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Polylactones. 59. Biodegradable Networks via Ring-Expansion Polymerization of Lactones and Lactides with a Spirocyclic Tin Initiator ¨ rn Fechner Hans R. Kricheldorf* and Bjo Institut fu¨r Technische und Makromolekulare Chemie, Bundesstrasse 45, D-20146 Hamburg, Germany Received January 15, 2002; Revised Manuscript Received April 23, 2002
Spirocyclic tin initiators were prepared by condensation of commercial hydroxyethylated pentaerythritol with Bu2Sn(OMe)2. These tin-containing spirocycles served as initiators for the ring-expansion polymerization of -caprolactone, β-D,L-butyrolactone or D,L-lactide. The in situ polycondensation of these expanded spirocycles with terephthaloyl chloride or sebacoyl chloride yielded the desired biodegradable networks with elimination of the Bu2Sn group. The segment length (pore size) could be controlled via the monomerinitiator ratio (M/I) of the ring-expansion polymerization. Biodegradable networks were also obtained when Sn-containing spirocyclic polylactones were polycondensed with diphenyl dichlorosilane, benzene phosphonic dichloride, and phenyl phosphoric dichloride. Introduction Biodegradable networks derived from lactones or lactides may be of interest as components of drug delivery devices, because the release profile may be quite different from that of devices based on linear polylactones or polylactides. For any application a good control of the segment lengths, and thus of the average pore size is advantageous, and a simple synthetic procedure allowing for a broad and systematic variation of these structural parameters is desirable. Recently we have published1,2 two “one-pot procedures” based on the ring-expansion polymerization of D,L-lactide or lactones with cyclic tin-alkoxides as initiators. Other synthetic strategies typically involving a two-step procedure (preparation of linear chain segments and cross-linking in separate steps) were reported by other authors.3-12 In the present work, we will describe a third synthetic approach based on ringexpansion polymerizations involving spirocyclic tin initiators. This work serves two purposes. First, it describes a new and simple approach to the synthesis of biodegradable gels. The second aspect is the demonstration that spirocycles of different structure are thermodynamically more stable than the corresponding networks but may be transformed into networks by kinetically controlled polycondensation steps. Experimental Section Materials. The hydroxyethylated pentaerythritols were purchased from Aldrich Co. (Milwaukee, WI) and dried over P4O10 in vacuo. Bu2Sn(OMe)2, β-D,L-butyrolactone, -caprolactone, terephthaloyl chloride, and sebacoyl chloride were all purchased from Aldrich. The lactones were distilled over freshly powdered calciumhydride prior to use. Racemic D,D,L,L-lactide (usually abbreviated D,L-lactide) was a gift of Boehringer GmbH (Ingelheim, Germany) and was recrystallized from dry ethyl acetate/ligroin. Diphenyl dichlo-
rosilane, benzene phosphonic dichloride and phenyl phosphoric dichloride were purchased from Aldrich Co. and used after distillation. Syntheses of the Spirocyclic Tin Initiators 2a and 2b. Dry hydroxylated pentaerythritol 1a or 1b, respectively (0.025 mol), was mixed with dry toluene (50 mL) with rapid stirring in a three-necked flask equipped with a dropping funnel containing dry toluene. Bu2Sn(OMe)2 (0.05 mol) was added at once, and the oil bath temperature was raised to 140 °C. Dry toluene (approximately 600 mL) was added constantly during the azeotropic distillation of the liberated methanol. The quantitative conversion and removal of methanol was checked by 1H NMR spectroscopy. Finally, the remaining toluene was removed and the product dried in vacuo. The remaining spiroinitiator was diluted with dry chlorobenzene to obtain a 0.2 M solution. 1a: Anal. Calcd for C27H56O7Sn2 (731.8): C, 44.31; H, 7.71. Found: C, 43.94; H, 7.76. 1H NMR (CDCl3/TMS): δ ) 0.93 (12 H, t) 1.1-1.5 (16 H, m), 1.5-1.9 (8 H, m) 3.14.15 (20 H, m). 2a: Anal. Calcd for C51H104O19Sn2 (1258.8): C, 48.66; H, 8.33. Found: C, 48.56; H, 8.24. 1H NMR (CDCl3/TMS): δ ) 0.93 (12 H, t) 1.1-1.5 (16 H, m), 1.5-1.85 (8 H, m) 3.2-4.0 (68 H, m). Synthesis of Spirocycle 3. Dry γ-thiobutyrolactone (0.022 mol) was added to 2b (0.005 mol) dissolved in form of a 0.2 M solution in dry chlorobenzene under nitrogen atmosphere in a small flask with silanized glass walls (pretreatment with Me2SiCl2). The reaction vessel was then immersed into an oil bath thermostated at 100 °C. The reaction mixture was allowed to stir for 96 h at the thermostated temperature. Finally, the chlorobenzene was removed and the product mixture dried in vacuo at 80 °C. 1 H NMR(CDCl3/TMS): δ ) 0.92 (12 H, t), 1,2-1.55 (16 H, m), 1.6-1.8 (8 H, m), 1,9-2.05 (8 H, m), 2.50 (8 H, t), 2.73 (8 H, t), 3.35-3,85 (60 H, m), 4.05-4.3 (8 H, m).
