Heat-induced morphological transformation of supramolecular nanostructures by retro-Diels-Alder reaction

Article abstract of DOI:10.1002/chem.201201670

Controlling the morphology of supramolecular nanostructures in response to external stimuli is an important challenge in the development of functional soft materials. Here we show that a morphological transformation from 2D nanosheets to a network of 1D nanofibers is triggered by heating, which induces molecular conversion of a bolaamphiphile to a hydrogelator by means of a retro-Diels-Alder reaction, thereby producing a new heat-set supramolecular hydrogel. We anticipate that our design will be a starting point for more sophisticated supramolecular systems that integrate the thermodynamics of molecular assembly and the kinetics of chemical reactions to create complex supramolecular nanostructures. The heat is on: We show that a morphological transformation from 2D nanosheets to a network of 1D nanofibers is triggered by heating (see figure), which induces molecular conversion of a bolaamphiphile to a hydrogelator by means of a retro-Diels-Alder reaction, thereby producing a new heat-set supramolecular hydrogel. Copyright

Full text of DOI:10.1002/chem.201201670

FULL PAPER
DOI: 10.1002/chem.201201670
Heat-Induced Morphological Transformation of Supramolecular
Nanostructures by Retro-Diels–Alder Reaction
Masato Ikeda,*[a, d] Rika Ochi,[a] Yu-shi Kurita,[a] Darrin J. Pochan,[c] and
Itaru Hamachi*[a, b]
Abstract: Controlling the morphology
a bolaamphiphile to a hydrogelator by
means of a retro-Diels–Alder reaction,
thereby producing a new heat-set su-
pramolecular hydrogel. We anticipate
that our design will be a starting point
of supramolecular nanostructures in re-
sponse to external stimuli is an impor-
tant challenge in the development of
functional soft materials. Here we show
that a morphological transformation
from 2D nanosheets to a network of
1D nanofibers is triggered by heating,
which induces molecular conversion of
for more sophisticated supramolecular
systems that integrate the thermody-
namics of molecular assembly and the
kinetics of chemical reactions to create
complex supramolecular nanostruc-
tures.
Keywords: amphiphiles
nanostructures self-assembly
supamolecular chemistry
·
gels
·
·
·
Introduction
rials for myriad bioapplications.[5,6] To install stimuli-respon-
sive structures and functions in supramolecular assemblies,
modulation of the noncovalent interactions between the
component molecules has been predominantly employed.[7,8]
Rearrangement of covalent bonds (their cleavage and for-
mation) has rarely been used to control morphological
transformation of supramolecular assemblies, whereas it was
well studied in the fields of cleavable surfactants.[9] We be-
lieve that the rational coupling of a change in molecular for-
mula driven by chemical reactions with noncovalent interac-
tions is a promising strategy to control supramolecular nano-
structures and functions in response to unique stimuli.
