Pure & Appl. Chem., Vol. 60, No. 3, pp. 353-364, 1988. Printed in Great Britain. @ 1988 IUPAC

Reactive polymers: design considerations, novel preparations and selected applications in organic chemistry J e a n M.J. Frkchet" , Graham D. D a r l i n g , S h i n i c h i I t s u n o , Pei-Zhi Lu, Mar ina V i v a s d e M e f t a h i , and Wesley A. R o l l s , Jr.

Department of Chemis t ry , U n i v e r s i t y of Ottawa, Ottawa, O n t a r i o , K1N-9B4, Canada.

A b s t r a c t - C r o s s l i n k e d r e a c t i v e polymers w i t h n o v e l s t r u c t u r e s h a v e been p r e p a r e d from t h e c o r r e s p o n d i n g monomers o r by newly d e v e l o p e d c h e m i c a l m o d i f i c a t i o n r e a c t i o n s . These i n c l u d e t h e p r e p a r a t i o n of po lymers w i t h two o r t h r e e c a r b o n s p a c e r groups between backbone and f u n c t i o n a l i t y , t h e f i r s t p r e p a r a t i o n of a G r i g n a r d r e a g e n t on a n i n s o l u b l e polymer , and some new copper media ted chemica l m o d i f i c a t i o n r e a c t i o n s r e s u l t i n g i n C-C bond f o r m a t i o n . Novel a p p l i c a t i o n s of t h e s e p o l y m e r s i n asymmetr ic s y n t h e s e s , r e g e n e r a b l e p o l y m e r i c p r o t e c t i n g g r o u p s , s u p e r n u c l e o p h i l i c c a t a l y s t s , p o l y m e r i c s e p a r a t i o n media f o r HPLC, as wel l as a i d s i n t h e d e t e r m i n a t i o n of r e a c t i o n mechanisms, h a v e been i n v e s t i g a t e d . Microenvi ronment e f f e c t s w i t h i n t h e p o l y m e r b e a d s a r e shown t o be i m p o r t a n t when c o n s i d e r i n g t h e u s e of an i n s o l u b l e r e a c t i v e polymer,

INTRODUCTION

The f i r s t s y n t h e t i c r e a c t i v e p o l y m e r s of some s i g n i f i c a n c e were u n d o u b t e d l y t h e ion-exchange r e s i n s [l] f i r s t p r e p a r e d as ear ly a s 1935 [2] f rom phenol - formaldehyde c o n d e n s a t e s , t h e n a d a p t e d i n t h e e a r l y 1950's t o t h e more s u i t a b l e s t y r e n e - d i v i n y l b e n z e n e s t r u c t u r e s [3,4] w h i c h a r e s t i l l i n u s e t o d a y . D e s p i t e t h e i r g r e a t i m p o r t a n c e , t h e i m p a c t o f i o n - e x c h a n g e r e s i n s on t h e s p e c i a l i z e d f i e l d of r e a c t i v e polymers i s overshadowed by M e r r i f i e l d ' s deve- lopment of t h e s o l i d - p h a s e method of s y n t h e s i s i n t h e e a r l y 1960's [5]. M e r r i f i e l d ' s c o n c e p t n o t o n l y r e v o l u t i o n i z e d [6] t h e f i e l d of p e p t i d e s y n t h e s i s f o r which it had been d e v e l o p e d , b u t a l s o s p r e a d q u i c k l y t o o t h e r areas of o r g a n i c s y n t h e s i s , ca ta lys i s , s e p a r a t i o n s c i e n c e , etc. I n t e r e s t i n g l y , t h e d e v e l o p m e n t o f n u m e r o u s new p o l y m e r i c r e a g e n t s , c a t a l y s t s , a n d s u p p o r t s , h a s r e s u l t e d i n a b e t t e r awareness of t h e f a c t t h a t p o l y m e r s c o u l d be d e s i g n e d t o h a v e s p e c i a l r e a c t i v i t i e s and t h i s , i n t u r n , h a s c o n t r i b u t e d t o a new i n t e r e s t i n r e a c t i v e polymers f o r a p p l i c a t i o n i n areas n o t d i r e c t l y r e l a t e d t o s y n t h e s i s , c a t a l y s i s , o r s e p a r a t i o n s c i e n c e .

T h i s r e p o r t w i l l make n o a t t e m p t t o b r o a d c o v e r a g e o f t h e f i e l d o f r e a c t i v e p o l y m e r s ; indeed , s e v e r a l books [7-91 and numerous o t h e r r e v i e w s h a v e a d e q u a t e l y c o v e r e d most of t h e v a r i o u s s y n t h e t i c o r c a t a l y t i c a p p l i c a t i o n s of t h e f i e l d . I n s t e a d t h i s w i l l f o c u s m a i n l y on t h e a u t h o r s ' own r e c e n t e x p e r i e n c e s and w i l l p r e s e n t a l i m i t e d and p e r h a p s somewhat b i a s e d v i e w o f t h a t p a r t of t h e f i e l d o f r e a c t i v e p o l y m e r s w h i c h is o f c l o s e s t i n t e r e s t t o t h e s y n t h e t i c o r g a n i c o r i n d u s t r i a l chemis t .

PREPARATION OF POLYMERIC REAGENTS, CATALYSTS, AND SUPPORTS

Although some v e r y i n t e r e s t i n g r e s u l t s h a v e been o b t a i n e d i n a p p l i c a t i o n s i n v o l v i n g s o l u b l e p o l y m e r s [ 101 t h e d i s c u s s i o n b e l o w w i l l f o c u s a l m o s t e x c l u s i v e l y on t h e p r e p a r a t i o n o f c r o s s l i n k e d r e a c t i v e r e s i n s , macroporous o r g e l - t y p e . Gel - type polymers , s u c h as t h e 1-279 c r o s s l i n k e d ( ch lo romethy1)po lys ty rene used by M e r r i f i e l d [ 51, h a v e no permanent p o r e s b u t swel l e x t e n s i v e l y i n some a p p r o p r i a t e l y chosen s o l v e n t s . F u n c t i o n a l g r o u p s a t t a c h e d t o t h e s e polymers h a v e h i g h r e a c t i v i t i e s , o f t e n comparable t o t h o s e of a n a l o g o u s small m o l e c u l e s i n

l u t i o n . S i m i l a r l y , as t h e c h a i n s h a v e e x c e l l e n t m o b i l i t i e s i n t h e s w o l l e n state, t h e i r 89C-NMR s p e c t r a c a n be measured e a s i l y a l b e i t w i t h some l i n e b r o a d e n i n g , under c o n v e n t i o n a l c o n d i t i o n s [ll]. In c o n t r a s t , more h i g h l y c r o s s l i n k e d macroporous r e s i n s p r e p a r e d by suspen- s i o n p o l y m e r i z a t i o n i n t h e p r e s e n c e of porogens [12,13] o f t e n h a v e h i g h p o r o s i t i e s and h i g h s u r f a c e areas which make them more s u i t a b l e i n c e r t a i n a p p l i c a t i o n s s u c h as t h o s e i n v o l v i n g f low-sys tems p r e v a l e n t i n t h e area of polymer-based s e p a r a t i o n media. A d e f i n i t e drawback of macroporous r e s i n s when compared t o s w e l l a b l e g e l s , i s t h e i r lower r e a c t i v i t y and r e l a t i v e l y poor mechanica l p r o p e r t i e s which o f t e n p r e c l u d e t h e i r use.

N o t e : a d d r e s s c o r r e s p o n d e n c e t o t h i s a u t h o r a t t h e D e p a r t m e n t of C h e m i s t r y , C o r n e l l U n i v e r s i t y , I t h a c a , New York 14853-1301, U.S.A.

353

354 J. M. J. FRECHET eta / .

Preparation by chemical modification The chemica l mod i f i ca t ion r o u t e i s p a r t i c u l a r l y a t t r a c t i v e wi th po lys ty rene based r e s i n s as t h e i r a r o m a t i c r i n g s can b e m o d i f i e d r e a d i l y by e l e c t r o p h i l i c a r o m a t i c s u b s t i t u t i o n o r through o t h e r s imple r eac t ions . Thus t h e ch lo romethy la t ion of po lys ty rene [ 3 ] was one of t h e impor tan t r e a c t i o n s used i n t h e development of i o n exchange r e s i n s and was a l s o used as t h e key polymer f u n c t i o n a l i z a t i o n r e a c t i o n i n M e r r i f i e l d ' s o r i g i n a l approach [ 51. Other wide ly a p p l i c a b l e f u n c t i o n a l i z a t i o n r e a c t i o n s which have been s t u d i e d e x t e n s i v e l y a r e t h e bromi- n a t i o n [14-161 and t h e l i t h i a t i o n [ 1 4 , 17-18] of c r o s s l i n k e d p o l y s t y r e n e . I n f a c t , i t i s l i k e l y t h a t w e l l o v e r h a l f t h e r e a c t i v e c r o s s l i n k e d r e s i n s prepared t o d a t e have been made through procedures i n v o l v i n g e i t h e r ch lo romethy la t ed o r l i t h i a t e d po lys ty rene . Th i s i s due t o t h e ease wi th which d isp lacement o r a d d i t i o n r e a c t i o n s (Fig. 1) can be c a r r i e d ou t on ( ch lo - romethy1)polys tyrene o r on ( 1 i t h i o ) p o l y s t y r e n e . These r e a c t i o n s which can be performed under c l a s s i c a l c o n d i t i o n s have been reviewed [ 193; i n t h e case of n u c l e o p h i l i c d i sp l acemen t s on (chloromethy1)polystyrene t h e r e a c t i o n s can a l s o be done us ing phase t r a n s f e r ca ta lys i s [20].

+CH,-CH+ + CH,-CH+ +cH,- CH +- +cH*- CH+ + * Q Q L 0 \

E CH,CI CH,Nu Li

Fig . 1. Typica l r e a c t i o n s invo lv ing (ch loromethyl ) o r ( 1 i t h i o ) p o l y s t y r e n e

Control of structure during chemical modification. A l t h o u g h t h e c h e m i c a l mod i f i ca t ion approach has been ex t r eme ly s u c c e s s f u l i n i t s a p p l i c a t i o n t o t h e p repa ra t ion of r e s i n s hav ing a g r e a t v a r i e t y of s t r u c t u r e s , i t i s a r o u t e which should be cons idered wi th g r e a t care . For example, it i s unwise t o assume t h a t a r e a c t i o n which has been optimized f o r t h e p r e p a r a t i o n of a small molecu le w i l l be d i r e c t l y a p p l i c a b l e t o t h e chemical mod i f i ca t ion of a polymer. Indeed t h e r e a c t i v e polymer l i t e r a t u r e i s f u l l of examples where t h e l a c k of r e a c t i v i t y , o r t h e s t r a n g e behavior of a p a r t i c u l a r f u n c t i o n a l polymer, is a t t r i b u t e d t o t h e d e l e t e r i o u s e f f e c t of a t t a c h m e n t t o a po lymer backbone , when i n f a c t i t i s t h e c h e m i c a l m o d i f i c a t i o n procedure which i s a t f a u l t . The term "polymer-analogous r eac t ion" may be a u s e f u l desc r ip - t o r f o r a p r o c e d u r e i n wh ich a known r e a c t i o n , o p t i m i z e d f o r t h e p r e p a r a t i o n o f a smal l m o l e c u l e , i s a p p l i e d t o t h e m o d i f i c a t i o n o f a p o l y m e r , b u t i t s h o u l d n o t l e a d t o t h e complacent assumption t h a t t h e r e a c t i o n a p p l i e d t o a po lymer ic s u b s t r a t e w i l l a f f o r d r e s u l t s which d u p l i c a t e e x a c t l y those of t h e model r eac t ion . I n f a c t t h i s te rminology which may be s e r i o u s l y mis l ead ing should probably be avoided a l t o g e t h e r .

