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Synthesis of bisbenzimidazo quinoline fluorescent receptor for Fe2+ ion in the aqueous medium – An experimental and theoretical approach
Journal of Molecular Structure 1099 (2015) 257e265
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Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis of bisbenzimidazo quinoline fluorescent receptor for Fe2þ ion in the aqueous medium e An experimental and theoretical approach Malathi Mahalingam a, *, Manikandan Irulappan a, Gayathri Kasirajan b, Mohan Palathurai Subramaniam b, Shankar Ramasamy c, Nusrath Unnisa a a b c
Department of Chemistry, Bannari Amman Institute of Technology, Sathyamangalam, India Department of Chemistry, Bharathiar University, Coimbatore, India Department of Physics, Bharathiar University, Coimbatore, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 August 2014 Received in revised form 23 June 2015 Accepted 23 June 2015 Available online 25 June 2015
Bisbenzimidazo quinoline receptor 1 bearing diethylene oxide spacer linkage was synthesized and characterized by spectral and analytical techniques. Metal binding properties of the receptor 1 in aqueous ethanol medium were studied through absorption, emission and electrochemical studies. Emission analyses were performed at higher excitation wavelength (lex 750 nm). Binding studies exhibited specific “turn-on-type” fluorescent enhancement character of the receptor 1 for the Fe2þ ion (Ka ¼ 6.67 105 Me1). The appreciable metal binding property of the receptor 1 was theoretically studied by the quantum mechanical calculation. In the illustration of metal binding mechanism three binding modes A, B and C for the receptor 1 with Fe2þ/Fe3þ ions were proposed and the active molecular sites were analyzed using DFT descriptors, fukui functions and molecular electron density map (MEP). Theoretically results were correlated to the experimentally observed results. © 2015 Elsevier B.V. All rights reserved.
Keywords: Bisbenzimidazo quinoline Fluorescence chemosensor Metal binding DFT Fugi function Molecular electron density map
1. Introduction Fluorometric analysis is the simplest method of detecting any charged species in solution by binding of fluorescent sensors with ions [1e5]. The principle behind the analysis involves either enhancement or diminishment of fluorescence intensity of the sensor in the contact with charged specie which in turn leads to the design and synthesis of suitable fluorescent sensors for the detection of ions [6,7] specifically essential traces of metallic minerals [8e12]. Iron is one of the most essential metals for human whose ionic state plays an important key role in human metabolism [13]. The lower content of iron in the human body leads to iron deficiency [14] in turn reduces the red blood cells or hemoglobin content [15]. If the deficiency becomes severe, the condition is diagnosed as iron-deficiency anemia. In contrast, the high content of iron in the human body has been considered as “iron overload” results liver
* Corresponding author. E-mail address: [email protected] (M. Mahalingam). http://dx.doi.org/10.1016/j.molstruc.2015.06.070 0022-2860/© 2015 Elsevier B.V. All rights reserved.
diseases [16], heart attack [17], diabetes mellitus [18], osteoarthritis [19], osteoporosis [20] and metabolic syndrome [21] etc., and the condition is diagnosed as hemochromatosis [22]. Fortunately, the human body can be able to maintain appropriate levels of available iron in the body, even if the iron consumption does not exactly match the body's iron loss ever. The regulation of blood-iron levels is mediated by the protein ferritin which hold the excess iron within the hollow sphere in the form of Fe(III) oxidation state [23]. It functions as a buffer against iron deficiency and, to lesser extent, against iron overload. In the case of iron deficiency, the protein releases the protein-bounded iron after the reduction of Fe(III) to Fe(II) oxidation state [24]. Accordingly, selective monitoring of Fe2þ/Fe3þ ions have become significant to understand the proteins and enzymes activities towards the medical diagnosis applications [25e27]. It fuel the need to develop fluorescence sensors that are capable of detecting the presence of Fe2þ or Fe3þ ions within the biological and environmental samples at various physiological pH value. Till date, few Fe2þ-selective fluorescent chemosensors have been achieved in aqueous medium [28e33]. All the reported fluorescence chemosensors show absorption and emission maxima in