Indeed, there are several examples of photochemical reac-
tions that involve photoresponsive supramolecular assem-
blies that undergo a photoinduced change in molecular for-
mula.[10] It has also been demonstrated that enzyme-coupled
chemical bond formation or cleavage can trigger nanofiber
assembly.[11] As an example using dynamic combinatorial
chemistry, supramolecular assemblies constructed by in situ
amphiphile formation that are responsive to external condi-
tions have been reported recently.[12] Very recently, we suc-
cessfully developed stimuli-responsive nanofiber assemblies
from a simple dipeptide scaffold, which can be selectively
degraded in response to redox or photo stimuli with simulta-
neous cleavage of a carbamate bond in the component mol-
ecules.[13]
Supramolecular chemistry based on molecular assembly is a
powerful approach to fabricate well-defined nanostructures
from small molecules.[1–3] To date, thermodynamically stable
supramolecular nanostructures of various shapes and sizes
have been constructed by using multiple weak noncovalent
interactions, such as hydrogen bonding, electrostatic interac-
tions, and van der Waals forces.[4] Recently, supramolecular
nanostructures that respond to stimuli in aqueous media by
changing their morphology and function have attracted
much attention in the development of intelligent soft mate-
[a] Prof. Dr. M. Ikeda, R. Ochi, Y.-s. Kurita, Prof. Dr. I. Hamachi
Department of Synthetic Chemistry
and Biological Chemistry
Graduate School of Engineering
Kyoto University, Katsura
Nishikyo-ku, Kyoto, 615-8510 (Japan)
E-mail: ikeda@sbchem.kyoto-u.ac.jp
ihamachi@sbchem.kyoto-u.ac.jp
[b] Prof. Dr. I. Hamachi
Japan Science and Technology Agency (JST), CREST
5 Sanbancho, Chiyoda-ku, Tokyo, 102-0075 (Japan)
[c] Prof. Dr. D. J. Pochan
Department of Materials Science and Engineering
University of Delaware
Newark, DE 19716 (USA)
In this report, we show that the “retro-Diels–Alder”
(retro-DA) reaction can be used to trigger morphological
transformation of supramolecular nanostructures.[14] As illus-
trated in Figure 1, a self-assembled 2D nanostructure that
consists of a heat-sensitive bolaamphiphile is converted into
a 1D nanostructure in response to heat stimuli by means of
a retro-DA reaction-based bond cleavage. This morphologi-
cal transformation was probed by transmission electron mi-
croscopy (TEM) and atomic force microscopy (AFM) obser-
[d] Prof. Dr. M. Ikeda
Present address:
Department of Biomolecular Science
Graduate School of Engineering
United Graduate School of Drug Discovery
and Medical Information Sciences
Gifu University, 1-1 Yanagido, Gifu, 501-1193 (Japan)
E-mail: m_ikeda@gifu-u.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201670.
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would facilitate molecular conversion from the bolaamphi-
phile to the hydrogelator by means of a retro-DA reaction,
which causes a drastic morphological transformation from a
bolaamphiphile with a soluble nanostructure to the 1D
nanofibers of the hydrogelator, and a consequent hydrogel
that consists of a 3D network. Three carboxylate groups
were attached to the water-soluble diene unit as a polar
head group to suppress extensive self-assembly of the bo-
laamphiphile by electrostatic repulsion. According to this
design principle, we simply needed to develop a hydrogela-
tor that bore a maleimide to develop a new heat-set supra-
molecular hydrogel.
Preparation of a bolaamphiphile by Diels–Alder reaction:
Hydrogelators that bear a maleimide group were deter-
mined by screening sugar-appended amphiphiles as shown
in Figure 3.[17] Two derivatives formed thermally reversible
Figure 1. Schematic representation showing heat-induced morphological
transformation (heat-set supramolecular hydrogel) of supramolecular
nanostructures that consist of a bolaamphiphilic self-assembly unit bear-
ing a site that can be cleaved by retro-Diels–Alder (retro-DA) reaction.
vations, as well as dynamic light scattering (DLS) and small-
angle X-ray scattering (SAXS) experiments. This study pro-
vides novel insights into the remaining challenges in control-
ling the morphology of supramolecular nanostructures
through a combination of thermodynamics of molecular as-
sembly and kinetics of chemical reactions.[15]
Results and Discussion
Rational molecular design of a self-assembling precursor:
Bolaamphiphiles that consist of two polar head groups
bridged by a hydrophobic unit can form a variety of water-
soluble nanostructures such as rods, disks, and hollow
spheres and tubes.[16] We thus sought to use a bolaamphi-
phile as a self-assembling precursor of a hydrogelator. We
also reasoned that a thermoreversible DA reaction would be
suitable to construct a heat-sensitive precursor from a hy-
drogelator that bears a dienophile and a water-soluble
diene, as shown in Figure 2. It was anticipated that heating
Figure 3. Screening hydrogel formation by amphiphilic maleimide deriva-
tives. A) Gelation test of sugar lipids. G, S, and P denote gel, sol, and pre-
cipitate, respectively. CGC [wt%] of gels is given in parentheses. B) Pho-
tograph of hydrogel 1 ([1]=0.4 wt% (7.2 mm), 200 mm HEPES (pH 7.2))
hydrogels by conventional heating/cooling treatment. In par-
ticular, compound 1 that bears d-glucose as a sugar head
and a C11 methylene linker exhibited the lowest critical gel
concentration (CGC) of 0.2 wt% (3.6 mm) in 200 mm
HEPES (pH 7.2), and its gel-to-sol phase transition temper-
ature (Tgel) exceeded 808C even at 0.2 wt% (see Figure S3
in the Supporting Information for concentration depend-
ence), above the temperature of which a typical maleimide–
furan pair can undergo retro-DA reaction (see below).[14]
Therefore, 1 was used as part of the bolaamphiphile.
