Cyclic and High-Polymeric Phosphazenes as Carrier Molecules for

3 Cyclic and High-Polymeric Phosphazenes as Carrier Molecules for Carboranyl, Metallo, or Bioactive Side Groups H. R. ALLCOCK

Downloaded by FUDAN UNIV on April 18, 2017 | http://pubs.acs.org Publication Date: September 30, 1983 | doi: 10.1021/bk-1983-0232.ch003

The Pennsylvania State University, Department of Chemistry, University Park, PA 16802

Cyclic and high polymeric phosphazenes can be modified by nucleophilic-type substitution reactions to generate a wide range of derivatives. Recent developments include the introduction of bioactive organic residues to yield biologically-active high polymers and the synthesis of transition metal derivatives of phosphazenes. In addition, hybrid phosphazene-carborane compounds have been prepared including examples in which nido-carboranyl units, attached to a phosphazene ring or chain, function as binding sites for transition metal organometallic units. Most i n o r g a n i c r e s e a r c h i n v o l v e s w o r k w i t h s m a l l m o l e c u l e s , and r e l a t i v e l y l i t t l e c o n c e n t r a t e d e f f o r t h a s b e e n d e v o t e d t o t h e macromolecular aspects o f t h e subject. The c o m p l e x i t y o f t h e macromolecular chemistry has undoubtedly c o n t r i b u t e d t o t h i s neglect. However, i t i s c l e a r f r o m r e c e n t w o r k t h a t d r a m a t i c a d v a n c e s i n b o t h f u n d a m e n t a l s c i e n c e and t e c h n o l o g y w o u l d b e p o s s i b l e i f t h e h i g h polymer c h e m i s t r y o f t h e r e p r e s e n t a t i v e e l e m e n t s w e r e t o be s t u d i e d i n d e t a i l . I n d e e d , t h e muchh e r a l d e d r e n a i s s a n c e i n M a i n Group c h e m i s t r y may u l t i m a t e l y depend on a c l o s e r i n v e s t i g a t i o n o f t h e m a c r o m o l e c u l a r a s p e c t s o f t h e field. My p u r p o s e h e r e i s t o i l l u s t r a t e what c a n be a c c o m p l i s h e d w i t h j u s t one i n o r g a n i c m a c r o m o l e c u l a r s y s t e m — i n t h i s c a s e c o n s t r u c t e d f r o m a b a c k b o n e o f p h o s p h o r u s and n i t r o g e n atoms. A l m o s t c e r t a i n l y , o t h e r s y s t e m s b a s e d o n t h e M a i n Group e l e m e n t s can be d e v e l o p e d t o an e q u a l o r g r e a t e r degree. I hope t h a t t h e f o l l o w i n g comments w i l l s t i m u l a t e a n i n c r e a s e d i n t e r e s t i n t h a t direction. I w i l l a l s o attempt t o i l l u s t r a t e the r e l a t i o n s h i p between t h e fundamental c h e m i s t r y and an approach t o s o l v i n g p r a c t i c a l problems.

0097-6156/83/0232-0049 $06.00/0 © 1983 American Chemical Society

Cowley; Rings, Clusters, and Polymers of the Main Group Elements ACS Symposium Series; American Chemical Society: Washington, DC, 1983.

50

RINGS, CLUSTERS, AND

POLYMERS


Guiding P r i n c i p l e s N e a r l y a l l s y n t h e t i c p o l y m e r s a r e s y n t h e s i z e d by t h e p o l y m e r i z a t i o n o r c o p o l y m e r i z a t i o n o f d i f f e r e n t "monomers." The c h a i n g r o w t h p r o c e s s may i n v o l v e t h e a d d i t i o n c h a i n r e a c t i o n s o f unsaturated small molecules, condensation r e a c t i o n s , or r i n g opening chain-coupling processes. In c o n v e n t i o n a l polymer c h e m i s t r y , t h e s y n t h e s i s o f a new p o l y m e r r e q u i r e s t h e use o f a new monomer. This approach i s o f t e n u n s a t i s f a c t o r y f o r i n o r g a n i c s y s t e m s , where r e l a t i v e l y few monomers o r c y c l i c o l i g o m e r s c a n be i n d u c e d to p o l y m e r i z e , at l e a s t under c o n d i t i o n s t h a t have been studied to date. The m a i n e x c e p t i o n t o t h i s r u l e i s t h e c o n d e n s a t i o n - t y p e growth t h a t occurs w i t h i n o r g a n i c d i - h y d r o x y acids. Because the o p p o r t u n i t i e s f o r c o n t r o l l e d c h a i n growth are more r e s t r i c t e d i n i n o r g a n i c t h a n i n o r g a n i c s y s t e m s , an a l t e r n a t i v e a p p r o a c h t o p o l y m e r s y n t h e s i s becomes a p p e a l i n g . This i n v o l v e s t h e use o f s u b s t i t u t i o n p r o c e s s e s c a r r i e d o u t on a preformed r e a c t i v e polymeric intermediate. I n t h i s way molecular d i v e r s i t y can be i n t r o d u c e d by d i f f e r e n t s u b s t i t u t i o n r e a c t i o n s r a t h e r t h a n by a d i v e r s i f i c a t i o n o f t h e p o l y m e r i z a t i o n p r o c e s s . I f t h i s p r i n c i p l e c a n be a p p l i e d , two p o t e n t i a l p r o b l e m s must be a v o i d e d : t h e s u b s t i t u t i o n r e a c t i o n s must l e a d t o n e i t h e r c h a i n cleavage nor c r o s s l i n k i n g . Simple S u b s t i t u t i o n Reactions

