Design and Development of Axially Chiral Bis(naphthofuran) Luminogens as Fluorescent Probes for Cell Imaging

Article abstract of DOI:10.1002/chem.202004942

Designing chiral AIEgens without aggregation-induced emission (AIE)-active molecules externally tagged to the chiral scaffold remains a long-standing challenge for the scientific community. The inherent aggregation-caused quenching phenomenon associated w

Full text of DOI:10.1002/chem.202004942

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&
Fluorescent Probes
Design and Development of Axially Chiral Bis(naphthofuran)
Luminogens as Fluorescent Probes for Cell Imaging
Valmik P. Jejurkar,[a] Gauravi Yashwantrao,[a] Pawan Kumar,[b] Suditi Neekhra,[c]
Parimal J. Maliekal,[d] Purav Badani,[d] Rohit Srivastava,[c] and Satyajit Saha*[a]
Abstract: Designing chiral AIEgens without aggregation-in-
duced emission (AIE)-active molecules externally tagged to
the chiral scaffold remains a long-standing challenge for the
scientific community. The inherent aggregation-caused
quenching phenomenon associated with the axially chiral
(R)-[1,1’-binaphthalene]-2,2’-diol ((R)-BINOL) scaffold, togeth-
er with its marginal Stokes shift, limits its application as a
chiral AIE-active material. Here, in our effort to design chiral
luminogens, we have developed a design strategy in which
2-substituted furans, when appropriately fused with the
BINOL scaffold, will generate solid-state emissive materials
with high thermal and photostability as well as colour-tuna-
ble properties. The excellent biocompatibility, together with
the high fluorescence quantum yield and large Stokes shift,
of one of the luminogens stimulated us to investigate its
cell-imaging potential. The luminogen was observed to be
well internalised and uniformly dispersed within the cyto-
plasm of MDA-MB-231 cancer cells, showing high fluores-
cence intensity.
Introduction
the advent of the phenomenon known as aggregation-induced
emission (AIE), the research on AIE luminogens (AIEgens) has
reached celestial heights.
The breakthrough in the discovery of luminescent materials
has unleashed a number of opportunities for research and de-
velopment in the area of light-emitting devices.[1,2] Understand-
ing the concept of luminescence has allowed the scientific
community to control the light-emitting properties of mole-
cules as well as propound innovative solutions in the field of
optical materials.[3–7] However, although fluorescent materials
have diverse applications in areas ranging from optoelectronic
devices and sensors to biological sciences, they often experi-
ence the iniquitous aggregation-caused quenching (ACQ)
effect.[8,9] These molecules, although highly fluorescent in the
solution state, become non-emissive in concentrated or aggre-
gated states, thereby limiting their applications. However, with
AIEgens are mostly characterised by rotor-like structures,
and the constrained motion of the rotors has been identified
as one of the major causes of AIE. However, aggregation alone
does not trigger fluorescence. The highly viscous microenvir-
onment as well as non-covalent supramolecular interactions
also contribute to trigger strong fluorescent emission.[10,11] The
AIE phenomenon has enhanced the number of organic fluoro-
phores, and significant endeavour has been made in the pur-
suit of novel AIEgens for optoelectronic materials.[12–16]
Among the plethora of AIEgens that have been developed,
chiral AIEgens specifically have received tremendous attention
owing to their ability to enantiodiscriminate chiral ana-
lytes.[17–28] AIE fluorophores are normally accessed by two well-
recognised approaches, either by structurally tuning the exist-
ing AIEgens or by appending AIEgenic molecules to ACQ lumi-
nophores. Analogously, chiral AIEgens have also been success-
fully synthesised by fusing well-known achiral AIEgens to chiral
scaffolds such as sugars, amino acids or axially chiral [1,1’-bi-
naphthalene]-2,2’-diol (BINOL; Figure 1).[17–28] Nevertheless,
design strategies that employ amino acids and sugars lead to
AIEgens with poor thermal stability that lack scope for wave-
length tunability. BINOL, vastly explored in asymmetric cataly-
sis[29–33] and bearing a tremendous resemblance to the rotor-
like structures of typical AIEgens such as tetraphenylethene
(TPE) or tetraphenylsiloles, has been used to design chiral lumi-
nogens through the appendage of well-known AIEgens at ap-
propriate positions of BINOL (Figure 1).[34–36] However, these ex-
isting design strategies are mostly limited to scaffolds such as
TPE or tetraphenylsiloles. The dearth of protocols to generate
[a] V. P. Jejurkar, G. Yashwantrao, Dr. S. Saha
Department of Speciality Chemicals Technology
Institute of Chemical Technology (ICT)
Mumbai 400019 (India)
E-mail: ss.saha@ictmumbai.edu.in
[b] P. Kumar
Department of Biotechnology, BIT Mesra
Ranchi (India)
[c] S. Neekhra, Prof. R. Srivastava
Department of Biosciences and Bioengineering
IIT Bombay
Bombay (India)
[d] P. J. Maliekal, Dr. P. Badani
Department of Chemistry
University of Mumbai
Mumbai (India)
Supporting information and the ORCID identification number(s) for the
author(s) of this article can be found under:
https://doi.org/10.1002/chem.202004942.
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Figure 1. Rational design of chiral AIEgens.
Figure 2. Structures of the designed AIEgens S1–S4.
chiral AIEgens without any AIEgens (e.g., TPE or tetraphenylsi-
lole) externally tagged to the chiral scaffold remains a long-
standing challenge. Therefore, modifying (R)-BINOL to design
an AIE probe without any externally appended luminogenic
material would be highly desirable to provide an alternative
strategy for the development of chiral AIE materials possessing
high thermal stability as well as colour tunability for diverse
applications. Yet, the molecular design of chiral AIEgens based
on the above-mentioned concept is highly challenging be-
cause of the inherent ACQ phenomenon associated with the
(R)-BINOL scaffold, which makes them unsuitable for use as ef-
ficient AIEgens and hence limits their applications.
the key step to access all four fluorophores in reasonably good
yields from commercially available starting materials. This easy
synthetic protocol not only allowed access to novel chiral AIE-
active molecules, but also established a new direction in the
design of next-generation chiral luminogens with easy synthet-
ic accessibility, high thermal stability and scope for wavelength
tunability.
Thus, the crystallographic packing of luminogens S1–S4,
supported by DFT calculations, their photophysical, electro-
chemical, thermal and AIE properties, together with their elec-
tronic circular dichroism (CD) spectra, are presented herein.
The results demonstrate that the above strategy offers an ef-
fective approach to the design of solid-state luminescent ma-
terials with a remarkable AIE effect and significantly large
Stokes shift.
