Modulating the selectivity by switching sensing media: a bifunctional chemosensor selectivity for Cd²⁺ and Pb²⁺ in different aqueous solutions

Abstract

A novel bifunctional fluorescent probe RI, based on rhodamine with isatin, was designed and synthesized. Switching of the selectivity of RI between various metal ions was achieved by judicious choice of sensing media. RI gives a turn-on fluorometric and colorimetric signal toward Cd²⁺ in 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) (10 mM, CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution and a turn-on colorimetric signal toward Pb²⁺ in Tris-HCl (70 mM, CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solution. To the best of our knowledge, this is the first example of a chemosensor based on a small molecule that can selectively recognize both Cd²⁺ and Pb²⁺ in different sensing systems. Fluorescence imaging of Cd²⁺ in living cells was also obtained.

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Introduction

In the past few years, tremendous efforts have been devoted to the development of fluorescent and/or colorimetric chemosensors for selective and sensitive detection of heavy and transition metal (HTM) ions because of their diverse physiological roles in living systems and their environmental impact.¹ HTM ions, in particular Cd²⁺ and Pb²⁺, have received focused attention due to their detrimental effects on public health. Recent studies indicate that human exposure to cadmium may cause lung, renal and prostate cancers and calcium metabolism disorders.² Similarly, prolonged accumulation of lead in the body leads to many serious human health problems, including muscle paralysis, mental confusion, memory loss and anaemia.³ Therefore, development of high performance Cd²⁺ and Pb²⁺ probes is a very active field of research. A number of fluorescent and/or colorimetric chemosensors for each were reported in recent literature.⁴

It is quite often that Cd²⁺ and Pb²⁺ are found to coexist, such as in organic-rich soil profiles in the vicinity of a zinc smelter, in biowaste and in edible marine products including molluscs and crustaceans.⁵ We believe that if there was a single probe that could perform Cd²⁺ detection under one condition and Pb²⁺ detection under another, the cost for their measurement could potentially be greatly reduced, from the point of view of both the necessary reagents and laboratory effort. Such bifunctional fluorescent probes for other metal pairs, such as Pb²⁺/Hg²⁺, Au³⁺/Hg²⁺ and Fe³⁺/Cu²⁺ are already known.⁶ Our group also reported two examples of bifunctional fluorescent probes.⁷ One is for selective recognition of Cd²⁺ and Hg²⁺ and the other for selective recognition of Zn²⁺ and Cu²⁺. Modulation of metal ion selectivity was achieved via judicious choice of aqueous buffer solution in these two cases.

In this paper, we report a new rhodamine-based fluorescent probe, RI, whose selectivity to Cd²⁺ and Pb²⁺ is modulated by switching sensing media.

Results and discussion

Molecular design and synthesis

Herein, rhodamine B was chosen as the fluorophore, by virtue of its excellent photophysical properties, such as good photostability and long-wavelength absorption and emission.⁸ Besides, it is a convenient platform to construct colorimetric “naked eye” and/or fluorescence “off-on” probes, taking advantage of the opening of the spirolactam ring. Three examples of reported bifunctional probes were also based on the rhodamine scaffold.^6a,6c,7b In this work, we incorporated an isatin moiety into the probe RI for metal coordination. Isatin and its derivatives are potent inhibitors of monoamine oxidase, caspase-3 and so on,⁹ while their potential for Cd²⁺ chelation was not examined. This is their first use in constructing a Cd²⁺ ligand.

Sensor RI was concisely synthesized from rhodamine B in two steps (Scheme 1). The structure of RI was verified by ¹H NMR, ¹³C NMR and high resolution mass spectrometry (HRMS) (Fig. S1, ESI†).

Scheme 1 Synthesis of RI.

The selectivity of RI toward Cd²⁺. Initial screening of the metal binding ability of RI was carried out in HEPES (10 mM, CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution. RI was nearly colorless and non-fluorescent in HEPES (10 mM, CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution, due to its stable spirolactam form. Upon addition of Cd²⁺ to a solution of RI, the solution instantaneously changed from nearly colorless to pink, and significant enhancement of fluorescence with an emission maximum at 581 nm was observed. However, the other ions, including Pb²⁺, produced only minor changes in the fluorescence spectra (Fig. 1). Therefore, RI was a highly selective fluorescence “off-on” probe for Cd²⁺ in HEPES (10 mM, CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution.

