The formation of core cross-linked star polymers containing cores cross-linked by dynamic covalent imine bonds

Article abstract of DOI:10.1039/c0cc00691b

Diblock copolymers possessing amino or aldehyde functions within one of their blocks were prepared using RAFT polymerization techniques. These polymers were shown to cross-link through dynamic imine bonds to form core cross-linked star polymers which display a size-dependency upon the concentration at which the cross-linking reactions are performed.

Full text of DOI:10.1039/c0cc00691b

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The formation of core cross-linked star polymers containing cores
cross-linked by dynamic covalent imine bondsw
Alexander W. Jackson and David A. Fulton*
Received 31st March 2010, Accepted 18th June 2010
DOI: 10.1039/c0cc00691b
Diblock copolymers possessing amino or aldehyde functions
within one of their blocks were prepared using RAFT poly-
merization techniques. These polymers were shown to cross-link
through dynamic imine bonds to form core cross-linked star
polymers which display a size-dependency upon the concentration
at which the cross-linking reactions are performed.
Recent pioneering work by the group of Otsuka and
7
Takahara describes
the programmed thermodynamic
formation of CCS polymers where the polymer chains are
cross-linked through thermally reversible TEMPO-based
alkoxyamine bonds. With the addition of a small molecule
alkoxyamine at high temperatures (B100 1C), these CCS
polymers can interconvert into linear polymer chains,
demonstrating that the incorporation of dynamic covalent
bonds into polymer nanostructures affords species with the
potential to undergo massive structural changes.
1
Core cross-linked star (CCS) polymers are a class of discrete
nano-sized polymer assembly whose structural features are
defined by a core consisting of cross-linked polymer chains
surrounded by a corona of polymeric arms. Much of the
interest in CCS polymers is as a consequence of their cross-
linked cores which can be utilized as carriers for small
molecules such as drugs or fragrances, with the coronal chains
helping to solubilize and shield the cargo from its external
environment. CCS polymers also possess solubilities and
viscosities similar to linear polymers of relatively low
molecular weight, additional properties which make them
potentially very useful in a diverse range of fields, most
Here, we describe the formation of CCS polymers through
dynamic covalent bonds which are reversible under ambient
conditions. These CCS polymers are constructed (Fig. 1) from
linear polymer chains possessing an ‘‘inert’’ block which
prevents macroscopic cross-linking and a ‘‘reactive’’ block
which contains aldehyde or amine functions which facilitate
cross-linking of polymer chains through reversible imine
5
bond formation, a well-studied reaction in DCC. Imine
condensation reactions are a particularly appealing dynamic
covalent reaction as it is possible to tune the stability of the
imine bond by altering stereoelectronic characteristics of the
reaction partners, in particular the carbonyl-derived part.
Furthermore, the position of the equilibrium can be sensitive
to pH, temperature and concentration of water, presenting the
possibility for polymer structures incorporating these bonds to
2
3
4
notably drug delivery as well as imaging and catalysis.
Conventionally, cross-linking within CCS polymers has
been facilitated by irreversible covalent bonds. We became
intrigued by the possibility of using ideas from the field of
5
dynamic covalent chemistry (DCC) to develop new CCS
polymers possessing responsive and adaptive properties.
DCC uses reversible covalent bond formation to link compo-
nent organic building blocks into larger structures, a process
operating under thermodynamic control. The reversible nature
of the dynamic covalent linkages enables product assemblies
to modify their constitutions by incorporating or releasing
components, in effect providing a mechanism for a polymer-
based assembly to reconfigure its covalent structure and
8
respond to a variety of environmental changes. Aldehyde and
amine functions are also synthetically straightforward to
incorporate into the ‘reactive’ block of the polymer chains,
ensuring ease of synthesis, and as reversible imine condensation
reactions are often preformed in the presence of an acid
catalyst, they can be kinetically fixed by quenching the acid
catalyst or reducing the double bond.
6
therefore its functional or material properties. The reversible
nature of the linkages may also instil the ‘‘intelligent’’ virtues
of controlled assembly, adaptability, and self-repair into the
resultant nanostructures. Furthermore, the strength of the
covalent bond ensures that product assemblies possess
chemical robustness, and as reversible covalent reactions are
usually performed with the help of a suitable catalyst to aid
kinetics, the option exists to halt these reversible processes and
kinetically ‘‘fix’’ the products simply by quenching the catalyst.
