A heterobifunctional linker bearing azide-reactive alkyne and thiol-reactive maleimide connected with N-(2-Nitrobenzyl)imide to synthesize photocleavable diblock copolymers

Article abstract of DOI:10.1246/cl.130235

A novel heterobifunctional linker 1 connected with photocleavable N-(2-nitrobenzyl)imide has been developed. Hydrophobic polystyrene (PS), hydrophilic poly(ethylene oxide) (PEO), and thermosensitive poly(N- isopropylacrylamide) (PNIPAM) containing thiol or azide at the terminal, synthesized by a living radical polymerization or a transformation of terminal functional groups, were coupled with the alkyne and maleimide protected as the furan adduct at both terminals of 1 to synthesize three types of photocleavable diblock copolymers in high yields.

Full text of DOI:10.1246/cl.130235

doi:10.1246/cl.130235
Published on the web May 28, 2013
791
A Heterobifunctional Linker Bearing Azide-reactive Alkyne and Thiol-reactive Maleimide
Connected with N-(2-Nitrobenzyl)imide to Synthesize Photocleavable Diblock Copolymers
Shota Yamamoto,1 Seiichi Nakahama,2 and Kazuo Yamaguchi*1,2
1Department of Chemistry, Kanagawa University, 2946 Tsuchiya, Hiratsuka, Kanagawa 259-1293
2Research Institute for Photofunctionalized Materials, Kanagawa University,
2946 Tsuchiya, Hiratsuka, Kanagawa 259-1293
(Received March 18, 2013; CL-130235; E-mail: kazu@kanagawa-u.ac.jp)
(1) R - N3
A novel heterobifunctional linker 1 connected with photo-
CH3O
O
O
CH3O
CH2
(2)
Δ
O
CH3
CH N
CH3
CH N
S R'
cleavable N-(2-nitrobenzyl)imide has been developed. Hydro-
phobic polystyrene (PS), hydrophilic poly(ethylene oxide)
(PEO), and thermosensitive poly(N-isopropylacrylamide)
(PNIPAM) containing thiol or azide at the terminal, synthesized
by a living radical polymerization or a transformation of
terminal functional groups, were coupled with the alkyne and
maleimide protected as the furan adduct at both terminals of 1 to
synthesize three types of photocleavable diblock copolymers in
high yields.
(3) HS - R'
CH2
O
O
R
N
N
O
NO2
N
1
NO2
O
Scheme 1. Synthesis of photocleavable diblock copolymer
using photodegradable heterobifunctional linker 1.
with azide at the terminal of R-N3 to form a triazole ring by the
Huisgen cycloaddition in the presence of CuIX and amine as the
catalyst. After deprotection by the retro-Diels-Alder reaction,
the generated maleimide undergo the Michael addition of R¤-SH
at the terminal in the presence of a tertiary amine. In this report,
azido-terminated PS is synthesized by the reaction of sodium
azide with bromo-terminated PS obtained by ATRP of styrene.
Thiol-terminated PNIPAM is synthesized by aminolysis of
terminal dithioester of PNIPAM obtained by RAFT polymer-
ization of NIPAM. Azido- and thiol-terminated PEOs are
employed for the coupling reaction. Three photocleavable block
copolymers were synthesized by the two-step coupling reaction
of end-functionalized PS, PNIPAM, and PEO. Three photo-
cleavable block copolymers were synthesized by the two-step
coupling reaction inserted with a deprotection step. The photo-
sensitivity of the block copolymers was estimated and compared
with that of a model compound 7a synthesized separately.
Turbidities of block copolymers containing PNIPAM as well as
the homopolymer as a precursor in aqueous solutions were
measured at different temperatures to determine the lower
critical solution temperature (LCST).
In the middle of the 1990s, atom-transfer radical polymer-
ization (ATRP) by Matyjaszewski and Sawamoto1,2 as well as
different types of living radical polymerization3 was developed
to obtain many kinds of end-functionalized polymers and block
copolymers very easily. In addition, a combination of click
chemistry proposed by Sharpless4 with living radical polymer-
izations promoted the synthesis and applications of a wide
variety of polymers.5 More recently, photosensitive structures
were introduced into such polymers.6 2-Nitrobenzyl derivatives
were mostly reported among the photosensitive units.7 Polymers
and block copolymers bearing 2-nitrobenzyl structure at the
side chain, were synthesized to phototrigger micelle disruption
and pattern thin films. Moreover, block copolymers connected
with one photosensitive linker were also reportedly receiving
attention as new materials such as a polymer assembly.7,8 Most
of block copolymers connected with 2-nitrobenzyl linkers were
synthesized by living radical polymerization such as ATRP,
reversible addition-fragmentation chain-transfer (RAFT) poly-
merization, and ring-opening polymerization.9-12 However,
it was reported that ATRPs of monomers containing 2-nitro-
benzyl group were partially inhibited and that the control of
molecular weights and their distributions was difficult.13-15
Even in the case of the macroinitiator containing only one
2-nitrobenzyl group, there could be both difficulty in the control
of molecular weight and limitation in the range of applicable
monomers.
