Acrylamide-based copolymers bearing photoreleasable thiols for subsequent thiol-ene functionalization

Article abstract of DOI:10.1021/ma202670d

A new set of monomers is presented in order to incorporate thiols into radical polymers using a protecting chemistry/photocleavage route. The (co)polymerization kinetics of an o-nitrobenzyl thioether-containing acrylamide derivative are reported. The pres

Full text of DOI:10.1021/ma202670d

Article
pubs.acs.org/Macromolecules
Acrylamide-Based Copolymers Bearing Photoreleasable Thiols for
Subsequent Thiol−Ene Functionalization
Guillaume Delaittre,†,‡,§ Thomas Pauloehrl,†,§ Martin Bastmeyer,‡,§ and Christopher Barner-Kowollik*,†,§
†Preparative Macromolecular Chemistry, Institut fur Technische Chemie und Polymerchemie, Karlsruhe Institute of Technology
̈
(KIT), Engesserstr. 18, 76128 Karlsruhe, Germany
‡Zoologisches Institut, Zell- und Neurobiologie, Karlsruhe Institute of Technology, Haid-und-Neu-Str. 9, 76131 Karlsruhe, Germany
§Center for Functional Nanostructures (CFN), Karlsruhe Institute of Technology (KIT), Wolfgang-Gaede-Str. 1a, 76131 Karlsruhe,
Germany
S
* Supporting Information
ABSTRACT: A new set of monomers is presented in order to
incorporate thiols into radical polymers using a protecting
chemistry/photocleavage route. The (co)polymerization ki-
netics of an o-nitrobenzyl thioether-containing acrylamide
derivative are reported. The presence of the o-nitrobenzyl
moiety is found to strongly affect the polymerization.
Nevertheless, water-soluble copolymers with N,N-dimethyla-
crylamide (DMAAm) as a comonomer are obtained either by
free radical polymerization (10 000 ≤ Mn ≤ 17 500 g mol−1;
1.5 ≤ PDI ≤ 1.8) or by reversible addition−fragmentation
transfer (RAFT)-mediated controlled/living radical polymerization (2000 ≤ Mn ≤ 5700 g mol−1; 1.1 ≤ PDI ≤ 1.2).
Deprotection under UV light (λ = 366 nm) at ambient temperature is followed by UV/vis monitoring of the protecting group
release, which proceeds to completion between 40 min and 2 h within the studied range of concentration as demonstrated by 1H
NMR spectroscopy. Thiol−maleimide addition is subsequently carried out and found to proceed with a nearly quantitative yield
1
(ca. 90%) as measured by H NMR. Different block copolymers (9400 ≤ Mn ≤ 16 500 g mol−1; 1.3 ≤ PDI ≤ 1.4) with a
PDMAAm water-soluble block, a polystyrene hydrophobic block, or a poly(N-isopropylacrylamide) thermosensitive block as the
first segment and possessing the photoreleasable thiol moieties in the second block are subsequently synthesized by RAFT-
mediated polymerization. We finally demonstrate the orthogonal sequential deprotection and reaction with benzyl maleimide of
two different thiol species originating from the thiocarbonylthio functionality and the o-nitrobenzyl protected lateral groups,
respectively.
addition.4 Furthermore, they are also able to strongly bind to a
INTRODUCTION
The past 5 years have witnessed a significant growth of interest
■
wide range of metal surfaces, for instance, silver or gold.11
Radical polymerization is arguably the most versatile
polymerization technique since it is tolerant to most functional
in the use of click methodologies in polymer and materials
chemistry.1 Since macromolecules are difficult to quantitatively
groups. However, there are some exceptions and thiols are one
modify and bear multiple functional groups, the efficiency and
of them due to their large transfer constants in the
orthogonality of click reactions has indeed very often proven to
polymerization of vinyl monomers.12 Indeed, they are regularly
be useful.2 Although the most prominent technique was initially
employed to reduce the molecular weight or introduce a
the azide−alkyne cycloaddition,3 its generally required use of
copper as a catalyst has led to a gradual shift of attention toward
copper-free chemistries such as thiol−ene and thiol−yne
additions,4 (hetero) Diels−Alder [4 + 2] cycloaddition,5
some very efficient nucleophilic substitutions,6 oxime for-
mation,7 nitrile oxide−alkyne cycloaddition,8 or ring-opening of
epoxides.9 Copper-free synthetic methods are particularly
interesting when bio-related applications are envisioned.
Thiol-based click conjugations have shown to be very powerful
in various fields of application.10 Thiols can react very
efficiently with themselves to form disulfide bridges and with
electron-withdrawing group-substituted enes such as (meth)-
acrylates or maleimides via a radical pathway or Michael
specific functionality in radically prepared macromolecules.13
Consequently, sulfhydryl groups need to be introduced after
the polymerization or to be protected (or masked) when they
are initially present. For example, the pyridyl disulfide group
(PyDS) has been often incorporatedespecially when
bioapplications were targetedby using functional mono-
mers,14 initiators,15 or RAFT agents.16 PyDS has also been
attached by amidation to amino-containing polymers using N-
succinimidyl 3-(2-pyridyldithio)propionate.17 Matyjaszewski
Received: December 9, 2011
Revised: January 26, 2012
Published: February 8, 2012
© 2012 American Chemical Society
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Scheme 1. General Sequential Deprotection/Thiol−Ene Functionalization Strategy Applied to a RAFT Polymerization-Made
Block Copolymer Possessing the Protected Thiol Groups as a Comonomer Unit in One Block
and colleagues employed a bifunctional ATRP initiator
composed of a disulfide linker to obtain midchain-functional-
ized polystyrene (PS) which was eventually reduced by DTT to
yield PS-SH.18 Li et al. also introduced thiols using an alkyl
disulfide yet as a lateral group.19 Classical protecting-group
chemistry has also been employed to prepare ATRP
initiators20−22 or nitroxides23 bearing a thiol group which was
subsequently activated after functioning to mediate the
polymerization. In the case of RAFT-mediated controlled/
living polymerization thiocarbonylthio compounds are used as
controlling agent, but they can also be regarded as masked
thiols since methods such as aminolysis, hydrolysis, and metal
hydride reduction will lead to the mercapto-end-functionalized
chains.24
In the context of pure postpolymerization (i.e., the
incorporation of previously absent sulfur atoms), alkyl halides
such as ATRP-made polymers have been substituted using
thiourea to form isothiouronium salts which were subsequently
hydrolyzed to give thiol-capped polymers.25,26 Very recently,
Boyer et al. reported a nucleophilic substitution of Br-capped
polymers employing methanethiosulfonate followed by basic
hydrolysis27 while Paris and co-workers used potassium
thioacetate to obtain end-thiolated polymers via hydrolysis of
the intermediate thioester-capped chains.28
to generate well-defined block copolymers incorporating the
masked thiols in one block. Finally, sequential Michael addition
reactions are performed at the chain end after aminolysis of the
thiocarbonylthio moiety and along the chain after photo-
deprotection (Scheme 1).
