PHOTOLYSES O F N-NITR OSAMIDES
IN ACIDIC AND NEUTRAL MEDIA
by
Antonio Chun Hung Lee
B.Sc., The univers i ty of Br i t i sh Columbia, 1958
A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF
THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE
i n the Department
Chemis t ry
ANTONIO CHUN HUNG LEE , MON FRASER UNIVERSITY
April , 1967
B.Sc., The Unive r s i ty of & r i t i s h Columbia, 1958
i n t h e Department
of
Chemistry
'Je accep t t h i s Thes is a s conforming t o t h e r e q u i r e d s tandard .
PARTTAL COPYRIGIIT LICENSE
I he reby g r a n t t o Simon F r a s e r U n i v e r s i t y t h e r i g h t t o lend
my t h e s i s o r d i s s e r t a t i o n ( t h e t i t l e of which i s shown below) t o u s e r s
o f t h e Simon F r a s e r U n i v e r s i t y L i b r a r y , and t o make p a r t i a l o r s i n g l e
c o p i e s o n l y f o r s u c h u s e r s o r i n r e s p o n s e t o a r e q u e s t from t h e l i b r a r y
of a n y o t h e r u n i v e r s i t y , o r o t h e r e d u c a t i o n a l i n s t i t u t i o n , on i t s own
b e h a l f o r f o r one of i t s u s e r s . I f u r t h e r a g r e e t h a t pe rmiss ion f o r
m u l t i p l e copying of t h i s t h e s i s f o r s c h o l a r l y purposes may be g r a n t e d
b y me o r t h e Dean of Graduate S t t ld ies . It is unders tood t h a t copying
o r p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l n o t be a l lowed
w i t h o u t my w r i t t e n pe rmiss ion .
T i t l e of T h e s i s / ~ i s s e r t a t i o n :
A u t h o r :
( s i g n a t u r e )
(name )
( d a t e )
ii
A13S11'ilACT
2ho to lyses of s e v e r a l IT-i~i t rosanides i n a c i d i c end n e u t r a l
media were s t u d i e d . .:he photochenical decomposition of J-
n i t r o o a n i d e s was fouud t o involve e x c l u s i v e l y n i t rogen-ni t rogen
bond cleavage of t h e 1:-nitrosarnide group i n c o n t r a s t t o t h e
p y r o l y t i c decomposition which involved cleavage of t h e a c y l
n i t r o g e n bond.
i n a c i d i c media, photolyses of IT-nitrosanides l e d t o t h e
l i g h t c a t a l y z e d d e n i t r o s a t i o n of t h e N-ni t rosanides by photo-
e l imi i i a t ion of t h e [NGH] group w i t h t h e f o r x a t i o n of
a l l y l i d e n i m i d e s . The a lkyl idenimides undervent secondary
r e a c t i o n s t o g ive t h e corresponding aldehydes. The photo-
e l i m i n a t i o n products were i d e n t i f i e d as the 2,4-dini t rophenyl-
hydrazones of t h e aldehydes.
In n e u t r a l media, t h e primary p h o t o l y t i c process of ii-
n i t rosa . : i ides was t h e , f o m a t i o n of n i t r o s o and anide r a d i c a l s .
The axide r a d i c a l was found t o a b s t r a c t i n t r a n o l e c u l a r l y a
hydrogen atom a t t ached t o t h e carbon atom i n t h e 5-pos i t ion #
t o g ive a $-carbon r a d i c a l . Th i s 5-carbon r z d i c e l then coupled
rniJ~h t h e n i t r o s o r a d i c a l t o give a C-nitroso compound which
e i t h e r t a u t o n e r i z e d t o i ' o m oxiine o r dimerized. A l t e r n a t i v e l y
t h e arnide r a d i c z l underwent e l i n i n a t i o n of an alpha hydrogen
t o g ive t h e a lkyl idenimide a s an in te rmedia te .
i The $ - p o s i t i o n was numbered i n r e fe rence t o t h e n i t r o g e n atom
o; the a r ~ i d e group. For exzmi~le, - - t h e fo r - .u la of 6-n i t roso-n- 41
hexyl f o n a m i d e would be CR3-CH2-F-CH2-CH2-CH2-:;H-$-;; N=O 0
iii
I n p r e s e n t i n g this t h e s i s i n p a r t i a l f u l f i l l i n e n t of
t h e requireinents f o r an advanced uegree a-L t h e Sixon F r a s e r
U n i v e r s i t y , I agree t h a t t h e Library s h a l l make i t f u l l y
a v a i l a b l e f o r r e f e r e n c e and s tudy. I f u r t h e r agree t h a t
permission f o r ex tens ive copying of t h i s t h e s i s f o r schol-
a r l y purposes may be granted by t h e Iiead of my Departraent
o r by h i s r e p r e s e n t a t i v e s . It i s understood t h a t cop j ing
o r p u b l i c a t i o n of t h i s t h e s i s f o r f i n a n c i a l gz in s h a l l not
be allowed wi thout my w r i t t e n pemiss ion .
2epartment of Chemistry .................................. The Sixon F r a s e r Unive r s i ty
aurnaby2, B O G o , Canada
Date....................
I would l i k e t o express my s i n c e r e thanks and a p p r e c i a t -
i o n t o D r . Y.L. Chow f o r h i s advice and encouragenent
throughout t h i s r e sea rch .
It i s a p leasure t o thank D r s . 'J.A. Ayer and D.D. Tanner
of t h e Unive r s i ty of Alber ta f o r provid ing t h e mass s p e c t r a .
The co-operat ion of L i s s ?,I. 3 i e s e r of t h i s department
i n p rov id ing t h e n.m.r. s p e c t r a i s deeply apprec ia ted .
6 . Cyclohexylacetamide ............................ 8 7 . Phenethylacetamide ............................. 8 8 . N-nethyl-o-toluamide .......................... 8 9 . Benzylformamide ................................ 9 10 . 4-Phenyl-n-butylacetsmide ...................... 9 11 . ?ieserVs Solution ............................. 10
C . PHEPAMTIOWS GP N.TU'I'I'HOSAi. IIDES General Procedure for Kitrosation of Amides .... 11 Preparations of h-nitrosoacetamides and
N-nitrosoformamides ............................ 11 D . PKGTOLYSES IN ACIDIC X d D I A
General Procedure of Photolysis in Acidic Ledia
vi
'l'Ai3LI;S 01' CO?:T~5:'I'S (Cont Id )
Pa ge
4 . N-nitroso-N-pheiiethylacetamide ................... 17 5 . N-nitroso-IT-cyclohexylacetamide .................. 18 f ..................... u . N-nitroso-N-n-butylformamide 18
E . PXOTOLYSdS IK UNJ'L'IUL I3ZDIA Generzl Procedure of Photolyses in IJeutral ; edia . . 19
...................... 4 . N-nitroso-14-benzylacetamide 28 ................... . 5 N-nitroso-N-pheiiethylacetamide 29
........ 6a . N-nitroso-N-methylcaproamide in n-pentane 29 . ...... 6b N-nitrooo-N-methylcaproamide in cyclohexane 31
6c . F-nitroso-3-methylcaproamide in petroleum ether .. 31 7a . N-nitroso-X-methyl-o-toluamide in petroleum
............................................ ether 32 ........ 7b . N-ni$roso-N-methyl-o-toluamide in benzene 35
............................... . 8 Control Photolysis 38 I11 . RESULTS
....................... Photolyses in Acetic Kedia 39 ...................... Photolyses in Xeutral Xedia 41
DISCUSSIONS
..... Pliotolyses of lj-nitrosamides in Acidic Iiledia 52 .... Photolyses of X-nitrosanides in Neutral +:edia 54
................. SUGGESTIDIS FGR 3'U;iTIIER ~i 'Sdb3CH 60 ..................................... BIBLIOGRAPHY 64
v i i
A c i d i c Liedia .......................................... 61 111. The l-'roducts of Pliotolyses of N-nitrosamjdes in
Cliart s Paqe - I. The Therxa l Decomposition of IJ-ni t rosanide ............ 1
11. The Photocheinical Iiechanism of ?I-chloramides .......... 2 ...... 111. The Yhotochenical Rearrangement of IT-chlorimides 3 ...... I V . The P h o t o l y s i s of X i t r i t e E s t e r i n X e u t r a l Eedia 3
V. P o s s i b i l i t y of Generat ing Xi t rogen 2 a d i c a l s .from t h e
......... P h o t o l y s i s of 2:-nitrosanides i n l l e u t r a l ILedia 4 VI. P h o t o - e l i n i n a t i o n of [ z c ~ ] from I
v i i i
C h a r t s (Cont ' d ) Pa ~ e
X I i I . The P h o t o l y s i s of 1:-nitroso-N-methyl-o-toluanide i n
X e u t r a l Media ..................................... 51 X I V . Xechanism o f t h e P h o t o l y s i s o f N-ni t rosamides i n
A c i d i c Xedia ...................................... 53 XV. Genera l .Photochemical Xechanisrn o f N-nitrosamide
i n X e u t r a l Xedia .................................. 55 X V I . P o s s i b l e S ide Reac t ion of t h e P h o t o l y s i s o f
F i g u r e
............. I. The n.m.r. Spectrum of Compound ;(;;";XI1 49
lTlie N-ni t rosanides a r e c h a r a c t e r i z e d by a s e r i e s of
a b s o r p t i o n s a t 390-430 rnp i n e i t h e r p o l z r o r non-polar s o l v e n t s . They a r e the rmal ly uns tab le . T h e i r thermal s t a b i l i t y i s depend-
e n t on t h e s t r u c t u r e of t h e parent amines (X group i n conpound
The 2:-nitroso-N-alkylamides were first pyepared by ?echmann
( 2 ) i n 1894 and by Chancel ( 3 ) i n 1895. Chancel and l a t t e r
Peclunann(4) r epor ted t h a t t h e decomposition of bl-nitrosamides
y i e l d e d e s t e r s , but n e i t h e r s t u d i e d t h e r e c c t i o n any f u r t h e r .
E.H. 'Xhite ( 5 ) uindertook f u r t h e r s tudy of t h e thermal decom-
p o s i t i o n of if-nitrossmides t o e s t e r s i n v a r i o u s s o l v e n t s
r a n g i n g from a c e t i c a c i d t o cyclohexane. On t h e b a s i s of
t h e s e s t u d i e s , he proposed t h a t N-nitrosamides rearranged
t o form in te rmedia te d i a z o e s t e r s which underwent n i t r o g e n
e l i m i n a t i o n t o y i e l d t h e ca rboxy l i c e s t e r . I n t h i s mechanism,
t h e ni t rogen-carbonyl bond cleavage took p lace a s t h e first
s t e p ( 6 ) .
Chart I.
The Thermal Decomposition of IT-nitrosamide.
Although i n v e s t i g a t i o n s of photochenica l ly l a b i l e conpounds
such a s B-halamides ( 7 ) , N-chloroimides (8) and a l k y l n i t r i t e
e s t e r s (9 ) have been comprehensive, no work has been done on
2
t h e pi lotolyscs of X-ixi L r o s m i d e s . T - 2. S. Xeole , s .L, i iarcus and ii. G. Sclieperr: r epor ted t h a t
-- A-ciiloro d e r i v a t i v e s of both f!-methyl and N-t-butgl pentano-
a n i d e s were rearranged upon i r r a d i a t i o n t o t h e 6-chloro isomers
i n benzene ( 7 ) . The N-chloroamide rearrangements m-re found
t o be a f r ee -md lca l chain process s i n c e t h e chloroaxidec r e -
a r r a n g e d r a p i d l y bu t only upon weak i r r a d i a t i o n . The photo-
c h e x i c a l inechanism of X-~h lo roa .~ l ides was found t o be a s
fo l lowing . - Chart I1
The Photochemical ;.;echani.sm of Z-chloroznides . -
3 . C . Pe te r son and A , '.'!anbs~ans (8) r e p o r t e d i ~ h o t a -
chemical r ea r rzngenen t o f 3-chloroimides t o 5 -ch lo ro in ides . d
Acycl ic i n i d y l r a d i c a l s such as IY (ZDOCB ) might r e z r r a n s e 3 t o X a t r a t e s P a s t enough t o permit s e l e c t i v e i n t r o d u c t i o n 1 B
n e u t r a l o rgan ic meaia.
Chart III
The Photochemical Rearraju-;ement of 1:-chloroimides -.- .
