Thermoresponsive dynamers: Thermally induced, reversible chain elongation of amphiphilic poly(acylhydrazones)

Article abstract of DOI:10.1021/ja2035909

A nanostructured poly(acylhydrazone), which is reversibly formed in acidic aqueous solution from di(aldehyde) and di(acylhydrazine) monomers with appended hexaglyme groups, was found to display lower critical solution (LCS) behavior. Remarkably, under aci

Full text of DOI:10.1021/ja2035909

ARTICLE
pubs.acs.org/JACS
Thermoresponsive Dynamers: Thermally Induced, Reversible Chain
Elongation of Amphiphilic Poly(acylhydrazones)
J. Frantz Folmer-Andersen† and Jean-Marie Lehn*
Institut de Science et d’Ingꢀenierie Supramolꢀeculaires, Universitꢀe de Strasbourg, 8 Allꢀee Gaspard-Monge, BP 70028, 67083 Strasbourg,
France
S Supporting Information
b
ABSTRACT: A nanostructured poly(acylhydrazone), which is
reversibly formed in acidic aqueous solution from di(aldehyde)
and di(acylhydrazine) monomers with appended hexaglyme
groups, was found to display lower critical solution (LCS)
behavior. Remarkably, under acidic conditions in which poly-
merization is reversible, large and reversible molecular weight
(Mw) increases were observed in response to elevated tempera-
tures, both below and above the LCS temperature. No variation
in Mw was evident under neutral and alkaline conditions, in
which the acylhydrazone condensation is essentially irreversible. Results of turbidometry studies, size-exclusion chromatographyÀ
multiangle laser light scattering (SECÀMALLS), and transmission electron microscopy (TEM) suggest that heating the polymer
below the LCS temperature leads to polymer growth with preservation of the characteristic nanostructured morphology, whereas
the onset of the microphase separated state causes a fundamental change in morphology, in which the polymer chains aggregate into
larger bundles and fibers. van’t Hoff analysis of a small molecule model system indicates that the acylhydrazone condensation is
enthalpy driven (ΔHeq = À8.2 ( 0.2 kcal molÀ1 and ΔSeq = À11.1 ( 0.4 = cal molÀ1
3
K
À1), which suggests that the observed
3
3
polymer growth with temperature is not a consequence of the intrinsic thermodynamics of the intermonomer linkage but is likely
the result of the thermoresponsive characteristics conferred by the multiple hexaglyme groups. The system described displays
double control of the dynamer state by two orthogonal agents, heat and protons (pH). It also represents a prototype for dynamic
materials displaying multiple control adaptive behavior.
’ INTRODUCTION
The realization of CDC in the field of polymer science has
engendered interest in dynamic polymers, or dynamers,6b,c as
stimulus-responsive materials.6,7 Dynamers are defined as poly-
meric species comprised of monomer units connected by either
noncovalent or reversible covalent interconnections.6b,c The
lability of the intermonomer linkages affords such systems the
possibility of undergoing effector-driven monomer exchange
and/or chain elongation/shortening processes (Scheme 1A),
which can in turn modulate the chemical and materials properties
exhibited by the VCL. Indeed, an eclectic range of polymeric
entities possesses such characteristics, including supramolecular
polymers,5c,6e,6g some coordination8 and condensation7 polymers,
cylindrical surfactant assemblies,9 and certain biomacromolecular
aggregates.10 Poly(azomethine)s,7 formed by polycondensation
of dicarbonyl and diamino (including di(hydrazino) and di-
(alkoxyamino)) containing monomers, represent a particularly
important class of covalent dynamers, in view of their synthetic
accessibility and controllable dynamic character. The exchange of
azomethine (CdN) moieties with alternate amino groups is
subject to Bronsted or Lewis acid catalysis11 and may there-
fore be controlled through the adjustment of pH or catalyst
Constitutional dynamic chemistry (CDC)1 is predicated on
the use of reversible interconnections to generate structurally
diverse dynamic libraries of molecular1À3 or supramolecular