DA reaction between 1 and water-soluble furan 2 (typical
diene) successfully generated bolaamphiphile 1·2. Interest-
ingly, we found that the endo isomer of 1·2 (namely, 1·2-
endo, endo/exo=92:8 determined by analytical reverse-
Figure 2. Molecular design of a bolaamphiphile constructed from a hy-
drogelator bearing a dienophile and a water-soluble diene (2) by means
of Diels–Alder reaction.
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Figure 4. A) Molecular structure of 1·2-endo and photographs of aqueous dispersions of 1·2-endo (18 mm, 200 mm HEPES (pH 7.2)) before and after
heating at B) 708C, C) 608C, and D) 408C for 1, 3, and 5 h, and E) after incubation at ambient temperature for 48 h. The sample vial was tilted in an oil
bath during heating to confirm that hydrogels formed without cooling. F) HPLC traces monitoring the change in composition during heat-induced hydro-
gelation of 1·2-endo (18 mm, 200 mm HEPES (pH 7.2)). HPLC conditions: acetonitrile/phosphate buffer (10 mm, pH 7.4)=0:100 to 5:95 (10 min) to
80:20 (60 min). G) Time-dependent change in the composition of each component estimated from HPLC traces during heat-set hydrogelation of 1·2-
endo at 608C. H) Time-dependent change in the composition of 1 estimated from HPLC traces at three different reaction temperatures (40, 60, and
708C).
phase (RP)-HPLC; see Figure 4A for the molecular struc-
ture of 1·2-endo) disperses well in aqueous media even at
5 times the CGC of 1 (5ꢁ3.6 mm), whereas 1·2-exo does not.
This difference in the dispersibility could be because the in-
termolecular electrostatic repulsions between carboxylate
groups in the bent conformation of 1·2-endo are stronger
than those in the extended conformation of 1·2-exo. In addi-
tion, 1·2-endo is a kinetically favorable product, and there-
fore is expected to dissociate by means of a retro-DA reac-
tion more rapidly than 1·2-exo. We thus investigated the
properties of the bolaamphiphile 1·2-endo in the following
studies.
ion increased when the temperature was raised from 60 to
708C (gelation time decreased from 5 to 3 h).[19] In contrast,
gel formation was not observed even after 5 h of heating at
408C (Figure 4B,D). Figure 4H shows plots of the concen-
tration of 1 generated over time at each temperature, clearly
revealing that gelation only occurred above the CGC of 1.