EXPERIMENTAL SECTION
■
Materials. Cysteamine hydrochloride (98%, ABCR), 2-nitrobenzyl
bromide (98%, ABCR), lithium hydroxide (98%, Alfa Aesar), acryloyl
chloride (96%, Alfa Aesar), methacryloyl chloride (97%, ABCR),
triethylamine (TEA, 99+%, Merck), sodium hydrogen carbonate
(NaHCO3, 99%, Roth), 2-aminoethanol (99%, Fluka), tri-n-
butylphosphine (TBP, ≥90%, Fluka), dimethylphenylphosphine
(DMPP, 99%, Sigma-Aldrich), 1,4-dioxane (99+%, Acros), and
acetonitrile (HPLC grade, Acros) were used as received. Ethanol,
methanol, chloroform, ethyl acetate, toluene, and n-hexane were of all
from VWR (Normapur grade) and also used as received. 2,2′-
Azobisbutyronitrile (AIBN, 98%, Sigma-Aldrich) was recrystallized
twice from methanol and stored at −19 °C. N,N-Dimethylacrylamide
(DMAAm, 99%, Sigma-Aldrich) and styrene (99%, Acros) were
passed through a column of basic alumina (VWR) to remove the
inhibitor and stored at −19 °C. N-Isopropylacrylamide (NiPAAm)
was recrystallized twice from toluene/n-hexane 1:1 v/v. Dichloro-
methane (VWR, Normapur) was dried on 4 Å molecular sieves.
Dibenzyltrithiocarbonate (DBTTC)33 and benzyl maleimide34 were
synthesized according to previously reported procedures.
Protecting group chemistry is very often employed in pure
organic chemistry, particularly when complex structures are
targeted.29 It consists in the reversible protection of one or
several functional groups which can potentially react while
performing a modification meant to occur on another part of
the molecule. It also allows in some applications the activation
of specific functions when desired. While chemically driven
deprotections have been employed to a high extent in polymer
chemistry, the use of light-induced deprotection has been the
subject of much less attention. The phototriggered release of
chemical groups is very attractive as it allows not only for
temporal control of the reaction but also for its spatial control.
For instance, the o-nitrobenzyl group and its methoxy-
substituted derivatives have been often used, e.g., for polymer
functionalization,30 reversible bioconjugation,31 or surface
photopatterning.32
Monomer Synthesis. 2-((2-Nitrobenzyl)thio)ethanamine (1).
1
was synthesized according to a previously reported procedure.35
In a 150 mL beaker, lithium hydroxide (1.2506 g, 51.2 mmol)
was dissolved in deionized water (25 mL) and ethanol (75 mL)
was added. The resulting suspension was subsequently
introduced into a 250 mL double-necked round-bottom flask
containing cysteamine hydrochloride (2.9141 g, 25.1 mmol). A
150 mL dropping funnel was connected and filled with a
solution of 2-nitrobenzyl bromide (5.5214 g, 25.0 mmol) in
ethanol (100 mL). The solution was subsequently added
dropwise to the cysteamine mixture over a period of 15 min at
ambient temperature. The mixture was further stirred at 35 °C
for 40 min. Ethanol was removed by rotary evaporation, and
100 mL of deionized water was added. The heterogeneous
mixture was poured into a separating funnel and extracted with
dichloromethane (3 × 150 mL). The organic fractions were
combined, dried over sodium sulfate, filtered, and evaporated.
The residue was subsequently purified by flash column
chromatography using dichloromethane/methanol 4:1 to give
the pure product as a yellow viscous oil (3.5365 g, 67%). The
compound was rapidly used for further reactions since limited
degradation was observed upon storage. 1H NMR (CDCl3, 250
MHz, δ): 7.96 (d, 1H), 7.26−7.59 (m, 3H), 4.07 (s, 2H), 2.85
(t, 2H), 2.57 (t, 2H), 1.67 (s, 2H) ppm.
In the current study, we introduce two novel functional
monomers which bear a light-cleavable protected-thiol
substituent. The polymerizability of the acrylamide monomer
via a free radical mechanism is studied. Subsequently, the ability
of the so-formed copolymers to release thiols and undergo
Michael addition is evidenced. The RAFT process is then used
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N-(2-((2-Nitrobenzyl)thio)ethyl)acrylamide (2). In a 250 mL
double-necked round-bottom flask, 1 (3.5365 g, 16.7 mmol) and
triethylamine (2.80 mL, 19.8 mmol) were dissolved in dry dichloro-
methane (150 mL). A dropping funnel was connected to the flask and
filled with a solution of acryloyl chloride in dry dichloromethane (20.2
mmol in 30 mL). The flask was cooled to 0 °C, and the acryloyl
chloride solution was added dropwise under vigorous stirring over a
period of 30 min. The mixture was then allowed to warm to ambient
temperature and left to stir for another 15 h. After washing with 2 × 40
mL of brine and 40 mL of a NaHCO3-saturated solution, the organic
phase was dried over magnesium sulfate, filtered, and evaporated. The
residue was purified by flash column chromatography using chloro-
form/ethyl acetate 9:1 as an eluent to give an opaque yellow oil which
gave a yellow solid upon standing (3.5143 g, 79%). 1H NMR (CDCl3,
250 MHz, δ): 7.91 (d, 1H), 7.32−7.54 (m, 3H), 6.17 (dd, 1H), 6.10−
5.90 (broad, 1H), 6.03 (dd, 1H), 5.59 (dd, 1H), 4.02 (s, 2H), 3.42 (q,
2H), 2.58 (t, 2H) ppm.
ambient temperature. The polymer was recovered as a slightly yellow
powder by 2-fold precipitation in n-hexane at ambient temperature
(1H NMR, acetone-d6) ([2]/[M])polymer = 14 mol % (30 wt %).
Synthesis of the PDMAAm-TTC-PDMAAm MacroRAFT Agent (7).
In a 50 mL round-bottom flask, DMAAm (3.9607 g, 39.6 mmol),
DBTTC (0.2320 mg, 0.80 mmol), and AIBN (0.0522 g, 0.32 mmol)
were dissolved in 1,4-dioxane (15.9 mL). The mixture was
deoxygenated by purging with nitrogen over a period of 1 h. The
polymerization was triggered by immersing the flask into an oil bath
preheated to 70 °C. After 40 min, the polymerization was stopped by
cooling the flask to ambient temperature. 1H NMR analysis of the raw
mixture in CDCl3 indicated a conversion of 35%. The reaction mixture
was concentrated by rotary evaporation, and the polymer was obtained
as a yellow powder by 2-fold precipipation in n-hexane followed by
filtration on a glass filter. (SEC/DMAC) Mn = 3000 g mol−1; PDI =
1.10 (1H NMR, acetone-d6) Mn = 2600 g mol−1.
Synthesis of PDMAAm-b-P(DMAAm-co-2)-TTC-P(DMAAm-co-2)-
b-PDMAAm (8). In a 10 mL round-bottom flask, macroRAFT agent 7
(0.1081 g, 0.04 mmol), DMAAm (0.2153 g, 2.15 mmol), monomer 2
(0.1018 g, 3.82 mmol), and AIBN (0.0083 g, 0.05 mmol) were
dissolved in 5 mL of 1,4-dioxane. The mixture was deoxygenated by
purging with nitrogen over a period of 30 min. The polymerization
was triggered by immersing the flask into an oil bath preheated to 70
°C. After 16.5 h, the polymerization was stopped by cooling the flask
down to ambient temperature. 1H NMR analysis of the raw mixture in
CDCl3 indicated a conversion of 86%. The reaction mixture was
slightly concentrated under vacuum, and the polymer was obtained as
a light-yellow powder by 2-fold precipipation in n-hexane at ambient
temperature followed by filtration on a glass filter. (SEC/DMAC) Mn
= 8200 g mol−1; PDI = 1.32. (1H NMR, acetone-d6) ([2]/[M])polymer
= 11 mol % (25 wt %); Mn = 9400 g mol−1.
