Organocatalytic Ring-Opening Polymerization Strategies for Synthesis of Poly(phosphothioesters) with a Pendent Phenyl Group

Article abstract of DOI:10.1055/s-0040-1707947

A novel type of phosphothioester substrate, 2-phenyl-1,3,2-dioxaphospholane 2-sulfide (PTP), has been synthesized and subjected to ring-opening polymerization. DBU/thiourea served as an efficient cooperative organocatalyst for the synthesis of poly(PTP),

Full text of DOI:10.1055/s-0040-1707947

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© Georg Thieme Verlag Stuttgart · New York
2020, 31, 1167–1171
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1167
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H. Yan et al.
Letter
Synlett
Organocatalytic Ring-Opening Polymerization Strategies for Syn-
thesis of Poly(phosphothioesters) with a Pendent Phenyl Group
Huating Yana,b
Guangqiang Xu*b
Rulin Yangb
S
Ph
DBU/TU
PPA
P
O
O
H
O
S
O
Ph
O
O
P
O
P
n
Ph
Ph
S
Chengdong Lvb
Li Zhoub
Xin-Qi Hao*a
Qinggang Wang*b
Organocatalytic ring-opening polymerization
Narrow molecular weight distributions (1.14–1.20)
High molecular weight (up to 45.2 kg/mol)
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8
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a College of Chemistry, Zhengzhou University, Zhengzhou,
450001, P. R. of China
xqhao@zzu.edu.cn
b Key Laboratory of Biobased Materials, Qingdao Institute of
Bioenergy and Bioprocess Technology, Chinese Academy of
Sciences, 189 Songling Road, Qingdao, 266101, P. R. of China
xu_gq@qibebt.ac.cn
wangqg@qibebt.ac.cn
Received: 24.03.2020
Accepted after revision: 21.04.2020
Published online: 05.05.2020
ester, so various structural and functional polyphospho-
esters can be smoothly synthesized through structural
modulation.
DOI: 10.1055/s-0040-1707947; Art ID: st-2020-l0167-l
previous work
Abstract A novel type of phosphothioester substrate, 2-phenyl-1,3,2-
dioxaphospholane 2-sulfide (PTP), has been synthesized and subjected
to ring-opening polymerization. DBU/thiourea served as an efficient co-
operative organocatalyst for the synthesis of poly(PTP), delivering the
polymer with a well-defined structure, a relatively narrow molecular-
weight distribution (1.14–1.20), and high molecular weight (up to 45.2
kg/mol). The ring-opening polymerization process showed a con-
trolled/living nature. In addition, diblock copolymers of PTP with rac-
lactide with well-defined structures were also synthesized.
O
O
O
O
O
O
O
O
P
P
P
OiPr
OEt
M-3
this work
Me
M-1
M-2
O
O
O
O
S
O
O
S
O
P
P
P
R
N
OR
Ph
H
Key words organocatalysis, ring-opening polymerization, polyphos-
phothioesters, living polymerization, phenyldioxaphospholane sulfide,
block copolymerization
M-5
M-4
PTP
Figure 1 Representative monomers for cyclic (thioxo)phosphoesters
As the third most broadly used group of catalysts after
enzymes and metal complexes, organocatalysts have shown
remarkable progress in recent years.1 Compared with other
methods of catalysis, organocatalysis has many advantages,
such as mild reaction conditions, functional-group toler-
ance, and easy preparation and recovery of catalysts, which
are in line with the requirements of green chemistry.2 Al-
though the latest research on organocatalysis has focused
on the enantioselective synthesis of small molecules, or-
ganocatalysis also provides many opportunities in polymer
synthesis.3
In recent years, the use of organocatalysts for the ring-
opening polymerization (ROP) of strained cyclic phospho-
esters (Figure 1) has been proven to be a promising strategy
for the synthesis of metal-free and well-defined poly-
phosphoesters.4 The pentavalent nature of the phosphorus
atom provides four modifiable sites in the cyclic phospho-
In 2010, Iwasaki et al. reported the ROP of 2-isoprop-
oxy-1,3,2-dioxaphospholane 2-oxide (M-1) by using 1,8-di-
azabicyclo[5.4.0]undec-7-ene (DBU) or 1,5,7-triazabi-
cyclo[4.4.0]dec-5-ene (TBD) as an organocatalyst (Figure 1).5
Later, Wurm and co-workers used 2-methyl-1,3,2-dioxa-
phospholane 2-oxide (M-2) and 2-ethoxy-1,3,2-dioxaphos-
pholane 2-oxide (M-3) to prepare water-soluble polyphos-
phonates.6,7 Wooley et al. used the phospholane amidate M-
4 as a substrate to synthesize acid-labile polyphosphorami-
dates.8 Recently, the Wang group replaced the P=O double
bond in a phosphoester with a P=S double bond and de-
signed a series of thioxophosphoester substrates M-5 with
alkoxy side chains.9 Compared with polyphosphoesters, the
resulting polythioxophosphoesters are more stable under
acidic or basic conditions and can be selectively hydrolyzed
by peroxide. However, the P–O on the side chain of the
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1167–1171
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

