Binding and Ratiometric Dual Ion Recognition of Zn2+ and Cu2+ by 1

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Binding and ratiometric dual ion recognition of Zn2+ and Cu2+ by 1, 3, 5-trisamidoquinoline conjugate of calix[6]arene by spectroscopy and its supramolecular features by microscopy V. V. Sreenivasu Mummidivarapu, Sateesh Bandaru, Deepthi S. Yarramala, Kushal Samanta, Darshan S. Mhatre, and Chebrolu Pulla Rao Anal. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.analchem.5b00905 • Publication Date (Web): 13 Apr 2015 Downloaded from http://pubs.acs.org on April 20, 2015

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Analytical Chemistry

Binding and ratiometric dual ion recognition of Zn2+ and Cu2+ by 1, 3, 5-tris-amidoquinoline conjugate of calix[6]arene by spectroscopy and its supramolecular features by microscopy# V.V. Sreenivasu Mummidivarapu, Sateesh Bandaru, Deepthi S. Yarramala , Kushal Samanta, Darshan S. Mhatre and Chebrolu Pulla Rao* a

Bioinorganic Laboratory, Department of Chemistry, Indian Institute of Technology Bombay, Powai, Mumbai 400 076, India.

KEYWORDS. 1,3,5-tri-quinoline derivative of calix[6]arene, Biological metal ions, 2D NOESY, ESI MS, SEM.

ABSTRACT

Lower rim amide linked 8-amino quinoline and 8-amino naphthalene moiety 1,3,5-tri-derivatives of calix[6]arene L1 and L2 have been synthesized and characterized. While the L1 acts as a receptor molecule, the L2 acts as a control molecule. The complexation between L1 and Cu2+ or

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Zn2+ was delineated by the absorption and ESI MS spectra.

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The binding ability of these

molecules towards biologically important metal ions was studied by fluorescence and absorption spectroscopy. The derivative L1 detects Zn2+ by bringing ratiometric change in the fluorescence signals at 390 nm and 490 nm, but in case of Cu2+ it is only the fluorescence quenching of 390 nm band that is observed, while no new band observed at 390 nm. The stoichiometry of both the complexes is 1:1 and was confirmed in both the cases by measuring the ESI mass spectra. The isotopic peak pattern observed in the ESI MS confirmed the presence of Zn2+ or Cu2+ present in the corresponding complex formed with L1. Among these two ions, the Cu2+ exhibit higher sensitivity. The DFT computational studies revealed the conformational changes in the arms and also revealed the coordination features in case of the metal complexes. The arm conformational changes upon Zn2+ binding were supported by NOESY studies. The stronger binding of Cu2+ over that of Zn2+ observed from the absorption study was further supported by the complexational energies computed from the computational data.

While the L1 exhibited

spherical particles, upon complexation with Cu2+ it exhibits chain like morphological features in SEM, but only small aggregates in case of Zn2+. Thus even the microscopy data can differentiate the complex formed between L1 and Cu2+ from that formed with Zn2+.

INTRODUCTION Zinc and copper are the second and third most abundant transition metal ions present in human body.1 Both these ions play diverse roles in biological processes.2 Zn2+ is present in higher quantities in pancreatic islets, while the liver has higher levels of Cu2+.3 Both the deficiency and the excess of Zn2+ leads to several disorders and in case of Cu2+ the same leads to anemia and neurodegenerative syndromes respectively.4 In the biological systems there exists a difference in


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the preferential binding regions of these two ions.

Therefore, the recognition of a

spectroscopically and magnetically silent Zn2+, and a paramagnetic Cu2+ deserves special attention by scientists across different disciplines.5,6 In this context, the ratiometric molecular probes are desirable for the quantification of these ions for their inherent quality in suppressing the errors via the internal calibration attained by utilizing the two bands involved.7 Therefore, this is an intriguing endeavour for researchers to study the binding and recognition of such ions using new molecular probes possessing different types of chemical entities in a pursuit of identifying these with sensitivity and selectivity. In the literature, there are only limited reports wherein a single molecular system selectively differentiates both these ions by fluorescence onoff.8 Therefore, the present paper deals with the binding and recognition of Zn2+ and Cu2+ by a carboxamidoquinoline appended 1,3,5-tris-conjugate of calix[6]arene (L1) by eliciting differences in their absorption and emission spectroscopy. Added advantage is that these systems exhibit different supramolecular aggregational species characteristic of the interaction of Zn2+ and Cu2+ with L1 which was explored by microscopy (L).

