Sub-Picomolar Recognition of Cr3+ through Bioinspired Organic

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Sub-Picomolar Recognition of Cr3+ Through Bioinspired Organic-Inorganic Ensemble Utilization Gourab Dey, Mangili Venkateswarulu, Venkateswaran Vivekananthan, Avijit Pramanik, Venkata Krishnan, and Rik Rani Koner ACS Sens., Just Accepted Manuscript • DOI: 10.1021/acssensors.6b00046 • Publication Date (Web): 05 Apr 2016 Downloaded from http://pubs.acs.org on April 9, 2016

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Sub-Picomolar Recognition of Cr3+ Through Bioinspired OrganicInorganic Ensemble Utilization

Gourab Dey, a,¤ Mangili Venkateswarulu, a,¤ Venkateswaran Vivekananthan,a Avijit Pramanik,b Venkata Krishnan,a* and Rik Rani Koner a*

a

School of Basic Sciences and Advanced Materials Research Center, Indian Institute of Technology Mandi, Kamand, Mandi-175005, Himachal Pradesh, India. b

Department of Chemistry and Biochemistry, Jackson State University, Jackson, Mississippi 39217, USA.

Abstract The work describes an integrated optical platform for recognition of Cr3+ at picomolar level (0.66 pM). The condensation of a fluorene unit with

L-leucine

led to the

development of a highly fluorescent molecular probe L which detects Cu2+ following a turn-off signaling mechanism. Further, the L-Cu2+ ensemble has been successfully utilized as light-up signaling tool for selective turn-on sensing of Cr3+, for the first time, at picomolar level through quencher displacement. This sensing process eventually detects selectively one paramagnetic cation through turn-on signaling by the displacement of another paramagnetic cation. We have successfully shown that the common sensitivity issues associated with displacement approaches can be overcome by suitable ligand design. The present integrated system, L-Cu2+, has been found to be sensitive enough to detect Cr3+ at picomolar level even in real samples, including water from different sources such as tap water, river water and drinking water.

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KEYWORDS: amino acid based probe, quencher displacement, fluorescence signaling, selective recognition, sub-picomolar Cr3+ detection. Inspired by nature, particularly from some biochemical processes where Cu2+ plays an important role in regulating various biological events, the exploration of the strong affinity of amino acid derivatives towards Cu2+ has been fascinating to chemists over the decades.1-13 This has led to the development of novel architectures based on copperamino acids hybrid (CAH) systems. The reactivity of such hybrid systems have widely been studied mainly to understand or to mimic biochemical processes.14-19 The strong binding potential of Cu2+ with amino acid derivatives has been explored further in recent times to develop specialized fluorescent probes based on amino acid hybrids, and the resultant hybrids have been utilized as optical signaling agents for Cu2+ ions.20-21 On the other hand, Cr3+ is an essential trace element in human nutrition which helps in regulating various biological events.22-25 The Cr3+ deficiency may lead to different health disorders including diabetes and cardiovascular diseases.26 However, high concentration of Cr3+ is equally detrimental to human health and can have negative impact on cellular structures. The environmental protection agency (EPA) has set the maximum permissible level of total chromium as 0.1 mg/mL. Therefore, efficient tools for sensitive detection of Cr3+ at very low level are highly desirable. Among the various techniques that are used for recognition and measurements of trivalent chromium, fluorescence based optical technique is gaining utmost interest of the researchers possibly because of its high sensitivity, selectivity, fast response time and cost efficiency. Though optical signaling technique has proven to be one of the most efficient techniques, Cr3+ is known for its notorious fluorescence quenching effect. Therefore, many small molecule based chemical tools detect chromium using quenching parameters. However, detection using turn-on signaling rather than the turn-off is more desirable. To date, only few promising Page 2 of 24


