Combining RAFT and staudinger ligation: A potentially new synthetic tool for bioconjugate formation

Article abstract of DOI:10.1021/ma2000724

We report a new route for biocompatible polymer end-group modification by means of the Staudinger ligation. This reaction allows the formation of a peptide bond in aqueous media between a phosphine-containing ester functionality and an azide group. Esterification of the two carboxylic acid-containing chain transfer agents (CTAs), 2-(dodecylsulfanylthiocarbonylsulfanyl)-2- methylpropionic acid (1) and 4-cyano-4-(dodecylsulfanylthiocarbonylsulfanyl) pentanoic acid (2), with different appropriate phosphines gave phosphine-containing CTAs. They allowed us to synthesize polystyrene of medium molecular weight via "reversible addition-fragmentation chain transfer" (RAFT) polymerization. 3,6,9-Trioxodecyl azide (TOD-N ₃) was then used as model compound to study the Staudinger ligation with the corresponding polymers. Among all CTAs tested, the phosphine- functionalized CTA-4, prepared from 2 and P-borane-(diphenylphosphanyl) methanethiol (6), not only proved to be suitable for RAFT polymerization of styrene but the polymer-bound P-borane-(diphenylphosphanyl)methyl thioester group also showed the best performance in the subsequent polymer analogous Staudinger ligation.

Full text of DOI:10.1021/ma2000724

ARTICLE
pubs.acs.org/Macromolecules
Combining RAFT and Staudinger Ligation: A Potentially
New Synthetic Tool for Bioconjugate Formation
Robert P€otzsch, Sven Fleischmann,† Christian Tock,‡ Hartmut Komber, and Brigitte I. Voit*
Leibniz Institute of Polymer Research Dresden, Hohe Strasse 6, 01069 Dresden, Germany
S Supporting Information
b
ABSTRACT: We report a new route for biocompatible polymer
end-group modification by means of the Staudinger ligation.
This reaction allows the formation of a peptide bond in aqueous
media between a phosphine-containing ester functionality and
an azide group. Esterification of the two carboxylic acid-con-
taining chain transfer agents (CTAs), 2-(dodecylsulfanylthio-
carbonylsulfanyl)-2-methylpropionic acid (1) and 4-cyano-
4-(dodecylsulfanylthiocarbonylsulfanyl)pentanoic acid (2), with
different appropriate phosphines gave phosphine-containing
CTAs. They allowed us to synthesize polystyrene of medium
molecular weight via “reversible additionꢀfragmentation chain transfer” (RAFT) polymerization. 3,6,9-Trioxodecyl azide
(TOD-N3) was then used as model compound to study the Staudinger ligation with the corresponding polymers. Among all
CTAs tested, the phosphine-functionalized CTA-4, prepared from 2 and P-borane-(diphenylphosphanyl)methanethiol (6), not
only proved to be suitable for RAFT polymerization of styrene but the polymer-bound P-borane-(diphenylphosphanyl)methyl
thioester group also showed the best performance in the subsequent polymer analogous Staudinger ligation.
’ INTRODUCTION
proper manipulation of macromolecules on a functional as well as
architectural level can be drawn from well-established, modified
techniques in organic chemistry.
During the past years strong efforts have been put in the
synthesis of well-defined polymer materials. Specifically, the
development of controlled radical polymerization (CRP) tech-
niques such as nitroxide-mediated radical polymerization
(NMRP),1 atom transfer radical polymerization (ATRP),2 and
reversible additionꢀfragmentation chain transfer (RAFT)3 has
prompted further the design of a large number of macromolecular
assemblies for distinct applications. Because of the good structural
control that can be achieved as well as the tolerance toward
many functional groups, these processes certainly belong to the
most rapidly expanding themes in polymer science. Highly
efficient reactions, often called “click” reactions, are another
important topic especially in polymer chemistry where specific
features have to be addressed.4 In particular, the combination of
CRP with “click” chemistry is foreseen to have a striking impact
on material science. Click reactions like the Cu(I)-catalyzed 1,3-
dipolar cycloaddition reactions5,6 between alkynes and azides
have been successfully employed not only for the construction of
telechelic polymers7ꢀ9 but also in the orthogonal side-group
modification10ꢀ12 and the synthesis of hyperbranched materials.13
Meanwhile the field has grown significantly, and several review
articles have been published.14ꢀ21 Nonetheless, the emergence of
azideꢀalkyne click chemistry in polymer science also provoked a
search for alternate reactions that can be counted as click reactions
with similar simplicity and versatility.22ꢀ26 In many cases, tradi-
tional organic reactions are reconsidered and combined with
controlled radical polymerizations to allow for the design of
tailor-made materials.27,28 Clearly spoken, the inspiration for a
With this philosophy, the traceless Staudinger ligation29,30 is
proposed to be a synthetic tool for reliable polymer analogous
reactions. The Staudinger ligation has to be regarded as a special
case of an aza-Wittig reaction31 where an intermediately formed
aza-ylide can be converted with a plethora of electrophiles.
Usually, the aza-ylide is being formed by the reaction of a
phosphine with an organic azide, which in general proved to be
the subject of very prosperous chemistry.32 Some years ago,
Bertozzi33,34 and Raines35 designed a system where such aza-
Wittig reactions can be conducted in aqueous media without the
reduction of the azide into the corresponding amine, i.e.,
Staudinger reduction. In this concept, the electrophile is placed
at the vicinity of a phosphine which can be easily reacted with an
azide to form the aza-ylide. A subsequent intramolecular reaction
links the former azide covalently to the electrophile while
eliminating the phosphine in its oxidized form. This seminal
work has drawn a lot of attention, and especially at the interface
of organic chemistry and life science a vast progress in the
development of organicꢀbioorganic conjugates has been
launched.36ꢀ41 The big advantage of this method over a classical
click reaction is that one is not restricted to the formation of a
rather non-biogene triazole ring. Depending on the nature of the
Received: January 12, 2011
Revised:
March 25, 2011
Published: April 11, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ma2000724 Macromolecules 2011, 44, 3260–3269
|

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ARTICLE
electrophile, the resulting link is an amide, imine, carbodiimide
bond, etc.30 Moreover, Cu(I) catalysis is entirely abandoned, and
the reactions can be carried out selectively in water and organic
media. In fact, phosphines have been developed that orthogonally
stimulate the acylation of organic azides rather than amines
which might be present in a reaction mixture.42 Therefore, with
the same right, the Staudinger ligation might be assigned to the
methodology of click chemistry.4
Inthe present work wedemonstrate for the first time the unique
combination of RAFT polymerization and Staudinger ligation.
