Supramolecular cross-linked networks via host-guest complexation with cucurbit[8]uril

Article abstract of DOI:10.1021/ja106362w

The ability to finely tune the solution viscosity of an aqueous system is critical in many applications ranging from large-scale fluid-based industrial processes to free-standing hydrogels important in regenerative medicine, controlled drug delivery, and 'green' self-healing materials. Herein we demonstrate the use of the macrocyclic host molecule cucurbit[8]uril (CB[8]) to facilitate reversible cross-linking of multivalent copolymers with high binding constants (K_a > 10¹¹-10¹² M^-2) leading to a supramolecular hydrogel. Multivalent copolymers were prepared by free radical polymerization techniques and contained either pendant methyl viologen (a good first guest for CB[8]) or naphthoxy derivatives (good second guests for CB[8]). A colorless solution of the two multivalent copolymers bearing first and second guests, respectively, can be transformed into a highly viscous, colored supramolecular hydrogel with the cross-link density being easily controlled through CB[8] addition. Moreover, the cross-links (1:1:1 supramolecular ternary complexes of CB[8]/viologen/naphthoxy) are dynamic and stimuli-responsive, and the material properties can be modulated by temperature or other external stimuli. Rheological characterization of the bulk material properties of these dynamically cross-linked networks provided insight into the kinetics of CB[8] ternary complexation responsible for elastically active cross-linking with a second guest dissociation rate constant (k_d) of 1200 s^-1 for the ternary complex. These materials exhibited intermediate mechanical properties at 5 wt % in water (plateau modulus = 350-600 Pa and zero-shear viscosity = 5-55 Pa?s), which is complementary to existing supramolecular hydrogels. Additionally, these supramolecular hydrogels exhibited thermal reversibility and subsequent facile modulation of microstructure upon further addition of CB[8] and thermal treatment. The fundamental knowledge gained from the study of these dynamic materials will facilitate progress in the field of smart, self-healing materials, self-assembled hydrogels, and controlled solution viscosity.

Full text of DOI:10.1021/ja106362w

Published on Web 09/16/2010
Supramolecular Cross-Linked Networks via Host-Guest
Complexation with Cucurbit[8]uril
Eric A. Appel, Frank Biedermann, Urs Rauwald, Samuel T. Jones,
Jameel M. Zayed, and Oren A. Scherman*
MelVille Laboratory for Polymer Synthesis, Department of Chemistry, UniVersity of Cambridge,
Lensfield Road, Cambridge CB2 1EW, United Kingdom
Received July 18, 2010; E-mail: oas23@cam.ac.uk
Abstract: The ability to finely tune the solution viscosity of an aqueous system is critical in many applications
ranging from large-scale fluid-based industrial processes to free-standing hydrogels important in regenerative
medicine, controlled drug delivery, and ‘green’ self-healing materials. Herein we demonstrate the use of the
macrocyclic host molecule cucurbit[8]uril (CB[8]) to facilitate reversible cross-linking of multivalent copolymers
11
12
-2
with high binding constants (K > 10 -10 M ) leading to a supramolecular hydrogel. Multivalent copolymers
a
were prepared by free radical polymerization techniques and contained either pendant methyl viologen (a good
first guest for CB[8]) or naphthoxy derivatives (good second guests for CB[8]). A colorless solution of the two
multivalent copolymers bearing first and second guests, respectively, can be transformed into a highly viscous,
colored supramolecular hydrogel with the cross-link density being easily controlled through CB[8] addition.
Moreover, the cross-links (1:1:1 supramolecular ternary complexes of CB[8]/viologen/naphthoxy) are dynamic
and stimuli-responsive, and the material properties can be modulated by temperature or other external stimuli.
Rheological characterization of the bulk material properties of these dynamically cross-linked networks provided
insight into the kinetics of CB[8] ternary complexation responsible for elastically active cross-linking with a second
-1
d
guest dissociation rate constant (k ) of 1200 s for the ternary complex. These materials exhibited intermediate
mechanical properties at 5 wt % in water (plateau modulus ) 350-600 Pa and zero-shear viscosity ) 5-55
Pa·s), which is complementary to existing supramolecular hydrogels. Additionally, these supramolecular
hydrogels exhibited thermal reversibility and subsequent facile modulation of microstructure upon further addition
of CB[8] and thermal treatment. The fundamental knowledge gained from the study of these dynamic materials
will facilitate progress in the field of smart, self-healing materials, self-assembled hydrogels, and controlled solution
viscosity.
Introduction
tunably responsive to various external stimuli including solvent
composition, pH, temperature, salt concentration, electric potential,
Supramolecular assembly encompasses the formation of struc-
turally well-defined aggregates associated noncovalently with
reversible interactions tunable by external stimuli. The desire to
and light. Self-assembled materials have led to the preparation of
1
1-13
14-16
1
supramolecular polymers,
hierarchical assemblies,
cross-linked gel materials,
1
7,18
19,21
metal-nanoparticle assemblies,
and
dictate and control the macroscopic properties of polymeric
materials has, in part, grown from the success of the rational design
of well-defined supramolecular interactions through small-molecule
22,23
metastable polymeric nanoparticles.
Supramolecular polymeric hydro- and organogels have re-
ceived much focus recently on account of the mechanical
properties gained from use of polymeric building blocks and
also the stimuli responsivity and processability inherent to the
supramolecular units used in cross-linking. Previously, organic
2-5
synthesis.
Self-assembled polymeric materials have proven to
act as ‘smart’ matter with specific stimuli-responsive material
properties on the macroscopic level.
advantage of specific, directional noncovalent interactions that are
6-10
These materials take
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A R T I C L E S
Appel et al.
Figure 1. (a) Schematic of the two-step, three-component binding of cucurbit[8]uril in water. (b) Thermodynamic and kinetic parameters of second-guest
binding.
polymer hydrogels have been demonstrated utilizing the well-
known cyclodextrin (CD)/adamantane (Ad) two-component
of glycoluril units determines the size of the cucurbituril cavity
without affecting the height of the molecular container (ap-
proximately 0.9 nm), similar to the case for the CD family.
