Synthesis of poly(l-lactide-co-5-amino-5-methyl-1,3-dioxan-2-ones)[P(L-LA-co-TAc)] containing amino groups via organocatalysis and post-polymerization functionalization

Article abstract of DOI:10.1016/j.polymer.2016.05.064

Poly(l-lactide-co-5-benzyloxycarbonylamino-5-methyl-1,3-dioxan-2-ones) (P(L-LA-co-TMAc)) containing amino groups were synthesized by the ring-opening polymerization of l-lactide(L-LA) and 5-benzyloxycarbonylamino-5-methyl-1,3-dioxan-2-one (TMAc), which wa

Full text of DOI:10.1016/j.polymer.2016.05.064

Accepted Manuscript
Synthesis of poly(L-lactide-co-5-amino-5-methyl-1,3-dioxan-2-ones)[P(L-LA-
co-TAc)] containing amino groups via organocatalysis and post-polymerization
functionalization
Peng Dong, Hao Sun, Daping Quan
PII:
S0032-3861(16)30463-3
10.1016/j.polymer.2016.05.064
JPOL 18725
DOI:
Reference:
To appear in: Polymer
Received Date: 7 March 2016
Revised Date: 21 May 2016
Accepted Date: 24 May 2016
Please cite this article as: Dong P, Sun H, Quan D, Synthesis of poly(L-lactide-co-5-amino-5-methyl-1,3-
dioxan-2-ones)[P(L-LA-co-TAc)] containing amino groups via organocatalysis and post-polymerization
functionalization, Polymer (2016), doi: 10.1016/j.polymer.2016.05.064.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
1
2
Synthesis
of
poly(L-lactide-co-5-amino-5-methyl-1,3-dioxan-2-ones)[P(L-LA-co-TAc)]
containing amino groups via organocatalysis and post-polymerization
functionalization
3
4
5
Peng Dong, Hao Sun and Daping Quan*
6
PCFM Lab, GD HPPC Lab, School of Chemistry and Chemical Engineering, Sun Yat-Sen
University, Guangzhou 510275, China
7
8
9
10
11
12
13
14
15
16
17
18
19
20
*To whom correspondence should be addressed.
TEL (86) 020-84114030
FAX (86) 020-84112245
21
22
E-mail: cesqdp@mail.sysu.edu.cn

ACCEPTED MANUSCRIPT
1
2
Abstract
Poly(L-lactide-co-5-benzyloxycarbonylamino-5-methyl-1,3-dioxan-2-ones) (P(L-LA-co-TMAc))
containing amino groups were synthesized by the ring-opening polymerization of L-lactide(L-LA)
and 5-benzyloxycarbonylamino-5-methyl-1,3-dioxan-2-one (TMAc), which was catalysed by
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in solution or 1,5,7-triazabicyclo[4.4.0]dec-5-ene
(TBD) in bulk. Followed by deprotection under acidic conditions, deprotected copolymer
3
4
5
6
7
poly(L-lactide-co-5-amino-5-methyl-1,3-dioxan-2-ones)[P(L-LA-co-TAc)]
was
prepared.
8
Compared to polymerization reactions catalysed by stannous octoate (Sn(Oct)2), a metallic
catalyst, organocatalysts showed precise control over the composition and polydispersity index of
the copolymers. Proton nuclear magnetic resonance (1H NMR), carbon-13 nuclear magnetic
resonance (13C NMR), gel permeation chromatography (GPC) and differential scanning
calorimetry (DSC) analyses confirmed the polymeric structure and sequence distribution of the
product, which indicated that L-LA and TMAc formed random copolymers. Relatively longer
PLLA segments were incorporated into the copolymer during the initial polymerization period due
to differences in the reactivity of the two monomers, especially in the DBU-catalysed system. And
copolymers with gradient property were obtained. The amino bearing deprotected copolymers
9
10
11
12
13
14
15
16
17
18
19
20
21
22
served
as
macro-initiator
of
the
subsequent
ROP
of
benzyl-L-glutamate-N-carboxyanhydride(BLG-NCA). Finally, the multi-composite graft
copolymer P(L-LA-co-TAc)-g-PBLG was obtained through post-polymerization functionalization.
Introduction
Traditional aliphatic polyesters based on L-lactic acid are widely used as drug delivery carriers

ACCEPTED MANUSCRIPT
1
2
and tissue engineering scaffolds due to their excellent biocompatibility and mechanical
properties[1,2]. However, these types of polyesters do not contain reactive groups for further
modification. To introduce functional groups into polyesters, post modification procedures must
be conducted, or functionalization must be performed at the beginning of the synthetic procedure.
Regarding post modification, polyesters can be treated with a plasma after moulding to generate
reactive groups[3,4] or can be coated with the desired functional material[5]. However, limited
functional groups were incorporated, depending on the strength of the plasma[6–8], and the
chemical groups distributed only on the surface of the material. In addition, the coating layer may
peel off, especially in cell culture environments. To introduce functionality in the beginning of the
synthetic procedure, the ring-opening polymerization (ROP) of lactides or glycolides can be
performed using cyclic monomers with reactive functional groups[9–11]. The content and
distribution of reactive groups in the copolymer chain can be conveniently controlled by changing
the feed ratio of the co-monomers. The chain sequences and topography of the copolymer can also
be designed and fabricated beforehand.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
For functionalization of polyesters, cyclic carbonate monomers bearing reactive groups are
generally adopted to copolymerize D,L/L-lactide and ε-caprolactone (ε-CL) due to their ease of
preparation[12,13]. Various poly(ester-carbonate)s containing functional groups such as
acryloyl[14], azido[15], halogen[16,17], propargyl[18,19], hydroxyl[20,21], carboxyl[22],
amino[23,24] and vinyl-sulfone[25] moieties have been designed and synthesized. Xiuli Hu
started with serinol to prepared cyclic carbonate bearing amino groups. And the monomer was
copolymerized with L-lactide by catalysis of unstable diethyl zinc. RGD peptide was conjugated

ACCEPTED MANUSCRIPT
1
2
to deprotected copolymer facilitating better cell performance[23]. Jinliang Yan used
trans-4-aminocyclohexanol to prepare lactone containing amino groups. The functional lactone
copolymerized with ε-caprolactone(ε-CL) by catalysis of Sn(Oct)2. After deprotection, biotin was
attached to the copolymer[24]. Compared to complex synthetic routes for the formation of
functionalized lactones[9,26], such as morpholine-2,5-dione derivatives[27,28], simpler synthetic
procedures and superior controllability of the polymerization reaction are achieved in the
functionalization of cyclic carbonates. Thus, the polymerization of functionalized carbonates has
received significant attention in recent years [29,30].
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Stannous octoate (Sn(Oct)2) is a general catalyst approved by the FDA for use in ROP. Several
functionalized poly(ester-carbonate)s have been synthesized using Sn(Oct)2 as a catalyst at high
o
temperatures (>100 C) and long reaction times (>24 h), either in bulk or in solution. The
incorporated carbonate monomer ratios were closely aligned with the feed ratios, especially
carbonate monomers containing stable and unprotected reactive groups, such as acryloyl[14] or
azido[31]groups. However, cyclic carbonate monomers with benzyl- and benzoic-protected groups
showed poor tolerance for the required high temperatures and long reaction times. Because side
reactions such as transesterification or cross-linking could occur under the conditions. As a
consequence, composition of the functional copolymer could derivated far form feed ratio[32].
Moreover, trace amounts of tin might be harmful for applications in biomedical fields[33]. Thus, a
suitable catalyst system must be selected to synthesize functional poly(ester-carbonate)s.
The development of organocatalysts used in ROP provides more options for controlling the