Heat-triggered morphological transformation of supramo-
lecular nanostructures: To obtain further insight into the
morphological transformation of nanostructures during
heat-set hydrogel formation of 1·2-endo, dynamic light scat-
tering (DLS) experiments, and TEM and AFM observations
were carried out. DLS measurements of an aqueous disper-
sion of 1·2-endo (18 mm) before heating showed an intensity
distribution with a broad peak that corresponded to an aver-
age hydrodynamic diameter of 88 nm, thus indicating that
1·2-endo self-assembled into a water-soluble nanoaggregate
(Figure S5A in the Supporting Information). When 8-anili-
no-1-naphthalene sulfonate (ANS), a typical environmental-
ly sensitive fluorescent dye, was added to the aqueous dis-
persion of 1·2-endo, a substantial increase of fluorescence in-
tensity was observed (Figure S5B in the Supporting Infor-
mation). This revealed that the nanoaggregates of 1·2-endo
contained hydrophobic domains. From a plot of fluorescence
intensity against the concentration of 1·2-endo, the critical
Heat-set hydrogel formation of bolaamphiphile 1·2-endo:
As expected, an aqueous dispersion of bolaamphiphile 1·2-
endo (18 mm (5ꢁCGC(1))) gradually became viscous and
formed a stable hydrogel (heat-set hydrogel) when the solu-
tion was heated continuously in an oil bath at 608C (Fig-
ure 4C). This strongly indicated that heating induced the
generation of a 3D network of nanostructures. HPLC/ESI-
MS analysis revealed that 1·2-endo gradually dissociated
into hydrogelator 1 and 2 and the conversion reached 23%
after 5 h (Figure 4F,G). In contrast, the aqueous dispersion
of 1·2-endo maintained its fluid state when left at room tem-
perature for 2 days (Figure 4E).[18] The rate of heat-set gelat-
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I. Hamachi, M. Ikeda et al.
association constant was found to be about 6 mm, which is a
typical value for bolaamphiphiles (Figure S5C in the Sup-
porting Information).[16] In good agreement with DLS data,
a TEM image of 1·2-endo before heating showed 2D nano-
structures with a size of 100–200 nm (Figure 5A). AFM
contained both short twisted ribbons and 1D long helical
ribbon in one construct, as shown in Figure 5C. This strongly
suggests the gelation mechanism of 1·2-endo, that is, associa-
tion of the twisted nanosheets gave twisted short ribbons,
followed by the transformation from the twisted to long hel-
ical ribbons. Both the twisted and helical ribbons are left-
handed, indicative of a chiral arrangement of component
molecules in the fibrous aggregates, which could arise from
the d form of the sugar moiety. Further heating (608C, 5 h)
produced an entangled 3D network of long, left-handed hel-
ical ribbons with a diameter of about 20 nm and helical
pitch of about 35 nm, as shown in Figure 5D. AFM observa-
tions consistently supported this structural transition, as
shown in Figure 5F–H, which is attributed to hydrogel for-
mation. We also confirmed that hydrogel 1 prepared by con-
ventional heating/cooling treatment formed similar 1D left-
handed helical ribbons (Figure S7A in the Supporting Infor-
mation). This further supports our view that the molecular
conversion of 1·2-endo to 1 by retro-DA reaction facilitates
a morphological transformation from 2D twisted nanosheets
to 1D helical supramolecular nanostructures.[20,21]
Further evidence of this morphological transformation
during heat-set hydrogel formation of 1·2-endo in solution
and the hydrogel state was obtained by X-ray solution scat-
tering (SAXS). Figure 6A shows SAXS patterns obtained
before and after heating an aqueous solution of 1·2-endo;
the heat-induced change of the slope from À2 to À1 in the
low q region suggests the structural transition from a 2D to
Figure 5. Microscopic observations during heat-induced hydrogelation of
1·2-endo (18 mm, 200 mm HEPES (pH 7.2)). TEM images A) before and
B,C) after 1 and D) 5 h at 608C; E–G) AFM height and H) amplitude
images E) before and F–H) after 5 h at 608C. Scale bar [nm]: A) 200,
B,C) 50, D) 500 (left), 100 (right), E,F) 500, and G,H) 100.
showed that the 2D nanostructures possessed a thickness of
approximately 4 nm, thereby suggesting that the aggregates
are a unilamellar structure of 1·2-endo (approximately 4 nm
in length) (Figure 5E), which is also characteristic of bo-
laamphiphiles.[16]
Upon heating the aqueous dispersion of 1·2-endo, the cor-
relation function of the scattered intensity (correlation coef-
ficient: g(2)(t)À1) in DLS experiments translated to a
longer decay time, thus indicating an increase in the size of
the aggregates (Figure S6 in the Supporting Information).
