Synthesis of novel copolymer: Poly(p-dioxanone-co-l-phenylalanine)

Article abstract of DOI:10.1016/j.cclet.2013.03.017

In order to expand the application of poly(p-dioxanone) or PPDO in biomedical area, a series of novel copolymers were synthesized successfully by one-step, melted copolymerization of p-dioxanone (PDO) and l-phenylalanine N-carboxyanhydride (l-Phe-NCA) monomers. With the in-feed molar ratio of l-Phe-NCA/PDO equal to 1/20, the conversions of the two kinds of monomers were calculated from ¹H NMR. The average molecular weight and polydispersity of the copolymer increase with the increasing reaction time and catalyst concentration. However, the conversions of the two kinds of monomers did not change with the reaction conditions. A three-step mechanism is presented and proved by high resolution ¹H NMR and IR spectrums.

Full text of DOI:10.1016/j.cclet.2013.03.017

Chinese Chemical Letters 24 (2013) 392–396
Contents lists available at SciVerse ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
Synthesis of novel copolymer: Poly(p-dioxanone-co-
L-phenylalanine)
a,b
a,b
a
a
c
a,
Bing Wang , Chi Ma , Zuo-Chun Xiong , Cheng-Dong Xiong , Quan-Hua Zhou , Dong-Liang Chen *
a
Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
b
University of Chinese Academy of Sciences, Beijing 100049, China
c
Sichuan Staff University of Science and Technology, Chengdu 610041, China
A R T I C L E I N F O
A B S T R A C T
Article history:
In order to expand the application of poly(p-dioxanone) or PPDO in biomedical area, a series of novel
copolymers were synthesized successfully by one-step, melted copolymerization of p-dioxanone (PDO)
Received 26 December 2012
Received in revised form 2 February 2013
Accepted 26 February 2013
Available online 12 April 2013
and L-phenylalanine N-carboxyanhydride (L-Phe-NCA) monomers. With the in-feed molar ratio of L-Phe-
1
NCA/PDO equal to 1/20, the conversions of the two kinds of monomers were calculated from H NMR.
The average molecular weight and polydispersity of the copolymer increase with the increasing reaction
time and catalyst concentration. However, the conversions of the two kinds of monomers did not change
Keywords:
1
with the reaction conditions. A three-step mechanism is presented and proved by high resolution
NMR and IR spectrums.
H
Copolymer
p-Dioxanone
ß 2013 Dong-Liang Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights
L
-Phenylalanine
reserved.
Mechanism
1
. Introduction
In this work, copolymers of poly(p-dioxanone-co-
nine) were synthesized using different polymerization conditions
by a one-step, melted reaction of PDO and -phenylalanine N-
carboxyanhydride ( -Phe-NCA). A three-step mechanism was
provided and proven by FTIR and H NMR.
L-phenylala-
Poly(p-dioxanone) (PPDO), as an aliphatic polyester, has been
L
used in biomedical applications, such as tissue engineering, bone
fracture fixation and controlled drug delivery, due to its
outstanding biodegradability, biocompatibility and flexibility [1–
L
1
5
]. However, the combination of high crystallinity, intrinsic
2. Experimental
hydrophobicity of PPDO and the absence of biological properties
have limited its further application [6]. The most frequently used
method to improve the performances of PPDO, such as crystallinity
and hydrophobicity of PPDO, is copolymerization [7–12].
2
.1. Synthesis of L-Phe-NCA [17]
The
L-Phe-NCA was synthesized from L-Phe (5.0 g) and
In recent years, functionalized polyesters, especially polyesters
triphosgene (3.7 g) in dry THF (50 mL) at 50 8C for 4 h under N
2
containing
a-amino acid, have attracted much attention. Many
atmosphere. After completion of the reaction, the mixture was
concentrated by rotary evaporator at 30 8C and dry hexane was
added to precipitate the crude product. The crude product was
papers have reported on the synthesis of
a
-amino acid containing
polyesters and revealed that, as copolymerization components,
amino acids could alter not only the physical properties, but also
the biological properties of polyesters [13]. However, there have
been only a limited number of published reports regarding the
copolymers of p-dioxanone (PDO) and amino acids [14] and
therefore, the aim of our research was to synthesize copolymers
purified by recrystallization from diethyl ether/hexane (1/2, v/v)
1
twice to yield
L
-Phe-NCA monomer of high purity. H NMR
(
(
300 MHz, CDCl
m, 1H, CH), 2.94–3.35 (m, 2H, CH
3
): d 7.19–7.41 (m, 5H, ArH), 5.60 (s, 1H, NH), 4.55
ꢀ
1
2
). FTIR (KBr, cm ): n 3351 (N–
H), 3031 (C–H from phenyl), 2905 (C–H), 1849 (C 55 O), 1779 (C 55 O).
.2. Synthesis of poly(p-dioxanone-co- -phenylalanine)
composed of PDO and
L-phenylalanine (L-Phe) by a new,
convenient method. -Phe was chosen as the copolymerization
L
2
L
component because its rigid benzyl group may alter the flexibility
of the copolymer chains and decrease the crystallinity, along with
specific inhibitions on cell proliferation [15,16].
To a 100-mL round-bottom flask containing PDO (5.0 g),
calculated quantities of -Phe-NCA and stannous octoate were
L
added. The flask was sealed using a long-neck piston connected
to an oil pump to remove moisture, oxygen, and solvent until
ꢀ3
*
Corresponding author.
the pressure was reduced to below 10 Pa. The polymerization
E-mail address: cdl921@yahoo.com.cn (D.-L. Chen).
was carried out under vacuum at 95 8C with magnetic stirring.
1
001-8417/$ – see front matter ß 2013 Dong-Liang Chen. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2013.03.017