entities from discrete sets of molecular subunits. The available
subunits, and their interconnectional capacities, define a virtual
combinatorial library (VCL)3a,b,d of constituents, formed by
all possible subunit permutations, with the actual distribu-
tion of entities present at equilibrium corresponding to the
global energy minimum of the system. A key aspect of such
thermodynamically controlled networks is their sensitivity to
physical and/or chemical factors that perturb equilibria under-
lying subunit association, thus shifting the observed distributions
of higher-order entities. In principle, a given external stimulus
may cause a directed reconfiguration of subunits, so that pre-
viously unexpressed members of the VCL become dominant
at the expense of those initially formed. Establishing control over
such dynamic assembly/disassembly processes has become
an overarching goal relating to the design of chemical sys-
tems of increasing complexity,1,4 with recent applications in
the areas of nanostructure fabrication,5 the development
of adaptive materials,6,7 and the identification of biologically
active compounds in the context of dynamic combinatorial
chemistry.2,3b,3e,4c
Received: April 19, 2011
Published: June 03, 2011
r
2011 American Chemical Society
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concentration. Additionally, the intimate relationship between
the covalent structure of a polymer and its associated properties
implies that adaptive behavior in dynamic covalent systems may
be dramatic. Molecular-level reorganization of dynamic azomethine-
based networks has been achieved in response to a variety of
factors (including H+,7f,12 temperature,12 metal ions,7h,12,13
electric fields,14 hydrogelation,15 biological agents,2,3b,3e,7d and
macromolecular architecture7i,16) and has been shown to mod-
ulate the optical,7b,e,f,h rheological,7g and mechanical7c character-
istics of poly(azomethine)s, both in solution and in neat films.
Stimulus-responsive behavior is also an important aspect of
conventional (constitutionally static) polymer chemistry.17 So-
called “smart” polymers undergo reversible conformational
and aggregation-state transitions in solution in response to
environmental triggers (i.e., pH, temperature, ionic strength)
that generally affect polymerÀsolvent interactions. In particular,
thermoresponsive water-soluble polymers18 (TWPs) have been
widely studied in view of potential biological and environmental
applications. As smart materials, TWPs also benefit from the
complete reversibility of thermal stimuli as well as the ease and
precision with which temperature can be controlled. TWPs are
typically nonionic, with a subtle balance of hydrophobicity and
hydrogen-bonding capacity along the main chain. As tempera-
ture increases, entropically unfavorable polymerÀsolvent hydro-
gen bonds are disrupted, leading to hydrophobic collapse
(Scheme 1B) and often to an abrupt and reversible precipitation
of the polymer at the lower critical solution temperature
(LCST).19 The most thoroughly investigated TWPs include
poly(isopropylacrylamide),20 poly(ethyleneglycol),21 and elastin-
like peptides22 (rich in the sequence Val-Pro-Gly-Xaa-Gly, where
Xaa is a variable residue). In recent years, these and other TWPs
have been integrated into numerous technologies, including
hyperthemic drug delivery,18c,23 bioengineering,24 the regulation
of nanoscale self-assembly,25 and the construction of hydrogel-
based thermo-26 and chemomechanical devices.27
Rationale. Our interest in CDC as a means of engineering
novel stimulus-responsive materials led us to pursue the devel-
opment of thermoresponsive poly(azomethine) dynamers. Such
systems may be capable of responding to thermal stimuli
both through compositional reorganization of the main chain
(Scheme 1A) and through changes in polymer conformation
and/or aggregation state (Scheme 1B). Although these two types
of stimulus-responsive behaviors have separate origins, it is
expected that they will operate jointly in influencing the structure
and properties of the system.
