A Chiral Recognition System Orchestrated by Self-Assembly: Molecular Chirality, Self-Assembly Morphology, and Fluorescence Response

Article abstract of DOI:10.1002/anie.201706142

The newly developed oligophenylenevinylene (OPV)-based fluorescent (FL) chiral chemosensor (OPV-Me) for the representative enantiomeric guest, 1,2-cyclohexanedicarboxylic acid (1,2-CHDA: RR- and SS-form) showed the high chiral discrimination ability, resu

Full text of DOI:10.1002/anie.201706142

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Accepted Article
Title: Chiral recognition system orchestrated by self-assembly: A
cascade of molecular chirality — self-assembly morphology —
fluorescence response
Authors: Takao Noguchi and Seiji Shinkai
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201706142
Angew. Chem. 10.1002/ange.201706142
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10.1002/anie.201706142
Angewandte Chemie International Edition
COMMUNICATION
Chiral recognition system orchestrated by self-assembly: A
cascade of molecular chirality — self-assembly morphology —
fluorescence response
Takao Noguchi,*[a,b,c] Bappaditya Roy,[a] Daisuke Yoshihara,[c] Junji Sakamoto,[c] Tatsuhiro
Yamamoto,[c] and Seiji Shinkai*[a,c]
Abstract: The newly developed oligophenylenevinylene (OPV)-
based fluorescent (FL) chiral chemosensor (OPV-Me) for the
representative enantiomeric guest, 1,2-cyclohexanedicarboxylic acid
(1,2-CHDA: RR- and SS-form) showed the high chiral discrimination
ability, resulting in the different aggregation modes of OPV-Me self-
assembly: RR-CHDA directed the fibrous supramolecular aggregate,
whereas SS-CHDA directed the finite aggregate. The consequent FL
intensity toward RR-CHDA was maximum 30 times larger than that
toward SS-CHDA. Accordingly, highly enantioselective recognition
was achieved. The application to the chirality sensing was also
possible: OPV-Me exhibited a linear relationship between the FL
intensity and the enantiomeric excess through the morphological
development of stereocomplex aggregates. These results clearly
offer a novel mechanistic view that the chiral recognition ability is
manifested by the amplification cascade of the chirality difference
through self-assembly.
toward one of the enantiomers, enantioselective recognition is
achieved. Although a number of chiral chemosensors bearing
chiral locks for targeted enantiomeric keys have been reported
so far,13 there still exist many targets for which satisfactory
enantioselectivity is not achieved. It is undoubted, therefore, that
to develop a novel chiral recognition method that is different
from the traditional lock-and-key binding mechanisms,14 and can
overcome these low enantioselectivity problems is a challenging
research target.
Recently, we demonstrated a novel molecular recognition
system through aggregation-induced FL signaling15 coupled with
a self-assembly mechanism. The underlying concept stems from
the specific self-assembly properties. Therein, a small change in
a molecular structure could dramatically alter the macroscopic
self-assembly morphology and consequently lead to the
characteristic materials properties through self-assembly.16,17 By
applying this principle to molecular recognition, we
demonstrated that the difference in guest structural information
at a molecular level directs the different self-assembly modes (J-
or H-type) of the oligophenylenevinylene (OPV)-based FL
chemosensor and leads to the distinct macroscopic self-
assembly morphologies and the FL outputs characteristic of the
initial guest information.17,18 One may regard, therefore, that self-
assembly can function as a system to amplify the difference in
molecular information into the macroscopic outputs. In this case,
selectivity for a targeted guest is attained by the mode of self-
assembly and the consequent relative FL intensity. Taking
advantage of self-assembly as an amplification system for
molecular recognition, we assumed that the self-assembly
system could be applicable to a chiral recognition purpose.
