A rationally designed fluorescence turn-on probe for the gold(III) ion

Article abstract of DOI:10.1021/ol902860f

Chemical Equation Presentation A latent fluorophore (1) was rationally designed to give rise to strong fluorescence through a selective gold ion-mediated hydroarylation reaction by a catalytic amount of the gold(III) lon. It is a highly selective and sensitive fluorescence turn-on probe for gold(III) ions and is operative even in protic solvents

Full text of DOI:10.1021/ol902860f

ORGANIC
LETTERS
2010
Vol. 12, No. 5
932-934
A Rationally Designed Fluorescence
Turn-On Probe for the Gold(III) Ion
Jung Ho Do,† Ha Na Kim,‡ Juyoung Yoon,*,‡ Jong Seung Kim,*,§ and
Hae-Jo Kim*,†
Department of Chemistry, Kyonggi UniVersity, Suwon 443-760, Korea, Department of
Chemistry, Department of Chemistry and Nano Science, Ehwa Womans UniVersity,
Seoul 120-750, Korea, and Department of Chemistry, Korea UniVersity,
Seoul 136-701, Korea
haejkim@kgu.ac.kr; jyoon@ewha.ac.kr; jongskim@korea.ac.kr
Received December 14, 2009
ABSTRACT
A latent fluorophore (1) was rationally designed to give rise to strong fluorescence through a selective gold ion-mediated hydroarylation
reaction by a catalytic amount of the gold(III) ion. It is a highly selective and sensitive fluorescence turn-on probe for gold(III) ions and is
operative even in protic solvents.
There is much current interest in gold with respect to its
chemical properties. Gold ions are known to activate
carbon-carbon multiple bonds, especially alkynes, toward
nucleophilic addition. Owing to the characteristic alkyno-
philicity of the gold ion, a variety of organic transformations
have been investigated by employing gold ions.1 Gold ions
also have anti-inflammatory properties and are used as
pharmaceuticals in the treatment of arthritis and tuberculosis.2
Despite the interesting chemical and medicinal properties
of gold ions, soluble gold salts such as gold chloride are
known to cause damage to the liver, kidneys, and the
peripheral nervous system.3 Some gold ions, especially
Au(III), are so tightly bound to a certain enzyme that they
are reported to cause cell toxicity in living organisms.4
Therefore, it is of great importance to develop gold ion
probes to assess the quantity of environmental gold ions by
luminescence methods. However, a few fluorescence probes
for gold metal ions have been reported very recently using
a propagylamide-derived rhodamine.5 Herein, we report on
a rationally designed latent fluorescence probe based on an
apocoumarin,6 which has shown an excellent selectivity and
sensitivity toward the gold(III) ion with fluorescence turn-
on in protic solvents.
In order to develop a fluorescent probe for gold ions, we
designed an aryl alkyne compound (1), which is weakly fluorescent
† Kyonggi University.
‡ Ehwa Womans University.
§ Korea University.
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10.1021/ol902860f  2010 American Chemical Society
Published on Web 01/29/2010