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the region of lmax 300e400 nm range. Such a lower wavelength region of the UVevisible light can damage cellulose part of the living cell during in vivo biological studies [34e36]. The problem could be avoided if the synthesised sensors have long wavelength optical property with aqueous solubility, which allows visualization of ions, small molecules, or enzymes in the living cells under lower energy radiation [37,38]. In addition, the selective detection of Fe2þ ion is always accompanied by interference of Cu2þ and Fe2þ ions [39e41]. Liang et al. [42] reported a colorimetric receptor for ferric ion while a notable interference of ferrous ion was also accounted in the same study. In the search of new fluorophores, we have synthesized and studied the optical properties of the benzimidazo quinoline (BIQ) compounds and the structure-photo activity relationship [43] was also demonstrated. During the studies the higher wavelength excitation property of the BIQ compounds in the aqueous ethanolic environment was identified. The studied optical properties illustrates that the BIQ fluorescent probe can be suitable for the designing and synthesis of NIR-wavelength fluorescent receptors for the metal ions detection. With a view to develop BIQ based receptors, herein we report the synthesis and characterization of bisbenzimidazo quinoline receptor 1 and its metal binding behavior with a large number of cations [Agþ, Ca2þ, Cd2þ, Co2þ, Cu2þ, Fe2þ, Fe2þ, Hg2þ, Kþ, Mg2þ, Mn2þ, Ni2þ, Pb2þ, and Zn2þ]. Cation binding property has also determined from electrochemical studies. From the experimental results, we try to explain the metal binding mode of the receptor 1 with Fe2þ/Fe3þ ions by doing density functional theory (DFT) calculations. The theoretical energy calculations are compared with the experimentally observed results.
2. Experimental
2.2. Synthesis receptor 1 1:1 M ratio of 0.5 g (1.8 mmol) 3-(1H-benzo[d]imidazol-2-yl)-2chloroquinoline (BIQ) [43] and 0.1 mL (0.9 mmol) diethylene glycol with 0.1 g (1.8 mmol) KOH in 5 mL THF solvent were refluxed with constant stirring (45 min). The solvent was removed under reduced pressure and the crude was transferred to a beaker containing crushed ice and neutralized using dil. HCl solution. The white precipitate was filtered, dried and adsorbed for the silica (120e200 mesh) column chromatography. The pure product was isolated in the 5% petroleum ether and ethyl acetate medium. M.p ¼ 157 C. IR (cm1): 3340, 3070 (C ¼ N) 1611. 1H NMR (CDCl3, 400 MHz, TMS): 4.18e4.26 (m, 4H), 4.89e4.96 (m, 4H), 7.28e7.35 (m, 4H), 7.41e7.51 (m, 4H), 7.65e7.70 (m, 2H), 7.80e7.90 (m, 6H), 9.31 (s, 2H), 10.98 (bs, 2H). 13C NMR (CDCl3, 400 MHz) d 61.75, 68.85, 111.19, 114.09, 119.11, 122.71, 123.29, 125.09, 125.23, 126.63, 128.37, 130.90, 133.50, 139.36, 142.92, 146.02, 147.61, 161.96. HRMS (FAB) C36H28N6O3 ¼ 592.6492, found 592.6497.
2.3. Electrochemical study The electrochemical analyzer (CHI 1120A) equipped with a three electrode compartment consisting of platinum disc working electrode, platinum wire counter electrode and Ag/AgCl reference electrode was used to record the cyclic voltammograms of the receptor 1 in 0.1 M tetrabutylammonium perchloates with respective concentration of Fe(ClO4)2 salt. All the potential values were calibrated versus the ferrocene/ferrocenium redox couple and then corrected to the saturated calomel electrode (SCE) on the basis of an Fe/Feþ redox potential 0.28 V and 0.16 V versus SCE in Ethanol/ water (deionized) mixed solution. The potential scan rate was 0.1 V/ s.
