Synthesis of carboxylic acid and ester mid-functionalized polymers using RAFT polymerization and ATRP

Article abstract of DOI:10.1071/CH06317

Polymers with a single central point of carboxylic acid functionality were prepared by living radical polymerization methods, RAFT and ATRP. A convenient water-based synthesis of a Y-branched ATRP initiator from 3,5-dihydroxybenzoic acid and 2-bromopropio

Full text of DOI:10.1071/CH06317

RESEARCH FRONT
Full Paper
CSIRO PUBLISHING
www.publish.csiro.au/journals/ajc
Aust. J. Chem. 2006, 59, 763–771
Synthesis of Carboxylic Acid and Ester Mid-Functionalized Polymers
using RAFT Polymerization and ATRP
Nino MalicA,B and Richard A. EvansA–D
A CSIRO Molecular & Health Technologies, Bag 10, Clayton VIC 3169, Australia.
B Cooperative Research Centre for Polymers, 8 Redwood Drive, Notting Hill VIC 3168, Australia.
C Centre for Advanced Macromolecular Design (CAMD), School of Chemical Engineering and
Industrial Chemistry, University of New South Wales, Sydney NSW 2052, Australia.
D Corresponding author. Email: richard.evans@csiro.au
Polymers with a single central point of carboxylic acid functionality were prepared by living radical polymer-
ization methods, RAFT and ATRP. A convenient water-based synthesis of a Y-branched ATRP initiator from
3,5-dihydroxybenzoic acid and 2-bromopropionyl bromide, from which the Y-branched RAFT agent is then
subsequently derived, is described. Polymerization occurred uniformly from both of the RAFT groups to give
chains of equal length as shown by hydrolysis. ATRP polymerization based on an ester derivative of 3,5-bis(2-
bromopropionyloxy)benzoic acid as initiator was well controlled, whereas the free carboxylic acid gave inconsistent
performance. The ability to couple functional molecules to the middle of polymers would provide better protection
or interaction of the functional molecule with the polymer than conventional end attachment. This would find appli-
cations such as in drug delivery where more efficient protection would allow the use of lower molecular weight
polymers.
Manuscript received: 29 August 2006.
Final version: 4 October 2006.
Introduction
Polymer conjugates, particularly biomolecule–polymer con-
jugates are of great current interest due to potential drug
delivery[1] and other applications.[2] Living radical polymer-
ization (LRP) methods are particularly amenable to polymer
conjugate synthesis. This is because, with suitable choice of
additional functionality, they can turn essentially anything,
from a simple molecule to a drug,[3] protein or peptide,[4,5]
oligonucleotide,[6] and even a silica surface,[7] into a radical
polymerization initiator with the benefit of also controlling
the molecular weight or length of the polymer. Atom-transfer
radical polymerization (ATRP)[8] has recently been used to
grow polymers directly from a 2-bromoisobutyryl amide ter-
minated oligonucleotide[6] and from the protein streptavidin
using a biotin-functionalized ATRP initiator.[4] Reversible
addition–fragmentation transfer (RAFT)[9–11] agents can be
expected to be applied in an analogous way. Similarly, poly-
mers have been grown from spirooxazine photochromic dyes
and shown to allow tuning of switching speeds in a host
polymer matrix.[12,13]
(a)
(b)
Fig. 1. Polymer conjugates where attachment of the functional
molecule (ꢀ) is in the (a) end and (b) middle of the polymer.
attachment of the active molecule to the middle of the
polymer through Y-branching gave better protection than
attachment at the end.[14,15] Alternatively, lower molecular
weightconjugatescouldbeused, whichmaximizesfunctional
molecule content and, in the case of drug delivery, would aid
reduction of adverse effects such as polymer poisoning by
accumulation.[1]
Precise attachment to the middle of a polymer is a chal-
lenge using conventional synthetic methods. However, the
application of living radical polymerization methods make it
considerably easier as the use of a multi-functional LRP agent
can allow the growth of two (or more) polymers from the one
point.The result being that the initiation point is in the middle
of the polymer. There are numerous reports of double headed
and star polymers being grown by free-radical methods from
a single point,[8,16–20] but there is no other functionality or
‘hook’attheorigin.WhatisneededisaY-branchingagentthat
However, such conjugates are predominantly linear in
that the functional molecule is attached to the end of the
polymer (Fig. 1a). To improve encapsulation, it is logically
better to attach it to the middle of the polymer (Fig. 1b).
This has been demonstrated generically for drug delivery
purposes where, for a given molecular weight polymer,
© CSIRO 2006
10.1071/CH06317
0004-9425/06/100763

RESEARCH FRONT
764
N. Malic and R. A. Evans
possesses two living radical polymerization functionalities,
such as RAFT or ATRP initiating groups, and a stable and
radically unreactive functionality such as carboxylic acid or
hydroxy group. There has been limited reporting of such
Y-branching agents in the literature,[21–24] and their synthesis
involves standard procedures using organic solvents under
anhydrous conditions and, in one example,[24] requiring
multiple synthetic steps.
In this paper we report a convenient water-based synthesis
of a novel branching agent which enables the facile synthesis
of mid-functionalized polymers using living radical polymer-
ization techniques (both RAFT andATRP), where the central
moiety is a carboxylic (benzoic) acid and ester derivative
thereof.
central core molecule simultaneously. If using RAFT as the
method of controlled polymerization then the core molecule
contained two identical trithiocarbonate moieties. On the
other hand, when ATRP was used then the core molecule
was functionalized with two α-bromopropionyl ester initia-
tor groups.The core molecule (herein referred to as the RAFT
agent and the ATRP initiator, respectively) also contained a
third but different functionality (carboxylic acid/ester) which
was inert to the polymerization conditions, neither taking
part nor interfering with it. The synthon which enabled
facile access to the type of RAFT agent and ATRP initiator
described above was 3,5-dihydroxybenzoic acid 1.