The photochemical genera t ion of amide r a d i c a l s from
X-chloroamides and of irnide r a d i c a l s from 2-chloroimides appear-
ed t o f o l l o w t h e same mechanist ic pathway a s t h e Barton . .
r e a c t i o n (10) . i'he Barton r e a c t i o n invo lv ing t h e photo lyses
of s u i t a b l y c o n s t i t u t e d organic n i t r i t e e s t e r i n to luene
r e s u l t s i n an in t ramolecu la r exchange of t h e IiO of t h e n i t r i t e
r e s i d u e wi th a hydrogen atom a t t a c h e d t o a carbon atom i n
t h e $ -pos i t ion from t h e amide n i t rogen . The C-nitroso compound
t h u s formed could be i s o l a t e d 2s t h e corresponding n i t r o s o
dirners o r , a f t e r t au tomer iza t ion , a s t h e oximes.
Chart I V
The Pho to lys i s of N i t r i t e E s t e r i n Neu t ra l Liedia.
/H /I1 "0, CH2 0-NO A" CX2 O * 6~~ 0-H CB, OH Pu + . N O - - - * u +.~Jo+-
( ~ 1 1 ) (XIII) (XIV ) (X 'J )
The mechanism of i r r a d i a t i o n of n i t r i t e X I 1 l e a d i n g t o
XV involved t h r e e s t e p s : f i r s t , t h e photochemical cleavage
of t h e 0-N bond t o f u r n i s h t h e zlkoxy r a d i a z l XI11 and *EG;
second, t h e intrainole c u l a r a b s t r a c t i o n of hydrogen t o f u r n i s h
t h e a l k y l r a d i c a l XIV; and f i n a l l y , t h e combination of X I V
w i t h .XO t o f u r n i s h t h e product XV.
A f u r t h e r p o s s i b i l i t y of g e n e r a t i n g u s e f u l n i t r o g e n
4
r a d i c a l s , by c?nalogy t o t h e photo lyses of U-chloroanides,
N-chloroimides and n i t r i t e e s t e r s was t h e p h o t o l y s i s of
E-nitrosarnides i n n e u t r a l media.
Chart V
P o s s i b i l i t y of Generating E i t rogen Radicals frw t h e
P h o t o l y s i s of nT-ni trosamides i n ITeutral I:edia. 0
Unlike t h e Barton r e a c t i o n , t h e p h o t o l y s i s of 1;-nitro-
samine i n a c i d i c media (11) s t u d i e d by Chow and h i s co-workers
involved t h e photoe l iminat ion of [NOH] . The photoe l iminat ion of [iioa] was shown i n t h e fo l lowing c h a r t .
Chart V I
Photoe l iminat ion of [XOH] from 14-nitrosamille. H
P 1
It w a ' s t h e r e f o r e of i n t e r e s t t o i n v e s t i g a t e t h e photo-
chemical behaviour of t h e G-nitrosamides i n a c e t i c and
n e u t r e l media i n o r d e r t o a f fo rd comparisons wi th t h e
mechanisms mentioned above.
A . CEX Z 1x4 L I n f r a r e d s p e c t r a ( i .r .) were obta ined wi th a Perkin-
Elmer 421 Infra-cord spec t ropho tone te r wi th f r equenc ies
l i s t e d i n cm-l; w = weak, n = medium, s = s t r o n g . Spec t ra
were obta ined on n u j o l mulls o r carbon t e t r a c h l o r i d e s o l -
u t i o n of s o l i d samples or on n e a t l i q u i d s u s i n g sodium
c h l o r i d e o p t i c s f o r a l l samples.
U l t r a v i o l e t s p e c t r a (uv) were taken on a Cary 1 4
Spectrophotometer o r on a Unicam SP 800 Spectrophotorneter
wi th wavelength l i s t e d a s ~ 2 : ~ ~ + . The uv s p e c t r a were obta ined u s i n g a 1 cm quar tz cuvet .
Xuclezr ; . ; a p e t i c Resonance s p e c t r a (n.m.r.) were tzken
on a Varian A-60 o r A 56/50 spectrophotometer ; the coupl ing
cons tan t ( J ) i s g iven i n c.p.s. , t h e resonance f requenc ies
given i n t based on t e t r a n e t h y l s i l a n e a s t h e i n t e r n a l
s t a n d ~ r d . The s o l v e n t s used were carbon t e t r a c h l o r i d e ,
deutero-chloroform, dimethyl su l fox ide o r acetone a s
s p e c i f i e d . Resonance peak m u l t i p l i c i t y i s repor ted i n t h e
fo l lowing manner: s = s i n g l e t , rn = m u l t i p l e t only p a r t i a l l y
r e s o l v e d , d = d o u b l e t , t = t r i p l e t , q = q u a r t e t and qu =
q u i n t e t . Xass s p e c t r a (a . s. ) were taken w i t h a Xetropol i tan-Vickers
i.:S-311 o r :JS-g mass spec t rometer a t t h e Unive r s i ty of Albe r t a ,
ddnont on.
PTicroanalyses were done by D r . Dassle o f 5757 Tlecelles
Ave. , TvUontreal, and by Alfred Rernhardt , Vkx-Planck T n s t i t u t f& Kohlenforschung , Yulheim ( ~ u h r ) , Best Germany.
Column chromatography was done on n e u t r a l alumina, 'Jloelm
Rrockman n e u t r a l alumina o r on s i l i c i c a c i d (Mal l ickrodt ) .
Thi n-layer chromatography (T.L. C . ) w a s done on p l a t e s
of alumina oxide ( ~ a m a g ) which were prepared with t h e Atahl
apparatus .
A l l chemicals used were of reagent grade and used without
p u r i f i c a t i o n u n l e s s otherwise spec i f i ed .
1. n-3utylz.ce-t anide was prepared by r e f l u x i n g n-butylamine
(36.5 g) wi th a c e t i c anhydride (365 m l ) fol lowed by d i s t i l l -
a t i o n a t reduced p e s s u r e (14g0/39 mm) t o g ive 38.89 g of t h e
acetamide.
i . : 1 6 5 0 ( s ) , 1555(s) .
n.m.r.: g . l ( t , J=6 c . ~ . s . , 3H); 8.5(m, 4x1;
8 .07(s , 3Ii ) ; 6.8(q , J=6 c.p.s. , 2 3 ) ;
2. Genzylacetamide v;as prepared by zdding a c e t i c anhydride
(102 g ) dropwise t o benzylanine (53.6 g ) i n an i c e ba th
wi th v igorous s t i r r i n g . The s o l u t i o n was re f luxed f o r one
hour and then d i s t i l l e d a t reduced p ressu re . The d i s t i l l a t e
c o l l e c t e d at 198-200•‹/17 r n soon s o l i d i f i e d a s white needle-
2 .77(s , 513).
3. n-Iiexylzcetamide was prepared a s d e s c r i b e d above f o r
n-butylacetamide.,The acetamide w a s c o l l e c t e d by vacuum
d i s t i l l a t i o n a t 139'/9 mm.
i : 3280(s) , 1 6 4 5 ( s ) , 1550(B).
n.m.r. : g . l ( t , J=5 c.p.s., 3 3 ) ; 8.65(m, 8 H ) ; 6.7(sY3H);
6 .7(q, J=5.5 c.p.s., 2H).
4. n-Butylf ormanide was prepared by r e f l u x i n g n - b u t y l a i n e
(36.2 g) wi th 90 75 formic a c i d (76.6 g) f o r 1; hour. The
8
n-butylfomamide was c o l l e c t e d by vacuum d i s t i l l a t i o n a t
122-125 O/9 (36.2 g ) . i : 324O(s) , 2ri50(w), l65O(s) , 1 5 4 0 ( s ) .
n.111.r.: 9 . l ( t , J=6 c.P.G., 3 H ) ; 8.35-8.8(m, 41:);
6.73(q, J=6 c.p.s. , 2H); 1.95(b.s., 1 H ) .
5. n-:;exglformarnide was prepared i n t h e same manner as i n
(4 ) . The n-hexylformanide was c o l l e c t e d a t 142-146O/9 n ~ .
i . : 3290(s ) , 2750(w), 1 6 6 0 ( s ) , 1540(9) ,
n.m.r.: 9 . l ( t , J=5 c.P.s., 3H); 8.4-8.8(m, 6i-1);
6.69(q, J=6 c.p.s., 2B); 1.72(b.a., 1H).
6. Cyclohexglacetanide was prepared i n t h e sane manner as
desc r ibed above f o r n-butylacetamide. The c y c l o h e x y l a c e t a ~ i d e
wzs c o l l e c t e d from vacuum d i s t i l l a t i o n a t 245O/9 mn. The
d i s t i l l a t e soon c r y s t a l l i z e d and was r e c r y s t a l l i z e d from 95 %
7. phenethylacetamide was prepared as i n procedure 2. The
d i s t i l l a t e was c o l l e c t e d a t 173-176'/13 mm and was r e - d i s t i l l -
ed t o g ive pure phenethylacetamide a t 167-170~/10 mm. The
d i s t i l l a t e c r y s t a l l i z e d , m.p. 44-45•‹C.
i : 3290(s) , 1 6 4 5 ( s ) , 1540(m), 7 5 2 ( s ) , 7 0 5 ( s )
n.m.r.: -8 .15(s , 3 H ) ; 7 . 2 4 ( t , J=7 c.p.s. , 2 H ) ;
6 .69( t , J=6 c .p . s . ) ; 2 .86(s , 514).
8. iT-xethyl-o-toluenide was prepared by bubbling gaseous
methylamine i n t o an e t h e r s o l u t i o n (500 ml) of o - t o l y l
9
c h l o r i d e (70.0 G) u n t i l t h e s o l u t i o n was a l k a l i n e t o moist
l i t m u s paper. The ~ i h i t e powdery methylamine hydrochlor ide
p r e c i p i t a t e v!as removed by f i l t r a t i o n . 'Yhen t h e e t h e r v~zs
removed from t h e f i l t r a t e , a s o l i d compound was obta ined .
It was r e c r y s t a l l i z e d from e thano l and water t o g ive 51.9
g of white n e e d l e s , map. 74-75'.
i : 3 3 6 0 ( ~ ) , l 6 3 8 ( s ) , 1 6 0 2 ( ~ ) , l55O(s) , 7 8 5 ( s ) ,
7 2 0 ( s ) , 695(m).
n.m.r.: 7 .77(s , 3 ~ ) ; 7.33(d, J=5 c.p.s . , 3 H ) ,
2.93(m, 4111,
9. Senzglfornamide was prepared i n t h e u s u e l rnznner a s des-
c r ibed above. The d i s t i l l z t e c o l l e c t e d a t 180-18j0/12 rn2
soon s o l i d i f i e d on coo l ing t o g ive a white s o l i d , m.p. 55-56'.
i . : 3270 (m), 2860(m), 1 6 3 5 ( s ) , 1530(m), 740(m), 7 0 0 ( d ,
1i .m.r . : 1 .94(b.s. , 1K); 2.78(s, 5H); 5.7(d, J=6 c.P.s.,
2H).
10. 4-Pheny1butylacetami.de was prepared by r e f l u x i n g t h e
4-phenylbutylamine wi th a c e t i c anhydride. The former was
ob ta ined by t h e l i t h i u m aluminum hydr ide reduc t ion of
p h e n y l b u t y r o n i t r i l e a s desc r ibed below.
To a s o l u t i o n of l i t h i u m altminum hydr ide (12.86 g ) i n
anhydrous e t h e r (50 ml) i n a l i t r e t h r e e neck f l a s k , phenyl-
b u t y r o n i t r i l e (25 g ) was added dropwise a t 0•‹C wi th s t i r r i n g .
The s o l u t i o n w a s r e f luxed f o r 48 hours . I c e water (15 n l )
and sodium hydroxide s o l u t i o n were added dropwise t o decompose
t h e unreac ted l i t h i u m aluminum hydride. The hydrolyzed
10
s o l u t i o n wzs allowed t o s t and f o r 2 hours a t room t e x p e r a t u r e ,
a f t e r which time t h e c l e a r superna tan t s o l u t i o n mas decanted.
The res idue was e x t r a c t e d a few t imes wi th e t h e r . The e t h e r
e x t r a c t and t h e decanted superna tan t s o l u t i o n were combined.
