A naphthalimide-based bifunctional fluorescent probe for the differential detection of Hg2+ and Cu2+ in aqueous solution

Article abstract of DOI:10.1039/c4dt00014e

A novel fluorescent probe NPM based on naphthalimide was designed and synthesized. Interestingly, NPM exhibited highly selective fluorescence turn-on for Hg²⁺ and turn-off for Cu²⁺ in aqueous solution (10 mM HEPES, pH 7.5). Its fluorescence intensity enhanced in a linear fashion with the concentration of Hg²⁺ and decreased in a nearly linear fashion with the concentration of Cu²⁺. Thus NPM could be potentially used for the quantification of Hg²⁺ and Cu²⁺ in aqueous solution. A series of model compounds were rationally designed and synthesized in order to explore the sensing mechanisms and binding modes of NPM with Hg²⁺ and Cu²⁺. This journal is the Partner Organisations 2014.

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A bifunctional fluorescent probe NPM exhibits highly selective
fluorescence turn-on for Hg2+ and turn-off for Cu2+ was synthesized.

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PAPER
A naphthalimide-based bifunctional fluorescent probe for the
differential detection of Hg2+ and Cu2+ in aqueous solution
Chang-Bo Huang,a Hao-Ran Li,b Yuanyuan Luoc and Lin Xu*a
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
A novel fluorescent probe NPM based on naphthalimide was designed and synthesized. Interestingly,
NPM exhibited highly selective fluorescence turn-on for Hg2+ and turn-off for Cu2+ in aqueous solution
(10 mM HEPES, pH 7.5). Its fluorescence intensity was enhanced in a linear fashion with the
concentration of Hg2+ and decreased in a nearly linear fashion with the concentration of Cu2+, respectively.
10 Thus NPM could be potentially used for the quantification of Hg2+ and Cu2+ in aqueous solution. A series
of model compounds were rationally designed and synthesized in order to explore the sensing
mechanisms and binding modes of NPM with Hg2+ and Cu2+.
molecular keypad lock devices.10 However, to the best of our
Introduction
knowledge, just two examples of bifunctional fluorescent probes
50 capable of the simultaneous detection of Hg2+ and Cu2+ have been
In the past few years, the development of fluorescent probes for
15 detecting of heavy and transition metal (HTM) ions has attracted
increasing attention owing to their simplicity, high sensitivity,
and real-time detection.1,2 Among various HTMs, Hg2+ and Cu2+
are of particular interest due to their diverse physiological roles in
living systems and their environmental impact. Hg2+, as one of
20 the most highly toxic metals, could easily pass through biological
membranes, such as skin, respiratory system, and gastrointestinal
tissues. Excessive exposure and accumulation of mercury could
lead to a number of severe health problems such as brain damage,
kidney failure, and various cognitive and motion disorders.3 Cu2+
25 is the third most abundant of the essential nutrient required for
normal cell growth and development, which plays critical roles in
many biological processes, such as blood formation and
functioning of various enzymes. Moreover, as well as its
deficiency, Cu2+ overload can result in a variety of diseases, such
30 as parkinson’s disease, epileptic seizures, renal and liver
damage.4 Therefore, the development of new fluorescent probes
for the determination of Hg2+ or Cu2+ is highly desirable. Up to
now, many fluorescent probes for Hg2+ or Cu2+ were reported in
recent literature.5,6 However, some of the reported fluorescent
35 probes for Hg2+ or Cu2+ can be used only in organic medium or
organic-containing solution, which limits their practical
application.7 Even then, some of the reported fluorescent probes
sometimes suffer from the intricate synthetic procedures.8
Therefore, there is a great need for the construction of new
40 fluorescent probes that can detect Hg2+ or Cu2+ in aqueous
solution by a simple synthetic approach.
reported.11 For example, Yin and co-workers reported
a
bifunctional probe that can recognize Hg2+ and Cu2+ only in
organic solvent (CH3CN).11a Tian and Zhu reported another
bifunctional probe DCPP.11b Although its sensing properties
55 could be investigated in organic-containing solution (containing
60% CH3CN as a co-solvent), DCPP displayed a relatively low
sensitivity. The addition of five equivalents of Hg2+ to the
solution of DCPP just induced 2.2-fold enhancement of the
fluorescence intensity. Thus, it is still a challenge to develop
60 bifunctional fluorescent probes for Hg2+ and Cu2+ in aqueous
solution with high selectivity and sensitivity.