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molecular materials have been developed by different research groups in the last two decades, but their limit of detection could not reach beyond nanomolar levels (Table S1).27-37 After the pioneering developmental work of Anslyn and coworkers,38 turn-on signaling through quencher displacement has become one of the most efficient light-up signaling techniques for the recognition of various analytes. The quencher displacement strategy stands superior to common light-up signaling technique (using optical materials) in terms of its multifold selectivity. Though this signaling strategy has been adapted widely to recognize various anions through replacement of cations, the recognition of cations through displacement of other cations is rarely reported.39-49 Recently, Li et al.50 reported an interesting assembly of a luminogenic compound with Cu2+ which was further utilized as turn-on chemosensing device for Cr3+ with nanomolar level detection limit. To the best of our knowledge, no optical chemosensing device has yet been reported that can detect Cr3+ with a light-up signal at picomolar level. The present manuscript describes, for the first time, the utilization of an in situ generated hybrid amino acid L-Cu2+ ensemble for detection of Cr3+ selectively at picomolar level with turn-on signaling through quencher displacement. Though it has been mentioned in some reports that the quencher displacement improves selectivity by many folds at the expense of sensitivity, we have successfully proved that suitable ligand architecture may overcome the sensitivity issues. The single crystal of the Cu2+ based ensemble (L-Cu2+) has been successfully isolated and characterized. Interestingly, this newly developed, highly fluorescent fluorene functionalized L-leucine derivative (L) (φ = 0.243) has also been found to be capable of recognizing Cu2+ with turn-off signaling and exhibits a high degree of selectivity.51

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Experimental section General information All chemicals were purchased from Merck, S.D. Fine and Sigma Aldrich, and were used without further purification. Methanol (AR grade) was used for the spectral studies. Freshly prepared solution of nitrate salts of metal ions (Al3+, Fe3+, Cu2+, Cd2+, Ni2+, Ag+, Mn2+, Zn2+, Na+, Mg2+, Hg2+, Co2+, Pb2+ and Cr3+) (1mM) in deionized (DI) H2O and ligand (1 mM) in methanol /buffer (4:1, v/v) buffered with HEPES (1 mM), pH = 7.2 were used as standard solutions to record the UV-vis and fluorescence spectra. FT-IR spectra were recorded on a Perkin Elmer Spectrum 2 spectrophotometer. 1H and

13

C NMR spectra in methanol-d4 were

recorded on Jeol-ECX-500 MHz spectrometer using tetra methyl silane as an internal standard. HRMS spectra were recorded on a Bruker impact-HD spectrometer. Absorption spectra were recorded with SHIMADZU UV-2450 spectrophotometer, using a quartz cuvette. The fluorescence spectra were recorded with Cary Eclipse spectrophotometer with slit widths of 5 nm for excitation and 5 nm for emission of the spectrophotometer respectively. The absolute quantum yield was determined by Horiba Fluorolog 3. Single-crystal X-ray diffraction studies Single crystal of L-Cu2+ suitable for X-ray diffraction were grown in methanol/ DMF by its slow evaporation. Diffraction studies were performed on Agilent Technologies X-ray diffractometer (λ = 1.5406 Å) by exposing the crystals using Cu Kα radiation (298(2) K). Data were collected and reduced using the standard ‘CrysalisPro’ Software .52 The molecular structure was solved by direct methods, OLEX2 and was refined using full-matrix leastsquares (F2) on SHELXL-97.53-54 The positions of all non-hydrogen atoms were located and refined anisotropically. After that, hydrogen atoms were obtained from the residual density Page 4 of 24


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map and refined with isotropic thermal parameters. The PLATON programme was used to refine the disordered solvent molecules.55 All parameters of crystal structures were given in Table S2. UV-Vis and fluorescence titrations UV-vis and fluorescence titrations were conducted using 1 µM and 2 µM solution of probe (L) in Methanol:H2O solution (4:1, v/v) buffered with HEPES (1 mM, pH = 7.2) respectively. All measurements were performed using 289 nm as an excitation wavelength by keeping excitation and emission slit widths as 5/5 respectively. Each time, a freshly prepared 3 mL stock solution of probe L was taken in the quartz cuvette (path length 1 cm), and the desired amount of metal ions was added with a micro syringe. UV-vis and fluorescence titrations were conducted using all stock solutions in high concentration to avoid dilution error.

