 4 .

Attempted preparation of diethylamino ethyl carbamate. C o n tin u ed . N o te:

The dieth y lam in o e th a n o l u s e d in t h i s e x p e rim e n t was r e a c te d w ith

p h e n y l is o c y a n a te .

The p ro d u c t o b ta in e d m elte d a t 2760~276.5°C .

A n a ly s is showed C, 71% and H, 4.35%, and o t t e r r e s u l t s i n d i c a t e t h a t th e d ieth y la m in o e th an o l u se d was a m ix tu re o f mono- and di e th y la m in o e th a n o l. The p r e p a r a tio n o f d ieth y la m in o e th y lc a rb a m a te was acco m p lish ed l a t e r by u s in g d ieth y lam in o e th a n o l p re p a re d i n t h i s l a b o r a to r y .

It

was p re p a re d by a s im i la r ms t hod o f p re p a rin g b e n z y l carb am t e (50) u s in g aluminum iso p ro p o x id e and u re th a n . P r e p a r a tio n o f die th y la m in o a c e to n it r i l e . HC(0)H + NaHSOg

H2G(0H)80^Na

EgC(0E)80gNa + EtgNE -» EtgN-GHgSO^Na

StgNCHgSOgNa + KCN -> (S t )âN-CHgC5N E s s e n t i a l l y t h e msthod o f L uten (51) i s u s e d ,

F iv e m oles o f

form aldehyde a re added to sodium b i s u l f i t e (5% e x c e ss) w ith good s tirrin g .

A f te r co m p letio n o f r e a c t i o n as ev id en ced by c e s s a tio n o f

e v o lu tio n o f h e a t , an e q u iv a le n t amount o f d ie th y la m in e i s added to th e s o lu t i o n a t room te m p e ra tu re . cyanide s o l u t i o n i s th e n added. la y e r.

A s a tu r a te d aqueous p o ta ssiu m The a m in o n itr ile fo a n s an o i l y upper

T his l a y e r i s s e p a r a te d and d r ie d o v e r p o ta s s iu m c a rb o n a te and

27

distilled.

The yield was 75% of theoretical value.

Preparation of M, N die thylethyl euediamine. The diethylaminoaceto nitrile previously prepared is reduced with sodium and butanol. Crude butanol is used and approximately 15% yield is obtained. One investigator (52) reported about 50% yield, but different quantities, and ethanol was used for the reduction. P r e p a r a tio n o f e t h y l , N -phenyl ca rb a m a te . i s added t o 150 m is . o f d r ie d b e n z e n e .

A n ilin e ( 1 .2 m oles)

Then, drop by d ro p , e th y l

chloroform a t e (0 .5 m ole) i s added to t h i s s o lu t i o n and sh a k en . p r e c i p i t a t e forms and th e s o lu t i o n becomes warm.

A

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

e x tr a c t e d w ith 10 m l. p o r tio n s o f 10% h y d ro c h lo ric a c id s o l u t i o n . T h is i s fo llo w e d by 10 m is. p o r tio n s o f w a te r. by d i s t i l l a t i o n un d er red u ced p r e s s u r e . 350-37°C . p e tro le u m e th e r .

The benzene i s removed

The re s id u e i s ta k e n up in

I t i s r e c r y s t a l l i z e d and m elte d a t 47*-

48°C. P henyl u re th a n i s a l s o p re p a re d from p h e n y l is o c y a n a te and e th a n o l. A ttem pted p r e p a r a tio n o f e t h y le n e s u lfa m id e . HgNCKgCHgNHg + CISOgCl

HN-SOgKH \ / (3H01) HaC-0Hs

E t h y l en edi amine was d i s t i l l e d from m e t a l l i c sodium . d i l u t i o n te c h n iq u e was u s e d .

High

A l e v e l i n g b u lb to w hich 0 .3 mole o f

s u l f u r y l c h lo r id e i n 300 m l. o f p e tro leu m e th e r (6 0 o-7 0 oC -) had been added, was co n n ected by ru b b e r tu b in g t o a c a p i l l a r y co n n e cte d t o a d i s t i l l i n g f la s k .

The d i s t i l l i n g f l a s k had a s id e arm w i t h c a p i l l a r y

28

tu b in g le a d in g i n t o a r e a c ti o n f l a s k .

I t a ls o had t h e same q u a n t i t i e s

o f s u l f u r y l c h lo rid e and p e tro le u m e th e r a s th e l e v e l i n g b u lb .

From

th e o t h e r s id e o f t h e f l a s k , an i d e n t i c a l s e tu p was u se d e x c e p t t h a t m ercury was added to th e l e v e l i n g b u lb to d is p la c e t h e e th y le n e diam ine and 250 m l, o f p e tro leu m e t h e r in th e d i s t i l l i n g f l a s k .

The

r e a c ti o n f l a s k was f i t t e d w ith a H ershberg s t i r r e r and c o n ta in e d 300 m l. o f p e tro le u m e th e r . 48 h o u r s .

The two r e a c t a n t s were added o v e r a p e rio d o f

D urin g t h i s tim e v ig o ro u s s t i r r i n g was c o n tin u e d .

A f te r

rem oving th e s o l v e n t , th e w h ite s o li d rem a in in g was found t o be h ig h ly s o lu b le i n w a te r and in s o lu b le in p r a c t i c a l l y a l l o t h e r s o lv e n ts . e f f o r t s to i s o l a t e proposed e th y le n e su lfam id e f a i l e d , m e ltin g p o in t could be d e te rm in e d .

A ll

No d e f i n i t e

E v id e n tly i t i s a lo n g c h a in

compound s in c e i t g r a d u a lly decomposed c o n s id e ra b ly over 200*0.

The

a d d it io n o f t h e two r e a c ta n t s a t te m p e ra tu re s a s low a s -4 0 * 0 . f a i l e d to giv e a compound which could be i d e n t i f i e d . P r e p a r a tio n o f g - a m in o e th y ls u lfu r ic a c id . EOCEg-CEgNEg + H2 S04 -> HOGHg-CEgEHg-H33 0 4 HOGHg-CHgKHg-ïïg S 0 4 +

0CHg-CK2 -NH3

1

^SOgO + HB0 T his i s p re p a re d by m o d if ic a tio n o f Wanker’ s method (3 3 ). S ix m oles each o f eth an o lam in e and 95% s u l f u r i c a d d , s e p a r a te l y a re d i l u t e d w ith h a l f t h e i r w e ig h t o f w ater and c o o le d .

A f t e r com bining

th e two p o r tio n s th e y a re h e a te d u n d e r reduced p r e s s u r e u n t i l 95% o f c a lc u la t e d amount o f w a te r i s rem oved.

29

Préparation of ethyleneim ine ( a z i r i d i n e ) .

O-CHg- CH3KH5 + 2K0H

H N H2d'-CH2 + K3S04 + HgO

\s o s To 282 g . o f 2 - a r a in o e th y ls u lfu r ic a c id t h e r e i s added 880 g . o f 40% p o ta ssiu m h y d ro x id e . fla s k .