While CB[5], CB[6], and CB[7] are all capable of binding single
24,25
complementary binding motif.
Ritter and co-workers dem-
onstrated the preparation of a random copolymer consisting of
N-isopropylacrylamide (NIPAM) and Ad-functional acrylamide
26-29
guests (typically cationic amines, metal or imidazolium ions),
3
monomeric units (M
the mixture of this copolymer and a discrete CD-dimer had
modest properties (η ) 1-10 Pa ·s @ 7.5 wt %) that could be
altered as a function of the lower critical solution temperature
n
≈ 50-75 kDa). Hydrogels formed from
CB[8] has a larger cavity volume of 479 Å and can simul-
30,31
taneously accommodate two guests (Figure 1a).
An electron-
o
deficient first guest such as viologen (MV) and an electron-
rich second guest such as 2-naphthol form a stable 1:1:1 ternary
complex with CB[8] through multiple noncovalent interactions
acting synergistically, including electrostatic and hydrophobic
effects. This ternary complex is accompanied by the quantitative
formation of a new visible absorbance on account of formation
of a charge-transfer complex between the MV and naphthol groups.
The utility of CB[8] as a dynamic interlink between MV and a
2
5
(
LCST) of the NIPAM-containing copolymer. The authors
subsequently demonstrated a system with greatly increased
mechanical properties (η ) 100-1000 Pa·s @ 10 wt %) from
a similar copolymer of the Ad-functional monomer copolymer-
ized with a negatively charged monomer (M
≈ 125 kDa) and
o
n
2
4
a globular CD polymer (M
n
≈ 90 kDa). Recently, supramo-
lecular polymer-clay hybrid hydrogels have been reported that
use multivalent ionic interactions from telechelic poly(ethyl-
eneglycol)s bearing guanidinium-functional dendritic end groups
with clay nanosheets that are surface-coated with poly(sodium
variety of electron-rich aromatic guests has been demonstrated,
32-35
exhibiting reversible redox-responsive behavior.
The forma-
tion of ternary complexes with CB[8] occurs in a stepwise
binding process whereby the electron-poor guest enters first (Ka1
followed by the electron-rich guest (Ka2). While there are two K
)
a
1
6
acrylate). These hydrogels exhibit very high mechanical
4
6
strength (10 -10 Pa), rapid self-healing ability, and stimuli
responsiveness and can be formed into shape-persistant, free-
standing macroscopic objects.
values associated with this binding scheme (resulting in the overall
-2
K reported in M ), focus may be placed on the dynamic
equilibrium and kinetics of the second guest binding (Figure 1b)
Another family of macrocylic host molecules is cucurbit[n]uril
(
CB[n]), which are cyclic, methylene-linked oligomers of
(
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1
4252 J. AM. CHEM. SOC. 9 VOL. 132, NO. 40, 2010

Cross-Linking via Complexation with Cucurbit[8]uril
A R T I C L E S
Figure 2. Supramolecular hydrogel preparation through addition of cucurbit[8]uril to a mixture of multivalent first and second guest functional polymers
in water.
as this binding step is primarily responsible for the dissociation
of the ternary complex.
ization technique used for the production of commercially
available polymers today. This is likely on account of several
important features: (a) compatibility with a wide variety of
monomers, including (meth)acrylates, (meth)acrylic acid, (meth)-
acrylamides, acrylonitrile, styrenics, dienes, vinyl acetate, and
other vinyl monomers; (b) tolerance of unprotected function-
3
5
The utility of CB[8] as a linking agent in polymeric and
multivalent systems has been reported previously. Our group
has recently demonstrated the CB[8]-mediated hierarchical self-
assembly of amphiphilic diblock copolymers consisting of PEG5k
and polyisoprene10k functionalized at their chain ends with MV
alities in both monomer and solvent (e.g., -OH, -NR
2
, -COOH,
1
7
and naphthoxy (Np) moieties, respectively. These polymers
were found to subsequently form compartmentalized nanostruc-
tures upon complexation of their end groups inside CB[8]. This
concept was extended further to the formation of ABA triblock
copolymers using a small bifunctional unit coupling two end-
-CONR , and SO ); (c) tolerance to aqueous or protic media; (d)
2
3
compatibility with a variety of reaction conditions (e.g., bulk,
solution, emulsion, and suspension); and (e) it is relatively
inexpensive and easy, requiring simple starting materials without
3
8,39
stringent or difficult practical implementation.
3
6
functional PEG5k polymers with CB[8]. Urbach and co-
workers reported the self-assembly of multivalent receptors
made from oligopeptides bearing either tryptophan residues or
Herein we use radical polymerization in the preparation of
two sets of multivalent side-chain functional polymers bearing
either viologen (MV) 2a-c (Scheme 1) or 2-naphthoxy (Np)
7a-c (Scheme 2) derivatives. MV-functional copolymers 2a-c
were synthesized by traditional ‘uncontrolled’ free radical
polymerization following a method substantially modified from
3
7
MV modified glutamine residues.
There have been a variety of reports concerning the formation
of 3D polymeric networks and gels from noncovalent interactions
in water; however, many of them are limited in use on account of
4
0
one recently reported (Table 1). A styrenic monomer bearing
an MV moiety (STMV, 1) was easily synthesized on a large
scale from 4-vinylbenzylchloride and methyl bipyridinium
iodide salt in high yields (>85%). Various comonomers with
differing ionic nature (neutral, positive, or negative, see
Scheme 1) were chosen in order to identify variations in the
properties of the resulting supramolecular hydrogels arising
from the structure of the parent polymers. N-Hydroxyethy-
lacrylamide was a neutral, nonresponsive, water-soluble
comonomer used to prepare copolymer 2a which contained
approximately 10 mol % loading of 1. The copolymerization
between various acrylamide monomers (including N-func-
tional acrylamides) and styrenics has been investigated
previously and demonstrated that copolymers were not
(a) a lack of reversible stimuli responsivity, (b) toxic metal ions
used for their formation, or (c) the use of a two-component binding
motif providing little control over macroscopic material properties.
