Article pubs.acs.org/Macromolecules
Chemical Synthesis of Functional Poly(4-hydroxybutyrate) with Controlled Degradation via Intramolecular Cyclization Li-Jing Zhang, Xin-Xing Deng, Fu-Sheng Du, and Zi-Chen Li* Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Polymer Chemistry & Physics of Ministry of Education, Department of Polymer Science & Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China S Supporting Information *
ABSTRACT: We report the synthesis, characterization, and degradation of a new type of functional poly(4-hydroxybutyrate) (P4HB). The polyesters were obtained via the Passerini multicomponent polymerization (MCP) of (E)-4-oxobut-2enoic acid with two different isocyanides at room temperature and the subsequent hydrogenation. The trans-double bond in the monomer was designed to inhibit the formation of fivemembered lactone and promote the polymerization. Two different side groups were incorporated into the side chains of the polyesters by varying the isocyanide component. All the polymers were thoroughly characterized by a variety of methods. Degradation of the polyester under acidic and neutral conditions was investigated by 1H NMR and GPC. In both cases head-to-tail degradation via intramolecular cyclization by the attack of the hydroxyl end group to the ester carbonyl moiety occurred and yielded a nonacidic γ-butyrolactone derivative as the single degradation product. On the basis of control experiments with small model compounds and other types of polyester, we proposed the degradation mechanism. In acidic condition, random scission of the ester group occurred simultaneously at a much slower rate than that of the head-to-tail degradation, while in neutral condition, random scission did not occur and the polymers degraded in a controllable unzipping depolymerization manner.
■
INTRODUCTION Biodegradable aliphatic polyesters like poly(lactic acid) (PLA), poly(glycolic acid) (PGA), and poly(ε-caprolactone) (PCL) have been used in biomedical fields as sutures, tissue engineering scaffolds, and drug delivery carriers.1 To meet different applications, the degradation rates of these polyesters have been modulated by copolymerization and postpolymerization modification with functional groups.2 To precisely regulate the degradation kinetics of biodegradable aliphatic polyesters, sequence-defined poly(lactide-co-glycolide)s have been developed.3 The hydrolytically and enzymatically degradation products of these polyesters are typically hydroxyl alkyl acids. Although these acids are recognized as being nontoxic, they may lead to a significant pH drop in the microenvironment of the degrading matrix, resulting in the denaturation or aggregation of the loaded agents and unwanted immunogenic reactions.4 More sophisticated control over both kinetics and products of the degradation of linear polymers is the design and synthesis of stimuli-responsive self-immolative polymers.5−9 In this context, polyesters or polycarbonates which degraded into nontoxic and nonacidic cyclic small molecules via intramolecular cyclization have been developed. This type of intramolecular cyclization proceeded by the nucleophilic attack of hydroxyl or amine group on the carbonate or ester group. These polymers may find wide applications in biomedical and pharmaceutical fields.10−13 © 2013 American Chemical Society
Poly(4-hydroxybutyrate) (P4HB) is a biodegradable polyester that has attractive applications in tissue engineering and absorbable sutures.14,15 It has a moderate absorption rate that can fill the gap between the rigid, fast-degrading poly(glycolic acid) (PGA) and the slow-degrading poly(ε-caprolactone) (PCL). Moreover, the degradation products of P4HB are easily cyclized to form nonacidic γ-butyrolactone (γ-BL).15,16 It has been reported that thermal decomposition of P(4HB) yielded γ-BL and its higher homologues by an intramolecular exchange mechanism.16 Generally, P4HB is produced by microbial fermentation process.17 The high crystallinity and molecular weight of P4HB made it good thermoplastics. However, functionalization is difficult by this method. Chemical synthesis of P4HB via ring-opening polymerization (ROP) of γ-BL has been tried for a long time and demonstrated to be difficult due to the small ring-strain of γ-BL.14,18 For example, at normal pressure, ROP of γ-BL only afforded oligomers in low yields.19 Therefore, it remains a challenge to develop an efficient chemical approach to functional P4HBs. Herein, we report a facile method to synthesize a new type of P4HB-type polyesters with controlled degradation behaviors and nonacidic degradation products. The polyesters were Received: October 24, 2013 Revised: November 28, 2013 Published: December 12, 2013 9554