with

Poly(dihalophosphazenes)

Poly(dichlorophosphazene) (II) i s a highly reactive inorganic macromolecule. I t can be p r e p a r e d by t h e c a r e f u l l y c o n t r o l l e d thermal p o l y m e r i z a t i o n of the c y c l i c t r i m e r , h e x a c h l o r o c y c l o t r i phosphazene ( I ) , i t s e l f s y n t h e s i z e d from phosphorus p e n t a c h l o r i d e and ammonium c h l o r i d e . I n s o l u t i o n , t h e c h l o r i n e atoms i n I I can be r e p l a c e d r e a d i l y by r e a c t i o n w i t h a w i d e v a r i e t y o f o r g a n i c n u c l e o p h i l e s (1,2., 3.) (Scheme 1 ) . The r e s u l t a n t p o l y m e r s ( I I I - V ) a r e s t a b l e and d i s p l a y a r a n g e o f p h y s i c a l and c h e m i c a l p r o p e r t i e s d e t e r m i n e d by t h e n a t u r e o f t h e o r g a n i c s i d e g r o u p s . This s y n t h e s i s p r o c e s s has b e e n r e v i e w e d i n d e t a i l e l s e w h e r e (4.-7) . Here i t i s s u f f i c i e n t to n o t e t h a t s e v e r a l hundred p o l y ( o r g a n o p h o s p h a z e n e s ) h a v e b e e n p r e p a r e d by t h i s method. Polymers of t h i s t y p e are a l r e a d y b e i n g used i n t e c h n o l o g y ; t h e y a r e a l s o o f considerable s c i e n t i f i c interest. S i m i l a r s y n t h e s e s have b e e n d e v e l o p e d b a s e d on p o l y ( d i f l u o r o p h o s p h a z e n e ) , (NPF2) (8). n

C y c l i c T r i m e r s and

T e t r a m e r s as R e a c t i o n

Models

From a t h e o r e t i c a l and m e c h a n i s t i c p o i n t o f v i e w , s m a l l m o l e c u l e r i n g s a r e much e a s i e r t o s t u d y t h a n l o n g m a c r o m o l e c u l a r chains. S u b s t i t u t i o n r e a c t i o n s c a r r i e d o u t on m a c r o m o l e c u l a r



3.

ALLCOCK

Cyclic and

High-Polymeric Phosphazenes

51

Scheme 1

s u b s t r a t e s may i n v o l v e s i d e r e a c t i o n s t h a t l e a d t o c h a i n c l e a v a g e or c r o s s l i n k i n g . Mechanistic s t u d i e s w i t h macromolecules are d i f f i c u l t to c a r r y out because o f s o l u t i o n v i s c o s i t y e f f e c t s , d i s t r i b u t i o n s i n c h a i n l e n g t h , and t h e p r o b l e m s o f c h a r a c t e r ization. H e n c e , i t i s p r u d e n t t o e x p l o r e p o t e n t i a l new reactions f i r s t w i t h t h e use o f s m a l l m o l e c u l e m o d e l s s u c h as I , V I , and V I I and t h e n t o e x t e n d t h e s e r e a c t i o n s t o t h e h i g h p o l y m e r s .


