Pathway-Dependent Phase Transitions of Supramolecular Self-assemblies Containing Cationic Amphiphiles with Azobenzene and Disulfide Groups

Article abstract of DOI:10.1002/chem.202102143

There have been several attempts to construct supramolecular chemical systems that mimic the phase transitions in living systems. However, most of these phase transitions are one-to-one and induced by one stimulus or chemical; there have been few reports

Full text of DOI:10.1002/chem.202102143

Accepted Article
Accepted Article
Title: Pathway-Dependent Phase Transitions of Supramolecular Self-
Assemblies Containing Cationic Amphiphiles with Azobenzene
and Disulfide Groups
Authors: Daichi Sawada, Kouichi Asakura, and Taisuke Banno
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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To be cited as: Chem. Eur. J. 10.1002/chem.202102143
Link to VoR: https://doi.org/10.1002/chem.202102143
01/2020

10.1002/chem.202102143
Chemistry - A European Journal
RESEARCH ARTICLE
Pathway-Dependent Phase Transitions of Supramolecular Self-
Assemblies Containing Cationic Amphiphiles with Azobenzene
and Disulfide Groups
Daichi Sawada,[a] Kouichi Asakura, [a] Taisuke Banno*[a]
[a]
Daichi Sawada, Prof. Dr. Kouichi Asakura, Dr. Taisuke Banno
Department of Applied Chemistry, Faculty of Science and Technology
Keio University
3–14–1 Hiyoshi, Kohoku-ku, Yokohama 223–8522, JAPAN
E-mail: banno@applc.keio.ac.jp
Supporting information for this article is given via a link at the end of the document.
Abstract: There have been several attempts to construct
supramolecular chemical systems that mimic the phase transitions in
living systems. However, most of these phase transitions are one-to-
one and induced by one stimulus or chemical; there have been few
reports on the pathway-dependent phase transition of
supramolecular self-assemblies in multi-step. To induce multistep
phase transitions, we prepared molecular crystals containing a
cationic amphiphile having azobenzene and disulfide groups. A
reducing agent caused the crystals to become vesicles, and adjacent,
non-touching vesicles fused under UV and subsequent visible light.
Adding a reducing agent to the worm-like aggregates that were
generated after UV irradiation of the original crystals resulted in the
growth of sheet-like aggregates. 1H NMR and fluorescence anisotropy
measurements showed that a series of phase transitions was induced
by changes in the phase structures from molecular conversions of the
reactive amphiphiles. The multiple pathway-dependent phase
chemistry, the continuous dynamic and transient structurization of
supramolecular assemblies via molecular conversions of building
blocks in the presence of polymerization initiators,[7] chemical
catalysts,[8] enzymes,[9] or fuels[10] has been reported. The time-
evolving formation process[11] and autocatalytic growth[12] of
supramolecular assemblies have also been investigated.
Reversibility in response to stimuli may lead to applications of self-
assemblies as recyclable, degradable, and self-healing
materials.[13] Despite the considerable progress made so far, most
of the structural transitions are one-to-one and induced by one
stimulus or chemical substance. Phase transitions with more than
two steps would provide us with a new aspect to systems
chemistry, which could be related to a pathway-dependent higher-
or lower-ordering structurization.[14] Although multistep motion at
the molecular level, such as unidirectional motion and rotation, by
using precisely designed synthetic molecules has been
reported,[15] it is still challenging to construct supramolecular
chemical systems where macroscopic structures are successively
transformed in conjunction with molecular conversions under
multiple different stimuli.[16]
transitions of supramolecular self-assemblies can provide
a
methodology for developing new stimuli-responsive materials that
exhibit the desirable properties under specific circumstances from
Systems Chemistry viewpoint.
Herein, we report pathway-dependent phase transitions in
supramolecular self-assemblies that respond to multiple stimuli.
To construct such a supramolecular chemical system, we
designed and synthesized a cationic amphiphile, AzoSS, which
has azobenzene and disulfide groups (Figure 1a). Because there
would be significant differences in the physicochemical properties
between the reduced and isomerized products, it was expected
that the application order of the stimuli would afford different
supramolecular self-assemblies depending on the initial
compositions, i.e., pathway-dependent phase transitions. We
therefore investigated the effects of the application order of a
reducing agent and UV irradiation (Paths 1 and 2 in Figure 1a) on
the phase transition of the supramolecular assemblies.
