ctAMorrHnATioK of fHB 5- ami eotb* ha3omss

«gr

Donald W elter Henn

A T O IS

Submitted t e
School fo r Advanced Or&duate Studios of Michigan
S ta ts U n iv ersity o f A g ricu ltu re and Applied Science
in p a r t i a l f u lfillm e n t of tb s requirem ents
f o r the d#gree o f
doctor

o f m b o so H o r

Department o f CSicseistry

1957

ProQuest Number: 10008601

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S incere a p p re c ia tio n i s expressed to Doctor Robert M. Herbat*
under whose d ir e c tio n t h i s in v e s tig a tio n was accompli shed, f o r h ie
in sp ira tio n * guidance* patience* end understanding which made th is
th e s is po ssib le*

A ppreciation i s a ls o extended to the American Viscose Corpora**
tio n fo r th e ir fin a n c ia l a s s is ta n c e in th e form o f a fello w sh ip
during th e academic year X955~1956# to th e Monsanto Chemical Company
f o r t h e i r fello w sh ip during th e academic year 1956-1957# and to
Michigan S ta te U n iv ersity f o r summer sch o larsh ip s during 1956 and 1957*

To my wife Pat

<3TAH0ifE S % ^ i^ or mm

By

J3en*a& w aiter nmm

ah mwm&m

Submitted to th e School f o r M toneed OrMimte S tu d ies o f Michigan
S ta te T M v ereity o f A g ricu ltu re and Applied Selene*
in p a r t i a l f u lfillm e n t o f th e requirem ents
f o r th e degree o f

DOdffOEK OF BflhOSGFHT
Department o f Chemistry
Tear

Approved

1957

ABSTfUdP

fh e o r ig in a l purpose o f t h i s in v e s tig a tio n was to study the
cyanoethyl& tion, chlorom ethylntion, and K&nnich re a c tio n s as ap p lied
to th e ^-am inotetyi^oX es.

A fter p relim in ary experim entation, re -

se ar oh was d lro o ted ex c lu siv e ly toward a study o f the re a c tio n o f
a o r y lo u it r l ie with l-b m sy i-^ -aia iiio tetr& so le and ^ a m in o te tra so le *
Since th e re i s no evidence i n the l i t e r a t u r e o f th e a p p lic a tio n of
the cyanoeth y latio n re a c tio n to th e fa m in e te tra x o la s , i t m s necessary
not only to study th e re a c tio n o f a c r y l o n itr ile with th e 5-amino~
te tr a s o le s hut a lso to e s ta b lis h th e s tru c tu re s o f th e p ro d u cts.
Hi* re a c tio n o f l-b en sy l-5 ~ am ln o tetrn zo le and a c r y l o n itr ile in
th e presence o f benzyltrimethylommonium hydroxide y ie ld ed two products*
Elemental a n a ly s is in d ic a te d th a t one o f th ese was a mono-cyanoethylated
and. th e o th e r a di*cymnoethyla t ed. i< *bsnsyl^^am inotetrasole.

The

m ono-eyanoethylated d e riv a tiv e was shown to be l~be«ssyl-5^0~cyanoe th y la m in o te tra so le .

$h# isom eric l-bensyl-h-j^-cyanoethy 1 -5 -imino-

te tr a s o lin e was prepared both by a lk y la tio n of l-.bensyl-f>-arainotetraso le w ith jj- h a lo p r o p r io a itr ile s and by beassylation o f i-^-oyanoetthyl*.
S-ami no t e t r a s o le .
Debensylaticm o f the di-o y an ceth y lated l-b e n sy l-^ -e m ln o te tra so le
produced a compound th a t was id e n tic a l with 5~W* If-di-|9-cyanoethylamine bet ra s o le prepared from |3 ^ 3 * -lm in o d ip ro p io aitril« by re a c tio n
w ith cyanogen bromide and hydm zoie a c id .

These r e s u lt s in d ic a te d

th a t th e di-cy an o eth y la t ad l-b e n sy l-5 -a ra ia o te tra z o le was l-b e n « y l-5 B, JJ-di-/5-oiy»noethyl<«ainotetr>»iol®.

Attempt* to sy n th e sise the l a t t e r

compound from

tK»* dl

@yAAo®thyl thltfwAft ft&d frsci b—

bdnsyl th lo sesal cnrbasi de ware unsuccessful*
Ciyanoethylati on o f ^-am lnotstrasole, again using a b e n sy ltr ihydroxide cato ly « b # reunited l a Iht formation o f two
mono-, eyano eth y l a t ed d e riv a tiv e s , os in d ic a te d by th e elem ental a a » lysas*

One o f those wa® id e n tic a l w ith 1«|SLoyanoethyl-5~aminotetra~

s o le prepared by th e re a c tio n o f f a m in e p ro p io n ilrIX e w ith cyanogen
bromide and hydm solo a c id successively*

fhe o th e r mono-oyanoethyl-

a ie d S-amino%e t ra s o le was postulated to be B-^-cyaao®thyl-5-aaiinote tr a s o le by a process o f e lim in a tio n and by is o la tio n o f an Id e n tic a l
compound from the re a c tio n o f ^3-bro£aoproplonltrlXe and 5 -am in o tetraMX* in a W « W u « u

Aleo produced in tfai, »m *U «* . . . i f -«?»*»-

eihyl-.5~af8inoletrasole*

Henry and flanagan (X) have dem onstrated

t h a t 1- and S-alkyX-5*e*(iidotetra«oXes a re th e c h ie f p ro d u ct3 obtained
from th e nlkyl&fcion o f fa m in e ie tiw ^ e le in a b a s ic s o lu tio n .
In an un su ccessfu l attem pt to prep are 5- ^ . syanoatby1am inot® traxole#
1 ,b-dibea*yl~ 5-iB »i»otetra*olin» was caused to re a c t w ith ac ry lo n i t r i l e
In th e presence o f bensyl trimethyXamBionium hydroxide*

fh e product

obtained e x h ib ite d p e c u lia r p ro p e rtie s and the proposed debsnxylation
to y ie ld 5*^-cyanoethyla«ainot^tw \zolo m s n o t effected*
Decsyanoethylatlon occurred during the h y d ro ly sis o f
ethyl**5-um inotetrase 1e with barium hydroxide*

i f - cyano-

H ydrolysis with concen­

tr a te d h y d ro ch lo ric a c id gave an a c id ic compound which was not charac­
t e r is e d .

P o ssib le mocrimnlsms f o r th e re a c tio n o f a c r y l o n ltr ile w ith 5am in o te tra ee lo and 1-hensyi-5-am lrxototrasjole hove been p o stu la te d
which employ an apparent analogy between th e be.so -c a ta ly se d oyanoe th y la ito n re a c tio n and th e a lk y la tio n o f 5 -am ln o tetraso le in &
b a s ic medium*

tUriferene* C ited
1* B* Jk* Henry and W. Q« Finnegan, J* Am* Che®. Son.,
(3.95k) .

9^3

xinm<nHK5fio»

* • .

*

.................................................................... ,

.

.

„

.

. . . . . . ........................
x a s m s x c n i....................... . . . . . . ....................................
SmRXHHRrAl, * . . , . ............................................

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

Frep&r&tion o f l-p h en y l-^ -afijin o tetraso la................................. ....
P re p a ra tio n o f X*.cyaloh*3cyX~^4^1no t etrassele . . . . . . .
P re p aratio n o f X~be»55yl-5~aralnotefcra aole . .
....................*
Bensyl&tion o f ^ M ts d n o te tra s o le ......................... ...
OyanoethyXation o f X-heasyX-Skas&no i e t r a s t o l e .........................
P re p aratio n o f 1-yS -cy an o e th y l-^ a& ln ete tr& so le * .................
P re p aratio n o f th e a c e ty l d e riv a tiv e o f \ * £ - cyuno e th y l5~ aM lnotetrasole.
....................
*
P re p a ra tio n o f X -beneyX -^0 ~cyanoethyl~5~teinoi«tm ~
.........................
ve o lin e hyd ro ch lo rid e . ' ..................... . . .
km B enaylation o f X~(3 -cyanoethyX«*$-eaaino te tra sso le. • •
! . Beaotlon o f l-b#n«yX-^&rainofcetrasc>X«j with
j^ -o h lo ro p ro p lo n itriX e
.........................................
Cm k eao tio n o f X-henayX-5-mainotetmssol© with
/S -brom oproplonitriX e . . . . . . . . . . . . . . .
BebenssyXatien o f X~be«2yX~*U/3 -ey&noeihyl-VXminQ £$tr&so lin o h y d ro ch lo rid e .............................. , ... .............................
Benetton o f ^ -an tin n tetraco le with a e ry X o n ttrile . . . . . .
F rep aratIo n o f an a c e ty l d e riv a tiv e o f 2-^3-cyanoebhyl**
^ •asln o tetra ao X e. . . . . . . . . . . . .................................
AXIsylation o f 5N-ondnotetra«oXe w ith /3 -ferotsopro p i emit r i l e .
F o rm tio n o f 1-henay l-5~UfH~di-i§ -cy&noethylaminot © tm zole
from l-benzyl-^-* p-oya& oethylam inotetrasol©
.....................
P re p aratio n of
~oyano©thyliuaino te ir& so le . . . .
D eterm ination o f the eq u iv alen t weight and ap p aren t pK
o f ^-H#ir*.di-/S*-oyanoethyia£iiinotetra»oXe . . . . . . . . .
D ebensyiatiott o f l-bensyl-$~ $,ft-di-^3 ~«yano©thylamino~
te tra s o l©
, . . / ..........................
P re p a ra tio n of ?l-benayX-W#*H *-di^S-oyaiioethyithiourea* . .
Attempted syntheses o f l-b© nsyX -^lit TI~&i«*3 -ey&noethylam liiotetraeoXe . . . . . . . . . . . . . . . . . . . . .
A. U sing U -b e n s y l-^ W -d i^ ^ c y a n o e th y lth lo u rm . . . .
B. Using U -b easy lth to sem lcarb & g id © .....................................

tmm or oenrram - continued
F&ge

Dobeii zyl& tioB o f X ^ b © n g y l-5 -y ^-cy an o eih y laiaiiio tetr& ao le • .
A ttem pted c y a n o e th y la tic m o f Xt h ^ d lb e n ^ y X ^ -tfflin o t® tra so iln ©
A t t e s t e d h y d r o ly s is o f X -^ 3 -c y » n o e th y l-‘3 -® ® in o t« traso l® . •
A* B a s ie h y d r o ly s is
........................ ..........................
» . A cid h y d r o l y s i s ..........................
Infs'CM-red a b s o r p tio n s p e c t r a . ♦ ..........................
B x n m m r ...............................
U fftRA ftm * o i t i o
A fm & z x

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

UB
30
51
51
53
53
5h

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

55
57

hut

of

$mJm

TABLE
X Bata f o r th e T itr a tio n o f 5»B#!&*Bi./3-c$yai*0elfeyXaxBittotetrasol© w ith Aqueous Sodium Hydroxide. . . . . .

Pag*
58

iis t

of

fiwsmm

FXOtmi

Page

X* In fra -re d Spectrum o f X-B«nayX~9^-eyiuao#bhyXaminotatracoX © ........................

59

8. In fr a - re d Spectrum o f l-B en sy l-^ /S -o y an o eth y l^ * *
im inotetyaaoX ine H ydrochloride
.....................

60

3* I n f r a - r e d Spectrum o f X-Bans5yl~5~H*!i-dt-y3 -cyanoeth y lam in o tetraao l* • * .............................................................

6l

b. I n fr a - ra d Spectrum o f 5-Ht H-Bi-jS-cyanoathylam inote tr a g o la . • • . . * ......................................................... .... . .

62

5.

In fra -ra d Spectrum o f H-lonayl-U1f - d i-/} -cyanoetfcylth io u re a •
................................. .................... ' . .
.................

63

fe. I n fr a - re d Spectrum o f X-|S -Cyanoet3^yX-5-^®inctetrastole •

6h

7* I n fr a - re d Spectrum o f X-/3 -Cyanouthyl-^-aeetyXmainota tr& s to le * ......................... ' * ........................................ . . ♦ • .

69

S* I n fr a - re d Spectrum o f 3-^0-0yanocthyX-5-aminot«traaoX« *

66

9 . I n fr a - re d Spectrum o f &*£> - OyanoefchyX-^-acety lets! no­
te tr a a o le . . . . . . . J ....................

67

The o r ig in a l purpose o f t h i s study was to in v e s tig a te th e cyanoe th y la tio n , d ilb raiaeth y latlcm , and th e Mannich re a c tio n s a p p lie d to
th e 5 -am in o tetraso ie system w ith th e p o s s ib ility o f o b ta in in g some
in te r e s ti n g s y n th e tic interm ediates*

I t was hoped th a t th e se compounds

could be I n te r r e la te d by r e la tiv e l y stra ig h t-fo rw a rd chemical re a c tio n s .
However, a f t e r p relim in ary experim entation, a tte n tio n was d ire c te d
e x c lu siv e ly toward an in v e s tig a tio n o f th e cyimaefchylation re a c tio n
w ith th e 5~iimiftoisir&gel0&*
Although th e r e s u l t s o f th e cynnoa th y la t ion o f v ario u s amines and
n itro g e n h e te ro e y e llc s have been recorded and discussed in th e l i t e r ­
a tu re ( l t £>, th e re i s no reco rd o f a p p lic a tio n o f th e re a c tio n to the
5-amino te tr a s o le e .

Because o f t h i s . I t has been necessary not only

to study th e re a c tio n o f a e r y l o n itr lle w ith th e 5 -am in o tetraao lea,
b u t a ls o to e s ta b lis h th e s tru c tu re o f th e products*
The g en eral method o f a tta c k follow ed in th is in v e s tig a tio n has
been th a t o f is o la tin g th e products r e s u ltin g from the oyanoethylation
re a c tio n s and th en p o s tu la tin g s tru c tu re s u sin g th e r e s u lts o f the
elem ental an aly ses in conjunction w ith ph y sical and chemical p ro p e rtie s .
F inal proof of s tr u c tu re was accomplished by sy n th e tic and degrad&tlve
procedures whenever p o s s ib le .

The p re p a ra tio n o f d e riv a tiv e s o f some

o f th ese compounds h as been attem pted*

HISTOHICM,
An ex ten siv e review o f th e cy an o eth y latio n re a c tio n has been
prepared by $ru»o» (X) end general d e s c rip tio n s of th i s re a c tio n may
be found In moat t r e a t i s e s on o rg an ic chem istry.

T herefore, only

those s p e c ific phases o f cyanoethyl© tion which o re p e rtin e n t to the
a p p lic a tio n to th e 5-amiaotetra$oX©s a re contained in t h i s se c tio n .
The b a se -c a ta ly se d cy&noethyl a tIo n re a c tio n h as been re fe rre d
to a s a s p e c if ic type of Michael condensation (3#^) where a compound
co n tain in g a l a b i l e hydrogen adds to th e a c r y l o n itr ile m olecule.

The

o v e ra ll r e s u lt i s th e replacem ent o f a l a b ile hydrogen w ith a ^ -q y a n o eth y l re sid u e , g.g*
«H-K + Cfig=CK~«H ^

X “ K-CHgCHgQER

A ddition always ta k es p lace In such a manner th a t th e more an io n ic
p o rtio n o f th e addend goes to th e ^ end o f th e 0(^3 double bond (3) *
The cy an o eth y latio n re a c tio n h as been observed to be an equi­
lib riu m re a c tio n .

When equimoiur p o rtio n s o f secondary amines and

a c r y l o n i t r i l e r e a c t, some unr©acted s ta r t in g m a te ria ls a re always r e ­
covered and th e y ie ld o f product i s never a s high a s when m excess
o f one o f th e r e a c ta n ts i s used ( $ ) .