The e t h e r was removed from t h e combined s o l u t i o n t o g ive
22.5 g of phenylbutylamine as a pa le yelloiTi l i q u i d .
i . . : 3450(m), 3380(m), 1610(m), 1595(m), 1550(m),
6 9 8 ( ~ ) , 7 4 8 ( ~ ) .
T h i s w i n e (15.4 g) was re f luxed i n a c e t i c anhydride (30
g ) Tor one hour. The excess a c e t i c a c i d was removed by d i s -
t i l l a t i o n a t 117-118•‹C. The 4-phenylbutylacetanide (16.44 g )
w a s c o l l e c t e d a t 195-204'/9 rnm.
i . . : 34OO(m), l66O(s) , 1 6 0 3 ( ~ ) , 1560(m), i'l4(rn), 695(s) .
11. P i e s e r t s s o l u t i o n (12) w a s prepared by d i s s o l v i n g 20
g of potassium hydroxide i n 100 r n l of water . Sodiuin a n t r a -
quinone k-su l fonate (2 g ) and sodium h y d r o s u l f i t e (15 g )
were then added wi th s t i r r i n g u n t i l a c l e a r , blood-red
s o l u t i o n w a s obta ined . The s o l u t i o n was used a f t e r i t was
cooled t o room temperature.
11
C. PHXPARATJON OF N-NTTROSAP IDES.
General Procedure f o r Ni t rosa t ion of Ami.des.
The amide w a s d isso lved i n a mixture of a c e t i c anhydride and
g l a c i a l a c e t i c a c i d . The s o l u t i o n was kept a t O•‹C i n an i c e
bath. An excess of g r a n u l a r sodium n i t r i t e w a s added, i n small
p o r t i o n s , t o t h e s o l u t i o n during a per iod o f 5 hours with cons tant
s t i r r i n g . The s o l u t i o n was then s t i r r e d f o r an addi t i o n a l 2 hours.
The s o l u t i o n w a s poured i n t o i c e water and ex t rac ted with e t h e r .
The e t h e r e x t r a c t w a s washed with 105 sodium carbonate t o
remove the a c e t i c a c i d u n t i l t he pH of the aqueous l a y e r w a s ca.
8. The e t h e r l a y e r w a s washed with a s m a l l amount of i c e water
and then d r i ed wi th anhydrous magnesium s u l f a t e . The e t h e r
s o l u t i o n w a s f i l t e r e d and e t h e r w a s removed from t h e f i l t r a t e
by r o t a r y e v ~ p o r a t o r a t a low temperature t o g ive t h e N-nitro-
samides a s yellow l i q u i d s o r yellow s o l i d s .
Prepara t ions of I?-nitrosoacetamides and FT-nitrosoformamides.
The K-nitroso-N-n-butylacetamide, N-nitroso-N-n-hexyl-
acetamide, N-nitroso-IT-benzylacetamide, N-nitroso-IT-aethgl-
acetamide, N-nitroso-N-phenethylacetamide, N-nitroso-B-methyl-
caproamide, N-nitroso-N-benzylformamide were prepared i n the
same manner as descr ibed i n the above procedure. Thei r charact-
e r i s t i c i.r., n.m.r. and uv absorp t ions a r e l i s t e d i n
Table I. The N-nitroso-If-methylacetamide, f o r example, has
n + x * absorpt ion peaks a t 376 ( € = l 8 8 ) , 390 (€=274), 426 ( ~ = 4 6 0 )
and x - t x * a t 276 mp (6=3,780) i n cyclohexane so lu t ion . I n
methanol s o l u t i o n , it has absorp t ion peaks a t 375 (6=77),
389 (&=log) , 405 ( t=142) , 424 (6=142) and 237 my (C =9,800). . .
Table I
The i .r . znd n.m.r. S p e c t r a l C h a r a c t e r i s t i c s of t h e :;-nitro-
san ides .
IT-nitroso- i .r . n.m.r. uv
e c e t m i d c s ( c n - l ) CH3C0 -CH,N- Solventa Absorption Peaks L
11-Cyclo- 1720 , 8.01 5.32(m) hexy l 1510
Table I ( c o n t l d )
0-Toluyl- amide
Caprcyl- amide
N-nit roso- forinamides
i . r . 1i.rn.r. (c) U-J ( c m - l ) CB, -il-Ci-I, Solvents Absorption Peaks
2 2
1715, 6 .84(s ) 7 . 8 ( s ) Pe t ro lem 390, 407, 1513 Xther 426 (man. )
1725 , 9 . 0 9 ( t , 6 .90(s) Cyclo- 376, 390 408 1500 J=Gc.p.s.) hexane 427 (mzx. 1
i .r . n.m.r. (t) uv
(cm-l) -COX -UGH.,- So lven t s Absorption Peaks L
1 4
11. Pi;CTOLYSaS I N ILCIDIC :.;,
15
axount of 3r3dy1s reagejnJi, was added T O 5C) LI.L 02 ;;L?t l.il.:,-;i!. 1.2:~
t o give a yel low c r y s t a l l i n e 2,4-dlaitrophenylhydr8zone (720.3
ng, 35 ; j y i e l d ) which was r e c r y s t a l l i z e d Cron aqueous e t h a n o l
t o g ive ye l low need les ; n.p, and mixed m.p. wi th t h e 2 , $ -
din i t rop l~enyl izydrazone of t h e a u t h e n t i c n-butanzl , 118-121' C
( l i t . 122') (13) .
TLe d i s t i l l a t i o n of the r e n a i n i n g s o l v e n t gave a brown
r e s i d u e (879.1 mg, 45 y i e l d ) which was p u r i f i e d b y washing
wi th 20 % sodium carbonate s o l u t i o n followed by e t h e r e x t r a c t -
i o n and vacuum evapora t ion t o g ive a l i q u i d . The i.r. aiid
n.m.r. s p e c t r a of t h e l i q u i d were i d e n t i c a l wi th those o f
an a u t h e n t i c sample of n-butylacetarnide.
2rom t h e o t h e r h a l f of t h e d i s t i l l a t e , t h e dixethone
d e r i v z t i v e ves p r e p r e d . 2S0 i~ t 4- g of ~ l e t h ~ i ~ ~ :72s 2rlr1.ed t c
t h e r e x a i n i n g d i s t i l l a t e . The s o l u t i o n was then ref luxed f o r
h a l f an hour. On coo l ing i n an i c e b a t h , white need les of
t h e d ize thone d e r i v a t i v e of n-but anal were obta ined which
were r e c r y s t a l l i z e d from 50:; aqueous e t h a n o l , m.p. 131-133OC
( l i t . 134') (14) .
2. ;;-nitroso-1;-n-hexylacet a ~ ~ l i d e .
The 1;-nitrosamide (3.44 g ) was photolyzed i n s o l v e n t A
0 (200 ml) w i t h 2 100 watt Xanovia lamp. The photo lyza te was
d i s t i l l e d under a t a o s p h e r i c p e s s u r e t o g ive a brolwn r e s i d u e
2nd a d i s t i l l a t e (100 ml) . No 2,4-dinitrophenylhydrazone was
obta ined when t h e d i s t i l l a t e was t r e a t e d wi th a c a l c u l a t e d
amount of t h e Srady ' s reagent . Treatment of t h e r e s idue
1 6
(one- th i rd ) wi th Urady's reagent gave yellow need les (165 ng,
9.1:;) which were r e c r y s t a l l i z e d from ethanol-water mixture ;
n.p. and mixed map . w i th t h e 2,4-dinitrophenylhydrazone of
a u t h e n t i c n-hexanal , 103-105 ' ( l i t . 104' ) (15) . The remaining r e s i d u e was e x t r a c t e d wi th e t h e r which was washed wi th 10.6
sodium carbonate and then water u n t i l t h e aqueous l a y e r was
n e u t r a l . The i.r. spectrum of t h e brown l i q u i d obtained from
t h e e t h e r e x t r a c t was v i r t u a l l y t h e same a s t h a t of an
a u t h e n t i c sample of t h e n-hexyl acetamide except f o r ve ry
weak peaks a t 1725 and 1280 cn-I which were a t t r i b u t e d t o
n-hexylzce ta te .
3. 17-nitroso-N-benzylacetmide.
The 1;-nitrosamide (3.677 g ) was photolyzed i n s o l u t i o n
A (206 ml) f o r 40 3/4 hours wi th a 100 wa t t Hanovia lanp.
The photo lyza te was d i s t i l l e d a t 30-31•‹/9 mm t o give 147 m l
of d i s t i l l a t e and a res idue . The r e s i d u e was taken up i n water
and e x t r a c t e d w i t h e t h e r . The e t h e r l a y e r was washed with
20% sodium carbonate and then wi th water u n t i l t h e aqueous
l a y e r was n e u t r a l . Uhen t h e e t h e r was evaporated, a brown
r e s i d u e (1.7 g ) was obta ined . A p a r t of t h i s brown res idue
(0.3 g ) and ha l? of t h e d i s t i l l a t e were r e a c t e d s e p a r a t e l y
wi th Brady l s reagent t o .give t h e 2,4-dinitrophenylhydrazone
d e r i v a t i v e of benzaldehyde (combined y i e l d 77$) which was
r e c r y s t a l l i z e d from e t h y l a c e t a t e ; m.p. 239-242'; mixed m.p.
wi th an a u t h e n t i c sa,nple of t h e 2,4-dinitrophenylhydrzzone
of benzaldehyde, 240-241.5•‹C. The aqueous l a y e r from e t h e r
e n t r a c t was evaporated t o g ive a brovm r e s i d u e . Subl imation
17
of t h e r e s i d u e under vacuum gave white needles . The i.r.
spectrum of t h e s e needles was super imp~aab le wi th t h a t of
an a u t h e n t i c sample of acetamide.
I n a s e p a r a t e experiment t h e Il-nitrosamide (5.54 g ) was
photolyzed i n s o l u t i o n B (200 ml) a 200 watt lianovia
lamp. Half of t h e photolyzate was reac ted wi th 3 rady1s
reagen t t o give t h e 2,4-dinitrophenylhydrazone of benzalde-
hyde (1.6 g ) which was r e c r y s t a l l i z e d from e thyl -e thanol
mix tu re , mop. and mixed mop. with an a u t h e n t i c sample of
t h e 2,4-dinitrophenylhydrazone of benzaldehyde was 241-243•‹C.
Tkle s o l v e n t from t h e o t h e r h a l f of the photo lyza te was r e -
moved t o g ive a brovm l i q u i d (3.89 g ) , 1 .64 g of n2s
chronatographed on n e u t r a l alumina. S l u t i o n wi th 10:; chloro-
form i n benzene gave benzylacetzmide (616 mg, 583;), t h e i .r.
and n.m.r. s p e c t r a of which were i d e a t i c a l wi th those of an
au t i l en t i c sample. E l u t i o n with chloroform gave white need les
(320 mg, 19.5;) which were i d e n t i f i e d a s 1 , l -diacetamido-
to luene . These c r y s t a l s were r e c r y s t a l l i z e d from an acetone-
benzene mixture , mop. 246-247OC.
i r e 3270(s) , 1 6 6 0 ( s ) , 1520(w)
n.m.r.: 2 .66(s , 5H); 5 .24(s , ca.lH); 8 .03(s , 6H);
impur i ty a t ca . 7.9.
Analys is Calcd. f o r CllH14N202: C,64.06$; ~ ~ 6 . 8 4 ' ; ;
N,13.58$.
Found: C,64.44; H,7.36; 1;,13.27.
18
The N-nil;rosamide (4.95 ;.;) was photolyzed i n s o l u t i o n 3
(330 n l ) wi th a 200 wat t fianovia lamp f o r one hour. Yhe
s o l v e n t was removed under vacuum t o g ive a brovm l i q u i d
(5.765 g ) . The brown l i q u i d ( 1 g ) was chromztographed on
n e u t r a l a l u n i n m oxide i n c h l o r o f o m t o g ive 1:-pheneth-1-
acetamide (686 mg, 94%) whose i.r. s g e c t r w was s ~ p e r i ~ p o s a b l e
wi th t h a t of an a u t h e n t i c sample. The amount of t h e -thermolysis
product , h e n e t h y l a c e t a t e , was very small a s i n d i c i i e d by
a very weak i.r. absorp t ion peak i n t h e 1765 cm-l reg ion .
