Alternating Sequence Controlled Copolymer Synthesis of α-Hydroxy Acids via Syndioselective Ring-Opening Polymerization of O-Carboxyanhydrides Using Zirconium/Hafnium Alkoxide Initiators

Article abstract of DOI:10.1021/jacs.7b04712

The ring-opening polymerization (ROP) of O-carboxyanhydrides (OCAs) can give diverse poly(α-hydroxy acid)s (PAHAs) with different functional groups because of easy modification of the side group of OCAs, which can extend applications of PAHAs widely. The stereoselective polymerization of O-carboxyanhydrides and further sequence controlled alternating copolymerization of OCAs were still big challenges until now for lack of suitable catalysts/initiators. In this work, a highly syndioselective ROP of OCAs system as the first stereoselective example in this area is reported using zirconium/hafnium alkoxides as initiators with the highest P_r value up to 0.95. Furthermore, these initiators were successfully applied in the precisely alternating sequence controlled copolymerization of PheOCA and Tyr(Bn)OCA, and alternating copolymerization of LacOCA and PheOCA was also achieved.

Full text of DOI:10.1021/jacs.7b04712

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Article
Alternating Sequence Controlled Copolymer Synthesis of #-Hydroxy
Acids via Syndioselective Ring-Opening Polymerization of O-
Carboxyanhydrides Using Zirconium/Hafnium Alkoxide Initiators
Yangyang Sun, Zhaowei Jia, Changjuan Chen, Yong Cong, Xiaoyang Mao, and Jincai Wu
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b04712 • Publication Date (Web): 17 Jul 2017
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Journal of the American Chemical Society
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Alternating Sequence Controlled Copolymer Synthesis of
ids via Syndioselective Ring-Opening Polymerization of O-
Carboxyanhydrides Using Zirconium/Hafnium Alkoxide Initiators
α
-Hydroxy Ac-
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a
a
a, b
a
a
a
Yangyang Sun, Zhaowei Jia, Changjuan Chen, Yong Cong, Xiaoyang Mao, and Jincai Wu*
a
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources
Utilization of Gansu Province, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
b
7
30000, People’s Republic of China. College of Chemistry and Pharmaceutical Engineering, Huanghuai University,
Zhumadian 463000, People’s Republic of China.
ABSTRACT: The ring-opening polymerization (ROP) of O-carboxyanhydrides (OCAs) can give diverse poly(α-hydroxy
acid)s (PAHAs) with different functional groups because of easy modification of the side group of OCAs, which can ex-
tend applications of PAHAs widely. The stereoselective polymerization of O-carboxyanhydrides and further sequence
controlled alternating copolymerization of OCAs were still big challenges until now for lack of suitable cata-
lysts/initiators. In this work, a highly syndioselective ROP of OCAs system as the first stereoselective example in this area
is reported using zirconium/hafnium alkoxides as initiators with the highest P value up to 0.95. Furthermore, these initi-
r
ators were successfully applied in the precisely alternating sequence controlled copolymerization of PheOCA and
Tyr(Bn)OCA, and alternating copolymerization of LacOCA and PheOCA was also achieved.
Introduction
Although various living alternating copolymerization ex-
amples for same type monomers have been reported, the
monomers mostly focus on olefins. The living alternating
Precisely controlling the microstructures of synthetic pol-
ymers including tacticity, region-regularity, and monomer
sequence is still a central challenge in polymer chemistry so
far, especially in living polymerization processes. Because
sequence controlled polymers such as natural DNA and
polypeptides may have some functions and properties that
are inaccessible from sequence unregulated polymers, in
last decades tremendous efforts have been devoted to the
synthesis of sequence controlled copolymers and many
1
copolymerization method for monomers derived from hy-
droxy acids has rarely been explored. In 2009 and 2014,
13
14
Thomas and Coates, Guillaume and Carpentier, and co-
workers succeeded in the alternating polymerization of β-
alkyllactones and alkyl-β-malolactonates giving different
alternating copolymers of poly(β-hydroxy acid)s via syndi-
oselective catalysts respectively. This stereospecifc alternat-
ing copolymerization method seems to be feasible for two
similar but different chiral monomers of opposite absolute
configuration. Irrespective of this, the monomers as suc-
cessful examples only focus on four-member ring β-
lactones thus far. And to our best knowledge, the living
alternating copolymerization approach for the synthesis of
poly(α-hydroxy acid)s (PAHAs) has not been investigated
1
pieces of excellent work have been reported. Alternating
copolymers as the simplest sequence controlled artificial
copolymers can be synthesized facilely, normally the living
alternating copolymerization methods are efficient for dif-
ferent type monomers which have high rates of cross-
propagation, for example, copolymerization of epoxides
2
,3
4
and CO /CO, epoxides and anhydrides, aziridines and
2
5
6
(
except syndiotactic homopolymer obtained from a racemic
CO, alkenes and CO, and so on. For different monomers
but belonging to a same type, like different olefins or cyclic
esters, the viable living approaches are still significantly
fewer. In the challenging living radical polymerizations,
successful alternating copolymerizations of some special
olefin monomer pairs have been reported, for example,
mixture of monomers).
α-Hydroxy acids (AHAs) are typically derived from food
products including glycolic acid, lactic acid, malic acid, and
so on. The related PAHAs have wide applications from bi-
omedical devices to packaging materials because of their
biocompatibility, biodegradability, and ability to partially
7
olefin pairs of electron-donor and –acceptor and olefin
pairs preassembled via coordination chemistry, supramo-
lecular chemistry, or a cleavable covalent bond. The
monomers of ethylene and -olefin can be alternatingly
copolymerized with some metallocene catalysts possessing
heterotopic active sites. Alternating ring-opening metath-
esis polymerizations (AROMP) of some olefins based on
catalyst and monomer designs also have been successfully
8
15
replace petrochemical-based thermoplastics. But most
9
10
conventional PAHAs, for instance, polylactide (PLA),
poly(glycolic acid) (PGA), and poly(lactic-co-glycolic acid)
(PLGA), are short of side-chain functionalities, thus it is
difficult to alter their structures for modulating their physi-
cochemical properties and the applications of PAHAs are
somewhat restricted. Actually, in order to enhance the
physical and mechanical properties of PAHAs, some
α
11
1
2
reported in the past decade.
