Aggregation-Induced Singlet Oxygen Generation: Functional Fluorophore and Anthrylphenylene Dyad Self-Assemblies

Article abstract of DOI:10.1002/chem.201703686

The assembly of monomeric building blocks can manifest the display of new properties, including optical, mechanical, and electrochemical functionalities. In this study, we sought to develop a functional fluorophore self-assembly that can generate reactive oxygen species only when aggregated. With an anthrylphenylene (AP) group, negatively charged and neutral fluorescein units form non-fluorescent H-aggregates in aqueous solution because of the weak intermolecular interaction between the anthracene and fluorescein moieties. In stark contrast, a boron dipyrromethene (BODIPY) and AP dyad produces two-color-emissive aggregates through the formation of an intermolecular charge-transfer (CT) complex between the electron-rich anthracene and electron-deficient BODIPY moieties. Furthermore, to our surprise, the BODIPY and AP dyad aggregates generate singlet oxygen (¹O₂) and photocytotoxicity upon excitation, indicating that the BODIPY–anthracene CT state favors an intersystem crossing process. Based on X-ray crystallographic analysis, the lattice-like molecular packing between the BODIPY and AP moieties was determined to bring about the unprecedented aggregation-induced ¹O₂ generation (AISG).

Full text of DOI:10.1002/chem.201703686

A Journal of
Accepted Article
Title: Aggregation-Induced Singlet Oxygen Generation: Functional
Fluorophore and Anthrylphenylene Dyad Self-Assemblies
Authors: Sooyeon Kim, Yang Zhou, Norimitsu Tohnai, Hirotaka
Nakatsuji, Michiya Matsusaki, Mamoru Fujitsuka, Mikiji
Miyata, and Tetsuro Majima
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Aggregation-Induced Singlet Oxygen Generation:
Functional Fluorophore and Anthrylphenylene Dyad
Self-Assemblies
Sooyeon Kim,[a] Yang Zhou,[a] Norimitsu Tohnai,[b] Hirotaka Nakatsuji,[c] Michiya Matsusaki,[c]
Mamoru Fujitsuka,[a] Mikiji Miyata[a], and Tetsuro Majima*[a]
[a]The Institute of Scientific and Industrial Research (SANKEN), Osaka University, Mihogaoka 8-1, Ibaraki,
Osaka 567-0047 (Japan). [b]Department of Material and Life Science, Graduate School of Engineering, Osaka
University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan). [c]Department of Applied Chemistry, Graduate
School of Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871 (Japan).
*Corresponding author: E-mail: majima@sanken.osaka-u.ac.jp. Phone: +81-6-6879-8495. Fax: +81-6-
6879-8499.
[Abstract] The assembly of monomeric building blocks can manifest the display of new properties,
including optical, mechanical, and electrochemical functionalities. In this study, we sought to develop a
functional fluorophore self-assembly that can generate reactive oxygen species only when aggregated. With
an anthrylphenylene (AP) group, negatively charged and neutral fluorescein units form non-fluorescent H-
aggregates in aqueous solution because of the weak intermolecular interaction between the anthracene and
fluorescein moieties. In stark contrast, a boron-dipyrromethene (BODIPY) and AP dyad produces two-
color-emissive aggregates through the formation of an intermolecular charge-transfer (CT) complex
between the electron-rich anthracene and electron-deficient BODIPY moieties. Furthermore, to our surprise,
the BODIPY and AP dyad aggregates generate singlet oxygen (1O2) and photocytotoxicity upon excitation,
indicating that the BODIPY-anthracene CT state favors an intersystem crossing process. Based on X-ray
crystallographic analysis, the lattice-like molecular packing between the BODIPY and AP moieties was
determined to bring about the unprecedented aggregation-induced 1O2 generation (AISG).
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Introduction
Fluorophore self-assemblies can manifest useful properties, and therefore, have been investigated as
potential fluorescent indicators, sensory materials, emitters, and sensitizers of photoinduced reactions. In
addition to well-aligned molecular assemblies such as those of chlorophyll,[1] irregularly aggregated
fluorophores can exhibit useful behaviors, as exemplified by aggregation-induced enhanced emission
(AIEE).[2–4] Tetraphenylethene, a well-known AIEE dye, emits more strongly in poor solvents since the
non-radiative decay process is interrupted by restricted molecular rotation.
As summarized in a recent review,[2] several underlying photochemical mechanisms can account for
AIEE phenomena. For example, a fluorophore connected to a triphenylamine group exhibited an
aggregation-induced intermolecular charge-transfer (CT) state, resulting in AIEE.[5] The CT emission
originates from the electronic interaction (either intra- or intermolecular) between the donor (D) and
acceptor (A) units.[5–8] Furthermore, AIEE from molecules designed with small singlet-triplet energy gaps
has recently attracted significant attention for the enhancement of delayed fluorescence and the
development of strongly emitting OLED materials.[8–10]
These studies suggest that aggregates of D-A dyads in which the A unit has a sufficiently low triplet
energy level to facilitate intersystem crossing (ISC) could be promising candidates for generating cytotoxic
singlet oxygen (1O2). In photodynamic therapy (PDT), an anti-cancer therapy using light-irradiation and
oxygen, an efficient heavy-atom free photosensitizer is urgently needed to reduce dark-toxicity. Thus, our
objective was to develop a functional organic self-assembly that generated 1O2 only when aggregated.