Chemical Nanoscience Laboratory, School of Chemistry,
Bedson Building, Newcastle University, Newcastle upon Tyne, UK.
E-mail: d.a.fulton@ncl.ac.uk; Fax: +44 (0)191 222 6929;
Tel: +44 (0)191 222 7065
w Electronic supplementary information (ESI) available: All experi-
mental procedures and characterization of all polymers (P1–P4);
photographs of gels formed from reaction of P1 and P2b (Fig. S1);
MALDI-TOF mass spectrum of 2-armed core cross-linked polymer.
See DOI: 10.1039/c0cc00691b
Fig.
1
Formation of dynamic covalent core cross-linked star
polymers by cross-linking polymer chains through dynamic covalent
imine bonds.
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Chem. Commun., 2010, 46, 6051–6053 | 6051

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left to equilibrate overnight before analysis by gel permeation
chromatography–multiangle laser light scattering (GPC-MALLS)
Table 1) which allows the measurement of M and the radius
(
w
of gyration (R ). Online dynamic light scattering measure-
g
ments also furnished the hydrodynamic radius (R ). No
h
macroscopic gelation was observed in any of these experi-
1
3
ments. All GPC traces (Fig. 2) show a disappearance of the
peaks at B14 min corresponding to diblock copolymers P3
and P4, and the appearance of a major peak at lower elution
volume indicative of the formation of high molecular weight
1
4
aggregates. These experiments indicate a concentration
dependence (Fig. 3) of the M of the CCS polymers formed
w
upon the concentrations of the starting diblock polymers used.
Mw measurements as determined by GPC-MALLS were
consistently larger than those determined by calibration
1
5
Scheme 1 Synthetic route to aldehyde- and amine-functionalized
against PS standards, an observation consistent with the
character of CCS polymers, which are more compact than
diblock copolymers.
Living radical polymerizations provide access to well-
defined diblock copolymers possessing uniform molecular
weights. In particular, reversible addition–fragmentation
9
chain transfer (RAFT) polymerization is appealing because
of its versatility and experimental simplicity. The RAFT chain
0
00
transfer agent S-1-dodecyl-S -(a,a-dimethyl-a -acetic acid)-
trithiocarbonate (DDMAT) was used (Scheme 1) to mediate
1
0
the copolymerization of a 1 : 1 mixture of styrene and
1
1
4
-vinylbenzaldehyde at 70 1C in dioxane to afford P1
Mw = 10.8 kDa, PDI = 1.17), which after purification was
used as a macro-initiator and extended via RAFT polymerization
with styrene at 70 1C in dioxane to afford P3 (M = 43.3 kDa,
(
w
Fig. 2 Differential refractive index (dRI) GPC traces for experiments
ꢁ1
PDI = 1.35). Likewise, the copolymer P2a was prepared
1, 3 and 6 in THF (1.0 mL min ). Traces for experiments 2, 4 and 5
via RAFT polymerization of a 1 : 1 mixture of N-boc-4-
have been omitted for clarity.
1
2
aminostyrene and styrene at 70 1C in dioxane, which was
then used as a macro-initiator and extended via RAFT
polymerization with styrene at 70 1C in dioxane to afford,
after the removal of the protecting groups, P4 (M = 28.3 kDa,
w
PDI = 1.40). A sample of the copolymer P2a was also
subjected to acidic conditions to remove the protecting groups
to yield P2b (Mw = 9.0 kDa, PDI = 1.13). Polymers P1–P4
1
were characterized by H NMR spectroscopy and gel permeation
chromatography (GPC) (see ESIw, Table S1).
The diblock copolymers P3 and P4 were then used as
components for the self-assembly of CCS polymers. These
were prepared by mixing equimolar solutions of P3 and P4 in
THF in the presence of TFA catalyst at a range of different
concentrations (0.5–5.0 wt%) and the resulting solutions were
Fig. 3 The dependence of Mw of the CCS polymers obtained on the
wt% of polymers P3 and P4 used.
