Nucleophilic Reactions of Superoxide Anion Radical - ACS Publications

14 Nucleophilic Reactions of Superoxide Anion Radical WAYNE C. DANEN,* R. JAY WARNER, and RAVINDRA L . ARUDI

Downloaded by PENNSYLVANIA STATE UNIV on February 26, 2013 | http://pubs.acs.org Publication Date: June 1, 1978 | doi: 10.1021/bk-1978-0069.ch014

Department of Chemistry, Kansas State University, Manhattan, KS

66506

Superoxide i o n , O , is the anion r a d i c a l d e r i v e d by a d d i t i o n of an e l e c t r o n to molecular oxygen. I t is one of the simplest anion r a d i c a l s and, undoubtedly, the most important. This species is capable of r e a c t i n g with a v a r i e t y of substrates owing to its a n i o n i c , r a d i c a l , and redox nature although the n u c e o p h i l i c and reducing e l e c t r o n t r a n s f e r processes appear to be the predominate r e a c t i o n pathways. T h i s r e p o r t will attempt to review the important f e a t u r e s of the n u c l e o p h i l i c behavior o f O with w e l l - d e f i n e d chemical r e a c t a n t s . No attempt will be made to cover the vast biochemical l i t e r a t u r e i n v o l v i n g o r implicating O . Although O i s a s t a b l e anion r a d i c a l , e a s i l y generated or even a v a i l a b l e commercially as the potassium s a l t , its chemical behavior has r e c e i v e d s i g n i f i c a n t a t t e n t i o n only w i t h i n the l a s t s e v e r a l years. Chemical i n t e r e s t was spawned by the d i s c o v e r y o f F r i d o v i c h and coworkers (1) that superoxide dismutase, an enzyme present i n all aerobic organisms s t u d i e d , has as its f u n c t i o n the dismutation o f O i n t o H O and O (equation 1 ) . Since 2

2

2

2

2

2

2

2

superoxide dimutase is so common among r e s p i r i n g organisms, O i s thought to be a d e l e t e r i o u s s p e c i e s whose c y t o t o x i c i t y has promoted the e v o l u t i o n o f such defenses. In f a c t , superoxide has been suggested to be i n v o l v e d i n v a r i o u s b i o l o g i c a l d i s o r d e r s such as r a d i a t i o n damage to t i s s u e , cancer, aging processes and oxygen t o x i c i t y ; i t may have b e n e f i c i a l e f f e c t s i n b i o l o g i c a l defense mechanisms. Chemical s t u d i e s have employed e i t h e r e l e c t r o g e n e r a t e d O or s o l u t i o n s or suspensions of Ko . D i p o l a r a p r o t i c s o l v e n t s are u s u a l l y used i n e i t h e r case as O i s q u i t e s e n s i t i v e to proton sources. The e l e c t r o g e n e r a t e d tetraalkylammonium superoxides are both s o l u b l e and s t a b l e i n a v a r i e t y o f d i p o l a r a p r o t i c s o l v e n t s (DMSO, DMF, CH CN, p y r i d i n e , acetone) ( 2 ) . The 2

2

2

2

3

© 0-8412-0421-7/78/47-069-244$05.00/0

In Organic Free Radicals; Pryor, W.; ACS Symposium Series; American Chemical Society: Washington, DC, 1978.

14.

DANEN E TAL.

Superoxide

Anion

Radical

245

s o l u b i l i t y of K 0 i n such solvents i s not p a r t i c u l a r l y high, e.g., the estimated concentration of saturated K 0 i n DMSO i s only about 0.02 M (3). However, the use of crown ethers such as 18-crown-6 g r e a t l y enhances the s o l u b i l i t y of K 0 (4) and the commercial a v a i l a b i l i t y of both K 0 and crown ethers has r e s u l t ed i n t h e i r r a t h e r common usage f o r chemical s t u d i e s of 0 ~. Superoxide ion e x h i b i t s s p e c t r a l p r o p e r t i e s i n the u l t r a v i o l e t region. The ^ f o r 0 ~ i s 250 nm i n a c e t o n i t r i l e with a reported e x t i n c t i o n c o e f f i c i e n t of 2580+300 Μ " ™ " (5). The reduction p o t e n t i a l f o r oxygen i n DMSO i s -0.77 V versus SCE (2) and the pK f o r Η00·, the conjugate a c i d of 0 ~, has been determined to be 4.8 (6). 2

2

2

2

2

m

a

x


1

a

I.