To achieve the self-assembly of D-A dyads, we designed dyads consisting of electron-deficient
fluorophores and electron-rich anthrylphenylene (AP) groups, referred to as the AP series. In 2015, we first
reported the slip-stacked J-aggregation of tetramethylrhodamine (TMR) derivatives and AP dyads assisted
by halide ions in aqueous solution (Fig. S1).[12,13] The J-aggregation of the TMR and AP dyads was
accompanied by a vivid colour change from pink to blue, and the aggregates exhibited good cell
permeability.[12] These findings inspired our idea that a variety of functional aggregates could be constructed
based on the AP series as a molecular template.
Herein, we expand the scope of the dyad fluorophores to explore the functional utility of the AP series,
by incorporating fluorescein (a xanthene derivative) and boron-dipyrromethene (BODIPY) to afford Fl-AP
and BODIPY-AP, respectively (Fig. 1). The distinct aggregation patterns of the AP series with fluorescein
and BODIPY were investigated using various spectroscopic techniques and X-ray crystallographic analysis.
1
Moreover, we reveal that the BODIPY and AP dyad aggregates successfully generate O2 and exert
photocytotoxicity in cancer cells by selective excitation of the intermolecular CT complex, realizing an
‘Aggregation-Induced 1O2 Generation (AISG)’ effect.
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Fig. 1 General dyad design comprising a fluorophore and AP group (AP series), and chemical structures of
dyads studied herein.
Results
Synthesis and optical properties in polar organic solvent
In this study, fluorescein and BODIPY were chosen since they are typical anionic and zwitterionic
fluorophores in aqueous solution, respectively, with high fluorescence quantum yields (Фfl). Our previous
study[12] showed that slip-stacked rhodamine derivatives are stabilized by the intermolecular interactions
between the electron-deficient rhodamine and electron-rich anthracene moieties and the π-π interactions
between the two C–N bonds of the rhodamine moieties. Thus, negatively charged fluorescein may exert a
repulsive interaction and fail to construct any supramolecular structure with the anthracene moiety, while
the zwitterionic BODIPY may interact with the anthracene moiety to some extent. However, the absence
of N,N-dialkylgroups which tie the slip-stacked rhodamine dyes may result in a different aggregation pattern
for the fluorescein and BODIPY dyes.
We prepared the three dyads shown in Fig. 1 via the syntheses as shown in Schemes 1 and 2. The final
products, Fl-AP and BODIPY dyads, were synthesized by a preparation of tertiary carbinol leuco bases[14]
and Suzuki coupling, respectively. Please find the details of synthesis procedures and structural
characterization in the Supporting Information. Then, we compared the absorption and fluorescence spectra
of the AP series in methanol (Fig. S2). The absorption spectra of Fl-AP and BODIPY-AP are
superpositions of the absorption spectra of the fluorophores and AP groups, indicating the negligible
electronic interactions between the two moieties in the ground state. Because free rotation between the
phenylene ring and fluorophore increases the rate of non-radiative decay, the Фfl of the AP series is
generally decreased by 5–10 times relative to the free fluorophore.[12] Thus, the Фfl values of fluorescein
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and Fl-AP are 0.91[15] and 0.13, respectively (Table 1). Interestingly, the Фfl of BODIPY-AP decreases by
160 times as compared to the BODIPY chromophore with 2′-methylbenzene (BODIPY-Me, Fig. S1),
which will be discussed later.
Scheme 1 Synthesis of Fl-AP
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Scheme 2 Syntheses of BODIPY-AP and –MeAP
Table 1. Photophysical parameters of the AP series in this study.
Material
Fl-AP
Solvent
MeOH
λabs / nm
503.5
471 / 506
495
λem / nm
525
Фfl
0.13
pH 2.1 buffer
pH 9.1 buffer
MeOH
515
0.001
0.043
0.004
0.004
0.003
0.003
Fl-AP
515
Fl-AP
498
517
BODIPY-AP
BODIPY-AP
BODIPY-MeAP
BODIPY-MeAP
H2O
521
521 / 662
519
MeOH
498
H2O
521
666
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Optical properties of aggregates in aqueous solution
Next, the aggregation behaviors of the AP series in aqueous solution were studied. From the results of
dynamic light scattering measurements, both Fl-AP and BODIPY-AP form a few tens of nanometer-sized
aggregates inside of the aqueous solution (Supporting Table 1). To understand the detailed intermolecular
interaction in the aggregated state, optical properties were measured.