or nonfluorescent. The dialkylamino group is located for the
intramolecular hydroarylation reaction in the para position of 1 with
a Michael acceptor, and the phenyl ester functionality is introduced
to cause a proper push-pull electronic effect on the fluorophore
2. Therefore, the latent fluorophore (1) can be rearranged into the
fluorescent 2 with strong fluorescence by a gold ion-mediated
hydroarylation reaction (Scheme 1).7
analogue (3) show any detectable transformation in the
presence of Au(III) ions (Figure S5, Supporting Information).
These control experiments indicate that both the alkyne and
the diethylamino groups of 1 are important for the gold(III)-
catalyzed hydroarylation.
Probe 1 has a UV absorption maximum centered at 263
nm (ε ) 4.29 × 104 M-1 cm-1) and exhibits negligible
fluorescence. The addition of the Au(III) ion triggers a
prominent bathochromic shift (ca. 130 nm) to λmax 390 nm
(ε ) 1.98 × 104 M-1 cm-1) with an apparent isosbestic point
at 333 nm (Figure 2). The rate constant for the conversion
of 1 (30 µM) to 2 in ethanol was measured in the presence
Scheme 1. Latent Fluorophore (1) and Control Compounds
of the gold(III) ion (10 equiv) and estimated to be kobs
)
(3.31 ( 0.62) × 10-5 s-1, whereas other metal ions such as
Hg(II), Pd(II), Pt(II), Cd(II), Cu(II), Zn(II), Cu(I), Ag(I), and
Au(I) did not induce any significant spectral changes even
in the presence of 100 equiv of metal ions.
The syntheses of 1 and its analogues (3 and 4) were
accomplished through EDC coupling reactions of each acid
and the corresponding phenols (see the Supporting Informa-
tion). The hydroarylation of 1 was monitored in ethanol8 by
applying a catalytic amount of Au(III) ion under a hand-
held UV-vis lamp. A new thin-layer chromatography (TLC)
spot at Rf 0.30 (EtOAc/Hex, 1:4, v/v) below that of 1 (Rf
0.57) appeared upon the addition of 10 mol % of Au(III)
ion to 1 (Figure 1A). The TLC chromatogram displayed
Figure 2. UV-vis spectral changes and its kinetics (inset) upon
addition of 10 equiv of Au(III) to 1 (30 µM) in EtOH.
The fluorescence responses of the latent fluorophore 1 (30
µM in EtOH) were examined after each addition of various
metal ions. The fluorescence spectra have shown a large
Stokes shift (∼100 nm), enough to block the spectral cross
talk between 1 and 2.9 Fluorescence intensity at 488 nm was
dramatically increased ca. 60 times by the Au(III) ion and
4.6 times by the Ag(I) ion, whereas other metal ions did not
induce any significant fluorescence changes (Figure 3).
Competitive fluorescence experiments have also corroborated
the selectivity of 1 toward the Au(III) ion. The fluorescence
was turned on again when the gold(III) ions were added to
the nonfluorescent mixtures of 1 and other metal ions (Figure
S7, Supporting Information). It is noticeable that 1 is inert
to the Lewis acids like copper(II) or zinc(II) ions as well as
other electrophilic metal ions such as Pd(II), Pt(II), and Cu(I).
To our surprise, the Au(I) ion did not turn on the fluorescence
of 1 even though 10 equiv of PPh3AuCl was added to 1 in
ethanol. This suggests the latent fluorophore 1 can be a useful
probe for the gold(III) chloride without any activation of gold
ions10 because there is possibly a significant interaction
between the more highly charged gold(III) ion and the alkyne
Figure 1. Time-dependent UV-vis (A) and fluorescence (B)
chromatograms of 1 (0.20 M) in ethanol with 10 mol % of Au(III)
ions: (a) 0 min, (b) 10 min, (c) 30 min, and (d) 2.
bright fluorescence under the UV-vis light at λex365 nm
(Figure 1B). After the reaction was complete, the fluorescent
compound was separated by column chromatography and
proven to be a hydroarylation product (2), whose structure
1
was confirmed by H and 13C NMR and mass spectral
analyses (Figure S2 in the Supporting Information). Notice-
ably, the hydroarylation reaction was not undergone with
compound 4 with an alkene moiety, nor did the alkyne ester
(7) (a) Balamurugan, R.; Gudla, V. Org. Lett. 2009, 11, 3116. (b)
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A. S. K. Gold Bull. 2004, 37, 51. (d) Weber, D.; Tarselli, M. A.; Gagne,
M. R. Angew. Chem., Int. Ed. 2009, 48, 5733. (e) Reetz, M. T.; Sommer,
K. Eur. J. Org. Chem. 2003, 3485. (f) Shi, Z.; He, C. J. Org. Chem. 2004,
69, 3669. (g) Song, C. E.; Jung, D.-u.; Choung, S. Y.; Roh, E. J.; Lee,
S.-g. Angew. Chem. Int.Ed. 2004, 43, 6183. (h) Yoon, M. Y.; Kim, J. H.;
Choi, D. S.; Shin, U. S.; Lee, J. Y.; Song, C. E. AdV. Synth. Catal. 2007,
349, 1725.
(8) The Au(III)-catalyzed reaction was dependent on solvents. The initial
rate analysis showed that the rate in dichloromethane was about 2-fold
slower than ethanol (Figure S6 in the Supporting Information).
(9) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic Chem-
istry; University Science Books: Sausalito, 2006.
Org. Lett., Vol. 12, No. 5, 2010
933