1

2

Reactions with A l k y l Halides and Sulfonate

Esters

A. Mechanism. A l k y l h a l i d e s undoubtedly represent the most w e l l - t e s t e d f u n c t i o n a l group f o r n u c l e o p h i l i c r e a c t i v i t y . That superoxide ion r e a c t s with a l k y l h a l d i e s by an S^2 mechanism has been demonstrated. D i e t z , e t a l . , (7), observed a r e l a t i v e r e a c t i v i t y which f e l l i n the s e r i e s n-BuBr > sec-BuBr > i-BuBr > t-BuBr f o r v a r i a t i o n of a l k y l group s t r u c t u r e and i n the s e r i e s n-BuBr > n-BuOTs > n-BuCl f o r v a r i a t i o n of l e a v i n g group. The former order i s c o n s i s t e n t with a S^2 r e a c t i o n mechanism and the l a t t e r order suggests that superoxide anion r a d i c a l i s a strong n u c l e o p h i l e . Results obtained by San F i l i p p o and co-workers (8) p a r a l l e l ed those of D i e t z concerning substrate r e a c t i v i t y but i n d i c a t e d f u r t h e r that s u b s t i t u t i o n was predominant with primary h a l i d e s , whereas s u b s t a n t i a l e l i m i n a t i o n occurred with secondary and t e r t i a r y systems. These workers, as w e l l as Johnson and Nidy (9) reported the e s s e n t i a l l y complete i n v e r s i o n of c o n f i g u r a t i o n at the c h i r a l center i n the carbon-oxygen bond formation which i s t y p i c a l of a S^2 Walden i n v e r s i o n mechanism (eq. 2 ) .

C

H

\ 2

H

6 13 1. K0..DMS0

H-'V CH

/6 13

2. H 0 o

2 3

/ V CH

H

3

In a s i m i l a r manner, Corey, e t a l . , (10) have reported that the p-toluenesulfonate of trans-4-t-butylcyclohexanol was con verted i n t o pure c i s - 4 - t - b u t y l c y c l o h e x a n o l i n 95% y i e l d (eq. 3) i n DMSO-DME. Likewise, the cis-methanesulfonate was transformed i n t o pure trans-4-t-butylcyclohexanol i n 96% y i e l d .


ORGANIC F R E E


246

RADICALS

These workers (10,11) have a l s o u t i l i z e d to achieve an important s y n t h e t i c o b j e c t i v e i n the p r o s t a g l a n d i n f i e l d , namely the e f f i c i e n t conversion of 15-R (unnatural) p r o s t a g l a n d i n s i n t o the 15-S^ (natural) isomers by n u c l e o p h i l i c displacement. These data a l l demonstrate the S^2 i n v e r s i o n character o f Of r e a c t i n g with a l k y l h a l i d e s and s u l f o n a t e e s t e r s . As noted by equation 2, the a l c o h o l i s the u l t i m a t e r e a c t i o n product i n DMSO s o l v e n t ^ However, there are s e v e r a l r e a c t i o n s that take p l a c e when 02* i s mixed with an a l k y l h a l i d e . Equa t i o n s 4-10 l i s t the o v e r a l l mechanism o r i g i n a l l y proposed by

+

RX

• Η0 · 2

H0 '

+

R0 -

+

V

R0 ~

+

RX

R0 ""

+

Me S0

2

2

2

2

« # ——

+

X

R(-H)

+

H0 *

H

•

2

+ Χ"

2

+

+

H0 "

+

R0 "

+

R0 R 2

+

R0~

+

2

•

(4)

R0 · ζ

2

(5) (6) (7)

°2

(8)

°2 X~

(9)

Me S0 2

2

(10)