Synthesis of the PS-TTC-PS MacroRAFT Agent (9). In a 10 mL
round-bottom flask, AIBN (0.0420 g, 0.26 mmol) and DBTTC
(0.1483 g, 0.51 mmol) were dissolved in styrene (4.0083 g, 38.1
mmol). The mixture was deoxygenated by purging with nitrogen over
a period of 30 min. The polymerization was triggered by immersing
the flask into an oil bath preheated to 60 °C. After 7 h, the
polymerization was stopped by cooling the flask down to ambient
temperature. 1H NMR analysis of the raw mixture in acetone-d6
indicated a conversion of 33%. The reaction mixture was diluted with a
small volume of THF, and the polymer was obtained as a yellow
powder by 2-fold precipipation in cold methanol followed by filtration
on a glass filter. (SEC/DMAC) Mn = 3800 g mol−1; PDI = 1.12.
Synthesis of PS-b-P(DMAAm-co-2)-TTC-P(DMAAm-co-2)-b-PS
(10). In a 10 mL round-bottom flask, macroRAFT agent 9 (0.1567
g, 0.04 mmol), DMAAm (0.2153 g, 2.15 mmol), monomer 2 (0.1018
g, 3.82 mmol), and AIBN (0.0083 g, 0.05 mmol) were dissolved in 5
mL of 1,4-dioxane. The mixture was deoxygenated by purging with
nitrogen over a period of 30 min. The polymerization was triggered by
immersing the flask into an oil bath preheated to 70 °C. After 16.5 h,
the polymerization was stopped by cooling the flask down to ambient
temperature. 1H NMR analysis of the raw mixture in CDCl3 indicated
a conversion of 77%. The reaction mixture was slightly concentrated
under vacuum, and the polymer was obtained as a light-yellow powder
by 2-fold precipipation in n-hexane at ambient temperature followed
by filtration on a glass filter. (SEC/DMAC) Mn = 6500 g mol−1; PDI =
1.27. (1H NMR, acetone-d6) Mn = 9950 g mol−1.
Synthesis of the P(DMAAm-co-2)-TTC-P(DMAAm-co-2) macro-
RAFT Agent (11). In a 10 mL round-bottom flask, monomer 2 (0.2805
g, 1.05 mmol), DMAAm (0.6125 g, 6.12 mmol), DBTTC (0.0404 g,
0.14 mmol), and AIBN (0.0262 g, 0.16 mmol) were dissolved in 1,4-
dioxane (13.7 mL). The mixture was deoxygenated by purging with
nitrogen for 1 h and then immersed in an oil bath preheated to 70 °C.
After 5.5 h, the flask was cooled down to ambient temperature. A
monomer conversion of 50% was determined by 1H NMR. The
polymer was recovered as a light-yellow powder by 2-fold precipitation
in n-hexane at ambient temperature. (SEC/DMAC) Mn = 3800 g
mol−1; PDI = 1.10. (1H NMR, acetone-d6) Mn = 3800 g mol−1.
Synthesis of the P(DMAAm-co-2)-b-PNiPAAm-TTC-PNiPAAm-b-
P(DMAAm-co-2) (12). In a 10 mL round-bottom flask, macroRAFT
N-(2-((2-Nitrobenzyl)thio)ethyl)methacrylamide (3). The same
procedure as for 2 was employed, except that methacryloyl chloride
was used instead of acryloyl chloride. Briefly, 1 (0.8278 g, 3.9 mmol)
and triethylamine (0.53 mL, 4.0 mmol) were dissolved in dry
dichloromethane (70 mL). Subsequently, a solution of methacryloyl
chloride in dichloromethane (4.1 mmol in 15 mL) was slowly added.
After purification by flash column chromatography using chloroform/
ethyl acetate 9:1 as an eluent, 3 was obtained as a viscous yellow oil
(0.5542 g, 51%). 1H NMR (CDCl3, 250 MHz, δ): 7.91 (d, 1H), 7.54−
7.32 (m, 3H), 6.37−6.17 (broad, 1H), 5.64 (m, 1H), 5.27 (m, 1H),
4.02 (s, 2H), 3.40 (q, 2H), 2.59 (t, 2H), 1.90−1.88 (m, 3H) ppm.
Polymerizations. (Co)polymerizations of 2 and DMAAm. In a
10 mL round-bottom flask, monomer(s), AIBN, andif
necessaryDBTTC were dissolved in 1,4-dioxane. For a
collation of all polymerization conditions, please refer to Table
1. The mixture was deoxygenated by purging with nitrogen
over a period of 30 min. The polymerization was triggered by
immersing the flask into an oil bath preheated to 70 °C.
Samples were periodically withdrawn to follow the reaction
kinetics. A portion was diluted in CDCl3 to determine the
1
conversion by H NMR. Another portion was evaporated and
dissolved in DMAC (+ 1 wt % LiBr) for size-exclusion
chromatography analysis.
Table 1. Experimental Conditions of the
(Co)polymerizations at 70 °C in 1,4-Dioxane of N-(2-((2-
Nitrobenzyl)thio)ethyl) Acrylamide 2 and DMAAm
Reported in the Present Study
[M]/
[AIBN]
2:DMAAm
(mol/mol)
[DBTTC]/
[AIBN]
c
entry symbol
a
A
20
20
100:0
15:85
15:85
15:85
0:100
39:61
59:41
15:85
15:85
a
B
b
C
D
●
×
■
⧫
○
▲
□
100
50
b
b
E
F
50
b
50
b
b
G
50
H
50
2
1
b
I
50
a
b
c
[M] = 2.6 M. [M] = 0.5 M. The symbols noted in the Table refer
to Figures 1 and 2.
Synthesis of P(DMAAm-co-2) (4). Test polymer 4 was produced to
evaluate the possibility of thiol photodeprotection followed by thiol−
maleimide addition. The mixture was prepared according to entry B
(Table 1): In a 10 mL round-bottom flask, monomer 2 (0.2063 g, 0.77
mmol), DMAAm (0.4345 g, 4.34 mmol), and AIBN (0.0423 g, 0.26
mmol) were dissolved in 1,4-dioxane (2 mL). The mixture was
deoxygenated by purging with nitrogen for 30 min and then immersed
in an oil bath preheated to 70 °C. After 21 h, the flask was cooled to
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agent 11 (0.0385 g, 0.01 mmol), NiPAAm (0.2187 g, 1.93 mmol), and
AIBN (0.7 mg, 4 μmol) were dissolved in 1,4-dioxane (3 mL). The
mixture was deoxygenated by purging with nitrogen over a period of
30 min. The polymerization was triggered by immersing the flask into
an oil bath preheated to 70 °C. After 14 h, the polymerization was
residual protecting groups. (SEC/DMAC) Mn = 6200 g mol−1; PDI =
1.17.
Michael Addition on Fully Deprotected ω-((1-Benzyl-2,5-
dioxopyrrolidin-3-yl)thio)-PDMAAm-b-P(DMAAm-co-2) 15 (16). Co-
polymer 15 (32.7 mg, 35 μmol thiol groups), benzyl maleimide
(0.0818 g, 0.44 mmol), and DMPP (0.04 mg, 0.3 μmol) were
dissolved in acetonitrile (3 mL). The mixture was deoxygenated by
purging with nitrogen for 30 min, after which deoxygenated TEA (40
μL, 0.29 mmol) was added using a nitrogen-purged syringe. After 15 h,
1
stopped by cooling the flask down to ambient temperature. H NMR
analysis of the raw mixture in CDCl3 indicated a conversion of about
90%. The reaction mixture was concentrated by rotary evaporation,
and the polymer was obtained as a yellow powder by 2-fold
precipitation in n-hexane followed by filtration on a glass filter.
(SEC/DMAC) Mn = 16 500 g mol−1; PDI = 1.36.
Polymer-Analogue Modifications. Photodeprotection Kinetics.
Copolymer 4 was dissolved in acetonitrile at different
concentrations and transferred to a 1 cm square quartz cell.
