65 Ozonation of Polycyclic Aromatics
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X V . Carcinogenicity and K - and/or L-Region Additivity towards Ozone EMIL
J.
MORICONI
and
LUDWIG
SALCE
Fordham University, Bronx, N. Y.
Ozonation of benzo[r,s,t]pentaphene (7) followed by oxidative workup led to benzo[r,s,t]pentaphene-5,8-dione (12) (14%), phthalic acid (13) (4%), p-terphenyl-2,2',3',2"-tetracarboxylic acid-2',3'-anhydride (14) (10%), and 2-(o-carboxyphenyl)-1,10-phenanthrenedicarboxylic acid anhydride (15) (3%), with a 56% recovery of unreacted 7. Ozonation of pentaphene (11) led to a peroxidic mixture which on oxidative workup led to 2,2'-binaphthyl-3,3'-dicarboxaldehyde (16) (16%), 2,2'-binaphthyl-3,3'-dicarboxylic acid (17) (16%), and 13 (2%), with a 28% recovery of unreacted 11. A comparison of the reactivity to ozone of carcinogenic polycyclic aromatics benzo[c]phenanthrene (1), 7,12-dimethylbenz[a]anthracene (2), 3-methylcholanthrene (3), dibenz[a,j]- (4), and dibenz[a,h]anthracene (5), benzo[a]pyrene (6) and 7, and the noncarcinogen 11, all determined in our laboratory, leads us to conclude that there is no simple, consistent correlation between carcinogenicity, K -and L-region additivity towards ozone and the Pullmans' electronic theory of carcinogenesis.
/^\ne of the most s t i m u l a t i n g theories
a d v a n c e d to relate
structure
w i t h c a r c i n o g e n i c a c t i v i t y of p o l y c y c l i c aromatics has b e e n
the
" e l e c t r o n i c theory of carcinogenesis" p r o p o s e d b y the F r e n c h s c h o o l of t h e o r e t i c a l chemists l e d b y A . P u l l m a n a n d B . P u l l m a n (30, 32) D a u d e l a n d R . D a u d e l (13).
and P.
T h i s q u a n t u m m e c h a n i c a l s t u d y of t h e
electronic structure of p o l y c y c l i c aromatics has d i s c l o s e d t w o regions of h i g h e l e c t r o n d e n s i t y w h i c h are of p a r t i c u l a r significance i n t h e i r 65 Mayo; Oxidation of Organic Compounds Advances in Chemistry; American Chemical Society: Washington, DC, 1968.
66
OXIDATION
chemical behavior.
OF
ORGANIC
COMPOUNDS
III
T h e s e sites c o r r e s p o n d to the 9,10-bond i n p h e n a n -
threne ( K - r e g i o n ) a n d the 9,10-positions
i n anthracene
(L-region).
A
t h i r d site ( M - r e g i o n ) i n v o l v e s the positions reactive i n m e t a b o l i c p e r hydroxylation. L-region M-region
T h e t w o most r e c e n t l y expressed f u n d a m e n t a l , q u a n t i t a t i v e p r o p o sitions of the theory are
(30):
( 1 ) T h e a p p e a r a n c e of c a r c i n o g e n i c a c t i v i t y i n a r o m a t i c h y d r o c a r bons is d e t e r m i n e d b y the existence of a K - r e g i o n , w h o s e c o m p l e x i n d e x is e q u a l to or smaller t h a n 3.31/2. ( T h e s e c o m p l e x i n d i c e s are d e f i n e d b y P u l l m a n a n d P u l l m a n ( 3 0 ) ; /? is expressed i n terms of resonance i n t e g r a l ( ^ 2 0 k c a l . / m o l e ) ; the n u m e r i c a l l i m i t s l i s t e d ( 3 . 3 l £ a n d 5.66)8) are those c a l c u l a t e d f o r the K - a n d L - r e g i o n s of d i b e n z [ a , / ] a n t h r a c e n e (4), c o n s i d e r e d as the weakest p o l y c y c l i c c a r c i n o g e n . ( 2 ) If, h o w e v e r , the m o l e c u l e contains also a n L - r e g i o n , its c o m p l e x i n d e x s h o u l d b e e q u a l to or greater t h a n 5.66/2 (see above). S i m p l y stated, one of the essential steps i n carcinogenesis