In our effort to design luminogens, we envisioned straight-
forward design criteria that accentuate the constrained rota-
tion of the freely rotatable groups in the molecule through
augmented intermolecular interactions as well as the disrup-
tion of molecular stacking in the solid state.[37] With this per-
spective, we considered furans that are non-emissive but if ap-
propriately fused to the BINOL scaffold will generate chiral AIE-
gens with extended conjugation. The inbuilt molecular distor-
tion due to the axial chirality of (R)-BINOL and the presence of
electron-deficient phenacyl derivatives (-COPh/CPhC(CN)2) at-
tached to the furyl ring are likely to disrupt the p–p interac-
tions and restrict internal rotations in the aggregated state ac-
companied by interrupted twisted intramolecular charge trans-
fer (TICT). The inherent molecular distortion will purposefully
restrict molecular stacking by the large-space hindering group,
thereby endowing the fluorophores with enhanced emissive
properties in the aggregated state (Figure 1).
Among the several established methods to acquire chiral in-
formation, circular dichroism (CD) is one of the most common-
ly used techniques and relies on the ground-state electronic
conjugation of the chiral molecule. The CD spectra confirmed
the transmission of the absolute stereochemistry of (R)-BINOL
to both S3 and S4, thereby converting them into chiral lumi-
nogens. However, chirality variation in the aggregated state
often results in the obliteration of circular dichroism, and has
frequently been observed in BINOL derivatives, which impedes
their application in the condensed state.[38] Interestingly,
straightforward functional group transformation to incorporate
the dicyanovinylidene group resulted in the reversal of the CD
behaviour of S4 in the aggregated state as compared with S3.
Although the axially chiral BINOL has been successfully em-
ployed as a scaffold to build several fluorescent probes, poor
water solubility and intrinsic p–p-stacking interactions along
with the appearance of an emission band in the UV region due
to a small Stokes shift have strictly limited their application as
bioprobes due to strong biological autofluorescence interfer-
ence.[39] However, the unique AIE properties exhibited by S4,
Based on this rationale, in this study we have designed and
synthesised four molecules (S1–S4; Figure ) to evaluate the in-
fluence of benzo- and naphthofuran rings possessing electron-
withdrawing phenacyl derivatives (-COPh/CPhC(CN)2) as well as
the influence of fusing the furan ring to the axially chiral (R)-
BINOL on AIE in the aggregated state (Figure 1).
Compounds S1 and S2 were model compounds designed to
compare the AIEgenic properties of achiral (S1 and S2) and
chiral luminogens (S3 and S4). The initial goal of our research
was to fuse the furan unit to phenol and naphthol rings to
obtain S1 and S2, respectively, and to derivatise the naphthol
core of (R)-BINOL with furan to generate S3 and S4. The
straightforward base-catalysed cyclocondensation of the ap-
propriate phenol derivatives with 2-bromoacetophenone was
which possesses a high fluorescence quantum yield (Fagg
=
4.34%) and large Stokes shift (180 nm), coupled with excellent
photo- and thermal stability as well as biocompatibility,
prompted us to explore the potential of S4 as a fluorescent bi-
oprobe for cell imaging.
Imaging studies revealed that S4 was well internalised
within MDA-MB-231 cancer cells and uniformly dispersed in
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the cytoplasm, showing high fluorescence intensity. Therefore,
the above rational design of fusing non-luminescent furans
onto an aromatic core could be a big boon for the develop-
ment of AIE-active luminogens in the future.
S3. Subsequent Knoevenagel condensation of S3 by heating
with malononitrile in pyridine at reflux afforded S4.
1
All the molecules were characterised by H and 13C NMR, IR,
and mass spectrometric techniques. The synthetic procedures
and spectral characterisation data of the luminogens S1–S4
are provided in the Experimental Section as well as in the Sup-
porting Information.
Results and Discussion
Synthesis and characterisation
X-ray crystallographic analysis
The AIEgens S1–S4, shown in Figure 2, were readily synthes-
ised in good yields following the methodology highlighted in
Scheme 1. The key steps were the base-catalysed substitution
reaction, followed by cyclocondensation to fuse the 2-phena-
cylfuran component onto the benzene or naphthalene ring to
construct benzo- and naphthofuran skeletons, respectively.
Thus, S1 and S2 were synthesised by treating 2-bromoaceto-
phenone (2) with salicylaldehyde (1a) or 2-hydroxynaphthalde-
hyde (1b), respectively, by base-catalysed substitution, fol-
lowed by cyclocondensation to generate the corresponding
phenacyl derivatives 3 and 4. Subsequent pyridine-mediated
Knoevenagel condensation of 3 and 4 with malononitrile fur-
nished S1 and S2, respectively. Similarly, S3 and S4 were syn-
thesised by the methylation of (R)-BINOL followed by formyla-
tion with nBuLi/N,N-dimethylformamide (DMF) to generate (R)-
To gain insights into the three-dimensional orientation of the
molecules and their crystal packing, interplanar distances and
torsion angles, we successfully grew single crystals of S1–S3
by slow evaporation from CHCl3.
The fluorophores S1 and S2 crystallised in the monoclinic
system and S3 in the triclinic system with space groups P21/c,
P21/n and P21, respectively. The X-ray crystal structures of S1–
S3 are presented in Figure 3.
The single-crystal structures of both S1 and S2 present a
twisted orientation. The phenyl ring has a non-coplanar orien-
tation with respect to both the benzofuran and naphthofuran
ring systems, making a dihedral angle of 52.95 and 52.268, re-
spectively. Images of the crystal packing in both S1 and S2 are
shown in Figures S13–S16 in the Supporting Information. In
S1, the molecules are partially stacked with two phenyl rings
of neighbouring CPhC(CN)2 groups facing each other with an
interplanar distance of 3.472 Š between two molecules. The
distinct deformation from planarity in the molecule is due to
the installation of the bulky electron-deficient -COPh group, as
manifested in the X-ray crystal structure, resulting in the mini-
2,2’-dimethoxy-[1,1’-binaphthalene]-3,3’-dicarbaldehyde
(7).
Subsequent demethylation with BBr3 in dichloromethane
(DCM) generated (R)-2,2’-dihydroxy-[1,1’-binaphthalene]-3,3’-di-
carbaldehyde (8). Base-catalysed substitution of 8 with 2-bro-
moacetophenone (2), followed by cyclocondensation furnished
Scheme 1. Synthesis of AIEgens S1–S4 and the appearance of the powdered forms of S1–S4 in daylight and under short-UV (254 nm) and long-UV (365 nm)
irradiation.
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Figure 3. Single-crystal X-ray crystallographic representation of (a) S1, (b) S2 and (c,d) S3, and the crystal packing of (e) S1, (f) S2 and (g) S3, all identified by
XRD analysis.
misation of p–p stacking. A similar arrangement was observed
in the crystal packing of S2. The dihedral angle between the
phenyl ring and the naphthofuran ring is 52.268, which ac-
counts for the non-existence of intermolecular stacking interac-
tions within the crystal lattice. The naphthofuran moiety of S2
is oriented in such a way that the molecules barely overlap
each other in the crystal packing, resulting in a linear distance
between the two molecules in the range 2.83–3.73 Š.
tice of S3 are 3.534 and 2.399 Š, which suggests disruption of
p–p-stacking interactions, resulting in the enhancement of
emission intensity in the aggregated state.