RINGS, C L U S T E R S , A N D P O L Y M E R S

52 CI

CI

F

F

Cl C1-P

Cl = N-

l Ν Il C 1 - P - N

Cl

Cl

Cl

Cl


I

VI

VII

Some o f t h e p o l y m e r i c r e a c t i o n s m e n t i o n e d b e l o w a r e s t i l l s t u d y a t t h e m o d e l compound l e v e l . Modern O b j e c t i v e s

i n Polymer

P-C1

II N I = P-C1

under

Synthesis

Polymers have been v a l u e d s i n c e a n t i q u i t y f o r t h e i r s o l i d state properties. By t h i s i s meant t h e i r a b i l i t y t o u n d e r g o c h a i n e n t a n g l e m e n t o r c o - l i n e a r o r i e n t a t i o n and m i c r o c r y s t a l l i zation i n the s o l i d state. T h i s u n d e r l i e s t h e i r use as s t r u c t u r a l m a t e r i a l s , f i l m s , f i b e r s , and e l a s t o m e r s . Such p r o p e r t i e s s t i l l c o n s t i t u t e t h e d r i v i n g f o r c e f o r most p o l y m e r oriented research, e s p e c i a l l y with respect to the synthesis of heat-stable, radiation-stable,or highly f l e x i b l e materials. The e l e c t r i c a l p r o p e r t i e s o f s o l i d p o l y m e r s h a v e a l w a y s b e e n o f interest. However, i n r e c e n t y e a r s a n o t h e r a p p r o a c h t o p o l y m e r c h e m i s t r y has r e c e i v e d i n c r e a s e d emphasis. I n t h i s , macrom o l e c u l e s a r e s t u d i e d i n terms o f t h e i r b e h a v i o r as s i n g l e m o l e c u l e s r a t h e r than as m o l e c u l a r c o n g l o m e r a t e s . In solution, polymer m o l e c u l e s behave d i f f e r e n t l y from s m a l l m o l e c u l e s because the l o n g c h a i n l e n g t h permits e x t e n s i v e c o i l i n g , reduced t r a n s l a t i o n a l m o b i l i t y , and an i n a b i l i t y t o p a s s t h r o u g h s e m i p e r m e a b l e membranes. L i g h t l y c r o s s l i n k e d polymers behave l i k e l i n e a r polymers i n s o l u t i o n except t h a t t h e s w o l l e n m a t r i x has a p h y s i c a l i m m o b i l i t y and an o p e n m a t r i x c h a r a c t e r u n l i k e any o t h e r system. For these reasons, polymers a r e o f great i n t e r e s t as " c a r r i e r molecules" f o r chemotherapeutic drugs o r t r a n s i t i o n metal c a t a l y s t s . F i n a l l y , s i n g l e macromolecules, because o f t h e i r oned i m e n s i o n a l c h a r a c t e r , o f f e r t h e promise o f s e q u e n t i a l s i d e group c o d i n g , i n f o r m a t i o n s t o r a g e , and t e m p l a t e f u n c t i o n i n t h e manner t h a t i s w e l l known i n b i o l o g i c a l p o l y m e r s ( F i g u r e 1 ) . Conventional s y n t h e t i c organic polymers are being s t u d i e d for a l l o f these reasons, b u t t h e g e n e r a l l a c k o f chemical r e a c t i v i t y i n t h e s e systems i s a s e r i o u s drawback. It i s for t h i s reason that polyphosphazenes, w i t h t h e i r s u b s t i t u t i v e


Cowley; Rings, Clusters, and Polymers of the Main Group Elements ACS Symposium Series; American Chemical Society: Washington, DC, 1983. I C

I D

I D

I C

I Β

I A

I A

1 Ά

I

C

Key: a, traditional use of the solid-state, chain entanglement behavior that gives rise to strength or elasticity; b, explor atory use as carrier molecules for bioactive agents in controlled-release drug therapy either as targeted macromolecular drugs or as immobilized biodegradable systems; c, use as immobilizing agent for transition metal catalysts for easier manipulation or recovery or to modify the catalytic activity; d, use as electrical conductors or semiconductors (conduction may occur along unsaturated chain sequences or between chains in crystalline domains); e, sequential arrangement of side groups along a linear polymer chain offers the prospect of (I) control of polymer conformation; (2) use as a template for the controlled construction of complementary polymer molecules; and (3) information storage at the molecular level.

Figure 1. Traditional and exploratory uses for polymers.

I Β

I Ά

BIOACTIVE AGENT


C*9

ο •s

I ο ^*

> r r η ο π *

54


method o f s y n t h e s i s , a r e o f c o n s i d e r a b l e i n t e r e s t . In the f o l l o w i n g s e c t i o n s , I w i l l i l l u s t r a t e why t h e p o l y p h o s p h a z e n e s y s t e m i s an a p p e a l i n g s t a r t i n g p o i n t f o r new d e v e l o p m e n t s i n two s p e c i f i c a r e a s — i n c h e m o t h e r a p y and p o l y m e r - b o u n d c a t a l y s t w o r k .