F requently, h ea tin g a cyano-

© thylated d e riv a tiv e near i t s b o ilin g p o in t w ill cause gradual de­
com position to th e o rig in a l compound and a c r y l o n itr ile o r some polymer
th e re o f f l ) .

E e v e rs iM lity has been observed ex te n siv e ly w ith th e

cyanoethyl& tion o f a lc o h o ls .

The cyanoethylated products have been

observed to undergo therm al d is s o c ia tio n in the presence o f a lk a lin e

3
m a te ria l* in to th e o r ig in a l n l cohol and a polymer of a e r y l o n i t r i l e (6)*
With compounds co n tain in g tmrm than one re p la cea b le hydrogen* th e
products o b tain ed a r e dependent upon th e co n d itio n s o f th e reaction*
Hono~eynnoathylatQd compounds predom inate a t lower tem peratures Cl)*
While re a c tio n o f a c ry lo u ifc rile w ith some compounds co n tain in g
l a b i l e hydrogens I s spontaneous and h i^ a ly exotherm ic, in most I a*
sta n c e s th e a s s is ta n c e o f a c a ta ly s t to h a ste n attain m en t o f eq u ilib riu m I s required*

Bensyltrlm ethylas^onlum hydroxide i s ap p a re n tly

a q u ite v e r s a t i l e cyan o eth ylatio n c a ta ly s t (i)*
P revious a p p lic a tio n s o f th e cyanoethylation re a c tio n to vnriom
amines and n itro g e n h e te ro c y c lic * have been ta b u la te d by Brusca (1) •
’fhe only more recen t re fe re n c e d ir e c tly a p p lic a b le to the p rese n t
In v e s tig a tio n concerns th e cyano© thyiation o f beozim.ldasole and I t s
2-Kiethyl analog*

u

ISfros and 3orai~Ko*hlt ( 2) found th a t both o f th e se

compounds gave B^cyanoebbylabed d e riv a tiv e s ,

ly d r o ly s ls of th ese

products In hot 10 p ercen t sodium hydroxide re s u lte d in decyanoethylatio n w ith th e recovery o f th e oorresponding b«mslaiida*ol*.

H ydrolysis

w ith barium hydroxide gave a 95 p ercen t y ie ld o f l-bensim idasoleprop*
lo n lo a c id a s th e barium s a l t .

Bacy&no©thyla t i on was not encountered

u sin g a h y d ro ch lo ric a c id h y d ro ly sis medium*

fiXSCBSSXOff
5-Aminot©tr&xole may be rep resen ted by a number o f im itom eric
structure® w ith th e hydrogens arranged in v ario u s p o s itio n s about
th e le tr u s o le nucleus and th e exocyclle amino n itro g e n .

D eriv ativ es

o f th e th re e tau to m eric forms rep resen ted below were encounter ad in
th e study o f th e oyaxioethylatl on o f th e %~mL%nate tr a s o l e system*

An In sp ec tio n o f th ese tautom eric stru ctu res re v e a ls th a t th re e
mon©*ayanoethylnted products could a r i s e from th e rm o tio n o f
t e tr a s o le with a e r y l o n i t r i l e .

*Tb®^-cyanoethyl re sid u e could be

a tta c h e d to th e 4, e* & n u clear p o s itio n s o r th e fa m in e n itro g e n .

An

even g r e a te r number o f isom ers o f &1- and tri~ o y an o eth y latsd 5 -aminote tr a s o ie i s p o s s ib le .

In view o f th e to ta l number o f products th a t

could conceivably r e s u l t fro® th e re a c tio n o f 5-afflinotetr&sole w ith
a c r y l o n i t r i l e , se p a ra tio n d i f f i c u l t i e s appeared to be In ev ita b le*
In o rd e r to lim it th e number o f p o ssib le isom ers, sev eral 1 -sub­
s t i t u t e d 5~*ualnotetrasoles were i n i t i a l l y chosen fo r the study.
an a lk y l o r an a ry l s u b s titu e n t in th e

With

p o s itio n , a m axim s of two

hydrogens could be rep laced by/3-eyanoethyl groups.

Although th e

p o s s ib ilit y o f obtaining quit® a number o f products s t i l l ©xisted» i t
was hoped that Just one or two d ifferen t cy&noetfcylaied 5-ami notetraso le s would bo produced in the reaction o f a X*>substituted 5~amlno~
te tr a s o le with aerylo n it r ile *

!lherefore# several X«*substituted 5-

am lnotetraseles were synthesised*
l-Fhenyl***)-malno t a tr&ssol© was prepared from phenyl th io u re a
u sin g th e method o f ftnnagan f | ,

(7)» m odified to perm it successive

s te p s w ithout I s o la tin g th e interm ediates*

She l*»oyolohexyl and X-

benayl-^-araino te tr a s o le s were prepared from th e corresponding amines
u sin g Wilson1s m o d ificatio n (8) o f th e method devised by darbreoht
and Her b at f 9 ) .

In both o f th e se methods, th e 5«.a*aiaeb©traseX# i s

presumably formed by th e e y e lis a tlo a o f a gnaayl a s id e interm ediate*

8 l® g

B ** a lk y l o r a r y l

6
I t i s conceivable that the guaayl a sid e oeuld c y c lis e in eith er o f two
n jr i to y ie ld a A*euhebt tubed S^amlnebetmsele or a 5~ su bstitu ted
am inotetresole*

However, * previous study (9) too* shown that l a a l l

in sta n ces, even with su b stitu en ts o f varying e le c tr o n e g a tiv itie s , the
only product obtained wee the X -eubetltuted *M ftlnotetrasole*
X~B<m«yX~*Hwai&®tetrasole was e ls e p r e p a r e d by b e a s y la tis ii o f
$ ~ an in o tetrftso le follow ing th© procedure o f fterb st and (2arbreohi (1 0 ).
AXwo is o l a te d tmm t h i s re a c tio n were tS-bensyXaminotetr&aole and I benzyl~.5~bensylamlnotetr&eQle*
Although th e l~phe&yX, .iMjyolehexyX, and X~be»*yl~$-ami»e betra~
so la* were prepared w ith th e in te n tio n o f in v e s tig a tin g th e p ro d u cts
from th e re a c tio n o f each w ith n c ry lo n X trlle , only th e l~bensyl~5-*
a m in o te tra so la was a c tu a lly used*

th e reason fo r th i s was th e appar­

ent ease w ith which th e benzyl group can he removed by c a ta ly tic
hy drdgenolyeX* according to th e method o f B irkofer (XX>* % th e use
o f t h i s degradetlvw procedure, the products from th e re a c tio n o f
a c r y l o n i t r i l s w ith l-henssyX -5-a^icoto tr a s o le could he r e la te d to 5-*
amino t o t r e s a le s co n tain in g only |?~eyai*c>e th y l su b stitu en ts*
V

In th e cyao o eth y latio n s tu d ie s , i t was found th a t in tim a te mining
o f the re a c ta n ts and the c a ta ly s t end th e use o f fre s h ly d i s t i l l e d
a o r y lo n lt r i le were n ecessary co n d itio n s f o r re a c tio n to occur*

A

survey o f p revious a p p lic a tio n s o f th e eyanoethylation re a c tio n in ­
d ic a te d th a t b e n z y ltr Imethyiaiaratmluia hydroxide wa* an extrem ely
v e r s a t i l e c a ta ly s t*

th e re fo re , a bO p ercen t aqueous so lu tio n o f

th is compound was u t i l i s e d In a l l experiments*

Ho attem p t was made

7
to determ ine whether mm» o th e r c a ta ly s t «©*X& have b««tt mere e e tle f a c to ry ,

Ethylene d ie h lo rld * «as ttsed a* th e i n i t i a l so lv e n t f o r th e

product* einoe th la so lv e n t hae bt«& found to d is s o lv e cyano eth y latsd
product* eeX eetlv ely ,

day polymers of a c r y l o n itr lle formed d u rin g

th e re a c tio n remained mstdleselved ( 1 ) .
Ihak a mole*to*»msie r a t i o o f X«*heasyl«*!5-i*iBiac>tetraselo and
f r e s h ly d i s t i l l e d a o r y lo n itr ile woo caused to r e a c t In th e presence
o f a ho p e rc e n t aqmemut so lu tio n o f heneyl triiwthyXa»»©»i«m hydroxide
c a ta l y s t, a c r y s ta llin e compound re s u lte d .
th a t monoeyatioethylatl on had eoearred*

£1omental a n a ly s is shooed

fh o too most reasen ah ls

p o s itio n s fo r th e In tro d u c tio n o f th e |9~eya*i©ethyX re sid u e appeared
to ho In tho h p o s itio n ( I ) o r attachm ent to tho amino n itro g en (1 1 ),

G gffi&W

NfCH20H2C£H

(i)

(XX)

X,h-B i safest!tu ted ^-im itioieiraaoX laes (X) e x h ib it q u ite b a s ic
p ro p e rtie s and r e a d ily form hydrochlorides o f d e f in ite ooaypooifcion (1 2 ).
The mono-cyano*thylat«d l-honKyi-5«-aml»otetra*olo was only s lig h tly
haalo and f a ile d to form a hydrochloride o f d e f in ite com position.
Since th l a behavior la c h a r a c te r is tic o f th e X ~aikyl-5-alkylarainote tra seX e s (1 3 ), te n ta tiv e assignm ent o f s tru c tu re a s 1 - h e n z y l-5 ^ eyaaoethylamlnotetrmaoXe ( I I ) to the mono-cyanoethylated l-feen*yl*>-aminotetra*ole ana made.

t e r com parative purpose*» th e sy n th e sis ©t l-b e n s y l~ h ^ L q y a a ©4
e th y l- 5- l» in o te trn so l4 a # ( I ) m * undertaken*

1$ m s f e l t th a t th e

most d»si;a!»i0 approach m s th e henayl&tion o f 1~|&» cyanosthyl-5~
a a ln o te tr a s o le i t t h i s compound could ho prepared*

Using t h i s method

and b a rrin g r e a r rangement s # th e attachm ent o f the |3 -ey aaeeth y l group
a t p o s itio n

o f tho tetrasso ls rin g m a id ho e s ta b lis h e d .

Prepara­

tio n o f l - |5 - eyanoafchyl^^-aminotetr&zolo ( I I I ) m s accomplished In
th e follo w in g mauler* jS -Jtoainopropionitrile, sy n th esised fro® ammonia
and a o r y l o a i t r l l e ( lh ) , m s used a s th e s ta r t in g m a te ria l.

In te ra c ­

tio n o f^ -a m in o p ro p io n itrile with cy&aogen bromide In d ie th y l o th e r
gave a oyanamide which reac ted with hydraaoic a c id in b o ilin g xylene,
according to th e method o f Ckurinresht and BerfestCf), to give th e
d e s ire d t s t r a s o l s a s a c o lo rle s s c r y s ta llin e product, a . p . 115-116^0*
f h i s s e r ie s o f re a c tio n s I s rep resen ted below*

BrOBff

HE,

/Wv
ni

EBCCHgCHgHHg.HBr

H

(X II)
S lsm eatal a n a ly s is supported the p o s tu la tio n th a t t h i s product
m s 1 -|3 - c^*m oethyl-5-am inoletrasole ( I I I ) , h u t could no t e x elude th e
p o s s i b i l i t y th a t

G yanoethylam lnotetrazole had formed,

fhe

n e u tra l c h a ra c te r o f th e product in d ic a te d th a t the r in g clo su re had
not produced a 5 -alh arlam in o tetm so lej a l l known 5-aikylfuaiaofceiraaoles
e x h ib it d e f in ite a c id ic p r o p e r tie s .

In a d d itio n , p revious in v e stig a ­

tio n s u sin g th e s y n th e tic ro u te employed in th e p rep aratio n o f ( I I I )

t

have shown th a t r in g c lo su re o f th e guanyl a s id e in te rm ed ia te occurs
only in th e d ir e c tio n y ie ld in g a 1 ~ su b stitu te d 5*^uainotetrasole ( 9 ) .
An a c e ty l d e riv a tiv e ( I l i a ) o f

cyanoathyl-^-am lnG tstr& sol*

was prepared by re f lu x ia g i t w ith a c e tic anhydride (10)*

( Ilia )
tshen a m ixture o f 1 - ^ - cyism oethyl-^-am lnotetrasole ( l i t ) and an
©quiiaolar q u a n tity of benzyl c h lo rid e was heated in an o il bath (i*>\
an exothermic re a c tio n ensued and th e m ixture s o lid if ie d .

B e c ry s ta lli-

natio n o f th e crude product gave a c o lo rle s s c r y s ta llin e s o lid whose
elem ental a n a ly s is was c o rre c t fo r X-ben*yl-U-|!3- ey&»oethyl-$-isainote tr a z o lin e hydrochloride ( I ? ) .

A compound of Id e n tic a l in f ra -r e d

spectrum, m eltin g p o in t, and m ixture m elting p o in t was prepared by
th e a lk y la tlo n o f lvbensyl-5-am inotetrassole wi t h ^ - ch io r opropi oni t r 11e,
u sin g th e same technique (!$ )•

P rep aratio n of th e X-benayX-b-^- cyana-

ethyl-5-lH rinotetraxolin© hydrochloride was a lso accomplished from
l-benayl-5-asaino te tr a a o la u sin ^ ^ -b ro m o p ro p io n itr 11 e as th e a lk y la tin g
reagent*

In th e l a t t e r case, th e crude ta tra x o lin e hydrobrotuide was

tr e a te d w ith aqueous sodium hydroxide to y ie ld an extrem ely b asic
p a le yellow o i l .

Hhen t h i s o il was caused to re a c t with gaseous

hydrogen c h lo rid e , l-benzyl-^-^!!?- cyanoethyl-^-itsinot © trasol in a hydro­
c h lo rid e (I? ) was formed instantaneously*

10
A fte r se v e ra l attem pts* c a ta l y tic debenaylation o f X-bensyl-**^3-eya*ioeihyl-5**im inotetrauoline hyd ro ch lo rid e (XV) u sin g th e method
o f B lrk o fo r (11) y ie ld e d a product shoes m elting p o in t was not de­
p ressed by adm ixture w ith 1 -^ -c y a n o e tb y l-5 -a m in o te tra so le ( i l l ) *

The

preceding tran sfo rm atio n s may he summarised schem atically!

(X II)

(IV)
from t h i s phase of th e in v e stig a tio n * th e follow ing in te rp r e ta ­
tio n s may be drawn*

Since l-b e n s y l-H -^ - cy an o eth y l-^ -im in o tetra-

ro lln e h y d ro ch lo rid e (IV) was formed re g a rd le ss o f the o rd er o f in tr o ­
d u ctio n o f th e bensyl and th e

-oyanoethyl groups and sin ce 1-^9-

cy an o eth y l-^ -am in o tetraso le ( I I I ) re s u lte d from the c a ta l y tic dehansyla tlo n o f t h i s compound* i t may be concluded th a t compound (IV) I s
l-bensyl-h ty ^u cynno « th y l-5 -i« in o te t raao l la s hydrochlori de•

f h i s con­

clu sio n i s supported by P erclral* s in v e s tig a tio n e s ta b lis h in g the
s i t e o f raono-alkylatlon of the 1 -s u b s titu te d $ -am in o tatm so les (1 2 ).

