A rapid Hg2+ sensor based on aza-15-crown-5 ether functionalized 1,8-naphthalimide

Article abstract of DOI:10.1016/j.tetlet.2011.07.056

A new 1,8-naphthalimide derivative bearing an aza-15-crown-5 macrocycle (1) has been synthesized as a chemosensor for Hg²⁺ by a two-step reaction. The sensor shows selectivity to Hg²⁺ over 11 other metal cations in aqueous media. Upo

Full text of DOI:10.1016/j.tetlet.2011.07.056

Tetrahedron Letters 52 (2011) 4903–4905
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Tetrahedron Letters
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A rapid Hg2+ sensor based on aza-15-crown-5 ether functionalized
1,8-naphthalimide
⇑
Chen Hou, Alysha M. Urbanec, Haishi Cao
Department of Chemistry, University of Nebraska at Kearney, Kearney, NE 68849, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new 1,8-naphthalimide derivative bearing an aza-15-crown-5 macrocycle (1) has been synthesized as a
chemosensor for Hg2+ by a two-step reaction. The sensor shows selectivity to Hg2+ over 11 other metal
cations in aqueous media. Upon addition of Hg2+, the fluorescence emission of the sensor at 537 nm is
significantly quenched along with 22 nm blue-shift that makes this compound a useful sensor for Hg2+
measurement.
Received 5 May 2011
Revised 7 July 2011
Accepted 12 July 2011
Available online 21 July 2011
Published by Elsevier Ltd.
Keywords:
Fluorescent sensor
Hg2+
1,8-Naphthalimide
ICT
As a detrimental metal ion, Hg2+ has continually received con-
cern for its deleterious effects on nature, environment, and human
health.1 There have been many reports on the toxicity of Hg2+ to
human’s central nervous system and immune system, conse-
quently resulting in brain damage, vision loss and death.2 In partic-
ular, the poisoning effect of Hg2+ is reflected on its efficient
bioaccumulation by methylating inorganic mercury to methylmer-
cury.3 In contrast to Hg2+, methylmercury is able to cross the cell
membrane and is accumulated in the cell, causing irreversible
damage to nucleic acids and proteins.4 Despite the high toxicity,
Hg2+ is still being used in many industrial processes that contribute
a significant portion of Hg2+ contamination.5 Therefore, developing
effective methods for Hg2+ detection keeps attracting great interest
in the sensing community.6
fluorescent sensors have been reported for the detection of various
molecules.12 Compared to other fluorophores, the fluorescence
emission spectra of 1,8-naphthalimides are significantly affected
by substituents on the naphthalene ring that provide an excellent
sensing switch for sensor design.13 Aza-15-crown-5 is a widely
used ligand with high coordinating ability with metal cations.14
Herein, we report a 1,8-naphthalimide-aza-15-crown-5 conjugate
(e.g. 1) that functioned as a Hg2+ sensor at pH 7.4. Sensor 1 displays
high binding ability to Hg2+ and selectivity against other competi-
tive metal cations in aqueous media. Upon binding Hg2+, 1 exhibits
strong fluorescence depletion and a blue-shift that indicates the
achievability of an ICT sensor for Hg2+ analysis.
The synthesis of 1 is shown in Scheme 1. Condensation between
4-bromo-1,8-naphthalic anhydride and 4-methoxyaniline gives 2
in pyridine (130 °C for 3 h).15 Then, 1-aza-15-crown-5 is refluxed
with purified 2 to afford a yellow solid 1 in 79% yield. The structure
of 1 is confirmed by 1H NMR, 13C NMR and elemental analysis (see
Supplementary data).16
Spectroscopic measurements are collected in aqueous buffer (i.e.,
10 mM HEPES containing 20% MeOH at pH 7.4) at ambient temper-
ature. Sensor 1 displays the maximum absorption at 432 nm and the
fluorescence emission at 537 nm, respectively. The optical re-
sponses of sensor 1 to various metal cations are investigated by
the UV–vis and fluorescence spectroscopy. In the presence of Hg2+
(40 mol equiv), the emission spectrum of 1 (1.0 Â 10À6 M) exhibits
substantial quenching at 537 nm (kex = 432 nm) together with a
22 nm blue-shift that is attributed to the formation of 1–Hg2+ com-
plex (Fig. 1). The coordination between Hg2+ and aza-15-crown-5
macrocycle may reduce the electron-donating ability of the amino
group on the naphthalene ring that results in fluorescence
Compared to traditional approaches for Hg2+ analysis relied on
complicated sample preparation or sophisticated instrumentation,
fluorogenic probes provide a rapid, facile, and sensitive tool for
Hg2+ detection.7 In the past years, many efforts have been devoted
to develop fluorescent sensors based on various sensing strate-
gies.8 However, for most of the reported fluorescent sensors, the
selectivity and signal intensity are still major challenges.9 There
continues to be a strong demand for fluorescent sensors of Hg2+
with high signal/noise ratio and affinity.10
Among diverse fluorophores providing signal for fluorescent
sensors, the N-aryl-1,8-naphthalimides attract particular interest
due to their brightness, photo stability, and internal charge transfer
(ICT) structure.11 Recently, numerous 1,8-naphthalimide-based
⇑
Corresponding author. Tel.: +1 308 8658105; fax: +1 308 8658399.
E-mail address: caoh1@unk.edu (H. Cao).
0040-4039/$ - see front matter Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2011.07.056

