Polymeric Reagents and Catalysts - ACS Publications - American

2 Soluble Polymer-Bound Reagents and Catalysts

Downloaded by UNIV OF CALIFORNIA SAN DIEGO on November 15, 2014 | http://pubs.acs.org Publication Date: May 5, 1986 | doi: 10.1021/bk-1986-0308.ch002

David E . Bergbreiter Department of Chemistry, Texas A & M University, College Station, TX 77843

Synthetic applications of soluble polymer-bound reagents and catalysts are reviewed. Examples show these soluble macromolecular reagents have many of the same advantages as insoluble polymeric reagents as replacements for conventional low molecular weight reagents or catalyst ligands. The homogeneity of reaction solutions employing such reagents or catalysts is their principal advantage over comparable chemistry using an insoluble reagent or catalyst derived from a cross-linked polymer.

The use of soluble polymer-bound reagents or catalysts is an attractive alternative to the use of insoluble polymer-bound reagents or catalysts when a substitute for a conventional homogeneous reagent or catalyst i s needed or is appropriate for a given application (1-5). Insoluble cross-linked polymer-bound reagents are most useful when an expensive or toxic reagent i s used and it is important to recover the reagent quantitatively at the end of a reaction (1-3). Similarly, when a reaction produces a by-product which is separated only with d i f f i c u l t y from the desired product, the facile separation of an insoluble cross -linked polymeric reagent can have advantages. Non-cross-linked polymers can be used i n much the same way as their heterogeneous counterparts. While a linear polymer can often be dissolved under certain conditions, addition of a second poorer solvent or cooling can i n many cases quantitatively precipitate such linear polymers. In other cases, the modification of a polymer-bound functional group which occurs during consumption of such a reagent during a stoichiometric reaction sufficiently changes the properties of the 0097 6156/ 86/0308-0017507.25/0 © 1986 American Chemical Society

In Polymeric Reagents and Catalysts; Ford, W.; ACS Symposium Series; American Chemical Society: Washington, DC, 1986.


18

POLYMERIC REAGENTS A N D CATALYSTS

polymer that the polymer precipitates from solution of i t s own accord as the reaction proceeds. Thus, a reagent attached to a l i n e a r polymer can be used i n homogeneous solutions and can s t i l l be recovered at the end of a reaction by p r e c i p i t a t i o n and f i l t r a tion. Catalysts attached to insoluble cross-linked polymers such as divinylbenzene (DVB) cross-linked polystyrene have the advantages of easy recovery of the catalyst and easy separation of the catalyst from the reaction products. In addition, insoluble polymer-bound catalysts can, at least i n p r i n c i p l e , be used i n continuous reactors much l i k e conventional heterogeneous catalysts. Catalysts bound to soluble polymers have the advantages of easy recovery and separation from reaction products. However, l i k e other homogeneous catalysts, they are not as e a s i l y used i n a continuous reactor. Soluble polymer-bound reagents and catalysts have received less attention than their heterogeneous counterparts. It i s not necessary or reasonable that t h i s should be the case considering some of the advantages of using soluble polymers. One reason for t h i s lack of attention i s the perceived d i f f i c u l t y of product i s o l a t i o n and separation from a soluble polymer. However, there are i n practice several r e l i a b l e and simple ways i n which soluble macromolecules can be separated from the products of s t o i c h i o metric or c a t a l y t i c reactions. Techniques available for recovery and separation of a l i n e a r soluble polymer-bound reagent or catalyst from low molecular weight reaction products include selective p r e c i p i t a t i o n of the polymeric reagent by addition of a non-solvent followed by f i l t r a t i o n , thermal p r e c i p i t a t i o n of the polymeric reagent and i t s removal by f i l t r a t i o n , the use of membrane f i l t r a t i o n with membranes whose porosity i s such that only low molecular weight species can r e a d i l y diffuse through the membrane, and simple f i l t r a t i o n when a polymeric by-product of a stoichiometric reaction i s insoluble. Membrane f i l t r a t i o n and solvent p r e c i p i t a t i o n are the most generally applicable of these four separation methods. Centrifugation can be used as an a l t e r native to conventional f i l t r a t i o n i n these procedures. Soluble macromolecular reagents have many of the advantages and disadvantages of their insoluble macromolecular counterparts. The most general advantage of each of these classes of reagents i s their f a c i l e separation from low molecular weight reaction products as discussed above. Soluble polymeric reagents may have other unique advantages i n i n d i v i d u a l cases and some examples are described below. A potential disadvantage of both soluble or insoluble macromolecular reagents i s the higher molecular weight of a macromolecular reagent versus a conventional reagent. While lower reagent equivalent weights (higher loadings of the reactive functional groups on a polymer) are possible and have been used, t y p i c a l equivalent weights for a macromolecular reagent are 1000 or more (1 mequiv of reactive f u n c t i o n a l i t y / g of polymer). Such loadings are p r a c t i c a l i n both small scale and medium scale reactions. Large scale syntheses would either require polymeric r e a -



2.