D i e t z , e t a l . , (7) which was subsequently expanded by G i b i a n and Ungermann (12). The course of the r e a c t i o n i s dependent upon both the a l k y l h a l i d e s t r u c t u r e and the r e a c t i o n solvent. For a primary a l k y l h a l i d e , the displacement o f h a l i d e i o n (eq. 4) i s dominant over the e l i m i n a t i o n r e a c t i o n (eq. 5) as determined by product a n a l y s i s ; e.g., f o r the r e a c t i o n of KO2 with 1-bromooctane and 2-bromooctane i n DMSO, o l e f i n s were i s o l a t e d i n y i e l d s of 1% and 34%, r e s p e c t i v e l y (8). I t i s apparent that secondary h a l i d e s give s i g n i f i c a n t o l e f i n y i e l d s under these experimental conditions. The ΗΟ2· formed i n equation 5 may i o n i z e to super oxide (eq. 6) or be reduced (eq. 7 ) . The bulk r e a c t i o n o f the a l k y l peroxy r a d i c a l with 0 " (eq. 8) i s the analogue to equation 9


14.

DANEN E T A L .

Superoxide

Anion

Radical

247

7 and i s e q u a l l y exothermic. F i n a l l y , the peroxy anion can under go e i t h e r r e a c t i o n 9 o r 10 to form products. The displacement r e a c t i o n o f RO2"" with an a l k y l h a l i d e i s q u i t e f a c i l e but equa t i o n 10 i s favored by a t l e a s t a f a c t o r of four when DMSO i s the solvent (12). Equation 9 can be made the p r i n c i p a l r e a c t i o n pathway and Johnson and Nidy (9) have reported a convenient and s y n t h e t i c a l l y u s e f u l p r e p a r a t i o n of d i a l k y l peroxides using benzene as solvent and s o l u b i l i z i n g the K 0 with crown ethers. A l c o h o l s were f r e q u e n t l y formed as by-products, probably r e s u l t i n g from reduc t i o n of the d i a l k y l peroxides with 0 ~ (13). I n t e r e s t i n g l y , Corey, e t a l . , (ΙΟ) produced a c y c l i c per oxide i n DMSO. The peroxide shown i n equation 11 was formed


2

2

CH ÇHCH CHCH CH C H

CH CHCH CHCH CH C.H, 0

31

OMs

0

0

Z|

Ζ

3

0

2

2

2

6

5

Z D .

OO" OMs

OMs

(11)

i n 35% y i e l d i n DMSO. Apparently, the c l o s e proximity o f the second mesylate group i n the proposed peroxy mesylate allowed the i n t r a m o l e c u l a r c y c l i z a t i o n process to compete f a v o r a b l y with r e a c t i o n with DMSO. Such a process may be of value i n the synthesis o f b i o l o g i c a l l y important p r o s t a g l a n d i n endoperoxides. B. K i n e t i c s o f Reaction with A l k y l H a l i d e s (14). P r i o r to the work of Danen and Warner, (14,15) few r a t e constants f o r the r e a c t i o n of 0 ~ with a l k y l h a l i d e s had been reported. In an e l e c t r o c h e m i c a l study, M e r r i t t and Sawyer (16) had determined the p s e u d o - f i r s t - o r d e r r a t e constants a t 28°C f o r three b u t y l c h l o r ides i n DMSO s o l v e n t . In a s i m i l a r manner, D i e t z , e t a l . , (7) had reported a p s e u d o - f i r s t - o r d e r _ r a t e constant f o r 1-bromobutane r e a c t i n g with electrogenerated 0 * i n DMF c o n t a i n i n g t e t r a - n butylammonium p e r c h l o r a t e . San F i l i p p o and coworkers (8) had determined the r e l a t i v e r e a c t i v i t y of s e v e r a l a l k y l h a l i d e s but had not reported any absolute r a t e constants. Danen and Warner (15) have reported the r a t e constants i n Table I f o r r e a c t i o n of K 0 i n DMSO w i t h a s e r i e s o f a l k y l bromides. The r a t e s were determined by stopped-flow spectrophoto metry under p s e u d o - f i r s t - o r d e r c o n d i t i o n s . The usual r e a c t i v i t y order c h a r a c t e r i s t i c of a S^2 process was evident i n the s e r i e s MeBr > EtBr > n-BuBr > jl-PrBr >> 1-bromoadamantane, which r e f l e c t s the i n c r e a s i n g i n a c c e s s i b i l i t y of the r e a c t i o n center. However, the 10-fold d i f f e r e n c e i n r e a c t i v i t y between C ^ B r and i - P r B r i s smaller than f r e q u e n t l y observed; S t r e i t w i e s e r (17) noted a 1000-fold d i f f e r e n c e i n average r e l a t i v e r e a c t i v i t y 2

