The Organic Chemistry of N-Nitrosamines: A Brief Review - ACS

1 The Organic Chemistry of N-Nitrosamines: A Brief Review JEAN-PIERRE

ANSELME

Downloaded by UNIV OF MISSISSIPPI on July 5, 2015 | http://pubs.acs.org Publication Date: June 20, 1979 | doi: 10.1021/bk-1979-0101.ch001

Department of Chemistry, University of Massachusetts at Boston, Harbor Campus, Boston, M A 02125

Although N-nitrosamines (I) have been known since the nine teenth century, it was not until quite recently that they became the subject of intensive investigations. This renewed interest was spurred i n large part by the report of Magee and Barnes (1) on the carcinogenicity of these compounds. Since then, research into the chemistry and b i o l o g i c a l properties of N-nitrosamines has ac celerated. This b r i e f survey is intended to serve both as a sum mary of some of the frontiers i n this area and as an introduction to the chemistry of N-nitrosamines discussed i n the remaining chap ters of t h i s Volume. N-Nitrosamines have the nitroso group attached d i r e c t l y to the amine nitrogen (2-7). As with C-nitroso compounds however, i n general only those N-nitrosamines where neither R nor R' is a hy drogen atom, have any existence; when one of the substituents i s a hydrogen, the equilibrium favors the tautomeric diazoic acid (A) (8). There are reported cases of stable primary N-nitrosamines;

R .rv

[R-N=N-OH]

N

do

r

R

I

Ο .

I'

I"

A

i t i s l i k e l y , however, that i n those i n s t a n c e s these N-nitrosamines e x i s t as the tautomeric N - n i t r o s i m i n e s (9.)· Although there i s a l a r g e body o f i n f o r m a t i o n on N-nitrosam ides (i.e., N-nitrosamines where one o f the s u b s t i t u e n t s i s e i t h e r a c y l o r s u l f o n y l ) , t h i s b r i e f survey w i l l d e a l mainly w i t h N,N-dia l k y l - and N,N-aralkylnitrosamines. Structure In 1957, Looney, P h i l l i p s and R e i l l y (10) were the f i r s t t o 0-8412-0503-5/79/47-101-001$05.00/0 ©

1979 A m e r i c a n C h e m i c a l Society

In N-Nitrosamines; Anselme, J.; ACS Symposium Series; American Chemical Society: Washington, DC, 1979.

2

N-NITROSAMINES

demonstrate t h a t α-hydrogens of Ν,Ν-dialkylnitrosamines are mag n e t i c a l l y non-equivalent as a r e s u l t o f the l a r g e c o n t r i b u t i o n of the d i p o l a r mesomeric s t r u c t u r e . The existence and the s e p a r a t i o n of c o n f i g u r a t i o n a l isomers ( I and I") have been reported (13.). These f i n d i n g s confirmed the suggestion t h a t N-nitrosamines are p o l a r and served t o usher a major advance i n the chemistry o f t h i s c l a s s of compounds. 1

Synthesis


The n i t r o s a t i o n o f secondary amines w i t h sodium n i t r i t e i n the presence of a c i d s i s by f a r s t i l l the most widely used method f o r the p r e p a r a t i o n of N-nitrosamines. S e v e r a l v a r i a t i o n s o f t h i s

RR'NH

+

ΝαΝ0

——>

2

RR'N-NO

(1)

procedure are known (2-7). Other n i t r o s a t i n g agents such as n i t r o s y l fluoroborate, dinitrogen t r i o x i d e , dinitrogen tetroxide have been u t i l i z e d . A recent m o d i f i c a t i o n jlk) i n v o l v e s the n i t r o s a t i o n o f the anion of the amines w i t h n i t r o s y l c h l o r i d e . Transn i t r o s a t i o n w i t h 3 - n i t r o - N - n i t r o s o c a r b a z o l e allows n i t r o s a t i o n to occur i n n e u t r a l medium (37)· Of p a r t i c u l a r i n t e r e s t i s the a b i l i t y o f n i t r o p r u s s i d e [Fe(CN)sNO ] t o n i t r o s a t e amines under aque ous a l k a l i n e c o n d i t i o n s (15). =

(CH CH )2NH 3

+

2

Fe(CN) NO 5

=

^

>

(CH CH )2NN=0 3

2

(2)

A novel method t o degrade t e r t i a r y amines proceeds through the formation of secondary N-nitrosamines ( l 6 ) .