B. Wang et al. / Chinese Chemical Letters 24 (2013) 392–396
393
Table 1
Synthesis of PDO and L-Phe-NCA copolymers.
c
c
Entry
[PDO]:[Phe]
mol/mol)
T (h)
[M]
0
:[C]
0
Conversion
Conversion
M
n
(g/mol)
w
M (g/mol)
a
b
(
(mol/mol)
of PDO%
of Phe-NCA%
1
2
3
4
5
6
7
8
9
20
20
20
20
20
20
20
20
20
20
10
72
96
3500
3500
3500
3500
3500
2000
2000
2000
2000
2000
2000
2000
86
82
76
81
82
75
79
79
79
81
80
84
76
100
88
2800
6784
7747
12,899
8716
5457
8707
9009
19,443
6163
7868
3071
3841
11,455
15,002
26,147
17,964
9141
120
144
168
72
90
88
94
96
100
84
15,932
19,274
37,292
12,069
14,513
4830
120
144
168
120
120
82
1
1
1
0
1
2
79
98
6.67
100
a
b
c
1
Calculated from H NMR of crude products of copolymerization.
1
Calculated from mol comparison of PPDO to
L-Phe from H NMR of copolymer after purification and the in-feed molar ratio of the two kinds of monomers.
Calculated by GPC using a system consisting of a Waters 1515 isocratic HPLC pump, Styragel HT 4 or HT 5 column, and Waters 2414 refractive index detector. Chloroform
was the eluent at a flow rate of 0.5 mL/min. Narrow molecular weight distribution polystyrene was used as the molecular weight basis.
The crude product was dissolved in chloroform and precipitat-
ed with diethyl ether, then redissolved in chloroform again and
precipitated with ethanol. The purified product was filtered
CH of
COCH
L
-Phe structure units), 4.34 (t, COCH
2
OCH
O), 3.16 (m, CH
ꢀ
-Phe structure units). FTIR (KBr, cm ): n 3413 (N-H), 2980–
2
CH
2
O), 4.17 (s,
2
OCH CH O), 3.79 (t, COCH OCH CH
2
2
2
2
1
2
2
of
L
1
and dried under vacuum at room temperature for 24 h. H NMR
2881 (C–H), 1749 (C 55 O), 1673 (amide I), 1525 (amide II),
(
300 MHz, CDCl
3
):
d
7.18–7.22 (d, NH), 7.26 (m, C
6
H
5
), 4.87 (m,
1137(O–C–O).
[(Fig._1)TD$FIG]
Fig. 1. (a) Weight-average molecular weight of poly(p-dioxanone-co-
weight of poly(p-dioxanone-co- -phenylalanine) with different in-feed molar ratios of [
Polydispersity of poly(p-dioxanone-co- -phenylalanine); (c) Conversion of PDO monomer; (d) Conversion of
L
-phenylalanine) with different reaction times and catalyst concentration, weight-average molecular
-Phe-NCA]:[PDO] (%) and same reaction time and catalyst concentration; (b)
-Phe-NCA monomer evolutions with polymerization time.
L
L
L
L

