Maleimidophenyl isocyanates as postpolymerization modification agents and their applications in the synthesis of block copolymers

Article abstract of DOI:10.1002/pola.29450

The maleimide structure is highly reactive, exemplified by thiol–ene click reactions with thiols and Diels–Alder reactions with furans. Although postpolymerization modifications and macromolecular conjugations involving maleimide units have been widely studied, mostly due to their selectivity and high reactivity, little has been reported on the one-pot postpolymerization introduction of maleimides in polymer chains. Herein, we report p-maleimidophenyl isocyanate and its derivatives as modification agents to introduce maleimide moieties by reaction with hydroxy groups into polymer chains. The high reactivity of the resulting modification agents and of the corresponding maleimide structures once inserted in the polymer chains was examined by studying their reaction kinetics. Furthermore, these modification agents were successfully applied to the synthesis of macromonomers for graft polymerization and various block copolymers, with, for example, AB-type, star-shaped, and H-shaped architectures.

Full text of DOI:10.1002/pola.29450

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ORIGINAL ARTICLE
Maleimidophenyl Isocyanates as Postpolymerization Modification Agents
and their Applications in the Synthesis of Block Copolymers
1
Rikito Takashima,1 Jumpei Kida,1 Daisuke Aoki
,
1,2 Hideyuki Otsuka
1Department of Chemical Science and Engineering, Tokyo Institute of Technology, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550,
Japan
2JST-PRESTO, 2-12-1 Ookayama, Meguro-ku, Tokyo 152-8550, Japan
Correspondence to: D. Aoki (E-mail: daoki@polymer.titech.ac.jp); H. Otsuka (E-mail: otsuka@polymer.titech.ac.jp)
Received 13 June 2019; Revised 13 July 2019; accepted 18 July 2019
DOI: 10.1002/pola.29450
ABSTRACT: The maleimide structure is highly reactive, exemplified
by thiol–ene click reactions with thiols and Diels–Alder reactions
with furans. Although postpolymerization modifications and
macromolecular conjugations involving maleimide units have
been widely studied, mostly due to their selectivity and high
reactivity, little has been reported on the one-pot post-
polymerization introduction of maleimides in polymer chains.
Herein, we report p-maleimidophenyl isocyanate and its deriva-
tives as modification agents to introduce maleimide moieties by
reaction with hydroxy groups into polymer chains. The high
reactivity of the resulting modification agents and of the
corresponding maleimide structures once inserted in the poly-
mer chains was examined by studying their reaction kinetics.
Furthermore, these modification agents were successfully
applied to the synthesis of macromonomers for graft polymeri-
zation and various block copolymers, with, for example, AB-
type, star-shaped, and H-shaped architectures. © 2019 Wiley
Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019
KEYWORDS: block copolymers; click chemistry; maleimide; poly-
mer modification; topological polymer
maleimides in polymer chains. The easy introduction of
maleimide moieties in common polymer chains, that is, those
easily synthesized or commercially available, would provide
powerful scaffolds and building blocks for the rapid construc-
tion of macromonomers and block copolymers. For that pur-
pose, we focused our attention on p-maleimidophenyl
isocyanate (PMPI)28–36 [Fig. 1(a)] as a modification agent,
which can be used to directly transform the hydroxy groups
in polymer chains into reactive maleimide groups via a one-
pot reaction with the reactive isocyanate group.
INTRODUCTION Functional polymers with reactive sites are
widely used as components for smart materials. Maleimides
are highly reactive, exemplified by their thiol–ene click reac-
tions with thiol reagents,1–7 reversible Diels–Alder reactions
with furans,8–10 alternating copolymerization reactions with
vinyl monomers such as styrene,11–13 and photoactivated
reactions.14,15 Due to their high and selective reactivity, mal-
eimides have been extensively studied, whereby growing
interest has been focused on the application of maleimides in
polymer chemistry for the development of well-designed func-
tional materials. For example, remendable crosslinked poly-
mers have been prepared by exploiting the reaction of
maleimides with dienophiles,16–21 as well as biocompatible
modifications using thiol-terminated reactive polymers facili-
tated by the advent of click chemistry.22,23 These applications
are based on the unique reactivity of maleimides, which
includes the reversibility of its reaction with furan derivatives
and high reactivity toward thiols in the absence of a metal cat-
alyst, which is a clear advantage for bio-oriented applications
and environmentally friendly syntheses.
It is well known that isocyanates are highly reactive toward
hydroxy groups, which are the most common functional groups
in organic chemistry, to afford a urethane structure.37–40 How-
ever, to the best of our knowledge, a comprehensive study of
the reactivity of the isocyanate group in PMPI and its deriva-
tives toward hydroxy moieties has not been reported so far. In
this study, we have explored the potential of PMPI derivatives
as hydroxy-modification agents to easily endow conventional
polymers with new functionality. The prominent feature of iso-
cyanate groups is the high reactivity toward hydroxy groups,
which is much faster than other reactions such as esterification
and amidation under facile conditions. We describe the synthe-
sis and kinetic studies of PMPI derivatives, which were
Although postpolymerization modifications using maleimides
as the scaffold have been widely studied,24–27 little has been
reported on the one-pot postpolymerization introduction of
Additional supporting information may be found in the online version of this article.
© 2019 Wiley Periodicals, Inc.
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synthesized from 3,5-diaminobenzoic acid in a similar manner
[Scheme 1(c)]. The products were fully characterized by nuclear
magnetic resonance (NMR) spectroscopy (Figs. S1–S14),
(a)
(b)
(e)
(d)
(d)
FIGURE 1 (a) PMPI; (b) MMPI; (c) OMPI; (d) the corresponding
Diels–Alder adduct of PMPI (PMPI-F); and (e) disubstituted
derivative DMPI. [Color figure can be viewed at
wileyonlinelibrary.com]
subsequently applied in postpolymerization modification reac-
tions of hydroxy-terminated polymers, to demonstrate their
promising potential for the development of functional
polymers.