In the present work, we strove to develop a system for the
preparation of three-dimensional supramolecular cross-linked poly-
meric materials that utilizes the strong yet reversible CB[8]-based
1
:1:1 ternary binding motif in water (Figure 2). Through the use
of multivalent polymeric scaffolds of relatively low molecular
weight (M < 40 kDa), bearing either MV or Np functionality
n
pendant to the polymer backbone, we have developed a system
for the preparation of supramolecular polymeric hydrogels. In the
case of a typical two-component binding motif, mixing of the
polymeric entities leads directly to gel formation. In contrast, the
unique CB[8] three-component binding motif allows for greater
control over bulk material properties through facile modulation of
the cross-link density by inherently separating the two steps of
polymeric solution preparation from cross-linking. Moreover, the
well-known stimuli-responsive nature of the ternary complex and
the ease of synthesis of the various components make this system
well-suited for the preparation of supramolecular polymeric
hydrogels.
4
1-43
completely random but formed gradient copolymers.
Despite these observations however, the initial monomer
concentration was retained in the isolated polymer (Table
1). (Vinylbenzyl)trimethylammonium chloride (SAM) and
styrene sulfonate (SS) were chosen as positively and nega-
tively charged styrenic comonomers for the synthesis of 2b
and 2c, respectively. These polymers were prepared in the
same manner as that for 2a with a 10% loading of functional
styrenic 1. As the majority of the polymer weight, the ionic
Results and Discussion
Synthesis and Characterization of Functional Polymers. Free
radical polymerization is arguably the most common polymer-
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1
0.1039/C0PY00197J. Published Online: Sept 7, 2010.
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J. AM. CHEM. SOC. 9 VOL. 132, NO. 40, 2010 14253

A R T I C L E S
Appel et al.
a
Scheme 1. Synthetic Scheme for Preparation of MV-Functional Polymers 2a-c
a
Copolymers 2b-c are depicted with ‘+’ and ‘-’ signs to demonstrate the charge along the polymeric backbone resulting from the comonomer.
Scheme 2. Synthetic Scheme for the Preparation of (a) Np-Functional Monomer 6 and (b) Np-Functional Polymers 7a-c
comonomer adopts a semirigid rod conformation in solution
as a result of charge-charge repulsion along the polymer
backbone. The effect of this rigidity on the overall material
properties of the resulting gels and the effects of the differing
ionic nature on 1:1:1 ternary complex formation and stability
were investigated (Vide infra).
1
4254 J. AM. CHEM. SOC. 9 VOL. 132, NO. 40, 2010

Cross-Linking via Complexation with Cucurbit[8]uril
A R T I C L E S
Table 1. Functional Polymers Used To Prepare Supramolecular
Hydrogels
Table 2. Thermodynamic Data for Second Guest Binding of
Functional Polymers
a
Functionality (%)
b
a
c
Polymer
M
n
(kDa)
PDI
a
∆G
kcal/mol)
∆H
(kcal/mol)
-T∆S
(kcal/mol)
Entry MV Np
K
a
(
b
b
b
b
c
c
c
2
2
2
7
7
7
a
b
c
a
b
c
10.1
10.0
9.8
4.3
10.1
4.6
27.4
37.1
26.8
10.1
10.1
21.8
1.53
2.42
2.09
1.11
1.12
1.15
b
b
c
c
c
4
1
2
3
4
5
6
2a
8
8.8 ((0.5) × 10 -6.7 ( 0.1 -13.3 ( 0.2 6.6 ( 0.2
4
2a 7a 9.3 ((0.5) × 10 -6.8 ( 0.1 -12.2 ( 0.2 5.4 ( 0.2
5
2a 7b 1.5 ((0.5) × 10 -7.0 ( 0.1 -8.8 ( 0.2 1.8 ( 0.2
4
2b
8
7.0 ((0.5) × 10 -6.6 ( 0.1 -9.6 ( 0.2 3.0 ( 0.2
4
2b 7a 7.6 ((0.5) × 10 -6.7 ( 0.1 -9.4 ( 0.2 2.7 ( 0.2
4
2b 7b 8.0 ((0.5) × 10 -6.7 ( 0.1 -8.7 ( 0.2 2.0 ( 0.2
a
Determined by 1H NMR. b Determined by GPC using H
eluent. Determined by GPC using DMF as eluent.
2
O as
c
a
Mean values measured from at least three ITC experiments at 25 °C
in 10 mM PBS buffer at pH 7.0. Gibbs free energy values calculated
b
c
from K
a a
values. Entropic contributions to ∆G calculated from K and
For the preparation of second-guest functional copolymers
an Np-functional acrylamide monomer was designed for facile
copolymerization with various acrylamide comonomers yielding
nonionic, water-soluble polymers. Starting with 2-naphthol, Np-
functional acrylamide monomer (NpAM) 6 was prepared after
several high yielding steps (Scheme 2a). 2-Naphthol could be
treated with a large excess of 1,2-dibromoethane in the presence
of potassium carbonate to yield a primary bromo-functional
naphthoxy moiety 3. Conversion of the bromine with sodium
azide and subsequent sodium borohydride reduction under phase
∆
H values.
35,37,46-48
host-guest systems.
With a range of multivalent
polymers in hand the quantitative investigation of their respec-
tive binding thermodynamic parameters was carried out utilizing
ITC. It was previously reported that no substantial decrease in
the association equilibrium constant was observed for second-
guests when attached at the end of a poly(ethylene glycol)
17,36
chain.
Our system contains both first and second guests
pendant to a polymer backbone which could potentially increase
the steric hindrance imposed on ternary complex formation with
CB[8]. Additionally, the polymer backbones themselves could
interact with (un)complexed CB[8] in a variety of ways.
