Synthesis of lactide/?-caprolactone quasi-random copolymer by using rationally designed mononuclear aluminum complexes with modified β-ketiminato ligand

Article abstract of DOI:10.1002/pola.28886

A series of novel aluminum complexes containing bulky aryl-β-ketiminato ligands [ArN?CH?C₁₀H₇C₆H₅O]Al(CH₃)₂ (3a, Ar = C₆F₅; 3b, Ar = C₆H₅; 3c, Ar = 2,6-ⁱPr₂C₆H₃) have been synthesized in high yields. These complexes were identified by ¹H and ¹³C NMR spectroscopy, elemental analysis, and X-ray structural analysis. All the aluminum complexes could efficiently catalyze the ROP of ?-caprolactone (?-CL) and Lactide (LA) in a controlled manner. It was found that the steric effect of the ligand has less effect on the ROP of CL, while the polymerization rate of L-LA was suppressed significantly. More interestingly, this kind of catalysts can promote the random copolymerization of ?-CL and L-LA. The transesterification side reaction and the polymer composition could be adjusted by modulating the electronic and steric effects of the ligand. In paticular, compound 3c could produce quasi-random copolymers without transesterification side reactions, as indicated by both the values of the reactivity ratios of the two monomers (r_LA = 1.31; r_CL = 0.99) and the similar average lengths of the caproyl and lactidyl sequences (L_CL = 2.34; L_LA = 2.44). Finally, a drug-random copolymer conjugates could be easily prepared by using 3c, indicating a potential application of 3c in pharmacutical and biomedical field.

Full text of DOI:10.1002/pola.28886

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Synthesis of Lactide/E-Caprolactone Quasi-Random Copolymer by Using
Rationally Designed Mononuclear Aluminum Complexes with Modified
b-Ketiminato Ligand
1,3
Hai-Chao Huang,1 Zong-Jun Li,2 Bin Wang ,1 Xiaolu Chen,1 Yue-Sheng Li
1Tianjin Key Lab of Composite & Functional Materials, School of Materials Science and Engineering, Tianjin University, Tianjin
300072, China
2State Key Laboratory of Electroanalytical Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences,
5625 Renmin Street, Changchun, Jilin 130022, China
3Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, China
Correspondence to: B. Wang (E-mail: binwang@tju.edu.cn) or Y.-S. Li (E-mail: ysli@tju.edu.cn)
Received 19 August 2017; accepted 30 September 2017; published online 00 Month 2017
DOI: 10.1002/pola.28886
ABSTRACT: A series of novel aluminum complexes containing
bulky aryl-b-ketiminato ligands [ArN@CHAC10H7C6H5O]Al(CH3)2
(3a, Ar 5 C6F5; 3b, Ar 5 C6H5; 3c, Ar 5 2,6-iPr2C6H3) have been
synthesized in high yields. These complexes were identified by
1H and 13C NMR spectroscopy, elemental analysis, and X-ray
structural analysis. All the aluminum complexes could effi-
ciently catalyze the ROP of E-caprolactone (E-CL) and Lactide
(LA) in a controlled manner. It was found that the steric effect
of the ligand has less effect on the ROP of CL, while the poly-
merization rate of L-LA was suppressed significantly. More
interestingly, this kind of catalysts can promote the random
copolymerization of E-CL and L-LA. The transesterification side
reaction and the polymer composition could be adjusted by
modulating the electronic and steric effects of the ligand. In
paticular, compound 3c could produce quasi-random copoly-
mers without transesterification side reactions, as indicated by
both the values of the reactivity ratios of the two monomers
(rLA 5 1.31; rCL 5 0.99) and the similar average lengths of the
caproyl and lactidyl sequences (LCL 5 2.34; LLA 5 2.44). Finally, a
drug-random copolymer conjugates could be easily prepared
by using 3c, indicating a potential application of 3c in pharma-
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cutical and biomedical field.
2017 Wiley Periodicals, Inc. J.
Polym. Sci., Part A: Polym. Chem. 2017, 00, 000–000
KEYWORDS: E-caprolactone; L-lactide; mononuclear aluminum
complexes; random aliphatic copolyesters; ring-opening
polymerization
Thus, fine adjusting the composition and distribution of lac-
tide and caprolactone repeat units along polymer chain will
produce the copolymers with balanced drug permeability
and biodegradable behavior, which can meet the requirement
of various applications and is always the goal pursued in the
pharmaceutical and medical fields. Thus, developing efficient
catalyst for LA/E-CL copolymerization is highly demanded
for this purpose.
INTRODUCTION Aliphatic polyesters, as represented by poly-
lactide (PLA) and polycaprolactone (PCL), have been
regarded as a promising alternative to petroleum-based poly-
meric materials, because of their “green environmentally-
friendly” features.1–10 More importantly, owing to remark-
able biodegradable, nontoxic, biocompatible properties, they
have also attracted considerable attentions in the pharma-
ceutical and biomedical field.9,11–14 Nonetheless, the draw-
backs of physical properties of PLA and PCL limit their
further application in certain field, such as drug delivery.
PLA and PCL exhibit supplementary physical properties to
some extent. For example, PLA exhibits good mechanical
strength but poor elasticity, and it has a high degradation
rate in vivo (about a few weeks) as well as low drug perme-
ability.15,16 In sharp contrast, PCL exhibits not only high elas-
ticity and thermal properties, but also remarkable drug
permeability and slow degradation rate in vivo (ꢀ1 year).17
So far, a great variety of organometallics have been used as
the catalysts for polymerizations of LA and E-CL, which
range from traditional stannous18,19 catalysts to main group
catalysts (Na,20–23Mg,24–26 Al27–33, and Ca34–36) and transi-
tion metal (Zn35,37–43 and Ti44) as well as rare earth cata-
lysts.2,45–48 Nonetheless, seldom catalysts can strictly
produce random copolymer poly(LA-r-CL), with the approxi-
mately equal in average length of lactidyl and caproyl
Additional Supporting Information may be found in the online version of this article.