5. N-nitroso-IT-cyclohexylacetarilide . The N-nitrosamide (1.05 g ) was photolyzed i n s o l u t i o n A
(100 m l ) f o r 33 hours wi th a 100 wa t t Hanovia lamp. One h a l f
of t h e pho to lysa te was reac ted wi th Brady's reagent a s u s u a i
but no 2,4-dinitrophenylhydrazone p r e c i p i t a t e was obta ined .
6. IT-nitroso-N-11-butylf orixmide.
The Ti-nitrosamide (3.78 g ) was photolyzed i n solutLon A
f o r 5 3/4 hours . The photo lysa te was d i s t i l l e d under atmos-
p h e r i c p ressu re t o give 164 m l of d i s t i l l a t e . Half of t h e
d i s t i l l z t e was ref luxed wi th i3radyts reagent f o r 3 hour t o
g ive 2,4-dinitrophenylhydrazone of n-but anal (76.3 mg,
3.0%) which was r e c r y s t a l l i z e d from ethanol-water mixture ,
mop. and n ixed mop. w i t h t h e 2,4-dinitrophenylhydrazone of
an a u t h e n t i c sample of n-butanal was 120-121QC.
- - General p y o c e d u r ~ of 2hotolyoes i n 1:eutrxl e c i a .
Photolyses were c a r r i e d out i~ ca . 0.1-0.4 -.. s o l u t i o n
under a n i t r o g e n atmosphere wi th a 100 n a t '; ;isnovia G t i l i t y
lamy, a General E l e c t r i c PAR 38 spot lamp (100 w a t t s ) o r
i n s u a l i g h t . I n t h e former two cases t h e s o l u t i o n i n a 2yrex
f l a s k wzs cooled e x t e r n a l l y wi th 2 n a t e r sc reen running
z long t h e e x t e r i o r of t h e f l a s k . The l i g h t c;as passed through
t h e nc,:ter s c r e e n i n t o t h e s o l u t i o n . I n t h e l a t t e r case , t h e
s o l u t i o n i n a 13yrex f l a s k was irmersed i n a b a t h of mnii ing
a s t e r and plzced i n s u n l i g h t (by t h e window). The p h o t o l y s i s
t e n o e r a t u r e was thus c o n t r o l l e d i n a i l cases i n the range
of 10-20•‹C throughout the p h o t o l y s i s per iod . The 2hoto lyses
were cont inued unt i l t h e t y p i c a l uv absorp t ion peaks of
L-nitrosainides disappeared. Dark r e a c t i o n s were pe r fomed i n
n o s t cases a c o n t r o l and uv ebsorp t ions a t 410 ap regions
v!ere t aken a t t h e end of t h e p h o t o l y s i s per iod . The photolyses
viere run i n 4 s o l v e n t systems: (1 ) i n n-pentane; ( 2 ) i n
benzene ( 3 ) i n cyclohexane ( 4 ) i n p e t r ~ l e u m e t h e r , b.p.
34-35OC. The y i e l d s of t h e 6-oximinoanide , s t a r t i n g a x i d e , e s t e r and o t h e r i d e n t i f i e d products were l i s t e d i n Table 111.
- - 1. i,-nitroso-X-n-hexylacetamide
The X-nitrosamide (6.5 g ) i n n-pentane (100 ml) was
-$iotolyzed i n s u n l i g h t (wi th t h e exc lus ion of ovgeiI) ;or
11 days. The s o l v e n t was removed t o g ive a mixture of c r y s t a l s
m d o i l (4.71 g ) . k por t ion ( 2 . 8 g ) of t h e crude product s a s
used for recrystallizz~bion in acetone-pentane mixture to give
the C-nitroso dimer X I X as flzke like clystals (755 mg), m.p.
Analysis calcd. for C15H32N404: C,55.82; ~~9.36; N916.27. --
Found: ~,55.07; K,9.35; li,16.51.
Xolecular weight: determinetion in H20:
The filtrzte from the acetone-n-pentane recrystallization
'Jas dissolved. The aqueous solution was then extracted with
ether. Zvaporation of ether from the ether fraction gave 511
ng of a liquid which was hydrolyzed in 1N HCl in 80:; ethmol-
aater solution (50 nl) at room temperature for 20 hours. A
yellow liquid (439 mg) was obtzined from the methylene
chloride extract of the hydrolysate. This was chromatographed
on neuJ~ral aluinina to give many smll fraction, none of which
contained a sufficient amount of pure substance for identi-
fication. . .
%'hen the water was removed from the aqueous fraction, a
yellow liquid (646 mg) was obtained. This yellow liquid (645
mg) was chromatographed on neutral alumina with chlorofora to
give the C-nitroso dimer XLX (303 me) described above. It
was hydrolyzed in 10 ml of 1X XC1 for 20 hours at room
8.04.(s, 31I), E.1-e07(rn, 42); 8 . 3 3 ( t , 311, \
J=7.2 c.P.s.).
ii dccoupl ing experiment ivsn done on t h c l i q u i d ;:XI v i i t h
a Varic:n 100 L:c n . n o r . spec trophotomet c r . ',-hen t h e i r i p l e t I a t 7;2..99 waq i r r a d i a t e d , t h e q ~ c r t e t n t ~ 7 . 5 6 c o l l r p s c d t o P
~ i n , c l e t . :?hen t h e q u a r t e t c7t - ~ 7 . 5 5 :.m5 i r r a d i a t e d , t h e
t r i p l e t ~t ~ 8 . 9 9 c o l l a p s e d t o 2, s i n g l e t .
L iquid XXI vaa t r ez . t ed w i t h S r a d y ' s r e c ~ e n t t o z i v e 30
mg of 2,4-dinitrophenylhydrazone which Y ! E 3 r e c r y s t a l l i z e d
from ~lcohol - - : la te r t o g i v e yel low needles (2Z
22
( i i ) Xlut ion wi th ch lo ro fo rn Cave t h e C-nitroso dirner
XiX (376 mg, 27.7::).
Xo n-hexylace ta te was i s o l e t e d . Its presence *::as i n d i c a t e d
only by t h e weak absorp t ion peak of carbonyl and a c e t a t e groups
a t ca. 1720 and 1220 cx-' i n t h e crude photo lyza te .
I n a s e p a r a t e experiment , t h e photolyses of i ;-nitroso-
2:-n-hexylacetamide (3.12 g) under n i t r o g e n i n s u n l i g h t f o r
5 days gave a d e p o s i t of s o l i d i n t h e photo lyza te . The s o l v e n t
was removed from .the photo lyza te t o g ive a mixture of brown
l i q u i d and c r y s t a l s ( 2 g ) , p a r t of which (1.98 g ) was
chroaatographed on n e u t r a l alumina:
( i ) B lu t ion wi th 25% ch lo ro fo rn i n benzene gave a l i q u i d
(512 me). 'The i.r. and n.m.r. s p e c t r a of t h i s l i q u i d were
superimposable wi th those of t h e l i q u i d XVIII from t h e pre-
ceding experiment.
( i i ) E l u t i o n wi th chloroform gave c r y s t a l s , mop. 125-
12T•‹C (791 mg). The i.r. and n.m.r. s p e c t r a of t h i s c rys-
t z l l i n e compound were superimposable wi th those of t h e C-nitroso
d i n e r 2 ~ 1 ~ i d e n t i f i e d i n t h e previous experiment. T h i s C-nitroso
d i n e r X I X (750 mg) was hydrolyzed wi th 111 aqueous hydroch lo r i c
a c i d s o l u t i o n (30 ml) a t room temperature f o r 48 hours and
then hea ted on steam ba th f o r a d d i t i o n a l 24 hours . The
e x t r a c t i o n of t h e hydrolysa te wi th methylene c h l o r i d e gave
a yel low l i q u i d (160 m g ) . Chromatography of t h e yel low l i q u i d
on i i e u t r a l a l m i n a wi th 255; chloroform i n benzene gave t h e
b -ke toa..xi.de A X 1 ( 5 G .g ;ng) . r : 3 3 3 0 ( s ) , 1 7 0 7 ( s ) , 1 6 5 0 ( s ) .
Treatinent of t h i s ketone wi th r: c a l c u l a t e d amount of 3 r a d y f s
r e a ~ e n t gave 2 hydrzzone LXII which x a s r e c r y s t a l l i z e d from
a l c o h o l and ;vater t o g ive yell-on n e e d l e s , mop. 119-121•‹C.
Analys is ca lcd . f o r Cl4;Il9W5O5: C,49.82; H , 5 .@; B,20.76.
Yound: C,49.89; H,5.85; X,20.81,
2. 4-Phenylbutyl-~S-~zitrozcetamide .
The X-nitrosamide (4.7 g ) i n ' p e t r o l e m e t h e r (100 n l )
was photolyzed i n d i f f u s e d s u n l i g h t f o r 21 days i n n i t r o g e n
a taosphere . 3hen t h e s o l v e n t mas removed from t h e photo lyza te ,
a brown l i q u i d was obta ined (4.322 g ) . k p a r t of t h e brown
l i q u i d (1.26 g ) was hydrolyzed i n met:ianolic .hydroch lo r i c
a c i d s o l u t i o n (16.35 m l of concent ra ted hydroch lo r i c a c i d i n
100 m l of methanol). The h y d r o l y s i s was cont inued f o r 25 hours.
Sodium carbonate s o l u t i o n (10:;) was added t o t h e hydrolyza te
x t i l t h e pH of t h e s o l u t i o n was ca. 9. The brown o i l which
apgeared i n t h e a l k a l i n e s o l u t i o n mas e x t r a c t e d wi th e t h e r .
When t h e e t h e r e x t r a c t was evnporated, a brown l i q u i d (477.7
mg) was obta ined . Aqueous hydroch lo r i c a c i d (6N) vizs zdded
t o t h e aqueous l a y e r u n t i l t h e s o l u t i o n was n e u t r z l . The
n e u t r a l s o l u t i o n was e x t r a c t e d w i t h ne thylene c h l o r i d e . The
ethylene c h l o r i d e e x t r a c t gave a brown l i q u i d (117 me) upon
e v a p ~ ~ a t i o x . The i .r . of t h e l i q u i d from t h e e t h e r and t h e
methylene c h l o r i d e e x t r z c t s were super inposable .
i . : 3350(m), l724(w), 1 6 3 0 ( s ) , ; 9 8 ( ~ )
2 4
Attempts t o p r z p r e 2-phenylpyrrol idine from t h e brown l i q u i d
were unsuccessfu l .
I n a s e p a r a b p h o t o l y s i s , 4-phenyl-n-butyl-2;-ni I roso- ace tax ide (5.03 g) i n petroleum e t h e r (100 m l ) was i r r a d i z t e d
w i t h a 100 wa t t Hanovia lamp a t 6-10•‹C i n a n i t r o g e n atmosphere
f o r 31 hours . The photo lyza te sepa ra ted i n t o two o rgan ic
phzses. :Then t h e so lven t was ~emoved f r o n t h e s u p e r n a t z n t
l i q u i d , a ye l low l i q u i d (1.42 c) was obta ined which was c h a r a c t e r i z e d a s 4-phenylbuty laceJ~ate ,
i : 292O(s), l 7 0 5 ( s ) , 1 6 3 0 ( n ) , 1604(w), 1 2 6 2 ( ~ ) ,
l 2 4 4 ( $ ) , 1 1 6 0 ( ~ ) , 695(s) .
n.m.r.: 8.38(qu, J=3.8 c o p . , 415); 6 .34( t , J=7.5 c.?.s.
2H); 2 .77(s , 5 H ) .
itYhen t h e s o l v e n t was renoved Irom t h e lower l a y e r , 2 t h i c k
brotm l i q u i d A (3.98 g ) was obtained.. About 1 / 4 of t h e brown
l i q u i d was separa ted by column chromatography and ca. 1 / 2 mas
hydrolyzed. The chromatography of t h e l i q u i d A wzs performed on
n e u t r a l alumina (Brockman A c t i v i t y 1).
( i ) d l u t i o n wi th chloroform-benzene (1:9 ) gave t h e pa ren t
amide (316.9 me;) a s i n d i c a t e d by i t s i.r. spectrum which
was superimposable wi th t h a t of the a u t h e n t i c saxple .
(ii) S l u t i o n wi th e thano l -ch lo ro fom (1:50) gave t h e
corresponding oxime (334.6 mg) which was r e c r j i s t a l l i z e d from
95;; ethai iol and petroleum e t h e r t o g ive white c r y s t a l s , m.?.
112-113•‹C,
i . : 3360(m), 3240(n) , 1 6 1 8 ( s ) , 1 5 7 2 ( s ) , 7 5 8 h ) , 590(m).