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A)
O
O
R
O
1
2
3
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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R
R
Cat. 1-2, toluene
- 2n CO2
(
S)
O
n
O
+
n
O
(R) O
O
O
n
O
R
O
tBu
O
tBu
OR
rac-OCA
Syndiotactic poly(rac-OCA)
O
O
tBu
M
N
O
tBu
R =
CH
3
OBn
tBu
LacOCA
PheOCA
Tyr(Bn)OCA
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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9
0
1
2
3
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7
8
9
0
1
2
3
4
5
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0
1
2
3
4
5
6
7
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9
0
tBu
B)
R2
O
i
O
1a M = Zr
1b M = Zr
-OR= -O Pr
-OR= -OCH(CH )CO CH
O
R1
R2
Cat. 2b, toluene
- 2n CO2
O
O
3
2
3
O
+
n
O
n
2
2
a M = Hf
b M = Hf
-OR= -O Pr
-OR= -OCH(CH )CO CH
i
n
O
O
O
R
1
3
2
3
O
O
Alternating copolymer
Poly(PheOCA-alt-Tyr(Bn)OCA)
Poly(PheOCA-alt-LacOCA)
R =
R2
=
1
OBn
R1
=
R2
=
CH3
Scheme 1. Synthesis of syndiotactic poly(α-hydoxy acid)s and alternating copolymers of α-hydroxy acids by zirconium and haf-
nium complexes.
analogues of ploylactide have been reported via the ring-
opening polymerization (ROP) of various substituted 1,4-
pendent on their stereo microstructures. In addition, a
highly stereoselective polymerization of different OCAs can
be used to synthesize alternating sequence controlled
poly(α-hydroxy acid)s when catalysts/initiators are highly
syndioselective, which can further enrich the diversity of
PAHAs with optimized properties for applications.
1
6
dioxane-2,5-diones derivatives. However, the syntheses of
this type monomers and the control of ROP progresses
sometimes are not easy. For example, replacing the methyl
group of polylactide with phenyl, Baker et al. reported the
polymer of mandelide can possess a high glass-tranistion
Thus, in this work we reported the first example of syn-
dioselective ring-opening polymerization of OCAs using
zirconium and hafnium alkoxide initiators. Furthermore,
these initiators were successfully applied in alternating
sequence controlled synthesis of poly(α-hydroxy acid)s
using OCA monomers.
o
temperature (T , 95-100 C) compared to a low T of pol-
g
g
o
16c
ylactide (30-60 C). But the synthesis of stereoregular
poly(mandelic acid) (PMA) is difficult because of unavoid-
able racemization of mandelide under polymerization con-
ditions; the monomer synthesis of mandelide also requires
long reaction time and high-boiling solvents, which just
gives a mixture of rac and meso diastereomers. Davidson
and Carbery, Chen and Tong et al. changed mandelide
to an activated O-carboxyanhydride (OCA) type mandelic
acid monomer of L-ManOCA, the racemization of mono-
mer does not happen in the ROP progress of L-ManOCA
and T of stereoregular isotatic PMA can reach high up to
05 C. In fact, inspired by the successfully controlled syn-
thesis of polylactide from the OCA activated monomer of -
LacOCA reported by Bourrisou, Dove, and others, great
efforts have been devoted to synthesize PAHAs via the ROP
of various OCAs in the past decades with the aim to enrich
the diversity of PAHAs and enhance their properties, be-
cause OCAs derived from natural α-hydroxy acid or amino
acids possess rich side-chain functionalities. Some exam-
ples demonstrated that the controllable ROP of OCAs, in-
1
7
18
Results and Discussion
Syndioselective ROP of OCAs
In order to achieve a highly syndioselective system for
the ROP of OCAs, a lot of excellent catalysts/initiators for
the ROP of chiral cyclic esters, like rac-lactide, were
screened by us. Among these tremendous stereoselective
catalysts/initiators, amine tris(phenolate) Zr/Hf/Ge alkox-
g
o
17
1
L
1
9
ide complexes attract our attention because of the special
23
C -symmetry of ligands and their excellent stereoselectivi-
3
ties towards the ROP of rac-lactide reported by Davidson
and coworkers. It is fortunate that amine tris(phenolate)
24
Zr/Hf alkoxides 1-2 also can show high syndioselectivies for
the ROP of OCAs (Scheme 1A). Firstly, rac-LacOCA was
chosen as a typical monomer of OCAs. The ROP of rac-
LacOCA at a 100:1 ratio of [monomer] /[Initiator] with
zirconium complex 1a and hafnium complex 2a as an initia-
tor can be completed with a 99 % conversion at room tem-
perature in 24 h and 1.5 h, respectively. However, the num-
cluding
LacOCA,
Thry(alkynyl)OCA,
L-PheOCA,
L-Ser(Bn)OCA,
L-GluOCA,
L-ManOCA,
L-
L-
0
0
Lys(Cbz)OCA and so on, can be efficiently achieved via
1
7-20
organocatalysts
and very few metal complex cata-
2
1
lysts/initiators. However, regardless of whether organo-
catalysts or metal complexes, no example of the stereose-
lective polymerization of OCAs has been reported until
now. Stereoselective polymerization of OCAs is still a chal-
lenging goal in the ROP of OCAs and undoubtedly it is also
a valuable research issue because the physical and chemical
ber-average molecular weight (M ) of gel permeation
n
chromatography (GPC) values are higher than expected
and the molecular weight distributions Đ = 1.57/1.63 are
broad (Table 1, entries 1−2, Figure S1A). Replacing isopro-
panolate Zr complex 1a with -methyl lactate Zr complex 1b,
L
the polymerization rate sharply increases offering a 99 %
conversion of monomer within 20 min under same
22
properties of PAHAs, such as polylactide, are highly de-
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Table 1. Syndioselective ROP of rac-OCAs initiated by zirconium/hafnium complexes 1-2.
