Synthesis of amphiphilic diblock copolymer using heterobifunctional linkers, connected by a photodegradable N-(2-Nitrobenzyl)imide structure and available for two different click chemistries

Article abstract of DOI:10.1246/bcsj.20150445

Two photodegradable heterobifunctional linkers (PHBL) connected by a N-(2-nitrobenzyl)imide structure have been developed as tools to obtain photodegradable diblock copolymers with precisely controlled molecular weight. They can undergo two different clic

Full text of DOI:10.1246/bcsj.20150445

Selected Paper
Synthesis of Amphiphilic Diblock Copolymer Using Heterobifunctional
Linkers, Connected by a Photodegradable N-(2-Nitrobenzyl)imide
Structure and Available for Two Different Click Chemistries
1
1
1
2
1,2
Shota Yamamoto, Hidemi Tochigi, Shuya Yamazaki, Seiichi Nakahama, and Kazuo Yamaguchi*
1Department of Chemistry, Kanagawa University, 2946 Tsuchiya, Hiratsuka, Kanagawa 259-1293
2Research Institute for Photofunctionalized Materials, Kanagawa University, Tsuchiya, Hiratsuka, Kanagawa 259-1293
E-mail: kazu@kanagawa-u.ac.jp
Received: December 26, 2015; Accepted: January 5, 2016; Web Released: January 15, 2016
Kazuo Yamaguchi
Kazuo Yamaguchi received his Master’s degree in Department of Chemistry from Tokyo Institute of
Technology (TIT), Japan in 1976. He became a Research Associate at Department of Polymer Chemistry of
TIT in 1978 before he received a Ph.D. degree in Department of Chemistry from TIT in 1982. He worked as a
postdoctoral fellow with Professor Regen at Marquette University, USA during 1982–1984. He moved to
Kanagawa University as an Assistant Professor in 1989 and has been a Professor since 1987. His current
research interests include the synthesis of photosensitive molecules and polymers, and application for
materials of electronics and biological sciences.
Abstract
Block copolymers containing photoresponsive groups, such
as 2-nitrobenzyl and cinnamoyl groups, and azobenzene and
coumarin derivatives that change their structure and character-
istics upon photoirradiation have a broad range of potential
applications, including drug delivery systems, thin film mate-
Two photodegradable heterobifunctional linkers (PHBL)
connected by a N-(2-nitrobenzyl)imide structure have been
developed as tools to obtain photodegradable diblock copoly-
mers with precisely controlled molecular weight. They can
undergo two different click reactions, i.e., Huisgen cyclo-
addition and Michael addition. One linker has an alkyne moiety
and maleimide protected as adduct with furan. Reaction of
azido-terminated polystyrene (PS), poly(ε-caprolactone) (PCL)
or poly(ethylene glycol) (PEG) with this PHBL followed by
deprotection affords the corresponding maleimide-terminated
polymer, which was coupled with thiol-terminated PEG or
poly(N-isopropylacrylamide) (PNIPAM) to synthesize PS-b-
PHBL-b-PEG, PCL-b-PHBL-b-PEG, and PEG-b-PHBL-b-
PNIPAM. The other linker has maleimide and an alkyne
protected by a trimethylsilyl group. This affords diblock
copolymers by the reverse route, i.e., maleimide reacts with
thiol-terminated PS to obtain a product by Michael addition,
and then after deprotection, Huisgen cycloaddition of the
generated alkyne- and azido-terminated PEG affords PEG-b-
PHBL-b-PS. The resulting photosensitive diblock copolymers
were characterized by UV spectroscopy in solution before
and after photoirradiation. The energy needed for photolysis
of the diblock copolymers in solution ranged from 12 to
1­4
rials and hydrogels. In particular, 2-nitrobenzyl derivatives
are efficiently cleaved by near-ultraviolet light under neutral
5
conditions. Consequently, photoresponsive amphiphilic block
copolymers connected with 2-nitrobenzyl groups are receiving
considerable attention as building blocks of polymeric assem-
6
,7
blies such as polymeric micelles and polymersomes.
On the other hand, in the middle of the 1990s, atom transfer
radical polymerization (ATRP) and various types of living radi-
cal polymerization were developed to provide easy access to
many kinds of end-functionalized polymers and block copoly-
8
­10
mers.
polymerization (SET-LRP) has been developed.
2-nitrobenzyl groups are available as a protecting group not
Furthermore, single electron transfer-living radical
11­13
Therefore,
1
4
only for organic synthesis, but also for polymeric materials.
For example, it was reported that micelles formed by a diblock
copolymer containing 2-nitrobenzyl groups in the side chain
broke up in response to photocleavage of the 2-nitrobenzyl
1
5
groups. Block copolymers connected via 2-nitrobenzyl junc-
6
,16
tions have also been reported.
For example, diblock copoly-
¹
2
1
7 J cm , and was independent of polymer type and molecular
mers with 2-nitrobenzyl junctions were synthesized by ATRP
1
7,18
weight.
and ring-opening polymerization.
However, the 2-nitro-
benzyl group prevents living radical polymerization, so it is dif-
ficult to precisely control the molecular weight of the polymer
Bull. Chem. Soc. Jpn. 2016, 89, 481–489 | doi:10.1246/bcsj.20150445
© 2016 The Chemical Society of Japan | 481

CH O
O
CH O
O
N
O
3
CH3
CH
3
CH3
(1) PolyA
2) anisole
N3
O
N
CH2
O
CH
O
CH2
(
PolyA N
N
NO
2
O
NO2
N
1
HS PolyB
CH O
O
CH O
3
3
O
CH3
CH
CH3
CH
S PolyB
Si
CH2
3
O
N
O
O
CH2
O
N
PolyA N
NO2
N
NO
2
O
N
PolyA N3
CH O
O
CH
3
O
O
N
O
S PolyB
3
CH3
CH
CH3
(1) HS PolyB
2) TBAF
R
CH2
O
CH
N
O
CH
2
O
(
NO2
NO
2
2
2
: R = (CH ) Si
3 3
' : R = H
Figure 1. Synthetic scheme of photodegradable diblock copolymer using two different photodegradable heterobifunctional
crosslinking linkers (PHBLs).
building block.19 Therefore, diblock copolymers have been syn-
thesized by polymeric reaction as well as by polymerization.