25
n .n . r . : 8.25(qu, J=6 .5 c.P.s. , 28) ; 8.04(=1, 3 3 ) ;
7 . l ( t , J=7 c .p.s . , 2H); 6.72(q, ~ = 6 . 5 c .p . s . ,
2 ~ ) ; 2.28-2.45(m, 215); 2.55-2.53(m, 3i:).
Analys is ca lcd . f o r C12H1602N2: C,65.42; Ii,7.32; X,12.72.
Zound: C,65.45; :i,7.35; X,12.92.
Liquid A (1.02 g) was sub jec ted t o h y d r o l y s i s f o r 2 4
hours by r e f luxing i c ne t h a n o l i c hydroch lo r i c a c i d s o l u t i o n
(16.35 m l of concent ra ted hydroch lo r i c a c i d i n k 100 n l ne thano l ) .
The hydrolyza te was evaporated t o ca. 30 m l which was
n e u t r a l i z e d wi th 105; potassium carbonate s o l u t i o n . The n e u t r a l
s o l u t i o n was e x t r a c t e d wi th e t h e r . The e t h e r e x t r z c t was
washed w i t h a smal l amount of wa te r and then d r i e d wi th mag-
nesium s u l f a t e . The e t h e r a l e x t r a c t was f i l t e r e d and a f t e r
evapora t ion of t h e e t h e r a b r o m l i q u i d was obta ined (676 m g ) .
3be aqueous l a y e r was e x t r a c t e d wi th methylene c h l o r i d e .
dvapora t ion of t h e methylene c h l o r i d e e x t r a c t gave a yellovl
l i q u i d (155.4 rag) which was chronatogrzphed on n e u t r a l alursina.
(i) B l u t i o n wi th benzene gave a c l e a r yel low l i q u i d (100
mg) vhich was t e n t a t i v e l y ass igned s t r u c t u r e XXIil on t h e
b a s i s of i t s i .r . and n.m.r. s p e c t r a .
i : 3 5 0 0 ( ~ ) , l 6 l 8 ( s ) , l M O ( s ) , ' / b ~ i s ) , 6 3 0 ( ~ ) . n.m.r. : 2.2-2,7(m, 5H); 5 . 9 ( t , 2H, J=7.5 C.P.S. );
7 . 1 2 ( t , 2X, J=9 c .P.s . ) ; 7.97(q, 2K, J=7 c . p . s . ) *
Th i s f r a c t i o n was d i s so lved i n 20 m l of t e t r ahydrofu ran .
Platinum oxide (7.2 mg) was added t o t h e s o l u t i o n . The s o l u t i o n
was then hydrogenated a t room temperature under a pressure of
60 l b s . p . s . i . f o r 2 hours . The s o l u t i o n was f i l t e r e d . Lvaporat-
i o n of t h e s o l v e n t from t h e f i l t r a t e gave a brown l i q u i d
r e s i d u e which was chroiaatographed on s i l i c i c a c i d t o give
5 sinall f r a c t i o n s . Jach f r a c t i o n was t r e a t e d wi th p i c c i c a c i d
but no p i c r a t e d e r i v a t i v e of compoundXXV11 w a s , i s o l a t e d .
( i i ) E l u t i o n wi th chloroform cave l i g h t yel low c r y a t a l s
(332 mg) which were r e c r y s t a l l i z e d from benzene-cyclohexane t o
n.m.r.: 2.15-2.9(m); 6.59(q, J=7.0 c .p . s . ) ;
6 . 9 4 ( t , J=7.0 c .p . s . ) ; 8 . 0 ( m )
Analys is ca lcd . f o r C12H15N02: C,70.22; H,7.37; N,6.82*
Pound: C,69,61; E,7.19; n,7.53.
The brown l i q u i d A (1.21 g) was hydrolyzed a second t i n e
i n 250 m l of 1 3 hydroch lo r i c a c i d methanol ic s o l u t i o n f o r
38 hours wi th r e f l u x i n g . The s o l v e n t was removed wi th a
r o t a r y evapora to r u n t i l t h e volume was rednced t o about 40
m l . The hydrolyza te was made b a s i c (pi-; 9.5) and e x t r a c t e d
wi th e t h e r t o give a yellow l i q u i d (408 mg). The y e l l o a l i q u i d
was t r e s t e d wi th l i t h i u m aluminum hydride (5.2 g ) i n r e f l u x -
iilg t e t r ahydrofu rzn (80 m l ) f o r 43 hours . a t h y l a c e t a t e (ca .
40 m l ) was added t o decompose t h e unreac ted l i t h i u m aluxinum
hydr ide . About 30 m l of 61: H SO was added t o the s o l u t i o n 2 4
i n an i c e ba th . Addit ion of concent ra ted s u l f u r i c ac id t o
t h e s o l u t i o n caused t h e f o r x a t i o n of z p r e c i p i t a t e . The
27
s o l u t i o r ; was f i l t e r e d and sodiu;i: hydroxide s o l u t i o n (165)
was added t o t h e f i l t r a t e u n t i l t he pIi was about 13. 'The
s o l u t i o n was t h e n e x t r a c t e d wi th methylene c h l o r i d e . ;'hen the
nethyleiie c h l o r i d e e x t r a c t was evapora ted , a brcnn l i q u i d
(195 ng) was obta ined . Th i s brown l i q u i d mas t r e a t e d wi th
f - t o l u e n e s u l f o n y l c h l o r i d e (205 mg) wi th v igorous shaking
i n the presence of sodium hydroxide s o l u t i o n (10:;) :vhich r:as
added t o t h e r e a c t i o n mixture u n t i l t h e pH was 10. ,This
s o l u t i o n was l e f t a t room temperature o v e r n i g h t , a f t e r dh ich
t ime t h e r e a c t i o n mixture was e x t r a c t e d wi th e t h e r . L v a ~ o r a t -
i o n of t h e e t h e r e x t r a c t gave a brown l i q u i d (357 rig).
Chroxatography of t h e brown l i q u i d on n e u t r a l alumina wi th
benzene gave a yel low l i q u i d which was f u r t h e r c h r o ~ a t o g r a p h e d
on s i l i c i c a c i d wi th chloroform t o give t h e p-toluenesulfon-
amide of 2-pnenyl-pyrrolidine. F i n a l p u r i f i c a t i o n was e f f e c t e d
by subl imat ion (120•‹/0.2 rim) t o g ive ga le yel low c r y s t a l s
follov~lea by r e c r y s t a l l i z a t i o n from methanol and p e t r o l e m
e t h e r t o g ive n e e d l e s , m.p. 103-105•‹C.
i : 173O(s) , 1 6 0 0 ( s ) , 1343(s ) , 1 1 5 4 ( ~ ) .
3 iq-aitroso-N-n-hexylf or;naixi.de . The B-nitrosofomamide (5.99 g) i n n-pentane (100 n l ) was
photolyaed under ni- t rogen f o r 10 days i n s u n l i g h t . Phe
photo lyza te sepa ra ted i n t o two l a y e r s . A brown l i q u i d (4 .6 g )
was obta ined a f t e r t h e ~ o l v e n t was removed f r o $ the
t h e superna tan t s o l v e n t J.ayer. The l i g h t y e l l o n l i (ju' r : p v c
an i.r. sbso2p t ion peak a t 1775 cn-l i n d i c a t i n g t h e presencc
of n-hesylforinz-be. The brown l i q u i d from t h e lower l a y e r
(1.39 g ) ?;!as chronatosraphed on alumina,
( i ) ~ l u t i o n w i t h chloroform: benzene ( 1 : l ) save t h e
pa ren t Torlilamide (405 mg); t h e i.r. and i l ,m.y . s p e c t r a of
which were superimposable wi th those of ail au t i i en t i c senp le
of n-hexylf orril&ide.
( i i ) B l u t i o n w i t h ethanol:chloroL'orrn (1:20) gave 4-
oxi:nino-11-hexylf ormarriid e (727 me) .
58(lOO:j).
Ana lys i s c a l c d . f o r C7EIl4X2O2: C,53.15; 9,S.92; Ry17.70. --
Y O U ~ ~ : ~ $ 5 3 . 3 7 ; ~ , 8 . 8 2 ; ~ ~ 6 . 3 3 . -- i \ - ~ ~ i t r o s o - i ? - b e n Z ~ l ~ ~ e t 8 ~ i d e . 4. - The 9-ni t rosamide (2.02 g ) i n cyclohexane (500 nl) nas
2hotolyzed under n i t r o g e n i:? s u n l i g h t f o r 17 d~ys. ?he s o l v e n t
nes renoved f r o 9 t h e photo lyzz te t o g ive a 'orem l i q u i d (2 .22 -
g), a p o r t i o n of which (1.14 g ) miis chromatog-cghed on 9 e c t r z l
a l u m i n a .
( i ) B l u t i o n w i t h chlorof orxi: benzene (1: 3 ) gai-e t h e p a ~ e n t
29
a:iide (734 g , 76.91;) which was i d e n t i f i e d by i t s i.r. and
11.m.r . s p e c t r z .
( i i ) S l u t i o n wiLh e thanol :chloroform ( l : g ) gave white
c r y s t a l s of 1 , l -d iace tanidoto l -uene (05 m g ) , m. p. 238.5-240•‹C. 1a.s.: n/e 147(9.70,;), 132(7.44,*3), 104(16.015),
77(18.12~3), 59 (16.015), 43(100,'7).
3 e n z y l a c e t a t e was n o t i s o l a t e d n o r was i t d e t e c t e d i n
t h e i.~. spect ru i i of the crude photo lyza te , - 3 . 1;-nitroso-X-ohenethyl~icetamide .
The B-nitroszni.de (5.05 g) was photolyzed i n cyclohexane
(200 n l ) i n s u a l i g h t Tor 7 days. The photo lyza te sepa ra ted
i n t o two l a y e r s . The s o l v e n t was removed from t h e e n t i r e
photo lyza te t o give a brown l i q u i d (3.82 g ) of which 2.00 g
was chroma t ographed on n e u t r a l alumina.
( i ) E l u t i o n viith benzene and benzene :chloroform (1:3)
gave t h e pa ren t amide (1.544 g, 77 i) whose i.r. and n.m.r.
s p e c t r a were super inposable wi th those of an a u t h e n t i c sanple
of phenethylacetzmide.
(ii) Zlu t io i l . w i th chloroforra gave 1, 1-diacetazido.-2-
phenylethane (45 mg, 2.5$), m.p. 213-217 C.
i r e 3300(rn), 1650(m) --
Analysis ca lcd . f o r C12H16b~202: C,65.43; H,7.32; ~ , 1 2 . 7 2
Found: C,63.94; B,7.33; s ,11.44.
-- 6a. 14-nitroso-17-nethylca7~oanide i n n-pentane ,
The 2:-nitrosarnide (4.95 g ) i n n-pentane (300 ml) was
photolyzed i n s u ~ l i g h t f o r 11 days i n a n i t r o g e n atnosghere.
30
When t h e solvei2t was reuuved from t h e pho to lyza te , a brown
l i q u i d (4.709 g ) w s obtained of which 1.15 g wss chroxato-
graphed on s i l i c i c a c i d . d l u t i o n wi th c h l o r o f o m gave a c l e a r
g e l l o v l i q u i d (540 ng, 46.8 ;). The i.r. and n.1a.r. s p e c t r a of
t h i s yel low l i q u i d were i d e n t i c a l w i t h those of cn a u t h e n t i c
s s z p l e of il-::.e thylcaproamide . The presence of ,x thy lcaproa te nas i n 2 i c a t e d by t h e 1-ieak a b o r p t i o n pesks a t 1720 and 1210
cm-I i n t h e i.r. spectrum of t h e crude product . The brovm
l i q u i d (2.02 g) from t h e photo lyza te was chroxatoeraphed on
n e u t r a l a l u ~ i n a and t h e f ol lovri . ;~ r e s u l t s were obta ined .
( i ) B lu t ion wi th chloroform: benzene ( 1 : 3) gave a c l z a r
yel low l iq-did (902 ng, 54.7 ;) whose i.r. and n.n.r . s p e c t r a
were i d e n t i c a l w i t h those of en a u t h e n t i c s a a p l e of >I- ethyl-
caproaxi.de . ( i i ) S l u t i o n wi th chloror^orm:benzene (1:l) gave c c y s t a l s
(86 ng) which were r e c r y s t a l l i z e d from acetone-n-pentane
mixture t o g ive white c ~ y s t a l s , m o p . 175-177 OC.
i.r. : 3 3 2 0 ( s ) , 1635 ( s ) , 1553(m), 1 5 3 7 ( d , 1418(d, 1380(n) , 1134(m).