T his m ix tu re i s d i s t i l l e d from a 5 l i t e r

The f l a s k i s h e a te d g r a d u a lly and e x te n s iv e bumping o c c u rs

u n le s s a gas stre a m i s le a d i n t o t h e s o lu t i o n .

Extrem e c a u tio n m ust

be ta k e n i n h e a tin g t h i s s o lu tio n , fb r th e r e i s p o s s i b i l i t y o f b re a k in g equipm ent "with t h e extrem e h e a t in v o lv e d . ab out 250 m l. i s c o ll e c t e d .

H eatin g i s c o n tin u e d u n t i l

P o tassiu m hydroxide i s added t o t h i s

d i s t i l l a t e u n t i l d i s t i n c t la y e r s a re o b ta in e d and s e p a r a te d . ene im ine l a y e r i s re p e a te d 1 y f i n a l l y w ith sodium .

The e t h y l ­

d r ie d w ith p o tassiu m hy d ro x id e and

D uring th e a d d itio n o f p o ta ssiu m hy d ro x id e and

sodium c a re must be ta k e n n o t to v o la tiz e th e e th y le ne im in e .

The

s o lu t i o n i s th e n d i s t i l l e d w ith V igereux column, b u t on ly a b o u t 4 g. b o i l a t 55e- 5 7 60 . 60o-120°C .

The l a r g e s t f r a c t i o n , a b o u t 30 g . , b o i l s betw een

There was a ls o c o ll e c t e d 3 .4 m l. o f e th y le n e im in e dim er

b o i li n g a t 126°-127®C.

The sm a ll y ie ld can p ro b a b ly be e x p la in e d b y

d i f f i c u l t y o f s e p a r a tin g th e monomer and dim er w ith V igereux colum n. I n a d d itio n , any a c id p re s e n t c a ta ly z e s p o ly m e riz a tio n . R e a c tio n betw een e th y le n e im in e dim er and dim et h y l s u l f amyl c h lo r i d e . H-CHg CHgKHg J^CH2CK2N302NMe2 (HC1 ) H3C-CH2 + HegNSOjjCl -> EgC-CEg To a benzene s o lu t i o n 3 .4 g. o f e th y le n e im in e dim er was added.

T h is s o l u t i o n was cooled w ith ic e w a te r and 5 .7 3 g. o f d im e th y l-

50

s u lfa m y l c ü a ? id 0 (0 -0 4 m ole) was added slo w ly w h ile s t i r r i n g v ig o ro u s ly f o r s e v e r a l h o u rs.

The s o lv e n t was rem oved and th e r e s id u e was a

l i g h t y e llo w v is c o u s s o l i d .

A ll a tte m p ts a t c r y s t a l l i z i n g o r

p u r i f i c a t i o n f a i l e d to y i e l d a pro d ie t w hich co u ld be p o s i t i v e l y id e n tifie d . A ttem pted p r e p a r a tio n o f 2 t 2 d im s th y le th y le n e im in e .

Four

hundred grams o f 2 am ino, 2 m e th y l, 1 p ro p a n o l, was ad d ed to 800 m l. > o f w a te r, and th e n t r e a t e d w ith 440 g . s u l f u r i c a c i d in 200 ml. w a te r .

of

T h is s o lu tio n was d i s t i l l e d by h e a tin g under red u ced p r e s s u re

to remove c a lc u la t e d w a te r .

The r e s id u e was t r e a t e d w ith e x c ess o f

40% sodium h y d ro x id e and th e m ix tu re d i s t i l l e d u n t i l 400 g. was c o l­ le c te d .

The d i s t i l l a t e was th e n s a tu r a te d w ith p o ta ssiu m h y d ro x id e .

A f te r s e p a r a tin g l a y e r s i t was d r ie d over p o tassiu m c a rb o n a te . F a ra b i nos and S e r i ja n (53) s ta t e s t h a t i t sh o u ld b o i l a t 6 9 °-7 0 C. However, th e p ro d u c t o b ta in e d l a r g e l y b o ile d above 70°C.

The

r e f r a c t i v e in d ex o f t h e p ro d u c t d id n o t agree w ith t h a t quoted i n th e lite ra tu re .

F u r th e r work was n o t a tte m p te d s in c e th e e th y le ne im in es

p o ly m erize so r e a d i l y . P r e p a r a tio n o f Ü -c a rb e th o x y , N' d im s th y ls u lfa m y l e th y le n e d iam in e . Me3NS03C l + HgN-CHaCHoNHC(0 ) OEt -> MehTS03NHCH3CE3EHC ( 0 ) OEt + H^CHgCHsHHg ( 2HC1 ) P r e p a r a tio n o f e t h y l , N- ( 2 a m in o e th y l) carbam ate i s accom plished from d ie th y lc a r b o n a te and e t h y lenediam ine (5 4 ). To 400 m l. o f r e d i s t i l l e d benzene i s added 44 g . (0 .5 5 m ole) o f e th y l , N -(2 a m in o e th y l) carb am ate.

Then t h e r e i s added to t h i s

31

s o l u t i o n , w ith c o n s ta n t s t i r r i n g , 2 3 .8 g . o f dirasth y ls u lf a m y l c h lo r id e (0 .1 6 m o le ).

The s o lu tio n i s co o led d u rin g th e a d d i t i o n p e r io d .

S t i r l i n g i s co n tin u e d f o r s i z h o u r s .

The s o lu t i o n i s th e n f i l t e r e d

and 24 g . o f w h ite s o li d i s c o l l e c t e d , w hich i s n e a r l y t h e o r e t i c a l amount o f th e h y d ro c h lo rid e o f t h e o r i g i n a l c a rb am ate. removed under reduced p r e s s u r e .

The s o lv e n t i s

The r e s id u e , a r a t h e r v is c o u s o i l ,

i s s u b je c te d to d i s t i l l a t i o n a t 0 .0 0 5 ram, p r e s s u r e .

The Hickman s t i l l

i s h e a te d w ith an o i l b a th , and the b a th i s g r a d u a lly r a i s e d t o 100°C. A s o l i d s e p a r a te s o u t on th e to p and s id e s o f th e s t i l l .

Hot o i l i s

p la c e d on to p o f t h e s t i l l in o rd e r f o r th e d i s t i l l a t i o n to c o n tin u e . The l i q u i d c o ll e c t e d i s r e d i s t i l l e d s e v e r a l tim e s a t t h i s low p r e s s u r e . On t h e b a s i s o f t h e amount o f th e h y d ro c h lo rid e o f t h e carbam ate re c o v e re d th e r e a c ti o n i s p r a c t i c a l l y q u a n t i t a t i v e . A n al, c a lc d . f o r C7E17M3O4S1 : Found:

N, 1 7 .5 7 .

N, 1 7 .4 2 .