In this paper, a novel heterobifunctional linker 1 that is
reactive to two types of click chemistry, the Huisgen cyclo-
addition and the Michael addition, connected with photocleav-
able 2-nitrobenzylimide was developed to synthesize photo-
cleavable block copolymers in high yields and with control of
the molecular weight. Alkyne and maleimide at the both
terminals of 1 are highly reactive and mostly used for click
chemistry with azido- and thiol-terminated polymers. Actually,
the maleimide is protected as a Diels-Alder adduct with furan.
Conceptual coupling reactions in three steps, including a
deprotection step, are shown in Scheme 1. The alkyne reacts
Photocleavable linker 1 was synthesized as shown in
Scheme 2. Compound 216 synthesized in four steps from
4-hydroxy-3-methoxyacetophenone was reduced with NaBH4
to alcohol 3 in 99% yield, reacting with PBr3 to obtain bromide
4 in 86% yield. Finally, coupling of 4 and an adduct17 of
maleimide with furan in the presence of potassium carbonate
afforded 1 in 91% yield identified by1H NMR, UV spectra, and
elemental analysis.18
Synthetic route of a model compound 7a and three different
types of photocleavable block copolymers 7b-7d are shown in
Scheme 3. Prior to synthesis of photocleavable block copoly-
mers using 1, a model compound 7a for the block copolymer
was synthesized as shown in Scheme 3. The Huisgen cyclo-
addition of 1 and 1-azidoethylbenzene as the first click
chemistry gave triazole 5a in 96% yield, which was heated at
120 °C in anisole for removal of the protecting group to obtain
maleimide 6a, quantitatively. The Michael addition of 6a with
octane-1-thiol in the presence of triethylamine as the second
click chemistry afforded model compound 7a in 84% yield, as
identified by H NMR, UV spectra, and elemental analysis.19
1
Chem. Lett. 2013, 42, 791-793
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

792
O
O
HN
CH3O
CH3O
O
CH3O
CH3
CH3
CH
CH3
NaBH4
PBr3 / pyridine
dry benzene
K2CO3
O
CH2
C
1
CH2
O
CH OH
Br
CH2
O
THF / methanol
O
dry DMF
(91%)
NO2
4 (86%)
2
NO2
NO2
3 (99%)
Scheme 2. Synthesis of photocleavable linker 1.
CH3O
O
O
Table 1. Characterization of diblock copolymer 7b-7d
CH3
CH
CuBr / PMDETA
dry DMF
CH2
N
O
Mn
R
N3 + 1
Mw/Mn
Exposure
R
N
¹2
calcd 1H NMR UV
SEC
7700 8400
N
O
(SEC) dose/J cm
NO2
N
5a : R = CH(Ph)CH3 (96%)
5b : R = PS6300 (52%)
5c : R = PS4000 (93%)
5d : R = PEO5000 (73%)
7b 7380
7c 9930
7750
9900
1.09
®
13
15
13
9700
®
®
7d 10630 10600 10400
®
CH3O
CH3
O
O
Δ
anisole
CH2
O
CH
N
5a - 5d
CH3O
R
N
O
CH3
S R'
N
NO2
N
hv
CH2
O
C
+
HN
7a - 7d
6a : R = CH(Ph)CH3 (99%)
6b : R = PS6300 (88%)
6c : R = PS4000 (94%)
6d : R = PEO5000 (69%)
O
R
N
N
NO
N
O
Scheme 4. Photolysis of model compound 7a and diblock
copolymer 7b-7d.
CH3O
O
CH3
CH
S
R'
Et3N
CH2
O
N
6a - 6d
HS R'
+
R
N
dry THF
N
copolymer of PEO with PNIPAM 7d was obtained in 94% yield
by reprecipitation against diethyl ether, while block copolymer
of PS with PNIPAM 7c was afforded in 63% yield by a silica
gel column chromatography because of no solvent adequate
for reprecipitation. In 1H NMR spectra of 7d in CDCl3
(Figure S1),26 peaks originated from PEO, PNIPAM, and 1
were observed at 0.64-2.74, 3.42-3.91, and 5.48-7.18 ppm,
confirming the structure of 7d. Based on the integral ratio of the
peaks of PEO and PNIPAM (at 3.7 and 3.9 ppm), the molecular
weight of 7d was determined. Molecular weights of the block
copolymers 7b and 7c were similarly determined from 1H NMR
(Figures S2 and S3).26 Molecular weights were also determined
by UV using the value of ¾ = 4100 at 341 nm of a model
compound 7a for the block copolymers. Table 1 summarizes
O
NO2
N
7a : R = CH(Ph)CH3, R' = (CH2)7CH3 (84%)
7b : R = PS6300, R' = PEO750 (75%)
7c : R = PS4000, R' = PNIPAM5300 (63%)
7d : R = PEO5000, R' = PNIPAM5300 (94%)
Scheme 3. Synthesis of model compound 7a and diblock
copolymer 7b-7d.