BERGBRE1TER

Soluble

Polymer-Bound

Reagents and

Catalysts

g e n t s of h i g h e r l o a d i n g o r the use o f polymer-bound c a t a l y s t s i n p l a c e o f s t o i c h i o m e t r i c r e a g e n t s . The degree o f f u n c t i o n a l i z a t i o n o f a p o l y m e r i c r e a g e n t i s l e s s o f a problem i n the case o f polymer-bound c a t a l y s t s . I t i s u s u a l l y p o s s i b l e t o use s u f f i c i e n t amounts of c a t a l y s t s t o a c h i e v e r e a c t i o n r a t e s comparable t o c o n v e n t i o n a l c a t a l y s t s w i t h most polymer-bound c a t a l y s t s . Perhaps more i m p o r t a n t l y , i n the case o f s o l u b l e polymer-bound c a t a l y s t s , the c o n c e n t r a t i o n o f s o l u b l e polymer-bound c a t a l y s t s can r e a d i l y be a d j u s t e d t o compare w i t h c o n c e n t r a t i o n s a t t a i n a b l e w i t h convent i o n a l catalysts. S o l u b l e m a c r o m o l e c u l a r r e a g e n t s and c a t a l y s t s have some gene r a l advantages o v e r t h e i r heterogeneous c o u n t e r p a r t s . First, because they a r e s o l u b l e , many o f the d i f f u s i o n a l c o n s t r a i n t s which a f f e c t t h e u t i l i t y o f r e a g e n t s o r c a t a l y s t s bound t o i n s o l u b l e polymer r e s i n s a r e m i n i m i z e d . However, the b e h a v i o r o f s o l u b l e p o l y m e r i c r e a g e n t s i s c o m p l i c a t e d by the p o s s i b i l i t y t h a t polymer c h a i n s can a g g r e g a t e i n s o l u t i o n and by the demonstrated l o w e r d i f f u s i o n r a t e s o f s o l u b l e macromolecules v e r s u s a s m a l l organic molecule i n s o l u t i o n (vide i n f r a ) . Nonetheless, r e a c t i o n of a s m a l l m o l e c u l e w i t h a s o l u b l e m a c r o m o l e c u l e has been shown t o be more f a c i l e than s i m i l a r r e a c t i o n s w i t h an analogous i n s o l u b l e p o l y m e r i c reagent. For example, the r e a c t i o n o f p r i m a r y a l k y l bromides w i t h n u c l e o p h i l e s c a t a l y z e d by g e l - t y p e DVB c r o s s - l i n k e d p o l y s t y r e n e s i s a f f e c t e d by the s i z e o f the a l k y l h a l i d e because of the k i n e t i c s i g n i f i c a n c e o f d i f f u s i o n o f the r e a c t a n t m o l e c u l e t h r o u g h the g e l polymer t o an a c t i v e s i t e (6). Our work has shown t h a t such e f f e c t s a r e decreased i n r e a c t i o n o f sodium i o d i d e w i t h p r i m a r y a l k y l bromides c a t a l y z e d by s o l u b l e a l k e n e o l i g o m e r bound crown e t h e r s ( 7 ) . The use o f macroporous DVB c r o s s - l i n k e d polystyrene should a l s o d i m i n i s h e f f e c t s o f i n t r a p a r t i c l e d i f f u s i o n . The r e a c t i v i t y o f the r e a c t i v e s i t e s i n a s o l u b l e p o l y m e r i c r e a g e n t has a l s o been shown t o be comparable f o r a l l o r nearly a l l of t h e i r reactive s i t e s while s i m i l a r studies of i n s o l u b l e p o l y m e r i c r e a g e n t s have shown t h a t t h e i r r e a c t i v e s i t e s have a w i d e r range o f r e a c t i v i t y (8). These s o l u b l e r e a g e n t s o r c a t a l y s t s s h o u l d a l s o be more p r a c t i c a l i n e x o t h e r m i c r e a c t i o n s because d i s s i p a t i o n o f r e a c t i o n heat i n t o the s u r r o u n d i n g s o l v e n t i s more e f f i c i e n t . L o c a l h e a t i n g e f f e c t s r e s u l t i n g from an e x o t h e r m i c r e a c t i o n have been d i s c u s s e d a s a d i s a d v a n t a g e f o r i n s o l u b l e c a t a l y s t s ( 9 ) and c o u l d l e a d t o d e g r a d a t i o n o f t h e o r g a n i c polymer s u p p o r t s o r more l i k e l y t o d e g r a d a t i o n of t h e c a t a l y s t complexes o r r e a g e n t s a t t a c h e d t o such polymers. T h i r d , s o l u b l e m a c r o m o l e c u l a r r e a g e n t s or c a t a l y s t s can be more r e a d i l y c h a r a c t e r i z e d t h a n t h e i r heterogeneous c o u n t e r p a r t s . While s o l i d s t a t e NMR s p e c t r o s c o p y i s d e v e l o p i n g i n t o a u s e f u l t o o l f o r c h a r a c t e r i z i n g i n s o l u b l e polymer-bound r e a g e n t s and c a t a l y s t s , (10). s o l u b l e m a c r o m o l e c u l a r r e a g e n t s and c a t a l y s t s can be c h a r a c t e r i z e d i n a much more r o u t i n e manner u s i n g s o l u t i o n s t a t e NMR s p e c t r o s c o p y . L i g h t l y c r o s s - l i n k e d p o l y s t y r e n e s have been a n a l y z e d by b o t h C and P NMR s p e c t r o s c o p y (11,12). However, 1 3

3 1



20

P O L Y M E R I C REAGENTS A N D CATALYSTS

s o l u b l e p o l y m e r s can be a n a l y z e d r o u t i n e l y by H NMR spectroscopy as w e l l . The a p p l i c a t i o n o f the o t h e r s p e c t r o s c o p i c t e c h n i q u e s commonly used i n o r g a n i c c h e m i s t r y i s s i m i l a r l y f a c i l i t a t e d when a p o l y m e r i c r e a g e n t o r c a t a l y s t can be s t u d i e d e i t h e r as a s o l i d o r as a s o l u t i o n . The use of a c r o s s - l i n k e d p o l y m e r i c reagent or c a t a l y s t can a l s o f a c e some p h y s i c a l problems r e l a t i n g t o m e c h a n i c a l breakdown of very r i g i d polymers. L e s s r i g i d polymers, w h i c h o f t e n have l e s s i n t r i n s i c p o r o s i t y , r e q u i r e good s w e l l i n g s o l v e n t s t o i n s u r e t h a t the polymer-bound s p e c i e s have good a c c e s s t o s p e c i e s i n s o l u t i o n . L i n e a r p o l y m e r s f a c e a s i m i l a r problem i n t h a t a s o l v e n t and t e m p e r a t u r e must be chosen such t h a t both the polymer and the r e a g e n t s a r e i n s o l u t i o n . F i n a l l y , c h e m i s t s a r e accustomed t o d e a l i n g both e m p i r i c a l l y and q u a n t i t a t i v e l y w i t h k i n e t i c s and thermodynamics of homogeneous r e a c t i o n s and, as a r e s u l t , can o f t e n make m i n o r m o d i f i c a t i o n s i n r e a g e n t or c a t a l y s t s t r u c t u r e or r e a c t i o n c o n d i t i o n s t o m a x i m i z e the y i e l d of a d e s i r e d process. E f f e c t i n g s i m i l a r improvements i n r e a c t i o n s which use heterogeneous r e a g e n t s o f t e n proves t o be more d i f f i c u l t . For example, we have found t h a t i t i s f e a s i b l e t o r e a d i l y p r e p a r e a range o f s t r u c t u r a l l y d i v e r s e p h o s p h i t e l i g a n d s bound t o a l k e n e o l i g o m e r s , and we have examined t h e i r use i n n i c k e l ( O ) c a t a l y z e d d i e n e c y c l o o l i g o m e r i z a t i o n (13). At l e a s t i n our hands, a t t e m p t s t o p r e p a r e a s e r i e s o f s t r u c t u r a l l y d i f f e r e n t w e l l c h a r a c t e r i z e d i n s o l u b l e p o l y m e r i c l i g a n d s were more difficult. P r e p a r a t i o n of N o n - c r o s s - l i n k e d