The amount of pure white c r y s t a l s was t o o smal l f o r iden t -
i c a t i o n .
( i i i ) 2 l u t i o n wi th e thano1:chloroforr~ ( 9 , 1 :3 , 1:l)
and 956 e t h a n o l gave a mixture of s t i c k y yel low c c y s t a l s
(307 :i&) which were r e f luxed wi th Zit hydroch lo r i c a c i d
f o r 2 hours. The hydrolyza te was s t e a n d i s t i l l e d . The r e s i d u e
was e x t r a c t e d with metnyiene ci i lor ida con t i luouc ly i o r
;vi th c t h c r , nh ich nken removed ,-,-eve a yc l low l i q t ~ i d ( l l C 1~1::) . .- 7 Lile l i q u i d 3 ob-Lrined fror.1 t h e e t h e r 2nd rnethylene c::loriCe
c x t r z c t were c?irol i r z t o ~ r ~ n ~ e d on c s i l i c i c c- c i d c o l u ~ r , . i;o?.i-
evey, t h e f r c - c t i o n s col l -cc tcd were p e e n rnd ap~e:lrcc: t o 11; ve
c; ~r i~,-ed.
61,. :T-ni t ro 30 -~~-~1e th : r l c :~ i~ r0~1 :1 idc in cgclolie;;r.nc~
A s e p a r ~ t e p h o t o l y s i s experiment ivz 3 run w i t h t h e I:-nitro-
c;ariide (4 .8 8 ) i n cjrclohexane and under n i t r o ~ e i n at :?os?here
a i t h a 300 ws,tt t u n g s t e n l a n p f o r 31 days. The sol-rent -:E-,
removed from t h e p h o t o l y z a t e ' t o g i v e 2 b r o m l i q u i d (5.76 g)
of vrhicii 4.56 g nccs hydrolyzed x: t h 2S I lydrochloric c c i d f o r k
3 hours on a s t c a n b a t h , 17he h y d r o l y z ~ t e 7i183 e x t r ~ c t e d con-
t i n u o u s l y ~ 5 t h c h l o r o f o r x f o r 24 hours . &- hrowr! l i q ~ - i d (3.1G g)
w a o b t s i n e d upon cvaporz t ion of t h e c h l o r o f o r n e x t r z c t .
Chromatoyxiphy of t h e brown l i q u i d (3.06 g olotc?.ined f r o n
h y d r o l y s i s ) on s i l i c i c a c i d gcve, w i t h c b l o r o f o m , r ; ~ e l l o v ~
l i q u i d (1.01 g, 32;z). #The i , r . ~ i ~ d n,m.r. s ~ e c t r a of t h i s
yell-om l i q u j d were super ixposzb le w i t h t h o s e of' r n c?ut;lentic
sample of IT-methylca proamide,
6c. T\;T-ni-l;roso-1'J-methylc,-,nror1~ide i n n e t r + o l earn e :;her.
A tl-lird p h o t o l y s i s of t h i s 2-nitrosay1i.de (5.38 g) i n
petroleum e t h e r (30 z i l ) f o r 03 days undeY n i :ro -e? nt-,!osphcl:.e
i n sun l i g h t , P e t r o l e u n e t h e r (100 ml) nc.3 r66es:. t o t ' : c
s o l u t i o n d u r i n ~ tl?c pho-tolysis t o :nri_ultain t::e s?mc
32
concen t ra t ion . The so lven t was removed from t h e photo lyza te
t o g ive a brown l i q u i d (5.65 g) . ',"'hen t h e byonn l iqu id . was
t r e z t e d wi th 2 r a d y ' s r e a g e n t , gw-ny yel low s o l i d s were
obta ined which decomposed dur ing r e c r y s t z l l i z a t i o n f r o 3
ethanol-wzte:-. The brown l i q u i d (1.47 g ) was chromatographed
on n e u t r a l alumina.
(i) E l u t i o n with ch1oroform:benzene (1:g) gave 2 yellow
l i q u i d (356.4 ng) which was f u r t h e r chromatographed on
s i l i c i c a c i d t o g ive , w i t h 505 chloroform i n benzene, 1;-nethyl-
caproamide (224.2 mg, 19.2:;).
(ii) 2 l u t i o n wi th ch1orofora:benzene ( 1 : l ) gave czproamide
(99.5 mg, 9.11%) which was mblimed (72"/0.2 mm) t o g ive s h i t e
n e e d l e s , m.p. 91-94OC, mixed m.p. w i th an a u t h e n t i c sanple
of caproamide (mop. 96-97•‹C) 95-96•‹C. The i.r. and n.m.r.
s p e c t r z of t h e s e need les were a l s o i d e n t i c a l wi th those o f an
a u t h e n t i c sanp le . * -- 7s. a-nitroso-I
33
a warm sc71ution o< 30 x1 e thanol 2nd 5 m l chloroTorm. i i f t e r
t h i s s o l u t i o n was in t roduced t o t h e n e i ~ t r a l a luxina ( z c t i v i t y
3 ) colurm, white s o l i d s soon formed i i l t h e sea sand a s beczene
was in t roduced a s t h e e l u e n t . d thano l (10 ml) nes a.;ded i n an
a t t e x p t t o d i s s o l v e t h e caked s o l i d s , but they d id not d i s s o l v e
completely. A c r y s t a l l i n e compound (396 mg, 38:;) wac e l u t e d
wi th benzene. It was r e c r y s t a l l i z e d Prom a c e t o n e - p e t r o l e m
e t h e r and i d e n t i f i e d a s compo~md XXXI, m.p. 134-137OC.
i : 3360(s ) , 3250(w), 1 6 2 4 ( s ) , 1595(w), 766(s)
n.m.r.: (ace tone) -0.6(broad); 1 . 3 3 ( s ) ; 2.0-2.6(m);
7 .02(s ) ; 7 . l ( d , J=5 c.p.s.)
Analysis ca lcd . f o r C9H10N202: C,60.66; H,5.66; X,15.72
Zound: C,60.55; H,5.54; N,15.73.
The recovery of products from t h e aluinina chromatography was
46.8,;.
3enzene (100 ml) was added t o t h e s t i c k y s o l i d s (910 ng)
sild warmed t o g ive a v i scous ye$low lower l a y e r (711 ng) and
a superna tan t benzene l a y e r . b7hen 50;; chlorofomn-ethanol (10 ml)
s o l u t i o n was added t o t h e lower l a y e r , a milky s o l u t i o n was
obta ined which was centrif 'uged t o g ive a white powdery
p r e c i 2 i t a t e (130 ng) . This p r e c i p i t a t e was r e c r y s t a l l i z e d Sron e t h a n o l t o give needles (63 mg). The n e e d l e s turned so f5 snd
no m.p. was taken. The c e n t r i f u g a t e decomposed t o dark l i q u i d
when i t was eva2orated. The i .r. s p e c t r m i n d i c a t e d t h a t t h e
s o f t c r y s t a l s contained a n i t r i l e group.
i . : 325O(tv), 2500(w), 2 2 2 0 ( ~ ) , 1 6 4 8 ( s ) , 7 5 4 ( s ) .
3 4- -- A s::cond eAiperii;Lent on the ? h n t o l y s i s of t h e L - L ~ ~ T O S O -
- - ,i-;;,e t:;yltolua;.,icle ( 5 . 4 2 C) i n pc t r o l e u n e t h e r ($00 nl) w2s
perToraeci u d e r n i l r o p n etmosphere w i t h a 100 wz:t General
d l e c t T i c PA2 38 s p o t la~1.3 Tor $7 hourc. ?he nhoto lyza te gave
3 stic:iy yellow s o l i d ( j .09 g). (This s o l i d (1.02 g ) as
hydrolyzed :or 39 hours i n n e t h a n o l i c hydroch lo r i c a c i d
s o l u t i o n (16.35 m l of concen - r z t e d hydroch lo r i c ac id i n 1CO - . I , n l of , .;ethanol). .,nen the s o l v e n t was removed from t h e
hydroiyza te t o reduce t h e volurie t o about 20 m l , needles
zppzeTed i n t h e s o l u t i o n . The s o l u t i o n was f i l t e r e d . 'he
a e e d l e s gave a i . spectrum v!hicil was superimgoszble w i t h
t h a t of p h t h a l i a i d e prepared according t o Herzog's methos
( 1 6 ) . The need les were r e c r y s t a l l i z e d fro:^ ethanol- 'uater
s o l v e n t , n.p. 197-19g•‹C.
i . : 3270(n), 1775(n) , 1610(m), 716(s) .
Analys is ca lcd . f o r C8H5MC2: C,65.42; 3,3.42. . Zound: C,64.78; Ii,3.61.
The a c i d i c f i l t r a t e (ca. 4/5) was e x t r a c t e d cont inuously
f o r 24 hours wi th methylene c h l o r i d e . :','hen t h e so lven t was
removed from t h e methylene c h l o r i d e e x t r a c t , a yel low l i q u i d
(705 3 g ) was obtained. Xo product was obta ined from t h e
chroaztography of t h e yellow l i q u i d .
.'he re; lz ining l / j of t h e ~ c i d i c f i l t r a t e was n e u t r c l i z e d
r:ith 10,; aqueous sodiun czrboilate and then e x t r a c t e d wi th - - e t h e r . .iothing was obtained a f t e l t h e removal of e t h e r from
t h e e t h e r e x t r a c t .
A p a r t of t h e s t i c k y crude product (364 mg) nas a d i e d t o
35
1 5 n l of e thano l and d i s so lved upon warming. Addit ion of a
c a l c u l a t e d amount of drady 's reagent gave 299 me of 2,4-
dini t rophenylhydri?zone L A X 1 1 which was r e c r y s t a l l i z e d from
e t h y i a c e t a t e , i2.p. 280-250.5•‹C.
i.r.: 3400(w), 1800(m), 1 7 4 6 ( s ) , 1 6 2 4 ( s ) , 1600(m),
l55O(w), 385(s), 8 3 5 ( s ) , 738(m), 700(s ) .
n.m.r.: (dimethyl s u l f o x i d e , see f i g 1)
-0.3 ' ( s , 1 E ) ; 1 .03(d , 1H); 1 . 9 8 ( ~ , 4H);
1.7-2 .42(~ ,U system, 211).
Analys is ca lcd . f o r C281!18i;8G11: C,52.34; H,2.84; 5,17.44.
Found: C,52.04; Ii,2.75; 1:,16.77.
7b. i;-aitroso-iu'-raethyltoluamide i n benzene.
I n a t h i r d experiment, t h e p h o t o l y s i s of 1;-nitrosanide
(5.43 g ) s a s performed i n benzene (400 m l ) w i th a 100 wa i t
General G l e c t r i c PAR 38 spot lamp under n i t r o g e n atnosphere.
The pho to lyzs te consis-Led of a brown p r e c i p i t a t e and a yel low
s u p e r n a t a n t l i q u i d . The s o l u t i o n iias f i l t e r e d t o give brown
c r y s t a l s A (2.91 g ) . A brown l i q u i d B (2.61 g ) was obta ined
from t h e f i l t r a t e a f t e r the renoval of t h e so lven t . A p a r t
of l i q u i d B (1.93 g ) was chromatographed on n e u t r a l e l m i n a
t o g ive t h e f o l l o v ~ i n g f r a c t i o n s .
( i ) The second benzene f r a c t i o n (400 ml) gave K-nethyl-
toluzmide (373.7 n i g , 3 1 . ~ ~ ~ )
( i i ) The f i r s t benzene f r n c t i o n (500 ml) gave a t h i c k
l i q u i d (235.5 mg) ~ h i c h was f u r t h e r chromatographed on
s i l i c i c a c i d t o g ive the fol lovl ing f r a c t i o n s .
a . E l u t i o n wi th chloroform i n i t i a l l y gave methyl 0- to lua te
36
(40.8 ixg, 0.12 ;).
i . . : 1 7 2 0 ( s ) , 1600(w), 1030(m), 734(m).
n.n.r . : 7 . 4 2 ( s ) ; 6 . 1 6 ( s ) ; 2.1-2.8(m).
b . F u r t h e r e l u t i o n wi th chloroform gave white need les
W:llch were p u r i f i e d by subl imat ion a t 5g0/0.2 rm, m.p. 57-61'~.