The Huisgen cycloaddition of azido-terminated PS (mo-
lecular weights of 4000 and 6300)20,21 and 1 with CuIBr and
PMDETA was carried out to obtain 5b and 5c in 52% and 93%
yields, respectively. The desired products were easily purified by
reprecipitation against methanol followed by silica gel chroma-
tography for removal of excess amount of PS used. Cyclo-
addition of azido-terminated PEO (molecular weights 5000)21
synthesized from PEO via tosylated PEO22 with 1 was similarly
carried out to get 5d in 73% yield. The products were purified
by extraction with aqueous EDTA solution to remove CuIBr,
followed by reprecipitation against ice-cooled diethyl ether. The
1
molecular weights of 7b-7d determined by H NMR and UV
spectra as well as that determined from the polydispersity index
from SEC. The molecular weights determined by different
methods are consistent with one another, showing the ability to
control the molecular weight of each block synthesized by living
radical polymerizations. To our knowledge, 7c and 7d are the
first examples of photocleavable block copolymers containing
PNIPAM. Synthetic methods for 1, 3-7, and end-functionalized
homopolymers are described.26
1
resulting polymers 5b-5d were characterized by H NMR and
SEC. The Diels-Alder adducts, 5b-5d were heated for 4 h at
120 °C in anisole to remove the protecting group of N-maleimide
through the retro-Diels-Alder reaction and to obtain N-male-
imido-terminated polymers 6b-6d in 88%, 94%, and 69%
yields, respectively. The Michael addition of the maleimides 6b
and 6d with excess amount of thiol-terminated PEO (molecular
weight 750)23 were carried out in the presence of triethylamine
to synthesize 7b in 75% yield, which was then purified by
reprecipitation against methanol. Block copolymers 7c and 7d
containing a PNIPAM segment were synthesized by the Michael
addition of 6c and 6d in the presence of triethylamine to thiol-
terminated PNIPAM generated in situ from a precursor,
dithiobenzoate-terminated PNIPAM (molecular weight 5300),24
by aminolysis using hexylamine.25 A photocleavable block
Photodecomposition of a model compound 7a for 7b-7d
was monitored by UV spectroscopy and HPLC. Exposure
¹2
dose of 12 J cm was required for the complete photodecom-
position, judging from no spectral change and disappearance
of 7a in HPLC. The nitroso compound was obtained from
the photodecomposed mixture by a preparative TLC as shown
in Scheme 4 (R = 1-phenylethyl).27 This structure is consistent
with those of products by the photoreaction of 2-nitrobenzyl
derivatives such as esters of carboxylic and carbamic acids, and
N-2-nitrobenzylamide reported previously.28 UV spectral change
of 7d in THF upon photoirradiation for 0-120 s is shown in
Figure 1. The absorption of original 7d at 341 nm decreased,
Chem. Lett. 2013, 42, 791-793
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

793
Commun. 2010, 31, 1588.
7
H. Zhao, E. S. Sterner, E. B. Coughlin, P. Theato, Macro-
molecules 2012, 45, 1723.
8
9
P. Theato, Angew. Chem., Int. Ed. 2011, 50, 5804.
M. Kang, B. Moon, Macromolecules 2009, 42, 455.
10 J.-M. Schumers, J.-F. Gohy, C. A. Fustin, Polym. Chem. 2010,
1, 161.
11 H. Zhao, W. Gu, E. Sterner, T. P. Russell, E. B. Coughlin, P.
Theato, Macromolecules 2011, 44, 6433.
12 E. Cabane, V. Malinova, W. Meier, Macromol. Chem. Phys.
2010, 211, 1847.
13 J. Jiang, X. Tong, D. Morris, Y. Zhao, Macromolecules 2006,
39, 4633.
14 J.-M. Schumers, C.-A. Fustin, A. Can, R. Hoogenboom, U. S.
Schubert, J.-F. Gohy, J. Polym. Sci., Part A: Polym. Chem.
2009, 47, 6504.
