Coordination properties of a Schiff base probe for Zn2+ ion in aqueous media having no Cu2+ ion interference

Inorganica Chimica Acta 448 (2016) 51–55

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Coordination properties of a Schiff base probe for Zn2+ ion in aqueous media having no Cu2+ ion interference Arturo Jiménez-Sánchez ⇑, Margarita Romero-Ávila Facultad de Química, Universidad Nacional Autónoma de México, 04510 México D.F., Mexico

a r t i c l e

i n f o

Article history: Received 4 March 2016 Received in revised form 14 April 2016 Accepted 15 April 2016 Available online 23 April 2016 Keywords: Zn2+ ion sensor Cu2+ ion quenching Cu2+ ion interference Fluorescent sensor Schiff base sensor

a b s t r a c t The coordination properties and acid–base behavior of 2-[{(1S,2R)-1-hydroxy-1-phenylpropan-2-ylimino}methyl]-4-bromophenol Schiff base probe (L1) were characterized by UV–Vis and fluorescence titrations in water. The dissociation constants for the ligand account for a keto–enamine tautomer at pH 7. Detailed complexation studies were carried out, observing the formation of stable 1:1 complex for Zn2+, where a ‘‘turn-on” fluorescence effect is obtained. More importantly, no Cu2+ interference is observed, which is a typical problem for Zn2+ probes, this is awarded to the keto–enamine tautomeric form of the probe L1 according to UV–Vis and X-ray structure data. Also, the Zn2+ vs. Cd2+ ion discrimination for L1 is proved. Finally, TD-DFT theoretical calculations were conducted in order to stablish the detection mechanism of the probe. Ó 2016 Elsevier B.V. All rights reserved.

1. Introduction Recently, several fluorescent molecular probes for a wide range of metal ions were reported in the literature [1]. However, one of the problems is that not a single optical probe known to date is completely specific [2], in particular for analytes in multicomponent pollutants [3] where the use of several probes leads to complications such as metal ion interference, sample contamination and cross-talk [4]. Particularly, the detection of metal ions of biological importance has attracted much attention. In this context, Zn2+ ion fluorescent probes or sensors have acquired special interest. Zn2+ is an essential trace element and the second most abundant metal ion in humans (after Fe2+) [5], and also one of the most common in natural environments [6]. However, the detection of Zn2+ ion requires high sensitivity and selectivity, particularly versus Cu2+ ion, the third most abundant metal ion in human body [7]. Unfortunately, the vast majority of Zn2+ sensors suffer from metal ion interference with Cu2+ ions [8] and in some cases Cd2+ ion also exerts interference [9], making the probe not really useful for continuous and large-time applications in real samples. In fact, the Irving–Williams series describe the affinities of divalent metal ions for ligands, where next to Cu2+ ions, Zn2+ have the highest affinity [10]. In addition, one more complication is that the ⇑ Corresponding author. Tel.: +55 5622 3813; fax: +55 5616 2010. E-mail addresses: [email protected] (A. Jiménez-Sánchez), mago_ro@msn. com (M. Romero-Ávila). http://dx.doi.org/10.1016/j.ica.2016.04.027 0020-1693/Ó 2016 Elsevier B.V. All rights reserved.

Irving–Williams series are based on the same concentrations of metal ions. This problem is aggravated in cancer cells, where the concentration of Fe2+, Zn2+ and Cu2+ ions changes tremendously, such that the concentration of Cu2+ can become the largest of these three ions. For example, the concentration of Fe2+, Zn2+ and Cu2+ in the serum of the peripheral blood of healthy children and children with acute lymphocytic leukemia changes from 68, 103 and 114 lg/dL to 96, 136 and 328 lg/dL, respectively [11]. Therefore, a practical method for the determination of Zn2+ in biological samples must consider a large excess of Cu2+ and also the probe must tolerate the presence of Fe2+ ion. On the other hand, in the field of protein sensors, Human Carbonic Anhydrase II (CA) has a relatively high selectivity to Zn2+ ion, unfortunately Cu2+ ion can also bind to the apoenzyme [12]. Regarding the Zn2+/Cu2+ ion interference, Canary and coworkers described an approach to improve the selectivity of Zn2+ ion by controlling the stereochemistry and increasing the rigidity of the ligand scaffold of a series of piperidine tripod ligands [13a]. However, so far there have been very few reports of Zn2+ fluorescent probes presenting an approach to improve the Zn2+ selectivity over Cu2+ [13]. In this work we describe a fluorescent ‘turn-on’ Schiff base probe L1 (Fig. 1) where the selectivity for Zn2+ ions is analyzed against other metals including Cu2+ and Cd2+ ions in pure water (pH = 7). Here we demonstrate that L1 probe is capable of detecting Zn2+ ion even in the presence of large amounts of Cu2+ ions. The structural of L1 is not characterized by the ligand preorganization (as is commonly observed for tripodal ligands) but rather in

