Structure-dependent cis/trans isomerization of tetraphenylethene derivatives: Consequences for aggregation-induced emission

Article abstract of DOI:10.1002/anie.201600244

The isomerization and optical properties of the cis and trans isomers of tetraphenylethene (TPE) derivatives with aggregation-induced emission (AIEgens) have been sparsely explored. We have now observed the tautomerization-induced isomerization of a hydroxy-substituted derivative, TPETH-OH, under acidic but not under basic conditions. Replacing the proton of the hydroxy group in TPETH-OH with an alkyl group leads to the formation of TPETH-MAL, for which the pure cis and trans isomers were obtained and characterized by HPLC analysis and NMR spectroscopy. Importantly, cis-TPETH-MAL emits yellow fluorescence in DMSO at -20 °C whereas trans-TPETH-MAL shows red fluorescence under the same conditions. Moreover, the geometry of cis- and trans-TPETH-MAL remains unchanged when they undergo thiol-ene reactions to form cis- and trans-TPETH-cRGD, respectively. Collectively, our findings improve our fundamental understanding of the cis/trans isomerization and photophysical properties of TPE derivatives, which will guide further AIEgen design for various applications. The cis and trans isomers of a tetraphenylethene derivative with aggregation-induced emission, TPETH-MAL, were characterized by HPLC analysis and NMR spectroscopy. cis-TPETH-MAL emits yellow fluorescence in DMSO at -20 °C whereas trans-TPETH-MAL shows red fluorescence under the same conditions.

Full text of DOI:10.1002/anie.201600244

Angewandte
Communications
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International Edition: DOI: 10.1002/anie.201600244
German Edition: DOI: 10.1002/ange.201600244
Aggregation-Induced Emission Very Important Paper
Structure-Dependent cis/trans Isomerization of Tetraphenylethene
Derivatives: Consequences for Aggregation-Induced Emission
Chong-Jing Zhang, Guangxue Feng, Shidang Xu, Zhenshu Zhu, Xianmao Lu, Jien Wu,* and
Bin Liu*
Abstract: The isomerization and optical properties of the cis
and trans isomers of tetraphenylethene (TPE) derivatives with
aggregation-induced emission (AIEgens) have been sparsely
explored. We have now observed the tautomerization-induced
isomerization of a hydroxy-substituted derivative, TPETH-
OH, under acidic but not under basic conditions. Replacing the
proton of the hydroxy group in TPETH-OH with an alkyl
group leads to the formation of TPETH-MAL, for which the
pure cis and trans isomers were obtained and characterized by
HPLC analysis and NMR spectroscopy. Importantly, cis-
TPETH-MAL emits yellow fluorescence in DMSO at À208C
whereas trans-TPETH-MAL shows red fluorescence under the
same conditions. Moreover, the geometry of cis- and trans-
TPETH-MAL remains unchanged when they undergo thiol–
ene reactions to form cis- and trans-TPETH-cRGD, respec-
tively. Collectively, our findings improve our fundamental
understanding of the cis/trans isomerization and photophysical
properties of TPE derivatives, which will guide further AIEgen
design for various applications.
isomerization is thus not only useful for fundamental studies
but also offers a unique opportunity to explore their practical
applications.
Tetraphenylethene (TPE) based derivatives generally
show aggregation-induced emission (AIE); they are non-
emissive in the molecularly dissolved state but become highly
emissive in the aggregated state.[4] These unique AIE proper-
ties are the opposite to the aggregation-caused quenching
(ACQ) observed for conventional fluorophores.[5] AIEgens
thus provide a novel and complementary approach for the
design of new-generation fluorescent probes.[6] TPE, as an
iconic AIEgen, has attracted tremendous research interest.