The cell was placed 5 mm in front of a hand-held TLC lamp (8
W) and irradiated at 366 nm at ambient temperature. At timed
intervals the cuvette was placed in a UV spectrometer to
monitor the absorbance of the solution at 345 nm,
corresponding to the maximum of absorption of photoreleased
o-nitrosobenzaldehyde.
Synthesis of Fully Deprotected P(DMAAm-co-2) 4 (5). Copolymer
4 (0.1044 g, 0.12 mmol protected thiol groups) was dissolved in
acetonitrile (39 mL). The solution was transferred in three 15 mL
headspace vials (Pyrex, diameter 20 mm), which were airtight crimped
employing SBR seals with PTFE inner linear. The mixture was
deoxygenated by purging with nitrogen for 30 min. The vials were
placed 5 mm in front of a hand-held TLC lamp (8 W) and irradiated
at 366 nm at ambient temperature for 2.5 h. Polymer 5 was recovered
by precipitation in cold n-hexane (0.7740 g, 89%). 1H NMR in acetone
(see Figure 4) showed no trace of residual protecting groups.
Michael Addition on Fully Deprotected P(DMAAm-co-2) 5 (6).
Copolymer 5 (60 mg, 81 μmol thiol groups), benzyl maleimide
(0.2046 g, 1.29 mmol), and DMPP (0.1 mg, 0.7 μmol) were dissolved
in acetonitrile (4 mL). The mixture was deoxygenated by purging with
nitrogen for 30 min, after which deoxygenated TEA (100 μL, 0.72
mmol) was added using a nitrogen-purged syringe. After 15 h, polymer
6 was recovered by precipitation in cold n-hexane. 1H NMR in acetone
(see Figure 4) revealed a functionalization yield of 92%.
Synthesis of PDMAAm-b-P(DMAAm-co-2)-SH (13). In a 10 mL
round-bottom flask, 8 (0.5996 g, ca. 64 μmol according to Mn
determined by 1H NMR) was dissolved in acetonitrile (9.7 mL)
together with TBP (21 μL, 85 μmol). The resulting yellow mixture
was deoxygenated by purging with nitrogen for 30 min. Using a
nitrogen-purged syringe, deoxygenated 2-aminoethanol (49 μL, 0.81
mmol) was added. After stirring 18 h at ambient temperature, a pale
yellow solution was obtained. Polymer 13 was recovered by
precipitation in cold n-hexane. (SEC/DMAC) Mn = 7200 g mol−1;
PDI = 1.37.
1
copolymer 16 was recovered by precipitation in cold n-hexane. H
NMR in acetone (see Figure 6) revealed a functionalization yield of
89%. (SEC/DMAC) Mn = 8200 g mol−1; PDI = 1.35.
Characterizations. 1H NMR spectroscopy was carried out on either
a Bruker AM 250 or a Bruker AM 400 spectrometers at 250 or 400
MHz, respectively. The δ-scale is referenced to tetramethylsilane (δ =
0.00 ppm) as internal standard. Size-exclusion measurements were
performed on a Polymer Laboratories/Varian PLGPC 50 Plus system
comprising a Polymer Laboratories 5.0 mm bead-size guard column
(50 × 7.5 mm2), followed by three PL columns and a differential
refractive-index detector. The eluent was N,N′-dimethylacetamide
(DMAc) at 50 °C with a flow rate of 1 mL min−1. The SEC system
was calibrated using linear poly(styrene) (PS) standards ranging from
160 to 6 × 106 g mol−1 and linear poly(methyl methacrylate)
standards ranging from 700 to 2 × 106 g mol−1. The resulting
molecular weight distributions were determined by universal
calibration using Mark−Houwink parameters for PS (K = 14.1 ×
10−5 dL g−1, α = 0.70).36 Molecular weights relative to PS are reported
in the current contribution. UV/vis spectra were recorded on a Varian
Cary 300 Bio spectrophotometer.
RESULTS AND DISCUSSION
■
Monomer Synthesis. When a statistical copolymerization
is conducted, one usually prefers to use comonomers of a rather
similar electronic and steric structure. For the sake of versatility,
we thus synthesized two monomers starting from the same
substituent building block: one acrylamide for copolymeriza-
tions with other acrylamides or acrylates and one methacryla-
mide to use together with other methacrylamides or
methacrylates (see Scheme 2). It could be verified that these
Scheme 2. Synthetic Routes to Photocleavable Protected
a
Thiol-Containing Monomers
Synthesis of ω-((1-Benzyl-2,5-dioxopyrrolidin-3-yl)thio)-
PDMAAm-b-P(DMAAm-co-2) (14). In a 10 mL round-bottom flask,
13 (0.4200 g, ca. 89 μmol end-chain thiol groups according to Mn(8)
determined by 1H NMR) and benzyl maleimide (0.1029 g, 0.55
mmol) were dissolved in acetonitrile (11.1 mL). The resulting slightly
yellow solution was deoxygenated by purging with nitrogen for 40
min. Using a nitrogen-purged syringe, deoxygenated TBP (12 μL, 49
μmol) was added, followed 20 min later by TEA (45 μL, 0.33 mmol).
After 18 h polymer 14 was recovered by precipitation in cold n-hexane.
1H NMR in acetone (see Figure 6) revealed a functionalization yield of
a
Reagents and conditions: (i) LiOH, cysteamine hydrochloride, H2O/
EtOH, 35 °C; (ii) acryloyl chloride, triethylamine, DCM, 0 °C →
ambient temperature; (iii) methacryloyl chloride, triethylamine, DCM,
0 °C → ambient temperature.
two monomers were photosensitive since a clear change in their
UV−vis spectra was observed after irradiation at 366 nm (see
Figure S3). In the current study, we will focus on the
incorporation of these photoreactive monomers into various
macromolecular architectures.
Polymerizability of the o-Nitrobenzyl-Protected 2-
Mercaptoethyl (Meth)acrylamides. The following part is
dedicated to a study on the polymerizability of acrylamide 2.
Indeed, incorporating nitrobenzyl moieties via a prepolymeriza-
tion approach does not seem straightforward since these groups
95%. (SEC/DMAC) Mn = 8000 g mol−1; PDI = 1.24.