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OH

Br

N H O

L1 Fig. 1. Keto–enamine structure of Schiff base probe L1: schematic representation (left) and X-ray ORTEP diagram (right).

their electronic properties, such that the keto–enamine structure is strongly favored, thus the imino-nitrogen lone pair is no longer available to coordinate with the highly azophilic Cu2+ ion. Further, L1 probe showed no fluorescent response with Cd2+ ion. 2. Results and discussion 2.1. Chemical structure of L1

A ¼ ðAL þ ALH  10ðpK a1 pHÞ þ ALH2  10ðpK a1 þpK a2 2pHÞ Þ=ð1 þ 10ðpKa1 pHÞ

The ligand L1 has been characterized by the crystal structure showing a keto–enamine tautomeric form, Fig. 1 [14]. The synthetic methodology and complete characterization is presented in Supplementary Material file. Analysis of the X-ray structure reveals that the 5-bromosalicylaldehyde fragment with keto–enamine preference adopts a planar conformation owing to the electronic conjugation, while (1S,2R)-norephedrine moiety is out of the molecular plane, overall this ligand conformation favors metal ion binding in the more pre-organized planar fragment with a keto–enamine structure. It is to be noted that no Nitrogen lone pair in the coordination plane is available for coordination with the strongly azophilic Cu2+ ion which comprise a successful design principle in the typical Cu2+ ion interference to other metals since, as is well-known, the fluorescence quenching effect of Cu2+ ions overrides the analytical detection of other metal ions in single-channel recording of fluorescence intensity methods. 2.2. Acid–base properties of L1 Fig. 2 shows the absorption spectra at variable pH. The spectra show the appearance of a blue-shifting in the low-energy band from 410 to 395 nm. However, during the course of titration the

0.6

Absorbance at 397 nm

2.0

Absorbance

1.5

0.5 0.4 0.3 0.2 7

1.0

8

9

10

11

12

pH

0.5

0.0 250

300

formation of two isosbestic points at 274 and 352 nm were observed. The profiles in Fig. 2(inset) fit to the Eq. (1) for two successive deprotonation processes with the respective pKa1 and pKa2 values, where A is absorbance at a given pH, AL, ALH and ALH2 are the absorbances of deprotonated, monoprotonated and doubly protonated forms of the ligand [15]

350

400

450

500

Wavelength (nm) Fig. 2. UV–Vis of 100 lM L1 at variable pH (25 °C and 0.05 M NaCl) in water. Inset shows the absorbance vs. pH profile at 397 nm. Arrows show directions of the spectral changes on increase in pH and the observed non-equivalent isosbestic points at 274 and 352 nm.

þ 10ðpK a1 þpK a2 2pHÞ Þ:

ð1Þ

The pKa1 and pKa2 values obtained from the fitting of these results are 12.72 and 6.78 for the aliphatic OH group and for the enol–imine – keto–enamine tautomerization, respectively. The results suggest that at pH 7 the enol–imine tautomer does not exist and the keto–enamine is the one present in solution. 2.3. Spectroscopic studies of probe L1 The UV–Vis and fluorescence titration experiments were carried out in pure water having 5 mM of cationic surfactant hexadecyltrimethylammonium bromide (HTAB), which is well above its critical micelle concentration. The pH was buffered at 7.0 with 50 mM 3-(N-morpholino) propanesulfonic acid (MOPS). In the case of Zn2+ ion, the UV–Vis titrations shows the formation of a new red-shifted band at 385 nm with the concomitant formation of an isosbestic point at 345 nm indicating the existence of an equilibrium of the ligand and the Zn2+ ion complex, Fig. 3A. In the case of fluorescence titrations, a ‘turn-on’ fluorescence effect is observed with the fluorescence maximum wavelength at 490 nm, indicating the formation of the Zinc complex, Fig. 3B. To further understand the interaction between probe L1 and Zn2+ ions, its observed stability constant (Kobs) was estimated by UV–Vis and fluorescence means at a pH 7. The fitting of the binding isotherm obtained by titration experiments leads to a 1:1 complex with the logarithms of the observed stability constants log(Kobs) of 4.12 and 4.45 for UV–Vis and fluorescence spectroscopy, respectively. Then, the log(Kobs) values were found to be in good agreement and revealed a strong interaction between probe L1 and Zn2+ ions. In addition, the complex formation was followed by 1H NMR in D2O. Fig. S1, Supplementary Material. Addition of 1 equiv. Zn2+ ion reveals the disappearance of the N–H proton signal, indicating the interaction of Zn2+ to the Keto–enamine fragment. 2.3.1. Competition experiments Then, UV–Vis and fluorescence spectroscopic titrations of L1 were performed with a large set of metals at pH 7 with the purpose to estimate the selectivity of complexation and to evaluate the applicability of L1 for optical sensing of metal ions. Importantly, the tested cations additions did not change neither UV–Vis no fluorescence spectra of L1 and ‘‘naked eye” detectable effect is only observed for Zn2+ ion due to the fluorescent ‘turn on’ effect. Fig. 4 shows the fluorescence competition experiment for Zn2+ toward Fe2+, Fe3+, Co2+, Mn2+, Ni2+, Pd2+, Hg2+, Cd2+, Al3+, Ca2+, Mg2+, Sn2+, Cr3+, Eu3+, Gd3+, Fe2+ and Tb3+ metal ions.

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0.4

3x106

6

Fluorescence Intensity (a.u.)

Abs at 385 nm

0.75

Absorbance

6

3.0x10

0.5

0.3

0.2

0.50 0.0000 0.0002 0.0004 0.0006 0.0008 0..0010

[Zn] M

0.25

IF at 490 nm

1.00

2.5x10

6

2.0x10

6

2x10

6

1x10

0.00000 0.00006 0.00012 0.00018 0.00024 0.0 00030

6

1.5x10

[Zn] M

6

1.0x10

5

5.0x10

0.0

0.00 300

350

400

450

500

400

550

450

Wavelength (nm)

500

550

600

650

700

Wavelength (nm)

A

B

Fig. 3. UV–Vis (A) and fluorescence (excitation at 345 nm) (B) spectra of 40 lM L1 in water at pH 7 and variable concentration of Zn2+ ion. Insets show absorbance or fluorescence vs. Zn2+ ion concentration profiles at selected wavelengths. Arrows show directions of the spectral changes on increase in Zn2+ ion concentration.

6

3x10

Zn Fe(II) Fe(III) Co(II) Mn(II) Ni(II) Pd(II) Hg(II) Cd(II) Al(III) ( ) Ca(II) Mg(II) Sn(II) Cr(III) Eu(III) Gd(III) Tb(III)

4.00E+06 3.00E+06 2.00E+06 1.00E+06 0.00E+00

Fig. 4. Fluorescence difference at 490 nm for L1 (1 equiv.) in the presence of 10 equiv. of different metals (front bars) and competition with 2 equiv. of Zn2+ ion (back bars).

Fluorescence Intensity (a.u.)