Table 1 Characterization of CCS polymers. Each experiment was performed in THF with equal molar ratios of P3 and P4 in the presence of TFA
10 equiv.)
(
Experiment
number
% Weight of total
polymer building blocks
Average number of
arms per assembly
a
n
ꢁ1
a
ꢁ1
a
a
h
a
b
M
/g mol
M
w
/g mol
PDI
R
/nm
R
g
/nm
R
g
/R
h
1
2
3
4
5
6
0.5
1
2
3
4
379 600
493 000
967 000
1 337 000
2 401 000
5 235 000
399 600
515 100
1 175 000
1 651 000
3 034 000
6 808 000
1.05
1.04
1.22
1.23
1.26
1.30
11.7
12.5
14.8
17.7
26.0
34.4
13.3
13.1
19.5
27.7
44.9
61.9
1.14
1.05
1.32
1.56
1.73
1.80
11
14
33
46
85
190
5
a
ꢁ1
ꢁ1
As determined by dynamic/static light scattering in THF (1.0 mL min ) using experimentally determined dn/dc value (0.204 mL g ).
b
w w
Calculated by dividing M for CCS polymers by the average M of P3 and P4.
6
052 | Chem. Commun., 2010, 46, 6051–6053
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their linear counterparts with the same molecular weights,
suggesting that the CCS polymers prepared possess a cross-
linked branched structure. Further evidence supporting the
CCS polymer architecture can be obtained from the structure
sensitive r parameter (r = R /R ) defined by Burchard
We envisage that the use of dynamic covalent imine bonds
will increase the scope and utility of these CCS polymers. We
are currently investigating the dependence of the CCS
polymers formed upon the structural features of their diblock
copolymer components and are also developing water-soluble
CCS polymer analogues.
g
h
1
6
and co-workers. Those CCS polymers prepared at lower
concentrations (0.5 and 1.0 wt%, Table 1, entries 1 and 2)
1
5
possess r values B1.1, which is consistent with mono-
disperse regular star architectures and suggests that these
lower concentrations are the optimum to form the most
monodisperse species. The upward trend in r values for those
CCS polymers prepared at higher concentrations (Table 1,
entries 3–6) indicates increasing polydispersity, which maybe
as a consequence of a degree of star–star couplings.
Notes and references
1
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2 J. T. Wiltshire and G. G. Qiao, Aust. J. Chem., 2007, 60, 699–705.
3
3
K. Fukukawa, R. Rossin, A. Hagooly, E. Pressly, J. Hunt,
B. Messmore, K. Wooley, M. Welch and C. J. Hawker,
Biomacromolecules, 2008, 9, 1329–1339.
The importance of the ‘‘inert’’ block in the formation of
discrete CCS polymers was emphasized by a cross-linking
experiment involving polymers P1 and P2b which do not
posses ‘‘inert’’ blocks. Equimolar solutions of P1 and P2b in
THF were combined in the presence of TFA catalyst at either
4 T. Terashima, M. Kamigaito, K.-Y. Baek, T. Ando and
M. Sawamoto, J. Am. Chem. Soc., 2003, 125, 5288–5289;
B. Helms, S. J. Guillaudeu, Y. Xie, M. McMurdo, C. J. Hawker
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and J. M. J. Frechet, Angew. Chem., Int. Ed., 2005, 44, 6384–6387;
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P. T. Corbett, J. Leclaire, L. Vial, K. R. West, J.-L. Wietor,
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0
1
.5 or 5 wt% and left to equilibrate. After approximately
5 min (5 wt%) or 2 h (0.5 wt%) a gel-like material was
obtained (see ESIw, Fig. S3) suggesting the formation of a
macroscopic cross-linked gel.
1
7
6 J.-M. Lehn, Prog. Polym. Sci., 2005, 30, 814–831; J.-M. Lehn,
Chem. Soc. Rev., 2007, 36, 151–160.