EXPERIMENTAL SECTION Synthesis and characterization of the precursors and control molecuels, are given in the supporting information along with the corresponding spectral data (S01 to S05). Fluorescence and absorption titrations: Fluorescence emission spectra were measured by exciting the samples at 330 nm and the emission spectra were recorded in 340 - 600 nm range. The bulk solutions of L1 and metal ions were prepared in C2H5OH in which, 100 µL of CHCl3 was used for dissolving L1. Bulk solution concentration of L1 & metal ion concentration were maintained at 6 × 10-4 M. All the measurements were made in 1 cm quartz cell and maintained


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the effective cuvette concentration of L1 as 5 µM in all the titrations. During the titration, the concentration of metal ions was varied accordingly in order to result in requisite mole ratios of these to L1 by taking a fixed volume of and varying volumes of the solution of the metal ions. The total volume of the solution used for the fluorescence measurements was maintained constant at 3 mL in all the cases by simply adding the requisite volume of ethanol as the making up solvent. In case of absorption titrations the bulk solutions of L1 and metal ions were prepared in C2H5OH in which, 100 µL of CHCl3 was used for dissolving L1. Bulk solution concentration of L1 & metal ion concentration were maintained at 6 × 10-4 M. All the measurements were made in 1 cm quartz cell and maintained the effective cuvette concentration of L1 as 5 µM in all the titrations. Microscopy Studies: The AFM samples of L1, [L1+Zn2+] and [L1+Cu2+] were prepared at 6 x 10-4 M concentration in ethanol. The receptor L1 was initially dissolved in 100 µL of CHCl3 then made up with ethanol to the desired concentration. The stock solutions of these were sonicated for 15 min. The 50-100 µL of aliquot was taken from this stock solution to spread over mica sheet using drop cast method. The samples were then dried and analyzed by AFM technique. The SEM samples of L1, [L1+Zn2+] and [L1+Cu2+] were prepared at 6 x 10-4 M concentration in ethanol. The receptor L1 was initially dissolved in 100 µL of CHCl3, and then in ethanol. The stock solution of L1, [L1+Zn2+] and [L1+Cu2+] were sonicated for 15 min, after which 20-30 µL of aliquot was taken and spread over aluminum foil using drop cast method.

RESULTS AND DISCUSSION


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Synthetic strategy and characterization: The receptor molecule, L1 has been synthesized in two steps starting from p-tert-butylcalix[6]arene (P1) by reacting with methyl iodide to form a tris-1, 3, 5 –methoxycalix[6]arene (P2).

Reaction of P2 with 2-chloro-N-(quinolin-8-yl)

acetamide results in the formation of L1. The control molecule, L2 has been synthesized by hydrolyzing the calix[6]tris ester (P3) to give 1,3,5-tris calix[6]acid derivative (P4) followed by the coupling of this with amino-1-naphthalene.9 Our attempts towards making L2 directly by reacting P2 with 2-chloro-N-(naphthalene-1-yl)acetamide failed because of the decomposition of the reaction upon heating. Due to this, L2 has been synthesized by going through four steps as A single arm analogue devoid of the calix[6]arene platform, L3 is

shown in Scheme 1.

synthesized by one step starting from p-tert-butylphenol instead of p-tert-butyl-calix[6]arene (Scheme 1). The P1, P2, P3, P4, L1, L2 and L3 were well characterized by 1H and FTIR and HRMS.

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C NMR,

H NMR spectrum of L1 supports the presence of a flattened cone

conformation based on the appearance of peaks at 3.47 and 4.77 ppm for the bridge –CH2 moiety. Appearance of another peak at 2.65 ppm corresponding to -OCH3 group suggests that this -OCH3 is oriented into the calix[6]arene cavity. All the conformational features were confirmed upon establishing the single crystal XRD structure of L1 as reported in this paper.