4904
C. Hou et al. / Tetrahedron Letters 52 (2011) 4903–4905
O
O
HN
O
O
N
O
O
N
O
O
O
O
O
H2N
OCH3
O
O
O
O
OCH3
OCH3
N
Br
Pyridine, reflux 15 hr
Pyridine, reflux 3 hr
Br
3
2
1
Scheme 1. Synthetic route of fluorescent chemosensor 1.
1.2
1.2
1.0
0.8
0.6
0.4
0.2
0.0
1.0
B
A
[Hg2+] 0-40uM
0.8
0.8
0.4
0.0
0.8
450
480
510
540
570
600
630
Wavelength (nm)
0.6
0.4
0.4
1E-7
1E-6
1E-5
1E-4
0.0
[Hg2+] M
300
400
500
500
600
Wavelength (nm)
Figure 2. Fluorescence titration of
1
(1.0 Â 10À6 M) in response to increasing
amounts of Hg2+ (kex = 432 nm) in aqueous buffer (i.e., 10 mM HEPES containing
Figure 1. Absorption (A) and fluorescence emission (kex = 432 nm) (B) spectra of 1
(1.0 Â 10À6 M) in aqueous buffer (i.e., 10 mM HEPES containing 20% MeOH at pH
7.4), prior to (—) and following addition of 20 mol equiv of Hg2+ (- - -).
20% MeOH at pH 7.4).
quenching and blue-shift.17 Upon addition of Hg2+, the absorption
spectrum of 1 also displays significant change, the peak at 432 nm
decreases and the peak at 346 nm increases (Fig. 1). The changes
of both of absorption and emission spectra indicate that the forma-
tion of 1–Hg2+ complex interrupts ICT between the nitrogen atom on
the aza-15-crown-5 macrocycle and the naphthalimide moiety, and
also make 1 have the necessary spectral properties to serve as a sen-
sitive chemosensor for Hg2+ detection. Further titration experiments
are conducted to investigate the binding ability between 1 and Hg2+
(Hg2+: 0–4.0 Â 10À5 M). As shown in Figure 2, with the gradual addi-
tion of Hg2+, the fluorescence emission of 1 at 537 nm keeps decreas-
ing. The maximal spectral change is observed upon addition of near
20 mol equiv of Hg2+ relative to 1 (1.0 Â 10À6 M) with 64% fluores-
cence depletion and a 22 nm blue-shift. Based on titration data,
0.6
0.5
0.4
0.3
0.2
0.1
0.0
the binding constant of 1 with Hg2+ is found to be 2.24 Â 105 MÀ1
.
The selectivity of 1 toward Hg2+ over other competitive species
is investigated in the presence of various biologically and environ-
mentally relevant metal ions. All of measurements are conducted
by using the perchlorate of metal ion (4.0 Â 10À5 M) and 1
(1.0 Â 10À6 M) in aqueous buffer (i.e., 10 mM HEPES containing
20% MeOH at pH 7.4). As shown in Figure 3, the introduction of
Hg2+ to 1 elicits significant fluorescence depletion at 537 nm be-
cause of ICT interruption caused by 1–Hg2+ complex. By contrast,
K+, Na+, Ag+, Ba2+, Ca2+, Cd2+, Co2+, Cu2+, Fe2+, Pb2+, and Mg2+ are
examined under the same condition, but no marked emission
quenching is observed. Fe2+ results in 19% quenching on a much
smaller scale than Hg2+. K+, Na+, and Mg2+ lead to slight fluores-
K+ Na+ Ag+ Pb2+ Hg2+ Cu2+ Mg2+Fe2+ Ba2+ Ca2+ Cd2+ Co2+
Figure 3. The gray bars represent the fluorescence change of 1 (1.0 Â 10À6 M) at
537 nm in presence of K+, Na+, Ag+, Pb2+, Hg2+, Cu2+, Mg2+, Fe2+, Ba2+, Ca2+, Cd2+, and
Co2+ (40 equiv) in 10 mM HEPES buffer (containing 20% MeOH at pH 7.4)
(kex = 432 nm).
complex also displays a 22 nm blue-shift that makes 1 more selec-
tive to Hg2+ over other metal cations (Fig. S1). The further investi-
gation for 1’s binding affinity to Hg2+ is carried out by competition
experiments. Possible competition between Hg2+ and other metals
against 1 are measured by using mixed solutions containing
cence enhancement that may be the result of interaction with
10
the O atom on naphthalimide moiety.
Moreover, the 1–Hg2+
4.0 Â 10À5 M Hg2+ and 4.0 Â 10À5 M each of K+, Na+, Ag+, Ba2+
,