Whenever chemica l mod i f i ca t ion of a polymer i s contempla ted , i t must be remembered t h a t any s i d e - r e a c t i o n which o c c u r s may r e s u l t i n t h e pe rmanen t a t t a c h m e n t of u n d e s i r e d o r e v e n d e l e t e r i o u s f u n c t i o n a l i t i e s t o t h e polymer backbone [21]. The same can be s a i d of incomple te r e a c t i o n s which a f f o r d m a t e r i a l s con ta in ing a t l e a s t two c l e a r l y d i s t i n g u i s h a b l e r e a c t i v e groups. These may have d i v e r g e n t r e a c t i v i t i e s which cou ld p o t e n t i a l l y reduce t h e e f f e c t i - veness of t h e f i n a l r e s i n . Although a t t empt s may be made t o e l i m i n a t e t h e p o t e n t i a l harmful e f f e c t s of undes i red f u n c t i o n a l i t i e s r e s u l t i n g from chemica l mod i f i ca t ion p rocesses [ 2 2 ] , it i s a lways b e s t t o opt imize t h e p rocess i t s e l f by deve lop ing procedures un ique ly s u i t e d t o t h e t a r g e t r e s i n [23-241. A t t h e same t ime , a n a l y t i c a l c o n t r o l s must be e s t a b l i s h e d t o confirm t h e q u a n t i t a t i v e n a t u r e of t h e f u n c t i o n a l i z a t i o n r e a c t i o n [23-241.

Consideration of microenvironment within a reactive polymer. This i s an i s s u e which i s a l l t o o o f t e n f o r g o t t e n i n t h e d e s i g n of r e a c t i v e p o l y m e r s . It s h o u l d be remembered t h a t whenever an i n s o l u b l e po lymer i s used as a r e a c t a n t o r c a t a l y s t i n a g i v e n r e a c t i o n , t h e microenvironment of t h e r e a c t i v e s i te i s very d i f f e r e n t from t h a t which p r e v a i l s i n c lass ical s o l u t i o n chemistry. Thus, t h e r e e x i s t s w i th in t h e r e a c t i o n medium an uneven d i s t r i b u t i o n of both t h e polymer-bound r e a c t i v e s p e c i e s and a l s o of t h e groups which make up t h e backbone of t h e polymer. For example, r e a c t i o n s c a r r i e d o u t w i th a r e a c t i v e s t y r e n e r e s i n wi th a degree of f u n c t i o n a l i z a t i o n of 0.1 may be a f f e c t e d by t h e f a c t a l l r e a c t i v e ends a r e c o n s t a n t l y surrounded by t h e s t y r e n i c moie t i e s t o which they are a t t ached , t h e s e may p rov ide a s p e c i a l non-polar microenvironment which i s no t no rma l ly obta ined i n t h e more u s u a l s o l u t i o n reac- t i o n s [25-271. I n a d d i t i o n , as t h e r e a c t i v e s i t e s are a l l a t t ached t o t h e i n s o l u b l e polymer and a r e t h e r e f o r e not e v e n l y d i s t r i b u t e d throughout t h e medium, h igh l o c a l c o n c e n t r a t i o n s l e a d i n g t o s i t e - s i t e i n t e r a c t i o n s may occur. Such i n t e r a c t i o n s of r e a c t i v e s i t e s which have been observed i n numerous polymer-supported r e a c t i o n s [21, 28-31] a r e examples of o t h e r t y p e s of microenvironment e f f e c t s which are a l s o o f t e n seen i n polymer-ass i s ted chemistry. These m i c r o e n v i r o n m e n t e f f e c t s c a n b e e x t r e m e l y i m p o r t a n t i f t h e y a r e h a r n e s s e d t o c o n t r i b u t e p o s i t i v e l y t o t h e u l t i m a t e des ign; t hey may a l s o be harmful e s p e c i a l l y i f they r e s u l t from u n c o n t r o l l e d , and t h e r e f o r e sometimes undetec ted , s ide - r eac t ions du r ing syn thes i s . A t t e m p t s t o des ign t h e microenvironment of r e a c t i v e s i t e s have been r epor t ed i n t h e l i t e r a t u r e [24-26, 28, 311.

Reactive polymers 355

Use of polymethylene spacers on polystyrene substrates. Though a v e r y l a r g e number of r e a c t i v e polymers h a v e been p r e p a r e d s a t i s f a c t o r i l y by m o d i f i c a t i o n of ( c h l o r o m e t h y 1 ) p o l y - s t y r e n e , i t h a s become a p p a r e n t t h a t t h e b e n z y l i c l i n k a g e between r e a c t i v e group and r e s i n may n o t a lways p r o v i d e t h e l o n g - t e r m s t a b i l i t y w h i c h i s d e s i r a b l e i n r e a c t i v e p o l y m e r s . H e n c e , i t i s w e l l known t h a t b e n z y l i c q u a t e r n a r y onium s a l t s a re e a s i l y d e a l k y l a t e d [ 321 w h i l e b e n z y l i c amines, s u l f i d e s , esters and e t h e r s may be s u s c e p t i b l e t o c l e a v a g e by a c i d o r t o h y d r o g e n o l y s i s [33] . It s h o u l d be emphasized however , t h a t i t i s t h i s v e r y l a b i l i t y of b e n z y l i c s u b s t i t u e n t s which made (chloromethy1)polystyrene t h e s u p p o r t of c h o i c e i n s o l i d - phase s y n t h e s i s [ 5 ] as c o n t r o l l e d r e l e a s e of t h e f i n i s h e d p e p t i d e can be a c h i e v e d r e a d i l y . N e v e r t h e l e s s , t h e r e a r e numerous i n s t a n c e s where r e a c t i v e p o l y m e r s h a v e undergone u n e x p l a i n e d c l e a v a g e s i d e - r e a c t i o n s w h i c h h a v e a f f e c t e d t h e i r a b i l i t y t o be r e g e n e r a t e d a n d r e u s e d . Though, a s was m e n t i o n e d e a r l i e r , n o n - b e n z y l i c r e a c t i v e p o l y m e r s c a n be p r e p a r e d f r o m ( 1 i t h i o ) p o l y s t y r e n e [ 1 4 ] , it appeared u s e f u l t o d e v e l o p r e a c t i v e polymers i n which a s h o r t s p a c e r g r o u p i s i n t r o d u c e d b e t w e e n t h e s t y r e n i c r i n g s a n d t h e r e a c t i v e g r o u p s . To t h i s e f f e c t , a s e r i e s of s y n t h e t i c a p p r o a c h e s h a v e b e e n d e v e l o p e d f o r t h e i n t r o d u c t i o n o f a d i m e t h y l e n e s p a c e r between f u n c t i o n a l i t y and a r o m a t i c r i n g [23-241 by s e q u e n t i a l modi f ica- t i o n s of c r o s s l i n k e d p o l y s t y r e n e . The common f e a t u r e of t h e s e m o d i f i c a t i o n s i s t h a t e a c h was o p t i m i z e d t o e n s u r e t h a t q u a n t i t a t i v e y i e l d s were o b t a i n e d i n e a c h of t h e key m o d i f i c a t i o n s t e p s . Though it i s g e n e r a l l y t r u e t h a t a d i m e t h y l e n e s p a c e r may be s u b j e c t t o u n w a n t e d e l i m i n a t i o n r e a c t i o n s , it is p o s s i b l e i n most c a s e s t o d e v e l o p r e a c t i o n c o n d i t i o n s f o r which s u c h e l i m i n a t i o n s a r e n o t p o s s i b l e , o r s t r u c t u r e s i n which t h e polymer-bound f u n c t i o n a l i t i e s a r e p o o r l e a v i n g g r o u p s u n d e r b a s i c c o n d i t i o n s . T h i s w o r k o n t h e i n t r o d u c t i o n of d i - m e t h y l e n e s p a c e r s i s of p a r t i c u l a r i n t e r e s t a s it d e m o n s t r a t e s t h e f r e q u e n t inadequacy of b l i n d l y a p p l i e d " p o l ymer-analogous" r e a c t i o n s : s p e c i a l r e a c t i o n c o n d i t i o n s a r e r e q u i r e d t o c o p e w i t h t h e u n u s u a l e n v i r o n m e n t w h i c h p r e v a i l s w i t h i n r e a c t i v e polymers . For example , w h i l e model r e a c t i o n s s u g g e s t t h a t (2-bromoethyl)polystyrene s h o u l d be r e a d i l y o b t a i n e d from t h e c o r r e s p o n d i n g 2-hydroxyethyl a n a l o g by r e a c t i o n w i t h l i t h i u m bromide and c h l o r o t r i m e t h y l - s i l a n e i n a c e t o n i t r i l e , it is found t h a t t h i s r e a c t i o n o n l y p r o c e e d s t o 90% c o m p l e t i o n . T h i s i s l i k e l y due t o t h e u n i q u e non-polar microenvi ronment w i t h i n t h e polymer ( s t y r e n i c r e s i d u e s h e l d i n p r o x i m i t y t o t h e a l c o h o l s i te) which a l l o w s t h e s i l y l a t i o n of some of t h e r e a c t i v e groups t o o c c u r i n c o m p e t i t i o n t o t h e normal b r o m i n a t i o n which i s u s u a l l y q u a n t i t a t i v e i n t h e p o l a r a c e t o n i t r i l e medium. The c h o i c e of o t h e r o p t i m i z e d r e a c t i o n c o n d i t i o n s [ 231 a f f o r d s t h e f u l l y brominated polymer as shown i n F ig . 2.

+cH,- CH+ I

I CH,CH,-Br

90% C o n v e r s i o n

I CH,CH,-OH

I C H,CH,-Br

100% C o n v e r s i o n

Fig . 2. Development of a q u a n t i t a t i v e b r o m i n a t i o n p r o c e d u r e f o r a h y d r o x y l a t e d r e s i n .

O t h e r s p a c e r groups which may be e v e n more s u i t a b l e c a n a l s o be used a d v a n t a g e o u s l y [26, 34- 3 6 1 b u t t h e work on d i m e t h y l e n e s p a c e r s c l e a r l y d e m o n s t r a t e s t h a t c h e m i c a l m o d i f i c a t i o n p r o c e d u r e s need t o be s t u d i e d and o p t i m i z e d on t h e t a r g e t po lymers and n o t j u s t t a k e n from t h e o r g a n i c l i t e r a t u r e w i t h o u t due c o n s i d e r a t i o n of t h e s p e c i a l r e q u i r e m e n t s which a p p l y t o r e a c t i v e polymers .

