Nonreaction-based fluorescent Au3+ probe that gives fast response in aqueous solution

Article abstract of DOI:10.1016/j.tet.2012.12.042

The design and synthesis of a simple, selective and efficient turn-off fluorescent Au³⁺ probe, namely, diethyl 1-phenyl-2,5-di(thiophen-2- yl)-1H-pyrrole-3,4-dicarboxylate (1), are highlighted. To our best knowledge, this is the first example of nonreaction-based fluorescent Au³⁺ probes.

Full text of DOI:10.1016/j.tet.2012.12.042

Tetrahedron 69 (2013) 2048e2051
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Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Nonreaction-based fluorescent Au3þ probe that gives fast response
in aqueous solution
€
*
Zahide Oztas¸ , Melek Pamuk, Fatih Algi
Laboratory of Organic Materials (LOM), C¸ anakkale Onsekiz Mart University, TR-17100 C¸ anakkale, Turkey
a r t i c l e i n f o
a b s t r a c t
The design and synthesis of a simple, selective and efficient turn-off fluorescent Au3þ probe, namely,
diethyl 1-phenyl-2,5-di(thiophen-2-yl)-1H-pyrrole-3,4-dicarboxylate (1), are highlighted. To our best
knowledge, this is the first example of nonreaction-based fluorescent Au3þ probes.
Ó 2012 Elsevier Ltd. All rights reserved.
Article history:
Received 17 September 2012
Received in revised form 2 December 2012
Accepted 17 December 2012
Available online 10 January 2013
Dedicated to Professor Metin Balci on the
occasion of his 65th birthday
Keywords:
Gold (III)
Fluorescent probes
Fluorescence
2,5-Dithienylpyrrole
1. Introduction
gold probes have not been explored so far. Therefore, the de-
velopment of nonreaction-based Au3þ probes, exhibiting favour-
Design and synthesis of functional organic compounds, in par-
ticular, fluorescent probes, which allow selective and sensitive
detection of target metal ions have attracted considerable attention
during the last two decades due to the fact that the metal ions play
essential and/or deleterious roles in biological and environmental
processes.1 Among these metal ions, gold is an important trace
element, which has anti-inflammatory properties. Gold ions can be
used as drugs for diseases like arthritis, tuberculosis and cancer.2
On the other hand, it is also known that some gold species (e.g.,
AuCl3) cause damage to the liver, kidneys, and the nervous system.3
Furthermore, Au3þ ions are bound to certain enzymes and DNA
leading to cell toxicity and/or DNA cleavage in living organ-
isms.4,5b,g Despite the significance of gold ions, efficient fluorescent
probes that can be used for their detection have been meagre. In-
deed, there exist only a few reports on fluorescent probes, which
can selectively recognize gold ions.5,6 Nevertheless, all of these
probes are reaction-based, where the alkynophilicity of gold ions is
generally utilized: either gold-ion mediated cyclization5 or hydra-
tion6 reactions take place. To our best knowledge, however, the
design and synthesis of nonreaction-based selective fluorescent
able features including simplicity, high efficiency, high selectivity
and fast response in physiological conditions, is in high and urgent
demand for quick monitoring of Au3þ ions in chemistry, bio-
chemistry, medicine and the environment.
To this purpose, we envisaged that a 2,5-dithienylpyrrole (SNS)7
motif could be amplified to create a simple, selective and viable
Au3þ probe. Herein we wish to report the design, synthesis and
properties of a novel SNS based material bearing strong electron-
withdrawing substituents, 1. It is noteworthy that this novel ma-
terial can be used as an efficient nonreaction-based fluorescent
Au3þ probe. Furthermore, this simple probe is highly selective and
it gives fast response to Au3þ among other ions. To our best
knowledge, this is the first example of nonreaction-based fluores-
cent Au3þ probes.
2. Results and discussion
The synthesis of the target compound was carried out via
a three-step reaction sequence (Scheme 1). First of all, pyrrole 2 was
coupled with bromobenzene (3) in the presence of CuI as catalyst
through a CeN bond formation8 reaction to afford 4 albeit in low
yield (ca. 40%) (Scheme 1). Bromination of 4 with Br2 in the pres-
ence of NaHCO3 gave 5 in 87% yield. This was followed by Stille
reaction of 5 and 2-tributylstannylthiophene (6),9 which, provided
* Corresponding author. Tel.: þ90 2862180018; fax: þ90 2862180536; e-mail
addresses: falgi@comu.edu.tr, falgi76@hotmail.com (F. Algi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.042

