Reversible crosslinking of polymers bearing pendant or terminal thiol groups prepared by nitroxide-mediated radical polymerization

Article abstract of DOI:10.1016/j.reactfunctpolym.2013.01.009

Monomers or N-alkoxyamine initiators containing protected thiol groups are utilized to prepare polymers via nitroxide-mediated radical polymerization. Following thiol deprotection, the macromolecular properties of these polymers are manipulated, by adjusting the redox conditions to either form or cleave disulfide bonds, or irreversibly cap free thiols by the rapid addition to a maleimide Michael acceptor. Formation of disulfide bonds under dilute conditions results in intramolecular disulfide formation, resulting in internal polymer collapse. Alternatively, disulfide formation under high concentration results in intermolecular crosslinking of polymers to form networked macromolecular assemblies.

Full text of DOI:10.1016/j.reactfunctpolym.2013.01.009

Reactive & Functional Polymers 73 (2013) 624–633
Contents lists available at SciVerse ScienceDirect
Reactive & Functional Polymers
journal homepage: www.elsevier.com/locate/react
Reversible crosslinking of polymers bearing pendant or terminal thiol
groups prepared by nitroxide-mediated radical polymerization
⇑
Rebecca Braslau , Frank Rivera III, Chittreeya Tansakul
Department of Chemistry and Biochemistry, 1156 High Street, University of California, Santa Cruz, CA 95064, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Monomers or N-alkoxyamine initiators containing protected thiol groups are utilized to prepare poly-
mers via nitroxide-mediated radical polymerization. Following thiol deprotection, the macromolecular
properties of these polymers are manipulated, by adjusting the redox conditions to either form or cleave
disulfide bonds, or irreversibly cap free thiols by the rapid addition to a maleimide Michael acceptor. For-
mation of disulfide bonds under dilute conditions results in intramolecular disulfide formation, resulting
in internal polymer collapse. Alternatively, disulfide formation under high concentration results in inter-
molecular crosslinking of polymers to form networked macromolecular assemblies.
Received 19 October 2012
Received in revised form 14 January 2013
Accepted 17 January 2013
Available online 29 January 2013
Keywords:
Disulfide
Thiol
Ó 2013 Elsevier Ltd. All rights reserved.
Nitroxide-mediated free radical
polymerization
Reversible
Crosslink
1. Introduction
was observed under bulk polymerization conditions [5]. Free radi-
cal polymerization of acrylates bearing acetate-protected thiol
Disulfide crosslinking of polymers is a ubiquitous theme in the
macromolecular world. Functional proteins utilize strategic cys-
teine-based disulfides to lock in critical tertiary structure, whereas
sidechains followed by amine deprotection and Michael trapping
has been demonstrated [6]. Using cationic polymerization, gelation
of disulfide crosslinked polyoxazoline was studied: reductive
cleavage returned the material to a soluble polymer [7]. In the
self-assembly of liposomes, thiol-substituted phosphatidylcholine
species formed bilayer vesicles that could be crosslinked reversibly
under redox control [8]. Rotaxanes with cleavable disulfide spin-
dles [9] have been developed, and dynamic disulfide exchange
has been studied in the formation of supramolecular hydrogen
bonded systems [10]. Thus disulfides are effective and reversible
crosslinking agents [11]. However thiol groups are incompatible
with free radical polymerization, as they act as chain transfer
agents, rapidly donating a hydrogen atom to carbon radicals with
rate constants typically on the order of 107–108 Mꢀ1 sꢀ1 [12]. Thus
protected thiols or disulfides must be utilized when carrying out
radical polymerization. A number of groups have investigated the
use of thiol crosslinking following ATRP (Atom Transfer Radical
Polymerization) [13–19] or RAFT (Reversible Addition Fragmenta-
tion Transfer) polymerization [20–28]. There is one report of the
conversion of polymers prepared by Nitroxide-Mediated Radical
Polymerization (NMRP) [29] to RAFT, followed by thiol crosslinking
[30]. However, there are two papers utilizing this strategy in
manipulating polymers prepared by NMRP: earlier work by our
group employing a thiol-terminated polymer [31], and a paper uti-
lizing NMRP or RAFT of thiolactone-substituted styrenes [32]. In
addition to applications in preparing reversible crosslinks, thiols
disulfide linkages in structural proteins such as
a-keratin control
the attributes of straight or curly hair. Vulcanization of natural
and synthetic rubber imparts rigidity via di, tri and higher order
sulfide crosslinkages. Using conventional (uncontrolled) free radi-
cal polymerization, a number of synthetic polymers containing
disulfide crosslinks have been prepared. For example, crosslinked
polyacrylamide hydrogels have been prepared by polymerization
of acrylamides mixed with acrylamide-disulfide crosslinking
agents [1]. Cysteine-functionalized polymethacrylamide formed
an insoluble crosslinked material [2]. Polyvinylidene fluoride con-
taining pendant protected thiol side groups was vulcanized by
deprotection to the free thiols and cured with 1,5-hexadiene [3].
Uncontrolled free radical polymerization of substituted styrenes
with and without pre-formed disulfide crosslinkers formed exten-
sively crosslinked networks, in which the reversibility of disulfide
formation was examined as a function of proximal cooperativity
or site isolation [4]. Emulsion copolymerization of styrenes with
vinylbenzyl S-thioacetate gave thiol-substituted microgels: disul-
fide crosslinks were avoided by the use of reducing agents during
deprotection of the thiol groups, although undesired crosslinking
⇑
Corresponding author. Tel.: +1 831 459 3087; fax: +1 831 459 2935.
E-mail address: rbraslau@ucsc.edu (R. Braslau).
1381-5148/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.reactfunctpolym.2013.01.009

R. Braslau et al. / Reactive & Functional Polymers 73 (2013) 624–633
625
+
R
R'
deprotect
O-Nit
O-Nit
S-PG
O-Nit
SH
m
R'm
SH
n
n
R'
S-PG
R
R
Ph
S
120 °C
Ph
Ph
random copolymerization
S
S
oxidation
reduction
SH
SH
S
S
S
SH
SH
SH
Scheme 1. Preparation of random co-polymers containing pendant thiol sidechains: redox control of crosslinking.
Scheme 2. Preparation of polymers containing a thiol terminus: redox control of crosslinking to prepare linear polymers of double the molecular weight.
and disulfides form bonds to metal surfaces such as gold, silver,
and CdSe and related quantum dots. Thiols are have also become
popular in appending groups to organic molecules utilizing the
thiol-ene [33] and thiol-yne [34] ‘‘click’’ reactions to unactivated
terminal olefins.
In this work, vinyl monomers containing protected thiol groups
were prepared and subjected to NMRP mixed with non-thiolated
monomers, followed by deprotection of the thiols to provide poly-
mer chains with intermittent pendant thiol groups (Scheme 1).