dx.doi.org/10.1021/ma402191r | Macromolecules 2013, 46, 9554−9562
Macromolecules
Article
Scheme 1. Synthesis of Functional P4HB by Passerini MCP and Subsequent Hydrogenation
monomer 1 with 2a would be prohibited. Thus, the polymerization could generate high molecular weight polymers, hydrogenation of which would lead to the desired P4HB derivatives (Scheme 1). Model Reactions. Before conducting the Passerini MCP of monomer 1 with isocyanides, we carried out the model reactions to optimize the reaction conditions and establish characterization methods. The design of the model reactions is shown in Scheme 3. It has been reported that α,β-unsaturated aldehyde or ketone is unable to undergo Passerini reaction probably due to the neutralization of the electrophilic center at the carbonyl group caused by the double bond.23 Indeed, our experiment confirmed that trans-2-hexenal could not react with 2a and 6. However, compound 4, which has an electronwithdrawing group next to the double bond, shows high reactivity toward the Passerini reaction with either acetic acid 5 or α,β-unsaturated acid 6 (Table 1). For example, compound 4, the ethyl ester of monomer 1, was allowed to react with 2a and 5 in THF at 30 °C. The conversion of 4 reached 93% after 24 h. Column separation gave two pure products, which were identified as two isomers (7a, 70% and 7b, 30%) by NMR and MS spectra (Table 1, Figure 2, and Figure S2). Similarly, Passerini reaction of 4, 6, and 2a was also highly efficient and produced two corresponding isomers 8a and 8b. Increasing the reaction temperature led to a slightly higher conversion of 4 and facilitated the isomerization (Table 1, Figures S3 and S4). The isomerized product 7b or 8b may be either formed directly from the reaction or transformed from the expected product 7a or 8a. To verify this, 7a was stirred at 30 °C in various solvents with different polarity in either the absence or presence of acetic acid (Table S1). We found that 7a cannot be converted to 7b under these conditions, indicating that 7b was formed during the process of Passerini reaction. Finally, both 7a and 7b can be hydrogenated to give the same saturated product (compound 9) in quantitative yields (Figure S5). Synthesis and Characterization of Functional P4HB. Monomer 1 was synthesized by a three-step procedure starting from (E)-ethyl 4-oxobut-2-enoate with a total yield of 55% (see Supporting Information for detailed synthesis and characterization). The Passerini MCP of monomer 1 with 2a was conducted under a variety of conditions, and the results are summarized in Table 2. Polymers with low to moderate molecular weights were obtained in all cases. Increasing the molar ratio of 2a to 1 (Table 2, entries 1−3), the initial concentration of the monomer (Table 2, entry 4), or the reaction temperature (Table 2, entry 5) can increase the molecular weights of the polymers. The structure of P1 was characterized by NMR (Figure 3) and matrix-assisted laserdesorption-ionization time-of-flight mass (MALDI-TOF-MS, Figure S7). In Figure 3a, the peaks were assigned ambiguously to the expected polymer structure, and the integration ratios are matched well with the theoretical values. As in the model reaction, isomerization of double bonds also occurred during the polymerization, generating two different repeating units in
prepared by Passerini multicomponent polymerization (MCP) and the subsequent hydrogenation (Scheme 1). Recently, the Passerini three-component reaction (3CR) 20 has been introduced to polymer science as a powerful synthetic approach to a variety of new polymers.21,22 Meier et al. first reported the synthesis of linear functional polyesters via the Passerini 3CR of a dicarboxylic acid, a dialdehyde, and an isocyanide.21a This polymerization can be considered as an A2 + B2 + C approach. Alternatively, linear functional polyester can also be synthesized from an AB + C approach. Therefore, we proposed that the Passerini MCP of (E)-4-oxobut-2-enoic acid (AB monomer, 1) and different isocyanides (C monomer, 2a, or 2b) would afford linear polyesters with functional side groups (P1 or P2). Hydrogenation of these precursor polymers would yield the functional P4HB-type polyesters (P3 or P4, Scheme 1). The degradation behavior and the degradation product of these polyesters under different conditions were then studied and elucidated.
