OZONE CHEMISTRY AND TECHNOLOGY

Ozonolysis of 4,22-Stigmastadien-3-one GEORGE SLOMP, Jr., and JAMES L. J O H N S O N

Downloaded by CORNELL UNIV on August 5, 2016 | http://pubs.acs.org Publication Date: January 1, 1959 | doi: 10.1021/ba-1959-0021.ch025

Research Laboratories, Upjohn Co., Kalamazoo, Mich.

The ozonolysis reaction was used to prepare the steroidal aldehyde, 3-ketobisnor-4-cholen-22-al from 4,22-stigmastadien-3-one. Methylene chloride was used as the solvent. W h e n aldehydes are prepared by ozonolysis, exactly the right amount of ozone must be a d d e d . A n infrared method makes it possible to follow quantitatively the rate of disappearance of double bonds a n d locate the end point exactly.

The o z o n o l y s i s r e a c t i o n h a s b e e n u s e d w i d e l y as a n a n a l y t i c a l t o o l f o r d e t e r m i n a t i o n of t h e s t r u c t u r e of olefins. A n excess of ozone i s u s u a l l y a d d e d a n d t h e s t r u c t u r e i s deduced f r o m whatever products c a n be isolated. I n this structure w o r k there is a r a t h e r b r o a d choice of s o l v e n t s . O z o n o l y s i s h a s b e c o m e m o r e u s e f u l of l a t e as a s y n t h e t i c m e t h o d . T h e a u t h o r s w i s h e d t o use t h e o z o n o l y s i s r e a c t i o n f o r t h e p r e p a r a t i o n of t h e s t e r o i d a l a l d e h y d e , 3-ketobisnor-4-cholen-22-al ( I I ) , f r o m 4,22-stigmastadien-3-one ( I ) .

I

II

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H e r e t h e objective was to cleave t h e side-chain double b o n d selectively a n d , at the s a m e t i m e , t o k e e p t h e n u c l e a r d o u b l e b o n d i n t a c t . T h i s i s a r e a s o n a b l e o b j e c t i v e , as t h e s i d e - c h a i n d o u b l e b o n d has a m u c h h i g h e r e l e c t r o n d e n s i t y t h a n t h e n u c l e a r d o u b l e b o n d w h i c h i s c o n j u g a t e d w i t h t h e e l e c t r o n - w i t h d r a w i n g c a r b o n y l g r o u p a n d , hence, the isolated b o n d s h o u l d react m u c h m o r e r a p i d l y w i t h the electrophilic ozone. I n u s i n g t h e o z o n o l y s i s r e a c t i o n as a p r e p a r a t i v e m e t h o d f o r a l d e h y d e s , c e r t a i n l i m i t i n g c o n s i d e r a t i o n s a r e i m m e d i a t e l y e n c o u n t e r e d . T h e r e i s a m o r e l i m i t e d choice of s o l v e n t s , a n d a n excess of ozone s h o u l d b e a v o i d e d . E t h y l acetate h a s f r e q u e n t l y b e e n u s e d as a s o l v e n t f o r o z o n o l y s i s r e a c t i o n s . I t r e a d i l y dissolves a v a r i e t y of c o m p o u n d s , b u t i n t h e p r e p a r a t i o n of a l d e h y d e s i t i s n o t a g e n e r a l l y s a t i s f a c t o r y s o l v e n t , as l a r g e a m o u n t s of acids a r e f o r m e d [ p o s s i b l y because of t h e presence of some e t h a n o l 162

OZONE CHEMISTRY AND TECHNOLOGY Advances in Chemistry; American Chemical Society: Washington, DC, 1959.

SLOMP A N D J O H N S O N - 4 , 22-STIGMASTADIEN-3-ONE

163


(1) ] . F o r m i c a n d acetic acids h a v e p r o v e d p a r t i c u l a r l y g o o d f o r t h e p r e p a r a t i o n of some a l d e h y d e s , b u t t h e s o l u b i l i t y of s t i g m a s t a d i e n o n e i n these s o l v e n t s i s l o w . C e r t a i n halogenated h y d r o c a r b o n solvents, w h i c h dissolved more stigmastadienone, have b e e n i n v e s t i g a t e d . W h e n ozone w a s p a s s e d i n t o c h l o r o f o r m ( s t a b i l i z e d w i t h e t h a n o l ) a t — 60° C , s o m e of t h e ozone r e a c t e d , p r e s u m a b l y w i t h t h e e t h a n o l , t o f o r m a c i d i c materials. W h e n the experiment was repeated on methylene chloride at —78°, a s a t u r a t e d s o l u t i o n of ozone i n m e t h y l e n e c h l o r i d e w a s f o r m e d , deep b l u e i n c o l o r , f r o m w h i c h n e a r l y a l l of t h e ozone c o u l d b e r e c o v e r e d b y s p a r g i n g w i t h n i t r o g e n . T h i s s o l v e n t w a s t h e r e f o r e c h o s e n f o r t h e o z o n o l y s i s of s t i g m a s t a d i e n o n e . W h e n a l d e h y d e s a r e p r e p a r e d b y o z o n o l y s i s , e x a c t l y t h e c o r r e c t a m o u n t of ozone m u s t b e a d d e d , because excess ozone c o n v e r t s a l d e h y d e s t o a c i d s a n d p e r a c i d s . I n a d d i t i o n , a l c o h o l s , ethers, d o u b l e b o n d s , o r o t h e r f u n c t i o n a l g r o u p s p r e s e n t i n t h e m o l e c u l e m a y be a t t a c k e d . T h i s b r i n g s u p t h e p r o b l e m of d e t e r m i n i n g w h e n t o s t o p t h e o z o n o l y s i s r e a c t i o n . T h e t h e o r e t i c a l a m o u n t o f ozone m a y b e a d d e d , b u t s e v e r a l cases a r e r e c o r d e d i n w h i c h m o r e t h a n one m o l a r e q u i v a l e n t of o z o n e i s r e q u i r e d t o cleave o n e d o u b l e b o n d . O n e m a y s t o p w h e n ozone a p p e a r s i n t h e effluent gas f r o m the reactor. H o w e v e r , p r e l i m i n a r y experiments have shown t h a t a t this l o w t e m p e r a t u r e ozone begins t o o v e r f l o w v e r y s o o n a f t e r t h e r e a c t i o n h a s s t a r t e d . A m o r e useful m e t h o d has been t o stop t h e ozonolysis w h e n t h e reaction m i x t u r e n o longer shows u n s a t u r a t i o n . T h i s m a y b e d e t e c t e d q u a l i t a t i v e l y b y t h e use of b r o m i n e i n c a r b o n tetrachloride, t e t r a n i t r o m e t h a n e , etc. A n i n f r a r e d m e t h o d makes i t possible to f o l l o w q u a n t i t a t i v e l y t h e r a t e of d i s a p p e a r a n c e of t r a n s d o u b l e b o n d s a n d t o l o c a t e t h e end p o i n t more exactly. T h e m e t h o d was a p p l i e d to the ozonolysis of stigmastadienone w i t h good results. T h e o z o n o l y s i s w a s p e r f o r m e d i n m e t h y l e n e c h l o r i d e , a n d a l i q u o t s of t h e r e a c t i o n m i x t u r e were r e m o v e d a t t i m e d i n t e r v a l s a n d assayed b y t h e i n f r a r e d m e t h o d f o r the a m o u n t s of e a c h d o u b l e b o n d r e m a i n i n g . P o r t i o n s of some of t h e s p e c t r a w h i c h were o b t a i n e d a r e s h o w n i n F i g u r e 1. T h e a b s o r p t i o n of t h e s i d e - c h a i n d o u b l e b o n d a p pears a t 10.26 m i c r o n s , of t h e n u c l e a r d o u b l e b o n d a t 6.2 m i c r o n s , a n d of t h e a l d e h y d e s (2) f o r m e d b y t h e o z o n o l y s i s of t h e s i d e - c h a i n d o u b l e b o n d a t 5.86 m i c r o n s . B y u s i n g the b a s e - l i n e t e c h n i q u e of H e i g l , B e l l , a n d W h i t e (4), i t w a s possible t o c a l c u l a t e t h e a m o u n t of s i d e - c h a i n d o u b l e b o n d p r e s e n t i n e a c h s a m p l e . T h e a m o u n t s of n u c l e a r d o u b l e b o n d a n d of a l d e h y d e p r e s e n t w e r e also c a l c u l a t e d . T h e s e r e s u l t s a r e r e c o r d e d g r a p h i c a l l y i n F i g u r e 2. T h e s e d a t a n o w i n d i c a t e e x a c t l y w h e n t o s t o p t h e o z o n o l y s i s r e a c t i o n so as t o h a v e m a x i m u m selectivity: a t t h e point i n t h e χ axis where t h e t w o double-bond dis a p p e a r a n c e c u r v e s a r e t h e f a r t h e s t a p a r t — i . e . , 1.1 ± 0.5 m o l a r e q u i v a l e n t s o f ozone. T h e y i e l d o f a l d e h y d e s h o u l d b e 7 0 t o 8 5 % a n d s h o u l d c o r r e s p o n d t o t h e s e p a r a t i o n of the t w o curves o n t h e y axis. T h e a l d e h y d e f o r m a t i o n c u r v e g a v e e v i d e n c e t h a t t h e cleavage of one m o l e o f s i d e c h a i n d o u b l e b o n d y i e l d e d one m o l e o f a l d e h y d e , t h e o t h e r e n d of t h e d o u b l e b o n d b e i n g c o n v e r t e d t o s o m e t h i n g else. T h i s w a s i n a g r e e m e n t w i t h t h e r e s u l t s o b s e r v e d b y C r i e g e e (1). T h e ozonolysis was therefore repeated u n d e r a v a r i e t y of conditions a n d n e w curves were c o n s t r u c t e d f o r e a c h . T h e r e s u l t s w e r e b e s t a t l o w t e m p e r a t u r e (—78° C . w a s b e t t e r t h a n — 5 3 ° C ) , a t a h i g h olefin c o n c e n t r a t i o n (as h i g h as t h e s o l u b i l i t y l i m i t a t i o n s w o u l d p e r m i t ) , i n n o n p o l a r s o l v e n t s , a n d w i t h a s m a l l a m o u n t of p y r i d i n e p r e s e n t i n t h e s o l v e n t . T h e d r a m a t i c effect o f t h e i n c l u s i o n o f a p p r o x i m a t e l y 1 % p y r i d i n e i s s h o w n i n F i g u r e 3. T h e s e l e c t i v i t y w a s g r e a t l y i m p r o v e d , t h e n u c l e a r d o u b l e b o n d r e maining intact u n t i l the side-chain double b o n d h a d almost completely reacted. T h e a l d e h y d e f o r m a t i o n c u r v e i n d i c a t e s t h a t a p p r o x i m a t e l y t w o m o l e c u l e s of a l d e h y d e w e r e f o r m e d f r o m t h e cleavage of e a c h d o u b l e b o n d . T h e s e c u r v e s r e p r e s e n t o p t i m a l c o n d i t i o n s a n d w e r e selected f r o m r u n s a t v a r i o u s p y r i d i n e c o n c e n t r a t i o n s . F i g u r e 3 indicates that m a x i m u m selectivity i n t h e p y r i d i n e - m e t h y l e n e chloride s y s t e m s h o u l d b e o b t a i n e d b y u s i n g 1.6 t o 1.7 m o l a r e q u i v a l e n t s of o z o n e . T h e e x p e r i -


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Figure 3.

1 1 ι 1 1 ι 1 ι ι ' ' »· V .6 .7 .8 .9 1.0 I.I 1.2 1.3 1.4 1.5 1.6 1.7 1.8 MOLAR EQUIVALENTS OF OZONE

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Ozonolysis of stigmastadienone in methylene chloride

merits w e r e r e p e a t e d u s i n g t h i s a m o u n t of ozone, t h e m i x t u r e w a s s u b j e c t e d t o z i n c decomposition, a n d the steroidal aldehyde was isolated b y crystallization. T h e yields were i n g o o d agreement w i t h t h e p r e d i c t i o n ( T a b l e I ) . Table I.

Yields of Bisnoraldehyde from Ozonolysis of Stigmastadienone Molar Equiv. Ozone 1.07 1.66

Solvent MeCl MeCls + 0.94% pyridine 2

Yield Predicted 70-85 95

Found 82 94

I t w a s of i n t e r e s t t o c o n s i d e r t h e role of t h e p y r i d i n e i n t h i s o z o n o l y s i s r e a c t i o n . S i x m a , B o e r , a n d W i b a u t (6) h a v e s h o w n t h a t t h e e l e c t r o p h i l i c r e a c t i v i t y o f ozone c a n be c a t a l y z e d b y acids o f t h e L e w i s t y p e . T h i s m a y b e d u e t o t h e f o r m a t i o n of a salt l i k e i n t e r m e d i a t e I V , w h i c h w o u l d be e x p e c t e d t o s h o w e n h a n c e d e l e c t r o p h i l i c r e a c t i v -

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i t y . N u c l e o p h i l i c agents, s u c h as p y r i d i n e a n d p y r i d i n e o x i d e , o n t h e o t h e r h a n d , w o u l d be e x p e c t e d t o f o r m c o m p o u n d s , o r a t least c o m p l e x e s ( i n these n o n p o l a r s o l v e n t s ) s u c h as V , V I , a n d V I I .

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T h e s e , i n t u r n , w o u l d be e x p e c t e d t o s h o w d i m i n i s h e d e l e c t r o p h i l i c r e a c t i v i t y a n d p o s s i b l y , i n some cases, n u c l e o p h i l i c r e a c t i v i t y (a). T h i s m a y e x p l a i n t h e loss of a l d e h y d e w h i c h w a s o b s e r v e d w h e n a l a r g e a m o u n t of p y r i d i n e w a s p r e s e n t d u r i n g t h e ozonolysis r e a c t i o n . W h e t h e r i t is a p y r i d i n e - o z o n e c o m p l e x w h i c h is r e a c t i n g w i t h t h e d o u b l e b o n d s i n a m o r e selective m a n n e r o r w h e t h e r t h e s e l e c t i v i t y arises because of t h e d i m i n i s h i n g


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of t h e i n s t a n t a n e o u s ozone c o n c e n t r a t i o n b y f o r m a t i o n of t h e p y r i d i n e o r p y r i d i n e oxide complex is n o t certain. T h e a p p e a r a n c e of t h e s e c o n d m o l e c u l e of a l d e h y d e i s a t t r i b u t e d t o a m o d e of s t a b i l i z a t i o n of t h e z w i t t e r i o n (1) i n t e r m e d i a t e b y r e a c t i o n w i t h t h e p y r i d i n e t o f o r m p y r i d i n e oxide a n d a s e c o n d m o l e c u l e of a l d e h y d e :

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A T h i s m a y o c c u r b y a d d i t i o n of t h e p y r i d i n e t o t h e z w i t t e r i o n ( V I I I ) solvates), followed b y rearrangement:

(which it probably

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II or III

P y r i d i n e oxide w a s s h o w n t o b i n d l a r g e q u a n t i t i e s of ozone, f r o m w h i c h a l l of t h e p y r i d i n e o x i d e c o u l d be r e c o v e r e d b y a d d i t i o n of m e t h a n o l . T h i s a p p a r e n t l y a c c o u n t s f o r t h e a d d i t i o n a l ozone r e q u i r e d f o r t h e o z o n o l y s i s w h e n p y r i d i n e i s p r e s e n t . U n f o r t u n a t e l y , p y r i d i n e oxide c o u l d n o t be d e m o n s t r a t e d i n t h e r e a c t i o n m i x t u r e . I t w a s shown, however, i n a separate experiment t h a t p y r i d i n e oxide reacted r e a d i l y w i t h b i s n o r a l d e h y d e a t r o o m t e m p e r a t u r e . T h e i s o l a t i o n w a s n o t a t t e m p t e d a t —-78°C. T h e o z o n o l y s i s m i x t u r e s s t i l l r e q u i r e d r e d u c t i v e t r e a t m e n t t o o b t a i n h i g h y i e l d s of a l d e h y d e . T h e r e d u c t i o n w a s a p p a r e n t l y necessary t o d e s t r o y t h e p y r i d i n e oxide-ozone i n t e r m e d i a t e s w h i c h were p o s t u l a t e d a b o v e . I t w a s possible, h o w e v e r , t o e l i m i n a t e t h e reduction step i f the more reactive formaldehyde was added to destroy the reactive i n t e r m e d i a t e s . T h e r e s u l t s o b t a i n e d b y t r e a t m e n t of s e v e r a l a l i q u o t s of a n o z o n o l y s i s reaction m i x t u r e are shown i n T a b l e I I . T a b l e II.

Decomposition Methods as A p p l i e d to Ozonolysis Reaction Mixtures

Treatment Formaldehyde Zinc reduction No reduction Dimethylsulfoxide Trioxymethylene a

Yield 91.8 93.0 77.2 82.2 75.9

[α]ϋ of Product* +81.4 +84.3 +80.1 +80.5 +80.8

[ « ] of pure 3-ketobisnor-4-22-al is + 8 5 ° (CHCh). D


SLOMP A N D

JOHNSON-4 22-STIGMASTADIEN-3-ONE #

167

F o r m a l d e h y d e w a s d i s t i n c t l y b e t t e r t h a n t h e o t h e r m e t h o d s of t r e a t m e n t , b u t n o t c o m p a r a b l e t o z i n c r e d u c t i o n . T h e f o l l o w i n g r e d u c i n g agents w e r e also t r i e d : a q u e o u s s o d i u m b i s u l f i t e , a q u e o u s f e r r o u s s u l f a t e , s u l f u r d i o x i d e , aqueous s o d i u m t h i o s u l f a t e , catalytic hydrogénation [ p y r i d i n e oxide is difficult t o hydrogenate ( 3 ) ] , c a l c i u m h y d r i d e a n d a c e t i c a c i d , a n d s t a n n o u s c h l o r i d e a n d acetic a c i d . O n l y s t a n n o u s c h l o r i d e - a c e t i c a c i d w a s effective. I t g a v e m a t e r i a l o f v e r y g o o d q u a l i t y , b u t t h e y i e l d w a s s l i g h t l y less (84 t o 8 5 % ) t h a n b y t h e u s u a l z i n c d e c o m p o s i t i o n m e t h o d . Acknowledgment


T h e authors are indebted to A . E . F o n k e n a n d M . Grostic for the measurement and both qualitative a n d quantitative interpretation of infrared spectra, to W i l l i a m A . S t r u c k a n d h i s associates f o r a n a l y t i c a l d a t a , a n d t o M e l v i n N e w m a n a n d D o n a l d C r a m f o r v a l u a b l e suggestions d u r i n g t h e course o f t h e w o r k . Literature C i t e d (1) (2) (3) (4) (5)

Criegee, R., Ann. 583, 1 (1953). Criegee, R., Lohaus, G., Ibid., 583, 6 (1953). Culvenor, C. C. J., Rev. Pure Appl. Chem. 3, 83 (1953). Heigl, J. J., Bell, M. F., White, J. W., Anal. Chem. 19, 293 (1947). Leffler, J. E., Chem. Revs. 45, 400 (1949).

(6) Sixma, F. L. J., Boer, H., Wibaut, J. P., Rec. trav. chim. 70, 1005 (1951). RECEIVED for review M a y 27, 1957. Accepted June 19, 1957.


OZONE CHEMISTRY AND TECHNOLOGY

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