Photophysical, electrochemical and thermal properties
The photophysical properties of the molecules S1–S4 were
evaluated by preparing a uniform 1 mm solution of each of the
fluorophores in acetone. The UV/Vis spectra depicted in
Figure 4 reveal that the absorption maxima of the compounds
S1–S4 range from 337 to 416 nm and can be attributed to p–
p* electronic transitions. Compared with S1, the absorption
maximum of S2 is bathochromically shifted, which suggests
strong intramolecular charge transfer within the molecule be-
cause of the extension of the fused ring system by one phenyl
ring, resulting in a larger p-conjugated system than in S1.[40,41]
A similar redshifted absorption maximum was also observed
for S4 as compared with S3.
The photoluminescence (PL) spectra of compounds S1--S4
in acetone solution are also presented in Figure 4. The spectra
exhibit emission maxima ranging from 410 to 561 nm, with
significantly high Stokes shifts of 152 and 180 nm for S3 and
S4, respectively, which can be attributed to intramolecular
charge transfer due to the donor–acceptor nature of the mole-
cules, as is evidenced from the calculated HOMO–LUMO
energy gaps (see Figure 7). It can also be noted that insertion
The crystal packing of S3 also confirms the absence of any
intermolecular p–p-stacking interactions, which is a conse-
quence of the twisted conformation of S3, originating from
the steric hindrance offered by the strong electron-withdraw-
ing phenacyl group as well as the axial chirality of the (R)-
BINOL scaffold with a dihedral angle of 102.58 between the
two naphthofuran moieties, which form a scissor-like geome-
try. The bulky aromatic groups successfully instigate a twist in
the molecular conformation, resulting in a torsion angle of
54.98 between the central BINOL plane and the -COPh group.
As observed in Figure 3g, the naphthofuran rings are nearly
orthogonal to each other, which impedes close p–p-stacking
interactions between neighbouring molecules. Multiple short
contacts, observed within the crystal lattice, are also beneficial
for rigidifying the network and restricting intramolecular rota-
tion, thereby greatly restraining non-radiative pathways and
thus avoiding the quenching of fluorescence in the solid or ag-
gregated state. The interplanar distances within the crystal lat-
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porting Information). The results revealed a normal
positive solvatochromic effect for S1, S3 and S4 (see
Table S1). Thus, in polar solvents, the formation of
TICT states is favourable for these compounds, and
increasing the solvent polarity promotes the intramo-
lecular charge-transfer (ICT) character of the excited
states of S1, S3 and S4. However, the bathochromic
shift of the absorption maximum displayed by S2 in
non-polar solvent can be attributed to probe–probe
interactions. The extended conjugation and skew ar-
rangement of the aromatic systems seem to be influ-
enced by the peri hydrogen atoms of the naphtha-
lene ring, causing such abnormal behaviour.[42]
Figure 4. Normalised absorption (solid lines) and emission spectra (dotted lines) of the
fluorophores S1–S4 and the corresponding absorption and emission wavelengths and
Stokes shifts. [a] labs =absorption maxima wavelengths. [b] lem =emission maxima wave-
lengths. The scan step width used for PL measurement was 0.5 nm.
of the powerful electron-accepting -C(CN)2 group into S4 re-
sulted in a bathochromically shifted emission spectrum com-
Cyclic voltammetry and DFT calculations
pared with S3, effectively shifting the bluish-green emission of
S3 to the reddish-orange emission of S4 in the solid state,
thereby generating colour-tunable AIEgens.
Cyclic voltammetry and DFT calculations were performed to
evaluate the electrochemical properties of the fluorophores
S1–S4 and the parameters obtained are presented in Figures 6
and 7, respectively. The redox potentials of S1, S2, S3 and S4,
which correspond to their HOMO energy levels, were deter-
mined to be À6.45, À6.39, À6.30 and À6.42 eV versus the
normal hydrogen electrode (NHE), respectively, and the corre-
sponding HOMO–LUMO bandgaps are 3.36, 2.99, 3.68 and
3.26 eV, respectively (Figure 6).
Although S2 and S4 have a similar structural framework, the
chirality enforced in the latter molecule leads to an apparent
difference in their emission intensity as well as their Stokes
shift.
The thermal stabilities of the fluorophores S1–S4 were as-
sessed by thermogravimetric analysis (TGA) and differential
scanning calorimetry (DSC). Excitingly, very high thermal stabili-
ties were observed for compounds S3 and S4 compared with
S1 and S2 (Figure 5), which is a result of the structurally robust
(R)-BINOL skeleton.
To better comprehend the electronic transitions as well as to
evaluate the theoretical bandgaps of the fluorophores S1--S4,
DFT calculations were performed at the DFT/B3LYP level of
theory using the Gaussian 09 suite of programs.[43] Energy mini-
misation of the structures was carried out by using the 6-31 G
basis set. Finally, the single-point energies of these optimised
structures were calculated by using the 6-311G+(d,p) basis
set. Also, the effect of solvent was accounted for by using a
conductor-like polarisable continuum model implicit solvent, in
this case dichloromethane. The cartesian coordinates along
with the optimised energy-minimised structures of S1–S4 are
provided in Figure 7.
The thermal degradation temperature (Td) indicates less than
2 and 8% degradation for S3 and S4 with 75 and 43% weight
loss observed at around 475 and 4468C, respectively. Although
S3 exhibited melting temperatures (Tm) of 265.89 and
464.708C in the first heating scan, no endo- or exothermic re-
actions were observed for S4, which implies exceptional ther-
mal stability of the molecule with apparently no glass transi-
tion, crystallisation or melting taking place.
The DFT calculations revealed that for the fluorophores S1
and S2, the electron distribution in the HOMO is centred on
the benzo- and naphthofuran rings. For S1, the electrons are
delocalised throughout the molecule in the LUMO. However, in
Solvatochromic properties of S1–S4
The high Stokes shifts of the fluorophores prompted us to in-
vestigate the effect of solvent polarity on the emission maxima
of compounds S1–S4. The PL spectra of compounds S1–S4
were recorded in solvents with graded polarity (toluene, THF,
acetone, DMSO and DMF; see Figures S1 and S2 in the Sup-
Figure 6. HOMO–LUMO energy gaps of S1–S4 calculated experimentally
Figure 5. TGA-DSC thermograms of S1–S4.
from cyclic voltammetry data.
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Table 1. Theoretically and experimentally calculated HOMO–LUMO
energy gaps of S1–S4.
Compd
EHOMO
[a.u.]
Theoretical
ELUMO
[a.u.]
Experimental
EHL
[eV]
EHL
[a.u.]