(PNIPAM5300
:
M = 5300),
27
and thiol-terminated PEG
n
2
0
28
(PEG750: M = 750) were synthesized according to the report-
n
For this reason, we recently developed a new heterobifunc-
tional linker (PHBL) 1 connected by a photocleavable 2-
nitrobenzylimide; the linker is reactive to two types of click
chemistry, i.e., Huisgen cycloaddition and Michael addition,
making it possible to synthesize photocleavable block copoly-
mers in high yields with well-controlled molecular weight
and polydispersity. The reaction of azido-terminated PolyA
with 1 followed by deprotection was carried out to obtain the
corresponding maleimide-terminated PolyA, which was cou-
pled with thiol-terminated PolyB to synthesize PolyA-b-PHBL-
b-PolyB (Figure 1).
ed methods as described in Supporting Information (exper-
imental procedures and Figures S1­S6 for synthetic schemes).
Synthesis of PHBL 2 and Model Compound of Diblock
Copolymer 10.
Compounds 2 and 10 were synthesized
according to Figures 2 and 3.
Synthesis of 1-(1-Bromoethyl)-5-methoxy-2-nitro-4-
(phenylmethoxy)benzene (5): Into a 500-mL three-necked
flask was placed 1.30 g (4.29 mmol) of 1-(4-benzyloxy-5-
2
1
2
9
methoxy-2-nitrophenyl)ethanol, 80 mL of dry benzene and 5
drops of dry pyridine. The mixture was stirred in an ice bath,
and 2.90-g PBr (10.7 mmol) in 30 mL of dry benzene was
3
In this paper, we describe a new heterobifunctional linker 2
containing maleimide and an alkyne protected by a trimethyl-
silyl group, which would enable us to obtain block copolymer
by the reverse route (Figure 1). The reaction of thiol-terminated
PolyB with 2 followed by deprotection was carried out to
obtain the corresponding alkyne-terminated PolyB, which was
coupled with azido-terminated PolyA to synthesize PolyA-b-
PHBL-b-PolyB. Finally, photodegradable diblock copolymers
with precisely controlled molecular weight were synthesized by
using 1 and 2, and photolysis of resulting diblock copolymers
added dropwise. The resulting solution was stirred for 4.5 h at
0 °C under nitrogen. The reaction mixture was concentrated in a
rotary evaporator and the residue was extracted with chloro-
form and H O. The combined organic layers were washed with
2
sat. NaCl aqueous solution, dried over magnesium sulfate, and
then concentrated in a rotary evaporator. The residue was
purified on a silica gel column using hexane and ethyl acetate
(1:1) to afford 5 as a yellow solid in 86% yield (1.35 g, 3.69
1
mmol). H NMR (400 MHz, CDCl ): ¤ 7.52 (1H, s), 7.44­7.33
3
(5H, m), 7.29 (1H, s), 6.02 (1H, q, J = 6.4 Hz), 5.21­5.15 (2H,
m), 4.01 (3H, s), 2.06 (3H, d, J = 6.4 Hz). IR (KBr): 1519,
1
in solution was confirmed by means of UV and H NMR
measurements.
¹
1
1339 cm .
Synthesis of 3a,4,7,7a-Tetrahydro-2-{1-[5-methoxy-2-
nitro-4-(phenylmethoxy)phenyl]ethyl}-4,7-epoxy-1H-iso-
indole-1,3(2H)-dione (6): Into a 50-mL two-necked flask
were placed 0.254 g (1.54 mmol) of 7-oxabicyclo[2.2.1]hept-5-
Experimental
Reagents and Materials. All reagents were purchased
from Wako, TCI, Sigma-Aldrich, or Kanto Chemical unless
otherwise stated. PHBL 1,21 azido-terminated PS (PS4 : M =
30
ene-dicarboxyimide, 0.966 g (6.99 mmol) of K CO , and 10
000
n
2
3
2
2,23
4
000, PS6000: Mn = 6000, and PS8000: Mn = 8000),
azido-
mL of dry DMF. The mixture was stirred for 30 min at room
temperature. To the flask was added 0.479 g (1.31 mmol) of 5.
The resulting solution was stirred for 3 h at 60 °C under nitro-
gen. The vessel was evacuated with a high-vacuum oil pump to
completely remove DMF, and the residue was extracted with
23,24
terminated PCL (PCL6500: M = 6300),
azido-terminated
n
PEG (PEG7 : M = 750, PEG : M = 2000, and PEG5000:
50
3,25
n
2000
n
2
M = 5000),
thiol-terminated PS (PS4000: M = 4000 and
n
n
PS6000: M = 6000),26 PNIPAM containing dithiobenzoate
n
482 | Bull. Chem. Soc. Jpn. 2016, 89, 481–489 | doi:10.1246/bcsj.20150445
© 2016 The Chemical Society of Japan

O
CH
PhCH
3
O
CH
3
O
CH
3
O
O
HN
O
2 3
/ K CO
CH
CH OH
3
CH
CH Br
3
CH
CH
3
PBr
3
/ bpy
O
2
PhCH O
N
O
2
O
PhCH
2
O
dry benzene
dry DMF
4
NO
2
5
NO
2
6
NO
2
O
CH
3
O
O
CH
CH
3
Si
CH
2
2 3
Br / K CO
HO
N
O
3
2
TFA
anisole
dry CH
3
CN
7
NO
2
O
Figure 2. Synthetic scheme of photodegradable heterobifunctional crosslinking linker (PHBL) 2.