Thus far, multiple functional groups have been attached to the
phenyl rings of TPE to fine-tune its optical properties for
sensing, imaging, and therapeutic applications.[7] Previous
studies have shown that the majority of the TPE derivatives
do not undergo photoinduced cis/trans isomerization under
the conditions normally applied for photoluminescence
spectroscopy.[8] The few separated isomers display different
mechanochromic properties,[8a] and the corresponding probes
show distinct biological responses to target enzymes.[9] These
findings highlight the importance of obtaining and investigat-
ing the cis/trans isomers of TPE derivatives. However, to
obtain TPE derivatives as pure isomers is not trivial. For
example, palladium-catalyzed coupling reactions can be
employed to directly synthesize pure isomers,[10] but generally
mainly the cis product is formed while the isomeric purity of
the obtained product is not very high.[8b] Another strategy is to
attach bulky groups to the TPE core to improve isomer
separation on a silica gel column.[8a] After successful separa-
tion, confirmation of the cis/trans geometry is another
challenging task. Current methods rely on growing single
crystals for X-ray diffraction to confirm the isomer geome-
try.[8] This approach is tedious and only applicable to those
isomers that can easily grow into single crystals. Owing to
these difficulties, mixtures of the cis and trans isomers were
reported and used in most studies,[11] which has compromising
effects on the functions and properties of these molecules in
various applications. With these considerations in mind, we
herein designed and synthesized various analogues of a tetra-
phenylethenethiophene derivative (TPETH), namely
S
tereochemistry plays an important role in modern organic
chemistry with significant influence in the material and life
sciences. The stereochemistry of carbon–carbon double bonds
holds great implications for drug discovery and dye develop-
ment. Geometric cis and trans isomers have been reported to
differ in their pharmacodynamic and pharmacokinetic prop-
erties.[1] For example, trans-tamoxifen is a potent estrogen
receptor antagonist, which is used for the treatment of breast
cancer, whereas cis-tamoxifen is a full estrogen agonist.[2]
Carbon–carbon double bonds are also built-in elements of
fluorescent dyes whose cis and trans isomers display different
optical properties.[3] The elucidation of the characteristic
properties of cis and trans geometric isomers and their
[*] Dr. C. Zhang, Dr. G. Feng, S. Xu, Dr. Z. Zhu, Prof. Dr. X. Lu,
Prof. Dr. B. Liu
Department of Chemical and Biomolecular Engineering
National University of Singapore
4 Engineering Drive 4, Singapore, 117585 (Singapore)
E-mail: cheliub@nus.edu.sg
Dr. J. Wu
Department of Chemistry, National University of Singapore
3 Science Drive 3, Singapore, 117543 (Singapore)
E-mail: chmwujie@nus.edu.sg
TPETH-OH,
TPETH-MAL,
and
TPETH-cRGD
(Scheme 1). Our results indicate that 1) TPETH-OH under-
goes tautomerization-induced cis/trans isomerization under
acidic but not under basic conditions; 2) cis- and trans-
TPETH-MAL can be easily resolved by HPLC and their
structures were confirmed by COSY and NOESY spectros-
copy; 3) the fluorescence of cis-TPE is blue-shifted compared
to that of the trans isomer in DMSO at À208C, a property that
Prof. Dr. B. Liu
Institute of Materials Research and Engineering
3 Research Link, Singapore 117602 (Singapore)
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under http://dx.doi.org/10.
1002/anie.201600244.
6192
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Scheme 1. Synthesis of TPETH-OH, TPETH-MAL, and TPETH-cRGD.
could potentially be employed to distinguish between the cis
and trans isomer with the naked eye; and 4) the geometry of
the TPE core remains unchanged during a reaction of the
maleimide (MAL) groups with thiols to form the biological
probe TPETH-cRGD.
respectively (Figures S6A,B). The photoluminescence (PL)
spectra of TPETH-OH were recorded in DMSO/water
mixtures with different water fractions (fw). With a gradual
increase in fw, the emission of TPETH-OH becomes more
intense (Figure S6B), a characteristic AIE phenomenon. The
PL spectra of TPETH-OH under acidic and basic conditions
are similar (Figure S6C), indicating that the cis/trans isomer-
ization does not affect its fluorescence in DMSO/water
(1:100, v/v).