Figure 1. UV-vis spectral change of compound 7d upon
photoirradiation for 0, 30, 90, and 120 s.
15 S. Kumar, Y. L. Dory, M. Lepage, Y. Zhao, Macromolecules
2011, 44, 7385.
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Chem. Soc. 2011, 133, 12.
17 H. Kwart, I. Burchuk, J. Am. Chem. Soc. 1952, 74, 3094.
18 1H NMR (400 MHz, CDCl3): ¤ 7.71 (1H, s), 7.15 (1H, s), 6.51
(2H, s), 6.04 (1H, q, J = 7.2 Hz), 5.29 (1H, s), 5.22 (1H, s),
4.80 (2H, d, J = 2.4 Hz), 3.92 (3H, s), 2.88 (1H, d, J =
6.6 Hz), 2.79 (1H, d, J = 6.6 Hz), 2.57 (1H, t, J = 2.4 Hz), 1.84
(3H, d, J = 7.2 Hz). Anal. Calcd for C20H18N2O7: C, 60.30; H,
4.55; N, 7.03%. Found: C, 60.36; H, 4.55; N, 6.82%. UV
measurement (in 0.10 mM THF solution): -max = 335 nm,
¾ = 5200.
and a new absorption at 370 nm close to that of the nitroso
compound from 7a27 in Scheme 4 was observed. When the
spectra have no change after photoirradiation for 120 s, there are
still isosbestic points at 250, 315, and 362 nm, similar to the
case of 7a. This suggests that no side reaction occurs during
photolysis of the 2-nitrobenzylimide of 7d. Exposure doses of
13-15 J cm¹2 are required for the photolysis of 7b-7d, similar to
that of 7a, as shown in Table 1, indicating that the photoreaction
rates are not significantly affected by the structures and
molecular weights of the block copolymers.
LCSTs of end-functionalized PNIPAM and the block
copolymers in an aqueous solution were determined by turbidity
change with temperature. LCST of PNIPAM (molecular weight
5300) terminated with dithiobenzoate was 36 °C, higher than
33 °C of PNIPAM synthesized by a conventional radical
polymerization.29 LCST of 7d was 39 °C comparable to 38 °C
of PEO-b-PNIPAM without a photocleavable linker by synthe-
sized by ATRP from a macroinitiator30 and much higher than
that of homopolymer.29
A novel photocleavable heterobifunctional linker 1 con-
nected with N-(2-nitrobenzyl)imide has been developed, which
is coupled with the Huisgen cycloaddition reaction and the
Michael addition reaction. Polymers containing thiol or azide
were coupled with alkyne and maleimide of 1 to synthesize
photosensitive (and thermosensitive) diblock copolymers, PS-b-
PEO, PS-b-PNIPAM, and PEO-b-PNIPAM connected with
photocleavable 2-nitrobenzylimide in high yields. The energy
needed for photolysis of diblock copolymer in solution was
found to be 13-15 J cm¹2, regardless of the type and molecular
weight of the polymers. It was demonstrated that 1 was very
useful for the synthesis of a variety of photocleavable block
copolymers applicable to functional polymer assembly such as
photosensitive polymer micelles and polymersomes.7,8
19 1H NMR (400 MHz, CDCl3): ¤ 7.67 (1H, s), 7.54 (1H, s),
7.40-7.28 (6H, m), 6.01 (1H, q, J = 7.1 Hz), 5.81 (1H, q,
J = 7.1 Hz), 5.25 (2H, s), 3.91 (3H, d, J = 2.1 Hz), 3.65 (1H,
dtd, J = 3.7 Hz, J = 3.8 Hz, J = 3.1 Hz), 3.13-3.03 (1H, m),
2.90-2.63 (2H, m), 2.49 and 2.44 (1H, dd, J = 3.3 Hz,
J = 3.3 Hz), 1.99 (3H, d, J = 7.1 Hz), 1.84 (3H, td, J =
9.4 Hz, J = 4.4 Hz), 1.62-1.53 (2H, br). 1.36-1.26 (10H, br),
0.87 (3H, td, J = 7.6 Hz, J = 1.5 Hz). Anal. Calcd for C32H41-
N5O6S: C, 61.62; H, 6.63; N, 11.23%. Found: C, 61.11; H,
6.71; N, 10.99%. UV measurement (in 0.10 mM THF solu-
tion): -max = 341 nm, ¾ = 4100.
20 M. Hikita, K. Tanaka, T. Nakamura, T. Kajiyama, A. Takahara,
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26 Supporting Information is available electronically on the CSJ-
Journal Web site, http://www.csj.jp/journals/chem-lett/index.
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Chem. Lett. 2013, 42, 791-793
© 2013 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/