Novel RAFT reagents were synthesized that allowed for the
synthesis of well-defined polymers with adjustable molecular
weights and low polydispersities. The utilized chain transfer
agent transferred a fragment into the macromolecule that could
be used for polymer analogous Staudinger ligation, giving rise to
the design of hybrid polymeric materials.43
(2) (2.0 g, 5 mmol), CDI (1.07 g, 5.94 mmol), and a catalytic amount
of DMAP. The mixture was dissolved in dry CH2Cl2 (60 mL) and stirred
at room temperature for 1 h. Then, pentafluorophenol (1.23 g, 6.7
mmol) in 3 mL of CH2Cl2 was added, and the mixture was left to react
overnight. CH2Cl2 was evaporated, and the crude product was purified
by silica column chromatography with hexane/CH2Cl2 (1:2) as eluent.
Finally, 0.57 g of a yellow oily product was obtained (yield: 20%). In the
second step, a round-bottom flask was charged under an argon atmo-
sphere with the activated ester 2-A (0.53 g, 0.93 mmol) and a catalytic
amount of DMAP and dry CH2Cl2 (10 mL). Then, P-borane-
(diphenylphosphanyl)methanethiol (5) (0.24 g, 0.96 mmol) in 10 mL
of CH2Cl2 was added, and the mixture was left to react overnight. The
solvent was evaporated, and the crude product was purified by silica
column chromatography with hexane/CH2Cl2 (1:2) as eluent. Finally,
1
0.1 g of a yellow-orange oily product was obtained (yield: 17%). H
NMR (CDCl3): δ (ppm) = 0.88 (3H, t, H19), 1.26 (16H, H11ꢀ18), 1.40
(2H, m, H10), 1.69 (2H, m, H9), 1.77 (3H, s, H5), 2.24 (1H, m, H3a),
2.38 (1H, m, H3b), 2.74 (2H, m, H2), 3.33 (2H, t, H8), 3.73 (2H, d, H20,
2JHP = 6.4 Hz), 7.47 (4H, m, H23), 7.53 (2H, m, H24), 7.70 (4H, m, H22).
The typical broad signal of the protons originating from the borane
protecting group appears between 0.7 and 1.4 ppm and is superposed
with the signal of the C12H25 alkyl chain. 13C NMR (CDCl3): δ (ppm) =
14.06 (C19), 22.63 (C18), 23.69 (C20, 1JPC = 34.5 Hz), 24.74 (C5), 27.62
(C9), 28.8ꢀ29.6 (C10ꢀ16), 31.85 (C17), 33.77 (C3), 37.08 (C8), 38.77
’ EXPERIMENTAL SECTION
Measurements. NMR spectra were recorded on a DRX 500
spectrometer (Bruker, Germany) operating at 500.13 MHz for 1H,
125.75 MHz for 13C, and 202.40 MHz for 31P using CDCl3 as solvent.
The spectra were referenced on the solvent signal (δ(1H) = 7.26 ppm;
δ(13C) = 77.0 ppm) and on external phosphoric acid (δ(31P) = 0 ppm).
The signal assignments were deduced from the combination of 1D and
2D NMR spectra.
1
(C2), 46.11 (C4), 118.69 (C6), 127.39 (C21, JPC = 55.4 Hz), 128.86
(C23, 3JPC = 10.1 Hz), 131.82 (C24, 4JPC = 2.2 Hz), 132.51 (C22, 2JPC
=
9.0 Hz), 194.44 (C1, 3JPC = 1.8 Hz), 216.62 (C7). 31P NMR (CDCl3): δ
(ppm) = 20.25 (Ph2P(BH3)CH2Sꢀ).
Gel permeation chromatography (GPC) with narrow dispersed poly-
styrene standards (PL EasiCal PS-1, Polymer Laboratories) was used to
determine molar masses and polydispersity indices (PDI) of the poly-
mers. GPC measurements with THF as eluent were performed employ-
ing a Polymer Laboratories PL-GPC 50 Plus Integrated GPC system
equipped with a microvolume double piston pump. Measurements were
conducted with a PL-RESIPORE 300 ꢁ 7.5 mm column using a RI or a
LS detector. In all GPC measurements the flow rate was set to 1 mL/min.
Matrix-assisted laser desorption/ionizationꢀtime-of-flight (MALDI-
TOF) mass spectra of the polymers were acquired on a Biflex II MALDI-
TOF MS system (Bruker Daltonics, Germany). The measurements
were carried out in the positive ion reflectron mode, and a continuous
ion acceleration voltage of 20 kV was used. 1,8,9-Trihydroxyanthracene
(dithranol) and 2-(4-hydroxyphenylazo)benzoic acid (HABA) were
used as matrices and dissolved in acetone, respectively. Sodium azide
was used as cationizing agent. The samples were exposed on a target to
the desorption/ionization process induced by pulsed N2 laser (337 nm).
The ionized molecules were accelerated and reflected by electric fields
and projected on a mass-sensitive detector. Each mass spectrum
represents the accumulation of about 300 single-laser-spot spectra.
Chemicals. The monomer styrene was filtered through basic
alumina oxide to remove the stabilizer. 2-(Diphenylphosphanyl)phenol
(3),44 thioacetic acid S-[P-borane-(diphenylphosphanyl)methyl] ester
(5),45,46 2-(dodecylsulfanylthiocarbonylsulfanyl)-2-methylpropionic acid
(1),47 and 4-cyano-4-(dodecylsulfanylthiocarbonylsulfanyl)pentanoic
acid (2)48 were synthesized according to the corresponding literature
procedures. All other reagents were purchased from Aldrich and used
without further purification. Further experimental details and character-
ization results on compounds CTA-1, CTA-2, CTA-3, P-borane-
2-(diphenylphosphanyl)phenol (4), P-borane-(diphenylphosphanyl)-
methanethiol (6), and 3,6,9-trioxodecyl azide (TOD-N3) can be found
in the Supporting Information.
PS-1c. A flame-dried Schlenk tube was charged with AIBN (0.1 M in
anisole, 192 μL, 19 μmol), CTA-1 (121.3 mg, 194μmol), styrene (2.037 g,
19.5 mmol), and PBu3 (6 mg, 30 μmol). The solution was degassed by
four freezeꢀpumpꢀthaw cycles and polymerized at 70 °C under a N2
atmosphere for 17 h. From the crude product the conversion was
determined by 1H NMR (65%). Generally, the styrene conversion was
determined from the integral of the vinyl protons signal of the residual
styrene and the integral of the aromatic protons signal taking into
account the integral contribution from one overlapping vinyl proton.