RESULTs AND DISCUSSION
Synthesis of Maleimidophenyl Isocyanates
PMPI and its derivatives, that is, its positional isomers, Diels–
Alder adduct, and disubstituted derivative prepared as modifi-
cation agents in this study, are shown in Figure 1. These com-
pounds were synthesized starting from commercially
available aminobenzoic acids (Scheme 1). The amino groups
of these starting materials were reacted with a furan-maleic
anhydride adduct, that is, exo-oxabicyclo[2.2.1] hept-5-ene-2,-
3-dicarboxylic anhydride, followed by a dehydrative cycliza-
tion to give furan–maleimide Diels–Alder-adduct-based
benzoic acids 1 [Scheme 1(a)]. It should be noted here that
the Diels–Alder adducts of these compounds are easily gener-
ated by simple mixing with furan, and as easily reverted by
heating in solution. Furan is thus an easy-to-remove
protecting group for maleimide derivatives, endowing the
resulting compounds with good solubility in common organic
solvents and desirable crystallinity for purification. The
corresponding acyl azides (2) were obtained from 1 using
diphenylphosphoryl azide (DPPA) in the presence of a base
catalyst under mild condition. A solution of 2 in toluene was
heated to reflux in order to induce the simultaneous Curtius
rearrangement and deprotection of furan, affording PMPI and
its isomers [m-maleimidophenyl isocyanate (MMPI) and o-
maleimidophenyl isocyanate (OMPI)]. Importantly, the Diels–
Alder-adduct-based phenyl isocyanate PMPI-F was synthe-
sized by refluxing a toluene solution of 2a (para) in the pres-
ence of excess furan to induce a Curtius rearrangement under
retention of the structure of the Diels–Alder adduct
(Scheme 1b). 3,5-(Dimaleimido)phenyl isocyanate (DMPI), a
di-maleimidation agent that provides further divergence, was
SCHEME 1 Synthesis of (a) PMPI and its isomers; (b) Diels–Alder
adduct PMPI-F; (c) disubstituted derivative DMPI; and (d) phenyl
maleimide-terminated PEG polymers. (e) Reversible Diels–Alder
reaction of monofunctional phenyl maleimide-terminated PEG.
[Color figure can be viewed at wileyonlinelibrary.com]
2
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O
3-phenyl-1-propanol as a model alcohol to quantitatively afford
the corresponding urethane derivatives that bear maleimide
units. The reactivity of each mono-maleimidophenyl isocyanate
(PMPI, PMPI-F, MMPI, and OMPI) was evaluated in detail in
the reaction between 3-phenyl-1-propanol and a 10-fold excess
of the isocyanate in CDCl3 at 30ꢀC in the absence of a catalyst,
0.5
-5
-5
OCN
N
O
k ' = 2 .2 5 ×1 0
PMPI
PMPI-F
MMPI
OMPI
PI
0.45
0.4
k ' = 1 .6 2 ×1 0
k ' = 3 .9 1 ×1 0
k ' = 1 .3 0 ×1 0
k ' = 7 .8 8 ×1 0
-6
-5
O
N
O
OCN
0.35
0.3
-7
O
O
1
and was monitored by H NMR spectroscopy (Figs. S15–S19).
N
0.25
0.2
O
As shown in Figure 2, the pseudo-first-order kinetics revealed
larger rate constants (k0) for the maleimide-substituted phenyl
isocyanates than for unsubstituted phenyl isocyanate (PI). The
reactivity of the isocyanate probably increases in the mono-
maleimidophenyl derivatives as the maleimide unit acts as an
electron-withdrawing group. In turn, the reactivity of the ortho-
and para-substituted phenyl isocyanates is greater than that of
the meta-substituted derivative, which is consistent with the
general theory. The k0 values of the para-substituted phenyl
isocyanates (PMPI and PMPI-F) were 20–30 times larger than
that of unsubstituted PI, and thus the largest of all derivatives.
OCN
O
0.15
0.1
OCN
N
O
0.05
0
OCN
0
2
4
6
Time / hour
FIGURE 2 Kinetic analysis of the reactions between 3-phenyl-
1-propanol and 10-fold excess of the corresponding
isocyanate reagents (blue: PMPI, red: PMPI-F, yellow: OMPI,
black: MMPI, and purple: PI) in CDCl3 at 30ꢀC. [Color figure can
be viewed at wileyonlinelibrary.com]
a
Postpolymerization Modification
Based on this model reaction, PMPI and PMPI-F were applied
in further polymer-modification reactions, along with DMPI as
a di-maleimidation agent. Poly(ethylene glycol) (PEG) with
hydroxy groups at the polymer ends was used as the model
hydroxy-containing polymer to demonstrate the reactivity of
the present modification agents. The postpolymerization mod-
ification of a variety of hydroxy-terminated PEG polymers
with different molecular weights and topology was carried
out with PMPI, PMPI-F, and DMPI in the presence of
dibutyltin dilaurate (DBTDL) as the catalyst [Scheme 1(d)]. It
should be noted that the modification reaction of hydroxy-
terminated PEG proceeded without catalyst, but it was not as
fast as that of model alcohol (Fig. S20). To achieve quick and
infrared (IR) spectroscopy, and fast atom bombardment mass
spectrometry (FAB-MS) or electron ionization MS (EI-MS) (see
Supporting Information for details). Although handling the acyl
azide derivatives needs a careful eye, the present protocol for
the preparation of PMPI derivatives via Diels–Alder adducts is
amenable to large-scale syntheses without the need for elabo-
rate purification procedures such as a column chromatography.
Reactivities of Maleimidophenyl Isocyanates
The reactivity of the isocyanate groups in the resulting deriva-
tives was studied. The prepared compounds were treated with
TABLE 1 Characterization of Phenyl-Maleimide-Terminated PEG Polymers
Samplea
Mnb (NMR)
Mnc (SEC)
Mw/Mnc (SEC)
Conv.d (%)
Yield (%)
mPEG2000-phe-MA
2300
5200
2800
6800
1,03
1.08
1.03
1.03
1.07
1.03
1.03
1.08
1.03
1.02
1.02
1.03
1.03
1.04
1.04
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
quant.
70
77
74
65
81
71
94
89
79
67
74
71
54
72
44
mPEG5000-phe-MA
mPEG10000-phe-MA
mPEG2000-phe-DMA
mPEG5000-phe-DMA
mPEG10000-phe-DMA
mPEG2000-phe-MA-F
mPEG2000-phe-MA-F
mPEG2000−phe-MA-F
PEG2000-phe-MA
9500
14,000
2900
2400
5300
6800
9600
14,000
2800
2400
5200
6900
9600
14,000
2700
2500
PEG2000-phe-DMA
2700
2800
Tetra-PEG10000-phe-MA
Tetra-PEG20000-phe-MA
Tetra-PEG10000-phe-DMA
Tetra-PEG20000-phe-DMA
12,000
23,000
12,000
24,000
11,000
22,000
11,000
20,000
a The subscript numbers indicate the molecular weight of the original
PEG with the chemical structures shown in Scheme 1(d).
b Estimated by 1H NMR analysis.
c Estimated by SEC using THF as the eluent.
d Estimated by 1H NMR analysis.
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1
FIGURE 3 (a) H NMR spectra (500 MHz, 25ꢀC, CDCl3) and (b) MALDI–TOF MS spectra (matrix: DHBA) of precursor mPEG2000 (blue)
and maleimide-terminated mPEG2000 polymers (red: mPEG2000-phe-MA; green: mPEG2000-phe-DMA; purple: mPEG2000-phe-MA-F).