The i , r . and n.m.r. s p e c t r a of t h e s e i n d i c a t e d t h a t t h e needles
could be phtha l ide .
i.r. 1 7 4 0 ( s ) , 1620(w), 1 6 0 0 ( ~ ) , 1 0 5 0 ( s ) , 1 0 0 0 ( s ) , 739(s) .
n .n .r . : 4.68(s, 23 ) ; 2.0-2.G(m, 4-52); smal l impur i ty
a t 6 ( s ) and 6 . 8 3 ( s ) .
(iii) Continued e l u t i o n wi th chloroform gave f i n z l l y t h e
pa ren t arlide (35.6 m g , 1.08%).
The c r y s t a l s "AY(1.02 g ) from t h e yhoto lyza te were
r e c r y s t a l l i z e d from acetone and petroleum e t h e r t o g ive
n e e a l e s (390.2 ~ g , 20.435), mop. 132-135'C. The i , r . and n.m.r.
s p e c t r a of t h e s e needles were superiniposable wi th those of
t h e oxime :(XCI. The f i l t r a t e from t h e acetone-petroleum e t h e r
r e c r y s t a l l i z a t i o n were evaporated t o give a yellow l i q u i d (600
m g ) which was civozatographed on s i l i c i c a c i d t o g ive t k e
fo l lowing f r z c t i o n s .
( i ) Z l u t i o n with chloroform i n i t i a l l y gave EW as a
vfhite c - q s t a l l i n e compound (22.5 ng, 1.4.;) which was p u r i f i e d - by sub l ima t ion st 40•‹/0.2 m.p. 129-131 '~ ( l i t . 132-133'~)
(19)
i.r.: 1756(w), 1 7 2 0 ( s ) , l G l o ( ~ ) , 7 1 4 ( ~ )
n.s . : m/e 161(100r~) , 132(11%),104(52.2$$), 76(50.1$).
37
( i i ) Continued e l u t i o n wi$h cliloroform gave st ran-coloured
need les (153.6 rng, 9.25';) ::hich were recrys ' ia l l ized from
e t h a n o l azd vt2te-r t o g ive white n e e d l e s , u .p . 218-221•‹C.
The i . r . s p e c J ~ r m of these need les was superimposzble wi th
(iii) Llu t ion wi th e thano l i n chioroform (2',:) gave
c r y s t a l s of I X j C I I I nild ZUI7 (150 mg) , m.p. 202-205'. 'TLe c r y s t a l s appeared t o be ~ r o n z t i c n i t r i l e s a s i n d i c z t e d by t h e
i . r . ebsorp t ion peaks a t 2240 and 1959 crn-l. Xowever, f u r t h e r
r e ~ ~ y s t e l l i z a t i o n from e thano l gave a s i n g l e c r y s t a l l i n e
comgound (2.5 mg) w i t h no absorp t ion a t 2240 cn-l . The a o t h e r
l i q u o r was t h e r e f o r e chronatographed on s i l i c i c a c i d but no
n i t r i l e compound was obta ined . I n s t e z d , t h i s chromatography
wi th chloroform gave c r y s t a l s (55.4 mg) whose i.r. s p e c t m
nas i d e n t i c z l wi th t h a t of XYJVI .
The brown l i q u i d 3 (1.93 g) was chromatographed on
n e u t r a l almnina wi th benzene t o give a t h i c k l i q u i d (238 mg)
which was f u r t h e r chromztographed on s i l i c i c a c i d wi th
chloroform t o g ive a l i g h t ye l low c ~ y s t s l l i n e compound (64.4
ng, 2.25:). This conpowd vias sublimed a t 7g0/0.2 m t o g ive
white c r y s t a l s XXX , m.p. 57-61•‹C, whose i.r. spectrum mas super inposable wi th t h a t of an a u t h e n t i c sample of ph tha l ide .
i.r.: 1 7 5 0 ( s ) , 1 6 1 6 ( ~ ) , 1282(n) , 1206jrn), 730(s) .
n . m . r . : 2.04-2.45(m, 4-5H); 4.69(s, 2 3 ) .
The c r y s t a l s "8" (1.18 g) d i s s o l v e d i n 20 m l e t i ~ a n o l -
t h e hydrolgza ie mas renoved, white need les were obta ined . The
i.r. spectrum of t h e s e need les was superimposable wi th t h a t
of compound XXXI.
Comgomd .CZI (150 mg) was d i s so lved i n 10 m l of 955
e thano l . Xitrogen was bubble6 through t h e s o l u t i o n f o r 15
minutes and then i t was photolyzed wi th a 100 watt General
i l e c t r i c PA2 38 s p o t lamp f o r 24 hours i n running water ba th
a t 1 2 O C . Yt'hite need les were obta ined a f t e r t h e removal of
s o l v e n t lrom t h e photo lyza te . The white need les appeared t o
be z n i x t u r e of compound XXXI and n i - l r i l e s .
i . : 334O(s), 32OO(s), Z23O(w), 1640(s) .
8. Control Experiments.
Cont ro l experiments weze performed i n t h e dark under t h e
sane r e a c t i o n cond i t ions f o r each H-nitrosamide. The uv s p e c t r a
viere t aken a t i n t e r v a l s dur ing t h e experiment per iods . There
nas l i t t l e ( l e s s tiisn 5 ; ) o r no change i n t h e uv absorbance
of t h e n i t r o s o peaks tnrouzhout t h e e n t i r e per iod of t h e I I c o n t r o l experiment.
39 . iil WSULTS.
l h o t o l y s e s I n Acidic, 1,:edi.s.
The 27-nit roso-N-zlkylace t z n i d e s and f ormamides were pre-
payad according t o ' ,!hiteta method (17) . The amide was n i t r o s a t e d
wi th n i t r o u s a c i d . The yellow B-nitrosamide t h u s obta ined was
used wi thout p u r i f i c a t i o n except i n t h e p repara t ion of Z-
nitroso-W-n-butylacetamide which was d i s t i l l e d a t room teaper -
a t u r e under vacuum.
The p h o t o l y s i s temperature was c o n t r o l l e d r i g i d l y a t
10-20bC i n o r d e r t o ninimize t h e thermal decomposition of
t h e N-nitrosamide. Desgi te t h i s c a r e f u l c o n t r o l , a smal l
amount of e s t e r , t h e product of t h e m o l y s i s , was observed i n
a few e x p e r i ~ e n t s a s i n d i c a t e d by the weak absorp t ion 2eak
a t ca . 1730 cm-l i n t h e crude product of p h o t o l y s i s . The
r a t e of pho to lys i s ranged from 0.005 mole 2 e r l i t e r pe r
hour t o 0.077 mole pe r l i t e r p e r hour , depending oil t h e type
of lamp used. Sowever, when comparable lamp and so lven t were --
used, t h e time requ i red f o r t h e p h o t o l y s i s of t h e A-niCroso-
S-Senzylace t 2mide was much longer than t h a t f o r t h e X-nitroso-
1;-phenetjlylacetarnide. The x a j o r ;products of p h o t o l y s i s kvere
t h e parent amides and t h e h y d r o l y s i s products which could be
de r ived from alkyl ideni inides . 'Ihe 2,4-dinitrophenylhydrazones of t h e aldehydes which forned upon h y d r o l y s i s of t h e l a t t e r
a e r e prepared f o r i d e n t i f i c a t i o n .
The y i e l d of t h e 2,4-dinitrophenylhydrazones of t h e aldehydes
2nd :he parent amides va r i ed over a wide range. The y i e l d
40
of t h e r e s p e c t i v e 2,4-dinitro~henylhydr2~011es der ived Proin
-- t h e photo lyza tes of the N-nitroso-ii-3-butylace bazide, . , -nitroso-
R-a-hexylace t a.rni.de and :T-nitro so-1;-n-butylfo-nnarnide ranzed
from f c i r (35:;) t o poor (3:;) ( s e e Table 11). 'i 'hile t h e - - photolyza tes of t h e IT-i~it~oso-Ti-phcnethyl and :he , : -ni t roso-
K-cyclohexyl-acetaaiides did n o t y i e l d any corresponding
2,4-dinitr~phenylhyd~azo~ie a t a l l , t h e photo lyza te of t h e
K-nitroso-X-benzylacetaanide i n both s o l v e n t s A and 3 gave .
e x c e l l e n t y i e l d s of t h e 2,4-dinitrophenylhydrazone of benzalde-
hyde (775 and 38;s r e s p e c t i v e l y ) . Repeated chrornatoeraphy
of t h e crude p roduc t s f r o n t h e p h o t o l y s i s of 1i-nitroso-N-
benzylacetamide i n s o l v e n t 3 gave a c r y s t a l l i n e compound
which was i d e n t i f i e d t o be 1 , l -d iace tan ido to luene X V I I .
Chart V I I . Pho to lgs i s of N-nitroso-IT-benzyl~cetamide.
0
Despite c a r e f u l a t t empts t o p u r i f y compound 3311 by
r e c r y s t a l l i z a t i o n , only reasonable a n a l y t i c a l r e s u l t s were
obta ined . Th i s i s apparen t ly due t o decomposition dur ing
r e c c y s t a l l i z a t i o n . The mass spectrum of compound XVII
suggested t h e l i k e l i h o o d of a f a c i l e thermal decomposition
a s t h e molecular i o n peak of comyound X V I I was absent i n t h e
spectrum. The h ighes t mass peak was m/e 147, equ iva len t t o
::-acetyl benzyl idenin ine . ; ; eve r the less , tLe i.r. and n.m.r.
s p e c t r a of compound X V I I c h a r a c t e r i z e d t h e s t r u c t u r a l
41
assig:.~r.lent. 'Tlie i.r. absorp t ion peaks a t 700, 750, 1660 2nd
3270 c::;-l i n d i c a t e d the preseiice of nono-subs t i tu ted benzene
r i n g and an amide group. I n the n.m.r., s p e c t r w , t h e s i ~ n a l s
a t ~ 2 . 5 6 , t 6 . 2 and t8.03 i i l t h e r a t i c of 5: ca.1 : 6H were
ass igned r e s p e c t i v e l y t o be aromat ic pro tons , methine and
methyl pro tons .
Photolysea i n Neut ra l Mediz.
The p repara t ion oP 19-nitroso-13-4-phenyl-n-butylacetamide,
i n s p i t e of c a r e f u l work-up, gave a mixture c o n s i s t i n g of
t h e m a l decomposition product , t h e 4-phenyl-n-butylacetate,
a s i n d i c a t e d by the i.r. and n.m.r. s p e c t r a . Separa t ion of
t h e N-nitroso-IT-4-phenyl-n-butylacetemide from t h e e s t e r by
vacuum d i s t i l l a t i o n a t room temperature was n o t p o s s i b l e ,
because of t h e thermal i n s t a b i l i t y of t h e if-nitrosoacetamide.
This mixture was then used a s t h e s t a r t i n g m a t e r i a l i n t h e
pho to lys i s . i
The pho to lys i s was performed i n a n i t r o g e n atmosphere
u s i n g a lamp o r d i f f u s e d s u n l i g h t a s t h e l i g h t source. The
temperature was c o n t r o l l e d i n t h e range of 10-20•‹C. The
c h a r a c t e r i s t i c yellow co lour of t h e N-nitrosamide s o l u t i o n
faded a s t h e pho to lys i s proceded. t h e pho to lys i s was
completed, t h e photolyzate sepa ra ted i n t o a c l e a r , c o l o u r l e s s
superna tan t and an o i l y o r c r y s t a l l i n e lower l z y e r . The
major products of the pho to lys i s were t h e parent an ides and
t 5 e rear ranged products a s shown i n Table 111. The major
rearrangement product was the 5-oximinoanide. The y i e l d s of
parent amides and t h e S-oxininoamides v a r i e d , depending
very nuch on t h e n a t u r e of the allcyl and a c y l groups a t t ached
t o t h e anide n i t r o g e n (-3 an6 - R t groups i n compound I ) .