Chemical modification of glycidyl methacrylate resins. Although t h e p r e v i o u s d i s c u s s i o n was f o c u s e d e n t i r e l y o n c r o s s l i n k e d p o l y s t y r e n e r e s i n s , i t i s w o r t h n o t i n g h e r e t h a t a n o t h e r r e a c t i v e r e s i n which h a s r e c e i v e d much a t t e n t i o n i s c r o s s l i n k e d g l y c i d y l m e t h a c r y l a t e . Most of t h e work on t h i s polymer h a s been c a r r i e d o u t on macroporous r e s i n s [12 , 37-38]. With few e x c e p t i o n s , t h e c h e m i c a l m o d i f i c a t i o n of t h e s e r e s i n s i s g e n e r a l l y n o t q u a n t i t a t i v e b u t t h i s h a s n o t o v e r l y a f f e c t e d t h e i r end use which h a s m a i n l y been i n t h e area of s e p a r a t i o n media.

New directions in chemical modification. It may be s a i d t h a t t h e r e a c t i v i t y of ( 1 i t h i o ) p o l y - s t y r e n e i s complementary t o t h a t of (chloromethy1)polystyrene as t h e former can be used as a n u c l e o p h i l i c r e a g e n t w h i l e t h e l a t t e r h a s e l e c t r o p h i l i c p r o p e r t i e s . In t h e o r y , ( c h l o r o - m e t h y 1 ) p o l y s t y r e n e i t s e l f c o u l d a l s o be t u r n e d i n t o a complementary n u c l e o p h i l i c r e a g e n t by t r a n s f o r m a t i o n i n t o t h e c o r r e s p o n d i n g l i t h i a t e d o r organomagnesium r e a g e n t . U n f o r t u n a t e l y a t t e m p t s a t l i t h i a t i o n of (chloromethy1)polystyrene under a v a r i e t y of c o n d i t i o n s a l l met w i t h f a i l u r e as t h e r e a g e n t c o u p l e s i n s t a n t l y t o y i e l d b i p h e n y l i c s p e c i e s t h e r e b y i n c r e a s i n g t h e d e g r e e o f c r o s s l i n k i n g o f t h e r e s i n a n d d e s t r o y i n g a l l d e s i r e d f u n c t i o n a l i t y [ 2 4 ] . S i m i l a r l y , s y n t h e s i s of t h e polymer-supported G r i g n a r d r e a g e n t i s made d i f f i c u l t by t h e f a c t b o t h ( ch lo romethy1)po lys ty rene and magnesium a r e s o l i d i n s o l u b l e r e a g e n t s . Numerous a t t e m p t s t o p r e p a r e t h e G r i g n a r d r e a g e n t e i t h e r d i r e c t l y o r v i a r e a c t i v e s p e c i e s such as magnesium bromide, o r s o l u b l e G r i g n a r d r e a g e n t s o p e r a t i n g as magnesium " s h u t t l e s " f a i l e d t o produce t h e d e s i r e d p o l y m e r i c G r i g n a r d [24] . We h a v e r e c e n t l y been a b l e t o s o l v e t h i s problem s a t i s f a c -

356 J. M. J. FRECHET era/.

t o r i l y [ 3 9 ] u s i n g magnesium anthracene-THF complex [ 4 0 ] as t h e m e t a l a t i n g s p e c i e s (F ig . 3) . Under t h e s e c o n d i t i o n s e x c e l l e n t y i e l d s of t h e i n s o l u b l e p o l y m e r - b o u n d b e n z y l i c G r i g n a r d s p e c i e s a r e o b t a i n e d ; t h e s e r e a g e n t s are c u r r e n t l y b e i n g used i n t h e deve lopment of s e v e r a l new and i n t e r e s t i n g r e a c t i v e polymers .

..&%I. 3 TH F

I CH,CI CH,MgCI CH,COOH

F i g . 3 . P r e p a r a t i o n and tes t r e a c t i o n of a n i n s o l u b l e G r i g n a r d r e a g e n t

4 CH,- FH+ +cH~- CH+ I

* Q Ts 0 C H, CH,R

cu +

Li CH,CH,R

F i g . 4 . Copper-mediated f o r m a t i o n of C-C bonds on i n s o l u b l e polymers .

S i m i l a r l y , t h e deve lopment of polymer m o d i f i c a t i o n r e a c t i o n s i n which l i n k a g e of r e a c t i v e m o i e t i e s t o p o l y s t y r e n e i s accompl ished t h r o u g h carbon-carbon bonds o n l y , as opposed t o t h e carbon-he teroa tom l i n k a g e s which are u s u a l l y o b t a i n e d i n t h e r e a c t i o n of ( c h l o r o m e t h y 1 ) p o l y - s t y r e n e w i t h n u c l e o p h i l e s , h a s l e d u s t o d e v e l o p organo-copper media ted r e a c t i o n s which can be c a r r i e d o u t u s i n g c r o s s l i n k e d p o l y s t y r e n e r e s i n s as r e a c t i v e s u b s t r a t e s (F ig . 4 ) . Such r e a c t i o n s promise t o be u s e f u l i n t h e p r e p a r a t i o n of c e r t a i n p o l y m e r i c c a t a l y s t s [ 4 1 ] .

F i n a l l y , o u r a t t e m p t s t o modify c l e a n l y c r o s s l i n k e d polymers d e r i v e d from 2-methyl-5-vinyl- p y r i d i n e t h r o u g h a c t i v a t i o n of t h e 2-methyl group (F ig . 5) were much less s u c c e s s f u l as w e were n o t a b l e t o e l i m i n a t e s i d e r e a c t i o n s . The i n t r o d u c t i o n of a c e t a t e , h a l o g e n , o r d i a l k y l - a m i n o f u n c t i o n a l g r o u p s , o f t e n v i a t h e N-oxide d e r i v a t i v e were u s u a l l y a c c o m p a n i e d by u n d e s i r e d s i d e - r e a c t i o n s such as a d d i t i o n a l c r o s s l i n k i n g and a l s o t h e i n c o r p o r a t i o n of some u n c o n t r o l l e d f u n c t i o n a l i t i e s i n t o t h e r e a c t i v e polymer [ 4 2 ] . Though t h e m o d i f i e d p o l y m e r s may s t i l l be u s a b l e i n some a p p l i c a t i o n s , t h e s e m o d i f i c a t i o n r e a c t i o n s c a n n o t be compared t o t h o s e d e s c r i b e d ea r l i e r i n t h i s r e p o r t as o p t i m i z a t i o n c o u l d n o t be c a r r i e d out .

-( CH,- CH+ --f CH,- CH+- + CH,- CH+- Q - 0 ---+ f$ R = OAc: NMez

\ N -0

\ N \ N

CH3 CH 3 CH,- R

F i g . 5. Chemical m o d i f i c a t i o n of poly(2-methyl-5-vinylpyridine)

Preparation from reactive monomers The p r e p a r a t i o n of u s e f u l c r o s s l i n k e d r e a c t i v e r e s i n s f rom f u n c t i o n a l monomers h a s r e c e i v e d much less s u s t a i n e d a t t e n t i o n t h a n t h e c h e m i c a l m o d i f i c a t i o n a p p r o a c h d e s c r i b e d above. T h i s i s due i n p a r t t o t h e l i m i t e d a v a i l a b i l i t y of f u n c t i o n a l monomers and t o t h e r e l u c t a n c e of many r e s e a r c h e r s t o v e n t u r e i n t o t h e p r e p a r a t i o n of bead polymers w i t h s u i t a b l e p h y s i c a l as w e l l as c h e m i c a l c h a r a c t e r i s t i c s . The p r e p a r a t i o n of 1-2% c r o s s l i n k e d g e l po lymers by s u s p e n s i o n p o l y m e r i z a t i o n i s a r e l a t i v e l y easy t a s k p r o v i d e d a s u i t a b l e c r o s s l i n k i n g a g e n t w i t h a r e a c t i v i t y comparable t o t h a t of t h e f u n c t i o n a l monomer i s a v a i l a b l e . I n p r a c t i c e , d i v i n y l b e n z e n e , e t h y l e n e d i m e t h a c r y l a t e o r b i s - a c r y l a m i d e a r e u s e d m o s t f r e q u e n t l y , t h o u g h s p e c i a l t y c r o s s l i n k i n g a g e n t s s u c h a s d i v i n y l p y r i d i n e h a v e a l s o been used. S e v e r a l p r o c e d u r e s f o r t h e p r e p a r a t i o n of g e l r e s i n s

Reactive polymers 357

h a v e b e e n d e s c r i b e d i n t h e l i t e r a t u r e [ 2 6 , 42-44]. I n c o n t r a s t , i t i s r e l a t i v e l y m o r e d i f f i c u l t t o p r e p a r e h i g h l y p o r o u s , h i g h s u r f a c e a r e a , m a c r o p o r o u s r e s i n s as n u m e r o u s v a r i a b l e s s u c h a s t h e n a t u r e a n d amount o f p o r o g e n i c a g e n t , t h e s t i r r i n g r a t e a n d r e a c t o r d e s i g n , t h e r e l a t i v e p r o p o r t i o n s of t h e v a r i o u s components i n t h e r e a c t i o n m i x t u r e , etc., a l l h a v e a s i g n i f i c a n t e f f e c t on t h e c h a r a c t e r i s t i c s of t h e f i n a l r e s i n s . F o r t u n a t e l y t h e r e e x i s t s e v e r a l e x c e l l e n t a c c o u n t s o f p r o c e d u r e s w h i c h a r e u s e f u l i n t h e p r e p a r a t i o n o f macroporous a c r y l i c [ 1 2 ] o r s t y r e n i c [ 1 3 , 451 r e s i n s .

F i g u r e 6 shows s e v e r a l r e l a t i v e l y e a s i l y a c c e s s i b l e s u b s t i t u t e d s t y r e n e monomers which a r e u s e f u l i n t h e p r e p a r a t i o n of r e a c t i v e p o l y m e r s . W h i l e some of t h e s e monomers a r e commer- c i a l l y a v a i l a b l e , o t h e r s , which are sometimes p r e p a r e d f o r p r o p r i e t a r y i n d u s t r i a l a p p l i c a - t i o n s , may be more d i f f i c u l t t o o b t a i n , S e v e r a l o t h e r i n t e r e s t i n g and c o m m e r i c a l l y a v a i l a b l e f u n c t i o n a l monomers s u c h as g l y c i d y l m e t h a c r y l a t e , 2 -hydroxyethyl m e t h a c r y l a t e , and o t h e r acrylics h a v e a l s o been used e x t e n s i v e l y t o p r e p a r e r e a c t i v e polymers . It i s e x p e c t e d t h a t as t h e marke t f o r s p e c i a l t y p o l y m e r s grows l a r g e r , o t h e r f u n c t i o n a l monomers w i l l be added t o t h e c a t a l o g s of c h e m i c a l s u p p l i e r s .

