Turn-on ratiometric fluorescent sensor for Pb2+ detection

Article abstract of DOI:10.1016/j.tetlet.2011.03.075

We report a ratiometric lead fluorescent sensor (LFS-1) with high affinity to Pb²⁺ that shows considerable selectivity over 12 other physiological related metal cations in aqueous media. Binding induces excimer formation, providing a highly sensitive ratiometric measure of lead concentrations.

Full text of DOI:10.1016/j.tetlet.2011.03.075

Tetrahedron Letters 52 (2011) 2692–2696
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Turn-on ratiometric fluorescent sensor for Pb2+ detection
Chen Hou a, Yijia Xiong b, Na Fu b, Caitlin C. Jacquot a, Thomas C. Squier b, Haishi Cao a,
⇑
a Department of Chemistry, University of Nebraska at Kearney, Kearney, NE 68849, USA
b Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA 99354, USA
a r t i c l e i n f o
a b s t r a c t
We report a ratiometric lead fluorescent sensor (LFS-1) with high affinity to Pb2+ that shows considerable
selectivity over 12 other physiological related metal cations in aqueous media. Binding induces excimer
formation, providing a highly sensitive ratiometric measure of lead concentrations.
Ó 2011 Elsevier Ltd. All rights reserved.
Article history:
Received 27 February 2011
Accepted 15 March 2011
Available online 22 March 2011
Keywords:
Pb2+
Sensor
Pyrene
As one of the major industrial pollutants, Pb2+ causes adverse
environmental impacts and human health related problems, par-
ticularly for children (where lead poisoning is defined as blood lev-
intensity and distinctive excimer emission that results in a large
spectral red-shift that facilitates measurements in complex envi-
ronments.9 Sensors were designed using the sulfur of a thio-ester
moiety as a receptor to recognize Pb2+, thereby facilitating forma-
tion of a dimeric interaction between pyrene moieties through a
coordinating interaction that is required for excimer formation
els above 5 l
M).1 Therefore, developing low-complexity sensing
approaches with high affinity for detecting Pb2+ remains an active
research area.2 In the past decade, considerable efforts have been
devoted to designing and synthesizing fluorescent chemosensors
for Pb2+ analysis due to their high sensitivity, simplicity, and adapt-
ability to different platforms that facilitate routine screening.3
Many Pb2+-responsive fluorescent sensors, in which biological
molecules, polymers, and small organic scaffolds are utilized as
recognition units, have been reported.4–6 However, compared to
other heavy metal ions sensors, the ion specificity and sensitivity
of current generation fluorescent sensors for Pb2+ limit their util-
ity.7 Currently, major challenges for Pb2+-responsive fluorescent
sensors require increases in both (i) the recognition affinity to
Pb2+ without interference from other competing metal ions and
(ii) the solubility in aqueous media to allow detection of Pb2+ in
biological samples.8 Herein, we report the synthesis and properties
of a highly soluble turn-on lead fluorescent sensor (LFS-1) that
binds Pb2+ with high affinity and displays selectivity against other
physiological metals in aqueous media. Upon binding Pb2+ LFS-1
exhibits a strong excimer peak at 469 nm resulting from contact
interactions between pyrene monomers within LFS-1 that are
brought together upon metal chelation, which is evident both in
model systems and in human blood plasma, indicating the feasibil-
(Scheme 1). LFS-1 was synthesized by
a two-step reaction.
1-Pyrenebutyric acid was refluxed with thionyl chloride for 3 h
to give 1-pyrenebutyric chloride. Esterification between 1 equiv
1, 2-ethanedithiol and 2 equiv of 1-pyrenebutyric chloride afforded
LFS-1 with 88% yield (Scheme 2). An alternative sensor (i.e., LFS-2)
with
a shorted linker connecting the thio-ester and pyrene
functionalities based on 1-pyrenecarboxylic acid also was prepared
O
O
S
S
S
Pb2+
S
Pb2+
O
O
ity of using LFS-1 to rapidly screen for Pb2+
.