CH
3
O
O
CH O
O
3
HS (CH
2
)
7
CH
3
3
/ Et N
CH
CH N
3
S
(CH
2
)
7
CH
3
TBAF / acetic acid
THF
CH3
CH N
2 7 3
S (CH ) CH
2
Si
CH
2
O
CH2 O
dry CH
3
CN
8
NO
2
O
9
NO2
O
CH
3
O
O
CH
CH N
3
S (CH ) CH
2 7 3
I
PhCH(CH
3
)-N
3
/ Cu Br / PMDETA
2
CH O
CH
3
CH N
dry DMF
N N
NO
2
O
1
0
Figure 3. Synthetic scheme of model compound 10.
ethyl acetate and H2O. The combined organic layers were
washed with sat. NaCl aqueous solution, dried over magnesium
sulfate, and then concentrated in a rotary evaporator. The
residue was purified on a silica gel column using hexane and
dried over magnesium sulfate, and then concentrated in a rotary
evaporator. The residue was purified on a silica gel column
using hexane and ethyl acetate (1:1) to afford 3 as a yellow paste
1
in 73% yield (1.22 g, 2.58 mmol). H NMR (400 MHz, CDCl ):
3
ethyl acetate (2:1) to afford 6 as a yellow solid in 69% yield
¤ 7.77 (1H, s), 7.14 (1H, s), 6.51 (2H, s), 6.05 (1H, q, J = 7.2
Hz), 5.29 (1H, s), 5.21 (1H, s), 4.77 (2H, s), 3.91 (3H, s), 2.88
(1H, d, J = 6.4 Hz), 2.79 (1H, d, J = 6.4 Hz), 1.83 (3H, d, J =
7.2 Hz), 0.15 (9H, s). IR (KBr): 2179, 1704, 1523, 1357 cm .
Synthesis of 3a,4,7,7a-Tetrahydro-2-[1-(4-hydroxy-5-meth-
oxy-2-nitrophenyl)ethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-di-
one (2): Into a 20-mL round-bottomed flask were placed
0.526 g (0.890 mmol) of 3, and 10 mL of anisole. The mixture
was stirred for 7 h at 120 °C, then the vessel was evacuated with
a high-vacuum oil pump to completely remove the anisole. The
1
(
0.407 g, 0.904 mmol). H NMR (400 MHz, CDCl ): ¤ 7.60
3
(1H, s), 7.44­7.33 (5H, m), 7.14 (1H, s), 6.51 (2H, s), 6.02 (1H,
¹
1
q, J = 7.2 Hz), 5.29 (1H, s), 5.21 (1H, s), 5.16 (1H, s), 3.92
(
(
3H, s), 2.87 (1H, d, J = 6.4 Hz), 2.78 (1H, t, J = 6.4 Hz), 1.83
¹
1
3H, d, J = 7.2 Hz). IR (KBr): 1699, 1518, 1337 cm
.
Synthesis of 3a,4,7,7a-Tetrahydro-2-[1-(4-hydroxy-5-meth-
oxy-2-nitrophenyl)ethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-di-
one (7): Into a 30-mL round-bottom flask were placed 0.782 g
(1.74 mmol) of 6, and 10 mL of trifluoroacetic acid (TFA). The
mixture was stirred for 18 h at room temperature. The vessel was
evacuated with a high-vacuum oil pump to completely remove
TFA and the residue was extracted with chloroform and H2O.
The combined organic layers were washed with sat. NaCl aque-
ous solution, dried over magnesium sulfate, and then concen-
trated in a rotary evaporator. Volatiles were completely removed
from the residue with a high-vacuum oil pump to afford 7 as a
residue was extracted with chloroform and H O. The combined
organic layers were concentrated in a rotary evaporator and
purified on a silica gel column using hexane and ethyl acetate
2
(2:1) to afford 2 as a yellow paste in 95% yield (1.22 g, 2.58
1
mmol). H NMR (400 MHz, CDCl ): ¤ 7.71 (1H, s), 7.32
3
(1H, s), 6.66 (2H, s), 6.08 (1H, q, J = 7.2 Hz), 4.78 (2H, s), 3.94
1
3
(3H, s), 1.88 (3H, d, J = 8.0 Hz), 0.15 (9H, s). C NMR (400
1
yellow solid in 99% yield (0.620 g, 1.72 mmol). H NMR (400
MHz, CDCl ): ¤ 171, 154, 147, 141, 135, 132, 112, 111, 99, 96,
3
¹1
MHz, CDCl ): ¤ 7.56 (1H, s), 7.13 (1H, s), 6.50 (2H, s), 5.98
59, 57, 48, 20, 0.28. IR (KBr): 2180, 1710, 1523, 1362 cm .
3
(
(
(
1H, q, J = 7.2 Hz), 5.7 (1H, s), 5.29 (1H, s), 5.12 (1H, s), 3.95
Synthesis of 1-[1-(5-Methoxy-2-nitro-4-trimethylsilyl-
prop-2-ynyloxyphenyl)ethyl]-3-octylsulfanylpyrrolidine-
2,5-dione (8): Into a 30-mL two-necked flask were placed
0.160 g (0.398 mmol) of 2, 49 ¯L (0.353 mmol) of triethyl-
amine, 80 ¯L (0.461 mmol) of 1-octanethiol, and 5 mL of
acetonitrile. The mixture was stirred for 3 h at room temper-
ature under nitrogen. The reaction mixture was concentrated in
a rotary evaporator and the residue was extracted with ethyl
3H, s), 2.87 (1H, d, J = 6.4 Hz), 2.78 (1H, d, J = 6.4 Hz), 1.83
¹
1
3H, d, J = 7.2 Hz). IR (KBr): 3266, 1693, 1525, 1351 cm .