Synthesis of Fully Deprotected ω-((1-Benzyl-2,5-dioxopyrrolidin-
3-yl)thio)-PDMAAm-b-P(DMAAm-co-2) 14 (15). Copolymer 14 (90.7
mg, 85 μmol protected thiol groups) was dissolved in acetonitrile (30
mL). The solution was transferred into three 15 mL headspace vials
(Pyrex, diameter 20 mm), which were airtight crimped employing SBR
seals with PTFE inner linear. The mixture was deoxygenated by
purging with nitrogen for 30 min. The vials were placed 5 mm in front
of a hand-held TLC lamp (8 W) and irradiated at 366 nm at ambient
temperature for 2.5 h. Polymer 15 was recovered by precipitation in
cold n-hexane. 1H NMR in acetone (see Figure 6) showed no trace of
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are known to act as retarders or even inhibitors in free-radical
polymerization.37 Nevertheless, some examples can be found in
the literature. For instance, although they were unable to obtain
homopolymers, Voit and co-workers succeeded in incorporat-
ing N-nitroveratryloxycarbonyl-protected amines into methyl
methacrylate-based polymers.32a Gohy and co-workers reported
the successful controlled synthesis of homopolymers of
nitrobenzyl methacrylate by ATRP, however, only up to 30%
conversion.38 Recently, Grubbs and colleagues successfully
employed alkoxyamines bearing nitrobenzyl groups on both the
nitroxide and the initiating fragment sides to efficiently control
the free-radical polymerization of methyl methacrylate.39
We initially proceeded to homopolymerize 2 employing
conditions similar to those reported by Voit and colleagues
(Table 1, entry A). Contrary to their findings, we observed a
conversion of 34% after 24 h at 60 °C (Mn = 22 500 g mol−1;
PDI = 1.8). The experiment proves the polymerizability of 2,
yet higher conversions are usually desirable. It was thus decided
that a copolymerization approach was feasible, since in most
applications (e.g., bioconjugation or surface grafting) the
incorporation of few reactive groups along the polymer chain
is sufficient for the final purpose. An alternative acrylamide was
selected for this purpose, namely N,N-dimethylacrylamide
(DMAAm). Indeed its polymer has the advantage of being
organo- and water-soluble and to some extent biocompatible.40
We initially employed a molar ratio 2/DMAAm of 15:85 since
it represents a reasonable minimal amount of incorporated
groups. The copolymerizations were conducted at 70 °C in 1,4-
dioxane with two initial AIBN concentrations. With [M]/
[AIBN] = 100, the polymerization proceeded relatively slowly
and only reached 50% after 8 h (refer to Figure 1): a value at
Increasing the proportion of 2 and keeping the overall
monomer concentration constant resulted in significantly
decreased polymerization rates (refer to Figure 1). Examination
of the macromolecular characteristics also revealed a strong
impact of the nitrobenzene groups on the chain length. Indeed,
while molecular weights ranging from ca. 65 and 40 kg mol−1
were obtained for the homopolymerization of DMAAm, 3−4
times lower molecular weights were found when 15 mol % of 2
was present in the copolymerization mixture. For a given
conversion range, a continuous decrease of MW was observed
for an increase in [2] (see Figure 2).
Figure 2. (top) Evolution of the number-average molar masses vs
conversion for the free-radical and RAFT-mediated living/controlled
radical (co)polymerizations of 2 with DMAAm at 70 °C in 1,4-dioxane
with different initiator concentrations and comonomer mixture
compositions (see Table 1). (bottom) Corresponding polydispersity
indices. The dashed lines are drawn to guide the eye.
We additionally found that 3 was able to copolymerize with
methyl methacrylate (see Figure S4). However, the remainder
of our study will focus on the acrylamide derivative 2. The use
of 3 for obtaining polymethacrylamide-based polymers will be
the subject of a future publication.
Figure 1. Evolution of the global monomer conversion vs time for the
free-radical (co)polymerization of 2 with DMAAm at 70 °C in 1,4-
dioxane with variable initiator concentrations and comonomer mixture
compositions (see Table 1). The dashed lines are drawn to guide the
eye.
In addition to providing a means to calculate the overall
1
monomer conversion, monitoring by H NMR revealed that
which a conversion plateau was observed. Using a higher
concentration of radical initiator ([M]/[AIBN] = 50)
permitted to convert 92% of the monomer mixture into
polymer in ca. 20 h (Figure 1). Subsequently, the initiator
concentration was kept constant and the monomer mixture
composition was varied (see Table 1). When DMAAm was
reacted alone, the polymerization proceeded relatively rapidly
with more than 90% of the monomer being consumed in 4 h.
the incorporation of 2 was rather similar to that of DMAAm.
Particularly, purified copolymer 4 (Scheme 3), obtained at the
highest monomer conversion (92%, entry D), revealed that the
o-nitrobenzyl thioether moieties remained intact throughout
the polymerization and that the comonomer ratio in the
copolymer was rather similar to the comonomer feed, 14:86
and 15:85, respectively (see Figure S5). Consequently, we
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Scheme 3. Photodeprotection of P(DMAAm-co-2)
Copolymer at 366 nm Followed by Base-Catalyzed Michael
Addition with Benzyl Maleimide
Figure 3. Normalized evolution of the absorbance at 345 nm of
copolymer 4 (P(DMAAm86-co-214)) solutions in acetonitrile vs time of
irradiation at 366 nm at ambient temperature for different
−1
■
●
▲
concentrations: 0.35 ( ), 1 ( ), and 3 g L ( ). The dashed
lines are drawn to guide the eye.
evaluated the possibility of releasing thiols along the polymer
chains and of subsequently reacting them with Michael
acceptors such as maleimide derivatives.
originating from the maleimide derivative: one at 4.65 ppm
accounting for the methylene protons in the α-position of the
benzyl ring and one between 7.15 and 7.45 ppm representing
the aromatic protons. The absence of ethylenic protons at 6.65
ppm confirms that all excess maleimide was efficiently removed
during purification and that the two aforementioned peaks are
contributions solely due to grafted benzyl maleimide. Taking as
a reference the side chain protons between 2.2 and 3.8 ppm and
comparing the aromatic protons of 6 to those of the protected
copolymer 4, we calculate a global deprotection/functionaliza-
tion sequence yield of 92%.
After having evidenced the efficiency of our system, we
focused on obtaining better-defined architectures such as
amphiphilic and thermosensitive block copolymers exhibiting
the photocleavable group in the hydrophilic block, which could
be of interest to construct surface-reactive nanoparticles,42
nanovesicles,43 or nanogels.44
Well-Defined Macromolecular Architectures. Although
nitroxide-mediated polymerization could have been chosen
since alkoxyamines are efficient controlling agents in radical
polymerization of acrylamides,45 we opted for reversible-
addition−fragmentation transfer (RAFT) polymerization since
we had in mind that the thiocarbonylthio moiety present at the
end or in the middle of RAFT polymers could provide an
additional and orthogonal source of thiols.24 Furthermore,
ATRP of acrylamide derivatives is not straightforward.46 We
employed dibenzyl trithiocarbonate (DBTTC) as RAFT agent
since trithiocarbonates allow to efficiently mediate the radical
polymerization of acrylamides.47
Two kinetic runs were performed using the best conditions
found for the free-radical copolymerization of 2 and DMAAm,
i.e., giving the highest conversion (entry D). Each experiment
was performed with a different concentration of RAFT agent
corresponding to [DBTTC]/[AIBN] = 2 or 1 respectively for
entries H and I. As expected, in the case of an ideal chain
transfer mechanism, the polymerization rate was not affected by
the presence of the RAFT agent as conversion vs time plots for
entries H and I were very similar to that of entry D (see Figure
S8). However, the macromolecular characteristics were strongly
altered (refer to Figure 2). Polymers with much lower
Deprotection and Subsequent Functionalization. The
deprotection reaction was performed using a simple hand-held
UV lamp (8 W) generally used in laboratories to read TLC
plates. The irradiation was carried out at ambient temperature
in acetonitrile at 366 nm (refer to Scheme 3), where the
absorbance of the polymer due to the presence of the o-
nitrobenzyl groups is substantial (see Figure S6). Although
irradiation at lower wavelengths (UV-C) would probably favor
a faster deproctection due to a relatively higher absorbance, we
reasoned that the employment of UV-A radiation was more
promising in view of potential bioapplications. The drawback is
that the photoreleased o-nitrosobenzaldehyde possesses a
maximum of absorbance at 345 nm.41 It is thus necessary to
work under diluted conditions: a polymer concentration of a
few g L−1, which is in fact a typical concentration range in
biochemistry.
For a concentration of 3 g L−1 of copolymer 4 (3.4 mM) the
absorbance at 345 nm does not show any further change after
1
being irradiated for ∼2 h. H NMR analysis of the purified
polymer indicates that at this stage quantitative deprotection is
achieved. Indeed, the spectrum of copolymer 5 (Figure 4,
middle spectrum) shows no more distinct aromatic peaks, and
the signal at ca. 4 ppm accounting for the methylene protons
bound to the carbon bridging the sulfur atom and the benzyl
ring in copolymer 4 completely disappeared.