Scheme 1. Stimulus-Responsive Behavior of Constitution-
ally Dynamic and Thermoresponsive Polymersa
Previously, we reported the synthesis, structural characteriza-
tion, and constitutionally dynamic behavior of a series of water-
soluble, aromatic poly(acylhydrazones) with appended hexa-
(ethylene glycol) solubilizing groups.28 In particular, monomers
1 and 2 were reacted to give the poly(acylhydrazone) poly(1À2)
(Scheme 2), which was determined to assume a helical con-
formation in aqueous solution that minimizes solvent-exposed
hydrophobic surface area. The proposed helical secondary
structure, which is supported by small-angle neutron scattering
(SANS), size-exclusion chromatography/multiangle laser light
scattering (SEC/MALLS), and transmission electron microscopy
(TEM) data, constitutes a water-soluble, organic nanotube, with
an inner diameter of approximately 1.3 nm. In addition, control
was demonstrated over the CDC of the system by exploiting the
pH dependence of acylhydrazone reactivity. Under acidic con-
ditions (pH 2.0), the acylhydrazone linkages of poly(1À2) can
form, break, and exchange reversibly,11c,29 causing the molecular
weight distribution to respond to changes in concentration,
whereas above pH ∼ 7 the acylhydrazone bonds are effectively
static, and poly(1À2) behaves as a conventional polymer. The
primary structure of poly(1À2) resembles those of several
known TWPs,21 as it contains a hydrophobic aromatic core,
onto which are grafted oligo(ethylene glycol) hydrophiles, and in
fact, LCST behavior was noted during its original preparation.
Herein, we explore the effects of thermal stimuli on poly(1À2) at
a (A) Dynamic polymers (dynamers)6b,c may be formed through the
reversible interconnection of complementary monomeric subunits.
Such polymeric entities may exhibit compositional changes in response
to external stimuli that perturb the equilibria underlying monomer
interconnection. (B) Thermoresponsive water-soluble polymers17,18
(TWPs) undergo reversible conformational and/or aggregation-state
transitions with temperature. TWPs usually consist of a hydrophobic
main-chain (black), on which are grafted a number of hydrogen bonding
groups (blue) that organize nearby solvent molecules. With increasing
temperature, unfavorable entropy of solvation causes a weakening of
polymerÀsolvent interactions and eventual hydrophobic collapse.
Scheme 2. Acid-Catalyzed Dynamic Polymerization of Di(aldehyde) 1 and Di(acylhydrazine) 2 to Give the Polyacylhydrazone
poly(1À2)a
a R = (CH2CH2O)6Me.
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such a sample above the LCST for prolonged periods of time
(90 °C for 16 h) causes the polymer to irreversibly precipitate
from solution as a fibrous material (Figure 1C). In contrast, no
discrete particles are observable by eye in the microphase-
separated state in neutral to alkaline solution, and the LCS
behavior remains completely reversible with extended heating
under such conditions.
In light of the above-mentioned pH dependence of acylhydra-
zone reaction kinetics,29 the irregularity of the low-pH turbidi-
metry profile can be attributed to the dynamic state of poly-
(1À2), which renders the covalent structure of the system
sensitive to external factors. It is likely that the transition from
a homogeneous solution to a microphase-separated state repre-
sents a compelling stimulus, capable of effecting significant con-
stitutional modification of the system. Accordingly, the erratic
low-pH LCS behavior becomes less severe if the sample is held
above the transition temperature for shorter periods of time, as
the constitutional modification likely proceeds to a lesser extent
in this case. Further, the effect appears to be reversible over
longer time periods, as an acidic solution of poly(1À2), that has
been made to exhibit broad transitions through heating, shows
regenerated LCS behavior after standing at room temperature for
five days. These observations imply that under acidic conditions
thermally induced microphase separation causes a relatively slow
modulation of the covalent structure of poly(1À2), which
initially manifests as a broadening of turbidimetry profile and,
upon further heating, by the formation of insoluble, fibrous
material, and very large objects up to the macroscale.