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
c
d
e
b
M
n,obsd
M
n,NMR
M
n,calcd
f
Entry
Cat. rac-OCA
[Cat.] /[OCA]0
t (h)
Conv.(%)
Đ
Pr
0
(g/mol)
10600
12400
6600
(g/mol) (g/mol)
1
1a
LacOCA
LacOCA
LacOCA
LacOCA
PheOCA
1:100
1:100
1:100
1:100
24
99
99
99
99
9000
10000
6700
7500
5700
7200
7200
7200
7200
1.57
1.63
1.23
1.12
0.80
0.83
0.80
0.84
2
3
4
2a
1b
2b
1.5
20 min
20 min
6700
g
5
2b
2b
1:50
1:50
14
81
5000
6100
1.11
0.93
0.95
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
h
Tyr(Bn)OCA
6
50
90
10500
12000
11500
1.18
a
Conditions: Reactions were carried out under a dry nitrogen atmosphere, 0.01 mmol of initiator, 2 mL of toluene, at room
temperature in addition to the annotated. Determined by H NMR spectrum. Experimental M and Đ determined by GPC in
THF against polystyrene standards, and corrected using the factor 0.58 for poly(LacOCA), and poly(PheOCA) and
poly(Tyr(Bn)OCA) are not corrected. Determined from the relative integration of the signals for the main-chain methine
units and chain ends. Calculated from the equation: (molar mass of OCA –molar mass of CO ) × [OCA] /[Cat.] × Conv. % +
the molar mass of the initiators. Determined by analyses of all of the tetrad signals in the methine region of the C NMR
b
1
c
n
26
d
e
2
0
0
f
13
g
h
spectrum. In 5 mL toluene. In 20 mL toluene.
Figure 1. (A) Plots of M and molecular weight distribution Đ of poly(rac-LacOCA) versus [rac-LacOCA] /[2b] ratio. (B) Repre-
sentative gel-permeation chromatography (GPC) traces of the poly(rac-LacOCA) prepared by 2b. (C) The methine region of H
NMR spectrum (left) and homonuclear-decoupled H NMR spectrum (right) of poly(rac-LacOCA) (Table 1, entry 4). (D) Detail of
the methine region of C NMR spectra (100 MHz, CDCl ) of poly(rac-LacOCA) synthesized from ROP of rac-LacOCA in the
presence of a) 2b (P = 0.84; Table 1, entry 4), b) 1b (P = 0.80; Table 1, entry 3), c) the DMAP/ PrOH system (P = 0.5 ); and d) D-
LacOCA in the presence of 1b (P = 1; Table S1, entry 10 ). E) P values determined for all tetrads on the basis of first-order Mar-
kov statistics (Table 1, entry 4, P = 0.84). F) The MALDI-TOF mass spectrum of poly(rac-LacOCA) prepared by initiator 2b
Table S1, entry 6), the minor population stands for [C H O (C H O ) OH] + K polymer chains.
4 7 2 3 4 2 n
n
0
0
1
1
1
3
3
i
r
r
r
m
r
4
2
r
+
(
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7
conditions (Table 1, entry 3). The M also becomes control-
ported by Coates and co-workers, but the statistical dis-
tributions of tetrads for different stereosequences are dif-
ferent because of using different type monomers. There is a
serious overlap at the methine region between tetrads sig-
n
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
lable and a slightly low molecular weight distribution Đ =
1.23 can be obtained. Considering the same ligand and met-
al ion but different alkoxy group in 1a and 1b, the different
catalytic performance of 1a and 1b may result from different
initiation rates at the beginning of ROP of LacOCA. The
similar phenomena also appeared in the BDI-Zn catalyst
system for ROP of OCAs reported by Cheng, Tong, and co-
workers, where the uncontrollable molecular weights and
low activities were ascribed to the existence of predomi-
nant inactive dimeric isomer of isopropanolate BDI-Zn
compared to monomeric L-methyl lactate BDI-Zn com-
1
nals of rrr, rrm, mrr, and mrm in decoupled H NMR spec-
trum, thus C NMR spectrum was analyzed for the methine
region and the distinct tetrads were assigned based on pre-
1
3
28
vious work of poly(meso-lactide) and poly(rac-lactide).
Atactic, isotactic, and syndiotactic-enriched poly(rac-
LacOCA) were also deliberately synthesized for comparison
via the ROP of rac-LacOCA and L-LacOCA with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
i
24
DMAP/ PrOH and 1b/2b as initiators, respectively (Figure
1D and Figure S8). After a careful comparison, the signals
from downfield to upfield in the methine region can be
assigned to the rmr, rrr, rrm, and mrr tetrads, respectively.