[Color figure can be viewed at wileyonlinelibrary.com]
quantitative conversion of polymer end, the catalyst was
added into the following modification reaction in polymer
chains.
remove excess amount of isocyanate reagents decreased the
isolated yield, modified polymers were easily obtained in
moderate to good yield. Concurrently, the Diels–Alder adduct
at the terminal structure of the polymer chain, that is, that
obtained using PMPI-F, was easily removed by heating and
introduced again under heating in the presence of excess
furan [Scheme 1(e), Fig. S38].
Maleimide-terminated PEGs were obtained from one-pot reac-
tions, and these polymers were characterized by 1H NMR
spectroscopy, size exclusion chromatography (SEC), and
matrix-assisted laser desorption ionization–time-of-flight
(MALDI–TOF) MS. Their conversion, as estimated by 1H NMR
As the undesired dimerization of maleimide units sometimes
leads to storage instability, mono-maleimide-terminated PEG
was irradiated with ultraviolet (UV) light in solution, that is,
mPEG2000-phe-MA dissolved in acetonitrile was exposed to
strong UV light in quartz glass for 7 h at room temperature.
The 1H NMR and SEC analyses revealed no reaction,
supporting the high stability of phenyl maleimide against
dimerization reactions (Figs. S39 and S40).41
1
spectroscopy, is summarized in Table 1. In the H NMR spec-
tra, the complete disappearance of the resonances associated
with the hydroxy groups and the consistency of the signal
integrals with the theoretical values confirmed the quantita-
tive progress of the modification reactions [Figs. 3(a) and
S21–S27].
The SEC profiles and MALDI–TOF MS clearly show the com-
plete progress of the reaction without any side reactions
[Figs. 3(b) and S28–S37]. Although purification process to
As the postmodification reactions with PMPI, PMPI-F, and
DMPI proceeded successfully, we subsequently explored the
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FIGURE 4 Color changes in the reactions between maleimide-terminated PEG polymers and dodecanethiol. (a) N-aryl maleimide
(mPEG2000-phe-MA) and (b) N-alkyl maleimide (mPEG2000-C2-MA). [Color figure can be viewed at wileyonlinelibrary.com]
reactivity of the maleimide-modified polymers toward dode-
canethiol. It should be noted here that the maleimide units
are connected to an aromatic ring that is in turn attached to
the polymer chain via a urethane moiety. Therefore, the reac-
tivity of a general maleimide unit connected to an aliphatic
alkyl group was also studied for comparison. To evaluate the
reactivity of maleimide at the polymer ends, the pseudo-first-
order kinetic rate constant k0 was determined for the reaction
with a 10-fold excess of dodecanethiol as a primary thiol
reagent and with modified PEGs that exhibit different
maleimide structures (alkyl or aryl) and molecular weights
(in CDCl3; T = 30ꢀC; catalytic triethylamine). All obtained rate
constants k0 were similar, regardless of the chemical struc-
tures or molecular weights, demonstrating the high reactivity
of the modified maleimide moieties from PMPI (Figs. S41–S46).
The progress of the reaction between the maleimide units
directly connected to aromatic rings and thiols could also be
confirmed by the change in color from yellow (derived from
the maleimide-substituted aromatic ring) to colorless, indicat-
ing one further advantage of the use of these modification
agents compared to the case of a maleimide unit connected to
an aliphatic alkyl chain (Fig. 4).
[Scheme 2(b)], as well as (b) a variety of block copolymers,
with, for example, AB-type, star-shaped, and H-shaped archi-
tectures [Scheme 2(c,d)].
The alternating copolymerization of mPEG-phe-MA with styrene
was carried out by free-radical polymerization. Prior to the poly-
merization with the macromonomer, a model monomer (MM)
was synthesized and subjected to alternating copolymerization
with styrene [Scheme 2(a)]. The progress of the free-radical
polymerization of MM to give the corresponding alternating
copolymer (AP) was only observed when styrene was added
1
(Figs. S47 and S48). In the H NMR spectrum of AP, the calcu-
lated composition ratios were consistent with the feed ratio
(1:1), and the differential scanning calorimetry (DSC) analysis of
AP revealed its excellent thermal properties (Tg = 240ꢀC), thus
demonstrating the successful synthesis of an alternating polymer
(Table S1, Figs. S49–S52). Then, maleimide-terminated PEG
(mPEG-phe-MA) was used as a macromonomer and subjected
to alternating copolymerization with styrene in a similar man-
ner, affording a graft polymer [Figs. 5(a) and S53].
As it is well known that Diels–Alder adducts with furan can be sub-
jected to ROMP due to their ring strain, we carried out a ROMP of
mPEG-phe-MA-F using Grubbs second generation catalyst
[Scheme 2(b), Figs. 5(b) and S54]. The polymerization of mPEG-
phe-MA-F proceeded to furnish a different type of graft polymer.
Applications of Phenyl Maleimide-Terminated PEG
Polymers
The modification agents were further applied to the synthe-
sis of (a) graft polymers by alternating copolymerization of
mPEG-phe-MA with styrene [Scheme 2(a)] or ring-opening
metathesis polymerizations (ROMP) of mPEG-phe-MA-F
As for the synthesis of block copolymers, the reaction between
maleimide-terminated PEGs and thiol-terminated polymers syn-
thesized by reversible addition–fragmentation chain transfer
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polymerization of such macroinitiators [Scheme 2(d)]. Modifica-
tion with 1-mercapto-3-propanol and subsequent ring-opening
polymerization of ε-caprolactone successfully proceeded to give
topological block copolymers with well-defined structures
[Figs. 5(d) and S65–S76, Table S3].
(a)
CONCLUSIONS
(b)
(c)
We have synthesized maleimidophenyl isocyanate derivatives
as modification agents that are able to transform the hydroxy
groups in polymer chains into reactive maleimide groups via a
one-pot reaction. The high reactivity of the modification
agents was demonstrated by the kinetics of the addition reac-
tions between a model alcohol and the isocyanates as well as
by coupling of the obtained maleimide-terminated polymers
with thiol-terminated polymers, enabling further applications
as building blocks for a variety of topological polymers, such
as graft, star-shaped, and H-shaped polymers. The present
protocol for the preparation of modification agents via Diels–
Alder adducts is attractive and suitable for large-scale synthe-
ses without the need for elaborate purification procedures
such as column chromatography, since the Diels–Alder
adducts of these compounds work as an easy-to-remove
protecting group for maleimide derivatives and endow the
resulting compounds with good solubility in common organic
solvent and excellent crystallinity for the purification process.
The present work thus represents a major contribution to
polymer chemistry and materials science, which is supported
by the convenience of the employed synthetic methodology
that can be employed to transform commercially available
materials, the wide availability and applicability of the present
modification agents, and the access to functional materials as
one further application of these modification agents.
(d)
SCHEME 2 Application of maleimide-terminated PEG polymers:
(a) alternating copolymerization with styrene; (b) ROMP of
mPEG-phe-MA-F; (c) synthesis of a block copolymer by reaction
with thiol-terminated PS; and (d) end-group functionalization
with a thiol reagent and synthesis of an H-shaped copolymer by
subsequent ring-opening polymerization.