Polymeric

Reagents

D e r i v a t i z a t i o n of l i n e a r polymers to form a s o l u b l e polymeric r e a g e n t can be a c c o m p l i s h e d by the use of c o n v e n t i o n a l c h e m i c a l r e a c t i o n s . S e v e r a l s t r a t e g i e s have been used. As i s the case w i t h p r e p a r a t i o n of i n s o l u b l e polymer-bound r e a g e n t s and c a t a l y s t s , the most common s t r a t e g y i l l u s t r a t e d by r e a c t i o n s 1-4 below i s t o use c o m m e r c i a l l y a v a i l a b l e p o l y m e r s or t o p r e p a r e an u n s u b s t i t u t e d a d d i t i o n o r c o n d e n s a t i o n polymer and t o then i n t r o duce the d e s i r e d f u n c t i o n a l groups. I n t h e case of l i n e a r p o l y s t y r e n e , b r o m i n a t i o n can be used t o p r e p a r e a f u n c t i o n a l i z e d p o l y s t y r e n e w h i c h c o n t a i n s e l e c t r o p h i l i c s i t e s . These e l e c t r o p h i l i c s i t e s can then be f u r t h e r t r a n s f o r m e d by r e a c t i o n w i t h n u c l e o p h i l e s i n t o a p o l y m e r i c reagent. I n t h i s example and i n E q u a t i o n s 3, 4 and 5, r e l a t i v e l y h i g h l o a d i n g s of f u n c t i o n a l i t y a r e p o s s i b l e s i n c e f u n c t i o n a l groups can be i n t r o d u c e d a t n e a r l y e v e r y monomer u n i t . A l t e r n a t i v e l y f u n c t i o n a l groups can be i n t r o duced a t a c h a i n t e r m i n u s . I t has been r e p o r t e d t h a t t h i s l a t t e r procedure i l l u s t r a t e d by E q u a t i o n s 2 and 6 produces a s o l u b l e p o l y m e r i c reagent whose r e a c t i v i t y more c l o s e l y r e s e m b l e s t h a t of a l o w m o l e c u l a r weight r e a g e n t ( 8 , 1 4 ) . There a r e a l s o examples where the n o n - c r o s s - l i n k e d p o l y m e r i c r e a g e n t i s most r e a d i l y a v a i l a b l e by d i r e c t p o l y m e r i z a t i o n of s u i t a b l y f u n c t i o n a l i z e d monomers. For example, p o l y m e r i z a t i o n o f a crown e t h e r which c o n t a i n s s t y r e n e u n i t s i s p o s s i b l e by f r e e r a d i c a l o r a n i o n i c methods (15). I n the case of a n i o n i c o l i g o m e r i z a t i o n (Equation 6) o r i n the case o f the m e t a l a t i o n shown i n E q u a t i o n 4, the r e a c t i v e i n t e r m e d i a t e macromolecule i s a n u c l e o p h i l i c polymer w h i c h can be d e r i v a t i z e d w i t h a v a r i e t y of e l e c t r o -


2.

BERGBREITER

Soluble

Polymer-Bound

Br

2

.

v


o

Reagents and

L

s

l

P

i ^

v >

Br

0

21

Catalysts

PPh,

pu Q-

H C-CH 2

*—~ C H 0 f CH CH 0] CH CH 0"

2

3

H*

2

2

2

4C0(CH ) C0NH(CH ) NH^ 2

4

2

2

^aCOC^

6

2

.

4

2

6

r ? r

-

( 3 )

I n (4)

TMEDA

o

( 2 )

2

-fCO(CH ) CONCKCH ) NCi

n

?

CH 0-fCH CH 0}n CH CH OH 3

2

? r

2

RLi

or

0 ^

2

(5)

hv

o

^ 9

H C~CH

AIBN,

RLi 2

TMEDA

R-[CH CH ^|-CH CH Li 2

2

2

2

(6)

R-[-CH CH ] CH CH E 2

2

? r

2

2


22

POLYMERIC REAGENTS AND CATALYSTS

philes (16). The molecular weight of the linear polymers prepared i n Equations 1-6 varies widely. For example, "n" can vary from 60 i n Equation 6 to 1000 or more i n Equation 4.


Stoichiometric Halogenating Reagents Soluble polystyrene-bound diphenylphosphine reagents have been used i n several applications i n place of triphenylphosphine i n substitution of halogen for hydroxyl groups. In these cases, the use of a polymeric reagent permits ready separation of the byproduct phosphine oxide from the halogenated organic derivative. For example, Hodge has reported that the use of non-cross-linked polystyrenediphenylphosphine i s nearly as e f f e c t i v e as the use of DVB cross-linked polystyrenediphenylphosphine i n formation of a l k y l chlorides from an alcohol and carbon tetrachloride, d i chloromethane or hexachloroethane (21). Phosphine containing l i n e a r polystyrene, prepared such that there i s 2.7-3.0 mmol of phosphine/g of polymer (which corresponds to having a phosphine group bound to every other styrene group i n the polymeric reagent), can be used as shown i n Equation 7. T y p i c a l l y these reactions were carried out using 2 equiv of the phosphinated polymer and 1 equiv of carbon tetrachloride (or one of the other chlorinated solvents) at 60-77 °C. These s t a r t i n g l i n e a r polystyrene reagents were soluble i n i t i a l l y but precipitated during the reaction. The polymeric reagent was thus e a s i l y separated from the reaction product by f i l t r a t i o n . The spent l i n e a r polymeric reagent was found to contain 0.8 Cl/P atom and was soluble i n methanol. Hodge postulated that the spent polymer contained both phosphine oxide and chloro- or dichloromethylphosphonium s a l t s . In q u a l i t a t i v e k i n e t i c studies, Hodge was also able to show that the l i n e a r soluble phosphinated polystyrene reagent was only s l i g h t l y less reactive than a s i m i l a r DVB cross-linked polystyrene reagent with the same alcohol substrate. Recycling of the soluble polystyrene reagent was not e x p l i c i t l y described. Recently our group has found that ethylene oligomers are an alternative to the use of non-cross-linked polystyrene as a polymer to which to bind a reagent (20). For example, we have found that diphenylphosphinated ethylene oligomers prepared by reaction 6 above can be used i n the same way as 1% DVB cross-linked (polystyryl)methyldiphenylphosphine to prepare a l k y l chlorides from a l cohols and carbon tetrachloride (Equation 8). These polyethylenediphenylphosphine reagents are comparable i n a c t i v i t y to these insoluble polymeric phosphines and could be recycled after reduction of the by-product polyethylenediphenylphosphine oxide with t r i c h l o r o s i l a n e , although the recycled polymeric reagent only had 65% of the a c t i v i t y of the fresh polyethylenediphenylphosphine reagent. Hodge e a r l i e r reported that s i m i l a r reduction allowed recycling of insoluble DVB cross-linked polystyrenediphenylphosphine with only 40% of the o r i g i n a l a c t i v i t y . Presumably the d i f f i c u l t i e s i n recycling these soluble polyethylene-bound phosphine reagents are due to reactions i n which halogenated phosphonium s a l t s form as unwanted and unreducible by-products as suggested by Hodge (21). Representative examples of a l k y l chloride syntheses using these polystyrene- and polyethylenediphenylphosphine reagents are l i s t e d i n Table I. I t also seems


BERGBREITER

2.

Soluble

Polymer-Bound

Reagents and

23

Catalysts

probable that these reagents could be used i n other reactions where cross-linked diphenylphosphinated polystyrene has been shown to be useful, although we have not yet s p e c i f i c a l l y examined t h i s question.


Table I . Synthesis of A l k y l Chlorides form Carbon Tetrachloride, a Phosphinated Soluble Polymer and an Alcohol or T h i o l

Alcohol or T h i o l 1-octanol

Polymeric Reagent "PE"-PPho "PEf'-PPho "PET-PPho* "DVB-PS"-CH PPh PS -PPh

3

A l k y l Chloride Yield (%) 96 65 41 93 93 91 91 69 76 42 61 57 91

0

?