1168
H. Yan et al.
Letter
Synlett
polymer is easily removed. We believed that the introduc-
tion of an alkyl or aryl group into the side chain of a thioxo-
phosphoester substrate would make the resulting polymer
much more stable.10
We therefore synthesized 2-phenyl-1,3,2-dioxaphos-
pholane 2-sulfide (PTP) as a substrate with a pendent phe-
nyl group and we subjected it to ROP. Various organic bases
(Figure 2), including DBU, TBD, and P1-t-Bu were used as or-
ganocatalysts to test the activity of the substrate. Precise
control over the molecular weight and molecular-weight
distribution was the primary goal of this research.
[PTP]0/[Cat.]0/[PPA]0 ratio of 25:1:1 with DBU as the sole
catalyst (Table 1, entry 1). The monomer conversion
reached 80% in 20 minutes, and the resulting polymer had a
molecular-weight distribution (MWD) of Ð = 1.40 and a
reasonable number-average molecular weight (Mn) of 4000
g/mol. Prolonging the reaction time to 80 min, did not in-
crease the monomer conversion, whereas the MWD (Ð =
1.50) was further broadened (entry 2). This result suggest-
ed that the polymerization of PTP and depolymerization of
poly(PTP)s are in equilibrium, and severe transesterifica-
tion occurs on increasing the polymerization time. A broad-
er MWD (Ð = 1.82) was obtained in the TBD-catalyzed ROP
of PTP (entry 3). On using P1-t-Bu as the catalyst, a relatively
narrow MWD (Ð = 1.29) and a low catalytic efficiency were
observed (entry 4).12 These results showed that the ROP of
PTP is more difficult to control than that of the other cyclic
phosphoester monomers M-1 to M-5 (Figure 1).
CF3
N
N
S(O)
N
N
P
N
N
N
N
H
CF3
N
H
N
H
N
TU(U)
P1-t-Bu
DBU
TBD
According to reports in the literature, co-catalysts such
as thiourea (TU) or urea (U) should effectively promote the
ROP of lactones.13 As expected, when TU or U was added to
the polymerization system of PTP, the polymerization rate
and conversion were significantly improved (Table 1, en-
tries 5 and 6), which is consistent with the experimental re-
sult of Jérôme and co-workers.10 More importantly, the re-
sulting poly(PTP)s exhibited a narrow and monomodal
MWD, showing that (thio)urea facilitated activation of the
monomer and suppressed transesterification.14 On increas-
ing the amount of thiourea to two equivalents (entry 7), the
MWD was not markedly reduced, but the polymerization
Figure 2 Organocatalysts for ring-opening polymerization of PTP
At the outset, we synthesized the PTP monomer (Figure
1) in one simple step by esterification of ethylene glycol
with phenylphosphonothioic dichloride.11 The product was
characterized by means of 1H, 13C , and 31P NMR spectrosco-
py and HRMS [see Supporting Information (SI); Figures S2–
S4], which indicated a successful synthesis of high-purity
PTP.
The polymerization of PTP was first investigated in di-
chloromethane
at
room
temperature
with
Table 1 Optimization of the Conditions for ROP of PTPa
b
Entry
[M]0/[Cat.]0/[I]0
Cat.
DBU
Temp ( °C)
Time (min)
Conv.c (%)
Mn, theod (g/mol)
Mn, GPCe (g/mol)
Ðe
1.40
1
2
25:1:1
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
0
20
80
80
80
84
76
86
80
85
80
88
90
89
88
66
4100
4100
4300
3900
4400
4100
4400
4100
4500
4600
9000
17700
65100
4000
4900
4600
4400
4800
4600
4500
4600
4400
4300
10000
15800
45200
25:1:1
DBU
1.50
1.82
1.29
1.26
1.28
1.24
1.23
1.19
1.20
1.17
1.14
1.14
3
25:1:1
TBD
20
4
25:1:1
P1-t-Bu
DBU/TU
DBU/U
DBU/TU
P1-t-Bu/TU
DBU/TU
DBU/TU
DBU/TU
DBU/TU
DBU/TU
20 h
15
5
25:1:1:1
25:1:1:1
25:1:2:1
25:1:1:1
25:1:1:1
25:1:1:1
50:1:1:1
100:1:1:1
500:1:1:1
6
15
7
40
8
50
9
20
10
11
12
13
–20
0
20
60
0
120
22 h
0
a Reaction conditions: [M]0 = 1 M in CH2Cl2, 3-phenylpropan-1-ol (PPA) initiator.
b Molar feed ratio of monomer, catalyst, and initiator.
c Determined 1H NMR spectroscopy of the crude product in CDCl3.
d Theoretical Mn calculated from [M]0/[I]0 and the monomer conversion.
e The apparent Mn and dispersity (Đ) were determined by gel-permeation chromatography (GPC) in THF (40 °C, polystyrene standards).
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1167–1171