U
Furtherm ore, th is s e rie s o f re a c tio n s s u b s ta n tia te s the Assumption
th a t th© ^HoaiinototruEoio prepared f r o m n o prop I ©nit r i l e coni. tt.
luted*

. . pr«*loualj' , o . ^

Most Im portant, however, i s th e b a s ic n a tu re o f th e o il

lib e r a te d by aqueous ©odium hydroxide from th e product o f th e re a c tio n
o f l-be»B yl-5-*u»i»otetraaole a n d ^ -b ro fso p ro p io n itrlie and from 1benzyl-U -^-cyanootihyl- 5-iuainotetrasolin© hydrochloride (IV)*

Al­

though no elem ental a n a ly s is was obtained f o r th e p a le yellow o i l ,
th e f a c t th a t l-.b«njsyi-**-|$* cy an o « th y i-9 -im i« o tetra» o lln e hydrochloride
(IV) was formed Immediately upon co n tact Of th is o il w ith hydrogen
c h lo rid e in d ic a te s th a t t h i s substance m s th e f re e base, l-b e n s y lo y a m e th y i-^ -lisin o te tra s o lln e {I}*

From a comparison of th e be­

hav io r o f t h i s compound w ith th a t o f th e *aono - cyan©e t hyla i ed l-benssyl5-amino to tr a s o l e , ( I I ) , i t was a p p a re n t th a t th ese compounds were no t
id e n tic a l*
An exam ination o f th e s tr u c tu ra l formula of l-^ -a y a » ® e th y l-$ am in o te tra so le ( I I I ) re v e a ls th a t th is compound could conceivably re­
s u l t from the oyanoethylation o f 5-am inotetraaole*

A lhylation s tu d ie s

involving the sodium s a l t o f 5-ami not e tra s o le (16) have demonstrated
th a t the form ation of s a l t s o f 5-ami no t e t r a sol® involves c h ie fly th e
^ and 2^ n u clear p o sitio n s*

f h ia may be in te rp re te d a s meaning th a t

th e anion r e s u ltin g from th e removal o f a proton i s s ta b ilis e d by
resonance and re a c ts m th o u # th e f r e e e le c tro n s a re lo c a lis e d in
th e n u c le a r p o sitio n s*

Sine# th#

nnd h p o s itio n s And th# £ and 3 p o sitio n e a t# e q u iv ale n t

In th# 5 -arain o te traao le nucleus which co n tain s no s u b s titu e n ts , only
two n u c le a r s u b s titu te d products can he formed*
fh# Hioh&el condensation, o f which b ase-cataly se d eyanoet h y ln t ion
i s a s p e c if ic ty p e, involves th# a d d itio n o f a compound co n tain in g a
l a b i l e hydrogen to an a c tiv a te d carbon to carbon double bond*

A

mechanism advanced fo r t h i s re a c tio n <3) Involves th# a b s tra c tio n o f
th# l a b i l e hydrogen by th e b a s ic c a ta ly s t follow ed fey th e a d d itio n
o f th e r e s u ltin g anion to th e more p o s itiv e end o f th# p o la ris e d
double bond*
^>»H + B~(tew»)
I^sif

„

♦

6*

S '

^

♦ HB

__

e tr^ r r^ ^ B -c % < a » - o s tr

^H-CE^&H-GEIt ♦ HB ^

3^W-CH2-C%-CBR ♦ B”

In view of th e predominance of th e 1 and £ - s u b s titu te d 5*
ami n e t e tr a so le s a r is in g from a re a c tio n which involves anion forma­
tio n and th# mechanism f o r th# b ase-cataly se d oyanoethyl&tlox! reac­
tio n which a ls o Involves anion formation* i t m s hoped th a t th# number
o f p rodu cts r e s u ltin g from th# cyanoethyiation o f 5 -am in o tetraso le
would be lim ite d .
ssol# was attem p ted .

With t h i s in mind* q y aaoethylatioa o f 5 -am in o tetra-

13
When a m ole-to-m ale r a t i o o f a c r y i e n l t r i l e was added to 5-amlao~
tstr& so l* c o n tain in g a few drops o f a ho p ercen t aqueous solu tion o f
benzyl triraethylmieaonium hydroxide c a ta ly s t and th e m ixture was w ell
blended* an exothermic re a c tio n occurred g iv in g a yellow so lu tio n .
A fter h e a tin g t h i s s o lu tio n f o r twelve hours a t re flu x tem perature
follow ed by s h illin g * a yellow c r y s ta llin e s o lid resu lted * sup. 97o

106 0.* whose m eltin g p o in t range was not ap p reciab ly narrowed by
rep ea ted r # c r y s ta ll1 za tio n s from a b so lu te eth an o l.

Separation in to

two components was accomplished* however* by e x tra c tio n o f th e s o lid
w ith h o t eth y len e d lo h lo rid s .

Idsen th e eth y len e d ic h lo rid e e x tra c t

was c h ille d , c o lo rle s s p la te le ts * (A), p r e c ip ita te d .
ta lliz a tio n * t h i s m a te ria l melted a t 117-0-117.5*$.
o f t h i s compound, (A>, w ill be discussed l a t e r ,

A fter re c ry s­
C h a ra cte rizatio n

fh e re sid u e from

th e eth y len e d ic h lo rld e e x tra c tio n upon r e c r y s ta llla a tio n from 95
p erce n t ethanol gave a c o lo rle s s c r y s ta llin e solid* (B ), m.p. 115116°0. * which was found to be id e n tic a l w ith l~^3~ oyanoethyl-5a m ln c te tra so le ( i l l ) .

M ixtures o f (A) and (B) m elted below 100°C.

Elem ental a n a ly s is In d ic a te d th a t product (a) was a lso a monocyanoethylated d e riv a tiv e o f 5 -n m in o te trazo le.

A survey o f th e pos­

s ib le p o s itio n s to which th e j 3 - oyanoethy1 group could be a ttac h ed
showed th a t th re e isom ers were p o s sib le t
so le (XXI)*

l*^-cyanoethyl-5-nm iaotetra-.

cy an o eth y l-5 -e^ ln o tetraz o le ( ? ) , and 5 -^ -c y a n o -

eth y lam in o tetm zo le dVl).

BtfCHgOHgO*!?

A

*
t v i)

(V>

n it)

fjince a m ixture m eltin g p o in t o f I b is compound and an a u th e n tic
sample o f

( I I I ) m s depressed by

2?d0t and because th e in f r a - r e d spectrum o f th e s o lid was u n lik e
« » .. . r

,h . .» • « * « . . r

( in ) .
r f

p o s itio n m e elim inated*

* > « - - —

«

" ■ '■ “ • ‘ * “ »

.to
*•

Sims* th e compound could not he a poly­

morphic m o d ificatio n o f (111).

In a d d itio n , th e a c e ty l d e riv a tiv e

o f t h i s su b stan ce, (&>» e x h ib ite d a m eltin g p o in t o f 13b-137°G* com­
pared to th a t o f 1O&-1050®* fo r th e a c e ty l d e riv a tiv e , ( I l i a ) , o f
1 -/3 - cjranoethyl-S -am inotetrasole ( I I I ) *
She f a c t th a t d if f e r e n t a c e ty l d e riv a tiv e s were o b tain ed l a a lso
evidence th a t th e m a te ria l, (A ), could not be
te tr a s o le (VI)*

ethylam ino-

I t has been dem onstrated th a t under th e co n d itio n s

employed, l-a lb y l-^ -a m ln o te tra s o le s and «>-alkylam inotetraaoles con­
ta in in g th e same a lk y l group form th e same a c e ty l d e riv a tiv e (10)*
A lso, a l l known 3 -^ lh y lam ln o te tra so le s a re a c id ic and th e r e s u lt s o f
an attem pted p o tsn tio m a tric t i t r a t i o n o f the second moao~cyanoethyla te d d e riv a tiv e o f ^-am iaotetr& sole in d ic a te d th a t i t s aqueous so lu tio n
was s li g h tly basic*

Upon examining th e in f ra -r e d spectrum of th e

s o lid obtained from an attem pted thermal rearrangem ent (17) of

15
compound (A), i t was found th a t th e minor d tffs re n c e a In th e spectrum
compared w ith an i n f r a r e d spectrum o f th e s ta r t in g m a te ria l could
probably be a t t r i b u t e d to some decomposition which was observed*

un­

le s s th e s u b s titu e n ts a r e r e l a t i v e l y e le c tro n e g a tiv e , i t has been
shown C1T) t h a t 5 - s u b s titu te d am ine tstr& so le s w i l l undergo therm al
rearrangem ent to t h e c o rre sp o n d in g 1- s u h s ti tubed 5~&sai»ob«trasoles.
On th e b a s is o f th e above f a c t s , ( I I I ) and (IT ) have been elim­
in a te d a s p o s s ib le s tr u c tu re s fo r th e ethylene d ic h lo rid e so lu b le
p ro d u c t, ( a ) , from th e cyanoe th y la tio n o f 5-aminotetmssoXe*
p o s s i b i l i t y th a t th e compound i s

*?h«

2-^^c^anoebhyl-5-*»®i»^b®bTn»oi#

(T) s t i l l remained*
Independent sy n th e sis m s not attem pted sin ce a l l known pro­
cedures f o r th e sy n th e sis o f &-«ub»ixtt&ed 5-»M l»otetrasoles re q u ire
h y d ro ly tic or re d u c tiv e procedure® too d r a s tic f o r the n i t r l l e group
to w ithstand*

In ste a d , an a lk y la tio a o f 5 - i^ in o te tr a s o le w ith y 0 -

bro m o p ro p io n itrile in a b a s ic aquaous-ethanolie medium was effected*
Henry and Tinnegan have re p o rte d ( lb ) th a t such an a lk y la tie a y ie ld s
"t
c h ie fly
and g substituted 5 -a » in o te tm s o le s w ith only tra c e amounts
o f o th e r products#

fwo products were is o la te d from th is re a c tio n ,

one a compound, m.p* 115-116°0*, th a t was id e n tic a l in a l l re sp e c ts
to 1-^?- cy«m oethyl-5-s»ai»ntetra»ole ( I I I) # and th e o th e r, a s o lid
e x h ib itin g a m eltin g p o in t o f 1X6-X1?°C*

A m ixture m eltin g p o in t

o f th e l a t t e r w ith product (A) from th e ey an o eth y latlo n of 5-aminote tr a s o le showed no depression*
were Id e n tic a l*

In a d d itio n , t h e i r in f ra -r e d sp e c tra

I t i s f e l t th a t on th e b a s is o f the evidence p re­

se n ted , I t I s reaso n ab le to assume th a t compound (A) i s 3 - ^ - cyanoethyi5-a m in o -te tra z c le (V).

16
*Fh« c y a n o o th y la tio n and th® a l k y l a t i o n o f 5 -a m in o -te trn a o l© which
J a v a b e en d is c u s s e d m y bo r e p r e s e n te d d ia^ raz o sa atica lly a s fo llo w s :

(III)

F u r th e r e x p e rira e n tn tio n w ith th© oy& noelhyl&bion o f l~h®nsyX~
5~&ffllfiot©tr&sol© r e v e a le d t h a t by th© u s e o f an e x c e ss o f a e r y lo n i t r i l e , v a ry in g am ounts o f a n o th e r p ro d u c t c o u ld be o b ta in e d In

.*u«„ «,

tin.

a n a l y s i s in d ic a te d th e p re s e n c e o f two c y a a a e th y l r e s i d u e s ,

fh is

compound c o u ld a ls o be p re p a re d by f u r t h e r r e a c t i o n o f 1 -b e n z y lcy ano athylam inototrassol© ( H ) w ith a c r y l o n l t r i l © l a th® p re s e n c e
o f bensyltrlm ethylam saonlusa h y d ro x id e a s a c a t a l y s t .

F o r t h i s com­

pound* s t r u c t u r e ( ? I I ) r e p r e s e n tin g 1 - b e n z y l - T i - d i - ^ o y a n o e t h y l a m in o te tra z o l® was p o s tu la te d *

r

m ^m asn

fCHgOH„C£M

°6»5® a

C83.CHCCT,

W

M

S
an

*

%
B(<afgCHgCBH)g

r T W
(T H )

s

XT
Hydf ogenolysi s o f
( T il) should le ad to

oy& noethylaciinotetrasole
& * ■ « . cyanoethyl&minotet r a s o l« ( f i l l ) *
H«m <B2G83f)g
CLH C&
% 5 3
(fill)

However, b e fo re hydrogeaolyaia m o attem pted, th© a n tic ip a te d product
was p rep ared by an independent sy n th e tic rout©,

ttban a so lu tio n o f

, -i£ a in o c iip ro p io n itrile l a eth y l &o©tat© m s tr e a te d w ith cyanogen
bromide and th© r e s u ltin g cyanamide refloated, with a benzene so lu tio n
o f hydrasoio ac id according to th© procedure o f derhrec&t and H erbst
( I S ) , a c o lo rle s s c r y s ta llin e product m s obtained whose aqueous
so lu tio n m s d e f in ite ly a c id ic ,
t e t r a stoic.

f h is in d ic a te d a ^ s u b s t i t u t e d amino*,

Jm ©1©mental a n a ly s is was c o rre c t f o r 5~$tT*~di.^3 -cy ano-

eth y lam fn o te traso le ( T U I ), th© d esire d compound.

fh© s e r ie s o f

re ­

a c tio n s le n d in g to th© form ation o f t h i s compound a re rep resen ted
below*

BaKJgEtf
B*.
(HB00%CHg)gHH — — > { ^ C 0% a ig )gHCTf ------♦
(KCCKgCHPgNH'HBr

9<08-aHLq?»)
ypC rf *
2
I
HT~S

(m i)
I t was found th a t th* W ia v lo r o f 5-TS,V-<A-@- qyaaosthylaailno.
t a t l S M l t (V III) in a p o ta n tio su itrio t i t r a t i o n w ith sodium hydroxids
was analogous to th a t o f a carb o x y lic a c id .

From th e t i t r a t i o n curve

115
an eq u iv ale n t weight o f 191*6 was obtained which agreed well w ith th e
m in e o f 191. £ c a lc u la te d from th e m olecular form ula.

C alcu latio n

o f th e pit h r th e $0 p ercen t n e u tra l! e a t ion method ( 19) gave an approx*
im ate value o f h .g ^ .
A fte r se v eral unsuccessful attem p ts, d eb em y latio n o f th e d icynnoethyX&ted l-b ettsy l-3 -a isln o te tra e o le (T il)* u sin g th e method o f
Birteofer (1 1 ), y ie ld e d a c r y s ta llin e s o lid . sup* 127-129^0.

Although

th e m eltin g p o in t could not he ra is e d by rep eated meery s t a l l ! g allo n s,
a m ixture m e ltin g p o in t d eterm in atio n o f t h i s compound and an authen­
t i c sample o f 5-H,?!<*aiy3~cyanoethylam lnotetrasole ( f i l l ) Soared no
depression*

I d e n tity o f th e compounds was a ls o e sta b lish e d by a com­

p a riso n o f in f r a - r e d spectra*

ffeis inform ation supported th e a s s ig n ­

ment o f s tr u c tu re ( ? I I ) fo r th e compound*
In o rd er to f u rth e r s u b s ta n tia te t h i s assignment o f s tr u c tu re ,
two d if f e r e n t ro u te s were explored f o r an unequivocal sy n th e sis o f
1- ben syl*9-^*

di-^3~ cyano eth y l amino t e t r a aoI e ( T il) .

Although numer­

ous attem p ts a t both o f th e se methods f e lle d , a b r ie f summary o f
each o f th e two approaches i s included*
flie f i r s t method, th a t o f Finnegan && g&j, ( ? ) , u t i l i s e d K*
benayl-Hf .