,f

9

,f

2

benzyl alcohol

»t

p E

rt_

p p h

ff

"PS -PPh "PE"-PPh "PS"-PPh PE"-PPh "PE"-PPh "DVB-PS"-CHoPPh? "PS"-PPh 2

octadecanol

2

2

lf

cyclohexanol cyclododecanol

2

2

phenylmethanethiol

at,

Reference

2

17 17 17 17 18 17 18 17 18 17 17 17 18

f

PE? -PPh stands for phosphinated ethylene oligomers containing 0.8 mmol of -PPh /g of polymer; PS"-PPh stands for l i n e a r polystyrene containing 2.69 mmol of -PPh /g of polymer; and "DVB-PS"CHoPPh stands for diphenylphosphinated polystyrene derived from chloromethylated 2% DVB cross-linked polystyrene by reaction of t h i s commercially a v a i l a b l e r e s i n with lithium diphenylphosphide. 2

ff

2

2

2

2

W i t t i g Reagents Many groups have described examples of polymer-bound W i t t i g reagents useful i n synthesis ( t h i s volume includes a comprehensive review by W. T. of t h i s subject) (24-28). The p r i n c i p a l advantage c i t e d for the use of a polymeric phosphine for formation of an phosphonium ion i n these cases i s the f a c i l e separation of the alkene product from the phosphine oxide by-product and the r e c y c l a b i l i t y of the polymeric phosphine oxide by t r i c h l o r o s i l a n e reduction (28). While DVB cross-linked polystyrene i s most commonly used as the support for polymer-bound Wittig reagents, several reports describe the use of l i n e a r polystyrene. One p a r t i c u l a r l y i n t e r e s t i n g example described by Hodge and coworkers i s the use of diphenylphosphinated l i n e a r polystyrene (M = 100,000) containing 1.0 mequiv of -PPh /g of polymer (27) Using t h i s soluble macromolecular phosphine and benzylchloride or 2-bromomethylnaphthalene, a phosphonium s a l t was r e a d i l y prepared (Equation 9). In t h i s example, the comparatively high a c i d i t y of the benzylic C-H s enabled weaker bases such as NaOH to be used to generate the y l i d intermediate. S i m i l a r reactions were also w

2

f




4CH CH ^—CH CH PPh 2

2

2

2

+

2

CCL

ROH

4CH CH ^-CH CH PPh 2

2

2

2

2

• RCl

(8)



2.

BERGBRElTER

Soluble

Polymer-Bound

Reagents and

Catalysts

effected using DVB cross-linked polystyrene. Ketone substrates examined included 9-formylanthracene and cinnamaldehyde (Table II). Since the the mild bases used i n these W i t t i g reactions were only soluble i n the aqueous phase, W i t t i g reactions using the insoluble cross-linked macro molecular phosphonium s a l t r e quired the presence of a phase-transfer catalyst. However, i n contrast, the soluble macromolecular phosphonium s a l t did not require t h i s added reagent, possibly because the soluble macromolecular reagent acted as i t s own phase transfer catalyst. Isolation of alkene products i n the examples using soluble macromolecular phosphonium ions required p r e c i p i t a t i o n of the byproduct polystyrenediphenylphosphine oxide by addition of methano l . A 50% excess of the polymeric phosphonium s a l t s was used i n these reactions and gave high yields of alkene product i n 2-3 h at 20 ° C . Hodge's group has also used linear phosphinated polystyrene to form haloolefins from carbon tetrabromide and aromatic aldehydes (27). Using 2 mol equiv of phosphine, 1 mol equiv of CBr/ and 1 mol equiv of £-tolualdehyde at 50 °C for 16 h formed a 54% y i e l d of the dibrominated alkene. Substitution of 1% or 8% DVB cross-linked polystyrene for l i n e a r polystyrene yielded 67% and 12% of dibrominated alkene under the same conditions (Table II). Soluble Polymer-Bound Oxidants A variety of groups have reported examples of the use of oxidizing agents i n which an organic polymer matrix i s used to i o n i c a l l y or to covalently bind an oxidizing reagent. Soluble polymers have also been used. For example, Schuttenberg has described the preparation and application of N-chlorinated nylon polymers which contained a high loading of N-chloro groups and which could be used to oxidize primary or secondary alcohols to aldehydes and ketones and which oxidized s u l f i d e s to sulfoxides (18). The N-chlorinated nylons were prepared by chlorination of l i n e a r polyamides using t e r t - b u t y l hypochlorite or chlorine monooxide i n CCl^. These halogenation reactions required 3 h at 15 °C using Nylon 66 and converted 94% of the N-H bonds i n the o r i g i n a l polyamide into N-Cl bonds. In addition, the polyamide which was o r i g i n a l l y insoluble became readily soluble i n chloroform, perhaps because of diminished intramolecular hydrogen bonding once the N-H bonds were replaced by N-Cl bonds. In a t y p i c a l oxidation such as i s shown below the chlorinated polymer was converted back into the s t a r t i n g polymer. Since the s t a r t i n g polyamide had poor s o l u b i l i t y i n benzene, i t was readily removed from the reaction products by f i l t r a t i o n . Alcohol oxidations were performed using endo-1,7,7-trimethylbicyclo[2.2.1 ]heptan-2-ol, cyclohexanol, l-phenyl-2-propanol, l-phenyl-3-butanol and with other secondary alcohols and with benzyl alcohol. Yields of ketone or benzaldehyde were t y p i c a l l y >90% as measured by GC i n oxidation reactions i n benzene with reaction times of 24 h at 35 °C. Unactivated primary alcohols did not react appreciably with t h i s polymeric oxidant under these conditions. Sulfide oxidation i n methanol was also successfully accomplished, although i n t h i s case the conversion of s u l f i d e to sulfoxide was incomplete due to methanol oxidation and sulfoxide rearrangement. Unlike the


25


26


a l c o h o l o x i d a t i o n r e a c t i o n s , t h e s u l f i d e o x i d a t i o n s were c a r r i e d out under c o n d i t i o n s where t h e N - c h l o r o p o l y a m i d e was i n s o l u b l e . I n t h i s work, S c h u t t e n b e r g a l s o d e s c r i b e d a t t e m p t s t o c a r r y o u t asymmetric o x i d a t i o n s of s u l f i d e s using a c h i r a l N-chloropolyamide d e r i v e d from (-)-poly-(S)-(-)-4-methylazetidinone. However, t h e s u l f o x i d e s d e r i v e d from t h i s r e a c t i o n were o p t i c a l l y i n a c t i v e .

a

Table I I . W i t t i g Reactions o f Soluble Macromolecular Y l i d s

Substrate

9-f orm y l a n t h r a c e n e

Reaction Time (h)

Phosphonium S a l t

+

"PS"-PPh CH C H C I " "1% DVB-PS"-#h CH C H C l " "1% DVB-PS"-PPh CH C H C l " "PS"-PPh CH C H Br" PS -PPh CH C H " C l " "P^-PPhoCBr^" B r " " 1 % DVB-PS^-PPh CBr B r " "8% DVB-PS"-PPh CBr B r " 2

2

6

5

+

2

2

6

5

+

2

2

6

5

+

2

cinnamaldehyde para-tolualdehyde

tt

2

10

6

5

t,

7

4

2

2

2

2

+

d

f

e

2

2

2 2 2 2 2 16 16 16

Yield (%)

92 98 35 100 75 54 67 12

a

R e a c t i o n s o f b e n z y l i c phosphonium s a l t s were c a r r i e d o u t a t 20 °C u s i n g 10 mL o f m e t h y l e n e c h l o r i d e , 1.5 mmol o f t h e p o l y m e r i c phosphonium s a l t , and 3 mL o f 50% NaOH (aq). The l i n e a r p o l y s t y r e n e had a MW o f 150,000 w i t h 2.7 mmol o f -PPho/g o f polymer. The 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 e d 3.0-3.5 mmol o f -PPh /g o f polymer. The halogenated phosphonium i o n was prepared f r o m phosp h i n a t e d p o l y s t y r e n e h a v i n g 0.4 mequiv o f -PPh /g o f polymer and was a l l o w e d t o r e a c t w i t h p a r a - t o l u a l d e h y d e a t 50 °C f o r 16 h. k 2 mmol-% h e x a d e c y l t r i m e t h y l a m m o n i u m bromide was added a s a phase t r a n s f e r c a t a l y s t . No phase t r a n s f e r c a t a l y s t was present. l % DVB 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 0.81 mequiv o f phosphonium i o n / g o f polymer. 8% DVB c r o s s - l i n k e d p o l y s t y rene c o n t a i n i n g 0.30 mequiv o f phosphonium i o n / g o f polymer. 2