Introduction
Phase transitions are essential for life. For example, cell
membranes become harder or softer as a result of a temperature-
dependent variation in amphiphile composition.[1] Liquid–liquid
phase separation in the cytoplasm, which occurs through
intermolecular interactions of the cytoplasm components, is also
thought to be related to the maintenance of living systems.[2] Such
behaviors are induced by complex hierarchical structures that
range in size from angstroms to micrometers. In the last several
decades, various supramolecular chemical systems have drawn
considerable attention as living system-mimetic materials to
induce the complex behaviors that lead to phase transitions.[3]
Because of the dynamic and reversible nature of non-covalent
interactions, supramolecular self-assemblies are stimuli-
responsive with structural phase transitions that include dynamic
behaviors, making them candidates for adaptive and smart
materials.[4] For example, the fusion and fission of vesicles can be
reversibly controlled by redox reactions using metal ions.[5] In
addition, the phase transition from micelles to vesicles can be
induced by
a dehydrocondensation reaction to produce
amphiphilic molecules.[6] Recently, in the field of systems
1
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10.1002/chem.202102143
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RESEARCH ARTICLE
the addition of DTT (Figure S3). In contrast, a blue shift of the
maximum fluorescence wavelength was observed for the 80/20
(mol/mol) AzoSS/DDAB dispersion in the presence of DTT
(Figure 2b), suggesting that the localized environment of Nile red
had changed after the addition of DTT. Because Nile red was
added to the dispersion after the sample preparation, Nile red was
not incorporated into the crystal but located in the crystal surface.
This indicates that Nile red was exposed to the bulk aqueous
phase, which is a highly polar environment, and its fluorescence
intensity was relatively low. After the addition of DTT, Nile red was
incorporated into the membrane, which has a lower polar
environment, resulting in
a blue shift of the maximum
fluorescence wavelength with a higher intensity. In addition, the
size distribution of nanometer-scale particles was measured by
dynamic light scattering. A broad peak with a maximum number
at 250 nm that was present in the dispersion without DTT became
bimodal peaks with maxima at 800 and 100 nm after the addition
of DTT. The peak at 800 nm slightly but steadily increased over
time, implying the growth of vesicles (Figure 2c). Changes in the
size distribution of assemblies at about 100 nm with time
suggested that the submicrometer-sized structures proceeded to
change during the observation period. Furthermore, 1H NMR
measurements were carried out to monitor the reduction ratio of
the disulfide group in AzoSS and clarify the effect of the change
in amphiphile composition on the phase transition from crystals to
vesicles (Figure S4). Since the water solubilities of AzoSS and
DDAB are quite low, it was assumed that the reaction mainly
occurred at the surface of the crystals. Therefore, the
concentrations of amphiphile and DTT were set to 10 mM and 40
mM, respectively, as one of a concentrated condition. As a result,
the reduction of AzoSS to AzoSH gradually proceeded, and the
reduction ratio was constant at ~65% within 10 min after the
addition of DTT (Figure 2d). Therefore, the chemical composition
of AzoSS, AzoSH, and DDAB was estimated to be 28/52/20
(mol/mol/mol). To investigate the effect of amphiphile composition
on the formation of supramolecular assemblies, we observed the
amphiphile dispersion at various molar ratios (Figure S5).
Vesicles were clearly confirmed in the dispersions containing 40
or 60 mol% AzoSH. These results suggested that the phase
transition from crystals to vesicles was induced by the reduction
of AzoSS causing changes in phase structures based on the
amphiphile composition.
Figure 1. (a) Molecular structures of the cationic amphiphiles and
reaction of AzoSS to the application of 1,4-dithiothreitol (DTT) and
light. (b) Application of the stimuli to crystals composed of AzoSS
and DDAB (80/20 mol/mol) shown in the micrograph by two
different pathways. Scale bar: 10 mm.
Results and Discussion
Supramolecular assemblies were formed in a 1 mM dispersion of
AzoSS and didodecyldimethylammonium bromide (DDAB) at
ratios of 100/0, 80/20, 50/50, and 20/80 (mol/mol). We added the
unreactive cationic amphiphile DDAB to the system because
crystals composed of AzoSS dissolved when DTT was added.
The hydrophobic fluorescent probe Nile red was added to the
amphiphile dispersion to make the phase structures of the
assemblies more visible under an optical microscope. Crystals
with an interference in the cross-Nicol alignment were observed
in the dispersion composed of AzoSS/DDAB = 80/20 (mol/mol)
(Figure 1b). The supramolecular assemblies were first subjected
to 1,4-dithiothreitol (DTT) followed by UV irradiation (Path 1).