The resulting poly(rac-LacOCA)s show a strong contribu-
tion correlating to rrr tetrad at 69.25 ppm which indicates
syndiotactic-enriched poly(rac-LacOCA) was achieved; and
the predominant stereoerror sequence can be ascribed to -
rrrmrrr- (-RSRSSRSR-/-SRSRRSRS-). The P value of final
polymer was assessed by fitting the tetrad resonances ob-
served in C NMR spectrum with the values predicted via a
first-order chain-end stereo control (or a Markov first-order
chain-end control, Mk1) (Figure 1E). As shown in Table 1,
18
plex. While in our system, only single set signals of 1b in
1
13
H and C NMR spectra cannot show the existence of some
1
isomers (see Supporting information). The H NMR spec-
trum of a mixture of same equivalents of 1a and 1b in tolu-
ene-d8 under same condition of polymerization did not
produce new signals belonging to a new compound (Figure
S2), which may rule out the existence of dimers and other
25
possible oligomers. When 1:1 ratio of complex 1a and D-
r
1
LacOCA was mixed for about 30 min in CDCl , H NMR
3
1
3
spectrum of this mixture exhibits that most molecules of 1a
keep unchanged (Figure S3). Just small amount of new sig-
nals appear at 1.27, 1.35, and 6.95 ppm, which are similar to
the related signals in 1b. At the same time most D-LacOCA
monomers were converted to polymers evidenced by the
obvious quartet peak at 5.16 ppm and doublet peak at 1.58
ppm. These results suggest that the initiation of the ROP of
D-LacOCA using complex 1a is slower than the propagation,
which also can be confirmed by the fact that the resulting
molecular weight distributions are broad and even bimodal
at high conversions, the ROP of rac-LacOCA initiated by 2a
is similar (Table 1 entries 1 and 2, Table S2, entries 1-4, Fig-
29
highly syndioselective P values ranging from 0.79 to 0.84
r
for complexes 1a, 1b, 2a, and 2b can be achieved at room
temperature in toluene, and the syndioselectivities of Hf
complexes (2a and 2b) are better than that of Zr complexes
(1a and 1b) possibly due to somewhat different subtle envi-
ronments around Hf and Zr metal ions (Table 1, entries 3
and 4), which also was discovered in some stereoselective
olefin polymerization systems. When the solvent was
changed to THF, the syndioselectivity using 2b does not
increase with a P value of 0.80 (Table S1, entry 5).
30
1
ure S1A). While the mixture H NMR spectrum of 1:1 ratio of
r
complex 1b and D-LacOCA does not produce polymers be-
cause no obvious quartet peak at 5.16 ppm occurs, which
hints complex 1b can quickly initiate the ROP of LacOCA
(Figure S4). Therefore, the difference between these two
complexes mostly results from the initiation step, which
possibly originates from the different coordination envi-
ronments around metal center of complexes 1a and 1b; we
failed to obtain the crystals of 1b and 2b for many times,
the real reason of this phenomenon evidenced by struc-
tures is still under investigation now. The analogue Hf
complex 2b displays a similar activity and a better control
compared with 1b giving polymer with a narrower Đ of 1.12
We then expanded the monomer scope to other OCAs
with side groups of benzyl (rac-PheOCA) and benzyl pro-
tected cresyl (rac-Tyr(Bn)OCA). The polymerization of 50
equiv. rac-PheOCA is somewhat slow with complex 1b as
an initiator at room temperature in toluene (conversion 80 %
in 24 h, Table S1, entry 13); when increasing temperature to
80 °C, the polymerization can almost be completed within
14 hours but with a lower experimental M value than cal-
n
culated and a relatively broad molecular weight distribu-
tion (Table S1, entry 14), which may result from decomposi-
tion and partial direct oligomerizaton of PheOCA at this
3
1
high temperature (Figure S10). The polymerization of rac-
PheOCA and rac-Tyr(Bn)OCA with 2b as an initiator pro-
ceeded slightly fast at room temperature, the experimental
NMR M values agreed well with the calculated M and the
(
Table 1, entry 4). The Mn values of obtained poly(rac-
LacOCA)s increased linearly with [rac-LacOCA] /[2b] rati-
0
0
os arranging from 30 to 200, and the Đ values keep narrow
at about 1.10 (Table 1, entry 4; Table S1, entries 6-8; Figures
n
n
Đ values of 1.11 and 1.18 are narrow (Table 1, entries 5 and 6).
The large steric side groups of rac-PheOCA and rac-
Tyr(Bn)OCA can hinder the transport of OCA to the active
metal center, thus the ROP activities of rac-PheOCA and
rac-Tyr(Bn)OCA were significantly lower compared to rac-
LacOCA with a small side group of methyl. The clear iden-
1A and 1B, see Figure S1B for Mn and Đ vs conversion). The
clear identification of the methoxy group at δ ~ 3.7 ppm in
1
H NMR spectrum showed the presence of end-capped
group of methoxy in the polymer (Figure S5), which can be
further confirmed by series of +1 charge peaks of 72n + 104
+
1
+ 23 (n(LacOCA - CO2) + HOCH(CH )COOCH ) + Na ) in
3
3
tification of the methoxy group at δ ~ 3.7 ppm in H NMR
MALDI-TOF spectrum (Figure 1F). Therefore, this ROP of
OCA was initiated by the alkoxy group of methyl lactate in
complexes. Stereo microstructural analysis of the resulting
spectrum of the resulting poly(rac-PheOCA)s and poly(rac-
Tyr(Bn)OCA)s confirmed that the methyl lactate is the
chain end group of polymers (Figures S11 and S15). The
MALDI-TOF MS of low molecular weight poly(OCA)s
demonstrated series of peaks at 148m + 104 + 23 (poly(rac-
PheOCA)) and 254m + 104 +23 (poly(rac-Tyr(Bn)OCA))
1
13
poly(rac-LacOCA) was analyzed by H NMR and C NMR
1
spectra. The methine regions of H NMR and homonuclear-
1
decoupled H NMR spectra of poly(rac-LacOCA) obtained
with 2b as an initiator (Figure 1C, Table 1, entry 4) is similar
with
a
charge of +1 (Figures 2E and 2F),
to syndiotactic poly(meso-lactide) obtained from meso-
i
lactide via a heteroselective catalyst of [(BDI)ZnO Pr] re-
2
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1
3
Figure 2. (A) Details of the methine region of the C NMR spectra (150 MHz, CDCl ) of atactic, isotactic-enriched, isotactic, and
3
sydiotactic poly(PheOCA)s synthesized via the ROP of a) rac-PheOCA, b) -PheOCA/ -PheOCA = 5/1, c) -PheOCA in the pres-
ence of DMAP/ PrOH catalyst system, and d) rac-PheOCA in the presence of 2b (P = 0.92, Table 1, entry 5). (B) Detail of the
methine region of the C NMR spectra (150 MHz, CDCl ) of atactic, isotactic-enriched, isotactic, and syndiotactic
poly(Tyr(Bn)OCA)s synthesized via ROP of a) rac-Tyr(Bn)OCA, b) -Tyr(Bn)OCA/ -Tyr(Bn)OCA = 9/1, c) -Tyr(Bn)OCA with
DMAP/ PrOH as a catalyst, and d) rac-Tyr(Bn)OCA with 2b as an initiator (P = 0.95, Table 1, entry 6). (C) P values of poly(rac-
PheOCA) determined for all tetrads on the basis of a first-order Markov statistics (Table 1, entry 5, P = 0.92). (D) P values of
poly(rac-Tyr(Bn)OCA) determined for all tetrads on the basis of first-order Markov statistics (Table 1, entry 6, P = 0.95). (E)
The MALDI-TOF spectrum of Poly(rac-PheOCA) prepared by initiator 2b (Table S1, entry 15). (F) The MALDI-TOF spectrum of
poly(rac-Tyr(Bn)OCA) prepared by inititor 2b (Table S1, entry 21).
