Novel Biodegradable Aliphatic Poly(butylene succinate-co

Biomacromolecules 2004, 5, 209-218

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Novel Biodegradable Aliphatic Poly(butylene succinate-co-cyclic carbonate)s with Functionalizable Carbonate Building Blocks. 1. Chemical Synthesis and Their Structural and Physical Characterization Jing Yang, Qinghui Hao, Xiaoyun Liu, Chaoyi Ba, and Amin Cao* Polymer Materials Laboratory, Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China Received August 28, 2003; Revised Manuscript Received October 19, 2003

This study presents chemical synthesis, structural, and physical characterization of novel biodegradable aliphatic poly(butylene succinate-co-cyclic carbonate)s P(BS-co-CC) bearing functionalizable carbonate building blocks. First, five kinds of six-membered cyclic carbonate monomers, namely, trimethylene carbonate (TMC), 1-methyl-1,3-trimethylene carbonate (MTMC), 2,2-dimethyl-1,3-trimethylene carbonate (DMTMC), 5-benzyloxytrimethylene carbonate (BTMC), and 5-ethyl-5-benzyloxymethyl trimethylene carbonate (EBTMC), were well prepared from ethyl chloroformate and corresponding diols at 0 °C in THF solution with our modified synthetic strategies. Then, a series of new P(BS-co-CC)s were synthesized at 210 °C through a simple combination of polycondensation and ring-opening-polymerization (ROP) of hydroxyl capped PBS macromers and the prepared carbonate monomers, and titanium tetraisopropoxide Ti(i-OPr)4 was used as a more suitable catalyst of 5 candidate catalysts which could concurrently catalyze polycondensation and ROP. By means of NMR, GPC, FTIR, and thermal analytical instruments, macromolecular structures and physical properties have been characterized for these aliphatic poly(ester carbonate)s. The experimental results indicated that novel biodegradable P(BS-co-CC)s were successfully synthesized with number average molecular weight Mn ranging from 24.3 to 99.6 KDa and various CC molar contents without any detectable decarboxylation and that the more bulky side group was attached to a cyclic carbonate monomer, the lower reactivity for its copolymerization would be observed. The occurrences of 13C NMR signal splitting of succinyl carbonyl attributed to the BS building blocks could be proposed due to the randomized sequences of BS and CC building blocks. FTIR characterization indicated two distinct absorption bands at 1716 and 1733∼1735 cm-1, respectively, stemming from carbonyl stretching modes for corresponding BS and CC units. With regard to their thermal properties, it is seen that the synthesized P(BS-co-CC)s exhibited thermal degradation temperatures 10∼20 °C higher than that of PBS. On the basis of the synthesized P(BS-co-BTMC)s, new aliphatic poly(butylene succinate-co-5-hydroxy trimethylene carbonate)s were further synthesized, bearing hydrophilic hydroxyl pendant functional groups through an optimized Pd/C catalyzed hydrogenation. These semicrystalline new biodegradable aliphatic copolymers with tunable physical properties and functionalizable carbonate building blocks might be expected as potential new biomaterials. Introduction Steadily increasing attention has been paid to biodegradable polymers in the past few decades.1-6 Efforts were motivated not only by practical needs for specific singleuse biomedical materials but also by seeking for biodegradable substitutes of conventional thermoplastics, as an active response to the increasing plastic waste problem. Among the biodegradable polymers, aliphatic polyesters have leading position for favorable features that their hydrolytic and/or enzymatic degradation products can be naturally metabolized into nontoxic substances. Up to date, as a more accessible synthetic route, polycondensation of a dicarboxylic acid and a diol as well as * To whom correspondence should be addressed. Phone: +86-21-64167152. Fax: +86-21-6416-6128. E-mail: [email protected].

hydroxyl carboxylic acids has been found to be capable of producing high molecular weight aliphatic polyesters such as poly(ethylene succinate) (PES),7,8 poly(butylene succinate) (PBS),9-11 poly(butylene adipate) (PBA)8, poly(lactic acid) (PLA),12 and so forth. Furthermore, to satisfy the demands in different application cases, a number of aliphatic copolyesters have also been developed, bearing readily tunable physical properties and biodegradabilities.7,13 Alternatively, ring opening polymerizations (ROP) of β,γ,ω-lactone, lactide, carbonate, as well as some reactive cyclic monomers provided another important feasible way to synthesize aliphatic polyesters and poly(carbonate)s such as poly(caprolactone) (PCL), poly(lactide)s (PLA), poly(β/γ-butyrolactone) (PBL), poly(trimethylene carbonate) (PTMC),14-17 etc.

10.1021/bm0343242 CCC: $27.50 © 2004 American Chemical Society Published on Web 11/21/2003

