RAPID COMMUNICATION. Synthesis of Disyndiotactic Polylactide INTRODUCTION EXPERIMENTAL

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1 RAPID COMMUNICATION Synthesis of Disyndiotactic Polylactide M. BERO, P. DOBRZYŃSKI, J. KASPERCZYK Centre of Polymer Chemistry, Polish Academy of Sciences, Zabrze, Poland, ul. M. Curie Sklodowskiej 34 Received 20 April 1999; accepted 2 August 1999 D,L-lactide; lithium tert-butoxide; disyndiotactic polylactide; transesteri- Keywords: fication INTRODUCTION Correspondence to: M. Bero ( polymer@uranos.cto. us.edu.pl) Journal of Polymer Science: Part A: Polymer Chemistry, Vol. 37, (1999) 1999 John Wiley & Sons, Inc. CCC X/99/ Polylactide is a well-known material used in medicine for biodegradable drug-delivery systems or resorbable medical implants. 1 3 The monomer, racemic D,L-lactide, consists of an equimolar mixture of stereoisomers with LL and DD configurations. When neither of the two structures is preferred during polymerization, their addition to the growing chain occurs randomly and is described by pair-addition Bernoullian statistics. 3 The resulting chain microstructure also is defined as predominantly isotactic. 4 Nonetheless, the polymerization of racemic D,L-lactide carried out in the presence of lithium tert-butoxide was demonstrated by us in a previous report 5 to be stereoselective, leading to the formation of a chain microstructure enriched with disyndiotactic segments. This resulted from the preference of alternating addition of LL and DD monomers to the growing polymer chain. Furthermore, in other reports, 6,7 an enhanced contribution of disyndiotactic structures was observed during polymerization of D,L-lactide in the presence of tin and zinc compounds. However, a possibility of preparing polylactide with a high degree (i.e., 90%) of disyndiotacticity has not been documented definitely. The moderate chain regularity reported elsewhere 5 7 may have resulted from the properties of the initiator, transesterification, or both. For example, during the polymerization of D,Llactide in the presence of Bu 2 Mg, the observed very low stereoselectivity (L i 3.3) was not accompanied by intermolecular transesterification. 8 In this study, when lithium tert-butoxide was used as the initiator, the opposite phenomena occurred. The polymerization process was characterized both by high stereoselectivity and an increased extent of intermolecular transesterification. The problem of the assignment of tetrads to respective signals in the methine carbon region of the carbon nuclear magnetic resonance ( 13 C NMR) spectrum was solved by us in a previous article. 9 Here we report on the polymerization conditions under which almost completely disyndiotactic polylactide was obtained. Particular attention was paid to the influence of temperature and time of the reaction on the polymer chain microstructure. EXPERIMENTAL Materials The monomer racemic D,L-lactide (Purac) was recrystallized several times from ethyl acetate. The solvent tetrahydrofuran (THF; Aldrich) was dried over a sodium/potassium alloy and kept under a dry argon atmosphere. Commercial grade lithium tert-butoxide (Aldrich) was used as the initiator. Polymerization Procedure The polymerization of racemic D,L-lactide was carried out in a closed glass reactor equipped with a 4038

2 RAPID COMMUNICATION 4039 Table I. Results of the Polymerization of Racemic D,L-Lactide Tetrad Intensities (%) Number Temperature ( C) Time (min) Yield (%) M n ( 10 3 ) MWD ssi sss isi iss sis, iis, siii, iii L i p 2 ( C) T g Disyndiostructure Bernoulian statistic M n number average molecular weight; MWD molecular weight distribution; p 2 coefficient of stereo selectivity; L i average length of isotactic blocks (in lactyl units). The polymerization in THF; the concentration of the monomer was mol/dm 3. The molar ratio of the initiator to the monomer 1 : 250. magnetic stirrer and dry argon supply. A solution of initiator in hexane was introduced by a syringe into a 1 M solution of racemic D,L-lactide in THF. The polymerization was stopped by adding methyl iodide to the reaction mixture. The reactor content then was poured into cold methanol to precipitate the polymer. The precipitated polymer was washed with methanol and dried under vacuum at 50 C. Measurements The molecular weights and polydispersity indices were determined by a liquid chromatography method using a Waters ALC/GPC 3M apparatus (THF as the eluent, polystyrene standards) and by gel permeation chromatography on a Spectra Physics SP 8800 chromatograph (THF as the eluent; flow rate 1 ml/min 1 ; Styragel columns, 104, 103, and 500 Å Shoedex SE 61 detector). The proton nuclear magnetic resonance ( 1 H NMR; 300 MHz) and 13 C NMR (75 MHz) spectra were recorded on a Varian Unity Inova spectrometer in 5-mm sample tubes using chloroform-d as a solvent and TMS as an internal standard. Acquisition time: 1.8 s ( 1 H NMR), 3.7 s ( 13 C NMR). Pulse width: 9 s. Pulse delay: 3 s. Digital resolution: 64 K. Spectral width: 4000 Hz ( 1 H NMR), 16,500 Hz ( 13 C NMR). Proton spectra: 64 scans. Carbon spectra: 10,000 scans. RESULTS AND DISCUSSION The results of the polymerization of racemic D,Llactide are provided in Table I. The data indicate that the polymerization proceeded very rapidly, even at 20 C. The molecular weights of the obtained polylactides were higher than assumed and increased distinctly with the conversion degree. Polydispersity of the polymers was moderate and likewise increased to some extent when the conversion increased. The microstructure of the polymers was determined by 13 C NMR spectroscopy. The microstructure of the polymers obtained in the initial step of the reaction (regardless of the temperature used) differed substantially from that of the polymer characterized by pairaddition Bernoullian statistics; that is, it was predominantly isotactic [Table I, pos. 1, 4, 6; Fig. 1(a,b)]. The microstructure of the examined polymers corresponded practically to completely disyndiotactic polymer (e.g., Table I, pos. 1). In contrast to the NMR spectrum of the predominantly isotactic polymer, the carbonyl carbon signals due to hexads containing ii sequences practically disappeared; this was accompanied by a dramatic increase in the intensities of the signals arising from isisi and sisis hexads [Fig. 1(a)]. The methine carbon region exhibited a strong increase in the