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2017 Wiley Periodicals, Inc.
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SCHEME 1 Typically reported complexes (A–D) and the catalyst (3a–c) used in present work for E-CL/LA random copolymerization.
sequence (LLA 5 LCL 5 2).15,49,50 As an undoubted fact, the
rates of homopolymerization of E-CL and LA are sharply dif-
ferent. The E-CL is consumed faster than LA in homopolyme-
rization, whereas much slower than LA in the
copolymerization.15,50,51 Their substantially distinct reactivity
ratios usually result in block-like copolymers or gradient
copolymers, whose degradation behavior and drug perme-
ability are very different from those of random counter-
parts.49–52 Although the transesterification side reaction can
gradually convert the blocky or gradient copolymers into
tendentially random ones in some case, it is hard to pre-
cisely control the distribution of LA or CL repeat units along
the polymer chain.53
that some chiral NNO-scorpionate zinc initiators also had
good capabilities in E-CL/LA random copolymerization (D,
Scheme 1).55
Our group has dedicated to developing novel aluminum cata-
lysts for LA/E-CL copolymerization, and many kinds of them,
ranging from mononuclear to binuclear catalysts, showed
great success in synthesizing block and gradient copolyest-
ers. For example, a mononuclear aluminum complexes con-
taining N,O-bidentate b-ketiminato ligands (M, Scheme 1)
could catalyze copolymerization of CL and LA in a controlled
manner.56 However, its less crowded space did not suppress
the coordination of LA to Al center enough, only yielding
gradient structure in the copolymerization of E-CL/LA. Con-
sidering that increasing the steric hindrance of the catalyst is
a straightforward strategy for reducing the reactivity of the
LA in the random copolymerization, bulky aryl groups were
introduced at the ortho position in the benzene ring (3a–c,
Scheme 1). Thus, we documented the synthesis of aluminum
complexes with modified b-ketiminato ligand and their appli-
cations in the random copolymerization of E-CL and LA in
present work. As expected, bulky group could retard the
ROP of LA, while showed no significant effects on the CL
copolymerization. Moreover, transesterification side reactions
can be avoided at high conversion and/or high temperature,
and quasi-random E-CL/LA copolymer with similar average
length of caproyl and lactidyl sequences can also be easily
prepared.
As far as we concern, only very limited organometallic cata-
lysts can successfully afford rigorously random E-CL/LA
copolymers without transesterification. The elegant work of
Nomura demonstrated a strictly random E-CL/LA copolymer
synthesized by a Salen-aluminum catalyst (A, Scheme 1).
Introducing bulky iPr3Si groups in the ortho position of
phenoxide groups significantly reduced the coordination abil-
ity of LA with Al center, which decreased the gap between
the reactivity of E-CL and LA in the copolymerization.51 Pel-
lecchia developed a monomethyl aluminum complex with a
pyrrolylpyridylamido ligand, which could promote the ran-
dom copolymerization of LA and E-CL (rLA 5 1.17; rCL 5 1.36)
and finally yield real random copolymer with very similar
average length of caproyl and lactidyl sequences (LLA 5 2.5;
L
CL 5 2.0) (B, Scheme 1).15 Ma and Kan synthesized the
EXPERIMENTAL
mono- and dinuclear aluminum complexes bearing the race-
mic 6,6-dimethylbiphenyl bridged salen ligands, the complex
was well-controlled, producing random copolymers with the
average lengths of the caproyl and lactidyl sequences
(LLA 5 1.93; LCL 51.91) in a feedstock of CL/LA 5 1 and the
values of the reactivity ratios of the two monomers
(rLA 5 1.17, rCL 5 0.80) (C, Scheme 1).54 Besides, it was found
General Procedures and Materials
All manipulations of air and/or moisture-sensitive com-
pounds were carried out under a dry and high purity nitro-
gen atmosphere using standard Schleck techniques or
glovebox unless otherwise noted. All solvents were purified
from an MBraun SPS system. The NMR data of ligands and
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complexes used were obtained using Bruker 400 MHz (400
MHz for 1H, 75.5 MHz for 13C) spectrometer at 25 8C with
CDCl3 as a solvent. Elemental analyses were recorded on an
elemental Vario EL spectrometer. Gel permeation chromato-
graphic (GPC) measurements were carried out using a
Waters instrument (515 HPLC pump) equipped with a Wyatt
interferometric refractometer, eluted with CHCl3 at 35 8C at
1 mL/min and narrow polystyrene standards as reference.
Differential scanning calorimetry (DSC) measurements were
carried out with a DSC1Star System (Mettler Toledo Instru-
ments, Switzerland) under nitrogen atmosphere at a rate of 10
8C min21, and Tg values were collected after the second heating
cycle. The geometries of the lactone-coordinated Al complexes
were optimized in the gas phase without molecular symmetry
constrains M06-2X57 level of theory as implemented in the
Gaussian software 09 program.58 The all-electron basis set
6–311G(d,p) was applied to all atoms in the systems.