10.1021/bm020011f CCC: $22.00 © 2002 American Chemical Society Published on Web 06/13/2002
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Polymerizations with Spirocyclic Tin Initiators 2a and 2b. (A) Networks Based on Polycaprolactone. Dry -caprolactone (50 mmol) was weighed into a small glass reactor with silanized glass walls (pretreatment with Me2SiCl2). The spiroinitiators 2a or 2b were injected in form of a 0.2 M solution in dry chlorobenzene. The reaction vessel was equipped with a mechanical glass stirrer, and the reaction mixture was stirred at room temperature for 10 min to achieve a homogeneous mixture. The reaction vessel was then immersed into an oil bath thermostated at 60 °C. The reaction mixture was allowed to stir for 2 h at the thermostated temperature. Afterward the cross-linker (terephthaloyl chloride, benzene phosphonic dichloride, phenyl dichlorophosphoridate, or diphenyl dichlorosilane), dissolved in 10 mL of dry toluene was added with stirring. The stirring was continued at 60 °C for another 6 h. After cooling to room temperature the reaction mixture was transferred into a Soxhlet extractor, and soluble byproducts were extracted with dry dichloromethane for 72 h. Finally, the gels were separated from dichloromethane and dried in vacuo at 40 °C. (B) Networks Based on Poly(D,L-lactide). The quantities of reactants and the procedure were identical to part A, but D,L-lactide was used as monomer and the polymerization time was extended to 6 h (at 80 °C). Sebacoyl chloride dissolved in 10 mL dry toluene was used as the cross-linker. C) Networks based on poly-D,L-butyrolactone The quantities of all reactants and the procedure were identical to (A), but β-D,L-butyrolactone was used as monomer and the polymerization time was extended to 12 h (at 80 °C). Sebacoyl chloride dissolved in 10 mL dry toluene was used as the cross-linker. Measurements. The 400 MHz 1H NMR spectra and the 100.4 MHz 13C NMR spectra were recorded with a Bruker AM 400 FT NMR spectrometer in 5 mm o.d. sample tubes. CDCl3 containing TMS served as solvent and shift reference. The DSC measurements were conducted with a Perkin-Elmer DSC-7 in aluminum pans under nitrogen. The MALDI-TOF mass spectra were recorded on a Bruker Biflex III in the reflection mode. A nitrogen laser (λ ) 337 nm) and an acceleration voltage of 20 kV were used. The irradiation targets were prepared from concentrated solutions of the substrate in dry tetrahydrofuran. Dithranol served as matrix and K-trifluoroacetate as dopant. Results and Discussion Syntheses of Spirocycles. For this study, two commercial hydroxyethylated pentaerythritols (1a and 1b) were used as starting materials. They were (poly)condensed with the double molar amount of Bu2Sn(OMe)2 in hot toluene to support an azeotropic removal of the liberated methanol. Regardless of the starting materials clear, gelfree solutions of low viscosity were obtained obviously containing the spirocycles 2a or 2b (eq 1). The quantitative conversion and removal of methanol was checked by 1H NMR spectroscopy. When the hot toluene solutions were cooled to roomtemperature waxy solids were formed, but upon heating, gelfree, clear solutions of low viscosity were again obtained. These observations are best explained by reversible associa-
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tions between O atoms (donor) and tin atoms (acceptor) which are known from numerous tin alkoxides.13 This interpretation is confirmed by the finding that the solid spirocycles (remaining after evaporation of the toluene in vacuo) were soluble at room temperature in more polar solvents (relative to toluene) such as tetrahydrofuran, dichloromethane, chloroform or chlorobenzene. Finally, it should be mentioned that the crude reaction mixture may contain smaller amounts of “dimeric spirocycles” of structure 3 and higher oligomers as components of an equilibrium. Unfortunately, the high sensitivity of the Sn-O bonds in 2a and 2b to hydrolytic or alcoholytic cleavage prevented a direct mass spectroscopic characterization of these spirocycles by “fast-atom-bombardment” or MALDI-TOF mass spectrometry. However, like other cyclic tin alkoxides the spirocycle 2b reacted with γ-thiobutyrolactone, yielding the expanded spirocycle 3. Only one γ-thiobutyrolactone was
