Anionic Polymerization of Azidoalkyl Glycidyl Ethers and Post-Polymerization Modification

Article abstract of DOI:10.1021/acs.macromol.9b02236

Polyethers like poly(ethylene glycol) have been widely used for a variety of valuable applications, although their functionalization still poses challenges due to the absence of functional handles along the polymer backbone. Herein, a series of novel azide-functionalized glycidyl ether monomers are presented as a universal approach to synthesize functional polyethers by post-polymerization modification. Three azide-functionalized glycidyl ether monomers possessing different alkyl spacers (ethyl, butyl, and hexyl) were designed and synthesized by a simple two-step substitution reaction. Organic superbase-catalyzed anionic ring-opening polymerization can proceed under mild conditions compatible with an azide pendant group, affording well-controlled azide-functionalized polyethers with low dispersity (? < 1.2). The azide pendant groups on the resulting polymers were readily modified to a variety of functional groups via copper-catalyzed azide-alkyne cycloaddition reactions and Staudinger reduction. Furthermore, copolymerization of azidohexyl glycidyl ether with allyl glycidyl ether was demonstrated to provide an additional orthogonal functional handle. We anticipate that this work provides a new platform for the preparation of diverse functional polyethers.

Full text of DOI:10.1021/acs.macromol.9b02236

Article
pubs.acs.org/Macromolecules
Cite This: Macromolecules XXXX, XXX, XXX−XXX
Anionic Polymerization of Azidoalkyl Glycidyl Ethers and Post-
Polymerization Modification
Joonhee Lee,
†
,‡
Sohee Han,† Minseong Kim,
†,‡
and Byeong-Su Kim*,†
†
Department of Chemistry, Yonsei University, Seoul 03722, Republic of Korea
‡
Department of Chemistry, Ulsan National Institute of Science and Technology (UNIST), Ulsan 44919, Republic of Korea
*
S Supporting Information
ABSTRACT: Polyethers like poly(ethylene glycol) have been widely used for a variety of valuable applications, although their
functionalization still poses challenges due to the absence of functional handles along the polymer backbone. Herein, a series of
novel azide-functionalized glycidyl ether monomers are presented as a universal approach to synthesize functional polyethers by
post-polymerization modification. Three azide-functionalized glycidyl ether monomers possessing different alkyl spacers (ethyl,
butyl, and hexyl) were designed and synthesized by a simple two-step substitution reaction. Organic superbase-catalyzed anionic
ring-opening polymerization can proceed under mild conditions compatible with an azide pendant group, affording well-
controlled azide-functionalized polyethers with low dispersity (Đ < 1.2). The azide pendant groups on the resulting polymers
were readily modified to a variety of functional groups via copper-catalyzed azide−alkyne cycloaddition reactions and
Staudinger reduction. Furthermore, copolymerization of azidohexyl glycidyl ether with allyl glycidyl ether was demonstrated to
provide an additional orthogonal functional handle. We anticipate that this work provides a new platform for the preparation of
diverse functional polyethers.
8
,9
INTRODUCTION
transformations, including azide−alkyne cycloaddition,
10 11
■
transesterification, thiol−ene addition, Diels−Alder reac-
tions, Suzuki−Miyaura coupling, and sulfur fluoride
exchange. For this strategy, the development of a suitable
monomer that is compatible with a polymerization needs to be
accompanied. In this manner, BN 2-vinylnaphthalene has been
introduced by the Klausen group to prepare poly(vinyl
alcohol) derivatives via post-polymerization organoborane
oxidation. The Hillmyer group has established a new route
to prepare poly(allyl alcohol) by post-polymerization mod-
ification of the polymer precursor synthesized from bis(tert-
butyloxycarbonyl) twisted acrylamide monomer. These
strategies highlight the importance of designing a functional
monomer suitable for post-polymerization modification to
access desired functional polymers that are otherwise
inaccessible by direct polymerization.
The development of efficient and reliable methods to
synthesize functional polymers with diverse properties and
architectures is essential to satisfy the demands of various
applications in materials science. Many functional polymers
have been prepared by direct polymerization of readily
polymerizable monomers accompanied by significant advances
in controlled polymerization techniques with tolerable func-
1
2
13
14
15
1
−3
tional monomers.
However, there are still some monomers
having reactive functional moieties that are not amenable to
direct polymerization.
Alternatively, post-polymerization modification offers an
avenue to access multifunctional polymers while circumventing
the incompatibility of desirable functional groups with
polymerization conditions. Many post-polymerization mod-
ification strategies are based on the increasing convergence of
organic chemistry and polymer synthesis, spearheaded by the
introduction of click chemistry by Sharpless and colleagues.
1
6
4
,5
6
7
Received: October 23, 2019
Revised: December 4, 2019
For example, post-polymerization modification of many classes
of polymers has been achieved through various chemical
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.macromol.9b02236
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Scheme 1. Post-Polymerization Modification of Azide-Functionalized Polyethers via Copper-Catalyzed Azide−Alkyne
Cycloaddition (CuAAC) and Staudinger Reduction
Polyethers like poly(ethylene glycol) (PEG) draw consid-
erable attention as one of the most valuable polymers in
biomedical applications by virtue of their excellent biocompat-
our ongoing effort in the development of novel functional
3
7−43
glycidyl ether monomer library,
herein, we introduce a
series of new azide-functional glycidyl ether monomers,
azidoethyl glycidyl ether (AEGE), azidobutyl glycidyl ether
(ABGE), and azidohexyl glycidyl ether (AHGE) that can be
polymerizable under organic superbase-catalyzed AROP
conditions. The homopolymerization of each monomer was
17,18
ibility and aqueous solubility.
However, they lack reactive
functional handles along their backbone, which limits their
implications in broader areas. The typical approach for the
preparation of multifunctional PEGs involves anionic ring-
opening polymerization (AROP) of functional epoxide
1
compared using in situ H NMR kinetic study. Among them,
1
9,20
monomers.