Therefore, ITC was used to determine the affinity of complex-
ation, and Table 2 displays the complete thermodynamic data
for second-guest binding based on the concentration of func-
tional units (i.e., not polymer concentration), excluding anionic
MV-functional polymer 2c as it was unable to solubilize CB[8]
sufficiently to perform the ITC measurements (Vide infra). In
order to identify the effect on binding stemming from both steric
hindrance and the explicit structure of the polymeric backbones,
ITC measurements were carried out on MV-functional polymers
4
4
transfer conditions adopted from a literature method by Rolla
gave the amine-functional naphthoxy moiety 5. Preparation of
naphthoxy-acrylamide monomer 6 was accomplished with
acryloyl chloride in the presence of triethylamine under standard
amide coupling conditions.
Reversible addition-fragmentation chain transfer (RAFT)
polymerization was then used for the preparation of several
multivalent, Np-functional copolymers with a well-known
trithiocarbonate-based chain transfer agent (CTA) 2-(dode-
45
canethiocarbonothioylthio)-2-methylpropanoic acid (DDMAT)
using standard RAFT conditions in DMF (Scheme 2b). DDMAT
was used as it successfully mediates the polymerization of a
wide variety of monomers (styrenics, (meth)acrylates, and
meth)acrylamides) in a variety of solvent conditions with high
control over molecular weight and yielding low polydispersities
PDI). A series of polymers 7a-c with varying molecular
weights ranging from 10 to 22 kDa and loadings of functional
NpAM monomer 6 ranging from 5 to 10% (Table 1) were
prepared. A copolymer bearing a 20% loading of NpAM was
2
a-b with both a monovalent small molecule 8 (2-naphthoxy
(
functionalized with a triethylene glycol unit, NpTEG, see
Supporting Information) and Np polymers 7a-b in the presence
of CB[8].
(
The ITC measurements highlighted in Table 2 showed that
no significant difference in thermodynamic properties were
observed between binding of either the monovalent small
molecule 8 (entries 1 and 4) or the multivalent Np polymers
1
synthesized; however, this polymer was not water-soluble. H
NMR analysis verified retention of the targeted loading of the
functional monomer and overall molecular weight by comparing
resonances resulting from the naphthoxy moiety, the methyl
groups from the DMA comonomer, and the methylene in the
R-position relative to the trithiocarbonate end group retained
in the final polymers. GPC analysis of 7a-c displayed that an
exact overlay existed with both refractive index and UV-vis
detectors (272 and 312 nm), demonstrating that each polymer
bears both Np moieties (272 nm) and the trithiocarbonate (312
nm) from the RAFT CTA. While the examples shown have
very specific structures, the use of free radical polymerization
techniques provides a versatile and general method allowing
for the incorporation of many other monomers or additional
functionalities.
7
2
a-b (entries 2, 3, 5, and 6) to the multivalent MV polymers
a-b in the presence of CB[8]. Both MV polymers 2a-b
exhibited almost equivalent association constants and binding
energies (Table 2) with all Np-functional materials tested,
despite their structural differences. Likewise, there was no
significant difference in association strengths observed for the
two Np polymers 7a and 7b, despite 7b bearing twice as many
Np units per chain. These measurements identified that neither
the added steric hindrance present around the Np moieties
pendant from the polymer scaffold nor the loading of the
functional monomer within that scaffold significantly affects
binding strength.
Additionally, in the case of polymer-polymer binding, the
multivalent binding interactions are noncooperative, i.e. the
strength of each binding interaction is independent of all others.
Self-Assembly of Multivalent Polymers. Isothermal titration
calorimetry (ITC) is a powerful physical technique for measuring
solution binding thermodynamics and stoichiometry and has
(
46) Rajgariah, P.; Urbach, A. R. J. Inclusion Phenom. Macrocyclic Chem.
2008, 62, 251–254.
a
been utilized previously to measure K values in CB[8]
(47) Bush, M.; Bouley, N.; Urbach, A. J. Am. Chem. Soc. 2005, 127, 14511–
1
4517.
(
(
44) Rolla, F. J. Org. Chem. 1982, 47, 4327–4329.
45) Skey, J.; O’Reilly, R. Chem. Commun. 2008, 35, 4183–4185.
(48) Heitmann, L. M.; Taylor, A. B.; Hart, P. J.; Urbach, A. R. J. Am.
Chem. Soc. 2006, 128, 12574–12581.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 40, 2010 14255

A R T I C L E S
Appel et al.
Figure 4. Inverted vial tests of (a) 2b, (b) 7b, (c) 1:1 mixture of 2b and
7
5
b, and (d) 1:1 mixture of 2b and 7b upon addition of 0.5 mol equiv (i.e.,
% cross-linking) of CB[8] (denoted 2b/7b/CB[8]5%).
Figure 3. ITC data for the binding of 7b to 2b/CB[8] at 25 °C in 10 mM
PBS buffer at pH 7.0. 7b was titrated at 1 mM into a 0.1 mM solution of
2
b/CB[8]. The top plot displays the power applied as a function of time.
The bottom plot displays integrated enthalpy values as a function of the
molar ratio of 7b titrated into 2b/CB[8] (black squares) and 10 mM PBS
buffer (gray dots).
Figure 3 displays the ITC data for the titration of 7b into a
buffered solution of 2b/CB[8] and shows an isotherm that fits
extremely well to a one-set-of-sites binding model and which
has an inflection point at the 1:1 molar ratio of 7b to 2b/CB[8].
The presence of the inflection point at perfect 1:1 stoichiometry
verifies that all Np and MV units are accessible and take part
in binding interactions. These observations further verify that
modern free radical polymerization techniques provide excellent
control over polymer structure. The observed noncooperativity
mentioned above is in contrast to a previous report by Urbach
et al. regarding the formation of multivalent oligopeptide
assemblies with CB[8]. This disparity is likely on account of
the highly variable nature and substantially longer average
spacing between functional monomers in our random copoly-
mers when compared with the well-defined aforementioned
oligopeptides. It is the random and long-range spacing of
functional monomers along the polymer scaffold that allows
for the formation of large, cross-linked aggregates and networks
instead of only dimers arising from the perfectly matched
multivalent species reported by Urbach and co-workers.