When DTT was added to the dispersion, aggregates with
membrane structures formed from the surface of the crystals and
enlarged while the crystals shrunk (Figure 2a). Since the
hydrophobic Nile red was localized in the membranes, the
generated structures were assumed to be vesicles. The phase
transition from crystals to vesicles was further confirmed by image
analysis using two different fluorescent probes: Nile red and
BODIPY (Figures S1 and S2). Crystals were also observed at
AzoSS/DDAB ratios of 50/50 and 20/80 (mol/mol); however,
these crystals gradually shrunk and dissolved into the bulk
solution when DTT was added. Therefore, 80 mol% AzoSS was
used for further investigations into the mechanism of the phase
transition from molecular crystals to vesicles.
Nile red is an environment-responsive probe whose maximum
fluorescence wavelength changes depending on the surrounding
polar environment,[17] which makes it useful for investigating the
phase structures of various molecular self-assemblies.[18] In a
DDAB dispersion, no fluorescence peak shift was observed after
2
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10.1002/chem.202102143
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RESEARCH ARTICLE
light irradiation, a similar instability in the phase structures, which
led to the vesicle fusion, was also considered to be occurred from
the result of fluorescence anisotropy (III in Figure 3c). The vesicle
fusion was observed when the vesicles were close together under
light irradiation. The Coulombic interaction based on the lipid
species is one of dominant force for vesicle aggregation and
fusion.[22] We thus carried out the measurement of ζ potential for
the dispersions. The ζ potential became slightly larger after both
DTT addition and UV irradiation (Figure 3d), indicating that
Coulombic interactions were not the dominant force for vesicle
fusion Therefore, the unusual fusion behavior of the vesicles was
probably attributable to membrane instability induced by
photoisomerization of the azobenzene compounds.
Figure 2. Phase transition from crystals to vesicles in a 1 mM dispersion of
80/20 (mol/mol) AzoSS/DDAB in the presence of DTT. (a) Sequential bright
field and fluorescence images of the transformation from crystals to vesicles. lex
= 559 nm and lem = 570-670 nm for the fluorescence mode. Scale bar: 50 µm.
(b) Fluorescence spectra of amphiphile dispersions containing Nile red before
(blue) and after (red) the addition of 4 mM DTT. The spectra were normalized
at the wavelength of 800 nm. (c) Particle size distribution in the dispersion
before (black) and 10 min (red), 20 min (blue), and 30 min (green) after the
addition of DTT by dynamic light scattering (d) Time-course of the reduction
ratio of AzoSS by 1H NMR analysis.
When
a
dispersion
of
28/52/20
(mol/mol/mol)
AzoSS/AzoSH/DDAB was irradiated with UV light, it could be
seen under confocal laser scanning microscopy (CLSM) in the
fluorescence mode that
a part of the vesicle membrane
Figure 3. Fusion of vesicles under light irradiation after the addition of DTT to
the 80/20 (mol/mol) AzoSS/DDAB dispersion. (a) Sequential bright field (left)
and fluorescence (right) micrographs under UV irradiation. The fluorescence
mode was the same as that for Fig. 2. Scale bar: 30 µm. (b) Time-course of the
cis-isomer ratio after reduction by DTT (N = 3). The purple and green
background colors indicate UV and visible light irradiation, respectively. (c)
Fluidity parameter 1/P estimated by fluorescence anisotropy measurements of
dispersions containing Nile red (red) and BODIPY (green). I: 30 min after the
addition of DTT, II: 10 min after UV irradiation that was performed after step I,
III: 10 min after visible light irradiation that was performed after step II. (d) Zeta
potential of the dispersions (N = 3). I and II represent the same conditions as
described in graph c.
disappeared and the vesicles fused together within 1 min by
connecting their edges (Figure 3a and Movies S1 and S2). A
similar fusion of vesicles was also observed under subsequent
visible light irradiation (Figure S6). The photoisomerization ratio
of the azobenzene-containing amphiphiles in D2O when UV
irradiation was applied to the dispersion after the reduction by
DTT was monitored by 1H NMR (Figure S7). The total amount of
the cis isomer of azobenzene gradually increased over 10 min of
UV irradiation. Under subsequent visible light irradiation, the
amount of cis-isomer clearly decreased within 10 min (Figure 3b).
The phase structures in the vesicular membrane under UV and
visible light irradiation were evaluated by fluorescence anisotropy
using Nile red[19] and BODIPY,[20] which are considered to be
located inside and on the surface of the membrane, respectively.