Conventional AROP is typically incompatible
AHGE was selected as a model monomer for the generation of
a modular and versatile synthetic route to post-polymerization
modified polyethers (Scheme 1). Polymerization of AHGE
provides functional polyethers bearing pendant azide groups,
which can be further reacted with functional alkynes to install a
broad range of functionalities along the polymer backbone. In
addition, Staudinger reduction of the azide group can afford a
pendant primary amine group, which is otherwise not tolerable
in typical AROP conditions.
with most functional groups, such as hydroxyl, carboxylic acid,
primary amine, nitrile, and halide groups, due to the highly
reactive conditions, leading to undesirable side reactions. An
alternative approach such as the activated monomer method
21−23
has been suggested to avoid such difficulties.
Nonetheless,
the development of epoxide monomers exhibiting functional
groups that are tolerable to typical AROP conditions is still
necessary to design a convenient post-polymerization mod-
ification strategy for polyethers.
To date, several monomers bearing functional groups stable
EXPERIMENTAL SECTION
■
19
to AROP conditions have been reported. As a representative
example, allyl glycidyl ether (AGE) is an epoxide monomer
widely used for imparting functionality to PEG. Not only are
allyl groups stable under typical AROP conditions but they can
also react with functional thiols via the thiol−ene reaction to
Materials. All reagents and solvents were purchased from Sigma-
Aldrich, Alfa Aesar, or Tokyo Chemical Industry and used as received
unless otherwise noted. Tetrahydrofuran (THF) and toluene were
dried, degassed using a solvent purification system (Vacuum
Atmospheres, USA), and collected to use immediately thereafter.
CDCl , DMSO-d , toluene-d , and D O were purchased from
24−26
3
6
8
2
decorate polyethers with myriad pendant functionalities.
Cambridge Isotope Laboratories. AEGE, ABGE, and AHGE were
Intensive studies and various applications of AGE-based
polymers by the Hawker and Lynd group have made a
significant impact on post-polymerization modification of
used for polymerization after the distillation over CaH .
2
1
13
Characterization. H and C NMR spectra were recorded on an
Agilent 400 MHz spectrometer or Bruker Avance III HD 400 MHz
spectrometer at room temperature. Chemical shifts are reported in
ppm relative to the signals corresponding to the residual non-
2
7−35
various polyethers.
Recently, Frey and co-workers have
also developed a novel epoxide monomer, 3,3-dimethoxypro-
panyl glycidyl ether, for homopolymerization or copolymeriza-
tion with ethylene oxide to afford PEG, displaying multiple
deuterated solvents: CDCl
, δH = 7.26 ppm and δC = 77.16 ppm;
3
(
CD ) SO, δH = 2.50 ppm; D O, δH = 4.79 ppm; and C D , δH =
3
2
2
7
8
36
2.09 ppm. Mass spectrometry was performed on a Bruker 1200 series
and HCT basic system using an electrospray ionization (ESI) source.
The number- and weight-average molecular weights (M and M ) and
aldehyde functionalities.
Inspired by the advent of click chemistry, the azide
functionality is regarded as a good candidate for the post-
polymerization modification of polyethers due to its potential
to undergo further modification by Cu-catalyzed azide−alkyne
cycloaddition (CuAAC) or Staudinger reduction. As a part of
n
w
molecular weight distributions (M /M ) were measured using size
w
n
exclusion chromatography (SEC). SEC analyses were performed on
an Agilent 1260 Infinity setup with two PLgel 5 μm mixed D columns
at 30 °C with either chloroform or THF as the mobile phase. The
B
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Table 1. Characterization Data of Poly(azidoalkyl glycidyl ether)s Prepared in This Study
a
a
a
entry
M (target)
n
M (NMR)
n
M (SEC)
n
Đ (SEC)
conv. (%)
DP (target)
DP
b
b
E1
E2
E3
B1
B2
B3
H1
H2
H3
H4
3000
3700
7300
3500
8700
17,200
2100
5100
7100
2970
3690
6700
3880
9870
17,400
2300
4690
7520
12,660
2700
3000
5600
4000
1.13
1.15
1.11
1.08
1.09
1.13
1.10
1.15
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
20
25
50
20
50
100
10
25
35
65
20
25
46
22
57
101
11
23
36
63
b
b
b
b
b
b
b
b
7400
b
b
11000
c
c
3000
4900
8400
c
c
c
c
1.21
1.03
c
c
13,000
11600
a
1
b
Determined from H NMR spectra of resulting polymers. Number-average molecular weight (M ) and dispersity (Đ) were measured by SEC in
n
c
THF. Number-average molecular weight (M ) and dispersity (Đ) were measured by SEC in CHCl with PMMA standard.
n
3
columns were calibrated against standard poly(methyl methacrylate)
(AEGE) and azidobutyl glycidyl ether (ABGE) were prepared from 2-
bromo-1-ethanol (1a) and 4-chloro-1-butanol (2a), respectively, by a
two-step substitution reaction, as described in the Synthesis of AHGE.
Synthesis of 2-Azido-1-ethanol (1b). 2-Azido-1-ethanol was
prepared by using 2-bromo-1-ethanol (1a) as a starting material,
samples (Sigma-Aldrich; M , 500−2,700,000). FT-IR spectra were
p
recorded on an Agilent Cary 630 FTIR spectrometer equipped with
an ATR module.
Synthesis of Azidoalkyl Glycidyl Ethers. Intermediates 2-azido-
1
-ethanol (1b), 4-azido-1-butanol (2b), and 6-azido-1-hexanol (3b)
according to the same procedure as described in the synthesis of 3b in
44
1
were prepared using a method derived by Hawker and co-workers.
We describe here a two-step synthesis of azidohexyl glycidyl ether
85% yield. H NMR (400 MHz, CDCl ): δ 3.78 (dd, J = 10.2, 5.5 Hz,
3
1
3
2H), 3.49−3.39 (m, 2H), 2.44 (t, J = 5.8 Hz, 1H). C NMR (101
(
AHGE) as a representative example.
MHz, CDCl ): δ 61.52, 53.59.