EXPERIMENTAL
Materials
All reagents and solvents were purchased from Sigma-Aldrich
(MO, USA), FUJIFILM Wako Pure Chemical Corporation (Tokyo,
Japan), Tokyo Chemical Industry (Tokyo, Japan), and Kanto
Chemical (Tokyo, Japan) and used as received, unless otherwise
noted. Commercially available maleimide-terminated PEG poly-
mers (SUNBRIGHT) were purchased from NOF Group (Tokyo,
Japan). Four-arm PEGs were purchased from Biochempeg Sci-
entific Inc. (MA, USA) and SINOPEG (Xiamen, China). Vinyl
monomers were purified by basic alumina column (Merck
KGaA) (Darmstadt, Germany) to remove the stabilizer and
ε-caprolactone was purified by distillation prior to use.
polymerization was conducted in the presence of a base cata-
lyst [Scheme 2(c)]. The characterization of the obtained poly-
mers was performed by 1H NMR analysis and diffusion ordered
spectroscopy (DOSY) experiments as well as SEC [Figs. 5
(c) and S55–S64]. AB-type, three-arm star-shaped, and ABA-
type block copolymers composed of PEG and polystyrene
(PS) chains were successfully prepared (Table S2). The macro-
molecular conjugation reactions proceeded very quickly and
reached saturation within 1 h, demonstrating the excellent
applicability of the modification agents in this study. Since PEG
is known as biocompatible polymer and soluble in water, fur-
ther application such as biomedical gel and drug delivery sys-
tem could be achieved by using present phenyl maleimide-
terminated PEG.
Measurements
1H and 13C NMR spectra were recorded on a Bruker AVANCE
III HD500 spectrometer. The LED method for DOSY measure-
ment was used. Pulse program: ledbpgp2s, diffusion time:
40 ms, diffusion gradient length: 2000 μs, maximum gradient
strength: 51 g cm−1 42
IR spectra were recorded on a JEOL
.
Finally, topological block copolymers, such as H-shaped,
three-arm star, and five-arm star polymers were also synthe-
sized by combination with thiol–ene click reactions, used here
to introduce an initiator moiety for subsequent living
FT/IR-4100 Fourier transform infrared (FTIR) spectrometer
as thin films with KBr. Analytical SEC (SEC) measurements
were carried out at 40ꢀC on TOSOH HLC-8320 SEC system
6
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FIGURE 5 (a) SEC charts in polymerization of mPEG2000-phe-MA and styrene at 70ꢀC (red: original mPEG2000-phe-MA, purple after
purification) (PS standard, eluent, THF; flow rate, 0.6 mL min−1, detected by RI). (b) SEC charts of ROMP experiment (red: PEG2000
-
phe-MA-F, purple: after ROMP) (PS standard, eluent, THF; flow rate, 0.6 mL min−1, detected by RI). (c) SEC charts of PS-PEG block
copolymer PS3000-b-PEG5000 and its precursors (black: mPEG5000-phe-MA and thiol-terminated PS PS3000-SH, red: reaction mixture 1 h
and after purification) (PS standard, eluent, THF; flow rate, 0.6 mL min−1, detected by RI) and DOSY spectrum of PS3000-b-PEG5000
(500 MHz, 25ꢀC, CDCl3). (d) SEC charts of five-arm star-shaped block copolymer and its precursor (pink: tetra-functional
macroinitiator PEG-TOH, black: five-arm star-shaped block copolymer) (PS standard, eluent, THF; flow rate, 0.6 mL min−1, detected
by RI) and DOSY spectrum of five-arm star-shaped block copolymer (500 MHz, 25ꢀC, CDCl3). [Color figure can be viewed at
wileyonlinelibrary.com]
equipped with a guard column (TOSOH TSK guard column
Super H-L), three columns (TOSOH TSK gel SuperH 6000,
4000, and 2500), a differential refractive index detector, and a
UV–visible detector. Tetrahydrofuran (THF) was used as the
eluent at
(Mn = 4430–3,142,000; Mw/Mn = 1.03–1.08) were used to
calibrate the SEC system. MALDI–TOF MS spectra were deter-
mined on a Shimadzu AXIMA-CFR mass spectrometer. The
spectrometer was equipped with a nitrogen laser (λ =
337 nm) and with pulsed ion extraction. The operation was
performed at an accelerating potential of 20,000 V by a linear-
a . PS standards
flow rate of 0.6 mL min−1
positive ion mode. The sample polymer solution (1 mg mL−1
)
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1
was prepared in THF, and 2,5-dihydroxybenzoic acid (DHBA)
1a, yield 72%. H NMR (DMSO-d6), δ (ppm): 8.05–8.03 (d, 2H,
J = 8.6 Hz, aromatic protons), 7.36–7.34 (d, 2H, J = 8.4 Hz, aro-
matic protons), 6.62 (br, 2H, CH CH CH CH ), 5.27 (br,
2H, CH CH CH CH ), 3.11 (s, 2H, OC CH CH CO).
as a matrix reagent and sodium trifluoroacetate as a cat-
ionizing agent were dissolved in THF (20 and 1 mg mL−1
,
respectively), and 50 μL of each solution was mixed prior to
MALDI analysis. DSC was carried out using a Shimadzu DSC-
60A DSC at a heating rate of 10ꢀC min−1 under N2 flow.
1b, yield 64%.1H NMR (DMSO-d6), δ (ppm): 8.00–7.98 (m, 1H,
aromatic proton), 7.79–7.78 (t, 1H, J = 1.8, 1.8 Hz, aromatic
proton), 7.66–7.62 (t, 1H, J = 7.9, 7.9 Hz, aromatic proton),
7.50–7.48 (m, 1H, aromatic proton), 6.62 (br, 2H,
CH CH CH CH ), 5.28 (br, 2H, CH CH CH CH ), 3.11
(s, 2H, OC CH CH CO).
Synthesis of 3-(Carboxyphenylcarbamoyl)-7-oxabicyclo
[2.2.1]hept-5-ene-2-carboxylic acid (Precursor of
Compounds 1-a, b, c) (a; para-, b; meta-, c; ortho-)
Precursor of Compounds 1a–1c was synthesized by the
reaction of acid anhydride and amino benzoic acids. A typi-
cal procedure is presented below. Exo-oxabicylco[2.2.1]
hept-5-ene-2,3-dicarboxylic anhydride (11.4 g, 68.6 mmol)
was dissolved in acetone (210 mL). To this solution, p-amino
benzoic acid (9.66 g, 70.5 mmol) was added. After stirring for 5 h
at room temperature, a white solid precipitated from the solution.