2

2

American Chemical Society Library

In Organic Free Radicals; Pryor, W.; 1155 Chemical 16th at.Society: N. W.Washington, DC, 1978. ACS Symposium Series; American

ORGANIC F R E E

248 Table I.

Rate Constants f o r the Reaction of K 0 Bromides i n DMSO a t 25.0° A l k y l Bromide

k^

CH Br 3

CH CH Br 3

2

CH (CH ) Br Downloaded by PENNSYLVANIA STATE UNIV on February 26, 2013 | http://pubs.acs.org Publication Date: June 1, 1978 | doi: 10.1021/bk-1978-0069.ch014

3

2

3

(CH ) CHBr 3

2

RADICALS

with A l k y l

2

1

(M^s

)

(6.7 + 0.2)

χ

10

2

(3.5 + 0.2)

χ

10

2

(1.5 + 0.1)

χ

10

2

(6.5 + 0.1)

χ

10

1

a

1-bromoadamantane

adding i n n u c l e o p h i l i c fashion to a carbon-carbon double bond. Although the r e a c t i o n mechanisms were not e l u c i d a t e d i n d e t a i l , i n both r e p o r t s the double bond was a c t i v a t e d f o r n u c l e o p h i l i c a d d i t i o n . Benzylidenefluorene, a hydrocarbon s u s c e p t i b l e to nucleo p h i l i c attack, was shown by D i e t z , e t a l . (7) to react w i t h electrogenerated 0 * i n the presence of 0 to produce fluorenone and benzoate. I t was proposed that 0 ~ i n i t i a t e d an autoxidat i o n r e a c t i o n (equation 24); one equivalent of 0 " was necessary to remove the hydrocarbon completely. T

2

2

2

2

2


14.

DANEN E T A L .

Superoxide Anion Radical

253


(24)

C H C0 6

5

2

These authors a l s o showed that e l e c t r o g e n e r a t e d reacted with cyclohexen-3-one to give the corresponding epoxide i n 30% y i e l d (equation 25). Cyclohexene, i n c o n t r a s t , gave no epoxide implying that a double bond a c t i v a t e d towards a Michael-type of addition i s required.

0 II

Ο

ι

ο

(25)

C. E l e c t r o n T r a n s f e r Reactions Mimicking N u c l e o p h i l i c Attack. There are s e v e r a l r e p o r t s i n which 0 nominally appears to r e a c t as a n u c l e o p h i l e but, i n f a c t , i n v o l v e an i n i t i a l e l e c t r o n - t r a n s f e r from 0 ~ followed by r e a c t i o n of 0 with the r a d i c a l anion generated from the organic s u b s t r a t e . These r e s u l t s appear appropriate f o r t h i s review. There are c e r t a i n l y other r e a c t i o n s which occur by such a process i n s t e a d of a simple n u c l e o p h i l i c displacement but i s o t o p i c l a b e l i n g s t u d i e s or c h i r a l reactants must be u t i l i z e d to d i s t i n g u i s h between the two mechanisms. Because of the r e l a t i v e l y low r e d u c t i o n p o t e n t i a l f o r 0 , -0.77 V versus SCE (2), any substrate with a more negative r e d u c t i o n p o t e n t i a l w i l l l i k e l y be reduced by 0 * v i a an e l e c t r o n t r a n s f e r process. Depending upon the substrate, the u l t i m a t e product(s) of such a r e a c t i o n may or may not resemble those expected from a simple n u c l e o p h i l i c r e a c t i o n . Frimer and Rosenthal (25) have demonstrated that the r e a c t i o n of 0 * with n i t r o s u b s t i t u t e d aromatic h a l i d e s occurs v i a an e l e c t r o n t r a n s f e r from 0 ' to the s u b s t i t u t e d benzene to y i e l d the anion r a d i c a l which i s subsequently scavenged by molecular oxygen (equation 26). They were able to d i s t i n g u i s h t h i s r e a c t i o n pathway from d i r e c t a d d i t i o n of 0 ' to the aromatic r i n g as i n normal n u c l e o p h i l i c aromatic s u b s t i t u t i o n by u t i l i z i n g T