Recently, we have reported a highly sensitive and selective
naphthalimide-based Ag+ fluorescent probe NPQ, which contains
a hydroxyquinoline moiety as part of the receptor.12 Herein, by
65 the replacement of hydroxyquinoline moiety in NPQ with
morpholine moiety,
a novel fluorescent probe NPM was
synthesized. Interestingly, NPM exhibited selective fluorescence
turn-on response toward Hg2+ and selective fluorescence turn-off
to Cu2+ in aqueous solution. With the aim to obtaining the insight
70 into the possible sensing mechanisms and binding modes of
In recent years, the construction of multi-ion responsive
fluorescent probes with multiple emission modes received
immense interest.9 Fluorescent probes with a differential response
45 towards multiple analytes are cost-effective and highly desirable
for real-time applications. Moreover, such kind of fluorescent
probes are indispensable for designing molecular logic gates and
Scheme 1 The structures of fluorescent probes of NPQ, NPM and model
compounds NBM and NPP.
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DOI: 10.1039/C4DT00014E
Hg2+
a)
600
500
400
300
200
100
0
Cl
Cl
O
N
O
O
N
O
O
N
O
X
piperazine
K2CO3, CH3CN,
reflux, 12h
2-methoxyethanol,
reflux, 6h
Br
N
N
N
Cl
N
H
X
1 (82%)
Cu2+
NPM and other ions
2, X = N (68%)
Y
HN
NPM, Y = O (75%)
3, X = CH (86%)
2
450 475 500 525 550 575 600 625 650 675 700
K2CO3, CH3CN,
reflux, 12h
NPP, Y = CH2 (69%)
Wavelength (nm)
b)
600
500
400
300
200
100
0
O
HN
3
NBM (78%)
K2CO3, CH3CN,
reflux, 12h
Scheme 2 Synthesis of NPM, NPP and NBM.
NPM with Hg2+ and Cu2+, two model compounds (NBM and
NPP) were designed and synthesized as shown in Scheme 1.
5
Results and discussion
Synthesis of NPM, NBM, and NPP
Fig. 1 (a) The fluorescence spectra and (b) fluorescent intensity at 529 nm
of NPM (10 ꢀM) in the presence of 20 ꢀM of various metal ions such as
45 Zn2+, Mn2+, Ba2+, Hg2+, Ni2+, Cu2+, Co2+, Pb2+, Mg2+, Cd2+, Fe2+, Al3+, Ag+,
and Li+ in aqueous solution (10 mM HEPES, pH 7.5). (λex = 405 nm.)
Compounds NPM, NBM, and NPP were readily synthesized
from N-butyl-4-bromo-1, 8-napthalimide via three step reactions
in good yield as shown in Scheme 2. The structures of all
10 compounds were verified by 1H NMR, 13C NMR, and HRMS.
competitive species coexisting is a very important feature to
evaluate the performance of the fluorescent probe NPM.