3
Synthesis of Azidohexyl Glycidyl Ether (AHGE). Synthesis of
Synthesis of AEGE. AEGE was prepared by using 2-azido-1-ethanol
(1b) as a starting material, according to the same procedure as
described in the synthesis of AHGE in 45% yield. H NMR (400
6
-Azido-1-hexanol (3b). A 250 mL round-bottom flask was charged
1
with 6-chloro-1-hexanol (3a) (15.0 g, 109.8 mmol), water (22.0 mL),
and sodium azide (10.7 g, 164.7 mmol), and then the solution was
stirred overnight under reflux conditions. The resulting solution was
extracted with ethyl acetate, and the combined organic layers were
washed with brine, dried over Na SO , and concentrated under
MHz, CDCl ): δ 3.84 (dd, J = 11.6, 2.8 Hz, 1H), 3.77−3.63 (m, 2H),
3
3.45 (dd, J = 11.6, 5.8 Hz, 1H), 3.41 (t, J = 5.0 Hz, 2H), 3.18 (m,
1H), 2.82 (dd, J = 5.0, 4.2 Hz, 1H), 2.65 (dd, J = 5.0, 2.7 Hz, 1H).
1
3
2
4
C NMR (101 MHz, CDCl ): δ 71.90, 70.31, 50.90, 50.88, 44.18.
3
+
reduced pressure to give 3b as a yellowish liquid (15.0 g, 98%). The
crude product was used for the next step without further purification.
ESI-MS (m/z): [M + Na] calcd for C H N O Na, 166.06; found,
5 9 3 2
166.06.
1
H NMR (400 MHz, CDCl ): δ 3.65 (t, J = 6.5 Hz, 2H), 3.27 (t, J =
Synthesis of 4-Azido-1-butanol (2b). 4-Azido-1-butanol was
3
6
5
2
.9 Hz, 2H), 1.67−1.53 (m, 4H), 1.49−1.32 (m, J = 4.6, 3.8, 1.8 Hz,
prepared by using distilled 4-chloro-1-butanol (2a) as a starting
H). 13C NMR (101 MHz, CDCl ): δ 62.66, 51.42, 32.56, 28.84,
material, according to the same procedure as described in the
3
1
6.56, 25.38.
synthesis of 3b in 60% yield. H NMR (400 MHz, CDCl ): δ 3.65 (t,
3
Synthesis of AHGE. A 40% solution of aqueous KOH was prepared
J = 6.2 Hz, 2H), 3.32 (t, J = 6.6 Hz, 2H), 2.52 (s, 1H), 1.74−1.58 (m,
1
3
by dissolving 38.18 g of KOH in 57.27 mL of H O.
4H). C NMR (101 MHz, CDCl ): δ 62.00, 51.30, 29.73, 25.39.
2
3
Tetrabutylammonium hydrogensulfate (TBAHSO ) (1.17 g, 3.44
Synthesis of ABGE. ABGE was prepared by using 4-azido-1-butanol
(2b) as a starting material, according to the same procedure as
described in the Synthesis of AHGE in 41% yield. H NMR (400
4
mmol) and epichlorohydrin (29.96 mL, 343.85 mmol) were added to
the completely dissolved KOH solution at 0 °C. The reaction mixture
was stirred for 30 min, and 3b (9.85 g, 68.77 mmol) was added slowly
at 0 °C. The reaction was allowed to proceed for 18 h at room
temperature, and reaction progress was monitored by thin-layer
chromatography. The mixture was diluted with water and extracted
with ethyl acetate (EtOAc). The organic layers were washed with
brine, dried over Na SO , and evaporated to give a crude liquid. The
1
MHz, CDCl ): δ 3.73 (dd, J = 11.5, 2.9 Hz, 1H), 3.59−3.45 (m, 2H),
3
3.36 (dd, J = 11.5, 5.9 Hz, 1H), 3.33−3.27 (m, 2H), 3.13 (m, 1H),
2.79 (dd, J = 5.0, 4.2 Hz, 1H), 2.60 (dd, J = 5.1, 2.7 Hz, 1H), 1.75−
1
3
1.60 (m, 4H). C NMR (101 MHz, CDCl ): δ 71.45, 70.69, 51.21,
3
+
50.77, 44.09, 26.81, 25.68. ESI-MS (m/z): [M + Na] calcd for
Na, 194.09; found, 194.16.
Homopolymerization of Azidoalkyl Glycidyl Ethers. The
C H N O
7 13 3 2
2
4
residue was purified by column chromatography (EtOAc/Hexane, 1/
) to give the desired product as a colorless oil (7.59 g, 55%). The
3
syntheses of all the homopolymers (E1−E3, B1−B3, and H1−H4)
were carried out by the Schlenk technique under Ar in flame-dried
glass tubes. An exemplary synthetic protocol is described as follows.
1
product was further purified by vacuum distillation over CaH . H
2
NMR (400 MHz, CDCl ): δ 3.72 (dd, J = 11.5, 3.0 Hz, 1H), 3.58−
3
3
2
.41 (m, 2H), 3.37 (dd, J = 11.5, 5.8 Hz, 1H), 3.27 (t, J = 6.9 Hz,
H), 3.19−3.08 (m, J = 5.8, 4.1, 2.9 Hz, 1H), 2.80 (dd, J = 5.0, 4.2
Homopolymerization of AHGE (H2). t-BuP (0.8 M in hexane,
4
125.5 μL, 0.1 mmol) was added to a solution of benzyl alcohol (10.39
μL, 0.1 mmol) in toluene (0.6 mL) and stirred for 30 min. AHGE
(500 mg, 2.51 mmol) was then slowly added to the solution to initiate
Hz, 1H), 2.61 (dd, J = 5.0, 2.7 Hz, 1H), 1.65−1.54 (m, 4H), 1.45−
1
5
.34 (m, 4H). 13C NMR (101 MHz, CDCl ): δ 71.57, 71.45, 51.44,
3
+
1
0.94, 44.32, 29.61, 28.85, 26.61, 25.75. ESI-MS (m/z): [M + Na]
the polymerization. The reaction was monitored by H NMR to
calcd for C H N O Na, 222.12; found, 222.04.