Figure 5. Column plot displaying quantitative zero-shear viscosities of
the various component mixtures identifying that only the mixture of both
types of functional polymers and CB[8] yields appreciable increases in
viscosity.
functional groups (2b/7b/CB[8]5%). The rigidity of 2b on
account of charge-charge repulsion along the polymer backbone
contributed greatly to the overall viscosity of the supramolecular
hydrogel, overcoming the slightly decreased association constant
when compared with 2a. Solutions of 2b, 7b, and a 1:1 (MV:
Np) mixture of 2b and 7b were prepared and are displayed in
Figure 4. In inverted vial tests of these solutions, no clear
increase in solution viscosity indicating an increase in apparent
molecular weight was observed, clearly demonstrating negligible
interaction between the polymeric species themselves when
dissolved in water at 5 wt %. As the MV dication moiety is
colored, the corresponding functional copolymer 2b is colored
and the mixture of 2b and 7b bears the same light color of 2b
alone (Figure 4a and Figure 4c, respectively). Upon addition
of CB[8] to the polymeric solution of 2b and 7b a brightly red
colored, supramolecular hydrogel is formed (Figure 4d). This
mixture contained 0.5 mol equiv of CB[8], leading to 5% cross-
linking in the system, and is denoted 2b/7b/CB[8]5%. Addition-
ally, quantitative zero-shear viscosities, shown in Figure 5, of
the various component mixtures possible from 2b, 7b, and CB[8]
clearly demonstrate that only the mixture of all three components
together yields an appreciable increase in viscosity while all
other mixtures lead to negligible increases over that of native
3
7
Preparation of Supramolecular Hydrogels. Preparation of
solutions of polymers from the various mixtures possible
between 2a-c and 7a-c identified a large dependence of
qualitative hydrogel properties on the ionic nature of the
comonomer present in 2a-c. The neutral variant 2a was
observed to form hydrogels with 7b, although on account of
the flexible nature of the backbone these materials exhibited a
high concentration dependence. This mixture yielded supramo-
lecular hydrogels only above 6 wt % with a 10% cross-link
density through addition of 1 mol equiv of CB[8] with respect
to MV and Np functional groups (i.e., 1 eq ×10% functional
monomer ) 10% cross-link density). This sample is denoted
-
3
water (η
o
) 1 × 10 Pa·s).
The high association between functional polymers upon
ternary complexation with the supramolecular ‘handcuff’ CB[8]
promotes dramatic increases in solution viscosity through 3D
network formation. The bright red color is characteristic of the
formation of a charge-transfer complex between the electron-
poor MV and the electron-rich Np moieties within the cavity
2
a/7b/CB[8]10% where the percentage associated with CB[8] is
the cross-link density of the network.
In comparison, the mixture of 7b and cationic 2b yielded
the most promising hydrogel with high viscosity at 5 wt % in
water and only requiring a 5% cross-link density through
addition of 0.5 equiv of CB[8] with respect to MV and Np
3
5,37
of the host molecule.
This provides strong evidence that
1
4256 J. AM. CHEM. SOC. 9 VOL. 132, NO. 40, 2010

Cross-Linking via Complexation with Cucurbit[8]uril
A R T I C L E S
Table 3. Rheological Characterization of Supramolecular
Hydrogels
a
Concn
(wt %)
Viscosity
b
(Pa·s)
Entry
MV Polymer
Np Polymer
% Cross-linking
1
2
3
4
5
2a
2b
2c
2b
2b
7b
7b
7b
7a
7c
5
5
5
5
5
6.6
5
6.6
5
8.7
21
0.061
5.4
5
19
a
%
Cross-linking is the % of monomer units participating in
cross-link formation and is determined by the molar equivalent
addition of CB[8]; therefore 5% cross-linking is achieved Via
addition of 0.5 equiv of CB[8] relative to functional monomer
b
incorporation. Zero-shear viscosity determined by steady shear rate
sweep performed at 25 °C.
the 1:1:1 CB[8] ternary complex is formed and is responsible
for 3D network formation from interchain complexation and
commensurate increases in viscosity resulting in hydrogel
formation.
In constrast, the negatively charged styrene sulfonate copoly-
mer 2c did not form hydrogels in the presence of CB[8] and
7
b, and the characteristic red color was only faintly observed.
For this particular case, only a portion of the CB[8] added to
the solution dissolved, identifying that the negative backbone,
although semirigid, has detrimental interactions with the CB[8]
host molecule upon complexation with the pendant MV
moieties, decreasing the propensity for ternary complex forma-
tion and providing no increase in solution viscosity.
Control experiments were performed using smaller cucurb-
it[n]uril analogues, CB[6] and CB[7], which resulted in no
increase in the viscosity of the polymeric solution of 2b and
Figure 6. Rheological analysis of the 1:1 mixture of 2b and 7b with
increasing cross-link densities from 0 to 10%. (a) Steady shear measurements
and (b) zero-shear viscosity as a function of the % cross-linking in the
supramolecular hydrogel determined by addition of CB[8] demonstrating
the ‘gel point’ of the supramolecular network.
7
b. CB[7] is capable of full encapsulation of one MV moiety
units yielding 2b/7a/CB[8]5% or 2b/7c/CB[8]5%) were character-
ized. As polymers 7a and 7c both have lower concentrations of
Np functionality (5% functional monomer), the overall viscosi-
ties were lower when compared to 7b as the concentration of
ternary complexes was lower in the network. The 21.8 kDa
polymer 7c also exhibited increased viscosity over 7a as the
polymer contains twice as many cross-links per chain compared
with 7a (9.2 and 4.3, respectively) and is twice the molecular
weight (21.8 and 10.1 kDa, respectively). These results clearly
indicate that both the density of cross-links and polymer
molecular weight affect the material properties.
but not a second guest while CB[6] only binds MV partially in
the portal region;
be formed in either case (i.e., no cross-linking is possible),
providing support for our molecular picture of cross-linking Via
ternary complexation with the CB[8].