Synthesis of 3a,4,7,7a-Tetrahydro-2-[1-(4-hydroxy-5-meth-
oxy-2-nitrophenyl)ethyl]-4,7-epoxy-1H-isoindole-1,3(2H)-di-
one (3): Into a 500-mL two-necked flask were placed 1.28 g
(3.56 mmol) of 7, 1.48 g (10.7 mmol, 2.9 equiv) of K CO , and
2 3
2
30 mL of dry acetonitrile. The mixture was stirred for 30 min
at room temperature. To the flask was added 0.820 g (4.29
mmol) of 3-bromo-1-(trimethylsilyl)-1-propyne. The resulting
solution was stirred for 1 h at 60 °C under nitrogen. The reac-
tion mixture was concentrated in a rotary evaporator and the
acetate and H O. The combined organic layers were washed
2
with sat. NaCl aqueous solution, dried over magnesium sulfate,
and then concentrated in a rotary evaporator. The residue was
purified on a silica gel column using hexane and ethyl acetate
residue was extracted with chloroform and H O. The combined
organic layers were washed with sat. NaCl aqueous solution,
(3:1) to afford 8 as a yellow oil in 90% yield (0.196 g, 0.357
2
1
mmol). H NMR (400 MHz, CDCl ): ¤ 7.77 (1H, s), 7.34 (1H,
3
Bull. Chem. Soc. Jpn. 2016, 89, 481–489 | doi:10.1246/bcsj.20150445
© 2016 The Chemical Society of Japan | 483

m), 6.03 (1H, q, J = 7.2 Hz), 4.78 (2H, s), 3.91 (3H, s), 3.69­
.62 (1H, m), 3.15­3.04 (1H, m), 2.91­2.66 (2H, m), 2.50­2.44
Synthesis of Maleimide-Terminated PS6000-PHBL 11b¤¤
by Deprotection of 11b¤: Into a 30-mL two-necked flask were
placed 0.207 g (0.0344 mmol) of 11b¤, and 3.5 mL of anisole.
The resulting solution was stirred for 3 h at 120 °C under
nitrogen, then the vessel was evacuated with a high-vacuum oil
pump to completely remove the anisole. The residue dissolved
in THF (5.0 mL) and precipitated from 100 mL of methanol to
afford 11b¤¤ as a white solid in 94% yield (0.910 g, 0.196 mmol,
3
(
(
1H, m), 1.88­1.79 (3H, m), 1.64­1.52 (2H, m), 1.36­1.26
10H, m), 0.89­0.86 (3H, m), 0.15 (9H, s).
Synthesis of 1-[1-(5-Methoxy-2-nitro-4-prop-2-ynyloxy-
phenyl)ethyl]-3-octylsulfanylpyrrolidine-2,5-dione (9): Into
a 20-mL round-bottom flask were placed 0.101 g (0.184 mmol)
of 8, 2 mL of THF containing 0.276 mmol tetrabutylammonium
fluoride, and 11 ¯L (0.184 mmol) of acetic acid. The mixture
was stirred for 15 min at 0 °C, and then concentrated in a rotary
evaporator. The residue was purified on a silica gel column
using hexane and ethyl acetate (3:1) to afford 9 as a yellow
1
M = 6400). H NMR (400 MHz, CDCl ): ¤ 7.66­7.61 (1H,
n
3
m), 7.38­6.27 (300H, m), 6.12­6.01 (1H, m), 5.19­5.02 (2H,
m), 3.86 (3H, s), 2.40­1.17 (180H, m), 1.04­0.87 (3H, m).
Synthesis of PS6000-b-PHBL-b-PEG750 11b: Into a 30-mL
two-necked flask were placed 0.0800 g (0.0123 mmol) of 11b¤¤,
1
oil in 94% yield (0.0820 g, 0.172 mmol). H NMR (400 MHz,
CDCl ): ¤ 7.66 (1H, s), 7.34 (1H, m), 6.03 (1H, q, J = 7.2 Hz),
0.110 g (0.123 mmol) of thiol-terminated PEG (M = 750), 5
3
n
4
3
2
1
.03 (2H, d, J = 2.4 Hz), 3.96 (3H, s), 3.72­3.59 (1H, m),
.18­3.01 (1H, m), 2.93­2.63 (2H, m), 2.57 (1H, t, J = 2.4 Hz),
.50­2.44 (1H, m), 1.90­1.82 (3H, m), 1.68­1.51 (2H, m),
.36­1.26 (10H, m), 0.89­0.86 (3H, m).
drops of Et3N, and 1.5 mL of dry THF. The resulting solution
was stirred for 16 h at room temperature under nitrogen. The
reaction mixture was concentrated in a rotary evaporator. The
residue was dissolved in THF (1.0 mL) and precipitated from
methanol to afford 11b as a white solid in 78% yield (0.114 g,
Synthesis of 1-[1-(5-Methoxy-2-nitro-4-{[1-(1-phenyl-
1
ethyl)-1H-1,2,3-triazol-4-yl]methoxy}phenyl)ethyl]-3-(octyl-
thio)pyrrolidine-2,5-dione (10): Into a 30-mL two-necked
flask were placed 0.0820 g (0.172 mmol) of 9, 2.60 mg (0.0179
mmol) of CuBr, 37.4 ¯L (0.172 mmol) of PMDETA, 0.0296 g
0.0158 mmol, M = 7100). H NMR (400 MHz, CDCl ): ¤
n
3
7.73­7.62 (1H, m), 7.63­6.35 (300H, m), 6.11­5.93 (1H, m),
5.35­4.93 (2H, m), 4.26­4.14 (2H, m), 3.88 (3H, s), 3.91­3.56
(77H, m), 3.38 (3H, s), 3.19­2.82 (4H, m), 2.71­2.65 (2H, m),
2.41­2.33 (1H, m), 2.37­1.46 (180H, m), 1.12­0.89 (3H, m).
Synthesis of Photodegradable Diblock Copolymer Using
Method B. Synthesis of Trimethylsilyl-Protected PHBL-
PS6000 14b¤: Into a 30-mL two-necked flask were placed
0.0306 g (0.0758 mmol) of 2, 0.504 g (0.0833 mmol) of thiol-
terminated PS (M = 6000), 0.129-g Et N (1.27 mmol), and
(0.172 mmol) of 1-ethylazidobenzene, and 5 mL of dry DMF.
