Chemical synthesis of functional poly(4-hydroxybutyrate) with controlled degradation via intramolecular cyclization

Article abstract of DOI:10.1021/ma402191r

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-2-enoic 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 five-membered 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.

Full text of DOI:10.1021/ma402191r

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-hydroxybuty-
rate) (P4HB). The polyesters were obtained via the Passerini
multicomponent polymerization (MCP) of (E)-4-oxobut-2-
enoic 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 five-
membered 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
1
conditions was investigated by H 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.
Poly(4-hydroxybutyrate) (P4HB) is a biodegradable poly-
ester 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.
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 postpolymeriza-
tion modification with functional groups.2 To precisely regulate
the degradation kinetics of biodegradable aliphatic polyesters,
sequence-defined poly(lactide-co-glycolide)s have been devel-
oped.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 intra-
molecular 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
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
© 2013 American Chemical Society
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Scheme 1. Synthesis of Functional P4HB by Passerini MCP and Subsequent Hydrogenation
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.
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 electron-
withdrawing 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).
RESULTS AND DISCUSSION
■
Polymerization of 4-Oxobutyric Acid and tert-Butyl
Isocyanide. Initially, we tried the Passerini MCP of 4-
oxobutyric 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 tert-
Butyl 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 4-
oxobutyric 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
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 character-
ization). 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 laser-
desorption-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
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1
Figure 1. H 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
a
b
entry
reactant
T (°C)
conv (%)
Piso (%)
1
2
3
4 + 5 + 2a
4 + 6 + 2a
4 + 6 + 2a
30
30
40
93
93
30
29
47
95
a
b
Calculated by the conversion of compound 4. The percentage of 7b
(or 8b) in the products.
1
Figure 2. H NMR spectra of (a) the reaction mixture of 4, 5, and 2a, (b) 7a, and (c) 7b recorded in CDCl3.
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Table 2. Results of the Passerini MCP of (E)-4-Oxobut-2-enoic Acid and Isocyanides
a
b
c
c
entry
monomer
equiv
C (mol/L)
T (°C)
Piso (%)
Mn
Mw/Mn
yield (%)
1
2
3
4
5
6
1 + 2a
1 + 2a
1 + 2a
1 + 2a
1 + 2a
1 + 2b
1.05
1.1
1.2
1.2
1.1
1.2
1.5
1.5
1.5
2
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
1.5
1.5
a
b
c
The molar ratio of isocyanide to (E)-4-oxobut-2-enoic acid. The percentage of the isomerized structure in the polymer. Measured 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.
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.
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.
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
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
1
polymers were characterized by both H NMR and 13C NMR
spectra (Figure S10). The tert-butyl ester groups along the
polymer main chains may offer the possibility of postfunction-
alization 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
1
hydrogenation. All the peaks in the H 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
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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.
1
Figure 5. (a) Degradation product of P4HB in acidic condition. (b) H 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.
1
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 H
NMR spectra were used to monitor the degradation (Figure
4b). In Figure 4b, peaks corresponding to the polymer (a, b,
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Figure 7. H NMR spectra of compound 9 monitored during the degradation process in CDCl3:DCl (10:1) at 37 °C.
1
Figure 8. H 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.
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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 biosyn-
thesis) 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 γ-
BL. 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
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
1
was not observed in the time-dependent H 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
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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.
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
indicated that the polyester degraded in a controllable manner
in neutral condition. The H NMR spectrum of compound 9
1
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 4-
hydroxybutyric 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 γ-
lactone moiety, for the improvement in the delivery character-
istics.24c We speculated that the degradation in pH 7.4/acetone
proceeded via consecutive intramolecular cyclization from the
hydroxyl end group (Scheme 4b).
1
compared via the time-dependent H 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 γ-
butyrolactone derivatives through two sequential intramolecu-
lar 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
To study the degradation process in more detail, degradation
of compound 10 was then conducted in the same condition.
1
Time-dependent H NMR measurement during the degrada-
tion 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
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(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.
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
■
(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
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 five-
membered 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-to-
tail 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 depolyme-
rization product.5−9 Further investigations are focused on the
synthesis of water-soluble functional P4HB with faster
depolymerization rate.
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,
ASSOCIATED CONTENT
■
́
K. N.; Jabbari, A.; Hall, H. K.; Aleman, C. J. Org. Chem. 2008, 73, 2674.
S
* Supporting Information
(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.
Experimental Section, Figures S1−S16. This material is
available free of charge via the Internet at http://pubs.acs.org.
(20) (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126. (b) Domling,
A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3169. (c) Banfi, L.; Riva, R.
̈
AUTHOR INFORMATION
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Corresponding Author
*Ph +86-10-62755543; Fax +86-10-62751708; e-mail zcli@pku.
edu.cn (Z.-C.L).
Org. React. 2005, 65, 1. (d) Domling, A. Chem. Rev. 2006, 106, 17.
̈
(e) Domling, 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.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(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.
■
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.
(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.
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.
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