R2NCH2R

n

+

(CH ) CHN0 3

2

o

p 2

P

r

„ , r

Ij.

2

y

n

d

> m

R9NNO

+

R'CHO + ( C H ) C O 3

2

(3)

e

Reactions Reactions o f the N i t r o s o Group. Up u n t i l r e c e n t l y , the chem i s t r y of N-nitrosamines was r e s t r i c t e d t o the r e a c t i o n i n v o l v i n g the n i t r o s o group. I t was not u n t i l the usefulness of N - n i t r o s amines i n synthesis [concept of "Umpolung" (3.)] was demonstrated, that the long-known d e n i t r o s a t i o n of N-nitrosamines became impor-


1.

ANSELME

Organic Chemistry of N-Nitrosamines

3

t a n t . Although numerous methods have been r e p o r t e d f o r t h i s purpose, the a c t i o n o f m i n e r a l a c i d s remains t h e most common procedure (Eq. k).

R NN=Q 2

+

HCI

*

^22

R NHHCI 2

+

HONO

(4)

There has been some controversy r e g a r d i n g the s i t e o f a t t a c k o f the proton; on t h e b a s i s o f t h e d i p o l a r s t r u c t u r e s I and I " , i t might be i n f e r r e d t h a t t h e proton attack should occur on t h e oxygen atom; the f a c t t h a t N-nitrosamines form O-complexes and 0 a l k y l a t e d products would seem t o support t h i s view (17)» However, i t i s c u r r e n t l y b e l i e v e d t h a t the N-protonated form i s t h e one t h a t l e a d s t o d e n i t r o s a t i o n , i r r e s p e c t i v e o f whether o r not i n i t i a l p r o t o n a t i o n occurs on oxygen ( l 8 ) .


1

R N-N=Q

R N-N=0 -H

2

R2N

r

... (PhCH ) N-N 2

L

2

_

N

o

PhCH CH Ph 2

2

(5)

J

the hydrocarbons (Overberger-Lombardino r e a c t i o n ) . The "abnormal" r e d u c t i o n o f N-nitrosamines presumably proceeds v i a the N-nitrene (or N - n i t r e n o i d ) which then may extrude n i t r o g e n t o y i e l d the observed hydrocarbons (6). N-Nitrosamines can be considered as Nn i t r e n e N-oxides and indeed are deoxygenated t o t h e p u t a t i v e N-


4

N-NITROSAMINES

n i t r e n e s with e t h y l diphenylphosphinite

a

Ν I,

EtOPPh

[Eq. 6]

(21),

Ο

N

r

DA

2

iron

NO

penta-

(6)

(PhCH ) NN=0 2

2

[(PhCH ) N-N]


2

ArN

PhCh^CH^Ph

2

(7)

3

carbonyl ( 2 2 , 2 3 ) , a r y l azides [Eq. 7] (2U) or phenacylcarbonium ions (25). N-Nitrosamines have been o x i d i z e d t o the corresponding N-nitramines. T r i f l u o r o p e r a c e t i c a c i d and n i t r i c acid/ammonium pers u l f a t e are the reagents o f choice f o r t h i s purpose.

R NNO 2

+

R NN0

CF3CO3H

2

2

(8)

I t has been found that, though s t a b l e t o l i g h t i n n e u t r a l so l u t i o n , N-nitrosamines can rearrange t o the corresponding amidoximes (j+,26^,27.) i n a c i d s o l u t i o n ; other products can a l s o be formed

(U).