[eV]
[eV]
[eV]
S1
S2
S3
S4
À0.246
À6.671
À0.231
À6.306
À0.221
À6.015
À0.223
À6.081
À0.124
À3.379
À0.128
À3.500
À0.104
À2.846
À0.126
À3.430
0.122
(3.371)
0.103
(2.806)
0.117
(3.168)
0.097
(2.650)
3.36
2.99
3.68
3.26
tures with different water contents (0–90%), and the recorded
PL spectra are displayed in Figure 8.[45]
AIEgen S1 displayed mild photoluminescence in pure ace-
tone, which could be because of the non-irradiative decay
pathway through a strong intramolecular charge-transfer pro-
cess as a result of the uninterrupted rotation of the phenyl
rings of the -CPhC(CN)2 group. However, sharp enhancement
of the photoluminescence intensity was observed when the
water fraction (fw) was increased from 10 to 40%. The en-
hancement in emission intensity is possibly due to the in-
creased solvent polarity. Because the fluorophore possesses a
larger dipole moment in the excited state (mE) than in the
ground state (mG), on excitation, the solvent dipoles have a
chance to reorient or relax around mE, which lowers the excit-
ed-state energy. As the solvent polarity gradually increased,
the effect became more prominent, resulting in emission at
longer wavelengths.[46]
Figure 7. (a) Frontier molecular orbital diagrams of S1–S4. The energy levels
were calculated in the gas phase by using DFT. The isosurface values of S1--
S4 are 0.022 a.u. (b) Energy-minimised structures of S1--S4.
the LUMO of S2, the electrons have shifted from the naphthyl
ring towards the benzofuran ring and -CPhC(CN)2. The distribu-
tion of electrons in the HOMO is quite similar for both S3 and
S4 and is localised on the BINOL moiety. However, the elec-
trons are distributed quite differently in the LUMOs of S3 and
S4. The electrons are homogeneously distributed over the
entire skeleton in the LUMO of S3, whereas in the LUMO of S4,
the electrons are localised on one ring system of (R)-BINOL.
This undoubtedly suggests electron transfer within S1–S4. As
predicted by the DFT calculations, the bandgaps for S1 and S2
are 3.371 and 2.806 eV, whereas those for S3 and S4 are 3.168
and 2.650 eV, respectively (Table 1). The decrease in the bandg-
ap as we move from S3 to S4 is possibly due to the presence
of the electron-withdrawing cyanovinylidene group, which is
in accord with the experimentally derived results. A similar re-
duction in both the theoretically as well as experimentally cal-
culated bandgaps is also evident as we move from S1 to S2,
which is possibly due to greater electron delocalisation within
the naphthalene ring. The significant shift of the electron
cloud upon excitation indicates the occurrence of TICT in the
AIEgens, resulting in a larger Stokes shift. However, there is a
slight discrepancy between the calculated and experimentally
observed bandgaps, which is probably due to the DFT calcula-
tions being performed in the gas phase.[44]
However, beyond 40% H2O, a sharp decrease in the lumines-
cence intensity was observed, which can be accounted for by
an intense ICT process. Careful evaluation of the X-ray crystal
structure revealed that although there is an inherent twist in
the molecule, the facially stacked phenyl rings separated by an
interplanar distance of 3.42 Š could be the reason for the pos-
sible ACQ effect.
However, S2 represents a perfect example of an aggrega-
tion-induced emissive luminogen, with the emission intensity
gradually intensifying with increasing fraction of water, becom-
ing a maximum at fw =90% H2O. The difference in lumines-
cence behaviour between S1 and S2 could be surmised by as-
sessing the crystal structures of S1 and S2 represented in
Figure 3. The analysis revealed that the naphthyl group is ben-
eficial for avoiding intermolecular stacking. Additionally, multi-
ple short intermolecular interactions were found throughout
the crystal structure of S2, which could help rigidify the molec-
ular conformation, thereby restraining the non-radiative path-
ways and enhancing the emission in the aggregated state. Fur-
thermore, upon severe aggregation, the rotational motions of
the phenyl rotors are also restricted, enhancing even further
the induced luminescence in the aggregated state.
Aggregation-induced emission properties of S1–S4
The intense emission enhancement observed in thin films of
the molecules encouraged us to explore their PL properties in
the aggregated state. Thus, the AIE features of the fluores-
cence probes S1–S4 were investigated in acetone/water mix-
In the case of fluorophore S3, the luminescence intensity in-
creased until 20% H2O and then decreased until 50% H2O.
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ed state. Further addition of water resulted in stronger emis-
sion until fw reached 90%. A 4.2-fold enhancement in the emis-
sion intensity was observed for the highest aggregated state
of S3 at 90% H2O compared with the pure acetone solution of
S3.
For luminogen S4, initially, a very high photoluminescence
intensity was observed, which then showed a dramatic drop in
the luminescence intensity followed by a gradual decrease
until fw equalled 50% H2O. The decrease in the emission inten-
sity with a concomitant bathochromic shift of the emission
peaks on increasing the solvent polarity could be because of
the initiation of the ICT process, resulting in the quenching of
the emission intensity through a non-radiative decay pathway.
The addition of water beyond fw =50% resulted in the rapid
enhancement of the photoluminescence intensity until reach-
ing a maximum at fw =70%, beyond which there was a slight
drop in the emission intensity until fw =90% H2O. The higher
solvent polarity resulted in the formation of the aggregated
state, which does not allow free rotation of the rotors, result-
ing in the enhanced emission intensity. Interestingly, no
change in the emission wavelength was observed beyond fw =
50% H2O.
A comparison of the AIE behaviour of S1--S4 revealed that
the minor structural variations in S1--S4 could explain the dif-
ferences in the AIE trends.
Abnormal AIE behaviour was observed for S1 as compared
with S2. The relatively small S1, in comparison with S2, did not
show substantial emission enhancement in the aggregated
state, whereas the naphthyl group in S2 was instrumental in
restraining the non-radiative pathways with the enhancement
of AIE. Moreover, the longer-wavelength emission of S2 is pos-
sibly due to the extension of the aromatic ring system, result-
ing in greater electron delocalisation. By contrast to S1 and S2,
on increasing the water fraction, S3 demonstrated ON/OFF/ON
AIE behaviour, with a bathochromic shift in emission that cor-
responds to the near coplanar orientation of the naphthofuran
rings in the axially chiral (R)-BINOL molecule. Although the lu-
minogens S3 and S4 have structural similarities, the introduc-
tion of the dicyanovinylidene group into S4 resulted in marked
differences in their AIE behaviour. The introduction of the di-
cyanovinylidene unit generated sufficient steric hindrance to
enhance the twist in the molecular conformation of S4. There-
fore, the sterically induced enhanced non-coplanarity and twist
in S4 as compared with S3 contributes to the enhanced TICT
effect, which led to redshifted emission. With increasing water
fraction, ACQ was predominant until fw =50%; however, a
steady enhancement of the emission intensity was observed
with further increasing water fraction, which encumbered the
rotation of the phenyl units and reduced the non-radiative
transition, ultimately enhancing the PL intensity.
Figure 8. AIE behaviour of the luminogens S1–S4 as evidenced by their PL
spectra (excitation wavelength=370, 416, 337, 381 nm for S1–S4, respec-
tively; concentration=1 mm in a mixture of acetone and 0–99% water) and
plots of emission intensity as a function of water content in the solvent. The
inserts display the PL of the highest and lowest aggregated states of S3 and
S4.