The fluidity parameter was calculated from P = (Iǁ − GI⊥)/(Iǁ + GI⊥),
where I⊥, Iǁ, i⊥, and iǁ are the emission intensities perpendicular
and parallel to the vertically and horizontally polarized light,
respectively, and G is the correction factor, G = i⊥/iǁ. A larger 1/P
value indicates higher fluidity in the vesicle membrane. The 1/P
for BODIPY decreased slightly after DTT addition and subsequent
UV irradiation, whereas that for Nile red decreased more
Next, we observed the phase transition of the molecular self-
assemblies in an 80/20 (mol/mol) AzoSS/DDAB dispersion
following Path 2 (Figure 1b). When the dispersion was irradiated
with UV light, the crystals in the irradiated area disappeared under
microscope observation (Figure 4a). From the 1H NMR analysis,
the amount of cis-AzoSS significantly increased 30 min after UV
irradiation (Figure S8). Since the melting point of trans-AzoSS
was >200 °C according to differential scanning calorimetry, most
crystals did not melt to a liquid but dissolved into the aqueous
phase owing to the high solubility of cis-AzoSS. Under
subsequent visible light irradiation, the crystals regenerated by
reversible photoisomerization from the cis to the trans isomer
(Figure S9).
significantly (Figure 3c). These results suggested that
a
significant difference in the fluidity between the inside of the
vesicle and the membrane surface may induce instability in the
phase structures, causing collapse of the local membrane which
results in the vesicle having a micrometer-sized pore as a defect.
Since the vesicles having such
thermodynamically stable,[21] when two vesicles were adjacent,
they fused by connecting their edges. Under subsequent visible
By adding DTT after UV irradiation, the remaining worm-like
aggregates gradually assembled to form larger sheet-like
aggregates (Figure 4a). The reduction ratio of AzoSS after 30 min
a
defect were not
1
was determined to be 40% by H NMR (Figure S10). Since the
amount of butanethiol produced was estimated to be below its
3
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10.1002/chem.202102143
Chemistry - A European Journal
RESEARCH ARTICLE
solubility limit in water, butanethiol was unlikely to be the cause of
the sheet-like aggregate formation, and we investigated the
possible production of a hydrophobic component. Considering the
interaction between thiol and quaternary ammonium, the
dissociation of thiol group would be expected to occur more easily
other aggregates, indicating that the observed phase transitions
were triggered by molecular conversions of AzoSS. Although
crystals composed of AzoSS and DDAB had a relatively high
orientation, neither the hydrophilic nor the hydrophobic groups
were completely oriented in an orderly manner (Figure 5a). By
adding DTT, the crystals transformed to vesicles having bilayer
structures, indicating spontaneous rearrangement of the
molecules through the reduction of AzoSS to produce AzoSH and
butanethiol. This probably resulted from a decrease in the
molecular packing that was based on the intermolecular
interactions of AzoSS, AzoSH and DDAB (Figure 5b).[23] The
isomerization that occurred under both UV and the subsequent
visible light irradiation generated instability that led to the local
collapse of vesicular membranes, inducing the vesicle fusion of
two adjacent vesicles (Figure 5c). In contrast, when UV irradiation
was applied first, most of the crystals that were composed of
AzoSS and DDAB were soluble in the aqueous phase as a result
1
in a higher polar environment. Significant differences in the H
NMR spectrum of AzoSH were observed depending on the NMR
solvent composition used. The methylene group in the vicinity of
thiol group was detected at 2.93 ppm in CD3OD, whereas a part
of that peak appeared at a lower field of 3.68 ppm in a mixed
D2O/CD3OD solvent (Figure 4c). In the 1H-1H COSY spectrum of
AzoSH using a mixed solvent, a clear correlation between the
methylene group in the vicinity of quaternary ammonium (d 3.15
ppm) and thiol groups (d 3.68 ppm) was also confirmed (Figure
S11), indicating that these functional groups interacted. In
addition, dissociation of the thiol group may occur in the highly
hydrophilic environment owing to the relatively strong acidity of
the thiol group. This suggested the production of cation–anion pair. of photoisomerization from the less soluble trans isomer to the
In the presence of 1 mM NaCl, no growth to sheet-like aggregates
was observed (Figure S12). These results suggested that the
interaction between the quaternary ammonium cations and the
thiol group (and thiolate anions) was essential for growth to sheet-
like aggregates. Therefore, it was considered that the formation
and growth of sheet-like aggregates was induced by hydrophobic
interactions owing to electrostatic shielding of the quaternary
ammonium groups.
more soluble cis isomer (Figure 5d). By subsequently adding DTT,
the aggregation of building blocks led to the formation of sheet-
like aggregates which grew as a result of the hydrophobic
interactions of the components (Figure 5e). Thus, a molecular
system composed of both azobenzene and disulfide provides a
strategy for constructing supramolecular self-assemblies that
exhibit multiple, pathway-dependent phase transitions. These
findings may also provide insight into the emergence of life.[24]
Although our chemical system consists of synthetic compounds,
vesicles can be considered as models for cells,[25] and therefore
the designed molecular system suggests one possibility for the
chemical evolution of protocells that can generate in
circumstances where various stimuli are applied.