Synthesis of Azidoethyl Glycidyl Ether (AEGE) and
Azidobutyl Glycidyl Ether (ABGE). Azidoethyl glycidyl ether
determine residual epoxide signals and if the reaction was complete.
When reaction completion was determined, an excess amount of
benzoic acid was added to terminate the polymerization. The mixture
9
17
3
2
C
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was passed through a basic alumina pad using THF to remove t-BuP4.
equiv) was dissolved in 1 mL of THF, and the solution was degassed
by N bubbling for 20 min. PPh (32.26 mg, 0.123 mmol, 0.25 equiv)
The polymer solution was concentrated in vacuo to obtain
2
3
1
poly(azidohexyl glycidyl ether), P(AHGE) (312 mg, 61%).
H
was completely dissolved in the solution. Water (0.05 mL) was added
to the mixture and stirred for 12 h at room temperature. THF was
removed under reduced pressure, and 1.0 M HCl solution was added
to acidify and dissolve the polymer. The mixture was washed three
times with diethyl ether to remove residual triphenylphosphine (TPP)
and triphenylphosphine oxide (TPPO). The aqueous phase was
lyophilized to give 80 mg of a viscous polymer.
NMR (H2) (400 MHz, CDCl ): δ 7.37−7.33 (m, 5H), 4.56 (s, 2H),
3
3
9
7
2
.70−3.38 (m, 161H), 3.28 (t, J = 6.9 Hz, 46H), 1.69−1.50 (m,
1
3
2H), 1.47−1.34 (m, 92H). C NMR (H2) (101 MHz, CDCl ): δ
3
9.08, 78.96, 78.82, 71.49, 71.10, 70.25, 70.01, 51.51, 29.76, 29.74,
8.97, 26.75, 25.90. Đ (H2) (SEC, CHCl , PMMA standard) = 1.15.
3
1
13
See the Supporting Information for H and C NMR spectra and
SEC trace for H2 (Table 1, Figures S1−S3).
Chain Extension Experiment for Diblock Copolymer Syn-
thesis. The synthesis of the diblock copolymer of AHGE and AGE
was carried out by the Schlenk technique under Ar in flame-dried
Homopolymerization of AEGE (E2). t-BuP (0.8 M in hexane,
4
1
04.7 μL, 0.08 mmol) was added to a solution of benzyl alcohol (8.68
μL, 0.08 mmol) in toluene (0.84 mL) and stirred for 30 min. AEGE
300 mg, 2.1 mmol) was then slowly added to the solution to initiate
glass tubes. t-BuP (0.8 M in hexane, 125.5 μL, 0.1 mmol) was added
4
(
to a solution of benzyl alcohol (10.39 μL, 0.1 mmol) in toluene (1.0
mL) and stirred for 30 min. AHGE (600 mg, 3.0 mmol) was then
slowly added to the solution to initiate the polymerization. The
1
the polymerization. The reaction was monitored by H NMR to
determine residual epoxide signals and if the reaction was complete.
When reaction completion was determined, an excess amount of
benzoic acid was added to terminate the polymerization. The mixture
was passed through a basic alumina pad using THF to remove t-BuP4.
The polymer solution was concentrated in vacuo to obtain
1
reaction was monitored by H NMR spectroscopy to determine
residual epoxide signals, and once the reaction was completed, a small
aliquot of the crude P(AHGE) polymer was taken for SEC analysis.
Additional allyl glycidyl ether (AGE) (343.5 mg, 3.01 mmol) was
1
1
poly(azidoethyl glycidyl ether), P(AEGE) (189 mg, 64%). H NMR
added to the reaction mixture, and the reaction was monitored by H
(
3
E2) (400 MHz, CDCl ): δ 7.39−7.28 (m, 5H), 4.54 (s, 2H), 3.78−
NMR to determine residual epoxide signals. When the reaction was
determined to be complete, an excess amount of benzoic acid was
added to terminate the polymerization. The mixture was passed
3
.49 (m, 175H), 3.42−3.29 (m, 25H). Đ (E2) (SEC, THF, PMMA
standard) = 1.15 (Table 1).
Homopolymerization of ABGE (B2). t-BuP (0.8 M in hexane,
through a basic alumina pad using THF to remove t-BuP . The
4
4
7
3.01 μL, 0.06 mmol) was added to a solution of benzyl alcohol (6.04
μL, 0.06 mmol) in toluene (1.2 mL) and stirred for 30 min. ABGE
500 mg, 2.92 mmol) was then slowly added to the solution to initiate
polymer solution was concentrated in vacuo to obtain P(AHGE)-b-
P(AGE) (480 mg). A small aliquot of the crude block copolymer was
taken for NMR and SEC analysis to determine the degree of
polymerization of each monomer (Mn,NMR: 10360; M /M : 1.09;
DPNMR: AHGE/AGE = 32/34).
Copolymerization of AHGE and AGE. The synthesis of a
(
1
the polymerization. The reaction was monitored by H NMR to
determine residual epoxide signals and if the reaction was complete.
When reaction completion was determined, an excess amount of
benzoic acid was added to terminate the polymerization. The mixture
was passed through a basic alumina pad using THF to remove t-BuP4.
w
n
statistical copolymer of AHGE and AGE was carried out by the
Schlenk technique under Ar in flame-dried glass tubes. t-BuP (0.8 M
4
The polymer solution was concentrated in vacuo to obtain
in hexane, 375 μL, 0.3 mmol) was added to a solution of benzyl
alcohol (31 μL, 0.3 mmol) in toluene (2.4 mL) and stirred for 30 min.
A premixed liquid of AHGE (600 mg, 3.0 mmol) and AGE (342 mg,
3.0 mmol) was then slowly added to the solution to initiate the
1
poly(azidobutyl glycidyl ether), P(ABGE) (403 mg, 68%).