2

2

2

2

2

2

2

2



254

ORGANIC F R E E

RADICALS

l^O-enriched Κ 0 · By conducting the r e a c t i o n with enriched K 0 i n benzene saturated with unlabeled 0 , mass s p e c t r o s c o p i c a n a l y s i s o f the r e s u l t i n g phenol revealed the presence of an 0 tag of l e s s than 10%. T h i s r e s u l t implied that the phenolic oxygen was i n c o r p o r a t e d i n l a r g e p a r t a f t e r the e q u i l i b r a t i o n with molecular oxygen d i s s o l v e d i n s o l u t i o n . Dougherty, e t a l . , (26) have observed a s i m i l a r r e a c t i o n i n the gas phase. The negative chemical i o n i z a t i o n s p e c t r a of 4-bromobenzophenone, 4-nitrochlorobenzene, and 2 , 4 - d i n i t r o c h l o r o benzene were a l l replaced by s p e c t r a o f the corresponding phenolate anions when 0 * was generated i n the system. Another nominally n u c l e o p h i l i c r e a c t i o n of 0 * i s the e f f i c i e n t production of c a r b o x y l i c a c i d s from chalcones (equation 27). Rosenthal and Frimer (27) have also studied t h i s r e a c t i o n 2

2

2

2

2

R

K§)^- = -©^ CH

CH

ι 0

*-@-C0H +

0 R-@>-C0H

0 +

R--CH C0H 2

18 utilizing O-enriched K 0 and determined that oxygen i s not incorporated i n t o the product c a r b o x y l i c acids by d i r e c t nucleo p h i l i c a t t a c k o f 0 . Instead, the r e a c t i o n proceeds by a p r e l i m i n a r y e l e c t r o n t r a n s f e r from 0 * to the enone system and the r e s u l t i n g anion r a d i c a l then r e a c t s with the surrounding molecular oxygen as d e p i c t e d i n equations 28-32. A s i m i l a r mechanism enabled the understanding of the s u r p r i s i n g formation of 2-hydroxy-2,4,5-triphenylfuranone-3 i n the r e a c t i o n o f K 0 with t e t r a c y c l o n e (28)(equation 33). 2

T

2

2

2


14.

DANEN E T A L .

0 ill R-C-CH=CH-R

Superoxide

Anion

Ο" +

0„

+

0

•CH=CH-R


+

O

(28)

0

o-

Ο ι I R-C-CH=CH-R

255

Radical

(29)

R-C-CH-CH-R

I I

o

0-0

ο

0"

til

-+>

R-C-CH-CH-R

I !

ο -

R-C-0

+

-

M

R-CH-CH

(30)

RCH C0

(31)

0-0 0

SH

II

RCH

CH

0 • II R-CH-CH 0 2 -—»>

0" • R-CH-CH

I

2

0

Il RCH

2

η ^ °2 ^ RC0

o

(32)

I

0—0

(33)

In conclusion of t h i s review of the n u c l e o p h i l i c p r o p e r t i e s of 0 ', the v e r s a t i l e nature of t h i s unique anion r a d i c a l should be emphasized. T h i s chapter attempted to cover only the main features of the n u c l e o p h i l i c r e a c t i o n s o f 02* with w e l l - d e f i n e d chemical substrates; no attempt was made to t r e a t any of the biochemical r e a c t i o n s . Moreover, i n a d d i t i o n to n u c l e o p h i l i c properties, i s capable o f r e a c t i n g as a free r a d i c a l as w e l l as an e l e c t r o n t r a n s f e r agent or e l e c t r o n acceptor. Thus, the understanding of t h i s ubiquitous anion r a d i c a l i s probably only i n i t s l a t e infancy even though a computer search o f the 1972mid 1977 Chemical Abstracts revealed 850 references to "super oxide . 2

11

III.