Figure 4. Phase transition of supramolecular self-assemblies in the 80/20
(mol/mol) AzoSS/DDAB dispersion by applying UV irradiation and DTT. (a)
Bright field (top) and fluorescence (bottom) images before and after UV
irradiation. Scale bar: 30 µm. (b) Bright field (top) and fluorescence (bottom)
images of aggregate growth after 10 min UV irradiation followed by 4 mM DTT
addition. Scale bar: 100 µm. The fluorescence mode was same as that in Fig.
2. (c) 1H NMR spectra of AzoSH in CD3OD (top) and 2/1 (v/v) CD3OD/D2O
(bottom).
Figure 5. Schematic illustration of the phase transitions via Paths 1 and 2. a)
Crystals composed of AzoSS and DDAB. b) Emergence of vesicles in the
presence of DTT. c) Pore formation at the vesicular membrane indicated by the
dotted square under UV irradiation. (d) Transformation to worm-like aggregates
under UV irradiation. e) Formation and growth of sheet-like aggregates in the
presence of DTT. Dashed lines indicate interactions between the quaternary
ammonium cation and the thiol group.
From the above results, the mechanism for the different pathway-
dependent phase transitions was interpreted as follows. In the
DDAB dispersion, no transformation occurred from crystals to
4
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Chemistry - A European Journal
RESEARCH ARTICLE
Finally, we examined the reverse process of the phase transitions
by adding H2O2 to the dispersions formed at the completion of
each path. When 5 mM H2O2 solution was employed at the end of
Path 1, the vesicles shrank and then the regeneration of crystals
was observed under both CLSM and a polarizing optical
microscope (Figure S13). A reversible transition between crystals
and vesicles was repeatedly observed by adding DTT and H2O2
in turn (Figure S14). For Path 2, the sheet-like aggregates
transformed to worm-like aggregates and eventually crystals by
adding H2O2 at the end of the path (Figure S15). 1H NMR showed
both hetero- and homo-disulfide compounds (Figure S16);
however, it was not possible to clearly estimate the precise
composition. Furthermore, in the dispersion containing Nile red, a
red shift was observed in the fluorescence spectra after the
addition of H2O2 (Figure S17), suggesting that Nile red was
located in a lower polar environment before the addition of H2O2
and a higher polar environment after the addition of H2O2. On the
basis of these results, we considered that though the mechanism
is not fully understood, the reversible phase transition was
triggered by changes in the phase structures based on the redox
reaction of AzoSS in both Paths 1 and 2. The pathway-
independent reversibility indicates robustness as a chemical
system, and could be an important factor for developing new
stimuli-responsive materials[26] exhibiting desirable properties
under specific circumstances.
Keywords: aggregation • amphiphiles • phase transitions • self-
assembly • vesicles
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We have demonstrated multiple pathway-dependent phase
transitions of supramolecular self-assemblies by using cationic
amphiphiles with azobenzene and disulfide groups. The original
molecular crystals showed different phase transitions depending
on the application order of a reduction agent and light irradiation.
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crystals to vesicles, which fused without initially contacting each
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formation of worm-like aggregates that then grew to sheet-like
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Acknowledgements
Mr. Tsuneyoshi Torii and Ms. Mitsuyo Matsubara (Malvern
Panalytical, a division of Spectris Co. Ltd.) is acknowledged for
the measurements of z potentials. We would like to thank Editage
(www.editage.com) for English language editing. This work was
supported by JSPS KAKENHI Grant Number 18K05066 for T.B.
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Entry for the Table of Contents
The original molecular crystals containing cationic amphiphiles with azobenzene and disulfide groups showed different phase
transitions depending on the application order of a reduction agent and light irradiation. The current molecular system can provide a
methodology for developing new stimuli-responsive materials that exhibit the desirable properties under specific circumstances from
Systems Chemistry viewpoint.
7
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