P r e p a r a tio n o f d i e t h y l s u l f amyl c h lo r id e . E t2NH + CISOgCl "> BtgHSOgCl + EtgNH-HCl + EtgNSOgKEtg The method u s e d i s e s s e n t i a l l y t h a t o f B in k ley and Dege r in g (5 2 ).

S eventy grams (0 .5 2 m ole) o f s u l f u r y l c h lo rid e i s added

to a 500 m l. round-bottom ed f l a s k equipped w ith g la s s p ad d le s t i r r e r and s e p a r a to r y f u n n e l .

The s o lu tio n i s co o led w ith ic e w ater and

v ig o r o u s ly a g i t a t e d a s 20 g . (0.27 m ole) o f r e d i s t i l l e d d ie th y la m in e i s added over a fo u r hour p e r io d .

A f te r a l l th e die th y lam in e i s

added th e s o lu t i o n i s s t i r r e d fo r a n o th e r two h o u rs. th e n a llo w ed to r e f l u x f o r 24 h o u rs o v e r a steam c o n e .

The s o lu t i o n i s The e x c e s s

s u l f u r y l c h lo r id e i s th e n removed b y u s in g an a s p i r a t o r pump.

The

32

r e a c t i o n p r o d u c ts a r e e x t r a c t e d w ith th r e e hundred and f i f t y m l. p o r ti o n s o f e t h e r .

There rem a in e d a v e ry l i g h t y e llo w s o l i d , a

m ix tu re o f d ie th y la m in e h y d ro c h lo rid e and d ie th y ls u lfa m id e . i s removed and th e re m a in in g l i q u i d vacuum d i s t i l l e d .

The e th e r

Tte y i e l d w as

low er th a n B in k le y r e p o r t e d , s in c e o n ly 14 g . o f t h e la c h ry m a to ry l i q u i d w ith a r e f r a c t i v e in d e x o f 1.4562 was re c o v e re d . The p r e p a r a tio n o f dime t h y l s u l f amyl c h lo rid e was p re p a re d from dime th y la m in e h y d ro c h lo rid e , a ls o by t h e msthod o f B in k le y and D e g e rin g .

A ttem pted p r e p a r a tio n o f N, N-dime t h y l , N t ~( 3 -d ie t h y l am inop ro p y l) s u lfa m id e . MegNSOgCl + HgU-CHgCHgGHgHBtg -» Me2N-S02MCE2CH2CH3N (H)Et2 ( C l ) To an ic e c o ld benzene s o lu tio n o f 3 5.7 g . dime t h y l s u l f amyl c h lo r id e (0 ,2 5 m ole) was added dropw ise 3 2 .5 g . (0 .2 5 m ole) o f N, U d ie th y lp ro p y le n e d ia m in e . h o u rs.

T his m ix tu re was s t i r r e d f o r a t o t a l o f e ig h t

At th e end o f t h i s p e rio d , an orange o i l h a d s e p a r a te d out o f

s o lu tio n .

T his s o lu t i o n was found to be b a s ic .

I t was s o lu b le in

w a te r , c h lo ro fo rm , and a c e to n e , b u t in s o lu b le in p e tro le u m e t h e r and to lu e n e .

A ttem pts to c r y s t a l l i z e w ere u n s u c c e s s fu l.

D is tilla tio n a t

re d u c e d p r e s s u r e y ie ld e d t e n m l. o f l i q u i d w ith th e same b o i li n g p o i n t a s s t a r t i n g am in e.

D ecom position o c c u rre d w ith some v io le n c e w h ile

d i s t i l l i n g a t 2 mm. p r e s s u r e . P r e p a r a tio n o f 1 . 2 -b is -(^ ,N -d im e th y ls u lfa m y la m in o ) e th a n e . E th y le n e diam ine i s r e c t i f i e d from c o n c e n tra te d sodium hy d ro x id e s o l u t i o n .

T his e th y le n ed ia m in e ( 7 .4 g . o r 0 .1 1 m ole) i s

added t o 16 g . o f d im e th y ls u lf amyl c h lo rid e in a 1 l i t e r f l a s k ,

33

c o n ta in in g 300 m l. of b e n z en e .

The s o l u t i o n i s v e ry v ig o r o u s ly s t i r r e d

w h ile b e in g cooled w ith i c e w a te r .

A f te r a l l th e dime t h y l s u l f am yl-

c h lo r id e i s ad d e d , th e s o lu t i o n i s h e a te d f o r s e v e r a l h o u r s .

On

f i l t r a t i o n a b o u t t e n grains o f a l i g h t yellow s o l i d i s o b ta in e d .

A f te r

rem oving th e benzene a p p ro x im a te ly 3 .5 g . o f w h ite s o l i d i s r e c o v e r e d . T his l a s t s o li d i s found t o be s o lu b le in m eth an o l, e th a n o l, s l i g h t l y s o lu b le in is o p r o p y l a lc o h o l, and in s o lu b le in p e tro le u m e t h e r .

It

i s r e c ry s t a l l i z e d from is o p ro p y l a lc o h o l s e v e r a l tim e s a n d s u b m itte d f o r a n a ly s i s a f t e r d ry in g in A bderhalden p i s t o l . i s 84°C. I u n c o r r e c te d ) .

The rem ainder o f th e s o l i d was n e u tr a li z e d

and found t o m elt above 200°C.

I t was n o t i d e n t i f i e d .

A n a l, c a lc d . f o r Found:

The m e ltin g p o in t

:

N, 2 0 .4 4 .

N, 2 0 .5 8 , 2 0 .3 5 .

A ttem pted p r e p a r a tio n o f p y ro c a rb o n ic e s t e r u s in g q u in in e . Two grams o f q u in in e and 20 m l. o f e th y l c h lo ro fo rm â te was d is s o lv e d i n 60 m l. o f c h lo ro fo rm i n a 500 m l. s e p a r a to r y f u n n e l.

T h is was

Then 18 m l. o f 10fo

shaken c a r e f u l l y w ith th e s to p c o c k open.

p o ta s s iu m hydroxide was added and th e fu n n e l was shalæ n v ig o ro u s ly f i r s t w ith s to p c o c k open and th e n c lo s e d .

Extrem e c a u tio n w as ta k e n

i n s h a k in g th e f u n n e l s in c e trem endous p r e s s u r e i s b u i l t u p .

It

r e q u ir e d 150 m l. o f 10$ p o ta ssiu m h y droxide d iv id e d i n to 8 p o r tio n s b e fo re th e s o lu tio n became a l k a l i n e . from th e c h lo ro fo rm .

The ch lo ro fo rm l a y e r was d r ie d and th e n removed

and th e r e s id u e was ta k e n up in e t h e r . q u in in e h y d ro c h lo rid e .