3
94
B. Wang et al. / Chinese Chemical Letters 24 (2013) 392–396
3
. Results and discussion
The structure of poly(p-dioxanone-co-
L
-phenylalanine) was
confirmed by H NMR and FTIR spectra. The triplet at 4.34 ppm
belonged to the COCH OCH CH O protons in PPDO segments, the
single peak at 4.17 ppm was attributed to the COCH OCH CH
protons in PPDO segments, and the triplet at 3.79 ppm was
attributed to the COCH OCH CH O protons in PPDO segments.
1
The synthesis of poly(p-dioxanone-co-
L
-phenylalanine) was
-Phe-NCA and PDO.
All subsequent polymerization experiments were performed at
5 8C. This temperature was chosen because higher temperature
105 8C) was found to result in low conversions of -Phe-NCA, an
2
2
2
carried out by a one-step copolymerization of
L
2
2
2
O
9
(
2
2
2
L
These characteristic peaks are in accordance with literature reports
of PPDO [1]. The multiplet at 7.26 ppm belonged to the benzyl
protons in the phenylalanine unit, and the peaks at 4.87 ppm and
indication of deactivation, whereas a lower temperature (85 8C)
was not sufficient for synthesis of the copolymers.
[(Scheme_1)TD$FIG]
Scheme 1. Mechanism of PDO and
L
-Phe-NCA copolymerization reaction.