Synthesis of Ligand (L):

Scheme 1. Synthesis of ligand L. A methanolic solution of fluorene-2-carboxaldehyde (0.296 g, 1.15 mmol) was added dropwise to a stirred mixture of L-leucine (0.20 g, 1.5 mmol) and LiOH.H2O (0.064 g, 1.5 mmol) in methanol (10 mL). Then the resulting mixture was refluxed at 80°C for 12 h to produce a bright yellow colour solution. After that the solution was treated with sodium borohydride (0.057 g, 1.15 mmol) with constant stirring at room temperature for 30 min. The solvent was evaporated after completion of the reaction using a rotary evaporator. The resulting sticky residue was dissolved in water and acidified with dilute HCl to pH 5 – 6 Page 5 of 24


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under stirring. The yellowish precipitate formed was filtered off through a sintered funnel and washed with water (20 mL) and air dried for 1h and the crude product was purified by column chromatography on silica gel (9:1 dichloromethane (DCM)–methanol) to afford a yellow solid as ligand (L) (63.2 %). Melting point: 208-210°C; FT-IR (KBr, ν in cm-1): 3625, 3177, 1574, 1514, 1455, 1438, 1394, 1255, 1217, 1106, 1059, 820, 737, 642, 576, 540, 432 cm-1. 1H NMR(Methanol-d4) : δ 7.76-7.72 (m, 2H), 7.54-7.50 (m, 2H), 7.36–7.30(m, 2H), 7.26-7.23 (m, 1H), 3.86-3.84(m, 2H), 3.64-3.61 (m, 2H), 3.16-3.13(m, 1H), 1.79-1.76 (m, 1H), 1.52-1.47(m, 1H), 1.43-1.38(m, 1H), 0.94(d, J= 6.2 Hz, 3H), 0.87(d, J= 6.2 Hz, 3H).13C NMR (Methanol-d4): 183.01, 144.81, 144.73, 142.88, 142.03, 139.81, 128.60, 127.86, 127.71, 126.57, 126.11, 120.77, 120.69, 63.95, 53.52, 44.64, 37.62, 26.41, 23.59, 23.23. MS (HRMS): m/z calculated for C20H23NO2 [M-H] + 308.1651, found 308.1589. Synthesis of Cu(II) complex [Cu(C40H44N2O4)(H2O)](DMF)(H2O)1.5(CH3OH)0.5: The ligand (L) (0.05 g, 0.161 mmol) was deprotonated with KOH (0.009 g, 0.161 mmol) in 10 mL methanol-DMF mixture (8:2). After that Cu(NO3)2.3H2O (0.02 g, 0.008mM) was added to the mixture and refluxed for 1h. The mixture was filtered and the solution was kept in room temperature for 3 days. Bluish intergrown crystals were obtained, which was filtered and washed with methanol. FT-IR (KBr, ν in cm-1): 3436, 3236, 3183, 2953, 1645, 1608, 1589, 1513, 1437, 1394, 1103, 980, 759, 736, 576, 418 cm-1.

Results and discussion The fluorene functionalized L-leucine derivative of ligand L was synthesized following a two-step one pot procedure (Scheme 1). Condensation of fluorene aldehyde and L-leucine followed by reduction resulted in the formation of ligand L in good yield. The structure of L was fully characterized using various spectroscopic techniques such as FT-IR, NMR, and Page 6 of 24


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HRMS (Figures S1 to S3).The newly synthesized ligand contains carboxylic acid and secondary amine groups, which serve as chelating agents for stabilization of Cu (II) complex.

Figure 1. (a) Chemical structure of L;(b) perspective ball and stick model view of Cu (II) complex. (c) The ORTEP figure of Cu(II) complex. (d) Packing diagram with hydrophobichydrophilic layer structure along c- axis. Description of Solid State Cu(II) complex: The complex is crystallized in monoclinic C2 symmetry space group. The ORTEP diagrams with atom numbering scheme and perspective ball-and-stick view of the complex are illustrated in Figures S4 and 1b, respectively. The mononuclear Cu(II) complex shows distorted square pyramidal geometry where two ligands are coordinated in equatorial sites, and one water molecule is connected in the apical position. The carboxylate oxygen atoms Page 7 of 24