CHz= CH CH,=CH CH,=CH CHz= CH

c H3 HZCI

CHZCI

CH,=CH CHF CH CH,=CH CH,= CH

QQQQ CI Br OH OCOOt-BU

F i g . 6 . Examples of f u n c t i o n a l i z e d s t y r e n e monomers,

C H g CH I

I COOH

C H p Y H

Preparation of resins containing pendant phenolic groups. C r o s s l i n k e d p o l y s t y r e n e r e s i n s c o n t a i n i n g pendant p h e n o l i c g r o u p s c a n be eas i ly o b t a i n e d by s u s p e n s i o n c o p o l y m e r i z a t i o n of p r o t e c t e d p - h y d r o x y s t y r e n e w i t h d i v i n y l b e n z e n e . We h a v e f o u n d t h a t a n e x t r e m e l y u s e f u l monomer f o r t h i s p r e p a r a t i o n i s 4- t -buty loxycarbonyloxys tyrene [45-461. T h i s monomer co- o r t e r - p o l y m e r i z e s w e l l w i t h d i v i n y l b e n z e n e a n d / o r s t y r e n e a n d a f f o r d s a t-BOC p r o t e c t e d p h e n o l i c r e s i n which can be e a s i l y d e - p r o t e c t e d by a v a r i e t y of r o u t e s s u c h as h y d r o l y s i s , a c i d o l y s i s , o r t h e r m o l y s i s . As w i l l be s e e n below, t h e t h e r m a l d e p r o t e c t i o n r e a c t i o n which o n l y a f f o r d s g a s e o u s b y - p r o d u c t s , c a r b o n d i o x i d e a n d 2 - m e t h y l - p r o p e n e ( F i g . 7), i s p a r t i c u l a r l y w e l l s u i t e d t o t h e p r e p a r a t i o n of t h e v e r y small porous beads of t h e t y p e which i s commonly used f o r HPLC packings .

+CH,-CH~ +cH,- CH 3 ,c H3 A 190' 8 + COrf CH,=C,

o r HO -w CH3

OH

+ OCOOt-Bu

F i g . 7 . Thermal removal of t-BOC p r o t e c t i n g g r o u p s

Monomers containinga trimethylenespacer. A c o n v e n i e n t a l t e r n a t i v e t o c h l o r o m e t h y l s t y r e n e f o r t h e p r e p a r a t i o n of r e a c t i v e monomers i s t h e p-(3-bromopropyl)styrene which was o r i g i n a l l y d e v e l o p e d by H a l l e n s l e b e n [34]. T h i s monomer and o t h e r s d e r i v e d from i t a r e p a r t i c u l a r l y s u i t a b l e f o r t h e p r e p a r a t i o n of r e a c t i v e polymers i n which t h e a c t i v e s i t e s are s e p a r a t e d by a s h o r t s p a c e r arm from t h e s t y r e n e r e s i d u e s . We h a v e used p-(3-bromopropyl)styrene as t h e s t a r t i n g material i n t h e p r e p a r a t i o n of s e v e r a l o t h e r more e l a b o r a t e d s t r u c t u r e s c o n t a i n i n g f o r e x a m p l e p e n d a n t a c t i v a t e d s i l i c o n or a d i a l k y l a m i n o p y r i d i n e g r o u p as shown i n F i g . 8. [26, 471

Miscellaneous reactive monomers. Numerous o t h e r r e a c t i v e monomers are b e i n g p r e p a r e d f o r u l t i m a t e a p p l i c a t i o n s i n polymer a s s i s t e d chemis t ry . For example s e v e r a l c h i r a l amino a l c o - h o l l i g a n d s h a v e been a t t a c h e d t o c h l o r o m e t h y l s t y r e n e (Fig, 9) f o r t h e p r e p a r a t i o n of p o l y - m e r i c r e a g e n t s o r c a t a l y s t s u s e d i n a s y m m e t r i c s y n t h e s i s [ 28, 48-50]. O t h e r i n t e r e s t i n g

358 J. M. J. FRECHET eta /

s t r u c t u r e s wh ich m a y f i n d v a r i e d a p p l i c a t i o n s i n c l u d e v i n y l t - b u t y l c a r b o n a t e [51] and numerous o t h e r ca rbona te s u b s t i t u t e d v i n y l compounds.

F ig . 8. P repa ra t ion of monomers having a t r ime thy lene spacer group.

CH,=CH I

CH2= CH Q CH2CI

Fig . 9. P r e p a r a t i o n of polymer-supported c h i r a l amino-alcohols.

POLYMER-ASSISTED CHEMISTRY

Q CHF CH

I

As most of t h e o rgan ic a p p l i c a t i o n s of r e a c t i v e polymers have been reviewed r e c e n t l y [ 7-9, 211, some w i l l be mentioned b r i e f l y i n t h e f o l l o w i n g paragraphs bu t d e t a i l e d cove rage w i l l be l i m i t e d t o a s m a l l s e l e c t i o n of newer e x a m p l e s , m a i n l y f rom t h e a u t h o r s ’ own l a b o r a t o r y , which p r o v i d e a v i e w o f some o f t h e d i r e c t i o n s i n which t h e f i e l d i s moving a t t h e p r e s e n t t ime.

With t h e cont inued expansion of t h e f i e l d of b io technology, immobilized enzymes and c e l l s a r e s t i l l r e c e i v i n g a c o n s i d e r a b l e amount of a t t e n t i o n . S e v e r a l i n d u s t r i a l p rocesses based on such i m m o b i l i z e d s p e c i e s h a v e b e e n i n o p e r a t i o n f o r some t ime now [52-541 and o t h e r s a r e l i k e 1 y t o f o l 1 ow, I n t h e area of polymer-supported t r a n s i t i o n metal ca ta lys t s s e r i o u s problems wi th t h e long- term s t a b i l i t y of t h e f u n c t i o n a l i z e d suppor t s have been encountered [55-561. Fu tu re deve lop- ments i n t h i s a r e a w i l l h inge on r e sea rch i n t o immobi l iz ing systems of improved s t a b i l i t y . Some v e r y imag ina t ive u s e s of s o l u b l e polymer ic r e a g e n t s and c a t a l y s t s have been desc r ibed by Bergbre i t e r [lo, 571 f o l l o w i n g t h e e a r l i e r s u c c e s s f u l a p p l i c a t i o n of s o l u b l e s u p p o r t s i n t h e s y n t h e s i s of po lypep t ides [58]. The polymer ic p h o t o s e n s i t i z e r s of Neckers and coworkers [59- 601 have now been s t u d i e d i n g r e a t d e t a i l and p rov ide an i n t e r e s t i n g and unique a l t e r n a t i v e t o t h e conven t iona l pho tosens i t i ze r s . Outs tanding work i n t h e a r e a of molecu la r r e c o g n i t i o n through t h e use of po lymer ic t e m p l a t e s by Wulff and coworkers [61-621 con t inues t o s t i m u l a t e r e sea rch towards polymeric enzyme models.

Polymer-assisted asymmetric synthesis W h i l e most e a r l y work i n t h e a p p l i c a t i o n of c h i r a l p o l y m e r s f o r a s y m m e t r i c p r o c e s s e s was d i r e c t e d towards m a t e r i a l s u s e f u l i n t h e chromatographic s e p a r a t i o n of enant iomers [62-641, s e v e r a l r e p o r t s of t h e use of polymers as c h i r a l a u x i l i a r i e s i n asymmetric syn theses have appeared. These i n c l u d e polymer ic phase t r a n s f e r ca ta lys t s [65 ] o r c h i r a l polymers used i n asymmetric a d d i t i o n [66-691 o r a l k y l a t i o n r e a c t i o n s [70-711. More r e c e n t l y , much a c t i v i t y has been concen t r a t ed on polymer-ass i s ted asymmetric r educ t ions [28, 48-49].

The s o l i d - p h a s e a p p r o a c h seems t o b e i d e a l l y s u i t e d f o r numerous a symmet r i c r e a c t i o n s i n which t h e c h i r a l a u x i l i a r y remains una f fec t ed i n t h e o v e r a l l p rocess a s c h i r a l mo lecu le s a r e o f t e n v a l u a b l e commodities f o r which r e c y c l i n g i s a v e r y p r a c t i c a l requirement. Attachment of t h e c h i r a l mo ie t i e s t o i n s o l u b l e r e a c t i v e polymers ensu res t h a t t h e i r r ecove ry w i l l be q u a n t i t a t i v e and may t h e r e f o r e f a c i l i t a t e t h e i r use. Th i s reasoning had c o n t r i b u t e d t o t h e

Reactive polymers 359

development of a number of c h i r a l po lymers f o r asymmetr ic r e d u c t i o n s , E a r l y work on polymer- bound l i t h i u m a luminium h y d r i d e c h i r a l complexes [73-751 h a v i n g a f f o r d e d r e s u l t s which were v a s t l y i n f e r i o r t o t h o s e o b t a i n e d w i t h many low m o l e c u l a r weight complexes, we under took a thorough s t u d y of t h e r e a c t i o n [28] . The c h i r a l a u x i l i a r y chosen f o r t h i s s t u d y was c r o s s - l i n k e d p o l y s t y r e n e c o n t a i n i n g ( l R , 2 S ) - e p h e d r i n e bound t h r o u g h n i t r o g e n t o some of i t s p- m e t h y l e n e - s u b s t i t u t e d a r o m a t i c r i n g s . The c h i r a l r e a g e n t i s p r e p a r e d by s u c c e s s i v e t r e a t m e n t of a s o l u t i o n of l i t h i u m a luminium h y d r i d e i n e t h e r w i t h 2 m o l a r e q u i v a l e n t s of a n a c h i r a l phenol and 1 e q u i v a l e n t of t h e polymer. The r e s u l t i n g complex i s t h e n used i n t h e s t o i c h i o - metric r e d u c t i o n of a p r o c h i r a l k e t o n e such as ace tophenone (Fig.10).

Q + LiAIH4 t

F i g . 10. Asymmet r i c h y d r i d e r e d u c t i o n u s i n g a polymer ic c h i r a l a u x i l i a r y .