■
RESULTS AND DISCUSSION Polymerization of 4-Oxobutyric Acid and tert-Butyl Isocyanide. Initially, we tried the Passerini MCP of 4oxobutyric acid (1.0 equiv) and tert-butyl isocyanide (2a, 1.2 equiv) to directly get the desired P4HB derivative (Scheme 2).
Scheme 2. Polymerization of 4-Oxobutyric Acid and tertButyl Isocyanide
After stirring the mixture in THF at 30 °C for 24 h, we measured the NMR spectrum of the mixture. The results showed that 4-oxobutyric acid was completely consumed. However, the GPC trace of the mixture indicated that there were no high molecular weight polymers. The main product was a small molecule eluted at 32 min with a small amount of oligomers (Figure S1). The small molecule was obtained by column chromatography and confirmed by NMR and ESI-MS to be a γ-BL derivative 3 (Figure 1). The failure of the polymerization can be attributed to the stability of the γ-BL structure, which was formed from the Passerini reaction of 4oxobutyric acid with 2a. Two important conclusions can be drawn from this experiment: first, the Passerini reaction of an AB monomer (4-oxobutyric acid) and monomer C (2a) can proceed in high efficiency under the current conditions; second, intramolecular cyclization with the formation of a stable γ-BL derivative is more favored than the linear intermolecular polymerization. Therefore, we reasoned that if a trans-double bond was introduced into 4-oxobutyric acid to get monomer 1, intramolecular cyclization during the Passerini MCP of 9555
dx.doi.org/10.1021/ma402191r | Macromolecules 2013, 46, 9554−9562
Macromolecules
Article
Figure 1. 1H NMR and 13C NMR spectra of compound 3 recorded in CDCl3.
Scheme 3. Passerini 3CR of (E)-Ethyl 4-Oxobut-2-enoate, Acid, and tert-Butyl Isocyanide
the polymer backbone. The ratio of isomerization, calculated by the integral of peaks c and d in the 1H NMR, is higher than that in the model reaction. In the 13C NMR shown in Figure 3b, the resonances of the two carbonyl groups in the polymer backbone were split into four peaks due to correlation with the neighboring units. The MALDI-TOF-MS spectrum of P1 (Figure S7) further confirms the integrity of the polymer structure. It consists of a series of main peaks each separated by 183 Da, corresponding to the mass of the repeating unit.
Table 1. Conversion and Isomerization of the Model Reactions entry
reactant
T (°C)
conva (%)
Pisob (%)
1 2 3
4 + 5 + 2a 4 + 6 + 2a 4 + 6 + 2a
30 30 40
93 93 95
30 29 47
a Calculated by the conversion of compound 4. bThe percentage of 7b (or 8b) in the products.
Figure 2. 1H NMR spectra of (a) the reaction mixture of 4, 5, and 2a, (b) 7a, and (c) 7b recorded in CDCl3. 9556
dx.doi.org/10.1021/ma402191r | Macromolecules 2013, 46, 9554−9562
Macromolecules
Article
Table 2. Results of the Passerini MCP of (E)-4-Oxobut-2-enoic Acid and Isocyanides entry 1 2 3 4 5 6
monomer
equiva
C (mol/L)
T (°C)
Pisob (%)
Mnc
Mw/Mnc
yield (%)
+ + + + + +
1.05 1.1 1.2 1.2 1.1 1.2
1.5 1.5 1.5 2 1.5 1.5
30 30 30 30 40 30
57 60 58 58 56 45
4600 7000 7600 8800 8300 5900
1.54 1.81 1.70 2.17 1.72 1.46
74 70 69 72 71 68
1 1 1 1 1 1
2a 2a 2a 2a 2a 2b
a
The molar ratio of isocyanide to (E)-4-oxobut-2-enoic acid. bThe percentage of the isomerized structure in the polymer. cMeasured by GPC in THF.