The aqueous l a y e r was th e n s e p a r a te d

The q u in in e was removed a s th e

The e th e r la y e r was d r ie d and d i s t i l l e d .

o f th e p y ro c a rb o n ic e s t e r b o i li n g a t 8 5 °C ./1 2 mm. p r e s s u r e was o b ta in e d (4 0 ).

None

34

A ttem pted p r e p a r a ti o n o f p y ro c a rb o n ic e s t e r from p o ta s s iu m e t h y l c a rb o n a te and e th y l e h lo ro fo rm a t e .

A b so lu te e th a n o l, t o which

some sodium had b e e n added was d i s t i l l e d im m ed iately p r i o r t o th e e x p e rim e n t.

One mole o f d i e th y l c a rb o n a te (Eastm an Kodak) was added

t o a 1 l i t e r , th re e -n e c k e d , rou n d -b o tto m ed f l a s k .

To t h i s f l a s k ,

one mole o f p o ta s s iu m h y d ro x id e i n 400 m is . o f a b s o lu te a lc o h o l was added d u r in g a two hour p e r io d . and h e a te d around 50o-60°C .

The s o lu t i o n was s t i r r e d v ig o ro u s ly

One m ole o f e t h y l c h lo ro fo rm â te w as th e n

added t o th e s o lu t i o n i n 2 h o u rs by d ro p s .

I n a su b seq u en t ru n th e

a lc o h o l was removed b e fo re th e a d d it io n o f e th y l c h lo ro fo im a te and r e s u l t s were e s s e n t i a l l y t h e s a n e .

No p y ro c a rb o n ic e s t e r could be

d e te c te d . P r e p a r a tio n o f p y ro c a rb o n ic e s t e r . KOEt + C02

KDC ( 0 ) OEt

K0C(0)0Et + ClC(0)OSt -> E t0 (0 )C -0 C (0 )0 E t + KOI Two m oles o f p o ta s s iu m was added t o 400 m l. o f r e d i s t i l l e d to lu e n e i n a 1 l i t e r , th re e -n e c k e d f l a s k .

The to lu e n e was h e a te d up to r e f l u x

te m p e ra tu re w h ile s t i r r i n g t h e s o lu t i o n a c t i v e l y .

From a dropping

fu n n e l 92 g . (2 m o le s ) o f a b s o lu te a lc o h o l ( p re v io u s ly d i s t i l l e d from c a lc iu m h y d rid e ) was ad d ed s lo w ly . th e s o l u t i o n was c o o le d .

A f te r a d d itio n o f a l l t h e a lc o h o l

Then carb o n d io x id e was p a sse d th ro u g h a

d ry in g t r a i n from a c y lin d e r u n t i l th e f l a s k no lo n g e r h e a ts u p .

A

good s t i r r e r , p r e f e r a b l y p a d d le ty p e , i s n e c e s s a ry t o keep t h i s s l u r r y m oving.

I t i s o f te n n e c e s s a ry to add more to lu e n e i n o rd e r to keep

th e s o lu t i o n f l u i d .

55

Then two m oles o f e th y l c h lo ro fo rm a te (217 g .) was added from a d ro p p in g fu n n e l d u r in g a s i x h o u r p e r io d . s t i r r e d f o r an a d d it io n a l th r e e h o u r s .

The s o l u t i o n was

At th e end o f t h i s tim e two

hundred m l. o f to lu e n e was added t o e x t r a c t m ost o f p y ro c a rb o n ic e s t e r . Then c o ld w a te r was added t o t h e f l a s k , and t h i s m ix tu re was shaken i n a s e p a r a to r y f u n n e l to remove s a l t s .

The to lu e n e e x t r a c t s and w a te r

in s o lu b le p o r tio n s combined and d i s t i l l e d w ith vacuum pump.

T o lu en e,

e t h y l c h lo ro fo rm a t e , and e th y l c a rb o n a te rem oved below 4 0 6C. a t 12 mm. p ressu re.

P y ro c a rb o n ic e s t e r was c o lle c te d from ?4*-76*C. a t 7 ram.

p ressu re.

C a r e fu l a t t e n t i o n must be p a id t o h e a tin g p y ro c a rb o n ic

e s t e r f o r i t i s e a s i l y decomposed around 1 0 0°C ., e s p e c i a l l y i f a c id o r b a se a re p r e s e n t .

Y ie ld o b ta in e d was 50% o f th e t h e o r e t i c a l v a lu e .

A d e r i v a ti v e was p re p a re d from h y d ra z in e h y d r a te , which m e lts a t 152°C.

I t r e a c t s w ith a lm o st e x p lo s iv e v io le n c e to form t h i s

s y m m e tric a lly s u b s t i t u t e d compound.

36

SUMMARY AND CONCLUSIONS 1.

The p r e p a r a tio n o f carbone th o x y and c arb e th o x y s u lf ami de

was a c co m p lish e d . 2.

A g e n e ra l method f o r t h e p r e p a r a tio n o f d ic a rb a lk o x y

d e r i v a ti v e s o f su lfam id e was worked o u t. 3.

A lk y l and a r y l s u b s t i t u t e d carb am ates w ere found n o t to

r e a c t w ith s u l f u r y l c h lo r id e under th e m ild c o n d itio n s u s e d . 4 . The r e a c t i o n o f d im e th y ls u lf amyl c h lo r id e w ith a number of

am ines was

i n v e s t i g a t e d and two new compounds w ere p re p a re d .

5 . An e x c e l le n t method f o r t h e p r e p a r a tio n o f e t h y l p y ro c a rb o n a te

was

fou n d .

T h is r e a g e n t was i n v e s t i g a t e d and found to be

e x tre m e ly r e a c ti v e w ith am ines and a lc o h o ls . 6.

The compounds p re p a re d have n o t been su b m itte d f o r

p h a rm a c o lo g ic a l t e s t i n g , b u t t h i s w i l l be c a r r ie d o u t .

37

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a n d Brown, U, S . P a t e n t , 2 ,3 0 2 ,2 2 8 (1 9 4 3 ).

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an d Brown, J . Am. Ghem. S oc. , 6 1 , 2142 (1 9 3 9 ).

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and Brown, J , Am. Ghem. S o c. , 6 2 , 925 (1 9 4 0 ).

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23.

B a tte gay and D e n i v e ll e , B u l l . S oc. Ohim. M ém oires, (1 9 3 3 ).

10

2

2573 (1 9 4 9 ).

69_, 170 (1 8 3 8 ).

1 7 , 129 (1 9 3 2 ).

5

53, 1242

38

24.

Ephraim, B er. , 5 5 , 776 (1 9 0 2 ).

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Am. Ghem. S o c . , 5 4 , 2928 (1 9 3 2 ).

and S on s, I n c . , New York, 1943. 29.

Carbide and. Carbon Chemical C orporation, French P a ten t 792,046 ( 1 9 3 5 ).

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P a r fe n tie v and Shamshurin, Trudy Uzbekskogo G osudarst. U niv. Sbornik Rabot Khim. , 15 , 67 (1 9 3 9 ); £ . A ., 35 , 435 (1 9 4 1 ).