The resulting solution was stirred for 20 h at room temperature
under nitrogen, then the vessel was evacuated with a high-
vacuum oil pump to completely remove the DMF. The residue
was extracted with chloroform and sat. NaCl. The combined
organic layers were washed with 0.065 M EDTA-Na aqueous
solution, dried over magnesium sulfate, and then concentrated
n
3
5.0 mL of dry THF. The resulting solution was stirred at room
temperature for 16 h under nitrogen, and then concentrated in a
rotary evaporator. The residue was dissolved in THF (1.0 mL)
in a rotary evaporator to afford 10 as a yellow solid in 74%
yield (0.0821 g, 0.132 mmol). H NMR (400 MHz, CDCl ): ¤
1
3
7
.67 (1H, s), 7.54 (1H, s), 7.40­7.28 (6H, m), 6.01 (1H, q,
and precipitated from methanol to afford 14b¤ as a white solid
1
J = 7.2 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),
in 96% yield (0.501 g, 0.0789 mmol, M = 6100). H NMR
n
(400 MHz, CDCl ): ¤ 7.77­7.54 (1H, m), 7.36­6.26 (300H, m),
3
3
.13­3.03 (1H, m), 2.90­2.63 (2H, m), 2.44 and 2.49 (1H, dd,
6.02­5.74 (1H, m), 5.25 (2H, s), 5.19­4.87 (2H, m), 3.84 (3H,
s), 2.92­2.69 (2H, m), 2.51­1.16 (180H, m), 1.20­1.05 (3H,
m), 1.01­0.86 (3H, m), 0.10 (9H, s).
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), 1.62­1.53 (2H, br), 1.36­1.26 (10H,
br), 0.87 (3H, td, J = 7.6 Hz, J = 1.5 Hz). Anal. Calculated for
C H N O S: 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
solution): ­max = 341 nm, ¾ = 4130.
Synthesis of Photodegradable Diblock Copolymer Using
Method A. Synthesis of PS6000-PHBL Maleimide Protected
as Adduct Furan 11b¤: Into a 30-mL two-necked flask were
placed 0.0600 g (0.151 mmol) of 1, 0.994 g (0.166 mmol) of
azido-terminated PS (Mn = 6000), 0.0238 g (0.166 mmol) of
CuBr, 95 ¯L (0.453 mmol) of PMDETA, and 6.5 mL of dry
DMF. The resulting solution was stirred for 18 h at room
temperature under nitrogen, then the vessel was evacuated with
a high-vacuum oil pump to completely remove the DMF. The
residue was dissolved in THF (10 mL), precipitated from 400
mL of methanol, and purified on a silica gel column using
Synthesis of Alkyne-Terminated PHBL-PS6000 14b¤¤ by
Deprotection of 14b¤¤: Into a 20-mL round-bottomed flask
were placed 0.500 g (0.0789 mmol) of 14b¤, 5 mL of THF
containing 0.261 mmol tetra-n-butylammonium fluoride, and
10 ¯L (0.174 mmol) of acetic acid. The mixture was stirred for
at 0 °C for 15 min, and then concentrated in a rotary evaporator.
The residue was dissolved in THF (1.0 mL), precipitated from
methanol and purified on a silica gel column using chloroform
32
41
5
6
and methanol (10:1) to afford 14b¤¤ as a white solid in 92%
1
yield (0.450 g, 0.0725 mmol, M = 6100). H NMR (400 MHz,
n
CDCl ): ¤ 7.70­7.56 (1H, m), 7.26­6.25 (330H, m), 6.03­5.84
3
(1H, m), 4.77 (2H, s), 3.96 (3H, s), 2.51­1.26 (200H, m), 1.33­
1.02 (3H, m), 0.98­0.84 (3H, m).
Synthesis of PEG750-b-PHBL-b-PS6000 14b: Into a 30-mL
two-necked flask were placed 0.100 g (0.0167 mmol) of 14b¤¤,
hexane and ethyl acetate (2:1) to afford 11b¤ as a white solid in
0.0267 g (0.0333 mmol) of azido-terminated PEG (M = 750),
n
1
8
5% yield (0.812 g, 0.129 mmol, Mn = 6400). H NMR (400
0.00264 g (0.0184 mmol) of CuBr, 0.0112 g (0.0501 mmol) of
PMDETA, and 3.0 mL of dry DMF. The resulting solution was
stirred at 40 °C for 3 h under nitrogen, and then the vessel was
evacuated with a high-vacuum oil pump to completely remove
the DMF. The residue was dissolved in THF (5.0 mL), pre-
MHz, CDCl ): ¤ 7.77­7.62 (1H, m), 7.40­6.22 (300H, m),
3
6
.13­5.92 (1H, m), 5.39­5.19 (2H, m), 5.19­4.87 (2H, m), 3.84
(
(
3H, s), 2.92­2.69 (2H, m), 2.51­1.16 (180H, m), 1.10­0.86
3H, m).
484 | Bull. Chem. Soc. Jpn. 2016, 89, 481–489 | doi:10.1246/bcsj.20150445
© 2016 The Chemical Society of Japan

cipitated from 100 mL of methanol, and purified on a silica gel
column using hexane and ethyl acetate (2:1) to afford 14b as a
out cleavage of the sulfide in the presence of TBAF (1.5 equiv)
and acetic acid (1.0 equiv) in THF at 0 °C to afford 9 in 94%
yield. Finally, Huisgen cycloaddition of 1-azidoethylbenzene
and 9 with Cu(I)Br and PMDETA was carried out to obtain 10
in 74% yield.
white solid in 80% yield (0.0900 g, 0.0134 mmol, M = 6800).
n
1
H NMR (400 MHz, CDCl ): ¤ 7.94­7.78 (1H, m), 7.73­7.59
3
(1H, m), 7.41­6.17 (330H, m), 6.03­5.81 (1H, m), 5.25 (2H, s),
3
.84 (3H, s), 3.66­3.55 (71H, m), 3.38 (3H, s), 2.31­1.25
Synthesis of Diblock Copolymer. First, Method A using
1 is shown in Figure 4. Huisgen cycloaddition of azido-
terminated PS, PCL, or PEG and 1 was carried out in the
(180H, m), 1.20­1.05 (3H, m), 0.99­0.82 (3H, m).