ACCEPTED MANUSCRIPT
1
2
copolymerization of functional cyclic carbonates and lactones under mild conditions[34,35].
Organocatalysts such as pyridine bases[36], N-Heterocyclic carbenes (NHCs)[37,38],
amidines[15], guanidines[39] and organic acids[40] have shown excellent catalytic activity and
can be easily removed from the system. One of the key issues for organocatalysts used in ROP is
their controllability to synthesize copolymer with composition similar to feed ratio. Recently,
Aline et al.[40] studied the sequential and simultaneous copolymerization of ε-caprolactone (ε-CL)
and trimethylene carbonate (TMC) using methanesulfonic acid as catalyst. They proposed
formation of gradient copolymers (PCL-co-PTMC). In fact, in the preparation of
poly(ester-carbonate)s via an organocatalyst, the reactivity ratio of cyclic carbonate monomers
was significantly different from that of the lactone, and statistically random poly(ester-carbonate)
copolymers were difficult to produce. Moreover, differences in the microstructure have a
significant impact on the thermal and mechanical properties of copolymers.And the heterogeneous
distribution of reactive groups along the main polymer chain also affect modification of fucntinal
groups. However, until now, in-depth studies on these important attributes have been not
performed.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Thus, in the present investigation, we aimed to optimize the polymeric system applying
1,8-diazabicyclo undec-5-ene (DBU) and 1,5,7-triazabicyclo [4.4.0] dec-5-ene (TBD) as
organocatalysts. Our work included the selection of the catalysts, exploring the microstructure and
determining
their
effects
on
the
copolymers
of
L-lactide
(L-LA)
and
5-benzyloxycarbonylamino-5-methyl-1, 3-dioxan-2-one (TMAc). Our purpose was synthesis of a
series of amino-containing poly(ester-carbonate) copolymers with well-defined sequences through

ACCEPTED MANUSCRIPT
1
2
simultaneous and sequential copolymerization from L-LA/TMAc. Based on the proposed system,
post-polymerization functionalization was carried out by grafting poly(γ-benzyl-L-glutamates)
(PBLG) onto amino-containing macro-initiator P(L-LA-co-TAc). The post-functionalization was
carried out in a 'graft from' method by ROP of benzyl-L-glutamate-N-carboxyanhydrides
(BLG-NCA). Finally, a comb-like copolymer was obtained, which exhibited interesting behaviour
in different solvents.
3
4
5
6
7
8
Experimental sections
9
Materials
10
11
12
13
14
15
16
17
18
19
20
21
22
Benzyl chloroformate (≥99.5%), 2-amino-2-methyl-1,3-propanediol (AMPD, ≥99.0%) and
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) were purchased from Acros. Stannous octoate
(Sn(Oct)2 96%) was purchased from Alfa Aesar, and ethyl chloroformate (≥99.5%) was purchased
from Energy Chemical, Shanghai. The above-mentioned reagents were used as received.
L-Lactide(L-LA) was purchased from Foryou Medical Devices Co., LTD, Huizhou, and was
recrystallized twice from dry ethyl acetate. 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU, 99%) was
purchased from Acros and distilled under vacuum over CaH2. Dodecanol (97%) was purchased
from Alfa Aesar and was dried using 4 Å molecular sieves. Sodium bicarbonate, anhydrous
magnesium sulfate and sodium chloride were obtained from Guangzhou, a chemical reagent
manufacturer. Ethyl acetate, anhydrous diethyl ether and n-hexane were purchased from Fuyu
chemical, Tianjin. Tetrahydrofuran (THF) was distilled in the presence of calcium hydride prior to
use. Triethylamine (Et3N) was sequentially distilled over phthalic anhydride and calcium hydride.
Toluene and dichloromethane (DCM) were distilled with calcium hydride and were stored in the

ACCEPTED MANUSCRIPT
1
2
presence of 4 Å molecular sieves.
3
Measurements
4
1H (300 MHz) and 13C NMR (75 MHz) spectra were obtained in deuterated chloroform (CDCl3,
99.5 atom % D with 0.03% v/v TMS), DMSO-d6 (D, 99.9%+0.03% v/v TMS) or a mixture of
deuterated chloroform and trifluoroacetic acid-d (for graft copolymers, v/v=90/10) using a
Mercury-Plus 300 spectrometer (Varian, Inc. America).
5
6
7
8
Gel permeation chromatography (GPC) measurements were performed on a Waters 1525 binary
high pressure liquid chromatography (HPLC) pump equipped with 3 Ultra Styragel columns and a
Waters 2414 refractive index detector (Waters Alliance GPC2000, Waters Corporation, America).
To characterize the copolymers, THF was used as an eluent at a flow rate of 1 mL/min at 40oC.
The number-averaged molecular weight (Mn) and polydispersity index (PDI) were calculated
using Waters GPC Software, and narrowly dispersed polystyrenes were employed as calibration
standards. To characterize the graft copolymers, DMF containing 0.5% LiBr was used as an eluent
at a flow rate of 1 mL/min at 40℃. The number-averaged molecular weight (Mn) and
polydispersity index (PDI) were calculated using Waters GPC Software, and narrowly dispersed
polyethylene oxide (PEO) was employed as calibration standards.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
The thermal properties of the polymers were determined on a TA Instruments Q10 Differential
Scanning Calorimeter (DSC). The enthalpy (cell constant) and temperature were calibrated by
running high-purity indium and gallium standards under conditions identical to those used to
measure the samples.