Figure 3. (a) 1H NMR and (b) 13C NMR spectra of P1 and P3, respectively (solvent: acetone-d6 for P1 and CDCl3 for P3). In the 13C NMR of P1, carbons a and e were split into two peaks. a-1 denotes the carbon a when the same repeating unit is adjacent to it while a-2 denotes the carbon a when the other repeating unit is adjacent to it, and so do the e-1 and e-2.
hydrogenation of model compound 4. The results revealed that both the double bonds and the aldehyde groups were completely hydrogenated (Figure S9) after the reaction. Therefore, the two end groups of P3 are hydroxyl and carboxylic acid group, respectively. This is also in accordance with the molecular weights obtained from the main peaks in the MALDI-TOF spectrum. The polymerization of 1 and 2b was also performed to generate polymer P2 (Table 2, entry 6). Hydrogenation of P2 yielded another type of P4HB-type polyester P4. The two polymers were characterized by both 1H NMR and 13C NMR spectra (Figure S10). The tert-butyl ester groups along the polymer main chains may offer the possibility of postfunctionalization after selectively removing the protecting groups.21 The glass transition temperatures of the four polymers (P1−P4) were investigated by DSC (Figure S11). All the polymers are amphorous polymers with much higher Tg values than that of P4HB due to the existence of bulky side groups and amide linkages.14 Besides, the Tgs of P3 and P4 are ca. 30 °C lower than that of P1 and P2, respectively, indicating that the rigidity of the polymer backbone decreased after hydrogenation. Degradation of the Polymers in Acidic Condition. Polymer P3 (Mn = 6700, PDI = 1.47) was used to study the degradation behaviors in solution. Degradation of P3 in acidic
According to the mechanism of Passerini MCR, the two end groups of P1 are aldehyde and carboxyl group, respectively (Scheme 1). The molecular weights obtained from the main peaks are very close to the theoretical values. Another series of peaks that shifted ca. 100 Da from the major peaks in the spectrum can be assigned to the cyclic oligomers. A P1 sample (Mn = 7600, PDI = 1.70, Table 2, entry 3) was used for hydrogenation to get the P4HB-type polyester P3. Hydrogenation was carried out at 5 MPa and 30 °C for 12 h. The 1H NMR spectrum (Figure 3a) showed that the resonances at 5.73 ppm (peak c) and 3.45 ppm (peak d) completely disappeared, and new peaks at 5.07 ppm (peak c′), 2.49 ppm (peak a′), and 2.15 ppm (peak b′) appeared, confirming the quantitative hydrogenation. The two different repeating units in P1 gave the same structure in P3 after hydrogenation. All the peaks in the 1H NMR spectrum can be assigned, and the integral ratios are matched well with the theoretical values. Furthermore, in the MALDI-TOF-MS spectrum of P3 (Figure S8), the existence of a series of peaks with a regular interval of 185 (calculated repeating unit mass) further confirmed the polymer structure. In the process of hydrogenation, it is anticipated that the aldehyde end groups in P1 could be reduced to hydroxyl groups under the current experimental conditions. To verify this, we conducted the 9557
dx.doi.org/10.1021/ma402191r | Macromolecules 2013, 46, 9554−9562
Macromolecules
Article
Figure 4. (a) Degradation product in acidic condition. (b) 1H NMR spectra and (c) GPC traces of P3 monitored during the degradation process in CDCl3:DCl (10:1) at 37 °C.
Figure 5. (a) Degradation product of P4HB in acidic condition. (b) 1H NMR spectra and (c) GPC traces of P4HB monitored during the degradation process in CDCl3:DCl (10:1) at 37 °C.
Figure 6. (a) Degradation product of PCL in acidic condition. (b) 1H NMR spectra and (c) GPC traces of PCL monitored during the degradation process in CDCl3:DCl (10:1) at 37 °C.
condition was first performed by adding 10% of DCl (DCl in D2O, 20% w/w) into the solution of P3 in CDCl3. Although D2O is immiscible with CDCl3, trace of DCl soluble in CDCl3
is sufficient to induce the degradation. Time-dependent 1H NMR spectra were used to monitor the degradation (Figure 4b). In Figure 4b, peaks corresponding to the polymer (a, b, 9558
dx.doi.org/10.1021/ma402191r | Macromolecules 2013, 46, 9554−9562
Macromolecules
Article
Figure 7. 1H NMR spectra of compound 9 monitored during the degradation process in CDCl3:DCl (10:1) at 37 °C.