Design and Synthesis
The esterification of 3,5-dihydroxybenzoic acid 1 at the two
phenolic hydroxy groups has been comprehensively studied
by Hawker and Fréchet[25] for its application in the synthe-
sis of dendritic polyesters. Although successfully applied in
Results and Discussion
In order to achieve mid-functionalization within a polymer
the chosen method was to grow two polymer chains from a
O
Benzoic acid
Cl3CCH2OH
OH
H2SO4
O
DCC
O
O
DPTS
61%
OCH2CCl3
89%
Method A
OCH2CCl3
OH
O
O
OH
O
1
OH
OH
O
O
Zn/HOAc
92%
Benzoyl chloride
K2CO3
Method B
O
H2O/PriOH
OH
(50% overall)
O
O
90%
2
Scheme 1. Comparison of the literature method[25] for the synthesis of 3,5-bis(benzoyloxy)benzoic acid
2 (Method A) with the interfacial Schotten–Baumann procedure (Method B).
O
O
S
S
HO
OH
Br
O
O
Br
n-Bu
2-Bromopropionyl bromide
O
54%
Bu SH, CS , Et N
n-Bu
O
S
S
S
S
O
O
n
K CO
2
3
2
3
i
OH
O
H O/Pr OH
2
OH
O
4
OH
1
O
81%
3
Scheme 2. Synthesis of bis(trithiocarbonate) functionalized benzoic acid 4 (RAFT agent) from a bis(2-bromopropionyloxy) functionalized benzoic
acid 3 (ATRP initiator).
S
S
S
S
O
O
Bun
Bun
O
O
Bun
Bun
S
S
S
S
S
S
S
S
O
O
O
O
n
n
R
R
AIBN and/or ∆
n-Butylacrylate or styrene
O
OH
O
OH
5 R ϭ (CO)OCH2CH2CH2CH3
6 R ϭ Ph
4
Scheme 3. RAFT polymerizations using n-butyl acrylate and styrene monomers.

RESEARCH FRONT
Synthesis of Carboxylic Acid and Ester Mid-Functionalized Polymers using RAFT Polymerization and ATRP
765
this field, the presence of the free carboxylic acid group posed
particular synthetic challenges due to its incompatibility with
the chemistry required.As a result, a protection–deprotection
strategy was employed, adding extra steps to the overall syn-
thesis. The literature shows this method still being applied
in recent times.[26–30] Of particular interest to us was the
chemistry surrounding the synthesis of first-generation den-
dron 2 (Scheme 1). There is little literature precedent for
the O-acylation of 1 (or mono-hydroxy benzoic acids) using
interfacial Schotten–Baumann conditions[31–33] (acid halides
under aqueous basic conditions), which is perhaps not gen-
erally considered due to its counter-intuitive nature. We have
been able to further demonstrate the great potential of this
method for the synthesis of at least first-generation dendrons,
giving high purity products in excellent yields in one easy
step without the need for protecting groups, and also as a
tool for the facile formation of Y-branching ATRP initiators
and RAFT agents.
ThelivingnatureoftheRAFTpolymerizationscanbeseen
from Fig. 2 which shows molecular weight (Mn) increasing
linearly with conversion as well as low and decreasing poly-
dispersities (see the Accessory Publication for the first-order
kinetic plots). The observed molecular weights derived from
GPC data conform well to calculated values based on con-
version (data summarized inTable 1). Close inspection of the
GPC plots revealed a small shoulder towards lower molecu-
lar weight which becomes increasingly more apparent with
increasing conversions (see the Accessory Publication for
actual GPC traces of compounds 5a–5f and 6a–6f).This phe-
nomenon was observed for both poly(n-butyl acrylate) and
polystyrene, with the effect being more evident for poly(n-
butyl acrylate). It is postulated that this could be a result of
chain termination through intramolecular radical coupling.
If this is indeed the case it would lead to a dead cyclic
polymer. In contrast, the relative amount of high molecular
weight polymer species resulting from intermolecular radi-
cal coupling was quite low, even at higher conversions. The
higher favourability of intra- versus intermolecular reactivity
is perhaps exemplified here.
The current literature synthesis of first-generation den-
dron 2 is achieved in three steps using a protection-
deprotection strategy in 50% overall yield[25] (Scheme 1).
We synthesized the same dendron in one step by reaction
of 3,5-dihydroxybenzoic acid 1 in a cold basic (K2CO3)
water/isopropanol solution with neat benzoyl chloride.
Although there are four possible functionalities available to
react (carboxylate, phenolate, water/hydroxide, isopropanol)
only the phenolate reacts with the acid chloride under these
conditions. Re-acidification post-reaction gave the pure prod-
uct in 90% yield which was simply isolated by filtration and
12000
10000
8000
6000
4000
2000
0
1.19
1.18
1.17
1.16
1.15
1.14
1.13
1.12
1.11
1.10
1.09
1
washed with water. The product was analyzed by H and
13C NMR and the spectra compared with that of the literature
assignments,[25] whichconfirmeditssuccessfulsynthesisand
purity. The same methodology was then applied for our pur-
poses in the synthesis of a RAFT agent and ATRP initiator
for use in living radical polymerizations.
