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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:
<
(calcd.
/ > 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)
:<
7, 12-Dimethylbenz[fl]anthracene (20)
7
Benz [a] anthracene (27) 9
Napthacene (28) 10
Pentaphene (26) 11
Mayo; Oxidation of Organic Compounds Advances in Chemistry; American Chemical Society: Washington, DC, 1968.
reported
68
OXIDATION
OF
ORGANIC
COMPOUNDS
HI
o n eight m o r e ( n a p h t h a l e n e (8), t r i p h e n y l e n e (11), p y r e n e (36), c h r y sene (11), b e n z o [g] chrysene (11), p i c e n e (11), d i b e n z [c,g] p h e n a n threne (11), a n d p e r y l e n e (12). A l l react w i t h ozone, a n d r e a c t i o n occurs u n i q u e l y at one or m o r e of the three relevant sites, the K - , L - , and M-regions. H e r e , w e r e p o r t o n the o z o n a t i o n of t w o s y m m e t r i c a l l y s t r u c t u r e d p o l y c y c l i c aromatics at opposite ends of the c a r c i n o g e n i c s p e c t r u m — t h e h i g h l y c a r c i n o g e n i c (18, 35) benzo[r,s,t~\pentaphene ( 7 ) a n d the i n a c t i v e (10) p e n t a p h e n e ( 1 1 ) — a n d s u m m a r i z e the results of o u r s t u d y of 1 - 7 a n d 11. T h e p r e p a r a t i o n of 7 a n d 11 a n d the i s o l a t i o n a n d i d e n t i f i c a t i o n of o z o n a t i o n p r o d u c t s 1 2 - 1 8 h a v e b e e n r e p o r t e d p r e v i o u s l y (26). Ozonation of Benzo[ r,s,t']pentaphene (7) m
and Pentaphene (11)
O z o n a t i o n of 7 i n m e t h y l e n e c h l o r i d e at — 78 ° C . w i t h 3.5 m o l e equivalents of o z o n e ( r e q u i r i n g passage of 5 - 6 m o l e e q u i v a l e n t s ) , f o l lowed b y oxidative w o r k u p (1:1 1 0 % sodium hydroxide: 3 0 % hydrogen p e r o x i d e ) l e d to benzo[r,s,t~\pentaphene-5,8-dione ( 1 2 ) ( 1 4 % ), p h t h a l i c acid ( 1 3 ) ( 4 % ) , p-terphenyl-2,2',3',2"-tetracarboxylic acid-2',3'-anhydride (14) ( 1 0 % ) , and 2-(o-carboxyphenyl)-l,10-phenanthrenedicarb o x y l i c a c i d a n h y d r i d e ( 1 5 ) ( 3 % ) , w i t h a 5 6 % r e c o v e r y of u n r e a c t e d 7, as s h o w n b e l o w . r
+
+
o
7
2,
12
13
14
15
OOH-
3, H 0 * 3
Mayo; Oxidation of Organic Compounds Advances in Chemistry; American Chemical Society: Washington, DC, 1968.
65.
MORICONI
A N D SALCE
Polycyclic
69
Aromatics
O z o n a t i o n of p e n t a p h e n e ( 1 1 ) ( s h o w n b e l o w ) i n m e t h y l e n e c h l o r i d e at — 78 ° C . w i t h one m o l e e q u i v a l e n t of o z o n e l e d to a p e r o x i d i c m i x t u r e w h i c h o n o x i d a t i v e w o r k u p l e d to 2 , 2 ' - b i n a p h t h y l - 3 , 3 ' - d i c a r b o x a l d e h y d e (16)
( 1 6 % ) , 2,2'-binaphthyl-3,3'-dicarboxylic acid (17)
phthalic acid ( 1 3 ) ( 2 % ) ; a c i d ) gave 16 ( 2 5 % ) . ered.
(16%),
and
r e d u c t i v e w o r k u p ( s o d i u m i o d i d e i n acetic
I n b o t h cases, 2 8 %
of u n r e a c t e d 11 w a s recov
O z o n a t i o n of 11 w i t h 4 m o l e e q u i v a l e n t s of o z o n e f o l l o w e d b y
o x i d a t i v e w o r k u p gave 2,2',4,4',5,5'-hexacarboxybiphenyl
(18)
(53%)
a n d p h t h a l i c a c i d ( 1 3 ) ( 9 % ).