Thus, whi le t h e y i e l d s of t h e b-oximinoanides from the - - pLotolysec ,of the J,-nitroso-X-4-phenyl-n-butylacet a ..ide ,
M-nitroso-N-toluylacetanide and N-nitroso-11-n-hexylforaamide
v a r i e d from 50-30~ ; , t he photo lyses of 7;:-nitroso-Z-benzyl-
ac2tamide and B-nitroso-N-phenethylacetamide gave no 6-oximino-
amide . Parthermore, t h e pho to lys i s of N-nitroso-X-n-herjl- ace tax ide y i e l d e d no corresponding 6-oximinoamide but t h e
2-n i t roso dimer X I X i n s t e a d .
The f o r n a t i o n of t h e dimer XIX was subs ' tan t ia ted by a
c ryoscopic molecular weight de te rmina t ion i n water. It was
shown t o be a trans-C.-ni-troso d i n e r by i t s i.r. absorp t ion
peak a t 1178 crn-l &ich i s t y p i c a l of a t r a n s d i n e r (18) .
The m u l t i p l e t a t t 4 . 6 5 (one pro ton) i n t h e n.m.r. spectrum 6
was ass ignab le t o t h e methine proton. The C-nitroso d i n e r
XIX was hydrolyzed u l t i m a t e l y t o t h e corresponding ketone
;
The methylene group a t r7.56 col lapsed t o a s i n g l e t nhen t h e
methyl was i r r a d i a t e d . '411ea thn ne thylene group was i r r a d i a t e d ,
t h e n e t h y l group a t t 8 . 9 9 co l l apsed t o a s i n g l e t . The n.m.r.
s p e c t r a of the h y d r o l y s i s product of X I X p l u s the decoupling
exper inen t l e f t no doubt t h a t t h e n i t r o s o group was a t t zched
t o t h e 6-carbon atom from t h e anide n i t r o g e n . Compound SXI
,zone. was f u r t h e r c h a r a c t e r i z e d a s i t s 2,4-dini t rophenylhydr-
Chart V
The Pho to lys i s of ~T-nitroso-l~-n-hexy1acetamide i n ; : eu t ra l
Xedia and t h e Hydrolysis of C-ni-troso Dimer.
0 I I Compound TI111
CH3 ( CS, ) 4C~2-g-C-CH3 (Not I d e n t i f i e d )
d 0 II ) 3ilHCCH3
11? H C 1 ; .
4 0 ll
OH CH3CH2CH(CH2 ) 3i!dHCCHs
i (XIXI CX CH C ICI12 ) 3NHjCH3
2 1 1 Brads ' s Reagent + 0 0 11 0
(XXI) i ' I 3 (IXXII)
1:02
compound possess ing i.r. absorp t ion peaks a t 3380 and 3240
cm-'. 3 i l e t h e t r i p l e t a t ~ 7 . 1 1 was cssigned t o t h e , :e thylene
LTroup -. n e s t t o t h e oxime group, t h e two superimposed t r i p l e t o
e q u i v a l e n t t o two protons a t t 6 . 7 3 could be a s - i g n e d t o t h e
me thylene group next t o t h e amide n i t r o s e n atom. "L'e d e ~ e n e r -
a t i o n of t h e l a t t e r t r i p l e t can be explained by t h e r e s t r i c t e d
r o t z t i o n 02 the carbon-nitrogen bond. The r e s t r i c t e d
r o t a t i o n of t h e carbon-ni$rogen bond was probably due t o t h e
d e l o c a l i z a t i o n of the non-bonded e l e c t r o n s of t h e n i t r o g e n
atom i n t h e amide grou? ( 1 3 ) . The n.m.r. spectrum, the re -
f o r e , c l e a r l y supported t h e s t r u c t u r a l a s ~ i g n n e n t of X X I Z I . ':,'hen t h e oxime X X I I I was hydrolyzed t o t h e corresponding
ketone XXV, t h e i.r. spectrum now showed a new absorp t ion
peak a t 1670 cm-I vlhich was ass ignab le a s t h e carbonyl
group conjugated wi th the benzene r i n g , The n.m.r. s p e c t r w
slioned a t r i p l e t a t t 6.79 which was ass igned t o t h e s e t h y l -
ene group next t o the anide group. It a l s o showed a t r i p l e t
a t t7.05 miiicii was zs:;igned t o t h e methylene group next
t o t h e benzoyl group. Despi te many a t t empts t o p u r i f y ;LXY
by r e c r y s t a l l i z a t i o n from acetone and cyclohexane, a good
a i c r o a n a l y s i s was not ob ta ined , apparen t ly t h i s was due t o
contaminat ion by compound X X I I I . The c o r r e c t n e s s of t h i s
assignment w x s f u r t h e r demonstrated by t h e r e a c t i o n of
co,.lpound ZIII i n t h e fo l lowing manner. The crude product
fro;,; t h e p h o t o l y s i s was redi~ced wi th l i t h i u m aluxinum hydride.
T r e a t ~ e ~ t of t h e reduced n a t e r i a l wi th s u l f u r i c a c i d followed
by Eiiisberg' s r e a c t i o n Lave compound :XVIII which x a s
45
cha rac te r i zed b-i t h e m.c.. The m/e 301 peak (Xt) indicrLed
t h e enpi i1icel formula or" compo~nd ~ , i ~ ~ i ; t o be Cl7Kl9iIl~J1O2*
The f o r n a t i o n of a 9 y r r o l i d i n e r i n g i n con7ound AXVII ?roved
t h a t t h e n i t r o s o sroug had indeed rearranged t o t h e $-carbon
a t o n Cram t h e anide n i t r o ~ e n .
Chart IIX.
The p h o t o l y s i s r e a c t i o n was nex t a p p l i e d t o 11-nitroso-N-
n-hexylforrnanide t o d e t e r n i n e i f t h e r e would be any change
i n t h e photochemical pathway, i f t h e a c e t y l group was replaced
4 G
by a f o r q l group. The corresponding 5 -o;tii-ainofor :z.niOe
:i;iX..
C-nitroso compound sirniln t o XIX nas i s o l a t e d .
Tne course of t h e photolyses of ; J - n i t r o s ~ : T - b e ~ ~ : / l ~ ~ ~ t a r r , i d e
and N-nitroso-N-phenylacetainide were q u i t e d i i T e r e n t from
those descr ibed above. These two X-ni t rosoacetanides have
no a l k y l group a t t h e $ -pos i t ion from t h e arnide n i t r o g e n
atom. Thus, only t h e parent an ides , i .e . , G-benzylecetanide end t i-phenethylacetanide , were recovered from t h e r e s p e c t i v e ghoto lyses . The y i e l d s of amide were good in both cases .
Chart X I .
The P h o t o l y s i s of N-nitroso-N-phenethylacetamide
in Feut r a l I.ledia . 0 0 II h b I I 0 CH CH HCCH3 > SCH2CH2h'HCCX3
2 l n-pentane
I n t h e photoche:~ical experiments i n n e u t r a l media d i s -
cussed so f a r , t he compounds s t u d i e d had hydrogen a t t ached
t o t h e $-carbon of t h e chain a t t a c h e d t o t h e n i t r o g e n atom
i n t h e amide group. It was a l s o of i n t e r e s t t o s tudy t h e
photochemical behaviour of iq-nitrosamides where t h e hydrogens
on t h e $-carbon were on t h e a c y l s i d e of t h e amide group.
X-nitroso-X-methylcaproanide and S-nitroso-il-methyltolualide
w e r e t h e r e f o r e photolyzed.
I n t h e p h o t o l y s i s of X-nitroso-3-methylcaproamide i n
48
petroleuin e t h e r , t h e r a t c of ~ l i o t o l y s i s was slow. I n c o n t r a s t
t o t h e pho to lys i s of X-nitroso-N-n-hexylacetamide, t h e
p h o t o l y s i s of ;;-izitroso-1;-caproamide gave n e i t h e r oxime nor
C-ni t roso dimer. l,'Jhile t h e l i q u i d crude product decomposed
d u r i n g t h e s i l i c i c ac id chromatography, t h e n e u t r a l alwnina
chronatography of t h e crude product sepa ra ted i n t o xzny
smal l f r a c t i o n s from which t h e s t a r t i n g amide and caproanide
were i d e n t i f i e d . Yhe l a t t e r was i d e n t i f i e d by mixed mel t ing
p o i n t de terminat ion znd coinparison of i t s i.r, and n.m,r.
s p e c t r a wi th those of an a u t h e n t i c sample of caproamide.
Chart X I I .
The Pho to lys i s of Ti-nitroso-N-methylcaproamide .
0 0 11 h v II
CH3 (CH ) CijCii3 - CH3 (CH2) 4CH=CH2 + [S!JO] 2 4 ~ I
CH3 (CH ) CNH2 411
+ HCX I1
F'hotolysis of t h e N-nitroso-N-ze thyl to luamide gave s t icky
s o l i d s which were separa ted by n e u t r a l alumina chromatography
t o give t h e c r y s t a l l i n e oxime, xX;~I. The i.r. absorp t ion
p e a l i s a t 3370, 3260, 1638 2nd 1598 cm-l supported t h i s
ass igned s t r u c t u r e . When t h e s t i c k y crude products were
t r e a t e d w i t h 3 r a d y 1 s r e a g e n t , a high mel t ing 2 ,4 -d in i t ro -
phenylhydrazone,XXXII, was obta ined . Th i s d imer ic liydrazone
49 - .. :dXI ~12s a l s o obtained when oxine ;'C;
50
peak ind ica ted the empirics.1 formula of the compound t o be
CgH7RO2. The m/e peaks 132, 104 and 76 suggested the l o s s e s
of the groups -KCH3 , -CONCH and -C 0 BTCH r e spec t ive ly . mhe 3 2 2 ' 3 melt ing po.int a t 129-131•‹C o f the ccmpound X'CVI ( l i t . 132-
133'C) (19) f u r t h e m o r e proved i t s i d e n t i t y . The high
mel t ing c r y s t a l s XXXVT were i d e n t i f i e d t o be phthalimide.
Compound XXXVT gave an i.r. spectrum which w a s superimposable
with t h a t of an a u t h e n t i c sample of phthalimide. The m/e
(I$+) peak i n the mass spectrum suggested the empir ica l
formula C8H5J02. Besides the lY+ peak a t 147, t h e m/e a t 104
and 76 peaks could be due t o the l o s s e s of t h e -CONH and the
-C202NH groups re spec t ive ly .
The first two f r a c t i o n s from t h e alumina chromatography
o f the crude photolyzate were f u r t h e r separa ted by s i l i c i c
a c i d chromatography t o give w h i t e c r y s t a l s which were
i d e n t i f i e d as XXX. The i.r. spectrum of these c r y s t a l s
w a s superimposnble wi.th t h a t of a n ' a u t h e n t i c sample of
phtha l ide .
Much d i f f i c u l t y was encountered i n the microanalysjs of
the compounds which gave absorpt ion peaks a t 3150, 2240,
1690, 1580 and 760 cm-l. These absorpt ion peaks suggested
t h e presence of n i t r i l e , carboxyl and amide groups i n the
compounds. These n i t r i l e compounds a r e suggested t o have the
s t r u c t u r e s of X X X T I I and XXXIV. The mass spectrum of these \
comounds ind ica ted t h a t these two compounds were p resen t a s
a mixture. Fur themore these compounds decomposed during
r e c r y s t a l l i z a t i o n .
2nd 102 p e a k s v:ere p robably due t o t h e 10s:; o f -Ci13, -hilCii 3
due -Lo tile l o s s o f b o t h ni-Lri3.e and N-riietl~yl-a::lidyl p o u p s . The m/e 147 peak i s e q u i v a l e n t t o CeI1211C2 nirich is t h e
f ri- , lula o f c0;;1po~md iXXIV. T t d i d n o t z p p e a r t o be nrro 'o~ble
t h a t t h e m/e 14'7 peak cou ld r e s u l t from t i le c l eavage of
cornpound XXXIII. The m/e 130 peak cou ld a l s o 'ue due t o t h e
l o s s of a hydroxy group f rom compouild .L,XiV. The l o s s 02 b o t h
t h e carboxy!.. and .the n i t r i l e g roups froill coinpou-nd 2';IIV would
g i v e t h e m/e 75 peek.
Cha r t XI11 \
yh? P h o t o l y s i s of ~ -n i t roso -3~- to lu -y lace ta rn ide i n Keu : r e 1 ;:e(?i?.
pi
Benzene o r . pe t ro l eum
e t h e r (2:: )
i-
\
I V DISCUSSIOIIT.
3l iotolyses of X-nitrosaxldez i n !icidic Kedia. -- The c o n t r o l exijeriments per forued i n t h e dark i n d i c z t e