L
D
L
i
r
1
3
3
L
D
L
i
r
r
2
9
r
r
29
r
2
9
which can be assigned to m(PheOCA
-
CO2)
+
(Table 1, entry 5, Figure 2C). This high syndioselectivity
also can be confirmed by the following alternating copoly-
merization experiments (vide infra). A consistent high syn-
+
HOCH(CH )COOCH ) + Na and m(Tyr(Bn)OCA - CO2) +
HOCH(CH )COOCH ) + Na , respectively. Thus MALDI-
3
3
+
3
3
TOF MS proved again that the methyl lactate of initiator 2b
initiated the ROP reaction. Stereo microstructural analyses
of the resulting poly(rac-PheOCA) and poly(rac-
Tyr(Bn)OCA) were performed by C NMR spectrum, which
were more challenging than that of poly(rac-LacOCA) due
to the lack of clear stereosequence assignment reported in
literatures. An assignment at the tetrad level of resolution
for methine region and triad level of resolution for meth-
ylene region were made after carefully comparing Bernoul-
dioselectivity of P = 0.95 was also achieved for the ROP of
r
rac-Tyr(Bn)OCA with 2b as an initiator (Table 1, entry 6,
Figure 2D). It is noted above MALDI-TOF spectra also can
indirectly confirm the high selectivities of this system for
the ROP of (rac-PheOCA) and poly(rac-Tyr(Bn)OCA). As
shown in Figure 2-E and 2-F, the intensities of even number
of degree of polymerization (DP) are stronger than that of
odd number which does not happen in the slightly lower
syndioselective ROP of rac-LacOCA (more spectra see Fig-
ures S25-27). Because the very good alternating sequence of
-OCA and -OCA and -methyl lactate is used in complex
1
3
13
lian statistics predicted values with those C NMR experi-
mental integrated values of different multiads (triads and
tetrads) of atactic, isotactic, and isotactic-enriched
poly(OCA)s, which were deliberately synthesized via the
D
L
L
2b, the start monomer mostly is -OCA, then as a statistical
D
result the chain end monomer mostly should be -OCA to
L
ROP of rac-OCA, -OCA and a mixture of L-OCA and D
-
agree with racemic mixture of OCA when conversion is
close to 100 % (Figure S25). When increasing the amount of
D-OCA, it is reasonable that the polymers with odd number
of DP become stronger which are end-capped with D-OCA
(Figure S25). It is also noted here that when D-methyl lac-
tate was used in complex 2b, the syndioselective results are
similar for above three racemic monomer (Table S3, entries
1-3). In this system it was not successful in trying to synthe-
size high molecular weight polymers of poly(rac-PheOCA)
and poly(rac-Tyr(Bn)OCA) with the ratio of [mono-
mer] /[2b] more than 50:1 even when changing reaction
L
i
19b
OCA with DMAP/ PrOH as a catalyst (Figures 2A and 2B,
see more details of assignment via statistical analyses in
supporting information and Figures S19 - S24). The meth-
ylene regions of poly(rac-PheOCA) and poly(rac-
Tyr(Bn)OCA) in C NMR shows single main peak corre-
sponding to rr triad (Figures S21 and S24), which indicates
the syndioselectivity of this system is very high. The me-
thine region of poly(rac-PheOCA) in C NMR shows three
peaks which can be ascribed to tetrads of rrm, rrr/mrr, and
rmr in the predominant stereoerror sequence of -rrrmrrr-
1
3
1
3
0
0
(
–RSRSSRSR-/-SRSRRSRS-). The P value of final polymer
was 0.92, which was calculated from the tetrads at methine
region by a first-order chain end stereo control statistics
solvent to THF; to synthesize syndiotactically enriched and
high molecular weight poly(OCA)s is still in progress in our
lab.
r
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Alternating polymerization of OCAs
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
It is also interesting that the ROP reactions initiated by
b are very slow (conversion < 5 % within 24 h) for enanti-
2
opure monomers of D-PheOCA, L-PheOCA, and L-
Tyr(Bn)OCA at 50:1 and 25:1 ratio of monomer to 2b, which
further confirms the high syndioselectivities of this system
in aspect of kinetics (Table S1, entries 23 - 25). These exper-
iments together with the high syndioselectivity also hinted
that the absolute configuration of -methyl lactate in com-
L
plex 2b does not play an essential role for the syndioselec-
tive polymerization which just affects the insertion of the
first monomer in the syndiotactic polymer chain. What is
more, this phenomenon gives us an exciting opportunity to
achieve highly alternating copolymer of PheOCA and
Tyr(Bn)OCA. Thus the alternating copolymerization of
enantiopure D-PheOCA and L-Tyr(Bn)OCA with opposite
absolute configurations initiated by complex 2b was per-
formed (Scheme 1B). Complex 2b was active under mild
conditions, allowing a full conversion of 15:15:1 and 7:7:1
ratios of [PheOCA] /[Tyr(Bn)OCA ] /[2b] within 12 hours.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Syndioselectivities of the ROP of rac-LacOCA
using 2b as an initiator at different temperatures [rac-
0
0
0
The resulting poly( -PheOCA-alt- -tyr(Bn)OCA) showed
D
L
LacOCA] :[2b] = 100 : 1.