inserted into each Sn-O bond, because for thermodynamic reasons this thiolactone does not polymerize. Sn-S bonds are more stable than the Sn-O bonds and enabled the measurements of a MALDI-TOF mass spectrum. The insertion of the γ-thiobutyrolactone was monitored by 1H NMR and 13C NMR spectra which display characteristic changes of the chemical shifts as discussed recently14 for the insertion of γ-thiobutyrolactone into monocyclic tin alkoxides. The MALDI-TOF spectrum of the spirocycle 4
(Figure 1) exhibited relatively broad signals due to the overlapping of 24 isotope signals of the two Sn atoms. Resolution of most of the isotope signals was feasible at the
Biodegradable Networks
Figure 1. MALDI-TOF mass spectrum of the spirocycles 4 derived from 2b by insertion of γ-thiobutyrolactone (x ) 12 or 16 means the number of ethylene oxide units).
expense of hte signal-to-noise ratio. This mass spectrum also displayed weak mass peaks of spirocycles containing only three γ-thiobutyrolactone units and mass peaks of higher oligomers which were not analyzed in detail. Since the syntheses of the spirocycles 2a and 2b are based on an equilibration process, it is clear that these compounds are the thermodynamically favored endproducts of this (poly)condensation process. This also means that these spirocycles are thermodynamically more stable than the corresponding networks. Obviously the spirocycles are more stable due to a gain in entropy resulting from their translational motion and external rotational motion. Other examples of thermodynamically controlled formations of spirocycles will be reported elsewhere.15 Formation of Networks. By analogy to the properties of other cyclic tin alkoxides it was expected that the spirocycles 2a and 2b are reactive enough to initiate the ring-expansion polymerization of lactones and lactides. A first series of polymerizations was performed with -CL using two different monomer/initiator (M/I) ratios, namely M/I ) 20 and M/I ) 100. Time-conversion curves were measured by means of 1H NMR spectroscopy for polymerizations of -caprolactone in bulk at 60 °C. A reaction time of 2 h proved to be sufficient in agreement with previous studies16 of ringexpansion polymerizations involving simple tin alkoxide cycles as initiators. Such an optimization of the reaction conditions is necessary to avoid the formation of large amounts of cyclic oligolactones by “backbiting degradation”.The resulting spirocyclic polylactones 5a-5d were in situ reacted with terephthaloyl chloride at 60 °C, and within 5-10 min, cross-linking occurred to such an extent that the stirrer stopped. None the less, this cross-linking polycondensation was continued for 6 h. Afterward the resulting gels 6a-6d were extracted with dry CH2Cl2 and characterized. To find out if other reactive dichlorides can be used for the polycondensation/cross-linking process, three more experiments were conducted using 2b as initiator. In one
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experiment, diphenyl dichlorosilane was added and crosslinking was observed after approximately 30 min. However, when benzene phosphonic dichloride or phenyl phosphoric dichloride was added, rapid cross-linking occurred and the networks 6e and 6f were formed within 2 min. In other words, the reactivity of the cross-linking agents decreased in the following order: C6H5POCl2 ≈ C6H5OPOCl2 > ClOC-C6H4-COCl > (C6H5)2SiCl2 Further syntheses were conducted with D,L-lactide as monomer and 2a as initiator. The M/I ratios of 20 or 100 were used again, and sebacoyl chloride served as the cross-linking agent. In this way, the networks 7a and 7b were obtained.