TICT through a non-radiative decay pathway is probably the
reason for the gradual quenching of the emission intensity
upon increasing the solvent polarity, and for the bathochromi-
cally shifted emission peak. The solvatochromic phenomenon
demonstrated here can be attributed to the donor–acceptor
(D–A) nature of the luminogen S3. The addition of water
beyond fw =70% reduced the solvating power of the aqueous
mixture to such an extent that luminogen S3 was unable to
dissolve, thereby initiating the process of aggregate formation.
The nanoaggregates possess an interior polarity higher than
the external surface polarity.[37,47] Therefore, the aggregates are
transformed into an aggregation-induced locally excited state
with a strained structure that is slightly destabilised energeti-
cally due to the low environmental polarity. This destabilisation
results in the widening of the HOMO–LUMO energy gap,
which causes the blueshifted emission (479 to 461 nm) ob-
served for S3. Moreover, severe aggregation resulted in re-
stricted intramolecular rotation of the phenyl ring and sup-
pressed the TICT-inducing enhanced emission in the aggregat-
The fluorescence quantum yields (F) of S1--S4 were subse-
quently measured in pure acetone as well as in acetone/H2O,
with fw =90% H2O, by a comparison method, taking quinine
sulfate as the standard (F=0.54 in 0.5 mLLÀ1 H2SO4). The
quantum yields of S1--S4 are presented in Table 2. The results
demonstrate that the quantum yields of the fluorophores and
the fluorescence efficiencies are directly correlated.
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The CD spectra of (R)-[9,9’-binaphtho[2,3-b]furan]-2,2’-diylbi-
s(phenylmethanone) (S3) and (R)-2,2’-([9,9’-binaphtho[2,3-
b]furan]-2,2’-diylbis(phenylmethylidene))dimalononitrile (S4) in
acetone (concentration=10À4 m) confirmed that after fusing
the furan ring to (R)-BINOL, both S3 and S4 retained its chirali-
ty (Figure 10), with the absolute stereochemistry being trans-
mitted from the (R)-BINOL to the AIEgens S3 and S4.
Table 2. Quantum yields of S1–S4 in solution and the aggregated state.[a]
Compd
Solution state
Aggregated state
In pure acetone
In acetone/H2O (10:90)
[b]
[c]
lem [nm]
Fsol [%]
lem [nm]
Fagg [%]
S1
S2
S3
S4
410
0.084
0.073
5.817
3.753
467
483.5
496
0.028
0.423
6.229
4.341
475.5
489.5
561
564
[a] Quinine sulfate in 0.1m H2SO4 was used as standard (F=0.54).
[b] Fsol =fluorescence quantum yield in solution. [c] Fagg =fluorescence
quantum yield in the aggregated state.
Contrary to the low quantum yields (almost 0.2%)[48] ob-
served for BINOL derivatives, the present strategy provides an
effective method for designing fluorophores possessing large
Stokes shifts that could effectively overcome imaging interfer-
ence and therefore be used as bioprobes for cell imaging.
It is reasoned that the enhancement of emission intensity is
induced by the formation of aggregates, which is confirmed
by the SEM images of the non-aggregated S3 and the aggre-
gate of S3 formed in 90% water/acetone, and by the observ-
ance of the Tyndall effect. The SEM images clearly distinguish
the non-aggregated and aggregated forms of the fluorophore
S3, supported by the observance of the Tyndall effect, an attri-
bute of aggregate formation (Figure 9a–c). A similar Tyndall
effect was also noticed when laser light was passed through
aggregates of the other fluorophores S1, S2 and S4 (Fig-
ure 9d–g).
Figure 10. CD spectra of S3 and S4 in acetone. The inset shows the UV/Vis
spectra of S3 and S4.
The CD wavelength maxima obtained from the CD spectra
of S3 and S4 at 411 and 397 nm, respectively, are more red-
shifted than that of (R)-BINOL (320 nm). The molar ellipticity
([q]) values of S3 and S4 at 411 and 397 nm are 244010 and
5927880 mdegmLmmolÀ1 mmÀ1, respectively. These CD data
indicate that the Knoevenagel condensation of S3 with malo-
nonitrile affects the chirality more than the fusion of the furan
ring to the (R)-BINOL skeleton. To evaluate the unique phe-
nomenon of the aggregation-induced CD effect, we recorded
the CD spectra of S3 and S4 in acetone/H2O mixtures with dif-
ferent fw (water fraction ranging from 0 to 99%).
Interestingly, the CD spectra of the AIEgens S3 and S4 were
redshifted by about 21 and 10 nm, respectively, with increasing
water fraction (fw) from 0 to 99% in the acetone/H2O mixture
(Figure 11).
Figure 9. SEM images of (a) the non-aggregated state and (b,c) the aggre-
gated state of S3. (d–g) Tyndall effect observed for (d) S1, (e) S2, (f) S3 and
(g) S4 in their highest aggregated state (at fw =40, 90, 90 and 70% H2O re-
spectively).
Figure 11. CD spectra of S3 and S4 in acetone/water mixtures with different
fw (concentration=0.00355 gLÀ1).
The AIEgen S3 displayed enhancement of the CD signal with
the addition of 10% H2O, followed by a sharp annihilation of
the CD signals, which continued until fw =70% H2O. The addi-
tion of water beyond 70% resulted in a slight enhancement of
the CD signal together with a redshift of the wavelength maxi-
mum, which thereafter remained constant until fw =99% H2O.
However, S4 demonstrated a continuous enhancement of the
Circular dichroism spectra of S3 and S4
Next, we explored whether the fused furans in the (R)-BINOL
scaffold could bestow the AIEgens with chirality. Thus, we ex-
amined the circular dichroism spectra of the prepared AIEgens
S3 and S4 to gain insights into their absolute configurations.
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CD signals up to fw =90% H2O addition, with a marginal fall of
the CD signal observed at fw =99% H2O addition. This CD anni-
hilation and enhancement are represented by a graphical plot
of the intensity of the circular dichroism signal versus fw for S3
and S4 in Figure 12.
Figure 13. Energy-minimised structures of the luminogens S3 and S4.
the precise control of circular dichroism in the aggregated
state remains a formidable challenge.[51,52]
Cell imaging
Figure 12. Plots of the relative molar ellipticity of S3 (@346 nm) and S4
(@396 nm) versus fw. [q]=molar ellipticity, [q]0 =molar ellipticity at fw =0%.