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B l a t t , e d . "O rganic S y n th e s e s " , C o ll. V o l. I I , 92, John W iley and S o n s, Mew Y ork, 1943.

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SOME DERIVATIVES OF SULFAIUDI

An A b s tra c t o f A T h e sis S u b m itted to th e F a c u lty of Purdue U n iv e r s ity by Benjamin E lb e r t Sanders I n P a r t i a l I b l f i l l m e n t o f th e R equirem ents f o r th e Degree of D octor o f P h ilo so p h y A ugust, 1949

SOME DERIVATIVES OF SULFAMIDE* By Ed. F . D egerin g, Glenn L. Jenkins and Benjamin E» Sanders (C o n trib u tio n from th e School o f Pharmacy and Department o f Chemistry) Purdue U n iv e r s ity L a fa y e tte , Indiana AN ABSTRACT The purpose o f t h i s r e se a r c h was to s y n th e s iz e d e r iv a t iv e s o f su lfam id e which m ight have v a lu a b le pharm acological a c t i v i t y . There have been few r e p o r ts on t h e ir p h y s io lo g ic a l a c tio n even though a co n sid er a b le number have now been prepared.

Aeschlim an (1) rep orted

th a t t e t r a e t h y l su lfam id e i n sm all doses has a s l i g h t a n a le p tic a c t io n .

I t was found not t o have any a n ti th y ro id a c t i v i t y ( 2 ) .

Tzanck (3 ) and coworkers found p-am inophenylsulfam idopyridine to be to o t o x ic f o r any m ed icin a l u s e . The N -s u b stitu te d su lfam id es and t h e ir methods o f p rep aration have been review ed by A udrieth and coworkers ( 4 ) .

S in ce th a t tim e a

c o n sid er a b le number o f a c y l , t r i - and t e t r a a lk y l and a r y l, h e te r o c y e lo and c y c lo d e r iv a t iv e s have been reported ( 5 , 6 , 7 , 8 , 9 ) . Some o f th e s e compounds have been t e s t e d and show co n sid era b le p h y s io lo g ic a l a c t i v i t y but th ey have not been reported in the lite r a tu r e . The s y n t h e s is o f N -su b stitu te d su lfa m id es has been a tta in e d through th e a c tio n o f primary arom atic amines or primary and secondary a l ip h a t i c amines upon s u lf u r y l c h lo r id e , or by th e a c tio n o f an amine upon an ( a r y l )- a r y ls u lf o n y l su lfam yl c h lo r id e , an (a c y l) a r y ls u l f amyl

+ C ontains m a te r ia l from Mr. Sanders* d o c to ra l t h e s i s .

ii

c h lo r id e , a d ia Ik y lsu lfa m y l c h lo r id e , p h th a ly lsu lfa m y l c h lo r id e , or phenyl e h lo r o s u lfo n a te ( 4 ) . The p r in c ip a l o b je c tiv e o f t h i s r e sea rch was th e p rep a ra tio n and stu d y o f carbalkoxy and o th e r d e r iv a tiv e s o f su lfa m id e.

L ite r a lly

thousands o f r e fe r e n c e s a re a v a ila b le on th e a c t i v i t y o f th e carbamates as h y p n o tic s, s e d a t iv e s , l o c a l a n e s t h e t ic s , and a v a r ie t y o f o th e r a c tio n s when o th e r fu n c tio n a l groups a re p r e s e n t. Chloroform âtes a r e n o t a c tiv e enough to r e a c t w ith sulfam id e even in th e p resen ce o f s u lf u r ic a c id , p y r id in e , or oth er c a t a l y s t s . Anderson and D egering (5 ) rep orted e x c e lle n t y ie ld s o f mono- and d ia c y la te d d e r iv a t iv e s o f sulfam ide u sin g s u l f u r i c a c id as c a t a l y s t . Glenn (9 ) rep orted th a t k eto n es r e a c t r e a d ily and O 'D ell (10) had e x c e l le n t s u c c e ss w ith aldehyde d e r iv a tiv e s o f su lfa m id e . The p rep aration o f mono- and di sodium and potassium s a l t s o f sulfam ide (11) has been rep o rted .

The monosodium s a l t may be

prepared by u se o f sodium e th o x id e , but sodium amide i s required f o r th e p rep aration o f th e disodium s a l t , and u n le s s e x c e ss o f sodium amide i s used a m ixture o f th e mono- and disodium s a l t s w i l l r e s u l t . The heterogeneous r e a c tio n o f sodium s a l t o f sulfam id e w ith chloroform âtes y ie ld s the d e sir e d carbalkoxy sulfam id e in poor y i e l d s . The sodium s a l t i s v e r y hygroscopic and n e c e s s it a t e s extreme care in h a n d lin g .

Numerous s o lv e n ts were t r ie d but none g iv e very s a t i s ­

fa c t o r y y i e l d s . The r e a c tio n o f s u lf u r y l c h lo rid e w ith urethan i s reported to g iv e e th y la llo p h a n a te ( 1 2 ) .

This e v id e n tly r e s u lt s from the

form ation o f cy a n ic a c id which im m ediately r e a c ts w ith unchanged urethan t o g iv e th e product d e sc r ib e d .

iii

S u lfu r y l c h lo r id e forms an a d d itio n compound w ith p y r id in e (1 5 ).

This a d d itio n product i s e x c e e d in g ly u n sta b le t o h e a t.

It

was proposed t h a t t h i s s u lf u r y l c h lo r id e p y r id in e a d d itio n compound would g r a d u a lly lib e r a t e s u lf u r y l c h lo rid e to r e a c t w ith th e carbamate.

As th e s o lu tio n was a llow ed t o warm up s lo w ly t o room

tem perature e x c e lle n t y ie ld s were obtain ed in th e case o f th e u n su b stitu te d carbam ate.

I n th e c a s e o f N -alkylcarbam ates, th e

o r ig in a l carbamate was la r g e ly recovered unchanged, under c o n d itio n s employed. A number o f r e a c tio n s o f d im sth ylsu lfam yl c h lo r id e w ith e th y le n e im in e s , N, N d ie th y ld k y le n e diam ines, and ethylcarbam ate gave p roducts th a t could n o t be i d e n t i f ie d .

However, th e r e a c t io n o f d i -

m ethylsulfam yl c h lo r id e w ith e th y le nedi amine, and w ith e t h y l, N -(2~ am inoethyl) carbamate gave products which co u ld be is o la t e d and id e n tifie d . E th y l pyrocarbonate f i r s t d escrib ed by Boehm and Mehta (14) was in v e s t ig a t e d .

S in c e i t i s such an extrem ely r e a c t iv e compound,

i t was thought th a t i t m ight r e a c t d i r e c t ly w ith su lfa m id e.