[2,6-iPr2C6H3N@CHAC10H7C6H5O]Al(CH3)2 (3c)
Synthesis for 3c was performed according to the procedure
as that of 3a, except 2c (0.818 g, 2 mmol) was used. Yield
0.81 g (86%). 1H NMR (400 MHz, CDCl3): d 7.37 (s, 1H,
N@CAH), 7.35 27.14 (m, 11H, ArAH), 3.10 (s, J 5 6.8 Hz,
i
2H, PrACH), 2.94 (t, J 5 6.8 Hz, 2H, ACH2A), 2.54 (t, J 5 7.2
i
Hz, 2H, ArACH2A), 1.20 (d, J 5 6.8 Hz, 6H, PrACH3), 1.07
(d, J 5 6.8 Hz, 6H, iPrACH3), 21.17 (s, 6H, AlACH3). 13C
NMR (100 MHz, CDCl3): d 173.18, 167.86, 143.47, 143.26,
143.22, 142.9, 142.6, 130.62, 130.41, 128.33, 127.64, 127.15,
126.75, 126.22, 123.85, 105.45, 30.65, 27.93, 26.25, 25.81,
22.83, 210.56. Anal. calcd. for C31H36AlNO: C, 79.97; H, 7.79;
N, 3.01. Found: C, 80.38; H, 7.92; N, 2.94.
Homopolymerization of E-CL and LA
The typical polymerization procedure is as follows (Table 2
Run 1). All glassware used for polymerizations was oven-
dried. In a glovebox, a 10 mL Schlenk tube was charged
3 mL toluene solution of aluminum complex (25 lmol),
BnOH (25 lmol). The mixture solution was stirred for 10
min, and 2 mL toluene solution of E-CL (5.0 mmol) was
added to the mixture solution. The reaction mixture was
then placed into an oil bath pre-heated at 70 8C. After the
desired time, the polymerization reaction stopped by adding
formic acid (0.5 mL), and aliquot of the reaction mixture
was sampled with a pipet for determining the monomer con-
L-lactide was purified by crystallization from dry toluene.
Benzyl alcohol was purified by distillation over sodium. E-
Caprolactone was dried with CaH2 for 24 h at room tempera-
ture and then distilled under reduced pressure. Reagent
grade Azidothymidine (AZT) which is widely used to prevent
HIV was purchased from Aladdin. AlMe3 in n-hexane was
purchased from Acros and stored in a bottle in the dry box
and was used as received.
1
version by H NMR spectroscopy. The resultant reaction mix-
Synthesis of b–Ketiminato Aluminum Complexes 3a–c
[C6F5N@CHAC10H7C6H5O]Al(CH3)2 (3a)
Into a stirred solution of 2a (0.83 g, 2 mmol) in toluene
ture was poured into methanol and the white polymer was
separated by filtration. The raw polymer was purified by dis-
solving in CH2Cl2 and precipitating from methanol three
times. Homopolymerization of LA was performed according
to the procedure as that of CL, except LA was used.
(10 mL), AlMe3 (1
M n-hexane solution, 2.05 mmol,
2.05 mL) was added dropwise over 10 min. After stirred for
8 h, the reaction mixture was concentrated in vacuo. The
chilled-concentrated CH2Cl2 and n-hexane mixture solution
was placed in the freezer (220 8C) and afforded complex 3a.
Yield 0.86g (91%). 1H NMR (400 MHz, CDCl3): d 7.47(d,
J 5 7.4 Hz, 1H, AN@CAH), 7.45–7.19 (m, 8H, ArAH), 2.99 (t,
J 5 6.4 Hz, 2H, ACH2A), 2.61 (t, J 5 6.8 Hz, 2H, ArACH2A),
21.15 (s, 6H, AlACH3). 19F NMR (377 MHz, CDCl3): d
2149.40 (td, J 5 13.7, 7.0 Hz, 2F, m-Ar-F), 2157.81 (s, 2F, o-
Ar-F) 2161.63 (td, J 5 22.5, 6.3 Hz, 1F, p-Ar-F). 13C NMR
(100 MHz, CDCl3): d 178.74, 166.89, 144.35, 143.74, 142.81,
131.81, 130.76, 130.39, 128.23, 127.76, 127.10, 126.49,
107.70, 30.40, 26.39, 211.53. Anal. calcd. for C25H19AlF5NO:
C, 63.70; H, 4.07; N, 2.98. Found: C, 63.98; H, 4.12; N, 2.92.
General Procedure of Random Copolymerization
The similar procedure is followed for the synthesis of all the
copolymers (Table 3 Run 3). In a glovebox, a 10 mL Schlenk tube
was filled with 1 mL toluene solution of aluminum complex (25
lmol), BnOH (25 lmol). The mixture solution was stirred for
10 min, then 1.5 mL toluene solution of E-CL (2.5 mmol) and LA
(2.5 mmol) was added simultaneously to the mixture solution.
The reaction mixture was placed into an oil bath stirred at
100 8C. After the desired time, the polymerization reaction
stopped by adding formic acid (1.0 mL), and an aliquot of the
reaction mixture was sampled with a pipet for determining the
monomer conversion by 1H NMR spectroscopy. The resultant
reaction mixture was poured into methanol. The obtained raw
copolymer was purified by dissolving in CH2Cl2 and precipitated
from rapidly stirring methanol, and the pure copolymer was col-
lected by filtration and then dried in vacuo at 40 8C overnight.
The drug–polymer conjugate was synthesized according to the
procedure aforementioned by using AZT as an initiator.
[C6H5N@CHAC10H7C6H5O]Al(CH3)2 (3b)
Synthesis for 3b was performed according to the procedure
as that of 3a, except ligand 2b (0.65 g, 2 mmol) was used.