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Scheme 1. Synthesis of L1, L2, L3 and its precursors and Crystal structure of L1 : (a) (CH2O)n, Rb(OH), xylene, 160°C, 8 h; (b) CH3I, K2CO3, dry Acetone, 70ºC, 5.5 bar, 24 h; (c) 2-chloro-Nt (quinolin-8-yl)acetamide, Cs2CO3, dimethylformamide, 90ºC, 24h; (d) BuOCOCH2Br, Cs2CO3, Dry DMF, 4h; (e) CF3COOH, CH2Cl2, 12 h; (f) 1-amino naphthalene, HOBT, EDCI.HCl, dry CH2Cl2, 12 h; (g) 2-chloro-N-(quinolin-8-yl)acetamide, Cs2CO3, dimethylformamide, 90ºC, 24h. P2 was reported by us earlier.9c

Single crystal X-ray structure of the receptor, L1: Single crystals of the receptor molecule L1 were obtained from a slow evaporation of its solution in 1:2 vol/vol ratio of CHCl3 : CH3CN. The L1 crystallizes in monoclinic and the corresponding crystallographic data is summarized in Table S1.

As tertiary butyl groups were disordered, the positions were along with occupancy

factor. The structure showing the disordered atoms was given in the supporting information (S06). The structure of L1 exhibit flattened cone conformation for the calix[6]arene platform as also deduced from the solution 1H NMR spectra . Out of the three arms present in L1, two are


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oriented in the same way so that their quinoline core is projected into the cavity direction while the third one is oriented in an opposite direction. This results in the orientation of two of the amide C=O groups to project out of the cavity and the third one into the cavity. The structure also reveals that at the lower rim of calix[6]arene, the methyl groups of two of –OCH3 are oriented into the cavity of calix[6]arene platform while the third projects out of the cavity (Scheme 1). All this brings a preformed core of N4O4 where two of the oxygens come from both the arms, third one from –OCH3 and the fourth from the amide –C=O. However, by bringing a marginal conformational change about the third arm, cores suitable for higher coordination than eight can be generated. Thus the L1 can act as a coordination chameleon. The metric data for the crystal structure of L1 is given in the supporting information (S06). The crystal packing diagram (S06) shows a well ordered arrangement of calix[6]arene conjugates in a head-to-tail fashion and the adjacent ones are opposite to each other (S06). The distance between the adjacent rows is ~16 Å. As L1 can exhibit different types of binding cores, its interaction towards transition and inner-transition ions is worthy to study. Thus, the present paper deals with the interaction between L1 and transition ions.

Selective binding and complexation of Zn2+ and Cu2+ by L1 using absorption spectroscopy: In order to confirm the binding of metal ions with L1, absorption spectral studies were carried out in ethanol. Among the metal ions, viz., Na+, K+, Mg2+, Ca2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Ag+ and Hg2+ studied, only the Cu2+ and Zn2+ showed isosbestic points in their absorption spectra indicating the binding of these ions by L1 leading to the complexation. In the titration of L1 by Zn2+, the absorbance of the bands observed at 263 and 363 nm increases, while that of 240 and 311 nm bands decreases.


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Figure 1. Absorption spectral traces for the titration of L1: (a) Cu2+; (b) Zn2+ and (c) Cd2+. (d & e) are the absorbance plots for different bands in case of Cu2+ and Zn2+ respectively. (f) Histogram for the absorbance at 260 nm band for different metal ions (1=L1, 2= Na+, 3= K+ 4= Mg2+, 5= Ca2+, 6= Mn2+, 7= Fe2+, 8= Co2+, 9= Ni2+, 10= Cu2+, 11= Zn2+, 12= Cd2+, 13= Ag+ and 14= Hg2+). Thus the spectral changes and the isosbestic points observed at 248, 283 and 333 nm clearly suggests the complex formation between L1 and Zn2+ (Figure 1a,d). Similar spectral behavior observed suggests the complex formation between L1 and Cu2+. The changes observed in the absorbance of all the bands viz., 240, 256, 311 and 369 nm in case of Cu2+ are around two times higher than the changes observed for Zn2+ with L1 (Figure 1b,e) suggesting a stronger interaction by Cu2+. The binding strength of Zn2+ and Cu2+ to L1 can be gauzed from their association constants, viz., Ka = 1.50 × 104 M-1 and 4.31 × 104 M-1 respectively (S07). This suggests that Cu2+ binds stronger by three fold as compared to that of the Zn2+. All the other metal ions exhibit no significant change in the corresponding absorption spectra, suggesting that no other ion among the studied ones forms a complex with L1 (Figure 1c,f and S08).