TPETH-OH and TPETH-MAL were synthesized as
shown in Scheme 1. Briefly, TPETH-OMe[12] was treated
with tribromoborane to remove one methyl group and yield
TPETH-OH, which further underwent alkylation and depro-
tection to generate TPETH-MAL. TPETH-OH was formed
as a mixture of the cis and trans isomers, which could not be
separated by column chromatography on silica gel. However,
TPETH-OH can be easily separated by HPLC using
a reverse-phase column with acetonitrile/water containing
0.1% TFA as the eluent. TPETH-OH can easily undergo cis/
trans isomerization, and it takes less than twelve hours for the
separated pure isomers to reach equilibrium (1:1 ratio;
Figure 1B; see also the Supporting Information, Figure S4).
We propose that the mutual conversion is due to keto–enol
tautomerization for TPETH-OH. As shown in Figure S5,
when the phenol tautomerizes to the keto form, the central
double bond becomes a single bond (shown in red). This
single bond could rotate freely to yield a transient isomer 2,
which will further tautomerize from the keto form to the
phenol form to complete the isomerization process. When
three equivalents of diisopropylethylamine (DIEA) had been
added to the HPLC eluent, no isomerization was observed
within 24 hours (Figure 1C), indicating that the proton is
essential for this isomerization.
Figure 1. A) HPLC spectrum of TPETH-OH. B) Time-dependent HPLC
traces of purified isomer 1 (eluted first). C) Time-dependent HPLC
traces of purified isomer 1 in the presence of DIEA (3 equiv).
TPETH-OH displays absorption and emission maxima at
450 nm in DMSO and 638 nm in DMSO/water (1:100, v/v),
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When the proton of the hydroxy group in TPETH-OH
was replaced by an alkyl group, TPETH-MAL was obtained,
the isomers of which were also successfully separated using
HPLC (Figure S7). The first eluted isomer has a retention
time of 7.5 min whereas the second one has a retention time
of 8.0 min. The NMR spectra indicate that these two isomers
of TPETH-MAL were obtained in high purity (Figures S8
and S9).
Once the pure isomers of TPETH-MAL had been
obtained, they were analyzed by NMR spectroscopy to
confirm their geometry. Both COSY and NOESY NMR
spectra were recorded for the two isomers. We here use the
isomer with a retention time of 8.0 min as an example to
illustrate the geometry analysis. In the 1H NMR spectrum, the
resonance at d = 3.75 ppm corresponds to the H13 protons,
and the resonance at d = 3.92 ppm is due to the H11 protons
(Figures S10–S12). Following this assignment and the obser-
vation of clear correlations in the NOESY spectrum (Fig-
ure S13), the protons with d = 6.62 and 6.66 ppm are H1 and
H4 in ring B and H5 and H8 in ring A, respectively. The
resonance at d = 6.96 ppm was assigned to H6 and H7 in
ring A because of their strong correlation with H5 and H8
(Figure 2). Among the four aromatic rings in TPETH-MAL,
only ring C has the ABX coupling pattern, suggesting that the
two protons (H9, H10) with d = 7.07 ppm are from ring C. As
can be seen in Figure 2, the cross-peaks in the green circles
indicate clear correlations between H6/H7 and H9/H10 in the
NOESY spectrum, which indicates that ring A and ring C are
close in space, that is, on the same side of the central double
bond. Therefore, the isomer with a retention time of 8.0 min is
the cis isomer (cis-TPETH-MAL), whereas the other one is
the trans isomer (trans-TPETH-MAL; for its NMR spectra,
see Figures S14–S18). The approach of using NMR spectros-
copy to confirm the cis and trans geometry could
Figure 2. NOESY spectrum of cis-TPETH-MAL.
low temperature restricted the free intramolecular motion of
the cis- and trans-TPETH-MAL molecules, turning on the
fluorescence. As the storage time was increased, the solidified
DMSO solution of trans-TPETH-MAL emitted stronger red
fluorescence, whereas the solidified DMSO solution of cis-
TPETH-MAL exhibited a change in the fluorescence color
from red to yellow (Figure 4A). This color change implies
that the conformation of cis-TPETH-MAL changed with
storage time. Next, we tested whether the same phenomena
were observed in other solvents. As shown in Figure 4B,
potentially be applied to other AIEgens and other
molecules, especially if their crystallization is
difficult.