is
the
" r e a c t i o n " b e t w e e n the c a r c i n o g e n i c p o l y c y c l i c a r o m a t i c a n d the " c e l l u l a r r e c e i v e r , " at or t h r o u g h the K - r e g i o n of the c a r c i n o g e n . A necessary b u t not sufficient c o n d i t i o n for " r e a c t i v i t y " is a n a c t i v e K - r e g i o n complex index: = complex index:
3.31)8). A too-reactive L - r e g i o n , h o w e v e r , ( c a l c d . 5.66/3) m a y d i v e r t the p o l y c y c l i c c a r c i n o g e n to
a
noncarcinogenic reaction. V e r i f i c a t i o n of these p r o p o s i t i o n s has taken t w o different p a t h w a y s : ( 1 ) T h e o r e t i c a l : q u a n t i t a t i v e calculations w h i c h , f o r e x a m p l e , pre d i c t e d (30) the c a r c i n o g e n i c i t y of b e n z o [ r , s , t ] p e n t a p h e n e (7) whose m e a s u r e d p o t e n c y (H—|—1-+) ranks it b e t w e e n 3 - m e t h y l c h o l a n t h r e n e (3 ) a n d b e n z o [a] p y r e n e (6) (18,35). ( 2 ) C h e m i c a l : c o m p a r i s o n of c y c l o a d d i t i o n reactions o c c u r r i n g either at t h e K - r e g i o n ( o s m i u m t e t r o x i d e ) (1, 2) or L - r e g i o n ( m a l e i c a n h y d r i d e a n d p h o t o - o x i d a t i o n ) (29, 31). T h e i n a d e q u a c i e s of this c h e m i c a l p r o o f seemed to us t w o f o l d : the c y c l o a d d i t i o n reactions w e r e u n r e l a t e d c h e m i c a l l y , each o c c u r r i n g at either the K - / L - r e g i o n s , whereas the t h e o r y c o n s i d e r e d b o t h regions s i m u l taneously; f u r t h e r , these reactions d i d not occur, or at least h a d not b e e n t r i e d w i t h a sufficient n u m b e r of c a r c i n o g e n i c a n d n o n c a r c i n o g e n i c p o l y c y c l i c aromatics.
Mayo; Oxidation of Organic Compounds Advances in Chemistry; American Chemical Society: Washington, DC, 1968.
65.
MORICONI
Polycyclic
A N D SALCE
67
Aromatics
F o r a c h e m i c a l r e a c t i o n to h a v e relevance, i t seemed necessary that the r e a c t i o n o c c u r s i m u l t a n e o u s l y at b o t h K - a n d L - r e g i o n s a n d w i t h a l l c a r c i n o g e n i c a n d n o n c a r c i n o g e n i c p o l y c y c l i c aromatics.
I n our view,
this c o m p e t i t i v e response to the c h e m i c a l reactant at the t w o sites w i t h i n the substrate m o l e c u l e c o u l d l e a d , i n t r a m o l e c u l a r l y , to a c o n c l u s i o n o n the r e l a t i v e r e a c t i v i t y of t h e K - a n d L - r e g i o n s . F u r t h e r , since t h e c h e m i cal reaction could be studied under identical reaction conditions, the results c o u l d also l e a d , i n t e r m o l e c u l a r l y , to v a l i d c o m p a r i s o n s of r e l a t i v e reactivity. W h e n this research b e g a n , t h e o z o n a t i o n r e a c t i o n seemed i d e a l l y suited. O z o n e w a s k n o w n to react at b o t h the K - r e g i o n [ i n p h e n a n t h r e n e (8)]
(4,5,34,37)
a n d L - r e g i o n ( i n a n t h r a c e n e ) (6,7,33).
D u r i n g the
d e c a d e since, w e h a v e i n v e s t i g a t e d the r e a c t i o n b e t w e e n ozone a n d some 11
p o l y c y c l i c aromatics
(1—11).
Other
laboratories
have
CARCINOGENS
CH Benzo[c]phenanthrene (19) 1
2
3-Methylcholanthrene (21)
Dibenz[a,/]anthracene (20)
Benzo [a] pyrene (25)
5
Benzo [r,s,f] pentaphene (26)
6
8
Dibenz [a,h] anthracene (24)
4
3
Phenanthrene (34)
:
