Grignard Reagents

Grignard Reagents THOMAS D. and RICHARD C. WAUGH

Downloaded by NORTH CAROLINA STATE UNIV on November 19, 2012 | http://pubs.acs.org Publication Date: January 1, 1959 | doi: 10.1021/ba-1959-0023.ch008

Arapahoe

Chemicals, Inc., Boulder, Colo.

A description of the application of the classical G r i g nard reaction to industrial syntheses in batchwise equipment is given. The discussion excludes reactions which involve the intermediate formation of other organometallic compounds from the G r i g n a r d reagent a n d applies particularly to the synthesis of alcohols from G r i g n a r d reagents a n d carbonyl compounds. The formation of G r i g n a r d reagent, reaction with a carbonyl compound, hydrolysis of the complex, a n d isolation of the product are discussed with reference to a fairly detailed flow sheet of a n operating plant. Other processes proposed for the industrial application of the G r i g n a r d reaction a r e mentioned briefly. Also included is a general discussion of the advantages a n d disadvantages of the G r i g n a r d reaction as a n industrial process, with some indication of the economics of the process.

A l t h o u g h t h e G r i g n a r d r e a c t i o n has b e e n i n c o n s t a n t w i d e s p r e a d use since i t s d i s c o v e r y b y V i c t o r G r i g n a r d i n 1900 ( 7 ) , i t has o n l y f a i r l y r e c e n t l y c o m e i n t o p r o m i n e n c e as a n i n d u s t r i a l t o o l . M o d e r n d e v e l o p m e n t s i n t h e fields o f h o r m o n e s , v i t a m i n s , p e r f u m e s , a n d silicones h a v e l e d t o i n c r e a s i n g c o m m e r c i a l a p p l i c a t i o n o f t h i s v e r s a t i l e a n d precise r e a c t i o n , a n d i n recent y e a r s c u s t o m m a n u f a c t u r i n g f a c i l i t i e s a n d G r i g n a r d solutions themselves have become c o m m e r c i a l l y available. T h e scope of t h e G r i g n a r d r e a c t i o n is so w e l l k n o w n a n d has been so w e l l r e v i e w e d t h a t n o a t t e m p t is m a d e here t o discuss i t i n d e t a i l . G i l m a n (6), R u n g e (15), a n d K r a u s e a n d v o n G r o s s e (11) h a v e r e v i e w e d t h e c h e m i s t r y o f o r g a n o m e t a l l i c c o m p o u n d s . M o s t r e c e n t l y K h a r a s c h a n d R e i n m u t h (10) h a v e p u b l i s h e d a n excellent t r e a t i s e w h i c h v e r y t h o r o u g h l y discusses t h e r e a c t i o n s o f G r i g n a r d reagents f r o m b o t h t h e o r e t i c a l a n d p r a c t i c a l l a b o r a t o r y s t a n d p o i n t s . T h e t e c h n o l o g i c a l aspects o f t h e G r i g n a r d process h a v e , h o w e v e r , been less e x t e n s i v e l y t r e a t e d (1, 22). T h e p u r p o s e of t h i s p a p e r i s , t h e r e f o r e , t o describe a s i m p l e c o m m e r c i a l - s c a l e p l a n t f o r c a r r y i n g o u t t h e G r i g n a r d r e a c t i o n a n d to discuss some o f t h e a d v a n t a g e s a n d d i s a d v a n t a g e s of t h i s r e a c t i o n i n c o m m e r c i a l o p e r a t i o n s . T h e p l a n t s h o w n i n F i g u r e s 1 a n d 2 was set u p i n 1953 to c a r r y o u t c u s t o m s y n t h e s i s v i a t h e G r i g n a r d r e a c t i o n a n d to p r o d u c e G r i g n a r d reagents for sale as s u c h . I t has been i n successful i n t e r m i t t e n t o p e r a t i o n ever since. I n i t t h e G r i g n a r d reagent is p r e p a r e d a n d a l l o w e d to react w i t h a c a r b o n y l or o t h e r r e a c t i v e c o m p o u n d , t h e r e s u l t a n t c o m p l e x is h y d r o l y z e d , a n d t h e f i n a l p r o d u c t is freed of s o l v e n t . Numerous o t h e r r e a c t i o n s of t h e G r i g n a r d reagent c a n b e c a r r i e d o u t i n t h e same or s l i g h t l y m o d i f i e d e q u i p m e n t . H o w e v e r , because t h e r e a c t i o n of t h e reagent w i t h c a r b o n y l 73

In METAL-ORGANIC COMPOUNDS; Advances in Chemistry; American Chemical Society: Washington, DC, 1959.


74

ADVANCES IN CHEMISTRY SERIES

SEPARATOR

Figure 1.

Flow diagram of plant for carrying out G r i g n a r d reactions Vessel schedule 500 650 R-3 650 R-4 1100 R-5 300 Storage tanks 1000 R-l R-2

gal. gal. gal. gal. gal. gal.

c o m p o u n d s i s o f w i d e u t i l i t y , t h a t r e a c t i o n was chosen felt t h a t the p r i n c i p l e s i n v o l v e d are g e n e r a l l y a p p l i c a b l e . T h e basic r e a c t i o n s i n v o l v e d a r e :

f o r d i s c u s s i o n here.

I t is

F o r m a t i o n o f G r i g n a r d reagent R X + Mg Reaction with carbonyl

RMgX

(1)

compound R"

R M g X + R'COR"-

IV—C—OMgX

(2)

ii H y d r o l y s i s of complex R"

R"

R ' — C — O M g X + H O H -> R ' — C — O H + M g ( O H ) X R Formation of Grignard

(3)

R Reagent

T h e G r i g n a r d reagent i s u s u a l l y p r e p a r e d i n t h e classic w a y b y a d d i n g a s o l u t i o n of t h e o r g a n i c h a l i d e i n ether t o a m i x t u r e o f e t h e r a n d m a g n e s i u m t u r n i n g s . T h e h a l i d e i s d i s s o l v e d i n ether i n t h e vessel, R-l, a n d t h e s o l u t i o n i s t h e n f e d i n t o R-2, w h i c h c o n t a i n s m a g n e s i u m t u r n i n g s a n d e t h e r . B o t h R-l a n d R-2 are p u r g e d w i t h n i t r o g e n before e t h e r is i n t r o d u c e d .



WAUGH—GRIGNARD REAGENTS

Figure 2.

75

General view of Grignard reactor line

T h e chief p r o b l e m i n t h e f o r m a t i o n of G r i g n a r d reagents results f r o m t h e d i f f i c u l t y w h i c h is often encountered i n starting the reaction. Hence, the literature contains a m u l t i t u d e of recommended procedures f o r initiating the G r i g n a r d reaction. Iodine, b r o m i n e , p r e f o r m e d G r i g n a r d reagent, s i l i c a t e esters, a n d i o d i n e - a c t i v a t e d m a g n e s i u m h a v e been suggested. N o m e t h o d has been d e v i s e d w h i c h w i l l w o r k i n a l l cases. Some h a l i d e s r e a c t r e a d i l y , w h i l e others a r e e x t r a o r d i n a r i l y d i f f i c u l t . I t is, h o w e v e r , essential t h a t a s u s t a i n e d r e a c t i o n b e i n i t i a t e d b y t h e first p o r t i o n o f h a l i d e before f u r t h e r a d d i tions are made. F a i l u r e t o observe t h i s p r e c a u t i o n m a y r e s u l t i n t h e b u i l d - u p o f s u c h a n excess of u n r e a c t e d h a l i d e t h a t t h e r e a c t i o n , w h e n i t finally s t a r t s , m a y b e c o m e so v i g o r o u s t h a t t h e t e m p e r a t u r e c a n n o t b e c o n t r o l l e d . A v i o l e n t increase i n p r e s s u r e w i l l r e s u l t . A d e q u a t e e x p l o s i o n lines m u s t t h e r e f o r e b e p r o v i d e d o n G r i g n a r d r e a c t o r s as p r o t e c t i o n a g a i n s t s u c h d e l a y e d r e a c t i o n s . M u c h o f t h i s h a z a r d c a n b e a v o i d e d b y t r a n s f e r r i n g t h e finished reagent t o a n o t h e r vessel, R-3 i n t h i s case, f o r r e a c t i o n w i t h a c a r b o n y l c o m p o u n d , b u t r e t a i n i n g a n excess of a c t i v a t e d m a g n e s i u m i n t h e r e a c t o r , R-2, t o assist i n s t a r t i n g t h e n e x t r e a c t i o n . E f f i c i e n t a g i t a t i o n i s essential t o t h e p r o d u c t i o n o f s a t i s f a c t o r y y i e l d s of t h e G r i g n a r d reagent. B y v i g o r o u s a g i t a t i o n a n d g r a d u a l a d d i t i o n o f t h e h a l i d e , l o c a l o v e r h e a t i n g a n d consequent losses b y W u r t z r e a c t i o n a n d d i s p r o p o r t i o n a t i o n are m i n i m i z e d . I n s p i t e o f i t s h a z a r d s , e t h y l e t h e r seems t o b e t h e m o s t 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 f o r p r e p a r i n g G r i g n a r d reagents. H i g h e r b o i l i n g ethers, t e t r a h y d r o f u r a n , t e r t i a r y a m i n e s , a n d h y d r o c a r b o n s h a v e been r e c o m m e n d e d b u t i n m o s t cases i t s g o o d s o l v e n t p o w e r , l o w cost, h i g h c o m m e r c i a l p u r i t y , a n d ease o f r e c o v e r y m a k e e t h y l e t h e r t h e s o l v e n t of choice f o r G r i g n a r d r e a c t i o n s . T h e r e a c t i o n i s u s u a l l y c a r r i e d o u t u n d e r a pressure of a b o u t 2 0 p o u n d s i n o r d e r t o raise t h e b o i l i n g p o i n t o f e t h e r t o a t e m p e r a t u r e w h e r e j a c k e t c o o l i n g i s sufficient t o p r e v e n t b o i l i n g . H i g h e r t e m p e r a t u r e s , however, often lead t o lower yields, p r e s u m a b l y t h r o u g h the W u r t z a n d d i s p r o p o r t i o n a t i o n r e a c t i o n s . S e v e r a l f a c t o r s m u s t t h e r e f o r e be b a l a n c e d t o a c h i e v e o p t i m u m o p e r a t i n g c o n d i t i o n s i n a n y p a r t i c u l a r case.



76


R e c e n t r e p o r t s b y N o r m a n t (12) a n d b y R a m s d e n a n d h i s associates (13), i n d i c a t e t h a t G r i g n a r d reagents m a y b e p r e p a r e d f r o m r e l a t i v e l y i n e r t h a l i d e s — e . g . , v i n y l a n d a r y l c h l o r i d e s — i f t e t r a h y d r o f u r a n i s u s e d as t h e s o l v e n t . P r e v i o u s l y these reagents c o u l d n o t b e p r e p a r e d i n c o n v e n i e n t w a y s , a l t h o u g h s e v e r a l p r o c e d u r e s (3, 19, 20, 23) w h i c h u t i l i z e d n o s o l v e n t o t h e r t h a n excess h a l i d e h a d b e e n r e p o r t e d f o r p r o d u c i n g phenylmagnesium chloride. T h e p r a c t i c a l s t r e n g t h of G r i g n a r d reagents is d e t e r m i n e d l a r g e l y b y t h e n a t u r e of t h e h a l i d e . T h u s m e t h y l m a g n e s i u m b r o m i d e c a n be m a d e i n g o o d y i e l d i n 4 M s t r e n g t h , w h i l e a t a b o u t 3 M s t r e n g t h t h e p u r i t y o f p h e n y l m a g n e s i u m b r o m i d e begins t o d e t e r i o r a t e , because o f t h e f o r m a t i o n of excessive a m o u n t s o f b i p h e n y l b y w a y o f t h e W u r t z reaction: 2 R X + M g -> R-2 + M g X

(4)

2

B e y o n d 3M s t r e n g t h the W u r t z r e a c t i o n a p p e a r s t o b e t h e m a i n r e a c t i o n . B e n z y l c h l o r i d e l i k e w i s e tends t o u n d e r g o the W u r t z r e a c t i o n a t s t r e n g t h s i n excess of a b o u t 1M. C h l o r i d e s , i n g e n e r a l , suffer f r o m t h e e t h e r - i n s o l u b i l i t y o f m a g n e s i u m c h l o r i d e e t h e r a t e w h i c h arises f r o m the S c h l e n k a n d S c h l e n k (16) e q u i l i b r i u m : 2 R M g X τ± R i M g + M g X

(5)

2

T h u s even a 1M s o l u t i o n of m e t h y l m a g n e s i u m c h l o r i d e deposits large q u a n t i t i e s o f m a g nesium chloride, and at higher strengths the m i x t u r e m a y become nearly solid. B e n z y l m a g n e s i u m c h l o r i d e s o l u t i o n s also deposit m a g n e s i u m c h l o r i d e w h i c h , i f a l l o w e d t o s t a n d , f o r m s a s o l i d c a k e . B e c a u s e m a g n e s i u m b r o m i d e i s r e a d i l y soluble i n e t h e r , b r o m i d e s c a n u s u a l l y be c a r r i e d t o h i g h e r s t r e n g t h t h a n c a n c h l o r i d e s . F l u o r i d e s u s u a l l y d o n o t e n t e r i n t o G r i g n a r d r e a c t i o n s , w h i l e iodides are s e l d o m u s e d because o f h i g h cost a n d excessive losses b y w a y of the W u r t z r e a c t i o n . O t h e r m a j o r side reactions are d i s p r o p o r t i o n a t i o n , r e a c t i o n w i t h a c t i v e h y d r o g e n , and reaction w i t h oxygen. T h e first of these m a y b e r e p r e s e n t e d b y t h e e q u a t i o n : 2 R X + M g -4 R

(

+

H

)

+ R _H) + M g X (

(6)

2

I n the f o r m a t i o n o f s e v e r a l of the m o s t u s e f u l reagents—e.g., m e t h y l , b e n z y l , a n d p h e n y l — t h i s r e a c t i o n is n o t a f a c t o r because t h e r e is n o o p p o r t u n i t y f o r olefin, R _ ) > formation. H o w e v e r , disproportionation m a y be a p r o b l e m w i t h other a l k y l halides, p a r t i c u l a r l y w i t h s e c o n d a r y o r t e r t i a r y h a l i d e s . T h i s r e a c t i o n is p r o b a b l y c a t a l y z e d b y m i n o r a m o u n t s of h e a v y m e t a l halides a n d m a y v e r y w e l l result f r o m i m p u r i t i e s i n t h e m a g n e s i u m . I n the a u t h o r s ' experience, a t least, s a t i s f a c t o r y y i e l d s h a v e u s u a l l y b e e n obtained b y using D o w ' s pure magnesium turnings w i t h p r i m a r y and secondary a l k y l chlorides, p r i m a r y a l k y l bromides, a n d a r y l bromides. C e r t a i n secondary and tertiary h a l i d e s m i g h t r e a c t m o r e s a t i s f a c t o r i l y i f a p u r e r m a g n e s i u m were u s e d . N o d i f f i c u l ties h a v e been e n c o u n t e r e d i n t h e use of m i l d steel reactors f o r the m a n u f a c t u r e o f G r i g n a r d reagents. (

H

T h e presence o f m o i s t u r e o r a l c o h o l i n c o m m e r c i a l o r r e c o v e r e d e t h e r leads t o t h e f o r m a t i o n of the p a r e n t h y d r o c a r b o n b y t h e r e a c t i o n : R M g X + H O R -> R H + M g ( O R ) X

(7)

I n m o s t cases t h i s i n h i b i t s the s t a r t i n g o f t h e r e a c t i o n , p o s s i b l y because t h e i n s o l u b l e g e l a t i n o u s M g ( O H ) X [ o r M g ( O R ) X ] coats the m a g n e s i u m a n d p r e v e n t s c o n t a c t w i t h t h e h a l i d e . A f u r t h e r , m i n o r p r o b l e m is i n t r o d u c e d w h e n t h e h y d r o c a r b o n f o r m e d i s noncondensable. I n t h a t case the h y d r o c a r b o n m u s t be v e n t e d f r o m the s y s t e m t o p r e v e n t excessive b u i l d - u p of pressure a n d hence o f t e m p e r a t u r e i n t h e vessel. These problems can often be avoided b y t r e a t i n g the ether w i t h a s m a l l a m o u n t of preformed G r i g n a r d reagent. T h e r e a c t i o n of G r i g n a r d reagents w i t h o x y g e n is s e l d o m a p r o b l e m i n c o m m e r c i a l o p e r a t i o n because t h e r e a c t o r is a l w a y s p u r g e d w i t h n i t r o g e n b e f o r e e t h e r is i n t r o d u c e d a n d traces o f o x y g e n are u s u a l l y n o t a p p r e c i a b l y deleterious t o t h e r e a c t i o n . I n some


WAUGH—GRIGNARD REAGENTS

77


i n s t a n c e s , h o w e v e r , v e r y s m a l l t r a c e s o f o x y g e n l o w e r t h e y i e l d i n t h e n e x t step v e r y d r a s t i c a l l y . G r e a t care i s t h e r e f o r e t a k e n t o exclude a l l o x y g e n w h e n e s p e c i a l l y s e n s i t i v e reagents are b e i n g p r e p a r e d . T h e q u e s t i o n of s t a b i l i t y o f G r i g n a r d reagents o n storage s o m e t i m e s arises. H o w e v e r , reagents w h i c h h a d been s t o r e d f o r as m u c h as 5 y e a r s i n steel d r u m s o r t i g h t l y sealed glass b o t t l e s h a d n o t d e t e r i o r a t e d d e t e c t a b l y as j u d g e d b y a c i d t i t r a t i o n , a l t h o u g h the reaction indicated i n E q u a t i o n 5 appeared t o have reached e q u i l i b r i u m , depositing magnesium chloride f r o m certain G r i g n a r d chlorides. Storage a t low temperatures m a y i n some cases—e.g., t h a t o f p h e n y l m a g n e s i u m b r o m i d e — c a u s e p a r t o f t h e reagent to c r y s t a l l i z e o u t . U p o n w a r m i n g , t h e c r y s t a l s dissolve a g a i n w i t h some d i f f i c u l t y . I n g e n e r a l , y i e l d s o f G r i g n a r d reagent i n excess o f 9 0 % h a v e b e e n o b t a i n e d i n t h e plant described here.

Reaction with Carbonyl Compounds T h e r e a c t i o n of the G r i g n a r d reagent w i t h a c a r b o n y l , o r o t h e r r e a c t i v e c o m p o u n d , is c a r r i e d o u t i n R-S. T h i s vessel i s e s s e n t i a l l y a d u p l i c a t e o f R-2 w i t h c e r t a i n a d d e d accessories, n o t a b l y t h e f r a c t i o n a t i n g c o l u m n a n d condenser. I n the o r d i n a r y case, t h e G r i g n a r d reagent i s t r a n s f e r r e d f r o m R-2 t o R-3 a n d t h e c a r b o n y l c o m p o u n d i s a d d e d to i t o v e r a p e r i o d o f t i m e f r o m t h e feed t a n k . T h e t e m p e r a t u r e is c o n t r o l l e d b y h e a t i n g o r c o o l i n g w i t h t h e j a c k e t . I n some cases m u c h o f t h e e t h e r i n t h e G r i g n a r d s o l u t i o n is r e p l a c e d b y a h i g h e r b o i l i n g s o l v e n t s u c h a s t o l u e n e , i n o r d e r t o m a i n t a i n a higher reaction temperature a t moderate pressure. T h e replacement is accomplished b y a d d i n g t o l u e n e s l o w l y , w h i l e d i s t i l l i n g e t h e r t h r o u g h t h e c o l u m n a n d condenser. W h e n t h i s is done some r e s i d u a l e t h e r , w h i c h a p p e a r s t o b e t i g h t l y h e l d b y t h e reagent, w i l l b e freed b y t h e a d d i t i o n o f t h e c a r b o n y l c o m p o u n d a n d m u s t b e a l l o w e d t o d i s t i l l out. T h e reverse a d d i t i o n — t h a t i s , t h e a d d i t i o n of G r i g n a r d reagent t o t h e c a r b o n y l c o m p o u n d d i s s o l v e d i n e t h e r — c a n b e c a r r i e d o u t i n t h e same e q u i p m e n t i f i t i s r e q u i r e d . I n t h a t case t h e G r i g n a r d s o l u t i o n i s t r a n s f e r r e d s l o w l y f r o m R-2 i n t o R-3 w h i c h contains the c a r b o n y l compound i n solution. I n e i t h e r case, a f t e r t h e r e a c t i o n is c o m p l e t e , i t is u s u a l l y c o n v e n i e n t t o r e p l a c e t h e ether w i t h toluene, distilling a n d condensing the ether a n d collecting i t i n the ether storage t a n k . T h i s d r y e t h e r i s used i n subsequent p r e p a r a t i o n s o f G r i g n a r d reagent. A n excess o f c a r b o n y l c o m p o u n d , i f i t i s v e r y v o l a t i l e , m u s t b e a v o i d e d i f e t h e r i s reclaimed i n this way, however. R e p l a c e m e n t of ether w i t h toluene often introduces a f u r t h e r c o m p l i c a t i o n , i n t h a t m a n y o f t h e m a g n e s i u m c o m p l e x e s o f the r e a c t i o n p r o d u c t s are i n s o l u b l e i n h y d r o c a r b o n s a n d m a y set u p i n t o n e a r l y s o l i d masses w h i c h are v i r t u a l l y i m p o s s i b l e t o r e m o v e f r o m t h e vessel. A c o n s i d e r a b l e a m o u n t o f b a l a n c i n g o f f a c t o r s i s t h e r e f o r e necessary i n t h i s stage o f t h e o p e r a t i o n .

Hydrolysis of Complex T h e m a g n e s i u m c o m p l e x w h i c h r e s u l t s f r o m t h e r e a c t i o n of t h e G r i g n a r d reagent w i t h c a r b o n y l c o m p o u n d s is h y d r o l y z e d w i t h d i l u t e a c i d i n R A . T h i s vessel is c h a r g e d w i t h t h e r e q u i r e d a m o u n t o f s u l f u r i c a c i d , w a t e r , a n d ice, a n d t h e m i x t u r e f r o m R-3 is p u m p e d i n r a p i d l y w h i l e v i g o r o u s a g i t a t i o n is m a i n t a i n e d t o assure i n t i m a t e c o n t a c t b e t w e e n c o m p l e x a n d a c i d . T h e t e m p e r a t u r e is a d j u s t e d b y t h e p r o p o r t i o n s o f ice a n d a c i d so t h a t t h e final t e m p e r a t u r e a f t e r h y d r o l y s i s a p p r o x i m a t e s 0 ° C . U n d e r these c o n d i t i o n s i t h a s been possible t o use a m i l d steel vessel f o r t h e h y d r o l y s i s w i t h o u t e n c o u n t e r i n g excessive c o r r o s i o n . A f t e r t h e h y d r o l y s i s i s c o m p l e t e , t h e aqueous l a y e r i s d r a w n off a n d t h e o r g a n i c l a y e r i s w a s h e d w i t h s u i t a b l e aqueous s o l u t i o n s t o r e m o v e a c i d a n d o t h e r u n d e s i r a b l e impurities w h i c h v a r y w i t h the p a r t i c u l a r materials i n v o l v e d . W h e r e especially a c i d -



78

s e n s i t i v e p r o d u c t s are e n c o u n t e r e d , the h y d r o l y s i s m a y b e c a r r i e d o u t w i t h a n excess of a m m o n i u m c h l o r i d e i n s t e a d o f s u l f u r i c a c i d . M o s t o f t h e m a t e r i a l s w h i c h h a v e been m a d e i n the p l a n t d e s c r i b e d here are n o n volatile a n d water-insoluble. Therefore the organic layer w h i c h contains the h y d r o l y z e d p r o d u c t i s f i n a l l y t r a n s f e r r e d t o R-5, w h e r e i t i s s t e a m - s t r i p p e d t o r e m o v e s o l v e n t s . T h e p r o d u c t is s e p a r a t e d f r o m t h e w a t e r b y s i m p l e décantation i f i t is a l i q u i d or b y filtration i f i t is a solid. F u r t h e r purification b y conventional means is carried out where i t is required.


Other Reactions A w i d e v a r i e t y o f o t h e r G r i g n a r d r e a c t i o n s c a n b e c a r r i e d o u t i n t h i s same e q u i p m e n t . M e t a t h e t i c a l r e a c t i o n s w i t h h a l i d e s , b o t h o r g a n i c a n d i n o r g a n i c , as w e l l as r e a c t i o n s w i t h c o m p o u n d s w h i c h c o n t a i n d o u b l e o r t r i p l e b o n d s are r e a d i l y h a n d l e d . A n u m b e r o f c o m p o u n d s w h i c h c o n t a i n a c t i v e h y d r o g e n s react w i t h G r i g n a r d reagents t o f o r m n e w reagents of t h e G r i g n a r d t y p e . A p a r t i c u l a r l y u s e f u l e x a m p l e is t h e I v a n o v r e a c t i o n (9), i n w h i c h the a l p h a h y d r o g e n o f s o d i u m p h e n y l acetate is r e p l a c e d b y M g X : C H C H C O O N a + R M g X -> C H C H C O O N a 6

5

2

6

5

(8)

MgX T h i s c o m p o u n d reacts w i t h c a r b o n y l c o m p o u n d s i n t h e n o r m a l f a s h i o n , t o p r o d u c e ^ - h y d r o x y o r unsaturated acids. A l t h o u g h i t has n o t been done i n t h i s p l a n t , o r g a n o c a d m i u m c o m p o u n d s ( 5 ) c a n be f o r m e d b y r e a c t i o n w i t h G r i g n a r d reagents, a l l o w i n g t h e p r e p a r a t i o n o f ketones f r o m acid chlorides to be carried out. 2 R M g X + C d C l -> R C d + 2 M g X C l 2

R C d + 2 R ' C O C l -> 2 R C O R ' + C d C l 2

(9)

2

2

(10)

F r o m t h e s t a n d p o i n t o f c u s t o m G r i g n a r d s y n t h e s i s , t h e p l a n t d e s c r i b e d here a c c o m p l i s h e s t h e m a j o r o b j e c t i v e o f c a r r y i n g o u t a l l o f t h e r e a c t i o n steps w h i c h r e q u i r e t h e use o f e t h y l e t h e r . T h e c u s t o m e r t h u s a v o i d s t h e m a j o r p r o b l e m o f t h e G r i g n a r d synthesis—the hazards of h a n d l i n g e t h y l ether. T h e p l a n t i s h o u s e d i n a s o m e w h a t i s o l a t e d steel b u i l d i n g , w i r e d t h r o u g h o u t w i t h explosion-proof, Class I , G r o u p D o r Class I I , G r o u p G fixtures a n d motors. I t is e q u i p p e d f o r b o t h g e n e r a l f o r c e d v e n t i l a t i o n a n d s p o t v e n t i l a t i o n a t p o i n t s o f greatest h a z a r d . N o serious a c c i d e n t s h a v e o c c u r r e d i n t h e o p e r a t i o n o f t h i s p l a n t .

Other Grignard Processes S e v e r a l o t h e r p r o c e d u r e s f o r p r o d u c i n g G r i g n a r d reagents s h o u l d b e m e n t i o n e d . O n e , o f t e n r e f e r r e d t o as a " c y c l i c r e a c t o r , " h a s been d e s c r i b e d b y R o w l a n d s , G r e e n l e e , a n d B o o r d {H). I t s p u r p o s e is t o m a k e possible t h e p r e p a r a t i o n o f G r i g n a r d reagents f r o m h i g h l y reactive halides w h i c h have a predilection f o r the W u r t z reaction. B e cause h i g h d i l u t i o n f a v o r s t h e G r i g n a r d r e a c t i o n , e t h e r i s d i s t i l l e d f r o m a flask, c o n densed, a n d a l l o w e d t o flow b a c k t h r o u g h a c o l u m n p a c k e d w i t h a m a l g a m a t e d m a g n e s i u m . T h e h a l i d e is i n t r o d u c e d v e r y s l o w l y i n t o t h e r e t u r n i n g condensate a t the t o p of t h e c o l u m n . I n t h i s w a y , i t i s r e p o r t e d , v e r y h i g h y i e l d s of G r i g n a r d reagents d e r i v e d f r o m h i g h l y a c t i v e h a l i d e s o f t h e a l l y l a n d b e n z y l t y p e s are o b t a i n e d . Com m e r c i a l u t i l i z a t i o n of t h i s process has n o t , h o w e v e r , been r e p o r t e d . A process has been p a t e n t e d (8, 17, 18, 21) w h i c h u t i l i z e s t h e h i g h l y a c t i v a t e d c o n d i t i o n o f f r e s h l y c u t m a g n e s i u m t o b r i n g a b o u t t h e f o r m a t i o n of G r i g n a r d reagents f r o m a r y l chlorides. A c c o r d i n g t o the patents, a solution of a n a r y l chloride i n e t h y l e t h e r o r i n a d i a l k y l e t h e r o f e t h y l e n e g l y c o l , i s a l l o w e d t o flow t h r o u g h a c h a m b e r s u r r o u n d i n g a r o t a t i n g c u t t i n g h e a d w h i l e t h e l a t t e r shaves c h i p s f r o m a p u r e m a g -


79

WAUGH—GRIGNARD REAGENTS nesium billet.

T h e process i s s a i d t o p r o d u c e h i g h y i e l d s o f a r y l m a g n e s i u m c h l o r i d e s

w h i c h are d i f f i c u l t t o o b t a i n b y o t h e r m e a n s .

H o w f a r t h i s process has been

commer

cialized is not k n o w n t o the authors, a l t h o u g h i t is k n o w n t h a t several machines have been u s e d i n p i l o t o p e r a t i o n s . A r y l m a g n e s i u m c h l o r i d e s h a v e also b e e n r e p o r t e d {3, 19, 20, 23) t o r e s u l t f r o m the so-called "solventless" reaction of a r y l chlorides w i t h magnesium. these processes h a v e u s u a l l y e m p l o y e d

r e p o r t e d y i e l d s h a v e n o t a l w a y s been v e r y a t t r a c t i v e . out under pressure a t elevated temperatures. been m a d e

I n point of fact

a n excess o f t h e h a l i d e a s s o l v e n t a n d t h e T h e reaction is usually carried

C o m m e r c i a l use o f t h i s p r o c e d u r e

has

(2).


B u c (4) h a s p a t e n t e d a process f o r p r e p a r i n g G r i g n a r d reagents b y c o n t i n u o u s l y f e e d i n g a n o r g a n i c h a l i d e i n t o a r e a c t i o n zone c o n t a i n i n g m a g n e s i u m t u r n i n g s a n d c o n t i n u o u s l y r e m o v i n g t h e reagents as i t i s f o r m e d .

I t is n o t k n o w n w h e t h e r t h i s process

has ever b e e n p l a c e d i n c o m m e r c i a l o p e r a t i o n .

Advantages and Disadvantages of the Grignard Reaction Many

of t h e r e a c t i o n s o f G r i g n a r d reagents c a n b e o r h a v e b e e n c a r r i e d o u t

t h r o u g h t h e use o f o t h e r o r g a n o m e t a l l i c c o m p o u n d s .

T h e reactions of sodium, l i t h i u m ,

z i n c , a n d c a d m i u m a l k y l s , f o r e x a m p l e , h a v e been s t u d i e d i n d e t a i l .

The

Grignard

reagents h a v e , h o w e v e r , b e e n m u c h m o r e w i d e l y used i n o r g a n i c s y n t h e s i s t h a n h a v e a n y of the others. P e r h a p s t h e first reason f o r t h e i r success i s t h a t G r i g n a r d reagents u t i l i z e t h e readily available a n d easily handled magnesium. M a g n e s i u m turnings are suitable for use as r e c e i v e d a n d c a n be s t o r e d f o r l o n g p e r i o d s w i t h o u t d e t e r i o r a t i o n . F u r t h e r m o r e , m a g n e s i u m does n o t p r e s e n t m a j o r h a z a r d s i n h a n d l i n g o r d i s p o s a l o f wastes n o r are its compounds generally considered t o be toxic. Its price is not exorbitant. T h e G r i g n a r d reagents t h e m s e l v e s are e a s i l y p r e p a r e d i n s i m p l e e q u i p m e n t . They a r e s t a b l e i n storage a n d are n o t g e n e r a l l y s p o n t a n e o u s l y f l a m m a b l e i n c o n t a c t w i t h a i r o r m o i s t u r e . M e t h y l m a g n e s i u m b r o m i d e i n 4M s t r e n g t h h a s , h o w e v e r , b e e n o b s e r v e d t o i g n i t e s p o n t a n e o u s l y w i t h w a t e r a n d p e r h a p s o t h e r G r i g n a r d reagents m i g h t do so u n d e r c e r t a i n c i r c u m s t a n c e s . F u r t h e r a d v a n t a g e s o f G r i g n a r d reagents a r e t h a t t h e y a r e m a r k e t e d c o m m e r c i a l l y a n d t h a t , f o r those w h o w i s h t o a v o i d e n t i r e l y t h e h a z a r d s of h a n d l i n g e t h y l e t h e r , c u s t o m m a n u f a c t u r i n g f a c i l i t i e s are a v a i l a b l e . F i n a l l y t h e r e a c t i o n s of G r i g n a r d reagents h a v e been so t h o r o u g h l y s t u d i e d t h a t t h e i r course c a n b e a c c u r a t e l y p r e d i c t e d i n m o s t cases. M a n y o f t h e i r r e a c t i o n s p r o ceed i n a c l e a n - c u t f a s h i o n t o p r o v i d e g o o d y i e l d s o f t h e d e s i r e d p r o d u c t . I n d e e d , f o r these reasons G r i g n a r d r e a c t i o n s h a v e been w i d e l y e m p l o y e d i n t h e e s t a b l i s h m e n t of the structures of new compounds. T h e h a z a r d s i n v o l v e d i n t h e h a n d l i n g of e t h y l e t h e r c a n n o t b e i g n o r e d ; i n f a c t , t h e p r o b l e m s o f t h e G r i g n a r d r e a c t i o n are l a r g e l y t h e p r o b l e m s o f h a n d l i n g e t h y l e t h e r w i t h safety. T h e u n r e a c t i v i t y o f c e r t a i n c h l o r i d e s , w h i c h forces one t o use t h e c o r r e s p o n d i n g b r o m i d e s , i s a serious d i s a d v a n t a g e o f t h e G r i g n a r d process, as i s t h e s e n s i t i v i t y o f m a n y of the more reactive halides t o the W u r t z a n d d i s p r o p o r t i o n a t i o n reactions. I t is also u n f o r t u n a t e t h a t G r i g n a r d reagents u s u a l l y d o n o t p r o d u c e k e t o n e s b y r e a c t i o n w i t h a c i d c h l o r i d e s o r a n h y d r i d e s . T h e r e a d y c o n v e r s i o n o f G r i g n a r d reagents t o o r g a n o c a d m i u m c o m p o u n d s (δ), h o w e v e r , m a k e s i t possible t o p r e p a r e ketones i n e x cellent y i e l d f r o m a c i d c h l o r i d e s . R e a c t i o n o f G r i g n a r d reagents w i t h n i t r i l e s l i k e wise f r e q u e n t l y gives p o o r r e s u l t s a n d r e d u c t i v e side r e a c t i o n s i n t e r f e r e i n s o m e r e a c tions w i t h c a r b o n y l compounds. These reductions appear t o be especially i m p o r t a n t i n r e a c t i o n s w i t h k e t o n e s , less so w i t h a l d e h y d e s a n d esters. T h e G r i g n a r d r e a c t i o n o f t e n p r o v i d e s t h e best m e t h o d f o r p r o d u c i n g a w i d e v a r i e t y of c o m p o u n d s . Its i n d u s t r i a l i m p o r t a n c e i s increasing as the d e m a n d for m o r e i n t r i cate a n d s p e c i a l i z e d c o m p o u n d s g r o w s .



80

Economic Factors I t i s possible here t o m a k e o n l y b r o a d g e n e r a l i z a t i o n s r e g a r d i n g t h e e c o n o m i c s o f the G r i g n a r d reaction. A c o n s i d e r a t i o n o f one of t h e m o r e u s e f u l G r i g n a r d r e a c t i o n s , t h e r e a c t i o n w i t h c a r b o x y l i c esters, w i l l serve t o i l l u s t r a t e a n u m b e r o f t h e e c o n o m i c f a c t o r s w h i c h e n t e r into G r i g n a r d reactions. Ο


2 R M g X + R C O R ' ->

R3COH +

2Mg(OH)X

(11)