For Fl-AP, both acidic and basic buffer solutions were used since the pKa of the hydroxyl group of the
xanthene moiety is approximately pH 6.3.[16] Thus, the net charge of Fl-AP is −1 and 0 at pH 9.1 and 2.1,
respectively (Fig. S3). In contrast to our expectations, the absorption spectra of Fl-AP obtained at both pH
9.1 and 2.1 show widened absorption bands and blue-shifted maximums (Fig. 2a). The relative Фfl of the
negatively charged Fl-AP decreases about 3 times upon aggregation (Table 1), indicating H-aggregate
formation for Fl-AP regardless of pH. This implies that the net charge of the fluorophore is not the sole
factor by which to judge the aggregation behavior of the AP series. In addition, the H-aggregates of Fl-AP
were not sensitive to the presence of cations or their identity (Fig. S4), in contrast to the TMR derivatives
and AP dyads, which formed J-aggregates only in the presence of halide anions.
In the case of the BODIPY-AP aggregate, the absorption spectrum is red-shifted by 23.5 nm with spectral
widening, compared to that of the monomer (Fig. 2a). Furthermore, BODIPY-AP exhibits a two-color
emission at 521 and 663 nm upon excitation at 470 nm (Fig. 2b). The green emission at 521 nm is assigned
to the local excited (LE) state, the lowest singlet excited state of BODIPY, while the red-shifted
structureless emission often implies the formation of either excimer or CT states. To clarify the origin of
the red emission, the changes in the emission ratio versus the BODIPY-AP concentration (Fig. S5) and
water fraction (Fig. S6) were tested. The emission in the red region was found to be closely correlated to
the extent of molecular aggregation. Furthermore, time-resolved photoluminescence measurements
revealed that the red emission of BODIPY-AP occurs instantaneously after excitation (time resolution: app.
30 ps) (Fig. S7).
Taken together, these results obviously exclude the possibilities of intramolecular CT and diffusion-
induced excimer (or exciplex) formation in aqueous solution. However, as depicted in the excitation
spectrum (Fig. S8), the red emission originates from the anthracene and BODIPY moieties. Therefore, the
BODIPY-AP aggregate exhibits intermolecular CT character in the ground state, delocalized over the
anthracene and BODIPY moieties. To scrutinize the detailed structure of the aggregates and their
functionality, we next focused on BODIPY and AP dyads.
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(a)
(b)
Fig. 2 Normalized (a) absorption and (b) fluorescence spectra of 10 μM Fl-AP (black) and BODIPY-AP
(red) in aqueous solution. Phosphoric acid (100 mM) and boric acid (100 mM) buffer solutions were used
to adjust the aqueous solution to pH 2.1 and 9.1 (solid and dashed lines, respectively). Fl-AP and BODIPY-
AP were excited at 470 nm.
Intermolecular CT complex and TICT formation of BODIPY-MeAP
The aggregation behavior of BODIPY-AP was compared with that of a dyad consisting of BODIPY and
the more-electron-rich 9-methylanthrylphenylene group, BODIPY-MeAP (Fig. 1). As discussed above,
BODIPY-AP exhibits two-color emission at 521 and 662 nm in aqueous solution, assigned to the LE and
intermolecular CT states, respectively. In contrast, BODIPY-MeAP emits only in the red region, with a
negligible spectral shift between the CT emissions of BODIPY-AP and BODIPY-MeAP (Fig. 3a). Thus,
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BODIPY-MeAP forms intermolecular CT states more easily, and the CT energy levels of BODIPY-AP
and BODIPY-MeAP are comparable.
Subsequently, the optical properties of monomeric BODIPY-MeAP were investigated in various
solvents. Whereas the absorption spectra of the BODIPY and AP dyads display nearly no solvent
dependence (Fig. S9), their emission spectra are greatly affected by solvent polarity (Fig. 3b). A gradual
red-shift of the CT emission is evident as the solvent polarity parameters[5,17] increases from 0.014 (toluene)
to 0.025 (1,4-dioxane). In nonpolar (cyclohexane) and highly polar solvents (dichloromethane, dimethyl
sulfoxide, and methanol), however, the CT emission becomes negligible (Fig. 3b). As for BODIPY-AP,
Фfl decreases 10-fold as the fraction of methanol in 1,4-dioxane increases (Supporting Table S2, Fig. S10).
Benniston et al. reported that a dyad of BODIPY and anthracene exhibited an exciplex-like emission
assigned to the intramolecular CT state.[18] They remarked that a CT emission was not observed for 1,3,5,7-
tetramethyl BODIPY due to the restricted rotation between the BODIPY and phenylene ring.[19] Since both
BODIPY-AP and BODIPY-MeAP can rotate around the phenylene ring to a certain extent, the red
emissions observed in toluene and 1,4-dioxane are assigned to a twisted intramolecular CT (TICT) state
delocalized over the BODIPY and anthracene moieties. In a nonpolar solvent, the decay of the LE state to
the TICT state is not favored because the polar TICT cannot be relaxed by surrounding solvent molecules.
