Synthesis and characterization of a naphthalimide-dye end-labeled copolymer by reversible addition-fragmentation chain transfer (RAFT) polymerization

Article abstract of DOI:10.1139/V10-134

We describe the synthesis of an end-functionalized copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA) and N-hydroxysuccinimide methacrylate (NMS) by reversible addition-fragmentation chain transfer (RAFT) polymerization. To control the polymer composition, the faster reacting monomer (NMS) was added slowly to the reaction mixture beginning 30 min after initating the polymerization (ca. 16% HPMA conversion). One RAFT agent, based on azocyanopentanoic acid, introduced a-COOH group to the chain at one end. Use of a different RAFT agent containing a 4-amino-1,8-naphthalimide dye introduced a UV-vis absorbing and fluorescent group at this chain end. The polymers obtained had molecular weights of 30000 and 20000, respectively, and contained about 30 mol% NMS active ester groups.

Full text of DOI:10.1139/V10-134

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317
Synthesis and characterization of a
naphthalimide–dye end-labeled copolymer by
reversible addition–fragmentation chain transfer
(RAFT) polymerization
Binxin Li, Daniel Majonis, Peng Liu, and Mitchell A. Winnik
Abstract: We describe the synthesis of an end-functionalized copolymer of N-(2-hydroxypropyl)methacrylamide (HPMA)
and N-hydroxysuccinimide methacrylate (NMS) by reversible addition–fragmentation chain transfer (RAFT) polymeriza-
tion. To control the polymer composition, the faster reacting monomer (NMS) was added slowly to the reaction mixture
beginning 30 min after initating the polymerization (ca. 16% HPMA conversion). One RAFT agent, based on azocyano-
pentanoic acid, introduced a –COOH group to the chain at one end. Use of a different RAFT agent containing a 4-amino-
1,8-naphthalimide dye introduced a UV–vis absorbing and fluorescent group at this chain end. The polymers obtained had
molecular weights of 30 000 and 20 000, respectively, and contained about 30 mol% NMS active ester groups.
Key words: RAFT, semi-batch polymerization, dye-labeled polymer, HPMA, N-hydroxysuccinimide methacrylate.
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Resume : On decrit la synthese d’un copolymere fonctionnalise aux extremites du N-(2-hydroxypropyl)methacrylamide
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(HPMA) et de methacrylate de N-hydroxysuccinimide (NMS) par polymerisation impliquant une addition et une fragmen-
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tation radicalaire avec transfert de chaıne (AFRT). Dans le but de controler la composition du polymere, le monomere qui
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reagit le plus rapidement (NMS) est additionne lentement au melange reactionnel 30 min apres que la polymerisation a ete
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initiee (conversion approximative de 16 % du HPMA). Un agent AFRT a base d’acide azocyanopentanoıque permet d’in-
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troduire un groupe –COOH a une extremite de la chaıne. L’utilisation d’un agent AFRT different, contenant un colorant
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4-amino-1,8-naphtalimide, introduit un groupe fluorescent et absorbant dans l’UV–vis a l’extremite de la chaıne. Les poly-
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meres obtenus possedent respectivement des poids moleculaires de 30 000 et 20 000 et ils contiennent approximativement
30 mol% de groupes esters du NMS.
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Mots-cles : polymerisation impliquant une addition et une fragmentation radicalaire avec transfert de chaıne (AFRT), poly-
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merisation semi-discontinue, polymere marque avec un colorant, N-(2-hydroxypropyl)methacrylamide (HPMA), methacry-
late de N-hydroxysuccinimide (NMS).
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[Traduit par la Redaction]
material with a narrower molecular weight distribution. This
is important in therapeutic applications because molecular
weight can influence the phamacokinetics, toxicity, and in-
hibitory potency of the conjugate.5,6
Introduction
Poly-N-(2-hydroxypropyl)methacrylate (PHPMA) is
a
nontoxic, nonimmunogenic, and biocompatible polymer that
offers great promise as the host carrier of polymer–drug
conjugates. These conjugates (polymer therapeutics) offer
some important advantages over conventional chemothera-
peutic agents, such as increased solubility, longer circulation
times, and lower nonspecific cytotoxicity.1,2 Early examples
of polymer–drug conjugates based on PHPMA involved pol-
ymers synthesized by traditional free radical polymeriza-
tion.3,4 This led to polymers with rather broad molecular
weight distributions. More recently, there has been a strong
interest in the synthesis of PHPMA and its copolymers by
controlled radical polymerization as a means of obtaining
Several groups have reported an indirect synthesis of
PHPMA by atom transfer radical polymerization (ATRP).
