Water-Soluble Polyphosphazenes and Their Hydrogels - American

Downloaded by COLORADO STATE UNIV FT COLLINS on October 30, 2013 | http://pubs.acs.org Publication Date: January 15, 1996 | doi: 10.1021/ba-1996-0248.ch001

1

Water-Soluble Polyphosphazenes and Their Hydrogels Harry R. Allcock Department of Chemistry, The Pennsylvania State University, University Park, PA 16802

Six different classes of water-soluble polyphosphazenes have been synthesized and characterized. Several of the new polymers have been cross-linked to yield materials that absorb water to form hydrogels. This chapter examines the underlying concepts used in this work and describes the use of this chemistry to prepare new materials with controlled surface structures and with special properties such as lower critical solution temperatures, bioerodibility, or biocompatibility. The incorporation of these polymers into membranes or microencapsules is also described.

WATER-SOLUBLE

SYNTHETIC

POLYMERS

AND

HYDROGELS

are

important

in areas as v a r i e d as b i o m e d i c i n e , adhesion, membranes, a n d viscosity enhancement. T h e y are possible replacements i n technology a n d m e d i c i n e for many naturally occurring polymers. Unfortunately, relatively few of the hundreds of k n o w n synthetic polymers are soluble in water. T h u s the design a n d synthesis of n e w water-soluble polymers or hydrogels are subjects of considerable interest. T h i s chapter is a r e v i e w of an approach to this p r o b l e m that makes use o f the concepts discussed in the next section.

Concepts Used in This Work P o l y m e r s o l u b i l i t y i n water results from two factors. First, s o l u b i l i t y i n water may result from the presence of certain h y d r o p h i l i c units i n 0065-2393/96/0248-0003$13.75/0 © 1996 American Chemical Society

In Hydrophilic Polymers; Glass, J.; Advances in Chemistry; American Chemical Society: Washington, DC, 1996.

4

HYDROPHILIC POLYMERS

the p o l y m e r backbone, e s p e c i a l l y units such as - Ο - , - N H - , or - N = that possess lone pair electrons for h y d r o g e n b o n d i n g to water. Sec o n d , s o l u b i l i t y i n water often results from the presence of h y d r o p h i l i c side groups such as - O H , - C O O N a , - N H , - N H C H , - S 0 " , or - C = 0 or of a m p h i p h i l i c units such as - O C H 2 C H 2 O - , etc. H i g h con centrations of h y d r o p h i l i c side groups may overcome a lack of h y d r o p h i l i c units i n the backbone, but a h y d r o p h i l i c backbone is the best starting p o i n t for d e s i g n i n g a water-soluble p o l y m e r . T h e second concept u s e d i n this w o r k is related to the m e t h o d of p o l y m e r synthesis. T w o general methods exist for b r i n g i n g about variations i n p o l y m e r structure: (1) the p o l y m e r i z a t i o n or copolymerization of different monomers a n d (2) macromolecular substitution re actions i n w h i c h side groups already attached to a p o l y m e r c h a i n are replaced b y other groups (Scheme I). T h e first m e t h o d is more w i d e l y u s e d than the second, m a i n l y because of the a v a i l a b i l i t y o f a w i d e range of petrochemical monomers but also because the side group


2

Scheme I. Macromolecular

3

substitution.


3


1.