The unique AIE properties exhibited by these chiral lumino-
gens are attractive features that render them as potential fluo-
rescent bioprobes for cell imaging. However, the problems of
solubility and cell internalisation as well as the inherent ACQ of
BINOL have limited the use of BINOL-based scaffolds for such
applications. However, the high fluorescence quantum yield
and large Stokes shift of S4, known not to show biological au-
tofluorescence, provoked us to evaluate the efficacy of S4 as a
bioprobe for cell imaging. Although AIEgens are potentially
useful agents for bioimaging, they must be biocompatible for
any potential biological application. Hence, the in vitro bio-
compatibility of S4 was evaluated in mouse fibroblast cells
L929.[49] The details of the experimental procedures are provid-
ed in the Supporting Information. Resorufin, a blue-coloured
non-fluorescent dye, was used to quantify the percentage cell
viability and it was found that S4 is highly biocompatible with
these cells at concentrations in the range 10–100 mgmLÀ1
(with ca. 100% viability; Figure 14; negative control: cells+
media only; positive control: cells+Triton-X+media; Triton-X:
non-ionic surfactant that is used for cell lysis).[53–55]
Interestingly, the luminogens S3 and S4 displayed dissimilar
aggregation-induced CD signals. As already reported in the lit-
erature,[49,50] the reduction of the CD signal is generally a con-
sequence of the decrease in the torsion angle between the ad-
jacent naphthalene rings of (R)-BINOL. Therefore, it is reasoned
that the corresponding torsion angle in S3 has reduced in the
aggregated state, observed beyond 40% water addition. How-
ever, the sharp spike observed in the CD spectrum with 10%
water could be a result of conformational unlocking, causing a
widening of the torsion angle, which then progressively lowers
as the extent of aggregation is enhanced, causing a steep fall
in the CD signal.
However, for S4, a non-bonding conformational locking aris-
ing from the incorporation of the dicyanovinylidene group
causes severe steric hindrance, resulting in the enhancement
of the torsion angle and an increase in the intensity of the CD
signal.[49,50] The increase in the torsion angle due to severe
steric strain is explained as follows: owing to the larger size of
the -C=C(CN)2 group in compound S4, as compared with -C=O
in S3, the phenyl group at the b position with respect to -CN
of the vinyl system is freer to adopt a coplanar disposition.
Thus, the close proximity of the -CN groups to the phenyl ring
allows a stronger interaction than is the case for -C=O in S3,
thereby enhancing the torsion angle.[49,50] The overlay of the
energy-minimised structures of the luminogens S3 and S4
shows a greater dihedral angle between the naphthyl rings of
the (R)-BINOL in S4 arising from steric hindrance (Figure 13).
Thereby, a small structural modification can result in the inver-
sion of aggregation-induced CD behaviour in the designed
molecules, and this provides us with a handle to tune the chi-
roptical properties of the molecules. The variation in the tor-
sion angle between the two naphthyl rings is responsible for
the abnormal aggregation-annihilated CD (AACD), which im-
pedes the observation of the CD phenomenon in the con-
densed state. Although a few attractive approaches have been
reported in the literature to surpass the AACD effect in BINOL,
After the confirmation of cellular uptake, a cellular localisa-
tion study was carried out on L929 cells by using confocal
laser imaging to determine the extent of internalisation in the
Figure 14. Histogram showing the viability of L929 cells with compound S4
at concentrations ranging from 10 to 100 mgmLÀ1. NC=negative control,
PC=positive control.
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cell and the effect on cell morphology.[56] The cellular uptake of
S4 in MD-MB-231 cancer cells was analysed by seeding the
cancer cells on sterile coverslips in 12-well plates (50000 cells
per well) and incubating for 24 h. Next, 25 mgmLÀ1 S4 was
added to the well plates and incubation performed for a fur-
ther 24 h. The excess material in the cells was washed gently
with phosphate-buffered saline (PBS), and then 4% paraformal-
dehyde was used to fix the cells for 15 min, followed by wash-
labels the cytoplasm over the nucleus with a high mean fluo-
rescence intensity as well as possesses excellent biocompatibil-
ity over a wide range of concentrations and could therefore be
used as an excellent imaging agent in living cells.
Conclusions
We have demonstrated the successful design and synthesis of
a new series of luminogens by fusing a 2-phenacylfuran com-
ponent to aromatic units possessing solid-state emitting prop-
erties. The systematic study of their photophysical, electro-
chemical, thermal and AIE properties, as well as their single-
crystal packing structures, revealed that the fusion of 2-phena-
cylfuran derivatives to the aromatic core of BINOL generated
an overall distorted geometry that is instrumental in reducing
intermolecular p–p stacking through the presence of large
sterically hindering groups, thereby endowing the fluoro-
phores with enhanced emissive properties in the aggregated
state. The CD spectra further confirmed the chirality transfer
from BINOL that renders both the luminogens S3 and S4
chiral. Both chiral luminogens demonstrated excellent solid-
state emissive properties, possessing high thermal stability and
the opportunity for wavelength tunability. Compared with typi-
cal BINOL derivatives, AIEgens S2–S4 exhibit large Stokes shifts
and high fluorescence quantum yields. In addition to its high
fluorescence quantum yield and large Stokes shift, S4 also
demonstrates excellent biocompatibility over the concentra-
tion range 10–100 mgmLÀ1. Therefore, the efficacy of S4 as a
fluorescent bioprobe for cell imaging was explored. It was ob-
served that S4 was well internalised and uniformly dispersed
within the cytoplasm in MDA-MB-231 cancer cells, showing
high fluorescence intensity. Altogether, the design strategies
demonstrated here could pave the way to the development of
next-generation chiral fluorescent probes for diverse applica-
tions.
ing with PBS. 4’,6-Diamidino-2-phenylindole (DAPI; 2 mgmLÀ1
)
was used for nuclear staining over a period of 5 min. The cells
were then mounted on a glass slide, sealed, and analysed by
confocal laser scanning microscopy (Leica SP8, Leica Microsys-
tems).[57,58]
DAPI stains the nuclei blue, and the appearance of green
fluorescence in the aggregate state can be explained by mem-
brane protein interactions, which restrict intramolecular rota-
tion as well as the non-radiative decay of the excitons, result-
ing in an enhancement of fluorescence intensity (Figure 15).
The interactions could be the result of strong hydrogen bond-
ing between the cyano groups of S4 and the peptide bonds
present in the cells.
Figure 15. Cellular internalisation of S4 in MDA-MB-231 cells. DIC=Differen-
tial interference contrast imaging, used to visualize unstained or transparent
samples
The overlay of the bright field and fluorescence images con-
firmed that the S4 taken up by the cells is uniformly dispersed
in the cytoplasm and not co-localised within the nuclei. No
green signals were observed in the control cells and all the
cells retained their morphology. The mean fluorescence inten-
sity was calculated, and the results are shown in the histogram
in Figure 16. This investigation revealed that S4 selectively
Experimental Section
Chemicals and reagents: Salicylaldehyde (1a), 2-bromoacetophe-
none (2), 2-hydroxynaphthaldehyde (1b) and (R)-BINOL (5) were
purchased from Sigma–Aldrich. Malononitrile, nBuLi, piperidine,
pyridine, N,N,N’,N’-tetramethylethylenediamine (TMEDA) and BBr3
were purchased from Spectrochem. Ultrapure water (>18 MWcm)
from a Milli-Q reference system (Millipore) was employed through-
out.
General experimental procedures, analysis and instrumental details
are provided in the Supporting Information.