Figure 8. 1H NMR spectra of compound 10 monitored during the degradation process in CDCl3:DCl (10:1) at 37 °C.
and c) decreased, while the peaks corresponding to the γ-BL derivative 3 (1, 2, 3) gradually increased, indicating that polymer P3 gradually degraded into the γ-BL derivative 3. The extent of degradation (Ed) denotes the percentage of the degraded repeating units and was estimated by the integrals of peak c and 3 (Ed = I3/(Ic + I3)). About half of the repeating units of P3 were transformed into 3 after incubation at 37 °C for 40 h. Time-dependent GPC traces of the degradation products also confirmed the decrease of molecular weights with
a progressively increase of the peak of γ-BL derivative 3 (Figure 4c). The Mn decreased significantly, but the formation of γ-BL derivative 3 was relatively slow. For example, after 4 h, the Mn of P3 decreased from 6700 to 2800, while only ca. 10% of the total repeating units were transformed into the lactones. After 144 h, there were no high molecular weight polymers; the cyclic small molecule was the main product with a small amount of oligomers. 9559
dx.doi.org/10.1021/ma402191r | Macromolecules 2013, 46, 9554−9562
Macromolecules
Article
Scheme 4. Plausible Degradation Mechanism of P3 in HCl/CDCl3 (a) and pH 7.4 Buffer/Acetone (b)
Figure 9. (a) Degradation product in neutral condition. (b) 1H NMR spectra and (c) GPC traces of P3 monitored during the degradation process in acetone-d6:0.1 M pH 7.4 phosphate buffered D2O (5:1) at 37 °C.
To study the mechanism of the degradation of P3, we then investigated the degradation of P4HB (obtained by biosynthesis) and PCL in the same condition for comparison. Figure 5 presents the time-dependent 1H NMR spectra and GPC traces during the degradation of P4HB under this acidic condition. The results indicated that P4HB also gradually degraded into γBL. About half of the repeating units of P4HB were transformed into γ-BL after incubation at 37 °C for 166 h. The degradation product is confirmed by comparing the spectra with that of pure γ-BL and also by FTMS. However, the degradation of PCL is very slow; generation of ε-caprolactone was not observed in the time-dependent 1H NMR spectra (Figure 6) even after 16 days. Instead, peaks corresponding to end hydroxyl groups slightly increased, indicating that a small amount of ester groups in the backbone was randomly broken. Only ca. 3% of the ester groups in the backbone were broken after incubation at 37 °C for 16 days. GPC traces shown in Figure 6b also indicated that the molecular weight of PCL
slightly decreased after 16 days. These control experiments indicated that P4HB and P3 have much faster degradation rate than that of PCL in HCl/CHCl3. To further verify this conclusion, we conducted the degradation of the three polymers (P3, P4HB, and PCL) in the mixture of CF3COOH and CHCl3 (v/v = 1:10). Although CF3COOH is a weaker acid than HCl, it is soluble in CHCl3. Degradation was monitored by time-dependent 1H NMR (Figures S13−S15), and the results are in accordance with the degradation in HCl/CHCl3. After 10.5 days, P4HB and P3 completely degraded into γ-BL derivatives while only ca. 14% of PCL repeating units were degraded into ε-caprolactone. From the above results, we speculated that the fast degradation of P3 was related to the rapid intramolecular cyclization of γ-hydroxylbutyrate to γ-BL. This type of cyclization was driven by the thermodynamic stability of γ-BL, which was formed by the intramolecular nucleophilic attack of hydroxyl group on the ester carbonyl group.24 9560
dx.doi.org/10.1021/ma402191r | Macromolecules 2013, 46, 9554−9562
Macromolecules
Article
Figure 10. 1H NMR spectra of compound 10 monitored during the degradation process in acetone-d6:0.1 M pH 7.4 phosphate buffered D2O (5:1) at 37 °C. Ed denotes the percentage of the degraded compound 10.