-d i« |3 -c y a n o o th y lth io u re a (IX) a s th e s ta r tin g m aterial*

This compound m s prepared from b en sy liso th io e y a m te
im in o d lp ro p lo a itrile u sin g a m o d ificatio n o f th e method o f Byson
and H unter (20)*
approachs

fhe follow ing diagram I l l u s t r a t e s t h i s sy n th e tic

19

i

W V " K ®fe0Ili80W)a
(ix>

oh_i
—
>

8c h ,.h i
C^I CHJf*bH( ® 2CH2 OEK) 2
5

m dma
\/

A«»0-

HMD,'

C!6^S H g»<»0»{aHgCHa OB«>a
HgH

2

-CgHcCHgBteOBf CHgCHgCBlOg

,HI®5

%S

.H I

SOI
^MWTOg
O X « JW»(CJj_OH_OSH)

f( ^g£®gG!rH) g

In each o f th e w s u o e b a s fu i attem p ts, th© r e a c tio n s appeared to
be p roceed in g s a t i s f a c t o r i l y to th e p o in t where s i l v e r n it r a t e solw t io n m s added to m e ta tb e tic a lly r e p la c e th e io d id e w ith a n it r a t e
ton*

Upon th # a d d itio n o f th« s i l v e r n it rat® , an in s o lu b le p l a s t i c

m a te r ia l p r e o lp i ta te d alon& w ith th e s i l v e r iod id e*

A fter th e pre­

c i p i t a t e m e removed by f i l t r a t i o n , d in tO tis a tio n o f th e f i l t r a t e
\

$&v© a red o i l whose in fr a -r e d spectrum was u n lik e th a t o f 1-benayX5-1$,l*-d i-|3 - oyanoethylaiainotetrassoi© (VII)*
The o th er approach to th© s y n th e s is o f (? I I ) in v o lv ed a d i f f e r ­
e n t procedure fo r the p rep aration o f th© amtno&u&nldlne h yd riod id e
in te r m e d ia te .

A lih a n # th e re i s no record o f t h is approach in th e

l i t e r a t u r e , th e method seemed to be a reason ab le one*
aem icarbazide was u sed a s the s t a r t in g m a te r ia l,

U -B en sy lth io -

The procedure lea d ­

in g to th e form ation o f th e guanidine fcydriodid© In term ed iate any

fee re p re se n te d a s follows*

9& 9 m r g * w

njjir'

* >

»

. hi

Evidence th a t 3-m ethylaticm occurred was th e ev o lu tio n o f methyl
meroaptan upon Hi# a d d itio n

*-i(nl nodiprop lo n i t r i l e .

A fte r

th e p re p a ra tio n o f a e l u t i o n o f th e compound assumed to fee th e tuoinoguani&ini

; h y d rio d ld # , th e same succession o f step # wee fallow ed a s

w ith th e o th e r method,

AgAln* th e same d i f f i c u l t i e s were encountered

end no i*.fe#»«yl~5-*?*H*dl-/3* cyan©ethylam in© tetrasele (?IX> wee obtained*
A1 though th e pestufeabloa th a t th e sfcruoture o f th e mono-cyan©e th y ia ta d i-.b«»syi~5-a*aln©tetra&ol# 1# rep resen ted fear (X) was stre n g th ­
ened by th e f a c t t h a t f a r th e r cyanoeihyi& tion o f this eompound y ie ld ed
l - f e e n * W - d i - ^ - c y a n o e t h y l a i a i n o t e t r a s o l # (VII) * a d d itio n a l proof
o f s tr u c tu re seemed to fee d e s ira b le .

Defeensylatlon o f t h i s compound

should r e s u lt in th e form ation o f 5**^-oyano#thylam inot e tr a s o le { ? !).
f h ls compound* (VI) * should fee a c id ic in nature* undergo thermal r e .
w n ttg a M D t to t h . J.^-o3raao*thyl.5-a»i*»«>t9t>»«>l« (III). «ad fora
t h . a—

a o o ty l d .r l T a t l r a , ( I I I * ) .

Sherofore. e s ta ly tlo d .b sa a jrla tlo n

fflJOKgCHgOSS
C6H5O T r f r \

— h«»t-------- ± ( I I I )

Hg-raog

(OHj OOj O— » ( I I I . )

(I)

(V I)

21
o f (1 ) was a ttem p ted * a g a in u s in g th e m ethod o f B lr k o f e r ( 1 1 ) .

Many attempt® were u n su ccessfu l and re u n ite d in th e recovery
o f s ta r t in g m a te ria l o r a substance e x h ib itin g th© c h a r a c te r is tic
odor o f an amine which was n o t Id e n tifie d *

One attem pted hydrogen*

o l y s i s u sin g g la c ia l a c e tic a c id as the so lv en t and palladium oxide
a s the c a ta ly s t gave evidence o f debenxylation having occurred*

fh e

orange o i l is o la te d from t h i s re a c tio n was acid ic* formed a s a l t
when n e u tra lis e d w ith aqueous sodium hydroxide* and reac ted w ith
a c e tic anhydride a t re flu x tem perature to y ie ld an a c e ty l d e riv a tiv e
which was Id e n tic a l w ith th a t formed from 1-^ -e y a n o ethyl-fM m incte tr a a o le f I I I ) and a c e tic anhydride*

th e in f ra -r e d spectrum of the

o i l was d if f e r e n t from th a t of the s ta r tin g m aterial* l-benssyl-5-^?cyanoethy iam ln o telraaei© CD*

When thermal rearrangem ent of the o i l

was attempted* no rearrangem ent occurred when th e o i l was h eated a t
13D®C. f o r two h o u rs.

Upon h e a tin g th e o i l a t Xb5°C* f o r fo u r hours*

some darkening occurred and a g lassy s o lid m s o b tain ed ,

th e in f r a ­

re d spectrum o f t h i s m a te ria l m s u n lik e th a t of th e o rig in a l o i l .
Attmnpts to is o l a te l-p -c y a a o e th y l-S -e m in o te tm s o le from th e g la ssy
s o lid were unsuccessful*

Although a sample o f th e o i l from the hydro-

g en o ly sis o f l-b e n sy l-^ -j3 * e y a n o e th y l^ sin d te tm so le ( 1) could not be
p u r if ie d s u f f ic ie n tly fo r elem ental analysis* i t appears th a t debeasyla tio n o f ( I ) y ie ld e d a substance some of whose p ro p e rtie s were those
p re d ic te d fo r 5- ^ - cyanoethylom iisctetrasole <YI).
In o rd er to o b ta in a eyamoethylated 5-am inoietm sol© w ith th e

^ -c y a n o e th y l resid u e In th e 5. p o sitio n * cy an o eth latio n o f 1 ,^ - d ib e n s y l-^ -im in o te tra so lin e was attem pted.

Bebengylation o f the

22
expsoted product Iro n th in reactio n , 1 , ^-dibsnssyi-rj-/3 - cysnoathylla iR o te tru a o ils a ( X ) , should produce
(V I).

cyano eth yl amino fcstr* sols

9h * proposed scheme nay be represented as follow s:

m gc6H5

(x)
V * ^
'(H^ca^anr
T O

u
(VI)
A re d viscous e l l which ev en tu ally s o lid if ie d to an orange s o lid ,

eup. 83-lhO^S* was obtained on i^ a n o sth y la tlo n o f 1, h-&ib»ni»yl-*»~
1mi no bet ra s e ! ino •

I to if ic a tic m was attem pted by s o lu tio n o f t h i s

m a te ria l In aceto n e, decolorism ilon w ith H o rite, and re p re e ip i t a t ion
w ith n-hexane.

A creamy white s o lid re s u lte d which darkened and was

transform ed in to an o i l upon exposure to the a i r .

A fter sev eral days

th e o i l s o lid if ie d to m orange mass, m*p. <g&» 123 w ith some decomposi­
tion*

Because o f t h i s b ehavior, debeasy latio n o f the product was not

attem pted*
Several attem p ts were made to o b ta in th e carboxyl1c ac id derived
from 1- ^ - cyanoethyl-^-am inotetrassole (111)*

Basic and a c id ic con­

d itio n s were employed to hydrolyse the n i t r i l e group o f ( 111) to

23
form th e corresponding a c id (XI)

Eaiy3!ywf

iOHgOHgCXSOH

<m >

(m

B eeyanoethylatlon occurred when barium hydroxide w e used a s th e
h y d ro ly tic reagent and f a m in e te tr a s o le was is o la te d from th e r e n o tio n m ixture.

Because o f th e eq u ilib riu m n a tu re o f th e oyano-

e th y la tio n reactio n # e lim in a tio n o f th e cyaaoethyl group in a lk a lin e
media i s n o t w ithout p reced en t.

A lk ali ca taly sed deoyanoethyiation

has bean observed In o th e r in sta n c e s {1#2*&>*

An a c id ic produet

which underwent decomposition w ith gas ev o lu tio n a t i t s m eltin g p o in t
was o b tain ed from one h y d ro ly sis u sin g concentrated h y d ro ch lo ric
add*

However# a t i t r a t i o n of th is substance w ith aqueous sodium

hydroxide rev ealed an eq u iv alen t weight o f l h l compared to th e c a l­
c u la te d value o f 15? ^»d no elem ental a n a ly s is was obtained f o r th is
substance.
in an a t t e s t to sy n th esize th e carboxylic a c id ( X I ) # o r some

d e riv a tiv e thereof# p re p a ra tio n o f th e 5-am inotetr& zolss from ^}-alan ln e and th e e th y l e s te r o f ^3-a la n in e was undertaken u sin g th e
method o f Ourbrecht and H erbst <9).

tth* d esired p ro d u cts could not

be I s o la te d from th e se re a c tio n * .
On th e b a s is o f th e r e s u lt s o f th e in v e s tig a tio n s concerning
th e uyanoethylation o f th e 5-am lnetelrassoles# th e re a c tio n o f a c ry lo n i t r i l e w ith 5-amino te tv a s o le in th e presence o f benxyltriraetbylafwaonium

2k

hydroxide was found to produce mono^cyaaoethylation on th e n itro g e n s
contained wi th in th e tetr& solo nucleus, y ie ld in g i^ $ -o y a n o e th y l-5 am inotetraaoXe ( I I I ) and 2*^3 -cyanostbyl& salttotetraaole (V ).

fhe re*

n o tio n o f a c r y l o n itr tle w ith l~benayi-.*?-aittinoi©ira»ole u sing th e same
c a ta ly s t caused cyanoethylstlcm o f th e e^ooyclic ataltso n itro g e n w ith
form ation o f l-benayX -*;-^- oyano©thylam lnotetr& sole ( I ) a n d l-b e n a y loyanoethylamino te tr a e o le ( H I ) .
In view o f th e p o s itio n s o f attachm ent o f th e ^ -cy&noelhyX
re sid u e in th e re a c tio n o f a e v y lo n ltr lle w ith ^ n m in o te tra s o le end
w ith l*heneyl*5*eiainc»tetreeolet some sp ecu latio n s can he made con­
cern in g th e mechanisms involved.*
pound end r e a d ily forma s a l t s .

^-A m inotetraacie la an a c id ic comAs p rev io u sly d iscu ssed , in v e stig a ­

tio n s concerning th e alkyX&tion re a c tio n s o f th© fa m in e tsbr& sel*
m olecule which proceed through anion form ation y ie ld c h ie fly x* and
?-*alkyl-^*aKiinotetraeoXee ae th e © ono-alkylation products (1 6 ).

Since

th e b a se -c a ta ly se d cyan© ethylation o f |>-aminotetr&sole a ls o produced
X* and ^ - s u b s titu te d ^^aninotetrasoX es, th e p o s s ib ility e x is ts th a t
t h i s re a c tio n occurred v ia form ation o f th e anion o f IIMus&not©treacle*
I t i s conceivable th a t benssyltHmstbyliwmammiium hydroxide could
a b s tr a c t th e l a b i l e hydrogen as a proton from ^ am in o tetraso l© to
V.

form th e anion*

f h i s anion could induce p o la ris a tio n o f th e acrylo**

n l t r i l e m olecule follow ed by a tta c k o f th e anion a t th e more p o s itiv e
end o f th e d ip o la r species*

The r e s u ltin g anion could then re a o t

w ith a w ater m olecule to g iv e th© cyanoethylated ^-am inotetr& sol*
and reg en e ra te th e c a ta ly s t,
follow s*

t h i s meehanisrn may be rep rese n ted as

29

♦

♦

oiT

KOH

HE.

□

V

r^Sw.

*

orf"

irrz tr
ms

Bine# d la lk y la lio n o f S»mai]iet#^x«uioX« in b a sic media r e s u lts
in the in tro d u c tio n of th e second a lk y l group c h ie fly on th e amino
group in th e

%p o sitio n *

Henry and Finnegan f 16) have suggested th a t

1- and B» a ik y i- 5-amij«*i«brassaies a re formed i n i t i a l l y and f u rth e r
a lk y la tio n proceeds through th ese compounds to y ie ld I - and 2 -a lk y l5-alkylam in o t e tr a sol #&•
Although l-a lk y l-^ -a m ln o te tm s o le s are s lig h t ly b a s ic , i t is
p o s s ib le th a t in the presence o f a stro n g er base* one o f th e amino

hydro&ens can b® removed to form a s an io n ic sp e c ie s.

Ckmoeiv&bly,

c o n trib u tin g s tr u c tu re s to th e resonance h y b rid o f the union could
have th e f r e e p a ir o f e le c tro n s lo c a liz e d a t th e
nltro&en* o r th e *>~®iaim nitrogen*

& ©r Jt n u c le a r

In view o f th e products formed,

th e anion behaves a s though th e n eg a tiv e dm rge was lo c a lis e d a t th e
5-atalno p o sitio n *

iTsing t h i s analogy w ith the b&se-oat&lysed ayanoethyl&fcion re ­
a c tio n , a mechanism sim ila r to th e one advanced f o r the oyano©thylatIon
o f 5-*min0 teim soX e can be p o stu la te d fo r the re a c tio n o f l-benajjrl-5ami no t e t r a sol e w ith a e r y lo n ttr tle *
fo llo w in g s e r ie s of equation* t

39aie way be represented, by th e

?7
m m 2c » * o $ rr

♦

HOH

♦ OR

HHOHgCiyJ£W

fo ex p lain th e form ation o f l-b e n 55y l - 5~ ?V 'l-di-p ~©ya»o«thyla»ii>#~
tetra& o l# th# rem aining hydrogen could be a b s tra c te d a s a proton from
th# m ono-cyanoethylalod l^ b o n sy l-^ -am in o tetra so l#*

F u rth e r re a c tio n

o f l- b e n s y l- W 3- cyanoethylam tiioteirasol# w ith a c r y l o n itr ile produced
th# di-cyim oethyl& ted compound and lend# support <tb th is su p p o sitio n ,
fh# form ation o f th# anion i s rep resen ted below,

fhi© anion could

r e a c t w ith th e a c r y lo n ltr il# m olecule a s p rev io u sly in d ic a te d to y ie ld
tmm2m Bcgn

*

1-ben sy

Off

♦

BOH

F~ di-/3 « cyanoethylamino te tra s o lo .

Although th# p reced in g mechanism fo r th* cy anoethylation o f 1b en sy l-3-nmlnote tr a s o le seems to be a reasonable one, th# p o s s i b ilit y
of a t le a s t on# o th e r mechanism remains*

In t h i s mechanism, th e I -

bensyI<-5*-cm inotetrasole m olecule could r e a c t w ith an a c r y l o n itr lle
m olecule whose d ip o la r c h a ra c te r has been enhanced by th e presence
o f the b a s ic c a ta l y s t.

This sp ecies could then undergo an in tr a ­

m olecular pro to n s h i f t to produce th e d esire d p ro d u ct, £•#.

SB

H

♦H

.. ,

s*

O I^ O ^ O ^ i

O ^CH g

raBLCHa « H
«*5«U

f u r th e r re a c tio n o f t h i s fciolecule with n o r y lo a itr ll# could produoe th e di~cyanoethylated product by ati analogous p a th .