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As for PBS, it has been commercialized as one of the most accessible biodegradable green plastics synthesized through an AA/BB type of polycondensation from corresponding succinic acid and 1,4-butanediol.18,19 Recently, Hong et al.20 reported preparation of biodegradable polymer microspheres from the prepared PBS/PLLA blend and preliminary studies on their drug analogue releasing behavior. From the biocompatible building blocks of glycerol and lactic acid, Ray et al.21 synthesized novel biodegradable poly(carbonate ester)s bearing secondary hydroxyl pendant groups and further successfully prepared a polymer nonsteroidal antiinflamatory drug. On account of the linear hydrophobic chain structures of PBS and its aliphatic copolyesters, the lack of chain hydrophilicity and functionalizable site actually limited their further extended possible applications as new biomaterials. With regard to biodegradable aliphatic poly(carbonate)s PC, they have been extensively studied for potential applications as biomedical and environmentally benign materials.22-24 Aliphatic poly(carbonate)s derived from ring opening polymerization of corresponding six-membered cyclic monomers have been found to be interesting materials for their favorable biocompatibilities, low cytotoxicities, and well tunable biodegradabilities, in particular, studies have been focused on for potential biomedical and pharmaceutical applications.17,25-27 Most of the aliphatic poly(carbonate)s appeared as synthetic rubbers or semicrystalline polymers with low crystallinities in a relaxed solid state, such as poly(ethylene carbonate) (PEC), poly(1,2-propylene carbonate) (PPC), poly(trimethylene carbonate) (PTMC), and poly[2,2(2-pentene-1,5-diyl) trimethylene carbonate] (PHTC),27 and that the increased crystallinities were reported to be detected for the these PC samples in the stretched state.17,27-28 For an easy modification of PC, ring opening copolymerization of six-membered cyclic carbonate monomers were reported with other kinds of cyclic monomers such as glycolide,29 lactide,30 -caprolactone,31 1,4-dixane-2-one,32 cyclic phosphates,33 as well as the other cyclic carbonates.34 In particular, biodegradable aliphatic poly(carbonate)s bearing various pendant groups are of great interest and importance for the presence of functionalizable sites.35-37 In a previous study,13 to tune the hydrophilic/hydrophobic balance and attach functionalizable sites for the PBS based biodegradable copolyesters, we reported the novel optically active biodegradable aliphatic copolyester poly(butylene succinate-co -butylene malate)s bearing pendant secondary hydroxyl groups. To take the advantages of aliphatic polyester PBS and poly(carbonate)s, it seems very interesting to prepare new poly(butylene succinate-co-cyclic carbonate) bearing functionalizable pendant groups such as hydroxyl, amino groups, etc. for three main reasons: (i) Physical and biomedical properties of P(BS-co-CC) can be readily regulated via copolymerization, and the prepared copolymers can share the merits of both BS and CC biodegradable building blocks. (ii) The pendant functionalizable sites will provide more possibilities for polymer post-modifications and further extend more biomedical and pharmaceutical applications. (iii) The newly attached functional side groups such as -OH or -NH2 should contribute to the interesting macromolecular

Yang et al.

self-assembly behavior via inter- and/or intramolecular interactions. However, to our knowledge, there were few related works reported. This paper will present our recent studies on chemical syntheses and characterization of novel biodegradable poly(butylene succinate-co-cyclic carbonates) P(BS-co-CC)s bearing various pendant functional groups. First, five kinds of six-membered cyclic functional carbonate monomers were synthesized, bearing different molecular structures with our modified synthetic strategies. Subsequently, a series of P(BSco-CC)s were synthesized through a simple combination of polycondensation and ring opening polymerization with well optimized catalyst. By means of NMR, FTIR, GPC, and thermal analytical instruments, their macromolecular structures and physical properties have been intensively characterized and discussed. Moreover, for the synthesized P(BS-coCC)s bearing benzyl pendant groups, Pd/C catalyzed benzyl deprotection reactions under H2 were conducted to provide corresponding novel linear P(BS-co-CC)s with functionalizable hydroxyl pendant groups, and their structures were simultaneously studied. Experimental Section Materials. Succinic acid (AR grade) was recrystallized twice in deionized water. 1,4-Butanediol (AR grade) was dried with calcium oxide overnight and then distilled under reduced pressure prior to use. Titanium tetraisopropoxide Ti(i-OPr)4 purchased from Acros Organics was pretreated with fractional distillation under nitrogen purge and reduced pressure. Reagents of diethyl zinc and trimethyl aluminum from Aldrich Chemical and aluminum isopropoxide from Acros Organics were used as-received. Solvents of toluene and tetrahydrofuran were dried over sodium and then distilled. In this study, all other raw materials were used aspurchased. Chemical Syntheses of 5 Six-Membered Cyclic Carbonates. For the sake of synthesizing novel biodegradable poly(butylene succinate-co-cyclic carbonate)s, 5 kinds of sixmembered cyclic carbonate monomers were first prepared with or without functional pendant groups, partially referring to the reported synthetic strategies.38-40 Synthesis of Trimethylene Carbonate Monomer (TMC). First, ethyl chloroformate (95.6 mL, 1.00 mol) and 1,3propanediol (36.3 mL, 0.50 mol) were dissolved in 500 mL of THF. Second, triethylamine (139.4 mL, 1.00 mol) was added dropwise into the stirring mixture kept under 5 °C over a 50-min period. The reaction mixture was then warmed to ambient temperature with further stirring kept overnight. After a filtration of triethylamine hydrochloride, the collected filtrate was allowed to evaporate the residual solvent. Thus, the obtained crude product was further purified by recrystallization repeated twice in THF solution under -25 °C, and white TMC crystals were finally attained with an overall yield of 35.5%, purity of 98.0% as analyzed by GC, and a melting point of 45 °C. 1 H NMR (CDCl3, δ in ppm) 4.44 (t, -OCH2-, 4H), 2.13 (m, -CH2CH2CH2-, 2H). FT-IR (in KBr) 2963 cm-1(νCHas), 2928 cm-1(νCHs), 1747 cm-1 (νCdO),1467 cm-1(νCH).

