Sugar-responsive block copolymers by direct RAFT polymerization of unprotected boronic acid monomers

Article abstract of DOI:10.1039/b802293c

Novel sugar-responsive block copolymers were prepared by RAFT block copolymerization of unprotected boronic acid monomers, providing a direct route to supramolecular assemblies that dissociate upon the addition of glucose. The Royal Society of Chemistry.

Full text of DOI:10.1039/b802293c

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Sugar-responsive block copolymers by direct RAFT polymerization of
unprotected boronic acid monomersw
Debashish Roy, Jennifer N. Cambre and Brent S. Sumerlin*
Received (in Cambridge, UK) 11th February 2008, Accepted 3rd March 2008
First published as an Advance Article on the web 28th March 2008
DOI: 10.1039/b802293c
Novel sugar-responsive block copolymers were prepared by
RAFT block copolymerization of unprotected boronic acid
monomers, providing a direct route to supramolecular assem-
blies that dissociate upon the addition of glucose.
styrenic boronic ester, and subsequent post-polymerization
deprotection led to well-defined boronic acid homo- and block
copolymers.6
As opposed to these previously reported methods, an at-
tractive alternative approach to well-defined boronic acid
(co)polymers is the direct controlled polymerization of free,
unprotected boronic acid monomers.12 In order to realize this
goal, a mechanism suitable for controlling the polymerization
of functional, Lewis acidic monomers is required. Herein, we
report the RAFT homo- and block (co)polymerization of a
free boronic acid acrylamido monomer. This represents the
first example of well-defined boronic acid-containing block
copolymers being prepared directly by any method, and as
such, represents an advancement in the synthesis of functional,
organometallic polymeric materials. We also describe the
solution properties of amphiphilic block copolymers that
result from copolymerization of a free boronic acid monomer
with a hydrophilic monomer. While the field of stimuli-
responsive block copolymers includes vast examples of, e.g.,
temperature-responsive systems, the block copolymers de-
scribed herein self-assemble–dissociate in response to changes
in pH and, importantly, the concentration of diols in the
surrounding medium. The latter aspect provides a route to
saccharide-responsive block copolymers.
Boronic acid-containing polymers demonstrate unique reac-
tivity and self-assembly capability that allow potential appli-
cations as self-healing materials, flame retardants, separating
agents, therapeutic agents, self-regulated drug delivery sys-
tems, and sensors for sugars and glycoproteins.1,2 To date, the
synthesis of free boronic acid-containing polymers by conven-
tional radical polymerization has resulted in ill-defined
random copolymers or crosslinked gels.3–5 While the robust
nature of radical polymerization provides a facile route by
which to polymerize many functional vinyl monomers, the
inability to prepare well-defined (co)polymers with controlled
topology significantly limits utility in many advanced applica-
tions. In particular, to more fully capitalize on the potential of
boronic acid-containing macromolecules in sensing and deliv-
ery applications that rely on supramolecular self-assembly
(e.g., block copolymer micellization), it is essential to prepare
boronic acid (co)polymers in a facile manner with precise
control over molecular weight, chain architecture, and com-
position.6
The particular choice of RAFT polymerization was based
on its functional group tolerance and particular applicability
for the synthesis of well-defined, water-soluble acrylamido
polymers.9,13 3-Acrylamidophenylboronic acid14 (APBA, 1)
was polymerized with 2-dodecylsulfanylthiocarbonylsulfanyl-
2-methylpropionic acid15 (DMP, 2) as the chain transfer agent
(CTA) and 2,20-azobisisobutyronitrile (AIBN) as the initiator
at 70 1C in 95% DMF–5% water (Scheme 1). The molar ratio
Controlled/‘‘living’’ radical polymerization (CRP) provides
accessibility to polymers with predictable molecular weights,
narrow molecular weight distributions, and preserved chain
end functionalities, the latter of which allows block copolymer
formation.7 Of the various methods of CRP, atom transfer
radical polymerization (ATRP)8 and reversible addition–frag-
mentation chain transfer (RAFT) polymerization9,10 have
been employed to prepare well-defined organoboron poly-
mers. For example, Jakle et al. reported the synthesis of
¨
boron-containing (co)polymers via ATRP of organoboron
monomers or silylated precursors that were borylated through
post-polymerization modification.11 Borylation and subse-
quent hydrolysis of a block copolymer with trimethylsilyl-
functionalized polystyrene units led to boronic acid block
copolymers capable of micellization in THF–water mixtures.