Size Exclusion Chromatography/Multiangle Laser Light
Scattering (SEC/MALLS). The response of poly(1À2) to ther-
mal stimuli was further investigated by SEC/MALLS. A solution
of poly(1À2) was prepared by reacting 1 (6.1 mM) and 2
(5.9 mM) in H2O (pH 2.0) for 48 h at ambient temperature, and
an aliquot was removed and analyzed to give a weight-averaged
molecular weight (Mw) of 310 kDa (Figure 2, trace A). Im-
mediately after heating the solution above the LCST (to 85 °C)
for 4 h, the Mw was found to have increased by over an order of
magnitude (Mw ∼ 3800 kDa; Figure 2, trace B), with increased
polydispersity and a poor correlation between injected and
calculated mass. This suggests that in this case the Mw of this
sample is too large for accurate determination and that some
material may have been retained on the SEC columns. The
solution was then allowed to stand at room temperature for 20 h,
after which the Mw had decreased to very near the initial value
(460 kDa; Figure 2, trace C). Under basic conditions, this
dramatic, thermally induced Mw increase is not observed, as
heating poly(1À2) above the LCST for 4 h at pH 11.4 causes no
appreciable change in Mw. It is therefore clear that heating
aqueous solutions of poly(1À2) above the LCST causes a large
and reversible increase in Mw under acidic conditions in which
the acylhydrazone bonds can break and form reversibly but has
little effect under basic conditions, where reaction of acylhydra-
zone bonds is intrinsically very sluggish.
Figure 1. (A) Photographs of aqueous solutions of poly(1À2) below
and above the lower critical solution temperature (LCST). (B) Turbid-
ity diagrams at 660 nm for aqueous solutions of poly(1À2) ([1]0 = [2]0
= 1.0 mM) under acidic and basic conditions as a function of heat/cool
cycles (rate = 1 °C sÀ1). C. Optical micrograph of precipitate irrever-
3
sibly formed by heating a solution of poly(1À2) ([1]0 = [2]0 = 5.0 mM,
pH = 2.0) to 90 °C for 16 h.
both the molecular and supramolecular levels and report the
reversible growth of the dynamic polymer with increased tem-
perature. When the monomer units of poly(1À2) react under
thermodynamic control, the system may respond reversibly to
changes in temperature through both compositional and con-
formational changes, thus establishing an interrelationship be-
tween molecular and supramolecular polymer structure that may
be regulated by the addition and removal of heat.
’ RESULTS
The thermal response of poly(1À2) was investigated by diff-
erent physiochemical techniques to establish the ability of these en-
tities to adapt to temperature changes by constitutional variation.
Turbidimetry. The hexa(ethylene glycol) moieties appended
to 1 and 2 provide thermal sensitivity to poly(1À2) in aqueous
solution. Such groups generally become more hydrophobic at
elevated temperatures because of negative dissolution entropies,
which reflect their tendency to organize solvating water mol-
ecules through hydrogen bonding.19 As anticipated on this basis,
poly(1À2) was found to display qualitatively reversible LCS
behavior (Figure 1A). Heating poly(1À2) in aqueous solution to
near reflux temperatures causes the sample to undergo micro-
phase separation, and cooling the sample to room temperature
results in the rapid redissolution of the polymer. At concentra-
tions greater than approximately [1]0 = [2]0 = 5 mM, thermally
induced microphase separation causes a noticeable increase in
the viscosity of the sample upon cooling to the homogeneous
state. The turbidimetry profiles shown in Figure 1B reveal that
the LCS behavior is markedly pH-dependent. At pH 11.5, a sharp
and reversible phase transition is observed at 81 °C with
significant hysteresis. Under acidic conditions (pH 2), on the
other hand, a sharp precipitation is initially seen at 76 °C, with
further changes becoming broad and erratic with repeated
thermal cycling. The irregularity of the low-pH response after
several transitions reflects the formation of visible particles from
the microphase-separated state that begin to settle out of solution
at high temperature but redissolve below the LCST. Maintaining
The influence of temperature on the Mw of poly(1À2) under
homogeneous conditions (below the LCST) was also exam-
ined. Figure 3 shows SEC traces of identical solutions of
poly(1À2) that were allowed to equilibrate for 3 days at various
temperatures. In all cases, the samples remained homogeneous
throughout their preparation. A clear increase in retention time
with temperature is observed, and with the exception of the
highest temperature sample prepared at 63 °C, polydispersities
and calculated-injected mass correlations are roughly consistent
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Figure 4. Weight-averaged molecular weight (Mw) determined by SEC/
MALLS as a function of temperature for samples of poly(1À2) from
Figure 3, as well as identical control samples, adjusted to pH 9.5 prior to
temperature adjustment. The Mw of the 65 °C sample (blue square) is
too large to be determined accurately and therefore represents a crude
estimate.