Novel Biodegradable Aliphatic P(BS-co-CC)

Synthesis of 1-Methyl-1,3-trimethylene Carbonate (MTMC). A mixture of 36.0 g (0.40 mol) of 1,3-butanediol, 52.0 g (0.44 mol) of ethyl carbonate, and 0.2 g of sodium was heated to 160 °C, and the byproduct of ethanol was removed via distillation. When the amount of alcohol was approximately collected, an equal volume of benzene was added into the reaction residue and washed with water. The reaction mixture was further dried over calcium chloride and then distilled twice under reduced pressure. As a result, a liquid product of MTMC (bp 100-105 °C/0.8 Torr) was obtained with 45.0% yield and 99.6% purity. 1 H NMR (CDCl3, δ in ppm) 4.60(m, -OCH(CH3)-, 1H), 4.40 (m, -OCH2CH2-, 2H), 2.06 (m, -CH(CH3)CH2CH2-, 2H), 1.41 (d, -CH3, 3H). FTIR (in KBr) 2985 cm-1(νCHas), 2937 cm-1(νCHs), 1782 cm-1 (νCdO), 1484 cm-1 (νCH). Synthesis of 2,2-Dimethyl-1,3-trimethylene Carbonate (2,2DMTMC). 2,2-DMTMC was synthesized in a similar way as applied for the TMC synthesis. The only difference was that 2,2-dimethyl-1,4-propanediol was utilized as compared with the TMC preparation. Finally, 2,2-DMTMC crystals were synthesized with a yield of 44.0%, a purity of 99.5% and a melting point of 52 °C. 1 H NMR (CDCl3, δ in ppm) 4.07 (s, -C(CH3)2CH2O-, 4H) 1.12(s, -CH3, 6H). FTIR(KBr) 2965 cm-1(νCHas), 2914 cm-1(νCHs), 1744 cm-1 (νCdO), 1474 cm-1 (νCH). Synthesis of 5-Benzyloxy-trimethylene Carbonate (BTMC). On account of a more complicated molecular structure of BTMC, its preparation was hereby accomplished through a following three-step synthetic strategy. First, into a mixture of glycerol (55.0 g, 0.60 mol) and benzaldehyde (50.0 g, 0.47 mol) in 80 mL of toluene was added a catalytic amount of p-toluenesulfonic acid monohydrate, and the resulted mixture was heated and refluxed with a Dean-Stark trap to separate the generated water under nitrogen purge. When the generation of water ceased (7.3 mL, 86.0%), the mixture was allowed to cool to room temperature, and solvent was further removed under reduced pressure. As a result, white solid 2-phenyl-1,3-dioxane-5-ol crystals with a melting point of 62.0 °C was obtained after a recrystallization in the ether/hexane mixed solvent. 1 H NMR(CDCl3, δ in ppm) 7.37-7.48 (m, -C6H5, 5H), 5.55 (s, -CHPh, 1H), 4.15 (m, -CH(OH)CH2O-, 4H), 3.60 (m, -CH2CH(OH)CH2-, 1H), 3.20 (br, -CH(OH)-, 1H). Second, 11.0 g (0.06 mol) of the prepared 2-phenyl-1,3dioxane-5-ol was added into a stirred suspension of NaH (2.6 g, 0.065 mol, 60% in oil) in 200 mL of THF under 0 °C. Then, the reaction mixture was warmed to room temperature and further stirred for 2 h. Moreover, 0.06 mol of benzyl bromide was added and kept stirring under ambient temperature overnight. Thereafter, the reaction mixture was evaporated to remove half amount of THF, and then 70 mL of water and 100 mL of 10 % hydrochloric acid aqueous solution were in turn added. The residual mixture was heated to reflux for 6 h, and then poured into a saturated sodium carbonate aqueous solution and extracted with ethyl acetate. Finally, the organic layers were collected and dried over anhydrous sodium sulfate and were further filtered and concentrated. The oily crude product was purified with aid of column chromatography employing hexane/ethyl acetate

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mixed solvent (V/V ) 1:4) as the eluent to obtain 2-benzyloxy-1, 3-propanediol product with a step yield of 90.0%. 1 H NMR (CDCl3, δ in ppm) 7.28-7.33 (m, -C6H5, 5H), 4.58 (d, -CH2Ph, 2H), 3.84 (m, -CH2CHCH2-, 1H), 3.68 (m, -CH2OH, 2H), 3.46 (m, -CH2OH, 2H), 3.12 (br, OH, 2H). Finally, with the prepared 2-benzyloxy-1,3-propanediol, a functional six-membered carbonate monomer BTMC was prepared via a third synthetic step similar as applied for preparation of TMC. As a result, the BTMC product with a melting point of 143 °C was synthesized with a third step yield of 58.0% and a final purity of 97.0%. 1 H NMR(CDCl3, δ in ppm) 7.31-7.38 (m, -C6H5, 5H), 4.51 (s, -OCH2Ph, 2H), 4.40-4.64 (m, -OCH2CH-, 4H), 3.88 (m, -CH2CHCH2-, 1H). FTIR (in KBr) 1499 cm-1 (νC-H), 3030 cm-1 (ν)CH), 1756 cm-1(νCdO), 1237 cm-1 (νC-O-Cas), 1054 cm-1 (νC-O-Cs). Synthesis of 5-Ethyl-5-benzyloxymethyl Trimethylene Carbonate Monomer (EBTMC). In a similar way, another functional monomer EBTMC was synthesized. As compared with the BTMC preparation, trimethylolpropane was utilized to replace the as-mentioned glycerol to synthesize a new EBTMC monomer. As a result, a liquid crude EBTMC product was further purified by a silica gel column, employing hexane/ethyl acetate mixed solvent (V/V ) 2:1) as the eluent with final product yield and purity of 77.0% and 97.0%, respectively. 1 H NMR (CDCl3, δ in ppm) 7.31-7.34 (m, -C6H5, 5H), 4.52 (s, -OCH2Ph, 2H), 4.34 (d, -CH2OCO-, 2H), 4.15 (d, -CH2OCO-, 2H), 3.43 (s, -CH2OCH2Ph, 2H), 1.54 (q, -CH2CH3, 2H), 0.88 (t, -CH2CH3, 3H). FT-IR (in KBr) 3030 cm-1(νdCH), 1761 cm-1(νCdO), 1499 cm-1(νCH), 1467 cm-1(νCH), 1238 cm-1 (νC-O-Cas), 1055 cm-1 (νC-O-Cs). Chemical Syntheses of Novel Biodegradable Poly(BSco-CC) Copolymers. For polymer synthesis, a flame-dried four-necked flask equipped with a mechanical stirrer, a Vigreaux fractionation condenser, and a gas inlet was first charged with 50.0 mmol of succinic acid and 55.0 mmol of 1,4-butanediol. Then, the flask was moved to a silicone oil bath and heated to 210 °C under nitrogen for 2.0 h to remove the esterification byproduct of water. When the water ceased to be generated, the predetermined amount of a catalyst was placed into the flask. After stirring the mixture for 1 h, a needed amount of the prepared carbonate monomer was added. The reaction was further kept for 2 h, and then the pressure was gradually decreased. The condensation copolymerization was continued at 210 °C under a final degree of vacuum less than 0.5 Torr and was finally terminated when a real-time torque of the mechanical stirrer (210 rpm, Eurostar, IKA Ltd, Germany) approximately approached a stable value. The synthesized crude polymer samples were dissolved in chloroform and then poured into an excess amount of dry cold methanol. Finally, the obtained P(BSco-CC)s were dried in a Vacuum oven to constant weight prior to physical characterization. Deprotection of the Benzyl Pendant Group. To deprotect the side benzyl groups, Pd/C (10%, 200.0 mg) catalyst was added into a polymer solution comprised of 300 mg of poly(BS-co-28.0 mol % BTMC), 15.0 mL of anhydrous