K xrauM sw m ' • ’ *

l~B ienyl~5*.amlxiotatrazole was prepared in & 75 p ercen t y ie ld from
phenyl th io u re a u sin g th e procedure o f Finnegan

(? ) m odified to

allo w su ccessiv e s te p s w ithout is o la tio n o f th e interm ediates*
A suspension o f 15& g# (1 mole) o f H -phenylthiourea in 300 ml*
o f a b s o lu te ethanol was c o tie d to 5° 0. and tr e a te d w ith 150 g . ( 1 .0 6
moles) o f methyl io d id e over & p erio d o f oae«*half hour w ith constant
s tir r in g *

S tir r in g was continued f o r an a d d itio n a l hour and a h a lf

a s th e low m elted and th e tem perature g rad u ally rose*

During th i s

tim e th e s lu r r y was transform ed to a d e a r yellow so lu tio n from which
a s o lid p re c ip ita te d *

fh e re a c tio n m ixture was h eated to re flu x

te m p e ra tu re and h eld th e re fo r one hour during which time th e s o lid
d isso lv e d to form an orange solution*
d i s t i l l a t e were removed*

One hundred m i l l i l i t e r s of

^h« re sid u a l so lu tio n was d ilu te d to th e

o r ig in a l volume w ith a b so lu te eth an o l, c h ille d , and 50 g* (l^mole)
o f 6h p erce n t hydras!a* were added slowly with s tirrin g *

($he methyl

mereapiittt evolved was trapped in aqueous potassium hydroxide*)
fo llo w in g t h i s a d d itio n , th e so lu tio n was h eated to re flu x and

•A ll a n a ly se s were done by Micro-Tech L ab o rato ries, Skokie, 111*
• • th e a c r y l o n i t r i l e usGhecalcal Oo* and th e

t h i s research was donated by Monsanto
’-im in o d ip ro p io n itrile by American Cyan-

30
mminfc*tiie& th e re f o r AH hour#

Upon s l i g h t cooling* w ater-vaouua was

a p p lie d and tho ethanol m o ro aav td .

th r e e hundred m illU | i t e r s of

w ater were added and 200 ml. o f d i s t i l l a t e wore c o lle c te d to r w » ? t
any re s id u a l e th a n o l.

$he so lu tio n woe d ilu te d w ith §00 ml* o f d ie -

t i l l e d w ater end a c id if ie d to litm u s w ith 1§ ml. o f co n cen trated
a t! tr ie a c id ,

fo t h i s was added dropwise* w ith s tirrin g * a so lu tio n

o f 1?0 g . (X mole) o f s il v e r n i t r a t e In 8§0 ml. of water over a
p erio d o f h a l f an h o u r.

F ifte e n m i l l i l i t e r s o f co n centrated hydro*

c h lo ric a c id was added to remove excess s ilv e r io n and s t i r r i n g was
continued f o r an h o u r,

fh e In so lu b le s ilv e r s a l t s were f i l t e r e d from

th e s o lu tio n and washed w ith h o t w ater.

Immediately the combined

f i l t r a t e s were c h ille d to §°0 * in an ic e - s a l t m ixture and 69 g .
(1 mole) o f sodium n i t r i t e In 200 ml. o f water were added w ith s t i r r i n g
a t a r a t e such th a t the tem perature d id n o t exceed d °0.

$he» an

excess o f n itro u s a c id was in d ic a te d by sta rc h - potassium io d id e
paper* th e m ixture was s ti r r e d f o r an a d d itio n a l 1§ minutes* n e u tra l­
is e d w ith aqueous potassium hydroxide and s t i r r e d f o r 30 minutes*
r s a c ld lf le d with 1§0 ml* concentrated hy d ro ch lo ric a c id , mrmsd to
3§°C. and allow ed to cool slow ly.

A fter room tem perature was a t ­

tained* th e m ixture was c h ille d and f i l t e r e d end the s o lid was washed
w ith co ld w ater.

Henry s t a l l ! c a tio n was e ffe c te d from Isopropyl

alco h o l u sin g Dareo a s th e d e c o lo risin g agent*

S eventy-eight grams

of X -pbef^i-3~ «m inotatrasols r e s u lte d a s c o lo rle s s p la te le ts * m.p.
159 • l 6o ° 0. ( 7) .

BSfflagSMaft g £ iU < w eloh«»l-6^Mrtnot»»;Mwa» I
One mole (99 g .) o f cyclohexyiamine d isso lv ed In 800 m l. o f 93
p ercen t ethanol m o cooled to U°0.

fo th i s s o lu tio n m o added w ith

s t i r r i n g a so lu tio n o f 106 g* (X mole) o f cyanogen bromide in 300 ml.
o f 99 p erce n t ethanol and 200 ml. o f d i s t i l l e d w ater a t such a r a t e
th a t the tem perature did n o t r i s e above X0°O#

f h is a d d itio n req u ired

about one and a h a l f hours*
f o r ty grams ( l mole) o f sodium hydroxide d isso lv ed in 100 ml* o f
d i s t i l l e d w ater were added slowly w ith continued s t i r r i n g keeping
th e tem perature q a.lQ°0*

Following t h i s a d d itio n the m ixture was

s t i r r e d f o r two hours in an ic e-w a ter b ath .

A so lu tio n o f 81 g.

(1*25 moles) o f sodium a sid e in 2^0 ml. o f d i s t i l l e d w ater was then
added in one portion*

One hundred m i l l i l i t e r s o f concentrated hydro­

c h lo ric a c id d ilu te d w ith 100 sal* o f d i s t i l l e d water were added
slow ly m ain tain in g a tem perature o f 10°C*

A fter t h i s a d d itio n m e

com pleted, th e so lu tio n m s h eated a t re flu x f o r s ix h o u rs, and then
was allow ed to stand overnight during which time c r y s ta lli s a ti o n oc­
curred*
dried*

She c o lo rle s s p l a t e l e t s were f i l t e r e d from th e so lu tio n and
fh e y ie ld o f p ro d u ct» sup# 217 •* 219°<3*. was 118 g*

An addi­

tio n a l 18 g . o f m a te ria l o f th e same m elting p o in t range m s o b tained
by co n c en tratin g th e f i l t r a t e *

Beery s t a l l ! s a iio n o f th e combined

f ra c tio n s from 3® p ercen t aqueous isopropyl alcohol r e s u lte d in the
recovery o f 119 g* o f I-c y clo h ex y l-5-asiinot e t r a s o le , m.p. 218 - 219° 0.
<19>.

fa g B a a ftffl. a t
P re p a ra tio n o f l-b en x y l-^ -am la o te tra so lo from on* Mole o f
bensylam ine by a procedure analogous to th a t used f o r th e p ra p a ra tio n
o f JUcy clohejtyl-4)*amino t e t re s o le r e s u lte d to an SO p ercen t y ie ld o f
a lA tlti c r y s ta lli n e product* sup* 1&9 - 19O°0* C19) .
1a m l n S l f t f o f 5^^ 1 a o t o t r a o o l ^
One mole

g*> o f anhydrous ^^om iaototraaole m o b sn sy lated

follow ing th e procedure o f Herbafc and G trbreeht ( 10) r e s u ltin g l a
th e recovery o f 1?*X g* (XO#)' o f 1-b e n sy l-

tetr& soI e * sup* IBS •

XS9#C#g 51 *1 $• ( 30^) o f 5~benayl amino t e t r a sole* m.p. 1&6 - 1SS°Q.*
and 1%*9 g . <?$} o f l-.ben«yX-5-*^oatyXa»Ii»ot©tin!t*oXef m*p* l 6g 170°G.

fh e co n d itio n s fo r th e re a c tio n o f a c r y l c s l t r i l e w ith i~b*mzyl«.
d o m in o te t r a m ! e were v arie d somewhat w ith each re a c tio n .

I t was

found th a t equtmeliir q u a n titie s o f l-b en sy l-S -a m in o ietraso le and
a e r y l e n i t r l l e produced a memo-cyan©ethyiated product*

$£*©» an exaass

o f a o ry lo n itril© one used* varying amounts of dleyaaoethyla t ed product
accompanied th e motsc*»eyano6tfcylat*d m aterial*
re a c tio n s a re d escrib ed )

$hree re p re s e n ta tiv e

One* a general method fo r o b ta in in g th e

mono-cyano ethyl** tad l-hen«yl~ 5~ ntainotetrasole5 another* a re a c tio n
l a which a sm all amount o f diuyonoethyiated product was obtained)
and a th ir d which r e s u lte d in a reasonable y ie ld o f dioyanoethy lu te d
1-b en ayl-^-omino te tr& e e le •

33
Seven grants (0 *0** male) o f 1-ben

no t e t r a i o l e were in*

tim a te ly mixed w ith fo u r drops o f a ho p ercen t aqueous so lu tio n o f
henry! trim s fchyXaaamtmiustt hydroxide and. the m ixture c h ille d l a an lo e b a th .

fwo and t welve-hundredtha grams (Q.Oh mole) o f r e d i s t i l l e d

a c r y l o n i t r i l e were added dropwise w ith s tirrin g *
f ie d and then s o lid if ie d to a yellow mass*

!£he m ixture liq u e ­

‘She l a t t e r liq u e fie d

ag ain upon h e a tin g on a steam hath fo r one hour and then alm ost inw
m ediately s o lid ifie d *

fha s o lid m s d isso lv ed In hot ethylene d i-

c h lo rid e and th e so lu tio n m e allowed to cool g rad u ally to room tem­
p e ra tu re du rin g which time snowball*! ik e c lu s te r s o f c r y s ta ls began
to p r e c ip ita te from th e orange solution*

C h illin g and f i l t r a t i o n

were e ffe c te d and th e r e s u ltin g product was r e c r y s ta llis e d frets 93
p erce n t ethanol to y ie ld

&. (59 # of theory) o f c o lo rle s s o lu s-

t o r s o f 1**be»ayX~5- ^ ~ ey&ao«thylam inotetr& solet si.p* 132. 5- 133*0° 0.
A nalysis^

C alcu lated f o r <3u %gHg*

C»

57*9h

H* 9 .# *

2ft 36**£«
Found*

C. 3 S .l^ j Ht 5 * 0 ; ». 3 6 . ^ .

A e l i c i t m o d ificatio n o f th e above procedure re s u lte d in th e
recovery o f some d leyanoethylated X -bensyl-^am inot e tra s o le •

A

small excess o f a c ry lo n i t r l l e was used with 1** g* (0 . 0H mole) o f
l- h e n s y l- 5» am in o tetraso le and eig h t drops o f the c a ta ly s t,

th is

re a c tio n m ixture m e h eated in a water bath a t 75° 0* f o r f iv e min­
u te s a f t e r which th e p a le yellow s o lid was allow ed to stand a t room
tem perature f o r one hour.

C r y s ta llis a tio n from ethylene di ch lo rid e

gave a crude product, m.p. 7 9 -i? l° 0 .

When r e c r y s ta llis a ti o n from

3**
95 P ercen t ethanol w»« attem pted, shimmering p l a t e l e t s aeparafced whil<
th e s o lu tio n was s t i l l m m *

Col lo o t ion by f i l t r a t i o n y ie ld e d 3«2 &»

Cl44 o f theory) o f l« * t8 D s y i - 5 * ® ia y & n o e th y l a m in a te t r a s o le ,
m.p. SO - S l .9e 0.
A nalysis!

C alculated fo r

C, 59.7^5 H, 5*3*^

W* 3^*9$
ftmsidi

0, 59*6$* Ht 5*35£ i

35.1$

On c h illin g th e f i l t r a t e * 13.0 g. ( 6£$ o f theory) of crude 1 b en ay l-5- |3 -cy an o eth y lam ln o tetraso le sep arated ,

fh e m elting p o in t

o f th e product recry s t a l l ! zed from 95 p ercen t ethanol was H 5~ ll6°C .
Ifurth er experiment* tlo n regarding © auditions fo r th e re a c tio n
rev ealed t h a t when l-b e n s y l- 5-amino t e tra a o ie was heated a t re flu x
f o r l b hours w ith a f iv e - f o ld excess o f a c r y l o n itr ile u sin g b en sy ltrimethylatesonlum hydroxide as the c a ta ly s t, a 46 p ercen t y ie ld of
th e d i cyanoe th y la ts d product was obtained.

f m m m t x m a t Ir/Sr
To a w e ll- s tir r e d so lu tio n of seven grass® (0 .1 mole) o f f £ ~

aminoproptoni t r 11© ( l4 ) and 100 ml. o f anhydrous d ie th y l e th e r Im­
mersed in an ic e -b a th was added dropwim a so lu tio n o f 1 0 .6 g.
( 0*1 mole) o f cyanogen bromide in 50 ml. o f anhydrous e th e r keeping
th e tem perature about i 0®0.

CDuring th is a d d itio n a w hite p re c ip i­

t a t e formed which presumably was th e amine hydrobromide.)

tJpoa Com­

p le tio n o f the a d d itio n , th e re a c tio n m ixture was allow ed to stan d
a t room tem perature f o r two h o u rs,

fhe s o lid was f i l t e r e d by su ction

35
I B illl

H ilm lf

«&»

under reflux with b© A t « f

syle&c co n tain in g b *5 g . ( o . l n e le ) o f h ydrasole a c id f o r twenty hours#
th e straw -co lo red so lu tio n m s c h ille d and th e ton p r e c ip ita te sol*
lo o te d by f i l t r a t i o n #

H e o ry s ta llis a tlo a was e ffe c te d from a b so lu te

eth an o l u sin g tteroo a s th e d ec o lo risin g a g e n t.

Four and tw o-tenths

#r»a* ( 19$ o f theory) o f c o lo rle s s c r y s ta ls o f l^ » o y an o o th y l-$ --aisin o t e t r a s o l e , n.p* 115- l l 6°C# # wore obtained*
Analysis*

C alculated f o r
Found*

C,

Ct 3S&$t H,

3l* M l H» Kf 60.0$.

0 , b0*?$*

Esaagftltea, s i Sfe* ssastiL j&t&Mxs, i t fci£- ssassj^^i-ssissr
laiiaasia*
A a U t w * a f 8«?6 «• (0*03 mela) o f
s o ls and 15 «X* o f a e e tte anhydride wen h eated a t r e f l u r f o r two hours*
F w enty-flve s ill i l l i t e r s o f 95 p ercen t ethanol were added and th e
s o lu tio n was evaporated to dryness*

th e r e s u ltin g yellow o i l was

p laced under dry be&sene and s h ille d w hile s t i r r i n g rigorously*
tf tllls a tio s i o ccu rred , r e s u ltin g i n a crude yellow p ro d u ct.

Crye-

ftecxys-

t o l l ! s a t ion was e ffe c te d frow 99 percent ethanol u sin g tfereo a s th e
d e c o lo risin g agent*

fw© and o n e-h alf grans o f 1-yS- ©yanoetbyl-5- a c e ty l-

a m ln o te tra so le were ob tain ed a s c o lo rle s s c r y s ta ls , sup* 10h - l05°G*
A nalysis*

C alculated f o r GgflgOHg*
Founds

0 , *tO*l$| H,

0, ho.0$* H,
S. H *«$.

H, bb.g$.

36
«£. k r & m k r h f e -

b x& ar

sKyudtosi
A*

B ensylation o f iy ^ o y « n o ® th y l-^ -S E iiao tetra* o iat
A m ixture o f 0*13® &• (0*001' mole) o f l-y & cyaaoathyl-.5-a©i»o-

t e t r a s o l e and 0 . 1£o g ( 0*001 Mole) o f h sasy l ch lo rid e was h eated l a
on o i l bath to 1&5*<5*
d is c e r n ib le .

At t h i s tem perature, two liq u id l a t e r e were

th e mixing o f th ese la y e r s fey s t i r r i n g r e s u lte d In an

exotherm ic re a c tio n follow ed h r immediate s o lid ific a tio n *

A minimum

amount o f h o t 95 p erae n t ethanol was used to di a solve th e orude product*
C h illin g t h i s so lu tio n follow ed fey f i l t r a t i o n produced a white powdery
solid*

Subsequent reo rar* U tilisatio n from 99 percent ethanol y ie ld ed

0 *£h g# <93$ o f theory) o f l-bifnayl-^-y#- eyaaoeihyl~5~imi»o to tr& so iin e
h y d ro ch lo rid e a s c o lo rle s s n eed les, sup* 219-3l6a G, w ith some decom­
p o sitio n *
A nalysiss

C alculated f o r
Foundi

C l, 13***$*

* t 3 1 * # I 01, 1 3 * ¥ .