Complex 3b was obtained 0.68g (89% yield) as yellow
microcrystals. 1H NMR (400 MHz, CDCl3): d 7.71 (s, 1H,
N@CAH), 7.43–7.14 (m, 13H, ArAH), 2.95 (t, J 5 6.8 Hz, 2H,
ACH2A), 2.61 (t, J 5 7.2 Hz, 2H, ArACH2A), 21.09 (s, 6H,
AlACH3). 13C NMR (100 MHz, CDCl3) d: 173.83, 164.08,
147.77, 143.42, 143.3 142.84, 131.07, 130.61, 130.55,
129.50, 128.30, 127.64, 126.78, 126.2, 126.08, 121.80,
106.53, 30.52 (s), 26.46, 29.69. Anal. calcd. for C25H24AlNO:
C, 78.71; H, 6.34; N, 3.67. Found: C, 79.15; H, 6.39; N, 3.62.
RESULTS AND DISCUSSION
Synthesis of Aluminum Complexes
and Structural Studies
The ligands were synthesized according to our previously
reported procedure (Scheme S1 in supporting information).56,59
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˚
TABLE 1 Selected Bond Distances (A) and Angles (8) for Com-
plexes 3a–c
˚
Bond Distances (A)
and Angles(8)
3a
3b
3c
AlAO
1.8097(9)
1.9567(11)
1.9486(14)
1.9514(15)
1.3329(16)
1.4210(15)
1.2956(14)
1.3942(17)
1.4052(17)
93.40(4)
1.7991(9)
1.9465(11)
1.9555(15)
1.9597(15)
1.3184(16)
1.4362(16)
1.3045(15)
1.4127(18)
1.3865(18)
93.45(5)
1.8046(8)
1.9452(9)
1.9512(12)
1.9595(13)
1.3150(13)
1.4471(12)
1.3046(12)
1.4131(14)
1.3949(13)
92.74(4)
AlAN
AlAC1
AlAC2
NAC3
NAC20
OAC5
C3AC4
C4AC5
SCHEME 2 The synthetic route for complexes 3a–c.
OAAlAN
C1AAlAC2
AlANAC3
OAAlAC1
OAAlAC2
NAAlAC1
NAAlAC2
C5AOAAl
C20ANAAl
OAC5AC4
C3AC4AC5
112.24(6)
122.20(8)
109.42(5)
112.99(5)
112.24(6)
103.81(6)
131.51(8)
119.89(8)
122.58(11)
122.62(11)
66.71
117.90(7)
122.00(9)
110.64(6)
110.89(6)
110.59(6)
110.71(6)
129.50(8)
120.58(8)
123.21(11)
121.96(11)
61.86
118.88(6)
118.40(7)
111.89(5)
109.92(5)
110.88(5)
109.44(5)
123.77(6)
124.04(6)
122.91(9)
121.06(9)
81.67
The aluminum complexes with bulky b-ketiminato ligands were
effectively prepared with good yield via the alkane elimination
reaction between AlMe3 (1.05 equiv.) and the corresponding
neutral ligand (Scheme 2). The complexes without aryl shelter
M1 and M2 were also prepared to investigate the effects of the
steric hindrance on the behavior of polymerization catalysis.
The successful formation of Al complexes can be clearly identi-
fied by 1H and 13C NMR spectra (Figs. S1–S7 in supporting
information). Resonance peaks assigned to AOH proton around
11.5 ppm disappeared and sharp single peaks assigned to
AlACH3 protons ranging from 21.09 to 21.17 ppm were clearly
traced. Meanwhile, the peaks of R2N@CH proton shifted to
upfield, indicating the formation of the desired complexes. Fur-
thermore, single crystals of complexes 3a–c suitable for X-ray
crystallographic analysis was grown from CH2Cl2 and n-hexane
solution. The data collection and refinement data of the analysis
are listed in Table S1 (see supporting information), and the
selected bond lengths and angles are summarized in Table 1.
NACACACAO planar/
N-substituent
Phenyl planar/
58.85
3.32
64.11
14.69
74.47
33.09
tetralone planar
OAAlAN planar/
NACACACAO
planar
indicating that the complexes 3a–c were not the real active
species in the polymerization. The homopolymerization of E-
CL and L-LA by complexes 3a–c in the presence of 1 equiv.
In the solid state, each of the Al centers was coordinated by
two alkyl groups, as well as oxygen and nitrogen atoms from
the ligand, forming a distorted tetrahedral geometry (Fig. 1
and Figs. S8 and S9 in supporting information). It is obvious
that the introduced aryl group serves as a shelter that pro-
tects the aluminum center. The dihedral angle C(6)-C(7)-
C(8)-C(9) between the benzene ring and tetralone plane of
3c (74.478) is much larger than those of 3b (64.118) and 3a
(58.858) (Table 1). The six-membered AlANACACACAO ring
in 3b is nearly planar, while it is distorted in 3a and 3c. The dihe-
dral angel between OAAlAN plane and NAC(3)AC(4)AC(5)AO
plane for 3a and 3c is 3.328 and 33.098, respectively. Moreover,
dihedral angle C(25)AC(20)ANAC(3) between NAC(3)AC(4)A
C(5)AO plane and C(20)AC(21)AC(22)AC(23)AC(24)AC(25)
plane increased in the order 3b (61.868) < 3a (66.718) < 3c
(81.678). All these results clear indicated that 3c exhibits more
crowded coordination environment than 3a and 3b.
Homopolymerization of L-LA and E-CL
The polymerization was conducted in the absence of an alco-
hol initiator. No monomer conversion was observed,
FIGURE 1 Molecular structure of complex 3c with thermal
ellipsoids at the 30% probability level. Hydrogen atoms are
omitted for clarity.