^ N - N - O

•

H*

RNHC=NOH

- J U L

1

(9)

R'

A v e r y recent communication (28)

2 R N N = 0 + R'SH 2

( N ? )

»

R N-NCQ 2

r e p o r t s the a d d i t i o n o f t h i y l

R

+ R2NH + N O


(10)

1.


ANSELME

5

r a d i c a l s t o N-nitrosamines t o give the corresponding n i t r o x i d e radicals. The c h e l o t r o p i c e l i m i n a t i o n o f n i t r o u s oxide from N-nitrosoa z i r i d i n e s i s a r e a c t i o n r e s t r i c t e d t o t h i s c l a s s o f compounds (29-36).


|^rN-N=0

=

>

+

N 0

(11)

2

D i a r y l n i t r o s a m i n e s undergo f i s s i o n at the n i t r o g e n - n i t r o g e n bond upon heating (37,38). In the presence o f oxygen, the r i n g n i t r o s u b s t i t u t e d amines are obtained (37); i n the absence o f /=V-N0

2

(θ2>*

Ar N-NO

>. £ Α Γ Ν ·

2

2

·ΝΟ ]

(12)

'

( N 2 N M Products

oxygen, products r e s u l t i n g from the diarylamino r a d i c a l are formed (38).

A much o l d e r r e a c t i o n o f N-nitroso α-aminoacids i s t h e i r c y c l i z a t i o n t o the mesoionic sydnones (39 ]+0,Ul.,U£) ; more r e c e n t l y , Nn i t r o s o α-aminonitriles have been c y c l i z e d t o the corresponding sydnone imines (U0,Ul,U2,U3). 5

RN-ÇR' R

^

H

(

R

NO

,

)

C

° 2

H

(CH ^

3

H

6b) 0 "

2

J

'

—

°

(13)

O

N

RN-CR' RNCH(R')CN NO

HCI L1£i

>

Λ Ν

N

*C - N H

O

2

CI"

(M)

x

Reactions Caused by the N i t r o s o Group. A major consequence of the s t r o n g l y d i p o l a r nature o f N-nitrosamines - a f a c t now f i r m l y e s t a b l i s h e d by the work o f P h i l l i p s (10) and o f Karabatsos ( l l ) - has been a b e t t e r understanding o f the chemistry o f N - n i -


6

N-NITROSAMINES

trosamines and the e l a b o r a t i o n o f new r e a c t i o n s based on the a c i d i c nature o f the α-hydrogens o f N-nitrosamines. Although reson ance s t a b i l i z a t i o n o f t h e negative charge may be d i f f i c u l t t o en v i s i o n {hk,k6), the experimental data leave l i t t l e doubt as t o the r e a l i t y o f the i n d u c t i v e e f f e c t .

R

\ /CH R +

2

Ν

II

—

X +

R

Ν

-H'

Ν*

Scheme

CHR

Ν ι _ Ν

«

11^

Ν


.^ίCαH R

2

The f i r s t i n d i c a t i o n o f the e f f e c t o f the p o s i t i v e charge on the α-hydrogen came from the i s o m e r i z a t i o n o f t r a n s - N - n i t r o s o - 2 , 5 d i p h e n y l p y r r o l i d i n e t o the c i s - i s o m e r i n aqueous base (^5). Keef er and Fodor (U6) were the f i r s t t o demonstrate the deuterium ex change o f the α-hydrogens and the a l k y l a t i o n o f anions o f N - n i t r o s amines. Seebach and h i s group (3) have developed t h i s d i s c o v e r y i n t o a major s y n t h e t i c process; they have coined the word "Umpol-

CH

ÇH3

3

ο

N>

D2O

OD"

(15) NO

NO

ung" t o i n d i c a t e t h a t the n i t r o s o group attached t o the amine n i -

V

N "

y 6+

^

Ν

/ ^ N u

Scheme

X

N

_+ X

Ν *

z

N

v /

3


1.