Therefore, the competition experiments were also conducted for
50 NPM. Fig. S3a indicated that when Hg2+ was added respectively
into the solution of NPM in the presence of other ions such as
Zn2+, Mn2+, Ba2+, Ni2+, Co2+, Pb2+, Mg2+, Cd2+, Fe2+, Al3+, Ag+,
and Li+, the emission spectra displayed a similar pattern at nearly
529 nm to that with Hg2+ only. Similarly, as shown in Fig. S3b,
55 when Cu2+ was added respectively to the solution of NPM in the
presence of the other metal ions including Zn2+, Mn2+, Ba2+, Ni2+,
Co2+, Pb2+, Mg2+, Cd2+, Fe2+, Al3+, Ag+, and Li+, the emission
spectra of NPM were almost identical to that in the presence of
Cu2+ alone. The results implied that NPM exhibited high
60 selectivity for Hg2+ and Cu2+ even in the presence of other
competitive metal ions.
pH effect of NPM
The absorption and emissive properties of NPM on changing the
pH were determined as shown in Fig. S1. A slight change in the
absorption spectra of NPM was observed when the pH>7.0.
15 However, when the pH<7.0, a slight blue shift of the absorption
spectra (from 398 nm to 387 nm) was found. As shown in Fig.
S1(c), there was nearly no change in fluorescence intensity of
NPM in the pH range from 10.0 to 7.5, suggesting that NPM was
stable. When pH<7.0, the emission intensity of NPM was gradual
20 increased, this may be due to the protonation of N atoms in
pyridine, piperazine, and morpholine moiety. Therefore, it
demonstrated that NPM could work in the pH range from 7.0 to
10.0.
Hg2+-titration and spectral responses
The selectivity of NPM
The responses of NPM to Hg2+ were investigated in detail as
shown in Fig. 2. Upon adding Hg2+, the fluorescence intensity
25 To evaluate the selectivity of NPM in aqueous solution (10 mM
HEPES, pH 7.5), various metal ions such as Zn2+, Mn2+, Ba2+,
Hg2+, Ni2+, Cu2+, Co2+, Pb2+, Mg2+, Cd2+, Fe2+, Al3+, Ag+, and Li+
were employed. As expected, NPM showed a weak fluorescence
in aqueous solution due to the photoinduced electron transfer
30 (PET) process from the electron-rich receptor to the excited
naphthalimide fluorophore. As shown in Fig. 1a, the addition of
Hg2+ to the solution of NPM induced a significant enhancement
of fluorescence (ca. 11-fold) with the emission maximum at 529
nm. By contrast, under the identical conditions, when Cu2+ was
35 added into the solution of NPM, an almost complete fluorescent
emission quenching was observed. However, the addition of the
other metal ions produced a negligible change in the fluorescence
spectra of NPM. Therefore, the results disclosed that NPM was a
Hg2+-specific turn-on yet Cu2+-specific turn-off fluorescent probe.
65 increased by about 11-fold, accompanied by
a slightly
hypsochromic shift from 533 nm to 529 nm in emission spectrum.
The extinction coefficients and the fluorescence quantum yields
of NPM and the complex of NPM with Hg2+ were determined to
be 6173, 6231, 0.016, and 0.139, respectively. Significantly, the
70 fluorescence enhancement at 529 nm was linear in regarding the
concentration of Hg2+ at low ꢀM levels (R2
= 0.9745).
Additionally, the limit of detection of NPM toward Hg2+ was
calculated to be 6.11 × 10−8 M. The results indicated that NPM
was sensitive to Hg2+ and could be potentially used to
75 quantitatively detect Hg2+ concentration in aqueous solution.