The solid was filtered and dried under vacuum (16.8 g, 81%).43
1c, yield 79%.1H NMR (DMSO-d6), δ (ppm): 8.04–8.02 (d, 1H,
J = 7.5 Hz, aromatic proton), 7.72–7.69 (t, 1H, J = 7.5, 7.2 aro-
matic proton), 7.61–7.58 (t, 1H, J = 7.5, 7.2 Hz, aromatic pro-
ton), 7.14–7.13 (d, 1H, J = 7.8 Hz, aromatic proton), 6.62 (br,
2H, CH CH CH CH ), 5.29 (br, 2H, CH CH CH CH ),
3.13 (s, 2H, OC CH CH CO).
Synthesis of 1,3-Dioxo-1,3,3a,4,7,7a-hexahydro-
2H-4,7-epoxyisoindol-2-yl benzoyl azide (Compounds
2-a, b, c)
Precursor of 1a, yield 81%. 1H NMR [dimethyl sulfoxide
(DMSO-d6)], δ (ppm): 10.15 (s, 1H, COOH), 7.89–7.87 (d, 2H,
J = 8.8 Hz, aromatic protons), 7.67–7.65 (d, 2H, J = 8.8 Hz,
aromatic protons), 6.52–6.48 (m, 2H, CH CH CH CH ),
The conversion of benzoic acid to benzoyl azide was carried
out by using DPPA as an azidation agent in the presence of a
base catalyst. A typical procedure is presented below. Com-
pound 1a (11.4 g, 40.0 mmol) was dissolved in acetonitrile
(50 mL) and triethylamine (11.0 mL, 78.9 mmol). To this
solution, DPPA (11.0 mL, 51.0 mol) was added under stir-
ring and the reaction mixture was stirred for 48 h at room
temperature.
5.14 (br, 1H,
CH CH CH CH ), 5.07 (br, 1H,
CH CH CH CH ), 2.83–2.81 (d, 2H,
HOOC CH CH CONH), 2.71–2.69 (d, 2H,
HOOC CH CH CONH).
J
=
9.2 Hz,
J
= 9.2 Hz,
Precursor of 1b, yield 83%. 1H NMR (DMSO-d6), δ (ppm): 9.99
(s, 1H, COOH), 8.22 (t, 1H, J = 1.5, 1.5 Hz, aromatic proton),
7.74–7.73 (m, 1H, aromatic proton), 7.62–7.60 (m, 1H, aro-
matic proton), 7.43–7.40 (t, 1H, J = 7.9, 7.9 Hz, aromatic pro-
ton), 6.52–6.49 (m, 2H, CH CH CH CH ), 5.14 (br, 1H,
Compound 2a: Precipitated solid was filtered and dried under
vacuum (7.56 g, 61%). 1H NMR [CDCl3, tetramethylsilane
(TMS)], δ (ppm): 8.14–8.11 (d, 2H, J = 8.6 Hz, aromatic pro-
tons), 7.47–7.44 (d, 2H, J = 8.6 Hz, aromatic protons), 6.59 (br,
2H, CH CH CH CH ), 5.41 (br, 2H, CH CH CH CH ),
3.05 (s, 2H, OC CH CH CO), 13C NMR (CDCl3), δ (ppm):
174.80 (C O imide ring), 171.62 (C O acyl azide), 136.78
( CH CH CH CH ), 136.82, 130.44, 130.28, and 126.51
(aromatic carbons), 81.54 ( CH CH CH CH ), 47.65
(OC CH CH CO), FTIR (KBr, cm−1): 2140 (CON3), 1720,
1680, 1600, 1500, 1380, 1250, 1180, 1000, 870, and
720, high-resolution mass spectrometry (HRMS) (FAB):
311.0780 [M + H]+, calculated for C15H11N4O4 [M + H]+:
311.0780.
CH CH CH CH ), 5.06 (br, 1H,
2.85–2.83 (d, 2H, 9.2 Hz, HOOC CH CH CONH),
2.72–2.70 (d, 2H, J = 9.2 Hz, HOOC CH CH CONH).
CH CH CH CH ),
J
=
1
Precursor of 1c, reaction solvent; CH3CN, yield 87%. H NMR
(DMSO-d6), δ (ppm): 11.03 (s, 1H, COOH), 8.47–8.45 (d, 1H,
J = 8.4 Hz, aromatic proton), 7.95–7.93 (d, 1H, J = 7.9 Hz, aro-
matic proton), 7.58–7.54 (m, 1H, aromatic proton), 7.14–7.11
(t, 1H, J = 7.0, 7.1 Hz, aromatic proton), 6.53–6.47 (m, 2H,
CH CH CH CH ), 5.19 (br, 2H,
CH CH CH CH ),
2.84–2.82 (d, 2H, 9.3 Hz, HOOC CH CH COONH),
J
=
2.76–2.74 (d, 2H, J = 9.3 Hz, HOOC CH CH COONH).
Compound 2b: Reaction mixture was chromatographed over
activated silica using acetone as an eluent. Except for 2b, col-
umn chromatography technique was not required. The elute
was evaporated in vacuo to give 2b (75%) as a white solid. 1H
NMR (DMSO-d6), δ (ppm): 8.03–8.01 (m, 1H, aromatic proton),
7.83–7.82 (t, 1H, J = 1.8, 1.8 Hz, aromatic proton), 7.73–7.70
(t, 1H, J = 7.8, 7.9 Hz, aromatic proton), 7.62–7.60 (m, 1H, aro-
matic proton), 6.62 (br, 2H, CH CH CH CH ), 5.28 (br,
2H, CH CH CH CH ), 3.12 (s, 2H, OC CH CH CO), 13C
NMR (DMSO-d6), δ (ppm): 176.00 (C O imide ring), 171.65
(C O acyl azide), 137.13 ( CH CH CH CH ), 133.30,
133.09, 131.44, 130.49, 129.33, and 127.52 (aromatic car-
bons), 81.29 ( CH CH CH CH ), 48.12 (OC CH CH CO),
Synthesis of 1,3-Dioxo-1,3,3a,4,7,7a-hexahydro-2H-
4,7-epoxyisoindol-2-yl benzoic acid (Compounds 1-a, b, c)
Compounds 1a–1c were synthesized by the dehydration cycli-
zation reaction of precursor of 1a–1c. A typical procedure is
presented below. Precursor of Compound 1a (16.8 g,
55.4 mmol) was dissolved in dimethylformamide (60.0 mL) at
55ꢀC. To this solution, acetic anhydride (60.0 mL, 635 mmol)
and sodium acetate (4.00 g, 122 mmol) were added under
stirring. After stirring for 5 h at 55ꢀC, the reaction mixture
was poured into 1 L of a 0.6 M aqueous hydrochloric acid
solution in an ice bath. The precipitated brown color solid
was filtered and dried under vacuum (11.4 g, 72%).43
8
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FTIR (KBr, cm−1): 2150 (CON3), 1710, 1690, 1590, 1490,
1450, 1380, 1180, 1030, 880, and 710, HRMS (FAB):
311.0782 [M + H]+, calculated for C15H11N4O4 [M + H]+:
311.0780.