Zn2+ add dition

2+

+ Cu addition 6

2x10

6

1x10

0

-10

As can be seen, the addition of a large excess (10 equiv.) of other metal ions does not interfere at all, particularly in the case of the common Cu2+ and Cd2+ interfering ions did not induce the fluorescence quenching, the addition of just two equivalents of Zn2+ ion activates the fluorescence response channel. The latter is attributed to the favored keto–enamine structure of the free ligand L1, where the Nimine lone pair is no longer available to interact with copper since it is well known that the Cu2+ ion coordination is strongly dominated by its azophilic character in Nitrogen containing ligands. 2.3.2. Fluorescence kinetics Further, steady-state fluorescence kinetic measurements for probe L1 were conducted in order to study the Zn2+/Cu2+ ion interference and the probe working time. The effect of reaction time on the fluorescence response in an L1 solution (2.5 mL, 40 lM) was first studied upon addition of a Zn2+ ion solution (10 lL, 40 lM) and then with the addition of a Cu2+ ion solution (100 lL, 0.4 mM), with up to 80 points per second scans during 120 h at a kex = 343 nm, Fig. 5. The fluorescence intensity profile showed a rapid enhancement when Zn2+ ion was added, then no substantial fluorescence intensity modifications were observed with time, such that after 40 h the fluorescence intensity decreased by 4.5%, then Cu2+ ion was added to the solution observing any decreasing pattern during a total of 120 h, even when more excess of Cu2+ ion was added to the solution. These results also highlight a large

2+

+ Zn addition

L1 0

10 20 30 40 50 60 70 80 90 100 110 120

Time (h) Fig. 5. Fluorescence kinetic experiment for 40 lM L1 upon addition of 40 lM Zn2+ ion (t = 120 s) to form the 1:1 complex. Then, Cu2+ ion addition (0.4 mM) at t = 40 h.

working time for the probe which is crucial for large-time applications such as the analysis of mobile Zn2+ ion in cells [16]. 2.3.3. Determination of stoichiometry Fig. 3 shows the absorption and fluorescence changes upon addition of Zn2+ ion. A strong increase in the fluorescence at variable Zn2+ ion concentrations is observed; the complex formation gives a non-linear partially saturated binding isotherm which is typical for a 1:1 association due to the dynamic equilibration of species. Thus, simple inspection of the molar ratio indicates a 1:1 stoichiometry of L1 to Zn2+ ion binding. To determine the quantitative relationship between L1 and Zn2+ ion, the continuous variations Job’s method was used, Fig. 6 [17]. As can be seen, the Job’s plot shows a well defined maximum (xmol evaluated at 490 nm) in the range of 0.48–0.53 mol fraction of Zn2+ ion corresponding to the formation of a 1:1 complex [Zn(L1)]. To corroborate the presence of this complex during the course of titrations, the value of xmol was evaluated at different wavelength values, according to this, Vosburgh and Cooper found that if only one complex is present, the xmol value should be independent of the wavelength value [18]. Here, just one maximum in the range of 0.45–0.55 was found

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Fluorescence Intensity ratio

0.10

0.08

0.06

0.04

0.02

0.00 0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

xmol [Zn(L1)] Fig. 6. Continuous variation curve (Job’s plot) for probe L1 vs. Zn2+ ion in water evaluated at 490 nm. The final concentration was 10 lM.

when evaluated at 430, 460, 490 and 520 nm. This 1:1 complex formation with Zn2+ has also been reported in the literature [19–21]. 2.3.4. Limit of detection To evaluate the sensibility of the probe, the determination of the limit of detection (LoD) were carried out for Zn2+ and also for Zn2+ in the presence of the typical interfering Cu2+ and Cd2+ metal ions in order to have a quantitative evidence of possible ion interference or cross-talk at low concentrations. The LoD were calculated according to IUPAC definition by Eq. (2)) [22]:

CL ¼

kSB m

surfaces, in most of the cases, conventional TD-DFT results in a description of an excited state in terms of several single electronic excitations from an occupied to a virtual orbital. Fortunately, the various contributions to the electronic excitation can be clarified by a Natural Transition Orbital (NTO) analysis [27], which provides a compact orbital representation of the electronic transition through a single configuration of a hole and electron interaction. Consequently, the photoinduced electron transfer (PET) process is not depicted by a simple change in the elementary molecular orbital occupancy, but in a hole–electron distribution. Then, to have a better understanding on the probe mechanism, the interaction of probe L1 with Zn2+ ion is shown in Fig. 7. This scheme shows the NTO single electronic transitions for L1 with Zn2+ ion, providing the NTO coefficients (w) which represent the extent to which the electronic excitation can be written as a single excitation. Thus, the hole and electron corresponding to the HOMO–LUMO level are localized along the salicylidene enamine moiety with a p ? p⁄ (Sal-p ? Sal-p⁄) character, a similar behavior was found for other NTO pairs corroborating a small displacement of charge. Then, the same single electronic transition in the Zinc complex falls 1.88 eV below the hole level of the free ligand which disfavors the ICT process and promotes the radiative decay. As a conclusion, the present contribution describes a Zn2+ ion ‘turn-on’ fluorescent probe having no Cu2+ and Cd2+ ion interferences. Through an integrated experimental and computational approach, the results demonstrate that compound L1 is a very sensitive and selective probe for Zn2+ ion. In the implemented strategy, a new designing concept was developed in which a keto–enamine tautomeric form of a Schiff base completely blocks the Nitrogen lone pair and then inhibits the coordination with the strongly azophilic Cu2+ ion. The acid–base properties of the probe revealed a pKa of 12.72 and 6.78, suggesting a complete

ð2Þ

where CL is the limit of detection expressed as a concentration, m is the analytical sensitivity and k is a numerical factor chosen in accordance with the desired confidence level, here a value of k = 3 is used in order to allow a confidence level of 99.86%, the recommended value [23]. Then, the obtained LoD values are shown in Table 1. It can be seen that no Cu2+ or Cd2+ ion interferences or cross-talk is observed since no significant signal variation and LoD values are obtained. Then, the Zn2+ ion lower detection of L1 varies from a modest 3–3.4 mM range, which is quite sufficient for Zn2+ ion detection in human cells where its total concentrations are 200–300 lM [24].

-1.17 eV Electron

-2.96 eV Electron

hv

2.4. Theoretical calculations: Zn2+ ion detection mechanism Theoretical calculations were conducted to elucidate the probe detection mechanism by DFT with Polarizable Continuum Model [25] (for water) as performed in the GAUSSIAN 09 code [26]. at a PBE0/6-31G(d) level of theory. Although TD-DFT provides a good benchmark in the determination of spectroscopic properties due to the accurate description of ground and excited potential energy

-4.47 eV Hole

-6.35 eV Hole

Table 1 Limit of detection (LoD) for 4 lM L1 probe in the presence of 1–40 lM Zn2+, Cu2+ and Cd2+ ions in water buffered at pH 7 and 25 °C. Analyt0065

Response signal

LoD [mM]

Zn2+ 1 equiv. Zn2+ + 1 equiv. Cu2+ 1 equiv. Zn2+ + 10 equiv. Cu2+ 1 equiv. Zn2+ + 1 equiv. Cd2+ 1 equiv. Zn2+ + 10 equiv. Cd2+

Fluorescence ‘turn-on’ at 490 nm Fluorescence ‘turn-on’ at 487 nm Fluorescence ‘turn-on’ at 487 nm Fluorescence ‘turn-on’ at 493 nm Fluorescence ‘turn-on’ at 493 nm

3.37 3.18 3.02 3.22 3.09

Fig. 7. Schematic representation of the fluorescent sensing mechanism showing the Molecular Orbital contribution; Oscillator strength (f); transition wavelength (nm) and energy (eV) values and NTO coefficient (w) for the free ligand L1, [Zn(L1)] complex according to Table S1, Supplementary Material, sulfate counter ions are not shown for clarity.

A. Jiménez-Sánchez, M. Romero-Ávila / Inorganica Chimica Acta 448 (2016) 51–55

keto–enamine tautomer formation at pH 7. However, the probe is capable of recognizing the Zn2+ ion through a single-channel recording of fluorescence intensity method. Importantly, this study contributes to the design of new simple and low-cost fluorescent probes of Zn2+ ion, where the common UV–Vis and fluorescence instrumentation can be used when both, Zn2+ and Cu2+ (or even Cd2+) ions are present in the same sample. Finally, the probe working time and its moderate stability constant for this metal ion allow this probe to be used in large-time and continuous applications.

[9]

Acknowledgement The author would like to thank to CONACYT for financial support and to Mistli cluster for supercomputer resources. Appendix A. Supplementary material

[10] [11]

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.ica.2016.04.027.

[12]

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