Upon increasing the solvent polarity, the solvated TICT state forms. In less polar solvents, the TICT of
BODIPY-MeAP is deactivated by the red emission. A further increase in the solvent polarity induces the
non-radiative relaxation of the TICT, resulting in the quenching of the CT emission. Hence, the 160-fold
fluorescence quenching of BODIPY-AP in methanol is due to TICT formation.[20,21]
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(a)
(b)
(c)
Fig. 3 (a) Normalized fluorescence spectra of BODIPY-AP (black) and BODIPY-MeAP (red) in MilliQ
water (λex = 470 nm). (b) Normalized fluorescence spectra of BODIPY-MeAP in various solvents (cHex:
cyclohexane, Tol: toluene, DiOx: 1,4-dioxane, DCM: dichloromethane, MeOH: methanol, and DMSO:
dimethyl sulfoxide). (c) BODIPY-MeAP in three solvents under room light (upper) and UV illumination
(lower).
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1O2 generation from aggregates of BODIPY and AP dyads
The Tang group previously reported that aggregated dyads of BODIPY and tetraphenylamine emitted
restricted TICT emissions in aqueous solution.[5] However, aggregates of BODIPY and AP dyads do not
show dramatic aggregation-induced ‘enhanced’ emission (Table 1, Fig. 3c). Hence, there must be another
non-radiative decay process in these aggregates in which rotational motion would be highly restricted.
The CT state can relax via three possible pathways: emission, non-radiative relaxation, and ISC. To
facilitate the ISC pathway, the triplet energy level of A should be lower than the CT energy level, and an
orthogonal orientation of molecular orbitals and strong electronic coupling between D and A are
prefered.[22,23] Even when the dihedral angle between the two moieties is not completely 90°, the efficient
ISC of intramolecular CT states with electronically separated D and A and exciplexes has been reported.[8,24–
26]
Based on the foregoing studies, we presumed that the intermolecular CT state of BODIPY and AP
1
aggregates would be deactivated through ISC. To prove our hypothesis, O2 generation by the monomer
1
and aggregates of BODIPY-MeAP was tested via a self-oxidation reaction, O2 fluorescence assay, and
1O2 phosphorescence measurement. 1O2 is the lowest singlet excited state of molecular oxygen, generated
by intermolecular triplet-triplet energy transfer between molecular oxygen and a photosensitizer in the
triplet excited state. 1O2 can be detected by a selective oxidation reaction with the central ring of anthracene
(Fig. 4a).
Figures 4b and 4c illustrate the structural and optical changes of BODIPY-MeAP aggregates in aqueous
solution with 10 vol% methanol under 511–551 nm irradiation. As highlighted by the black arrows, the
absorption by the anthracene moiety of BODIPY-MeAP and emission from the intermolecular CT complex
gradually disappear, resulting in a structureless emission spectrum (Fig. 4c). This emission comes from
non-specific aggregates of BODIPY-MeAP by hydrophobic interactions. The same phenomenon is
observed for BODIPY-AP (Fig. S11). Self-oxidation tests were also carried out in N2-saturated solutions,
which gave negligible oxidation of the anthracene moiety (Fig. S12). Furthermore, the fluorescence
1
intensity of Si-DMA, a far-red fluorescence probe of O2 (Fig. S13),[27] increased when incubated with
BODIPY and AP dyads aggregate in aqueous solution under continuous irradiation. Taken together, both
1
BODIPY-AP and BODIPY-MeAP aggregates can generate O2 through photochemical reaction with
dissolved molecular oxygen.
1
To ascertain the corresponding excited state for O2 formation, the spectral changes of monomeric
BODIPY-MeAP absorption in cyclohexane, 1,4-dioxane, and methanol were monitored under the selective
excitation of BODIPY. Consequently, BODIPY-MeAP in 1,4-dioxane generates 1O2 and is easily oxidized
under irradiation (Figs. 4e and S14a), whereas monomeric BODIPY-MeAP in methanol and cyclohexane
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is not oxidized at all during 30 min irradiation (Figs. 4f and S14b, respectively). O2 phosphorescence
measurements in 1,4-dioxane and methanol further support the results of self-oxidation tests (Figs. 4e-4g).
Recently, several reports have described that heavy-atom-free BODIPY undergoes ISC in aqueous
solution.[28–32] Akkaya et al. developed dimeric BODIPY, in which the two BODIPY moieties were
orthogonally connected.[28,29] Ortiz et al. confirmed that the intrinsic intramolecular CT character of the
orthogonal BODIPY dimers was related to 1O2 generation.[31] We considered that BODIPY-MeAP in 1,4-
dioxane would follow a similar decay process to these BODIPY derivatives. Density functional theory
(DFT) calculations support this idea, clearly showing the well-separated locations of the HOMO and
LUMO orbitals in BODIPY-MeAP (Fig. S15). During the preparation of this paper, there have been a
report that directly connected BODIPY and anthracene dyad can facilitate 1O2 formation by photoinduced
electron transfer, followed by charge recombination and triplet excited state formation.[32] We would like
1
to emphasize that our finding enabled not only monomer-mediate O2 formation in organic solvents, but
also AISG effect in water without a chemical modification of hydrophilic groups.
It is indeed surprising that 1O2-formation is enabled only when BODIPY and AP dyads aggregate upon
increasing the water fraction of the methanol solution. In general, the singlet excited state of the molecular
aggregates tends to be deactivated via solvation and molecular vibrational motion.[26] Concerning the
discrepant 1O2 formation by BODIPY-MeAP in various solvents, the intermolecular CT state must play a
crucial role that drives the AISG effect of BODIPY and AP dyad aggregates.