The product was thereafter isolated by repeated precipitation in
methanol. According to 31P NMR, 5% of the phosphine moieties were
1
oxidized. H NMR (CDCl3): δ (ppm) = 0.72 and 0.86 (H3), 0.89
(H16), 1.1ꢀ2.3 (H6ꢀH15, CH and CH2 of the backbone), 3.25 (H5),
4.6ꢀ5.0 (ꢀC(S)ꢀSꢀCHPhꢀ), 6.3ꢀ7.5 (Ho, Hm, Hp, aromatic pro-
tons of the phosphine group). 13C NMR (CDCl3): δ (ppm) = 14.1
(C16), 22.7 (C15), 24.5ꢀ26.2 (C3), 27.9 (C6), 28.5ꢀ29.5 (C7ꢀC13),
31.8 (C14), 36.7 (C5), 40.0ꢀ41.0 (CH of the backbone), 41.0ꢀ47.0
(C2, CH2 of the backbone), 52.9 and 53.2 (ꢀC(S)ꢀSꢀCHPhꢀ), 122.2
(C22), 125.0ꢀ127.0 (C20, Cp), 127.0ꢀ129.0 (C25, Co, Cp), 128.8 (C26),
129.5 (C18, C21), 133.3 (C19), 133.9 (C24), 135.9 (C23), 144.0ꢀ147.0 (Ci),
152.9 (C18), 175.2 (C1), 222.3 (C4). 31P NMR (CDCl3): δ(ppm) =ꢀ15.5
to ꢀ16.0 (Ph2PC6H4Oꢀ, 95%) and 27.8 (Ph2P(O)C6H4Oꢀ, 5%). SEC
(THF): Mn = 6900 g molꢀ1; Mw = 7600 g molꢀ1; PDI = 1.10.
PS-1a. The same procedure was followed as for PS-1c, but no PBu3
was added: AIBN (1.0 mg, 6 μmol) CTA-1 (30.3 mg, 48 μmol), and
styrene (1.00 g, 9.7 mmol) at 70 °C for 25 h. Conversion: 62%.
According to 31P NMR, 30% of the phosphine moieties were oxidized.
SEC (THF): Mn = 11 800 g molꢀ1; Mw = 12 800 g molꢀ1; PDI = 1.09.
PS-1b. The same procedure was followed as for PS-1c, but no PBu3
was added: AIBN (0.1 M in anisole, 96 μL, 9.6 μmol), CTA-1 (60.3 mg,
96 μmol), and styrene (1.04 g, 10 mmol) at 70 °C for 70 h. Conversion:
82%. SEC (THF): Mn = 8600 g molꢀ1; Mw = 9400 g molꢀ1; PDI = 1.09.
PS-2b. A flame-dried Schlenk tube was charged with AIBN (0.1 M in
anisole, 100 μL, 10 μmol), CTA-2 (60 mg, 90 μmol), styrene (1 g, 9.6
mmol), and PBu3 (5 mg, 25 μmol). After degassing via four freezeꢀ
pumpꢀthaw cycles, the mixture was heated to 70 °C under a N2
CTA-4. CTA-4 was prepared in a two-step procedure. First, 2 was
transformed into the activated ester 2-A, i.e., the pentafluorophenyl
ester. Then, the activated ester was reacted with phosphine 6. For the
first step, a round-bottom flask was charged under an argon atmosphere
with 4-cyano-4-(dodecylsulfanylthiocarbonylsulfanyl)pentanoic acid
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ARTICLE
atmosphere and left to polymerize overnight (15 h). After twice being
precipitated from MeOH, 263 mg of slightly yellow PS-2b was obtained.
Conversion = 69%. According to 31P NMR, 25% of the phosphine
functionalities were oxidized. 1H NMR (CDCl3): δ (ppm) = 0.89 (H19),
0.77 and 0.97 (H5), 1.1ꢀ2.3 (H3, H9ꢀH18, CH and CH2 of the
backbone), 2.23 (H2), 3.25 (H8), 4.6ꢀ5.0 (ꢀC(S)ꢀSꢀCHPhꢀ),
protected state. SEC (THF): Mn = 4500 g molꢀ1; Mw = 5000 g molꢀ1
;
PDI = 1.11.
PS-1c-TOD. A round-bottom flask was charged with a solution of PS-
1c (204 mg, 30 μmol) and 3,6,9-trioxodecyl azide (TOD-N3) (36.6 mg,
193 μmol) in 4.4 mL of THF/H2O (9:1). After stirring at room
temperature overnight a small quantity was taken out to determine
the conversion by 1H NMR (15%). Thereafter, the solution was heated
at 50 °C, stirred for another 48 h, and worked up by repeated
precipitation in water and methanol. According to 1H NMR, the amide
bond was formed to an extent of 43%. Yield: 134 mg. SEC (THF): Mn =
7100 g molꢀ1; Mw = 7800 g molꢀ1; PDI = 1.10.
6.3ꢀ7.5 (Ho, Hm, Hp, aromatic protons of the phosphine group). 13
C
NMR (CDCl3): δ (ppm) = 14.0 (C19), 22.6 (C18), 23.5ꢀ24.5 (C5),
27.8 (C9), 28.5ꢀ29.5 (C10ꢀC16), 29.6 (C2), 31.8 (C17), 34.0ꢀ36.0
(C3, C4), 36.7 (C8), 40.0ꢀ41.0 (CH of the backbone), 41.0ꢀ47.0 (CH2
of the backbone), 52.8 and 53.2 (ꢀC(S)ꢀSꢀCHPhꢀ), 122.3 (C21),
122.9 and 123.9 (C6), 125.0ꢀ127.0 (C23, Cp), 127.0ꢀ129.0 (C28, Co,
Cp), 129.0 (C29), 129.8 (C22), 130.1 (C25), 133.8 (C24), 133.9 (C27),
PS-2b-TOD. A round-bottom flask was charged with PS-2b (100 mg,
12 μmol) and 3,6,9-trioxodecyl azide (TOD-N3) (24 mg, 127 μmol) in
2 mL of THF/H2O (9:1). The mixture was stirred overnight. The
solvents were then evaporated, and the polymer was twice precipitated
135.3 (C26), 144.0ꢀ147.0 (Ci), 152.4 (C20), 170.0 (C1), 222.3 (C7). 31
P
NMR (CDCl3): δ (ppm) = ꢀ15.0 to ꢀ15.6 (Ph2PC6H4Oꢀ; 75%) and
26.5 (Ph2P(O)C6H4Oꢀ; 25%). SEC (THF): Mn = 8500 g molꢀ1; Mw =
9000 g molꢀ1; PDI = 1.06.
1
in MeOH. According to H NMR, the amide bond was formed to an
extent of 30%. Yield: 76 mg. SEC (THF): Mn = 9400 g molꢀ1; Mw =
10 300 g molꢀ1; PDI = 1.10.