Figure 2. Size exclusion chromatography (SEC) traces of a sample of
poly(1À2) prepared by mixing 1 (6.1 mM) and 2 (5.9 mM) in water at
pH 2.0 for 48 h (black trace, Mw = 310 ( 30 kDa), immediately after heat-
ing the sample above the lower critical solution temperature (to 80 °C)
for 4 h (blue trace, Mw ∼ 3800 kDa) and after allowing the sample to
cool to room temperature and stand for 20 h (green trace, Mw = 460 (
50 kDa). A poor correlation between calculated and injected masses
prohibits an accurate determination of the high Mw sample (blue trace).
Mw values determined by multiangle laser light scattering (MALLS).
Figure 5. Weight-averaged molecular weight (Mw) determined by
SEC-MALLS as a function of time after cooling a sample of poly(1À2)
which had equilibrated for 3 days at 55 °C to ambient temperature.
MALLS analysis of fractionated SEC samples revealed details
related to the effects of temperature on the structure of poly-
(1À2). Figure 6 shows variations in radius of gyration (Rg) with
molecular mass (m.m.) as determined by SEC-MALLS for
samples from Figures 2, 4, and 5. The observed linear relation-
ship is consistent with the classical description of Rg for rodlike
objects30 and indicates that the linear density (mass per unit
length) of poly(1À2) is 720 ( 60 Da ÅÀ1. This value closely
3
agrees with those both previously measured by SEC-MALLS and
small-angle neutron scattering and predicted by a molecular
model of a helically folded, single chain of poly(1À2).28b The
colinearity of the data in Figure 6 indicates that the basic
morphology is unchanged upon heating and cooling (lateral
aggregation of two polymer chains would reduce the slope of Rg
vs m.m. by a factor of 2), implying that the resultant changes in
Mw correspond to the lengthening and shortening of the polymer
along the rod axis. The single distinctly nonlinear curve in
Figure 6 is the high-molecular weight sample from Figure 2,
which is the only sample that was analyzed immediately after
heating above the LCST; all other samples had been homo-
geneous for an extended period (20 h) prior to analysis or had
remained so throughout their preparation. The nonlinearity of
this outlier indicates an alternative solution state morphology,
suggesting that above the LCST poly(1À2) undergoes a differ-
ent mode of growth relative to the elongation of the well-
characterized28 rods that occurs with heating under homoge-
neous conditions.
Figure 3. Size exclusion chromatography traces of aqueous solutions of
poly(1À2) ([1]0 = [2]0 = 550 μM, pH = 1.8) equilibrated for 3 days at
different temperatures.
among the samples. For the sample prepared at 63 °C, the high
molecular weight portion of the peak is truncated, and the
material did not pass completely through the SEC columns,
which suggest that the Mw is too large for accurate analysis.
Figure 4 shows a plot of determined Mw values at various
equilibration temperatures for the samples from Figure 3, as
well as several control samples, prepared under alkaline condi-
tions. In the dynamic (low-pH) state, a dramatic increase in
polymer size with temperature, beginning above around 40 °C,
is observed, whereas no change in Mw occurs under alkaline
conditions, which further supports the interpretation that
thermally induced polymer growth involves acylhydrazone
polycondensation. Upon cooling a high-Mw sample that had
equilibrated for 3 days at 55 °C under acidic conditions to room
temperature, a steady decrease in Mw is observed over time
(Figure 5), thus demonstrating the qualitative reversibility of
the process.
Transmission Electron Microscopy (TEM). The system was
further investigated by TEM, which allows for the direct visua-
lization of thermally induced changes in polymer structure.
Figure 7a shows a micrograph of a 1.1 mM sample of poly(1À2)
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that had been prepared under acidic conditions at room tem-
perature. In accordance with previous studies,28 negatively
stained rodlike structures with a constant diameter of around
5 nm and lengths ranging from 50 to 80 nm are observed (see
also Supporting Information). Aggregates of two or more rods
are also visible. The physical dimensions of these filaments agree
with a structural model previously proposed28 on the basis of
SANS, TEM, and SEC/MALLS measurements, and the objects
have therefore been interpreted as being single polymer entities.