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(a)
(b)
(e)
(c)
(d)
(g)
(f)
Fig. 4 (a) Endoperoxide reaction of BODIPY-MeAP with 1O2. (b, c) Changes in absorption and emission
spectra of 50 μM BODIPY-MeAP in aqueous solution with 10 vol% methanol under continuous irradiation
(shaded in green, 32 mW cm−2 at 511–551 nm). Black arrows indicate spectral changes due to
endoperoxidation of anthracene moiety and dissociation of the CT complex. (d) 1O2 fluorescence assay of
BODIPY-AP and BODIPY-MeAP aggregates in aqueous solution using 50 μM Si-DMA.[27] (e, f) Changes
in absorption and emission spectra of 50 μM BODIPY-MeAP in (e) 1,4-dioxane and (f) methanol under
1
continuous irradiation (shaded in green, 540 mW cm−2 at >488 nm). (g) O2 phosphorescence spectra of
BODIPY-MeAP in 1,4-dioxane (black) and methanol (red) excited at 355 nm.
Lattice-like crystal structures of BODIPY and AP dyads
To elucidate the various photophysical properties of the supramolecular structures, one should
understand how the molecules are assembled.[6,7] X-ray crystallographic analyses of BODIPY-AP and
BODIPY-MeAP were performed to ascertain the details of their molecular packing and the intermolecular
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interactions between the anthracene and BODIPY units. BODIPY-AP was crystallized by solvent-vapor
exchange between hexane and chloroform, while crystals of BODIPY-MeAP were more easily obtained
from concentrated methanol solution. BODIPY-AP and BODIPY-MeAP crystallize in the orthorhombic
space group P212121 and triclinic space group P-1, respectively.
Following the intrinsic characteristics of P212121 crystals, the four BODIPY-AP molecules in a unit cell
are regularly aligned in a helical manner with the aid of extended anthracene and BODIPY stacks (An-An
and BD-BD in Fig. 5a, respectively). In addition, the BODIPY and anthracene moieties interact via a CH-
π interaction (3.2 Å) with a dihedral angle of 35.5°. On the other hand, the BODIPY and anthracene moieties
of BODIPY-MeAP face each other through a CH-π interaction (2.9 Å) with a larger dihedral angle of 59.2°
(An-BD in Fig. 5b). The dense molecular packing of BODIPY-MeAP is stabilized by π-π stacking between
two anthracene moieties (An-An in Fig. 5b).
By careful observation of the crystal structures, the various photophysical phenomena of BODIPY and
AP dyads become clearer based on their molecular interactions. First, the BODIPY moieties in the
BODIPY-AP crystal can form either BODIPY-anthracene or BODIPY-BODIPY (space appears in the
former one but omitted in latter one surrounding “-”) stacks (Fig. 5a), whereas those of BODIPY-MeAP
interact only with anthracene moieties through CH (An)-π (BODIPY) interactions, and vice versa (An-BD
and BD-An in Fig. 5b, respectively). The presence of BODIPY-BODIPY weak molecular interactions
clearly explains the simultaneous LE and CT emissions of the BODIPY-AP aggregates (Fig. 3a).
It is still unclear why the substitution of one methyl group on the anthracene moiety results in different
crystal structures and photophysical behaviors. We consider that there are three main intermolecular
interactions that govern the overall crystal structure of BODIPY-AP: a herringbone-type van der Waals
force between anthracene moieties, a face-to-face van der Waals force between halogen-containing
BODIPY moieties, and a CH-π interaction between the anthracene and zwitterionic BODIPY moieties (Fig.
5a). Substitution of a methyl group at the 9-position of anthracene interrupts the herringbone-type stacking,
resulting in the π-π stacking of the anthracene moieties, as shown in Fig. 5b. This small change in the
molecular structure that prevents a specific molecular stacking mode indeed leads to a complete
rearrangement of the whole crystal structure.
Despite their distinct crystal structures, both BODIPY-AP and BODIPY-MeAP exhibit close contact
between the BODIPY and anthracene moieties. This is considered the origin of the intermolecular CT
emission and AISG effect observed in aqueous solution. Although BODIPY-AP and BODIPY-MeAP
have different dihedral angles between BODIPY and anthracene planes, 35.5º and 59.2º, respectively, their
geometries in the aqueous solution probably resemble each other because λems of the CT emission are nearly
the same (Table 1). For example, Zhang et al. reported that emission color of BODIPY crystal changes with
a different dihedral angle between BODIPY and biindenyl bridge.[33] Moreover, the simultaneous oxidation
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1
and dissociation processes of anthracene and the intermolecular CT complex induced by O2 (Fig. 4),
respectively, clearly match with the molecular packing patterns of BODIPY-AP and BODIPY-MeAP; the
endoperoxide formation at the central ring of anthracene will disrupt either the herringbone-structured or
π-π stacking of the anthracene moieties, and finally, dissociate the BODIPY-anthracene moieties, halting
the AISG process.