ACCEPTED MANUSCRIPT
1
2
Monomer synthesis. 5-Benzylcarbonylamino-5-methyl-1,3-dioxan-2-one (TMAc) was prepared
in two steps, according to the method of Xiabing Jing and coworkers, with several
modifications[41]. Briefly, benzyl chloroformate (16.2 mL, 104 mmol) was dissolved in THF, and
the resulting solution was added dropwise into a 1 M sodium bicarbonate solution of AMPD (10 g,
95 mmol). The mixture was stirred for one day at room temperature. Subsequently, the THF was
removed by rotary evaporation under vacuum, and the residues were extracted with ethyl acetate
(3×200 mL). The organic phase was collected to afford the crude product, which was
recrystallized from ethyl acetate/n-hexane to obtain the product as white crystals (AMPD-Cbz,
18.6 g, 77.8 % yield): 1H NMR(300 MHs, CDCl3): δ =7.35-7.40（s, -CH2C6H5, 5H）, 5.05-5.10 (s,
-CH2C6H5, 2H), 3.6-3.7 ( d, HOCH2C[CH3]-, 2H), 3.75-3.85 (d, HOCH2C[CH3]-, 2H), 1.20 ( s,
HOCH2C[CH3]-, 3H) ppm.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Dried Et3N (14.46 mL, 40 mmol) in 50 mL of anhydrous THF was added dropwise to a solution of
ethyl chloroformate (8.74 mL, 40 mmol) and AMPD-Cbz (10 g, 37.7 mmol) over 2 hours in an ice
bath. The reaction was performed at room temperature for another 8 hours after Et3N addition.
Next, the mixture was filtered, and the filtrate was concentrated. The crude product was
recrystallized twice from THF/diethyl ether to obtain the product as pale white crystals (7.9 g,
71.3 % yield). 1H NMR (300 MHs, CDCl3): δ =7.35 (s, -CH2C6H5, 5H), 5.13-5.23 (br,
-C[CH3]NHCO, 1H), 5.09 (s, -CH2C6H5, 2H), 4.63 (d, -COOCH2C[CH3]-, 2H), 4.19 (d,
-COOCH2C[CH3]-, 2H), 1.43 (m, -C[CH3]NHCO-, 3H) ppm.

ACCEPTED MANUSCRIPT
1
2
Typical Procedure for the random copolymerization of L-LA and TMAc catalysed by DBU
in DCM. The random copolymerization of L-LA and TMAc was conducted in DCM. Specifically,
0.206 g of TMAc (0.74 mmol), 1.0 g of L-LA (6.94 mmol) and 17.4 ꢀL of dodecanol (7.68×10-2
mmol) were dissolved in 3.6 mL of solvent to maintain a monomer concentration of 1 M. After the
monomers were completely dissolved, 561 ꢀL of a solution of DBU (10 ꢀL/mL in DCM,
7.68×10-2 mmol) was added to the system. The polymerization was conducted at 25 °C and was
terminated by adding acetic acid after 4 hours. The polymer was precipitated by adding 100 mL of
anhydrous diethyl ether twice to remove unreacted monomers. The final precipitate was dried in a
vacuum oven for 48 hours to yield approximately 1.103 g of white polymer (91.4 % yield).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Typical procedure for the block copolymerization of L-LA and TMAc catalysed by DBU in
DCM. Sequential polymerization was performed to obtain block copolymers of L-LA and TMAc.
In a typical synthesis of PL-LA-b-PTMAc ([TMAc]/[L-LA]=10/90], 1.0 g of L-LA (6.94 mmol)
and 17.45 ꢀL of dodecanol (7.68×10-2 mmol) were dissolved in 3.6 mL of anhydrous DCM to
maintain a monomer concentration of 1 M. After the monomers were completely dissolved, 561
ꢀL of DBU (10 ꢀL/mL in DCM) was added. The polymerization was performed for 4 hours, then
0.206 g of TMAc (0.74 mmol) was added under argon. The polymerization was continued for
another 4 hours and was terminated by adding acetic acid. The polymer was purified as described
above, providing 1.192 g of white polymer (98.8 % yield).
Typical procedure for the random copolymerization of L-LA and TMAc catalysed by
Sn(Oct)2 in toluene. To 4 mL of anhydrous toluene, 0.206 g of TMAc (0.74 mmol), 1.0 g of L-LA

ACCEPTED MANUSCRIPT
1
2
(6.94 mmol) and 5.4 ꢀL of dodecanol (2.38×10-2 mmol) were added and were dissolved
completely. After the dissolution of the monomers was complete, 1.24 mL of Sn(Oct)2 in toluene
(10 ꢀL/mL in toluene, 3.84×10-2 mmol) was added to the system. The polymerization was
conducted for 48 hours at 100°C and was terminated by immersing the system in an ice bath.
Finally, the polymer was purified as described above.
3
4
5
6
7
Typical procedure for the random copolymerization of L-LA and TMAc catalysed by TBD in
the bulk state. To a vial that was subsequently sealed under vacuum, 0.204 g of TMAc (0.77
mmol), 1 g of L-LA (6.94 mmol), 16.1 mg of TBD (0.115 mmol) and 17 ꢀL of 1-dodecanol
(7.5×10-2 mmol) were added. The polymerization was conducted at 110 °C for 2 hours and was
terminated by adding acetic acid. The polymer was purified twice in accordance with the
previously described procedure.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Typical deprotection procedure for P(L-LA-co-TMAc). To 10 mL of trifluoroacetic acid (TFA),
0.5 g of P(L-LA-co-TMAc7.5%) (0.056 mmol) was added, and the mixture was stirred until
complete dissolution was achieved. Subsequently, 10 mL of 33 % HBr in acetic acid was added,
and the deprotection reaction was performed for 2 hours. Upon completion, diethyl ether was
added to precipitate the product. The deprotected copolymers were dissolved in CH2Cl2, and
triethylamine (TEA) was added to the neutralize acid used in the deprotection reaction. After
filtering off the TEA salts, diethyl ether was added to the solution. The resulting precipitate was
collected and dried in a vacuum oven for 48 hours.

ACCEPTED MANUSCRIPT
1
2
Typical procedure for the ROP of BLG-NCA. To dry DMF, 0.05 g of P(L-LA-co-TAc6.2%)
(5.6x10-3 mmol) was added, followed by addition of 0.741 g BLG-NCA (2.8 mmol). After
complete dissolution, the polymerization reaction was conducted under vacuum. After 4 hours,
diethyl ether was added to terminate the reaction. The precipitate was collected and dried in a
vacuum oven for 48 hours.
3
4
5
6
7
Results and discussions
8
Kinetics of the DBU-catalysed ring-opening copolymerization of L-LA and TMAc
DBU has been used to catalyse the ROP of L-LA and many other carbonate monomers under mild
conditions[42]. To investigate the copolymerization behaviour of L-LA and TMAc, equal
concentration of the monomers ([TMAc]/[L-LA] =50:50) was polymerized in DCM using
9
10
11
12
13
14
15
16
17
18
19
20
21
22
dodecanol
as
an
initiator
at
a
monomers/initiator/catalyst
ratio
of
( [TMAc]/[L-LA]/[dodecanol]/[DBU])=50:50:1:1. The polymerization kinetics of L-LA and
TMAc were monitored by 1H NMR, and the results are shown in Figure 1. After 15 minutes, the
conversion of L-LA reached 49%, while only 30% TMAc conversion was observed. These results
1
were directly obtained from the H NMR spectra of aliquots of the copolymerization mixture in
CDCl3. At a reaction time of 65 minutes, the conversion rates of the two monomers were nearly
the same. As the reaction time increased continuously, the polymerization rate of TMAc increased.
Specifically, after 3 hours, the conversion of TMAc reached 80%, while the conversion of L-LA
was only 71%. In the beginning of the reaction (<15 minutes), the polymerization rate of L-LA
was
faster
than
that
of
TMAc,
and
it
reversed
later.
Therefore,
poly(L-lactide-co-5-benzyloxycarbonylamino-5-methyl-1,3-dioxan-2-one) (P(L-LA-co-TMAc))