1169
H. Yan et al.
Letter
Synlett
rate was slower. These results implied that a higher loading
of thiourea might form a stable complex with DBU, thereby
inhibiting the polymerization.15
As shown in Figures 4a and 4b, all the polymers showed
sharp and unimodal GPC peaks with MWD (Ð) values of
less than 1.20, which remained low even at high DPs. To fur-
ther understand the characteristics of polymerization, we
conducted a kinetic experiment. A distinct first-order ki-
netic relationship between ln([M]0/[M]t) and the reaction
time was observed, confirming the highly controlled nature
of the DBU/TU catalytic system (Figure 4c). This well-con-
trolled characteristic was also highlighted by the observa-
tion of a linear correlation between Mn and the conversion
(Figure 4d). Moreover, a chain-extension experiment pro-
ceeded smoothly (Figure 4e).19 After completion of a first
polymerization, 25 equivalents of PTP were added to the
preformed polymer (Mn = 4500 g/mol; Ð = 1.24) and the re-
action was continued for 40 minutes. The polymerization
retained an 89% conversion while the Mn increased to 9500
g/mol and MWD remained narrow. This experiment
showed that the ROP process displays rapid kinetics and a
living behavior.
Thiourea anions derived from thioureas and strong bas-
es, introduced as ROP catalysts by Waymouth and co-work-
ers in 2016, have been widely used in the ROP of lactones.16
In this context, we surveyed cooperative catalysis by P1-t-
Bu and thiourea in the ROP of PTP (Table 1, entry 8). Sur-
prisingly, the MWD decreased to 1.23, but the polymeriza-
tion rate decreased significantly (15 min versus 50 min).
This was different from the results for the polymerization
of lactones catalyzed by the P1-t-Bu/thiourea system, which
can be complete within seconds.17
In an attempt to improve the polymerization, we then
examined the effect of temperature. On reducing the reac-
tion temperature from room temperature to 0 or –20 °C
(Table 1, entries 9 and 10, respectively), it was observed
that the MWDs of the polymerizations were narrow,
whereas the rate of polymerization and the conversion re-
mained high, which was consistent with the results for the
ROP of -butyrolactone.18 Taking all the conditions into
consideration, the conditions shown in entry 9 were select-
ed as optimal for obtaining well-defined polymers.
Copolymerization of PTP monomer with rac-lactide
(rac-3,6-dimethyl-1,4-dioxan-2,5-dione) was also per-
formed by using the DBU/TU catalytic system (Figure 4f).
After ROP of PTP, the same number of equivalents of rac-
lactide were added to the polymerization system to con-
tinuing the reaction. A 91% conversion of rac-lactide was
observed, while the Mn increased to 11700 g/mol and the
MWD value remained below 1.18, showing that a block co-
polymer was formed and that the polymerization was a liv-
ing process.20 The microstructure of the resulting copoly-
mers was also determined by analysis of the methine region
1
The resulting polymers were characterized by H NMR
spectroscopy (Figure 3). The peaks a–g in the polymers
were clearly visible at  = 1.89 - 8.00 ppm in the 1H NMR. By
comparison with the spectrum for the alcoholysis product,
the presence the well-defined end group PhCH2CH2CH2O–
(peaks a, c, d, and e) was confirmed. Next, we examined the
ROP of PTP at various monomer/initiator feed ratios (Table
1, entries 11–13). When the degree of polymerization (DP)
was increased to 50, the polymerization proceeded well
with a conversion of 89% within one hour and a MWD of
only 1.17 (entry 11). The highest molecular weight of 45.2
kg/mol with a narrow MWD of 1.14 was achieved when the
DP was increased to 500 (entry 13).
1
of the homonuclear-decoupled H NMR spectrum (SI; Fig-
ure S7). A higher isoselectivity of Pm = 0.71 (based on Ber-
nouillian statistics) was obtained, suggesting that pre-
formed poly(PTP) has a positive influence on the isoselec-
tivity of the subsequently formed polylactide.21
In summary, the ROP of the new thioxophosphoester
monomer PTP catalyzed by the DBU/TU cooperative system
proceeded smoothly to give poly(PTP) with a well-defined
structure, narrow MWD (Đ = 1.14–1.20) and a high molecu-
lar weight (up to 45.2 kg/mol).22 A kinetic experiment and a
chain-extension experiment confirmed the controlled/liv-
ing nature of the ROP process. This new monomer PTP en-
riches the toolbox for the synthesis of poly(phosphothio-
ester)s. Further investigations on PTP are in progress in our
laboratory.
Funding Information
We gratefully acknowledge the generous support by the National Nat-
ural Science Foundation of China (21901249, 21950410529), National
Key R&D Plan (2017YFC1104800), Taishan Scholar Foundation of
Shandong Province (tsqn201812112), and the “135” Projects Fund of
Qingdao Institute of Bioenergy and Bioprocess Technology, Chinese
Figure 3 1H NMR spectra of the alcoholysis product and poly(PTP)
(400 MHz, CDCl3, 298 K)
Academy of Sciences.
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© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1167–1171