The bis-acylation of 3,5-dihydroxybenzoic acid 1 with
2-bromopropionyl bromide (or chloride) under aqueous basic
conditions proceeded very efficiently giving the intermediate
product 3,5-bis(2-bromopropionyloxy)benzoic acid 3 in 81%
yield and in good purity. This was subsequently converted
to the RAFT agent 4 using the literature procedure[34] (i.e.
reaction with n-butyltrithiocarbonate anion formed from a
mixture of 1-butanethiol, carbon disulfide and triethylamine)
in 54% yield after chromatography (Scheme 2). Both 3 and
0
20
40
60
80
100
(a)
Conversion [%]
12000
10000
8000
6000
4000
2000
0
1.13
1.12
1.11
1.10
1.09
1.08
1.07
1
4 were characterized by H and 13C NMR spectroscopy as
well as ESI-MS giving mass values and isotope patterns that
correlate well with those calculated.
RAFT-Controlled Polymerization
RAFT-mediated polymerizations were conducted with
styrene and n-butyl acrylate monomers in degassed ben-
zene solutions containing the RAFT agent, 4, and monomer
in a 1:100 molar ratio (Scheme 3). Styrene polymeriza-
tions were conducted at 110◦C and were thermally initiated,
whereasAIBN (10 mol-% with respect to RAFT agent 4) was
used to initiate n-butyl acrylate polymerizations, which were
conducted at 60◦C.
0
10 20 30 40 50 60 70 80 90
Conversion [%]
(b)
Fig. 2. Molecular weight and polydispersity (Mn ꢀ, PD ꢁ) versus
conversion for the RAFT polymerization of (a) styrene at 110◦C and
(b) n-butyl acrylate in benzene solution at 60◦C. Conversions derived
from 1H NMR spectra. Calculated molecular weight versus conversion
plot represented by dotted line. Polymerization times were from 2 to 24 h
for polystyrene 5a–5f and 40 min to 4 h for poly(n-butyl acrylate) 6a–6f.

RESEARCH FRONT
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N. Malic and R. A. Evans
Table 1. Polymerization characteristics of mid-functional polystyrene 5a–5f and poly(n-butyl acrylate) 6a–6f, and
9-fluorenylmethyl mid-functional poly(n-butyl acrylate) 9a–9f
For 5a–5f and 6a–6f refer to Scheme 3 and Fig. 2; for 9a–9f refer to Scheme 5 and Fig. 5
Sample
Polymerization time
[min]A
ConversionB
[%]
Expt.C Mn
Theor. Mn
[g mol−1
]
PDI
[g mol−1
]
5a
5b
5c
5d
5e
5f
120
240
360
480
960
14.0
25.9
38.1
47.7
69.8
74.9
1600
2600
3700
4700
7100
8300
2053
3292
4563
5563
7865
8396
1.19
1.17
1.14
1.12
1.11
1.10
1440
6a
6b
6c
6d
6e
6f
40
60
95
120
170
240
3.7
21.6
44.8
56.4
69.2
79.9
1300
3300
6500
8200
10000
11600
1069
3363
6337
7824
9464
10836
1.12
1.11
1.08
1.08
1.07
1.07
9a
9b
9c
9d
9e
9f
35
60
120
240
480
960
16.5
25.2
40.1
58.1
73.7
89.0
2300
3600
5800
8200
10700
13300
2717
3832
5780
8049
10048
12009
1.15
1.17
1.12
1.12
1.11
1.11
A Polymerizations were performed neat at 110◦C for polystyrene, 5a–5f, with RAFT agent 4 (0.192 mmol) and styrene
(19.20 mmol); in benzene solution at 60◦C for poly(n-butyl acrylate), 6a–6f, with RAFT agent 4 (0.156 mmol, 0.039 M),
n-butyl acrylate (15.6 mmol, 3.9 M) and AIBN (0.0156 mmol); in benzene solution at 90◦C for poly(n-butyl acrylate)
via ATRP, 9a–9f, with initiator 8 (0.156 mmol, 0.039 M), n-butyl acrylate (15.6 mmol, 3.9 M), CuBr (0.156 mmol),
4,4ꢀ-dinonyl-2,2ꢀ-bipyridine (0.312 mmol).
B Determined using 1H NMR spectra recorded on a Bruker AV400 spectrometer.
C Determined by GPC of pre-purified polymers and expressed in polystyrene equivalents.
c (terminal CH only)
S
S
e
O
O
S
S
S
S
b
O
O
n
n
O
O
O
O
d
a
OH
O
d
e
a
b
c
9.0 8.5 8.0 7.5 7.0 6.5 6.0 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0
Fig. 3. 1H NMR spectrum of carboxylic acid mid-functionalized poly(n-butyl acrylate) 6b (Mn 3300 g mol−1) in CDCl3.
Polymer Structure Analysis
a triplet signal at 3.34 ppm corresponding to CH2S of the
n-butyl moiety (Fig. 3). Signals for the aromatic protons of
the benzoic acid mid-functionality could also be seen at 7.68
(2H) and 7.13 (1H) ppm as broad singlets.
Analysis of a low molecular weight poly(n-butyl acrylate)
polymer 6b (Mn 3300 g mol−1) by 1H NMR showed clearly
the presence of the n-butyltrithiocarbonate end-groups with

RESEARCH FRONT
Synthesis of Carboxylic Acid and Ester Mid-Functionalized Polymers using RAFT Polymerization and ATRP
767
S
S
O
Bun
Bun
O
O
SH
S
S
S
S
Aq. KOH
HO
O
O
n
n
n
THF 50°C
O
OH
Mn 4300 g molϪ1
5f Mn 8800 g molϪ1
Scheme 4. Base (hydroxide) catalyzed hydrolysis of the central ester moieties of the carboxylic acid mid-functionalized polystyrene RAFT polymer
5f, resulting in halving of the polymer length/molecular weight and removal of RAFT end-groups.