PS-2a. The same procedure was followed as for PS-2b, but no PBu3
was added: AIBN (0.1 M in anisole, 48 μL, 4.8 μmol), CTA-2 (60 mg, 90
μmol), and styrene (1.00 g, 9.6 mmol) at 70 °C for 9 h. According to 31P
NMR, 40% of the phosphine functionalities were oxidized. SEC (THF):
Mn = 7600 g molꢀ1; Mw = 8400 g molꢀ1; PDI = 1.10.
PS-4b-TOD. A round-bottom flask was charged with PS-4b (380 mg,
0.12 mmol), 1,4-diazabicyclo[2.2.2]octane (DABCO) (271 mg, 2.4
mmol), and 3,6,9-trioxodecyl azide (TOD-N3) (441 mg, 2.33 mmol)
in 10 mL of THF/H2O (9:1) under an argon atmosphere. The mixture
was stirred at 40 °C for 22 h overnight. The solvents were then
evaporated, and the polymer was twice precipitated from MeOH.
PS-3. A flame-dried Schlenk tube was charged with AIBN (0.1 M in
anisole, 52 μL, 5.2 μmol), CTA-3 (19 mg, 52 μmol), and styrene (339 mg,
3.26 mmol). After degassing via four freezeꢀpumpꢀthaw cycles, the
mixture was polymerized at 70 °C under an argon atmosphere over-
night (16 h). After twice being precipitated from MeOH, 66 mg of
slightly yellow PS-3 was obtained (yield: 26%). Conversion = 64%.
According to 31P NMR, 49% of the phosphine functionalities were
oxidized, 33% were unprotected, and 18% were present in their borane-
protected state. 1H NMR (CDCl3): δ (ppm) = 0.77 and 0.97 (H5), 0.90
(H19), 1.10ꢀ2.70 (H2, H3, H9ꢀH18, CH and CH2 of the backbone),
3.26 (H8), 4.6ꢀ5.0 (ꢀC(S)ꢀSꢀCHPhꢀ), 6.30ꢀ7.85 (Ho, Hm, Hp,
aromatic protons of the phosphine group). 31P NMR (CDCl3): δ
(ppm) = ꢀ15.6 (Ph2PC6H4Oꢀ, 33%), 18.7 (Ph2P(BH3)C6H4Oꢀ,
18%), 25.9 (Ph2P(O)C6H4Oꢀ, 49%). SEC (THF): Mn = 5400 g
molꢀ1; Mw = 5900 g molꢀ1; PDI = 1.08.
PS-4b. A flame-dried Schlenk tube was charged with AIBN (0.1 M in
anisole, 176 μL, 17.6 μmol), CTA-4 (111 mg, 176 μmol), and styrene
(1.16 g, 11.1 mmol). After degassing via four freezeꢀpumpꢀthaw
cycles, the mixture was heated to 60 °C under an argon atmosphere
and left to polymerize overnight (19 h). After twice being precipitated
from MeOH, 447 mg of slightly yellow PS-4b was obtained. Conversion
= 40%. According to 31P NMR, 12% of the phosphine functionalities
were oxidized, 6% were unprotected, and 82% were present in
their borane-protected state. 1H NMR (CDCl3): δ (ppm) = 0.80 and
0.95 (H5), 0.90 (H19), 1.1ꢀ2.5 (H2, H3, H9ꢀH18, CH and
CH2 of the backbone, BH3), 3.26 (H8), 3.68 (H20), 4.6ꢀ5.0
(ꢀC(S)ꢀSꢀCHPhꢀ), 6.3ꢀ7.8 (H22ꢀH24, Ho, Hm, Hp). 13C NMR
(CDCl3): δ (ppm) = 14.1 (C19), 22.6 (C18), 23.5 (C20, 1JPC = 34.7 Hz),
23.8 and 24.3 (C5), 27.9 (C9), 28.8ꢀ29.6 (C10ꢀ16), 31.9 (C17),
34.0ꢀ35.2 (C3), 35.2ꢀ36.2 (C4), 36.7 (C8), 38.9 and 39.1 (C2),
40.0ꢀ41.0 (CH of the backbone), 41.0ꢀ47.0 (CH2 of the backbone), 52.8
and 53.2 (ꢀC(S)ꢀSꢀCHPhꢀ), 122.4ꢀ123.2 (C6), 125.0ꢀ126.0
(Cp), 127.0ꢀ129.0 (C21, Co, Cm), 128.8 (d, C23), 131.7 (C24), 132.5
(d, C22), 138.5ꢀ141.0 (Ci at ꢀSꢀCHPhꢀ), 144.5ꢀ146.0 (Ci), 195.2
(C1), 222.2 (C7). 31P NMR (CDCl3): δ (ppm) = ꢀ14.2 (Ph2PCH2Sꢀ,
6%), 20.1 (Ph2P(BH3)CH2Sꢀ, 82%), 29.3 (Ph2P(O)CH2Sꢀ, 12%).
SEC (THF): Mn = 3200 g molꢀ1; Mw = 3400 g molꢀ1; PDI = 1.08.
PS-4a. The same procedure was followed as for PS-4b: AIBN (0.1 M
in anisole, 30 μL, 3 μmol), CTA-4 (19mg, 30 μmol), and styrene (193 mg,
1.85 mmol) at 70 °C for 15 h. Conversion = 45%. Yield = 31 mg.
According to 31P NMR, 21% of the phosphine functionalities were
oxidized, 4% were unprotected, and 75% were present in their borane-
1
According to H NMR, the amide bond was formed to an extent of
82%. Phosphorus-containing moieties could not be proved by 31P NMR.
Yield: 312 mg. 1H NMR (CDCl3): δ (ppm) = 0.84 and 1.03 (H5), 0.89
(H19), 1.1ꢀ2.3 (H2, H3, H9ꢀH18, CH and CH2 of the backbone), 3.25
(H8), 3.37 (Hg), 3.40 (Ha), 3.5ꢀ3.6 (Hb, Hf), 3.63 (Hc, Hd, He),
4.6ꢀ5.0 (ꢀC(S)ꢀSꢀCHPhꢀ), 5.9ꢀ6.1 (CONH), 6.3ꢀ7.3 (Ho, Hm,
Hp). 13C NMR (CDCl3): δ (ppm) = 14.1 (C19), 22.6 (C18), 23.5ꢀ24.5
(C5), 27.9 (C9), 28.8ꢀ29.6 (C10ꢀC16), 31.7 (C2), 31.8 (C17),
34.7ꢀ36.2 (C3, C4), 36.7 (C8), 39.2 (Ca), 40.0ꢀ41.0 (CH2 of the
backbone), 41.0ꢀ47.0 (CH of the backbone), 52.8 and 53.2
(ꢀC(S)ꢀSꢀCHPhꢀ), 58.9 (Cg), 69.7 (Cb), 70.1, 70.4, 70.5 (Cc, Cd, Ce),
71.9 (Cf), 123.0ꢀ123.7 (C6), 125.0ꢀ127.0 (Cp), 127.0ꢀ129.0 (Co,
Cm), 138.5ꢀ141.0 (Ci at ꢀSꢀCHPhꢀ), 144.5ꢀ146.0 (Ci), 171.2
(C1), 222.2 (C7). SEC (THF): Mn = 3200 g molꢀ1; Mw = 3500 g molꢀ1
;
PDI = 1.09.