Fig. 5 Crystal structures of (a) BODIPY-AP and (b) BODIPY-MeAP. The BODIPY, anthracene, and 9-
methylanthracene moieties are colored in orange, yellow, and olive, respectively. Blue arrows indicate the
intermolecular interactions present in the crystal structures (An and BD represent anthracene and BODIPY
moieties, respectively). (Right) Representative illustrations to depict the intermolecular interaction between
anthracene and BODIPY moieties.
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Photocytotoxicity of BODIPY and AP dyads
Finally, the biological usages of BODIPY and AP dyads as PDT agents are validated in terms of cell
permeability, dark toxicity, and light-induced cytotoxicity to cancer cells. We have confirmed that BODIPY
and AP dyads were well internalized inside of A549 cells upon 3-hr incubation, and cytotoxicities of
BODIPY-AP and BODIPY-MeAP up to 20 μM were negligible (Fig. S16). During monitoring the cellular
localization using a fluorescence microscope, a rapid translocation from vesicular structures to cell
cytoplasm was observed (Fig. 6a). Considring short incubation time (1-3 hr), relatively large size of the
aggregates (a few tens of nanometer, Supporting Table 1), and our previous observation of a lysosomal
porphyrin that quickly changes its location to other organelle upon light excitation,[27] we assume both
BODIPY and AP dyads reside in endosomes. In short, the BODIPY and AP dyad aggregates exhibit
moderate cell permeability and undergo the endocytosis pathway.
Subsequently, the light-induced cytotoxicity of BODIPY-AP and BODIPY-MeAP aggregates is studied.
Interestingly, the membrane structures of the A549 cells treated with dyads start to be collapsed from 20-
min irradiation at 510-550 nm (Fig. S17). After 30-min irradiation and overnight incubation, the cells only
in the irradiated area (beam diameter = app. 0.8 cm) are almost detached, indicating a light-induced
cytotoxicity of BODIPY and AP dyads (Fig. 6b). When the whole area of cell dish is irradiated, BODIPY
and AP dyads-treated cells resulted in approximately 25% and 2% viability by 10- and 20-min light
irradiation, respectively (Fig. 6c). There was not a significant difference in photocytotoxicity of BODIPY-
1
AP and BODIPY-MeAP, in accordance with the result of O2 fluorescence assay (Fig. 4d). It should be
noted that the light intensity was mild enough that there was no heat-induced cytotoxicity.
As scrutinized earlier, the monitored photocytotoxicity is considered due to the AISG effect of BODIPY
and AP dyads aggregates. One advantage of these dyads is that the self-oxidized property of the BODIPY
1
and AP dyads (Fig. 4) would be useful to halt photocytotoxicity after forming a certain amount of O2.
Provided with the appropriate drug delivery system (DDS), hence, BODIPY and AP dyads aggregates can
be applied to a controllable 1O2 generating agents. We are currently carrying out to clarify the cell killing
mechanism of BODIPY and AP dyads and develop a suitable DDS.
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(a)
(b)
(c)
Fig. 6 (a) Fluorescence microscopic images of the A549 cells treated with 20 μM BODIPY-MeAP for 3
hours. During 30 seconds of irradiation (511-551 nm, 42 mW cm-2), the fluorescence intensity of BODIPY-
MeAP aggregates (> 561 nm) decreased, and changes in localization occurred. (b) Bright field images of
the A549 cells treated with 20 μM BODIPY-AP (left) and BODIPY-MeAP (right) after 30-min irradiation
followed by overnight incubation in the dark. Irradiated areas are shown with green curve lines. (c) Cell
viability tests of bare A549 cells (control) and treated with 20 μM BODIPY-AP (BD-AP) and BODIPY-
MeAP (BD-MeAP), exposed to 10- and 20-min light irradiation. N = 3.
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Discussion
While positively charged rhodamine derivatives stack with anthracene in a slipped-stacked manner and
form sub-micrometer J-aggregates, the Fl-AP and BODIPY derivatives studied here show distinct
aggregation patterns, as summarized in Fig. 7. First, neither the anionic nor neutral fluorescein moieties
form supramolecular assemblies other than H-aggregates. Based on previous studies, a comparison among
various fluorophores (fluorescein, rhodamine, coumarin, and pyrene) reveals that rhodamine derivatives
are the most prone to form H-dimers when they are adjacent.[34,35] Brand et al.[34] claimed that a symmetric
fluorophore with a delocalized charge and strong transition dipole is adequate for H-dimer formation. In
addition, based on calculations, rhodamine has half of a positive charge localized on its carbons, whereas
the fluorescein moiety exhibits neutral character.[34] Thus, the fluorescein moiety in Fl-AP, which is
electron-richer than rhodamine and -poorer than anthracene, results in a non-fluorescent H-dimer due to
antiparallel π-π stacking (Fig. 7).