Photolysis of Diblock Copolymer in THF Solution. The
I
photodegradable diblock copolymer solution (0.1 mM in THF)
was placed in a quartz cell and irradiated with near-UV light
from a Hg arc lamp (USHIO, BA-H250) in an Optical Modulex
presence of Cu Br and PMDETA to obtain PS derivatives 11a¤­
11c¤, PCL derivative 12¤, and PEG derivatives 13a¤ and 13b¤ in
high yields (Table 1). The desired products 11a¤­11c¤ and 12¤
were easily isolated by reprecipitation followed by silica gel
column chromatography. In the case of 13a¤ and 13b¤, the
desired products were isolated by washing with 0.065 M
EDTA-Na aqueous solution to remove CuBr, followed by
reprecipitation using cold diethyl ether. The resulting furan
adducts 11a¤­11c¤, 12¤, 13a¤, and 13b¤ were heated in anisole
for 4 h at 120 °C (same conditions as for 3) to remove the
protecting group of N-maleimide through retro-Diels­Alder
reaction to give the N-maleimide-terminated polymers 11a¤­
(USHIO, H250) via copper sulfate solution (­ > 320 nm).
UV­vis spectra were acquired on a V570 spectrophotometer
(JASCO) at room temperature.
Characterization. 1H NMR spectra were measured with
an ECA-400 NMR spectrometer (JEOL) in CDCl . Calibration
was done with tetramethylsilane. Polymer molecular weights
and PDIs were estimated using a GPC (TOSOH) with THF
as the eluent (flow rate: 0.7 mL min ) at 40 °C, and with
refractive-index (RI) and UV detectors.
3
¹
1
11c¤, 12¤, 13a¤, and 13b¤ quantitatively. Michael addition of
Results and Discussion
the generated maleimides 11a¤­11c¤ and 12¤ with an excess
of thiol-terminated PEG (Mn = 750) was carried out in the
presence of triethylamine, and 11a­11c and 12 were isolated
by reprecipitation using methanol. Although thiol-terminated
polymer was partially air-oxidized to the disulfide, amphiphilic
diblock copolymers containing PS and PCL segments 11a­11c
and 12 were isolated simply by reprecipitation using methanol
to remove unreacted PEG. Block copolymers containing PEG
and PNIPAM segments 13a¤ and 13b¤ were synthesized by
Michael addition (in the presence of triethylamine) to thiol-
terminated PNIPAM generated in situ from a precursor, di-
thiobenzoate-terminated PNIPAM, by aminolysis using hexyl-
Synthesis of Photodegradable Heterobifunctional Linker
2
. Compound 4 was synthesized as reported.29 Synthetic route
for 2 is shown in Figure 2. Although Ph P­CBr is available
3
4
for bromination under mild conditions, Ph P reacts with nitro
3
groups of 4. Therefore, bromination reaction was carried out
using PBr . In this reaction, the styrene derivative is formed as
3
a by-product via elimination reaction even at below 0 °C, and
it was difficult to separate by column chromatography, so the
obtained 5 (86% yield) contaminated with the by-product was
used for the following reaction without purification. Compound
6
was obtained in 69% yield from 5 and 7-oxabicyclo[2.2.1]-
3
2
hept-5-enedicarboxyimide by Williamson synthesis. At this
stage, the styrene derivative generated during bromination was
removed by column chromatography, because 6 and the by-
product have very different polarity. The benzyl ester of 6
was easily deprotected with trifluoroacetic acid to obtain 7,
which was coupled with 3-bromo-1-(trimethylsilyl)-1-propyne
to afford 3. Finally, PHBL 2 was obtained in 95% yield
by retro-Diels­Alder reaction of 3 in anisole at 120 °C. The
amine. The resulting diblock copolymers 12a and 13b were
isolated simply by reprecipitation using cold diethyl ether. The
diblock copolymers soluble in water below the lower critical
solution temperature (LCST) become amphiphilic above the
LCST. The results of Michael addition by Method A are shown
in Table 1. Photodegradable diblock copolymers were obtained
from 1 in high yields by applying the two types of click
1
reactions. H NMR spectra of 11b in CDCl3 are shown in
1
structures of 2­7 were confirmed by H NMR and IR.
Figure 6a, and those of 11a, 11c, 12, 13a, and 13b are shown
in Figures S7­S11. Peaks originated from PS, PEG, and 1 were
observed at 0.64­2.74, 3.42­3.91, and 5.48­7.18 ppm, con-
firming the structure of 11b. The molecular weight of 11b was
determined based on the integral ratio of the peaks of PS and
PEG (at 1.5 and 3.9 ppm) (Table 2). The diblock copolymer
11b was a single component with a very narrow molecular
weight distribution (M /M = 1.07), as determined by GPC
Synthesis of Model Compound 10. Before synthesis of
diblock copolymers using PHBL 2, we synthesized low-
molecular model compound 10 to investigate the synthetic
conditions. Additionally, the molar absorption coefficient of 10
was obtained and used to determine the molecular weight of the
block copolymers described below. Synthetic route for 10 is
shown in Figure 3. To investigate click chemistry, Michael
addition of 2 with octane-1-thiol in the presence of triethyl-
amine was carried out, and afforded 8 in 90% yield. In our
previous report, when 2¤ without alkyne protection (Figure 1)
was used for Michael addition, side reaction occurred and the
yield was 60%, i.e., much lower than that of the reaction
w
n
measurement of 11a­11c (Figure S12). Other diblock copoly-
mers were similarly characterized.