R e p e titio n s o f th e above procedure w ith q u a n titie s up to 0*03
mole Were c a rr ie d o u t, however, w ith 'th ese q u a n titie s th e re a c tio n
feeoame q u ite v io le n t and some ch a rrin g o f th e product occurred*
B.

R eaction o f i^fesm syl-^aiainotetrazoX e w ith ^ - o h lo r o p r o p io n lt r i le i
A m ixture o f l*?5 g* (0*01 mole) o f l-b e a s y l^ ^ a a d a o te tra s o le

a n t 0* f?5 g* <0*01 mole) o f ^5 -* ch lo ro p ro p io n itrile m s h eated in an
o i l h a th a t 15O°0* f o r one h a l f hour*

During t h i s tim e, no apparent

r e a c tio n occurred m th e m ixture was h eated a t 150°S* f o r m a d d itio n a l

hour and a h a l f ,

ffee r e s u ltin g m elt s o lid if ie d upon aooling*

He-

c r y s ta l11 station o f t h i s crude stolid from 95 p ercen t ethanol gave a
w hite pro duet* m.p. ^ 3 - £15° S.

fh e product o btained war id e n tic a l

w ith th a t prepared by b en sy latio n o f 1-

cyanoethyi~5-« a ia o te t ra s o le

a# shewn V ^ m ixture e e l tin g p o in t determ ination and correspondence
o f th e i n f r e - re d s p e c tra .
C.

R eaction o f l~benzyl~5~aiiti n o te tra e o le wi ihj$~brom proptonl t r i l e s
A m ixture o f 1.75 0* (0.01 mole) o f l-b e n a y l-^ -^ m in c te tra so le

and 1. 3** €* ( 0.01 mole) o f ^ -b v o ia o p ro p lo n lb rlie was h eated a t i ^ ° C .
f o r o n e -h a lf h o u r.
s o lid ifie d .,

An exothermic re a c tio n occurred and th e m elt

fh e crude hydrobromide wm tr e a te d w ith an aqueous solu­

tio n o f sodium hydroxide.

I s o la tio n o f th e r e s u ltin g yellow o il* the

re a c tio n o f t h i s f r e e base w ith hydrogen ch lo rid e gas* follow ed by
re c ry s t a l l ! station from 99 p erce n t ethanol gave 1.97 0* ( 6b$ o f theory)
Of l-b e n s y l-h -^ -o y a n o e th y l-9-im lno te tr a s o lin # hydrochloride* aup.
31b -£ i5 °$ .
Dahanzylotlon q £ X-baaay l-M

?

to&SSr

M ssM at
A so lu tio n o f one g r a . o f l-b en ay l-^ iS -o y n n O B th y l-^ -iB iiio to tra-

sol in s in 75 ml* o f $0 p ercen t aqueous ethanol was p laced in a BurgessP a rr hydrogenation f la s k .

3?wo-tenths o f a gram o f palladium oxide

c a ta ly s t was added and th e m ixture was shaken under an I n i t i a l hydrogen
p re ssu re o f **9 .0 p . s . i . fo r 3.29 h o u rs.

A tem perature s l i ^ t l y above

room tem perature was m aintained by means of a h ea tin g Jack et c o n tro lle d

3«
toy «, P ow erstat M i a t 10 v o lts*

th e c a ta ly s t was f i l t e r e d from tb s

s o lu tio n and washed w ith hot 95 p ercen t eth an o l.

S o lid sodium c ar-

b e a s ts s a s added to tb s combined f i l t r a t e , which s a l t te d s d e te s ta b le
odor o f to lu e n e , to n e u tr a lis e tb s hydrogen o b lo rid s rele ase d d aring
tb s r e s e t %m»

f h s efh a n o lie s o lu tio n was fre e d from s o lid M aterial

to? f i l t r a t i o n and th en concentrated#

C h illin g th e co n cen trate re*

s u ite d in tb s form ation o f s o le rle s a c r y s ta llin e m aterial*

Becxyst&l-

11n a tio n o f t h i s m a te ria l from 99 p ercen t ethanol y ie ld e d a small
amount o f product* m*p* ll£~ilh°<3,

A m ixture m elting p o in t o f th is

substance w ith 1- ^ ^ eyano e th y l- 5- amino teb raao lo shewed no d ep ression,
l a a d d itio n , a comparison o f tb s in fn w re d spent r e o f th e se products
la d io e te d t h e i r id e n tity *
BeaoMon $|£ ^ M 3BlSlSB^lSL t i J E
lb a cooled, in tim a te m ixture o f &*5 g# (0 .1 mole) o f 5-aminot e t r a s o l e and fo u r drops o f a bo percent aqueous so lu tio n o f bensiyltrimethylammosttum hydroxide were added with s t i r r i n g 5*3 £* (0 .1 mole)
o f f re s h ly d i s t i l l e d a c r y l o a i t r i l e .

A fter th e i n i t i a l exothemie re -

a c tio n bad ceased, th e m ixture was h eated to re flu x and m aintained
th e re fo r twelve hours during which time the p asty m ixture was tra n s ­
formed in to a yellow ish-orange so lu tio n which s o lid if ie d to yellow
c r y s ta ls , sup* 97-106 G.* when cooled*

Beery s t a l l ! s a tie a o f th i s

m a te ria l from a b so lu te ethanol d id not appear to narrow tb s m elting
p o in t range*

Upon attem pted so lu tio n o f th e crude product i n b e t

eth y len e d ie h lo rld e , i t was found th a t only about h a l f o f th e m a te ria l

39
d iss o lv e d ,
p ro d u c ts,

Advantage was taken o f th is f o o t in o b ta in in g two d i s t i n c t
flam h o t eth y len e d ie h lo rid e e x tra c t m o ooolati to room

tem perature and than c h ille d , follow ed by f i l t r a t i o n to remove tho
c o lo rle s s p la te s which had p r e c ip ita te d .

Beery s ta lllz & t ion o f t h i s

m a te ria l from 95 p erce n t ethanol re s u lte d in th e recovery o f 3*7 g*
( 27$ o f theory) o f p roduct, «#p, 117~117«5°0** which i s ap p aren tly
2-^3*cyanoethyl-5-am ijiotetrazole
Analysis*

C alculated f o r
Founds

C, 3M $ * H,

©,

Ht H.hf* H, 60.8$.
H, 60, 7$ .

Follow ing too r e o r y s ta llim tlo n * from 95 p ercen t e th a n o l, th e
e th y l one d le h lo rid e in so lu b le p o rtio n o f th e erade product y ie ld e d
^ *6 g* (33$ o f theoryV o f c o lo rle s s d u s t e r s , sup* H 9 - l l6 ae .

©or*

respon&eaae o f th e in f r a - r e d ep ectra o f t h i s compound and %<y3*<3yane~
e th y l ~9~aml»o te tr c s o le prepared from ^3 *amlnopropi oni Ar11 e e s ta b lis h e d
i t * id e n tity .

A m ixture m eltin g p o in t o f th e two product * erne n o t

depressed.
R e p e titio n o f t h i s re a c tio n under e s s e n tia lly id e n tic a l condition*
did no t appear to r e s u lt in a fix e d r a t i o o f th e 1* and 5?*s u b s titu te d
p ro iu o te .

pf.parfttAftP

g a a s t lU t e t e s U i a a £

fo a suspension o f 1.5 g. o f

cyanoethyl*5*am inotetraxole in

15 ml. o f chloroform were added fiv e m i l l i l i t e r s of reagent grade
n o e tic anhydride,

f h ie suspension which g rad u ally became a c le a r

s o lu tio n m s h eated to re flu x and m aintained th e re fo r fo u r and oneh a l f h ou rs.

A fte r cooling to room tem perature, the s o lu tio n

was

*40

placetI in a refrig era to r for 2b hour* during slileh time a c o lo r le ss
c r y s ta llin e p rec ip ita te formed*

$fae p rec ip ita te wa* removed V fix *

tra U o n , washed w ell with cold chloroform and then dried in an even
a t 90°0*

One and sevens tenths grams (87$ o f theory) o f 2* ^ * cyan©**'

ethyX*9*no#tyXaainotetraseoX«t m*p* 136-137°G* ( shrinking at 133*0-).
were otmtlaed*
Analysis*

Calculated fo r Og^OS^j
rounds

0, bo.ogj M, h.y&t f t b6.6g.

0, bQ*8$* E# K0>1 Y, b6*6$*

M k y to tlo n g £

nf-M f e t o f l m t a & f f i l U t e a y

fo a w e ll* s tirre d so lu tio n o f 8*9 &• (0 *X mole) o f 9-amine t e t r a so le in 190 ml* 95 p ercen t ethanol m aintained a t re flu x tem perature
was added dropwls* 6*2 g* ( 0 .09 mole) of sodium carbonate saanfeydrate
dieeoXved In 39

o f w ater,

e v o lu tio n o f carbon d io x id e .)

(to o rap id a d d itio n caused v io le n t
Upon com pletion o f th is a d d itio n , th e

so lu tio n was s t i r r e d on a stoauwhath fo r one hour, follow ed by th e
dropwise a d d itio n o f 13-b g . (0 .1 mole) o f ^3-b ro m a p ro p lo n itrile die*
solved in 19 m l. o f f 5 p ercen t ethanol*

S tir r in g and reflu x !n g were

continued fo r an a d d itio n a l two hours*

fhe so lu tio n was then concen­

tr a te d under a vacuum w hile g ra d u a lly adding a b so lu te ethanol to r e ­
p la ce th e eth an o l-w ater solvent*

A small amount o f a w hite c r y s ta llin e

p r e c i p ita t e , presumably sodium bromide, which had formed during th l s
p ro cess was removed by f iltr a t io n *

fh e f i l t r a t e was evaporated to

dryness and th e r e s u ltin g crude product was e x tra c te d w ith h o t ethylene
d ic h lo rid e*

A fte r c o n c en tratin g and c h illin g th e eth y len e d i ch lo rid e

%
e x t r a c t , a mass o f c o lo r le s s p l a t e l e t s was obtained*

R e c r y a ta lliz a -

i i o a ©f t h i s m a te ria l from 99 p ercent ethanol y ie ld e d b .2 g. (32$
o f th eo ry ) o f th e compound assumed to be S -^-cyim a-eifcyl-S -ataioote t r a s o le * a.p * iX 6~ ii7°0*

fh e rem aining p o rtio n of th e crude product m e e x tra c te d w ith
acetone*

E vaporation o f th is e x tr a c t, washing th e rem aining s o lid

m a te ria l w ith d ilu t e aqueous sodium hydroxide so lu tio n to remove any
u n re la te d 5-am ln o te tra a o le , follow ed by sev eral recry s t a l 11 sa t Ions

twm 99 p erce n t eth an o l, y ie ld e d 3*7 g* (27H of theory ) of a c r y s ta lo
l i n e p ro d u ct, ©*p* 119-116 0 .

C o rre la tio n o f in f r a - r e d sp e c tra and

m ixture m eltin g p o in t d a ta showed t h i s m a te ria l to be X «^~eyaaaethyl9-a m ln o te tm so le .
& £»& & » s £ l~hmxyl-5-K.l!~dt-£-<&ma«thylmlaatetrB*Ql<> £&&

An in tim a te m ixture o f 2*28 g« (0*01 mole) o f l-b e n s y l-9^ cyanoothyliw aitiotetraaole, f iv e m i l l i l i t e r s o f r e d i s t i l l e d a c ry lo n i t r i l e , and fo u r drops o f th e bo p ercen t aqueous benzyl tri& e th y lasamo&iu© hydroxide c a ta ly s t was h eated a t re flu x on a ste&m-b&th
f o r two ho u rs,

fh e red o i l which re s u lte d was d isso lv ed i n hot

eth y len e di c h lo rid e and th e so lu tio n was allow ed to cool g ra d u a lly ,
then c h ille d *

Yellow p l a t e l e t s formed which were c o lle c te d and r e -

c r y s ta l 11 sod fro© 99 p ercen t ethanol using Barco a s th e d eco lo riz­
in g agent*

A fter drying, th e c o lo rle s s p la te l e ts o f l-b e n s y l-9-H,

-cyaB oethylsm inotetrazole ex h ib ited a m eltin g p o in t o f 79jS!®0.

A comparison o f th e in f ra -r e d sp e c tra and th e m eltin g p o in t

o f t h i s compound end th a t o f the d l-ey u n o eth y lo ted compound is o la t e d
from th e o y a n o eth y la tio n o f l-b en 3yl«5-»m in ot#ira2ol© e s ta b lis h e d
th e s e compounds a s id e n tic a l*

f e a w e l l- s t i r r e d s o lu tio n o f «?h*6 g , (0*S m ole) o f
tmi nodi p r e p la n ! t r ile d is s o lv e d In 50 m l, o f e th y l a c e ta te and C h illed
to about 5°C. was added dropwiea a s o lu tio n o f 10*$ g* (0*1 m ole) o f
cyanogen bromide and 50 m l. o f e th y l a c e ta t e a t such, a r a te t o main*
t a in a tem perature below 10^0.

upon com pletion o f th e ad d ition *

s t i r r i n g m s con tin u ed f o r one hour in an ic e -b a th and then a t room
tem perature fo r e ig h t h o u rs.

Hurlng t h i s tim e a w h ite p r e c ip ita te *

presum ably th e amine hydrohromide, became e v id e n t.

$h ia p r e c ip it a t e

was removed by f i l t r a t i o n and washed w ith hot e th y l a c e t a t e ,

fh e f i l ­

t r a t e was th en con cen trated under a vacuum to about 50 m l. to t h i s
s o lu tio n were added 100 m l. o f bensene c o n ta in in g 15 g* o f hydrasoio
a c id and th e r e s u lt in g s o lu tio n was m aintained a t r e flu x tem perature
f o r « i # t h o u rs.

Oise hundred more m i l l i l i t e r s o f th e bensene s o lu tio n

o f h y d ra so ic a c id were added and th e r e a c tio n s o lu tio n was r e f lured
f o r an a d d itio n a l 1$ hours*

H asses o f c o lo r le s s c r y s t a l a became d is ­

c e r n ib le in th e pin k s o lu tio n .

C h illin g o f th e s o lu tio n fo llo w ed

by f i l t r a t i o n to remove th e p r e c ip it a t e y ie ld e d 11 .S &• (62$ o f theory)
o f p in k t in t e d c r y s ta ls * sup* 129-132°C*
fr o m

A fter one r e c r y s t a l l is a t io n

95 p ercen t ethanol* 9 * 0 g* o f 5 -H ,$ * d i-y $ -cy a a o eth y la m ln o tetra so le

were o b ta in ed a s c o lo r le s s c r y sta ls* sup* 133*5^13^*0°C.

Analysis*

Oaloulated fo r O^LX^t
Xoaadi

0,

U3 . 9 * , x ,

C, Wt.OjSj B, H .« fj X, 5 1 .2<
x , 5 1 . 2 JS.

On occasion stum reaction mas Incomplete, attempted Is o la tio n
o f U m to tra s o la r t m lt n l in tbs rsoovery o f a lo p a d t la g w ild ,
s .p . 1*8»50°C.

£1 amenta! analysis o f ttiis substance indicated th at

th is compound was probably tbs X ,X -dl-/3-cyan o eth yl oyananlda.
A aalysisi

Qaleulated fo r OjVgV^t

Foundt

C, 5$*7*S H. 5*5^8 » , 37

O. 96.3^5 H, «5*®£| ir, 36.H9

M«g&»Ugft a£ &a a^.y&ktafr ssk&k sat qaamiMBi, s i s£ 5 ra.t-dlr
A w e ir e d stuajplwp 0*5508 g#« o f 5~tV M i ~^-syanoethylm aino to t r e sol© wes d isso lv ed in 800 ml« o f d i s t i l l e d w ater.

f h is s o lu tio n was

t i t r a t e d w ith 0*1038 M aqueous sodium hydroxide a t 87°C*
BeUtastut pH
has#.