After heating the sample to 60 °C for 4 h, a clear elongation of the
rods is apparent (Figure 7b), with many growing to lengths of
more than 200 nm, although the diameter remains identical to
that seen prior to heating, which indicates that the basic polymer
architecture is maintained. Upon standing at room temperature,
the gradual shortening of the rods occurs over time (Figure 7c),
with qualitative reversion to the initial state (prior to heating)
after 1 week (Figure 7d). With the onset of phase transition
above the LCST, a dramatic deviation from the prevailing
morphology is observed, as the rods become intertwined to form
larger fibers that exhibit multiple branching points and achieve
micrometer lengths (Figures 7e,f). A fundamental structural
change upon heating above the LCST is also reflected by the
anomalous nonlinear variation of Rg with molecular mass for a
similarly prepared sample offset in Figure 6. These observations
corroborate the SEC/MALLS data and unambiguously demon-
strate the reversible, thermally induced growth of poly(1À2).
More precisely, when the system is heated while maintaining
solution homogeneity (T < LCST), smooth and reversible
polymer growth occurs along the rod axis. In contrast, thermally
induced microphase separation causes relatively uncontrolled
growth, coupled with aggregation, which leads to the assembly of
large polymer bundles (Figure 7F) and ultimately the precipita-
tion of fibrous material (Figure 1c).
’ DISCUSSION
The growth of poly(1À2) with temperature may appear
counterintuitive in view of the fact that dynamic polymers usually
tend to break apart at elevated temperatures to minimize en-
tropic costs associated with polymerization.31 Known exceptions
include certain reversible ring-opening processes, such as the
formation of molten sulfur from S8 rings,32 as well as some
coordination33 and supramolecular polymerizations34 of ditopic
subunits capable of forming macrocycles. In each of these cases,
the favorable entropy of ring fragmentation apparently over-
whelms the entropic penalty of polymerization, rendering the
overall process endoentropic. Along different lines, the thermally
Figure 6. Radius of gyration vs molecular mass relationships deter-
mined by MALLS analysis of SEC fractions for samples from Figures 2,
4, and 5. A linear relationship is indicative of rodlike objects,30 and the
slope is related to the linear density of the rods. The nonlinear green
curve corresponds to the high Mw sample from Figure 2 and has been
offset for clarity.
Figure 7. Thermally induced growth of poly(1À2) as observed by transmission electron microscopy. (a) Image of a solution of poly(1À2) ([1]0 = [2]0 =
1.1 mM, pH = 1.9) after equilibration for 3 days at 20 °C. (b) Image of sample from (a) immediately after heating to 60 °C for 4 h. (c) Image of sample
from (b) after standing at 20 °C for 4 h. (d) Image of sample from (b) after standing at 20 °C for 1 week. (e) Image of a solution of poly(1À2) ([1]0 =
[2]0 = 6.6 mM, pH = 2.0) after equilibration for 3 days at 20 °C. (f) Image of sample from (e) taken immediately after heating to 85 °C for 4.5 h.
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Scheme 3. Acid-Catalyzed Dimerization of an Acylhydrazone
Model Systema
a R = (CH2CH2O)6Me.
induced elongation of cationic wormlike micelles has been re-
ported in the presence of particular counterions and over specific
concentration regimes.35 This anomalous behavior was explained
in terms of the temperature dependence on counterion binding
to the charged micelle surface, which influences the effective
surface charge and morphology of the micelles. Neither of these
known mechanisms for thermally induced dynamic polymer
growth are likely to apply in the present case, as poly(1À2) is
nonionic and there is no evidence of macrocyclic species.