In this approach, one begins with the polymerization of N-
methacryloxysuccinimide (NMS) followed by treatment of
the PNMS obtained with excess 1-amino-2-propanol.7 This
approach takes advantage of the fact that the succinimide es-
ter group of NMS can react with amines to form amides. For
therapeutic applications, complete removal of the Cu ion
catalyst can be problematic. This is one reason that a greater
effort has been devoted to the development of the synthesis
of PHPMA and its copolymers by reversible addition–
Received 26 April 2010. Accepted 29 July 2010. Published on the NRC Research Press Web site at canjchem.nrc.ca on 22 February
2011.
This article is part of a Special Issue dedicated to Professor J. C. Scaiano.
B. Li, D. Majonis, P. Liu, and M.A. Winnik.1 Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON
M5S 3H6, Canada.
1Corresponding author (e-mail: mwinnik@chem.utoronto.ca).
Can. J. Chem. 89: 317–325 (2011)
doi:10.1139/V10-134
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318
Can. J. Chem. Vol. 89, 2011
fragmentation chain transfer (RAFT) polymerization. Mc-
Cormick and co-workers8 prepared hydrophilic–cationic
block copolymers of HPMA and N-[3-(dimethylamino)pro-
pyl]methacrylamide (DMAPMA) by RAFT polymerization
in water. These polymers lack pendant functionality for
attachment of drugs or dyes. To address this issue, they
developed a synthesis of copolymers of HPMA with N-(3-
aminopropyl)methacrylamide) (APMA). Here, APMA provided
amine functional groups for bioconjugation. They described
modification of these copolymers with folic acid9 or with N-
succinimidyl 3-(2-pyridyldithio)-propionate to attach 5’-
thiolated RNAs through a thiol–disulfide exchange reaction.10
Hong and Pan11 reported the synthesis of P(HPMA-b-NIPAM)
(NIPAM = N-isopropylacrylamide) block copolymers by
RAFT polymerization. These polymers were obtained with
molecular weights in the range of 7 800–26 300 g/mol with
narrow polydispersites (PDI = 1.15–1.29). Zentel and co-
workers12 synthesized functional amphiphilic poly(N-(2-
hydroxypropyl) methacrylamide)-b-lauryl methacrylate) by
RAFT polymerization. They investigated the influence of
nanoaggregates formed by this block polymer on cell viabil-
ity and on the motility of adherent cells.
A more general strategy for the preparation of functional
HPMA copolymers involves the synthesis of an activated
polymer with pendant active ester groups along the back-
bone. A random copolymer of HPMA and NMS would be
an effective scaffold for the attachment of amine derivatives
of dyes or drugs. The challenge in this synthesis is that the
reactivity ratios (rHPMA = 0.12 and rNMS = 3.46)13 favor
rapid consumption of the NMS comonomer. Kane and co-
workers13,14 addressed this problem by using a ‘‘semi-batch’’
approach to the synthesis,15 by adding the more reactive
monomer slowly as the RAFT polymerization proceeded.
They monitored the kinetics of the reaction and the compo-
sition of the polymer as the reaction proceeded, obtaining
polymer that contained ~20 mol% NMS groups throughout
the reaction. These polymers could be functionalized with a
peptide known to disrupt anthratoxin assembly. The reaction
in DMSO involved substitution of the active ester with an
amino group from the peptide.
We are interested in this approach to the synthesis of
functional HPMA copolymers, but with a higher NMS con-
tent. Here, we report a modified synthesis that follows the
Kane and co-workers13 strategy, but introduces functional
and dye-containing chain-transfer agents (CTAs). As is
well-established for RAFT polymerization, these transfer
agents allow one to introduce functional groups or dyes at
the initiating end of the polymer chains.16–18 We are particu-
larly interested in dyes based on the naphthalimide ring
structure. The 1,8-naphthalimide chromophore and its deriv-
atives have been studied for many years.19–22 Many of these
derivatives are easily synthesized from the corresponding
naphthalic anhydrides. They have relatively high fluorescent
quantum yields, high photostability, and tunable spectro-
scopic properties. Many 1,8-naphthalimide derivatives have
been incorporated covalently or non-covalently into various
polymeric materials to study the properties and behavior of
the polymers. Our group has examined a family of 1,8-naph-
thalimide derivatives as donor–acceptor pairs to monitor
mers containing the 1,8-naphthalimide group have also been
studied for other applications such as sensors, probes,
OLEDs, and solar cells, as well as photochemotherapy.24
Here, we describe the synthesis of a copolymer of HPMA
and NMS with a naphthalimide-labeled end through RAFT
polymerization. This dye-containing polymeric precursor
can be further modified and potentially used in bioconjuga-
tion, drug delivery, and gene delivery applications.