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are covalently bonded opposite to each other in equatorial sites of Cu(II) complex and the other two equatorial sites are connected with the amine nitrogen atoms of two separate ligands (L). Both of the water’s hydrogens (apical) are involved in O–H•••O hydrogen bonding (O5–H•••O9 = 2.687Å, O5–H•••O6 = 2.837Å) with the carboxylate oxygen atoms of different units in the crystal lattice. Apart from the coordinated part, there is one more water molecule in the crystal lattice involved in hydrogen bonding with nearby secondary amine NH and carboxylate oxygen through N–H•••O (N2–H•••O97 = 2.938 Å) and O–H•••O (O97– H•••O1 = 2.938 Å) hydrogen bonding interactions. Another secondary amine -NH is bonded to a molecule of DMF through N–H•••O (N1–H•••O15 = 3.012 Å) interaction (Figure 1c). Additionally, other supramolecular interactions such as, πc•••πc (πc•••πc = 3.012 Å,) C– H•••π (C81–H•••πc = 3.463 Å, C33–H•••πc = 4.131 Å, C34–H•••πc = 3.656 Å) and C– H•••O (C9–H•••O7 = 3.461 Å) also play an important role in forming a three dimensional hydrophobic-hydrophilic layer structure along the C axis (Figure 1d).

Photo Physical Properties: With the successful development of L, we investigated first its photophysical properties. Probe L (1 µM) showed a strong absorption band at 266 nm (ε ~ 194000 M-1cm-1), and two weak absorption bands at 289 nm (ε ~ 94000 M-1cm-1) and 300 nm (ε ~ 77000 M-1cm-1) in methanol/H2O (4:1, v/v) buffered with HEPES (1 mM), pH = 7.2 (Figure S5). These bands arose mainly due to the π-π* transitions of aromatic moieties. Next the fluorescence response of L (2 µM) was identified in methanol/H2O (4:1, v/v) buffered with HEPES (1 mM), pH = 7.2 (Figure S6). The probe was found to be highly fluorescent with excitation and emission wavelengths at 289 nm and 305 nm respectively, and the fluorescence property was found to be pH dependent. The strong emission was observed at a pH range 5.0 - 7.4 (Figure S7). The fluorescence intensity of L is weak at alkaline pH (>8, Figure S7) which was mainly due to

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favoured photoinduced electron transfer (PET) from donor (amine moiety) to the acceptor fluorophore, which is also known as acceptor-excited photoinduced electron transfer or aPET.56-57 Protonation of the amine functionality at neutral or acidic pH led to an increase in oxidation potential of the amine, which in turn prevented PET process resulting in strong fluorescence emission.58-61

(a)

Fluorescence Intensity(a.u.)


500

ligand + other metal ions

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with other metal ions.

150 100 50 0 300

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(d) 9.3%

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15.1%

0.666

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17.7%

20.1%

2.333

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Concentration of Cr3+ ion in pM

Figure 2. a) Fluorescence spectra of probe L (2 µM) in methanol: H2O (4:1, v/v) buffered with HEPES (1 mM), pH = 7.2 (at λex 289 nm) upon the addition of Al3+, Fe3+, Cu2+, Cd2+, Zn2+, Na+, Mg2+, Hg2+, Co2+, Pb2+ and Cr3+ (1 µM), b) fluorescence spectra of probe L-Cu2+ (1 µM) in methanol: H2O 4:1, v/v) (at λex 289 nm) upon the addition of increasing quantities of Cr3+ (0 to 1 µM), c) Fluorescence spectra of probe L-Cu2+(1 µM) in methanol: H2O (4:1, v/v) buffered with HEPES (1 mM), pH = 7.2 (at λex 289 nm) upon the addition of Al3+, Fe3+,