ANSELME

t r o g e n h a s r e v e r s e d t h e n o r m a l " p o l a r i t y " o f t h e α-carbon (Scheme 3). N - N i t r o s a m i n o a n i o n s have a l s o b e e n added t o c a r b o n y l compounds, t o α,β-unsaturated k e t o n e s a n d n i t r o o l e f i n s , t o n i t r i l e s a n d o t h e r

Y

+

RX

—

N

>


NO

+

V

X

( 1 6 )

"

NO

e l e c t r o p h i l e s (3.). I t i s o f h i s t o r i c a l i n t e r e s t t h a t as e a r l y as in 19^ K o e l s c h (kj) u s e d t h e N - n i t r o s o g r o u p a s a r e m o v a b l e p r o t e c t i v e group i n t h e s y n t h e s i s o f U - ( p i p e r i d i n o ) p r o p i o n i c a c i d . 9

ON-N

^-CH Br 2

+ (Et0 C) CH~ 2

2

> Na

>

H N ^ ^ C H

2

C H

2

C 0

2

H

(17)

+

Some d i f f i c u l t i e s may be e n c o u n t e r e d d u r i n g t h e m e t a l l a t i o n o f N-nitrosamines. E l i m i n a t i o n may o c c u r i n e i t h e r o f two ways. F o r example, N - n i t r o s o m o r p h o l i n e y i e l d s t h e N-nitrosoenamine w h i l e l o s s

o f [HNO] r e s u l t s i n t r a n s - s t i l b e n e from c e e d b y a mechanism i n i t s e a r l y stages

t h e f o r m a t i o n o f i m i n e s (3.). The f o r m a t i o n o f t h e a n i o n o f N - n i t r o s o d i b e n z y l a m i n e may p r o a k i n t o t h a t o f t h e Ramberg-Backlund, a t l e a s t (3,).


8

N-NITROSAMINES

PhCH.

Ph.

.CH Ph

^Ph

2

Ν

H

*

^δΝ

N-cr Ph

(19)

/Ph -N

NJ

2

PhCH=CHPh

-OH'


N - O H

The i n t e r e s t i n g " d i m e r i z a t i o n " o f l i t h i a t e d N - n i t r o s a m i n e s t o c y c l i c t e t r a z e n e N - o x i d e s h a s b e e n d e s c r i b e d (HQ) a n d p r o v i d e s a n o t h e r r o u t e t o t h e n o v e l c y c l i c t e t r a z e n e s (^9?50) · A r a d i c a l p a t h h a s b e e n s u g g e s t e d f o r t h i s r e a c t i o n [Scheme k] (3)·

CH

CH3 3

I

C H ^ N * ° :

•CH

CH

J

INK

/ 2

CH

3

I

3

II

—

TI

Ν

N' I

>0

CH

CH 3

CH

3

M 3

Scheme 4 The r e a c t i o n o f o r g a n o m e t a l l i e s w i t h N - n i t r o s a m i n e s h a s b e e n i n v e s t i g a t e d i n t h e e a r l y p a r t o f t h i s c e n t u r y m a i n l y by Wieland and h i s s t u d e n t s (51,52,53,5*0 - More r e c e n t w o r k ( 5 5 , 5 6 , 5 7 ) i n d i c a t e s t h a t G r i g n a r d a n d o r g a n o l i t h i u m r e a g e n t s may e i t h e r a b s t r a c t α-hydrogen o r a d d t o t h e n i t r o s o g r o u p . Some o f t h e a z o m e t h i n e i m i n e s have b e e n i n t e r c e p t e d w i t h 1 , 3 - d i p o l a r o p h i l e s .

Et NN=0 2

+

•

Et NNC 2

Q

J

_Q -> H

Et NN=CH 2

2

CH M Br or C H L i 3

g

3


(20)

1.


ANSELME

9

C < ~Hr l33 N i N^

H

2

°

E

t

N N H p h

(CH3)2NN=0 + PhLi

ru3 C

M ^ 2 - -

(21)

H

H

N

N

Ph


P h '

N

- ^ C H

3

With phenylcopper (58) or with l i t h i u m or magnesium metal (59.) s d e n i t r o s a t i o n t o t h e amines i s the major r e a c t i o n path; N,Ndiphenylhydroxylamine a s i g n i f i c a n t by-product o f the r e a c t i o n , i s b e l i e v e d t o a r i s e as shown i n Eq. 22 a f t e r h y d r o l y s i s (58).