ALLCOCK

Water-Soluble Polyphosphazenes and Their Hydrogels

5

Figure 1. Cross-linking of water-soluble polymers generates hydrogels. replacement reactions of organic polymers are often relatively inefficient. Nevertheless, as w i l l be demonstrated, the macromolecular substitution approach is an excellent m e t h o d for the synthesis of watersoluble polymers because it allows a h i g h degree of utilization of molecular design a n d either extensive or subtle structural m a n i p u l a t i o n . T h e t h i r d p r i n c i p l e is this: O n e of the most effective routes to hydrogel formation is v i a the c r o s s - l i n k i n g of water-soluble polymers (Figure 1). Cross-links b e t w e e n hitherto water-soluble p o l y m e r m o l e cules prevent dissolution of the p o l y m e r i n water. H o w e v e r , the crossl i n k e d material absorbs water a n d swells to an extent that is d e f i n e d b y the n u m b e r of cross-links per chain. T h u s the d e s i g n of hydrogels ( w h i c h are of critical importance i n the field of b i o m e d i c i n e ) depends on the development of c r o s s - l i n k i n g methods that are appropriate for side groups that impart water-solubility. T h e fourth concept, w h i c h w i l l be referred to later, concerns the stability of a water-soluble p o l y m e r or h y d r o g e l to hydrolysis i n aqueous m e d i a . I n most technological applications, h y d r o l y t i c instability is considered a detrimental property. H o w e v e r , i n b i o m e d i c i n e , hydrolytic b r e a k d o w n of the p o l y m e r or a h y d r o g e l may be an essential requirement i f the p o l y m e r must eventually " e r o d e " as it is replaced b y l i v i n g cells or after it has b e e n used as a d r u g d e l i v e r y platform (Figure 2). H y d r o l y t i c instability can often be d e s i g n e d into a p o l y m e r b y the selection of the m a i n c h a i n units, the side groups, or both. T h e last concept to be illustrated i n this chapter is that a group of polymers k n o w n as polyphosphazenes (structure 1) have many advantages for development as water-soluble polymers or hydrogels. T h e backbone is h y d r o p h i l i c , the chain structure has a h i g h degree of flexib i l i t y , and (depending o n the side groups) the backbone may be i n d u c e d to undergo hydrolysis. H o w e v e r , the m a i n advantage of these polymers is the ease w i t h w h i c h w a t e r - s o l u b i l i z i n g side groups can


6

HYDROPHILIC

POLYMERS

H0

V

2

I


Harmless Small Molecules

Figure 2. Hydrolytic instability may be utilized as

bioerodibility.

R

R

η

1 be l i n k e d to the c h a i n v i a macromolecular substitution reactions. A s w i l l be demonstrated, the backbone is sufficiently stable to h i g h - e n ergy radiation that X rays, gamma rays, electron beams, or ultraviolet irradiation can be used as a clean and effective way to cross-link the polymers through the side groups i n order to generate hydrogels.

Methods of Phosphazene Polymer Synthesis T h e m a i n m e t h o d for the synthesis of polyphosphazenes is illustrated i n Scheme II (1—6). T h e m e t h o d consists of a r i n g - o p e n i n g p o l y m e r i z a tion of a heterocyclic " m o n o m e r , " s h o w n as 2, f o l l o w e d b y replace ment of the c h l o r i n e atoms i n the resultant p o l y m e r (3) b y organic groups through macromolecular n u c l e o p h i l i c substitution reactions. T h e c h l o r i n e replacement step can be carried out either to introduce only one type of side group or, b y simultaneous or sequential substitu tion, to introduce two or more different types of side groups. T h e most important feature of this reaction is that the h i g h reactivity of the P - C l bonds allows a l l the halogen atoms to be replaced. Because the average c h a i n length of p o l y m e r 3 is 15,000 repeating units, 30,000 c h l o r i n e atoms are replaced per p o l y m e r chain. B u l k y n u c l e o p h i l e s (such as aryloxide) may s l o w this reaction to the point that elevated tempera tures may be r e q u i r e d to a l l o w the reaction to proceed to c o m p l e t i o n . A variation o n this synthesis method, i n w h i c h some of the organic groups are i n t r o d u c e d before r i n g - o p e n i n g p o l y m e r i z a t i o n , is s h o w n i n Scheme III (7—9). B o t h of the routes s h o w n i n Schemes II a n d III were discovered a n d d e v e l o p e d i n our research program; they have so far l e d to the synthesis of more than 300 different polyphosphazenes.


1.

ALLCOCK


1.

Water-Soluble Polyphosphazenes

PC1 + NH C1 5

4

and Their Hydrogels

a j CI

Heat

La Ρ

y

α Ρ X

α

Ρ

Ρ

HQ Cl

α

α κ

X

C1

CI I 4-N=P—I J 11

CI

Scheme II.


7

8


X = ForCl X

X.

V RM


x

/

^

Ρ

Ν

/

Ρ

\ χ

R

Ν* X'

X

R

RM = Organometallic Reagent

V

•J

Ρ

V

Heat

N=

P—t

Ρ

Scheme 111. Alternative synthesis routes, w h i c h i n v o l v e condensation-type processes, have b e e n d e v e l o p e d i n other laboratories. T h e s e routes are s h o w n i n Scheme I V (10-15).

