High-Molecular-Weight [L]-Polylactides Containing Pendant

Chapter 10

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High-Molecular-Weight [L]-Polylactides Containing Pendant Functional Groups 1,4

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Xianhai Chen , Youqing Shen , and Richard A . Gross

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Polymer Group, Aspen Systems, Inc., 184 Cedar Hill Street, Marlborough, M A 01752 Department of Chemical Engineering, McMaster University, 1280 Main Street West, Hamilton, Ontario L8S 4L7, Canada Polymer Research Insitiute, Polytechnic University, 6 Metrotech Center, Brooklyn, N Y 11201 2

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This paper reviews our previous work on the functional carbonate monomers design, synthesis and their applications for introducing functional groups into polylactides. A number of cyclic carbonate monomers with functional groups have been synthesized and used for the copolymerization with [L]-lactide ([L]-LA). High molecular weight copolymers have been prepared by using Sn(Oct) as catalyst. Structural investigations by NMR revealed that [L]– LA/carbonate copolymers had short average carbonate repeat unit segment lengths. This work has resulted in a new family of [L]– PLA-based copolymers that contain C=C, epoxy, ketal, and vicinal diol functional groups. These new copolymers will be of great value for the development of bioresorbable medical materials. 2

Functional Carbonate Monomers and Homopolymers We have prepared a series of 6-membered cyclic carbonate monomers, i.e., 2, 2[2-pentene-l, 5-diyl] trimethylene carbonate ( HTC), 1, 2-0-isopropylidene-[D]xylofuranose-3, 5-cyclic carbonate (IPXTC), 9, 9-dimethyl-2, 4, 8, 10-tetraoxaspiro [5, 5] undecane-3-one (DMTOS), and 2, 4, 8, 10-tetraoxaspiro [5, 5] undecane-3-one (DOXTC) (Scheme 1). The monomers HTC, IPXTC, DMTOS and DOXTC were synthesized in 81%, 41%, 70% and 80% yields respectively by a one-pot reaction in THF at 0°C starting from the corresponding diols (Scheme 2). It should be mentioned that the diol for DMTOS was synthesized from pentaerythritol by i) total ketal protection of OH group by reacting with (CH ) C(OCH ) in the presence of ptoluenesulfonic acid in > 95% yield, and ii) partial deprotection catalyzed by C

C

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3

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Current address: 3 River Place, A-1106, Lowell, MA 01852.

© 2000 American Chemical Society In Polymers from Renewable Resources; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

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130 CF COOH in about 20 % yield. 1, 2-0-Isopropylidene-[D]-xylofuranose can also be synthesized by one step reaction from xylose in high yield (~ 80%) under appropriate [H ] concentration without deprotection procedure. 3


+

Scheme 1. Structure offunctional cyclic carbonate monomers. Ο

Scheme 2. Synthesis of cyclic carbonate monomers. See Scheme 1 for corresponding Χ], X2 andX$ structures. !

The structure and purity of these monomers were confirmed by FTIR, H-NMR, C-NMR and melting point analysis. The melting points of HTC, IPXTC, DMTOS and DOXTC were 79.5~80.5°C, 143~144°C, 154~156°C and 126.5~127.5°C respectively. Compared to the yields of HTC (i), DMTOS or 2,4,8,10-tetraoxaspiro [5,5] undecane-3-one (DOXTC) (2), the yield of IPXTC was relatively lower. This may be explained by the followings: i) the equilibrium of 5- and 6-membered ring monosaccharides where the latter does not form the desired cyclic carbonate monomer and ii) while HTC, DMTOS and DOXTC are formed by the reaction of two primary hydroxy groups, IPXTC synthesis involves the reaction of a relatively lower reactivity secondary 1,2-O-isopropylidene-D-xylofuranose hydroxyl functionality (5). Polymerizations of HTC using organometallic catalysts including aluminoxanes, ZnEt and in-situ Ζ η Ε ν Η 0 resulted in the corresponding functional homopolymer in high molecular weight (M from 80,000 to 260,000). The pendant vinyl groups of P( HTC) offer a wide range of opportunities for further modification and/or fimctionalization. For example, P( HTC) vinyl groups were converted to epoxides with little molecular weight decrease (i). The C=C and epoxy would provide useful handles for further fimctionalization or crosslinking. The polymerization of IPXTC gave a homopolymer with M up to 13,200 by using yttrium isopropoxide as catalyst. 13

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C

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In Polymers from Renewable Resources; Scholz, C., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2001.