Development of methodologies to detect and discriminate chiral
compounds is of pivotal importance not only in biomedical
sciences but also in industrial applications.1 One of the
fundamental challenges underlying the chirality sensing has
been focused on the development of chemosensory systems
utilizing optical spectroscopic methods because of their
feasibility and accessibility.2–5 Many molecular chemosensors to
access chirality information have been demonstrated so far by
applying the traditional technique of lock-and-key molecular
recognition.6 Therein, the chemosensors translate the chirality
information on a target, through the formation of a lock-and-key-
type complex, into the detectable signals such as colorimetric,
circular dichroic, and fluorescence (FL) ones, thus visualizing
the information on the molecular chirality and the enantiomeric
excess (ee).7–12 In these systems, when a chemosensor for the
chirality sensing exhibits an optical response more preferentially
In this study, we demonstrate a novel chiral recognition
system coupled with an emerging self-assembly-based FL
sensory system. A newly developed OPV chemosensor bearing
two chiral spacers (OPV-Me with R-configuration, Figure 1a)19
showed the high chiral discrimination ability for the
representative enantiomeric guest, 1,2-cyclohexanedicarboxylic
acid (1,2-CHDA: RR- and SS-form in Figure 1b)20 through self-
assembly. Moreover, its application to the chirality sensing
revealed that the FL intensities obtained under the mixed
enantiomer conditions of RR- and SS-CHDA are linearly
correlated to the enantiomer fractions, indicating that this system
is useful as a FL sensing system for the estimation of the ee.
Here, we emphasize that such a unique chiral discrimination
ability is achieved when the amplification cascade of molecular
information through self-assembly is integrated in a chiral
recognition system.
[a]
Dr. T. Noguchi, Dr. B. Roy, Prof. Dr. S. Shinkai
Institute for Advanced Study, Kyushu University
744 Moto-oka, Nishi-ku, Fukuoka 819-0395 (Japan)
E-mail: tnoguchi@mail.cstm.kyushu-u.ac.jp
shinkai_center@mail.cstm.kyushu-u.ac.jp
Dr. T. Noguchi
Department of Chemistry and Biochemistry, Graduate School of
Engineering, Kyushu University
Dr. T. Noguchi, Dr. D. Yoshihara, Dr. J. Sakamoto, Dr. T.
Yamamoto, Prof. Dr. S. Shinkai
[b]
[c]
Nanotechnology Laboratory
Institute of Systems, Information Technologies and
Nanotechnologies (ISIT)
4-1 Kyudai-Shinmachi, Nishi-ku, Fukuoka 819-0388 (Japan)
Supporting information for this article is given via a link at the end of
the document.
While OPV-Me was virtually nonfluorescent in water
containing methanol (MeOH) (Figure S1 in the Supporting
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10.1002/anie.201706142
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Information (SI)), the addition of the RR- or SS-CHDA made its
FL turn-on. We found that the FL intensity maximum of OPV-Me
(10 μM) toward RR-CHDA (1.0 mM) at 515 nm is ca. 10 times
larger than that toward SS-CHDA (1.0 mM) in HEPES buffered
water containing 15 vol% MeOH, its difference being clearly
distinguishable by our naked eyes (Figures 2a,b and S2 in the
SI). This result guarantees that enantioselective recognition of
RR-CHDA over SS-CHDA is basically possible. Next, we
evaluated the performance level of OPV-Me for the
enantioselectivity under the optimal conditions. We previously
reported that in the self-assembly-based FL sensory system, the
selectivity for a targeted analyte can be modified by the
competitive binding interference (e.g., by medium pH, salts, etc.)
operating in the self-assembly process.18 In the present study,
we examined the effect of the MeOH volume in water on the
enantioselectivity in order to directly perturb the self-assembly
behavior of OPV-Me. Upon increasing the MeOH volume in
water from 3.0 vol% to 30 vol%, the FL intensities of OPV-Me
(10 μM) toward RR- and SS-CHDA (1.0 mM, fixed) were both
reduced but the degree of its reduction appeared differently
(Figures 2c and S3 in the SI). While the FL intensity of OPV-Me
toward RR-CHDA remained strong enough, the FL intensity
toward SS-CHDA decreased more steeply and eventually
reached the background level. Indeed, the selectivity evaluated
from the relative FL intensity of OPV-Me for RR-CHDA over SS-
CHDA (IRR/ISS) was most enlarged at 20 vol% MeOH (IRR/ISS = ca.
30, Figure 2d), where the FL intensity toward SS-CHDA was the
background level (Figure 2c). In order to evaluate the
relationship between the FL intensity and the ee, however, it is
necessary to allow SS-CHDA to have some FL intensity (vide
post). Therefore, we selected the solvent condition of 15 vol%
MeOH (MeOH/water 15:85, v/v) for the following experiments,
because at 15 vol% MeOH the FL intensity of OPV-Me toward
RR-CHDA remained strong while the FL intensity toward SS-
CHDA was weak but still precisely detectable as supported by
Figure 2a.