4
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TABLE 2 Homopolymerization of E-CL and L-LA by Complexes 3a–ca
Conv.b (%)
TOFc (h21
)
Mn;theo (3104)
Mn (3104)
Mw/Mn
d
e
Run
Complex
Mono
[Mono]:[OH]:[Al]
Time (min)
1
3a
3b
3c
E-CL
E-CL
E-CL
E-CL
E-CL
E-CL
E-CL
E-CL
E-CL
E-CL
E-CL
L-LA
L-LA
L-LA
L-LA
L-LA
L-LA
L-LA
rac-LA
L-LA
L-LA
200:1:1
200:1:1
200:1:1
200:1:1
200:1:1
200:1:1
200:1:1
200:1:1
200:1:1
200:1:1
200:1:1
100:1:1
100:1:1
100:1:1
100:1:1
100:1:1
100:1:1
100:1:1
100:1:1
100:1:1
100:1:1
60
96.3
97.2
26.3
37.2
64.0
72.5
84.3
90.7
95.4
93.2
>99
69.4
62.3
30.6
42.3
54.6
63.2
69.5
52.1
90.4
76.1
192
194
631
446
384
290
252
217
190
186
200
19.8
17.8
12.3
14.1
15.6
15.8
15.4
14.9
25.8
21.7
2.20
2.22
0.60
0.85
1.50
1.65
1.91
2.06
2.18
2.10
2.28
1.01
0.91
0.45
0.62
0.79
0.91
1.01
0.75
1.30
1.10
3.16
2.56
0.87
1.24
1.82
2.04
2.47
2.57
2.87
2.65
2.41
1.11
0.98
0.47
0.69
0.84
0.95
1.03
0.87
1.66
1.47
1.26
1.27
1.18
1.17
1.20
1.24
1.28
1.25
1.28
1.25
1.29
1.23
1.20
1.23
1.25
1.27
1.27
1.28
1.29
1.25
1.22
2
60
3
5
4
3c
10
5
3c
20
6
3c
30
7
3c
40
8
3c
50
9
3c
60
10
11
12
13
14
15
16
17
18
19
20
21
M1
M2
3a
3b
3c
60
60
210
210
120
180
210
240
270
210
210
210
3c
3c
3c
3c
3cf
M1
M2
a
e
25 lmol of Al complex, [CL] 5 1 mol L21and [LA] 5 2 mol L21 in tolu-
Experimental Mn values were determined by GPC analysis and cali-
ene, [OH] 5 BnOH, 70 8C for CL and 80 8C for LA.
brated against polystyrene standard and corrected by the equation:
b
Monomer conversion was determined by 1H NMR analysis.
Mn 5 0.56 3 Mn(GPC) for PCL and Mn 5 0.58 3 Mn(GPC) for PLA.
c
f
Non-optimized turnover frequency calculated over the whole reaction
Pm of PLA can be derived from the methine region of 13C NMR spec-
time.
trum, Pm 5 0.45, [mmm] 5 Pm(1 1 Pm)/2 5 0.33.
d
Calculated Mn,theo 5 [E-CL]o/[OH] 3 conv. (E-CL) 3 MCL 1 MBnOH, Calcu-
lated Mn,theo 5 [LA]o/[OH] 3 conv.(LA) 3 MLA 1 MBnOH
.
of benzyl alcohol was further investigated, and the typical
results were summarized in Table 2. The complexes of 3a–c
displayed very similar catalytic activity for the ROP of E-CL,
the monomer could be consumed almost completely within
60 min (Table 2). A linear relationship was observed
between the monomer conversions and the number-average
molecular weight (Mn) of the polymers (Fig. 2 and Figs. S10
and S11 in supporting information). The rate of the ROP was
first-order dependent on the monomer concentration by cat-
alyst 3c (Fig. 3 and Figs. S12 and S13 in supporting informa-
tion). The apparent rate constant of ROP of E-CL was found
to be 0.049 min21 for 3a, 0.051 min21 for 3b, and 0.046
FIGURE 2 Mn and Mw/Mn versus monomer conversion in the
ROP of E-CL initiated by 3c/BnOH system.
FIGURE 3 The kinetcis of ROP of CL catalyzed by 3c/BnOH
system.
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TABLE 3 Copolymerization of E-CL and L-LA with Different Catalystsa
Conv.c (%)
g
d
Mn;raw (104)
Mn (104)
Mn;th (104)
PDI
b
b
e
f
Run
Cat
T (8C)
LLA
LCL
LA
CL
FLA (%)
1
2
3
4
5
6
7
8
9
10
M1
M2
3a
80
3.92
2.94
2.85
3.78
2.62
2.68
2.75
2.44
1.93
2.20
1.75
1.91
2.55
2.99
1.65
1.90
1.97
2.34
1.88
2.39
98.0
99.1
94.3
100
96.2
95.3
92.6
98.0
70.1
91.9
73.5
97.9
99.9
38.7
53.3
48.9
51.7
50.7
60.2
54.8
53.7
50.1
50.5
54.1
3.23
3.61
4.83
5.43
3.94
4.65
4.71
4.81
5.04
2.07
1.84
2.05
2.75
3.09
2.25
2.63
2.68
2.74
2.89
1.18
2.44
2.53
2.42
2.56
2.13
2.41
2.07
2.52
2.58
1.04
2.07
1.60
1.53
1.56
1.40
1.47
1.39
1.42
1.40
1.31
100
80
3a
100
80
3b
3b
3c
88.3
94.3
85.5
97.1
99.9
41.6
100
80
3c
100
120
100
3c
3ch
a
e
Reaction conditions: 25 lmol of catalyst in 2.5 mL of toluene, [E-CL]/
[L-LA]/[Al]/BnOH 5 100:100:1:1, and copolymerization at 80 8C for 8 h or
100 8C for 10 h.