131 Three different repeat unit linkages (i.e., head-head, head-tail, and tail-tail) have been observed by C-NMR spectroscopy. The prepared PIPXTC has a melting transition temperature at 228°C and a glass transition temperature at 128°C. Subsequent deprotection of ketal in PIPXTC was successfully carried out by using CF3COOH/H2O (4). The vicinal diols may impart unique properties to the prepared materials that facilitate a variety of potential applications. For example, linear and crosslinked hydroxyl containing polyesters can permit the formation of strong hydrogen bonding and non-bonding interactions with organic and inorganic species (5). Also, hydroxyl containing aliphatic polycarbonates have been reported to be bioerodible and of importance in medical and pharmaceutical applications (6). DMTOS or DOXTC can also be polymerized by using various organometallic catalysts such as aluminoxanes, in-situ A1R -H 0 or ZnR -H 0, Tin(IV) catalysts, and Sn(Oct) . However, these two homopolymers were not soluble in common organic solvents.


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Preparation of [L]-PoIylaetides with Pendant Functional Groups

Table L Copolymerization of [L]-Lactide with Cyclic Carbonate Monomers* Monomer LA ΙΑ-ΉΤΟ

100/0

82/18 67/33 49/51 30/70 0/100

LA-IPXTC

83/17 71/29 66/34 52/48 36/64 93/7 85/15 77/23 66/34 53/47

LA-DMTOS

t(h) 6 6 6 6 6 6 6 6 6 6 24 22 22 22 22 22

yield(%) 99 82 68 47 43 91 82 71 70 54 48 95 84 76 67 54

a

b

c

M 86,000 99,700 82,200 49,800 35,300 55,700 78,400 64,500 44,500 27,900 13,900 60,000 48,800 28,500 21,200 n

17,100

M /M 2.1 2.0 2.1 2.2 1.9 2.0 1.9 1.7 2.0 1.6 1.7 3.2 3.8 3.6 4.0 2.8 w

n

F /F LA

d c

100/0

93/7 86/14 72/28 48/52 0/100

93/7 91/9 85/15 79/21 61/39 96/4 92/8 88/12 78/22 n.d.

C

120°C, Sn(Oct) as catalyst, M/C = 200. Monomer feed ratio in mol/mol. GPC results, polystyrene as standard. Copolymer composition in mol/mol determined by 'H-NMR. 2

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It is well known that Sn(Oct) is a preferred catalyst for the formation of high molecular weight polylactide via ring opening polymerization. We have screened a 2


132 variety of organometallic catalysts including (methyl and isobutyl) aluminoxanes, insitu A1R -H 0, in-situ ZnEt2-H 0, Sn(IV)-compounds, and Sn(Oct) for the copolymerization of [L]-lactide with the prepared functional carbonate monomers except DOXTC. As expected, Sn(Oct) gave higher molecular weight copolymers all copolymerization systems especially at high [L]-LA monomer feed ratios. 3

2

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2

Ο

A:

CH 0

0

3

=

a,

M C

o

Œ

W

Ο

ο CH [L]-LA

X

T

ο

0

3

Λ 0

3

Ο

Ο

°~h-CH CH

CH

0

CH ' ο

Ο

3

3

Œ3

°

C H / CH DMTOS

^

°

V^OH OH

Ο

3

Ο

0 3

j

r

3

C

O

C

3

ο

CH

CH.

Ό

[L]-LA

CH

Ο

+

[L]-LA

B: Η,

Ο

Ο C H

3

CH 1

J

3

3

O - ^ C H

3

Ο

Ο

II

II

OH OH Scheme 3. Preparation of [L]-polylactides with various pendantfunctional groups. The monomer reactivity ratio of [L]-lactide is much higher than those of cyclic carbonate monomers. For example, the reactivity ratios were 4.15/0.255 for [L]LA/IPXTC system and 8.8/0.52 for [L]-LA/ HTC system by using Sn(Oct) as C

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133 catalyst at 120°C. Table 1 summarizes the [L]-LA-cyclic carbonates copolymerization results with Sn(Oct) as catalyst at variable monomer feed ratios. The copolymer yields and molecular weights were inversely proportional to the cyclic carbonate monomer feed ratios. However, since our objective was to prepare [L]PLA based polymers containing controlled low level of functional groups, high molecular weight copolymers could be readily prepared with desired structure. The prepared copolymers can be easily modified into variable functionality, as illustrated in Scheme 3. The C=C group in [L]-LA-co- HTC can be converted into epoxy by using 3-(chloroperoxy)benzoic acid with only little molecular weight decrease (7). It is anticipated that epoxy group can be further functionalized into diols, -CH(OH)CH(NHR)-, and -CH(OH)CH(OR)- under mild reaction conditions. Furthermore, the epoxy containing [L]-PLA can be used as macro-initiator to prepare graft copolymers. The ketal structures of [L]-LA-co-IPXTC or [ L ] - L A - C O - D M T O S copolymers can be removed by using CF COOH with slight molecular weight decrease. The vicinal-diol groups in PLAs provide a variety of opportunities for their use as functional biomedical materials (5,5). 2