B. Wang et al. / Chinese Chemical Letters 24 (2013) 392–396
395
3
.16 ppm were attributed to the protons of the methenyl groups
L
-Phe-NCA. From Fig. 1, M
w
increased with increasing polymeriza-
and methylene groups in the phenylalanine unit, respectively. The
characteristic peaks at 7.18 ppm and 7.22 ppm were assigned to
the protons of the amide group in poly(p-dioxanone-co-L-
phenylalanine). All of the characteristic peaks indicate that the
copolymers were successfully obtained. In addition, the absorp-
tion time and catalyst quantity before 144 h. The polydispersity of
the copolymers also increased with increasing polymerization
time. However, the conversions of the two monomers did not
change with reaction time. It also could be concluded from Fig. 1(a)
w
that the M decreased with increasing L-Phe-NCA content while
ꢀ
1
ꢀ1
tions at 1849 cm and 1779 cm in FTIR spectrum, which are
characteristics of -Phe-NCA acid anhydride groups, disappeared
after copolymerization. The amide I and amide II absorptions
the reaction times and catalyst concentrations are constant.
In order to explain these phenomena, a possible mechanism is
proposed in Scheme 1 [1,18]. Initially, when the temperature of the
polymerization system becomes higher than the melting point of
PDO but lower than the temperature at which PDO can polymerize
L
ꢀ1
ꢀ1
appeared at 1673 cm
and around 1525 cm , respectively,
indicating that the polymerization of
occurred.
L-Phe-NCA monomers
successfully,
trace amount of OH groups in the system initiates the polymeri-
zation of -Phe NCA. Next, the oligopeptide can initiate the
L-Phe-NCA dissolves in the melted PDO, and then the
The influences of reaction conditions on copolymerization were
studied by changing the monomer-to-catalyst ratio ([M] /[C ]),
where C is stannous octoate, and reaction time. With the fixed in-
feed molar ratio of [PDO]/[ -Phe-NCA] equal to 20, a series of
polymerization experiments were carried out in which the [M]
] ratio and reaction times were systematically varied. Copoly-
merization reactions of PDO and -Phe-NCA with different in-feed
0
0
L
polymerization of PDO monomers along with the increasing
temperature to yield the copolymers. This step of the copolymeri-
zation is shown as Reaction 1 of Scheme 1. Meanwhile, the residual
L
0
/
[
C
0
L
-Phe-NCA monomers can also initiate the polymerization of PDO
monomers as the temperature reaches the proper value, yielding
the -Phe-NCA end-capped PPDOs. This step of the copolymeriza-
L
molar ratios were also carried out. The results are summarized in
Table 1. The increase of polymer molecular weight during
polymerization was monitored using GPC. PDO conversions were
L
tion is shown as Reaction 2 of Scheme 1. Finally, for the reactions
among macromolecules, the hydroxyl end caped macromolecules
react with L-Phe-NCA end caped macromolecules, which lead to an
obvious increase in the molecular weight, as shown in Reaction 3 of
Scheme 1. This mechanism indicates that the extent of Reaction 3
1
determined using
H
NMR spectroscopy by comparison of
OCH CH O protons of the PDO residue
of the monomer and polymer. -Phe-NCA conversions were
integrations of the COCH
2
2
2
L
1
determined using H NMR spectroscopy (in deutero-dichloro-
methane) by comparison of the benzene proton integrations of
w
increases with increasing reaction time, so the M increased with
the reaction time before 168 h when depolymerization occurred.
At the same time, the inhomogeneity of the length of copolymer
chains increases with the extent of Reaction 3, leading to the
increase of polydispersity. Use of more catalyst resulted in reaction
phenylalanine in the polymer to the COCH
the PDO in the polymer after purification. The results showed that
the [M] /[C] ratio and reaction time can affect the molecular
2 2 2
OCH CH O protons of
0
0
weights of the copolymers. Together with the information
provided in Table 1, plots a–d of Fig. 1 show the evolution of
of larger amounts of
Reaction 2. This means that the active centers for PDO polymeri-
zation decrease with the catalyst amount, and M increases with
the catalyst amount. According to the mechanism mentioned
L-Phe-NCA via Reaction 1 and less reaction via
monomer conversion, M
w
, polydispersity with polymerization
w
time and the evolution of M
w
with in-feed molar ratio of PDO to
[(Fig._2)TD$FIG]
1
Fig. 2. 600 MHz H NMR of poly(p-dioxanone-co-
L
-phenylalanine) (entry 8, Table 1) in CDCl
3
.

[
(
F
i
g
.
_
3
)
T
D
$
F
I
G
]
396
B. Wang et al. / Chinese Chemical Letters 24 (2013) 392–396
4. Conclusion
The poly(p-dioxanone-co-
L-phenylalanine)s were successfully
synthesized using PDO and
L-Phe-NCA as copolymerization
monomers. The structure of the copolymer was characterized
1
using H NMR spectra from which characteristic peaks were easily
identified. The average molecular weight and polydispersity of the
copolymer increased with increasing reaction time, though the
conversions of the two types of monomers remained almost
unchanged. The average molecular weight of the copolymers
increased with increasing quantities of catalyst when reaction time
remained the same. With fixed reaction conditions, the average
molecular weights of the copolymers decreased with increasing in-
feed L-Phe-NCA content. A three-step reaction mechanism for the
polymerization was also proposed on the basis of high resolution
1
H NMR and IR analysis. Further investigations of the copolymer
and its application in the biomedical area where cell proliferation
should be inhibited, such as anti-adhesion, are planned in the
immediate future.
Fig. 3. IR (KBr) of (a) poly(p-dioxanone-co-
contents (entry 12, Table 1), (b) poly(p-dioxanone-co-
smallest weight-average molecular weight (entry 1, Table 1), (c) poly(p-
dioxanone-co- -phenylalanine) with largest weight-average molecular weight
entry 10, Table 1).
L
-phenylalanine) with highest
L-Phe
L
-phenylalanine) with
Acknowledgment
L
(
This work was supported financially by the ‘‘Western Light’’
joint researcher program of Chinese Academy of Science.
above, when the copolymerization proceeds under same condi-
tions, more -Phe-NCA content as in-feed, means more active
L
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