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THF, and 10.0 mL of methanol. The benzyl deprotection reaction was implemented under 5.0 MPa of H2 and 40 °C for a predetermined period. Then, the Pd/C catalyst was filtered off and washed with THF. After complete evaporation of solvent in the combined filtrate, a white benzyl deprotected product was thus finally attained. Characterization Procedures. GPC Characterization. Molecular weights of the synthesized polymer samples were measured on a Perkin-Elmer 200 series gel permeation chromatography (GPC), equipped with a refractive index detector (RI) and a network chromatography interface NCI 900. Double PLgel 5 µm mixed-D type of 300 × 7.5 mm columns (PL, England) were applied in series under 40 °C with chloroform as eluent at a flowing rate of 1.0 mL/min. Polystyrene standards (Showa Denko Ltd, Japan) with narrow molecular weight distributions were employed to make a calibration curve. Hence, molecular weights (Mw,Mn) and polydispersity indexes (Mw/Mn) were thus evaluated for the synthesized polymer samples. NMR Characterization. Measurements of NMR spectra were conducted in CDCl3 solution under ambient temperature on a Varian VXR 300 Fourier transform NMR spectrometer, operating at 300.0 and 75.5 MHz for the corresponding 1H and 13C nuclei. Tetramethylsilane (TMS) was applied as an internal chemical shift standard. Fourier Transform Infrared Spectroscopy. FTIR spectra were measured on a Nicolet AV-360 FTIR spectrometer under ambient temperature for the synthesized polymer samples. For an amorphous polymer sample, its polymer solution in chloroform was first mixed with KBr pellets, and then dried in a vacuum oven for 24 h. Then, the FTIR spectrum of the amorphous polymer was measured with a pressed KBr tablet. In addition, all FTIR spectra were averaged with 32 accumulations at a resolution of 4.0 cm-1. Gas Chromatography. Purities of the prepared functional carbonate monomers were analyzed on a Hewlett-Packard 6890 gas chromatography, which was equipped with a PEG 20M chromatographic column and an EID detector. Thermal Characterization. Thermal analyses were conducted on a Perkin-Elmer Pyris 1 differential scanning calorimeter (DSC) and a Perkin-Elmer Pyris 1 thermal gravimeter (TGA) for the prepared polymers. A total of 8.0∼10.0 mg of a synthesized polymer sample was first encapsulated in an aluminum pan and then heated to 150 °C to remove its thermal history and further kept under the room temperature for more than 3 weeks to prompt equilibrium crystallization. DSC trace was measured from 25∼150 °C at a scanning rate of 20 °C/min (the first heating run). Then the sample was kept at 150 °C for 1.0 min and continuously quenched to -80 °C at -450 °C/min. Hereafter, a second DSC scan was measured from -80 to 150 °C at a heating rate of 20 °C/min. Melting points (Tm) and the heat of fusion (∆Hm) were evaluated as the corresponding main peak top temperatures and integrals of the endothermic curve in the first DSC runs. Glass transition temperatures (Tg) were taken as the midpoint temperature of the heat capacity change that occurred in the second DSC traces. With regard to TGA analyses, 2.0∼3.0 mg of the prepared copolymer sample was scanned at 10 °C per minute from 30 to 500 °C under