Fig. 1 Fluorescence spectra of RI (10 μM) in the presence of 100 μM solutions of various metal ions in HEPES (10 mM, CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution.

The selectivity of RI toward Pb²⁺. As it has been shown that the selectivity of the chemosensor could be profoundly affected by switching various parameters of the sensing media, such as the solvent, pH, buffer, ionic strength and so on,¹⁰ further investigations of the selectivity of RI in alternative systems were also carried out.

The solution of RI in Tris-HCl (70 mM, CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solution was also nearly colorless and did not exhibit apparent absorption above 500 nm, due to the formation of the stable spirolactam. Addition of Pb²⁺ to a solution of RI led to an obvious absorption enhancement at 563 nm, along with an obvious color change from colorless to purple (Fig. 2). However, no enhancement of fluorescence was observed, and we supposed that the fluorescence quenching caused by Pb²⁺ belonged to static quenching.¹¹ In this solvent system, it is interesting to see that all the other metal ions including Cd²⁺ did not lead to the same absorption enhancement under the same conditions. The selectivity was again confirmed via competition experiments (Fig. S5, ESI†). The above results suggest that RI can serve as a highly selective “naked eye” probe for Pb²⁺ in Tris-HCl (70 mM, CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solution.

Fig. 2 UV-vis absorption spectra of RI (10 μM) in the presence of 160 μM solutions of various metal ions, such as Fe²⁺, Zn²⁺, Cd²⁺, Pb²⁺, Ba²⁺, Hg²⁺, Mg²⁺, Co²⁺, Ni²⁺, Ca²⁺, Mn²⁺, Cu²⁺, Fe³⁺, Cr³⁺, Li⁺, Ag⁺ and K⁺ in Tris-HCl (70 mM, CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solution. Inset: the photograph shows the color change of RI (10 μM) in the presence of 160 μM solutions of various metal ions; from left to right: RI, Cd²⁺, Hg²⁺, Zn²⁺, Pb²⁺, Cu²⁺, Ni²⁺, Fe³⁺, Co⁺, other mixtures.

Cd²⁺-titration and Pb²⁺-titration. The UV-vis and fluorescence titrations were carried out by gradual addition of various amounts of Cd²⁺ and Pb²⁺, respectively (Fig. 3; Fig. S3, ESI†). A nearly linear relationship was obtained between the fluorescence intensity of sensor RI and the low concentration of Cd²⁺ in HEPES (10 mM, CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution and Pb²⁺ in Tris-HCl (70 mM, CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solution, respectively. The results indicate that RI is sensitive towards Cd²⁺ and Pb²⁺ in the corresponding sensing media.

Fig. 3 Fluorescence spectra (a) and UV-vis absorption spectra (b, c, d) of RI (10 μM) upon addition of (a) Cd²⁺ (10 μM∼150 μM), (b) Pb²⁺ (10 μM∼40 μM) in HEPES (10 mM, CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution and (c) Cd²⁺ (5 μM∼30 μM), (d) Pb²⁺ (5 μM∼260 μM) in Tris-HCl (70 mM, CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solution.

Job plot analysis of Cd²⁺ and Pb²⁺. The binding stoichiometries between RI and Cd²⁺ and Pb²⁺ were determined via Job plot analysis. The results indicated that RI forms a 1 : 1 stoichiometric complex with both Cd²⁺ and Pb²⁺ (Fig. 4). The association constants between RI and Cd²⁺ and Pb²⁺ in different systems were determined, as shown in Table 1.

Fig. 4 Job plot of (a) RI and Cd²⁺ ([RI] + [Cd²⁺] = 80 μM) in HEPES (10 mM, CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) and (b) RI and Pb²⁺ ([RI] + [Pb²⁺] = 80 μM) in Tris-HCl (70 mM, CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solutions.