C. Hou et al. / Tetrahedron Letters 52 (2011) 4903–4905
4905
Ca2+, Cd2+, Co2+, Cu2+, Fe2+, Pb2+, and Mg2+. With the addition of
mixture solution, 1 shows significant quenching in all of the sam-
ples that suggests the strong interaction between 1 and Hg2+
(Fig. S2 in Supplementary data). Moreover, several anions, includ-
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2À
3À
ing ClÀ, NO3À, ClO4À, AcOÀ, SO42À, CO3 and PO4 (obtained by
using their sodium salt; 4.0 Â 10À5 M), also are used to examine
possible interference in the binding interaction between 1 and
Hg2+. No fluorescence quenching triggered by these anions is ob-
served (Fig. S3 in Supplementary data), indicating that 1 represents
a robust sensor for high-throughput measurements against Hg2+
.
In conclusion, we have successfully devised a naphthalimide-
aza-15-crown-5 conjugate that behaved as a selective fluorescent
Hg2+ sensor by a simple two-step synthesis. Sensor 1 displays sig-
nificant turn-off and blue-shift responses of fluorescence following
Hg2+ recognition. Although 1 requires MeOH as co-solvent to
increase solubility in aqueous media, this sensor still offers a facile
analysis method for Hg2+ detection and also may contribute to the
development of more efficient chemosensors based on the 1,8-
naphthalimide platform.
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Acknowledgments
This research is supported by Mini-Grant, URF, and URCA in the
University of Nebraska at Kearney.
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15. A mixture of 4-bromo-1,8-naphthalic anhydride (0.277 g, 1.0 mmol) and 4-
methoxyaniline (0.123 g, 1.0 mmol) in 10 mL pyridine was refluxed for 3 h
under argon atmosphere. The reaction mixture was poured into 40 mL 1.0 M
cold HCl solution to collect precipitate. The crude product was purified by
column chromatography (silica, 220–400 mesh, dichloromethane/EtOAc = 3:1
v/v). The product was isolated as a brown powder 2 (0.35 g, 91%). 1H NMR
(300 MHz, DMSO-d6) d: 3.82 (s, 3H), 7.06 (d, J = 8.9 Hz, 2H), 7.29 (d, J = 9.8 Hz,
2H), 8.05(t, J = 7.4 Hz, 1H), 8.26 (d, J = 7.5 Hz, 1H), 8.35 (d, J = 8.9 Hz, 1H), 8.60
(d, J = 6.1 Hz, 2H); 13C NMR (75 MHz, DMSO-d6) d: 55.8, 114.6, 123.2, 124.0,
128.7, 129.4, 129.7, 130.6, 131.4, 131.9, 132.1, 133.1, 159.4, 163.8. MS: m/z
(MH)+ 381.23. Anal. Calcd for C19H12BrNO3: C, 59.71; H, 3.16; N, 3.66. Found: C,
59.34; H, 3.28; N, 3.49.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.056.
References and notes
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16. Compound 2 (0.191 g, 0.5 mmol) and 1-aza-15-crown-5 (0.153 g, 0.7 mmol) in
5 mL pyridine were refluxed for 15 h under argon atmosphere. Then pyridine
was removed by rotary evaporation to afford crude product 1 that was purified
by column chromatography (silica, 220–400 mesh, MeOH/EtOAc = 1:4 v/v).
Product was collected as a bright yellow powder 1 (0.14 g, 53%). 1H NMR
(300 MHz, DMSO-d6) d: 3.75 (m, 20H), 3.90 (s, 3H), 7.07 (m, 2H), 7.25(m, 2H),
7.52 (d, J = 8.9 Hz, 1H), 7.71 (t, J = 7.4 Hz, 1H), 8.55 (d, J = 9.0 Hz, 1H), 8.62 (d,
J = 7.6 Hz, 1H), 8.75 (d, J = 9.5 Hz, 1H); 13C NMR (75 MHz, DMSO-d6) d: 54.2,
55.5, 69.4, 70.8, 71.2, 114.6, 116.1, 117.2, 123.3, 125.3, 127.1, 128.3, 129.4,
131.4, 131.5, 132.3, 155.7, 159.4, 164.3. MS: m/z (MH)+ 520.65. Anal. Calcd for
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