3 Figure 1. (a) 75 MHz 13 C spectra of polylactide (carbonyl region): (A) Bernoullian statistics polylactide (predominately isotactic) and (B) disyndiotactic polylactide (p , Table I, pos.1). (b) 75 MHz 13 C spectra of polylactide (methine region): (A) Bernoullian statistics polylactide (predominately isotactic) and (B) disyndiotactic polylactide (p , Table I, pos.1).

4 RAPID COMMUNICATION 4041 amount of isi tetrad, exceeding 45% [Fig. 1(b); Table I, pos. 1, 4, 6). In an earlier study, 5 we introduced p 2 as a coefficient of stereoselectivity, describing a contribution of disyndiotactic structures in the chain. When no ss sequences are present in the polymer chain, this coefficient may be defined as p 2 (isi)/50 2/L i Figure MHz 13 C spectra of polylactide (methine region): (A) Table I, pos.1, (B) Table I, pos.2, and (C) Table I, pos.3. where L i is the average length of the isotactic microblocks. The obtained values of the coefficient of stereoselectivity were found to be within a range of 0.90 to 0.94, depending on the temperature in which the reaction was carried out, with lower values of p 2 corresponding to higher temperatures. In time, regardless of the reaction temperature, changes in the microstructure as a result of intermolecular transesterification processes were observed. For yields greater than 35 to 45%, the alterations in the microstructure of the chain are easily observed in the methine carbon range of the 13 C NMR spectra (Fig. 2; Table I). The spectra are characterized by the appearance of the signals ascribed to ssi, sss and iss tetrads resulting from the bond cleavage in the lactidyl segments of the chain of DD and LL type, followed by the formation of DLD and LDL sequences via transesterification. 3 Nevertheless, the disyndiotactic character of the chain microstructure partially was retained (Table I). The contribution of isi tetrad remained higher than that observed in Bernoullian statistics and may be defined as partially disyndiotactic. The results of this study clearly demonstrate that in the initial step of D,L-lactide polymerization initiated by lithium tert-butoxide, it is possible to form disyndiotactic polymer with a p 2 value close to 1. During the further course of the reaction, the transesterification process tended to reduce the regular microstructure of the chain. This fact accounts for the relatively low degree of the chain regularity, which we discussed in another study. 5 The data presented in Table I (pos. 1, 4, 6) show the glass-transition temperature of the disyndiotactic polymer to be lower than that of the polymer described by Bernoullian statistics. We think this is related closely to the presence of isotactic segments in the latter polymer. This study has been supported by the research program (Project 3T0 9B 09112) of the Committee of Scientific Research in Poland.

5 4042 J. POLYM. SCI. PART A: POLYM. CHEM.: VOL. 37 (1999) REFERENCES AND NOTES 1. Spenlehauer, G.; Veillard, M.; Benoit, J. P. J Pharm Sci 1996, 75(8), Kricheldorf, H.; Kreiser-Saunders, I.; Jurgens, C.; Walter, D. J Macromol Symp 1996, 103, Chabot, F.; Vert, M. Polymer 1983, 24, Bero, M.; Kasperczyk, J.; Jedliñski, Z. Makromol Chem 1990, 191, Kasperczyk, J. Macromolecules 1995, 28, Schwach, G.; Coudane, J.; Engel, R.; Vert, M. J Polym Sci 1997, 35, Thakur, K.; Kean, R.; Hall, E.; Kolstad, J.; Lindgren, T.; Doscotcg, M.; Siepman, J.; Munson, E. Macromolecules 1997, 30, Kricheldorf, H. R.; Lee, S.-R. Polymer 1995, 36, Kasperczyk, J. Polymer 1999, 40, 5455.