Procedures and characterisation: Compounds 3, 4 and 6–8 have
been previously reported in the literature and were synthesised fol-
lowing the reported protocols. The spectral data were in agree-
ment with the literature values.[59–63]
Synthesis of benzofuran-2-yl(phenyl)methanone (3):[51] A mixture
of 2-hydroxybenzaldehyde (1a; 0.290 g, 2.374 mmol) and 2-bromo-
1-phenylethanone (2; 0.519 g, 2.611 mmol) were dissolved in ace-
tone, K2CO3 (0.984 g, 7.122 mmol) was added, and the mixture was
heated to reflux under continuous stirring for 12 h. After consump-
tion of compound 1a (as monitored by TLC), the reaction mixture
was quenched by the addition of water and the organic layer was
Figure 16. Histogram depicting the mean fluorescence intensity per cell of
S4 in comparison with the control.
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extracted with ethyl acetate (3”10 mL). The combined organic
layers were dried over anhydrous sodium sulfate, filtered and
evaporated to dryness. The residue was purified by column chro-
matography over silica gel (cyclohexane/ethyl acetate, 90:10) to
afford the desired product 3 (0.503 g, 2.256 mmol, 95%) as a white
127.4, 126.2, 123.8, 123.4, 119.3, 114.1, 113.8, 112.5, 77.8 ppm;
HRMS (ESI): m/z calcd for C22H12N2O: 320.0949 [M]+; found:
320.0940.
Synthesis of (R)-2,2’-dimethoxy-1,1’-binaphthalene (6):[49] K2CO3
(4.855 g, 35.131 mmol) and methyl iodide (2.43 mL, 39.035 mmol)
were added to a solution of (R)-BINOL (5; 2.235 g, 7.807 mmol) in
acetone (50 mL), and the mixture was then stirred while heating at
reflux for 12 h. The mixture was then cooled to room temperature
and water (40 mL) was added. The resulting suspension was stirred
for 4 h at room temperature and filtered. The resulting white solid
was washed with water and dried to give the desired product 6
(2.43 g, 7.73 mmol, 99%) as a white solid. 1H NMR (300 MHz,
CDCl3): d=3.77 (s, 6H), 7.08–7.36 (m, 6H), 7.46 (d, 2H, J=9.3 Hz),
7.87 (d, 2H, J=7.3 Hz), 7.98 ppm (d, 2H, J=8.8 Hz); 13C NMR
(75 MHz, CDCl3): d=57.0, 114.7, 120.1, 123.9, 125.7, 126.7, 128.3,
129.6, 129.8, 134.4, 155.4 ppm; IR (neat): n=3065, 3010, 2954,
1
powder H NMR (300 MHz, CDCl3): d=8.06 (d, J=8.1 Hz, 2H), 7.70
(d, J=7.9 Hz, 1H), 7.61 (t, J=8.1 Hz, 2H), 7.53 (s, 1H),7.54–7.45 (m,
3H), 7.29 ppm (dd, J=7.3, 15.1 Hz, 1H); 13C NMR (75 MHz, CDCl3):
d=184.4, 155.7, 152.2, 137.1, 132.8, 128.7, 128.2, 127.0, 124.0,
123.3, 116.5, 112.5 ppm; IR (neat): n=3140, 3056, 1641, 1543, 1329,
1215, 970, 744, 692 cmÀ1
Synthesis of 2-[benzofuran-2-yl(phenyl)methylene]malononitrile
(S1): Compound (0.500 g, 2.231 mmol) and malononitrile
.
3
(0.442 g, 6.695 mmol) were added dropwise to pyridine (10 mL) in
a round-bottomed flask maintained at 08C. After complete addi-
tion, the mixture was stirred for 10 min and then heated at reflux
overnight. After the consumption of starting material 3 (monitored
by TLC), the reaction mixture was quenched with water and ex-
tracted with DCM. The organic layer was collected, dried over an-
hydrous Na2SO4 and evaporated to dryness. The crude product
was subjected to column chromatography using ethyl acetate/pe-
troleum ether (1:9) as eluent to afford compound S1 (0.444 g,
1.64 mmol, 73%) as a yellow solid. M.p. 177–1818C; 1H NMR
(400 MHz, CDCl3): d=7.62 (t, J=8.9 Hz, 3H), 7.53 (dt, J=10.9,
7.8 Hz, 5H), 7.31 (t, J=7.5 Hz, 1H), 7.04 ppm (s, 1H); 13C NMR
(126 MHz, CDCl3): d=157.8, 156.8, 150.7, 133.1, 131.8, 129.7, 129.5,
129.0, 127.3, 124.5, 123.0, 120.5, 113.8, 113.4, 112.5, 79.4 ppm;
HRMS (ESI): m/z calcd for C18H10N2O: 270.0793 [M]+; found:
270.0810.
2934, 2837, 1618, 1590, 1505, 1460 cmÀ1
.
Synthesis of (R)-2,2’-dimethoxy-[1,1’-binaphthalene]-3,3’-dicar-
baldehyde (7):[50] TMEDA (2.40 mL, 16.41 mmol) was addded por-
tionwise to a suspension of 6 (2.0 g, 6.56 mmol) in dry diethyl
ether (40 mL) under N2 at room temperature. After cooling the
mixture to 08C, a 2.5m solution of n-butyllithium in hexanes
(10.2 mL, 29.02 mmol) was added dropwise and the mixture stirred
at 08C for 1 h before warming up to ambient temperature and
heating at reflux overnight. The resulting yellow-brown suspension
was cooled to À788C, anhydrous DMF (4.0 mL, 52.5 mmol) was
added dropwise and the white suspension stirred at room temper-
ature for 2 h. Next, 2n aq. HCl (40 mL) was added and the mixture
stirred for 30 min. The aqueous and organic phases were separated
and the organic layer was washed successively with 1m HCl
(20 mL), saturated aqueous sodium bicarbonate (20 mL) and brine
(20 mL) before finally drying with anhydrous Na2SO4. The solvent
was evaporated and the resulting sticky yellow mass was purified
by silica gel column chromatography (EtOAc/hexane, 3:7) to give 7
(2.14 g, 5.78 mmol; 88%) as a pale-yellow solid. 1H NMR (CDCl3,
400 MHz): d=3.42 (s, 6H), 7.17 (d, J=8.4 Hz, 2H), 7.46 (t, J=6.6 Hz,
2H), 7.56 (t, J=6.4 Hz, 2H), 8.09 (d, J=8.8 Hz, 2H), 8.97 (s, 2H),
10.56 ppm (s, 2H); IR (KBr): n=1678, 1460, 1390, 1254 cmÀ1; MS:
m/z: 370.12 [M]+.