OH
O
O
Br
Br
O
O
Br
Br
O
O
O
O
Triethylamine
O
O
O
X
3
7
(COCl)2
X ϭ OH
X ϭ Cl
8
DMF cat.
O
O
O
O
Br
Br
O
O
n
n
O
O
O
O
CuBr
dinonyl-bipy
O
O
9a–9f
Scheme 5. Synthesis of 9-fluorenylmethyl functionalized ATRP macroinitiator 8, and subsequent polymerization
with n-butyl acrylate.
(a)
(b)
In order to determine whether both polymer chains grew
uniformly from the RAFT agent, 4, a high molecular weight
polystyrene polymer 5f (Mn 8800 g mol−1) was subjected
to hydrolysis under basic conditions. The polymer was dis-
solved in THF and treated with aqueous KOH with gentle
heating for 18 h (Scheme 4). If polymer growth was uniform
then cleavage of the two ester bonds at the central benzoic
acid moiety should therefore result in a polymer of half the
original length (half the molecular weight) with the polydis-
persity remaining constant. This was indeed shown to be the
case as analysis of the recovered polymer by GPC gave a
molecular weight Mn of 4300 g mol−1 with the polydisper-
sity remaining low at 1.06 compared to 1.07 pre-hydrolysis
(Fig. 4). In addition, it was observed that the hydrolysis
conditions also cleaved the n-butyltrithiocarbonate (RAFT)
end-groups. This could be visualized by the disappearance of
the typical yellow colouration of the initial polymer, result-
ing in a colourless product. Confirmation was obtained by
Mn 8800 g molϪ1
Mw/Mn 1.07
Mn 4300 g molϪ1
Mw/Mn 1.06
100000
10000
1000
100
Molecular weight
Fig. 4. GPC traces of (a) carboxylic acid mid-functionalized
polystyrene 5f and (b) the same polymer after hydrolysis (aqueous KOH
in THF at 50◦C).
RAFT end-groups by hydroxide[35,36] and amine bases[37–40]
has been demonstrated previously in the literature. Taking
this into account the calculated molecular weight expected
for the polymer post-hydrolysis is 4200 g mol−1 which is in
good agreement with the GPC result.
1
analysis using H NMR spectroscopy showing an absence
of the characteristic signal at 3.34 ppm of the n-butyl CH2S
hydrogen atoms (usually a triplet, however signal is broad
for polystyrene and multiplicity not observed). Cleavage of

RESEARCH FRONT
768
N. Malic and R. A. Evans
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6000
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0
1.18
1.17
1.16
1.15
1.14
1.13
1.12
1.11
1.10
the desired copper/dinonyl-bipyridine complex.The dinonyl-
bipyridine now competes with the carboxylic acid for ligation
to the copper centre, thus the integrity of the catalyst can-
not be maintained. These results however only indicate the
inadequacy of this particular catalyst system. A previous
work[41] has demonstrated the successful use of carboxylic
acid functionalized initiators with ATRP using PMDETA as
the copper chelating ligand, which most probably gives a
more stable and therefore more effective catalyst system. Yet
even in this case the initiator efficiency was reduced (ca.
0.7) leading to higher molecular weights of product poly-
mers with respect to calculated values. When the carboxylic
acid group was subsequently protected, no interference
with the catalyst was detected and the polymerizations
were well controlled with the initiator efficiency close
to unity.
To be able to applyATRP to initiator 3 with a high level of
predictability, aswellasallowingtheuseoftheCuBr/dinonyl-
bipyridine catalyst system, the free carboxylic acid moiety
must be coupled directly to the intended functionality (or pro-
tecting group if a carboxylic acid mid-functionalized polymer
is ultimately required) before polymerization. The use of the
central carboxylic acid group as a ‘hook’for tethering to var-
ious chemical species is particularly useful when that species
has a free hydroxy or amine (primary or secondary) func-
tionality, thus allowing for ester and amide derivatization.
However, this species must itself be free of additional func-
tionality present on the molecule which could potentially
poison the catalyst system. This approach has been suc-
cessfully applied previously[12,13] where polymers have been
grown from non-Y-branched ATRP macroinitiators based on
photochromic dyes. In an analogous fashion, we have herein
demonstrated the efficient application of ATRP in the for-
mation of a mid-functionalized polymer. We tethered a fluo-
rescent molecule, 9-fluorenemethanol, as a model functional
group to the bis-initiator 3 by means of acid chloride chem-
istry (Scheme 5). 3,5-bis(2-bromopropionyloxy)benzoic acid
3 was converted to the acid chloride 7 by reaction with oxalyl
chloride in CH2Cl2 using a trace amount of DMF as catalyst,
which was subsequently reacted with 9-fluorenemethanol
giving the ester product 8. This fluorene-functionalized
ATRP macroinitiator was then used in polymerizations of
n-butyl acrylate using CuBr/4,4ꢀ-dinonyl-2,2ꢀ-bipyridine as
the catalyst system. The initiator, catalyst, and monomer
ratio was 1:1:100 and the polymerizations were performed
at 90◦C.
0
10 20 30 40 50 60 70 80 90 100
Conversion [%]
Fig. 5. Molecular weight and polydispersity (Mn ꢀ, PD ꢁ) versus
conversion for polymerizations (ATRP) of n-butyl acrylate using
9-fluorenylmethyl functionalized ATRP macroinitiator 8, in benzene
solutionat 90◦C, giving polymers 9a–9f. Conversions were derived from
1H NMR spectra. Calculated molecular weight versus conversion plot
represented by dotted line. Polymerization times ranged from 35 min
to 16 h.