LFS-1 was prepared by using pyrene as the fluorophore, which
has been studied extensively because of its strong fluorescence
⇑
Corresponding author. Tel.: +1 308 8658105; fax: +1 308 8658399.
E-mail address: caoh1@unk.edu (H. Cao).
Scheme 1. Fluorescent sensor for Pb2+
.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.075

C. Hou et al. / Tetrahedron Letters 52 (2011) 2692–2696
2693
OH
Cl
S
S
O
HS
SH
O
SOCl2/CH2Cl2
Reflux 3hr
O
O
CH2Cl2
LFS-1
88%
O
O
O
O
S
S
OH
Cl
HS
SH
SOCl2/CH2Cl2
Reflux 3hr
CH2Cl2
LFS-2 79%
Scheme 2. The synthetic route of LFS-1 and LFS-2.
using the same synthetic route. The structures of LFS-1 and LFS-2
were confirmed by 1H NMR, 13C NMR, and elemental analysis.10,11
Spectroscopic measurements were carried out in aqueous buf-
fer (i.e., 10 mM HEPES containing 10% DMSO at pH 7.4). LFS-1 dis-
plays characteristic spectral features of pyrene, with absorption
bands at 326 and 342 nm and fluorescence emission bands at
375 and 395 nm (kex = 355 nm). Upon addition of 10 M equiv of
spectral properties to serve as a sensitive ratiometric probe in
response to Pb2+ 12
Specifically, as the excimer fluorescence appar-
ent at 469 nm is absent prior to Pb2+ binding, it is apparent that the
intensity ratio at 469 nm normalized by that at 395 nm (I469/I395
.
)
represents a sensitive means to measure Pb2+ levels in complex
environments using the LFS-1 sensor. While, additional sensitivity
is possible by selecting excitation wavelengths that limit excitation
of the LFS-1 sensor prior to Pb2+ binding, which shifts the absorp-
tion spectra toward the red (Fig. 1A), we emphasize the use of LFS-
1 under conditions that excite both the free (unbound) and Pb2+
chelated species that facilitate ratiometric measurements of the
apparent binding affinity.
Pb2+, LFS-1(1.0
lM) displays large changes in the absorption spec-
trum, resulting in decreases in absorption bands at 328 and
342 nm and the appearance of a new peak at 357 nm (Fig. 1A). In
the presence of Pb2+, the fluorescence emission spectrum of LFS-
1 also exhibits a new band at 469 nm together with a substantial
quenching in the 365–425 nm spectral region (Fig. 1B). Observed
spectral changes are indicative of the formation of an excimer com-
plex resulting from contact interactions between pyrene mono-
To explore further the binding properties of LFS-1, titration
experiments were conducted by using Pb2+ with concentrations
ranging from 0 to 10 l
M (Fig. 2). Upon addition of Pb2+ to LFS-1,
mers in the presence of Pb2+ that arise due to
p
–p
stacking
there is a 92% decrease in the fluorescence of monomer coincident
interactions. Coupled with the large depletion of fluorescence at
with detection of an excimer fluorescence at 469 nm that provides
365–425 nm, these results indicate that LFS-1 has the necessary
a high signal-to-noise measurement using 1 lM LFS-1. Based on
the titration data, maximal spectral changes are observed upon
addition of a near equimolar stoichiometry of Pb2+ relative to the
LFS-1 (i.e., 1 lM), indicating that the binding affinity of LFS-I for
1.0
Pb2+ is in the submicromolar range needed for practical measure-
ments of Pb2+ in drinking water.13
A
0.8
0.6
0.4
0.2
0.0
The selectivity of LFS-1 to bind Pb2+ relative to other common
metals was investigated by ratiometric measurements (i.e., I469
/
I395) in the presence of various biologically and environmentally
relevant metal ions. All of measurements were conducted by using
the perchlorate of different metal ions (100 lM) and LFS-1(1.0 lM)
in aqueous buffer (i.e., 10 mM HEPES containing 10% DMSO at pH
7.4). LFS-1 displayed an extremely selective turn-on response to
Pb2+ with a maximum I469/I395 ratio of 2.1 (no corrections for con-
tributions of scattered light at 469 nm were made). In contrast,
300
1.0
350
400
450
500
upon addition of K+, Na+, Ag+, Ba2+, Ca2+, Cd2+, Co2+, Cu2+, Fe2+
,
B
Hg2+, and Mg2+, LFS-1 exhibited no significant excimer emission
at 469 nm; albeit fluorescence quenching at 375 nm leads to small
increases in the calculated I469/I395 ratio (<0.5) that can be reduced
by correcting for scattered light by using suitable blank subtraction
or modifying the detection wavelength used to monitor excimer
formation toward the red (Fig. 3A). Especially for Ag+, Cu2+ and
Hg2+, the fluorescence at 395 nm was quenched more than 96%.