Alkoxyamine initiators bearing protected thiols were also pre-
pared. Polymerization, followed by deprotection, yielded thiol-ter-
minated polymer chains (Scheme 2). The redox control of polymers
bearing pendant thiols or a terminal thiol was adjusted by oxida-
tion to form disulfides, or reduction to cleave the disulfides. Thus
the macromolecular properties can be manipulated following
polymerization.
aminopropyl)-3-ethylcarbodiimide (EDC) (98+%), and N,N0-dicy-
clohexyl dicyclocarbodiimide (DCC) (99%). The following
reagents were purchased from Fisher Scientific: sodium hydrox-
ide (ACS certified), trifluoroacetic acid (reagent grade), sodium
borohydride (98%), and triethylamine. Trityl chloride was pur-
chased from EMD. Triisopropylsilane was purchased from Oak-
wood Products, Inc. Granular copper (20–30 mesh) was
purchased from J.T. Baker. Flash chromatography was performed
using EM Science Silica Gel 60. Analytical TLC was performed
using commercial Whatman plates coated with silica gel
(0.25 mm thick). PAA TLC stain was made from a mixture of eth-
anol (37.5 mL), concentrated sulfuric acid (2.08 mL), glacial acidic
acid (0.427 mL), and p-anisaldehyde (2.5 mL). Polymerizations
were carried out in sealed ampoules under argon. NMR spectra
were recorded at ambient temperature in CDCl3 or CD3OD on
either a Varian UNITY plus 500 MHz or INOVA 600 MHz spec-
trometer as noted. Size exclusion chromatography (SEC) was per-
formed using a Waters apparatus equipped with five Styragel
2. Experimental
columns (300 ꢁ 4.6 mm, 5
lm bead size), HR 0.5 (pore size
50 Å, 0–1000 Da), HR 1 (pore size 100 Å, 100–5000 Da), HR 2
(pore size 500 Å, 500–20,000 Da), HR 4 (pore size 10,000 Å, 50–
1,000,000 Da), HR 5E (linear bed, mixed pore sizes, 2000–
4 ꢁ 106 Da). Tetrahydrofuran (THF) was used as the eluent at a
flow rate of 0.35 mL/min at ambient temperature. A refractive in-
dex detector was used, and the molecular weights were cali-
brated against seven polystyrene standards ranging from 2000
to 156,000 Da. SEC traces are shown with absorbance on the y-
axis, and minutes on the x-axis.
2.1. Materials and instrumentation
Styrene (99%, Acros Organics) and t-butyl acrylate (98%, Al-
drich) were distilled under vacuum immediately before use. Tet-
rahydrofuran (THF) was distilled from sodium/benzophenone.
Acetonitrile, dichloromethane, methanol and toluene were ob-
tained from a PureSolv solvent purification system (SPS) manu-
factured by Innovative Technologies, Inc. when anhydrous
conditions were required. All other solvents were used as re-
ceived. Water was deionized. Manganese(salen) catalyst was pre-
pared following the procedure of Choudary et al. [35]. All other
reagents were used without further purification. The following re-
agents were purchased from Sigma–Aldrich: tert-butyldimethylsi-
lyl chloride (TBDMS) (97%), DL-dithiothreitol (DTT) (99%), N-
phenylmaleimide (97%), acryloyl chloride (96%), and acrylic acid.
2.2. Synthesis and characterization of monomers and initiators
2.2.1. Synthesis of 2-(4-vinyl-benzyl) isothiourea hydrochloride [36]
(1)
Thiourea (3.517 g, 46.20 mmol) was dissolved in methanol
(15 mL) in a flask containing 4-vinylbenzyl chloride (7.077 g,
46.37 mmol). The reaction was heated at 60 °C overnight. Upon
cooling, diethyl ether was added to the reaction mixture until a
constant turbidity was observed; this solution was left in the
The following reagents were purchased from Acros Organics: L-
cysteine methyl ester hydrochloride (98%), 4-vinylbenzyl chloride
(90%, tech.), thiourea (reagent grade, ACS), sodium hydride (60%
dispersion in mineral oil), copper chloride (99%), 1-(3-dimethyl-

626
R. Braslau et al. / Reactive & Functional Polymers 73 (2013) 624–633
freezer overnight. The next day, the isothiouronium salt was fil-
tered, and rinsed with diethyl ether to give 9.728 g (92% yield) of
the title product as a white powder. 1H NMR (600 MHz, CD3OD):
d 7.45 (d, 2H, J = 8.4 Hz), 7.38 (d, 2H, J = 8.4 Hz), 6.74 (dd, 1H,
J = 17.4, 10.8 Hz), 5.81 (dd, 1H, J = 17.4, 0.6 Hz), 5.27 (dd, 1H,
J = 10.8, 0.6 Hz), 4.42 (s, 2H) ppm. 13C NMR (125 MHz, CD3OD): d
172.2, 139.4, 137.5, 134.8, 130.6, 127.9, 115.2, 36.3 ppm.
2.2.5. Synthesis of (4-vinyl-benzyl)-trityl sulfide (5)
Following a modified literature procedure [38], to a solution of
freshly
prepared
4-vinyl-phenyl
methanethiol
(2.407 g,
16.02 mmol) in DMF (9.6 mL) was added trityl chloride (5.359 g,
19.23 mmol). This solution was stirred overnight. The next day,
CH2Cl2 (50 mL) was added and the mixture was washed with
H2O (4 ꢁ 50 mL), brine (1 ꢁ 50 mL), dried over MgSO4, filtered,
and the filtrate concentrated to give a yellow solid. This was dis-
solved in a minimal amount of CH2Cl2 and recrystallized from
diethyl ether to give 5.317 g (85%) of the title compound.
Mp = 91–95 °C. IR (CDCl3) 699 (S–C). Rf = 0.38 (hexanes:ethyl ace-
tate, 20:1, UV, I2, PAA). 1H NMR (500 MHz, CDCl3): d 7.47–7.26
(m, 19H), 6.64 (dd, J = 14.5, 9.0 Hz, 1H), 5.68 (d, J = 14.5 Hz, 1H),
5.18 (d, J = 9.0 Hz, 1H), 3.30 (s, 2H) ppm. 13C NMR (125 MHz,
CDCl3): d 144.8, 136.6, 136.5, 136.5, 129.7, 129.3, 128.0, 126.8,
126.4, 113.7, 67.5, 36.8 ppm.