filtered and the filtrate was evaporated in vacuo to give PMPI-
F (5.19 g, 95%) as an orange color solid. 1H NMR (CDCl3,
TMS), δ (ppm): 7.28–7.26 (d, 2H, J = 8.8 Hz, aromatic protons),
7.19–7.17 (d, 2H, J = 8.9 Hz, aromatic protons), 6.58 (br, 2H,
CH CH CH CH ), 5.40 (br, 2H, CH CH CH CH ), 3.02
(s, 2H, CO CH CH CO), 13C NMR (CDCl3), δ (ppm): 175.18
(C O imide ring), 136.73 ( CH CH CH CH ), 133.79,
129.12, 127.79, and 125.40 (aromatic carbons), 81.45
( CH CH CH CH ), 47.56 (OC CH CH CO), FTIR (KBr,
cm−1): 2280 (NCO), 1710, 1600, 1530, 1380, 1190, 1100,
940, and 870, HRMS (FAB): 283.0721 [M + H]+, calculated for
Compound 2c: Precipitated solid was filtered and dried under
1
vacuum (55%). H NMR (CDCl3, TMS), δ (ppm): 8.12–8.11 (d,
1H, J = 8.0 Hz, aromatic proton), 7.72–7.70 (t, 1H, J = 7.5,
7.4 Hz, aromatic proton), 7.55–7.52 (t, 1H, J = 7.5, 7.7 Hz, aro-
matic proton), 7.31–7.29 (d, 1H, J = 7.8 Hz, aromatic proton),
6.58 (br, 2H,
CH CH CH CH ), 5.41 (br, 2H,
CH CH CH CH ), 3.11 (s, 2H, OC CH CH CO), 13C NMR
(CDCl3), δ (ppm): 175.43 (C O imide ring), 170.80 (C O acyl
azide), 136.71 ( CH CH CH CH ), 134.90, 132.12, 131.77,
130.23, 129.75, and 127.25 (aromatic carbons), 81.23
( CH CH CH CH ), 48.11 (OC CH CH CO), FTIR (KBr,
cm−1): 2140 (CON3), 1715, 1680, 1600, 1490, 1450, 1380,
1180, 1000, and 870, HRMS (FAB): 311.0781 [M + H]+, calcu-
lated for C15H11N4O4 [M + H]+: 311.0780.
C
15H11N2O4 [M + H]+: 283.0719.
Synthesis of 3,5-Dimaleimide Benzoic Acid
Precursor of 3,5-dimaleimide benzoic acid was synthesized by
the reaction of acid anhydride and 3,5-diaminobenzoic acid.
Maleic anhydride (2.94 g, 30.0 mmol) was dissolved in chloro-
form (100 mL). To this solution, 3,5-diaminobenzoic acid
(1.52 g, 1.00 mmol) was added. After stirring for 20 h at reflux,
a yellow solid precipitated from the solution. The solid was fil-
tered and dried under vacuum (3.34 g, 96%). 1H NMR (DMSO-
d6), δ (ppm): 10.58 (s, 1H, COOH), 8.33–8.32 (t, 1H, J = 1.9,
1.9 Hz, aromatic proton), 7.98–7.97 (d, 2H, J = 2.0 Hz, aromatic
protons), 6.48–6.45 (d, 2H, J = 12 Hz, HNOC CH CH )COOH),
6.35–6.32 (d, 2H, J = 12 Hz, HNOC CH CH )COOH).14
Synthesis of Maleimidophenyl Isocyanate (PMPI,
MMPI, OMPI)
Maleimidophenyl isocyanates were synthesized by the Curtius
rearrangement reaction and deprotection from furan of ben-
zoyl azide. A typical procedure is presented below. 2a (3.00 g,
9.67 mmol) and toluene (120 mL) were added to a round-
bottom flask and the mixture was heated at reflux condition
for 7 h. Then the solution was filtered to remove by-products
and the filtrate was evaporated in vacuo to give PMPI (1.83 g,
89%) as a yellow solid.
The obtained solid (3.34 g, 9.59 mmol), acetic anhydride
(75.0 mL, 793 mmol), and sodium acetate (250 mg, 30.5 mmol)
were added to a round-bottom flask. After stirring for 1.5 h at
100ꢀC, the reaction mixture was poured into 1 L of 0.6 M
aqueous hydrochloric acid solution in an ice bath twice. Then
beige color solid was precipitated from solution. The solid14
was filtered and dried under vacuum (2.01 g, 64%).1H NMR
(DMSO-d6), δ (ppm): 7.98–7.97 (d, 1H, J = 2.0 Hz, aromatic
proton), 7.65–7.64 (t, 2H, J = 1.9 Hz, aromatic protons), 7.21
(s, 4H, CH CH ).
1
PMPI,35 yield 89%. H NMR (CDCl3, TMS), δ (ppm): 7.28–7.26
(d, 2H, J = 8.9 Hz, aromatic protons), 7.20–7.18 (d, 2H,
J = 8.9 Hz, aromatic protons), 6.87 (s, 2H, CH CH ).
MMPI,35 yield 83%. 1H NMR (CDCl3, TMS),
δ (ppm):
7.44–7.40 (t, 1H, J = 8.1, 8.1 Hz, aromatic proton), 7.24–7.22
(m, 1H, aromatic proton), 7.15–7.14 (t, 1H, J = 2.0, 2.0 Hz, aro-
matic proton), 7.12–7.10 (m, 1H, aromatic proton), 6.88 (s,
2H, CH CH ).
Synthesis of 3,5-Bis(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-
4,7-epoxyisoindol-2-yl)benzoyl azide (DMBA-F)
The conversion of benzoic acid to benzoyl azide was carried
out by using DPPA as an azidation agent in the presence of a
base catalyst after the protection of 3,5-dimaleimide benzoic
acid by furan. 3,5-Dimaleimide benzoic acid (2.01 g, 6.44 mmol)
was dissolved in acetonitrile (80 mL) and triethylamine (1.50 mL,
10.8 mmol). To this solution, furan (30.0 mL, 413 mmol) was
added and stirring for 7 h under reflux condition. After cooling to
room temperature, DPPA (1.53 mL, 7.10 mmol) was added to the
reaction solution under stirring and the mixture was stirring for
24 h at room temperature. After the reaction mixture was concen-
trated by evaporation in vacuo, a white solid precipitated from
the solution. The solid was filtered and dried under vacuum
(1.62 g, 56%). 1H NMR (CDCl3, TMS), δ (ppm): 8.05 (d, 2H,
J = 1.9 Hz, aromatic protons), 7.67–7.66 (t, 1H, J = 1.9 Hz, aro-
matic proton), 6.59 (br, 4H, CH CH CH CH ), 5.42 (br, 4H,
CH CH CH CH ), 3.04 (s, 4H, OC CH CH CO), 13C NMR
(CDCl3), δ (ppm): 174.52 (C O imide ring), 170.65 (C O acyl
azide), 136.77 ( CH CH CH CH ), 132.74, 132.22, 129.43 and
127.01 (aromatic carbons), 81.46 ( CH CH CH CH ), 47.63
OMPI, yield 75%. 1H NMR (CDCl3, TMS), δ (ppm): 7.44–7.40
(m, 1H, aromatic proton), 7.33–7.29 (m, 1H, aromatic proton),
7.28–7.26 (m, 1H, aromatic proton), 7.23–7.21 (m, 1H, aro-
matic proton), 6.92 (s, 2H, CH CH ), 13C NMR (CDCl3), δ
(ppm): 168.98 (C O imide ring), 134.72 ( CH CH ), 132.10,
130.51, 129.83, 126.60, 126.43, and 125.67 (aromatic car-
bons), FTIR (KBr, cm−1): 2260 (NCO), 1710, 1600, 1530,
1460, 1390, 1270, 1150, 1100, 1060, 950, and 830, HRMS
(FAB): 215.0451 [M + H]+, calculated for C11H7N2O3 [M + H]+:
215.0457.