Determined by GPC in CHCl3 using polystyrene as a standard.
f
M
n 5 Mn,GPC(raw) 3 CL (mole percent in copolymer) 3 0.56 1 Mn,GPC(raw)
3 LA (mole percent in copolymer) 3 0.58.
g
b
Average sequence length of caproyl unit and lactidyl unit was deter-
M
n,th 5 ([E-CL]/[BnOH]) 3 conv. (CL) 3 MCL 1 ([LA]/[BnOH]) 3 conv.
mined by 13C NMR.
c
(LA) 3 MLA 1 MBnOH
.
h
Monomer conversion was determined by 1H NMR.
LA content in the copolymer determined by 1H NMR.
Copolymerization at 100 8C for 4 h.
d
min21 for 3c, further suggesting the similar activity of 3a–c
in the ROP of CL. The predicable molecular weights (MWs)
and narrow molecular weight distributions (MWDs) sug-
gested that the ROP of E-CL catalyzed by 3a–c proceeded in
a controlled manner.
Al enter via the carbonyl oxygen of the lactone through the
van der Walls complex. To understand the effects of the aryl
group on the coordination of CL and LA with Al complex,
density functional theory (DFT) calculations were conducted.
However, it was suggested that the introduction of aryl
group had negligible effects on the coordination of CL and
LA with Al complexes (Fig. S15 in supporting information).
Thus, we envisioned that the aryl group may have more pro-
found influence on the intermediates and transition state in
the nucleophilic attack and ring-opening steps.61 The corre-
sponding DFT calculations are in progress.
It was noted that introducing bulky substituent has negligible
effects on E-CL polymerization, as evidenced by the very similar
catalytic activities of complexes with bulky group as the corre-
sponding counterparts without aryl group shelter (Run 1 vs. 10;
Run 9 vs. 11, Table 2). This observation kept good consistent
with the results documented by Nomura who also found that
the bulky groups showed less effect on the ROP of smaller CL.48
The ROP of L-LA catalyzed by 3a–c proceeded in a con-
trolled manner as well, as evidenced by the predictable
molecular weight and narrow molecular distributions. The
resulting macromolecular chain is capped with the hydroxyl
group at one end and the BnOA group at the other end (Fig.
S14 in supporting information). In addition, no monomer
conversion was observed in a controlled experiment without
BnOH initiator (Run 8, Table S4). These results suggested
that the ROP of LA may proceed via a coordination insertion
mechanism. rac-LA polymerization was further conducted to
evaluate the stereo-control of complex 3c (Run 19, Table 2).
There is no obvious difference between the homopolymeriza-
tion of rac-lactide and L-Lactide, suggesting that the enan-
tiomers L-LA and D-LA have similar polymerization kinetics.
The Pm of PLA obtained by 3c was determined by 13C NMR
spectrum (Table 2). It was found that Pm 5 0.45 and the
[mmm] 5 Pm(1 1 Pm)/2 5 0.33.37 Therefore, 3c exhibits no
stereo-selectivity in the ROP of rac-LA.
By sharp contrast, introducing bulky group significantly
retarded the polymerization of LA (Runs 12–21, Table 2).
For example, high monomer conversion up to 90.4% could
be achieved in 3.5 h by complex M1. However, only 69.4% of
LA was consumed within 3.5 h under the same conditions
by 3a. Similar phenomenon was also observed in the ROP of
LA by using M2 and 3c. This observation is significant for
the goal of synthesizing random LA/CL copolymer whose
properties will be different from the gradient and block
copolymer. Meanwhile, the catalytic activities of complexes
3a–c decreased in the order 3a > 3b > 3c, exhibiting strong
dependences on the substituent groups of the imino moiety.
Complex 3a with electron-withdrawing group AC6F5 exhib-
ited relatively higher catalytic activity (TOF: 19.8 h21), owing
to its stronger Lewis acidity of Al center. While complex 3c
containing bulky 2,6-iPr2C6H3 group showed lowest activity
among these complexes (TOF: 15.6 h21). It is noted that the
ROP of lactone proceeds via coordination-insertion mecha-
nism and involves many transition states and key spe-
cies.29,60 The first step is the coordination of lactide to the
Copolymerization of L-LA and E-CL
To confirm the optimal catalyst for synthesizing random
copolymers, copolymerizations of E-CL and L-LA with
6
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with benzene group (3b) in the imine moiety, the transester-
ification could be eliminated at 80 8C while maintaining the
random microstructure of the copolymer (LLA 5 2.62 and
L
CL 5 1.65) (Run 5, Table 3).
Considering that the transesterification side reaction could
be favored at higher temperature, LA/CL copolymerizations
catalyzed by 3b were further conducted at 100 8C. As shown
in Figure 5, the resonance peak assigned to CLC segment
could be clearly observed, suggesting the presence of trans-
esterification at high temperature by using 3b. Excitingly, the
transesterification side reaction could be eliminated
completely by using catalyst 3c with bulkier substituent
group 2,6-iPr2C6H3 even when the copolymerization was
conducted at higher temperature (100 8C and 120 8C) (Runs
8 and 9, Table 3). By contrast, transesterification side reac-
tion could be observed in the copolymerization catalyzed by
M2, as evidenced by the appearance of the CLC resonance
peak at 171.1 ppm. This observation further supported that
the aryl group in 3c could eliminate the transesterification
reaction. The resultant copolymer obtained by 3c shows a
quasi-random structure, as evidenced by the very similar
average length of the lactidyl (LLA) and caproyl (LCL) sequen-
ces (Table 3). To further confirm complex 3c could produce
random copolymer, the reactivity ratios rLA and rCL were fur-
ther determined by conducting CL/LA copolymerization with
low monomer conversion (Table S4 and Fig. S17 in support-
ing information). The values of monomer reactivity ratios
were found to be rCL 5 0.99 and rLA 5 1.31, which indicated
that the two monomers were almost synchronously incorpo-
rated into the polymer chain during the copolymerization,
and quasi-random polymer would be obtained. Taking all
FIGURE 4 1H NMR spectrum of PLA-co-PCL synthesized using
3c (Run 3, Table 3, CDCl3, 25 8C). [Color figure can be viewed
at wileyonlinelibrary.com]
complexes 3a–c were investigated under the conditions of a
E-CL/L-LA/Al/BnOH ratio of 100/100/1/1 at different tem-
perature. Besides, complexes M1 and M2 were also used as
the references to catalyze CL/LA copolymerization, to inves-
tigate the effects of introduced benzene ring on the copoly-
merization behavior and microstructures of the copolymer.