Yang et al. Scheme 1

nitrogen atmosphere at a flowing rate of 45.0 mL/min. Peak top temperature (Td’s) occurring in the differentiated TGA traces (dTGA) were employed to quantitatively assess thermal degradation behavior and stabilities for the synthesized P(BS-co-CC) samples. Results and Discussion Syntheses of Six-Membered Cyclic Carbonates with Various Functional Groups. As an experimental result, synthetic yields of different cyclic carbonate monomer products 1∼5 as seen in Scheme 1 were found to range from 35.5 to 77.0%, strongly depending on their distinct structures. Product purities, melting points of the crystals, and the detailed assignments of 1H NMR resonance signals and FTIR absorption bands were described in the Experimental Section. In general, these experimental results demonstrated successful chemical constructions of 5 kinds of functional cyclic carbonate monomers, bearing respective R1, R2, and R3 pendant functional groups as observed in Scheme 1. Catalyst Dependence of Poly(butylene succinate-cocyclic carbonate) Syntheses. As for biodegradable aliphatic poly(carbonate) synthesis, a number of organometallic catalysts have already been investigated, including various aluminum alkoxides, organo tin, organo zinc compounds, etc, and some of them were revealed very effective for ring opening polymerization of the corresponding cyclic carbonates.27,36,41 On the other hand, aliphatic polyesters prepared by condensation polymerization of aliphatic diacid and diol have recently been reported to be capable of reaching high molecular weights with various organo titanium, tin, or aluminum compounds as catalysts.7,42 Here, to find an efficient catalyst which would concurrently catalyze polycondensation and ring opening polymerization of poly(butylene succinate-co-cyclic carbonate), and aliphatic poly(butylene succinate-co-trimethylene carbonate) P(BS-coTMC) with simple linear chain structure was first studied as a model copolymerization reaction to investigate the effects of catalyst. Table 1 compiles experimental results for the PBS and P(BS-co-TMC)s synthesized with 5 kinds of candidate organometallic catalysts. It can be seen that ZnEt2 catalyzed condensation polymerization led to PBS bearing a number average molecular weight of Mn up to 37.8 KDa within 9 h. However, its molecular weight distribution became very broad with a Mw/Mn value equal to 6.67. In the cases of



Table 1. Catalyst Dependence of Condensation and Ring Opening Copolymerization of Aliphatic Poly(butylene succinate-co-trimethylene carbonate) under 210 °C TMC unit/BS unit TMC/SA molecular weightd molar ratio in reaction yield feeding copolymere time (h)c (%) entry catalyst molar ratiob Mn × 10-4 Mw × 10-4 Mw/Mn 1a 2a 3a 4a 5a 6a 7a 8a 9a

Ti(i-OPr)4 ZnEt2 AlMe3 Al(i-OPr)3 SnOct2 Ti(i-OPr)4 ZnEt2 AlMe3 SnOct2

0 0 0 0 0 0.20 0.20 0.20 0.20

4.0 9.0 9.0 21.0 8.5 3.0 11.0 15.0 13.0

74 72 78 69 70 71 73 67 68

3.82 3.78 1.58 4.81 6.75 2.93 7.49 3.81 5.89

11.62 25.28 4.80 13.25 19.99 8.25 24.99 12.38 19.71

3.04 6.67 3.03 2.75 2.96 2.81 3.34 3.33 3.34

0 0 0 0 0 0.19 0.20 0.20 0.20

a All samples were synthesized with the fixed initial 1,4-butanediol (BD)/succinic acid (SA) molar ratio equal to 1.10 and catalyst/ SA molar ratio equal to 1/200. b Indicates the initial TMC/SA feeding molar ratio. c Express times for polymerization under reduced pressure. d Molecular weights were measured by GPC in chloroform solution with PS standards. e The TMC/BS unit molar ratios were estimated by 1H NMR.

organo tin and aluminum, the prepared PBS samples (entries 3-5) obviously exhibited slower polymerization rates, indicating their lower catalytic activities toward the PBS synthesis. Generally, Ti(i-OPr)4 was found to be able to catalyze PBS synthesis with Mn up to 38.2 KDa within 4.0 h (entry 1), demonstrating the highest catalytic reactivity toward the PBS polycondensation among the investigated 5 kinds of catalysts. With respect to aliphatic poly(carbonate) synthesis, Zn-, Al-, or Sn-based catalysts have already been reported for ring opening polymerization of various reactive cyclic carbonates.25 Here, further studies on the model copolymerization reaction of P(BS-co-TMC) were implemented with the aforementioned organometallic catalysts, and the results are also presented in Table 1 (entries 6-9). ZnEt2 and AlMe3 were found to be able to catalyze copolymerizations of the trimethylene carbonate monomer with hydroxyl capped PBS macromers preparatively synthesized with an excess amount of 1,4-butanediol through the AA-BB type of polycondensation, and that the TMC comonomer contents involved in the prepared poly(ester carbonate)s well agreed with their initial feeding molar ratios. In contrast, their corresponding rates of copolymerization were obviously observed to be much lower than that for the Ti(i-OPr)4 catalyst. On the basis of these results, Ti(i-OPr)4 was thus applied as a more efficient catalyst with an optimized concentration for these poly(butylene succinate-co-cyclic carbonate) syntheses. Chemical Syntheses of Novel P(BS-co-CC)s with Various Functional Pendant Groups. According to the general synthetic procedure as shown in Scheme 2, various novel biodegradable P(BS-co-CC)s were prepared, and their different pendant functional groups R1, R2, and R3 in the carbonate building blocks were illustrated in Scheme 1. Table 2 summarizes the synthetic results. It can be seen that, with the Ti(i-OPr)4 catalyst, biodegradable P(BS-co-CC)s bearing a series of carbonate comonomer units (CC) and molar contents were successfully prepared to bear molecular weights of Mn, spanning a range from 24.3 to 99.6 KDa with good yields of 62.0∼82.0%. With regard to structural characterization of the synthesized P(BS-co-CC)s, Figures 1 and 2 show typical proton NMR spectra of copolymers with distinct carbonate building blocks, and the 1H NMR resonance signals were reasonably