0
0
narrow molecular weight distribution (Đ < 1.1) with desira-
ble NMR M values, which suggests this ROP is a highly
It is interesting that when we decrease the temperature of
reaction for the ROP of rac-LacOCA using 2b as an initiator,
n
controlled process (Table 2, entries 1 and 2). The consump-
tion rates of two monomers almost are same (Figure S29).
the P value of syndioselectivity decreases from 0.83 at 25 °C,
r
to 0.75 at -40 °C, and further decreases to 0.72 at -60 °C
(Figure 3, Table S4, entries 1-4). A stereoselective mecha-
nism that only chirality of the growing chain end controls
the configuration of next monomer cannot explain well this
kind of decrease of syndioselcetivity. While a mechanism
termed as “enhanced” chain end control seems to be suita-
Because of the poor solubility of
nating polymerization of 50 equiv. (25 equiv. + 25 equiv.)
monomers of -PheOCA and -Tyr(Bn)OCA mixtures with
L
-Tyr(Bn)OCA, the alter-
D
L
a 1:1 ratio was performed in a dilute toluene solution (Table
2, entry 3) and the rate of reaction decreased obviously
(only accomplished in a 85 % conversion after 36 h). To
24
13
ble, which was suggested by Davidson and coworkers for
heteroselective ROP of rac-lactide. In this mechanism, both
the growing chain end and the chiral center of metal are
important for the highly syndioselective system. As shown
in Scheme 2, there are two diastereoisomers of (S)-(M)-Hf
understand the control of alternating sequence, C NMR
spectra of polymers were analyzed. The signals of methine
and methylene regions of both monomers were assigned to
tetrad and triad sequences respectively according to the
related syndiotactic homopolymer (Figure 4A, Table 2, en-
try 3), because the overall pattern of these signals remains
persistent irrespective of the changing substituted group of
and (S)-(P)-Hf for complex 2b ( -methyl lactate was used in
L
2b) which can invert to each other via the inversion of the
1
3
axial chirality, (P or M), of metal center. Actually, this in-
version for complex 2b is quick at room temperature be-
cause the energy barrier is just about 12.4 kcal/mol in tolu-
OCAs incorporated in the alternating copolymers. Com-
pared with the random copolymer synthesized with
i
DMAP/ PrOH as a catalyst, the methylene region of result-
ene-d , which is calculated by the merged signal of two
ing polymer features two main peaks which correspond to
A-centered BAB triad at δ = 36.74 ppm and B-centered ABA
triad at δ = 35.83 ppm (A and B stand for PheOCA and
8
1
doublet peaks of methylene in ligand at 10 °C (VT H NMR,
23
Figure S28). Although both diastereoisomers exist in the
system, one is more active and highly syndioselective (for
example, (S)-(M)-Hf). Then (S)-(M)-Hf selectively opens R-
OCA to form less active and less syndioselective intermedi-
ate of (S)-(R)-(M)-Hf, which can be inverted to active and
highly syndioselective (S)-(R)-(P)-Hf to further selectively
open next S-OCA, then syndiotactic propagation can pro-
ceed. When temperature decreases, the transformation
from (S)-(R)-(M)-Hf to (S)-(R)-(P)-Hf becomes slow, a large
amount of less active and less syndioselective species of (S)-
Tyr(Bn)OCA repeating units minus one molecular CO ,
2
respectively), and the wrong triad sequences of AAB/BAA,
BBA/ABB, and AAA/BBB almost do not occur (Figure 4A-a).
The percentage of alternation reached a very high level (~
1
3, 14
95 % alternation, Table 2, entries 1-3, Figure 4B).
Based
on above analysis, the two main peaks at δ = 73.51 ppm and
1
3
73.41 ppm of methine region in C NMR can be attributed
to BABA and ABAB tetrads reasonably (Figure 4A-b).
Therefore, the resulting poly( -PheOCA-alt- -Tyr(Bn)OCA)
D L
(
R)-(M)-Hf can be accumulated to unselectively open OCAs,
revealed a highly controlled alternating monomer sequence
13
which causes the whole syndioselectivity decreases. The
above “enhanced” chain end control mechanism is possible.
But the interplays between chiral metal center, the end
group of growing chain, and monomers are complicated,
the stereoregulating mechanism for the ROP of OCAs may
be somewhat different from that in the ROP of rac-lactide.
Therefore more reliable details of mechanism are under
investigation now in our lab.
via the analysis of C NMR spectra.
The MALDI-TOF mass spectrum of poly( -PheOCA-alt-
D
L-Tyr(Bn)OCA) prepared with 2b as an initiator (Table 2,
entry 3, Figure 4C and 4D) shows two primary series peaks
of An+1B and A B alternatingly separated by 148 and 254 ~
n
n n
Da (corresponding to the mass of PheOCA and
Tyr(Bn)OCA minus molecular mass of CO ); because
2
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50
51
52
53
54
55
56
57
58
59
60
Scheme 2. Proposed “enhanced” chain end control stereoselective mechanism for the ROP of OCAs.
a
Table 2. Alterlating ROP of Enantiopure -OCA and -OCA initiated by 2b.