The resultant distribution was too polydisperse to obtain
size information from DLS measurements after heating at
608C for just 1 h. TEM images obtained after heating for
1 h at 608C (Figure 5B) showed short ribbons with a left-
handed twist, an average diameter of 30 nm, and length of
several hundred nanometers, which is dramatically different
from the 2D structures observed before heating. More inter-
estingly, we successfully observed a transient structure that
Figure 6. A) SAXS patterns of 1·2-endo in aqueous solution a) before
and b) after 5 h at 608C. ([1·2-endo]=18 mm, 200 mm HEPES (pH 7.2)).
B) Morphological transformation during heat-set supramolecular hydro-
gel formation of 1·2-endo. Pie charts show compositions before and after
heating at 608C for 5 h.
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(Figure 6B).
Conclusion
In conclusion, we demonstrated that a bolaamphiphile that
contaisns a heat-triggered cleavage site exhibits thermally
induced morphological transformation from 2D nanosheets
to a 3D network of 1D nanofibers. The well-defined mor-
phological transformation of supramolecular architectures
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Acknowledgements
This work was partially supported by Japan Science and Technology
Agency, the CREST program, a Grant-in-Aid for Young Scientists (A),
and the global COE program “Integrated Materials Science” of the Min-
istry of Education, Culture, Science, Sports, and Technology (Japan). We
thank Prof. Y. Chujo and Mr. N. Kitamura (Kyoto University) for helping
with TEM, Prof. S. Kitagawa and Prof. T. Uemura (Kyoto University) for
WAXS, Prof. M. Inoue and Dr. K. Saijo (Kyoto University) for SAXS,
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thanks Prof. K. Sada (Hokkaido University) and Prof. A. Tsuda (Kobe
University) for helpful discussion.
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[18] The retro-DA reaction was very slow at room temperature (HPLC
analysis revealed that more than 99% of 1·2-endo remained after
48 h at room temperature.).
[19] Continuous heating at 708C for 5 h weakened the gel, which sug-
gested that the gel state is kinetically stable but not thermodynami-
cally stable. Upon careful elucidation of the heat-induced hydrogel
formation process by HPLC, we noticed that the concentration of
1·2-exo increased constantly (Figure S4 in the Supporting Informa-
tion). This indicates that DA reaction between released 2 and 1
took place again. We speculate that the newly generated 1·2-exo col-
lapses the network of supramolecular nanofibers required for hydro-
gelation.
[20] To evaluate the distribution of each component (1, 2, 1·2-endo, 1·2-
exo) in the soluble and insoluble parts, the hydrogel obtained after
5 h at 608C was subjected to centrifugation (5000 g, 5 min). We
found that 1 and 1·2-exo were mainly recovered from the insoluble
part (probably mostly nanofibers), whereas 2 and 1·2-endo were
mainly recovered from the soluble one. This suggests that 1·2-exo is
incorporated into self-assembled nanostructures of 1 and/or the DA
reaction proceeded between self-assembled 1 and 2 (Figure S8 in
the Supporting Information). The detailed influence of 1·2-exo on
the morphology of the nanostructures is not yet fully understood.
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Received: May 12, 2012
Revised: July 4, 2012
Published online: && &&, 0000
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

Supramolecular Nanostructures
FULL PAPER
The heat is on: We show that a mor-
phological transformation from 2D
nanosheets to a network of 1D nano-
fibers is triggered by heating (see
figure), which induces molecular con-
version of a bolaamphiphile to a
hydrogelator by means of a retro-
Diels–Alder reaction, thereby produc-
ing a new heat-set supramolecular
hydrogel.
Supramolecular Chemistry
M. Ikeda,* R. Ochi, Y.-s. Kurita,
D. J. Pochan, I. Hamachi* . . &&&& — &&&&
Heat-Induced Morphological Transfor-
mation of Supramolecular Nanostruc-
tures by Retro-Diels–Alder Reaction
Chem. Eur. J. 2012, 00, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!