Cu2+-titration and spectral responses
The absorption and fluorescence titrations of NPM with Cu2+
40
Achieving high selectivity toward Hg2+ and Cu2+ over the other
2
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DOI: 10.1039/C4DT00014E
60
50
40
30
20
10
0
700
600
500
400
300
200
100
0
a)
a)
Cu2+
Hg2+
450 475 500 525 550 575 600 625 650 675 700
450 475 500 525 550 575 600 625 650 675 700
Wavelength (nm)
Wavelength (nm)
60
700
b)
b)
600
500
400
300
200
100
0
50
40
30
20
10
0
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
[Cu2+]/10-5
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0
[Hg2+]/10-5
M
M
600
500
400
300
200
100
0
Equation
y = a + b*
c)
c)
50
40
30
20
10
Adj. R-Squar 0.94343
Value
Intercept 43.38958
Slope -64.0279
Standard Erro
2.1102
B
B
6.96977
Equation
y = a + b
Adj. R-Squa 0.97453
Value
Intercept -7.08905
Slope 578.4617
Standard Err
19.28705
B
B
31.12435
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
[Hg2+]/10-5
0.0
0.1
0.2
[Cu2+]/10-5
0.3
0.4
0.5
M
M
Fig. 3 Fluorescence spectra of NPM (10 ꢀM) upon the addition of Cu2+
30 (1–20 ꢀM) in aqueous solution (10 mM HEPES, pH 7.5); (b) and (c)
curve of fluorescence intensity at 529 nm of NPM (10 ꢀM) versus
increasing concentrations of Cu2+. (λex = 405 nm.)
Fig. 2 (a) Fluorescence spectra of NPM (10 ꢀM) upon the addition of
Hg2+ (2–20 ꢀM) in aqueous solution (10 mM HEPES, pH 7.5); (b) and (c)
curve of fluorescence intensity at 529 nm of NPM (10 ꢀM) versus
increasing concentrations of Hg2+. (λex = 405 nm.)
5
equiv. of Hg2+ or Cu2+ (Fig. 2b and 3b) to NPM. The association
constants between NPM and Hg2+ and Cu2+ were determined to
35 be 6.06 × 106 M−1 and 3.51 × 106 M−1 by using nonlinear least-
square analysis, respectively.
were performed as well as shown in Fig. 3 and Fig. S4. The
stepwise Cu2+ addition to NPM led to a decrease in the
10 fluorescence intensity at 529 nm, where the intensity became
almost zero upon addition of 1 equiv. of Cu2+. However, the
addition of Cu2+ to NPM did not induce the wavelength change.
The extinction coefficients and the fluorescence quantum yields
of the complex of NPM with Cu2+ were determined to 5978 and
15 0.003, respectively. A nearly linear relationship was observed
between the fluorescence intensity at 529 nm and the Cu2+
concentration at the range of 2.0–5.0 ꢀM. This observation
clearly supported that NPM enabled the quantitative detection of
Cu2+ in aqueous media.
PET quenching mechanism NPM
In order to get insight into the possible fluorescence sensing
mechanism of NPM, the fluorescence spectra of free NPM and
40 model compounds NBM and NPP were examined as shown in
Fig. 5 and Fig. S6. A direct comparison between the fluorescence
intensity of compound NPM with NBM at the same
concentration clearly showed that nitrogen atom in the pyridine
ring in NPM played a significant role in quenching the
45 fluorescence of the naphthalimide moiety through a PET
mechanism. The oxygen atom in morpholine moiety was not
involved in quenching the fluorescence since the fluorescence
intensity of compound NPP resembled that of NPM. It was
possible that the piperazine nitrogen and morpholine nitrogen
50 could also quench the fluoresence. However, the extent would be
20 Job’s plot analysis of Hg2+ and Cu2+
In order to understand the coordination ratio of NPM with Hg2+
and Cu2+, Job’s plot analyses were carried out (Fig. 4). The
results indicated that NPM formed 1 : 1 stoichiometrical complex
both with Hg2+ and Cu2+, which were further supported by the
25 observation that the spectra change almost stopped upon adding 1
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175
150
125
100
75
a)
50
25
0
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
[Hg2+]/( Hg2+
[1]+[ ])
160
140
120
100
80
b)
Scheme 3 Proposed binding modes of NPM with Hg2+ and Cu2+.