O
O
Br
Br
b
O
O
n
n
O
O
O
O
a
O
O
c
d
e
h
f
g
g
b
f
e
c
d
h
a
990..0 885..5 880..0 775..5 770..0 665..5 6.0 55..5 55..0 445..5 440..0 335..5 33..0 225..5 220..0 115..5 11..0 005..5 000..0
Fig. 6. 1H NMR spectrum of 9-fluorenemethyl mid-functionalized
poly(n-butyl acrylate) 9a (Mn 2300 g mol−1) in CDCl3.
Atom Transfer Radical Polymerization (ATRP)
The RAFT and ATRP methods are known for their com-
patibility with many functional groups, whether they be
present on the monomer, the solvent, the RAFT agent or
the initiator (for ATRP).[8,9] The functional group tolerance
of the RAFT method versus ATRP was demonstrated in
this particular case. The presence of the carboxylic acid
functionality present on the bis-n-butyltrithiocarbonate func-
tionalized RAFT agent 4 did not interfere with the polymer-
ization, which showed good living behaviour (as outlined
earlier), and therefore allows for the derivatization of the
carboxylic acid group (e.g. to an ester or amide) either pre-
or post-polymerization. On the other hand, our attempts at
usingATRP with 3,5-bis(2-bromopropionyloxy)benzoic acid
3 as initiator and CuBr/(4,4ꢀ-dinonyl-2,2ꢀ-bipyridine) as the
catalyst system (1:1:2 ratio of initiator, CuBr, and dinonyl-
bipyridine) gave inconsistent results. The poor performance
of the polymerization can be attributed to the interference
of the carboxylic acid functionality with the formation of
As with the RAFT polymerizations described earlier the
use of ATRP in this case showed good living characteristics
(see the Accessory Publication for first-order kinetic plots)
with molecular weight increasing linearly with conversion
and with polydispersities generally decreasing (Fig. 5). The
observed molecular weights (Mn from GPC) conform well to
calculated values based on conversion, demonstrating cata-
lyst efficiency close to unity (data summarized in Table 1).
The presence of the central 9-fluorenylmethyl moi-
ety intact and unaffected post-polymerization was estab-
lished by analysis of the purified polymer product 9a
(Mn 2300 g mol−1) by 1H NMR. Both the aromatic and

RESEARCH FRONT
Synthesis of Carboxylic Acid and Ester Mid-Functionalized Polymers using RAFT Polymerization and ATRP
769
aliphatic proton signals are observed in the spectrum and
remain unshifted with respect to the signal positions pre-
polymerization (Fig. 6). The signals for the aromatic protons
of the linker moiety are however broadened and shifted
slightly upfield (2H signal shifted from 7.75 to 7.70 ppm
and 1H signal 7.25 to 7.15 ppm), which is expected due to
the change in the adjacent ester functionalities as a result of
the migration of the bromine atom away from the linker as
polymerization proceeds.
3,5-Bis(benzoyloxy)benzoic Acid 2
3,5-Dihydroxybenzoic acid 1 (5.0 g, 32.5 mmol) was dissolved in water
(130 mL) to which isopropanol (50 mL) was then added followed by
K2CO3 (22.4 g, 162.5 mmol).The mixture was kept under an inert atmo-
sphere of argon and cooled to ca. 0◦C. The temperature was maintained
between 0◦C and 5◦C during the addition of neat benzoyl chloride
(9.36 g, 66.6 mmol) to the vigorously stirred reaction mixture, over
which time a thick white precipitate developed. Upon completion of
addition the mixture was stirred for an additional 20 min before being
cautiously quenched with 6 M HCl (50 mL), ensuring the reaction mix-
ture remained cool. The solid was collected by filtration, washed with
generous amounts of cold water, and dried in a vacuum oven at 60◦C
to give the product as a white solid of high purity (10.6 g, 90%). δH
(200 MHz, [D6]acetone) 8.20–8.25 (4H, m, PhH), 7.92 (2H, d, J 2.2,
ArH), 7.58–7.80 (7H, m, ArH, PhH). δC (50 MHz, [D6]acetone) 165.2,
164.3, 151.7, 134.0, 132.9, 130.0, 129.2, 128.8, 120.7, 120.6.
Conclusions
The use of 3,5-dihydroxybenzoic acid 1 has enabled easy
access to mid-functionalized polymers viaY-branching. Only
simple chemistry is required to convert it to an ATRP
macroinitiator from which two equivalent polymer chains
propagate. This macroinitiator can itself be converted to a
RAFT agent in one step.The chemistry thus provides a choice
of two of the most dominant living radical polymerization
methods currently in use for the synthesis of low polydis-
persed polymers with mid functionality.The technology aims
to provide a further improvement in biomolecule or other
functional moiety encapsulation/protection compared with
typical end functionalization.
3,5-Bis(2-bromopropionyloxy)benzoic Acid 3
3,5-Dihydroxybenzoic acid 1 (5.0 g, 32.44 mmol) and K2CO3 (13.45 g,
97.33 mmol) were dissolved in a mixture of water (50 mL) and PriOH
(25 mL). The mixture was then cooled to −15◦C and 2-bromopropionyl
bromide (14.01 g, 64.88 mmol) added dropwise over 10 min with vigor-
ousstirring.Afteranadditional5 minofstirringthereactionmixturewas
quenched by the slow dropwise addition of 6 M aqueous HCl (38 mL)
over 30 min while maintaining the temperature between −15◦C and
−10◦C. Another portion of water (20 mL) was then added and the mix-
ture stirred while allowing it to reach room temperature over ∼30 min.