-4 ,CH~CH+- I

9, \ -7-Q

P h-C- C H, II 0 * up to

9 7 % e e

F i g . 11. Asymmetric r e d u c t i o n w i t h a polymer ic c h i r a l borane complex,

A s e r i e s of e x p e r i m e n t s w i t h v a r i o u s p o l y m e r s h a v i n g d i f f e r e n t d e g r e e s of f u n c t i o n a l i z a t i o n (DF) showed c l e a r l y t h a t t h e r e e x i s t e d a n i n v e r s e r e l a t i o n s h i p b e t w e e n p o l y m e r DF a n d e n a n t i o s e l e c t i v i t y . T h i s i s due t o t h e i n t e r a c t i o n of r e a c t i v e s i tes i n t h e h i g h e r c a p a c i t y polymers f o r which s e l e c t i v e f o r m a t i o n of t h e d e s i r e d c h i r a l complex is n o t f a v o r e d . T h i s r e s u l t s i n b i n d i n g of t h e h y d r i d e t o s e v e r a l r a t h e r t h a n t o a s i n g l e c h i r a l c e n t e r , a s wel l a s i n t h e f o r m a t i o n of o t h e r f u l l y a c h i r a l h y d r i d e m o i e t i e s w i t h a c o n c o m m i t a n t l o s s o f s e l e c t i v i t y . H o w e v e r , a t l o w e r d e g r e e s of f u n c t i o n a l i z a t i o n , t h e p o l y m e r - b o u n d s p e c i e s b e h a v e i n d e p e n d e n t l y o f one a n o t h e r a s i s t h e c a s e w i t h s o l u b l e c o m p l e x e s f o r m e d w i t h N - benzyl -ephedr ine and good s e l e c t i v i t y i s observed .

A b e t t e r s y t e m f o r p o l y m e r - a s s i s t e d a s y m m e t r i c r e d u c t i o n s h a s been s t u d i e d e x t e n s i v e l y by I t s u n o e t a l . [ 481. I n t h i s w o r k i t was f o u n d t h a t t h e asymmetric r e d u c t i o n o f p r o c h i r a l k e t o n e s w i t h complexes formed from c e r t a i n polymer-bound c h i r a l amino a l c o h o l s and borane g a v e e x c e l l e n t r e s u l t s as t h e sys tem i s f r e e from t h e t y p e of m u l t i p l e b i n d i n g i n t e r a c t i o n s w h i c h a r e p r e v a l e n t w i t h l i t h i u m a l u m i n i u m h y d r i d e complexes, A t y p i c a l r e a c t i o n scheme (Fig . 11) i n v o l v e s t h e f o r m a t i o n of a n a c t i v e complex by r e a c t i o n of t h e c h i r a l polymer w i t h two m o l a r e q u i v a l e n t s of b o r a n e . T h i s r e a g e n t c a n r e d u c e a r o m a t i c k e t o n e s w i t h o p t i c a l y i e l d s a p p r o a c h i n g 100% [76-771. An i n t e r e s t i n g e x t e n s i o n of t h e method i s i t s a d a p t a t i o n t o a c o n t i n u o u s f l o w sys tem where borane and k e t o n e are s u p p l i e d c o n t i n u o u s l y t o a s p e c i a l l y d e s i g n e d c o l u m n f i l l e d w i t h t h e c h i r a l p o l y m e r w h i c h i s c o n s t a n t l y r e g e n e r a t e d i n t h e p r o c e s s [78] . The same polymer-bound borane complex can be used i n t h e r e d u c t i o n of oxime e t h e r s t o o p t i c a l l y a c t i v e a m i n e s ; h e r e a g a i n o p t i c a l y i e l d s a p p r o a c h 100%. A l t h o u g h t h e e x a c t s t r u c t u r e s of t h e c h i r a l complexes i n v o l v e d i n t h e r e d u c t i o n of oxime e t h e r s a r e no t c l e a r , t h e f o l l o w i n g o b s e r v a t i o n s [49 , 791 p r o v i d e some i n s i g h t i n t h e r e a c t i o n :

- The r e d u c t i o n i s much f a s t e r w i t h t h e amino a l c o h o l - b o r a n e t h a n w i t h borane a l o n e . - The p r o d u c t d o e s n o t b ind t o t h e complex a l l o w i n g t h e u s e of a f l o w system. - The c h i r a l complex need n o t be p r e s e n t i n s t o i c h i o m e t r i c amount i f a f low-sys tem i s

360 J. M. J. FRECHET eta/.

used, ra t ios of o v e r 1 O : l h a v e produced s a t i s f a c t o r y r e s u l t s . These r e s u l t s are e x t r e m e l y e n c o u r a g i n g and s u g g e s t t h a t i n d e e d c h i r a l po lymers may h a v e a promis ing f u t u r e as a u x i l i a r i e s i n asymmetric r e a c t i o n , T h i s i s p a r t i c u l a r l y t r u e f o r r e a c - t i o n s i n which t h e p r o d u c t d o e s n o t remain a t t a c h e d t o t h e s o l i d c h i r a l complex as t h e s e may be a d a p t e d t o f l o w systems.

Regenerability in the design of polymeric reagents or protecting groups R e g e n e r a b i l i t y i s a v e r y i m p o r t a n t c o n s i d e r a t i o n i n t h e d e s i g n of a r e a c t i v e polymer used as r e a g e n t o r p r o t e c t i n g group i n o r g a n i c s y n t h e s i s [21] . T h i s is p a r t i c u l a r l y i m p o r t a n t as, w i t h a few n o t a b l e e x c e p t i o n s s u c h as t h e p o l y v i n y l p y r i d i n e s [80-821 most p o l y m e r i c r e a g e n t s are n o t r e a d i l y a v a i l a b l e . F o r e x a m p l e , s e v e r a l y e a r s a g o , we h a d p r e p a r e d a p o l y m e r i c s i l y l a t i o n r e a g e n t 4-( c 1 i l o r o d i m e t h y l s i l y l ) p o l y s t y r e n e by r e a c t i o n of ( 1 i t h i o ) p o l y s t y r e n e w i t h a n e x c e s s of d i c h l o r o d i m e t h y l s i l a n e [14] . Though t h i s r e a g e n t c o u l d be used e f f e c t i v e l y i n t h e p r o t e c t i o n of a l c o h o l s o u r r e s u l t s were n o t r e p o r t e d as w e found t h e p o l y m e r i c r e a g e n t l a c k i n g i n i t s a b i l i t y t o be r e g e n e r a t e d . The main problem was t h e s t r u c t u r a l d e s i g n of t h e r e a g e n t whereby s i l i c o n was bound d i r e c t l y t o t h e a r o m a t i c r i n g s of t h e s t y r e n i c backbone. A s p h e n y l - s i l i c o n bonds a r e n o t o r i o u s l y l a b i l e t o e l e c t r o p h i l e s , r e g e n e r a t i o n of t h e r e a g e n t c o u l d n o t be c a r r i e d o u t w i t h o u t o b s e r v i n g a d r a s t i c l o w e r i n g of t h e s i l i c o n c o n t e n t of t h e polymer. T h i s problem can be remedied by u s i n g a d i f f e r e n t d e s i g n f o r t h e r e a g e n t i n which s i l i c o n i s n o t e i t h e r l i n k e d d i r e c t l y t o a p h e n y l r i n g o r p l a c e d i n a l a b i l e b e n z y l i c p o s i t i o n . T h i s was accompl ished [ 4 7 ] by p r e p a r i n g c r o s s l i n k e d beads of 4-[3-(phenyldimethyl- s i l y 1 ) p r o p y l ] p o l y s t y r e n e by s u s p e n s i o n p o l y m e r i z a t i o n of t h e c o r r e s p o n d i n g monomer w i t h s t y r e n e a n d d i v i n y l b e n z e n e t h e d e g r e e of f u n c t i o n a l i z a t i o n o f t h e f i n a l p o l y m e r b e i n g a f u n c t i o n of t h e monomer f e e d r a t i o . I n t h i s c a s e t h e l a b i l i t y of t h e p h e n y l - s i l i c o n bond of t h e p e n d a n t g r o u p i s u s e d t o a d v a n t a g e i n t h e s u b s e q u e n t c r e a t i o n of t h e a c t i v e c e n t e r by c l e a v a g e w i t h a c i d t o y i e l d t h e d e s i r e d s i l y l a t i o n r e a g e n t . T h o u g h c l e a v a g e t o y i e l d a c h l o r o d i m e t h y l p r o p y l pendant group is p o s s i b l e w e o p t e d f o r t h e n o v e l t r i f l u o r o a c e t y l s i l y l group as s i l y l a t i n g s p e c i e s . T h i s a f f o r d s a polymer which r e a c t s w e l l w i t h a l c o h o l s and c a n be used f o r t h e i r t emporary p r o t e c t i o n (F ig . 12). R e c y c l i n g a f t e r c l e a v a g e of t h e a l c o h o l i s done e a s i l y and q u a n t i t a t i v e l y t h r o u g h t r i f l u o r o a c e t y l a t i o n o r t h e more u s u a l c h l o r i n a t i o n . I n e i t h e r c a s e n o l o s s o f s i l i c o n i s o b s e r v e d u p o n r e p e a t e d r e c y c l i n g . T h i s e x a m p l e i s i n t e r e s t i n g a s it i l l u s t r a t e s a d e s i g n where n o v e l c h e m i s t r y on a s o l i d polymer was d e v e l o p e d w i t h o u t t h e need f o r p r i o r "analogous" s o l u t i o n exper iments .

+CH,- CH+ I

+CH,- CH-)- I

CF,COOH R- OH

Me- Si-Me Me- &-Me Me- Si-Me I 0-R

I OCOCF,

t C F,COOH

F i g . 12 . Regenerable s i l i c o n - c o n t a i n i n g p o l y m e r i c p r o t e c t i n g group.

Use of reactive polymers in the determination of reaction mechanisms A s c r o s s l i n k e d p o l y m e r s remain i n s o l u b l e t h r o u g h o u t t h e c o u r s e of r e a c t i o n s i n which t h e y are i n v o l v e d , t h e i r c o n f e r t h e i r i n s o l u b i l i t y t o any r e a c t i v e s p e c i e s which becomes a t t a c h e d t o them d u r i n g r e a c t i o n . T h i s phenomenon can be u s e f u l i n h e l p i n g t o d e t e r m i n e t h e n a t u r e of c e r t a i n r e a c t i v e i n t e r m e d i a t e s i n complex c h e m i c a l r e a c t i o n s . For example, s e v e r a l g roups h a v e used t h e " three-phase test" i n v o l v i n g two r e a c t i v e p o l y m e r s suspended i n t h e same medium t o d e t e r m i n e whether c e r t a i n i n t e r m e d i a t e s are f r e e o r bound i n some chemica l r e a c t i o n s [83- 851.