We recently employed RAFT for the polymerization of a
Department of Chemistry, Southern Methodist University, 3215
Daniel Avenue, Dallas, Texas 75275-0314, USA. E-mail:
bsumerlin@smu.edu; Fax: (+1) 214-768-4089; Tel: (+1) 214-768-
8802
w Electronic supplementary information (ESI) available: Experimental
procedures and selected 1H NMR spectra and SEC traces. See DOI:
10.1039/b802293c
Scheme 1 Synthesis of 3-acrylamidophenylboronic acid homo- and
block copolymer by reversible addition–fragmentation chain transfer
(RAFT) polymerization.
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of [monomer] : [CTA] : [initiator] was varied to observe the
effect on polymerization kinetics and molecular weight con-
trol. After a brief inhibition period, pseudo first-order kinetics
were observed up to high conversion (Fig. 1A). Molecular
weight analysis by size exclusion chromatography (SEC)
necessitated protection of the boronic acid residues by ester-
ification with pinacol, after which good agreement between
theoretical and experimental molecular weights was observed.
For instance, with [monomer] : [CTA] : [initiator] = [100] : [1] :
[0.2], 67% conversion was obtained in 150 min, resulting in
polymer with Mn = 19 200 g molꢁ1 (Mw/Mn = 1.13), in good
agreement with the theoretical Mn of 18 500 g molꢁ1. During
polymerization, the Mn of poly(3-acrylamidophenylboronic
acid) (PAPBA, 3) increased linearly with a slight deviation
at low conversion, potentially due to inefficient chain transfer
early in the polymerization (Fig. 1B). Despite this, the mole-
cular weight distributions for the polymers remained narrow
confirmed by comparison of the SEC molecular weight dis-
tributions (ESIw), though low molecular weight tailing may
indicate either the presence of a small amount of dead macro-
CTA or inefficient pinacol protection prior to analysis. None-
theless, the polydispersity index (Mw/Mn) of the resulting
block copolymer remained below 1.2. Block copolymer com-
1
positions calculated with data from both H NMR spectro-
scopy and SEC were in good agreement.
The solution behavior of the resulting block copolymers is
of particular interest. Boronic acids are uniquely stimuli-
responsive, in that their water solubility is tunable by changes
in both pH and solution diol concentration, the latter of which
has led to boronic acids being exploited as saccharide recep-
tors.2 In aqueous media, boronic acids exist in equilibrium
between forms that are neutral (typically insoluble) (6) and
anionic (soluble) (7) (Scheme 2).16 Cyclic ester complexes
between 6 and 1,2- or 1,3-diols are usually hydrolytically
unstable, but 7 readily forms boronate esters (8) in the
presence of vicinal diols.17 An increase in concentration of 8
shifts the ionization equilibria, effectively lowering the pKa of
the acid. Thus, complexation adjusts the overall equilibrium
from neutral/insoluble boronic acid moieties to anionic/hydro-
philic boronates. Therefore, the extent of ionization (and
water solubility) of boronic acid-containing polymers in-
creases with diol concentration.4,18 This principle was
exploited to induce self-assembly of the PAPBA-b-PDMA
block copolymers at pH o pKa of the boronic acid, and the
subsequent diol (glucose)-dependent solubility was used to
trigger aggregate dissociation.
(Mw/Mn
= 1.04–1.16) throughout the polymerizations
(Table 1).