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Z. Oztas¸ et al. / Tetrahedron 69 (2013) 2048e2051
2049
1 in 88% yield. All new compounds were initially characterized on
the basis of 1H, 13C NMR, FTIR, elemental and HRMS analysis, which
firmly established the structures (see Supplementary data).
EtO2C
a
CO2Et
Br
EtO2C
CO2Et
N
N
H
3
2
4
b
EtO2C
CO2Et
EtO2C
Br
CO2Et
Br
c
N
N
S
S
Fig. 2. Relative fluorescence emission intensity of 1 (1.50ꢁ10ꢂ5 M) in the presence of
various metal ions (1 equiv) in phosphate buffer (pH¼7.2) (0.15% CH3CN, v/v)
1
(
lexc¼312 nm).
5
Scheme 1. Reaction conditions: (a) CuI, K3PO4, DMEDA, C6H5CH3, 110 ꢀC, 40%; (b) Br2,
NaHCO3, CH2Cl2, 0 ꢀC, 87%; (c) Pd[P(Ph)3]4, 6, C6H5CH3, 110 ꢀC, 88%.
and Hg2þ are serious interferences5g,6 in the detection of Au3þ ions it
is noteworthy that 1 shows excellent selectivity towards Au3þ
(Fig. S11).
First of all, the absorption profile of 1 was examined in solution.
The UVevis spectrum (Fig. S10) of 1 (1.7ꢁ10ꢂ5 M) in phosphate
buffer (pH¼7.2) containing 0.15% CH3CN (v/v) is characterized by
a broad band between 270 and 360 nm (lmax¼312 nm) with
Fig. 3 shows the fluorescence spectral changes of 1 as a function
of Au3þ concentration (0e120
m
M) in phosphate buffer (pH¼7.2)
(0.15% CH3CN, v/v) at room temperature. It is important to note that
a progressive decrease in the fluorescence emission intensity at
440 nm was observed as the concentration of the ion was increased.
Upon binding of Au3þ ion to 1, the fluorescence emission of
dithienylpyrrole was quenched. The quenching mechanism might
presumably be based on the electron and/or charge transfer be-
tween the dithienylpyrrole and metal cation, thus providing an
efficient nonradiative decay of the excited state.
a molar extinction coefficient (
) of 49,652 Mꢂ1 cmꢂ1. On the other
3
hand, the fluorescence spectra of 1 exhibited a broad emission peak
with a lmax(emis) at 440 nm.
Next, the metal cation binding response of 1 has been explored by
spectrophotometric titrations with different metal ions in phosphate
buffer (pH¼7.2) containing 0.15% CH3CN (v/v). It was found that the
addition of Agþ, Al3þ, Cd2þ, Co2þ, Cuþ, Cu2þ, Fe2þ, Hg2þ, Kþ, Mg2þ
,
Mn2þ, Naþ, Ni2þ, Pb2þ, Pd2þ, Pt2þ or Zn2þ ions did not induce sig-
nificant changes in the emission profile of 1 as depicted in Fig. 1. To
our delight, however, the emission intensity of 1 was decreased upon
addition of Au3þ ions (Figs. 1 and 2). Considering the fact that Pd2þ
Clearly, the changes in the emission profile of 1 upon addition of
Au3þ indicated the formation of a well-defined complex between 1
and Au3þ. Evaluation of a Job plot for the determination of the
Fig. 1. Fluorescence spectra of 1 (1.50ꢁ10ꢂ5 M) in the presence of various metal ions
(1 equiv) in phosphate buffer (pH¼7.2) (0.15% CH3CN, v/v) (lexc¼312 nm).
Fig. 3. Fluorescence spectra of 1 (1.65ꢁ10ꢂ5 M) as a function of added Au3þ ions in
phosphate buffer (pH¼7.2) (0.15% CH3CN, v/v) (lexc¼312 nm).