Bioactive

Polyphosphazenes

S p e c i f i c i n o r g a n i c macromolecules a r e unusual because they c a n be h y d r o l y z e d t o r e l a t i v e l y i n n o c u o u s p r o d u c t s o r t o s m a l l m o l e c u l e s t h a t c a n be m e t a b o l i z e d . Most c o n v e n t i o n a l o r g a n i c p o l y m e r s do n o t h a v e t h i s a t t r i b u t e . Thus, t h e s e i n o r g a n i c s y s t e m s a r e o f s p e c i a l i n t e r e s t as c a r r i e r m o l e c u l e s i n chemo therapy. R e c e n t w o r k i n o u r l a b o r a t o r y h a s shown t h a t c e r t a i n s i d e groups a t t a c h e d to a polyphosphazene c h a i n impart a s e n s i t i v i t y to h y d r o l y t i c c h a i n c l e a v a g e ; o t h e r s i d e groups g e n e r a t e w a t e r solubility. Both of these c h a r a c t e r i s t i c s are important i n chemotherapy. Polyphosphazenes are a l s o v a l u a b l e i n b i o l o g y b e c a u s e two o r more s u b s t i t u t e d g r o u p s c a n be r e a d i l y a t t a c h e d t o t h e same c h a i n . Thus, i n d i v i d u a l s i d e groups t h a t p o s s e s s chemotherapeutic, w a t e r - s o l u b i l i z a t i o n , h y d r o l y t i c - d e s t a b i l i z a t i o n , o r "homing" c h a r a c t e r i s t i c s c a n be c o m b i n e d i n one m o l e c u l e t o form a drug w i t h a s e t o f s y n e r g i s t i c p r o p e r t i e s . P o l y m e r s c o n t a i n i n g t h e r e p e a t i n g u n i t s shown i n V I I I - X I h a v e b e e n shown t o be h y d r o l y t i c a l l y d e g r a d a b l e a n d / o r w a t e r s o l u b l e (9-13). Amino a c i d e s t e r d e r i v a t i v e s ( V I I I ) d e g r a d e t o e t h a n o l , amino a c i d , p h o s p h a t e , and ammonia, w h i c h c a n e i t h e r be metabolized or excreted. Thus, such s i d e u n i t s used t o g e t h e r w i t h chemotherapeutic c o s u b s t i t u e n t groups, provide a f a c i l e drug d e l i v e r y system. I m i d a z o l y l s i d e groups (IX) a l s o c o n f e r h y d r o l y t i c s e n s i t i v i t y , but the biochemical response to the h y d r o l y s i s p r o d u c t s has n o t y e t been e s t a b l i s h e d . Methylamino s i d e g r o u p s (X) p r o v i d e w a t e r - s o l u b i l i t y , as do g l u c o s e r e s i d u e s (XI).

NHCH COOEt I - Ν = Ρ l

! NHCH COOEt 2

VIII

IX


3.

ALLCOCK

55

Cyclic and High-Polymeric Phosphazenes CELOH ι ^

H

° J

OH °

H

NHCH„

I

3

Ν = Ρ -

Ν = Ρ

I Downloaded by FUDAN UNIV on April 18, 2017 | http://pubs.acs.org Publication Date: September 30, 1983 | doi: 10.1021/bk-1983-0232.ch003

NHCfi\

CH OH 2

XI

T h e s e p o l y m e r s w e r e s y n t h e s i z e d b y t h e g e n e r a l methods shown i n Scheme 1. T h e i r h y d r o l y s i s b e h a v i o r has been t h e s u b j e c t o f s e v e r a l f u n d a m e n t a l m e c h a n i s t i c s t u d i e s a t t h e m o d e l compound level (10,11). The a t t a c h m e n t o f b i o l o g i c a l l y - a c t i v e s i d e g r o u p s h a s a l s o been e x p l o r e d . At t h e present time s e v e r a l d i f f e r e n t approaches have been developed w h i c h l e a d t o t h e s y n t h e s i s o f polymers such as X I I - X V I I .

o - Ν

Ρ NHCH C00Et 2

XII

OPh XIII


N

56



OH

y

OH

CH CH NH

Ν = Ρ I OPh

2

2

2

XVI

o/f \J -λ.

\,/-v,u - C H N NEt E 0

2

I

0

0

Heparin

3

Ν = Ρ 0

Cyclic and High-Polymeric Phosphazenes as Carrier Molecules for

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