Dynamic light scattering (DLS) was employed to investigate
the preliminary solution behavior of the double-hydrophilic
block copolymers. PAPBA-b-PDMA was expected to be both
pH- and diol-sensitive. pH sensitivity arises as a result of the
responsive organoboron block remaining soluble above the
pKa of its boronic acid moieties. PAPBA131-b-PDMA138 was
dissolved at pH 10.7 to give unimers with a hydrodynamic
diameter (Dh) of approximately 7 nm (Fig. 2). When the pH
was slowly reduced below the pKa of the PAPBA block
(pKa E 9)5 by dialysis against deionized water, it was expected
that self-assembly would lead to micelles. Indeed, aggregates
with an average hydrodynamic diameter of 35 nm were
observed by DLS (Fig. 2). While we cannot be certain of the
exact solution morphology, it is reasonable to assume the
aggregates are micelles composed of a hydrophilic PDMA
corona and a hydrophobic PAPBA core.
Fig. 1 (A) Pseudo first-order kinetic plot with selected molar ratios of
monomer (M) : chain transfer agent (CTA) : initiator (I); (B) Mn versus
monomer conversion ([Mon] : [CTA] : [Init] = 100 : 1 : 0.1) for RAFT
homopolymerizations of 3-acrylamidophenylboronic acid (APBA, 1)
at 70 1C in 95% DMF–5% water.
PAPBA homopolymers were used as macro-chain transfer
agents (macroCTAs) to synthesize diblock copolymers with
1
N,N-dimethylacrylamide (DMA, 4). H NMR and SEC ana-
lyses of the resulting block copolymer confirmed successful
incorporation of DMA. After copolymerization of DMA with
a PAPBA macroCTA (3) of Mn = 25 000 g molꢁ1, the
molecular weight of the resulting block copolymer increased to
Mn = 38 700 g molꢁ1 (Mn,theory = 35 000 g molꢁ1), and a new
signal in the 1H NMR spectrum was observed at d = 2.93 ppm,
arising from the methyl groups of the poly(N,N-dimethyl-
acrylamide) (PDMA) units. Block copolymer formation was
In addition to pH susceptibility, PAPBA-b-PDMA was also
expected to respond to the concentration of diols in the
Table 1 Reversible addition–fragmentation chain transfer (RAFT) homo- and block copolymerization of 3-acrylamidophenylboronic acid
(APBA, 1) at 70 1C
[M] : [CTA] : [I]a
Conv.b (%)
Mn,theob/g molꢁ1
Mnc/g molꢁ1
Mw/Mn
c
PAPBA
PAPBA
PAPBA
PAPBA-b-PDMAd
[100] : [1] : [0.1]
[100] : [1] : [0.2]
[200] : [1] : [0.1]
[100] : [1] : [0.2]
71
67
74
96
19 500
18 500
40 600
35 000
19 700
19 200
37 800
38 700
1.16
1.13
1.16
1.17
a
b
Molar ratio of monomer (M) : chain transfer agent (CTA) : initiator (I). Determined by 1H NMR spectroscopy (theoretical molecular weights
c
d
(Mn,theo) calculated assuming 100% protection with pinacol). Determined by SEC of the pinacol-protected polymers. PAPBA-b-PDMA:
PAPBA-b-poly(N,N-dimethylacrylamide).
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tantly, sugar-responsive self-assembly. In principle, the sensi-
tivity of these copolymers is not limited to glucose. Our future
investigations will explore other saccharides and/or naturally-
occurring diols that also trigger aggregate disassembly.
We thank Dr Sudershan R. Gondi for synthesizing DMP.
Acknowledgment is made to SMU, the Donors of the Amer-
ican Chemical Society Petroleum Research Fund (45286-G7),
Oak Ridge Associated Universities (Ralph E. Powe Junior
Faculty Enhancement Award), and the Defense Advanced
Research Projects Agency (HR-0011-06-1-0032) for partial
support of this research.
Scheme 2 Ionization and diol complexation equilibria of boronic
acids in aqueous media.
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The ability to prepare well-defined boronic acid-containing
(co)polymers without resorting to protection–deprotection
strategies may enable utilization of controlled topology orga-
noboron polymers in a variety of biological and catalytic
applications. For the first time, we have demonstrated a facile
method to prepare block copolymers via direct RAFT poly-
merization of unprotected boronic acid monomers. In addi-
tion to expanding the range of functionality that can be
directly incorporated into well-defined polymers, this route
provides simplified access to a new class of ‘‘smart’’ block
copolymers that demonstrate unique pH-, and more impor-
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Chem. Commun., 2008, 2477–2479 | 2479