Examples of Water-Soluble Polyphosphazenes Chart I shows six different polyphosphazenes that are soluble i n water. A l l of t h e m were synthesized i n our laboratory v i a variations of the


1. ALLCOCK

Water-Soluble Polyphosphazenes and Their Hydrogels R

(CH3) SiN=P- OCH CF


3

2

3

I R ^ (In solution)

J

Scheme IV. The asterisk indicates a potentially explosive intermediate that is not isolated but is both prepared and decomposed in solution.

Chart 1. Water-soluble

polyphosphazenes.


9


10


chemistry s h o w n i n Scheme I I . E a c h has the same h y d r o p h i l i c backbone structure, a n d a l l bear h y d r o p h i l i c side groups. T h r e e o f them, possibly four, are stable to hydrolysis at room temperature or b o d y temperature. T w o o f them (6 a n d 7) h y d r o l y z e at detectable rates i n neutral aqueous m e d i a at 100 °C and are p r e s u m e d to h y d r o l y z e s l o w l y at l o w e r temperatures. T h e discussion that follows w i l l consider each of these examples i n turn, illustrating the differences a n d opportunities for molecular d e s i g n a n d property o p t i m i z a t i o n . Poly[bis(methylamino)phosphazene] (4). T h e p o l y m e r p o l y [bis(methylamino)phosphazene] was the first water-soluble p o l y phosphazene to b e synthesized (16). It is prepared b y the a d d i t i o n o f a tetrahydrofuran solution of poly(dichlorophosphazene) (3) to a large excess o f m e t h y l a m i n e i n the same solvent at 0 °C. T h e s e reaction conditions were chosen to m i n i m i z e the p o s s i b i l i t y that an - N ( H ) - C H 3 side unit c o u l d cross-link the chains d u r i n g synthesis through reaction w i t h a P - C l u n i t or another c h a i n . T h i s p o l y m e r has a glass transition temperature ( T ) o f 14 °C. T h e water-solubility o f 4 is b e l i e v e d to be d u e to (1) the small size o f the side groups, w h i c h exposes the skeletal nitrogen atoms to hydrogen b o n d i n g to water, a n d (2) strong hydrogen b o n d i n g b e t w e e n water a n d the N H units o f the side groups. T h i s p o l y m e r appears to be stable to neutral a n d basic aqueous m e d i a but hydrolyzes to phosphate a n d a m m o n i u m salts i n strong acids. P o l y m e r 4 is sensitive to cross-linking w h e n it is exposed to gamma rays (17). T h e mechanism o f this process is illustrated i n Scheme V . C r o s s - l i n k i n g is b e l i e v e d to result from radiation-induced, c a r b o n hydrogen b o n d cleavage f o l l o w e d b y cross-combination o f the N H C H - radicals p r o d u c e d . T h i s cross-linking process has b e e n used to stabilize a m p h i p h i l i c membranes prepared from polyphosphazenes that contain both methylamino a n d fluoroalkoxy or aryloxy cosubstituent groups (17). g

2

Poly[bis(methoxyethoxyethoxy)phosphazene] (5) (MEEP). O n e o f the most interesting a n d potentially most useful p o l y p h o s p h a zenes yet synthesized is p o l y m e r 5. T h i s p o l y m e r is prepared b y the reaction of poly(dichlorophosphazene) (3) w i t h the s o d i u m salt o f methoxyethoxyethanol i n tetrahydrofuran solution (Scheme V I ) (18). Because the p o l y m e r is i n f i n i t e l y water-soluble at 25 °C, it can b e p u r i f i e d b y dialysis. M E E P has unusual solution properties i n water, e x h i b i t i n g the p h e n o m e n o n k n o w n as a l o w e r critical solution temperature ( L C S T ) . Polymers that possess this characteristic are soluble b e l o w a specific temperature b u t become i n s o l u b l e at temperatures above this point


ALLCOCK Cl I N= Ρ I CI

11


CH NH 3

—I

NHCH

3

rliHCH

3

2

-Ν—Ρ

HC1

J η

Water-Soluble


Gamma-ray

NHCH I

3

•N= Ρ — NHCH, J η

NHCH I

3

-N= Ρ — pliHCH. NHCH I Ρ —

-N =

2

pifiHCH. Scheme V.