’ RESULTS AND DISCUSSION
Nowadays, a large variety of chain transfer agents (CTAs)
can be found in the literature.3,49 In order to prepare a RAFT
reagent prone to polymer analogous Staudinger ligation, it seems
reasonable to resort to carboxyl-functionalized CTAs since
promising phosphine groups for Staudinger ligation42 can be
linked to the substrate in an esterification reaction via their
hydroxyl or thiol groups. We chose 2-(dodecylsulfanyl-
thiocarbonylsulfanyl)-2-methylpropionic acid (1) since it is
simple to synthesize in a one-pot procedure47 and 4-cyano-4-
(dodecylsulfanylthiocarbonylsulfanyl)pentanoic acid (2).48 The
phosphine 2-(diphenylphosphanyl)phenol (3) could be ob-
tained in a rather elaborated procedure44 and was converted
with 1 and 2 to yield the phosphine-functionalized chain transfer
agents CTA-1 and CTA-2, respectively (Scheme 1).
In both cases the esterification with 3 was conducted in
dichloromethane at room temperature overnight using 1,
10-carbonyldiimidazole (CDI) and 4-(dimethylamino)pyridine
(DMAP) as activating agents (Scheme 2). The products were
purified by column chromatography and obtained in acceptable
yields (see Supporting Information).
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Scheme 1. Structures of the Different Chain Transfer Agents Prepared in This Work
Scheme 2. Preparation of CTA-1, CTA-2, and CTA-3 Using Standard Steglich Esterification
The controlled radical polymerization (CRP) of styrene in
bulk was mediated with CTA-1 and CTA-2, respectively
(Scheme 3). As radical source, AIBN was used and the reaction
temperature of 70 °C provided its acceptable decomposition.
The kinetic experiment with CTA-1 clearly demonstrated the
controlled nature of the polymerization process. This can be
deduced from the molecular weight evolution that followed
linear dependency and the low polydispersity values throughout
the polymerization process(Supporting Information, Figure SI7).
A test experiment using 1 as chain transfer agent was conducted
under the same conditions to yield polystyrene PS. The reaction
followed the same kinetics; hence, we assume that the phos-
phine group present in CTA-1 does not interfere with the
polymerization process. For all polymers the molar masses could
be adjusted as desired, and the isolated products exhibited
narrow molecular weight distributions (Table 1).
phosphine moiety (∼ꢀ15 ppm) another phosphorus-containing
structure with δ(31P) ∼ 26.5 ppm appears (Figure SI10). This
pronounced low-field shift indicates that the phosphine has been
oxidized upon reaction.50 Obviously, at elevated temperature in
the presence of a radical source, the formation of the correspond-
ing phosphine oxide occurred. This situation is, of course, not
acceptable since it reduces the amount of accessible phosphine
groups for the Staudinger ligation.
Although there are methods known in the literature to reduce
a phosphine oxide efficiently to the phosphine species,51 our
interests aimed for the avoidance of phosphine oxide formation.
This, we thought, can be accomplished by either vigorous degassing
of the polymerization batch or addition of an antioxidizing
agent. It is well-known that trialkylphosphines are oxidative less
stable than triarylphosphines. In fact, tributylphosphine even
tends to ignite under ambient atmosphere. Hence, in a compet-
ing process of oxidation the trialkylphosphine should be pre-
dominately oxidized compared to triarylphosphine. As expected,
Nonetheless, one issue arose concerning the phosphine
moiety. The 31P NMR spectra indicate that besides the
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Scheme 3. Controlled Radical Polymerization of Styrene with Different Chain Transfer Agents CTA-1, CTA-2, and CTA-3,
Respectively, and Subsequent Polymer Analogous Modification of the Obtained Polystyrenes with TOD-N3 in a Staudinger
Ligation
Table 1. Characteristics of Polystyrenes Obtained by RAFT Polymerization Using Different CTAsa
entry
CTA
molar ratio styrene/CTA/AIBN
Xpd [%]
Mn,cale [g molꢀ1
]
Mn,SEC [g molꢀ1
]
PDI
oxidized phosphine groups [%]
PS
1
100/0.5/0.05
100/0.5/0.05
100/1/0.1
100/2/0.2
100/1/0.1
100/1/0.1
63/1/0.1
97
62
82
85
60
69
64
45
40
22300
13100
8900
6900
7400
8300
4900
3600
3300
22500
11800
8600
6900
7600
8400
5400
4500
3200
1.10
1.09
1.09
1.10
1.10
1.07
1.08
1.11
1.08
PS-1a
PS-1b
PS-1cb
PS-2a
PS-2bb
PS-3
CTA-1
CTA-1
CTA-1
CTA-2
CTA-2
CTA-3
CTA-4
CTA-4
30
n.d.
5
40
25
49
21
12
PS-4a
PS-4bc
62/1/0.1
63/1/0.1
a The polymerization was carried out in bulk at 70 °C. b Addition of PBu3 (1.5 and 2.5 equiv with respect to AIBN). c Carried out at 60 °C. d Conversion
of monomer. e Theoretical molar mass determined from monomer conversion, n.d. = not determined.
upon addition of tributylphosphine the amount of phosphine
oxide could be drastically reduced for the RAFT polymerization
utilizing CTA-1. In the 31P NMR spectrum the remaining signal
of phosphine oxide was determined to be 5% only (PS-1c,
Figure SI10). In contrast, if the feed solution was extensively
degassed prior to polymerization, once more 30% side product
formation was detected (PS-1b).
As promising as the polymerizations with CTA-1 were, the
polymer analogous end-group modifications were rather disap-
pointing. The reaction of PS-1a with 3,6,9-trioxodecyl azide
(TOD-N3) (Scheme 3, bottom), as simple model compound for
a proof of principle reaction, conducted in a 9:1 mixture of THF/
H2O at room temperature overnight only yielded 15% of the
desired amido glycol PS-1a-TOD. Heating improved this situa-
tion only slightly. After 48 h at 50 °C a conversion of 43% was
reached. However, this scenario is in good accordance with the
literature.42 Hereby, it was found that Staudinger ligations
proceeded fast and under smooth conditions when the electro-
phile resembled a glycyl structure. The rate of reaction drastically
decreased if non-glycyl motifs were used, i.e., when a R-methyl
group was present in the electrophile and the conversions could
go as low as 27%.