Method B using 2 is shown in Figure 5. The method is the
same as that for the model compound 10. Although Michael
addition was carried out by the same method as used for 13a
and 13b, the trimethylsilyl group of 2 was also deprotected by
hexylamine, resulting in by-product formation. Therefore, 2
was reacted with separately synthesized thiol-terminated PS
in the presence of triethylamine. The desired products were
easily isolated by reprecipitation using methanol. The results
2
1
through 8. Deprotection of the trimethylsilyl group was
examined under various conditions. First, when 5 equivalents
of TBAF at room temperature was used,31 cleavage of the
sulfide bond occurred as well as deprotection of the trimethyl-
silyl group. Deprotection reaction was found to proceed with-
Bull. Chem. Soc. Jpn. 2016, 89, 481–489 | doi:10.1246/bcsj.20150445
© 2016 The Chemical Society of Japan | 485

Method A
CH
O
3
O
O
CH
3
CH
2
CH
2
N
O
CH
3
CH CH
2
CH
N
n
N
NO
O
N
1
1a' : n = 40, PolyA = PS4000
1b' : n = 60, PolyA = PS6000
1c' : n = 80, PolyA = PS8000
1
1
CH
O
3
O
O
CH
CH
3
CH
O
3
O
O
CH
CH
3
O
O
CH
2
N
Cu(I)Br / PMDETA
dry DMF
CH
2
N
O
PolyA
N
PolyA
N
3
+ 1
CH
2
O
C
(CH
2
)
5
O
C
n-1
2
(CH )
5
N
anisole
N
O
NO
2
N
N
N
NO2
O
1
2' : PolyA = PCL6500
11a'' : PolyA = PS4000
1b'' : PolyA = PS6000
11c'' : PolyA = PS8000
2'' : PolyA = PCL6500
13a'' : PolyA = PEG2000
3b'' : PolyA = PEG5000
1
CH
O
3
O
O
CH
CH
3
1
CH
2
N
O
CH
3
(OCH
2
CH
2
)
n
N
N
N
NO
2
O
1
13a' : n = 44, PolyA = PEG2000
13b' : n = 144, PolyA = PEG5000
O
O
CH
O
3
O
O
CH
CH
3
11a : PolyA = PS4000, PolyB = PEG750
1b: PolyA = PS6000, PolyB = PEG750
11c : PolyA = PS8000, PolyB = PEG750
2 : PolyA = PCL6500, PolyB = PEG750
HS (CH
2
)
2
C
(OCH
2
CH
2
)
17 OCH3 / Et
N
2 2 2 2
S (CH ) C (OCH CH )
17 OCH
3
3
1
CH
2
N
11a'' - 11c'', 12''
PolyA
N
dry THF
N
N
NO2
O
N
1
S
S
O
CH
CN
CH
3
CH
CH CH2 48 CN
CH
O
NH
3
CH CH
NH
2
4
CH
O
/
hexylamine / Et
3
N
3
CH
CH
O
8
3
S
13a : PolyA = PEG2000, PolyB = PNIPAM5300
13b : PolyA = PEG5000, PolyB = PNIPAM5300
3
CH
2
O
N
3
13a'', 13b''
PolyA
N
dry THF
N
NO
2
O
Figure 4. Synthetic scheme of photodegradable diblock copolymer using 1 (Method A).
Table 1. Synthesis of diblock copolymers by Method A
Huisgen cycloaddition reaction
Michael addition reaction
PolyA-PHBR-PolyB
PolyA
PolyA-PHBR
Yield/%
PolyB
Yield/%
a)
b)
PS4000
PS6000
PS8000
PCL6500
PEG2000
PEG5000
11a¤
11b¤
11c¤
12¤
13a¤
13b¤
93
PEG750
PEG750
PEG750
PEG750
PNIPAM5300
PNIPAM5300
11a
11b
11c
12
13a
13b
83
a)
b)
89
78
a)
b)
91
93
a)
b)
85
92
b)
b)
82
73
94
b)
b)
94
The product was isolated a) by column chromatography, b) by reprecipitation.
Table 2. Molecular weight of diblock copolymers and the photodecompositions
Mn
M /M
GPC
PEG
/wt %
Exposure dose
w
n
GPCa)
a)
¹2
NMR
UV
/J cm
1
1
1
1
1
1
1
1
1a
1b
1c
5700
7600
9300
7700
7600
10600
5400
6500
5340
7300
8740
8000
7800
10400
5300
6100
5500
7800
9100
11000
®
1.05
1.07
1.05
1.03
®
14.7
11.1
9.0
11.7
26.0
47.0
13.9
11.5
15
13
15
16
13
13
16
17
2
3a
3b
4a
4b
®
®
4900
6800
1.02
1.03
a) Determined by PS standards.
are shown in Table 3. This reaction gave the oxidative dimer of
the polystyrene derivative as a by-product in about 2% yield.
Nevertheless, compounds 14a¤ and 14b¤ were employed for the
following reaction without purification. Deprotection of the
trimethylsilyl group was carried out in the presence of TBAF
and acetic acid under similar conditions to those used for 9.