Second, BODIPY with an AP group forms aggregates with red-shifted and widened absorption spectra
in aqueous solution. BODIPY-AP emits two-color emission upon selective excitation of the BODIPY
moiety, while only red emission is observed in BODIPY-MeAP. This aggregation-induced red emission
of BODIPY and AP dyads is due to the formation of an intermolecular CT complex between the BODIPY
and anthracene moieties, as visualized by the X-ray crystal analysis (Fig. 5). We consider the distinct
molecular assembly and photophysical characteristics of the BODIPY and AP dyads are induced by (1) the
moderate electron-deficiency and zwitterionic character of the BODIPY moiety that enables the CH-π
interaction with anthracene, and (2) the phenylene linker that prevents intramolecular photoinduced electron
transfer.
Taken together, the most critical factor that influences the aggregation pattern of the AP series is the
manner and extent to which the anthracene and fluorophores interact with each other. The positively
delocalized charge seemed to be the most important feature to strengthen the interaction between the
anthracene and fluorophore. As a preliminary screening, however, we confirmed that positively charged
indolinium and AP dyads connected by a vinylene group did not form J-aggregates (Fig. S18). This result
implies that the nature of the linkage between the AP group and fluorophore is also critical. Also, this result
is in accordance with a previous report in which molecular symmetry was an important factor for inducing
H-dimers, based on observations with coumarin and rhodamine.[34] When we compare BODIPY and AP
dyads to SiR-AP (Figs. S1 and S19), the interaction between the anthracene and BODIPY moieties is not
as strong as the complete π-π stacking of SiR-AP. Thus, this weaker intermolecular interaction in the
ground state does not lead to J-aggregation, but rather, to the intermolecular CT state.
Finally, the formation of the intermolecular CT state by self-assembly of the BODIPY and anthracene
moieties is found to enable the ISC process and realize AISG (Fig. 7). Concerning the X-ray
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crystallographic analysis results and previous studies on perpendicular BODIPY derivatives,[28–31] the
lattice-like molecular assembly with a dihedral angle (35.5°–59.2°) and spatially separated BODIPY and
anthracene may evolve spin-flipping during the decay of the intermolecular CT state. When the orbitals
engaged in CT excitation are located on perpendicular and separated D-A moieties, the electronic transition
is accompanied by a large change in orbital angular momentum, which must be compensated by a change
in the spin angular momentum. This phenomenon is known as spin-orbit charge-transfer ISC (SOCT-
ISC).[22,26] In addition, the low-lying triplet energy level of the BODIPY is another factor enabling AISG
among the other AP series (Supporting Table 4).
(a)
(b)
(c)
Fig. 7 (a) Chemical structures of the representative AP series and bird’s-eye views of the optimized
conformations. (b) Probable aggregation patterns in aqueous solution based on crystal structures (SiR-AP[12]
and BODIPY-MeAP) and a previous report (Fl-AP).[35] Expected locations of excitons are depicted with
ellipses. (c) Tentative decay processes of the AP series aggregates. J, H, and TBD represent J- and H-
aggregates, and the BODIPY moiety in the triplet excited state, respectively.
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Conclusions
In the present work, an AP series with fluorescein and BODIPY fluorophores was investigated to
generalize the aggregation patterns and develop a novel AISG agent. The AISG mechanism suggested in
this study takes advantage of the intermolecular CT state formed by a sophisticated self-assembly of the
1
AP series. As evidenced by a O2 fluorescence assay (Fig. 4d) and cell tests (Fig. 6), moreover, both
BODIPY-MeAP and BODIPY-AP exhibit good photocytotoxicity. We hope to emphasize that the
mechanism of AISG suggested here is clearly different from the current approaches of heavy-atom free 1O2
sensitizer that elongate the lifetime of the singlet excited state of photosensitizers by restricting rotational
motion.[36–38] Compared to the perpendicular BODIPY dimers[28,31] and push-pull-type BODIPY
1
derivatives,[29] BODIPY and AP dyads have a great advantage in that O2 generation can be regulated by
self-assembly formation in aqueous solution with an adequate drug delivery system (for instance, embedded
in the lipophilic region of the micelle which can be ruptured by light irradiation[39, 40]).
To conclude, this study clearly suggests the AP group is a potential molecular template upon which to
construct various functional assemblies of fluorophores. Since anthracene is a versatile building block for
singlet fission, triplet sensitization, photoinduced dimerization, exciplex emission, solid photoluminescence,
and 1O2 generation and detection, we believe there will be numerous possible molecular designs for the AP
series that will induce facile molecular self-assembly and promote the hidden functionality activated by
aggregation.
Acknowledgements
We thank Prof. Tsuyoshi Kawai (NAIST) and Dr. Dae Won Cho (Korea University) for fruitful discussion,
Dr. Akira Sugimoto (Osaka University) for advices in chemical synthesis and characterization. This work
was partly supported by a Grant-in-Aid for Scientific Research (Project 25220806, and others) from the
Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of the Japanese Government.