Rheological Characterization of Supramolecular Hydro-
gels. The successful design and preparation of supramolecular
hydrogels affords the opportunity to employ complementary
characterization techniques for these materials such as rheo-
logical studies which cannot be used for small molecule
analogues of the supramolecular complexes. In order to probe
the molecular dynamics of the reversible supramolecular hy-
drogels as well as quantify their mechanical properties rheo-
logical characterization was performed. Rheological analysis was
carried out on supramolecular hydrogels prepared from the 1:1
mixture of each of the series of MV-functional polymers 2a-c
and Np-functional polymer 7b with 0.5 mol equiv of CB[8]
29,49
therefore the 1:1:1 ternary complex cannot
As the mixture of cationic polymer 2b and 7b with CB[8]
(2b/7b/CB[8]5%) yielded the supramolecular hydrogels with the
greatest viscosity, further rheological analysis was performed
at 5 wt % in water with variable amounts of CB[8]. Steady
3
shear analysis revealed dramatic increases (>10 ) in viscosity
upon addition of CB[8] (Figure 6a) on account of 3D network
formation. The viscosities of the 3D networks range between 5
and 55 Pa ·s and increase linearly with the cross-link density
(and therefore with CB[8] concentration) from 2.5% to 10%
(Figure 6b). These viscosities between 10 and 100 Pa ·s place
our materials uniquely in a viscosity region for excellent
processability. Additionally, our system seems to have several
regions of rate dependent viscosity: Newtonian, shear-thickening
(
relative to functional units yielding 2a-c/7b/CB[8]5%) corre-
sponding to a 5% cross-link density in the networks. Quantitative
zero-shear viscosities clearly verify the qualitative observations
mentioned previously as hydrogels prepared with the cationic
MV polymer 2b exhibit much greater viscosities than either
the neutral or anionic variants, even at lower concentrations
5
0
(
Table 3, entry 2 compared to entries 1 and 3). Additionally,
and dramatically shear-thinning. Craig et al. have recently
noted similar behavior in a related polymeric organogel as being
dominated by shear-induced changes in microstructure, where
the number of elastically active chains increases with shear as
intramolecular rings are converted to intermolecular cross-links.
supramolecular hydrogels prepared from the 1:1 mixture of MV-
functional polymer 2b and the remaining polymers in the series
of Np-functional polymers (7a and 7c, Table 3 entries 4 and 5,
respectively) with 0.5 mol equiv of CB[8] (relative to functional
(
49) Kim, H.; Jeon, W.; Ko, Y.; Kim, K. Proc. Natl. Acad. Sci. U.S.A.
002, 99, 5007–5011.
(50) Xu, D.; Hawk, L. L.; Loveless, D. M.; Jeon, S. L.; Craig, S. L.
2
Macromolecules 2010, 43, 3556–3565.
J. AM. CHEM. SOC. 9 VOL. 132, NO. 40, 2010 14257

A R T I C L E S
Appel et al.
Figure 7. Complex viscosity plot obtained from dynamic oscillatory
rheology at 10% strain of the 1:1 mixture of 2b and 7b with increasing
cross-link densities from 0 to 10%.
As both the system described by Craig et al. and our system feature
dynamic cross-links, it is reasonably inferred that our system is
similarly capable of reorganization upon mechanical deformation.
o
A plot of the zero-shear viscosity (η ) versus the % cross-linking
(Figure 6b) clearly demonstrated an inflection point characterizable
as the ‘gel point’ where the cross-link density is great enough to
induce full network formation. The ‘gel point’ was determined to
be 1.25% (0.125 equiv of CB[8] relative to functional monomer)
for the 1:1 mixture of 2b and 7b at 5 wt % in water.
Oscillatory rheological analysis also provided insight into
dynamic mechanical properties of the supramolecular hydrogels.
Figure 8. (a) Storage (G′) and loss (G′′) modulus of supramolecular
Figure 7 clearly demonstrates large increases in complex viscosity
3
hydrogels obtained from dynamic oscillatory rheology at 10% strain of the
(
>10 ) upon addition of CB[8] (2.5% cross-link density, just above
1
1
:1 mixture of 2b and 7b with increasing cross-link densities from 0 to
0%. (b) Zoom displaying decrease in G′ and G′′ crossover frequency ꢀ.
the gel point). The complex viscosity continues to increase as more
CB[8] is added (up to 10% cross-link density). It should be noted
here that our system clearly does not follow the Cox-Merz rule,
an empirical rule stating that the viscosity from steady shear
measurements in hertz (Figure 6) should overlay the complex
viscosity from the dynamic frequency sweep in rad/s (Figure 7).
The dynamic frequency sweep identifies shear thinning behavior
while the steady shear measurements demonstrate much more
complicated rate-dependent behavior, as mentioned above. This
corroborates the explanation for the observed rate dependent
viscosity given above as shear can induce reorganization of the
network structure through deformation of the material, while
dynamic oscillatory measurements leave the network intact.
The dynamic measurements provide excellent insight into
dynamic mechanical properties for viscoelastic materials, which
contain both an elastic and a viscous response to mechanical
perturbation. The elastic component, G′ (storage modulus), is a
measure of the energy stored in the active network after perturba-
tion, while the viscous component, G′′ (loss modulus), is a
complementary measure of the energy lost through dissipated heat
or relaxations in material. A simple representation of viscoelasticity
in a material is the single mode Maxwell model that is typically
used to describe viscous materials with some elastic response and
can be described by a single relaxation rate ꢀ. The frequency
dependencies of G′ and G′′ according to the single mode Maxwell
model are as follows:
the plateau of G′. According to our molecular picture, the reversibly
cross-linked 3D network responds to stress applied by the rheometer
(oscillatory perturbations) by relaxing back to equilibrium at a rate
ꢀ
. At very slow oscillations (ω , ꢀ) the viscous component G′′
dominates as the reversible cross-links dissociate faster than the
experimental time scale, demonstrating that they are not active
cross-links capable of responding to the deformation energy.