Figure 1. Chemical structures of OPV-Me (a) and enantiomeric RR- and SS-
CHDA (b).
1000
(a)
515 nm
800
600
400
200
0
RR-CHDA
(b)
no guest
RR
SS
no guest
SS-CHDA
400
450
500
550
600
650
Wavelength / nm
800
600
400
200
0
30
20
10
0
(c)
(d)
RR-CHDA
SS-CHDA
To understand the FL behavior of OPV-Me, a FL titration
experiment was performed (Figures 2e and S4 in the SI). Upon
0
5
10
15
20
25
30
0
5
10
15
20
25
30
addition of RR-CHDA
a
steep nonlinear FL increase
characteristic of the self-assembly phenomena21 was observed
whereas upon addition of SS-CHDA a weak FL increase was
observed. Accordingly, highly enantioselective recognition of
RR-CHDA was achieved. Here, one important question arises:
what is the predominant factors operating for the chiral
recognition event?
MeOH volume in water / vol%
MeOH volume in water / vol%
1000
(e)
RR-CHDA
SS-CHDA
800
600
400
200
0
To address the question, we also studied the self-assembly
behavior of OPV-Me. In a UV-Vis titration experiment, OPV-Me
showed different spectral changes toward RR- and SS-CHDA.
When the concentration of RR-CHDA was increased, the
original absorption band of OPV-Me at 370 nm was decreased,
concomitantly giving a significant increase in a shoulder band at
425 nm (Figure 3a). This spectral change is in good agreement
with that reported previously, attributable to a slip-stacked
arrangement of the OPV skeletons with respect to the direction
of the molecular long axis.22 Herein, we classify this mode of
arrangement as J-type. In contrast, addition of SS-CHDA only
showed a decrease in the absorption band at 370 nm without
0
250
500
750
1000
1250
1500
[CHDA] / μM
Figure 2. (a) Fluorescence spectra of OPV-Me in the presence of RR- and
SS-CHDA (1.0 mM for both) and (b) the corresponding photograph. (c) Plots
of the fluorescence intensities of OPV-Me/CHDA (1.0 mM, fixed) at 515 nm
against the MeOH volume, and (d) the corresponding change in the relative
fluorescence intensity of OPV-Me for RR-CHDA over SS-CHDA (IRR/ISS). (e)
Changes in the FL intensity of OPV-Me at 515 nm upon increasing
concentrations of RR- and SS-CHDA. Conditions: [OPV-Me]
= 10 μM,
[HEPES] = 10 mM (pH 7.4), MeOH/water 15:85 (v/v), 25 oC, λex = 390 nm.
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10.1002/anie.201706142
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COMMUNICATION
1
0.8
0.6
0.4
0.2
0
(a)
370 nm
370 nm
[RR‐CHDA]
1500 μM
[SS‐CHDA]
1500 μM
(b)
(a)
0.6
0.5
0.4
0.3
0.2
0.1
0
0.6
0.5
0.4
0.3
0.2
0.1
0
0 μM
0 μM
R2 = 0.992
425 nm
0
10
20
30
40
50
60
70
80
90
100
RR-fraction / %
250
300
350
400
450
500
250
300
350
400
450
500
Pure SS
Pure RR
Wavelength / nm
Wavelength / nm
ሾோோሿ
Poorly developed
morphology
Well-developed
morphology
×100
ோோ ାሾௌௌሿ
(c)
(d)
370 nm
(b)
(c) 0.32
1
0.8
0.6
0.4
0.2
0
RR‐CHDA
fraction
0.26
0.2
R2 = 0.996
425 nm
0.14
250
300
350
400
450
500
0
10 20 30 40 50 60 70 80 90 100
Wavelength / nm
RR-fraction / %
Figure 3. (a,b) Changes in the UV/Vis spectrum of OPV-Me upon increasing
concentrations of RR-CHDA (a) and SS-CHDA (b). Conditions: [OPV-Me] = 10
μM, [HEPES] = 10 mM (pH 7.4), MeOH/water 15:85 (v/v), 25 oC. (c,d)
Fluorescence microscopic images of the dispersions of OPV-Me/RR-CHDA (c)
and OPV-Me/SS-CHDA (d). Conditions: [OPV-Me] = 50 μM (to visualize
morphologies clearly), [CHDA] = 1.0 mM. Scale bar: 10 μm.