Experimental
General characterization
1H NMR (400 MHz) spectra were recorded on a Varian
Mercury 400 spectrometer. CDCl3 and d6-DMSO were
purchased from Cambridge Isotope Laboratories, Inc. 3-
(Trimethylsilyl)propionic acid-d4 sodium salt (TSP) was
purchased from Sigma-Aldrich. For gel permeation chroma-
tography (GPC) measurements, the eluant was 1-methyl-2-
pyrrolidinone (NMP) containing 0.2 wt% LiCl, and the
column was calibrated with poly(methyl methacrylate)
(PMMA) standards. The analysis was carried out at 80 8C
at a flow rate of 0.6 mL/min using a Viscotek VE1121
GPC solvent pump, with a Viscotek VE 3580 refractive in-
dex detector and a Viscotek VE3210 UV–vis absorbance de-
tector. UV–vis measurements were carried out with a
PerkinElmer Lambda 6 spectrometer.
Materials
4-Bromo-1,8-naphthalimide anhydride (BNA) (95%,
Sigma-Aldrich), isobutylamine (99%, Sigma-Aldrich), ethyl-
enediamine (99%, Sigma-Aldrich), oxalyl chloride (98%,
Sigma-Aldrich), 2,2’-azobis(2-methylpropionitrile) (AIBN)
(98%, Sigma-Aldrich), 1,3,5-trioxane (‡99%, Sigma-Aldrich),
tert-butyl alcohol (t-BuOH) (‡99.5%, Sigma-Aldrich), N,N-
dimethylformamide (DMF) (99.8%, Sigma-Aldrich), 1-methyl-
2-pyrrolidinone (NMP) (‡99%, Sigma-Aldrich), and other
chemicals were used as received. N-(2-Hydroxypropyl)meth-
acrylamide (HPMA) was prepared according the literature
procedure reported by Ulbrich et al.25 N-Methacryloxysucci-
nimide (NMS) was synthesized according to the literature
procedure reported by Shunmugam and Tew.26 4-Cyanopen-
tanoic acid dithiobenzoate (CIDB) was synthesized as de-
scribed previously.27
Synthesis of 9-isobutyl-4-ethylenediamino-1,8-
naphthalimide
9-Isobutyl-4-ethylenediamino-1,8-naphthalimide was syn-
thesized in two steps. 4-Bromo-1,8-naphthalic anhydride
(1.4 g, 5.1 mmol) and isobutylamine (2.0 mL, 21 mmol)
were added to 1,4-dioxane (40 mL) at room temperature.
The solution was stirred for 4.5 h at 100 8C. The solvent
was removed by rotary evaporation. The yellow solid was
purified by silica column chromatography using heptanes–
acetone (12:1, v:v) as the eluent. Finally, the yellow solid
product (9-isobutyl-4-bromo-1,8-naphthalimide) was dried
under vacuum at 50 8C overnight. Yield: 1.14 g (72%); mp
1
130.0–131.5 8C. H NMR (CDCl3, ppm) d: 0.98 (d, 6H),
2.24 (m, 1H), 4.04 (d, 2H), 7.85 (dd, 1H), 8.04 (d, 1H),
8.42 (d, 1H), 8.58 (d, 1H), 8.66 (d, 1H). Elemental anal.
calcd: C 57.85, H 4.25, N 4.22; found: C 57.98, H 4.32, N
4.50.
¨
polymer morphology or the diffusion of polymers by Forster
resonance energy transfer (FRET) measurements.23 Poly-
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Li et al.
319
Table 1. Characteristics of the naphthalimide–dye end-labeled poly(HPMA-co-NMS).