The resulting white solid was filtered, washed with water, and dried in a
vacuum oven at 45◦C (11.10 g, 81%). δH (400 MHz, CDCl3) 7.80 (2H,
d, J 2.20, ArH), 7.29 (1H, t, J 2.20, ArH), 4.60 (2H, q, J 6.95, CH), 1.96
(6H, d, J 6.95, CH3). δC (100 MHz, CDCl3) 170.1, 168.1, 150.8, 131.6,
120.8, 120.1, 39.0, 21.3. m/z (ESI) 421.0 [M − H]− (C13H11Br2O6
requires 420.9).
Accessory Publication
GPC traces of compounds 5a–5f and 6a–6f and first-order
kinetic plots for 5a–5f, 6a–6f, and 9a–9f are available from
the author or, until November 2011, the Australian Journal
of Chemistry.
3,5-Bis[2-(n-butyltrithiocarbonato)propionyloxy]benzoic Acid 4
To a mixture of 1-butanethiol (2.13 g, 0.0236 mol) and CS2 (17.95 g,
0.236 mol) in chloroform (25 mL) was added triethylamine (2.39 g,
0.0236 mol) under nitrogen. The mixture was stirred for 4 h at
room temperature after which a solution comprising of 3,5-bis(2-
bromopropionyloxy)benzoic acid 3 (2.50 g, 0.0059 mol) and triethyl-
amine (0.60 g, 0.0059 mol) in chloroform (10 mL) was added. The
mixture was stirred at room temperature for a further 18 h, washed
twice with 1 M aqueous HCl then water and dried with MgSO4. The
solvent was evaporated in vacuo and the oily residue purified by col-
umn chromatography using silica gel and eluting with EtOAc/hexane
(2/5), to give a yellow oil which slowly solidified on standing (1.89 g,
54%). δH (200 MHz, CDCl3) 7.74 (2H, d, J 2.19, ArH), 7.21 (1H, t,
J 2.19, ArH), 4.99 (2H, q, J 7.31, CH), 3.40 (4H, t, J 7.31, SCH2), 1.74
(6H, d, J 7.31, CHCH3, overlap with quintet, 4H, J 7.31, SCH2CH2),
1.44 (4H, sextet, J 7.31, CH2CH3), 0.94 (6H, t, J 7.31, CH2CH3). δC
(50 MHz, CDCl3) 221.6, 170.1, 169.2, 150.9, 131.4, 120.8, 120.5, 47.6,
37.2, 29.8, 22.0, 16.3, 13.5. m/z (ESI) 593.0 [M − H]− (C23H29O6S6
requires 623.0).
Experimental
Materials
N-Butyl acrylate (99+% purity) and styrene (99% purity) were pur-
chased from Aldrich. n-Butyl acrylate was passed through a column
of activated basic alumina while styrene was passed through activated
neutral alumina immediately before use to remove inhibitor. All other
reagents were obtained from Aldrich at the highest purity available and
used without further purification.
Measurements
Molecular weight and polydispersity of polymers were obtained by Gel
Permeation Chromatography (GPC) analyses performed in tetrahydro-
furan(THF, 1.0 mL min−1)at25◦CusingaWatersGPCinstrument, with
a Waters 2414 Refractive Index Detector, a series of four Polymer Lab-
oratories PLGel columns (3 × 5 µm Mixed-C and 1 × 3 µm Mixed-E),
and Millennium Software.The GPC was calibrated with narrow polydis-
persity polystyrene standards (Polymer Laboratories EasiCal, Mw from
264 to 256000). 1H and 13C NMR spectra were obtained with a Bruker
Av400 or a Bruker AC200 spectrometer. Chemical shifts are reported
in ppm from external tetramethylsilane. Monomer conversions were
obtained from 1H NMR spectra. The resonances integrated to obtain
conversions for n-butyl acrylate polymerizations were the vinyl peaks
at 5.86, 6.16, 6.36 ppm (monomer only) and the OCH2 peak at 4.14 ppm
(monomer and polymer). For styrene polymerizations the integrated res-
onances were the vinyl peaks at 5.24 and 5.82 ppm (monomer) and the
entire region between 6.4 and 7.7 ppm (monomer and polymer). Posi-
tive and negative ion electrospray mass spectra (ESI-MS) were acquired
with aVG Platform mass spectrometer using a cone voltage of 50V with
the source maintained at 80◦C. Methanol was used as solvent system
General Polymerization Procedures
(a)The RAFT polymerization of styrene using the carboxylic acid func-
tionalized RAFT agent 4 was performed using the following procedure:
A stock solution comprising the RAFT agent 4 dissolved in styrene
monomer in a 100:1 molar ratio was prepared. The required quantity
of this solution was administered to a glass ampoule via pipette which
was then thoroughly degassed by four freeze–pump–thaw cycles on a
high vacuum Schlenk line and sealed. The polymerizations were carried
out by heating at 110◦C in a constant temperature oil bath. The remain-
ing styrene monomer was then removed by evaporation with the aid of
CHCl3 and a nitrogen stream blowing across the surface of the solu-
tion. The remaining residue was then dissolved in a minimum amount
with a flow rate of 0.04 mL min−1
.