In t h e c o u r s e o f o u r d e v e l o p m e n t o f new p o l y m e r - b o u n d c a t a l y s t s f o r asymmetric a d d i t i o n r e a c t i o n s , we h a v e used t h e i n s o l u b i l i t y of t h e p o l y m e r i c c a t a l y s t t o d e t e r m i n e t h e mechanism of t h e a d d i t i o n r e a c t i o n . The tes t r e a c t i o n we s t u d i e d was t h e a d d i t i o n of d i e t h y l z i n c t o b e n z a l d e h y d e [ 861; t h i s r e a c t i o n i s c a t a l y z e d by a v a r i e t y o f a l c o h o l s a n d a m i n e s a n d we c h o s e t o tes t f i r s t t h e a p p l i c a b i l i t y of t h e polymer-bound e p h e d r i n e d e s c r i b e d ea r l i e r [28]. W h i l e o u r work was i n p r o g r e s s , s e v e r a l r e p o r t s f rom o t h e r l a b o r a t o r i e s on similar d i e t h y l - z i n c a d d i t i o n r e a c t i o n s u s i n g s o l u b l e c a t a l y s t s a p p e a r e d [87-881. Our f i n d i n g s conf i rmed t h a t t h e polymer-bound e p h e d r i n e as w e l l as o t h e r polymer-bound amino a l c o h o l s c o u l d be used e f f i c i e n t l y as ca ta lys t s i n t h i s asymmetr ic a d d i t i o n r e a c t i o n b u t t h e mechanism proposed by o t h e r s [ 8 8 ] d i d n o t m a t c h o u r o b s e r v a t i o n s w i t h t h e i n s o l u b l e c a t a l y s t . Here a g a i n , t h e

Reactive polymers 36 1

i n s o l u b l e n a t u r e of t h e c a t a l y s t f a c i l i t a t e s t h e e x p l o r a t i o n of t h e r e a c t i o n mechanism as t h e d i s t i n c t p h a s e s which can be s e p a r a t e d from t h e r e a c t i o n m i x t u r e a t d i f f e r e n t s t a g e s of t h e r e a c t i o n p r o v i d e e x c e l l e n t c l u e s as t o t h e n a t u r e of t h e o v e r a l l p r o c e s s , I n t h i s c a s e , o u r r e s u l t s show a two z i n c s p e c i e s mechanism i n which t h e i n i t i a l l y formed polymer-bound z i n c complex o n l y acts t o b ind t h e a l d e h y d e i n a c h i r a l e n v i r o n m e n t w h i l e a l k y l t r a n s f e r o c c u r s i n e n a n t i o s e l e c t i v e f a s h i o n f rom unbound d i e t h y l z i n c .

Development of high activity polymeric supernucleophilic catalysts The d i s c o v e r y of t h e r e m a r k a b l e a c c e l e r a t i o n of a c y l a t i o n r e a c t i o n s by N , N - d i m e t h y l a m i n o - p y r i d i n e catalysts [89 ] h a s l e d t o t h e r a p i d deve lopment of numerous o t h e r ca ta lys t s w i t h similar s t r u c t u r e s [go]. A s t h e s e ca ta lys t s are r e l a t i v e l y c o s t l y and are used i n a p p l i - c a t i o n s where t h e i r c o m p l e t e removal f rom r e a c t i o n medium a f t e r r e a c t i o n may be r e q u i r e d , t h e y are i d e a l c a n d i d a t e s f o r a t t a c h m e n t t o i n s o l u b l e polymer s u p p o r t s . P r e v i o u s work by s e v e r a l g r o u p s [91-951 h a s conf i rmed t h e f e a s i b i l i t y of t h i s approach b u t t h e p o l y m e r s which h a v e been r e p o r t e d t o - d a t e o f t e n l a c k e d i n r e a c t i v i t y , s t a b i l i t y , o r p h y s i c a l p r o p e r t i e s . We h a v e p r e p a r e d and s t u d i e d a number of new ca t a ly t i c s t r u c t u r e s , b o t h low m o l e c u l a r weight and p o l y s t y r e n e - b a s e d [24, 26-27] and succeeded i n producing i n s o l u b l e p o l y m e r i c ca ta lys t s (F ig . 13) p o s s e s s i n g both h i g h r e a c t i v i t i e s and good c h e m i c a l s t a b i l i t y .

T h i s s t u d y a l s o c o n f i r m s t h a t t h e small b u t c l e a r l y d e t e c t a b l e d i f f e r e n c e s i n r e a c t i v i t y b e h a v i o r between t h e p o l y m e r s and model c a t a l y s t s i n s o l u t i o n c a n be a t t r i b u t e d d i r e c t l y t o t h e microenvi ronment which e x i s t s w i t h i n t h e p o l y m e r i c catalysts. Even a t modera te d e g r e e s of f u n c t i o n a l i z a t i o n r e a c t i v e sites are l o c a l l y more c o n c e n t r a t e d i n t h e polymer t h a n would be t h e case i n a homogenous s o l u t i o n . T h i s i n c r e a s e s t h e l o c a l p o l a r i t y a t t h e s i t e of reac- t i o n , which, i n t u r n , a f f e c t s a t t a c k of t h e a l c o h o l on t h e charged i n t e r m e d i a t e and c a u s e s a small b u t d e t e c t a b l e d r o p i n polymer c a t a l y t i c a c t i v i t y when compared t o t h e f r e e models i n s o l u t i o n . S i m i l a r l y , i n a less f a v o r a b l e p o l a r r e a c t i o n medium t h e polymer shows a r e l a t i v e e n h a n c e m e n t i n i t s a c t i v i t y when c o m p a r e d t o t h e f r e e c a t a l y s t a s t h e l o c a l ( s t y r e n i c ) envi ronment of t h e c a t a l y t i c s i tes p r o v i d e s a ' p o l a r i t y s h i e l d ' which c a n n o t be i m i t a t e d i n homogeneous medium. O v e r a l l , t h i s s t u d y c o n f i r m s t h e p o t e n t i a l u s e f u l n e s s of p o l y m e r i c a c y l a t i o n c a t a l y s t s and t h e i m p o r t a n c e of s p a c e r groups and microenvi ronment c o n s i d e r a t i o n s i n t h e s t r u c t u r a l d e s i g n of t h e catalysts.

+cH~- YH +- +H,- CH I -)-

I N-C H,

Me b H OH

F i g . 14. New p h e n o l i c s e p a r a t i o n media

F i g . 13. S u p e r n u c l e o p h i l i c c a t a l y s t r e s i n s

New reactive polymers as media for HPLC column packings Though a l a r g e v a r i e t y o f s o r b e n t s f o r HPLC h a v e b e e n d e s c r i b e d i n r e c e n t y e a r s , t h e v a s t m a j o r i t y of t h e s e a r e based on i n o r g a n i c matriccs such as s i l i ca . Numerous s o r b e n t s c o n t a i - n i n g bound o r g a n i c g r o u p s h a v e been p r e p a r e d [96 ] b u t a l l s i l i c a - b a s e d media s u f f e r f rom t h e same l i m i t a t i o n which i s t h e i r l a c k of s t a b i l i t y a t h i g h pII. T h i s h a s l e d t o t h e deve lopment of more c h e m i c a l l y i n e r t polymer-based s o r b e n t s s u c h a s t h e m a c r o p o r o u s s t y r e n e - d i v i n y l - benzene r e s i n s [97 ] , ion-exchange r e s i n s [98-991, o r a v a r i e t y of m e t h a c r y l i c r e s i n s [loo- 1021. W i t h v e r y f e w n o t a b l e e x c e p t i o n s , l i t t l e w o r k h a s b e e n d o n e i n t h e s p e c i f i c deve lopment of r e a c t i v e r e s i n s s u i t a b l e f o r HPLC though t h e r e may be s i g n i f i c a n t a d v a n t a g e s i n t h e i r u s e f o r s p e c i a l i z e d s e p a r a t i o n s as materials w i t h v e r y s p e c i f i c i n t e r a c t i o n s and e x c e l l e n t c h e m i c a l r e s i s t a n c e c o u l d r e s u l t .

We h a v e u n d e r t a k e n [ 451 t h e d e v e l o p m e n t of m a c r o p o r o u s r e s i n s b a s e d on s t y r e n e monomers c o n t a i n i n g f r e e p h e n o l i c groups. These materials are e x p e c t e d t o show i n t e r e s t i n g p r o p e r t i e s i n t h e i r i n t e r a c t i o n s with a v a r i e t y of s u b s t r a t e s of d i f f e r e n t a c i d i t i e s . I n v i e w of t h e c o m p l i c a t i o n s which arise i n t h e f r e e - r a d i c a l p o l y m e r i z a t i o n of v i n y l - p h e n o l s , t h e monomers we c h o s e a1 1 h a d t h e i r p h e n o l i c h y d r o x y l s p r o t e c t e d as t h e t - b u t y l o x y c a r b o n y l (t-BOC) d e r i v a t i v e . As was s e e n above , t h i s t-BOC p r o t e c t i n g group i s removed eas i ly by a c i d o r b a s e h y d r o l y s i s o r by t h e r m o l y s i s n e a r 190°C. I n g e n e r a l , p u r i f i c a t i o n of smal l 5-10pm b e a d s a f t e r t h e i r p r e p a r a t i o n by s u s p e n s i o n p o l y m e r i z a t i o n o r a f t e r t h e i r c h e m i c a l m o d i f i c a t i o n

362 J. M. J. FRECHET ef a/.

( i . e . d e p r o t e c t i o n ) i s a v e r y t e d i o u s o p e r a t i o n . I n t h i s i n s t a n c e h o w e v e r , t h e u s e o f a t h e r m a l l y l a b i l e p r o t e c t i n g group f a c i l i t a t e s g r e a t l y t h e p r e p a r a t i o n of HPLC-grade beads as no p u r i f i c a t i o n i s r e q u i r e d a f t e r removal of t h e t-BOC groups s i n c e a l l t h e by-products of t h e d e p r o t e c t i o n a r e gaseous. The v a r i a b l e s which c o n t r o l t h e s i z e , s u r f a c e area, pore s i z e , and pore s i z e d i s t r i b u t i o n f o r bead polymers h a v e been e x p l o r e d i n d e t a i l i n an e x c e l l e n t s t u d y by S v e c and coworkers [ l o 2 1 d e a l i n g w i t h g l y c i d y l m e t h a c r y l a t e - e t h y l e n e d i m e t h a c r y l a t e r e s i n s . Though n o t d i r e c t l y a p p l i c a b l e t o a l l monomer sys tems t h e i r f i n d i n g s are e x t r e m e l y u s e f u l and may b e a d a p t e d i n t h e d e t e r m i n a t i o n o f t h e r e l a t i v e p r o p o r t i o n s o f t h e v a r i o u s components i n t h e p o l y m e r i z a t i o n mixture , t h e c h o i c e of porogen, etc. Using such t e c h n i q u e s and a v a r i e t y of o t h e r t-BOC p r o t e c t e d d e r i v a t i v e s of 2 , 6 - d i a l k y l - 4 - v i n y l - p h e n o l s a number of new 5-10pm s i z e h i g l y p o r o u s p o l y m e r i c a d s o r b e n t s of v a r i o u s a c i d i t i e s (F ig .14) h a v e b e e n p r e p a r e d and shown t o be e f f e c t i v e i n HPLC s e p a r a t i o n s .

Other developments in reactive polymers R e a c t i v e polymers are i n c r e a s i n g l y f i n d i n g new a p p l i c a t i o n s as s p e c i a l t y materials i n a g r e a t v a r i e t y of a p p l i c a t i o n s w h i c h c a n n o t b e d i s c u s s e d h e r e . T h e s e i n c l u d e among o t h e r s , new g e n e r a t i o n s of membrane m a t e r i a l s which show e x c e l l e n t c h e m i c a l o r s i z e s e l ec t iv i ty , polymer- a s s i s t e d t r a n s p o r t s y s t e m s , s p e c i a l t y b i n d e r ma te r i a l s , p h o t o r e s i s t s a n d o t h e r i m a g i n g systems [ 1 0 3 ] , photo- o r e l e c t r o c o n d u c t i v e materials, e t c . A s t h e s e i n c r e a s e i n impor tance t h e f i e l d of r e a c t i v e polymers w i l l c o n t i n u e t o e v o l v e and grow i n many new d i r e c t i o n s .