Conversely, at very fast oscillations (ω . ꢀ) the elastic component
G′ dominates as the reversible cross-links are active on this
timescale and capable of responding to the deformation energy.
Our hydrogel materials are viscoelastic, demonstrated in
Figure 8, on account of the dynamic nature of the ternary
complexation with CB[8]. These materials are rubbery (elastic)
at shorter time scales (i.e., ω . ꢀ) as the elastic component
dominates, while they are viscous and flow at longer timescales
(
i.e., ω , ꢀ) as the viscous component dominates. In the case
of 2b/7b/CB[8], ꢀ decreases upon addition of CB[8] from 562
to 149 Hz between 2.5% and 10% cross-link density, demon-
strating that the storage modulus of the supramolecular hydrogel
has an increasingly important role in the system rheology as
the cross-link density increases upon addition of CB[8]. Increas-
ing CB[8] concentration, therefore, correlates to a greater
number of active cross-links present in the supramolecular
network, inducing faster relaxation of the network after oscil-
latory perturbation (i.e., greater elasticity). Additionally, the
plateau modulus increases proportionally with CB[8] concentra-
tion from 350 to 600 pascals (Pa). This material therefore
exhibits intermediate mechanical properties (i.e., plateau modu-
lus ≈ 10-1000 Pa) and provides an excellent complement to
the polymer-clay hybrid hydrogel system recently reported by
Aida and co-workers, which exhibits a much higher mechanical
2
2
G' ) G (ω/ꢀ) /(1 + (ω/ꢀ) )
(1)
(2)
o
2
G'' ) G (ω/ꢀ)/(1 + (ω/ꢀ) )
o
where the bulk relaxation rate ꢀ is found from the crossover
frequency of G′ and G′′ and the plateau modulus G is found from
4
6
16
o
strength (plateau modulus >10 -10 Pa). These observations
1
4258 J. AM. CHEM. SOC. 9 VOL. 132, NO. 40, 2010

Cross-Linking via Complexation with Cucurbit[8]uril
A R T I C L E S
ultrafast network recovery after destruction of the existing
network Via shear stress, etc. Furthermore, it is worth noting
that while dissociation rate constants have been measured and
5
4-58
57,59
reported for CB[6]
di)cationic guests, no report on the binding dynamics of a CB[8]
ternary complex has appeared in the literature to date. In both
CB[6] and CB[7] complexes, the reported k and k values are
and CB[7]
1:1 complexes with
(
a
d
much lower and can be measured by NMR, while in our system
we are only measuring the rate constants for second guest
binding which is largely driven by hydrophobic interactions and
3
5
desolvation of the second guest.
Microstructure of Supramolecular Hydrogels. The micro-
structure of these supramolecular hydrogels (2b/7b/CB[8]) were
investigated using scanning electron micrography (SEM) after
cryo-drying. The supramolecular networked systems retain the
characteristic bright red color of the ternary complex charge-
transfer band, identifying that the supramolecular network is
still intact while in the solid state. Figure 10 shows SEM images
of the 1:1 mixture of 1b and 2b at 5 wt % in water with
increasing cross-link densities demonstrating that each of the
hydrogels has a very uniform, highly ordered microstructure.
As the cross-link density increases, the pore size within the
polymeric matrix decreases from approximately 12 to 3 µm
between 2.5% and 10% cross-linking, corroborating the rheo-
logical observations. The decrease in pore size with increasing
cross-link density is consistent with typical covalent cross-linked
hydrogels.
Figure 9. Network relaxation rate ꢀ (the G′ and G′′ crossover frequency
in hertz) as a function of the % cross-linking in the supramolecular hydrogel
formed from the 1:1 mixture of 2b and 7b with CB[8].
further confirm that the observed increase in viscosity is due to
cross-linking through 1:1:1 heteroternary complexation.
Looking further into the oscillatory rheology of the system,
ꢀ
changes as a function of cross-link density according to an
-1
inverse power law with a dependence of (% cross-link) (Figure
), consistent with theoretical models for supramolecular
9
51
transient networks. According to the seminal studies by Craig
et al.
52,53
the kinetics of molecular cross-links in supramolecular
systems are of greater importance than binding thermodynamics
in determining the bulk viscoelastic properties of the material.
It has been demonstrated that extrapolation of the relaxation
rate plot back to the cross-link density at the gel point yielded
the ‘apparent’ intrinsic relaxation rate (ꢀint) of the network (i.e.,
the dissociation rate of supramolecular cross-links), found to
The hydrogel microstructure was also used as a platform to
probe the hydrogel response to thermal stimuli. A sample of
2b/7b/CB[8]2.5% cross-linked with 0.25 mol equiv of CB[8] gave
the hydrogel depicted on the left of Figure 11. SEM micrographs
clearly demonstrate that the microstructure consists of large
pores approximately equal in size to those described previously
d
be equivalent to the k determined from corollary NMR studies
5
3
of the small-molecule supramolecular motif. Applying the
same method by using the cross-link density at the gel point
determined from viscosity titrations (1.25%), extrapolation of
the plot in Figure 9 yields a dissociation rate constant of the
(
1
12 µm) for the 2.5% cross-linked sample depicted in Figure
0d. Qualitative evidence for the thermal reversibility of this
-
1
hydrogel is demonstrated with an inverted vial test. Upon
heating, the hydrogel undergoes a gel-to-sol conversion and
readily flows as the second guest K value decreases at increased
a
ternary complex k
This k value is remarkably high when considering the
intrinsic motion limitations of the ternary complex within the
D cross-linked network. The implication of such a high k when
considering the solution K value for second guest binding from
ITC measurements (Table 3, entry 6) is an association rate
d
) 1200 s .