Fluorescence quenching is possible by two mechanisms involving
either excimer formation with concomitant decreases in the fluo-
rescence of the pyrene monomer or through spin-orbital coupling
that arises from a coupling between metal ions and pyrene.14,15
Due to the high I469/I395 ratio, the fluorescence quenching trigged
by Pb2+ binding was attributed mainly to the excimer formation
rather than in intrinsic quenching. In comparison, some other met-
als (e.g., Hg2+) exhibit no excimer fluorescence upon binding LFS-1
0.8
0.6
0.4
0.2
0.0
400
450
500
550
600
Wavelength (nm)
Figure 1. Absorption (A) and fluorescence emission (kex = 355 nm) (B) spectra of
LFS-1 (1.0 M) in aqueous buffer (i.e., 10 mM HEPES containing 10% DMSO at pH
7.4), prior to (___) and following addition of 10 M Pb2+ (- - -).
l
l

2694
C. Hou et al. / Tetrahedron Letters 52 (2011) 2692–2696
2.5
1.0
0.8
0.6
0.4
0.2
0.0
C
1.0
A
0.8
2.0
0.6
0.4
1.5
0.2
0.0
0.1
1
10
400
450
500
550
600
Wavelength (nm)
1.0
0.5
0.0
1.0
0.8
0.6
0.4
0.2
0.0
B
0.1
1
10
0.01
0.1
2+
1
10
2+
[
Pb
µM
)
[
Pb
]
(
µ
M
)
]total (
total
Figure 2. Fluorescence (A), excimer (B), and calculated ratiometric signal (C) of LFS-1 (1.0 l
M) in response to increasing amounts of Pb2+ (kex = 355 nm) in aqueous buffer
(i.e., 10 mM HEPES containing 10% DMSO at pH 7.4).
despite substantial decreases in their fluorescence intensity, which
are attributed to spin-orbital coupling (Fig. 3B).
1.0
A
For the practical analysis of Pb2+, it is important that the binding
affinity between LFS-1 and Pb2+ is not substantially affected by the
Free, K+,Na+,Ag+,Ba2+,Ca2+,
Cd2+,Co2+,Cu2+,Fe2+,Hg2+,Mg2+
0.8
presence of other cations, such as Ca2+, Cd2+, Fe2+, and Hg2+ that
16
commonly cause significant interference.
Possible competition
between Pb2+ and other metals against LFS-1 was measured by
0.6
0.4
using mixed solutions containing 100 l lM each
M Pb2+ and 100
of K+, Na+, Ag+, Ba2+, Ca2+, Cd2+, Co2+, Cu2+, Fe2+, Hg2+, Mg2+. Irre-
spective of the addition of any of the mixed solution to LFS-
1(1.0 lM), the observed pyrene excimer signal was observed at
469 nm with no appreciable changes to the calculated spectro-
Pb2+
0.2
0.0
scopic ratio (I469/I395) ( Fig. S2). These results indicate that the
high-affinity interaction between LFS-1 and Pb2+ is selective rela-
À
tive to other catiÀons. Moreover, several anions, including Cl
,
NO3À, ClO4À, AcO , SO42À, CO32À, and PO43À, (obtained by using
their sodium salt; 100 M), also were used to examine possible
interference in the binding interaction between LFS-1 and Pb2+
400
450
500
550
600
Wavelength (nm)
l
.