Figure 3 clearly evidences the influence of the concentration
on the deprotection kinetics. While quantitative deprotection
was achieved in about 2 h at 3 g L−1, only 25 min was sufficient
to reach 97% deprotection at 0.35 g L−1.
After purification by precipitation, the fully deprotected
copolymer 5 was subsequently subjected to reaction with
benzyl maleimide in presence of a catalytic amount of
dimethylphenylphosphineacting as a reducing agent to
suppress disulfide bridgingand triethylamine as basic catalyst.
The reaction was performed at ambient temperature overnight.
After removal of the excess maleimide and catalysts, copolymer
1
6 was recovered and analyzed by H NMR (Figure 4, see
bottom spectrum). Two new peaks could be observed, both
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Figure 4. 1H NMR spectra of purified copolymers after, from top to bottom, free-radical copolymerization of 2 with DMAAm (4),
photodeprotection of a 3 g L−1 solution of 4 for 2 h (5), and reaction of 5 with benzyl maleimide (6).
Figure 5. Synthesis of functional triblock copolymers by RAFT-mediated polymerization exhibiting the o-nitrobenzyl-protected thiols in either their
inner (top and middle rows) or their outer (bottom row) block(s).
molecular weights ranging between 2000 and 5000 g mol−1 and
polydispersity indices between 1.06 and 1.21 were identified by
size-exclusion chromatography. Particularly, the progressive
complete shift of the SEC traces with increasing monomer
conversion demonstrated the controlled character of the
polymerization (see Figure S9). Using PDMAAm or PS
macromolecular RAFT agents 7 and 9, respectively, allowed
us to synthesize well-defined bishydrophilic and amphiphilic
block copolymers, respectively (Figure 5). In each case, triblock
copolymers comprising a middle block possessing the protected
thiol units were obtained with rather low polydispersities, i.e.,
1.32 and 1.27 for copolymers 8 and 10, respectively. To further
prove the living character of copolymers of 2 and DMAAm
obtained in the presence of DBTTC, we synthesized
P(DMAAm-co-2) macromolecular RAFT agent 11 using
conditions similar to those of entry H (Table 1) and stopped
the polymerization at a monomer conversion of 0.5 (Figure 5).
We subsequently performed the RAFT polymerization of N-
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isopropylacrylamide (NiPAAm) in the presence of 11 and
AIBN at 70 °C in 1,4-dioxane. The targeted degree of
polymerization of the PNiPAAm block was purposely set at a
high value (ca. 200) and the polymerization performed to a
high monomer conversion (95%) to clearly evidence the
consumption of 11. The overlay of the SEC traces of 11 and of
the corresponding product of the NiPAAm RAFT-mediated
polymerization (Figure 5, bottom right) shows a distinct shift
toward higher molecular weights together with a shoulder and a
tail, both at lower molecular weights. The latter certainly
originates from dead chains present in macroRAFT agent 11,
while the nonsymmetrical distribution may have arisen from
irreversible termination by recombination, highly possible for
polymerization of acrylamide derivatives at high conversion.
With the synthesis of copolymers by RAFT-mediated
polymerization, we had not only in mind to produce well-
defined (block) copolymers but also to introduce an additional
masked thiol moiety. Indeed, aminolysis of the thiocarbonylthio
compounds eliminates the RAFT end or middle group to yield
ω-mercapto polymers (see Introduction). We envisaged that it
should be possible to orthogonally deprotect/functionalize
both types of thiols in a sequential manner. We thus reacted the
block copolymer 8 with 2-aminoethanol in acetonitrile at
ambient temperature in presence of tri-n-butylphosphine as a
reducing agent (see Scheme 4). The effectiveness of the
reaction can be assessed via both SEC and UV/vis spectros-
copy. Although the number-average molecular weight of
polymer 13 was not the half of that 8which can be explained
by a nonsymmetrical structure or potential disulfide coupling as
suggested by the increase in polydispersitythe successful
removal of the trithiocarbonate moiety could be evidenced by
disappearance of its characteristic UV absorbance maximum at
∼310 nm (see Figure S10). 1H NMR performed on the purified
diblock copolymer 13 showed that the o-nitrobenzyl protecting
group was insensitive to the aminolysis process (Figure 6,
second row).
Scheme 4. Synthetic Strategy for the Orthogonal Double
Thiol-Maleimide Michael Addition via Sequential
Aminolysis of the Thiocarbonylthio Moieties and o-
Nitrobenzylthioether UV Deprotection
The released end-chain thiol functionality present in
copolymer 13 was subsequently reacted with benzyl maleimide
employing conditions previously described for the Michael
addition on the deprotected thiol lateral groups of free-radical
polymer 4 to produce benzyl maleimidothioether-capped
1
copolymer 14. A similar yield of 95% was calculated by H
NMR (refer to Figure 6). The purified copolymer 14 was then
subjected to the same treatment as copolymer 4, i.e., UV
irradiation at 366 nm for 2 h to quantitatively produce
copolymer 15 bearing multiple lateral thiol groups followed by
triethylamine-catalyzed Michael addition with benzyl maleimide
at ambient temperature to yield copolymer 16. Again, a similar
thiol−ene reaction yield of 89% was calculated from the relative
integration of the aromatic protons signal to that of other
lateral group protons between 2.2 and 3.8 ppm. Finally, it is
important to note that the integrity of the well-defined
polymeric backbones was maintained throughout all the
consecutive modifications as demonstrated by similar molecular
weight distributions (1.17 ≤ PDI ≤ 1.25) within a similar
molecular weight range (7200 ≤ Mn ≤ 8200 g mol−1) for
copolymers 13, 14, 15, and 16. However, it remains difficult to
draw any numerical interpretation due to the different nature of
these copolymers and thus a different hydrodynamic behavior
in size-exclusion chromatography.
CONCLUSIONS
■
The synthesis of two new (meth)acrylamide derivatives bearing
a UV-sensitive o-nitrobenzyl protected thiol group is reported.
Despite the disturbing nature of the o-nitrobenzyl group in free-
radical processes which retards the polymerization, it was
possible to obtain statistical copolymers with N,N-dimethyla-
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Figure 6. 1H NMR spectra of purified copolymers after, from top to bottom, RAFT-mediated copolymerization of 2 with DMAAm (8), aminolysis
of 8 (13), capping of end-chain released thiol by benzyl maleimide (14), photodeprotection of 14 for 2 h (15), and reaction of 15 with benzyl
maleimide (16).
crylamide (DMAAm) in relatively high yields with an
appropriate design of the reaction conditions. The protecting
group remained intact throughout the polymerization process
and could thus be used to trigger the release of multiple thiol
groups along polymeric chains by UV irradiation. The
deprotection rate was found to be concentration-dependent,
probably due to the strongly absorbing nature of the
photoreleased caging group in the irradiation wavelength
domain. Nevertheless, full deprotection and close-to-quantita-
tive subsequent thiol-maleimide functionalization (92%) could
be achieved. In a further effort to create well-defined functional
polymeric materials, RAFT-mediated polymerization was
utilized to produce block copolymers possessing one statistical
block consisting of DMAAm units and the protected thiol
acrylamide derivative as a first segment and hydrophilic
PDMAAm, hydrophobic polystyrene, or thermosensitive poly-
(N-isopropylacrylamide) as a second one. Importantly, a
PDMAAm-based block copolymer was employed to demon-
strate the effective orthogonal double deprotection/Michael
addition of thiols originating from aminolyzed RAFT
thiocarbonylthio midchain group and light-cleavable o-nitro-
benzylthioether lateral groups, with high efficiency (95 and
89%, respectively).