Synthesis of naphtho[2,1-b]furan-2-yl(phenyl)methanone (4):[52]
A
mixture of 2-hydroxy-1-naphthaldehyde (1b; 0.335 g,
1.945 mmol) and 2-bromo-1-phenylethanone (2; 0.425 g,
2.14 mmol) were dissolved in acetone, K2CO3 (0.806 g, 8.84 mmol)
was added and the reaction mixture heated at reflux for 12 h. After
consumption of the starting material 1b (as monitored by TLC),
the reaction was quenched with water and the organic layer was
extracted with ethyl acetate (3”10 mL). The combined organic
layers were dried over anhydrous sodium sulfate, filtered and
evaporated to dryness. The residue was purified by column chro-
matography over silica gel (cyclohexane/ethyl acetate, 95:5) to
afford the desired product 4 (0.493 g, 1.810 mmol, 93%) as a
brown powder. 1H NMR (300 MHz, CDCl3): d=8.00 (d, J=8.1 Hz,
1H), 7.94–7.98 (m, 2H), 7.92 (dd, J=9.0, 4.1 Hz, 1H), 7.59–7.72 (m,
7H), 7.56 ppm (d, J=4.3 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=
182.1, 162.0, 155.2, 138.3, 132.6, 130.1, 130.0, 129.9, 128.9, 128.8,
128.3, 127.1, 127.3, 127.2, 125.0, 124.0, 121.6, 116.6, 111.3 ppm; IR
Synthesis of (R)-2,2’-dihydroxy-[1,1’-binaphthalene]-3,3’-dicarbal-
dehyde (8):[51] Compound 7 (2.318 g, 6.259 mmol) was dissolved in
DCM (30 mL) in an oven-dried two-necked flask. BBr3 (1.8 mL,
18.78 mmol) in DCM (10 mL) was then added dropwise at 08C. The
mixture was stirred for 12 h at room temperature and then water
(20 mL) was added dropwise. After stirring at room temperature
for 2 h, the aqueous layer was extracted with DCM (3”30 mL) and
the combined organic layers were dried over Na2SO4, filtered and
evaporated. Purification over silica with ethyl acetate as eluent fur-
nished product 8 (2.1 g, 6.134 mmol, 98%) as a yellow solid.
1H NMR (300 MHz, CDCl3): d=7.11–7.15 (m, 2H), 7.32–7.36 (m, 4H),
7.93–7.97 (m, 2H). 8.32 (s, 2H), 9.13 (s, 2H), 10.53 ppm (s, 2H); ele-
mental analysis calcd (%) for C14H10O4: C 69.42, H 4.16; found: C
69.40, H 4.10
(neat): n=3130, 3045, 1668, 1545 cmÀ1
.
Synthesis of 2-[naphtho[2,1-b]furan-2-yl(phenyl)methylene]ma-
lononitrile (S2): Pyridine (10 mL) was added dropwise to a mixture
of
naphtho[2,1-b]furan-2-yl(phenyl)methanone
(4;
0.457 g,
1.681 mmol) and malononitrile (0.442 g, 6.695 mmol) in a round-
bottomed flask, maintained at 08C. The mixture was stirred for
10 min and then heated at reflux overnight. After the consumption
of starting material 4 (monitored by TLC), the reaction was
quenched by water and extracted with DCM. The collected organic
layer was dried over anhydrous Na2SO4, filtered and evaporated to
dryness. The crude product was subjected to column chromatogra-
phy using ethyl acetate/petroleum ether (1:9) as eluent to afford
compound S2 (0.399 g, 1.24 mmol, 68%) as a yellow solid. M.p.
157–1648C; 1H NMR (400 MHz, CDCl3): d=8.03 (d, J=7.4 Hz, 1H),
7.93–7.96 (m, 2H), 7.72 (dd, J1 =4.1 Hz, J2 =9.0, 1H), 7.53–7.65 (m,
7H), 7.48 ppm (d, J=4.3 Hz, 1H); 13C NMR (126 MHz, CDCl3): d=
157.1, 155.9, 150.2, 133.3, 131.8, 130.6, 129.5, 129.3, 129.0, 128.0,
Synthesis of (R)-[9,9’-binaphtho[2,3-b]furan]-2,2’-diylbis(phenyl-
methanone) (S3): K2CO3 (6.136 g, 44.40 mmol) was added to a so-
lution of compound 8 (1.9 g, 5.55 mmol) and 1-phenyl-2-bromoe-
thanone (2.66 g, 13.32 mmol) in acetone under N2. The resulting
mixture was heated at reflux with stirring overnight. After removal
of the solvent, water and ethyl acetate were added. The aqueous
layer was extracted three times with ethyl acetate. The combined
organic layers were washed with brine, dried over MgSO4, filtered
and concentrated under reduced pressure. The residue was puri-
fied by column chromatography over silica gel with ethyl acetate/
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petroleum ether (1:9) as eluent to afford S3 (2.46 g, 4.54 mmol,
82%) as a yellow solid. M.p. 240–2428C; H NMR (400 MHz, CDCl3):
1
d=8.45 (s, 2H), 8.13 (d, J=8.3 Hz, 2H), 7.87–7.82 (m, 6H), 7.55–
7.49 (m, 4H), 7.45 (t, J=7.4 Hz, 2H), 7.39–7.35 (m, 2H), 7.24 ppm (t,
J=7.6 Hz, 4H); 13C NMR (126 MHz, CDCl3): d=112.9, 12.3, 124.6,
126.0, 126.6, 127.4, 128.2, 129.1, 129.7, 131.3, 132.5, 132.9, 136.5,
152.8, 154.58, 183.9 ppm; HRMS (ESI): m/z calcd for C38H22O4:
542.1518 [M+H]+; found: 543.1572.
Synthesis of (R)-2,2’-([9,9’-binaphtho[2,3-b]furan]-2,2’-diylbi-
s(phenylmethanylylidene))dimalononitrile (S4): Compound S3
(0.200 g, 0.3686 mmol) and malononitrile (0.073 g, 1.10 mmol)
were added dropwise at 08C to pyridine (10 mL) in a round-bot-
tomed flask in an ice bath. After stirring for 10 min, the mixture
was heated at reflux overnight. After consumption of S3 (as moni-
tored by TLC), the reaction was quenched by the addition of water
and the mixture extracted with DCM. The collected organic layer
was dried over anhydrous Na2SO4 and evaporated to dryness. The
residue was subjected to column chromatography using ethyl ace-
tate/petroleum ether (1:9) as eluent to afford S4 (0.141 g,
0.22 mmol, 60%) as
a
red solid. M.p. 214–2168C; 1H NMR
(400 MHz, CDCl3): d=7.10 (s, 2H), 7.36 (t, J=8.0 Hz, 2H), 7.61–7.45
(m, 14H), 8.09 (d, J=8.2 Hz, 2H), 8.33 ppm (s, 2H); 13C NMR
(126 MHz, CDCl3): d=80.4, 112.1, 112.8, 113.9, 120.7, 123.4, 124.8,
125.9, 127.3, 127.8, 128.9, 129.6, 131.2, 131.7, 132.9, 133.2, 153.6,
153.7, 157.3 ppm; HRMS (ESI): m/z calcd for C44H22N4O2: 638.1742
[M+H]+ ; found: 639.1756.
Crystallographic data: Deposition numbers 1984512 (S1), 1984513
(S2), and 1984516 (S3) contain the supplementary crystallographic
data for this paper. These data are provided free of charge by the
joint Cambridge Crystallographic Data Centre and Fachinforma-
tionszentrum Karlsruhe Access Structures service.
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Manuscript received: November 13, 2020
Accepted manuscript online: December 23, 2020
Version of record online: February 25, 2021
Chem. Eur. J. 2021, 27, 5470 –5482
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5482
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