2.2.2. Synthesis of 4-vinyl-phenyl methanethiol [37] (2)
Following a modified procedure from Yamaguchi et al. [37], 2-
(4-vinyl-benzyl) isothiourea hydrochloride 1 (3.000 g, 13.12 mmol)
was dissolved in DMF (5 mL). This system was purged with N2 be-
fore adding 2 N NaOH (19.8 mL); a white precipitate formed imme-
diately. The solution was stirred at room temperature under N2 for
2 h. To this was added 2 N HCl (19.8 mL) and the solution was stir-
red for 5 min. Ether (20 mL) was added and the solution was
washed with H2O (4 ꢁ 60 mL) and brine (1 ꢁ 60 mL), and then
dried over MgSO4. The solid was removed by filtration and the vol-
atiles were removed in vacuo to afford 1.601 g (10.66 mmol, 91%)
of a yellow oil which was used without further purification. 1H
NMR (500 MHz, CDCl3): d 7.39 (d, 2H, J = 8.4 Hz), 7.30 (d, 2H,
J = 8.4 Hz), 6.73 (dd, 1H, J = 17.5, 10.5 Hz), 5.76 (dd, 1H, J = 17.5,
1.0 Hz), 5.26 (dd, 1H, J = 10.5, 1.0 Hz), 3.75 (d, 2H, J = 7.5 Hz), 1.77
(t, 1H, J = 7.5 Hz) ppm. 13C NMR (125 MHz, CDCl3): d 140.9,
136.6, 129.7, 128.8, 126.6, 114.0, 28.9 ppm.
2.2.6. Synthesis of S-trityl-L-cysteine methyl ester hydrochloride (6)
Following the literature procedure [38], to a solution of
L
-cys-
teine methyl ester hydrochloride (300 mg, 1.76 mmol) in DMF
(2 mL) was added trityl chloride (735 mg, 2.64 mmol). The reaction
mixture was allowed to stir for 3 days at room temperature. An
aqueous solution of 10% sodium acetate (10 mL) was added and a
white precipitate formed. The sticky white mass was isolated by
filtration. Column chromatography (hexanes:ethyl acetate, 1:1)
afforded 653 mg (90%) of the title compound as a white solid. 1H
NMR (600 MHz, CD3OD): d 7.41 (d, J = 4.0 Hz, 6H), 7.27 (dd,
J = 4.0, 4.0 Hz, 6H), 7.20 (t, J = 4.0 Hz, 3H) 3.65 (s, 3H), 3.14 (dd,
J = 5.4, 5.4 Hz, 1H), 2.59 (dd, J = 6.6, 5.4 Hz, 1H), 2.49 (dd, J = 6.6,
5.4 Hz, 1H) ppm.
2.2.3. Synthesis of 1,2-bis(4-vinyl-benzyl) disulfide [4] (3)
The synthesis began by adding 2 N NaOH (5 mL) to a solution of
4-vinyl-phenyl methanethiol (1.000 g, 4.372 mmol) in H2O
(9.9 mL). This solution was heated to 50 °C and air was bubbled
through the reaction mixture overnight. The reaction was
quenched with a saturated solution of NH4Cl (5 mL) before being
extracted with ether (3 ꢁ 20 mL). The solution was dried over
MgSO4, filtered and concentrated to give 503 mg (65%) of the de-
sired product as a yellowish oil. IR: (neat) 1445, 759, 699,
2.2.7. Synthesis of L-cysteine-N-acryl-S-(triphenylmethyl)-methyl
ester (7)
Following the literature procedure [39], a flame-dried 250 mL
round bottom flask was charged with dry methylene chloride
(106 mL), S-trityl-
L
-cysteine methyl ester hydrochloride
6
(3.945 g, 9.530 mmol), acryloyl chloride (0.85 mL, 949 mg,
10.5 mmol), and triethylamine (2.80 mL, 2.02 g, 20.0 mmol). The
solution was stirred at room temperature overnight. The reaction
mixture was washed with water (1 ꢁ 100 mL). The aqueous layer
was extracted with methylene chloride (2 ꢁ 50 mL). The combined
organic layers were dried over sodium sulfate, filtered, and then
concentrated to give the title product in quantitative yield
(4.336 g). 1H NMR (500 MHz, CD3OD): d 7.39–7.20 (m, 15H), 6.28
(dd, J = 14.3, 1.0 Hz, 1H), 6.06 (dd, J = 14.3, 8.5 Hz, 1H), 5.67 (dd,
J = 8.5, 1.0 Hz, 1H), 4.69 (ABX, JAX = 4.6, JBX = 3.9 Hz, 1H), 2.89
(ABX, JAB = 10.5, JAX = 4.6 Hz, 1H), 2.51 (ABX, JAB = 10.5, JBX = 3.9 Hz,
1H) ppm.
638 cmꢀ1 1H NMR (600 MHz, CDCl3): d 7.38–7.20 (m, 8H), 6.71
.
(dd, 1H, J = 17.4, 10.8 Hz), 5.75 (dd, 1H, J = 17.4, 2.4 Hz), 5.25 (dd,
1H, J = 10.8, 2.4 Hz), 3.63 (s, 1H) ppm. 13C NMR, DEPT (125 MHz,
CDCl3): d 146.8 (C), 136.9 (C), 136.4 (CH), 129.6 (CH), 127.9 (CH),
127.2(CH), 126.4 (CH), 114.0 (CH2), 43.1 (CH2) ppm.
2.2.4. Synthesis of 4-t-butyldimethylsilylthiomethylstyrene (4)
Following a modified procedure from Yamaguchi et al. [37], a
solution of 60% NaH in mineral oil (611 mg, 15.3 mmol) and THF
(20.4 mL) was cooled to 0 °C under N2 before adding freshly pre-
pared 4-vinyl-phenyl methanethiol. Effervescence was observed.
This mixture was allowed to warm to room temperature before
2.2.8. Synthesis of N-[1-(4-tritylthiomethyl-phenyl)-ethoxy]-N-tert-
butyl-2-methyl-1-phenylpropan-1-amine (8)
adding
a solution of t-butyldimethylsilyl chloride (2.303 g,
15.28 mmol) in THF (14 mL). The reaction mixture was allowed
to stir at room temperature under N2 overnight. The THF was re-
moved and the remaining oil was taken up in CH2Cl2 and washed
with a 5% solution of NaOH (75 mL) followed by brine (75 mL).
The combined aqueous layers were extracted with CH2Cl2
(50 mL). The combined organic layers were dried over MgSO4, fil-
tered and concentrated to give a yellow oil. This crude product
was run through a short chromatography column of silica using
hexanes as the eluent to yield 1.497 g (56%) of the product as a col-
orless oil. Rf = 0.6 (hexanes:ethyl acetate, 20:1, UV, I2, PAA). 1H
NMR (500 MHz, CDCl3):): d 7.32 (d, J = 8.5 Hz, 2H), 7.29 (d,
J = 8.5 Hz, 2H), 6.69 (dd, J = 17.5, 10.8 Hz, 1H), 5.77 (d, J = 17.5 Hz,
1H), 5.21 (d, J = 10.8 Hz, 1H), 3.71 (s, 2H), 0.97 (s, 9H), 0.26 (s,
6H) ppm. 13C NMR (125 MHz, CDCl3): d 140.51, 136.70, 136.37,
128.83, 126.51, 113.73, 30.61, 26.53, 19.21, ꢀ3.38 ppm.