indicated that the polyester degraded in a controllable manner in neutral condition. The 1H NMR spectrum of compound 9 showed that it is stable after incubation in pH7.4/acetone (v/v = 1:5) for 15 days at 37 °C (Figure S16), indicating that random scission of the ester bonds did not occur under this condition. It has been reported that methyl and ethyl ester of 4hydroxybutyric acid underwent a quantitative cyclization in neutral aqueous solution at 37 °C to γ-butyrolactone.24b Especially, the alkyl and aralkyl esters of pilocarpic acid were evaluated as prodrugs for pilocarpine, a drug containing γlactone moiety, for the improvement in the delivery characteristics.24c We speculated that the degradation in pH 7.4/acetone proceeded via consecutive intramolecular cyclization from the hydroxyl end group (Scheme 4b). To study the degradation process in more detail, degradation of compound 10 was then conducted in the same condition. Time-dependent 1H NMR measurement during the degradation is shown in Figure 10. The first cyclization completely finished within 7 days. However, the second cyclization was not observed after 14 days. We inferred that the difficulty of the second cyclization might be due to the lack of polar substitute on the carbon next to the ester oxygen atom (carbon b). Bundgaard et al. have reported that the rates of lactonization of the alkyl or aralkyl γ-hydroxylbutyrates can be totally accounted for in terms of the different stability of the leaving alcohol group as expressed by the pKa values of the alcohols.24c The rate of lactonization greatly depends on the polar effect by the alcohol portion of the ester. Meanwhile, we carried out the degradation of ethyl 4-hydroxybutyrate (compound 11) in pH 7.4 buffer/acetone. The time-dependent 1H NMR spectra (Figure S17) showed that the lactonization was not clearly observed even after incubation for 8 days. The lactonization is quite slow compared with the first lactonization of compound 10. Therefore, it is concluded that the polar effect of the amide substitute on the carbon next to the ester oxygen atom is
To verify our speculation, we synthesized two small molecules, 9 and 10 (Figures 7 and 8). Compound 9 was obtained by the hydrogenation of 7a, and compound 10 was synthesized by a three-step procedure (see Supporting Information for detailed synthesis). Degradation of the two compounds in the same acidic condition were studied and compared via the time-dependent 1H NMR measurements. The results showed that degradation of compound 9 is much slower than that of 10. Only ca. 10% of 9 was transformed to lactone 3 after incubation at 37 °C for 1 day. However, after 1 day, compound 10 was completely transformed to two γbutyrolactone derivatives through two sequential intramolecular cyclizations by the attack of the hydroxyl group to the nearest ester carbonyl group. This indicated that the hydrolysis of the ester bond is much slower than the intramolecular cyclization. On the basis of these results, a plausible mechanism for the degradation of P3 was proposed as shown in Scheme 4a. Degradation of P3 in HCl/CDCl3 proceeded in two ways: a slow random scission of the main chain ester bonds and a fast head-to-tail depolymerization by the consecutive attack of the hydroxyl end groups to the ester groups; the latter process dominates the whole degradation. Degradation in Neutral Condition. The degradation of P3 was further studied in neutral condition. A solution of P3 in a mixture of 0.1 M pH 7.4 phosphate buffered D2O and acetone-d6 (v/v = 1:5) was incubated at 37 °C and monitored by NMR and GPC (Figure 9). The results confirmed that the degradation product was only the γ-BL derivative 3. But the kinetics was much slower than that in the acidic condition. Moreover, the molecular weight of P3 slowly decreased other than dropping dramatically as in the acidic condition. After 2 days, the Mn decreased from 6700 to 5300, while ca. 20% of the total repeating units were transformed into the lactones. Subsequently, the Mn decreased gradually with the increase of formation of γ-BL derivative 3. The gradual loss of MW 9561