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Z. Oztas¸ et al. / Tetrahedron 69 (2013) 2048e2051
stoichiometry of the complex between 1 and Au3þ revealed a 1:1
ratio (Fig. S12). Interestingly, diethyl 2,5-di(thiophen-2-yl)-1H-
pyrrole-3,4-dicarboxylate (7)10 or 2,5-dithienylpyrrole (8),11 which
did not have phenyl and phenyl/ester units at the pyrrole core
(Fig. 4), did not exhibit any selectivity towards Au3þ ions in phos-
phate buffer (pH¼7.2) (0.15% CH3CN, v/v) (Fig. S13). 1H NMR spec-
trum of 1 in the presence of Au3þ ions (Fig. S14) revealed slight
chemical shifts of the thiophene protons, which probably suggested
that the interaction was between the Au3þ ions and thiophene ring
of SNS system. It is also noteworthy that probe 1 is still responsive
to Au3þ ions when a mixture of different cations are used (Fig. 5).
line is currently underway in our laboratory, and the results will be
reported in due time.
4. Experimental section
4.1. General
All chemicals were purchased from SigmaeAldrich or Merck
and used as received unless otherwise noted. FTIR spectra were
recorded on Perkin Elmer Spectrum 100 model FTIR with an at-
tenuated total reflectance (ATR). 1H (400 or 300 MHz) and 13C (100
or 75 MHz) NMR spectra were recorded on a Bruker DPX-400 or
Ultrashield 300 NMR spectrometer. Combustion analyses were
carried out by using an LECO CHNS-932 analyzer. High-resolution
mass spectra (HRMS) were recorded on Waters SYNAPT MS system
(TOF MS ES). UVevis and fluorescence measurements were recor-
ded on Varian Cary 50 and Varian Cary Eclipse spectrophotometers,
respectively. Melting points were determined on a Schorrp MPM-
H2 model apparatus and are uncorrected. Column chromatogra-
phy was performed on silica gel (60e200 mesh) from Merck
Company. TLC was carried out on Merck 0.2 mm silica gel 60 F254
analytical aluminium plates. The syntheses of 6,9 710 and 811 were
carried out according to the published procedures. Metal solutions
were freshly prepared from the corresponding perchlorate salts
with the exceptions of Au3þ [prepared from AuCl3], Pd2þ [prepared
from Pd(OAc)2] and Pt2þ [prepared from K2PtCl4].13
EtO2C
S
CO2Et
S
N
H
N
H
S
S
8
7
Fig. 4. Structures of compounds 7 and 8.
4.2. Synthesis of diethyl-1-phenyl-1H-pyrrole-3,4-
dicarboxylate (4)
To a screw-cap test tube were placed CuI (20 mg), 2 (422 mg,
2.0 mmol), K3PO4 (2.10 mmol) and a stir bar. The reaction vessel
was fitted with a rubber septum, evacuated and back-filled with
argon, and this sequence was repeated two times. Then 3 (377 mg,
2.4 mmol), N,N-dimethylethylenediamine (DMEDA, 0.04 ml,
0.4 mol) and toluene (1 ml) were added successively under
a stream of argon. The reaction tube was sealed and immersed in
a pre-heated oil bath at 110 ꢀC for 24 h. The reaction mixture was
removed from heating, allowed to cool to ambient temperature and
filtered through a plug of Celite. The filtrate was concentrated and
the resulting residue was subjected to column chromatography
eluting with hexane/CH2Cl2 (1:1, v/v) to give 4: 0.32 g (1.12 mmol),
56% yield, crystalline solid, mp 48e49 ꢀC. 1H NMR (300 MHz, CDCl3)
Fig. 5. Fluorescence spectra of 1 (1.40ꢁ10ꢂ5 M) in the presence of a mixture of (Agþ
,
d
/ppm: 7.58 (s, 2H), 7.49e7.34 (m, 5H), 4.33 (q, J¼9.6 Hz, 4H), 1.35 (t,
Al3þ, Cd2þ, Co2þ, Cuþ, Cu2þ, Fe2þ, Hg2þ, Kþ, Mg2þ, Mn2þ, Naþ, Ni2þ, Pb2þ, Pd2þ, Pt2þ and
J¼9.6, 6H); 13C NMR (75 MHz, CDCl3)
d/ppm: 163.4, 139.0, 129.9,
Zn2þ) metal ions and Au3þ ions in phosphate buffer (pH¼7.2) (0.15% CH3CN, v/v)
127.6, 126.0, 121.2, 117.8, 60.4, 14.3; FTIR (cmꢂ1): 3130, 3064, 2976,
1714, 1684, 1601, 1536, 1422, 1288, 1235, 1063. Anal. Calcd for
C16H17NO4: C, 66.89; H, 5.96; N, 4.88. Found: C, 66.85; H, 5.95; N,
4.85. HRMS calcd for C16H17NO4Na: 310.1059, found: 310.1055.
(
lexc¼312 nm).
On the basis of the above spectrophotometric titrations, the
binding constant (Ka) of 1 with Au3þ was determined from the
emission intensity data following the steady-state fluorometric
method12 in which I0 referred to the fluorescence intensities of
solutions of 1. When I0/(IꢂI0) is plotted against [M]ꢂ1, Ka was cal-
culated to be 2.54ꢁ104 Mꢂ1 from the ratio of intercept/slope with
a good correlation coefficient (R¼0.99786) as depicted in Fig. S15.
4.3. Synthesis of diethyl-2,5-dibromo-1-phenyl-1H-pyrrole-
3,4-dicarboxylate (5)
Br2 (0.06 ml, 1.10 mmol) was added dropwise to a suspension of
4 (0.15 g, 0.5 mmol) and NaHCO3 (1 mmol) in CH2Cl2 at 0 ꢀC. The
mixture was stirred at room temperature overnight. The solvent
was removed under vacuum after filtration and the residue was
subjected to column chromatography with hexane/CH2Cl2 (1:1, v/v)
as eluent to give 5 as colourless liquid: 0.19 g (0.42 mmol), 84%
3. Conclusion
In summary, the design and synthesis of a simple and efficient
Au3þ probe 1, which is based on SNS core unit with strong electron-
withdrawing ester substituents, are described. It is noteworthy that
this novel probe 1 gives selective response to Au3þ ions. Last, but
not least, this latent probe 1 is the first example of nonreaction-
based fluorescent gold probes, which paves the way to explore
nonreaction-based fluorescent gold probes. Further work in this
yield. 1H NMR (400 MHz, CDCl3)
d/ppm: 7.54e7.59 (m, 2H),
7.22e7.27 (m, 3H), 4.35 (q, J¼7.2 Hz, 4H), 1.36 (t, J¼7.2 Hz, 6H); 13C
NMR (100 MHz, CDCl3) d/ppm: 162.6, 136.6, 130.1, 129.3, 128.8,
117.9, 108.2, 61.1, 14.1; FTIR (cmꢂ1): 3065, 2981, 1712, 1596, 1488,
1268, 1196, 1065, 1032, 762. Anal. Calcd for C16H15NO4Br2: C, 43.17;
H, 3.40; N, 3.15. Found: C, 43.15; H, 3.44; N, 3.19. HRMS calcd for
C16H15NO4NaBr2: 465.9271; found: 465.9266.