ACCEPTED MANUSCRIPT
1
2
copolymers with gradient distributions were formed, possessing higher L-LA contents at
beginning near initiator and higher TMAc contents at the end. The reactivity ratio of L-LA and
TMAc (γL-LA, and γTMAc) was determined using the K-T method[43] which required conversions of
the monomers were less than 10%. The conversion, feed ratio (f) and composition (F) of the
monomers were converted to K-T parameters[44], including G, F′, α, η and ξ, as shown in Figure
S1. Based on the intercept and slope of the figure, we got γL-LA=0.95, and γTMAc=0.073. The
reactivity ratio of L-LA and TMAc suggested they could form random copolymers. The relatively
longer PLLA segment may have been incorporated into the copolymer during the initial
polymerization period (scheme 1) due to differences in the copolymerization activities of the
monomers.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Figure 1. Consumption of L-LA and TMAC versus reaction time which was catalysed by DBU, the red line and dash line were guidance
of monomer consumption.
19
20
21
22

ACCEPTED MANUSCRIPT
1
O
O
1.DBU, 25 oC.
O
O
O
O
2.TBD, 110 oC
O
O
11
H
y
OH
11
+
x
O
O
O
O
O
+
O
1. DCM.
2. Bulk state
O
N
y
O
HN
H
2x
O
O
O
O
11
H
33% HBr in HOAc, TFA
O
11
H
O
O
O
O
O
O
y
O
HN
O
y
O
NH2
2x
2x
O
2
3
Scheme 1. Synthesis of P(L-LA-co-TMAc) catalysed by either DBU in solution or TBD in bulk. And deprotection of P(L-LA-co-TMAc)
4
5
via combination of 33% hydrobromic acid in acetic acid and trifluoroacetic acid.
6
Copolymerization of L-LA and TMAc catalysed by DBU in DCM
7
To investigate the controllability of the copolymerization of L-LA and TMAc, we carried out the
simultaneous copolymerization of L-LA and TMAc in a single step. DBU served as the catalyst
and [TMAc]/[L-LA] feed ratios were set of 10/90, 20/80 and 50/50 in DCM at 25°C (Table 1,
entry 1-3). n-Dodecanol was used as an initiator. The reaction time was set to 4 h because the
conversion of L-LA and TMAc exceeded 90 % and 81-84 %, respectively. The obtained
P(L-LA-co-TMAc) copolymer was terminated by adding acetic acid after 4 hours. The copolymer
was precipitated by adding 100 mL of anhydrous diethyl ether twice to remove unreacted
8
9
10
11
12
13
14
15
16
17
1
monomers. The signal corresponding to the methyl group of n-dodecanol was observed in the H
NMR spectra of all of the copolymers. It was used to determine the composition and the molecular
weight (Mn,NMR) of the copolymers. Moreover, the presence of the methyl signal confirmed the
fidelity of the end group.

ACCEPTED MANUSCRIPT
1
2
As shown in Table 1, the number-averaged molecular weight (Mn,NMR) of the resulting
1
copolymer, which was estimated from the H NMR data, decreased with an increase in the
3
monomer feed ratios of [TMAc]/[L-LA]. It deviated from the theoretical number-averaged
molecular weight (Mn,theo), which was calculated from the initial ratio of [M]/[initiator]. The
corresponding GPC curves (Figure 2) were unimodal, but the molecular weight distributions were
slightly broader than that of the DBU-catalysed system reported in the literature[42]. However,
upon changing [TMAc]/[L-LA] during the simultaneous copolymerization catalysed by DBU
indicated in Table 1(run 1-3), the copolymer composition matched well. Whereas, for the system
applying Sn(Oct)2 as catalyst, the content of incorporated TMAc units was less than 10%, even
though the monomer feed ratios of [TMAc]/[L-LA] reached 50/50 (Table 1, entry 4-6). For DBU,
the final molecular weights of the obtained copolymers did not perfectly match the targeted values
only for entry with a high TMAc content. However, the composition of the copolymers matched
the feed ratios well regardless of TMAc contents. In these cases, the situation was quite different
from what Sn(Oct)2 did. Both molecular weight and functional monomer ratio of the copolymer
catalysed by Sn(Oct)2 were derivative from the feed.
4
5
6
7
8
9
10
11
12
13
14
15
16
17
Table 1. Copolymerization results catalysed by DBU, Sn(Oct)2 and TBD
[TMAc]/[L-LA]/[I]/
CL-LA/%
3
CTMAc/%
Mn/(kg
mol-1)6
Mn/(kg
mol-1)7
group
entry
f
/%1
T/oC4
Time/h5
PDI8
Tg/oC9
Tm/oC9
[C]2
3
DBU
random
1
2
3
10.0
19.8
49.6
10/90/1/1
20/80/1/1
50/50/1/1
>90
>90
>90
82
81
84
25.0
25.0
25.0
4
4
4
14.0
14.8
17.8
14.7
9.33
6.67
1.36
1.36
1.34
43.6
27.9
3.90
133.3
109.9
NA
copolymeriz
ation
Sn(Oct)2
random
4
5
6
3.71
5.73
8.20
10/90/1/0.1
20/80/1/0.1
50/50/1/0.1
>87
>90
>85
42
38
30
100
100
100
48
48
48
12.6
12.6
10.3
13.4
8.41
6.74
1.33
1.25
1.22
48.7
47.3
39.8
144.6
139.1
131.1
copolymeriz
ation
DBU block
copolymeriz
ation
7
8
10.0
18.2
10/90/1/1
20/80/1/1
>90
>90
85
82
25.0
25.0
8
8
14.1
14.9
11.7
9.30
1.31
1.24
38.3
49.4
138.4
136.3
9
7.50
17.1
30.5
100
10/90/1/1.5
20/80/1/1.5
50/50/1/1.5
100/0/1/1.5
>90
>90
>90
/
84
70
73
80
110
110
110
110
2
2
2
2
15.5
16.6
20.6
26.7
13.9
10.4
3.01
1.30
1.34
1.30
1.10
1.01
45.2
42.6
158.8
NA
TBD
random
10
11
12
copolymeriz
ation
-9.90
-32.4
NA
NA
18
19
20
21
1.TMAc ratio in copolymers; 2.Feed ratio of TMAc, L-LA, initiator and catalyst. The amount of catalyst has been optimized by pre-experiment; 3.
Conversion of L-LA and TMAc was determined by 1H NMR; 4. Temperature of polymerization conducted; 5. Polymerization time; 6. Theoretical
molecular weight calculated via 186+144
×(1-f)×CL-LA+265×f× ×186+I5.2 ppm/2×144+I7.3
CTMAc; 7. Molecular weight characterized by 1H NMR via I1.9 ppm/3
ppm/5 265; 8. Molecular weight distribution characterized by GPC; 9. Glass transition temperature and melting temperature determined by DSC.
×

ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Figure 2. GPC traces of P(L-LA-co-TMAc10.0%), P(L-LA-co-TMAc19.8%) and P(L-LA-co-TMAc49.6%) using THF as eluant at 313K.
The chemical structure of P(L-LA-co-TMAc) was confirmed by 1H NMR and 13C NMR analyses.
1
16
17
18
19
20
21
22
23
24
25
26
27
28
The H NMR spectrum of P(L-LA-co-TMAc49.6%)(Figure 3, Table 1, entry 3) revealed the
distinct peaks of the methyl and methylene group of the PL-LA segment, which were observed in
the range of 1.56 ppm and 5.6 ppm. The peaks corresponding to phenyl and benzylic protons, as
well as the methylene protons adjacent to the carbonate linkage and the methyl group of TMAc
residual segments, appeared between 7.3 ppm and 7.5 ppm, 5.0 ppm, 4.2 ppm and 4.4 ppm and 1.3
ppm, respectively. In addition, the peak due to the methyl protons adjacent to the α-chain end of
the initiator was also clearly observed at 0.9 ppm, indicating that n-dodecanol successfully
initiated the ring-opening copolymerization of L-LA with TMAc.

ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
8
Figure 3. 1H NMR spectrum of P(L-LA-co-TMAc49.6%) using DMSO-d6 as solvent at 298K. 49.6% means TMAc ratio in the
copolymer.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Further details of the sequence distribution were obtained from the 13C NMR spectrum (Figure 4,
Table 1, entry 1). The carbonyl group in both the carbonate and ester bonds showed the expected
shifts due to the presence of the predicted triad sequences of L-LA units (L) and TMAc units (T),
including LLL, TTT, LLT, LTL, TLL, TTL, TLT and LTT. Therefore, upon enlarging the carbonyl
region of the spectrum, five resonance signals were observed (168.9, 168.7, 168.6, 154.4, 153.2
ppm) and were assigned to the carbonyl group of the copolymer. Compared to homopolymers of
PL-LA and PTMAc, the strong signal at 168.9 ppm was attributed to the LLL triad, and the signals
at 168.7 ppm and 168.6 ppm were assigned to the LLT and TLL triad, respectively. The observed
shift in the latter two peaks was due to the incorporation of TMAc blocks. The signal at 154.4 ppm
was assigned to the LTL triad, and the peak at 153.2 ppm was attributed to the LTT or TTL triad.
The TTT triad was not detected because the average length of the TMAc units (LTMAc) was 1.2
(Table S1) for run 2, and the content of the TTT triad in the chain was low, as shown in the 13C
NMR spectrum. Conversely, the average length of L-LA units (LL-LA) was 11.2 for run 1 and 4.8

ACCEPTED MANUSCRIPT
1
2
for run 2; thus, LLL was clearly obtained. Moreover, differential scanning calorimetry (DSC,
Figure S2a) showed a melting point associated with a relatively longer PLLA segment for run 1-2
and a fully amorphous copolymer for run 3, which is in accordance with the sequence distribution
observed in the13C NMR spectrum. In addition, as the amount of TMAc increased from 10 to 50
percent, only one glass transition temperature (Tg) was observed (microphase separation did not
occur) (Figure S2b), which decreased from 43.6 to 3.9 °C due to the lower chemical regularity of
the polymer chains, as well as the lower molecular weight. Further, the 13C NMR spectra (Figure 5,
Table 1, entry 7) of the PL-LA-b-PTMAc block copolymer synthesized according to the method
shown in Scheme S1. It possessed a similar composition and molecular weight compared to the
aforementioned gradient copolymer. For the block copolymer, only two sequences of LLL (169.7
ppm) and TTT (155.2 ppm) were detected, and the DSC curve (Figure S2c) showed that the Tg of
block copolymers was higher than that of random copolymers with the same composition due to
their semi-crystalline characteristics.
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Figure 4. 13C NMR spectrum of P(L-LA-co-TMAc10.0%) using DMSO-d6 as solvent at 298K. Inserted graph showed traid signals of
carbonyl groups in the copolymer. 10.0% means TMAc ratio in the copolymer.

ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
Figure 5. 13C NMR spectrum of PL-LA-b-PTMAc10.0% using DMSO-d6 as solvent at 298K. Inserted graph showed traid signals of
8
carbonyl groups in the copolymer.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
Copolymerization of L-LA and TMAc catalysed by TBD in the bulk and deprotection
Considering that the proposed method is an environmentally friendly and easy procedure for
industrial processes, we hoped that the copolymerization of L-LA and TMAc could be conducted
during bulk polymerization. Hence, we conducted the ROP copolymerization of L-LA and TMAc
catalysed by TBD in the bulk. TBD effectively catalysed the ROP copolymerization of L-LA and
TMAc in 2 hours at 110 °C. But the same reaction failed using the DBU catalysis system, even
after 24 hours. As shown in Table 1 (run 9-12), the molecular weight of the copolymer was less
than the theoretical value for the TBD-catalysed system, but the resulting composite was similar to
the feed ratios, and the distribution of the molecular weight was narrow, especially for the
copolymer with a higher TMAc ratio. Considering that the reactivity ratio of L-LA and TMAc
catalysed by TBD in bulk was γL-LA=1.396 and γTMAc=0.017, respectively (Figure S3), and the
average length of L-LA units (LL-LA) was 5.12 for run 9 and 3.3 for run 10, as determined by13C
NMR, transesterification likely occurred during the copolymerization process, which increased the

ACCEPTED MANUSCRIPT
1
2
random orientation of the polymer chains compared to the DBU system.
To produce free amino groups in the copolymers, hydrobromic acid combined with trifluoroacetic
acid was used to remove carbobenzoxy groups[45,46]. Residual acid can be easily removed by
neutralization after deprotection (scheme 1). Copolymer P(L-LA-co-TMAc7.5%)(Table 1, entry 9)
was used to removed the carbobenzoxy group. The1H NMR spectra showed that the signals of the
phenyl protons (7.3-7.5 ppm) and methylene protons present in benzyl groups (5.0 ppm) were
nearly gone after 2 hours, as shown in Figure 6a and 6b. The molecular weight of P(L-LA-co-TAc)
decreased from 13.9 kg/mol to 10.3 kg/mol when the carbobenzoxy groups were removed, and the
degradation occurred during this process both indicated in 1H NMR spectra and GPC
curves(Figure 6). Free amino groups did not cause obvious depolymerization, which was
illustrated by a unimodal peak of P(L-LA-co-TAc). Besides, amino groups were protonated in the
acidic condition, transesterification caused by the amino groups could be reduced. And the strong
acidic condition was responsible for the degradation. Moreover, the Degradation of
P(L-LA-co-TAc) can be suppressed when the deprotection was carefully conducted in ice bath in
dicated by GPC traces (Figure S4).
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29