H
NMR (B2) (400 MHz, CDCl ): δ 4.54 (s, 2H), 3.68−3.39 (m,
3
3
99H), 3.30 (t, J = 6.4 Hz, 114H), 1.72−1.61 (m, 228H). Đ (B2)
1
(
SEC, THF, PMMA standard) = 1.09 (Table 1).
polymerization. The reaction was monitored by H NMR to
In Situ 1H NMR Polymerization Kinetic Experiments. A
determine residual epoxide signals. When the reaction was
determined to be complete, an excess amount of benzoic acid was
added to terminate the polymerization. The mixture was passed
mixture of benzyl alcohol (1.0 equiv) and monomer (20 equiv) in
toluene-d (1.0 M to the monomer) was transferred by a syringe to a
8
conventional NMR tube sealed with a rubber septum. To the NMR
through a basic alumina pad using THF to remove t-BuP . The
4
tube was added t-BuP (1.0 equiv), and it was shaken to homogenize
polymer solution was concentrated in vacuo to obtain P(AHGE-co-
4
the mixture before placing in the NMR spectrometer. The sample
temperature was set to 27 °C, and spectra were recorded every 10 min
with 16 scans for 4 or 5 h. The integrals of methylene protons of
monomer (δ = 2.28 and 2.15 for AEGE, δ = 2.31 and 2.16 for ABGE,
and δ = 2.32 and 2.18 for AHGE) were monitored to calculate
monomer consumption, referenced to the residual signal of toluene (δ
AGE) (630 mg). The degree of polymerization of each monomer was
1
determined by H NMR analysis (Mn,NMR: 3330; M /M : 1.10;
w
n
DPNMR: AHGE/AGE = 11/9).
Copolymerization Kinetics of AHGE and AGE. A mixture of
benzyl alcohol (1.0 equiv) and AHGE and AGE (20 equiv each) in
toluene-d (2.5 M to the total amount of monomers) was transferred
8
=
2.09 ppm).
by a syringe to a conventional NMR tube sealed with a rubber
Procedures for CuAAC Click Reactions. Click reactions for
septum. To the NMR tube was added t-BuP (1.0 equiv), and it was
4
H3a, H3b, and H3c proceeded using a method derived by Hawker
shaken to homogenize the mixture before placing in the NMR
spectrometer. The sample temperature was set to 27 °C, and the first
spectrum was recorded 21 min after t-BuP4 was added and
continuously recorded every 16 min with 256 scans for 6 h by an
29
and co-workers. A typical procedure for the click reaction for H3a is
as follows: H3 (80 mg, 0.39 mmol of azides, 1.0 equiv) and 5-hexyne
(
2
3
67.8 μL, 0.59 mmol, 1.5 equiv) were dissolved in 3 mL of THF in a
1
3
0 mL reaction tube. The solution was degassed by N bubbling for
inverse-gated C mode. The integrals of methine carbon of each
monomer (δ = 50.77 ppm for AHGE and δ = 50.64 ppm for AGE)
were monitored to calculate monomer conversion, referenced to the
residual signal of toluene (δ = 20.40 ppm).
2
0 min. CuBr (5.59 mg, 0.039 mmol, 0.10 equiv) and N,N,N′,N″,N″-
pentamethyldiethylenetriamine (PMDETA) (8.14 μL, 0.039 mmol,
0
.10 equiv) were added to the mixture, and the solution was stirred
for 2 h at room temperature. Saturated ammonium chloride aqueous
solution (10 mL) was added to the solution, and then the solution
was extracted with dichloromethane (10 mL × 3). The organic layer
was washed with brine, dried over Na SO , and concentrated under
Orthogonal Functionalization of P(AHGE-co-AGE). CuAAC of
Azide Moieties with Phenylacetylene (H5). The CuAAC of
P(AHGE-co-AGE) was performed by using CuBr and PMDETA in
THF as described above for H3b. P(AHGE-co-AGE) (50 mg, 0.16
mmol of azide, 1.0 equiv) and phenylacetylene (26.3 μL, 0.24 mmol,
1.5 equiv) were dissolved in 1.5 mL of THF in a 10 mL reaction tube.
2
4
vacuum to yield 108 mg (99%) of a yellow polymer. See the
1
Supporting Information for H NMR spectra for H3a, H3b, and H3c,
respectively (Figures S4−S6).
The solution was degassed by N bubbling for 30 min. CuBr (2.3 mg,
2
Procedures for Staudinger Reduction. Staudinger reductions
for H2a−H2c and HAm proceeded using a method derived by
0.016 mmol, 0.10 equiv) and PMDETA (3.3 μL, 0.016 mmol, 0.10
equiv) were added to the mixture, and the solution was stirred for 2 h
at room temperature. An aqueous solution of saturated ammonium
chloride (8 mL) was added to the solution, and the resulting mixture
45
Johnsson and co-workers. A typical procedure for the Staudinger
reduction for H2a is as follows: H2 (100 mg, 0.49 mmol of azide, 1.0
D
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was extracted with dichloromethane (10 mL × 3). The organic layer
the direct polymerization of glycidyl azide under the
monomer-activated AROP condition only in the presence of
an excess amount of triethyl borane. In general, the
hydrogens on the β-carbon of the epoxide monomer exhibit
a different acidic character in relation to the type of the
substituents. Thus, we designed several azide-functional
glycidyl ether monomers possessing different lengths of alkyl
spacers to avoid such side reactions wherein the alkyl chain
and ether linkage reduce the acidity of the β-protons (Figure
1b).
was washed with brine, dried over Na SO , and concentrated under
2
4
vacuum to yield 70 mg of a yellow polymer.
47
Thiol−Ene Addition of Allyl Moieties with Thioacetic Acid (H6).
Thiol−ene addition of H5 by using thioacetic acid and 2,2-
dimethoxy-2-phenylacetophenone (DMPA) under UV irradiation to
give H6 was proceeded using a method derived by Hawker and co-
34
workers. H5 (30 mg, 86 μmol of alkene, 1.0 equiv), thioacetic acid
12.3 μL, 4.3 μmol, 0.05 equiv), and DMPA (1.1 mg, 172 μmol, 2.0
(
equiv) were dissolved in 1.0 mL of THF in a 10 mL reaction tube.