2

c

d

e

S o l u b l e polymer c a t a l y s t s f o r o x i d a t i o n have a l s o been d e s c r i b e d . One such example w o u l d be t h e use o f v a r i o u s p o l y b a s i c polymers as polydentate l i g a n d s f o r copper(II) i n o x i d a t i v e p o l y m e r i z a t i o n o f p h e n o l s (29,30). P o l y b a s i c p o l y m e r s such a s p o l y ( v i n y l p y r i d i n e ) have been used. I n t h i s example, t h e n e i g h b o r i n g group e f f e c t c o n s i s t i n g o f h a v i n g a d j a c e n t p y r i d i n e groups on t h e p o l y ( v i n y l p y r i d i n e ) capable o f complexing a copper(II) i o n l e d t o a s i g n i f i c a n t l y h i g h e r complex f o r m a t i o n c o n s t a n t f o r c o m p l e x a t i o n of c o p p e r ( I I ) v e r s u s t h e c o m p l e x a t i o n c o n s t a n t measured f o r p y r i d i n e . The complex formed c o n t a i n e d f o u r pendant p y r i d i n e u n i t s o f t h i s p o l y b a s i c polymer.


2.

BERG BREITER

Soluble

Polymer-Bound


S o l u b l e Polymer-Bound Reducing

Reagents and

Catalysts

27

Agents

The use o f polymer-bound s t o i c h i o m e t r i c r e d u c i n g agents has n o t r e c e i v e d much a t t e n t i o n , perhaps because r e m o v a l o f i m p u r i t i e s o r r e c y c l i n g a r e a g e n t i s o f l e s s e r i m p o r t a n c e i n most r e d u c t i o n r e a c t i o n s u s i n g M a i n Group m e t a l h y d r i d e complexes. One example o f a s o l u b l e p o l y m e r i c m e t a l h y d r i d e t h a t has been r e p o r t e d i s t h e use o f l i n e a r p o l y ( v i n y l p y r i d i n e ) t o b i n d BHg (31). H a l l e n s l e b e n has shown t h a t such a borane complex behaves l i k e p y r i d i n e - b o r a n e , r e d u c i n g c a r b o n y l groups t o hydroxy groups. Examples o f such r e d u c t i o n s i n c l u d e ( t i m e i n h i n r e f l u x i n g benzene, a l c o h o l y i e l d using pyridine-borane, alcohol y i e l d using polystyrene-poly(vinylp y r i d i n e ) - b o r a n e ) benzaldehyde (0.5, 76, 7 4 ) , p a r a - c h l o r o b e n z a l d e h y d e (1.25, 75, 5 1 ) , b e n z o p h e n o n e (2.5, - , 4 0 ) , a n d c y c l o p e n t a n o n e (2.5, 2 5 , 1 2 ) . The use o f i n s o l u b l e p o l y s t y r e n e - b o u n d a l k a l i m e t a l a r o m a t i c r a d i c a l a n i o n s , r e l a t e d a l k a l i m e t a l - g r a p h i t e i n t e r c a l a t i o n compounds and a l k a l i m e t a l d e r i v a t i v e s o f w e a k l y a c i d i c p o l y s t y r e n e d e r i v a t i v e s i n r e a c t i o n s l i k e those d e s c r i b e d f o r a l k a l i metal a r o m a t i c r a d i c a l a n i o n s and a l k a l i m e t a l o r g a n o m e t a l l i c s i n e t h e r s o l u t i o n s has been r e p o r t e d (19,32). S i m i l a r s o l u b l e a l k a l i metal aromatic r a d i c a l anions d e r i v e d from poly(vinylnaphthalene) and p o l y a c e n a p h t h y l e n e have been r e p o r t e d (33). A l k a l i m e t a l d e r i v a t i v e s o f p o l y ( v i n y l n a p h t h a l e n e ) prepared r e p o r t e d l y i n c l u d e d t h e d i l i t h i u m s a l t , t h e sodium s a l t and t h e p o t a s s i u m s a l t , a l l prepared by r e a c t i o n o f a s o l u t i o n o f t h e p o l y m e r i c naphthalene d e r i v a t i v e w i t h t h e a l k a l i m e t a l a t 25 °C f o r 24 h. The l i t h i u m p o l y ( v i n y l n a p h t h a l e n e ) was found t o r e a c t q u a n t i t a t i v e l y w i t h some o r g a n i c h a l i d e s such a s b e n z y l c h l o r i d e , b u t y l bromide and a l l y l c h l o r i d e b u t n o t a t a l l w i t h iodobenzene o r o t h e r h a l o g e n a t e d a r e n e s o r w i t h c y c l o h e x y l c h l o r i d e . The l a c k o f r e a c t i o n o f t h e l a t t e r h a l i d e s was a s c r i b e d t o t h e i r h a v i n g a r i n g s t r u c t u r e w h i c h t h e a u t h o r s s a i d r e s u l t e d i n s t e r i c h i n d r a n c e w i t h t h e naphthalene groups a t t a c h e d t o t h e v i n y l polymer backbone. I n c o n t r a s t , t h e a l k a l i metal s a l t s of polyacenaphthylene d i d react w i t h these h a l i d e s . The a u t h o r s r a t i o n a l i z e d t h i s d i f f e r e n c e i n r e a c t i v i t y i n t e r m s o f t h e g r e a t e r f l e x i b i l i t y and r e s u l t a n t d i m i n i s h e d s t e r i c h i n d r a n c e o f t h e naphthalene groups i n t h e l a t t e r polymer. Regardless of the correctness of t h i s explanation, the lack of r e a c t i o n o f iodobenzene w i t h a d i l i t h i o n a p h t h a l e n e d e r i v a t i v e i s r e m a r k a b l e . A thorough s t u d y o f a l l t h e p r o d u c t s o f t h e s e r e a c t i o n s i n c l u d i n g the nature of the poly(vinylnaphthalene) a f t e r r e a c t i o n was n o t performed so i t i s d i f f i c u l t t o a s c e r t a i n i f t h i s apparent d i f f e r i n g r e a c t i v i t y o f a s o l u b l e p o l y m e r i c a l k a l i m e t a l a r o m a t i c r a d i c a l a n i o n and a s i m p l e a r o m a t i c r a d i c a l a n i o n i s g e n e r a l o r o f some p a r t i c u l a r s y n t h e t i c v a l u e . An u n u s u a l s y n t h e t i c a p p l i c a t i o n o f a s o l u b l e m a c r o m o l e c u l a r r e d u c i n g r e a g e n t d e s c r i b e d by S m i t h i s t h e use o f aqueous s o l u t i o n s o f hydrazonium p o l y a c r y l a t e o r hydrazonium p o l y [ 2 - { a c r y l amido)-2-methylpropanesulfonate] t o prepare s t a b l e c o l l o i d a l d i s p e r s i o n s o f r e d , amorphous s e l e n i u m . (34). I n t h e s e r e a c t i o n s , t h e s o l u t i o n s were p r e p a r e d s u f f i c i e n t l y d i l u t e so t h a t each m a c r o m o l e c u l a r hydrazonium p o l y a c r y l a t e c o u l d r e a c t i n d i v i d u a l l y . When a s o l u t i o n o f l^SeO^ was added t o t h i s p o l y m e r i c r e d u c i n g agent, t h e s e l e n i o u s a c i d m o l e c u l e s i n t h e