No fluorescence quenching or dimer emission triggered by these
anions is observed (Fig. S3, Supplementary data), indicating that
LFS-1 represents a robust sensor for high-throughput measure-
B
2.0
1.5
1.0
0.5
0.0
ments against Pb2+
.
To further explore the possibility of using LFS-1 as a useful re-
agent for Pb2+ analysis in biological systems, LFS-1 was examined
in human blood plasma. After incubating with blood plasma di-
luted 10-fold in an aqueous buffer containing 1.0
37 °C for 5 min, LFS-1 showed fluorescence quenching at 395 nm
and substantial excimer fluorescence emission at 469 nm
l
M Pb2+ at
a
(Fig. 4). Although the light scattering interference from the plasma
contributed to the signal (i.e., I469/I395 = 0.1), these results confirm
the biocompatibility of LFS-1 for Pb2+ detection. The measured sig-
nal can be further optimized using more favorable sample geome-
tries and excitation to minimize sample scattering.
Free K+ Na+ Ag+ Pb2+ Hg2+Cu2+Mg2+Fe2+Ba2+Ca2+ Cd2+Co2+
As a comparison, LFS-2 was synthesized by 1-pyrencarboxylic
acid and 1, 2-ethanedithiol to investigate the influence of distance
between pyrene and receptor to forming excimer of pyrene. Com-
pared to LFS-1, the thioester of LFS-2 was appended directly to pyr-
ene without a spacer. Based on our previous results, the decreased
distance between thioester acceptor and pyrene fluorophore are
Figure 3. Selective association between LFS-1 and Pb2+. (A) Fluorescence emission
spectra of LFS-1 (1.0 l ,
M) upon addition of K+, Na+, Ag+, Ba2+, Ca2+, Cd2+, Co2+, Cu2+
Fe2+, Hg2+, Mg2+, and Pb2+ (100 equiv) in 10 mM HEPES buffer (containing 10%
DMSO at pH 7.4) (kex = 355 nm). (B) The gray bars represent the ratio of excimer
emission fluorescence at 469 nm to monomer emission at 395 nm (I469/I395) in
presence of indicated cations.

C. Hou et al. / Tetrahedron Letters 52 (2011) 2692–2696
2695
LFS-1, LFS-2 showed fluorescence quenching upon addition to
Pb2+ but without emission of the pyrene excimer, indicating dis-
tinct mechanisms underlying fluorescence quenching and the for-
mation of the pyrene dimer necessary for excimer formation. These
measurements emphasize a requirement for sufficient flexibility in
the probe scaffold in the rational design of fluorescent sensors
requiring pyrene–pyrene interactions.
Free LFS-1
1.0
0.8
0.6
0.4
0.2
0.0
LFS-1 + Pb2+
Acknowledgments
This research is supported by Mini-Grant, Undergraduate Re-
search Fellows Program, and University Research and Creative
Activity in the University of Nebraska at Kearney. Authors would
also like to acknowledge Sara Basiaga in University of Nebraska
at Lincoln for her assistance in collecting fluorescence spectra.
400
450
500
550
Wavelength (nm)
Supplementary data
Figure 4. Excimer formation upon chelation of Pb2+ by LFS-1 in blood plasma.
Fluoresence emission spectra of LFS-1 (1.0 M) in human blood plasma following
l
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.075.
a 10-fold dilution to reduce scattering prior to (black line) and following (red line)
addition of 1.0
Figure 2.
l
M Pb2+. Sample conditions are as described in the legend to
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Pb2+
Hg2+
400
450
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Wavelength (nm)
Figure 5. Selective fluorescence quenching of LFS-2 upon metal binding with no
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of K+, Na+, Ag+, Ba2+, Ca2+, Cd2+, Co2+, Cu2+, Fe2+, Hg2+, Mg2+, and Pb2+ (100 equiv) in
1.0 mM HEPES buffer (pH 7.4) containing 10% DMSO (kex = 355 nm).