R2NNO

PhCu

R NN

/Ph

2

N

OCu

PhCu

R NCu 2

+

Ph NOCu 2

(22)

In the short span o f t w e n t y - f i v e y e a r s , the h i t h e r t o r a t h e r p r o s a i c N-nitrosamines have revealed themselves t o possess a r i c h and v a r i e d chemistry as subsequent chapters o f t h i s volume w i l l f u r t h e r demonstrate.


10

N-nitrosamines

Literature Cited


1.

Magee, P. N., and Barnes, J . Μ., Brit. J. Cancer, 10, 114 (1956). 2. Fridman, A. L., Mukhametshin, F. Μ., and Novikov, S. S., Russ. Chem. Rev., 1971, 40, 34. 3. Seebach, D., and Enders, D., Angew. Chem. Intern. Eng. E d . , 14, 15 (1975). 4. Chow, Y. L., Accounts Chem. Res., 6, 354 (1973). 5. Smith, P. A. S . , "Open-Chain Nitrogen Compounds," Vol. 2, p. 470, 499, W. A. Benjamin, New York, N . Y . , 1966. 6. Overberger, C. G . , Anselme, J . - P . and Lombardino, J. G . , "Or ganic Compounds with Nitrogen-Nitrogen Bonds," Chapter 7, The Ronald Press C o . , New York, N . Y . , 1966. 7. Sidgwick, Ν. V., "The Organic Chemistry of Nitrogen," p. 592, The Clarendon Press, Oxford, 1966. 8. Muller, Ε., Η . , and Rundel, W., Chem. B e r . , 93, 1541 (1960). 9. Gelen, Η . , and Dost, J., Ann., 665, 144 (1963). 10. Looney, C. Ε., P h i l l i p s , W. D . , and R e i l l y , E . L., J. Am. Chem Soc., 79, 6136 (1957). 11. Karabatsos, G. J., and T a l l e r , R. A., J. Am. Chem. Soc., 86, 4373 (1964). 12. Suhr, H., Chem. B e r . , 96, 1720 (1963). 13. Manschreck, Α . , Munsch, Η . , and Mattheus, Α., Angew. Chem. Intern. Eng. Ed., 5, 728 (1966). 14. Lyle, R. Ε., Saavedra, J . Ε., and Lyle, G. G . , Synthesis, 462 (1976). 15. Maltz, Η . , Grant, Μ. Α., and Navaroli, M. C., J. Org. Chem., 36, 363 (1971). 16. Franck, Β. J., Conrad, J., and Misbach, P., Angew. Chem. In tern. Eng. Ed., 9, 892 (1970). 17. Buttner, G., Cramer, J., Geldern, L., and Hunig, S., Chem. Ber., 104, 1118 (1971) and references therein. 18. Fish, R. H., Homstead, R. L., and Gaffield, W., Tetrahedron, 32, 2689 (1976). 19. Fischer, Ε., B e r . , 8., 1587 (1879). 20. Wieland, Η . , and Fressel, Η . , Ann., 392, 133 (1912). 21. Cadogan, J. I. G., and Thomas, J. Β., Chem. Comm., 770 (1969). 22. Alper, Η., and Edward, J. T., Can. J. Chem., 48, 1543 (1970). 23. Tanaka, Α . , and Anselme, J.-P., Tetrahedron L e t t . , 3567 (1971). 24. Nishiyama, Κ . , and Anselme, J.-P., J . Org. Chem., 42, 2636 (1977). 25. Nishiyama, Κ . , and Anselme, J.-P., J . Org. Chem., 43, 2045 (1978). 26. Burgess, Ε. Μ., and Lavanish, J. Μ., Tetrahedron L e t t . , 1227 (1964). 27. Chow, Y. L., Tetrahedron L e t t . , 2333 (1964). 28. Waters, W. Α., Chem. Comm., 741 (1978). 29. Bumgardner, C. L., McCallum, K. S . , and Freeman, J. P . , J. Am. Chem. S o c . , 83, 4417 (1961).