By u sin g a

Mods! 0* th e pH was recorded a f t or each a d d itio n of

From a p lo t o f th e pH versus th e volume o f huso added (See

Fable X in th e Appendix) * th e equivalence p o in t wee determ ined.

It

was found th a t 87*75 ml* o f 0.XO38 I aqueem® sodium hydroxide were
required*

From t h i s value* an eq u iv alen t weight o f 191*6 was c a lc u ­

la te d compared w ith 191*8 c a lc u la te d from th e eaolecular form ula,

me

apparent pK deten sln ed from the pH a t 50 percent n e u tr a lis a tio n (19)
was. **-85*
BebeuaarXatlon o £ V b e i i i i y l ^ W ,:^
One gram o f l-beaayl~5~Hf8 - d i ^ -cyimo^thylswalno te tr a s o le d is ­
solved in 50 ^X* o f 95 p erce n t ethanol and one m i l l i l i t e r o f co n cen trated

Uk
h y d r o c h lo r ic a c id were p la ced in a 9BQ »1* Bargess-I'arr p ressu re b o t t l e ,
f a tM « m e added 0*1 g* o f 5 p ercen t palladium on charcoal c a t a ly s t
end th # m ixture was shaken tinder an i n i t i a l hydrogen p ressu re o f **9*5
# « ••£ « f a r f t v a bourn*

fh e c a t a ly s t was f i l t e r e d from th e s o lu tio n

and m ailed w ith hot 95 p ercent ethanol*
ea#!© sable in th e f i l t r a t e *

A stro n g odor o f to lu en e was

Evaporation o f the solvent r e s u lte d in

th e form ation o f an orange p asty mass*

A t t e s t e d re e ry s ta ll!s ta tio n

o f t h i s m a te ria l from 95 percent ethanol u sin g Bareo a s th e decolorI s in g agent y ie ld e d a c le a r v i «es$*e.ibil * By s t i r r i n g t h i s o il w ith
se v e ra l p o rtio n s o f e th e r w hile c h illin g , cry s t a l l i m t i on was induced*
H e o ry o ta llis a tio n o f th e s h ite eem i-so lid m a te ria l y ie ld ed a small
amount o f a c o lo rle s s c r y s to l lts e s o lid , sup* 1^7«lg9°G.

th e in f r a ­

re d spectrum o f t h i s product was Id e n tic a l w ith th a t o f an Independent­
l y sy n th esised sample o f 5-H*2f*.<ii*y3-cyano@thylfusiinotetraj5ole.

A

m ixture m olting p o in t o f th e se compounds s&ewsd no depression*

In an

a t t e s t to i s o l a t e more o f th e hydrogenolysi a product, th e ethanol io
so lu tio n was evaporated alm ost to dryness.

C h illin g of t h i s so lu tio n

y ie ld e d a s o lid m a te ria l which liq u e fie d on the f i l t e r paper.
rr«pttr*»ltm g£
<f!he bensyl iso th io e y a n a te used in th is sy n th e sis was prepared in
a fb p e rc e n t y i e l d from bensylaraine and carbon d isu lp h id e fo llo w in g
th e procedure o f P erciv al (2 1 ).

A w e ll- s tir r e d s o lu tio n o f 7**»5

(0*5 mole) o f bsnayl Is o th io -

oyan&t© and 25 ml* o f a b s o lu te ethanol was c h ille d to approxim ately
10° C. In an lc«~w ater bath*

fo th i s so lu tio n was added dropwiee a

*
s o lu t io n o f f ii.5 g (0*5 n o lo ) o f / 3 j 3 •-im iaod l’p r o p io iiit r ile i n 25 ml*
o f a b s o lu te eth an ol w h ile m ain tain in g & tem perature o f le e * than 2 0 °C.
tfpen co m p letion o f th e a d d itio n , s t i r r i n g erne continu ed w h ile th e
tem perature o f th e e o la tio n was g ra d u a lly ra id ed to th e r e flu x p o in t
!

end m ain tain ed th e r e fo r one hour,

th en t h i s e o la tio n wee c o o led to

foom tem perature and then c h i ll e d , o n ly a few o r y s ta le were « v id « a l
In a eyrupy e o la tio n *

C r y s ta llis a tio n was induced by th e a d d itio n

o f 500 m l. o f h o t a b s o lu te e th a n o l, a llo w in g th e s o lu tio n to c o o l grad­
u a l l y w ith p e r io d ic c h illin g *

fh e erode product was e o lle e t e d by

f i l t r a t i o n and th en v e o r y s t a llis e d tw ic e from a b so lu te e th a n o l.

One

hundred tw enty-one and th r e e -te n th s g r e a t (£ 9$ o f theory) o f JM>easyl«»
W* ,U t - d i - f i -ey a iio e th y lth io u r e a were ob tain ed no c o lo r le s s , f l a t e r y s-

t.X » , ».*>. xU9-iM5.5°0.
A M O jr.l«t

C a lo u la ta d f o r

C, 6 l .7 # i K, 5-9®£|

» , a o .W t s . n . « * .
Founds

0 , 61.8^5 H. 5.99*1 I , SO.U^t 8. U . 6*.

AUwapt.a BCTliSSaaa. SC
A lth o o # a l l o f th e many attem p ts le a d in g to th e sy n th e sis o f
t h i s compound were u n su ccessfu l, two independent ro u tes were in v e s ti­
g ated - a ty p ic a l example o f each I s described below.

E s s e n tia lly ,

th e procedure i s th a t u t i l i s e d i n th e p re p a ra tio n o f th e i-p}*n jr l- 5 a a ln o t.t r a s o l.*
A,

U sin g ff-b en sy l-lf1 tH*-di

-c y a n o e th y lth ic u r e a t

tin a waXX-nttrrad solution o f X0.9 «• (O.oU a o l.) o f S-b»n*yX-

- ay anoe thy 1 th io u re a and 150 wl. of ab so lu te ethanol

immersed in an i c e 'bath 10 g . o f methyl io d id e was added in one por­
tio n .

S t ir r in g a t iee-h& th tem perature was continued f o r two hours

a f t e r which th e s o lu tio n m e s t ir r e d a t room tem perature fo r two ad­
d it io n a l h o u rs, mid then under r e flu x c o n d itio n s fo r one hour.

One

hundred m i l l i l i t e r s o f d i s t i l l a t e were c o lle c t e d under a vacuum to
remove any e x c e s s methyl io d id e .

A b solute eth anol m s then added to

r e s t o r e th e o r ig in a l volume, fo llo w e d by th e d r o p sie s a d d itio n o f
i*@s g» ( O .d h W ie ) o f anhydrous hyd raslne d is s o lv e d In $0 *&• o f
a b s o lu te ethanol*

S t ir r in g m e continued fo r 15 m inutes a t roost

tem perature a f t e r which th e m ethyl mereaptaa th a t had formed mas ex­
p e lle d by h e a tin g th e s o lu tio n a t r e flu x f o r h a l f an hour.

The eth anol

w oe removed under reduced p r e ssu r e , adding water during th e f i n a l
s ta g e s o f th e d i s t i l l a t i o n to f lu s h any rem aining eth an ol from th e sy s­
tem and to e f f e c t a com plete tra n sfe re n c e to an aeneous s o lu tio n with­
o u t a llo w in g a so X v sn tle ss co n d itio n to In ter v en e.

S h is s o lu tio n was

a c i d i f i e d t o litm u s w ith con cen trated n i t r i c a c id ,

f o t h i s was added

dropw lse w ith s t i r r i n g a s o lu tio n o f 6 .8 g* (0 .0 ^ m ole) o f s i l v e r
n i t r a t e i n 50 m l. o f d i s t i l l e d w ater.

(At t h i s p o in t, a lo n g w ith th e

co a g u la ted s i l v e r io d id e , a red p l a s t i c p r e c ip it a t e was formed which
s o l i d i f i e d to an extrem ely hard substance fo r which o n ly one s o lv e n t,
g l a c i a l a c e t i c a d d , was found,

fh e o r ig in a l m a teria l could n o t be

recovered from I t s s o lu tio n in g la c i a l a c e t ic a c id .)

A fte r th e addi­

t io n e f con cen trated h y d ro ch lo ric a d d to p r e c ip it a t e th e e x c e ss
s i l v e r , th e in s o lu b le m a teria l was f i l t e r e d from th e s o lu tio n and th e
r e s id u e was washed w ith h ot water*

B lase t i s a t i on o f t h i s s o lu tio n was

«*t
e ffe c te d w ith io H u i f t ilv U t i but e a lf a fo u l-sm ellin g , red e l l could
be is o la te d which eltowed 00 tendency toward c ry s ta l form ation.

The

in fra -re d i ^ ie ln a o f th e rod 0 U was q ulto unlikse the spectrum o f
l*bsnsyl~5-1?, !K*dl«^ -cyan®* th ia m in e to tra s o le .
B*

U sin g b -b im s y lth lo e e m le a rh a s id e t
t h e b -b « n sy lth i© a m i o&rbasido u sed in t h i s r e a c tio n m s prepared

u s in g a m o d ific a tio n o f th e method employed bp yulverraaehsr ( 2 2 ) .

A

m ixtu re o f 29 . B g* ( 0 .2 mole) o f benzyl iso tM o c y a n a te and 9$ m l. o f
95 p ercen t eth anol m e c h ille d in an lee-b & ih .

To t h is m e added

slo w ly w ith s t i r r i n g t s o lu tio n o f 6 .6 g . o f 95 p ercen t hydrazine In
90 m l. o f 99 p ercen t e th a n o l.
t a t e formed.

During t h i s a d d itio n , a w hite p r e c ip i­

A fte r th e a d d itio n was com pleted, th e s o lu tio n was a l -

lowed to stand in an ic e -b a th fo r one hour.

The c r y s t a ls were removed

by f i l t r a t i o n , washed w ith c o ld e th a n o l, and a ir * d r ie d .

Tw enty-eight

and e i ^ t - t e n t h s grams (150$ o f theory) o f U-beazjrlthioseraicurb®si de,
m.p* l2 b -t2 S °© * f were o b ta in ed .
I n th e a tte m p te d s y n th e s is o f l-b e n a y W i-J ^ lf-d i-jS **oya»©ethyX~
a m l m t e t r a s o l e , 9*09 g* (0 .0 9 m ole) o f b -b e n a y i-th lo s s m io a rb a s id e
d ie so lv e d i n 90 m l. o f a b s o lu te e th a n o l w ere c h i l l e d t o k ° G.

To t h i s

s o l u t io n was added d ropw ise w ith s t i r r i n g a s o l u t io n o f 7 .5 g .
(0*052 m ole) o f m ethyl io d id e i n 25 m l. o f e th a n o l.

Open c o m p letio n

o f t h i s a d d i t i o n , s t i r r i n g was c o n tin u e d f o r one and o n e -h a lf h o u r*
a t i c a - b a t h te m p e ra tu re and two an d o n e - h a lf h o u rs a t room tem p eratu re*
f h l s s o l u t i o n was e o a e e a tr e te d u n d e r a vacuum t o remove t h e wnre& eted

k$

methyl io6169»

Absolute ethanol m e used to resto re the o rig in a l vol­

ume end the so lu tio n m e c h ille d .

A so lu tio n o f 6.15 g. (0.05 e» le)

© # , ^ 3 , ~lm i nodi p rep lan ! t r i l e in 25 a l . o f a b s o lu te ethanol was added
dropw lse w ith s t i r r i n g .

S tir r in g m i o o iU iO id f o r too hour* a f t or

th e removal o f th e ic o -b a th .
m s observed *)

(She d i s t i n c t odor o f methyl mereaptan

lining reduced p r e ssu r e , th e eth an ol m e removed w h ile

g r a d u a lly r e p la c in g th e eth an ol w ith d i s t i l l e d w a ter.

Hhm

aqueous

S o lu tio n m s c o o le d and 3.3 m l, (on» 0*05 oq.) o f con cen trated n i t r i c
a c id were added, fo llo w e d by the drop w ise a d d itio n « t i i « s t i r r i n g , o f

£ .5 #* ( 0 .0 5 nolo) o f s ilv e r n it r a t e d is s o lv e d i n 75 m l. o f d i s t l l l o d
w a ter.

Again* a p l a s t i c m a teria l p r e c ip ita te d along w ith the coagu­

la te d s i l v e r io d id e .

then th e p r e c ip ita te d m a teria l m o removed and

th e f i l t r a t e d la s e tls a d , the only produo % I s o la te d m s a reddish-brown
o i l which m s re a d ily so lu b le in hen seae.

fh e l~hen& yl-5*tf,& -di<^ -

oyanoethylafidnoi# t ra s o le prepared from the oyan oeth ylat1on o f l-b e a s y l~
^ -a m la e te tr a s e le e x h ib ite d very lim ite d s o l u b i l i t y in be&seae*

A fter numerous attem p ts to debensylate 1-ben ayl-5<y^«Qyano« thy 1am inotebrasole u sin g a v a rie ty o f so lv en ts and c a ta ly s ts , th e f o lio * ,
lu g procedure gave th e b e s t evidence th a t re a c tio n had occurred*

In

some o f th e a tte m p ts, no hy&rogenolysis re s u lte d and th e s ta r tin g
m a te ria l m s recovered*

In o th e rs , m a terial e x h ib itin g a d e f in ite

am ine-lltee odor was recovered, but not id e n tifie d *
One gram o f l-bensyl-5-^S -cyanoeth y lam in o tetraso ie d isso lv ed in
35 ml* o f mrm g la c ia l a c e tic ac id and 0*7 g* o f palladium oxide

**9
C atalyst were M o m together In a Burgsss-Parr hydrogenation fla s k
fa r f iv e hours under an i n i t i a l hydrogen pressure o f 9® p . s . i .

The

c a ta ly st was removed by f ilt r a t io n and washed with h o i g la c ia l a c e tic
a cid .

Svaporation o f the solvent from the combined f i l t r a t e s unitor

reduced p re ssu re y ield ed an orange o i l which Increased l a v is c o s ity
s&en stir r e d with su ccessive portions o f g^hexane.

Shan th is material

was placed under anhydrous benzene and Allowed to stand fo r a few days*
n e e d le -lik e cry sta l a dispersed bhrau^aout the o i l ware observed.
Complete c r y s ta lli s a ti o n could not ha Induced by c h illin g and vigorous
s tirrin g .
Some o f th e crude product was r e flu x e d w ith an e x c e ss o f a c e t i c
anhydride f o r th ree h o u rs.

Twenty m i l l i l i t e r * o f 95 p ercen t ethanol

wars added and th e s o lu tio n was concen trated to remove th e unrwasted
a c e t i c anhydride.

S o lu tio n o f th e r e s u lt in g red o i l in 95 p ercen t

eth a n o l was a ff e c t e d fo llo w ed by d e c o lo r l nation w ith Tforite.

Svapor-

a t!a n o f th e b&tetnol produced a d e a r v isc o u s o i l which e v e n tu a lly
c r y s t a l l i s e d when s t ir r e d w ith s u c c e s s iv e p o r tio n s o f anhydrous h sn sen s.
A fte r r e o r y s ta ll!s ta tio n o f t h i s m a teria l from a b so lu te e th a n o l, a
sm all amount o f a c o lo r le s s c r y s t a l l in e s o l i d , su p . 103-10h°G ., was
o b ta in ed .

A m ixture m a ltin g p o in t detexwdnatlon rev e a le d th a t t h i s

compound m s id e n t ic a l to th a t obtain ed from th e a c e t y la tio n o f 1 ^ 3 cyanoeth yl»5»am in otetrasolw .
S in ce t h i s in d ic a te d th e p o s s ib le p resen ce o f th e d e sir ed confound
( 1 0 ) f 5-^S^oyano®thyliM ainotetraaole# fu r th e r attem p ts were made to
o b ta in a pure p rod u ct.