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4.4. Synthesis of diethyl 1-phenyl-2,5-di(thiophen-2-yl)-1H-
References and notes
pyrrole-3,4-dicarboxylate (1)
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J¼7.0 Hz, 4H), 1.23 (t, J¼7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
d/
ppm: 164.5, 136.6, 130.4, 130.2, 130.0, 129.0, 128.7, 128.7, 127.7, 126.3,
116.7, 60.8, 14.0; FTIR (cmꢂ1): 3099, 2989, 2949, 1720, 1688, 1486,
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4.69; N, 3.10; S, 14.20. Found: C, 63.81; H, 4.71; N, 3.12; S, 14.18;
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We are grateful to the Scientific and Technological Research
Council of Turkey (TUBITAK, Grant Nos. 109R009 and 110T871),
European Cooperation in Science and Technology (COST), and
€
€
C¸ anakkale Onsekiz Mart University for financial support. Z.O. and
M.P. are indepted to TUBITAK for graduate fellowships.
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Supplementary data
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13. Excess amount of chloride ions were added to the solution of probe 1 in order
to show that the chloride ions in AuCl3 do not play any role in the response of
the probe (see Fig. S16)
Copies of 1H, 13C NMR and HRMS spectra for all new compounds.
Supplementary data associated with this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2012.12.042.