Following a modified procedure of Hawker et al. [40], 2,2,5-
trimethyl-4-phenyl-3-azahexane-3-nitroxide
(TIPNO,
43 mg,
0.20 mmol) was dissolved in 2:3 v/v of toluene (0.70 mL) and eth-
anol (0.95 mL) followed by the addition of (4-vinyl-benzyl)-trityl
sulfide (5, 150 mg, 0.38 mmol). Manganese(salen) catalyst [35]
(17 mg, 0.048 mmol) was then added followed by sodium borohy-
dride (23 mg, 0.61 mmol) and the reaction was allowed to stir open
to the atmosphere overnight. The reaction mixture was concen-
trated, combined with dichloromethane (10 mL), water (10 mL),
and a few drops of 10% hydrochloric acid was added (until
pH ꢂ 7) to break the resulting emulsion. The aqueous layer was ex-
tracted with dichloromethane (3 ꢁ 10 mL). The combined organic
layer was washed with saturated sodium bicarbonate (30 mL),
dried over magnesium sulfate, and concentrated in vacuo to give
231 mg of a brownish oil. The resulting oil was purified by silica

R. Braslau et al. / Reactive & Functional Polymers 73 (2013) 624–633
627
gel column chromatography with 3:2 hexanes/dichloromethane to
give 69 mg (58% yield) of the title product as a white solid, as a
mixture of two diastereomers. TLC: 3:2 hexanes/dichloromethane,
UV, p-anisaldehyde stain, Rf = 0.67. Melting point: 62–63 °C. IR:
(500 MHz, CDCl3, two diastereomers): d 7.50–7.10 (m, 18H), 4.89
(q + q, 2H, J = 6.5 Hz), 3.75 (d, 2H, J = 7.5 Hz), 3.72 (d, 2H,
J = 7.5 Hz), 3.41 (d, 1H, J = 10.5 Hz), 3.29 (d, 1H, J = 10.5 Hz), 2.30
(m, 1H), 1.74 (td, 2H, Jt = 7.5 Hz, Jd = 2.5 Hz), 1.60 (d, 3H,
J = 6.5 Hz), 1.52 (d, 3H, J = 6.5 Hz), 1.40 (m, 1H), 1.29 (d, 3H,
J = 6.5 Hz), 1.03 (s, 9H), 0.91 (d, 3H, J = 6.5 Hz), 0.77 (s, 9H), 0.52
(d, 3H, J = 6.5 Hz), 0.21 (d, 3H, J = 6.6 Hz) ppm.
(neat) 2973, 1489, 1444, 1361, 1206, 1061, 740, 700 cmꢀ1 1H
.
NMR (600 MHz, CDCl3, diastereomers): d 7.50–7.07 (m, 40H),
4.87 (q + q, 2H, J = 6.6 Hz), 3.40 (d, 1H, J = 10.8 Hz), 3.33 (s, 2H),
3.29 (s, 2H), 3.29 (d, 1H, J = 10.8 Hz), 2.32 (m, 1H), 1.58 (d, 3H,
J = 6.6 Hz), 1.51 (d, 3H, J = 6.6 Hz), 1.37 (m, 1H), 1.29 (d, 3H,
J = 6.6 Hz), 1.03 (s, 9H), 0.91 (d, 3H, J = 6.6 Hz), 0.76 (s, 9H), 0.54
(d, 3H, J = 6.6 Hz), 0.22 (d, 3H, J = 6.6 Hz) ppm. 13C NMR
2.3. Polymerization: the following procedure is representative: trityl-
protected thiol terminated polystyrene (P9)
(125 MHz, CDCl3, two diastereomers):
d 144.8, 144.7, 143.9,
142.5, 142.4, 135.9, 135.2, 131.0, 131.0, 129.7, 128.9, 128.9,
128.0, 127.4, 127.3, 127.2, 126.8, 126.4, 126.3, 126.2, 83.2, 82.4,
72.1, 67.4, 60.5, 60.4, 59.3, 36.8, 36.8, 32.0, 31.6, 28.3, 28.2, 24.6,
23.1, 22.1, 21.9, 21.1, 21.0 ppm. HRMS: M + 1 (C42H48NOS+)
614.3451 calcd; 614.3436 obsd.
Following the procedure of Hawker et al. [41], to a 5 mL ampule
was added N-[1-(4-tritylthiomethyl-phenyl)-ethoxy]-N-tert-butyl-
2-methyl-1-phenylpropan-1-amine (8, 25 mg, 0.040 mmol), and
styrene monomer (913 mg, 8.77 mmol). The ampule was subjected
to three freeze/pump/thaw cycles, sealed under argon and heated
in an oil bath at 120 °C for 3.25 h. After cooling, an aliquot was ana-
lyzed by 1H NMR to determine the percent monomer conversion:
52%. The reaction mixture was dissolved in tetrahydrofuran, and
methanol was added dropwise to precipitate a white polymer.
The polymer was filtered and dried in vacuo to afford 480 mg
(50% yield) of the title product as a white powder. The GPC trace
showed Mn = 12,700 amu, PDI = 1.08. 1H NMR (500 MHz, CDCl3):
d 7.2–6.9 (br, aromatic H), 6.7–6.3 (br, aromatic H), 2.0–1.7 (br,
PhCH), 1.7–1.3 (br, PhCHCH2) ppm.