Experimental Section
Materials and basic optical measurements. All chemical reagents and solvents used for the synthesis
were purchased from Sigma-Aldrich Chemical Co., Tokyo Chemical Industries, Nacalai Tesque, and Wako
Pure Chemical Industries, and used without further purification. BODIPY-AP, Fl-AP, BODIPY-MeAP,
and BODIPY-Me (Fig. S1) were synthesized as described in the Supporting Information. Synthesized dyes
were stored in dimethyl sulfoxide (DMSO) at −20°C in the dark. Spectroscopic grade organic solvents and
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MilliQ water were used. Absorption and photoluminescence spectra were measured using Shimadzu UV-
3100 and Horiba FluoroMax-4 spectrometers, respectively. Continuous light irradiation of the sample was
carried out using a xenon light source (HAL-320, Asahi Spectra) with appropriate wavelength filters
(Brightline® 531/40, 488 nm EdgeBasicTM, Semrock) under magnetic stirring.
Syntheses and characterizations
Fl-AP (Scheme 1): A solution of 2,2′,4,4′-tetramethoxy-4″-anthracenyltrityl alcohol 1 (1 mmol, 557 mg)
in dry dichloromethane (20 mL) was cooled to −78°C. BBr3 (15 mL) was added dropwise to the solution.
The mixture was allowed to warm to room temperature gradually before quenching with distilled water (20
mL). The mixture was extracted 3 times with dichloromethane. The combined extracts were dried over
anhydrous sodium sulfate and concentrated. The residue was purified by chromatography using
EtOAc:methanol (from 1:1 to 100% methanol), affording an orange-red solid (87 mg, 19%). 1H-NMR (400
MHz, DMSO-d6) δ 8.70 (s, 1H), 8.16 (d, J = 8.2 Hz, 2H), 7.72–7.45 (m, 10H), 7.14 (d, J = 9.2 Hz, 2H),
13
6.48 (d, J = 9.6 Hz, 2H), 6.36–6.25 (m, 2H). C-NMR (176 MHz, DMSO-d6) δ 157.46, 150.54, 139.23,
136.03, 133.27, 131.55, 131.39, 130.80, 130.06, 128.96, 127.27, 126.67, 125.95, 111.68, 103.76, 79.62,
79.42, 79.23, 55.38. HRMS (ESI) = calculated for C33H22O3, m/z 464.1412; found, 464.1406.
General method for the preparation of BODIPY-AP and -MeAP (Scheme 2): To a flask flushed with
argon, the anthraphenylene boronic acid (1.0 mmol) and 8-chlorinated BODIPY 3 (1.0 mmol, 226 mg) were
mixed in THF (20 mL). Potassium carbonate (2.0 M, 20 mL) was added, and the mixture was stirred
magnetically. Then, tetrakis(triphenylphosphine)palladium(0) (0.015 mmol, 20 mg) was added to the
mixture. The reaction solution was heated under reflux overnight under argon. After cooling the reaction
solution to room temperature, the solvent was extracted 3 times with dichloromethane. The organic layer
was washed with brine and dried over anhydrous sodium sulfate. The organic solution was concentrated,
and the solid residue was purified by column chromatography (silica, 60–210 mesh; Kanto Kagaku, Tokyo,
Japan, hereinafter the same) using dichloromethane:n-hexane (from 8:1 to 2:1) as eluent to obtain an orange
solid.
BODIPY-AP: obtained as a dark orange solid (6% yield). 1H-NMR (400 MHz, CDCl3) δ 8.57 (s, 1H), 8.10
(d, J = 8.2 Hz, 2H), 8.02 (s, 2H), 7.82 (d, J = 8.2 Hz, 2H), 7.66 (dd, J = 19.2, 8.2 Hz, 4H), 7.55–7.40 (m,
13
4H), 7.19 (d, J = 4.1 Hz, 2H), 6.64 (d, J = 4.1 Hz, 2H). C-NMR (151 MHz, CDCl3) δ 147.17, 144.26,
141.92, 135.29, 134.99, 133.05, 131.75, 131.48, 131.33, 130.66, 129.99, 128.58, 127.33, 126.25, 125.86,
125.29, 118.68. HRMS (ESI) = calculated for C29H19BF2N2, m/z 444.1609; found, 444.1606. Anal. Calcd.
for C29H19BF2N2: C, 78.40; H, 4.31; N, 6.31. found: C, 78.62; H, 4.63; N, 6.35.
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BODIPY-MeAP: The reaction solvent (45 mL) was changed to toluene:water = 1:5. The product was
obtained as an orange solid (48% yield). 1H-NMR (600 MHz, CDCl3) δ 8.41 (d, J = 8.9 Hz, 2H), 8.02 (s,
2H), 7.80 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.56 (t, J = 8.2 Hz, 2H),
7.43 (d, J = 9.6 Hz, 2H), 7.19 (d, J = 4.1 Hz, 2H), 6.64 (d, J = 4.1 Hz, 2H), 3.21 (s, 3H). 13C-NMR (151
MHz, CDCl3) δ 144.31, 142.62, 135.19, 134.10, 133.01, 131.77, 130.54, 129.82, 128.21, 127.75, 127.58,
127.17, 125.27, 124.84, 123.10, 121.11, 118.73, 14.43. HRMS (ESI) = calculated for C30H21BF2N2, m/z
458.1766; found 458.1764.
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TOC
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