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Determining the complex formed between L1 and Zn2+ or Cu2+ by ESI Mass spectra: The formation of 1:1 complex between L1 and Zn2+ or Cu2+ were further confirmed by ESI MS, where the spectra shows molecular ion peaks at m/z of 1632.31 and 1629.68 respectively for the complex of Zn2+ and Cu2+. The observed isotopic peak pattern supports the presence of the corresponding metal ion in these, and the pattern agrees well with the predicted one (S09). The ESI MS study was carried out even with non-complexing ions, viz., Ni2+ and Co2+, and found no m/z peak corresponding to their 1:1 complex with L1. The corresponding mass spectra are given in the supporting information (S09). Based on the absorption and ESI MS, it is understood that L1 binds selectively to Cu2+ and Zn2+ among all the thirteen ions studied and forms 1:1 complex only with these two ions and not with the other ions studied.

Demonstration of the conformational changes occurred in L1 by the complexation with Zn2+ using 2D NOESY: Whether the binding of Zn2+ brings any conformational changes in L1 or not is being addressed by 2D NOESY and the corresponding data can be seen from Figure S23. In NOESY spectrum of L1, correlations were observed between H11 & H8, H9 & H8 and H1 & H2 (S10). On the other hand, upon complexation of this with Zn2+, some new correlations appeared (Figure S23) between H10 and those of H6, H9 and H12. The aromatic protons, viz., H11 and H12 correlate with H8. All these indicate that upon complexation the quinoline moiety in L1 bends towards the –OCH3 group. Thus the arm undergoes conformational change in the presence of Zn2+ in order to effect the complexation.


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Ion recognition by fluorescence spectroscopy: Since the absorption and ESI MS studies clearly showed the complexation of L1 by Zn2+ and Cu2+ ions, the ion recognition of L1 has been studied by exciting the solutions at 330 nm and measuring its emission spectra where the spectral maximum lies at 390 nm. Among Na+, K+, Mg2+, Ca2+, Mn2+, Fe2+, Co2+, Ni2+, Cu2+, Zn2+, Cd2+, Ag+ and Hg2+ ions studied, Zn2+ and Cu2+ exhibits considerable fluorescence spectral changes in L1. As the mole ratio of [Zn2+]/[L1] increases, the 390 nm emission band of L1 decreases and a new emission band emerges at 490 nm with increasing intensity by exhibiting bluish green colour (Figure 2b). The changes observed in the emission spectra are ratiometric with I490/I390 being 6 ± 1 (Inset 2e). However, in case of Cu2+ titration, the fluorescence intensity of 390 nm emission band decreases without the emergence of any new band and it finally diminishes to zero (Figure 2a). This corresponds to the de-colorization of the blue fluorescence emission. Thus, in case of Cu2+ and Zn2+, the existing band at 390 nm gradually decreases as the concentration of the metal ion increases, however, a complete quenching of this band is observed only in case of Cu2+ and not with the Zn2+(Figure 2d).

The L1 responds to Zn2+ ratiometrically, however, only a

quenching is observed with Cu2+. As the fluorescence spectral behavior of L1 by these two ions differ distinctly, the method can respond to both these ions using different spectral changes and hence L1 can act as a dual sensor for Zn2+ and Cu2+, by observing the changes in the respective bands. However, when L1 is titrated with Cd2+, only marginal changes were observed in the fluorescence emission in both the bands (Figure 2c). Indeed, even the changes observed in the absorption spectra of L1 in presence of Cd2+ were insignificant when compared to the same in presence of Zn2+ as reported earlier in this paper. Other than these three, no other ion studied affects the fluorescence spectra of L1 (S11) suggesting their non-complexation behavior with L1 under the present experimental conditions. All this was confirmed from the absorption and ESI MS study. The fluorescence increase in 490 nm emission band is 37 ± 2 fold in case of Zn2+,


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however, it is only 3 ± 1 fold in case of Cd2+. Thus over a dozen fold difference is observed in the fluorescence intensity of L1 and this will act in favour of its selectivity towards Zn2+ over its congener. This implies that the binding strength of Cd2+ is much lower than that of Zn2+ for L1 so that Cd2+ does not pose any interference in the detection of Zn2+ by L1. The binding constants of L1 with Zn2+ and Cd2+ are derived by Benesi – Hildebrand equation and these are, Ka = (6.2±0.20) × 104 M-1 and (1.4±0.04) × 103 M-1 respectively (S12), supporting that the binding strength of Zn2+ is ~50 fold higher than that of Cd2+ and hence Zn2+ can easily bind to L1 even in the presence of Cd2+.