In contrast, the fluorescence quenching of NPM upon titration
30 with Cu2+ was due to the well-known paramagnetic effect of Cu2+,
which quenched excited state of fluorophore by energy and/or
electron transfer.6e
60
40
20
Binding models of NPM with Hg2+ and Cu2+
0
To understand the binding modes of NPM with Hg2+ and Cu2+,
35 the fluorescence responses of NPM, NBM, and NPP to Hg2+ and
Cu2+ were conducted as shown in Fig. 5 and Fig. S6. Model
compound NPP lacking the oxygen atom showed the similar
fluorescence response toward Hg2+ and Cu2+, which indicated that
the morpholine oxygen atom in NPM played a negligible role in
40 the binding with Hg2+ and Cu2+. Moreover, the results revealed
that NPP was also a Hg2+-specific turn-on yet Cu2+-specific turn-
off fluorescent probe. The lower binding ability of NBM with
Hg2+ and Cu2+ compared to NPM verified that the pyridine
nitrogen played a major role in both Hg2+ and Cu2+ binding.
45 Furthermore, it is commonly observed that a hypsochromic shift
in absorption or emission maximum usually occurs when the
nitrogen, which is also the donor of a push–pull system, chelates
to metal ions.13 Therefore, we believe that the pyrazine nitrogen
that links to the naphthalimide ring was involved in Hg2+
50 chelation.
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
[Cu2+]/([1]+[Cu2+])
Fig. 4 (a) Job’s plot of NPM and Hg2+ ([NPM] + [Hg2+] = 10 ꢀM) and (b)
Job’s plot of NPM and Cu2+ ([NPM] + [Cu2+] = 10 ꢀM) in aqueous
solution (10 mM HEPES, pH 7.5). (λex = 405 nm.)
5
b)
600
500
400
300
200
100
0
NPM + Hg
NPP + Hg
NBM
NBM + Hg
NBM + Cu
NPM
NPP
NPM + Cu
NPP + Cu
Fig. 5 Fluorescent intensity at 529 nm of NPM, NBM, and NPP (all
compounds were 10 ꢀM) in the absence and presence of Hg2+ (20 ꢀM)
Based on the absorption and fluorescence titration spectra, the
Job’s plots, and the coordination chemistry of Hg2+ and Cu2+, we
proposed the plausible fluorescence sensing mechanisms and
binding modes of the probe NPM with Hg2+ and Cu2+ as shown
55 in Scheme 3.
and Cu2+ (20 ꢀM) in aqueous solution (10 mM HEPES, pH 7.5). (λex
10 405 nm.)
=
expected to be minimal due to its high pKa value.12 In addition to
the fluorescence quenching via PET mechanism, we believe that
the higher degree of molecular flexibility of NPM also has
fundamental implications.
The fluorescence enhancement of the NPM response to Hg2+
might be attributed to photoinduced electron transfer (PET) and
chelation-enhanced fluorescence (CHEF) mechanisms as follows.
Before coordination with Hg2+, NPM gave a weak fluorescence
because of the lone electron pairs of the N atoms in pyridine,
Conclusions
15
In conclusion, a novel naphthalimide-based fluorescent probe
NPM was developed successfully. NPM displayed high
selectivity and sensitivity for Hg2+ and Cu2+ with fluorescence
60 turn-on and turn-off in aqueous solution, respectively. Moreover,
it was found that its fluorescence intensity was enhanced in a
linear fashion with the concentration of Hg2+ and decreased in a
nearly linear fashion with the concentration of Cu2+, respectively,
which indicated that the probe NPM could be potentially used as
65 a bifunctional probe for the quantification of Hg2+ and Cu2+. The
sensing mechanisms and binding modes of NPM with Hg2+ and
20 piperazine, and morpholine moiety being located close to the
naphthalimide fluorophore, which resulted in an intramolecular
photoinduced electron transfer (PET). However, when NPM was
coordinated with Hg2+, the PET process was blocked
synchronously and the complex was more rigid, thus a significant
25 enhancement of fluorescence was observed.
4
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aDepartment of Chemistry, East China Normal University, 3663 N.