D
L
c
%
terna-
tion
Al-
d
e
f
Conv.(%)
b
M
n,obsd
M
n,NMR
M
n,calcd
(g/mol)
Entry
D-OCA
L-OCA
DP
t (h)
Đ
(
g/mol)
(g/mol)
g
D-OCA/ -OCA
L
h
1
PheOCA
PheOCA
PheOCA
LacOCA
LacOCA
LacOCA
LacOCA
PheOCA
LacOCA
Tyr(Bn)OCA 1/7/7
Tyr(Bn)OCA 1/15/15
Tyr(Bn)OCA 1/25/25
12
12
36
1
99/99
99/99
85/85
99/87
99/85
99/85
83/70
88/74
86/73
2900
5700
8300
2400
3400
5800
7600
7300
7100
3100
2900
6100
8600
2100
3100
5000
8300
8700
8600
1.04
1.12
1.18
1.06
1.10
1.10
1.16
1.18
1.18
~ 95
h
2
6300
8900
2400
3500
5200
8600
8900
8300
~ 95
i
h
3
~ 95
4
5
6
7
8
PheOCA
PheOCA
PheOCA
PheOCA
LacOCA
PheOCA
1/10/10
1/15/15
81
1
80
80
80
79
80
1/25/25
1/50/50
1/50/50
1/50/50
4
6
6
j
9
6
a
Conditions: Reactions were carried out under a dry nitrogen atmosphere, 0.01 mmol of initiator 2b, 5 mL of toluene, at room
b
temperature in addition to the annotated. DP refers to the ratio of the amount of the initiator to the amount of monomer.
c
1
d
e
Determined by H NMR spectroscopy. Experimental M and Đ determined by GPC in THF against polystyrene standards. De-
n
f
termined from the relative integration of the signals for the main-chain methine units and chain ends. Calculated from the equa-
tion: (M of OCA - M of CO ) × [OCA] /[Cat.] × Conv. % + the molar mass of the initiators. The percentage of alternation is the
g
w
w
2
0
0
1
3
probability of alternating linkages between two monomer units of opposite configurations and was determined by C NMR spec-
h
trum. The existence of only two singlet peaks for alternating triad sequences of ABA and BAB proves the alternating sequence is
controlled very well (A and B stand for D-PheOCA and -Tyr(Bn)OCA minus one molecular CO respectively), the probability of
L
2
i
j
alternation is more than 95 % after simulation. In 10 mL toluene. D-methyl lactate was used in 2b.
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8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
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4
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4
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5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
3
Figure 4. A) Regions of the main-chain methylene (a) and methine (b) in the C NMR spectra (125 MHz, CDCl ) of Poly( -
3
D
i
PheOCA-alt- -Tyr(Bn)OCA) prepared from the i) DMAP/ PrOH, ii) complex 2b (Table 2, entry 3), iii) Poly( -Tyr(Bn)OCA), and
iv) Poly( -PheOCA) prepared from DMAP/ PrOH. B) The simulation of the probability of alternating linkages between two
monomer units using signals of methylene region belonging to PheOCA monomer (Table 2, entry 3). C) Details of the MALDI-
TOF MS of Poly( -PheOCA-alt- -Tyr(Bn)OCA) prepared by the ROP of -Tyr(Bn)OCA and D-PheOCA with 2b (Table 2, entry 1)
L
L
i
D
D
L
L
using HCCA as matrix. D) The monomer number distribution of -pheOCA and -Tyr(Bn)OCA in polymer chains (A and B stand
D
L
for -pheOCA and -Tyr(Bn)OCA minus one molecular CO respectively).
D
L
2
1
3
Figure 5. A) Regions of the main-chain a) methyl, b) methylene and c) methine in the C NMR spectra (100 MHz, CDCl ) of
poly( -PheOCA-alt- -LacOCA) prepared from i) DMAP/ PrOH, ii) complex 2b (Table 2, entry 7), iii) Poly( -PheOCA) prepared
from DMAP/ PrOH, and iv) Poly( -LacOCA) prepared from complex 2b (Table S1, entry 10). B) The simulation of the probability
of alternating linkages between two monomer units using signals of methyl region belonging to LacOCA monomer in C NMR
Table 2, entry 7). C) The monomer number distribution of D-pheOCA and -LacOCA in polymer chains (A and B stand for D
3
i
D
L
L
i
D
1
3
(
-
L
pheOCA and L-LacOCA minus one molecular CO respectively). D) Details of MALDI-TOF MS of a poly( -PheOCA-alt- -
LacOCA) prepared by ROP of -pheOCA (A unit) and -LacOCA (B unit) with 2b using HCCA as matrix (Table 2, entry 4).
2
L
D
D
L
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enantiopure -methyl lactate was used in complex 2b and
phenomenon agrees well with the slightly higher consump-
L
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
consequently the first monomer inserted in the polymer
chains is A unit of D-PheOCA, the two primary type polymer
tion rate of D-LacOCA than that of -PheOCA (Table 2, en-
L
tries 4-7). The percentage of correct alternating sequence for
1
3, 14
chains of -CH CO CH(CH )O-(A-B) -A abbreviated as
1/0
D-LacOCA was about 80 % (Figure 5B and Figure S38).
L
3
2
3
n
An+1Bn and A B were desirable and have no sequence error.
Accordingly, the methine region peak at δ = 68.98 ppm
mostly originated from alternated ABAB/BABA tetrad signal
despite the overlap between ABAB/BABA and BBBB tetrads.
n
n
The distribution of two monomers in primary polymer
chains (red square and blue triangle in Figure 4D) in MALDI-
TOF mass spectrum also demonstrates the primary alternat-
ing propagation process, e.g. from A B to A B to A5B4 to
1
3
The analysis results of the C NMR spectrum demonstrated
the control of alternating monomer sequence was slightly
4
3
4 4
A B and so on. The weak series peaks of A B and An+2Bn
lower than that in alternating copolymer of poly( -PheOCA-
5
5
n
n+1
D
can be attributed the copolymers with a single alternating
sequence error. Other peaks with more sequence errors for
example, AnBn+2, An+3B , A Bn+3, could not be detected. There-
alt- -Tyr(Bn)OCA), which was consistent with the slightly
L
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
lower syndioselectivity of the ROP of rac-LacOCA than that
of rac-PheOCA and rac-Tyr(Bn)OCA. When -methyl lactate
n
n
L
fore, the MALDI-TOF mass spectrum can prove again that
the alternating monomer sequence in polymer chain of
poly( -PheOCA-alt- -Tyr(Bn)OCA) was controlled very well.