dx.doi.org/10.1021/ma402191r | Macromolecules 2013, 46, 9554−9562
Macromolecules
Article
(3) (a) Li, J.; Stayshich, R. M.; Meyer, T. Y. J. Am. Chem. Soc. 2011, 133, 6910. (b) Li, J.; Rothstein, S. N.; Little, S. R.; Edenborn, H. M.; Meyer, T. Y. J. Am. Chem. Soc. 2012, 134, 16352. (4) (a) Ding, A. G.; Schwendeman, S. P. Pharm. Res. 2008, 25, 2041. (b) Fu, K.; Pack, D. W.; Klibanov, A. M.; Langer, R. Pharm. Res. 2000, 17, 100. (c) van de Weert, M.; Hennink, W. E.; Jiskoot, W. Pharm. Res. 2000, 17, 1159. (d) Ye, M. L.; Kim, S.; Park, K. J. Controlled Release 2010, 146, 241. (5) Sagi, A.; Weinstain, R.; Karton, N.; Sabat, D. J. Am. Chem. Soc. 2008, 130, 5434. (6) Peterson, G. I.; Larsen, M. B.; Boydston, A. J. Macromolecules 2012, 45, 7317. (7) (a) DeWit, M. A.; Gillies, E. R. J. Am. Chem. Soc. 2009, 131, 18327. (b) Chen, E. K. Y.; McBride, R. A.; Gillies, E. R. Macromolecules 2012, 45, 7364. (c) McBride, R. A.; Gillies, E. R. Macromolecules 2013, 46, 5157. (8) (a) Seo, W.; Phillips, S. T. J. Am. Chem. Soc. 2010, 132, 9234. (b) DiLauro, A. M.; Robbins, J. S.; Phillips, S. T. Macromolecules 2013, 46, 2963. (c) Olah, M. G.; Robbins, J. S.; Baker, M. S.; Phillips, S. T. Macromolecules 2013, 46, 5924. (9) (a) Esser-Kahn, A. P.; Sottos, N. R.; White, S. R.; Moore, J. S. J. Am. Chem. Soc. 2010, 132, 10266. (b) Esser-Kahn, A. P.; Odom, S. A.; Sottos, N. R.; White, S. R.; Moore, J. S. Macromolecules 2011, 44, 5539. (10) de Gracia Lux, C.; Almutairi, A. ACS Macro Lett. 2013, 2, 432. (11) Mejia, J. S.; Gillies, E. R. Polym. Chem. 2013, 4, 1969. (12) (a) Darensbourg, D. J.; Wei, S. Macromolecules 2012, 45, 5916. (b) Darensbourg, D. J.; Wei, S.-H.; Wilson, S. J. Macromolecules 2013, 46, 3228. (13) (a) Geschwind, J.; Frey, H. Macromolecules 2013, 46, 3280. (b) Zhang, H.; Grinstaff, M. W. J. Am. Chem. Soc. 2013, 135, 6806. (14) Moore, T.; Adhikari, R.; Gunatillake, P. Biomaterials 2005, 26, 3771. (15) Martin, D. P.; Williams, S. F. Biochem. Eng. J. 2003, 16, 97. (16) Abate, R.; Ballistreri, A.; Montaudo, G.; Impallomeni, G. Macromolecules 1994, 27, 332. (17) Chen, G. Q.; Patel, M. K. Chem. Rev. 2012, 112, 2082. (18) (a) Saiyasombat, W.; Molloy, R.; Nicholson, T. M.; Johnson, A. F.; Ward, I. M.; Poshyachinda, S. Polymer 1998, 39, 5581. (b) Houk, K. N.; Jabbari, A.; Hall, H. K.; Alemán, C. J. Org. Chem. 2008, 73, 2674. (19) (a) Dong, H.; Wang, H. D.; Cao, S. G.; Shen, J. C. Biotechnol. Lett. 1998, 20, 905. (b) Kadokawa, J.; Iwasaki, Y.; Tagaya, H. Green Chem. 2002, 4, 14. (c) Nobes, G.; Kazlauskas, R. J.; Marchessault, R. H. Macromolecules 1996, 29, 4829. (20) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Dömling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169. (c) Banfi, L.; Riva, R. Org. React. 2005, 65, 1. (d) Dömling, A. Chem. Rev. 2006, 106, 17. (e) Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083. (21) (a) Kreye, O.; Toth, T.; Meier, M. A. R. J. Am. Chem. Soc. 2011, 133, 1790. (b) Sehlinger, A.; Kreye, O.; Meier, M. A. R. Macromolecules 2013, 46, 6031. (c) Jee, J.