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Figure 2. Fluorescence spectral traces for the titration of L1 (5 µM) with (a) Cu2+; (b) Zn2+; (c) Cd2+ in ethanol (λex = 330 nm). (d) Histogram showing the fluorescence intensity of L1 titrated with metal ions with λem = 390 nm. (e) Same as in (d) but for λem = 490 nm. (Left inset: Intensity


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ratio as a function of mole ratio for Zn2+. Right inset: Fluorescence intensity for λem = 490 nm band as a function of mole ratio for Zn2+). (f) Colorimetric titration of L1 (20 µM) with different metal ions (80 µM) in ethanol as observed under UV (365 nm) incident light.

The minimum concentration of Zn2+ that can be detected by L1 is obtained from an experiment carried out by keeping the mole ratio of L1 to Zn2+ as 1:1 but by varying the concentration and measuring the fluorescence intensity. The fluorescence study yielded a minimum detection of 570±10 ppb for Zn2+ and 15±1 ppb for Cu2+ by L1 (S13). The quenching constant of L1 by Cu2+ has been derived by Stern – Volmer equation and the Kq = (2.9 ± 0.15) x 105 M-1 (S14). Since the detection limit of Cu2+ is several fold lower than that of the Zn2+, the former can act as a deterrent in the analytical detection of the latter. The L1 is more sensitive to Cu2+ as compared to Zn2+.

Competition by other ions for the recognition of Zn2+ by L1 was studied by fluorescence spectroscopy. The titration of {L1+Mn+} by Zn2+ as well as {L1+Zn2+} by Mn+ exhibited no change in the fluorescence intensity of L1 in presence of different ions studied except for Cu2+ and hence a selective recognition of Zn2+ is restricted to the presence of the Mn+ other than Cu2+ (S15). The recognition of Zn2+ by L1 was further supported by the fluorescent color exhibited by {L1+Mn+} under an incident light of 365 nm. This resulted in green fluorescence only in case of Zn2+, while the other ions do not show such emission (Figure 2f). When {L1+Zn2+} is titrated with Mn+, no change was observed in the green fluorescence except for Cu2+ (S16). All these results suggest that the L1 recognizes Zn2+ even in the presence of all the other ions except Cu2+.


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Supramolecular aggregation in L1 by complexation with Cu2+ or Zn2+ using microscopy: Since calixarenes are known to form supramolecular structures through self aggregation, it is intriguing to see whether such structures are intact or form newer types in presence of metal ions. The study will provide unprecedented data for L1 to recognize ion even in a thin layer. The receptor L1 exhibits spherical shape particles which are well spread all over the mica surface as studied by AFM. However, in the presence of Cu2+, these particles merge to result in aggregation as noticed by their increased size. Thus the size of the particles change from 150±30 nm in simple L1 (Figure 3a,d) to 540±80 nm in the presence of Cu2+ as a result of the metal ion induced aggregation thus exhibiting a four fold increase (Figure 3b,e). In the presence of Zn2+ these particles are smaller, however, aggregated more than that of the simple L1 (Figure 3c,f). In SEM, the receptor L1 alone shows uniformly distributed globular features with approximate diameter of 600±100 nm (Figure 3g). Upon addition of Cu2+ to L1, these tend to aggregate to form chain like structures (Figure 3h), while the addition of Zn2+ exhibit small aggregates but not chain like structures (Figure 3i). A number of 1,3-di-derivatives of calix[4]arene have shown spherical nano structural features as recently reported by us.7g, 10 The formation of such spherical particles is indeed expected when the hydrophylic arms of the calixarene conjugate aggregate to result in smaller size particles, which further joins through hydrophobic interactions leading to larger spherical particles as noticed even in case of L1. Thus the trend observed in the supramolecular features in the present study is almost same in AFM and SEM, though the size of the particles differ between these two owing to the difference in the surface of the substrate used. All the microscopy data supports the induced supramolecular aggregation in L1 upon interaction followed by complexation by Cu2+ to


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a greater extent as compared to that with Zn2+. Thus the L1 can differentiate these two ions even based on microscopy data.