7
Interestingly, all dRI GPC traces displayed the presence of a
minor species eluting after B14.5 min. This species was
isolated and analyzed by matrix-assisted laser desorption
ionization–time of flight (MALDI-TOF) mass spectrometry
Y. Amamoto, Y. Higaki, Y. Matsuda, H. Otsuka and
A. Takahara, J. Am. Chem. Soc., 2007, 129, 13298–13304;
Y. Amamoto, T. Maeda, M. Kikuchi, H. Otsucka and
A. Takahara, Chem. Commun., 2009, 689–691; Y. Amamoto,
M. Kikuchi, H. Masunaga, S. Sasaki, H. Otsucka and
A. Takahara, Macromolecules, 2010, 43, 1785–1791.
For a recent example of micelle structures containing imine bonds
see: C. B. Minkenberg, L. Florusse, R. Eelkema, G. J. M. Koper
and J. H. van Esch, J. Am. Chem. Soc., 2009, 131, 11274–11275.
G. Moad, E. Rizzardo and S. H. Thang, Aust. J. Chem., 2006, 59,
(
see ESIw, Fig. S4). The mass spectrum suggests the presence
of an aggregate with a molecular weight of approximately
0–65 kDa, strongly suggesting the formation of a 2-armed
8
9
6
CCS polymer formed by the cross-linking between a single P3
chain and a single P4 chain. This evidence, to the best of our
knowledge, is arguably the most convincing to date supporting
the formation of 2-armed CCS polymers as a by-product
6
69–692.
10 J. T. Lai, D. Filla and R. Shea, Macromolecules, 2002, 35, 6754–6756.
11 R. Manzotti, T. S. Reger and K. D. Janda, Tetrahedron Lett., 2000,
41, 8417–8420.
1
8
during the formation of CCS polymers.
1
2 J. Jiang and S. Thayumanavan, Macromolecules, 2005, 38,
886–5891.
To demonstrate the potential of these CCS polymers to
undergo structural reconfiguration, a large excess of propyl-
amine was added to CCS polymers (as prepared in Table 1,
experiment 3) and the solution left to equilibrate overnight
before GPC analysis (see ESIw, Fig. S5). The chromatogram
obtained displayed the loss of the peak at B11.5 min corres-
ponding to CCS polymers and the appearance of a peak at
B14.0 min which corresponds to diblock copolymers. This
observation confirms that all the imine bonds present within
the CCS polymer have undergone trans-imination reactions,
resulting in disassembly of the CCS polymer species and the
generation of P4 and propylimine-capped P3. We do not
envisage that these products of the CCS polymer disassembly
can easily be reconverted back into CCS polymers, as this
transformation would effectively require the removal of
propylamine from the system.
5
13 dRI traces and light scattering traces can display differences as the
dRI response only depends on the concentrations of the molecules
whereas the light scattering response depends on the molecular
weights as well as concentrations. Complete sets of dRI and light
scattering traces are presented in the ESIw (Fig. S1 and S2).
14 Samples of CCS polymers were stored for one week at concentrations
lower and higher than the concentration at which they were
prepared. Subsequent GPC analysis showed no change suggesting
that the CCS polymers formed are kinetically very stable and do
not ‘shrink’ or ‘grow’ in response to concentration changes.
1
5 P. Lang, W. Burchard, M. S. Wolfe, H. J. Spinelli and L. Page,
Macromolecules, 1991, 24, 1306–1314.
1
6 W. Burchard, M. Schmidt and W. H. Stockmayer, Macromolecules,
1
980, 13, 1265–1272.
17 This macroscopic cross-linked gel could potentially hold promiseas
a so-called covalently adaptable network (CAN). For a recent
review of CANs, see: C. J. Kloxin, T. F. Scott, B. J. Adzima and
C. N. Bowman, Macromolecules, 2010, 43, 2643–2653.
18 Based on GPC chromatograms, Qiao and co-workers have
postulated the formation of 2-armed CCS polymers as a minor
component of polymers prepared through the so-called ‘arm-first’
methods employing irreversible cross-linking of the polymer
chains. See: M. Spiniello, A. Blencowe and G. C. Qiao,
J. Polym. Sci., Part A: Polym. Chem., 2008, 46, 2422–2431.
In conclusion, the cross-linking of polymer chains through
imine bonds affords new dynamic covalent CCS polymers
whose molecular weights are dependent upon the concentra-
tion at which the cross-linking reactions are performed.
This journal is ꢀc The Royal Society of Chemistry 2010
Chem. Commun., 2010, 46, 6051–6053 | 6053