Table 1 The association constants of RI with Cd²⁺ and Pb²⁺ in different buffer solutions

Buffer	Cd^2+/M^−1	Pb^2+/M^−1
a ND: The association constant could not be accurately measured through spectroscopic titration due to the low affinity.
10 mM HEPES	2.6 × 10^4	ND^a
70 mM Tris-HCl	ND^a	2.4 × 10^4

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The proposed binding modes of RI with Cd²⁺ and Pb²⁺

To further study the specific binding model, the ¹H NMR titration experiments were measured. As shown in Fig. S6,† a set of new peaks appeared with the addition of Cd²⁺ into the solution of RI in CD₃CN. The apparent downshift of H₁ and H₂ in the presence of Cd²⁺ suggests the formation of the ring-opened form of rhodamine.¹² The downshift of H₃ indicates that the oxygen atom of the amide group participates in the binding. In addition, the H₄ upshift from 7.98 to 7.89 is due to the “O” on the hydrazide group participating in the binding. Taken together, based on the ¹H NMR titration, the coordinating properties of Cd²⁺ and the Job plot, a possible binding mode between RI and Cd²⁺ is shown in Scheme 2. Since Pb²⁺ belongs to static quenching, the ¹H NMR titration experiment failed. We proposed a possible binding mode between RI and Pb²⁺ similar to Cd²⁺. The energy-minimized structures of RI with both Cd²⁺ and Pb²⁺ were calculated by the Gaussian program (Fig. 5).

Fig. 5 Energy-minimized structures of (a) RI, (b) RI with Cd²⁺, (c) RI with Pb²⁺ and (d) the overlap of (b) and (c) were calculated by the B3LYP method with the 6-311G basis set (Gaussian 09 programme).

Scheme 2 Proposed binding modes of RI with (a) Cd²⁺ and (b) Pb²⁺.

The influences of buffer and solvent on the selectivity of RI

The influences of buffer on the selectivity of RI were determined. As shown in Fig. 6(a, c) and Fig. 7(a, c), the response of RI to Cd²⁺ is barely affected by the concentration of HEPES; however, it is significantly affected by the concentration of the Tris buffer. As shown in Fig. 6(b, d) and Fig. 7(b, d), the response of RI to Pb²⁺ is barely affected by the concentration of neither the HEPES nor the Tris buffer. It is known that Tris contains hydroxy and amino groups, which could chelate different metal ions with varied affinities. The above results indicate that Tris competes with the probe for the binding of Cd²⁺ but not Pb²⁺. The affinity between RI and Cd²⁺ was totally overwhelmed when a bolus concentration of Tris buffer was used.

Fig. 6 Fluorescence spectra (a) and UV-vis absorption spectra (b) of RI (10 μM) in the presence of (a) Cd²⁺ (100 μM) and (b) Pb²⁺ (100 μM) in 10 mM or 35 mM HEPES (CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution. UV-vis absorption spectra of RI (10 μM) in the presence of (c) Cd²⁺ (160 μM) and (d) Pb²⁺ (160 μM) in 10 mM or 70 mM Tris-HCl (CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solution.

Fig. 7 The ratiometric (a) fluorescence and (b) UV-vis absorption changes of RI (10 μM) in the presence of (a) Cd²⁺ (100 μM) and (b) Pb²⁺ (100 μM) in 10 mM or 35 mM HEPES (CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution. The ratiometric UV-vis absorption changes of RI (10 μM) in the presence of (c) Cd²⁺ (160 μM) and (d) Pb²⁺ (160 μM) in 10 mM or 70 mM Tris-HCl (CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solution.

Fluorescence imaging of cadmium in living cells

To further demonstrate the practical biological applications of the sensor RI, fluorescence imaging experiments were carried out in living cells. Hela cells were incubated with RI for 30 min, followed by the addition of 6.0 equivalents Cd²⁺ at 37 °C, and then incubated for another 30 min. The cells were washed three times with PBS buffer solution (containing 2.0% ethanol).¹³Fig. 8 shows that when Hela cells were treated with sensor RI only, no fluorescence was detected; by contrast, bright red fluorescence was noted when Hela cells were incubated with the sensor RI treated with Cd²⁺. The results suggest that sensor RI is cell membrane permeable and can also be used for imaging of Cd²⁺ in living cells and potentially in vivo.

Fig. 8 (a) Bright-field transmission image of Hela cells pre-incubated with sensor RI (10 μM) for 30 min, washed three times, and then treated with Cd²⁺ (6.0 equiv); (b) fluorescence image of (a); (c) bright-field transmission image of Hela cells pre-incubated with sensor RI (10 μM) for 30 min, washed three times; (d) fluorescence image of (c).