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Figure 3. Non contact mode of AFM: (a) and (d) are for L1; (b) and (e) are for {L1 + Cu2+}; (c) and (f) are for {L1 + Zn2+}. SEM images: (g) for L1; (h) to (j) are for {L1+Cu2+} and (k) to (l) are for {L1+Zn2+}.

Importance of the quinoline moiety and the calixarene platform: The reference compounds L2 and L3 were synthesized in order to understand the binding nature of the metal ion with L1 while keeping in mind the importance of the functional groups and the platform present in L1. Fluorescence intensity of L2 remains unaltered during the addition of metal ions owing to the


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absence of the quinoline moiety (Figure S30 a-d). But in case of L3, spectral changes were observed with both Cu2+ and Zn2+ because of the presence of quinoline moiety though the calixarene platform is absent (Figure S30 e-h) suggesting that both the ions bind to this moiety. The enhancement observed for L3 with Zn2+ is much less as compared to L1 with Zn2+ owing to the presence of three such arms and their simultaneous utility on the calix[6]arene platform resulting in a cooperative binding. Since there is only one arm in L3, the increase in the fluorescence intensity of the 490 nm band is around one-third of that observed for L1 possessing three arms. Thus the fold of enhancement with L1 is 37 ± 2, while it is only 6 ± 1 in case of L3. Comparison of all these results supports the necessity of both the quinoline nitrogen and the calix[6]arene platform for sensitive recognition of Zn2+ (Figure S30 i-l). Comparison of the fluorescence quenching of L3 with that of L1 by Cu2+ suggests that the binding nature of Cu2+ is similar in both the cases.

Computational support for the coordination features of 1:1 complexes: The experimental work clearly supported the formation of 1:1 complex in case of both Cu+2 and Zn+2 with L1. The association constants revealed that the Cu2+ forms a stronger complex than that of Zn2+. In order to substantiate this and also to provide the nature of the coordination in both the cases, the DFT computations were carried out by Gaussian 09 using wB97xD level of theory.11

For this, the

crystal structure of L1 was taken as the initial input and the corresponding de-tertiarybutylated version (L1') was optimized at wB97xD level of theory using 6-31G(d,p) basis set.12 The optimized structure of L1' obtained at this stage was used for the metal ion complexation study which was also carried out in DFT. Thus both the metal ion complexes, viz., [ZnL1'] and [CuL1'], were optimized at the same level of theory. All the optimized structures are given in


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Figure 4 and the corresponding metric data for the coordination cores were given in the caption. The coordinate data for the optimized structures were given in the supporting information (S18).

Figure 4. Structures obtained from the optimization carried out at wB97xD/6-31G(d,p) level of theory: (a) L1'; (b) [ZnL1']; (c) [CuL1']; (d) primary coordination for Zn2+ and (e) primary coordination for Cu2+. Bond lengths and bond angels for the coordination spheres are given in Å and degrees (°): In case of (d), N1-Zn= 2.061, N2-Zn=1.947, N3-Zn=2.048, N4-Zn=1.951; N1Zn-N2=83.8, N1-Zn-N3=119.0, N1-Zn-N4=100.4,N2-Zn-N3=108.1,N2-Zn-N4=163.5, N3-ZnN4=83.9, N3-Zn-N1=119.0. In case of (e), N1-Cu=2.058,N2-Cu=1.919,N3-Cu=1.942, N4Cu=1.968, N1-Cu-N2=82.8, N1-Cu-N3= 94.7, N1-Cu-N4=120.6, N2-Cu-N3=155.2, N2-CuN4=117.7, N3-Cu-N4=84.6, N3-Cu-N1=94.7.

In both the complexes, the corresponding metal ion is connected to the conjugate through four nitrogen centers resulting in a four coordinated complex in each case. In these complexes, the M-N distances vary from 1.947 to 2.061 Å (average is 2.002 Å) and from 1.919 to 2.058 Å (average is 1.972 Å) for Zn2+ and Cu2+ respectively suggesting a relatively stronger binding in case of Cu2+. Though the coordination number is four in both the cases, the N-M-N angles differ largely from the expected tetrahedral or square planar geometry.