28



v i c i n i t y of a given hydrazonium polyacrylate macromolecule were reduced to selenium atoms. Presumably these selenium atoms then aggregated to form a single hydrophobic selenium p a r t i c l e which remains bound to the polyacrylate. In these reactions, only 75% of the pendant acid groups of the p o l y a c r y l i c acid were neutralized by added hydrazine to insure that the macromolecular reagents would contain some residual acid. These residual acid groups presumably catalyzed the reduction of I^SeOg by the polymeric hydrazine. Site I s o l a t i o n Using Soluble Polymer-Bound

Species

The practice of using an insoluble polymer to i s o l a t e and k i n e t i c a l l y s t a b i l i z e a reactive intermediate has been addressed i n several reports, most commonly using DVB cross-linked polystyrene as a support. In these cases, the three dimensional structure of the polymer and r i g i d i t y of the polymer backbone diminish i n t r a molecular r e a c t i v i t y between two s i t e s on the same polymer bead. Physical constraints preclude any s i g n i f i c a n t reaction between two d i f f e r e n t polymer beads. Similar, less dramatic reduced i n t r a molecular r e a c t i v i t y has also been noted for reactive i n t e r mediates bound to l i n e a r polystyrene. For example, o_-benzyne bound to linear polystyrene has been shown by Mazur to have enhanced s t a b i l i t y r e l a t i v e to non-polymer-bound o-benzyne (35). In t h i s case, o_-benzyne was generated by lead tetraacetate oxidation of a 2-aminobenzotriazole precursor, 1. Analysis of the reaction products a f t e r cleaving the benzyne derived products from the polymer by hydrolysis showed a 60% y i e l d of a r y l acetates was obtained (Equation 11). In contrast, the monomeric aryne forms only coupled products under s i m i l a r conditions. Further comparisons of the r e a c t i v i t y of o-benzyne bound to insoluble 2% or 20% DVB cross-linked polystyrene showed the intermediate o_-benzyne had an even longer l i f e t i m e . Overall, the r e a c t i v i t y of jo-benzyne bound to the soluble polymer was found to be intermediate between that of non-polymer bound benzyne and benzyne bound to 20% DVB cross-linked polystyrene. The 10 sec l i f e t i m e reported for benzyne i n t h i s case presumably r e f l e c t s d i f f u s i o i m l constraints associated with the polymer chain whose M was 10 . I s o l a t i o n of a cobalt phthalocyanine catalyst known to be active i n autooxidation and to be deactivated by dimerization has been reported by Schutten (36). In t h i s case, a polyvinylamine polydentate ligand was added to a d i l u t e aqueous solution of the cobalt(II) phthalocyanine tetra(sodium sulfonate) i n order to prepare a t h i o l oxidation catalyst. By employing d i l u t e solutions, the polydentate polyamine polymer i n e f f e c t i s o l a t e d the cobalt(II) c a t a l y s t within an i n d i v i d u a l polyamine c o i l minimizing dimerization and s i g n i f i c a n t l y increasing c a t a l y s t a c t i v i t y . Soluble polymer-bound substrates have also been used as part of an experimental protocol to probe the homogeneity of a catalyst (37). In these experiments, the r e a c t i v i t y of a substrate bound to a soluble or insoluble polymer i s compared to the react i v i t y of the same substrr*-** not hound to a polymer. No reaction of an insoluble polymer-bound substrate with a c a t a l y s t under conditions where a soluble polymer-bound substrate or a nonpolymer-bound substrate did react with the same catalyst would w


2.

BERGBREITER

Soluble

Polymer-Bound

Reagents and

Catalysts

29


imply that the catalyst i n question was heterogeneous. In these experiments, as i n Mazur's work described above, the soluble polymer-bound substrate's r e a c t i v i t y was found to be intermediate between that of a free substrate and that of a substrate bound to a cross-linked polymer. Influences of Polymer Size on Reactivity While many of the reactions discussed i n t h i s review can be viewed as d i r e c t analogies of s i m i l a r reactions of small molecules, i t i s important to remember that the r e a c t i v i t y of a soluble polymeric reagent can be affected by factors other than those a f f e c t i n g small molecules (38,39). S p e c i f i c a l l y , i n d i l u t e solutions soluble macromolecular reagents exist as isolated c o i l s separated one from another by solvent. The s i z e of the c o i l (and therefore the concentration of reagent within the c o i l volume) vary with solvent and ternperature. At higher concentrations of polymer, aggregation of the polymer chains can occur. These sorts of e f f e c t s have been most thoroughly studied and discussed for reactions involving polybasic catalysts and polyelectrolytes but are of equal importance and significance for reactions involving soluble polymeric reagents and catalysts i n nonaqueous systems. Peptide Synthesis Using Soluble Polymeric Reagents Peptide syntheses using polymeric reagents have served as a stimulus to develop the general area of polymer supported reagents and catalysts useful i n organic synthesis. While s o l i d phase peptide syntheses pioneered by M e r r i f i e l d have developed into a widely recognized and used peptide synthesis strategy (3), alternat i v e procedures employing non-cross-linked polymers have been developed into a useful peptide synthesis procedures (3,14). Several polymers have been studied for t h i s purpose, including both polystyrene and poly(ethylene glycol). However, for reasons enumerated below, polyethylene glycol) i s the polymer support of choice i n these l i q u i d phase peptide syntheses. The general strategy i n a l l of these procedures i s to carry out a reaction i n a homogeneous solution and to thereby avoid the disadvantage of d i f f u s i o n a l constraints and r e a c t i v i t y problems often encountered using the now c l a s s i c a l s o l i d phase peptide synthesis strategy. While these peptide syntheses employing soluble reagents thus have the advantages normally associated with reactions of a low molecular weight substrate i n a homogeneous solution, they also confer desirable s o l u b i l i t y properties on an attached growing peptide chain. S p e c i f i c a l l y , a polyethylene glycol)-bound peptide possesses the desirable features of solub i l i t y during peptide bond formation but i n s o l u b i l i t y a f t e r a reaction. Such a change i n s o l u b i l i t y can be induced by addition of a solvent i n which the l i n e a r polymer support i s insoluble. As i n the M e r r i f i e l d synthesis, advantage i s taken of t h i s i n s o l u b i l i t y to more conveniently separate excess s t a r t i n g materials or soluble reaction by-products from the growing peptide chain attached to the macromolecule. A disadvantage of polyfunctional supports such as functionalized l i n e a r polystyrene i s the observation that the functional groups do not a l l have equivalent r e a c t i v i t y i n spite of l i n e a r polystyrene's s o l u b i l i t y .