2.2.9. Synthesis of N-tert-butyl-O-{1-[4-(4-{1-[N-tert-butyl-N-(2-
methyl-1-phenyl-propyl)-aminooxy] ethyl}-benzyldisulfanylmethyl)-
phenyl]-ethyl}-N-(2-methyl-1-phenyl-propyl)-hydroxylamine [31] (9)
Following a modified procedure of Hawker [40] 2,2,5-trimethyl-
4-phenyl-3-azahexane-3-nitroxide (TIPNO, 72 mg, 0.33 mmol) was
dissolved in 2:3 v/v of toluene (0.45 mL) and ethanol (0.65 mL) fol-
lowed by the addition of 4-vinyl benzyl disulfide (3, 38 mg,
0.13 mmol). Manganese(salen) catalyst [35] (11 mg, 0.030 mmol)
was then added followed by sodium borohydride (22 mg,
0.58 mmol), and the reaction was allowed to stir open to the atmo-
sphere overnight. The reaction mixture was concentrated, com-
bined with dichloromethane (10 mL), water (10 mL), and a few
drops of 10% hydrochloric acid was added (until pH ꢂ 7) to break
the resulting emulsion. The aqueous layer was extracted with
dichloromethane (3 ꢁ 10 mL). The combined organic layer was
washed with saturated sodium bicarbonate (30 mL), dried over
magnesium sulfate, and concentrated in vacuo to give 64 mg of a
brownish oil. The resulting oil was purified by silica gel column
chromatography with 3:2 hexane/dichloromethane to give 39 mg
(41% yield) of the title product as a yellowish oil, as a mixture of
diastereomers. TLC: 3:2 hexanes/dichloromethane, UV, p-anisalde-
hyde stain, Rf = 0.52. 1H NMR (600 MHz, CDCl3, two diastereo-
mers): d 7.48–7.12 (m, 36H), 4.91 (q + q, 4H, J = 6.6 Hz), 3.68 (s,
4H), 3.57 (s, 2H), 3.56 (s, 2H), 3.42 (d, 1H, J = 10.8 Hz), 3.40 (d,
1H, J = 10.8 Hz), 3.31 (d, 1H, J = 10.8 Hz), 3.30 (d, 1H, J = 10.8 Hz),
2.34 (m, 2H), 1.62 (d, 3H, J = 6.6 Hz), 1.61 (d, 3H, J = 6.6 Hz), 1.54
(d, 3H, J = 6.6 Hz), 1.53 (d, 3H, J = 6.6 Hz), 1.40 (m, 2H), 1.31 (d,
3H, J = 6.6 Hz), 1.30 (d, 3H, J = 6.6 Hz), 1.06 (s, 9H), 1.05 (s, 9H),
0.94 (d, 3H, J = 6.6 Hz), 0.93 (d, 3H, J = 6.6 Hz), 0.76 (s, 9H), 0.75
(s, 9H), 0.56 (d, 3H, J = 6.6 Hz), 0.55 (d, 3H, J = 6.6 Hz), 0.21 (d,
3H, J = 6.6 Hz), 0.20 (d, 3H, J = 6.6 Hz) ppm. 13C NMR (150 MHz,
CDCl3): d 145.2, 145.1, 144.3, 144.2, 142.4, 142.2, 136.3, 136.2,
135.8, 135.6, 131.0, 130.9, 129.2, 127.4, 127.2, 127.1, 126.3,
126.2, 126.1, 83.3, 82.5, 82.4, 72.2, 60.5, 60.4, 43.2, 43.1, 43.0,
32.1, 31.7, 28.4, 28.2, 24.8, 24.7, 23.3, 23.2, 22.2, 22.0, 21.2,
21.1 ppm.
2.4. Post-polymerization modification of polymers
2.4.1. Deprotection of thiotrityl terminated polymer (P9) and disulfide
formation to form central disulfide polystyrene (P10)
Following the procedure of Wang et al. [42], trityl-protected
thiol terminated polystyrene (P9, 100 mg, 0.8 mmol) was dissolved
in tetrahydrofuran (2 mL) followed by the addition of copper (I)
chloride (22 mg, 0.22 mmol) and water (0.1 mL) as a co-solvent.
The reaction was conducted under ultrasonic irradiation open to
the atmosphere for 3 days. Tetrahydrofuran was added regularly
to maintain the original volume; and the reaction flask was capped
each night without ultrasonication. The reaction mixture was
taken up in dichloromethane (5 mL) and water (5 mL), and then
the aqueous layer was extracted with dichloromethane
(2 ꢁ 5 mL). The combined organic layer was dried over magnesium
sulfate, filtered, and concentrated in vacuo to give 89 mg of a yel-
lowish powder as a mixture of starting material and product. The
GPC trace showed Mn = 19,900 amu, PDI = 1.23.
2.4.2. Disulfide cleavage of central disulfide polymer (P10) and
trapping of the terminal thiol to prepare N-phenylmaleimide sulfide
terminated polystyrene (P11)
Following the procedure of Hill et al. [31], central disulfide poly-
styrene (P10, 26 mg, 0.0010 mmol) was dissolved in dimethyl-
formamide (3 mL) followed by the addition of dithiothreitol
(DTT, 25 mg, 0.16 mmol). The reaction flask was subjected to three
freeze/pump/thaw cycles and then heated at 60 °C for 2 days. After
cooling, N-phenylmaleimide (34 mg, 0.20 mmol) was added, and
the reaction mixture was stirred for an additional 7 h. The solution
was taken up in tetrahydrofuran (1 mL), and methanol was added
dropwise to precipitate a white polymer. The polymer was col-
lected by centrifugation to afford 15 mg of a white powder. The
GPC trace showed Mn = 16,600 amu, PDI = 1.24. There was a small
shoulder of high molecular weight polymer in GPC trace, so the
polymer was subjected to further reduction using the same condi-
tions for 2 additional days. The resulting GPC trace showed no
shoulder: Mn = 12,800 amu, PDI = 1.10.
2.2.10. Synthesis of N-tert-butyl-O-[1-(4-mercaptomethyl-phenyl)-
ethyl]-N-(2-methyl-1-phenyl-propyl)-hydroxylamine [31] (10)
Following the procedure of Hill et al. [31], disulfide initiator (9,
95 mg, 0.13 mmol) was dissolved in dimethylformamide (2 mL)
followed by the addition of dithiothreitol (DTT, 41 mg, 0.27 mmol).
The reaction flask was subjected to three freeze/pump/thaw cycles
to remove oxygen, and then stirred at 60 °C overnight under N2.
Upon cooling, the reaction mixture was taken up in dichlorometh-
ane (10 mL), washed five times with water (10 mL), dried over
magnesium sulfate, filtered, and concentrated in vacuo to give
40 mg (85% yield) of the title product as a yellowish oil. 1H NMR

628
R. Braslau et al. / Reactive & Functional Polymers 73 (2013) 624–633
3. Results and discussion
Mn =20,800
3.1. Sulfur-containing monomers to provide pendant thiol
functionality
3.1.1. Thiol-substituted styrene monomers
The first thiol-substituted monomer investigated was as styrene
derivative, prepared from the vinyl benzyl chloride via the isoth-
ioruronium salt [43] 1 (Scheme 3). This polar salt was insoluble
with styrene, however copolymerization with the alkoxyamine de-
rived from TIPNO [41] was carried out using DMF as a co-solvent,
with poor control over polydispersity at 9:1 or 1:1 styrene:isoth-
ioruronium salt 1 ratios. The isothioruronium salt was hydrolyzed
to prepare the benzylic thiol 2 in excellent yield, which was repro-
tected using three different strategies. Mild oxidation of the so-
dium salt with air provided the disulfide 3, whereas protection
with tributyldimethylsilyl (TBDMS) or trityl gave the substituted
styrene monomers 4 and 5 (Scheme 3). The tritylated vinyl mono-
mer 5 was a stable, slightly yellow solid.