1 compared to gold(I) in a protic solvent as similarly
observed in the gold ion-enzyme interaction.11 The fluo-
rescence turn-on of 1 was apparently observed to the naked
eye for the gold(III) ion under a UV lamp (λex 365 nm),
whereas the fluorescence for other metal ions was not clearly
observed (Figure S8, Supporting Information).
observed as fluorescent in the cytoplasm when viewed
through a confocal microscope, whereas those treated with
the Au(III) ions or 1 only were not fluorescent.
Figure 4
.
Fluorescence images of HaCaT cells (×600) after 30
min incubation with Au(III) ions (10 µM) and 10 min with 1 (50
µM) in PBS buffer: (A) fluorescence images (λex) 405 nm, λem
)
505-530 nm); (B) bright field images; (C) their overlay images.
From the chromatographic and spectroscopic evidence
(TLC, NMR,and fluorescence data), we propose a plausible
mechanism for the gold-catalyzed hydroarylation (Figure 5).
Latent fluorophore 1 is activated by a reactive and alkyno-
philic Au(III) ion, followed by the intramolecular electro-
philic aromatic substitution with a Michael acceptor, and will
complete the hydroarylation reaction to afford a fluorescent
probe 2, where the gold(III) ion is regenerated.
Figure 3. (A) Fluorescence spectra of 1 (30 µM, λex 390 nm) in
EtOH upon addition of various metal ions (10 equiv of Au3+ and
Au+, whereas 100 equiv of other ions). (B) Relative fluorescence
responses at λem488 nm, where F0 is the intensity of 1 only.
A sensitivity curve of 1 toward gold(III) ions was obtained
by measuring the emission spectra of 1 (10 µM in EtOH,
λem 488 nm) according to the varying concentrations of gold
Figure 5. Proposed gold-mediated hydroarylation of 1.
ions. The fluorescence intensity of 1 was almost fully
expressed even in the presence of 0.1 equiv of Au(III) ions.
It increases linearly over the concentration ranges from 20
to 100 ppb of gold(III) ions, with a limit of detection (LOD)
of 64 ppb of the Au(III) ion (Figure S9, Supporting
Information12 Gold(III) ions are reported as toxic as over
90% of K562 human cells are dead at a concentration of 40
ppm.4c Therefore, probe 1 is sensitive enough to distinguish
the toxic levels of gold.
Fluorescence microscopic imaging for the Au(III) ion-
mediated hydroarylation of 1 was successful using the HaCaT
cells in a PBS buffer (Figure 4). Cells exposed to 10 µM of
the Au(III) ion and stained with 1 (50 µM) were clearly
In conclusion, we have rationally designed a highly selective
and sensitive fluorescent probe for the gold(III) ion using a latent
fluorophore, which is operating in protic solvents and shows a
fluorescence turn-on property through a selective gold(III)-
mediated hydroarylation reaction. The application of the latent
fluorophore to an effective catalyst screening is the subject of
ongoing research.
Acknowledgment. We thank the National Research Foun-
dation of Korea (KRF 2008-2-C00508), NRL (20090083065),
and CRI (2009-0081566) programs (KOSEF/MEST) for their
financial support.
Supporting Information Available: Experimental pro-
cedure and selected spectral data for compounds 1-4. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Most of the gold(I) ions are used by the in situ activation of
Ph3PAuCl with AgSbF6.
(11) Lee, M.-T.; Ahmed, T.; Haddad, R.; Friedman, M. E J. Enzyme
Inhibition 1989, 3, 35.
(12) We obtained the LOD as the concentration of gold ions at F/F0 )
3, which is similar to the analytical definition of 1.
OL902860F
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Org. Lett., Vol. 12, No. 5, 2010