In order to obtain higher yield, we decided to avoid the sterical
hindrance in the R-position of the ester group by using CTA-2 as
transfer agent. Unfortunately, it appears that in this case the
phosphine group is more prone to oxidation than it was in the
case when CTA-1 had been used. After the synthesis and the
unavoidable purification of CTA-2 by column chromatography,
15% of the phosphine groups were transformed into phosphine
oxide. Again, this evolution could be easily monitored by 31P
NMR spectroscopy (Figure SI5). The subsequent controlled
radical polymerization of styrene with CTA-2 yielded the desired
polystyrenes (PS-2a, PS-2b) with control over molecular weight
and low polydispersity indices (PDI = 1.10 and 1.07,
respectively). Similar to the polymerization with CTA-1, the
addition of PBu3 reduced the formation of phosphine oxide, in
this case from 40% to 25%. Knowing that 15% of CTA-2 was
already oxidized before the polymerization, another 10% of
phosphine oxide had been formed (Figure SI11). Nevertheless,
polymer PS-2b was used to perform a Staudinger ligation with
TOD-N3 in a 9:1 mixture of THF/H2O at room temperature,
1
stirred for 20 h. Analysis via H and 31P NMR spectroscopy
revealed that, on the one hand, the amount of phosphine oxide
had risen to 35% but, on the other, 30% of the ester groups were
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Scheme 4. Two-Step Preparation of CTA-4, RAFT Polymerization of Styrene Using CTA-4, and Subsequent Polymer Analogous
Staudinger Ligation with TOD-N3
successfully transformed into the corresponding amide function
to yield polymer PS-2b-TOD. At room temperature, the less
sterically hindered ester derived from CTA-2 was converted into
a peptide bond with slightly higher yields than the ester function
derived from CTA-1. This is even more remarkable if we keep in
mind that 25% of the phosphine groups in PS-2b were already
inactive before carrying out the Staudinger ligation, compared to
5% in PS-1a. This confirms the assumption that the Staudinger
ligation is sensitive to sterically hindering groups in the R-position
of the ester group. Nevertheless, the rapid oxidation of CTA-2
during its synthesis, purification, as well as the polymerization
and the Staudinger ligation is a major drawback.
On the basis of these initial results, we resorted to phosphine
groups that are inherently more stable toward oxidation and also
broadened the spectrum of phosphine groups used in this study.
From the literature, it is well-known that, besides 2-diphenylpho-
sphanylphenol (3), diphenylphosphanylmethanethiol shows one
of the best reactivity profiles among the phosphines tested until
today.30,42 Therefore, diphenylphosphanylmethanethiol was in-
cluded in our consideration. The compound is often handled in a
form where the phosphorus atom in the phosphine group is
protected by a borane group to prevent it from oxidation. This
form is here labeled as P-borane-(diphenylphosphanyl)-
methanethiol (6). We decided to apply the same borane com-
plexation strategy to the 2-diphenylphosphanylphenol (3).
For this purpose, 3 was treated with borane dimethyl
sulfide complex solution at ꢀ15 °C, and the complex P-bor-
ane-2-(diphenylphosphanyl)phenol (4) was obtained in excel-
lent yield. P-Borane-(diphenylphosphanyl)methanethiol (6) was
prepared following a modified procedure from Raines and co-
workers.46 The thiol was thereby freshly liberated from its acyl
protecting group prior to its use in the esterification reaction. On
the basis of the comparison of CTA-1 and CTA-2 in terms of
sterical hindrance within the Staudinger ligation, 4-cyano-
4-(dodecylsulfanylthiocarbonylsulfanyl)pentanoic acid (2) was
retained as basic CTA structure to prepare the functionalized
CTAs. P-Borane-2-(diphenylphosphanyl)phenol (4) was reacted
with 2 to give CTA-3 in acceptable yield (Scheme 2). The same
esterification strategy using classical Steglich conditions did not
work out for the preparation of CTA-4 starting from 2 and
P-borane-(diphenylphosphanyl)methanethiol (6). A major side
reaction emerged consisting in a concurrent nucleophilic attack
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Figure 1. 1H (a), 13C (b), and 31P (c) NMR spectra of CTA-4 in CDCl3.
of the thiol group of 6 at the trithiocarbonate group in 2. We
tried to circumvent this side reaction by rendering the carboxyl
group in 2 more reactive. Therefore, the more reactive penta-
fluorophenyl ester 2-A was prepared and reacted with 6 to give
CTA-4 in acceptable yield and relatively high purity (Scheme 4).
The side reaction still appeared but could be suppressed to a
large extent. The 1H, 13C, and 31P NMR spectra of CTA-4 are
depicted in Figure 1.
The two new CTAs, CTA-3 and CTA-4, were then tested in
the controlled radical polymerization of styrene. Again, AIBN
was used as initiator and the polymerization was carried out in
bulk. Polystyrenes with control over molar masses and low
polydispersity indices were obtained (Table 1). Furthermore, a
kinetic experiment was conducted using CTA-4. The controlled
nature of the polymerization process could be deduced from the
rather linear dependency of ln(c/c0) on polymerization time
(Figure 2a) and the linear molecular weight evolution on
monomer conversion as well as the low polydispersity values
(Figure 2b).
However, for PS-3, which had been obtained using CTA-3, 31P
NMR spectroscopy (Figure SI12) revealed that only 17% of the
phosphine groups were present in their borane-protected state.
50% had been oxidized, and 33% were present in the unpro-
tected, but yet not oxidized, form. It appears that the coordina-
tive bond between the borane and the phosphine was, in this
case, not strong enough to survive the polymerization process at
70 °C. In contrast, PS-4a, obtained upon mediation of CTA-4 in
the RAFT process, showed only 21% of oxidized phosphine
groups and a rather small amount of 4% of unprotected
phosphine groups. This means that in total 79% of the phos-
phine groups in the polymer had survived the RAFT process and
were still active groups for Staudinger ligation. This result
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Figure 2. Kinetic plot of the controlled polymerization of styrene mediated with CTA-4 (a). Dependency of molecular weight from conversion and
polydispersity indices over conversion (b).
Figure 3. MALDI-TOF mass spectrum (reflectron mode) of PS-4b with NaN3/dithranol matrix: global spectrum (a) and enlargement (b).
appears even more striking if one recalls the fact that unpro-
tected diphenylphosphanylmethanethiol is much more prone to
oxidation than it is the case for 2-(diphenylphosphanyl)phenol
(3). The coordinative bond between borane and phosphine
seems to be much stronger in this case. Reducing the reaction
temperature within the RAFT polymerization from 70 to 60 °C
resulted in polystyrene (PS-4b) with an even lower content of
oxidized phosphine groups (12%) as shown in Figure SI13.