NPMA mol%a
69
NMS mol%a
31
DPHPMA
54
DPNMS
24
Mn (NMR)a
16 000
Mn (NMR)b
18 000
Mn (UV)c
18 000
a
a
Note: HPMA, N-(2-hydroxypropyl)methacrylamide; NMS, N-methacryloxysuccinimide; DPHPMA, mean number of HPMA units per
polymer; and DPNMS, mean number of NMS units per polymer.
aCalculated with eqs. [1] and [2].
bFrom the determination of the moles of the dye end group using TPS as an internal standard, calculated as Mn = [mass of poly(HPMA-co-
NMS)]/[moles of naphthalimide–dye].
cFrom the absorbance at 430 nm using a value of " = 1.3 Â 104 (mol/L)–1 cm–1.
9-Isobutyl-4-bromo-1,8-naphthalimide (3.020 g, 9.123 mmol)
was added to ethylenediamine (50 mL, 0.75 mol). The solu-
tion was stirred at 50 8C for 2.5 h. The reaction mixture was
treated with toluene (200 mL), and then the volatile liquids
were removed by rotary evaporation. The crude product was
dissolved in 1 mol/L aq HCl (70 mL). The product was pre-
cipitated by adding 1 mol/L aq NaOH until the solution be-
came weakly basic (pH ~8). The mixture was then filtered.
The yellow solid product (9-isobutyl-4-ethylenediamino-1,8-
naphthalimide) was dried under vacuum at 50 8C overnight.
diyl)bis(4-cyanopentanoyl chloride). Yield: 1.820 g (95.6%).
1H NMR (CDCl3, ppm) d: 1.72 (d, 6H), 2.62 (m, 4H), 3.14
(m, 4H).
9-Isobutyl-4-ethylenediamino-1,8-naphthalimide (1.557 g,
4.788 mmol) was dissolved in 100 mL anhyd CH2Cl2. The
solution was cooled to 0 8C. A solution of 4,4’-(diazene-
1,2-diyl)bis(4-cyanopentanoyl
chloride)
(0.632
g,
2.19 mmol) and N,N-diisopropylethylamine (2.29 mL,
13.1 mmol) in 20 mL anhyd CH2Cl2 was added dropwise to
the dye solution via an addition funnel under N2 protection.
The reaction was stirred for 12 h at room temperature and
then concentrated with a rotary evaporator. The mixture
was washed with saturated sodium bicarbonate solution, 1%
aq HCl, and finally 2 mol/L aq NaCl. The organic layer was
dried over magnesium sulfate, filtered, and concentrated.
The naphthalimide–dye-labeled CTA precursor was precipi-
tated in diethyl ether and lyophilized overnight. Yield:
1.36 g (79%). 1H NMR (CDCl3, ppm) d: 0.98 (d, 12H,
CH3), 1.69 (d, 6H, CH3), 2.22–2.52 (m, 8H, CH2CH2), 3.44
(m, 4H, CH2), 3.68 (t, 4H, CH2), 4.01 (d, 4H, CH2), 6.57 (d,
2H), 7.60 (t, 2H), 8.12 (d, 2H), 8.35 (d, 2H), 8.51 (d, 2H).
1
Yield: 2.66 g (94%); mp 162–164 8C. H NMR (CDCl3,
ppm) d: 0.98 (d, 6H), 1.24 (broad, 2H), 2.25 (m, 1H), 3.18
(t, 2H), 3.42 (m, 2H), 4.03 (d, 2H), 6.14 (broad, 1H), 6.72
(d, 1H), 7.62 (t, 1H), 8.16 (d, 1H), 8.45 (d, 1H), 8.58 (d,
1H). Elemental anal. calcd.: C 69.43, H 6.80, N 13.49;
found: C 68.52, H 6.66, N 13.66.
Synthesis of bis(benzenethiocarbonyl) disulfide
Magnesium turnings (3.00 g, 0.125 mol) were placed into
a round-bottom flask with a catalytic amount of iodine. Bro-
mobenzene (18.84 g, 0.1200 mol) was mixed with dry THF
(90 mL). Then a 10 mL mixture of bromobenzene and THF
was added to the flask and heated slightly. The remaining
mixture was added slowly, while the temperature of reaction
remained below 40 8C. The reaction was then stirred at
room temperature for 1 h, after which the flask was cooled
to 0 8C. Carbon disulfide (9.15 g, 0.120 mol) was added to
the Grignard mixture at 0 8C. When the reaction finished
after 2 h, deionized water (350 mL) was added, and the salts
were removed by filtration. Concentrated HCl (~10 mL) was
added to the filtrate and the mixture was extracted with di-
ethyl ether. After evaporating the solvent with a rotary evap-
orator, absolute ethanol (100 mL) was added into the
dithiobenzoic acid along with DMSO (18.75 g, 0.24 mol)
and a catalytic amount of iodine. The reaction proceeded at
room temperature for 2 h, and then the mixture was filtered.