Copolymerizations of derivatives 4 and 5 with styrene (9:1 sty-
rene:protected benzyl thiol derivative) were carried out at using
0.5% of the alkoxyamine initiator (Scheme 4). The trityl protected
monomer gave rise to random copolymer P2 with excellent control
over polydispersity (Mn = 20,800, PDI = 1.15), whereas the TBDMS-
protected monomer gave rise to random copolymer P1 with a GPC
trace showing a larger molecular weight shoulder, that indicated a
small amount of disulfide incorporated into each chain
(Mn = 14,600, PDI = 1.44). For the clean tritylated random co-poly-
mer P2 (the GPC peak was symmetric, with no visible shoulders,
Fig. 1), the trityl group was removed by deprotection with trifluo-
roacetic acid [44] (TFA), followed by concentration, and precipita-
tion upon addition of cold methanol. This material was then
dissolved in THF, and basified by addition of aqueous sodium
Fig. 1. Overlay of GPC chromatographs of protected random tritylated copolymer
P2 [(---) PDI = 1.15, Mn = 20,800] and partially deprotected, oxidized polymer
network P3 (___).
hydroxide while bubbling air through the sample to promote disul-
fide formation (CAUTION: do not concentrate solution in case of
peroxide formation) (see Scheme 5). The resulting GPC trace of P3
(Fig. 1) illustrates the formation of large crosslinked networks,
probably formed during concentration of the free thiol in the pres-
ence of air, however a significant amount of uncrosslinked polymer
(presumably P2) remained (Mn = 20,800).
Varying the conditions, deprotection with TFA in THF was re-
peated with a new sample of P2, after which the volatiles were re-
moved to provide a concentrated sample. After dilution with
dichloromethane to 6 ꢁ 10ꢀ4 M, copper granules were added and
air bubbled through the mixture overnight. A crosslinked network
of polymers P4 was formed, indicating that significant disulfide
formation occurred upon exposure to air in the concentrated
sample, prior to dilution and treatment with Cu and air. Again, a
Scheme 3. Preparation of protected benzylic thiol derivatives of styrene.
Scheme 4. Random copolymerization of protected benzylic thiol styrene derivatives 4 and 5 with styrene by NMP.

R. Braslau et al. / Reactive & Functional Polymers 73 (2013) 624–633
629
Scheme 6. Deprotection of tritylated random copolymer P2, concentration of the sample, and crosslinking to form P4.
Fig. 2. GPC chromatograph of the crosslinked polymer P4 (Mn = 33,300).
Fig. 3. Overlay of GPC chromatographs of crosslinked polymer P4 (---, Mn = 33,300)
and reduced and NMP-capped polymer P5 (___, PDI = 1.44, Mn = 28,100).
shoulder to the right on the GPC trace of P4 indicated incomplete
deprotection (Fig. 2) (see Scheme 6).
Cleavage of the disulfide linkages by treatment with dith-
iolthreitol [45] (2,3-dihydroxy-1,4-butanethiol, DTT), followed by
capping the free thiol groups by Michael addition to N-phenyl-
maleimide (NPM) returned most of the crosslinked material P4
to the lower molecular weight polymer P5 (Scheme 7 and Fig. 3).
Thus one can manipulate the crosslinking by controlling the redox
properties of thiol/disulfide functionalities.
trityl-protected thiol-substituted acrylamide 7 (Scheme 8). Use of
standard coupling agents EDC or DCC provided only moderate
yields of the desired acrylamide. Alternatively, a stoichiometric
yield of acrylamide 7 was obtained using acryloyl chloride.
Copolymerization with nine equivalents of tert-butyl acrylate
(TBA) to every one equivalent of tritylated cysteine-derived acryl-
amide 7 (Scheme 9) provided random copolymer P6 (Mn = 12,800,
PDI = 1.55). Instead of allowing the sample to concentrate, depro-
tection and crosslinking of the thiol group was carried out under
dilute conditions to enhance intramolecular disulfide formation.
3.1.2. Thiol-substituted acrylamide monomers
Following the work of Endo et al. [2], tritylated
L-cysteine
methyl ester was coupled to acrylic acid to provide
6
Scheme 5. Partial deprotection of tritylated random copolymer P2, followed by crosslinking to form P3.
Scheme 7. Disulfide reduction with DTT, followed by capping the free thiol groups with NPM to reform linear polymer.

630
R. Braslau et al. / Reactive & Functional Polymers 73 (2013) 624–633
O
OH
CH2Cl2
Et3N
EDC 41%
O
O
S
O
H
N
HCl•H2N
Tr-Cl
HCl•H2N
or DCC 44%
OMe
SH
OMe
Tr
OMe
S-Tr
O
DMF
90%
7
O
6
Cl
CH2Cl2
Et3N
>99%
Scheme 8. Preparation of trityl protected cysteine derived acrylamide 7.
Scheme 9. Random copolymerization of protected cysteine acrylamide 7 with TBA by NMP to form P6.
Scheme 10. Deprotection of tritylated random copolymer P6 and crosslinking under dilute conditions to form a collapsed nanoparticle P7.
To optimize trityl group removal, deprotection using triisopropyl
silane/TFA (5% v/v with respect to dichloromethane) [46] was first
examined on monomer 7 at room temperature overnight in dichlo-
romethane. After work-up, complete removal of the trityl group
was observed by TLC and NMR. Thus random copolymer P6 was
dissolved in dichloromethane at 3.7 ꢁ 10ꢀ3 M, and then exposed
to triisopropyl silane/TFA to remove the trityl group overnight.
Upon exposure to air under these dilute conditions, intramolecular
disulfide formation occurred (Scheme 10). This was evident from
the GPC trace of P7 (Mn = 8,700, PDI = 1.50), which reflected a poly-
mer of apparent size 68% of that of the trityl-protected linear poly-
mer P6, indicative of a collapsed nanoparticle. Work by Harth
[47,48] has demonstrated collapsed nanoparticles with apparent
masses of 62% and 68% of the weight of the linear polymer precur-
sors, respectively. 1H NMR indicated that most of the tBu groups
remained intact. Partial reduction of the disulfide bonds by treat-
ment with DTT followed by capping the free thiols with N-phenyl-
maleimide (Scheme 11) provided a mixture of the collapsed
nanoparticle, the linear polymer P8, and a higher weight compo-
nent indicating crosslinking between two or more polymer chains.
Apparently the DTT reagent was unable to access some of the more
deeply buried disulfide crosslinks within P7. There was also a high
molecular weight shoulder, indicating intermolecular crosslinking
prior to capping the free thiol groups with N-phenylmaleimide
(Fig. 4).