ACCEPTED MANUSCRIPT
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
Figure 6. a) 1H NMR spectrum of P(L-LA-co-TMAc7.5%). Circles indicated signal of phenyl proton (blue) and methylene of benzyl
proton (red). b) 1H NMR spectrum of P(L-LA-co-TMAc6.2%). c) GPC traces of P(L-LA-co-TMAc7.5%) and P(L-LA-co-TAc6.2%)
using THF as eluant at 313K.
Post-polymerization functionalization of P(L-LA-co-TAc)
30
31
32
33
34
35
The pendent amino groups in P(L-LA-co-TAc) copolymer can act as anchor sites for further
functionalization. A typical example is the ROP of α-amino acid N-carboxyanhydrides (NCA)
initiated by the primary amines in the copolymer for the synthesis of P(L-LA-co-TAc)-grafted
peptide copolymers (Scheme 2). Following the 'graft from' method, the multi-composite graft
copolymer of P(L-LA-co-TAc)-grafted poly(γ-benzyl-L-glutamate) [P(L-LA-co-TAc)-g-PBLG]
was produced under vacuum[50] for 2 or 4 hours. Results of the copolymerization were shown in

ACCEPTED MANUSCRIPT
1
2
Table 3. In order to decrease the possible degradation of the precopolymers, the ROP reaction of
NCA was carried out under vacuum to accelerate the ROP reaction. For the entry 3, 4 hours
reaction time was selected considering the high amount of NCA monomer. It was also found that
the final degrees of polymerization were similar to the feed ratios, indicating the good
controllability of the ROP polymerization of NCA by the prepolymers bearing primary amino
groups.
3
4
5
6
7
Gel permeation chromatography (GPC) was used to confirm successful synthesis of the
[P(L-LA-co-TAc)-g-PBLG]. The GPC curve of P(L-LA-co-TAc) (Fig. 7 b) disappeared, and
elution curve for the PBLG-modified P(L-LA-co-TAc) copolymers (Fig. 7 b) appeared at an
earlier time in a monomodal manner. Shift of GPC trace indicated efficient ROP of NCA.
However, the molecular weights obtained from the GPC and NMR was quite different (Table 3).
Inherent structure difference of P(L-LA-co-TAc)-g-PBLG and PEO, a standard calibration used in
GPC, should be responsible for the Mn difference in Table 3. After graft polymerization, the
polydispersity index of the grafting copolymer increased.
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1
In the H NMR spectrum (Figure 7 a, Table 3, entry 3), the peaks at 7.21 ppm, 5.03 ppm, 4.10
ppm and 2.00-2.75 ppm were assigned to the hydrogen in the benzene ring, methylene hydrogen
of benzyl, methine and methylene hydrogen of PBLG. The DP of the PBLG was calculated based
on methine of lactide and methylene of benzyl group on grafted PBLG, DPPBLG=0.5×I5.03 ppm/5.0,
5.0 was average number of amino groups on deprotected copolymer P(L-LA-co-TAc6.2%)
.
Thus we revealed that DBU and TBD were efficient organocatalysts for the ROP of L-LA and
TMAc in solvent and in bulk respectively, affording higher content of amino groups to synthesis
well-defined P(L-LA-co-TAC)-g-PBLG. In other words, a multi-composite grafting copolymer
can be obtained through post-polymerization functionalization.
24
25
26

ACCEPTED MANUSCRIPT
1
2
Scheme 2. Synthesis of P(L-LA-co-TAc)-g-PBLG via “graft from” method.
3
4
Table 3. Grafting PBLG to P(L-LA-co-TAc6.2%) via “graft from” method
4
DP of
PBLG2
4.50
Mn/ (kg
mol-1)3
16.3
Mn/(kg
mol-1)4
14.1
Mw/Mn
Entry
Time/h
[BLG-NCA]/[-NH2]1
1
2
3
2
2
4
5.0
20
50
1.34
1.30
1.40
20.0
49.8
35.9
71.5
27.0
38.7
5
6
Where 1 was feed ratio of BLG-NCA to amino groups in deprotected copolymer; 2 was calculated based on methyne of lactide and
methylene of benzyl group on grafted PBLG. DPPBLG=0.5×I5.03 ppm/5.0, 5.0 was average number of amino groups on deprotected
7
copolymers P(L-LA-co-TAc6.2%) 3. molecular weight characterized by H NMR, Mn=0.5×I5.0 ppm/N×264+Mn,
chain; 4.
main
8
characterized by GPC, mobile phase was DMF containing 0.5%(m/v) LiBr
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34

ACCEPTED MANUSCRIPT
1
2
3
Figure 7. a) 1H NMR spectrum of P(L-LA-co-TAc6.2%)-g-PBLG49.8. 49.8 means degree of polymerization(DP) of PBLG. b) GPC traces
of P(L-LA-co-TAc6.2%) and P(L-LA-co-TAc6.2%)-g-PBLGx (x is DP of PBLG) using DMF containing 0.5%(w/v) LiBr as eluant at
313K..
4
5
Conclusions
6
Amino bearing poly(ester-carbonate)s were synthesized using DBU (in solvent) and TBD (in bulk)
as organocatalysts. L-LA and TMAc formed random copolymers, but relatively longer PLLA
segments were likely incorporated into the copolymer in the initial polymerization period (scheme
1) due to differences in the copolymerizing activity of the comonomer, especially in the DBU
system. However, compared to the Sn(Oct)2 system, which can be used to initiate NCA, highly
functionalized groups were incorporated into the copolymer. Finally, P(L-LA-co-TAc)-g-PBLG, a
multi-composite grafted copolymer, was obtained via post-polymerization functionalization.
7
8
9
10
11
12
13
14
15
16
17
18
19
Acknowledgements
The authors acknowledge financial support from the National Natural Science Foundation of
China (Grant No. 5107378 and U1134007), Guangdong Natural Science Foundation
(2015A030311025) and the Major Project of Health and Medical Collaborative Innovation of
Guangzhou (201508020251)
20
21
22
23
24
25
26
References
[1]
S. Bose, M. Roy, A. Bandyopadhyay, Recent advances in bone tissue engineering scaffolds,
Trends in Biotechnology. 30 (2012) 546–554.
[2]
L. He, Y. Zhang, X. Zeng, D. Quan, S. Liao, Y. Zeng, et al., Fabrication and characterization of
poly(l-lactic acid) 3D nanofibrous scaffolds with controlled architecture by liquid-liquid phase
separation from a ternary polymer-solvent system, Polymer. 50 (2009) 4128–4138.
W. Liu, J. Zhan, Y. Su, T. Wu, C. Wu, S. Ramakrishna, et al., Effects of plasma treatment to
[3]