30


( 4 0 ) . T h i s problem has been s u c c e s s f u l l y overcome through the use o f t e r m i n a l l y f u n c t i o n a l i z e d p o l y ( e t h y l e n e g l y c o l ) . Presumably, t e r m i n a l l y f u n c t i o n a l i z e d p o l y s t y r e n e d e r i v e d from a n i o n i c p o l y m e r i z a t i o n r e a c t i o n s w o u l d a l s o a v o i d t h i s problem. However, p o l y ( e t h y l e n e g l y c o l ) i s a l s o a more p o l a r polymer and i s r e a d i l y a v a i l a b l e i n v a r i o u s r e l a t i v e l y monodisperse f r a c t i o n s i n v a r i o u s m o l e c u l a r w e i g h t ranges. P o l y ( e t h y l e n e g l y c o l ) a l s o has a t e r m i n a l h y d r o x y l group which can e a s i l y be f u r t h e r m o d i f i e d t o i n c o r p o r a t e an anchor f o r a g r o w i n g p e p t i d e c h a i n or a p o l y m e r i c reagent. The d r a w i n g s below i l l u s t r a t e t y p i c a l groups used t o anchor a g r o w i n g p e p t i d e onto p o l y ( e t h y l e n e g l y c o l ) as a p a s s i v e support t o f a c i l i t a t e p u r i f i c a t i o n and i s o l a t i o n of the g r o w i n g p o l y p e p t i d e . I n s y n t h e s e s u s i n g these groups, the p o l y ( e t h y l e n e g l y c o l ) p o r t i o n o f the m a c r o m o l e c u l e b e i n g formed d e t e r m i n e s the s o l u b i l i t y p r o p e r t i e s of the m o l e c u l e as a whole (41). Thus i t i s p o s s i b l e t o s e l e c t i v e l y p r e c i p i t a t e the p o l y ( e t h y l e n e g l y c o l ) - p e p t i d e product i n the presence o f o t h e r low m o l e c u l a r w e i g h t i m p u r i t i e s . Moreover, w h i l e i s o l a t i o n o f a p e p t i d e a f t e r an i n d i v i d u a l c o u p l i n g or a c t i v a t i o n s t e p has been f a c i l i t a t e d , k i n e t i c s t u d i e s show t h a t the a c t u a l c h e m i c a l r e a c t i o n s proceed as e f f i c a c i o u s l y as t h e i r a n a l o g s which use low m o l e c u l a r w e i g h t r e a g e n t s (42) P e p t i d e s y n t h e s i s u s i n g s o l u b l e p o l y m e r s commonly i n v o l v e s a t t a c h m e n t of the g r o w i n g peptide's c a r b o x y l t e r m i n u s t o the p o l y e t h y l e n e g l y c o l ) . W h i l e a t t a c h m e n t can be a c c o m p l i s h e d v i a a s i m p l e e s t e r l i n k a g e , the e v e n t u a l r e q u i r e m e n t f o r c l e a v a g e o f the f i n a l p e p t i d e product u s u a l l y r e q u i r e s use of o t h e r a n c h o r i n g groups which can be c l e a v e d under m i l d c o n d i t i o n s . M i l d e r c o n d i tions minimize epimerization possible i n a conventional a l k a l i n e e s t e r h y d r o l y s i s . V a r i o u s anchor groups have been used i n c l u d i n g both r e a c t i v e b e n z y l e s t e r s and p h o t o l a b i l e e s t e r and amide groups ( c f . 2-4). Many of the same groups a r e used i n s o l i d phase pept i d e syntheses. However, the homogeneity of the p o l y m e r - p e p t i d e adduct i n the l i q u i d phase method p e r m i t s the use o f o t h e r h e t e r o geneous r e a g e n t s such as Pd c a t a l y s t s f o r h y d r o g e n o l y s i s of p o l y e t h y l e n e g l y c o l ) - b o u n d p e p t i d e s (43). The methodology f o r f o r m i n g p e p t i d e bonds i n the l i q u i d phase method i s the same as t h a t used i n c o n v e n t i o n a l p e p t i d e bond s y n t h e s e s u s i n g low m o l e c u l a r w e i g h t r e a g e n t s . Most commonly, the N-groups of the added amino a c i d s a r e p r o t e c t e d by t e r t - b u t o x y c a r b o n y l groups d u r i n g the c o u p l i n g of a new amino a c i d r e s i d u e t o the f r e e amino group of the polymer a t t a c h e d p e p t i d e . One i n t e r e s t i n g d i f f e r e n c e between the l i q u i d phase method and the s o l i d phase s y n t h e s i s i s the a b i l i t y t o use r e a g e n t s such as d i c y c l o h e x y l c a r b o d i i m i d e t o e f f e c t the c o u p l i n g r e a c t i o n . The i n s o l u b l e urea b y - p r o d u c t i s r e a d i l y removed from s o l u t i o n s o f the p e p t i d e - p o l y m e r adduct and o t h e r s o l u b l e r e a g e n t s and the p e p t i d e polymer adduct can t h e n i n t u r n be s e p a r a t e d from the r e m a i n i n g s o l u b l e s p e c i e s by s e l e c t i v e p r e c i p i t a t i o n w i t h d i e t h y l e t h e r and f i l t r a t i o n . T y p i c a l s o l v e n t s used d u r i n g the p e p t i d e s y n t h e s i s i n c l u d e p o l a r a p r o t i c s o l v e n t s such as d i m e t h y l f o r m a m i d e and d i m e t h y l s u l f o x i d e as w e l l as m e t h y l e n e c h l o r i d e . A u t o m a t i o n of l i q u i d phase p e p t i d e s y n t h e s i s i s a l s o p o s s i b l e . However, as the s i z e of the p e p t i d e a t t a c h e d t o the p o l y ( e t h y l e n e g l y c o l ) s u p p o r t i n c r e a s e s , the p r o p e r t i e s o f the



2.