After the structural confirmation, we first
measured the spectroscopic properties of the two
isomers at 248C. cis-TPETH-MAL and trans-
TPETH-MAL have identical UV absorption
spectra with an absorption maximum at 440 nm
(Figure 3A). Both are non-emissive in DMSO as
they are in a molecularly dissolved state. They
become very emissive with an emission maximum
at 635 nm in aqueous media (DMSO/water, 1:100,
v/v; Figure 3B). Laser light scattering studies
indicate that cis-TPETH-MAL and trans-
TPETH-MAL form aggregates in aqueous
media with average diameters of 66 nm and
77 nm, respectively (Figures 3C,D). Collectively,
these results indicate that both cis-TPETH-MAL
and trans-TPETH-MAL are AIE active.
When cis-TPETH-MAL and trans-TPETH-
Figure 3. A) UV/Vis absorption spectra of 10 mm cis- and trans-TPETH-MAL in
DMSO. B) PL spectra of cis- and trans-TPETH-MAL in DMSO and DMSO/water
(1:100, v/v), lex =440 nm. C,D) Hydrodynamic diameters measured by laser light
scattering (LLS) for 10 mm solutions of trans-TPETH-MAL (C) and cis-TPETH-MAL
(D) in a mixture of DMSO/water (1:100, v/v). All measurements were conducted at
248C.
MAL were dissolved in DMSO (2 mm) and stored
for 12 min at À208C, the solutions became solid
with red fluorescence upon excitation with a UV
lamp (Figure 4A). As DMSO has a low melting
point of 198C, the solidification of the solution at
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molecules, which is more restricted for cis-TPETH-MAL.
When kept at À208C for a few hours, cis-TPETH-MAL will
gradually adopt a more stable state to yield blue-shifted
fluorescence. Accordingly, intramolecular motion is much
easier in trans-TPETH-MAL than in cis-TPETH-MAL,
which is in agreement with the observation that the fluores-
cence of the former disappears faster when its solidified
DMSO solution is slowly warmed to room temperature. The
different optical properties of cis-TPETH-MAL and trans-
TPETH-MAL could also be used to distinguish them with the
naked eye.
As thiol–ene reactions between maleimides and thiols are
widely used for bioprobe synthesis,[13] we were interested in
whether the purified isomers would be able to maintain their
geometry during such reactions. cRGD-SH was selected to
react with both cis-TPETH-MAL and trans-TPETH-MAL
(Scheme 1). This reaction proceeded fast in the presence of
triphenylphosphine and DIEA. The final conjugation prod-
ucts (cis-TPETH-cRGD and trans-TPETH-cRGD) were
obtained in good yields, and their structures were confirmed
by 1H NMR spectroscopy and high-resolution mass spec-
trometry (Figures S20–S23). Comparison of the 1H NMR
spectra of the conjugation products and cis-TPETH-MAL
and trans-TPETH-MAL revealed that the resonance of the
proton highlighted in blue is shifted downfield in trans-
TPETH-MAL compared to that of cis-TPETH-MAL (Figur-
es 5A,B). As shown in Figures 5C,D, the same pattern was
also observed for the cis/trans isomers of TPETH-cRGD,
which indicates that the geometry of the AIEgens is not
changed by the reaction.
Figure 4. A) Photographs showing the fluorescence of trans-TPETH-
MAL (2 mm, top row) and cis-TPETH-MAL (2 mm, bottom row) in
DMSO at À208C. B) Photographs showing the fluorescence of cis-
TPETH-MAL (1 mm, top row) and trans-TPETH-MAL (1 mm, bottom
row) in different solvents kept at À208C for 3 days. C) Photographs
showing the fluorescence of trans-TPETH-MAL (2 mm, top row) and
cis-TPETH-MAL (2 mm, bottom row) in DMSO, allowed to warm from
À208C to room temperature for various periods of time. All photo-
graphs were taken with 365 nm excitation.