Boehm

and Mehta prepared th e compound from em etin e, e th y l chloroforma t e , and potassium h yd roxid e, and p o stu la te d th e fo llo w in g r e a c tio n : 2R3N( CI ) COOCgHg + K0H-» RgNH(Cl) + EgC^-OC( 0 ) 0-C( 0 ) -OCgHg + KC1 T h eir y i e l d s w ith em etine w ere about 60 per c e n t, b u t th ey were a b le to prepare i t in v e r y sm all q u a n titie s o n ly , and em etine a t # 3 .5 0 a gram made t h e r e a c tio n ex p en siv e and im p r a c tic a l. I t was proposed th a t e th y l chloroforma t e should r e a c t w ith potassium e th y l carbonate t o g iv e th e eth ylpyrocarbonate in any q u a n titie s d e s ir e d .

The b e s t p rep aration o f potassium e th y l carbonate

iv

fo p t h i s experim ent was found to be made by th e a d d itio n o f C03 to p otassium e th e x ld e ( 1 5 ) . w ith e t h y l chloroform a t e .

The potassium eth ylcarb on ate then re a cte d This r e a c tio n was found to be very s a t i s ­

fa c to r y and sim p le; th u s , a new p rep aration o f a most v a lu a b le r e a g e n t.

I t r e a c t s w ith am ines, am in oalcoh ols, and a v a r ie t y o f o th e r

compounds th a t have not been thoroughly in v e s t ig a te d .

I t i s much

more r e a c t iv e than d ie t h y l carbonate, o r th e ch lo ro fo rm â tes.

There

i s no reason why a s e r i e s o f t h e s e pyrocarbonic e s t e r s could n o t be prepared in t h e same way.

EXPERIMENTAL P r e p a r a tio n o f c a rb o m eth o x y su lf a m id e .

A sam ple o f 4 .4 g.

(0 ,0 4 5 m ole) o f d ry s u lfa m id e i s d is s o lv e d i n 100 m l. o f a b s o lu te a lc o h o l ( d i s t i l l e d from magnesium m e th y la te ) i n a f l a s k f i t t e d w ith r e f l u x c o n d e n se r. m e t a l l i c sodium .

To t h i s f l a s k i s ad d ed 1 .2 g. (0 .0 5 m ole) o f The mono sodium s a l t o f s u lfa m id e p r e c i p i t a t e s d u rin g

th e r e f l u x i n g o f t h e a lc o h o l ic s o l u t i o n .

T h is s a l t i s th e n f i l t e r e d

w ith s u c ti o n and h e a te d o v e r a ste a m p l a t e u n t i l t h e odor o f a lc o h o l no lo n g e r can be d e te c te d .

T h is i s th e n added from a s o l i d - a d d i t i o n

f l a s k to 50 m l. o f r e d i s t i l l e d m eth y l c h lo ro fo rm a te (E. K. C o.) i n a 200 m l. th re e -n e c k e d f l a s k .

I t i s added o v er a p e rio d o f a b o u t th r e e

h o u rs w ith s t i r r i n g , and t h e te m p e ra tu re i s m a in ta in e d a t t h a t o f r e f lu x in g c h lo ro fo rm a te .

I t i s h e a te d f o r an a d d i t i o n a l two h o u rs

a f t e r a l l th e sodium s a l t o f su lfam id e i s added.

I t i s a llo w e d to

s ta n d o v e rn ig h t and 1 ,4 g . o f c r y s t a l l i n e s u b sta n c e s e t t l e d o u t. a re s e v e r a l grains o f th e amorphous sodium s a l t o f su lfa m id e .

There

The

c r y s t a l l i n e m a t e r i a l i s washed w ith p e tro le u m e t h e r , and i s o p r o p y l e th e r.

I t i s r e c r y s t a l l i z e d from e th y l a c e t a t e and t h e m e ltin g p o in t

i s 1 2 4 °-1 2 5 6C.

The y i e l d on t h e b a s i s o f su lfa m id e u sed w as ab out

23 p e r c e n t . P r e p a r a tio n o f t h e sodium s a l t of s u lfa m id e a n d i t s r e a c t i o n w i t h e th y l c h lo ro fo rm a te .

Commercial 200 p ro o f e th a n o l i s d r ie d by

means o f magnesium m e th y la te and l a t e r d i s t i l l e d .

Four grams o f

su lfa m id e (0 .0 4 1 m ole) i s added t o 100 m l. o f th e hot a lc o h o l.

One

gram (0 .0 4 3 m ole) o f m e t a ll ic sodium i s added th ro u g h the c o n d e n se r.

¥i

The sodium s a l t p r e c ip it a t e s alm ost im m ed iately.

The s o lu t io n i s

f i l t e r e d w ith s u c tio n and t h e w h ite powder d r ie d in a vacuum d e s ic c a t o r . F i f t y m l. o f e th y l chloroform ate i s added to a 200 m l., th ree-n eck ed , round-bottomed f la s k f i t t e d w ith a s t i r r e r , a condenser, and a s o lid - a d d it i on f l a s k .

The sodium s a l t o f su lfam id e i s added

from t h i s a d d itio n f la s k to the r e flu x in g e th y l chloroform ate over a p e r io d o f fou r h ou rs.

About 1 g . o f w h ite product i s ob tain ed and a

dark y e llo w product i s ob tain ed in la r g e r amounts.

The dark y e llo w

product appears t o be a sodium s a l t , which i s in s o lu b le in a lc o h o l and e th e r .

The l i g h t c r y s t a llin e m a te r ia l i s v e r y s o lu b le in

a lc o h o l, w ater, and s l i g h t l y s o lu b le in e th e r .

I t i s d is s o lv e d in

e t h e r , th en l a t e r r e c r y s t a lliz e d from chloroform . su lfam id e m elted a t 1340-135°C .

The carbethoxy*

This rep resen ts o n ly about 16 per

cent y ie ld . A n al, c a lc d . fo r CgSgNgO^S: Found:

N, 1 6 .6 7 .

N, 1 7 .1 3 .

P rep aration o f carbethoxysulfam ide in d i lu t e a l k a l i . S u lfam id e, 5 g . (0 .0 5 2 mole) i s added t o 3 per c e n t NaOH in a 200 m l. round-bottomed f l a s k , f i t t e d w ith a u t i l i t y head (con d en ser, s t i r r e r , and dropping fu n n e l, a l l connected t o one j o i n t ) .

W ithin two h ou rs,

4 .9 m l. (0 .0 5 2 m ole) o f e th y l chloroform ate i s added to th e co ld a lk a lin e s o lu t io n o f su lfa m id e .

A fte r th e a d d itio n th e f la s k i s

allow ed to warm up t o room tem perature and s t i r r i n g i s continued fo r s e v e r a l h ou rs. a s p ir a t o r . e th y l e t h e r .

Removal o f w ater i s th en accom plished by u se o f an

The w h ite s o l i d rem aining i n th e f la s k i s d is s o lv e d in That w hich remains u n d isso lv e d proves to be m ainly

v il

sodium c h lo r id e . a t 132e-134°G . c o n s is t e n t ly .