3.2. Sulfur-containing N-alkoxyamine initiators to provide thiol-
functionalized polymer termini
The use of functionalized azo initiators, [49,50], or pre-formed
N-alkoxyamine initiators provides the opportunity to functionalize
the phenethyl ‘‘foot’’ of the polymer [51]. Given the robust nature
of the trityl protecting group in forming thiol-bearing monomers 5
and 7, we decided to re-visit our preparation of a thiol functional-
ized N-alkoxyamine initiator, in which TBS had been the protecting
group [31]. In that previous work, polystyrene prepared from the
TBS-protected thiol initiator showed a high molecular weight
shoulder in the GPC trace, even though the initiator had been puri-
fied by flash column chromatography, indicating that a small
amount of disulfide initiator was a contaminant. Thus rigorous

R. Braslau et al. / Reactive & Functional Polymers 73 (2013) 624–633
631
Scheme 11. Deprotection of collapsed nanoparticle P7 by cleavage of solvent accessible disulfide bonds by DTT, followed by capping with NPM.
catalytic amount of copper(I) chloride and air under sonication
for 3 days. The resulting polymer P10 (Mn = 19,900, PDI = 1.23)
showed a small low molecular weight shoulder, indicating depro-
tection or oxidation did not go to completion (see Fig. 5).
Disulfide cleavage with DTT, and capping of the free thiol
groups with N-phenylmaleimide to prevent reoxidation to disul-
fide provided polymer P11 of similar molecular weight
Fig. 4. Overlay of GPC chromatographs of tritylated random co-polymer P6 (black
line, PDI = 1.55, Mn = 12,800), deprotected, intramolecular crosslinked collapsed
nanoparticle P7(grey line, PDI = 1.50, Mn = 8,700), and reduction and capping to give
a mixture of linear capped polymer P8 (Mn = 12,800), collapsed nanoparticle, and a
higher molecular weight crosslinked polymer network (dashed line).
chromatography by HPLC was needed to prepare clean TBS-thiol
substituted initiator. To avoid this need for extensive purification,
the trityl-protected analogue 8 was prepared. Thus styryl benzyl
tritylthiol 5 was converted to the N-alkoxyamine 8 following a
modified procedure of Hawker [40], utilizing TIPNO nitroxide,
Mn(salen) reagent [35], sodium borohydride and air (Scheme 12).
This N-alkoxyamine was easily handled and purified by simple col-
umn chromatography, with no lability of the protecting group.
Polymerization of styrene (219 equivalents of styrene to 1 equiva-
lent of N-alkoxyamine 8 for 3.25 h at 120 °C) provided polystyrene
P9 bearing a terminal S-trityl group (Mn = 12,279, PDI = 1.08). Re-
moval of the trityl protecting group and disulfide formation was
carried out by simultaneous detritylation and oxidation using a
Fig. 5. Overlay of GPC chromatographs of trityl-protected polystyrene P9 (right,
Mn = 12,700, PDI = 1.08) and the resulting disulfide linked polystyrene P10 (left,
Mn = 19,900, PDI = 1.23).
Scheme 12. Preparation of N-alkoxyamine initiator 8 bearing a trityl-protected thiol, NMP polymerization of styrene, one-pot trityl deprotection and disulfide formation, and
cleavage of the central disulfide bond by DTT, followed by capping with NPM.

632
R. Braslau et al. / Reactive & Functional Polymers 73 (2013) 624–633
Acknowledgements
The University of California Santa Cruz Committee on Research
is acknowledged for partial support of this research. The authors
thank the NSF (CHE-0342912) for NMR support. CT thanks the Roy-
al Thai Government for a Higher Education Strategic Scholarship
for Frontier Research Network.
References
[1] H. Lee, T.G. Park, Polym. J. 30 (1998) 976–980.
[2] H. Kudo, F. Sanda, T. Endo, Macromol. Chem. Phys. 200 (1999) 1232–1239.
[3] B. Ameduri, B. Boutevin, G.K. Kostov, P. Petrova, Des. Monomers Polym. 2
(1999) 267–285.
[4] G. Wulff, I. Schulze, Angew. Chem., Int. Ed. Engl. 17 (1978) 537–538.
[5] N. Kihara, C. Kanno, T. Fukutomi, J. Polym, Part A: Polym. Chem. 35 (1997)
1443–1451.
[6] E. Hrsic, H. Keul, M. Möller, Eur. Polym. J. 48 (2012) 761–768.
[7] Y. Chujo, K. Sada, A. Naka, R. Nomura, T. Saegusa, Macromolecules 26 (1993)
883–887.
[8] N.K.P. Samuel, M. Singh, K. Yamaguchi, S.L. Regen, J. Am. Chem. Soc. 107 (1985)
42–47.
[9] T. Oku, Y. Furusho, T. Takata, Angew. Chem., Int. Ed. 43 (2004) 966–969.
[10] A.T. ten Cate, P.Y.W. Dankers, R.P. Sijbesma, E.W. Meijer, J. Org. Chem. 70
(2005) 5799–5803.
Fig. 6. Overlay of GPC chromatographs of disulfide linked polystyrene P10 (left,
Mn = 19,900, PDI = 1.23) and maleimide-trapped thiol terminated polystyrene P11
following disulfide cleavage (right, Mn = 12,800, PDI = 1.10).
[11] M.D. Rikkou, C.S. Patrickios, Prog. Polym. Sci. 36 (2011) 1079–1097.
[12] C. Chatgilialoglu, Helv. Chim. Acta 89 (2006) 2387.
[13] L. Garamszegi, C. Donzel, G. Carrot, T.Q. Nguyen, J. Hilborn, React. Funct. Polym.
55 (2003) 179–183.
[14] N.V. Tsarevsky, K. Matyjaszewski, Macromolecules 35 (2002) 9009–9014.
[15] N.V. Tsarevsky, J. Huang, K. Matyjaszewski, N. Kihara, C. Kanno, T. Fukutomi, J.
Polym. Sci. Part A: Polym. Chem. 47 (2009) 6839–6851.
[16] C.M. Li, J. Madsen, S.P. Armes, A.L. Lewis, Angew. Chem., Int. Ed. 45 (2006)
3510–3513.
Ph
Ph
Ph
N
N
N
O
O
O
DTT
Mn (salen), NaBH4
DMF
[17] J. Madsen, S.P. Armes, K. Bertal, H. Lomas, S. MacNeil, A.L. Lewis,
Biomacromolecules 9 (2008) 2265–2275.
[18] K. Yoshimoto, T. Hirase, J. Madsen, S.P. Armes, Y. Nagasaki, Macromol. Rapid
Commun. 30 (2009) 2136–2140.
[19] T. He, D.J. Adams, M.F. Butler, A.I. Cooper, S.P. Rannard, J. Am. Chem. Soc. 131
(2009) 1495–1501.
[20] H. Kitano, H. Nakada, K. Mizukami, Colloids Surf. B 61 (2008) 17–24.
[21] J.Q. Liu, H.Y. Liu, Z.F. Jia, V. Bulmus, T.P. Davis, Chem. Commun. (2008) 6582–
6584.
85%
toluene:EtOH
air
S
S
41%
2
3
SH
9
2
10
Scheme 13. Preparation of N-alkoxyamine free thiol initiator 10 via the disulfide 3.