ACCEPTED MANUSCRIPT
1
2
nanofibers on initial cell adhesion and cell morphology, Colloids and Surfaces B: Biointerfaces.
113 (2014) 101–106.
3
[4]
L.S. Dolci, S.D. Quiroga, M. Gherardi, R. Laurita, A. Liguori, P. Sanibondi, et al., Carboxyl
Surface Functionalization of Poly( <scp>L</scp> -lactic acid) Electrospun Nanofibers through
Atmospheric Non-Thermal Plasma Affects Fibroblast Morphology, Plasma Processes and
Polymers. 11 (2014) 203–213.
4
5
6
7
[5]
[6]
G. Wu, P. Li, H. Feng, X. Zhang, P.K. Chu, Engineering and functionalization of biomaterials
via surface modification, J. Mater. Chem. B. 3 (2015) 2024–2042.
8
9
Z. Kolská, A. Řezníčková, M. Nagyová, N. Slepičková Kasálková, P. Sajdl, P. Slepička, et al.,
Plasma activated polymers grafted with cysteamine improving surfaces cytocompatibility,
Polymer Degradation and Stability. 101 (2014) 1–9.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
[7]
[8]
S. Sarapirom, L.D. Yu, D. Boonyawan, C. Chaiwong, Effect of surface modification of
poly(lactic acid) by low-pressure ammonia plasma on adsorption of human serum albumin,
Applied Surface Science. 310 (2014) 42–50.
S. Rimpelová, L. Peterková, N.S. Kasálková, P. Slepička, V. Švorčík, T. Ruml, Surface
Modification of Biodegradable Poly(L -Lactic Acid) by Argon Plasma: Fibroblasts and
Keratinocytes in the Spotlight, Plasma Processes and Polymers. 11 (2014) 1057–1067.
W.W. Gerhardt, D.E. Noga, K.I. Hardcastle, A.J. García, D.M. Collard, M. Weck, Functional
lactide monomers: methodology and polymerization., Biomacromolecules. 7 (2006) 1735–42.
M. Trollsås, V.Y. Lee, D. Mecerreyes, P. Löwenhielm, M. Möller, R.D. Miller, et al.,
Hydrophilic aliphatic polyesters: design, synthesis, and ring-opening polymerization of
functional cyclic esters, Macromolecules. 33 (2000) 4619–4627.
[9]
[10]
[11]
[12]
[13]
[14]
A.M. Fischer, R. Thiermann, M. Maskos, H. Frey, One-pot synthesis of poly(l-lactide)
multi-arm star copolymers based on a polyester polyol macroinitiator, Polymer. 54 (2013)
1993–2000.
S. Daniel P., F. Kazuki, C. Daniel J., N. Alshakim, F. Masaki, Y. Manabu, et al., A Simple and
Efficient Synthesis of Functionalized Cyclic Carbonate Monomers Using a Versatile
Pentafluorophenyl Ester Intermediate, J. Am. Chem. Soc. 132 (2010) 14724–14726.
J. Undin, P. Olsén, J. Godfrey, K. Odelius, A.-C. Albertsson, Controlled copolymerization of
the non-homopolymerizable, functional monomer α-bromo-γ-butyrolactone via selective
organocatalysis, Polymer. 87 (2015).
W. Chen, H. Yang, R. Wang, R. Cheng, F. Meng, W. Wei, et al., Versatile synthesis of
functional biodegradable polymers by combining ring-opening polymerization and
postpolymerization modification via michael-type addition reaction, Macromolecules. 43 (2010)
201–207.
[15]
[16]
J. Xu, F. Prifti, J. Song, A Versatile Monomer for Preparing Well-Defined Functional
Polycarbonates and Poly(ester-carbonates)., Macromolecules. 44 (2011) 2660–2667.
S. El Habnouni, V. Darcos, J. Coudane, Synthesis and Ring Opening Polymerization of a New
Functional Lactone, α-Iodo-ε-caprolactone: A Novel Route to Functionalized Aliphatic
Polyesters., Macromolecular Rapid Communications. 30 (2009) 165–9.
J. Mindemark, T. Bowden, Synthesis and polymerization of alkyl halide-functional cyclic
carbonates, Polymer. 52 (2011) 5716–5722.
[17]
[18]
B. Parrish, R.B. Breitenkamp, T. Emrick, PEG- and Peptide-Grafted Aliphatic Polyesters by
Click Chemistry PEG- and Peptide-Grafted Aliphatic Polyesters by Click Chemistry,

ACCEPTED MANUSCRIPT
1
2
Biomaterials. 127 (2005) 7404–7410.
[19]
[20]
A. Vora, K. Singh, D.C. Webster, A new approach to 3-miktoarm star polymers using a
combination of reversible addition-fragmentation chain transfer (RAFT) and ring opening
polymerization (ROP) via “Click” chemistry, Polymer. 50 (2009) 2768–2774.
Z. Xie, C. Lu, X. Chen, L.I. Chen, Y.U. Wang, X. Hu, Synthesis and Characterization of Novel
Poly ( ester carbonate ) s Based on Pentaerythritol, J. Polym. Sci. Part A: Polym. Chem. 45
(2007) 1737–1745.
3
4
5
6
7
8
[21]
[22]
[23]
R.H. Lambeth, T.J. Henderson, Organocatalytic synthesis of (poly)hydroxyurethanes from
cyclic carbonates and amines, Polymer. 54 (2013) 5568–5573.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
W.Y. Seow, Y.Y. Yang, Functional polycarbonates and their self-assemblies as promising
non-viral vectors., Journal of Controlled Release. 139 (2009) 40–7.
H. XIULI, C. XUESI, X. ZHIGANG, C. HAIBO, J. XIABIN, Anionic Amphiphilic
End-Linked Conetworks by the Combination of Quasiliving Carbocationic and Group Transfer
Polymerizations, J. Polym. Sci. Part A: Polym. Chem. 46 (2008) 7022–7032.
J. Yan, Y. Zhang, Y. Xiao, Y. Zhang, M. Lang, Novel poly(ε-caprolactone)s bearing amino
groups: Synthesis, characterization and biotinylation, Reactive and Functional Polymers. 70
(2010) 400–407.
[24]
[25]
[26]
R. Wang, W. Chen, F. Meng, R. Cheng, C. Deng, J. Feijen, et al., Unprecedented Access to
Functional Biodegradable Polymers and Coatings, Chemical Engineering. (2011) 6009–6016.
M. Liu, N. Vladimirov, J.M.J. Fre, A New Approach to Hyperbranched Polymers,
Macromolecules. 2 (1999) 6881–6884.
[27] N. Qiang, W. Yang, L. Li, P. Dong, J. Zhu, T. Wang, et al., Synthesis of pendent
carboxyl-containing poly(ε-caprolactone-co-β-malic acid)-block-poly(l-lactide) copolymers for
fabrication of nano-fibrous scaffolds, Polymer. 53 (2012) 4993–5001.
[28]
Z. Xie, H. Guan, X. Chen, C. Lu, L. Chen, X. Hu, et al., A novel polymer–paclitaxel conjugate
based on amphiphilic triblock copolymer, Journal of Controlled Release. 117 (2007) 210–216.
C. Jérôme, P. Lecomte, Recent advances in the synthesis of aliphatic polyesters by
ring-opening polymerization., Advanced Drug Delivery Reviews. 60 (2008) 1056–76.
J. Feng, R.-X. Zhuo, X.-Z. Zhang, Construction of functional aliphatic polycarbonates for
biomedical applications, Progress in Polymer Science. 37 (2012) 211–236.
X. Zhang, Z. Zhong, R. Zhuo, Preparation of Azido Polycarbonates and Their
Functionalization via Click Chemistry, Macromolecules. 44 (2011) 1755–1759.
P. Olsén, J. Undin, K. Odelius, A.-C. Albertsson, Establishing α-bromo-γ-butyrolactone as a
platform for synthesis of functional aliphatic polyesters – bridging the gap between ROP and
SET-LRP, Polymer Chemistry. 5 (2014) 3847.
[29]
[30]
[31]
[32]
[33]
M. Tanzi, P. Verderio, M. Lampugnani, M. Resnati, E. Dejana, E. Sturani, Cytotoxicity of
some catalysts commonly used in the synthesis of copolymers for biomedical use, Journal of
Materials Science: Materials in Medicine. 5 (1994) 393396.
[34]
[35]
M.K. Kiesewetter, E.J. Shin, J.L. Hedrick, R.M. Waymouth, Organocatalysis: Opportunities
and Challenges for Polymer Synthesis, Macromolecules. 43 (2010) 2093–2107.
F. Suriano, O. Coulembier, J.L. Hedrick, P. Dubois, Functionalized cyclic carbonates: from
synthesis and metal-free catalyzed ring-opening polymerization to applications, Polymer
Chemistry. 2 (2011) 528.
[36]
Y.C. Yu, S.J. Shin, K.D. Ko, W.R. Yu, J.H. Youk, One-pot synthesis of poly(vinyl