The solution was degassed by N bubbling for 30 min. The reaction
2
mixture was stirred under UV light (λ = 365 nm) for 4 h. The reaction
The AEGE, ABGE, and AHGE monomers were prepared by
a two-step reaction from corresponding haloalkanols (Scheme
1
was monitored by H NMR to determine the complete disappearance
of the alkene peaks at 5.22 and 5.91 ppm. The reaction mixture was
precipitated in hexane and recovered by dissolving in chloroform. The
organic layer was concentrated under vacuum to yield 25 mg of a dark
yellow polymer.
2
). The substitution reaction of haloalkanol with sodium azide
under aqueous conditions yielded the azide-functionalized
alcohol, which was subsequently coupled with epichlorohydrin
to afford AEGE, ABGE, and AHGE after column chromatog-
1
raphy purification. Various characterizations including H and
RESULTS AND DISCUSSION
■
13
1
1
C NMR, H− H correlation spectroscopy (COSY), and ESI-
Design and Synthesis of Azide-Functionalized Gly-
cidyl Ethers. The simplest glycidyl monomer containing azide
functionality for the synthesis of polyethers with multiple
azides is glycidyl azide (GA). Initially, we prepared GA as a
monomer to demonstrate the versatility of azide-functional
polyethers. However, the direct polymerization of simple
glycidyl azide under organic superbase-catalyzed highly basic
AROP condition was found to suffer from side reactions, such
as elimination, in agreement with the previous report (Figure
MS supported the successful synthesis of azidoalkyl glycidyl
ethers (Figures S8−S24).
Polymerization of Azidoalkyl Glycidyl Ethers. Organic
superbase t-BuP -catalyzed AROP of AEGE, ABGE, and
4
AHGE were conducted using benzyl alcohol as an initiator
in toluene at room temperature (Table 1). We employed a
commercially available metal-free organic phosphazene as a
base due to its high basicity and, most importantly, its facile
48
46
polymerization at room temperature. For AHGE, monomer
1
a and Figure S7). In this regard, the synthesis of azide-
1
conversion was monitored by H NMR spectroscopy by
observing the reduction of methine and methylene signals of
the epoxides at 3.15, 2.80, and 2.60 ppm (Figure 2a). The
Figure 1. (a) Typical anionic ring-opening polymerization of glycidyl
azide suffers from elimination side product. (b) Direct synthesis of
azide-functionalized polyethers using a series of azidoalkyl glycidyl
ethers.
1
Figure 2. Synthesis of P(AHGE)s by AROP. Representative H NMR
functionalized polyethers has been achieved by the post-
polymerization of polyepichlorohydrin that can be converted
to the poly(glycidyl azide). Feng et al. recently introduced
spectra of (a) AHGE monomer and (b) P(AHGE) (H4) in CDCl at
3
22
25 °C.
Scheme 2. Synthesis of Azidoalkyl Glycidyl Ether Monomers
E
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Figure 3. Demonstration of controlled AROP of azidoalkyl glycidyl ethers. (a−c) M and Đ of (a) P(AEGE)s, (b) P(ABGE)s, and (c) P(AHGE)s
n
at various monomer-to-initiator ratios, [M]/[I]. (d−f) SEC chromatograms of (d) P(AEGE)s, (e) P(ABGE)s, and (f) P(AHGE)s.
47
AROP of AHGE (H4) proceeded successfully, achieving 99%
polymerization. In general, AROP of certain glycidyl ether
monomers is accompanied by a chain transfer reaction due to
the abstraction of methylene proton adjacent to the epoxide
ring by actively propagating chain end, leading to the
formation of allyl alkoxide, which can serve as new initiating
species. This phenomenon has been observed in the previous
conversion within 10 h. When the monomer was completely
consumed, as evidenced by H NMR, the polymerization was
quenched by the addition of benzoic acid to protonate the
chain end. Filtration through a short pad of basic aluminum
oxide was used to remove phosphazene salts. Successful
1
removal of t-BuP was confirmed by completely disappeared
literature for the polymerization of phenyl glycidyl ether,
4
1
49,50
H NMR signals at 2.66 ppm (Figure 2b and Figure S25).
According to H NMR and FT-IR analyses, the azide groups
propylene oxide, and ethoxyethyl glycidyl ether.
Further-
1
more, monomer purity is another critical consideration in the
33
remained intact after polymerization (Figure S26).
chain transfer reaction as reported by Lynd group. According
to the proven stability of 1-azido-6-methoxyhexane, we assume
that the chain transfer is probably not originated from the
azide functionality.
Following this result, we evaluated the stability of the azide
group under the polymerization condition. We first prepared a
model compound, 1-azido-6-methoxyhexane, to exclude ring
opening of epoxide by the nucleophilic attack from alkoxide
species. Surprisingly, treatment of 1-azido-6-methoxyhexane
1
In Situ H NMR Polymerization Kinetic Study. The
homopolymerizations of AEGE, ABGE, and AHGE were
1
(
20 equiv) with t-BuP (1.0 equiv) in the presence of benzyl
investigated by in situ H NMR kinetic studies to evaluate the
4
alcohol (1.0 equiv) in toluene at room temperature did not
result in any changes in the model compound for 3 days
living characteristics and the effect of the monomer structure.
The polymerizations were conducted at a monomer concen-
tration of 1.0 M in deuterated toluene. The signals of
methylene protons of the monomers were monitored to
observe monomer conversion by calculating the integration
value in reference to the residual signal of toluene (δ = 2.09
ppm), which remained constant during polymerization
(Figure S27 and Table S1). The inertness of the azide group
under the AROP condition highlights the compatibility of
azidoalkyl glycidyl ether monomers and thus provides the
potential to expand the functional polyether platform by
attachment of azide moieties in the designer monomer.