Figure 4. (a) Plot of the FL intensity (λex = 390 nm) of OPV-Me at 515 nm
against RR-CHDA fraction. (b,c) Changes in the relative absorbance of OPV-
Me at 425 nm (A425/A370) upon increasing RR-CHDA fraction. Conditions:
[OPV-Me] = 10 μM, [RR-CHDA] + [SS-CHDA] = 1.0 mM, [HEPES] = 10 mM
(pH 7.4), MeOH/water 15:85 (v/v), 25 oC.
clear appearance of the shoulder band (Figure 3b). To gain
more insights into the self-assembly behavior, the effect of the
MeOH volume in water was examined. At 5 vol% MeOH a
shoulder band at 425 nm which could be ascribable to a slip-
stacked arrangement of OPV-Me was clearly observed and this
shoulder band disappeared upon increasing MeOH volume from
5 vol% to 15 vol% (Figure S5a in the SI). This is correlated well
with reduction of the degree of aggregation and with the
consequent FL decrease (Figure 2c, SS-CHDA). Thus, the
decrease in the absorbance (Figure 3b) is attributed in origin to
a slip-stacked arrangement of OPV-Me. It should be taken into
consideration that the inherent self-assembly and the FL
properties of OPV-Me attained by SS-CHDA are different from
those attained by RR-CHDA as supported by Figure 2c. Here,
we tentatively classify the mode of the OPV arrangement
attained by RR-CHDA as JRR-type and that attained by SS-
CHDA as JSS-type.
achieved
a
well-developed fibrous morphology, whereas
sterically less favored SS-CHDA for OPV-Me self-assembly
afforded a poorly developed morphology. Therefore, the UV-Vis
and the morphological studies provided a clear view that the
chirality difference between RR- and SS-CHDA is amplified into
the different modes of OPV-Me self-assembly through the
aggregation process. A scenario of the enantioselective chiral
recognition can be summarized on the basis of the molecular
chirality – self-assembly – FL response cascade: OPV-Me
associated with RR-CHDA self-assembles favorably in a JRR
type stacked fashion to form well-developed fibrous
-
a
morphology and accordingly leads to an intense FL emission,
whereas OPV-Me associated with sterically demanding SS-
CHDA self-assembles in a JSS-type stacked fashion to form a
poorly developed morphology affording a much weaker FL
emission. As supported by the evaluation of the performance
level for the enantioselective recognition (Figure 2c), the
enantioselectivity is tunable by skillfully utilizing the difference in
the self-assembly properties in a solvent medium.24
The difference in the self-assembly modes is further
supported by the appearance of their macroscopic self-assembly
morphologies. The FL microscopic observation for the aqueous
dispersions revealed that JRR-type aggregates of OPV-Me (50
μM) associated with RR-CHDA (1.0 mM) afforded a well-
developed fibrous morphology (Figure 3c).23 In contrast, JSS-type
aggregates of OPV-Me (50 μM) associated with SS-CHDA (1.0
mM) afforded a poorly developed morphology (Figure 3d), which
is less affected by the MeOH addition (Figure S5b in the SI).
Since highly enantioselective recognition of RR-CHDA over
SS-CHDA was achieved as shown in Figure 2e, we next studied
the FL response of OPV-Me under the mixed enantiomer
conditions of RR- and SS-CHDA toward the chirality sensing.
Here, the FL titration experiment was conducted with
a
continuous variation method about the mole fractions of RR- and
SS-CHDA ([RR-CHDA] + [SS-CHDA] = 1.0 mM). Interestingly,
we found that changes in the FL intensity of OPV-Me exhibit a
linear relationship against the RR-CHDA fraction from 0% to
80% and reach the plateau (Figures 4a and S6 in the SI). It is
worthy to mention that the sensitivity of OPV-Me toward RR-
Such
a
macroscopic difference in the self-assembly
morphologies is undoubtedly originated from the chirality
difference in the enantiomeric RR- and SS-CHDA. Obviously,
sterically favorable RR-CHDA for OPV-Me self-assembly
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10.1002/anie.201706142
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COMMUNICATION
CHDA is enhanced: for example, OPV-Me can sense 10%
fraction of RR-CHDA ([RR-CHDA] = 100 μM and [SS-CHDA] =
900 μM) although OPV-Me exhibits virtually no FL response to
100 μM of RR-CHDA in a single RR-CHDA condition (Figure 2e).