RESEARCH FRONT
770
N. Malic and R. A. Evans
of CHCl3 and added dropwise to a large volume of methanol with vigor-
ousstirring.Theprecipitatedpolymerwascollectedbyfiltration, washed
with methanol, and dried in a vacuum oven at 40◦C.
twice). The polymer was precipitated from CH2Cl2/methanol solution
(5:50 mL) by slow and partial evaporation (down to ca. 1/4 of ini-
tial solvent volume, the supernatant then decanted). The pure polymer
was dried in a vacuum oven at 40◦C to remove residual solvent. Mn
(GPC) 1300 g mol−1 (unpurified; polystyrene equivalents); polydisper-
sity 1.12. δH (400 MHz, CDCl3) 7.68 (2H, br s, ArH), 7.13 (1H, br s,
ArH), 4.81 (2H, m, CHBr), 4.04 (br, polymer butyl OCH2), 3.34 (4H, t,
SCH2), 2.78–1.45 (br, polymer backbone CH and CH2), 1.59 (br, poly-
mer butyl OCH2CH2), 1.36 (br, polymer butyl CH2CH3), 0.93 (br t,
polymer butyl CH3).
(b) The RAFT polymerization of n-butyl acrylate using the car-
boxylic acid functionalized RAFT agent 4 was performed using the
following procedure:A stock solution (25 mL) comprising n-butyl acry-
late (12.50 g, 97.53 mmol), the RAFT agent 4 (0.580 g, 0.975 mmol) and
AIBN (0.016 g, 0.0974 mmol) in benzene was prepared (molar ratio of
100:1:0.1). An aliquot (4 mL) was added to a glass ampoule which was
then degassed with four freeze–pump–thaw cycles using a high vac-
uum Schlenk line. The ampoule was sealed and polymerization effected
by heating at 60◦C in a constant temperature oil bath. The remaining
n-butyl acrylate monomer was then removed by evaporation with the aid
of CHCl3 and a stream of air blowing across the surface of the solution.
The polymer was precipitated from CH2Cl2/methanol solution by slow
and partial evaporation (down to ca. 1/4 of initial solvent volume, the
supernatant then decanted).
Hydrolysis of Benzoic Acid Mid-Functionalized Polystyrene 5f
To a solution of the benzoic acid mid-functionalized polystyrene 5f
(Mn 8800 g mol−1, 0.30 g in 25 mL THF) was added a solution of KOH
(0.038 g in 2 mL water). The mixture was stirred at 50◦C for 18 h during
which time the yellow solution became colourless. It was then poured
into Et2O (50 mL) which was then washed with 1 M HCl, water and
brine, subsequently dried with MgSO4 and the solvent evaporated. The
residue was dissolved in CH2Cl2 (ca. 2 mL) and this solution then added
dropwise into MeOH (100 mL) with vigorous stirring. The precipitated
polymer was filtered, washed with MeOH, and dried giving a white
powder (0.223 g). Mn (GPC) 4300 g mol−1, polydispersity 1.06. δH
(400 MHz, CDCl3) 7.35–6.90 (br,ArH), 6.90–6.35 (br,ArH), 2.45–1.72
(br, polymer backbone CH), 1.72–1.25 (br, polymer backbone CH2),
1.07–0.90 (br m, CH3).
(c) The ATRP polymerization of n-butyl acrylate using the
9-fluorenylmethyl functionalized macroinitiator 9 was performed as
follows: A stock solution (25 mL) containing n-butyl acrylate (12.50 g,
97.53 mmol),
9-fluorenylmethyl
3,5-bis(2-bromopropionyloxy)
benzoate 9 (0.5869 g, 0.974 mmol) and dinonyl-bipyridine (0.7969 g,
1.95 mmol) in benzene was prepared. To a glass ampoule was added
CuBr(0.0224 g, 0.156 mmol)anda4 mLaliquotofstocksolution, which
was then degassed with four freeze–pump–thaw cycles and sealed. Poly-
merization was effected by heating at 90◦C in a constant temperature
oil bath. The remaining n-butyl acrylate monomer was then removed
by evaporation with the aid of CHCl3 and a stream of air blowing
across the surface of the solution. The polymer was precipitated from
CH2Cl2/methanol solution by slow and partial evaporation (down to
ca. 1/4 of initial solvent volume, the supernatant then decanted). The
remaining small amount of copper catalyst was removed by passing
through a short plug of silica gel eluting with diethyl ether. Evaporation
of the solvent gave the pure polymer.
9-Fluorenylmethyl 3,5-bis(2-bromopropionyloxy)benzoate 8
3,5-bis(2-bromopropionyloxy)benzoic acid 3 (1.50 g, 3.54 mmol) was
dissolved in dry CH2Cl2 (10 mL) together with 1 drop of DMF under
argon. Oxalyl chloride (1.35 g, 10.61 mmol) was added in one portion
and the mixture stirred for 30 min at room temperature. The solvent and
excess reagent was evaporated in vacuo leaving a viscous oil which crys-
tallized to a colourless waxy solid on standing at room temperature. A
portion of this acid chloride derivative 7 (1.50 g, 3.39 mmol) was taken
and dissolved in anhydrous diethyl ether (15 mL) together with triethy-
lamine (0.686 g, 6.78 mmol) under argon. To this mixture was slowly
added a solution of 9-fluorenemethanol (0.665 g, 3.39 mmol) in anhy-
drous diethyl ether (10 mL) via syringe and stirred for 30 min at room
temperature. The solvent was then evaporated in vacuo and the residue
purified by column chromatography (silica, CHCl3/hexane 1/1) yield-
ing a colourless glassy solid (0.973 g, 48%). δH (400 MHz, CDCl3) 7.79
(2H, d, J 7.32,ArH), 7.75 (2H, d, J 1.83,ArH), 7.63 (2H, d, J 7.32,ArH),
7.42 (2H, t, J 7.32, ArH), 7.34 (2H, t, J 7.32, ArH), 7.25 (1H, overlap
with CHCl3,ArH), 4.63 (2H, d overlap, J 7.32, CH2O), 4.61 (2H, q over-
lap, J 6.95, CHBr), 4.38 (1H, t, J 7.32, ArCHAr), 1.97 (6H, d, J 6.95,
CH3). δC (100 MHz, CDCl3) 168.07, 164.39, 150.84, 143.46, 141.32,
132.50, 127.91, 127.23, 125.02, 120.24, 120.11, 119.28, 67.59, 46.77,
39.06, 21.31. m/z (ESI) 622.8 [M + Na]+ (C27H22Br2O6Na requires
623.0).