Finally, we employed cis-TPETH-cRGD for cell imaging.
cis-TPETH-cRGD has almost the same absorption spectrum
as TPETH-MAL when dissolved in DMSO (Figure S24).
Because of the high hydrophilicity of the cRGD group, cis-
TPETH-cRGD has a lower fluorescence than cis-TPETH-
MAL in aqueous media (Figure S24). As the cRGD group is
able to target cells with integrin overexpression (e.g., MDA-
solutions of cis- and trans-TPETH-MAL in acetone, acetoni-
trile (ACN), dichloromethane (DCM), dimethylformamide
(DMF), isopropyl alcohol (IPA), and tetrahydrofuran (THF)
emit weak fluorescence as the solutions did not solidify at
À208C. However, aqueous dispersions of both isomers
emitted red fluorescence. As cis- and trans-TPETH-MAL
form aggregates in water, this observation implies that the
subtle conformation alteration at low temperature does not
occur in the aggregated state. Moreover, when the solidified
DMSO solutions at À208C were transferred to the bench at
room temperature, trans-TPETH-MAL became almost non-
emissive within 40 s but cis-TPETH-MAL remained emissive
for up to 5 min while the fluorescence intensity decreased
with time (Figure 4C).
These different optical properties of cis- and trans-
TPETH-MAL could be ascribed to their structural differ-
ences. In cis-TPETH-MAL, the two bulky side chains are
located on the same side of the double bond, which leads to
more steric hindrance than in trans-TPETH-MAL (Fig-
ure S19). This difference in the steric hindrance between the
two isomers directly affects the intramolecular motion of the
Figure 5. 1H NMR spectra of trans-TPETH-MAL (A), cis-TPETH-MAL
(B), trans-TPETH-cRGD (C), and cis-TPETH-cRGD (D) in [D6]DMSO.
The peaks indicated by the blue line belong to the proton in the
thiophene ring highlighted in blue.
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the Institute of Materials Research and Engineering of
Singapore (IMRE/14-8P1110) for financial support.
Keywords: aggregation induced emission · fluorescent probes ·
imaging agents · isomerization
How to cite: Angew. Chem. Int. Ed. 2016, 55, 6192–6196
Angew. Chem. 2016, 128, 6300–6304
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In conclusion, we have studied the cis/trans isomerization
and optical properties of the cis and trans isomers of various
TPE-based AIEgens. With a free hydroxy group, TPETH-OH
undergoes cis/trans isomerization under acidic conditions but
not under basic conditions, which was ascribed to keto–enol
tautomerization. By replacing the proton of the hydroxy
group in TPETH-OH with an alkyl group, the pure cis and
trans isomers of TPETH-MAL were obtained and charac-
terized by HPLC and NMR spectroscopy. cis-TPETH-MAL
and trans-TPETH-MAL have roughly the same spectroscopic
properties at room temperature. However, cis-TPETH-MAL
emits yellow fluorescence and trans-TPETH-MAL emits red
fluorescence when they are stored in DMSO at À208C for
a few hours. The differences in the photophysical properties
can be ascribed to the higher steric hindrance in cis-TPETH-
MAL than in trans-TPETH-MAL. Finally, the geometry of
TPETH-MAL is maintained in a thiol–ene reaction, and the
generated probe, cis-TPETH-cRGD, can selectively stain
integrin-overexpressing cancer cells. This study improves our
fundamental understanding of the cis/trans isomerization and
photophysical properties of TPE derivatives, which offers
new opportunities to explore the unique properties of
AIEgens.
Acknowledgements
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We thank the Singapore NRF Investigatorship (R279-000-
444-281), the Ministry of Education (R279-000-391-112), and
Received: January 9, 2016
Published online: April 13, 2016
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