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H. Yan et al.
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Figure 4 (a) Plots of DP ([M]0/[I]0) versus Mn and Đ. (b) GPC analysis of ROP of PTP for various DPs using DBU/TU as catalyst and PPA as initiator. (c)
Plots of monomer conversion {ln([M]0/[M]t)} versus time for DP = 50. (d) Plots of monomer conversion versus Mn and Đ for DP = 50. GPC analysis of
polymerization before and after supplementary addition of (e) 25 equiv PTP or (f) 25 equiv rac-lactide.
Supporting Information
2010, 48, 1919. (c) Stukenbroeker, T. S.; Solis-Ibarra, D.;
Waymouth, R. M. Macromolecules 2014, 47, 8224. (d) Zhu, W.;
Du, H.; Huang, Y.; Sun, S.; Xu, N.; Ni, H.; Cai, X.; Li, X.; Shen, Z.
J. Polym. Sci. Part A: Polym. Chem. 2013, 51, 3667. (e) McKinlay,
C. J.; Waymouth, R. M.; Wender, P. A. J. Am. Chem. Soc. 2016, 138,
3510. (f) Bauer, K. N.; Tee, H. T.; Velencoso, M. M.; Wurm, F. R.
Prog. Polym. Sci. 2017, 73, 61.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0040-1707947.
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n
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References and Notes
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(22) Poly(2-phenyl-1,3,2-dioxaphospholane 2-sulfide) (Table 1,
Entry 9)
In a typical polymerization reaction, a 5 mL Schlenk tube
equipped with a stirring bar was dried and charged with argon
three times, and then placed in a glovebox. In the glovebox, TU
(7.4 mg, 0.02 mmol), a 1 M solution of DBU in toluene (20 L,
0.02 mmol), a 1 M solution of PPA in toluene (20 L, 0.02
mmol), CH2Cl2 (0.5 mL), and PTP (100 mg, 0.5 mmol) were
added sequentially to the Schlenk tube. The tube was then
removed from the glovebox and kept in an ice bath for 20 min.
The reaction was quenched by addition of a 1 M solution of
AcOH in CH2Cl2 (50 L). The polymer was precipitated several
times from cold Et2O, and dried under vacuum to a constant
weight. The molecular-weight distribution and number-
average molecular weight of the polymer were determined by
GPC: Mn = 4400 g/mol; Ð = 1.19.
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Polym. Chem. 2016, 54, 692.
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Chem. 2020, 44, 1648.
© 2020. Thieme. All rights reserved. Synlett 2020, 31, 1167–1171