CI

NaOCH CH OCH CH OCH 2

N=P—I CI

2

2

2

OCH CH OCH CH OCH 2

2

2

2

3

~ N =

•NaCI

Ρ —

I

0CH CH 0CH CH 0CH 2

2

2

2

5 MEEP

Scheme VI.


3

3


12


Figure 3. LCST for a polymer solution and hydrogel.

(Figure 3). M E E P has an L C S T of 65 °C. A n u m b e r of polymers related to M E E P but w i t h different etherie side groups, different a l k y l ether c h a i n lengths, a n d different terminal alkoxy groups have also b e e n synthesized (10-13). Several of these also exhibit L C S T s , as s h o w n i n T a b l e I (19). P r e s u m a b l y the L C S T behavior of these polymers reflects the d o m i n a n c e of the " h y d r o p h o b i c " character of the C H 2 C H 2 units a n d the a l k y l e n d units over the h y d r o p h i l i c effect of the etherie oxygen atoms above the L C S T . Replacement of a h y d r o p h o b i c a l k y l terminal group b y a h y d r o p h i l i c a m i n o u n i t eliminates the L C S T effect. A characteristic of M E E P - t y p e polymers is their l o w T s , w h i c h can be attributed to the c o m b i n a t i o n of a h i g h l y flexible backbone a n d f l e x i b l e side groups. M E E P (5) itself has a T o f - 8 4 °C, p o l y m e r 10 has a T of - 7 5 °C, a n d the T s for 11 a n d 12 are - 7 6 a n d - 8 4 °C, respectively. F o r 13, w i t h a t e r m i n a l N H u n i t at each side group, the T rises to - 1 8 °C, presumably because side group h y d r o g e n b o n d i n g restricts the thermal motions of the macromoleeules. M E E P is of interest from several points of v i e w . First, it is an excellent s o l i d solvent for salts such as l i t h i u m triflate. T h e s o l i d s o l u tions function as s o l i d p o l y m e r i c i o n i c conductors, a n d as such they g

g

g

g

2

g


1.

ALLCOCK

Water-Soluble Polyphosphazenes

13

and Their Hydrogels

Table I. Lower Critical Solution Temperature (LCST) for M E E P and Related Polymers LCST (°C)

Polymer


OCH2CH2OCH3 30

— N = P —

I OCH2CH2OCH3 10

OCH2CH20CH2CH20CH3 65

— N = P —

I OCH2CH OCH CH OCH3 J 5 2

2

2

OCH CH OCH CH OC H 2

2

2

2

2

5

38

OCH CH20CH CH OC H5 2

2

2

2

11

OCH CH OCH CH OC H 2

2

2

2

4

9

51

-N=:>— OCH CH OCH CH OC H 2

2

2

2

4

9

12

OCH CH OCH CH NH 2

2

2

2

2

None

-N=P— OCH CH OCH CH NH 2

13

2

2

2

2

Jn

NOTE: Hydrogels extrude water at the L C S T . All of the polymers shown here are water-

soluble at 25 °C.



14


Figure 4. MEEP, cross-linked by exposure to approximately 2 Mrad of gamma rays, before and after immersion in water. (Reproduced with permission from reference 5. Copyright 1992 Prentice Hall.) have generated w i d e s p r e a d interest as potential electrolytes i n largearea, light-weight, rechargeable l i t h i u m batteries (Figure 4) (20-23). Second, M E E P can be cross-linked readily b y exposure to gamma rays or ultraviolet light (24-26). T h e m e c h a n i s m o f this reaction, as illustrated i n Scheme V I I , is b e l i e v e d to i n v o l v e C - H b o n d homolytic cleavage f o l l o w e d b y cross-combination o f the resultant carbon radicals. T h e sensitivity of M E E P to radiation c r o s s - l i n k i n g is attributed to the presence of 22 C - H bonds on every repeating unit. C r o s s - l i n k e d M E E P swells i n water to form stable hydrogels (Figure 4), the water contents of w h i c h are a function o f the degree o f cross-linking. T h e cross-linking process has b e e n used to entrap and i m m o b i l i z e enzymes w i t h retention o f e n z y m i c activity (27). D i f f u s i o n - r e l e a s e o f s m a l l m o l e c u l e solutes from the hydrogels has also b e e n studied (24). F i n a l l y , radiation-cross-linked M E E P has b e e n converted to s w o l l e n organogels b y absorption o f organic v i n y l monomers (Figure 5). P o l y m e r i z a t i o n a n d c r o s s - l i n k i n g of the organic monomers has y i e l d e d a range of interpenetrating p o l y m e r network materials (28). Interpenetrating p o l y m e r networks prepared w i t h acrylonitrile and acrylic a c i d polymers show good component c o m p a t i b i l i t y , a n d this c o m p a t i b i l i t y


1.