I t i s r e c r y s t a l li z e d from e th a n o l and m elted T his method was n o t found t o g iv e good r e s u lt s

An e x p la n a tio n probably can be found in th e

i n s t a b i l i t y o f su lfam id e in a l k a li and t h e r e a c tio n o f th e chloroform ate w ith th e a lk a lin e s o lu tio n # P rep aration o f N, Nf dicarb eth oxysu lfam id e from s u lf u r y l c h lo r id e , u reth a n e, and p y rid in e *

To a 1 l i t e r , th ree-n eck ed , round-

bottomed f l a s k , f i t t e d w ith a s t i r r e r , cond en ser, and dropping fu n n e l, i s added 500 m l. o f benzene (d r ie d over sodium and d i s t i l l e d ) .

To

th e benzene in th e f l a s k , 15 g . (0 .1 6 9 mole) o f urethan ( r e c r y s t a lliz e d from benzene and d ried in vacuum d e s ic c a to r ) and 1 3 .4 g . (0 .1 6 9 mole) o f p y r id in e i s added.

Over a p eriod o f th r e e h ou rs, 1 1 .4 g . (0 .0 8 5 mole)

o f s u lf u r y l c h lo r id e i s added, w h ile th e tem perature i s kept around 0*0.

The f la s k i s allow ed to warm up to 30*0. and th e s o lu t io n i s

s t ir r e d v ig o r o u s ly f o r 14 h ours.

From th e benzene s o lu tio n 3 6 .1 g . o f

w h ite , amorphous s o l i d i s ob tain ed .

I t i s washed s e v e r a l tim es w ith

10 m l. p o r tio n s o f d i lu t e h yd roch loric a c id and f i l t e r e d .

The

p r e c ip it a t e i s washed w ith co ld w ater t o remove any h yd roch loric a c id rem aining. p y r id in e .

I t i s extrem ely d i f f i c u l t to g e t r id o f th e l a s t

tr a c e s o f

The p r e c ip it a t e i s r e c r y s t a lliz e d from 95 per cen t eth a n o l

form ing r a th er t h ic k , g la s s y c r y s t a l s .

I t i s r e c r y s t a lliz e d from

a lc o h o l f i v e t im e s , p laced in an Abderhalden p i s t o l and d ried a t 10 mm. p ressu re fo r s e v e r a l h ours, a t th e tem perature o f r e flu x in g t o lu e n e .

The m eltin g p o in t i s 163°-164eC. (u n c o r r e c te d ).

A 90# y ie ld

was o b ta in ed . A n al, c a lc d . f o r CgH^gNgOgSî Found:

C, 3 0 .1 ; 3 0 .1 .

C, 3 0 .1 } H, 5 .0 } N, 1 1 .7 .

H, 5 .2 , 5 .2 .

N, 1 1 .6 2 .

v iil

P rep aration o f N, N* dicarbopropoxy su lfa m id e .

There i s

added to 400 m l. o f anhydrous e th e r 2 0 .6 g . ( 0 .2 m ole) o f p ro p y lcarbamate, and r e d i s t i l l e d , d r ie d , p y r id in e ( 0 .2 m ole) in a th r e e necked f l a s k .

S u lfu r y l c h lo r id e ( 0 .1 m ole) p r e v io u sly d i s t i l l e d and

d ilu te d w ith 100 m l. o f e th e r i s added over a 3 hour p erio d to th e s o lu t io n .

During t h i s tim e th e s o lu t io n i s cooled t o 0 * 0 . and s t i r r e d

v ig o r o u s ly .

The s t i r r i n g i s continu ed f o r an a d d itio n a l tw en ty-fou r

hours w h ile a llo w in g the s o lu t io n to r i s e t o 30*0. crude product i s obtained*

F i f t y grains o f

A fte r washing w ith d ilu t e h yd roch loric

a c id , 25 g . o f com p aratively pure product i s ob tain ed , which i s about 94 p er c e n t o f t h e o r e t ic a l y i e l d .

The compound i s found to be v e r y

s l i g h t l y s o lu b le in w a ter, in s o lu b le in benzene and e th e r .

I t was

r e c r y s t a lliz e d from d ilu t e a lc o h o l and m elted a t 135*0. A n al, c a lc d . f o r Og%gNgO@S: Found:

C, 3 5 .3 8 , 3 5 .5 5 .

0 , 3 5 .8 2 ; N, 1 0 .4 5 .

N, 1 0 .7 4 , 1 0 .9 2 .

P rep a ra tio n o f 1 , 2 - b is - ( M .N -dlm ethylsuif amylamino ) e th a n e . E th ylen e diamine i s r e c t i f i e d from con cen trated sodium hydroxide s o lu t i o n .

This e th y le n e diamine ( 7 .4 g . or 0 .1 1 m ole) i s added to

16 g . o f d im eth y lsu lfa m y lch lo rid e in a 1 l i t e r f la s k con tain in g 300 ml# o f benzene.

The s o lu t io n i s v e r y v ig o r o u sly s t ir r e d w h ile b ein g cooled

w ith i c e w a te r .

A fte r a l l th e d im eth y lsu lfa m y lch lo rid e i s added

th e s o lu t io n i s h eated f o r s e v e r a l h ou rs. grams o f a l i g h t y e llo w s o li d i s o b ta in ed .

On f i l t r a t i o n , about t e n A f t e r removing th e benzene,

approxim ately 3 g . o f w h ite s o l i d i s reco v ered .

This l a s t s o l i d i s

found t o be s o lu b le in m ethanol and e th a n o l, s l i g h t l y s o lu b le in iso p r o p y l a lc o h o l, and in s o lu b le in petroleum e th e r .

I t is

Iz

r e c r y s t a ll iz e d from iso p r o p y l a lc o h o l s e v e r a l tim es and subm itted fo r a n a ly s is a f t e r dryin g i n Abderhalden p i s t o l . 8 4 eC. ( vm corrected ).

The m e ltin g p o in t i s

The remainder o f th e s o l i d w hich c o n s titu te d

th e major p o r tio n o f th e y i e l d gave halogen t e s t and has n o t been id e n tifie d . A n al, c a lc d . fo r C6% 8N404S2 : Found:

N, 2 0 .4 4 .

N, 2 0 .3 8 , 2 0 .3 5 .

P rep aration o f N -carbethoxy, N« d im eth ylsu lfam yl e th y le n e d iam ine. MegHSOgCl + H2N-CHaCH2HHC( 0 )0 2 t -> MeaNS02NHCH2CH2NH0(0 ) 0 Et + H2NCH2CH2NH2(2HG1) P rep aration o f e t h y l, N -(2-am in oeth yl) carbamate i s accom plished from d ieth ylcarb on at e and eth y l e nediam ine. To 400 m l. o f r e d i s t i l l e d benzene i s added 44 g . ( 0 .3 3 mole) o f e t h y l, N -(2 -a m in o eth y l) carbamate.