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Cu2+, Cd2+, Zn2+, Na+, Mg+2, Hg2+, Co2+, Pb2+ Ni2+, Ag+, Mn2+ and Cr3+ (1 nM), d) Fluorescence intensity of L-Cu2+ (1 µM) in methanol: buffer (4:1, v/v) excitation at 289 nm as a function of the concentration of Cr3+. In order to study the binding affinity of L toward metals, we examined the absorption/emission spectra in the presence of different metal ions in aqueous solution. Upon the addition of aqueous solution of Cu2+ (0 - 4.0 × 103 pM) to a solution of L (1 µM) resulted in slight enhancement in intensity of absorption bands but it remained insensitive upon addition of Cr3+ solution (Figures S8 and S9). As L showed significant fluorescence response at neutral pH, further investigations were performed at pH 7.2. The fluorescence emission of L remained unaffected in the presence of a large number of mono, di and trivalent metal ions except strong quenching by Cu2+ and very weak quenching by Fe3+/Hg2+ (Figures 2a and S10). Though Cr3+ is well known fluorescence quencher, interestingly the presence of Cr3+ enhanced the emission intensity of L to some extent (Figure S10). The remarkable quenching of the fluorescence intensity of L in the presence of Cu2+ was found to be highly selective under identical conditions except in the presence of Cr3+ (Figure S10) and practical limit of detection for Cu2+ was calculated to be 330 nM (Figure S11). Therefore, L could be considered as potential molecular optical material for detection of Cu2+ through turn-off signaling. This Cu2+ induced fluorescence quenching was largely due to favored PET from fluorene fluorophore (donor) to Cu2+ (acceptor).62-66 Though similar hybrid molecular systems have been developed earlier in combination with different aminoacids and bulky fluorophore, and their Cu2+ induced fluorescence quenching has been studied extensively,67-68 the ensemble stoichiometry were determined based on the optical results obtained from the solution chemistry upon metal ligand interaction, but no evidence at the molecular level has been reported to date. In the current work, the ligand specifically designed to have a favourable chemical architecture allowed the ensemble to crystallize out from the solution. A Page 10 of 24


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detailed analysis of single crystal structure revealed that the stoichiometry (ligand:metal) of the Cu-L ensemble is 2:1 which was in agreement with stoichiometry obtained from solution analysis (Figure S12). From the observations mentioned in previous sections, we became curious to investigate in detail the fluorescence enhancement of L-Cu2+ in the presence of Cr3+. Upon addition of a aqueous Cr3+(0 – 1 µM) lighted up the quenched signal of L-Cu2+ ensemble at 305 nm (Figure 2b) in 4:1 (methanol : buffer, v/v) whereas no appreciable changes of fluorescence signals were observed in the presence of commonly used mono, di and trivalent metal ions (Figure 2c). The UV-vis spectroscopy studies were also performed in similar way which showed slight enhancement of absorption intensity (Figure S13). These observations clearly indicated that Cr3+ has strong binding affinity toward L as compared to Cu2+, and therefore Cr3+ replaces Cu2+ from L-Cu2+ ensemble. It is worth mentioning that signal light up happened by replacing a paramagnetic (Cu2+) cation by another paramagnetic cation (Cr3+). This in fact resulted in regeneration of fluorescence signal. The sensitivity of LCu2+ system was found to be water percentage (in methanol-water mixed solvent system) dependent. The effect of water percentage was studied by performing the sensing experiments in 1:1 mathanol-water system. In this system, the detection limit was found be 600 pM, which is much higher that the detection limit in 1:4 water: methanol system (Figure S14). The fluorescence life time measurements also supported the replacement of Cu2+ from L-Cu2+ ensemble by Cr3+. The life time spectrum of L revealed bi-exponential decay indicating two emitting species having life times of τ1 (2.15 ns, 83%) and τ2 (4.39 ns, 17%) respectively, with an average life time τavg of 4.12 ns (Figure S15). It was found that the average lifetime (tavg) of L decreased from 4.12 to 3.75 ns upon addition of Cu2+ to the same solution whereas the average lifetime of L-Cu2+ ensemble (tavg) increased from 3.75 to 4.13 ns upon addition of Cr3+ to the same L-Cu2+ ensemble solution (Figure S15).

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(a)

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150 300

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2+ Ligand (L) with Cu 2+ 3+ L+ Cu + 0.333 pM Cr 2+ 3+ L+ Cu + 0.666 pM Cr 2+ 3+ L+ Cu + 1 pM Cr 2+ 3+ L+ Cu + 1.333 pM Cr 2+ 3+ L+ Cu + 2 pM Cr 2+ 3+ L+ Cu + 2.666 pM Cr 2+ 3+ L+ Cu + 3.666 pM Cr 2+ 3+ L+ Cu + 4.666 pM Cr

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(b) 1.2%

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Concentration of Cr3+ ion in pM