The notable points to understand this result are associated with
the linearity and the plateau: that is, if OPV-Me could form a J-
type aggregate preferentially with RR-CHDA under the mixed
RR- and SS-CHDA conditions, then changes in the FL intensity
of OPV-Me could show a sigmoidal nonlinear relationship as
shown in Figure 2e. Thus, the linear FL change (Figure 4a)
strongly supports the view that OPV-Me forms a stereocomplex
(co-aggregate) with RR-CHDA and SS-CHDA. Taking into
consideration the fact that OPV-Me forms a poorly developed
finite morphology with SS-CHDA (0% fraction of RR-CHDA in
this case) and a well-developed fibrous morphology with RR-
CHDA (100% fraction of RR-CHDA), the linear FL change
provides a rationale to explain the FL sensing mechanism: that
is, the linearity in the FL changes stems from a continuous
change in the self-assembly morphologies from a finite one to a
fibrous one. This is also supported by the UV/Vis titration result
and the FL microscopic observation. Therein, the increase in the
relative absorbance at 425 nm indicative of the well-developed
was supported by JSPS Grant-in-Aid for Young Scientists (B)
(grant no. 16K17937). The measurement of 1H and 13C NMR,
and MALDI-TOF MS was made at the Analytical Center in
Fukuoka Industry-academia Symphonicity. The measurement of
HRMS was performed using JEOL JMS700 at the Evaluation
Center of Materials Properties and Function, Institute for
Materials Chemistry and Engineering, Kyushu University.
Keywords: Chirality • Molecular recognition • Self-assembly •
Fluorescent probes • Supramolecular chemistry
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the
enantioselective
recognition.
By
virtue
of
the
enantioselectivity based on self-assembly, a crucial mechanism
toward the determination of the ee has been unveiled: that is,
the linear correlation between the FL intensity and the ee can be
obtained through the morphological development of the
stereocomplex aggregates. These results exemplify the
emergent property of self-assembly18b,25 for the application to
chiral recognition, which can be regarded as the striking feature
realized by the self-assembly-based chemosensory system. We
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a
molecular level orchestrates self-assembly modes and
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Acknowledgements
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We are grateful for one Reviewer who raised a few constructive
comments on the further applicability of this system. This work
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10.1002/anie.201706142
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COMMUNICATION
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[19] The chiral OPV chemosensors with the branched substituents in the
spacer (Me, sec-Bu, tert-Bu, and Bn in Figure 1a) were designed.
Among them, OPV-Me showed the highest chiral discrimination ability
through self-assembly because the smallest volume of the side-chain
substituent is advantageous for the OPV self-assembly.
[22] S.-J. Yoon, S. Y. Park, J. Mater. Chem. 2011, 21, 8338 –8346.
[23] This correlation between the J-type aggregation mode and the fibrous
supramolecular polymer is in good agreement with our previous result
(ref. 17).
[24] In other words, the enantioselectivity is controllable by the solubility
difference between the diastereomer aggregates (OPV-Me/RR-CHDA
vs OPV-Me/SS-CHDA) in a solvent medium.
[25] Q.-F. Sun, J. Iwasa, D. Ogawa, Y. Ishido, S. Sato, T. Ozeki, Y. Sei, K.
Yamaguchi, M. Fujita, Science 2010, 328, 1144–1147, and references
cited therein.
[20] The enantiomeric CHDA is suitable to demonstrate our concept and
sensing mechanism clearly. The applicability of this system to other
chiral acids was also confirmed.
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10.1002/anie.201706142
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Chiral recognition
Chiral recognition of a guest
enantiomer has been achieved by
self-assembly of a fluorescent (FL)
chiral chemosensor. The highly
enantioselective recognition is due to
the amplification of the small steric
difference through self-assembly into
the macroscopic aggregation
properties (see graphic). This
molecular assembly system
T. Noguchi,* B. Roy, D. Yoshihara, J.
Sakamoto, T. Yamamoto, S. Shinkai*
RR
SS
Page No. – Page No.
Chiral recognition system
orchestrated by self-assembly: A
cascade of molecular chirality — self-
assembly morphology —
fluorescence response
possesses a great advantage for
chiral discrimination by the FL sensing
technique.
This article is protected by copyright. All rights reserved.