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expected to result in a direct quenching of the pyrene monomer
and an inability to form the pyrene dimer upon metal binding
due to insufficient scaffold flexibility.17 Fluorescence titration
experiments using different metal ions were performed under
the same condition used for LFS-1. Fluorescence quenching was
observed without excimer emission upon addition of following
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10. A mixture of 1-pyrenebutyric acid (0.504 g, 1.7 mmol) and thionyl chloride
(3 mL, 41.0 mmol) in 20 mL dichloromethane was refluxed for 3 h under argon
atmosphere. The reaction mixture was distilled to remove excess thionyl
chloride and dichlormethane to afford the compound 2 as a white solid, which
was used for the next reaction without further purification. To a solution of
Mg2+, and Pb2+. While ion binding, particularly apparent in the
presence of Hg2+, significantly reduced the fluorescence emission
spectra of LFS-2––in no case is there emission of the pyrene exci-
mer (Fig. 5). This result is consistent with our observations using
LFS-1, indicating that geometrical considerations associated with
the linker between receptor moiety and fluorophore are essential
factors that contribute to the sensor design, which requires the for-
mation of the pyrene excimer upon Pb2+ binding.
unpurified
2 in 20 mL of dichloromethane was added 1,2-ethanedithiol
(0.072 mL, 0.8 mmol) and the solution was refluxed for 1 h under argon
protection. After the reaction mixture was cooled down to room temperature,
dichloromethane was removed by rotary evaporation to give the crude product
that was purified by column chromatography (silica, 220–400 mesh, hexane/
EtOAc = 2:1 v/v). The product is isolated as a pale powder LFS-1 (0.48 g, 88%).
1H NMR (300 MHz, DMSO) d: 1.21 (m, 4H), 2.03 (m, 4H), 2.39 (m, 4H), 3.45(m,
4H), 7.92–9, 124.6, 124.7, 125.2, 125.5, 126.7, 127.1, 127.7, 127,9, 128.0, 128.7,
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tions as a fluorescent probe for Pb2+ sensing with high selectivity.
LFS-1 coordinates Pb2+ with 1:1 complex stoichiometries. LFS-1
displayed significant pyrene excimer emission as well as the
quenching of monomer in the presence of Pb2+. In contrast to

2696
C. Hou et al. / Tetrahedron Letters 52 (2011) 2692–2696
129.8, 130.9, 131.4, 136.9, 175.2. MS: m/z (MH)+ 634.29. Anal. calcd for
42H34O2S2:C, 79.46; H, 5.40. Found: C, 79.68; H, 5.36.
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(3 mL, 41.0 mmol) 20 mL dichloromethane was refluxed for 3 h under argon
atmosphere. The reaction mixture was distilled to remove excess thionyl
chloride and dichlormethane to afford the compound 4 as a white solid,
which was used for the next reaction without further purification. To a solution
128.9, 129.3, 130.1, 130.4, 131.2, 133.4, 171.5. MS: m/z (MH)+ 550.18. Anal.
calcd for C36H22O2S2:C, 78.52; H, 4.03. Found: C, 78.34; H, 4.09.
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C
of unpurified
4
in 20 mL of dichloromethane was added 1,2-
ethanedithiol(0.084 mL, 1.0 mmol) and the solution was refluxed for 1 h
under argon protection. After the reaction mixture was cooled down to room
temperature, dichloromethane was removed by rotary evaporation to give the
crude product that was purified by column chromatography (silica, 220–400
mesh, hexane/EtOAc = 2:1 v/v). The product is isolated as a pale powder LFS-2
(0.43 g, 79%). 1H NMR (300 MHz, DMSO) d: 1.22 (m, 4H), 8.15 (t, 2H, J = 7.5),
8.18–8.42 (m, 12H), 8.58(d, 2H, J = 7.4), 9.23 (d, 2H, J = 8.4); 13C (75 MHz,
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