Then th ere i s added t o t h is

s o lu t io n , w ith con stan t s t i r r i n g , 2 3 .8 g . o f dime th y lsu lfa m y l c h lo r id e (0 .1 6 m o le ). p e r io d .

The s o lu t io n i s cooled during th e a d d itio n

S t ir r in g i s continued f o r s i x hours.

The s o lu t io n i s th en

f i l t e r e d and 24 g . o f w h ite s o l i d i s c o lle c t e d , which i s n e a r ly th e t h e o r e t ic a l amount o f t h e hydrochloride o f th e o r ig in a l carbamate. The s o lv e n t i s removed under reduced p r e ssu re .

The r e s id u e , a r a th er

v is c o u s o i l , i s su b je cte d t o d i s t i l l a t i o n a t 0 .0 0 5 mm. p r e ssu r e . Hickman s t i l l i s heated w ith an o i l r a is e d to 100*0. s till.

The

b a th , and th e bath i s g r a d u a lly

A s o l i d se p a ra tes out on th e top and s id e s o f th e

Hot o i l i s p la ced on to p o f th e s t i l l in order fo r th e

d i s t i l l a t i o n to c o n tin u e.

The liq u id c o lle c t e d i s r e d i s t i l l e d s e v e r a l

z

tim es a t t h i s low p r e ssu r e . On th e b a s is o f th e amount o f th e hydroch lorid e of th e carbamate re co v e r e d , th e r e a c t io n i s p r a c t i c a ll y q u a n t it a t iv e . A n al, c a lc d . f o r C7Ht7Ng04S1 5 Found:

N, 1 7 .5 7 .

N, 1 7 .4 2 .

P rep aration o f pyrocarbonic e s t e r . KQEt + C02 -* K0C(0)0Et K 0C(0)01t + C lC(0)0Et

E t0(0)C -0C (0)0E t + KOI

Two m oles o f potassium was added to 400 m l. o f r e d i s t i l l e d to lu e n e in a 1 l i t e r , th ree-n eck ed f la s k .

The to lu e n e was heated up

t o r e f lu x tem perature w h ile s t i r r i n g th e s o lu tio n a c t i v e l y . dropping fu n n e l, 92 g .

(2

From a

m oles) o f a b so lu te a lc o h o l (p r e v io u s ly

d i s t i l l e d from calcium hydride) was added s lo w ly . a l l the a lc o h o l th e s o lu tio n was c o o le d .

A fte r a d d itio n o f

Then carbon d io x id e was

p assed through a drying t r a in from a c y lin d e r u n t i l the f la s k no lo n g er h e a ts u p .

A good s t i r r e r , p r e fe r a b ly paddle ty p e , i s n ecessa ry to

keep t h i s s lu r r y moving.

I t i s o f te n n ecessary to add more to lu e n e in

order to keep th e s o lu tio n f l u i d . Then two m oles o f e th y l chloroform ate (217 g .) i s added from a dropping fu n n e l during a s i x hour p e r io d . f o r an a d d itio n a l th r e e h ou rs.

The s o lu tio n i s s t ir r e d

At th e end o f t h is tim e two hundred

m l . o f to lu e n e i s added to e x tr a c t most o f pyro carbonic e s t e r .

Then

c o ld w ater i s added to th e f la s k , and t h i s m ixture i s shaken in a sep a ra to ry fu n n el to remove s a l t s .

The to lu en e e x tr a c ts and w ater

in s o lu b le p o r tio n s a re combined and d i s t i l l e d w ith vacuum pump. TOluene, e th y l chloroform ate, and e th y l carbonate are removed below

xi

4G°C. a t 12 ram. p r e s s u r e .

P y ro c a rb o n ic e s t e r i s c o ll e c t e d from

7 4 °-7 6 eC. a t 7 ram. p r e s s u r e .

C a r e fu l a t t e n t i o n must be p a id t o h e a tin g

p y ro c a rb o n ic e s t e r f o r i t i s e a s i l y decomposed around 100*0 . , e s p e c i a l l y i f a c id o r base i s p r e s e n t . t h e o r e t i c a l v a lu e .

Y ie ld o b ta in e d i s 50$ o f th e

A d e r i v a ti v e i s p re p a re d from h y d raz in e h y d r a te ,

w hich m e lts a t 152*0.

I t r e a c t s w ith a lm o st e x p lo s iv e v io le n c e to

form t h e sy m m e tric a lly s u b s t i t u t e d compound. SUMMARY 1.

The p r e p a r a ti o n o f carbom ethoxy and c a rb e th o x y

su lfa m id e was acco m p lish ed . 2.

A g e n e ra l method f o r t h e p r e p a r a tio n o f d ic a rb a lk o x y

d e r i v a ti v e s o f su lfa m id e was worked o u t, 5.

The r e a c ti o n o f dime t h y l s u l f amyl c h lo r id e w i t h a number

o f amines was i n v e s t ig a t e d and tw o new compounds w ere p r e p a r e d . 4.

An e x c e l le n t method f o r th e p r e p a r a tio n o f e t h y l

p y ro c a rb o n a te was fo u n d .

T h is r e a g e n t was i n v e s t ig a t e d and found t o

be e x tre m e ly r e a c t i v e w ith am ines and a lc o h o ls , 5.

P h a rm a c o lo g ic a l t e s t i n g o f t h e compounds p re p a re d w i l l

be c a r r i e d o u t a t a l a t e r d a te .

x ii

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McGinty and B yw ater, J . P h arm aco l. , 8 4 , 342 (1 9 4 2 ).

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VW k Benjamin O ctober 1 9 , 1918. M a r ie tta , G eorgia.

E lb e r t Sanders was born in B o w e r s v ille , G eorgia, He atten d ed th e elem entary and h ig h sc h o o ls o f In June, 1939, he r e c e iv e d th e degree o f

B achelor o f S cien ce from Wofford C o lle g e , Spartanburg, S . C.

He

pursued graduate stu d y a t th e U n iv e r s ity o f G eorgia, a t which tim e he was a graduate a s s i s t a n t , and r e c e iv e d th e degree o f M aster o f S c ie n c e in Chemistry in 1942.

In June, 1942, he en tered th e

U n ited S ta te s Army a s 2nd L t. in Corps o f E n g in eers. se rv e d in th e S a n ita ry Corps as a b io c h e m ist.

He la t e r

He en tered Purdue

U n iv e r s ity in 1946, where he h eld an American Chemical s o c ie t y f e llo w ­ sh ip fo r th r e e y e a r s .

In A ugust, 1949, he r e c e iv e d th e degree o f

D octor o f P h ilo so p h y . Mr. Sanders i s a member o f Phi Lambda U p silo n , Sigma X i, The American Chemical S o c ie t y and th e American Pharm aceutical A s s o c ia t io n .