Scheme 2

attributed to the proton nuclei locating at different sites. Furthermore, to evaluate the carbonate comonomer molar contents in the copolymer samples, proton resonance signals coming from the methylene of succinyl (-OCCH2CH2CCO-) moieties were hereby applied to express the butylene succinate comonomer units (BS), whereas different carbonate comonomer units were respectively expressed by corresponding proton signals originating from β-methylene (-OCH2CH2CH(R)O-) for TMC and MTMC, methyl (-OCH2C(CH3)2CH2O-) for DMTMC, benzyl methylene (-OCH2Ph) for BTMC, and benzyl methylene (-CH2-OCH2-Ph) for EBTMC. In general, Table 2 also compiles the results of carbonate comonomer molar content for each prepared poly(ester carbonate) sample. It could be observed that the P(BS-co-TMC) copolymers bearing a lower TMC molar content (entries 1 and 2) exhibited TMC unit molar contents in close agreement with their feeding molar ratios. However, the larger the TMC/BS feeding molar ratio, the more detectable deviation could be revealed between the feeding TMC/BS molar ratio and the measured TMC unit

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Table 2. Chemical Syntheses of Poly(butylene succinate-co-cyclic carbonate)s Bearing Various Carbonate Building Blocks with Ti(i-OPr)4 as the Catalyst under 210 °C carbonate carbonate unit/ molecular weighte monomer/SA feeding BS unit reaction yield molar ratioc molar ratiof time (h)d (%) entry sampleb Mn × 10-4 Mw × 10-4 Mw/Mn 1a 2a 3a 4a 5a 6a 7a 8a 9a 10a 11a

P(BS-co-17.4 mol % TMC) P(BS-co-26.5 mol % TMC) P(BS-co-28.6 mol % TMC) P(BS-co-11.5 mol %MTMC) P(BS-co-16.7 mol %MTMC) P(BS-co-13.0 mol %DMTMC) P(BS-co-18.7 mol %DMTMC) P(BS-co-6.5 mol % BTMC) P(BS-co-13.0 mol % BTMC) P(BS-co-21.9 mol % BTMC) P(BS-co-7.4 mol % EBTMC)

0.20 0.35 0.50 0.20 0.35 0.20 0.35 0.10 0.20 0.35 0.10

4.0 4.0 4.0 6.0 4.0 3.0 8.0 3.0 5.0 16.0 12.0

72 69 67 78 76 82 72 79 74 62 67

4.53 6.08 6.37 3.25 9.96 4.19 6.08 5.91 5.64 6.07 2.43

11.77 20.24 22.37 12.26 26.93 19.07 28.87 22.86 25.46 22.28 8.70

2.60 3.33 3.51 3.77 2.70 4.55 4.74 3.87 4.51 3.67 3.58

0.21 0.36 0.40 0.13 0.20 0.15 0.23 0.07 0.15 0.28 0.08

a All samples were synthesized with a fixed initial 1,4-butanediol /succinic acid molar ratio equal to 1.1 and optimized catalyst/ SA molar ratio equal to 1/800. b The carbonate comonomer unit (CC) molar contents were evaluated as [CC] × 100 mol %/([CC]+[BS]) by 1H NMR where BS expresses the butylene succinate unit. c Indicates the initial carbonate monomer/SA feeding molar ratio. d Express times for polymerization under reduced pressure. e Molecular weights were measured by GPC in chloroform solution with PS standards. f The carbonate comonomer unit /butylene succinate unit molar ratios in the synthesized copolymers were estimated by 1H NMR.

Figure 1. %BTMC).

1H

NMR spectrum for copolymer P(BS-co-21.9 mol Figure 3. %MTMC).

Figure 2. 1H NMR spectrum for copolymer P(BS-co-7.4 mol %EBTMC).

molar content. As compared with TMC, the other 4 kinds of carbonate monomers of MTMC, DMTMC, BTMC, and EBTMC bearing more bulky side constituents exhibited lower reactivities toward copolymerization. These experimental phenomena might be suggested for the effect of steric hindrance stemming from the side constituents. Sarel et al.43 have even reported a similar result for polycondensation of 1,3-propanediol derivatives and diethyl carbonate, and the

13C

NMR spectrum for copolymer P(BS-co-16.7 mol

constituents at the 2-site of 1,3-propanediol were found to suppress the polycondensation to form high polymer and accelerate generation of cyclic carbonate byproducts. The decarboxylation side reaction has been well-known to commonly occur in either polymerization or copolymerization of reactive cyclic carbonates under a high reaction temperature.44-45 It is noteworthy that there was no detectable signal from methylene proton nuclei of ether structural moieties (-CH2-O-CH2-, δ ) 3.5 ppm) within experimental limits for all proton NMR spectra of a series of synthesized P(BS-co-CC)s, and this demonstrated the absence of decarboxylation occurred during the copolymerization. On the other hand, 13C NMR techniques have been known as powerful tools capable of revealing macromolecular fine structures and important sequential information for an investigated copolymer. Here, Figures 3-6 depict the typical 13 C NMR spectra for the synthesized P(BS-co-CC)s bearing different carbonate building blocks. Referring to the 13C NMR spectrum of each corresponding homopolymer,14,46-47 the resonance signals of 13C nuclei were attributed to carbon atoms at different sites of each kind of carbonate comonomer. The carbonyl 13C resonances of the PBS were exhibited as



Figure 4. 13C NMR spectrum for copolymer P(BS-co-18.7 mol %DMTMC).

Figure 7. FTIR spectra of poly(butylene succinate-co-cyclic carbonate)s bearing various carbonate building blocks.

Figure 5. %BTMC).

13C


Figure 6. %EBTMC).