Acknowledgement This work was w r i t t e n while W. C. Danen was on s a b b a t i c a l


ORGANIC F R E E RADICALS

256

leave a t the Los Alamos S c i e n t i f i c Laboratory, Los Alamos, New Mexico. T h i s author would l i k e to express h i s a p p r e c i a t i o n to the personnel of AP D i v i s i o n , i n p a r t i c u l a r John H. B i r e l y and Samuel M. Freund, f o r t h e i r h o s p i t a l i t y during that time. IV.

Literature Cited

(1)

F r i d o v i c h , I . , A c c t . Chem. Res., (1972), 5, 321, and references t h e r e i n . Peover, M. E., and White, B. S., E l e c t r o c h i m . A c t a , (1966), 11, 1061. Danen, W. C., and A r u d i , R. L., unpublished r e s u l t s . V a l e n t i n e , J . S., and C u r t i s , A. B., J . Amer. Chem. Soc., (1975), 97, 224. Fee, J. Α., and Hildenbrand, P. G., FEBS L e t t . , (1974), 39, 79. Behar, D., Czapski, G., Rabani, J . , Dorfman, L. Μ., and Schwarz, Η. Α., J. Phys. Chem., (1970), 74, 3209. D i e t z , R., Forno, A. E. J . , Larcombe, Β. Ε., and Peover, M. E., J. Chem. Soc. (Β), (1970), 816. San F i l i p p o , J r . , J., Chem, C-I., and V a l e n t i n e , J . S., J . Org. Chem., (1975), 40, 1678. Johnson, R. Α., and Nidy, E. G., J . Org. Chem., (1975), 40, 1680. Corey, E. J., Nicolaou, K. C., Shibasaki, Μ., Machida, Υ., and Shiner, C. S., Tetrahedron L e t t . , (1975), 3183. Corey, E. J., Nicolaou, K. C., and Shibasaki, Μ., J.C.S. Chem. Comm., (1975), 658. Gibian, M. J . , and Ungermann, T., J. Org. Chem., (1976), 41, 2500. P e t e r s , J. W., and Foote, C. S., J. Amer. Chem. Soc., (1976) 98, 873. These authors r e p o r t the r e a c t i o n o f O w i t h hydroperoxides. D i - t - b u t y l peroxide was reported to be unreactive but the primary and secondary d i a l k y l peroxides generated by Johnson and Nidy (9) may be more s u s c e p t i b l e to r e d u c t i o n . This s e c t i o n taken l a r g e l y from the M.S. t h e s i s of R. Jay Warner, Kansas State U n i v e r s i t y , 1976. Danen, W. C., and Warner, R. J . , Tetrahedron L e t t . , (1977), 989. M e r r i t t , M. V., and Sawyer, D. T., J. Org. Chem., (1970), 35, 2157. S t r e i t w i e s e r , J r . , Α., " S o l v o l y t i c Displacement Reactions," p. 13, McGraw-Hill Book Co., New York, N.Y., (1962). Danen, W. C., and Warner, R. J . , unpublished r e s u l t s . Hine, J . , Thomas, C. Η., and Ehrenson, S. J., J. Amer. Chem. Soc., (1955), 77, 3886. Hine, J . , and Brader, W. H., J. Amer. Chem. Soc., (1953), 75, 3964. Reference 17, p. 16. Johnson, R. Α., Tetrahedron L e t t . , (1976), 331.


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2

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14.

DANEN E TA L .

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Superoxide

Anion

Radical

257

San F i l i p p o , J r . , J., Romano, L. T., Chem, C-I. and V a l e n t i n e , J . S., J . Org. Chem., (1976), 41, 586. Magno, F., and Bontempelli, G., J . E l e c t r o a n a l . Chem., (1976), 68, 337. Frimer, Α., and Rosenthal, I . , Tetrahedron L e t t . , (1976), 2809. Levonowich, P. F., Tannenbaum, H. P., and Dougherty, R. C., J.C.S. Chem. Comm., (1975), 597. Rosenthal, I . , and Frimer, Α., Tetrahedron L e t t . , (1976), 2805. Rosenthal, I . , and Frimer, Α., Tetrahedron L e t t . , (1975), 3731.

R E C E I V E D D e c e m b e r 23, 1977.


Nucleophilic Reactions of Superoxide Anion Radical - ACS Publications

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