Specific Example of the RAFT Polymerization of Styrene Using
the Carboxylic Acid Functionalized RAFT Agent 4: Carboxylic
Acid Mid-Functionalized Polystyrene 5a
An aliquot of stock solution (see General Polymerization Procedure
above) containing RAFT agent 4 (0.1142 g, 0.192 mmol) dissolved in
styrene (2.0 g, 19.20 mmol) was added to a glass ampoule and degassed
by four freeze–pump–thaw cycles using a high vacuum Schlenk line. It
was then heated at 110◦C in a constant temperature oil bath for 2 h. The
remaining styrene monomer was then removed by evaporation with the
aid of CHCl3 (50 mL) and a nitrogen stream blowing across the surface
of the solution (this procedure performed twice). The remaining residue
was then dissolved in a minimum amount of CHCl3 and added dropwise
to methanol (ca. 100 mL) with vigorous stirring. The precipitated poly-
mer was collected by filtration, washed with methanol, and dried in a
vacuum oven at 40◦C giving a pale yellow coloured powder. Mn (GPC)
1600 g mol−1 (unpurified); polydispersity 1.19. δH (400 MHz, CDCl3)
7.52 (2H, br, linker ArH), 7.40–6.35 (br, polymer ArH), 5.25–4.75 (2H,
br, CHS), 3.32 (4H, br s, end-group SCH2), 2.70–1.25 (br, overlap poly-
mer backbone CH, CH2 and end-group SCH2CH2CH2CH3), 1.11 (6H,
br, COCHCH3), 0.91 (6H, br s, end-group CH3).
Specific Example of the ATRP Polymerization of n-Butyl Acrylate
Using the 9-Fluorenylmethyl Functionalized Macroinitiator 8:
9-Fluorenylmethyl Mid-Functionalized Poly(n-Butyl Acrylate) 9a
An aliquot (4 mL) of stock solution (see general polymerization
procedure above) containing n-butyl acrylate (2.0 g, 15.60 mmol),
9-fluorenylmethyl 3,5-bis(2-bromopropionyloxy)benzoate 8 (0.0939 g,
0.156 mmol) and dinonyl-bipyridine (0.1275 g, 0.312 mmol) was added
to a glass ampoule containing CuBr (0.0224 g, 0.156 mmol), which was
then degassed with four freeze–pump–thaw cycles using a high vac-
uum Schlenk line and sealed. Polymerization was effected by heating
at 90◦C in a constant temperature oil bath for 35 min. The remaining
n-butyl acrylate monomer was then removed by evaporation with the
aid of CHCl3 (50 mL) and a stream of air blowing across the surface
of the solution (this procedure performed twice). The polymer was pre-
cipitated from CH2Cl2/methanol solution (5/50 mL) by slow and partial
evaporation (down to ca. 1/4 of initial solvent volume, the supernatant
then decanted). The remaining small amount of copper catalyst was
removed by passing through a short plug of silica gel eluting with
Specific Example of the RAFT Polymerization of n-Butyl Acrylate
Using the Carboxylic Acid Functionalized RAFT Agent 4:
Carboxylic Acid Mid-Functionalized Poly(n-Butyl Acrylate) 6a
An aliquot (4 mL) of stock solution (see general polymerization proce-
dure above) containing n-butyl acrylate (2.0 g, 15.60 mmol), the RAFT
agent 4 (0.0928 g, 0.156 mmol), and AIBN (2.56 mg, 0.0156 mmol)
was added to a glass ampoule which was then degassed with four
freeze–pump–thaw cycles using a high vacuum Schlenk line and sealed.
Polymerization was effected by heating at 60◦C in a constant temper-
ature oil bath for 40 min. The remaining monomer was then removed
by evaporation with the aid of CHCl3 (50 mL) and a nitrogen stream
blowing across the surface of the solution (this procedure performed

RESEARCH FRONT
Synthesis of Carboxylic Acid and Ester Mid-Functionalized Polymers using RAFT Polymerization and ATRP
771
diethyl ether. Evaporation of the solvent gave the pure polymer. Mn
(GPC) 2300 g mol−1 (unpurified; polystyrene equivalents) at a conver-
sion of 16.5%; polydispersity 1.15. δH (400 MHz, CDCl3) 7.79 (2H, d,
J 7.32, ArH), 7.70 (2H, br, linker ArH), 7.62 (2H, d, J 7.32, ArH), 7.41
(2H, t, J 7.32, ArH), 7.32 (2H, t, J 7.32, ArH), 7.15 (1H, br s, linker
ArH), 4.59 (2H, d, J 7.32, fluorenyl CH2O), 4.38 (1H, br t, ArCHAr),
4.22–4.15 (m overlap, CHBr), 3.89–4.20 (br m overlap, polymer butyl
OCH2), 2.78–1.45 (br, polymer backbone CH and CH2), 1.61 (br, poly-
mer butyl OCH2CH2), 1.37 (br, polymer butyl CH2CH3), 0.94 (br m,
polymer butyl CH3).
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