Synthesis of 2-(4-Isocyanatophenyl)-3a,4,7,7a-tetrahydro-
1H-4,7-epoxyisoindole-1,3(2H)-dione (PMPI-F)
PMPI-F was synthesized by the Curtius rearrangement reac-
tion of 2a under an excess amount of furan. 2a (6.00 g,
19.3 mmol), toluene (160 mL) and furan (40.0 mL, 550 mmol)
were added to a round-bottom flask and the mixture was
heated at reflux condition for 24 h. Then, the solution was
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1
(CO CH CH CO), FTIR (KBr, cm−1): 2145 (CON3), 1715, 1600,
1450, 1370, and 1190, HRMS (FAB): 474.1061 [M + H]+, calcu-
lated for C23H16N5O7 [M + H]+: 474.1050.
mPEG-phe-MA, H NMR (CDCl3, TMS), δ (ppm): 7.54–7.52 (d,
2H, J = 8.8 Hz, aromatic protons), 7.27–7.25 (d, 2H, J = 8.8 Hz,
aromatic protons), 7.05 (s, 2H,
4.34–4.32 [t, 2H, 4.6 Hz,
CH CH CH CH ),
J
=
CH2 CH2 O (C O) ],
3.66–3.58 [m, 4H × n, ( OCH2CH2O )n), 3.38 (s, 3H, CH3O ].
Synthesis of DMPI
DMBA-F (1.00 g, 2.11 mmol) and toluene (120 mL) were
added to a round-bottom flask and the mixture was heated at
reflux condition for 7 h. Then, the solution was filtered to
remove by-products and the filtrate was evaporated in vacuo
to give DMPI (499 mg, 76%) as a yellow solid. 1H NMR
(CDCl3, TMS), δ (ppm): 7.41–7.40 (t, 1H, J = 1.9, 1.9 Hz, aro-
matic proton), 7.20 (d, 2H, J = 1.9 Hz, aromatic protons), 6.89
(s, 4H, C CH CH )C ), 13C NMR (CDCl3), δ (ppm): 167.76
(C O imide ring), 133.36 ( C CH CH )C ), 131.81, 127.60,
119.74, and 118.49 (aromatic carbons), FTIR (KBr, cm−1):
2280 (NCO), 1710, 1600, 1530, 1380, and 1190, HRMS (EI):
309.0382 [M]+, calculated for C15H7N3O5 [M]+: 309.0386.
mPEG-phe-MA-F, 1H NMR (CDCl3, TMS), δ (ppm): 7.55–7.53
(d, 2H, J = 8.8 Hz, aromatic protons), 7.20–7.19 (d, 2H,
J
=
8.8 Hz,
CH CH CH CH ), 5.38 (br, 2H,
4.33–4.31 [t, 2H, 4.6 Hz,
aromatic
protons),
6.57
(br,
2H,
CH CH CH CH ),
J
=
CH2 CH2 O (C O) ],
3.66–3.58 [m, 4H × n, ( OCH2CH2O )n], 3.38 (s, 3H, CH3O ),
3.00 (s, 2H, OC CH CH CO).
1
mPEG-phe-dimethylacetamide (DMA), H NMR (CDCl3, TMS),
δ (ppm): 7.55 (br, 2H, aromatic protons), 7.16 (t, 1H,
J = 1.8 Hz, aromatic proton), 6.86 (s, 4H, CH CH CH CH ),
4.34–4.32 [t, 2H,
J
=
4.6 Hz,
CH2 CH2 O (C O) ],
3.66–3.58 [m, 4H × n, ( OCH2CH2O )n], 3.38 (s, 3H, CH3O ).
Kinetics Experiment
PEG-phe-MA, 1H NMR (CDCl3, TMS), δ (ppm): 7.54–7.52 (d,
J = 8.8 Hz, 2H, aromatic protons), 7.27–7.25 (d, J = 8.8 Hz, 2H,
To estimate the reactivities of isocyanate reagents with alcohol,
1H NMR analysis was carried out. Pseudo-first-order kinetics
rate constant k0 was measured in reaction between excess
amount of isocyanate reagents and 3-phenyl-1-propanol or
mPEG2000 as a primary alcohol reagent in CDCl3 at 30ꢀC. A typ-
ical measurement is presented below. PMPI (43.0 mg,
200 μmol) was dissolved in CDCl3 including 0.03% of trimet-
hoxy silane (2.00 mL). Then, 10 vol % of benzene propanol
solution (27.2 μL, 20.0 μmol) was added and stirred. A total
volume of 1 mL of this solution was taken to an NMR tube as a
sample and heated at 30ꢀC. Measuring its 1H NMR spectrum
every hour, OH group conversion rate x was determined by
the ratio of original signal (t, 2H, CH2 OH) at 3.6 ppm to
appearing signal [t, 2H, CH2 O (C O) NH ] at 4.2 ppm.
Rate constant k0 was calculated from the following equation:
aromatic protons), 7.05 (s, 2H,
4.34–4.32 [t, 2H, 4.6 Hz,
CH CH CH CH ),
CH2 CH2 O (C O) ],
J
=
3.66–3.58 [m, 4H × n, ( OCH2CH2O )n].
1
PEG-phe-DMA, H NMR (CDCl3, TMS), δ (ppm): 7.55 (br, 2H,
aromatic protons), 7.16 (t, 1H, J = 1.8 Hz, aromatic proton),
6.86 (s, 4H, CH CH CH CH ), 4.34–4.32 [t, 2H, J = 4.6 Hz,
CH2 CH2 O (C O) ],
( OCH2CH2O )n].