The purple solid (bis(thiocarbonyl) disulfide) was dried
under vacuum at room temperature overnight. Yield:
A
solution of bis(thiocarbonyl) disulfide (0.156 g,
0.510 mmol) and the naphthalimide–dye-labeled CTA pre-
cursor (0.213 g, 0.246 mmol) in ethyl acetate was degassed
with nitrogen and heated at 80 8C for 20 h. The solvent was
removed with a rotary evaporator, and the residue was puri-
fied by silica column chromatography using ethyl
acetate – hexane as the eluent. Yield: 0.049 g (34%); mp
1
90–93 8C. H NMR (CDCl3, ppm) d: 0.99 (d, 6H, CH3),
1.93 (s, 3H, CH3), 2.44–2.71 (m, 4H, CH2CH2), 3.54 (t, 2H,
CH2), 3.77 (t, 2H, CH2), 4.04 (d, 2H, CH2), 6.17 (broad, 1H,
NH), 6.60 (d, 1H, naphthalic-H), 6.91 (broad, 1H, NH), 7.66
(t, 1H), 7.35 (m, 2H, m-ArH), 7.38 (t, 1H, p-ArH), 7.84 (dd,
2H, o-ArH), 8.24 (d, 1H), 8.45 (d, 1H), 8.57 (d, 1H). Ele-
mental anal. calcd.: C 65.01, H 5.63, N 9.78; found: C
64.83, H 5.77, N 9.23.
The homopolymerization of HPMA
1
11.04 g (60%); mp 96–98 8C. H NMR (CDCl3, ppm) d:
The polymerizations were carried out under an Argon
(Ar) atmosphere using the Shlenck technique. A typical pol-
ymerization procedure is described in the following. A stock
solution was prepared comprised of AIBN (140.08 mg,
0.851 mmol), CIDB (41.08 mg, 0.155 mmol), and 1,3,5-tri-
oxane (internal standard, 449 mg, 4.98 mmol) in degassed
DMF (5 mL). HPMA (0.458 g, 3.55 mmol) was evacuated
and back-filled with Ar three times. The degassed t-BuOH
(3.2 mL) was injected into a round-bottom flask containing
HPMA to form a 1 mol/L solution, and a solution of AIBN,
CIDB, and 1,3,5-trioxane in DMF (200 mL) was transferred
7.45 (t, 4H), 7.61 (t, 2H), 8.07 (t, 4H).
Synthesis of the naphthalimide–dye-labeled CTA
(NapDB)
Oxalyl chloride (5.3 mL, 62 mmol) was added to a stirred
suspension of 4,4’-azobis(4-cyanovaleric acid) (1.708 g,
6.775 mmol) in anhyd CH2Cl2 with a catalytic amount of
N,N-dimethylformamide at room temperature. After 3 h, the
reaction mixture turned clear and was evaporated with a ro-
tary evaporator to leave a yellow solid of 4,4’-(diazene-1,2-
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Can. J. Chem. Vol. 89, 2011
Scheme 1. Reversible addition–fragmentation chain transfer
(RAFT) copolymerization of N-(2-hydroxypropyl)methacrylamide
(HPMA) and N-methacryloxysuccinimide (NMS).
into the same flask. The reaction was carried out at 80 8C
immediately and finally quenched in an acetone – dry ice
bath. Aliquots (0.1 mL) were taken out for NMR analysis
throughout the reaction. The final polymer was precipitated
using a mixture of anhydrous diethyl ether and anhydrous
acetone (1:1 v/v), recovered by centrifugation, and then
lyophilized overnight for further analysis by NMR and GPC.
The copolymerization of HPMA and NMS
The copolymerization reactions were carried out under an
Argon (Ar) atmosphere on a Shlenck line. A typical copoly-
merization procedure (Table 1) is described in the following.