ALLCOCK

Water-Soluble Polyphosphazenes and Their Hydrogels X/Np/V/V'

ι


15

fJH

Gamma-rays orUV 2

?

CH

3

\ζν\ρ/\κ Scheme VII. is consistent w i t h the expected h y d r o p h i l i c interactions. M E E P has also b e e n used as the linear p o l y m e r i c component i n ceramic compos ites prepared v i a the s o l - g e l process, a n d these composites show a range o f interesting and potentially useful properties (29). Polymers with Glucosyl Side Groups. Perhaps the ultimate i n h y d r o p h i l i c side group interactions m i g h t be expected from gluco syl units o f the type s h o w n i n p o l y m e r 6. W i t h four free h y d r o x y l groups o n every side group, the opportunities for Η b o n d i n g to water molecules appear to be almost unprecedented i n a synthetic p o l y m e r . T h e synthesis of glucosyl-substituted polyphosphazenes presents a special challenge. G l u c o s e itself has five functional sites p e r m o l e c u l e , a n d any attempt to treat poly(dichlorophosphazene) w i t h glucose w o u l d result i n extensive cross-linking a n d p o l y m e r precipitation l o n g before halogen replacement was complete. T h u s four o f the five h y droxy units must be protected d u r i n g c o u p l i n g o f the side group to the backbone a n d must be deprotected d u r i n g a final step. T h i s process is s h o w n i n Scheme V I I I (30). T h e second challenge is this: T h e protected diacetone glucose used i n the i n i t i a l macromolecular substitution is an exceedingly b u l k y n u c l e o p h i l e . Replacement of h a l f the available c h l o r i n e atoms proceeds i n a conventional manner. H o w e v e r , replacement o f the re mainder is s l o w e d considerably b y steric hindrance effects. I n d e e d , j u d g i n g from molecular graphics simulations ( F i g u r e 6), replacement of the last c h l o r i n e i n a three-repeat-unit sequence appears to be ex-



2

2

2

2

2

3

3

Gamma Rays or Heat

Gamma Rays

Swell in Organic Monomer

Styrène MMA Acrylonitrile* AcrylkAdd*

Figure 5. Interpenetrating polymer networks based on MEEP with various organic polymers. MMA is methyl methacrylate.

2

2

— N= Ρ — I OCH CH OCH CH OCH

2

OCH CH OCH CH OCH


ο 53 Ο *β χ r ο *d ο ζ

Η;

Ci


1.

ALLCOCK


17

c e e d i n g l y difficult, a n d i t is not s u r p r i s i n g that l o n g reaction times a n d elevated reaction temperatures are n e e d e d for this final replacement. T h u s from a practical point of v i e w , it is easier to incorporate the glucosyl units as part of a mixed-substituent p o l y m e r , w i t h the second n u c l e o p h i l e b e i n g less b u l k y than diacetoneglucoxide (31). T h i s procedure is illustrated i n S c h e m e I X . A great deal of additional w o r k needs to be done w i t h sugar derivatives of polyphosphazenes. T h i s work w i l l u n d o u b t e d l y b e carried out as the b i o m e d i c a l properties o f the polyphosphazenes are s t u d i e d i n more detail.



18


Figure 6. Molecular graphics simulation of the steric hindrance involved in the replacement of the last chlorine atom (arrow) in a three-repeat unit segment of a polyphosphazene by a diacetone glucose anion (A) and the close crowding that exists in a completely substituted segment of the chain (B).

Scheme IX.


1.

ALLCOCK

CH C H 3

CH

Ρ—I

CH "

3

3

3

Ο Ο I I 0- C H - C H — C H

Water-Soluble Polyphosphazenes and Their Hydrogels - American

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