18
Summary and Conclusions T a b l e I s u m m a r i z e s the d a t a n o w a v a i l a b l e f r o m o u r l a b o r a t o r y o n the o z o n a t i o n of 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 h y d r o c a r b o n s 1 - 7 a n d the n o n c a r c i n o g e n , 11. A l l the c o m p o u n d s h a v e at least one K r e g i o n ( w i t h s i m i l a r electronic i n d i c e s , 3.16-3.41/?). D e s p i t e some i n i t i a l l y e n c o u r a g i n g results w h i c h suggested that u n s u b s t i t u t e d p o l y c y c l i c aromatics of i n c r e a s i n g c a r c i n o g e n i c a c t i v i t y d i d react m o r e s t r o n g l y w i t h ozone at the K - r e g i o n a n d to a c o r r e s p o n d i n g l y lesser degree at the L - r e g i o n (20, 23, 28), w e h a v e o b s e r v e d several exceptions.
Mayo; Oxidation of Organic Compounds Advances in Chemistry; American Chemical Society: Washington, DC, 1968.
70
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OF
ORGANIC
COMPOUNDS
III
I n t h e i r s t u d y of p r o t e i n b i n d i n g as a necessary, b u t not sufficient, p r e r e q u i s i t e f o r h y d r o c a r b o n carcinogenesis, H e i d e l b e r g e r a n d M o l d e n h a u e r (16)
h a v e e x p e r i m e n t a l l y d e m o n s t r a t e d that 2, 3, a n d 6 w e r e
b o u n d to s k i n p r o t e i n to a large a n d a p p r o x i m a t e l y e q u a l extent.
A
p o r t i o n of this tissue i n t e r a c t i o n most p r o b a b l y occurs at the K - r e g i o n ( 9 ) , i n a c c o r d a n c e w i t h the t h e o r e t i c a l s p e c u l a t i o n of the P u l l m a n s 32).
(30,
Thus, any direct correlation between carcinogenicity and reactivity
to ozone w o u l d result i n p r e d o m i n a n t e l e c t r o p h i l i c ozone attack at the C o m p o u n d s 2, 3, a n d 6,
K - r e g i o n of these three -|—|—|—f- carcinogens.
h o w e v e r , r e a c t e d w i t h ozone e x c l u s i v e l y at the L - a n d M - r e g i o n s . C e r t a i n l y 3 w a s not a p r i v i l e g e d c o m p o u n d (30)
i n w h i c h the L - r e g i o n w a s
p r o t e c t e d f r o m attack b y ozone. T h e lesser carcinogens b e n z o [c] p h e n a n t h r e n e benz[a,/]anthracene (24)
(4)
(20)
( + ),
(l)
(19)
( + ), d i -
and dibenz[a,K]anthracene
(5)
(-)—f-) r e a c t e d w i t h ozone p r e d o m i n a n t l y at the K - r e g i o n . R e l a
tive to 6, this response to ozone is the r e v e r s a l of w h a t w o u l d h a v e b e e n p r e d i c t e d b y the electronic t h e o r y of carcinogenesis. Both benzo[r,s,t]pentaphene
( 7 ) a n d 6 are + + H—h
carcinogens,
a n d some i d e n t i t y of response to e l e c t r o p h i l i c ozone w o u l d be p r e d i c t e d . Y e t the f u s i o n of a b e n z e n e r i n g to the 1,2-bond i n 6 has e n h a n c e d the K - r e g i o n a c t i v i t y of 7 to ozone ( 1 3 %
t o t a l of 14 a n d 1 5 ) , l o w e r e d the
T a b l e I.
O z o n a t i o n of P o l y c y c l i c
Pu llman-Pullman Electronic Indices'
1
Polycyclic
Aromatic
Pentaphene (11) Benzo [c] phenanthrene (1) D i b e n z [A,/] anthracene (4) D i b e n z \a,h~\ anthracene (5) 7,12-Dimethylbenz [ a ] anthracene 3-Methylcholanthrene (3) Benzo [a] pyrene (6) Benzo [r,s t] pentaphene (7) 9
K-Region
(2)
L-Region
5.56
3.23 3.41 3.31 3.30
5.66 5.69
3.16 3.16
Ozone-Poly cyclic Mole Ratio
1.0 0.6 1.0 1.0 1.0 1.5 1.0 3.5
" See Ref. 2. "Reaction conditions: ozonation at — 7 8 ° C . in methylene chloride or 3:1 methylene chloride: methanol, followed by alkaline hydrogen peroxide workup (unless otherwise stated). Ozonation of 7 and 11 also produced 13 (4% and 2%, respectively). These yields are not included in either K- or L - region product totals since the site of ozone attack to produce 13 is unknown. l-(o-Carboxyphenyl)-2-naphthoic acid. 1,4-Dimethyl-3-hydroxymethyl-2-phenylnaphthalene-2 -carboxylic acid. Yield of biphenyl from the presumed primary ozonation product, 2,2',3,4,5-pentacarboxybiphenyl. 0
d
/
c
Mayo; Oxidation of Organic Compounds Advances in Chemistry; American Chemical Society: Washington, DC, 1968.
65.