ASSOCIATED CONTENT
* Supporting Information
■
S
Additional NMR spectra, UV/vis absorption curves, and SEC
traces. This material is available free of charge via the Internet
at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: christopher.barner-kowollik@kit.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
C.B.-K. acknowledges financial support from the Karlsruhe
Institute of Technology (KIT) in the context of the Excellence
■
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(14) (a) Nagel, B.; Gajovic-Eichelmann, N.; Scheller, F. W.; Katterle,
M. Langmuir 2010, 26, 9088. (b) Crownover, E. F.; Convertine, A. J.;
Stayton, P. S. Polym. Chem. 2011, 2, 1499.
(15) (a) Bontempo, D.; Heredia, K. L.; Fish, B. A.; Maynard, H. D. J.
Am. Chem. Soc. 2004, 126, 15372. (b) Heredia, K. L.; Bontempo, D.;
Ly, T.; Byers, J. T.; Halstenberg, S.; Maynard, H. D. J. Am. Chem. Soc.
2005, 127, 16955. (c) Iwasaki, Y.; Omichi, Y.; Iwata, R. Langmuir
Initiative for leading German universities as well as the German
Research Council (DFG) and the Ministry of Science and Arts
of the state of Baden-Wurttemberg. G.D. thanks the Alexander
̈
von Humboldt Foundation for financial support via a Humboldt
Research Fellowship for Postdoctoral Researchers. T.P.’s Ph.D.
studies are funded by the Fonds der Chemischen Industrie.
́
2008, 24, 8427. (d) Vazquez-Dorbatt, V.; Tolstyka, Z. P.; Chang, C.-
REFERENCES
W.; Maynard, H. D. Biomacromolecules 2009, 10, 2207.
(16) (a) Liu, J.; Bulmus, V.; Barner-Kowollik, C.; Stenzel, M. H.;
Davis, T. P. Macromol. Rapid Commun. 2007, 28, 303. (b) Boyer, C.;
Liu, J.; Wong, L.; Tippett, M.; Bulmus, V.; Davis, T. P. J. Polym. Sci.,
Part A: Polym. Chem. 2008, 46, 7207. (c) Chang, C.-W.; Nguyen, T.
H.; Maynard, H. D. Macromol. Rapid Commun. 2010, 31, 1691.
(17) van Dijk-Wolthuis, W. N. E.; van de Wetering, P.; Hinrichs, W.
L. J.; Hofmeyer, L. J. F.; Liskamp, R. M. J.; Crommelin, D. J. A.;
Hennink, W. E. Bioconjug. Chem. 1999, 10, 687.
■
(1) (a) Hawker, C. J.; Wooley, K. L. Science 2005, 309, 1200.
(b) Binder, W. H.; Sachsenhofer, R. Macromol. Rapid Commun. 2007,
28, 15. (c) Barner-Kowollik, C.; Inglis, A. J. Macromol. Chem. Phys.
2009, 210, 987. (d) Iha, R. K.; Wooley, K. L.; Nystrom, A. N.; Burke,
D. J.; Kade, M. J.; Hawker, C. J. Chem. Rev. 2009, 109, 5620. (e) Golas,
P. L.; Matyjaszewski, K. Chem. Soc. Rev. 2010, 39, 1338. (f) Sumerlin,
B. S.; Vogt, A. P. Macromolecules 2010, 43, 1. (g) Barner-Kowollik, C.;
Du Prez, F. E.; Espeel, P.; Hawker, C. J.; Junkers, T.; Schlaad, H.; Van
Camp, W. Angew. Chem., Int. Ed. 2011, 50, 60.
(18) Tsarevsky, N. V.; Matyjaszewski, K. Macromolecules 2002, 35,
9009.
(2) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004.
(19) Li, L.; Jiang, X.; Zhuo, R. J. Polym. Sci., Part A: Polym. Chem.
2009, 47, 5989.
(3) (a) Meldal, M.; Tornøe, C. W. Chem. Rev. 2008, 108, 2952.
(b) Lutz, J.-F. Angew. Chem., Int. Ed. 2007, 46, 1018. (c) Dirks, A. J.;
Cornelissen, J. J. L. M.; van Delft, F. L.; van Hest, J. C. M.; Nolte, R. J.
M.; Rowan, A. E.; Rutjes, F. P. J. T. QSAR Comb. Sci. 2007, 26, 1200.
(d) Meldal, M. Macromol. Rapid Commun. 2008, 29, 1016.
(e) Lundberg, P.; Hawker, C. J.; Hult, A.; Malkoch, M. Macromol.
(20) Carrot, G.; Hilborn, J.; Hedrick, J. L.; Trollsas, M. Macro-
̊
molecules 1999, 32, 5171.
(21) Ye, M.; Zhang, D.; Han, L.; Tejada, J.; Ortiz, C. Soft Matter
2006, 2, 243.
(22) Javakhishvili, I.; Hvilsted, S. Biomacromolecules 2009, 10, 74.
(23) Hill, N. L.; Jarvis, J. L.; Pettersson, F.; Braslau, R. React. Funct.
Polym. 2008, 68, 361.
(24) (a) Barner, L.; Perrier, S. In Handbook of RAFT Polymerization;
Barner-Kowollik, C.; Wiley-VCH: Weinheim, 2008; p 455. (b) Will-
cock, H.; O’Reilly, R. K. Polym. Chem. 2010, 1, 149. (c) Moad, G.;
Rizzardo, E.; Thang, S. H. Polym. Int. 2011, 60, 9.
(25) Garamszegi, L.; Donzel, C.; Carrot, G.; Nguyen, T. Q.; Hilborn,
J. React. Funct. Polym. 2003, 55, 179.
(26) Uygun, M.; Tasdelen, M. A.; Yagci, Y. Macromol. Chem. Phys.
2010, 211, 103.
(27) Boyer, C.; Soeriyadi, A. H.; Roth, P. J.; Whittaker, M. R.; Davis,
T. P. Chem. Commun. 2011, 47, 1318.
(28) Liras, M.; García, O.; Quijada-Garrido, I.; París, R. Macro-
Rapid Commun. 2008, 29, 998. (f) Aragao-Leoneti, V.; Campo, V. L.;
̃
Gomes, A. S.; Field, R. A.; Carvalho, I. Tetrahedron 2010, 66, 9475.
(4) (a) Hoyle, C. E.; Bowman, C. N. Angew. Chem., Int. Ed. 2010, 49,
1540. (b) Hoogenboom, R. Angew. Chem., Int. Ed. 2010, 49, 3415.
(c) Hoyle, C. E.; Lowe, A. B.; Bowman, C. N. Chem. Soc. Rev. 2010,
39, 1355.
(5) (a) Sinnwell, S.; Inglis, A. J.; Davis, T. P.; Stenzel, M. H.; Barner-
Kowollik, C. Chem. Commun. 2008, 2052. (b) Inglis, A. J.; Sinnwell, S.;
Stenzel, M. H.; Barner-Kowollik, C. Angew. Chem., Int. Ed. 2009, 48,
2411. (c) Nebhani, L.; Gerstel, P.; Atanasova, P.; Bruns, M.; Barner-
Kowollik, C. J. Polym. Sci., Polym. Chem. 2009, 47, 7090. (d) Paulohrl,
̈
T.; Inglis, A. J.; Barner-Kowollik, C. Adv. Mater. 2010, 22, 2788.
(e) Inglis, A. J.; Nebhani, L.; Altintas, O.; Schmidt, F.-G.; Barner-
Kowollik, C. Macromolecules 2010, 43, 5515. (f) Goldmann, A. S.;
Tischer, T.; Barner, L.; Bruns, M.; Barner-Kowollik, C. Biomacromo-
lecules 2011, 12, 1137.
molecules 2011, 44, 1335.