PS-4b was additionally investigated by MALDI TOF mass
spectrometry (Figure 3). The measurement was carried out in
the positive ion reflectron mode using dithranol as matrix
material. Sodium azide was added to enhance the ionization of
the polymer by cationization. The major peak series corresponds
to polystyrene as evidenced by the consecutive peak distance of
104 g/mol, which corresponds to the mass of one styrene unit.
Furthermore, the starting group can been assumed consisting of
the unprotected phosphine form originating from the reinitiating
group of CTA-4 and the end group of dodecyltrithiocarbonate
derived from CTA-4 as exemplarily shown for the peak at 2202.6
(104.06 ꢁ 15 þ 340.1 þ 277.1 þ 23 = 2201.1). There is a good
chance that the cleavage of the borane protecting groups from
the phosphine groups is due to the high laser energy entry inside
the MALDI-TOF mass spectrometer during the measurement.
PS-4b was then used to perform a Staudinger ligation with
TOD-N3 in a 9:1 mixture of THF/H2O at 40 °C (Scheme 4).
1,4-Diazabicyclo[2.2.2]octane (DABCO) was added as a tertiary
base to cleave the borane protecting group from the phosphine
group prior to ligation. The cleavage process as well as the
subsequent consumption of the unprotected phosphine groups
had been followed before via 31P NMR spectroscopy in an online
kinetic experiment (Figure SI8) using PS-4a and TOD-N3.
Thereby, it was found that the cleavage process was accom-
plished after 7 h. The content of the unprotected phosphine
groups reached a maximum after about 3 h, and complete
conversion was found after 13 h. Besides the 31P NMR signal
of released phosphine oxide thiol as known byproduct during the
Staudinger ligation, several other signals were detected but could
not be assigned to specific byproducts up to now. For a more
detailed mechanistic study, including discussion of side reactions,
the reader is referred to a paper published by Soellner et al.42
1
The H NMR spectra of PS-4b, TOD-N3, and PS-4b-TOD
are depicted in Figure 4. The phosphine moiety of PS-4b can be
well identified by the signals of H20 and H22ꢀH24 (Figure 4a).
These signals completely disappear in the spectrum of the
modified polymer PS-4b-TOD, indicating that there are no
phosphine groups left in the polymer (Figure 4c). This is
confirmed by a 31P NMR spectrum showing no signals. In
addition, the 1H NMR signal of the CH2 group adjacent to the
thioester group (H2) shifts from 2.43 to 2.12 ppm due to a
change in chemical environment from thioester to amide group.
Finally, the appearance of the signals of HaꢀHg between 3.33 and
3.70 ppm originating from the TOD group and the NH signals at
∼6.00 ppm prove the successful modification of the chain end.
For PS-4b-TOD, the degree of conversion by polymer analogous
Staudinger ligation was determined to be 82% by comparing the
integral value of signals HaꢀHg (representing 15 H) to the one of
signal H8 (representing 2 H) (Figure 4c). Taking into account
that 82% of the phosphine groups at the end of each polymer
chain in PS-4b were present in the borane-protected state and
assuming that the 6% of the phosphine groups originally present
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Figure 4. 1H NMR spectra of PS-4b (a), TOD-N3 (b) and PS-4b-TOD (c) in CDCl3.
in the unprotected state might have been oxidized while storing,
one can assume that the polymer analogous ligation has been
accomplished in quantitative manner. The comparison of GPC
curves of PS-4b and PS-4b-TOD did not show any significant
difference (Figure SI9), indicating that no side reaction with
significant change of molecular weight had occurred. This is,
apart from a high degree of conversion, generally seen as a
prerequisite for a polymer analogous reaction in order to be
widely applicable.
groups’ sensitivity toward oxidation presented the major draw-
backs for the breakthrough of the Staudinger ligation as a new
efficient polymer analogous reaction. Sterical hindrance could
be avoided by using a CTA structure where the ester group is
bound to a methylene group. The sensitivity toward oxidation
was significantly reduced by using the borane protected form
of the phosphine moiety. Decrease in temperature during the
polymerization process lowered the amount of oxidized phosphine
groups even more. Finally, for the proof of principle, the
Staudinger ligation of polystyrene prepared by RAFT using
CTA-4 and TOD-N3 as simple model compound could be
accomplished in almost quantitative manner. We believe that
this concept, the combination of Staudinger ligation and RAFT
polymerization, will become an appropriate method for the
preparation of bioconjugates. Future work will be dedicated
to further improvements in terms of oxidation stability and
the reaction pathways toward the phosphine-functionalized
CTAs.
’ CONCLUSION
New phosphine-containing chain transfer agents were
synthesized and used in RAFT polymerization to obtain the
corresponding polystyrenes displaying low polydispersity and
high control over molar mass. Staudinger ligation of the thus-
obtained products was investigated. Thereby, it was found that
sterical hindrance at the ester function as well as the phosphine
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’ ASSOCIATED CONTENT
(20) Evans, R. A. Aust. J. Chem. 2007, 60, 384–395.
(21) Golas, P. L.; Matyjaszewski, K. Chem. Soc. Rev. 2010,
39, 1338–1354.
(22) Gress, A.; Volkel, A.; Schlaad, H. Macromolecules 2007,
40, 7928–7933.
(23) Chan, J. W.; Hoyle, C. E.; Lowe, A. B. J. Am. Chem. Soc. 2009,
131, 5751–5753.
(24) Sinnwell, S.; Inglis, A. J.; Davis, T. P.; Stenzel, M. H.;
Barner-Kowollik, C. Chem. Commun. 2008, 2052–2054.
(25) Inglis, A. J.; Barner-Kowollik, C. Macromol. Rapid Commun.
2010, 31, 1247–1266.
S
Supporting Information. Synthetic procedures and
b
NMR data of TOD-N3, 4, 6, phosphine-functionalized CTAs
CTA-1 to CTA-4, 1H, 13C, and 31P NMR spectra of polymers,
GPC curves of PS-4b and PS-4b-TOD, MALDI-TOF mass
spectrum of PS-4b-TOD, kinetic plot of the RAFT polymeriza-
tion using CTA-1, and the online kinetic experiment of the
Staudinger ligation using 31P NMR spectroscopy. This material is
available free of charge via the Internet at http://pubs.acs.org.
(26) Kade, M. J.; Burke, D. J.; Hawker, C. J. J. Polym. Sci., Part A:
Polym. Chem. 2010, 48, 743–750.
’ AUTHOR INFORMATION
(27) Cheng, C.; Sun, G.; Khoshdel, E.; Wooley, K. L. J. Am. Chem.
Soc. 2007, 129, 10086–10087.
(28) Klinger, D.; Chang, J. Y.; Theato, P. Macromol. Rapid Commun.
2007, 28, 718–724.