The simplest explanation of the results presented herein
would be that the growth of poly(1À2) with temperature is a
consequence of the intrinsic thermodynamic parameters govern-
ing acylhydrazone condensation. If the equilibrium coupling of
acylhydrazine (hydrazide) and aldehyde termini to give an acyl-
hydrazone linkage proceeds with a positive (favorable) entropy,
the TΔSeq contribution to the overall Gibbs free energy will
becomeincreasinglynegative (favorable) withtemperature, which,
assuming a negligible change in heat capacity, would stabilize
intermonomer bonds and drive the system toward an increased
degree of polymerization. Intuitively, a positive reaction entropy
seems unlikely, however, as the acylhydrazone product will
probably possess less conformational freedom than the reactants,
and the translational entropies of reactants and products should
be similar. Nevertheless, this hypothesis was tested through the
study of the monomerÀdimer model system shown in Scheme 3
by means of variable-temperature 1H NMR spectroscopy. While
Figure 8. van’t Hoff analysis of the acylhydrazone condensation from
Scheme 3. (A) The aromatic region of the H NMR spectrum of a
1
solution of 3 ([3]0 = 2.0 mM) and 4 ([4]0 = 2.3 mM) in D2O (5 mM
phosphate buffer, pD = 2.0) at representative temperatures. The singlet
at ∼9.9 ppm corresponds to the signal for the aldehyde CH proton of 3,
and the singlet at ∼8.4 ppm is assigned as the hydrazone CH resonance
of 5. (B.) A van’t Hoff plot for the sample from A, in which the apparent
equilibrium constant for the formation of 5 (Keq) was calculated from
the integrated signal intensities of the aldehyde and hydrazone CH
resonances of 3 and 5, respectively. The determined thermodynamic
parameters are: ΔHeq = À8.2 ( 0.2 kcal molÀ1 and ΔSeq = À11.1 (
3
0.4 = cal molÀ1 KÀ1
.
3
3
imparted by the hexaglyme moieties. This aggregation process
amounts to an increase in the local concentration of poly(1À2),
which promotes further polymerization (molecular response)
through dynamic acylhydrazone condensation under Le Chate-
lier’s principle. When the system remains homogeneous (heating
below LCST), the interpolymer associations are imagined to be
relatively fleeting and mild, resulting in smooth polymer growth
along the rod axis, with preservation of the basic rodlike mor-
phology. On the other hand, the onset of a microphase-separated
state above the LCST represents a much more severe supramo-
lecular stimulus, causing rapid and uncontrolled polymer aggre-
gation and growth with the formation of large bundles of
intertwined rods as observed by TEM. Cooling such elongated
polymer assemblies causes a return toward the initial state, as the
increased hydrophilicity of the polymer at lower temperatures
will promote its deaggregation, followed by covalent reorganiza-
tion (through preferential acylhydrazone hydrolysis) to accom-
modate the decrease in local polymer concentration. It has
previously been suggested that thermally induced phase transi-
tions will lead to large alterations in the degree of polymerization
of dynamic polymers and should therefore be included among
the mechanisms of dynamic polymerization.37
1
the H NMR spectrum of poly(1À2) is extremely broad28
(as expected for rapid T2 relaxation characteristic of macro-
molecules),36 the equilibrium composition of the model system
is readily estimated from the integrated signal intensities of the
singlets at approximately 9.9 and 8.4 ppm, which arise from the
aldehyde and hydrazone CH protons of 3 and 5, respectively. As
shown in Figure 8A, a pronounced shift toward hydrolysis
products with increasing temperature is evident, and van’t Hoff
analysis of equilibrium ratios determined from 25 to 70 °C at
5 °C intervals (Figure 8B) confirms that the reaction is enthalpy
driven, with ΔHeq = À8.2 ( 0.2 kcal molÀ1 and ΔSeq = À11.1 (
3
0.4 = cal molÀ1
K
À1. Purely on this basis, the degree of
3
3
polymerization of poly(1À2) would be expected to diminish
with temperature, as is commonly observed for dynamic poly-
mers. Therefore, the intrinsic thermodynamic characteristics of
the acylhydrazone condensation can be ruled out as the major
factor underlying the thermally induced growth of poly(1À2).