ACCEPTED MANUSCRIPT
1
2
alcohol)-based biocompatible block copolymers using a dual initiator for ROP and RAFT
polymerization, Polymer. 54 (2013) 5595–5600.
3
[37]
[38]
A.P. Dove, R.C. Pratt, B.G.G. Lohmeijer, D.A. Culkin, E.C. Hagberg, G.W. Nyce, et al.,
N-Heterocyclic carbenes: Effective organic catalysts for living polymerization, Polymer. 47
(2006) 4018–4025.
4
5
6
N.E. Kamber, W. Jeong, S. Gonzalez, J.L. Hedrick, R.M. Waymouth, N-Heterocyclic Carbenes
for the Organocatalytic Ring-Opening Polymerization of ε-Caprolactone, Macromolecules. 42
(2009) 1634–1639.
7
8
9
[39]
[40]
L. Simón, J.M. Goodman, The mechanism of TBD-catalyzed ring-opening polymerization of
cyclic esters., The Journal of Organic Chemistry. 72 (2007) 9656–62.
A. Couffin, D. Delcroix, B. Martín-Vaca, D. Bourissou, C. Navarro, Mild and efficient
preparation of block and gradient copolymers by methanesulfonic acid catalyzed ring-opening
polymerization of caprolactone and trimethylene carbonate, Macromolecules. 46 (2013)
4354–4360.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
[41]
[42]
X. Hu, X. Chen, Z. Xie, H. Cheng, X. Jing, Aliphatic Poly ( ester-carbonate ) s Bearing Amino
Groups and Its RGD Peptide Grafting, Polymer. (2008) 7–9.
B.G.G. Lohmeijer, R.C. Pratt, F. Leibfarth, J.W. Logan, D.A. Long, A.P. Dove, et al.,
Guanidine and amidine organocatalysts for ring-opening polymerization of cyclic esters,
Macromolecules. 39 (2006) 8574–8583.
[43]
[44]
[45]
K. Makiguchi, C. Asakura, K. Yanai, T. Satoh, T. Kakuchi, Diphenyl Phosphate-Catalyzed
Ring-Opening Polymerization of 1,5-Dioxepan-2-one, Macromolecular Symposia. 349 (2015)
74–84.
T. Kelen, K. Tüdõs, Analysis of the Linear Methods for Determining Copolymerization
Reactivity Ratios. I. A New Improved Linear Graphic Method, Journal of Macromolecular
Science: Part A - Chemistry. 9 (1975) 1–27.
C. Deng, X. Chen, H. Yu, J. Sun, T. Lu, X. Jing, A biodegradable triblock copolymer
poly(ethylene glycol)-b-poly(l-lactide)-b-poly(l-lysine): Synthesis, self-assembly, and RGD
peptide modification, Polymer. 48 (2007) 139–149.
[46]
[47]
[48]
C.D. Vacogne, S.M. Brosnan, A. Masic, H. Schlaad, Fibrillar gels via the self-assembly of
poly(l-glutamate)-based statistical copolymers, Polym. Chem. 6 (2015) 5040–5052.
Y.S. Nam, T.G. Park, Biodegradable polymeric microcellular foams by modified thermally
induced phase separation method., Biomaterials. 20 (1999) 1783–1790.
F.J. Hua, G.E. Kim, J.D. Lee, Y.K. Son, D.S. Lee, Macroporous poly(L-lactide) scaffold 1.
Preparation of a macroporous scaffold by liquid-liquid phase separation of a
PLLA-dioxane-water system, Journal of Biomedical Materials Research. 63 (2002) 161–167.
A. Niehoff, A. Mantion, R. McAloney, A. Huber, J. Falkenhagen, C.M. Goh, et al., Elucidation
of the structure of poly(γ-benzyl-l-glutamate) nanofibers and gel networks in a helicogenic
solvent, Colloid and Polymer Science. 291 (2013) 1353–1363.
[49]
[50]
R.A. Kowtoniuk, T. Pei, C.M. DeAngelo, J.H. Waldman, E.N. Guidry, J.M. Williams, et al.,
Optimization of an α-(Amino acid)- N -carboxyanhydride polymerization using the high
vacuum technique: Examining the effects of monomer concentration, polymerization kinetics,
polymer molecular weight, and monomer purity, J. Polym. Sci., Part A: Polym. Chem. 52
(2014) 1385–1391.

ACCEPTED MANUSCRIPT
ꢀ
High amount of functional cyclic carbonate, TMAc, was incorprated into
poly(ester-carbonate)s by organocatalysts in a short period of 2 to 4 hours.
Gradient poly(ester-carbonate)s was formed during the copolymerization.
Free amino groups was achieved by deprotection in acidic environment.
Poly(γ-benzyl-L-glutamate)(PBLG) was introduced to the amino bearing macro-initiators via
"graft from" method with high control.
ꢀ
ꢀ
ꢀ