MORICONI
Polycyclic
A N D SALCE
r e a c t i v i t y of the L - r e g i o n ( 1 4 %
71
Aromatics
of 1 2 ) , a n d decreased the o v e r - a l l ease
of o z o n a t i o n of 7 r e l a t i v e to 6. T h e y i e l d s of K - r e g i o n cleavage p r o d u c t s , u n d e r the same c o n d i t i o n s of o z o n a t i o n v a r y f r o m 0 - 4 5 %
(Table I).
E v e n c o n s i d e r i n g the e x p e r i
m e n t a l errors i n v o l v e d i n o z o n a t i o n a n d o x i d a t i v e w o r k u p , there is n o s i m p l e , observable c o r r e l a t i o n b e t w e e n the P u l l m a n s ' t h e o r e t i c a l K - r e g i o n values a n d the r e a c t i v i t y of these sites to e l e c t r o p h i l i c ozone. A l t h o u g h three of the c o m p o u n d s l i s t e d i n T a b l e L - r e g i o n s , the most potent carcinogens
I have
( 2 , 3, 6, a n d 7) d o not.
formal Two
( 6 a n d 7) c a n be c o n s i d e r e d to h a v e s u c h sites w h o s e a c t i v i t y has b e e n suppressed b y a f u s e d r i n g , a n d t w o ( 2 a n d 3 ) are essentially s u b s t i t u t e d at the L - r e g i o n . T h u s , the o z o n a t i o n results for these f o u r c o m p o u n d s , summarized in Table
I, cannot
t r u l y be c o n s i d e r e d
L-region quinoid
p r o d u c t s . D e s p i t e this, the r e l a t i v e y i e l d s of s u c h q u i n o n e s c l e a r l y s h o w a n inverse r e l a t i o n s h i p b e t w e e n the theoretical, p r e d i c t e d l o w L - r e g i o n a c t i v i t y a n d the course of the ozone reaction. T o s u m u p , a c o m p a r i s o n of the o b s e r v e d r e l a t i v e r e a c t i v i t y of 7 a n d 11 to ozone w i t h that p r e d i c t e d b y P u l l m a n s ' t h e o r e t i c a l calculations (30, 32), a n d a n analysis of a l l the a v a i l a b l e o z o n a t i o n d a t a l e a d us to c o n c l u d e that there is no s i m p l e , consistent c o r r e l a t i o n b e t w e e n c a r c i n o Aromatic
Hydrocarbons
Actual % Yields of K- and L-Region Ozonation Products
b
Total K-Region Cleavage Products 32 30 42 45 14* 4 0 13' c
C
L-Region Quinoid Products 0 0 10 0 29 32 27-30* 14' 9
h
% Recovery Unreacted Polycyclic Aromatic 28 40 32.5 0 0 0 60-65 56
Carcinogen Potency 0
+ + ++ ++++ ++++ ++++ ++++
Total yield of 14 and 15. ' Composed of 23% of benz[a]anthracene-7,12-dione and 6% of 1,2-anthraquinonedicarboxylic acid. Composed of 15% of 8,9-dimethylbenz[a]anthracene-7,12-dione and 18% of 1,2dimethylanthraquinone. Undoubtedly the yields of primary ozonization products, 9-methylbenz[a]anthracene-7,12-dion-8-acetic acid, and 2-methyl-5,6-dicarboxyanthraquinon-1-acetic acid are higher. No alkaline hydrogen peroxide workup required. Compound 12. r
,l
1
J
Mayo; Oxidation of Organic Compounds Advances in Chemistry; American Chemical Society: Washington, DC, 1968.
72
OXIDATION
O F ORGANIC
COMPOUNDS—HI
g e n i c i t y , K - a n d L - r e g i o n a d d i t i v i t y t o w a r d s ozone, a n d the P u l l m a n s ' electronic t h e o r y of carcinogenesis. F i n a l l y , even t h e o b s e r v a t i o n (14, 21) that the m e t a b o l i c reactions l i k e l y to b e r e l a t e d to the course of these ozone reactions are those of detoxification rather t h a n of c a r c i n o g e n i c r e s p o n s i b i l i t y is n o t w i t h o u t exception—cf., e.g., the seven m e t a b o l i c o x i d a t i o n p r o d u c t s of 5 (22) to the single o z o n a t i o n p r o d u c t (24).
Acknowledgment T h i s research e x t e n d i n g over a d e c a d e w a s e n t i r e l y s u p p o r t e d b y U . S . P u b l i c H e a l t h Service grants f r o m t h e N a t i o n a l C a n c e r Institute, t h e most recent of w h i c h h a v e b e e n CA-07808-01-3. T h i s p a p e r c o n c l u d e s t h e series e n t i t l e d " O z o n o l y s i s of P o l y c y c l i c A r o m a t i c s " [ P a p e r I, (34); Paper X I V , (26)].
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