[22] E. Setijadi, L. Tao, J.Q. Liu, Z.F. Jia, C. Boyer, T.P. Davis, Biomacromolecules 10
(2009) 2699–2707.
[23] J.Q. Liu, L. Tao, J.T. Xu, Z.F. Jia, C. Boyer, T.P. Davis, Polymer 50 (2009) 4455–
4463.
[24] Z.S. Ge, D.Y. Chen, J.Y. Zhang, J.Y. Rao, J. Yin, D. Wang, X.J. Wan, W.F. Shi, S.Y.
Liu, N. Kihara, C. Kanno, T. Fukutomi, J. Polym. Part A: Polym. Chem. 45 (2007)
1432–1445.
[25] Y.Q. Liu, K.A. Cavicchi, Macromol. Chem. Phys. 210 (2009) 1647–1653.
[26] Y.Z. You, C.Y. Hong, W.P. Wang, P.H. Wang, W.Q. Lu, C.Y. Pan, Macromolecules
37 (2004) 7140–7145.
[27] G. Delaittre, T. Pauloehrl, M. Bastmeyer, C. Barner-Kowollik, Macromolecules
45 (2012) 1792–1802.
[28] R. Nicolaÿ, Macromol. 45 (2012) 821–827.
[29] C.J. Hawker, A.W. Bosman, E. Harth, Chem. Rev. 101 (2001) 3661–3688.
[30] L. Petton, A.E. Ciolino, M.M. Stamenovic, P. Espeel, F.E. Du Prez, Macromol.
Rapid Commun. 33 (2012) 1310–1315.
[31] N.L. Hill, J.L. Jarvis, F. Pettersson, R. Braslau, React. Funct. Polym. 68 (2008) 361.
[32] P. Espeel, F. Goethals, M.M. Stamenovic, L. Petton, F.E. Du Prez, Polym. Chem. 3
(2008) 1007–1015.
[33] C.E. Hoyle, A.B. Lowe, C.N. Bowman, Chem. Soc. Rev. 39 (2010) 1355.
[34] R. Hoogenboom, Angew. Chem., Int. Ed. 49 (2010) 3415.
[35] B.M. Choudary, M.L. Kantam, B. Bharathi, C.R.V. Reddy, J. Mol. Catal. A: Chem.
168 (2001) 69–73.
[36] S. Watanabe, S. Nakahama, K. Yamaguchi, Macromol. Chem. Phys. 192 (1991)
1891–1902.
[37] K. Yamaguchi, T. Kato, A. Hirao, S. Nakahama, Macromol. Chem. Rapid
Commun. 8 (1987) 203–207.
[38] H. Zheng, L.M. Weiner, O. Bar-Am, S. Epsztejn, Z.I. Cabantchik, A. Warshawsky,
M.B.H. Youdim, M. Fridkin, Bioorg. Med. Chem. 13 (2005) 773–783.
[39] M.L. Bushey, A. Hwang, P.W. Stephens, C. Nuckolls, Angew. Chem., Int. Ed. 41
(2002) 2828.
[40] J. Dao, D. Benoit, C.J. Hawker, J. Polym, Part A: Polym. Chem. 36 (1998) 2161–
2167.
[41] D. Benoit, V. Chaplinski, R. Braslau, C.J. Hawker, J. Am. Chem. Soc. 121 (1999)
3904–3920.
[42] M. Ma, X. Zhang, L. Peng, J. Wang, Tetrahedron Lett. 48 (2007) 1095–1097.
[43] L. Garamszegi, C. Donzel, G. Carrot, T.Q. Nguyen, J. Hilborn, React. Funct. Polym.
55 (2003) 179–183 [41].
[44] M. MacCoss, D.J. Cameron, Carbohydr. Res. 60 (1978) 206–209.
[45] J. Houk, G.M. Whitesides, J. Am. Chem. Soc. 109 (1987) 6825.
(Mn = 12,800, PDI = 1.10) (Fig. 6) to that of the trityl-protected
polymer P9, demonstrating the reversibility of the disulfide form-
ing process.
The bidirectional initiator 9 was prepared from vinyl benzyl
disulfide 3, again using the Mn(salen) procedure (Scheme 13).
This material was identical to that prepared in our previous pub-
lication by a different route [31]. Reduction of the disulfide with
DTT gave the free thiol initiator 10. Although the free thiol 10
cannot be used directly in free radical polymerizations, it should
be useful for anchoring the initiator to a variety of metal sur-
faces, or adding to olefins via the versatile thiol-ene or yne
‘‘click’’ reactions.
4. Conclusion
In summary, NMRP with protected thiol functionalities on
either the monomer or N-alkoxyamine initiator provides polymers
that can be manipulated by deprotection and redox control be-
tween thiol and disulfide. The trityl protecting group was found
to be superior to the TBDMS protecting group for both applications.
For pendant thiol groups, crosslinking under concentrated condi-
tions resulted in the formation of crosslinked polymer aggregates,
whereas crosslinking under dilute conditions (10ꢀ3 M) provided
collapsed nanoparticles. Reduction of the disulfide bonds and cap-
ping of the free thiol groups by Michael addition to N-phenylmale-
imide was effective in preventing reformation of disulfide linkages.
The synthesis of an initiator bearing a free thiol is presented, pro-
viding access to an N-alkoxyamine with potential applications to
bonding to a variety of metal surfaces, as well as thiol ene ‘‘click’’
reactions to unactivated terminal olefins prior to NMRP.

R. Braslau et al. / Reactive & Functional Polymers 73 (2013) 624–633
633
[46] P. Majer, P.F. Jackson, G. Delahanty, B.S. Grella, Y.-S. Ko, W. Li, Q. Liu, K.M.
Maclin, J. Poláková, K.A. Shaffer, D. Stoermer, D. Vitharana, E.Y. Wang, A.
Zakrzewski, C. Rojas, B.S. Slusher, K.M. Wozniak, E. Burak, T. Limsakun, T.
Tsukamoto, J. Med. Chem. 46 (2003) 1989.
[47] T.A. Croce, S.K. Hamilton, M.L. Chen, H. Muchalski, E. Harth, Macromolecules
40 (2007) 6028–6031.
[48] E. Harth, B. Van Horn, V.Y. Lee, D.S. Germack, C.P. Gonzales, R.D. Miller, C.J.
Hawker, J. Am. Chem. Soc. 124 (2002) 8653–8660.
[49] C.J. Hawker, J.L. Hedrick, Macromolecules 28 (1995) 2993–2995.
[50] B. Lepoittevin, X. Perrot, M. Masure, P. Hemery, Macromolecules 34 (2001)
425–429.
[51] I.Q. Li, D.M. Knauss, D.B. Priddy, B.A. Howell, Polym. Int. 52 (2003) 805–812.