(29) Greene’s Protective Groups in Organic Synthesis; Wuts, P. G. M.,
Greene, T. W., Eds.; John Wiley and Sons: New York, 2007.
(30) Pauloehrl, T.; Delaittre, G.; Bastmeyer, M.; Barner-Kowollik, C.
Polym . Chem. 2012, DOI: 10.1039/C1PY00372K.
(31) (a) Kostiainen, M. A.; Smith, D. K.; Ikkala, O. Angew. Chem., Int.
Ed. 2007, 46, 7600−7604. (b) Kostiainen, M. A.; Kasyutich, O.;
Cornelissen, J. J. L. M.; Nolte, R. J. M. Nature Chem. 2010, 2, 394−
399.
(32) (a) Braun, F.; Eng, L.; Trogisch, S.; Voit, B. Macromol. Chem.
Phys. 2003, 204, 1486. (b) Ryan, D.; Parviz, B. A.; Linder, V.; Semetey,
V.; Sia, S. K.; Su, J.; Mrksich, M.; Whitesides, G. M. Langmuir 2004,
20, 9080. (c) Brown, A. A.; Azzaroni, O.; Huck, W. T. S. Langmuir
2009, 25, 1744.
(33) (a) Aoyagi, B.; Endo, T. J. Polym. Sci., Part A: Polym. Chem.
2009, 47, 3702. (b) Bivigou-Koumba, A. M.; Kristen, J.; Laschewsky,
A.; Mueller-Buschbaum, P.; Papadakis, C. M. Macromol. Chem. Phys.
2009, 210, 565.
(34) Clevenger, R. C.; Turnbull, K. D. Synth. Commun. 2000, 30,
1379.
(6) (a) Ott, C.; Hoogenboom, R.; Schubert, U. S. Chem. Commun.
2008, 3516. (b) Becer, C. R.; Babiuch, K.; Pilz, D.; Hornig, S.; Heinze,
T.; Gottschaldt, M.; Schubert, U. S. Macromolecules 2009, 42, 2387.
(c) Babiuch, K.; Becer, C. R.; Gottschaldt, M.; Delaney, J. T.; Weisser,
J.; Beer, B.; Wyrwa, R.; Schnabelrauch, M.; Schubert, U. S. Macromol.
Biosci. 2011, 11, 535.
(7) (a) Li, R. C.; Broyer, R. M.; Maynard, H. D. J. Polym. Sci., Part A:
Polym. Chem. 2006, 44, 5004. (b) Heredia, K. L.; Maynard, H. D. Org.
Biomol. Chem. 2007, 5, 45. (c) Heredia, K. L.; Tolstyka, Z. P.;
Maynard, H. D. Macromolecules 2007, 40, 4772. (d) Kopping, J. T.;
Tolstyka, Z. P.; Maynard, H. D. Macromolecules 2007, 40, 8593.
(e) Christman, K. L.; Broyer, R. M.; Schopf, E.; Kolodziej, C. M.;
Chen, Y.; Maynard, H. D. Langmuir 2011, 27, 4715.
(8) (a) Singh, I.; Zarafshani, Z.; Lutz, J.-F.; Heaney, F. Macromolecules
2009, 42, 5411. (b) Singh, I.; Zarafshani, Z.; Heaney, F.; Lutz, J.-F.
Polym. Chem. 2011, 2, 372.
(9) Tsarevsky, N. V.; Bencherif, S. A.; Matyjaszewski, K. Macro-
molecules 2007, 40, 4439.
(35) Gosh, S.; Tochtrop, G. P. Tetrahedron Lett. 2009, 50, 1723.
(36) Strazielle, C.; Benoit, H.; Vogl, O. Eur. Polym. J. 1978, 14, 331.
(37) Bajpai, U. D. N.; Bajpai, A. K.; Bajpai, J. J. Appl. Polym. Sci. 1991,
42, 2005.
(10) Kade, M. J.; Burke, D. J.; Hawker, C. J. J. Polym. Sci., Part A:
Polym. Chem. 2010, 48, 743.
(11) Love, J. C.; Estroff, L. A.; Kriebel, J. K.; Nuzzo, R. G.;
Whitesides, G. M. Chem. Rev. 2005, 105, 1103.
(38) Schumers, J.-M.; Fustin, C.-A.; Can, A.; Hoogenboom, R.;
Schubert, U. S.; Gohy, J.-F. J. Polym. Sci., Part A: Polym. Chem. 2009,
47, 6504−6513.
(39) Greene, A. C.; Grubbs, R. B. Macromolecules 2010, 43, 10320.
(40) Nakayama, Y.; Matsuda, T. Langmuir 1999, 15, 5560.
(12) Ueda, A.; Nagai, S. In Polymer Handbook, 4th ed.; Brandrup, J.,
Immergut, E. H., Grulke, E. A., Eds.; Wiley: New York, 1999; p II/97.
(13) Chiefari, J.; Rizzardo, E. In Handbook of Radical Polymerization,
2nd ed.; Matyjaszewski, K., Davis, T. P., Eds.; John Wiley and Sons:
New York, 2002; p 629.
1801
dx.doi.org/10.1021/ma202670d | Macromolecules 2012, 45, 1792−1802

Macromolecules
Article
(41) (a) Il’ichev, Y. V.; Schworer, M. A.; Wirz, J. J. Am. Chem. Soc.
̈
2004, 126, 4581. (b) Marriott, G.; Miyata, H.; Kinosita, K. Biochem.
Int. 1992, 26, 943.
(42) (a) Nagasaki, Y.; Okada, T.; Scholz, C.; Iijima, M.; Kato, M.;
Kataoka, K. Macromolecules 1998, 31, 1473. (b) Lu, J.; Shi, M.;
Shoichet, M. S. Bioconjugate Chem. 2008, 20, 87. (c) Nicolas, N.;
Bensaid, F.; Desmaele, D.; Grogna, M.; Detrembleur, C.; Andrieux, K.;
̈
Couvreur, P. Macromolecules 2008, 41, 8418. (d) Bae, J. W.; Lee, E.;
Park, K. M.; Park, K. D. Macromolecules 2009, 42, 3437. (e) Delaittre,
G.; Justribo-
Macromol. Rapid Commun. 2011, 32, 19.
́ ́
Hernandez, G.; Nolte, R. J. M.; Cornelissen, J. J. L. M.
(43) Opsteen, J. A.; Brinkhuis, R. P.; Teeuwen, R. L. M.; Lowik, D.
̈
W. P. M.; van Hest, J. C. M. Chem. Commun. 2007, 3136.
(44) Meng, Z.; Hendrickson, G. R.; Lyon, L. A. Macromolecules 2009,
42, 7664.
(45) Delaittre, G.; Rieger, J.; Charleux, B. Macromolecules 2011, 44,
462 and references therein.
(46) (a) Teodorescu, M.; Matyjaszewski, K. Macromolecules 1999, 32,
4826. (b) Rademacher, J. T.; Baum, M.; Pallack, M. E.; Brittain, W. J.;
Simonsick, W. J. Macromolecules 1999, 33, 284. (c) Xia, Y.; Yin, X.;
Burke, N. A. D.; Stover, H. D. H. Macromolecules 2005, 38, 5937.
̈
(47) (a) Moad, G.; Rizzardo, E.; Thang, S. H. Aust. J. Chem. 2005, 58,
379. (b) Favier, A.; Charreyre, M.-T. Macromol. Rapid Commun. 2006,
27, 653.
1802
dx.doi.org/10.1021/ma202670d | Macromolecules 2012, 45, 1792−1802