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Structure and Properties of Functional [L]-PolyIactides Even though the monomer reactivity ratios of cyclic carbonate monomers were much lower than that of [L]-lactide, *H-NMR and C-NMR results showed that the prepared copolymers had randomness coefficient R values in the range of 0.65 to 0.87 where R is 0 for a diblock copolymer and 1 for a statistically random copolymer (9). Such copolymer structures may be explained by i) cyclic carbonate polymerization occurs by intrachain insertion reaction or intermolecular exchange reactions, and ii) chain transfer reactions occur at high conversion. For [L]-LA-coHTC and [ L ] - L A - C O - I P X T C copolymers, the average lengths of HTC and I P X T C repeat units were 1.0-1.7 and 1.04-1.13 respectively (5,7). The random distribution of functional groups on [L]-PLA backbone provides desired structure for their applications in biomedical areas. The thermal properties of the prepared copolymers have been extensively characterized by differential scanning calorimetry (DSC). The presence of carbonate units in copolymer disrupted ordering of the [L]-PLA crystalline phase. Decreased melting transition temperature (T ) and enthalpy (AH ) were found for the copolymers relative to pure [L]-PLA. For the copolymers containing high percentage carbonate units, totally amorphous phases were observed. Thus, one outcome of introducing cyclic carbonate units into [L]-PLA is a method to regulate the melting temperature and crystallinity of [L]-PLA based materials and to improve their processability. Depending on the structure of carbonate, the glass transition temperature (Tg) can be varied in a wide range. For example, the T 's of [L]-LA-coHTC and [L]-LA-co-IPXTC were in the range of 33~60°C (7) and 60~128°C (3,4,10) respectively. The deprotected [L]-LA-co-IPXTC copolymers showed very similar thermal property compared to their corresponding original copolymers. 13

C

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g

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Potential Applications This work has explored new routes to prepare high molecular weight functional PLAs. These pendant functional groups will facilitate covalent prodrug attachment and a variety of other potential applications. For example, the presence of hydroxyl groups in vicinal positions of the deprotected repeating units imparts unique properties to the prepared materials that allows one to establish strong hydrogen bonding and non-bonding interactions with organic and inorganic species (5). The epoxy structure in the polymer can be readily converted into other functionality, such as di-hydroxyl, alkoxyl-hydroxyl, amine-hydroxyl, etc. This will expand the availability of novel [L]-PLA with pendant functional groups. Therefore, these high molecular weight functional [L]-PLAs will have many valuable applications in biomedical field. The examples include i) biocompatible matrix materials which provide available sites for modifying their surfaces with biological active moieties for tissue engineering; ii) implantable biomaterials; and iii) drug delivery systems. In addition, the hydroxyl- or epoxy- containing PLAs will provide handles to form macro-initiator for grafting copolymerization. One application of these graft copolymers will be for the design of improved interfacial agents for biodegradable blends.

References 1. 2. 3. 4. 5.

Chen, X.; McCarthy, S. P.; Gross, R. A. Macromolecules 1997, 30, 3470. Chen, X.; McCarthy, S. P.; Gross, R. A. J. Appl. Polym. Sci. 1998, 67, 547. Chen, X.; Gross, R. A. Macromolecules 1999, 32, 308. Shen, Y.; Chen, X.; Gross, R. A. Macromolecules 1999, 32, in press. Chiellini, E.; Bemporad, L; Solaro, R. J. Bioactive and Biocompatible Polymers 1994, 9, 152. 6. Acemoglu, M . ; Bantle, S.; Mindt, T.; Nimmerfall, F. Macromolecules 1995, 28, 3030. 7. Chen, X.; McCarthy, S. P.; Gross, R. A. Macromolecules 1998, 31, 662. 8. Shen, Y.; Chen, X.; Gross, R. A. Manuscript in preparation. 9. Kasperczyk, J.; Bero, M . Makromol. Chem. 1993, 194, 913. 10. Shen, Y.; Chen, X.; Gross, R. A. submitted to Macromolecules.


High-Molecular-Weight [L]-Polylactides Containing Pendant

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