13C


a singlet signal occurring 172.45 ppm. In contrast, carbonyl 13 C resonances of the succinyl moieties attributed to the BS units were found to divide into 3-4 sub-signals appearing at 171.63, 172.10, 172.14, and 172.16 ppm for the synthesized poly(ester carbonate)s bearing TMC, MTMC, DMTMC, BTMC, and EBTMC building blocks. Additionally, 13C

resonance signals occurring around 155 ppm were assigned to the carbonyl 13C nuclei pertaining to the carbonate units as referred to the published literature.21 The occurrence of signal splitting of succinyl carbonyl resonance as detected for the synthesized P(BS-co-CC)s could be suggested due to the randomized sequences of the BS and carbonate building blocks as studied for P(BS-co--CL).48 Figure 7 shows typical FTIR spectra for the synthesized P(BS-co-CC)s bearing TMC, MTMC, BTMC, and EBTMC carbonate building blocks, and the main absorption bands at 1716, 1471, 1264, and 1047 cm-1 were assigned to the respective carbonyl bond stretching vibration, C-H bond stretching vibration, C-O-C bond asymmetric stretching vibration, and C-O-C bond symmetric stretching vibration modes attributed to the BS comonomer units. Moreover, it is noteworthy that the characteristic FTIR absorption bands occurring between 1733 and 1735 cm-1 were attributed to the stretching vibration modes of carbonyl bonds for the carbonate building blocks, and that lower carbonyl stretching frequencies were detected as compared with those of corresponding cyclic carbonate monomers, indicating a different tendency for the FTIR characterization of poly(5benzyloxyl-1,3-dioxan-2-one) as reported,21 where a shift of carbonyl stretching toward higher frequency was detected when ROP of six-membered cyclic carbonate happened. Deprotection of the Pendant Benzyl Groups of P(BSco-BTMC). To prepare novel biodegradable aliphatic P(BSco-CC)s bearing pendant hydroxyl functional groups, in this study, benzyl deprotection reactions were implemented through hydrogenation using Pd/C as the catalyst in an optimized way (5.0 MPa of H2 and 40 °C) as referred.13,49 On account of the low solubility of the P(BS-co-BTMC) in

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Yang et al.

Figure 8. 1H NMR spectrum for the benzyl deprotected P(BS-co21.9mol %BTMC) after 30 h hydrogenation. Figure 10. Debenzylation time dependence of GPC elution trace for the P(BS-co-21.9mol %BTMC). Table 3. Reaction Time Dependence of Catalytic Benzyl Deprotection for P(BS-co-21.9 mol % BTMC) with Pd/C Catalyst in THF under 40 °C

entry

catalytic hydrogenation time (h)

Mn × 10-3a

Mw/Mna

degree of benzyl deprotection (mol %)b

1 2 3 4

0 16 24 30

60.7 53.5 21.3 3.7

3.67 4.27 10.70 2.24

0 31 64 100

a Molecular weights were measured by GPC in chloroform with PS standards. b Degrees of benzyl deprotection in the prepared copolymers were estimated by 1 H NMR.

Figure 9. Debenzylation time dependence of FTIR spectrum for the P(BS-co-21.9mol %BTMC).

ethyl acetate and acetonitrile, benzyl deprotection performed in these individual solvents did not occur even under a high pressure of H2. Also, attempts in chloroform solution seemed unsuccessful no matter whether the copolymer samples were well dissolved. Fortunately, THF was hereby found to be a suitable solvent and in which the benzyl deprotection did happen well to certain extents provided that the temperature of reaction system was elevated. For the synthesized P(BSco-BTMC), degrees of benzyl deprotection were evaluated on the basis of 1H NMR resonance signals at 4.6 and 2.6 ppm respectively attributed to methylene protons of the benzyl and succinyl moieties (see Figure 1). Figure 8 shows the 1H NMR spectrum for a 30-h benzyl deprotection product of the synthesized P(BS-co-BTMC) with 21.9 mol % BTMC, and the entire disappearances of benzyl proton resonance

signals demonstrated achievement of novel poly(butylene succinate-co-5-hydroxyl trimethylene carbonate) P(BS-co5HTMC) bearing pendant hydroxyl groups. Furthermore, Figures 9 and 10 depict the benzyl deprotection time dependence of the FTIR spectrum and the GPC elution trace for the P(BS-co-21.9 mol % BTMC), respectively. It can be observed that the newly born broad IR absorption band around 3450 cm-1 became stronger in parallel with the benzyl deprotection time, confirming the efficient deprotection of benzyl groups and concurrent formation of hydroxyl functional groups. However, a remarkable decrease in molecular weight was detected, especially for the samples prepared after 24 h hydrogenation. It was noteworthy that the benzyl deprotection product synthesized with 24 h showed a bimodal GPC elution trace, leading to much broad molecular weight distribution, and this might be suggested for the concurrently occurring hydrolysis of the polymer chain during the hydrogenation. Similar result was reported by Tasaka et al.50 In general, Table 3 summarized the benzyl deprotection results for the P(BS-co-BTMC) bearing 21.9 mol % BTMC, and a novel aliphatic P(BS-co-5HTMC) was successfully synthesized with favorable hydroxyl side groups. Thermal Characterization. Thermal analyses were carried out by DSC and TGA for the synthesized novel poly(ester carbonate)s. In general, results of thermal characterization were summarized in Table 4. For the synthesized poly(BS-co-CC)s, it can be seen that melting points and heat of fusions tend to remarkably decrease with an increase in a



Table 4. Thermal Characteristics of Poly(butylene succinate-co-cyclic carbonate)s Bearing Various Carbonate Building Blocks

entry

sample

carbonate unit content (mol %)a

1 2 3 4 5 6 7 8 9 10 11

P(BS-co-17.4 mol % TMC) P(BS-co-26.5 mol % TMC) P(BS-co-28.6 mol % TMC) P(BS-co-11.5 mol %MTMC) P(BS-co-16.7 mol %MTMC) P(BS-co-13.0 mol %DMTMC) P(BS-co-18.7 mol %DMTMC) P(BS-co-6.5 mol % BTMC) P(BS-co-13.0 mol % BTMC) P(BS-co-21.9 mol % BTMC) P(BS-co-7.4 mol % EBTMC)