BERGBREITER

Soluble Polymer-Bound

Reagents and

31

Catalysts

p o l y m e r - p e p t i d e complex change. These changes i n s o l u b i l i t y and p e r m e a b i l i t y have s e r v e d t o l i m i t developments i n a u t o m a t i o n t o s y n t h e s e s i n w h i c h s m a l l e r p e p t i d e s a r e prepared. A major advantage of the l i q u i d phase p e p t i d e s y n t h e s i s over a s o l i d phase p e p t i d e s y n t h e s i s i s t h e f a c i l i t y w i t h which t h e p r o g r e s s of the r e a c t i o n can be m o n i t o r e d . Quantitative fluorescence a n a l y s i s o f t h e p r o d u c t s of r e a c t i o n of t h e p o l y m e r - p e p t i d e complex w i t h f l u o r e s c a m i n e o r n i n h y d r i n can be used as s i m p l e and d i r e c t measures o f t h e e x t e n t of r e a c t i o n (14). Another s i g n i f i c a n t advantage o f t h e l i q u i d phase s y n t h e s i s i s i t s p o t e n t i a l f o r ready a n a l y s i s by s o l u t i o n s t a t e NMR s p e c t r o s c o p y . While long a c q u i s i t i o n times f o r NMR s p e c t r a were r e q u i r e d i n r e p o r t e d examples o f a p p l i c a t i o n of C NMR s p e c t r o s c o p y t o a n a l y s i s o f p o l y ( e t h y l e n e g l y c o l ) - p e p t i d e complexes, the i n c r e a s e d a v a i l a b i l i t y o f 400 and 500 MHz NMR i n s t r u m e n t a t i o n w i l l s i g n i f i c a n t l y i n c r e a s e the f a c i l i t y o f t h e s e a n a l y s e s . One can a l s o a n t i c i p a t e t h a t H NMR s p e c t r o s c o p y w i l l become e x t r e m e l y u s e f u l a t t h e s e h i g h e r f i e l d s because o f the d i s p e r s i o n a f f o r d e d by t h e s e f i e l d s and because o f the s e n s i t i v i t y of H NMR spectroscopy. Water S o l u b l e M a c r o m o l e c u l a r C a t a l y s t s Enzymes a r e the a r c h e t y p a l w a t e r - s o l u b l e m a c r o m o l e c u l a r c a t a l y s t s . Indeed, the a p p l i c a t i o n o f such s o l u b l e b i o c h e m i c a l c a t a l y s t s t o r e a c t i o n s both i n aqueous and i n o r g a n i c media i s a t o p i c o f g r e a t c u r r e n t i n t e r e s t . W h i l e e n z y m a t i c c a t a l y s i s i s o u t s i d e t h e scope of t h i s r e v i e w ( t h i s a r e a has been r e c e n t l y r e v i e w e d ) (44,45) p r o t e i n s have been employed as m a c r o m o l e c u l a r l i g a n d s t o i n c r e a s e o r a l t e r t h e s e l e c t i v i t y o f more t r a d i t i o n a l c a t a l y s t s . For example, homogeneous a s y m m e t r i c h y d r o g e n a t i o n s o f amino a c i d p r e c u r s o r s have been r e p o r t e d i n w h i c h t h e c a t i o n i c rhodium c a t a l y s t was l i g a t e d by N , N - b i s ( 2 - d i p h e n y l p h o s p h i n o e t h y l ) b i o t i n a m i d e w h i c h had been i r r e v e r s i b l y complexed t o the p r o t e i n a v i d i n (46). The b e s t r e p o r t e d examples had t u r n o v e r numbers i n e x c e s s o f 500 and enant i o m e r i c e x c e s s e s r a n g i n g f r o m 33-44% i n r e d u c t i o n o f a-aceta m i d o a c r y l i c a c i d t o N - a c e t y l a l a n i n e . In t h i s case the products of t h e r e a c t i o n were s e p a r a t e d f r o m t h e p r o t e i n - r h o d i u m c o n j u g a t e by f i l t r a t i o n through a 10,000 m o l e c u l a r w e i g h t c u t o f f u l t r a f i l t r a t i o n membrane. T

Other p r o t e i n - r h o d i u m c o n j u g a t e s c o n t a i n i n g c a t i o n i c rhodium c a t a l y s t s have a l s o been p r e p a r e d u s i n g b i s ( d i p h e n y l p h o s p h i n o e t h y l ) a m i n o d e r i v a t i v e s 5-7 and s o l u t i o n s o f t h e s e b i s ( p h o s p h i n e ) l i g a n d s i n t h e presence o f c a r b o n i c anhydrase, a - c h y m o t r y p s i n and b o v i n e serum a l b u m i n (47). However, t h e e x a c t n a t u r e of t h e comp l e x e s formed has not been d i s c e r n e d i n any o f t h e s e c a s e s , and t h e s e l a t t e r e n z y m e - t r a n s i t i o n m e t a l complexes e v i d e n t l y do n o t e x h i b i t e n a n t i o s e l e c t i v i t y i n hydrogenation of a - a c e t a m i d o a c r y l i c acid. Water s o l u b l e i o n exchangers have been used by P i t t m a n ' s group as s u p p o r t s f o r c o n v e n t i o n a l homogeneous Reppe and h y d r o f o r m y l a t i o n c a t a l y s t s (48). These p r o c e d u r e s employ r e s i n p a r t i c l e s o f p o l y ( v i n y l a l c o h o l ) and p o l y ( v i n y l a c e t a t e ) w h i c h c o n t a i n e d a m i x t u r e o f a c r o s s - l i n k e d p o l y ( a c r y l i c a c i d ) or p o l y ( m e t h a c r y l i c a c i d ) and a c r o s s - l i n k e d p o l y m e r i c secondary o r



POLYMERIC REAGENTS AND CATALYSTS


BERGBREITER

2.

Soluble

Polymer-Bound

Reagents and

33

Catalysts

t e r t i a r y amine. By changing the temperature, the acid-base equilibrium below can be shifted to entrap a cationic or an "Poly"-NR

+

2

"Poly"-COOH

+

Na

+

+

Cl" (12)


^

"Poly"-NR HCl

f

+

2

"Poly' -COONa

anionic t r a n s i t i o n metal complex either as a carboxylate or an ammonium s a l t , respectively. At higher temperatures, the equilibrium 12 s h i f t s to form more of the amine and carboxylic acid, thus releasing a t r a n s i t i o n metal into solution. At the end of a reaction, cooling the reaction mixture favors formation of the insoluble r e s i n containing ammonium and carboxylate s a l t s . Using t h i s scheme, Pittman was able to use RhClo^CHo^N as a catalyst for carbonylation of 1-pentene as shown below (J_3). S i g n i f i cant amounts of alcohol were also found i n the product mixtures. The authors also noted that isomerization of 1-pentene to 2pentene was rapid when trimethylamine was present. Conversions of RhClo C H CH=CH 3

7

2

+ CO + H 0

C H CHO + C H CH(CH )CHO

2

5

n

4

9

(13)

3

600 p s i alkenes of 64-69% were obtained i n the f i r s t cycle of these reactions i n 24 h at 150 °C and conversions were i d e n t i c a l with or without the added polymer. However under these conditions, recovery of the rhodium by the r e s i n was not complete on cooling. The conversion to aldehyde i n subsequent reactions was 23% and 7% i n the second and t h i r d cycles. Consistent a c t i v i t y through 11 cycles was obtained by carrying out the reaction at a pH near 7 i n the absence of (CHo^N but only at the cost of having the reaction take 10 d to achieve ca. 60% conversion. Hydroformylations using 1:1 Ho/C0 were more successful and 0.5% RhCl , 600 p s i C0/H and 150 °C led to a 49 % conversion of 1-pentene to an equal r a t i o of hexanal/2-methylpentanal i n 3 h. A homogeneous catalyst under comparable conditions i n the absence of the inorganic ion exchange r e s i n was about 10 times more active. Loadings of catalyst onto the ion exchange resin i n these experiments were r e l a t i v e l y low, 5 x 10 moles of Rh being used with 1 g of the ion exchange polymer. 3

2

Linear Polystyrene Bound Transition Metal Catalysts Bayer's group was one of the f i r s t groups to describe the use of soluble macromolecular ligands for t r a n s i t i o n metal catalysts (49). In t h e i r work, they used soluble polystyrenes, polyethylene glyc o l s , poly(vinylpyrrolidinone)s and poly(vinyl chloride)s. For example, using l i n e a r polystyrene (M of ca. 100,000), chloromethylation followed by treatment with potassium diphenylphosphide could used to prepare a soluble polydiphenyl(styrylmethyl)phosphanes containing varying amounts of unreacted CI and phosphino groups as indicated below( 1M). Ligand exchange or substitution using various rhodium, palladium and platinum complexes could then be used to prepare w


34


PS-CH C1 2

+

KPPh

2

PS-CH PPh 2

(14)

2


8a: 2.59 % C I , 0.45 % P 8b:

Polymeric Reagents and Catalysts - ACS Publications - American

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