d
temperatures. This conversion is completely reversible, and the
hydrogel reforms upon cooling (Figure 11a). If more CB[8] is
then added to the vial (up to a total of 1 mol equiv), heating of
the gel and subsequent shaking allow for dissolution of the
additional CB[8], yielding a hydrogel with 10% cross-linking
upon cooling. This hydrogel, now formed with a higher cross-
link density, remained fully thermally reversible. An immediate
observation is that the red color of the hydrogel is much more
intense on account of a higher concentration of ternary
complexes within the network structure. This is consistent with
observations made previously in CB[8] ternary complex sys-
3
d
a
7
-1 -1
constant (k
a
) 9.6 × 10 M s ) which is approaching the
diffusion limit (Figure 2b). Studies are currently underway to
further analyze binding dynamics for CB[8] ternary complex-
ation both with small molecules and with polymeric materials.
While the association rate constant obtained using the method
developed by Craig et al. is high, it is a reasonable value as k
d
is expected to be greater than 200 s- (limit of the NMR) due
1
to the appearance of singular, broad peaks observed in previ-
37
1
7
tems. Additionally, SEM micrographs identify a drastic change
in the hydrogel microstructure as much smaller pore sizes are
now measured which are consistent with those previously
measured for a directly prepared sample of 10% cross-linking
ously published NMR studies. These studies clearly demon-
strate fast exchange of the second guest for MV/Np/CB[8]
ternary complexes in both small molecule and polymeric
systems. These observations offer important insight into the
binding mechanism of CB[8] ternary complexation as the
primary driving force for complexation is an extremely high
association rate (as opposed to a very low dissociation rate),
yielding dynamically cross-linked materials with potentially
(
54) Mukhopadhyay, P.; Zavalij, P. Y.; Isaacs, L. J. Am. Chem. Soc. 2006,
128, 14093–14102.
(
(
(
55) Mock, W. L.; Shih, N. Y. J. Org. Chem. 1986, 51, 4440–4446.
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(
(
(
51) Jongschaap, R.; Wientjes, R.; Duits, M.; Mellema, J. Macromolecules
001, 34, 1031–1038.
52) Yount, W.; Loveless, D.; Craig, S. Angew. Chem., Int. Ed. 2005, 44,
746–2748.
53) Yount, W.; Loveless, D.; Craig, S. J. Am. Chem. Soc. 2005, 127,
4488–14496.
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126, 5808–5816.
2
(59) Jeon, W.; Moon, K.; Park, S.; Chun, H.; Ko, Y.; Lee, J.; Lee, E.;
Samal, S.; Selvapalam, N.; Rekharsky, M.; Sindelar, V.; Sobransingh,
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2
1
J. AM. CHEM. SOC. 9 VOL. 132, NO. 40, 2010 14259

A R T I C L E S
Appel et al.
Figure 10. Scanning Electron Microscopy (SEM) images of the cryo-dried supramolecular hydrogels from 2b and 7b with decreasing cross-link densities
from (a) 10%, (b) 7.5%, (c) 5%, and (d) 2.5%.
lecular hydrogels indicates that the material properties and
hydrogel pore sizes can be modulated with the amount of CB[8]
added to the system. Moreover, rheological analysis allowed
for the kinetics of CB[8] ternary complexation to be determined
for the first time. The rates of second guest association and
dissociation are undoubtedly important parameters to consider
in the design of future CB[8]-containing systems that has only
become characterizable using rheological analysis of these
polymeric networked materials on account of time scale
limitations of analytical techniques typically used. These materi-
als exhibited intermediate mechanical properties (plateau modu-
lus ) 350-600 Pa and zero-shear viscosities ) 5-55 Pa ·s),
placing them as a complement to existing supramolecular
hydrogels and identifying their potential for use in industrial
applications requiring this processing window. Additionally,
these supramolecular hydrogels exhibited thermal reversibility
and subsequent facile modulation of microstructure upon further
addition of CB[8] and thermal treatment. This previously
unexplored approach offers a versatile method for the prepara-
tion of sophisticated supramolecular hydrogels facilitating
progress in the field of smart, self-healing materials, self-
assembled hydrogels, and controlled solution viscosity.
Figure 11. (a) Inverted vial test demonstrating thermal reversibility of the
supramolecular hydrogel. (b) SEM images demonstrating network revers-
ibility as further addition of CB[8] to a hydrogel of low cross-link density
(
2.5%) following heating elicits network restructuring as cross-link density
increases (2b/7b/CB[8]2.5% f 2b/7b/CB[8]10%).
(
3-4 µm, Figure 10a). These observations verify that the
hydrogels formed using CB[8] ternary complexation are ther-
mally sensitive and fully reversible and that the material
properties are easily modulated through the addition of CB[8].
Conclusion
In summary, we have demonstrated the preparation of a series
of multivalent side-chain functional polymers bearing either a
good first (viologen) or second (naphthoxy) guest using versatile
free radical polymerization techniques. Additionally, these
polymers have been used as a platform demonstrating that 1:1:1
ternary complexation mediated by the supramolecular host
molecule CB[8] is a powerful and effective motif for the
preparation of dynamic supramolecular hydrogels. The use of
this strong and highly directional, stimuli-responsive supramo-
lecular motif takes full advantage of a unique three-component
binding mode inducing supramolecular cross-linking and large
Acknowledgment. The authors would like to acknowledge Dr.
Simon Butler and Prof. Malcolm Mackley for their helpful
discussions regarding rheological characterization. This work was
supported in part by Schlumberger and the Walters-Kundert Trust.
Supporting Information Available: Experimental procedures
1
and H NMR, GPC, and ITC measurements can be found in
the Supporting Information. This material is available free of
charge via the Internet at http://pubs.acs.org.
3
viscosity increases (>10 ). Characterization of the supramo-
JA106362W
1
4260 J. AM. CHEM. SOC. 9 VOL. 132, NO. 40, 2010