3.66–3.58
[m,
4H × n,
Maleimide-terminated four-arm PEG polymers (Tetra-PEG-phe-
MA and Tetra-PEG-phe-DMA) were synthesized by the one-pot
reactions of hydroxy groups in four-arm PEGs and PMPI or
DMPI. The products were purified by preparative high-
performance liquid chromatography (HPLC). Although precipita-
tion technique gave the modified four-arm PEG polymers, it has
been difficult to efficiently remove small molecular byproducts
originated from isocyanate. This tendency was remarkable for
PEG with number of branches. It should be noted that conver-
sion of hydroxy groups is quantitative and HPLC preparation is
not required if purity is not emphasized. A typical procedure is
presented below. PMPI (344 mg, 1.60 mmol) and four-arm PEG
[Mn(SEC) 10000 g mol−1, PDI 1.03] (200 mg, 20.0 μmol) were
added to a round-bottom flask. Dichloromethane (48 mL) and
eight drops of 10 vol % DBTDL in dichloromethane were added
under inert atmosphere. After stirring for 72 h at 30ꢀC, the reac-
tion mixture was evaporated in vacuo. An oily residue was puri-
fied by preparative HPLC using chloroform as an eluent and
dried under vacuum to obtain Tetra-PEG10000-phe-MA as a yel-
low solid (71%). Yields of all other maleimide-terminated PEG
polymers are shown in Table 1 in the main text.
k0t = − lnð1−xÞ
Same experiment was carried out to estimate reactivities of
polymer terminated-maleimide to thiol reagents (see
Supporting Information for details).
Synthesis of Phenyl Maleimide-Terminated PEG Polymers
Maleimide-terminated PEG polymers were synthesized by the
one-pot reaction of hydroxy groups and each phenyl
maleimide isocyanate (PMPI, PMPI-F, and DMPI). A typical
procedure is presented below. PMPI (172 mg, 800 μmol) and
PEG monomethyl ether (Mn 2000 g mol−1
)
(400 mg,
200 μmol) were added to a round-bottom flask. Dehydrated
toluene (24.0 mL) and four drops of 10 vol % DBTDL in tolu-
ene were added under inert atmosphere. After stirring for
24 h at 70ꢀC, the reaction mixture was poured into 200 mL of
a poor solvent (diethyl ether/ethanol, 30/1, v/v) in an ice
bath. The precipitate was separated by filtration and dried
under vacuum to obtain mPEG2000-phe-MA as a yellow solid
(70%). The reaction was carried out at 30ꢀC only when modi-
fying with PMPI-F. Yields of all other maleimide-terminated
PEG polymers are shown in Table 1.
Tetra-PEG-phe-MA, 1H NMR (CDCl3, TMS),
δ (ppm):
7.54–7.52 (d, 2H, J = 8.8 Hz, aromatic protons), 7.27–7.25 (d,
2H, aromatic protons), 7.05 (s, 2H, CH CH CH CH ),
4.34–4.32 [t, 2H,
J
=
4.6 Hz,
CH2 CH2 O (C O) ],
3.66–3.58 [m, 4H × 4n, ( OCH2CH2O )n].
10
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Tetra-PEG-phe-DMA, 1H NMR (CDCl3, TMS), δ (ppm): 7.55
(br, 2H, aromatic protons), 7.16 (t, 1H, J = 1.9, 1.9 Hz, aromatic
proton), 6.86 (s, 4H, CH CH CH CH ), 4.34–4.32 [t, 2H,
J = 4.6 Hz, CH2 CH2 O (C O) ], 3.66–3.58 [m, 4H × n,
( OCH2CH2O )n].
12 B. Saha, K. Bauri, A. Bag, P. K. Ghorai, P. De, Polym. Chem.
2016, 7, 6895.
13 M. G. Mohamed, K. Hsu, J. Hong, S. Kuo, Polym. Chem.
2016, 7, 135.
14 J. Guy, K. Caron, S. Dufresne, S. W. Michnick, W. G. Skene,
J. W. Keillor, J. Am. Chem. Soc. 2007, 129, 11969.
15 B. D. A. Hook, W. Dohle, P. R. Hirst, M. Pickworth,
M. B. Berry, K. I. Booker-Milburn, J. Org. Chem. 2005, 70, 7558.
Reversible Diels–Alder Reaction of Monofunctional Phenyl
Maleimide-Terminated PEG
16 X. Chen, M. A. Dam, K. Ono, A. Mal, H. Shen, S. R. Nutt,
K. Sheran, F. Wudl, Science 2002, 295, 1698.
mPEG2000-phe-MA was synthesized by the deprotection of
furan from mPEG2000-phe-MA-F. mPEG2000-phe-MA-F
(200 mg, 83.3 μmol) and toluene (10 mL) were added to a
round-bottom flask and the mixture was refluxed overnight.
The solution was evaporated in vacuo to give mPEG2000-phe-
MA (quant.) as a yellow solid. Then, mPEG2000-phe-MA-F
was synthesized by protecting mPEG2000-phe-MA with furan.
mPEG2000-phe-MA, acetonitrile (3 mL), and furan (2.0 mL,
23 mmol) were added to a round-bottom flask and the mix-
ture was refluxed overnight. The solution was evaporated in
vacuo to give mPEG2000-phe-MA-F (quant.) as a brown solid.
17 M. Watanabe, N. Yoshie, Polymer 2006, 47, 4946.
18 B. T. Houseman, E. S. Gawalt, M. Mrksich, Langmuir 2003,
19, 1522.
19 C. Zeng, H. Seino, J. Ren, K. Hatanaka, N. Yoshie, Macromol-
ecules 2013, 46, 1794.
20 T. Ikeda, D. Oikawa, T. Shimasaki, N. Teramoto, M. Shibata,
Polymer 2013, 54, 3206.
21 K. Sugane, R. Takagi, M. Shibata, React. Funct. Polym. 2018,
131, 211.
22 S.-J. Xiao, M. Textor, N. D. Spencer, H. Sigrist, Langmuir
1998, 14, 5507.
23 J. Huwyler, D. Wu, W. M. Pardridge, Proc. Natl. Acad. Sci.
1996, 93, 14164.
Applications of Phenyl Maleimide-Terminated PEG
Polymers
24 D. J. Hall, H. M. Van Den Berghe, A. P. Dove, Polym. Int.
2011, 60, 1149.
Maleimide-terminated PEG polymers we synthesized were
successfully applied to the macromonomers for graft polymer-
ization and various block copolymers, with, for example, AB-
type, star-shaped, and H-shaped architectures. The detailed
information about syntheses of them are present in the
Supporting Information.
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Phys. 2014, 215, 2237.
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ACKNOWLEDGMENTS
29 M. S. Shoichet, A. Chemistry, Bioconjug. Chem. 2007, 16, 874.
30 T. Haoyu, Y. Lichen, H. K. Kyung, C. Jianjun, Chem. Sci. 2013,
4, 3839.
This work was supported by KAKENHI grant 18K14272
(D. Aoki) from the Japan Society for the Promotion of Science
(JSPS), as well as by JST, PRESTO grant JPMJPR18L1 (Japan).
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