However, when these

coordination spheres are considered as five coordinate ones with a vacant site, these fit better to a trigonal bipyramidal (TBP) geometry as compared to the four coordinated tetrahedral or square planar ones. Upon comparing with the ideal geometry, it is evident that the fitting to TBP geometry is better in case of Cu2+ as compared to the Zn2+ and both are better when compared to


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the tetrahedral or square planar geometry. Thus the coordination cores in both these complexes fit to a distorted TBP with one site being vacant in the equatorial plane where the nitrogen ligation emerges from two of the arms. The quinoline moiety of the third arm is stabilized by π-π stacking interaction with one of the neighbor arms with distance being 4.52 Å and 4.03 Å in Zn2+ and Cu2+ complexes respectively (Figure 4). The calculated binding energies for these two complexes differ by -12.3 kcal/mol in favour of the Cu2+ complex over that of the Zn2+ complex. This is in conformity with the higher association constant observed in case of the Cu2+ complex as compared to that of Zn2+ as reported in this paper. The highest occupied molecular orbital (HOMOs) and lowest unoccupied molecular orbitals (LUMOs) were calculated for the Zn2+ as given in Figure S31. In the Zn2+ complex, the HOMOs have the contribution from quinoline and amide nitrogen of two of the arms in the conjugate. The aggregational differences observed from microscopy in case of Cu2+ and Zn2+ complexes are attributable to the differences observed in bond lengths and bond angles in the coordination sphere, geometry at the metal center and the arm orientation as derived from the computational studies (Figure S32).

Isolated complexes of [CuL1] and [ZnL1]:

Since the absorption and mass spectrometry

supported the formation of 1:1 complex between of L1 and Cu2+ or Zn2+, these were prepared by mixing L1 with Cu(II)- or Zn(II)- acetate in methanol respectively followed by refluxing the reaction mixture for 12 h. The resultant complexes were isolated as solid products and were characterized by 1H NMR and ESI MS. 1H NMR spectrum of the isolated complexes in CDCl3 supports the presence of flattened cone conformation based on the appearance of 3.47 and 4.77 ppm peaks for the bridge –CH2 moiety. These complexes exhibit absorption bands at 263 and


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363 nm in ethanol which are characteristic of the complex, while 311 nm band that corresponds to the free L1 disappears. (Figure S33 a,b). In case of L1 the absorption band is present at 330 nm, upon complex formation with Cu2+ or Zn2+ this band shifts towards higher wavelength, viz., ~390 nm.

The [ZnL1] complex exhibits strong fluorescence emission when measured in ethanol, supporting that the L1 is indeed bound to Zn2+. On the other hand, the [CuL1] complex does not show any significant fluorescence intensity due to the paramagnetic quenching of Cu2+. The ESI MS of these complexes showed molecular ion peaks corresponding to them and the presence of the metal ion in these is authenticated by the observed isotopic peak pattern that suits Zn2+ and Cu2+ respectively (S09). The isolated complexes exhibited morphological features in SEM which are similar to that observed from the in situ generated complexes (Figure S33 c,d). Thus all the spectral and microscopy characteristics of the isolated [ZnL1] and [CuL1] complexes are same as that obtained from their in situ generated ones. While the powder XRD exhibits high crystalline nature for L1, it shows low crystallinity for the zinc complex and amorphous nature for the copper complex (Figure S33 e,f). As a result of this, no single crystals could be obtained for either of the complexes and hence their structures could not be established by single crystal XRD and hence the coordination characteristics of these were addressed by the computational studies as reported in this paper.

CONCLUSIONS AND CORRELATIONS Carboxamidoquinoline based 1, 3, 5 -tris-conjugate of calix[6]arene (L1) has been synthesized and characterized by various spectral methods. The receptor L1 exists in cone confirmation in


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both the solution as well as in the solid states as evident from the 1H NMR spectrum and single crystal XRD structure respectively. L1 showed binding towards Cu2+ and Zn2+ among all the thirteen metal ions studied by absorption. The 1:1 complex formed between L1 with Cu2+ and Zn2+ has been confirmed by ESI-MS.