Acknowledgements F i n a n c i a l s u p p o r t o f t h i s r e s e a r c h by t h e N a t u r a l S c i e n c e s a n d E n g i n e e r i n g R e s e a r c h C o u n c i l o f C a n a d a i s g r a t e f u l l y a c k n o w l e d g e d .

REFERENCES

1. 2. 3 . 4 .

5 . 6 . 7 .

8 .

9 .

10 * 11. 1 2 .

13.

1 4 . 15. 1 6 .

1 7 . 18.

19.

20.

2 1 . 22 *

2 3 . 2 4 . 2 5 . 2 6 .

2 7 . 2 8 .

F. H e l f f e r i c h , I o n E x c h a n g e , McGraw H i l l , N . Y . ( 1 9 6 2 ) . B . A . Adams a n d E . L . H o l m e s , J . Chem. S O C . I n d . , 2, 1 T ( 1 9 3 5 ) . K . W . P e p p e r , H . M . P a i s l e y a n d M . A . Y o u n g , J . Chem. S O C . , 4 0 9 7 ( 1 9 5 3 ) . R . M . W h e a t o n a n d D.F. H a r r i n g t o n , I n d . E n g . C h e m . , 4 _ 4 , 1 7 9 6 ( 1 9 5 2 ) . J . R . M i l l a r , D . G . S m i t h , W.E. Marr a n d T.R.E. K r e s s m a n , J . C h e m . S O C . , 2 1 8 ( 1 9 6 3 ) . R . B . M e r r i f i e l d , J . A m . Chem. S O C . , 85, 2 1 4 9 ( 1 9 6 3 ) . R . B . M e r r i f i e l d , An , 2 4 , 7 9 9 ( 1 9 8 5 ) . P. H o d g e a n d D.C. S y m e r - S u p p o r t e d R e a c t i o n s i n O r g a n i c S y n t h e s i s , W i l e y , N e w Y o r k ( 1 9 8 6 j . N . K . M a t h u r . C . K . N a r a n e . R.E. W i l l i a m s . P o l v m e r s as A i d s i n O r g a n i c

- I

C h e m i s t r , ’ A c a d e m i c P r e s s , N . Y . ( 1 9 8 O j . W.T. For ; ( E d i t o r ) , P o l y m e r i c R e a g e n t s a n d C a t a l y s t s , ACS S y m p o s i u m S e r i e s # 3 0 8 , A m e r i c a n C h e m i c a l S o c i e t y , W a s h i n g t o n ( 1 9 8 6 ) . D.E. B e r g b r e i t e r , C h a p t e r 2 i n r e f . 9 , 1 7 ( 1 9 8 6 ) .

-

W.T. F o r ; , S . M o h a n r a n j , M. P e r i y a s a m y , B r i t . P o l y m . J . , 16, 1 7 9 ( 1 9 8 4 ) . F. S v e c , J . H r a d i l , J. C o u p e k , J . K a l a l , A n e , e w . ! 4 a k r o m o l . C h e m . , 48, 1 3 5 ( 1 9 7 5 ) . H. J a c o b e l l i , M. B a r t h o l i n , A . G u y o t , Angew.Makromo1. Chem., so, 31 ( 1 9 7 9 ) ; J . A p p l . P o l y m . S c i . , 23 , 9 2 7 ( 1 9 7 9 ) . M.J. F a r r a l l , J.M.J. F r b c h e t , J . O r g . C h e m . , 41, 3 8 7 7 ( 1 9 7 6 ) . H . M . R e l l e s , R . U . S c h l u e n z , J . % C h e m . S O C . , 96, 6 4 6 9 ( 1 9 7 4 ) . F. C a m p s , J . C a s t e l l s , M. F e r r a n d s , J. F o n t , T e t r a h e d r o n L e t t . , 1 7 1 3 ( 1 9 7 1 ) . D . B r a u n , M a k r o m o l . C h e m . , 30, 85 ( 1 9 5 9 ) . D . C . E v a n s , M . H . G e o r g e , J . A . B a r r i e , J. P o l y m . S c i . P o l y m . C h e m . E d . , 1 2 . 2 4 7 ( 1 9 7 4 ) . J.M.J. Frechet and M.J. Farrall, Chemistry and Properties of Crosslinked Polymers (S.S. Labana, Editor), p. 59, Academic Press (1977). w n Ethers and Phase-Transfer Catalysis in Polymer Science (L.J. Mathias and C.E. Carraher, editors), p . 1, Plenum Press (1984). J.M.J. F r b c h e t , T e t r a h e d r o n , 37, 6 6 3 ( 1 9 8 1 ) . T.M. F y l e s , C . C . L e z n o f f , J. W e a t h e r s t o n , C a n . J. C h e m . , 5 6 , 1 0 3 1 ( 1 9 7 8 ) . G . D . D a r l i n g a n d J . M . J . F r C c h e t , J . O r g . C h e m . , 2, 2 2 7 0 ( 1 9 8 6 ) . G . D . D a r l i n g , Ph.D. D i s s e r t a t i o n , U n i v e r s i t y o f O t t a w a ( 1 9 8 7 ) . E.H. U r r u t i , T. K i l p , M a c r o m o l e c u l e s , l7, 50 ( 1 9 8 4 ) . A . D e r a t a n i , G.D. D a r l i n g , D. H o r a k , J.M.J. F r b c h e t , M a c r o m o l e c u l e s , i n p r e s s ( 1 9 8 7 ) . A . D e r a t a n i , G . D . D a r l i n g , J.M.J. F r b c h e t , P o l y m e r , i n p r e s s ( 1 9 8 7 ) . J.M.J. F r b c h e t , E . B a l d , P . L e c a v a l i e r , J . O r g . C h e m . , 51, 3 4 6 2 ( 1 9 8 6 ) .

Reactive polymers 363

2 9 . 3 0 . 31. 3 2 . 3 3 .

3 4 . 35. 3 6 .

3 7 . 38. 3 9 .

4 0 .

4 1 . 4 2 . 4 3 . 4 4 .

45 *

4 6 .

4 7 . 4 8 . 4 9 . 5 0 .

5 1 . 5 2 .

5 3 *

5 4 . 5 5 . 5 6 . 57 * 58. 5 9 .

6 0 . 6 1 . 6 2 . 6 3 .

6 4 .

6 5 .

6 6 .

6 7 . 6 8 .

6 9 . 7 0 .

7 1 .

7 2 .

J . I . C r o w l e y , H . R a p o p o r t , Acc. Chem. Res . , 9 , 135 ( 1 9 7 6 ) . 1 4 . A . K r a u s , A . P a t c h o r n i k , I s r . J . Chem. , 117 2 9 8 ( 1 9 7 8 ) . W.T. F o r d i n r e f . 9 , 247 ( 1 9 8 6 ) . M. T o m o i , W.T. F o r d , J . A m . Chem. S O C . , 103, 3 8 2 1 ( 1 9 8 1 ) . J. M a r c h , A d v a n c e d O r g a n i c C h e m i s t r y , W i l e y , N e w York ( 1 9 8 5 ) a n d r e f e r e n c e s t h e r e i n . M.L. H a l l e n s l e b e n , Angew. Makromol . Chem., 31, 1 4 7 ( 1 9 7 3 ) . G . M a n e c k e , A . Kramer, Makromol . Chem. , 1 8 2 , 7 0 1 7 ( 1 9 8 1 ) . !I. T o m o i , M . G o t s , H. K a k i u c h i , Y . N o g u c h i , M a k r o m o l . Chem. R a p i d C o m n u n . , 6, 3 9 7 ( 1 9 8 5 ) . J . H r a d i l , F . S v e c , P o l y m . B u l l . , 2, 2 6 5 ( 1 9 8 5 ) . J.:I.J. F r C c h e t , E . B a l d , F . S v e c , Reac t . P o l y m . , 1, 2 1 ( 1 9 8 2 ) .