The resultant polymers were characterized by 1H and 13C
NMR spectroscopy, GPC (Table 3). The CL/LA molar ratio in
the copolymer was determined through the integrated values
of the methylene signal of CL segment around 4.0 ppm and
the methine signal of LA around 5.2 ppm (Fig. 4). The aver-
age length of the lactidyl (LLA) and caproyl (LCL) sequences
can be calculated from the integrals of the triads sequences
signals according to previously reported methods.62,63 The
average length of L-LA (LLA) sequence in the copolymer pro-
duced by M1 is 3.92, whereas the average length of CL (LCL
)
sequence is 1.75 (Run 1 in Table 3), indicating that the con-
sumption of L-LA was faster than CL and the copolymer had
gradient microstructure (LCL 5 LLA 5 2 for an ideal random
copolymer). The conversion of LA and CL in the copolymeri-
zation was traced by 1H NMR (Fig. S16 in supporting infor-
mation), further confirming that L-LA was converted more
rapidly in the copolymerization.
By contrast, complex 3a showed great tendency to produce
a
quasi-random copolymer (LLA 5 2.85 and LCL 5 2.55).
These results clearly indicated that increasing the steric hin-
drance of catalyst could significantly narrow the gap in poly-
merization rate of LA and CL, which was beneficial for
preparing random copolymer (Run 3, Table 3). However, a
sharp resonance peak at 171.1 ppm assigned to a single lac-
tic ester unit between two CL units (CLC) was detected in
the resultant copolymer obtained by M1 and 3a, indicating
the presence of transesterification side reaction (Fig. 5). The
presence of transesterification may induce a broader molecu-
lar weight distribution (Runs 1 and 3, Table 3). Compared
with complex M1, 3a could produce copolymer with less
CLC content, suggesting that the bulky steric hindrance could
also suppress the transesterification side reaction. Further
substituting the electron-withdrawing group AC6F5 (3a)
FIGURE 5 13C NMR spectra of the copolymers obtained at dif-
ferent temperatures (CDCl3, 25 8C). [Color figure can be viewed
at wileyonlinelibrary.com]
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TABLE 4 Copolymerization of E-CL and L-LA with Different Molar Ratio by Using 3ca
Conv.c (%)
g
FLA (%) Mn (104) Mn;th (104) PDI Tg;th (8C) Tg;DSC (8C) Tm;DSC (8C)
b
b
d
e
f
h
h
Run [LA]:[CL] (mol:mol) LLA
LCL
LA
Cl
1
2
3
4
5
40:160
80:120
100:100
120:80
160:40
1.61 4.08 100 98
2.45 2.46 100 94
19.1
45.9
2.90
2.47
2.68
2.59
2.41
2.56
2.40
2.07
2.21
2.18
1.42 241.1
1.49 212.2
1.39 23.1
1.38 16.1
1.41 35.0
240.4
29.9
21.46
14.5
39.5
–
2.75 1.97 85.5 73.5 53.7
4.27 1.90 91.4 78.7 69.5
7.22 1.40 89.1 78.1 84.1
–
–
34.9
145.0
a
f
Reaction conditions: 25 lmol of Al complex in 2.5 mL of toluene, 80
M
n,th 5 ([E-CL]/[BnOH]) 3 conv. (CL) 3 MCL 1 ([LA]/[BnOH]) 3 conv.
8C for 8 h, ([LA]1[CL]):[Al]:[OH] 5 200:1:1.
Average sequence length of the caproyl unit and the lactidyl unit was
determined by 13C NMR analysis.
(LA) 3 MLA 1 MBnOH.
Theoretical values calculated by Fox equation, by using for the Tg of
b
g
the homopolymers the following literature values: PCL: 260 8C; PLLA:
57 8C.
c
Monomer conversion was determined by 1H NMR analysis.
d
h
LA mole ratio in the copolymer determined by 1H NMR.
Determined by DSC.
e
M
n 5 Mn,GPC(raw) 3 CL (mole percent in copolymer) 3 0.56 1 Mn,GPC(raw)
3 LA (mole percent in copolymer) 3 0.58.
these into account, complex 3c was a promising catalyst for
synthesizing random E-CL/LA copolymers without transes-
terification. For a 1:1 ratio of the CL/LA in the feed, the LCL
and LLA values were ꢀ2 not only at full conversion but also
at low monomer conversion (41.6% for LA and 38.7% for
CL, Run 10 in Table 3).
cases, the copolymer samples showed only one Tg between
260 8C of PCL and 45 8C of PLA, and the Tg increased with
the increasing of the LA content in the copolymer chain (Fig.
S18 in supporting information). The experimental values of
the Tg were in good agreement with the theoretical values
calculated by the Fox equation, further indicating that the
copolymers exhibited random structures (Fig. 7).