-A.; Spagnuolo, L. A.; Rudick, J. G. Org. Lett. 2012, 14, 3292. (d) Rudick, J. G. J. Polym. Sci., Part A: Polym. Chem. 2013, 51, 3985. (22) (a) Deng, X. X.; Li, L.; Li, Z. L.; Lv, A.; Du, F. S.; Li, Z. C. ACS Macro Lett. 2012, 1, 1300. (b) Li, L.; Kan, X. W.; Deng, X. X.; Song, C. C.; Du, F. S.; Li, Z. C. J. Polym. Sci., Polym. Chem. 2013, 51, 865. (c) Wang, Y. Z.; Deng, X. X.; Li, L.; Li, Z. L.; Du, F. S.; Li, Z. C. Polym. Chem. 2013, 4, 444. (23) Baker, R. H.; Schlesinger, A. H. J. Am. Chem. Soc. 1945, 67, 1499. (24) (a) Capon, B.; McDowell, S. T.; Raftery, W. V. J. Chem. Soc., Perkin Trans. 2 1973, 1118. (b) Bundgaard, H.; Larsen, C. Int. J. Pharm. 1980, 7, 169. (c) Bundgaard, H.; Falch, E.; Larsen, C.; Mikkelson, T. J. J. Pharm. Sci. 1986, 75, 36. (d) Sanders, G. C.; van Ravensteijn, B. G. P.; Duchateaua, R.; Heuts, J. P. A. Polym. Chem. 2012, 3, 2200.
essential for the intramolecular cyclization in pH 7.4/acetone. The head-to-tail depolymerization characteristic may offer polymer materials longer retaining time of physical properties during the degradation than the random disruption, where one cleavage may result in the decrease of MW by ca. 50%.
■
CONCLUSIONS We demonstrated a new method to synthesize functional P4HB that can be degraded into a nonacidic γ-BL derivative via intramolecular cyclization. The incorporation of trans-double bonds into the monomer prohibited the generation of fivemembered lactone and thus promoted the Passerini MCP under mild conditions. Changing the isocyanide component offers an access to P4HB with different side groups. Degradation of the polyester gives the nonacidic lactone compound as the product. The degradation mechanism has been proven with a variety of control experiments. Degradation of the polyester in acidic condition proceeded via the simultaneous hydrolysis of the ester bonds and the head-totail depolymerization by intramolecular cyclization. The latter is fast and dominates the degradation process. Degradation in neutral condition is much slower than that in the acidic condition. The polymers undergo a cascade intramolecular cyclization with the formation of the lactone product. In one way, our new polymers expand the scope of degradable polyesters available for biomedical applications, especially in the cases where neutral microenvironment is essential. In another way, this kind of polymer maybe a new type of self-immolative polymer with simple structure and nontoxic neutral depolymerization product.5−9 Further investigations are focused on the synthesis of water-soluble functional P4HB with faster depolymerization rate.
■
ASSOCIATED CONTENT
* Supporting Information S
Experimental Section, Figures S1−S16. This material is available free of charge via the Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*Ph +86-10-62755543; Fax +86-10-62751708; e-mail zcli@pku. edu.cn (Z.-C.L). Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work is financially supported by National Natural Science Foundation of China (Nos. 21090351, 21074002, and 21225416) and National Basic Research Program of China (No. 2011CB201402). We thank Prof. Guoqiang Chen of Tsinghua University for P4HB sample.
■
REFERENCES
(1) (a) Albertsson, A. C.; Varma, I. K. Biomacromolecules 2003, 4, 1466. (b) Place, E. S.; George, J. H.; Williams, C. K.; Stevens, M. M. Chem. Soc. Rev. 2009, 38, 1139. (c) Uhrich, K. E.; Cannizzaro, S. M.; Langer, R. S.; Shakesheff, K. M. Chem. Rev. 1999, 99, 3181. (2) (a) Pounder, R. J.; Dove, A. P. Polym. Chem. 2010, 1, 260. (b) Seyednejad, H.; Ghassemi, A. H.; van Nostrum, C. F.; Vermonden, T.; Hennink, W. E. J. Controlled Release 2011, 152, 168. (c) Williams, C. K. Chem. Soc. Rev. 2007, 36, 1573. 9562
dx.doi.org/10.1021/ma402191r | Macromolecules 2013, 46, 9554−9562