Conformational changes occurred in L1 by the

complexation of Zn2+ were demonstrated by 2D NOESY. In order to differentiate the complex formed between L1 and Cu2+ or Zn2+, its supramolecular features were studied by AFM and SEM. Results obtained from both these techniques supported the metal ion induced aggregation, where the effect is greater in case of Cu2+ leading to chain like structures, while these are simple aggregated ones in case of Zn2+. Even the isolated complexes of both [CuL1] and [ZnL1] showed similar supramolecular aggregation as that shown by the in situ generated ones. The L1 showed selectivity towards Cu2+ and Zn2+ among all the metal ions studied by fluorescence spectroscopy by eliciting changes in different emission bands. Competitive studies suggested that L1 can sense Zn2+ even in the presence of several other metal ions excepting Cu2+. The absorption studies clearly suggest that the Cu2+ binds to L1 by at least three fold stronger than that of Zn2+ and in turn the Zn2+ binds stronger by ~50 fold as compared to that of Cd2+.

Thus the binding

preferences of these ions towards L1 follows a trend, Cu2+ > Zn2+ >>> Cd2+. The detection limit of Cu2+ is far greater than that of the Zn2+ and this supports the fact that the Cu2+ is more sensitive towards L1. The differences exhibited by these two ions towards L1 can be easily noted from Scheme 2.


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Scheme 2. Various characteristics of L1 towards the thirteen different Mn+ studied.

1,3-Di-amidoquinoline conjugate of calix[4]arene (L) as a ratiometric and colorimetric sensor for Zn2+ has been previously reported by us.7g The L1 with three arms built on to the lower rim of calix[6]arene, as reported in this paper, exhibits a higher association with Zn2+ by a factor of two when compared to that of L possessing only two arms built on a calix[4]arne platform. The competitive studies carried out with L showed that it can detect Zn2+ even in the presence of other metal ions except Fe2+, Cu2+ and Hg2+. But in the present case of L1, only the Cu2+ ion acts as a competitor for Zn2+ which is due to the presence of three quinoline moieties on the calix[6]arene platform. In the fluorescence spectral study carried out in case of the calix[4]arene based receptor L, the 400 nm is quenched to ~80% upon addition of 10 equivalents of Cu2+, and even large equivalents does not bring complete quenching of this band. But, in the present case of L1, a complete quenching takes place within 5 equivalents of Cu2+. Thus L1 can be used as a selective receptor towards both Cu2+ and Zn2+ with a high sensitivity of detection being imparted


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for Cu2+ (15±1 ppb) by L1, while only the Zn2+ can be sensed by L. This is further reflected in the chain like aggregation observed for L1 in presence of Cu2+ in SEM and AFM, while Zn2+ does not show much of aggregation. Conversely, the Zn2+ brings Koosh flower like structure in case of L, supporting that the calix[4]- and calix[6]- platforms behave differently due to the differences present in the number of arms, cavity size and the orientation of the arms. Thus, a new carboxamidoquinoline calix[6]arene based chemosensor L1, shows highly selective, sensitive, and fluorescence off-on responses toward Cu2+ and Zn2+ in ethanol medium. On the basis of the recognition studies, L1 displays efficient sensitivity and selectivity toward Cu2+ rather than Zn2+ ions while it can be used for both these ions independently.

ASSOCIATED CONTENT SUPPORTING INFORMATION. The data corresponding to 1H and

13

C NMR, mass spectra

of P3, P4, L1, L2 and L3, fluorescence and absorbance spectra of all metal ions and crystal structure of L1, are given in the supporting information. This material is available free of charge via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Author •

To whom correspondence should be addressed. Phone: 91 22 2576 7162. Fax: 91 22 2572 3480. Email: [email protected]

•

#

We dedicate this paper to our mentor, Professor C.N.R. Rao, FRS.

ACKNOWLEDGMENTS


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CPR acknowledges the financial support from DST (SERB & Nano Mission), CSIR and DAEBRNS. VVSM acknowledge CSIR for the award of SRF. We acknowledge FIST (Physics)IRCC central SPM facility of IIT Bombay for AFM studies and SAIF of IIT Bombay for SEM facility. REFERENCES

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Binding and Ratiometric Dual Ion Recognition of Zn2+ and Cu2+ by 1

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