was changed to D-methyl lactate in 2b, the alternating prob-
ability is similar; and the copolymerization of D-LacOCA and
L-PheOCA also can give similar results (Table 2, entries 7-9,
Figure S38). In MALDI-TOF mass spectrum (Figure 5C and
5D), there are two series peaks of A B and A B alternat-
D
L
It is interesting the intensities of two correct main sequence
chains of A B and An+1Bn can be inverted via changing ratio
n
n
n
n
n n+1
between A and B. When D-PheOCA : -Tyr(Bn)OCA : com-
ingly separated by 148 and 72 ~ Da confirmed again the main
L
plex 2b = 7 : 7 :1 and -methyl lactate was used in 2b, A B
alternating sequence in poly( -PheOCA-alt- -LacOCA) pre-
L
n
n
L
D
series are stronger; when the ratio is changed to 8:7:1 (Figure
S33B), An+1Bn series become stronger than that of AnBn. When
rac-methyl lactate was used in 2b and the ratio is 7:7:1, the
two series signals have similar intensities (Figure S33C). This
phenomenon is a statistical result and can be attributed to
the very high alternating probability of this copolymerization
system, which is similar to the MADLI-TOF spectra of
poly(rac-PheOCA) and poly(rac-Tyr(Bn)OCA) obtained us-
ing 2b as an initiator.
pared from 2b. It is noted here that the first monomer insert-
ed in the polymer chains is B unit of -LacOCA because there
D
is one -methyl lactate in 2b. The obvious presence of series
L
signals of An+1B and A B indicates again the slightly lower
n
n n+2
control of alternating monomer sequence compared to that
in alternating copolymer of poly( -PheOCA-alt- -
D
L
Tyr(Bn)OCA) (Figures 5C and 5D). Anyway the signals of
An+2B , A Bn+3, and even other peaks with more sequence
n
n
errors were weak, which suggests the alternating polymeriza-
tion of -LacOCA and -PheOCA was also successful.
Although the homopolymerization of enantiopure LacOCA
and PheOCA initiated by complex 2b showed very different
L
D
Conclusions
rates (Table S1, entries 10 and 23), both rates of the ROP of D-
In summary, we have developed the first syndioselective
system for the ring-opening polymerization of racemic OCAs
LacOCA and -PheOCA are slower than that of rac-PheOCA
L
or rac-LacOCA, which suggest the alternating polymeriza-
tion of -LacOCA and -PheOCA is also possible. The in situ
here. The syndioselectivity can be high up to P = 0.95 for
r
D
L
Poly(rac-Tyr(Bn)OCA), P = 0.92 for Poly(rac-PheOCA), and
r
1
H NMR monitoring of copolymerization of 1:1 different enan-
tiopure monomer mixture of D-LacOCA and -PheOCA with
Pr = 0.84 for Poly(rac-LacOCA). This system also was applied
in the precisely syndiospecific alternating copolymerization
of -PheOCA and -Tyr(Bn)OCA; the alternating polymeriza-
L
2
b as an initiator showed similar monomer consumption
rates (Figure S34), where it is just slightly fast for D-LacOCA
Table 2, entries 4-7). The GPC analysis of the copolymer
D
L
tion of -PheOCA and D-LacOCA was also successful. There-
L
(
fore, the syndioselective ROP of OCAs presents an efficient
and powerful method to synthesize alternating copolymers
resulted from 2b showed narrow molecular weight distribu-
tions with NMR M values close to calculated values. Micro-
n
of α-hydroxy acids, which can further enrich the diversity of
structural analysis of resulting poly( -PheOCA-alt- -LacOCA)
L
D
PAHAs with optimized properties for applications. Our re-
sults also proved that the syndioselectivity of a cata-
lyst/initiator in this method should play an important role
for the alternating sequence control.
1
3
was also performed by C NMR spectrum (Table 2, entry 7).
1
3
Although the resolution of C NMR is limited for the regions
of PheOCA monomer in this copolymer, the signals of me-
thine and methylene regions also can be assigned to tetrad
and triad sequences respectively according to the related
syndiotactic homopolymer of poly(rac-PheOCA) (Figure 5A).
Compared to the random copolymer, there is only one obvi-
ous strong peak at δ = 36.93 ppm belonging to methylene
ASSOCIATED CONTENT
Supporting Information. Experimental details, NMR spec-
tra of the complexes 1-2, the spectra of polymers, the information
of copolymer of poly(Tyr(Bn)OCA-alt-LacOCA), statistical
analyses for poly(α-hydroxy acid). This material is available free
of charge via the Internet at http://pubs.acs.org.
group of A-centered traid BAB (A and B stand for -PheOCA
L
and D-LacOCA repeating units minus one molecular CO2,
respectively); correspondingly δ = 73.44 ppm belonging to
methine group of tetrad BABA/ABAB also is strong; signals
for other A-centered error sequences of methylene triads and
methine tetrads were not obvious, which suggested the in-
AUTHOR INFORMATION
Corresponding Author
sertion sequences of most -PheOCA are right in the whole
L
*
wujc@lzu.edu.cn
polymerization progress. The peaks at δ = 16.49, 16.44, and
16.36 ppm can be attributed to methyl groups of B-centered
triads of ABA and ABB/BBA. These obvious signals of triads
of ABB/BBA indicate the presence of some insertion se-
quence errors for D-LacOCA in the polymer chains. This
ACKNOWLEDGMENT
Financial support from the National Natural Science Founda-
tion of China (No. 21671087 and 21271092). We thank Dr.
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Elling, B. R.; Xia, Y. J. Am. Chem. Soc. 2015, 137, 9922-9926. (e)
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Academy of Sciences for the MALDI-TOF mass measure-
ments; we also thank Prof. Hua Wei in College of Chemistry
and Chemical Engineering, Lanzhou University for analyses
of molecular weights of polymers.
Parker, K. A.; Sampson, N. S. Acc. Chem. Res. 2016, 49, 408-417.
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