A stock solution was prepared consisting of AIBN (6.6 mg,
0.040 mmol), NCTA (45.7 mg, 0.0799 mmol), and 1,3,5-tri-
oxane (internal standard, 77.6 mg. 0.861 mmol) in degassed
DMF (1 mL). The monomers were evacuated and back-
filled with Ar three times. The solvents were degassed by
bubbling with Ar gas. t-BuOH (1.9 mL) was added to a
round-bottom flask containing HPMA (0.275 g, 2.13 mmol)
to form a 1 mol/L solution, and then the solution of AIBN,
NCTA, and 1,3,5-trioxane in DMF (200 mL) was transferred
into the flask. The mixture was heated at 80 8C for 30 min,
and then a solution of NMS in DMF (0.5 mol/L) was added
continuously into the reaction mixture at 0.43 mL/h through
an airtight syringe by a syringe pump (KD Scientific, model
780100). After the addition of the NMS solution, the reac-
tion was kept at 80 8C for an additional 30 min and was
then quenched in an acetone – dry ice bath. Aliquots
(0.1 mL) were taken out for NMR analysis throughout the
reaction. The final polymer was precipitated using a mixture
of anhydrous diethyl ether and anhydrous acetone (1:1 v/v),
recovered by centrifugation, and then lyophilized overnight.
A sample for end-group analysis was subjected to a second
precipitation from DMF into ether–acetone. The polymer
product (26 mg) was stored at 4 8C.
was synthesized as described in ref. 27. This CTA introdu-
ces a carboxylic acid into the R-group. If the R-group bears
important functionality (such as a fluorescent dye) for appli-
cations in aqueous media, it is important that the attachment
of the dye not involve ester groups which can slowly hydro-
lyze in water. In the design of the naphthalimide chain
transfer agent used in these experiments, it is incorporated
as an amide. The synthesis of this CTA is shown in
Scheme 2. It was synthesized from bis(benzenethiocarbonyl)
disulfide and the dye-containing azo-initiator in a single
step. The yield was only 34% after column chromatography,
1
but H NMR and elemental analysis indicated that the prod-
uct was pure. It showed only one spot by TLC.
We initially examined the kinetics of the polymerization
of HPMA at 80 8C in the presence of CIDB as the chain-
transfer agent and AIBN as the initiator. The ratio of
[HPMA]–[CIDB]–[AIBN] was 320:2:1. As shown in the
Supplementary data, ln([M]0/[M]t) increased linearly with re-
action time over the first 4 h of the polymerization. Later,
the rate of the polymerization became slower. The molecular
weight increased monotonically but not quite linearly
throughout the polymerization (see Fig. S2 in the Supple-
mentary data), and maintained a narrow polydispersity. At
70% conversion, the sample was characterized by GPC
(PMMA standards), yielding Mn = 32 000 with PDI = 1.3.
These results establish that CIDB is an effective CTA for
this RAFT polymerization. These results also provide infor-
mation about the monomer conversion kinetics that we used
to design the addition rate of NMS for the copolymerization
of HPMA and NMS.
Molecular weight determination
A sample of the dye-labeled polymer was examined by UV–
vis spectroscopy. A sample of the dye-labeled poly(HPMA-co-
NMS) (1.134 mg) was dissolved in 1.0 mL DMF to form a
1.13 g/L solution. The calibration curve of the UV absorb-
ance of the naphthalimide–dye was built using 9-isobutyl-4-
ethylenediamino-1,8-naphthalimide (BEAN) as a model
compound. A series of solutions of BEAN in DMF was pre-
pared with accurately known concentrations. The absorbance
of these solutions at 440 nm was measured by UV–vis spec-
1
trometry. For the H NMR experiments, dye-labeled copoly-
mers were dissolved into DMSO-d6 to form solutions at
10 mg/mL. In the GPC experiments, dye-labeled polymers
were dissolved in NMP containing 0.2 wt% LiCl to form
1 mg/mL solutions.
Semi-batch copolymerization of HPMA and NMS with
CIDB as the CTA
Initial studies of the copolymerization of HPMA and
NMS were carried out using CIDB as the RAFT agent. This
reaction is shown in Scheme 1. In this copolymerization, all
of the reactants except NMS (that is, AIBN, the CTA, 1,3,5-
trioxane as an internal standard, and HPMA monomer, in a
mixture of DMF and tert-butyl alcohol as the solvent) were
introduced into a flask on a Schlenk line equipped with a
septum and thoroughly outgassed as described in the Exper-
imental section. The reaction was initiated by heating the
solution to 80 8C and, after 30 min, a solution of NMS
Results and discussion
In a RAFT polymerization employing a thiocarbonylthio
compound ZC(=S)SR as a chain transfer agent, the R group
will become attached to the initiating end of the chain. The
–SC(=S)Z at the other end can act as a protected thiol for
further transformation of the polymer. In the initial polymer-
ization reactions described below, CIDB (see below,
Scheme 1) was used as the chain-transfer agent (CTA). It
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