Because of its superior catalytic performance to 3a and 3b,
the copolymerizations of CL and LA with different feed ratio
were further conducted by complex 3c and the typical
results are summarized in Table 4. The copolymer composi-
tions kept good consistent with CL/LA molar ratio in the
feed. Obviously, both the LCL and LLA increased as the rela-
tive monomer amount in the feed increased (Fig. 6). The
glass transition temperature (Tg) of the resultant copolymers
was further analyzed by the DSC. The copolymers with molar
ratio [CL]:[LA] 5 40:160 and [LA]:[CL] 5 160:40 are semi-
crystalline, with Tm of 39.5 8C and 145 8C, respectively. In all
Finally, the possibility of preparing drug–polymer conjugates
by means of direct random copolymerization of CL and LA
initiated by a hydroxyl function of the drug was explored.
Such drug–polymer conjugate is a promising drug delivery,
because the permeability and release of the drug could be
controlled by modulating the relative CL/LA content in the
polymer chain. A conjugate of Azidothymidine (AZT, 30-
Azido-30-deoxythymidine) and a random CL/LA copolymer
was prepared form ROP of CL and LA promoted by the com-
bination of the drug and complex 3c in present work. AZT
was the first reverse transcriptase inhibitor licensed for clini-
cal use by food and drug administration (FDA) and it
remains an important component in highly active
FIGURE 6 Carbonyl range of 13C NMR spectra of copolymers
of Runs 1–5 in Table 4. [Color figure can be viewed at wileyon-
linelibrary.com]
FIGURE 7 Experimental and theoretical Tg of CL/LA copoly-
mers as a function of the mole fraction of E-CL unit.
8
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5 A. Arbaoui, C. Redshaw, Polym. Chem. 2010, 1, 801.
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pound and tends to partition between the lipid bilayers and
the aqueous milieu of liposomes, thus resulting in a low
drug entrapment and significant drug leakage from the
vesicles over time. Modifying the molecular structure may
improve the stability and extend the half-life of the human
body.64,65 The successful formation of the drug–polymer con-
6 M. A. Woodruff, D. W. Hutmacher, Prog. Polym. Sci. 2010,
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jugates could be confirmed by H NMR (Fig. S19 in support-
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enabling the preparation of drug–polymer conjugates with
tuned properties.
13 B. Jeong, Y. H. Bae, D. S. Lee, S. W. Kim, Nature 1997, 388,
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CONCLUSIONS
16 L. E. Chile, P. Mehrkhodavandi, S. G. Hatzikiriakos, Macro-
molecules 2016, 49, 909.
We developed
a
series of novel Al complexes
[ArN@CHAC10H7C6H5O]Al(CH3)2
(3a,
Ar 5 C6F5;
3b,
17 K. J. Z. Y. Q. Shen, Z. Q. Shen, K. M. Yao, J. Polym. Sci. A:
Polym. Chem. 1996, 34, 1799.
Ar 5 C6H5; 3c, Ar 5 2,6-iPr2C6H3) that could catalyze the ran-
dom copolymerization of E-CL and L-LA by rationally design-
18 W. A. Ma, Z. X. Wang, Dalton Trans. 2011, 40, 1778.
ing
a modified b-ketiminato ligand with bulky steric
19 M. S. Weimer, B. Hu, S. J. Kraft, R. G. Gordon, C. U. Segre,
A. S. Hock, Organometallics 2016, 35, 1202.
hindrance. Introducing an aryl group at the ortho position in
the benzene ring significantly reduced the gap between the
reactivity of LA and CL in the polymerization, allowing to
synthesize random CL and LA copolymer. The transesterifca-
tion side reaction and the polymer composition could be
adjusted by modulating the electronic and steric effects of
the ligand. Especially, compound 3c could produce quasi-
random copolymer with similar average lengths of the cap-
royl and lactidyl sequences (LCL 5 2.34; LLA 5 2.44). The ran-
dom copolymerization could be further confirmed by the
values of the reactivity of the two monomers (rLA 5 1.31;
20 Z. Dai, Y. Sun, J. Xiong, X. Pan, N. Tang, J. Wu, Catal. Sci.
Technol. 2016, 6, 515.
21 H. W. Ou, K. H. Lo, W. T. Du, W. Y. Lu, W. J. Chuang, B. H.
Huang, H. Y. Chen, C. C. Lin, Inorg. Chem. 2016, 55, 1423.
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23 B. B. Wu, L. L. Tian, Z. X. Wang, RSC Adv. 2017, 7, 24055.
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ꢀ
25 A. Garces, S. L. F. Barba, F. J. Baeza, A. Otero, L. A.
ꢀ
ꢀ
Sanchez, A. M. Rodrıguez, Organometallics 2017, 36, 884.
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26 Y. Wang, B. Liu, X. Wang, W. Zhao, D. Liu, X. Liu, D. Cui,
Polym. Chem. 2014, 5, 4580.
copolymers also indicated amorphous materials whose Tg
were modifiable in the range of 260 and 80 8C by adjusting
the relative content of L-LA and CL. A drug-random copoly-
mer conjugates could be easily prepared by using 3c,which
made these catalysts possess potential applications in bio-
medical field.
27 P. McKeown, M. G. Davidson, G. Kociok-Kohn, M. D. Jones,
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30 J. Wei, M. N. Riffel, P. L. Diaconescu, Macromolecules 2017,
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31 K. Press, I. Goldberg, M. Kol, Angew. Chem. Int. Ed. 2015,
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The authors are grateful for financial support by the National
Natural Science Foundation of China (21474100).
32 Y. Wang, H. Ma, Chem. Commun. 2012, 48, 6729.
33 W. Zhao, Y. Wang, X. Liu, X. Chen, D. Cui, E. Y. Chen,
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