In light of the inverse temperatureÀsolubility relationship of
poly(1À2) and the tendency of the acylhydrazone linkage to
fragment at elevated temperatures, an interplay between the
temperature stimulus-responsiveness of poly(1À2) at the mo-
lecular and supramolecular levels can be evoked to explain the
observed behavior. By the mechanism outlined in Scheme 4,
elevated temperature would initially cause polymer aggregation
(supramolecular response) by virtue of increased hydrophobicity
The kinetics of equilibration within the macromolecular sys-
tem are found to be dramatically slower than those observed for
the small-molecule system of Scheme 3. At the molecular level,
this effect is attributed to the proposed helical conformation of
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Scheme 4. Proposed Mechanism for the Thermally Induced
Growth of poly(1-2) under Conditions of Reversible
Acylhydrazone Condensationa
thermally induced growth of poly(1À2) is tentatively attributed
to a prior aggregation of the polymer, which increases its local
concentration and drives the equilibrium system toward the
expression of higher molecular weight species.
From a broader perspective, the present results demonstrate
the utility of CDC in reversibly influencing the structural and
morphological features of chemical systems at the nanoscale and
beyond. The use of heat as a controlling effector is especially
advantageous in this context, as it is operationally simple, com-
patible with a wide range of systems, and completely reversible
(no byproducts are accumulated). The anomalous polymer
growth/degradation behavior represents an adaptation of a
constitutionally dynamic system in response to a physical stimulus,
heat. In addition, it is important to note that the behavior of the
present system is as well dependent on the pH of the medium. It
therefore is subject to double control through two orthogonal
agents: heat and protons. On this basis, constitutionally dynamic
systems exhibiting a higher level of adaptive behavior and multi-
ple control can be envisioned, which would undergo thermally
controlled morphological or component selection processes,
thus allowing for species of radically different shape or chemical
composition to be reversibly expressed from a given set of
constituents under the influence of added or removed heat.
Efforts along these lines are presently underway.
a Heating an equilibrated solution causes polymer aggregation, which in
turn leads to polymer growth in regions of increased local concentration.
Cooling the resultant elongated polymer assemblies breaks up the
aggregation, causing the system to return toward the initial state.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental section detailing
b
syntheses of monomers and experimental methods. This material
is available free of charge via the Internet at http://pubs.acs.org.
poly(1À2),28 in which the folded aromatic backbone is thought
to shield the acylhydrazone linkages from bulk solution. The lack
of completely reversible Mw changes in response to thermal
stimuli may be due to such kinetic effects and/or to minor irrever-
sible side processes including denaturing and aggregation of the
polymer. In terms of supramolecular structure, poly(ethylene
glycol) has been reported to form kinetically stable aggregates in
water,38 and so it is possible that the depolymerization of poly-
(1À2) upon cooling could be protracted by similar phenomena.
’ AUTHOR INFORMATION
Corresponding Author
lehn@unistra.fr
Present Addresses
†Department of Chemistry, The State University of New York at
New Paltz, 75 S. Manheim Blvd, New Paltz, NY 12561 (USA).
’ CONCLUSIONS
’ ACKNOWLEDGMENT
The present study demonstrates the thermally induced growth
of a nonionic, water-soluble dynamic polymer (dynamer) under
conditions in which the intermonomer acylhydrazone linkages
can break and form reversibly. This behavior is unusual, as
reversible polymerizations typically shift toward the formation
of lower molecular weight species with increased temperature to
minimize the entropic costs of polymerization. As evidenced
from SEC/MALLS and TEM measurements, heating solutions
of poly(1À2) under acidic conditions (pH ∼ 2.0) causes a
steady increase in Mw with the preservation of the rodlike
morphology, up until the LCST is reached. Above this tempera-
ture, abrupt microphase separation occurs, and the Mw increases
rapidly, with the formation of mesoscopic polymer bundles and,
ultimately with prolonged heating, insoluble fibrous material.
The qualitative reversibility of polymer growth with heating both
above and below the LCST has been demonstrated, and no
polymer growth is observed under alkaline conditions, in which
the intermonomer bonds are effectively static. In light of
the inverse temperatureÀsolubility relationship of poly(1À2)
(Figure 1) and van’t Hoff analysis indicating the enthalpy-driven
nature of acylhydrazone condensation (Figure 8), the anomalous,
We thank Prof. J. Candau for helpful discussions and A. Rameau
and Dr. M Schmutz for performing SEC/MALLS and TEM
analyses, respectively. J. F. F.-A. was supported by an International
Research Fellowship from the National Science Foundation.
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