1. Anselme 30. 31. 32. 33. 34. 35. 36.


37. 38. 39. 40.

41.

42. 43. 44.

45. 46. 47. 48. 49. 50. 51. 52. 53. 54. 55. 56. 57.


11

Rundel, W., and Muller, Ε., Chem. Ber., 96, 2528 (1963). Clark, R. D., and Helmkamp, G. Κ., J. Org. Chem., 29, 1316 (1064). Carlson, R. Μ., and Lee, S. Υ., Tetrahedron L e t t . , 4001 (1969). Mock, W. L., and Isaac, P. A. H., J. Am. Chem. Soc., 94, 2749 (1972). Loeppky, R. Ν., and Smith, D. H., J. Org. Chem., 41, 1578 (1976). Haire, M. J., and Boswell, G. Α., J. Org. Chem., 42, 4251 (1977). For a special exception, see Duran, N., J. Org. Chem., 39, 1791. Drake, N. L., Winkler, H. J. S . , Kraebel, C. Μ., and Smith, T. D., J. Org. Chem., 27, 1026 (1962). Welzel, P., Chem. B e r . , 104, 808 (1971). E a r l , J . C., and Mackney, A. W., J. Chem. Soc., 899 (1935). O l l i s , W. D., and Ramsden, C. Α., "Advances in Heterocyclic Chemistry," A. R. Katritzky and A. J. Boulton, E d s . , V o l . 19, p. 3, Academic Press, New York, N . Y . , 1976. Ohta, Μ., and Kato, H., "Nonbenzenoid Aromatics," J. P. Sny der, Ed., V o l . 1, p. 117, Academic Press, New York, N.Y., 1969. Stewart, F. H. C., Chem. Rev., 64, 129 (1964). Brookes, P., and Walker, J., J. Chem. S o c . , 4409 (1957). Fraser, R. R., Boussard, G., Postescu, I. D., Whiting, J. J., and Wigfield, Υ. Υ . , Can. J. Chem., 51, 1109 (1973) and Fraser, R. R., and Ng, L . K., J. Am. Chem. S o c . , 98, 5895 (1976). Overberger, C. G., Valentine, Μ., and Anselme, J.-P., J . Am. Chem. S o c . , 91, 687 (1969). Keefer, L . Κ., and Fodor, C. H., J. Am. Chem. Soc., 92, 5747 (1970). Koelsch, C. F., J. Am. Chem. Soc., 66, 1611 (1944). Seebach, D., Enders, D., Reuger, Β., and Brugel, W., Angew. Chem. Intern. Eng. E d . , 12, 495 (1973). Mataka, S., and Anselme, J.-P., Chemistry L e t t . , 51 (1973). Nelsen, S. F., and Fibiger, R., J. Am. Chem. S o c . , 94, 8497 (1972). Wieland, Η., and Fressel, Η., B e r . , 44, 898 (1911). Wieland, Η., and Reverdy, Α., B e r . , 48, 1112 (1915). Wieland, Η., and Roseeu, Α., B e r . , 48, 1117 (1915). Gilman, Η., and Heck, L . L., Rec.Trav. Chim. Pays-Bas, 50, 522 (1931). Farina, P. R., and Tieckelmann, H., J . Org. Chem., 38, 4259 (1973). Michejda, C. J., and Schluenz, R. W., J. Org. Chem., 38, 2412 (1973). Farina, P. R . , and Tieckelmann, H., J. Org. Chem., 40, 1070 (1975).


12 58. 59.

N-Nitrosamines Rahman, M. T., Ara, I., and Salahuddin, A. F. Μ., Tetrahedron Lett., 959 (1976). Rahman, M. T., and Salahuddin, A. F. Μ., Tetrahedron Lett., 1235 (1976).


Received February 21, 1979.


The Organic Chemistry of N-Nitrosamines: A Brief Review - ACS

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