Finally, β-D,L-butyrolactone was used as monomer in combination with 2b as initiator and M/I ratios of 20 and 100. However, in the case of D,L-lactide and β-D,L-butyrolactone, the times of the polymerization processes were increased to 6 and 12 h, respectively, because it was known from previous ring-expansion polymerization studies17 that these monomers are less reactive and polymerize more slowly than -CL. Sebacoyl chloride was also used for the crosslinking of the spirocyclic poly(butyrolactone)s, and the networks 8a and 8b were isolated. The reaction conditions and the yields of the extracted gels are summarized in Table 1. Characterization. All networks swelled well in CDCl3, and thus, it was feasible to record 1H NMR spectra with a
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Table 1. Syntheses of Networks from Spiroinitiators 2a or 2b and Various Lactones polymer no.
initiator (I)
monomer (M)
M/Ib (feed)
cross- linkera (Cr)
M/Crc (feed)
temp (°C)
time of polymerization/ acylation (h)
M/Crd (1H NMR)
yielde (%)
6a 6b 6c 6d 6e 6f 6g 7a 7b 8a 8b
2a 2a 2b 2b 2b 2b 2b 2a 2a 2b 2b
-CL -CL -CL -CL -CL -CL -CL D,L-lactide D,L-lactide β-D,L-butyrolactone β-D,L-butyrolactone
20 100 20 100 20 20 20 20 100 20 100
U U U U V W X Y Y Y Y
10 50 10 50 10 10 10 10 50 10 50
60 60 60 60 60 60 60 80 80 80 80
2/6 2/6 2/6 2/6 2/6 2/6 2/6 6/6 6/6 12/6 12/6
12 46 10 54 12 10 12 13 53 7 23
73 68 79 84 81 75 86 86 77 52 45
a U ) ClCO-C H -COCl; V ) C H -POCl ; W ) C H O-POCl ; X ) (C H )(SiCl ) ; Y ) ClCO-(CH ) -COCl. b Molar monomer/initiator ratio used 6 4 6 5 2 6 5 2 6 5 2 2 2 8 for the ring-expansion polymerization. c Molar monomer/cross-linker ratio. d Molar monomer/cross-linker ratio found in the isolated gels. e After 72 h of extraction with refluxing CH2Cl2.
rather narrow line width (Figures 3 and 4). For all experiments the structure of the cross-linking agent was selected, so that its protons were clearly detectable in the 1H NMR spectra of the gels. Hence, the quantification of signal intensities allowed for a determination of the monomer/crosslinker ratio (M/Cr in Table 1). These M/Cr values were in satisfactory agreement with the feed ratios when -CL or D,L-lactide were used as monomers, but they were far too low for gels derived from β-D,L-butyrolactone. Obviously the polymerizations of β-D,L-butyrolactone initiated by the spirocycle 2b were slower than expected from previous experiments with other cyclic initiators.16 The DSC measurements revealed the following trends (Table 2): In the case of 6a-d, the longer poly(-CL) chain segments had the consequence of lower glass-transition temperatures (Tgs) and higher melting temperatures (Tms) along with higher melting enthalpies (∆Hm). These trends are quite logical and were also found for other gels based on poly(-CL) segments.2 However, in the case of networks derived from D,L-lactide or β-D,L-butyrolactone, lower Tgs were found for the samples having a higher density of crosslinks. A higher density of cross-links also means shorter polylactone segments, and due to the use of hydroxyethylated spiroinitiators, the ratio of oligo(ethylene oxide) to polylactone blocks also increases with shorter polylactone blocks. Furthermore, poly(D,L-lactide) and poly(β-D,L-butyrolactone) possess higher Tgs than poly(ethylene oxide). Therefore, the most likely explanation of the inverse Tg/lactone block trends
Figure 2. Time-conversion curves recorded by 1H NMR spectroscopy for 2b-initiated polymerizations of -caprolactone in bulk at 60 °C: (A) M/I ) 20; (B) M/I ) 100.
Figure 3. 400 MHz 1H NMR spectrum of a poly(-caprolactone) network cross-linked with terephthaloyl chloride (5c, swollen in CDCl3).
is the assumption that the higher oligo(ethylene oxide)/ oligolactone ratios are responsible for the lower Tgs. Finally, swelling factors were determined in three different solvents (SF in Table 2). The following trends were found. First, for all pairs of gels having short and long linear segments the higher volume expansion upon swelling was observed for the gels having longer linear segments. Second, the solution quality of the solvents increased in the order acetone < toluene < dichloromethane when gels derived
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variation of only one unit in the linear segments has such a strong influence on the swelling properties of the gels. Conclusion
Figure 4. 400 MHz 1H NMR spectrum of a poly(D,L-lactide) network cross-linked with sebacoyl chloride (6a, swollen in CDCl3). Table 2. Thermal Properties and Swelling Factors (SF) of the Networks Prepared via the Spiroinitiators 2a or 2b polymer no.