F o r each p o u n d m o l e o f u s e f u l p r o d u c t o b t a i n e d , 2 p o u n d moles of basic m a g n e s i u m halide are formed. Unless the operation is v e r y large, i t is n o t economical t o recover this m a t e r i a l , b u t i t contains magnesium w o r t h about $25, a n d , i n reactions where the b r o m i d e is r e q u i r e d , $ 4 0 w o r t h o f b r o m i n e . I t i s i m m e d i a t e l y seen t h a t c h l o r i d e s w o u l d be m u c h more economical than bromides, i n the G r i g n a r d reaction. F u r t h e r m o r e , ketones, w h i c h r e q u i r e o n l y 1 m o l e of G r i g n a r d reagent, w i l l a p p e a r t o b e p r e f e r r e d o v e r esters, w h i c h r e q u i r e 2 moles, f o r p r o d u c i n g t e r t i a r y a l c o h o l s . S o m e o f t h i s a d v a n t a g e o f ketones is o f t e n l o s t , h o w e v e r , b y side r e a c t i o n s , a n d i n m a n y instances the desired ketone is n o t readily available. I t m a y be concluded that few compounds can be produced b y this reaction for a r a w m a t e r i a l cost o f less t h a n $1.00 p e r p o u n d . T h e r e f o r e , t h e c o m m e r c i a l use o f t h e G r i g n a r d reaction is p r a c t i c a l l y restricted t o the m a n u f a c t u r e of r e l a t i v e l y expensive m a t e r i a l s , s u c h as p e r f u m e s , p h a r m a c e u t i c a l s , silicones, a n d e v e n c e r t a i n a g r i c u l t u r a l c h e m i c a l s . I n g e n e r a l , t h e n , w h e r e g r e a t s p e c i f i c i t y of s t r u c t u r e i s a c o n t r o l l i n g f a c t o r , m a n y p r o d u c t s m a y be m a d e m o s t e c o n o m i c a l l y b y t h e G r i g n a r d r e a c t i o n .

Acknowledgment T h e p e r m i s s i o n o f t h e B o a r d o f D i r e c t o r s of A r a p a h o e C h e m i c a l s , I n c . , t o p r e s e n t t h e process i n f o r m a t i o n c o n t a i n e d i n t h i s p a p e r a n d t h e k i n d l y a d v i c e o f H e n r y G i l m a n are gratefully acknowledged.

Literature Cited (1) Boord, C. E., Henne, A. L., Greenlee, K . W., Perilstein, W. L., Derfer, J . M . , Ind. Eng. Chem. 41, 609 (1949). (2) Britton, E . C., private communication. (3) Britton, E. C., Slagh, H . R. (to Dow Chemical Co.), U . S. Patents 1,996,746 (1935) ; 2,056,822 (1936). (4) Buc , H . E . (to Standard Oil Development Co.), Ibid., 2,066,198 (Dec. 29, 1956). (5) Cason, J., Chem. Revs. 40, 15 (1947). (6) Gilman, H., "Organic Chemistry," 2nd ed., Vol. I, Chap. 5, Wiley, New York, 1943. (7) Grignard, V., Compt. rend. 130, 1322 (1900). (8) Hill, J. S. (to Cincinnati Milling Machine Co.), U . S. Patent 2,522,676 (May 1951). (9) Ivanov, D., Spassoff, Α., Bull. soc. chim. 49 (4), 19, 371, 377 (1931). (10) Kharasch, M . S., Reinmuth, O., "Grignard Reaction of Nonmetallic Substances," Prentice-Hall, New York, 1954. (11) Krause, E., Grosse, A. von, "Die Chemie der Metall-organischen Verbindungen," Borntraeger, Berlin, 1937. (12) Normant, H., Compt. rend. 239, 1510 (1954). (13) Ramsden, H . E., Balint, A. E., Whitford, W. R., Rosenberg, S. D., Wallburn, J . J., Leebrick, J . R., Cserr, R., Abstracts of Papers, 130th Meeting, A.C.S., Atlantic City, N . J., September 1956, p. 80-O. (14) Rowlands, D. C., Greenlee, K . W., Boord, C. E., Abstracts of Papers, 117th Meeting, A.C.S., Philadelphia, Pa., April 1950, p. 8-L. (15) Runge, F., "Organo-metallverbindungen," Wissenschaftliche Verlagsgesellschaft, Stutt gart, 1944; Edwards Bros., Ann Arbor, Mich. (16) Schlenk, W., Schlenk, W., Jr., Ber. 62B, 920 (1929). (17) Shaw, M . C. (to Cincinnati Milling Machine Co.), U . S. Patent 2,416,717 (March 4, 1947). In METAL-ORGANIC COMPOUNDS; Advances in Chemistry; American Chemical Society: Washington, DC, 1959.

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(18) Shaw, M . C., J. Appl. Mechanics 15, No. 1, 37 (1948). (19) Shorigin, P. P., Isagulyantz, V. I., Guseva, A. R., Poliakov, K . S., French Patent 738,227 (June 7, 1932). (20) Shorigin, P. P., Ber. 66B, 1426 (1933). (21) Stevens, A. H . (to Cincinnati Milling Machine Co.), Brit. Patent 571,539 (Aug. 29, 1945). (22) Waugh, T. D., "Grignard Reactions," in Kirk, R. E., Othmer, D. F., "Encyclopedia of Chemical Technology," Vol. 7, p. 314, Interscience, New York, 1951. (23) Weissenborn, A. (to Winthrop Chemical Co.), U . S. Patent 2,058,373 (Oct. 20, 1936). RECEIVED for review May 10, 1957. Accepted June 1, 1957.


Grignard Reagents

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