S . I t s u n o , G . D . D a r l i n g a n d J.M.J. F r k c h e t , m a n u s c r i p t s u b m i t t e d f o r p u b l i c a t i o n . C . L . R a s t o n , G . S a l e m , J . Chem. S O C . Chem. Commun. ( 1 9 8 4 ) . H. B o n n e m a n , B . B o d s a n o v i c , R. B r i n k m a n n , D.W. He, B. S p l i e t h o f f , An ew. Chem; I n t . Eld. En l,., '22, 7 2 8 ( 1 9 8 3 ) . -Tetrahedron L e t t . , 2 5 , 3305 ( 1 9 8 4 ) . S . I t s u n o a n d J.M.J. F r C c h e t , u n p u b l i s h e d d a t a . M. V i v a s d e M e f t a h i a n d J.M.J. F r C c h e t , u n p u b l i s h e d d a t a . C i . H e i t z , Adv. P o l y m . S c i . , 23, 1 ( 1 9 7 7 ) . %.I. Z a c h a r i e v a , M . B l e h a , E . Z u r k o v a , F . M i k e s , J . K a l a l , Angew. f l a k r o m o l . Chem. , z, 2 0 1 ( 1 9 7 8 ) . 1d.A. Rolls a n d J.M.J. F r C c h e t , P o l y m . Mat. S c i . E n g . , 51, ( 1 9 8 7 ) , i n p r e s s . J.M.J. F r C c h e t , E. E i c h l e r , C . G . W i l l s o n , II. I t o , P o l y m e r , 2, 9 9 5 ( 1 9 8 3 ) . P . Z . L u , G . D . D a r l i n g a n d J.M.J. F r C c h e t , u n p u b l i s h e d d a t a . S . I t s u n o , J . S y n t h , O r g . Chem. J a p a n , 45, 1 0 1 ( 1 9 8 7 ) . S. I t s u n o , Y . S a k u r a i , K . I t o , A . l l i r a o , S . Nakahama , P o l v m e r , i n p r e s s . F. V i l l e d o n - D e n a i d e , P . L e c a v a l i e r , J.M.J. F r C c h e t , P o l y m . B u l l . , 15, 4 9 1 ( 1 9 3 6 ) . Y. J i a n g , J.M.J. F r C c h e t a n d C . G . M i l l s o n , P o l y m . B u l l . , 17, 1 ( 1 9 8 7 ) . I . C h i b a t a , L . B . W i n g a r d J r , ( E d i t o r s ) , I m m o b i l i z e d M i c r o b i a l C e l Is , A c a d e m i c P r e s s , New Y o r k ( 1 9 8 3 ) . I. C h i b a t a , I m m o b i l i z e d E n z y m e s : R e s e a r c h a n d D e v e l o p m e n t s , W i l e y , New York ( 1 9 7 8 ) . T . H . Mough, S c i e n c e , 223, 272 ( 1 9 6 4 ) . P . E . G a r r o u , Chem. R e v . , 85, 1 7 1 ( 1 9 3 5 ) . P . E . G a r r o u , C h a p t e r 5 i n r e f , 9 , 8 4 ( 1 9 8 6 ) . D . E . B e r g b r e i t e r , B . J . C h a n d r a n , J . A m . Chem. S O C . , 107, 4 7 9 2 ( 1 9 8 5 ) . V . N . R . P i l l a i , M . M u t t e r , T o p i c s i n C u r r e n t Chem. , 106, 1 1 9 ( 1 9 3 2 ) . E . C . B l o s s e y , D . C . N e c k e r s , A . G . T h a y e r , A.P. S c h a a p , J. A m . Chem. S O C . , - 9 5 , 5 3 2 0 ( 1 9 7 3 ) . D . C . T l e c k e r s , C h a p t e r 6 i n r e f . 9 , 1 0 7 ( 1 9 8 6 ) . G . W u l f f , A . S a r h a n , Angew. C h e n . I n t . E d . , ll, 3 4 1 ( 1 9 7 2 ) . G . W u l f f , C h a p t e r 9 i n r e f . 9 , 1 8 6 ( 1 9 8 6 ) . B. L e f e b v r e , R . A u d e b e r t , C . Q u i v o r o n , J. L i q . C h r o m a t o g r . , 1, 7 6 1 ( 1 9 7 8 ) . J . BouC, R . A u d e b e r t , C. Q u i v o r o n , J . C h r o m a t o g r . , 2 0 4 , 185 ( 1 9 3 1 ) . A . A . X u r g a n o v , A . B . T e v l i n , V . A . D a v a n k o v , J. C h r o m a t o g r . , 261, 2 2 3 ( 1 9 8 3 ) . Y. O l c a m o t o , J . S y n t h . , O r g . Chem. J p n , 4 2 , 9 9 5 ( 1 9 3 4 ) . Y . O k a m o t o , S . l l o n d a , I. O k a m o t o , I-!. Y u k i , S . M u r a t a , R . N o y o r i , I I . T a k a y a , J . Am. Chem. S O C . , 103, 6 9 7 1 ( 1 9 3 1 ) . Y . O l c a m o t o , X. S u z u k i , I<. H a t a d a , 1-1. Y u k i , J . A m . Chem. S O C . , 101, 4 7 6 9 ( 1 9 7 9 ) . E . C h i e l l i n i , R . S o l a r o , J . Chem. S O C . , Chem. Commun., 231, ( 1 9 7 7 ) . J. K e l l y , D.C . S h e r r i n g t o n , P o l v m e r , 25 , 1 4 9 9 ( 1 9 8 4 ) . J.M.J. F r k c h e t , J. K e l l y , D . C . S h e r r i n g t o n , P o l y m e r , 2 5 , 1 4 9 1 ( 1 9 3 4 ) . PI. K a w a n a , S . E m o t o , T e t r a h e d r o n L e t t . , 48, 4 3 5 5 ( 1 9 7 2 ) . S . C o l o n n a , 8. M o l i n a r i , S . B a n f i , S . J u l i a , J . M a s a n a , A . A l v a r e z , T e t r a h e d r o n , 3 9 , 1 6 3 5 ( 1 9 8 3 ) . M. K o b a y a s h i , D r i t . P o l y m . J . , l6, 2 0 5 ( 1 9 8 4 ) . P. I l o d g e , E. I o s h d e l , J. U a t e r h o u s e , J.14.J. F r C c h e t , J . Chem. S O C . , P e r k i n T r a n s . I , 2 3 2 7 ( 1 9 8 5 ) . C . R . M c A r t h u r , P.M. W o r s t e r , J . - L . J i a n g , C . C . L e z n o f f , C a n J . Chem. , g, 1 8 3 6 ( 1 9 8 2 ) . J.M.J. F r b c h e t , J. X a l g a s , D . C . S h e r r i n g t o n , R e a c t . P o l y m . , I, 2 2 7 ( 1 9 8 3 ) .

364 J. M. J. FRCCHET eta/.

73 . P. L e c a v a l i e r , E. D a l d , Y . J i a n p , J.M.J. F r B c h e t , P . H o d p e , R e a c t . P o l y m . 2, 3 1 5 ( 1 9 8 5 ) . S. I t s u n o , K . I t o , A . A i r a o , G . N a k a h a m a , J. C h e m . S O C . , P e r k i n T r a n s . I , 2 8 8 7 ( 1 9 8 4 ) . -

7 4 . J . H . L i u , K . K o n d o , 1. T a k e m o t o , N a k r o m o l . C h e m . , 184, 1547 ( 1 9 8 3 ) . 75 . H . S u d a , S . K a n o h , N . U m e d a , M . I k k a , !I. N o t o i , Chem. L e t t . 3 9 9 ( 1 9 8 4 ) 76. S . I t s u n o , M . N a k a n o , I(. M i y a z a l c i , 11. M a s u d a , K . I t o , A . E i r a o , S .

M a k a h a m a , J . Chem. S O C . P e r k i n T r a n s . I , 2039 ( 1 9 8 5 ) . 7 7 . S . I t s u n o . M. N a l t a n o , I(. I t o , A. H i r a o , H. O w a . N . K a n d a . S. N a k a h a m a .

i b i d . , 2615 ( 1 9 8 5 ) . .

Chem. S O C . J p n , 5 9 , 3329 ( 1 9 8 6 ) .

Jpn, 60 , 395 ( 1 9 8 7 ) .

( 1 9 7 8 ) .

7 8 . S. I t s u n o , X. I t o , T . M a r u y a m a , N . K a n d a , A . H i r a o , S . N a k a h a m a , B u l l .

7 9 . S. I t s u n o , Y . S a l c u r a i , I(. I t o , A . A i r a o , S. M a k a h a m a , B u l l . C h e m . S O C ,

8 0 . J.M.J. F r B c h e t , J. W a r n o c k , M.J. F a r r a l l , J. O r g . C h e m . , 4 1 , 2 6 1 8 - 8 1 . J.M.J. F r B c h e t , M . V i v a s d e M e f t a h i , a r i t . P o l y m . J . , 16, 1 9 3 ( 1 9 8 4 ) . 8 2 . R e i l l e x r e p o r t s , R e i l l y T a r a n d C h e m i c a l C o . , I n d i a n a p o l i s . 8 3 . J . R e b e l : , F . G a v i n o , J . A m . Chem. S O C . , 97, 3453 ( 1 9 7 5 ) . 8 4 . J . R e b e l c , T e t r a h e d r o n , 3 5 , 723 ( 1 9 7 9 ) . 8 5 . 3. J. C o h e n , M . A . K r a u s , A . P a t c h o r n i k , J. A m . C h e m . S O C . , 99, 4 1 6 5

( 1 9 7 7 ) . 8 6 . N . O g u n i , T . O m i , T e t r a h e d r o n L e t t . , g , 2823 ( 1 9 8 4 ) . 87 . 14. K i t a m u r a , S . S u g a , X. Kawai , R . N o y o r i , J . A m . C h e m . S O C . , 108, 6 0 7 1

( 1 9 8 6 ) . 8 8 . 8 9 .

9 0 . 91 .

9 2 . 93 *

9 4 . 9 5 .

9 6 .

9 7 .

9 9 .

1 0 0 .

1 0 1 ,

9 8 .

A . A . S m a a r d i j k , H . W y n b e r g , J . O r g . C h e m . , 5 2 , 135 ( 1 9 8 7 ) . L.M. L i t v i n e n l c o , A . I . R i r i c h e n k o , D o k l . A k a d . Haul< SSSR, S e r . K h i m . , 1 7 6 , 9 7 ( 1 9 6 7 ) ; C h e m . A b s t r . , 68, 6 8 3 2 5 ( 1 9 6 8 ) . T S t e g l i c h , G . H o f l e , A n ~ e w . Chem. I n t . E d . E n g l . , 2, 9 8 1 ( 1 9 6 9 ) . E . F . V . S c r i v e n , M . T o m o i , Y . A i c a d a , il . K a k i u c h i , l * l a k r o m o l . C h e m . , R a p i d C o m m u n . , 3, 5 3 7 ( 1 9 8 2 ) . M . T o m o i , El. G o t o , i I . K a k i u c h i , M a k r o m o l . C h e m . , R a p i d C o m m u n . , - 6 , 3 9 7 ( 1 9 8 5 ) . F.11. i ‘ i e n g e r , D . J . M c C a n n , J . O r g . C h e m . , 2, 3 9 2 8 ( 1 9 8 5 ) . F. G u e n d o u z , R . J a c q u i e r , J . V e r d u c c i , T e t r a h e d r o n L e t t . , 3, 4 5 2 1 ( 1 9 8 4 ’ , . , -_- , _ E . J . D e l a n e y , L . E . Wood, I . M . K l o t z , J . Am. Chem. S O C . , 104, 799 ( 1 9 8 2 ) . L.J . M a t h i a s , R . A . V a i d z a , R . X . B l o o d w o r t h , J . c i . , P o l y m . L e t t . , 2 3 , 289 ( 1 9 8 5 ) . R.J. Hamilton and P . A . Sewell (Editors), Introduction to High Performance Liquid Chromatography, 2nd edition, p. 80-125, Chapman and Hall. London (1982). D.P.. L e e a n d J.H: K i n d s v a t e ; , A n a l . C h e m . , 5 2 , 2425 ( 1 9 8 0 ) . Y . 3 . Y a n g , F . N e v e j a n s , H . V e r z e l e , C h r o i n a t o r a h i a , 20 , 735 ( 1 9 8 5 ) . P . H a j o s , J . I n c z e d y , J . C h r o m a t o g r . , 2 0 1 , 2F3 T 1 9 8 O ) T

R . M a t s u d a , T. Yamamiya, M . T a t s u z a w a , A . E j i m a , W . T a l c a i , J- C h r o m a t o g r . , 173, 75 ( 1 9 7 9 ) . A . N . A g e e v , A . A . A r a t s k o v a , L . D . B e l y a k o v a , T.N. G v o z d o v i c h , A . V . K i s e l e v , Y . A . I . Y a s h i n , J. K a l a l , F. S v e c , C h r o m a t o g r a p h i a , l7, 545 ( 1 9 8 3 ) .

1.1. D r e s s l e r , J . C h r o m a t o g r . , E, 1 6 7 (1979).

1 0 2 . D. B o r a l c , F. S v e c , EI. B l e h a , J . K a l a l , A n g e w . M a k r o m o l . C h e m . , 2, 1 0 9 ( 1 9 8 1 ) .

1 0 3 . J.M.J. F r C c h e t , F. B o u c h a r d , E . E i c h l e r , F.M. I I o u l i h a n , T. I i z a w a , 5 . K r y c z k a , C . G . W i l l s o n , P o l v m . J . , 9, 3 1 ( 1 9 8 7 ) . C . G . l i i l l s o n , :-I. I t o , J.M.J. F r B c h e t , T.G. T e s s i e r , F.M. i i o u l i h a n , J. E l e c t r o c h e m . S O C . , 133, 1 0 1 ( 1 9 8 6 ) .