Tga (°C)
Tma (°C)
∆Hma (J/g)
SF in toluene
SF in CH2Cl2
SF in acetone
6a 6b 6c 6d 6e 6f 6g 7a 7b 8a 8b
-44.7 -58.9 -47.8 -56.6 -47.0 -49.9 -53.9 33.3 40.3 -23.0 -1.0
44.6 56.3 40.7 52.7 43.0 40.4 36.0
40.4 57.6 32.5 54.3 34.3 35.4 37.2
8.5 14.0 9.0 19.0 10.0 9.0 18.5 9.0 17.5 9.0 12.0
12.5 22.5 16.0 31.5 23.5 18.0 34.0 14.0 26.0 18.5 30.5
5.5 9.0 8.0 10.0 9.0 12.0 16.5 11.0 15.0 12.5 21.0
a
From DSC measurements with a heating rate of 10 °C/min.
from -CL or D,L-lactide were examined. In the case of β-D,Lbutyrolactone, CH2Cl2 proved to be again the best solvent, but here acetone was slightly better than toluene. Third, it is conspicuous that the swelling factor is particularly high for gels cross-linked with phenyl-substituted heteroatoms (6e, 6f, and 6g). Obviously, the steric demands of the phenyl groups reduce the electronic interaction between neighboring chains and favor intensive solvation. Regardless of the explanation, it is an interesting effect that the structural
The results obtained in this work demonstrate that soluble spiroinitiators can be prepared from hydroxyethylated pentaerythritol and Bu2Sn(OMe)2. These spirocycles are reactive initiators for ring-expansion polymerizations of lactides and lactones. The in situ polycondensation of the resulting spirocyclic polylactones with dicarboxylic dichlorides, diphenyl dichlorosilane or phosphonyl dichlorides yields biodegradable gels in a “one-pot procedure”. Additional advantages of this approach are: first, that the segment lengths can be varied via the M/I ratio of the ring-expansion polymerization, and second, that functional groups (e.g., double or triple bonds) may be incorporated into the chain segments via the cross-linking agent. References and Notes (1) Kricheldorf, H. R.; Stricker, A. Macromolecules 2000, 33, 696. (2) Kricheldorf, H. R.; Fechner, B. Macromolecules 2001, 34, 3517. (3) Storey, R. F.; Wiggins J. S.; Puckett, A. D. J. Polym. Sci., Part A: Polym. Chem. 1994, 32, 2345. (4) Storey, R. F.; Warren, S. C.; Allision, C. J.; Puckett, A. D. Polymer 1997, 38, 6295. (5) Hubbell, J. A.; Han, D. K. Macromolecules 1997, 30, 6077. (6) Ansetz, K.; Svaldi, D. C.; Laurencin, C. T.; Langer, R. ACS Symp. Ser. 1997, 673, 189. (7) Matsuda, T.; Mizutani, M.; Arnold, S. C. Macromolecules 2000, 33, 795. (8) Park, T. G.; Cohen, S.; Langer, R. Macromolecules 1992, 26, 116. (9) Sawhney, A. S.; Pathak, C. P.; Hubbel, J. A. Macromolecules 1993, 26, 581. (10) Sawhney, A. S.; Pathak, C. P.; Ranburg, J. J.; Punn, R. C.; Hubbel, J. A. Biomed. Mater. Res. 1994, 28, 831. (11) Hubbel, J. A.; Pathak, C. P.; Sawhney, A. S. Polym. Prepr. (Am. Chem. Soc., Polym. DiV.) 1993, 34, 846. (12) Palmgren, R.; Karlsson, S.; Albertsson, A.-C. J. Polym. Sci., Part A, Polym. Chem. 1997, 35, 1635. (13) Davies, A. G. Organotin Chemistry; VCH Publishers: Weinheim, Germany, and New York, 1997; Chapter 12. (14) Kricheldorf, H. R.; Lee, S.-R.; Schittenhelm, N. Macromol. Chem. Phys. 1998, 199, 273. (15) Kricheldorf, H. R.; Rost, S. Macromolecules submitted. (16) Kricheldorf, H. R.; Stricker, A. Macromol. Chem. Phys. 2001, 202, 2525. (17) Kricheldorf, H. R.; Lee, S.-R. Macromolecules 1995, 28, 6718.
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