We also conducted AROP of AEGE and ABGE under
identical reaction conditions, and the resulting polymers were
(Figures S30−S32). The linear correlation between ln([M] /
0
[M] ) and the reaction time supported the successful living
t
1
characterized by H NMR analysis (Figures S28 and S29). The
characteristics of the polymerization of azidoalkyl glycidyl
ethers (Figure 4). Interestingly, the kinetic plots obtained by
different monomers indicated the increasing order of AHGE,
ABGE, and AEGE for the polymerization rate. As the only
difference between monomers is the length of alkyl spacer, thus
the faster polymerization rate of AEGE can be attributed to the
shorter alkyl spacer and larger polarity among three monomers.
On the other hand, the longer AHGE monomer showed a
lower polymerization rate possibly due to the steric effect of
the alkyl chain that might disturb the propagating chain end.
Moreover, to explore a correlation between monomer
molecular weights of the homopolymers of AEGE, ABGE, and
AHGE (E1−E3, B1−B3, and H1−H4) were well controlled in
the range of 2300−17,400 g/mol by adjusting the ratio of
1
monomer to initiator as verified by H NMR spectroscopy
(
Table 1 and Figure 3). Moreover, the azide-functionalized
homopolymers exhibited a narrow dispersity (Đ) ranging from
.03 to 1.21, as confirmed by size exclusion chromatography
SEC) (Table 1 and Figure 3). The small shoulder peak
1
(
observed in the higher molecular weight region possibly
originates from chain transfer reactions during anionic
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transformation of pendant azide groups into alkyl, phenyl, and
hydroxyl functionalities (Figure 5a−c). The protons adjacent
to the azide, corresponding to the peak at 3.26 ppm (Figure
2
b, peak f′), clearly disappeared, whereas the peak around 4.30
ppm (Figure 5, peak a′) appeared after CuAAC due to the
53
inductive electron-withdrawing character of triazole. The
characteristic peak of the triazole proton (Figure 5, peak b)
was observed, presenting a clear evidence supporting the
successful formation of the triazole group by CuAAC. To
further confirm the successful click reaction, FT-IR analysis
was conducted (Figure S34). The FT-IR spectra revealed that
−
1
the characteristic azide peak at 2088 cm for H3 clearly
1
Figure 4. First-order kinetic plots of ln([M] /[M] ) vs time for the
disappeared after the click reactions, in accordance with the H
0
t
polymerization of AEGE (black square), ABGE (red circle), and
AHGE (blue triangle) monomers targeting a degree of polymerization
of 20.
NMR analysis.
Staudinger Reduction of P(AHGE). Investigations of the
synthesis of the polyethers having pendant primary amine
groups along the polymer backbones are limited. Satoh and co-
workers demonstrated the synthesis of primary amine-
hydrophobicity and the polymerization rate, we calculated the
octanol/water coefficient (log P) of the monomers using the
functionalized polyether by t-BuP -catalyzed AROP of dibenzyl
protected monomer, followed by subsequent hydrogenation.
4
51,52
54
computational software ALOGPS 2.1 (Table S2).
The
hydrophobicity increased as the length of alkyl spacer
increased as expected. Coincidentally, we found that the
polymerization rate is inversely proportional to the hydro-
phobicity of monomer (Figure S33).
Frey and Herzberger reported polymerization by monomer
activation of epicyanohydrin that can be converted to amine-
23
functional PEG. However, the drawback of both approaches
is a time-consuming deprotection step after polymerization.
Alternatively, the Staudinger reduction of azide-functional
polyethers can yield pendant amines from the presented azides
in this study. We demonstrated Staudinger reduction of H2 as
a representative example (Figure 6). The reaction of H2 with
triphenylphosphine (TPP) and water in THF under ambient
conditions resulted in the successfully reduced product, HAm,
within 12 h. Moreover, the degree of reduction was controlled
by the equivalency of TPP used during the reduction to afford
polyethers with varying ratios of amine relative to azide,
yielding orthogonal pendant groups for post-polymerization
modification (H2a−H2c). As the equivalency of TPP was
increased, the reduced amine to the unreacted azide ratio also
increased, correlating well to the relative peak integrations
Copper-Catalyzed Azide−Alkyne Cycloaddition of
P(AHGE). Having synthesized the desired P(AHGE) homo-
polymers, the potential post-polymerization modification of
the pendant azide moieties via CuAAC was demonstrated by
the reaction with 1-hexyne, phenylacetylene, and 5-hexyn-1-ol
to give the functional polyethers H3a, H3b, and H3c,
1
respectively (Figure 5). H NMR confirmed the successful
1
determined by H NMR (Figure 6a and Figures S35−S38).
FT-IR analyses displayed the disappearance of the character-
−
1
istic azide peak at 2088 cm , providing further evidence
supporting the successful reduction (Figure 6b).
Copolymerization of AHGE and AGE. As previously
mentioned, AGE is by far the most widely used functional
epoxide monomer for post-polymerization modification in
polyethers. Thus, we demonstrated the copolymerization of
AHGE with AGE to impart a second orthogonal functionality
to facilitate further modification. First, the one-pot sequential
addition of AGE after the polymerization of P(AHGE) was
performed to obtain P(AHGE)-b-P(AGE) (Figure 7). The
complete shift of the SEC traces to the higher molecular
weight diblock copolymer P(AHGE)-b-P(AGE) was observed,
without the presence of the unreacted chain end of P(AHGE)
(
Figure 7a). This observation supports the livingness of the
propagating chain end of P(AHGE)s. The complete
consumption of AGE yielded a well-defined P(AHGE)-b-
1
P(AGE), as evidenced by H NMR spectrum (Figure S39).
Furthermore, a well-defined statistical copolymer, P(AHGE-
co-AGE), was prepared by taking advantage of the living
character of AROP with the use of two monomers in a one-pot
reaction (Figure 7). The molecular weight and the degree of
polymerization of each monomer were characterized by SEC
and H NMR (Figure 7b and Figure S40). As shown in Figure
S33, the characteristic allyl peaks at 5.22 and 5.91 ppm (peaks
Figure 5. Post-polymerization modification of H3 via CuAAC with
1
1
various alkynes. (a−c) H NMR spectra after CuAAC of H3 with (a)
1
-hexyne, (b) phenylacetylene, and (c) 5-hexyn-1-ol.