17.4 26.5 28.6 11.5 16.7 13.0 18.7 6.5 13.0 21.9 7.4

Tmb (°C)

∆Hmb (J/g)

Tgc (°C)

Tdd (°C)

84.7 88.6 64.3 105.3 79.3 94.1 85.9 103.6 79.9 56.9 99.7

56.1 40.3 22.5 53.2 40.9 49.5 36.2 52.1 29.8 17.2 51.3

-35.8 -35.2 -34.6 -35.1 -33.6 -34.3 -31.6 -32.2 -28.3 -30.1 32.5

386.4 385.1 386.6 393.7 393.4 398.3 398.7 385.7 386.8 383.8 401.1

a The carbonate unit (CC) molar contents were evaluated as [CC] × 100 mol %/([CC]+[BS]) by 1H NMR, where BS expresses the butylene succinate unit. bMelting point and heat of fusion were measured by the first DSC heating scan at a rate of 20 °C/min. c Glass transition temperature was estimated from the second DSC heating trace at 20 °C/min. d Thermal degradation temperatures were evaluated from the dTGA traces recorded at a scanning rate 10 °C/min.

secondary carbonate unit content, whereas linear structural PBS exhibited a higher melting point around 114 °C as reported,48,51 To investigate the carbonate comonomer structural dependences of macromolecular chain flexibility and properties, glass transition temperatures were measured for these P(BS-co-CC) samples with or without pendant groups. The experimental results indicate that these P(BS-co-CC) copolymers with low CC molar contents showed similar the Tg values no matter they bear different carbonate building blocks as TMC, MTMC, DMTMC, BTMC, and EBTMC. In addition, to make a quantitative assay of thermal degradation and stability, peak top temperatures (Td) of the corresponding differentiated TGA traces (dTGA) were applied and were also compiled in Table 4. Linear structural PBS showed a Td value of 379 °C, and Td’s of the synthesized P(BS-co-CC)s were found to be 10∼20 °C higher than that of PBS. So, copolymerization with a carbonate comonomer was demonstrated to be capable of keeping or slightly improving thermal stability for the obtained copolymer. This might be proposed for the fact that suitable constituents at the carbonate building blocks could suppress the thermal unzipping reaction to produce cyclic oligomers, and the steric repulsion between constituents along the polymer chains would be responsible for the thermodynamic stabilities as reported for the polymerization of spiro ortho ester.52 Conclusions In summary, to synthesize novel biodegradable aliphatic poly(butylene succinate-co-cyclic carbonate)s with functionalizable carbonate building blocks, five six-membered carbonate monomers of TMC, MTMC, DMTMC, BTMC, and EBTMC were first synthesized. Then, a series of P(BS-coCC)s were skillfully prepared with a simple combination of polycondensation and ring opening polymerization of hydroxyl capped PBS macromers and the corresponding prepared cyclic carbonates. As for the copolymerization catalyst, the experimental results demonstrated Ti(i-OPr)4 as a more suitable catalyst in terms of polymerization rate, molecular weight, and polydispersity for these poly(ester carbonate)s among Ti(i-OPr)4, ZnEt2, AlMe3, Al(i-OPr)3, and

SnOct2, and the copolymerization results indicated that novel biodegradable P(BS-co-CC)s bearing TMC, MTMC, DMTMC, BTMC, and EBTMC were prepared with Mn ranging from 24.3 to 99.6 KDa and various CC molar contents under the conditions of Ti(i-OPr)4 catalyst and its optimized concentration. 1H and 13C NMR experimental results demonstrated successful chemical construction of the P(BS-coCC)s bearing functionalizable carbonate building blocks without any detectable decarboxylation. It was also revealed that the more bulky pendant group was attached to the cyclic carbonate monomer, the lower copolymerization reactivity would be observed, and the occurrences of signal splitting of succinyl carbonyl 13C resonances for these P(BS-co-CC)s could accordingly be proposed due to the randomized sequences of the BS and carbonate building blocks. FTIR analytical results indicated distinct absorption bands of carbonyl stretching vibration modes occurring at 1716 and 1733∼1735 cm-1 attributed to the corresponding BS and CC building blocks, respectively. With regard to thermal analyses, DSC and TGA characterization indicated that copolymerization with a secondary CC building block decreased the melting points and crystallizabilities of the achieved P(BSco-CC) copolymers, and thermal degradation temperatures of the P(BS-co-CC)s were found to be 10∼20 °C higher than that of PBS. With the synthesized P(BS-co-BTMC), a new biodegradable poly(butylene succinate-co-5-hydroxy trimethylene carbonate) was further synthesized bearing functionalizable hydroxyl side groups through a Pd/C catalyzed hydrogenation. These new aliphatic P(BS-co-CC)s with functionalizable sites and tunable properties will provide possibilities as new biomaterials. A forthcoming paper will present further studies concerning hydrolysis, lipase-catalyzed enzymatic biodegradation, surface property and assay of cytotoxcity, and biocompatibility for these new biomaterials. Acknowledgment. The authors appreciate the financial supports partially from the Hundreds of Talents Project, Chinese Academy of Sciences, National Science Foundation of China (No.20204019), Shanghai Municipal Basic Research Fund (No. 02DJ14071).

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BM0343242

Novel Biodegradable Aliphatic Poly(butylene succinate-co

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