(29) Baskin, J. M.; Bertozzi, C. R. QSAR Comb. Sci. 2007,
26, 1211–1219.
Corresponding Author
*Fax (þ49) 0351-4658-565; e-mail voit@ipfdd.de.
Present Addresses
†BASF SE, GKS/M - B001, 67056 Ludwigshafen, Germany.
‡18, rue de Roeser, L-5865 Alzingen, Luxembourg.
(30) Kohn, M.; Breinbauer, R. Angew. Chem., Int. Ed. 2004,
43, 3106–3116.
(31) Fresneda, P. M.; Molina, P. Synlett 2004, 1–17.
(32) Brase, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem.,
Int. Ed. 2005, 44, 5188–5240.
(33) Saxon, E.; Armstrong, J. I.; Bertozzi, C. R. Org. Lett. 2000,
2, 2141–2143.
(34) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007–2010.
(35) Nilsson, B. L.; Kiessling, L. L.; Raines, R. T. Org. Lett. 2000,
2, 1939–1941.
’ ACKNOWLEDGMENT
The authors thank J. Hegewald for the supply of the transfer
reagent 4-cyano-4-(dodecylsulfanylthiocarbonylsulfanyl)pentanoic
acid (2). K. Sahre is acknowledged for conducting MALDI-TOF
mass spectrometry measurements. Ch. T. gratefully acknowledges
the financial support by BASF SE.
(36) Gaeta, A.; Woodcraft, J.; Plant, S.; Goggi, J.; Jones, P.; Battle,
M.; Trigg, W.; Luthra, S. K.; Glaser, M. Bioorg. Med. Chem. Lett. 2010,
20, 4649–4652.
(37) Gattas-Asfura, K. M.; Stabler, C. L. Biomacromolecules 2009,
10, 3122–3129.
(38) Kleineweischede, R.; Hackenberger, C. P. R. Angew. Chem., Int.
Ed. 2008, 47, 5984–5988.
(39) Loka, R. S.; Sadek, C. M.; Romaniuk, N. A.; Cairo, C. W.
Bioconjugate Chem. 2010, 21, 1842–1849.
(40) Nisic, F.; Andreini, M.; Bernardi, A. Eur. J. Org. Chem.
2009, 5744–5751.
(41) Watzke, A.; Kohn, M.; Gutierrez-Rodriguez, M.; Wacker, R.;
Schroder, H.; Breinbauer, R.; Kuhlmann, J.; Alexandrov, K.; Niemeyer,
C. M.; Goody, R. S.; Waldmann, H. Angew. Chem., Int. Ed. 2006,
45, 1408–1412.
(42) Soellner, M. B.; Nilsson, B. L.; Raines, R. T. J. Am. Chem. Soc.
2006, 128, 8820–8828.
(43) Klok, H. A. J. Polym. Sci., Part A: Polym. Chem. 2005, 43, 1–17.
(44) Herd, O.; Hessler, A.; Hingst, M.; Machnitzki, P.; Tepper, M.;
Stelzer, O. Catal. Today 1998, 42, 413–420.
(45) Farrington, G. K.; Kumar, A.; Wedler, F. C. Org. Prep. Proced.
Int. 1989, 21, 390–392.
(46) Soellner, M. B.; Nilsson, B. L.; Raines, R. T. J. Org. Chem. 2002,
67, 4993–4996.
(47) Lai, J. T.; Filla, D.; Shea, R. Macromolecules 2002,
35, 6754–6756.
(48) Moad, G.; Chong, Y. K.; Postma, A.; Rizzardo, E.; Thang, S. H.
Polymer 2005, 46, 8458–8468.
’ REFERENCES
(1) Hawker, C. J.; Bosman, A. W.; Harth, E. Chem. Rev. 2001,
101, 3661–3688.
(2) Tsarevsky, N. V.; Matyjaszewski, K. Chem. Rev. 2007,
107, 2270–2299.
(3) Moad, G.; Rizzardo, E.; Thang, S. H. Polymer 2008,
49, 1079–1131.
(4) 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, 60–62.
(5) Huisgen, R. Angew. Chem., Int. Ed. 1963, 2, 565–632.
(6) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B.
Angew. Chem., Int. Ed. 2002, 41, 2596–2599.
(7) Binder, W. H.; Kluger, C. Macromolecules 2004, 37, 9321–9330.
(8) Fleischmann, S.; Komber, H.;Appelhans, D.;Voit, B. I. Macromol.
Chem. Phys. 2007, 208, 1050–1060.
(9) Lutz, J. F.; Borner, H. G.; Weichenhan, K. Macromol. Rapid
Commun. 2005, 26, 514–518.
(10) Fleischmann, S.; Komber, H.; Voit, B. Macromolecules 2008,
41, 5255–5264.
(11) Iha, R. K.; Wooley, K. L.; Nystrom, A. M.; Burke, D. J.; Kade,
M. J.; Hawker, C. J. Chem. Rev. 2009, 109, 5620–5686.
(12) Malkoch, M.; Thibault, R. J.; Drockenmuller, E.; Messerschmidt,
M.; Voit, B.; Russell, T. P.; Hawker, C. J. J. Am. Chem. Soc. 2005,
127, 14942–14949.
(13) Wu, P.; Feldman, A. K.; Nugent, A. K.; Hawker, C. J.; Scheel, A.;
Voit, B.; Pyun, J.; Frechet, J. M. J.; Sharpless, K. B.; Fokin, V. V. Angew.
Chem., Int. Ed. 2004, 43, 3928–3932.
(49) Barner-Kowollik,C.Handbook of RAFT Polymerization; Wiley-VCH:
Weinheim, 2008.
(50) Berger, S.; Braun, S.; Kalinowski, H. O. NMR Spectroscopy of the
Non-Metallic Elements; John Wiley & Sons: Chichester, 1997.
(51) Wu, H. C.; Yu, J. Q.; Spencer, J. B. Org. Lett. 2004,
6, 4675–4678.
(14) Appukkuttan, P.; Mehta, V. P.; Van der Eycken, E. V. Chem. Soc.
Rev. 2010, 39, 1467–1477.
(15) Binder, W. H.; Sachsenhofer, R. Macromol. Rapid Commun.
2008, 29, 952–981.
(16) Fournier, D.; Hoogenboom, R.; Schubert, U. S. Chem. Soc. Rev.
2007, 36, 1369–1380.
(17) Franc, G.; Kakkar, A. K. Chem. Soc. Rev. 2010, 39, 1536–1544.
(18) Hein, J. E.; Fokin, V. V. Chem. Soc. Rev. 2010, 39, 1302–1315.
(19) Sumerlin, B. S.; Vogt, A. P. Macromolecules 2010, 43, 1–13.
3269
dx.doi.org/10.1021/ma2000724 |Macromolecules 2011, 44, 3260–3269