Conclusions

In conclusion, we have developed a new bifunctional fluorescent probe RI based on rhodamine, with a novel receptor. We modulated the selectivity of RI to various metal ions by switching the sensing media. RI gives a turn-on fluorometric and colorimetric signal toward Cd²⁺ in HEPES (10 mM, CH₃OH–H₂O, 4 : 6, v/v, pH 7.6) buffer solution and a turn-on colorimetric signal toward Pb²⁺ in Tris-HCl (70 mM, CH₃OH–H₂O, 6 : 4, v/v, pH 7.6) buffer solution. To the best of our knowledge, this is the first example of a chemosensor based on a small molecule that can selectively recognize both Cd²⁺ and Pb²⁺ in different sensing systems. Furthermore, we have demonstrated that the sensor RI was applicable for Cd²⁺ imaging in the living Hela cells.

Experimental

Materials and measurements

Unless otherwise mentioned, all the reagents were of analytical grade. ¹H NMR and ¹³C NMR spectra were measured on a Bruker AM-400 spectrometer, with chemical shifts reported in ppm (in CDCl₃, TMS as internal standard). Mass spectra were obtained with a HP 5989A spectrometer. All pH measurements were made with a Sartorius basic pH-Meter PB-20. Absorption spectra were determined on a Varian Cary 100 Spectrophotometer. Fluorescence spectra were determined on a Varian Cary Eclipse. HPLC traces were determined on a HP-1100 spectrometer.

Synthesis of probe RI

Rhodamine B hydrazide (1). In this work, 1 was synthesized according to ref. 14. In a 50 mL flask, rhodamine B (0.48 g, 1.0 mmol) was dissolved in 12 mL ethanol. 1.2 mL (excess) hydrazine hydrate (85%) was then added. After the addition, the mixture was heated under reflux for 2 h. The solution changed from dark purple to light orange and became clear. Then the mixture was cooled and the solvent removed under reduced pressure. 1 M HCl (about 20 mL) was added to the solid in the flask to generate a clear red solution. After that, 1 M NaOH (about 28 mL) was added slowly with stirring until the pH of the solution reached 9∼10. The resulting precipitate was filtered and washed 3 times with 6 mL water, and then dried in air. The product was then chromatographed on silica gel using CH₂Cl₂–CH₃OH (30 : 1, v/v) as the eluent, to afford 0.37 g (81%) 1 as a pink solid.

RI. 1 (0.64 mmol, 300 mg) was dissolved in 10 mL absolute methanol, then 2,3-indolinedione (0.76 mmol, 112 mg) was added. Then the mixture was heated under reflux and stirred for 6 h. After that, the solvent was removed under vacuum to give an orange solid. The crude product was then chromatographed on silica gel using CH₂Cl₂–CH₃OH (20 : 1, /v) as the eluent, to afford 242 mg (63%) RI as an orange solid. ¹H NMR (CDCl₃, 400 MHz): δ 1.15 (t, J = 7.0 Hz, 12H), 3.28–3.34 (m, 8H), 6.25 (dd, J₁ = 8.8 Hz, J₂ = 2.4 Hz, 2H), 6.41 (d, J = 2.0 Hz, 2H), 6.61 (d, J = 8.8 Hz, 2H), 6.76 (d, J = 8.0 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 7.19–7.27 (m, 3H), 7.50–7.57 (m, 2H), 8.02 (d, J = 6.8 Hz, 1H), 8.37 (s, 1H). ¹³C NMR (CDCl₃, 100 MHz): δ 12.69, 44.28, 68.56, 98.12, 106.09, 108.01, 111.04, 118.08, 122.59, 123.98, 124.24, 127.92, 128.10, 128.43, 128.76, 132.93, 133.59, 143.82, 148.76, 151.64, 152.58, 153.45, 160.72, 165.14. HRMS (ES+): Calcd for ([M+H])+, 586.2818, found, 586.2819.

Acknowledgements

We are grateful for the financial support from National Basic Research Program of China (973 Program, 2010CB126100), the China 111 Project (Grant B07023), the Key New Drug Creation and Manufacturing Program (Grant 2009ZX09103-102) and the Shanghai Leading Academic Discipline Project (B507). We also thank Professor Youjun Yang of ECUST for discussions and suggestions.

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Footnote

† Electronic supplementary information (ESI) available: Synthetic details and spectroscopic data. See DOI: 10.1039/c2ra20840g

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