The o i l co n ta in in g d isp e rse d c r y s t a llin e m a teria l

50
m s d is s o lv e d in a b s o lu te eth an ol and d e c o lo r is e d w ith H o rlt* .

i&vapor-

a t i e a o f th e %thaaoI under reduced p r e ssu re y ie ld e d a p a le y e llo w e l l *
An a q u eou s-eth an © lie s o lu tio n o f a m a l l amount o f t h i s o i l e s s
a c id ic and upon n e u tr a l 1 a c tio n w ith aqueous sodium h yd roxid e, a w h ite
p r e c ip it a t e formed which gave a resid u e when ig n it e d .

Another p o r tio n

o f th e o i l was d is s o lv e d l a a b so lu te eth an ol and petroleum e th e r ( b .p .
3Q-6G°G»5 was added u n t i l th e s o lu tio n became cloudy*

O h lllla g pro­

duced a w h ite floeotiXemt p r e c ip it a t e which m s transform ed In to a red
e l l a few seconds a f t e r removal by f i l t r a t i o n ,

fu r th e r attem p ts to

i s o l a t e a pure sample o f t h i s m a terial were u n su c c e s sfu l.

I n an attem p t to determ ine whether th e o i l would undergo therm al

mrM8|- ‘ 60 fow

* :«u — »

C«a|. one m i l l i l i t e r ) o f t h i s o i l

h eated fo r two hours In an o i l -

bath a t 130°C. .Mo . change in th e In fra -r ed spectrum o f th e o i l was
n o ted a f t e r t h i s treatm en t.

When another sample was h eated a t 165°0 .

i n on o i l- b a t h fo r fou r h ou rs, some darkening occurred.

Upon c o o lin g

to roots tem perature,, a g la s s y s o l i d was o b ta in ed from Shi oh no 1 y 0 *
c y a n o o th y l-9 -a isin o te tr a so le cou ld be i s o l a t e d .

Although th e in fr a ­

red spectrum o f t h i s s o l i d wee d if f e r e n t from the in fr a -r e d spectrum
o f th e o r ig in a l o i l and con tain ed some peaks s im ila r to th o se p re sen t
In asi In fr a -r e d spectrum o f l-^ - c y a a o e t h y l- 9 - a a in o t e t r a s o le , the r e ­
s u l t s o f th e thermal rearrangement were in c o n c lu siv e .
Att«Hiptftd caran o.tb ylatloa $ t
1 ,h -m b e n sy l-5 -lr n in o te tr a z o l in e

hydrochloride m s prepared by

a lk y la t io n o f l-b e u sy X -^ a m tn o te tr a so le w ith benzyl c h lo r id e ( 1 3 ) .

51

A bonsono s o lu tio n

tho Ivm b&M m

prepared ^ d isso lv in g 13*2 g .

(G.OU i t t l t ) o f th o kydroohlorldo in « am wator do wfaieb a small amount
o f othanol had boon added* tro& ting Ohio s o lu tio n w ith an excess o f
aquoem* oodtna hydroxide* and thou i x t m t l a g tho im in o to tra io lta s

booo w ith se v eral p o rtio n s o f hoasono*
fh o bonoono so lu tio n containing 10*7 «* (0 .0 b malm) o f l**MLiboo a y l~>*i raiso to tm so lin © (assuming q u a n tita tiv e roeov*vy o f th o fre e
booo) m o co n cen trated to tho p o in t where s o lid n o to r ia l J u s t began
to separate*

fo Ohio s o lu tio n m o oddod 2$ «1* o f fre s h ly d io tlllo d

a e r y l o n l t r t l e and a few drops o f *40 percent aqueous b e a s ty l(rlw ltjrU
oamonina hydros!do c a ta ly st*

A fter tho m o t i o n m ixture had reflu x ed

f o r 16 hours* a d ark rod o il* shleh s o lid if ie d when tho so lu tio n was
ch ille d * beeaske ov id o n t.

th e oolid t a i c o lle c te d by f i l t r a t i o n and

washed w ith oold bensene to remove any unr©noted istla e te tra so lin e *
In on attem pt to p u rify tho erudo product* su p . tS3-lb0oC*f i t wno
diooolvod in acetone h eated to i t s b o ilin g point* doooiorisod w ith
tferite* and thorn p r e c ip ita te d by tho a d d itio n o f jj^pontano*

When tho

creasy w hite p r e c ip ita te m o f ilto r o d and eaqposed to tho air* immedi­
a te darkening and so ften in g to an o i l occurred.

Upon standing f o r
o
•evflffil days* th o o i l deposited an orange solid* ®*p. go. 123 0. w ith

sows decom position.
Attempted hydroXyglB o£
A*

Basic h y d ro ly sisi (23)
Ulus and ei* * ie» th s grams (0*032 taolo) of barium hydroxide oota*.

h y d rate woro h eated on a steam bath u n til s e lf* s o lu tio n had occurred.

9*
$ h is s o lu t io n was s t ir r e d m echan ically and a s o lu tio n o f H.lU g . o f
l<^~oy&tieethyX-5~aml!M»feetras0Xa In 50 ml* o f hot wator was added
dropwloe w b il o m a in tain in g a tem perature o f 85*96* <3* Upon completion
o f th o a d d itio n * th o r e a c tio n m ixture was heated on a stoosi bath fo r
fh o odor o f ammonia oould be d sto eto d over tho roaotlon

two hours*
m ixture*

Two grans o f powdered a sb e s to s and 250 aX* o f h o t wator

wars addod*

fh o m ixture was than naturalod w ith carbon d io x id e hr

gradual a d d itio n o f dry loo*

T h is m ixture was f i l t e r e d through

f l u t e d f i l t e r paper and th e f i l t e r eaho was washed w ith se v er a l p e r t io n s o f h o t water*

fh o combined f i l t r a t e s were evaporated under re*

C r y s t a llis a tio n o f the r e s u ltin g o i l was induced by

dueed p r e ssu r e .

treatm en t w ith s u c c e s s iv e p o r tio n s o f b easen e.

I g n itio n o f a p o r tio n

o f t h i s m a ter ia l on th e end o f a sp atu la in d ic a te d th e p resen ce o f
In o rg a n ic matter*

fh erefo re* th e crude product was d is s o lv e d i n mater

and s u c c e s s iv e p o r tio n s o f d ilu t e aqueous s u lf u r ic a c id were added
fo llo w e d each tim e by c e n tr ifu g a tio n to remove th e p r e c ip ita te d barium
s u lfa te *

When th e c e n tr ifu g a te remained c le a r fo llo w in g th e a d d itio n

o f th e s u lfU r ic a c id , i t was concen trated on a steam bath, then a l ­
lowed to cool*

C h illin g produced a c o lo r le s s c r y s t a llin e p r e c ip it a t e

which was removed by f ilt r a t io n *

B e o r y s ta ll!c a tio n was e ff e c te d from

d i s t i l l e d water and a f t e r d ryin g, the product e x h ib ite d a m eltin g p o in t
o f 20O-2Old C. w ith some decom position.

D etonation o f th e m aterial

occu rred upon h e a tin g in a fr e e flame*

ffais behavior and the m eltin g

p o in t range in d ic a te d th a t t h i s m aterial mis 5-iu ain otetrasole*

A mix­

tu r e m e ltin g p o in t and e q u iv a len t w eight determ ination confirm ed t h i s
assum ption*

53

B*

Acid h y d ro ly sis:
A m ixture o f 5»5& &• (0 .0 b mole) of l-^S -cyanosthyl-^-^^iao-

t s t r a s e l * and $& «&. o f con cen trated h yd roeh lorio a c td was h eated on
a steam hath f o r fou r hoars and then s i lowed to stand a t rooa tetapers t a r s overn igh t*

$h* c o lo r le s s n e e d le - lik e c r y s ta l* were removed by

f i l t r a t i o n sad a i r d r ie d , m.p* Ih 7 * l5 0 °0 .

la order to determ ine

whether t h i s m a te r ia l sms f r e e from ammonium c h lo r id e , s o lu tio n in
a b s o lu te eth an ol m s attempted*
in s o lu b le .

A email amount o f r e sid u e remained

Some o f th e m a teria l was then r e e r y s t a ll! s o d from a b so lu te

e th a n o l, f i l t e r i n g o f f th e in s o lu b le ammonium c h lo r id e sfc ile the
s o lu t io n was hot#

A fter two r e e v y s ta ll!s ta tio n s , a e o lo r le s s c r y s ­

t a l l i n e m a te r ia l m s o b ta in ed , m.p# lbb*.ib7°<3* w ith mush e v o lu tio n
o f gas*

An e q u iv a le n t w eight d eterm in ation by t i t r a t i o n o f t h i s sub­

sta n ce w ith aqueous sodium hydroxide
th e m a c u la te d va lu e o f 157*

a va lu e o f i k l compared to

Because o f t h i s discrepancy* no elem en tal

a n a ly s is was obtained*

Iftfiu -red ab so rp tio n sp e c tra :
The in f ra -r e d ab so rp tio n sp ectra (See Appendix) were obtained
u sin g a Perkin-Sim er B soordiag Spectrophotom eter, Model 21*
pounds were run a s l u j o l mulls*

A ll com­

mmMm
X.

Cyanoethy lo t io n o f X~toanxy3l~3~qm$iiot e tra so 1© in th e p resen ce o f

a ben*yitrimethylftKuaoninm hydroxide c a t a ly s t produced
cyanoet hylaiainQ t e tr a a o le and X~b«ttsyl«*§~sr#ll~di-^J ~cyaaoethyla/aiao-.
te tr a z o ie .
f%e r e a c tio n o f ^ e& in otetraeoX e w ith a o r y lo n itr tl© u sin g b en zy ltriraethylatn&oniuia hydroxide a s a c a ta ly s t y ie ld e d X-^3~cyanoethyl-5~
a m in o te tr a so le end ^ -/S ^ m n o e th y l-^ a m in o te tr a z o le .
3#

Other n ee compound* c o n ta in in g th©^3 ~eyaa©«tfeyX r e sid u e hare

heen prepared during th e p r o cess o f e s ta b lis h in g the str u c tu r e s o f
th e cyano e th y l a ted d erivative® o f 5~@ minotet?asole and X -henzyl-$~
cu n ln o tetrascle by aynthet 1 c and d e ^ a d a tiv e procedure®.
l~ b * n sy l~

$hese are

~© y»noethyl-*>•i*al no t c t rassolin® h yd roch lorid e, 5-&.3F-di-

- cynnoethylinalnot e tr a s o le , H-benzyX-K* ,11*-&!->£? - oyanoetby Xth i our a a .
X-^3 - cyano ©<hyl-5-ncetylam ino i et r a s o l©, and 2*^3• cy«mo©ihyl-5~eo«tyl
amlnotetr&coX*.
h.

P o s s ib le mechanisms fo r th e o y a n o eih y la lio n o f 5«am ln otetrasole

and X~ben»yX~$~®®inotebrazole have been proposed.

IXYBBATUBS OlfSD
1.

H. A, HptL9&kf "Orgfthlo Hcacticm**, John Wilsy and Sons, i n c .,

8«w York, 19% , VoX. 7, pp. 79- 135*
2*

It. 8* BYros and 1 . A. F o ra l-K a sh lt, 2h\ir. Obehsi f& lm ., 3 3 . 697i
O.A. Jg^ T S a p ( 1 9 § ^ #

3*

8* 8 . Alerandsr, “P rin cip les o f Ionic Organic Bsactlons*, John
M l * y and Sons* l a ? . , !?«w York, 1953# p . 152.

**•

0* B. In fo ld , "S tru c tu re and Mechanism in Organic Chemistry",
eoimAiX U n iv e r s it y ,£**#*, I th a c a , If. Y .# 1 955. p . 391-

9*

F. 0* Whitmore, H. S. Mosher, 1* H. Adana, H. B. S aylor, 3. 0*
Chapin, 0. W eieel, and W. Yanks, J* An* Ghata. S ee.,
739 (1 9 ^ )*

6.

J . !!. M a n a g er and 0. Fagfe, J . Cham. So©., 13%. 939.

7»

w. a . Finnegan, H. A* Henry, and B* L ieh sr, J . Org. Chan., IE,
779 (1953)*

8* K» B. Wilson, Alkyl&tion S tad ias with Anlnotri& aolaa and Aminota tr a s o le a , 8h.D . f h e s is , Michigan S ta ts U n iv ersity , 1957*
%

W.h. Carbredht and

1 . M. H erbst, J . Org* Cham., J&,
J . Org. Cham., ££,

XOlU (1993) *

10.

B. H» H arbat and W. X*. a&rhrecht,

1383 (1993).

U.

U Blrfeofer, B o r., j a , **29 ( 1 9 ^ ) .

12.

B . M. K erbst and D. F . Farciv&l, J . Org. Cfcem., £ 2 , % 9 (195**) •

13.

B. F. Ferciw&X, A lkylated 5-Aml n o te tra so le s, S heir P rep aratio n
and ProperA iea, Ph.D. f h e s is , Michigan S ta ts Collago, 1955*

lk .

8. B. Buc, “Organic Symthes#e% Col. Vol. I l l , John Wiley and
Sons, I n c ., Wav York, 1959# P* 93*

19.

B. II. H erb st, 0 . W. H eberts, and 8. J . H a rv ill, J . Org. Ohsm.,

i g , 139 (195D*
16.

H. A. Hsxiry and W. O. Finnegan, J . Am. Ghem. So©., £&, 923 (195**)»

17.

W. Ii« Sarbraafct and B. M. K erbet, J . Org. Chem.,

1269 (1993).

18.

W. I*. Oarbrecht and

1003 (1953)*

E. H.

H arbst, J . Qrg. Cham., £8 ,

5*
19*

A* W elsik rg w r, # d .f
Methods o f Organic Gh«siiatryn>
Sad* ed*# l a t e r odieiia* P u b lish ers In c ., Bow York, 19**9, Vol. I ,
y t . 2* g . l|$ fc,

20*

0

21#

B# y . P a ro lv a l, A lkylated Ouanldinea, Ylielr P re p aratio n and
P roper t i e et H. S. $feo»is, Mieblgaa S ta te College, 1952*

22.

0. m v e r m d h e r , B a r., gj^ 613 (189*0.

23•

J* H. F ord, "Organic Syntheses", Ooi. Vol. I ll# John Wiley aad
Soae* In * ., lew York, 1995* p* 3^*

. IS# Pyoon oiid » . W* Htmter, Hoc* fraw* Chisi.,

jgfc, t e l ( 1 9 2 6 )#

58
TABX.2 I

Bata f o r th e f itr a ti c m o f 0.5508 £• of 5~^*^-4i^$-eyunoethylm ainote tra * o l« w ith 0.1032 IT Aqueous Sodium Hydroxide:
Volume o f
m m

(m l.)

Volume o f
pH

Ha0H (m l.)

pH

0 .0 0

3 .4 4

3 6 .0 0

6.l4

3 .0 0

3 .8 8

2 6 .5 0

6 .3 0

h.oo

4 .xU

2 7 .0 9

6 .6 5

6 .0 0

4 .3 4

2 7 -5 0

7 . 6s

^ .0 0

h. 5 0

2 7 -7 0

8 .0 1

1 0 .0 0

4 .6 5

PS. 0 0

9*77

1 3 .0 0

4 .7 8

2 3 .2 0

1 0 .0 6

13*00

4 .8 4

26*54

1 0 .3 5

lU.OO

4 ,6 9

2 0 .0 1

1 0 .5 5

1 4 ,5 0

4 ,9 1

3 0 .0 0

1 0 .3 2

15*00

4 .9 7

3 2 .0 0

1 1 .0 7

15*50

U.qq

3 4 .0 0

U

1 6 .0 0

5*01

36*00

11*35

1 8 .0 0

5 *l 4

3 8 .0 0

U . 4l

3 0 .0 0

5 .2 9

4 0 .0 0

U

3 3 .0 1

5*98

5 0 .0 0

1 1 .7 1

2 4 .0 0

5*72

.1 9

.5 1

59

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