Dimerized polystyrene generated in the Michael reaction was
removed by column chromatography after this deprotection
step. Azido-terminated PEG was coupled with 14a¤¤ or 14b¤¤ by
Huisgen cycloaddition reaction to obtain 14a and 14b, which
were isolated by reprecipitation using methanol to remove
excess PEG. Although 14b contained 2% alkyne-dimers after
486 | Bull. Chem. Soc. Jpn. 2016, 89, 481–489 | doi:10.1246/bcsj.20150445
© 2016 The Chemical Society of Japan

Method B
CH3
CN
CH3
CH3O
O
O
CH3O
O
O
S
PolyB
CH3
CN
CH3
Et3N
CH3
CH
S
CH CH2 n
TBAF / acetic acid
dry THF
CH3
CH
2
+
SH CH CH2 n
Si
CH2
N
CH2
N
dry THF
NO2
O
NO2
O
1
4a' : Poly B = PS4000
4b' : Poly B = PS6000
14a'' : Poly B = PS4000
14b'' : Poly B = PS6000
1
CH3O
O
O
N
CH3
CH
S
PoyB
CH3 (OCHCH2)17 N3 / Cu(I)Br / PMDETA
dry DMF
14a : PolyA = PEG750, Poly B = PS4000
4b : PolyA = PEG750, Poly B = PS6000
CH2
1
CH3 (OCHCH2)17
N
N
N
NO2
O
Figure 5. Synthetic scheme of photodegradable diblock copolymer using 2 (Method B).
Table 3. Synthesis of diblock copolymers by Method B
Michael addition reaction
PHBR-PolyB
Huisgen cycloaddition reaction
PolyA-PHBR-PolyB
PolyB
Yield/%
PolyA
Yield/%
a)
b)
PS4000
PS6000
14a¤
14b¤
91
PEG750
PEG750
14a
14b
45
a)
b)
98
80
The desired product was isolated a) by reprecipitation, b) by column chromatography.
h
a
n
a
h
O
g
e
b
CH
e
d
i
f
CH
3
O
l
O e
CH
3
O
h
b
O
j
3
S
e
CH
2
CH
2
C O CH
2
CH
2
OCH
2
CH
2
16OCH
3
CH3
CH
g
S
b
CN
l
i
b
a
b
CH
2
O
CH N
d
b
2
CH O
f
N
CH
3
CH CH
2
CH 6
N
k
c
O
3
N
m
NO2
O
N
n
N
b
N
c
d
j
NO2
O
N
l
(b)
(a)
Figure 6. 1H NMR spectra of (A) 11b, (B) 14b.
purification, 14a with lower molecular weight was completely
purified by column chromatography (Figure S13). The results
are shown in Table 3. Photodegradable diblock copolymers
with a very narrow molecular weight distribution (M /M =
w n
1.03) by GPC measurement (Figure S13).
The molecular weights of 11a­11b, 12, 13a, 13b, 14a, and
1
1
were also synthesized in good yields by the use of 2. H NMR
14b determined by H NMR, UV, and GPC, and the molecular
spectra of 14b in CDCl are shown in Figure 6b, and that of
weight distributions measured by GPC, are shown in Table 2.
The molar absorbance coefficient of model compound 10
was used for determination of the molecular weight by UV
measurement. The molecular weights determined by different
methods are consistent, confirming that the molecular weight
of each block synthesized by living radical polymerization can
be controlled. Furthermore, hydrophilic PEG contents in the
3
1
4a is shown in Figure S14. Signals originated from PS,
PEG, and 2 were observed at 0.68­2.66, 3.38­3.98, and 5.48­
.18 ppm, confirming the structure of 14b. The molecular
6
weight of 14b was determined based on the integral ratio of
the peaks of PS and PEG (at 1.5 and 3.9 ppm) (Table 2). The
diblock copolymer 14b was found to be a single component
Bull. Chem. Soc. Jpn. 2016, 89, 481–489 | doi:10.1246/bcsj.20150445
© 2016 The Chemical Society of Japan | 487

CH O
O
CH
3
O
3
CH3
CH3
O
S
PolyB
O
hv
S
PolyB
CH
2
O
CH
N
CH
2
O
C
+
HN
PolyA
N
N
PolyA
N
N
NO
N
NO
2
O
N
O
(a)
(b)
Figure 7. Change of UV­vis spectra upon photoirradiation in THF (a) 11b, (b) 14b. The polymer solution was irradiated with near-
UV light for (bold line) 0 s (dotted line), 20 s (thin line), and 60 s.
polymer can be finely tuned by this approach. LCSTs of 13a
This work was financially supported by MEXT (No.
S1311032)-Supported Program for the Strategic Research
Foundation at Private Universities on “Creation of new fusion
materials by integration of highly-ordered nano inorganic
materials and ultra-precisely controlled organic polymers”.
and 13b determined according to previous papers3
9 °C, comparable to the value of 38 °C for PEG-b-PNIPAM
without a photocleavable linker, synthesized by ATRP from a
3,34
were
3
3
5
macroinitiator.
Photolysis of Diblock Copolymer. UV spectra of 11b, 14b
and the spectral change upon photoirradiation are shown in
Figure 7, and those of 11a, 11c, 12, 13a, 13b, and 14a are
shown in Figure S15. Photolysis of 11b was also confirmed
Supporting Information
Experimental section of end-functionalized polymer and
photodegradable diblock copolymer. H NMR and UV spectra
of 11a, 11c, 12, 13a, 13b, and 14a. GPC charts of 11a­11c,
14a, and 14b. This material is available on http://dx.doi.org/
10.1246/bcsj.20150445.
1
1
by H NMR (Figure 16S). The resulting diblock copolymers
(
11a­11c, 12, 13a, 13b, 14a, and 14b) had absorption maxima
at 340­347 nm, regardless of the molecular weight of the
polymer. Photodegradation of the diblock copolymer in THF
was observed, based on UV­vis spectral change. Photolysis of
diblock copolymer 13b synthesized from 1 has already been
reported in our previous paper.21 The absorption of 11b at 340
nm decreased with increased absorption at 371 nm (close to that
of the nitroso compound isolated from 10).21 Spectral changes
of 14b as well as 11a, 11c, 12, 13a, 13b, and 14a were similar
to those of 11b. Photolysis of the 2-nitrobenzylimide of 14b
is completed when the spectrum changes no further. Rates of
photolysis of 11b and 14b synthesized by different methods
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Bull. Chem. Soc. Jpn. 2016, 89, 481–489 | doi:10.1246/bcsj.20150445
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