55 Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: lxu@chem.ecnu.edu.cn
bFutian Second People’s Hospital, Shenzhen 518049, P. R. China.
cSchool of Pharmacy, East China University of Science and Technology,
Shanghai 200237, P. R. China.
Cu2+ were confirmed by Job’s plot analyses and the comparison
with a series of model compounds. Considering its obvious
advantages such as convenience in preparation, excellent sensing
ability towards Hg2+ and Cu2+, and mild detection environment,
NPM was expected to have a variety of applications such as
environmental monitoring and surveillance.
5
60 † Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
Experimental
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Materials and measurements
65
Unless otherwise mentioned, all the reagents were of analytic
10 grade. 1H-NMR and 13C-NMR spectra were measured on a
Bruker AM-400 spectrometer with chemical shifts reported as
ppm (in CDCl3). Mass spectrometry data were obtained with a
HP 5989A spectrometer. Absorption spectra were determined on
a Varian Cary 100 Spectrophotometer. Fluorescence spectra were
15 determined on a Varian Cary Eclipse. Emission slit widths of the
experiment of Job’s plot of NPM and Cu2+ were 5 and 10, the
influence of pH on and fluorescence of NPM were 2.5, 5 nm, the
other slit widths were 5, 5.
70
75
The metal salts used were Fe(ClO4)2, Zn(ClO4)2·6H2O,
20 Co(ClO4)2·6H2O,
Pb(ClO4)2·3H2O,
Ni(ClO4)2·6H2O,
Cd(ClO4)3·6H2O,
Ba(ClO4)2·3H2O,
Cu(ClO4)2·6H2O,
80
Mn(ClO4)2·6H2O, LiClO4·3H2O, NaClO4·H2O, AgClO4·H2O,
Hg(ClO4)2·3H2O, Mg(ClO4)2·6H2O.
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85
Synthesis
25 Compound NPM. Anhydrous potassium carbonate (138 mg, 1.0
mmol), compounds 2 (238 mg, 0.5 mmol) and morpholine (435
mg, 5.0 mmol) were dissolved in acetonitrile (10 mL), and the
reaction mixture was refluxed for 12 h under argon atmosphere.
The mixture was filtered, and the solvent was removed in a
30 vacuum to give a yellow solid. The crude product was then
chromatographed on silica gel using dichloromethane–methanol
30 : 1 (v/v) as eluant to afford 198 mg (75%) NPM as a yellow
90
95
1
solid. H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 7.2 Hz, 1H),
8.50 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.4 Hz, 1H), 7.73–7.65 (m,
35 2H), 7.47 (s, 2H), 7.21 (d, J = 8.0 Hz, 1H), 4.15 (t, J = 7.6 Hz,
2H), 3.88 (s, 2H), 3.80 (s, 6H), 3.35 (s, 4H), 2.91 (s, 4H), 2.65 (s,
4H), 1.74–1.63 (m, 2H), 1.49–1.37 (m, 2H), 0.96 (t, J = 7.2 Hz,
3H). 13C NMR (CDCl3, 100 MHz) δ: 164.49, 164.03, 155.66,
137.29, 132.51, 131.10, 130.13, 129.83, 126.13, 129.83, 126.13,
40 125.72, 123.32, 116.94, 115.04, 66.43, 64.16, 53.45, 53.28, 52.71,
40.11, 30.26, 20.42, 13.90. ESI-MS for C31H38N5O3 [(M + H)+]:
528.47. HR-ESI-MS calcd for C31H38N5O3 [(M + H)+]: 528.2969,
found: 528.2994.
100
105
3
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The other model compounds were synthesized as shown in 110
45 Schemes S1–S2.†
Acknowledgements
115
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The work was financially supported by the National Natural
Science Foundation of China (No. 21302058), the Research Fund
for the Doctoral Program of Higher Education of China (No.
50 20130076120006), and the Fundamental Research Funds for the
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120
Central Universities. We also appreciate valuable discussion with
Prof. Hai-Bo Yang (East China Normal University).
Notes and references
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