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1
Figure 6. Staudinger reduction of H2. (a) H NMR spectra of partially reduced polymers (H2a−H2c) and fully reduced polymer (HAm) in D O.
2
(
b) FT-IR spectra of H2a−H2c and HAm.
b and c) were observed along with the peak corresponding to
the proton adjacent to the azide (peak a), indicating successful
incorporation of both monomers. Allyl groups often show a
tendency toward isomerization under potassium alkoxide base-
reactivity ratios for the pair of monomers: rAHGE = 0.77 ± 0.01
and rAGE = 1.31 ± 0.02 (Figure 8b). As shown in Figure 8b, the
copolymerization of AHGE and AGE tends to yield a random
statistical microstructure (rAHGE × rAGE = 1.01 ± 0.02) of the
resulting copolymer. A slightly lower reactivity of AHGE
compared to AGE is possibly originated from the steric effect
of the longer alkyl chain.
28
catalyzed polymerization conditions at high temperature;
however, no isomerized alkenes were observed under the
organic superbase-catalyzed AROP conditions due to the
relatively low reaction temperature. The polymerization of
both block and statistical copolymers were conducted in a
controlled manner, exhibiting minor deviations from the
targeted monomer ratio (Table S3).
Orthogonal Modification of P(AHGE-co-AGE). Finally,
we demonstrated two selective sequential reactions utilizing
the orthogonal azide and allyl functionalities of the copolymer.
Using the conditions, we established that for the CuAAC of
P(AHGE), the copolymer was first derivatized via the click
reaction with phenylacetylene and then was subsequently
To determine the reactivity ratios of AHGE and AGE, we
13
monitored the copolymerization using in situ C NMR
spectroscopy with inverse-gated decoupling (Figure 8). The
copolymerization of AHGE and AGE at a total concentration
1
modified by thiol−ene addition (Figure 9). H NMR
spectroscopy was used to verify the success of the CuAAC
reaction by observing the large downshift of the peak
corresponding to the methylene unit adjacent to the azide
from 3.26 to 4.3 ppm (Figure 9a, peaks a and a′). The
characteristic peaks corresponding to the allyl group (Figure
9a, peaks b−d) were not shifted, suggesting that the
orthogonality of CuAAC leaves the allyl groups intact for
subsequent modification by thiol−ene addition. To modify the
allyl moieties, thiol−ene addition, using thioacetic acid and
of 2.5 M in toluene-d was performed in the NMR tube at 27
8
°
C. Both monomer conversions and total conversion as a
function of time were measured, and the reactivity ratios of
AHGE and AGE were obtained based on the nonterminal
5
5
model. The methine peaks of AHGE (peak a, 50.77 ppm)
and AGE (peak b, 50.64 ppm) were integrated to calculate the
monomer conversion using the toluene peak (20.40 ppm) as
an internal standard (Figure 8a). The plot of total conversion
against monomer conversion was presented to determine
1
photoinitiator, proceeded in THF under UV irradiation. H
H
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Figure 7. Synthesis of P(AHGE)-b-P(AGE) or P(AHGE-co-AGE) by sequential or one-pot monomer addition, respectively. SEC chromatograms
of (a) P(AHGE) (black) and P(AHGE)-b-P(AGE) (red) and (b) P(AHGE-co-AGE) measured in CHCl3.
Figure 8. (a) Time-resolved 13C NMR spectra of copolymerization of AHGE and AGE in toluene-d under polymerization conditions. (b) Total
8
polymerization conversion versus monomer conversion for the copolymerization of AHGE (blue square) and AGE (orange circle). The initial
compositions: nAHGE = 0.58 and nAGE = 0.42.
NMR observation of the complete disappearance of the signals
corresponding to the allyl group and the appearance of the new
signal at 2.29 ppm (peak f) corresponding to the methyl group
of the thioester confirmed the successful functionalization of
the allyl groups.
polymerization modification of polyethers with both azide and
alkene pendant groups along the polymer backbone have not
been introduced to date. These systems present a unique
avenue for orthogonal post-polymerization modification, which
is the subject of our ongoing research endeavor.
FT-IR analysis indicated the smooth progress of the
sequential reactions, evidenced by the disappearance of the
CONCLUSIONS
−
1
■
band corresponding to the azide (2088 cm ) and the
appearance of a new band at 1691 cm− corresponding to
the thioester group (Figure 9b). These results suggested that
azide and alkene can be orthogonally functionalized without
any cross-reactivity. There are many reports demonstrating
1
In conclusion, a series of azide-functionalized glycidyl
monomers with different alkyl spacers have been introduced,
including AEGE, ABGE, and AHGE. Interestingly, azide
moieties of azidoalkyl glycidyl ethers were intact under the
highly basic AROP condition, which were not in the case of
19
multifunctional polyethers; however, synthesis and post-
I
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1
Figure 9. Orthogonal modification of P(AHGE-co-AGE) via sequential CuAAC and thiol−ene addition. (a) H NMR and (b) FT-IR spectra of
P(AHGE-co-AGE), H5, and H6.
glycidyl azide. The investigation on polymerization kinetics of
the monomers revealed that the AEGE shows a much faster
reaction rate than those of ABGE and AHGE. Using AHGE as
a model monomer, versatile multifunctional polyethers were
synthesized and primed for post-polymerization modification.
Azide pendant groups appended to the polyether backbone
enable diverse chemical modification to afford a variety of
functionalities via CuAAC and Staudinger reduction. Copoly-
merization with other epoxide monomers, such as AGE, was
used to access a variety of combinations of orthogonal
functionalities. The introduction of the azide-functionalized
epoxide monomer further diversifies the library of functional
epoxide monomers, increasing the potential to develop new
multifunctional polyethers.
ACKNOWLEDGMENTS
■
This work was supported by the National Research
Foundation of Korea (NRF-2017R1A2B3012148 and NRF-
018R1A5A1025208).
2
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