Figure 3. (a) Fluorescence spectra of probe L-Cu2+ (1 µM) in methanol: river water (4:1, v/v) (at λex 289 nm) upon the addition of increasing quantities of Cr3+ (0 to 7 pM), (b) Fluorescence intensity of L-Cu2+(1µM) in methanol: river water (4:1, v/v) excitation at 289 nm as a function of the concentration of Cr3+. In order to check the formation of L-Cr3+ ensemble the fluorescence life time of ligand (L) with Cr3+ has been measured separately. The tavg of L-Cr3+ ensemble is 4.13 ns which is comparable to the Tavg value of L-Cr3+ ensemble obtained from in situ addition of Cr3+ to LCu2+ ensemble. These results supported displacement of Cu2+ and in situ formation of L-Cr3+. Binding constant calculations indicated higher affinity of L toward Cr3+ than Cu2+ (Figures S16and S17). Whereas the binding constant for L-Cu2+ ensemble is 6.62x 102 M-1/2, the same for L-Cr3+ ensemble is 1.34 x 105 M-1/2.69 Next, we investigated the effect of Cr3+ on the fluorescence behavior of L-Cu2+ in the presence of various metal ions in identical conditions. No interference of other metal ions on this Cr3+ induced light up process was observed (Figures 2c and S18). These results further indicated that the current quencher displacement process is highly selective for Cr3+ ion. Limit of detection is always important for any

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analytical tool which supports the efficiency of that particular tool. The current L-Cu2+ ensemble can detect as low as 0.666 picomolar of Cr3+ (Figures 2d and S19) in mixed aqueous solution.68-70 To the best of our knowledge, this is the first optical material which can detect Cr3+ ion at picomolar level. Though we could not isolate any single crystal of LCr3+ensemble, the Job plots and mass spectral analysis revealed that the complex stoichiometry is similar to L-Cu2+ensemble (Figures S20 and S21). In Job plots, the maximum fluorescence intensity at molar ratio ~0.6 indicated the formation of 2:1 (L: Cr3+) complex. Similarly, a peak in mass spectra appeared at m/z 666.1407 (Calculated 666.2550), which corresponds to [2L+Cr3+] + (Figure S22). Finally, to investigate whether L-Cu2+ could be applied for detecting Cr3+ ions in real samples ions, three different types of water samples were collected from different sources (drinking, tap and river water). Drinking water was collected from water filter located at Kamand campus of IIT Mandi, tap water from the water tap installed in our synthesis lab, and the river water from Uhl river (Kamand region, Himachal Pradesh, India). The fluorescence titrations were performed in methanol:H2O solution (4:1, v/v) buffered with HEPES (1 mM, pH = 7.2) respectively. Here, buffer solutions were prepared using real water instead of deionised water. Then the samples were filtered using 0.2 micron syringe filter to remove larger particles in order to avoid optical interference during fluorescence studies. The same method as described previously was followed to investigate the potential of L-Cu2+ ensemble in real sample. The L-Cu2+ ensemble efficiently detected very low concentrations of Cr3+ (Figures 3a and S23 – S24). The practical detection limits for Cr3+, evaluated based on 10 % increment of fluorescence emission of L-Cu2+ upon the addition of Cr3+, were found to be in the range of picomolar level (see in table S3, Figures 3b and S25 – S26). 70-72

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Conclusion In conclusion, we have developed a highly fluorescent chiral organic molecular probe L by integrating fluorene unit with a L-leucine moiety. The resulting fluorescent species has the capability of detecting Cu2+ through turn-off signalling, and forming bioinspired organicinorganic hybrid ensemble. We also report herein the crystal structure of L-Cu2+ where the amino acid based ligand contains a bulky non-coordinating fluorophore unit. The in situ generated L-Cu2+ ensemble has been explored for turn-on fluorescence signaling of Cr3+, at picomolar level following quencher displacement approach. Given their high selectivity and remarkable sensitivity, we have proved that these two integrated systems could be used for recognition of Cu2+/Cr3+ by two different optical signaling mechanisms in real samples. ASSOCIATED CONTENT Supporting Information Available. The following files are available free of charge. Crystallographic data in CIF, characterization data and additional spectroscopy data; these information are available via the Internet at http://pubs.acs.org. AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] *E-mail:[email protected] Author Contributions ¤ These authors equally contributed to the work reported in this paper

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Acknowledgement: Financial support from DST, India (SR/FT/CS-57/2010(G)) is thankfully acknowledged. G. D. thanks MHRD, India for research fellowship. M. V. thanks CSIR, India for research fellowship. V. K. acknowledges DST, India for INSPIRE faculty award. We thank Advanced Materials Research Center (AMRC), IIT Mandi, for sophisticated instrumentation facility.

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