2.1. General information and materials 2.4. Theoretical studies All of the materials for synthesis were purchased from commercial suppliers and used without further purification. All of the solvents used were analytical reagent grade. Thin-layer chromatography (TLC) was conducted using silica gel 60 F254 plates (Merck KGaA). Column chromatography was carried out using silica gel powder 60e120 mesh (Ranbaxy). IR spectra were recorded on a VERTEX 70 FT-IR (Bruker Optics) IR spectrophotometer. 1H NMR spectra were recorded on a Bruker Avance 400 (400 MHz) spectrometer, using CDCl3 as solvent and tetramethylsilane (TMS) as an internal standard. Melting points were determined on an XD-4 digital micro melting point apparatus. HRMS spectra were recorded on a Q-TOF6510 spectrograph (Agilent). UVevis spectra were recorded on a PerkineElmer Lambada-35 spectrophotometer. Fluorescence measurements were recorded on a Shimadzu RF5301PC spectrofluorometer. All pH measurements were made with a pH-10C digital pH meter. HEPES-buffer (5 mM, pH 7.4) were prepared in deionized water. The solution of metal ions was prepared from their perchlorate salts. All the measurements for metal binding studies were performed at room temperature (25 C) unless otherwise stated. Receptor 1 and various metal ions were dissolved in aqueous ethanol (1:4, EtOH:H2O, respectively) as a stock solution (1 103 M) respectively. In experiments, the required concentration of the receptor 1 with HEPES-buffer (5 mM, pH 7.4) and the various metal ions solutions were diluted in the same way. The excitation and emission slit widths were kept constant (5 nm) throughout the optical studies. The fluorescence quantum yields (FX) were determined by using 2-aminopyridine in 0.1 M sulfuric acid (Fstd) as standard and calculated by following the reported procedure [34].
The geometrical electronic structure of free receptor and metal chelated systems (LeFe2þ and LeFe3þ) were optimized using the B3LYP/6-311 þ G** basis set with Becke's three parameter exact exchange functional combined with the gradient corrected correlation functional of Lee, Yang and Parr represented as B3LYP [44] of the density functional theory (DFT) method. The vibrational frequency calculations were performed at the same level of theory, confirming that the structures were on real minima without imaginary frequencies. To study the physicochemical property relationships of the compound, electron density map analysis was carried out. The total electron density of the compounds was constructed by B3LYP/6-311G(d,p) method and viewed using Gauss View visualization program. All calculations were performed using the Gaussian 09 W program [45].
3. Results and discussion 3.1. Synthesis of the receptor 1 A condensation reaction of 3-(1H-benzoimidazol-2-yl)-2chloro-quinoline 2 with diethylene glycol (1:1 M ratio respectively) was performed in the THF solvent medium using potassium hydroxide as base [Scheme 1]. The pure product was isolated through silica column chromatography and the structure was characterized by spectral and analytical techniques. The 1H and 13C NMR spectral studies (Fig. S1 and S2), micro analytical and HRMS mass data confirmed the formation of the receptor 1.
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Scheme 1. Synthesis of dipodal receptor 1.
3.2. Optical properties of the receptor 1 3.2.1. Absorption and emission spectral studies The UVevis absorption spectrum of the receptor 1 in aqueous ethanol medium exhibited a peak at lmax 377 nm (Fig. S3). The emission spectrum of receptor 1 at the excitation wavelength lex 377 ± 5 nm (single excitation) illustrated two fluorescent peaks (Fig. S4). The first peak appears at shorter wavelength region with lem 436 nm and second peak at longer wavelength with lem 849 nm. However the same receptor 1 solution showed similar emission property with low fluorescence intensity at lex 754 nm (double excitation). 3.2.2. Solvent polarity study Optical studies of fluorescent molecule with respect to the solvent polarity are essential to optimize their applications in the opto-analytical studies [46]. Fig. 1 illustrated the absorbance and emission (lex 754 nm, double excitation) spectrum of the receptor 1 [0.5 106 M, HEPES-buffer, pH 7.4] under different solvent medium [petroleum ether, toluene, DCM, THF, ethyl acetate, ethanol, acetonitrile, acetic acid and DMSO]. In the combined spectra, shifting of absorption and emission wavelengths were observed within the range of lmax 280e390 nm and 370e470 nm respectively [Table S1] which clearly exhibited the bathochromic shifts in both studies with respect to solvent polarity. In absorbance, a pronounced shift in wavelength was noted with respect to the increase in solvent polarity from petroleum ether (0.1 p0 ) to toluene (2.4 p0 ) (Fig. 1a). 3.2.3. pH titration The pH titration was performed at lex 754 nm to find the fluorescence efficiency of the receptor 1 [0.3 106 M] in aqueous ethanol medium under a wide range of pH (Fig. S5). Fig. 2 showed
Fig. 2. The fluorescence stability of the receptor 1 upon pH titration at lex ¼ 754 nm in aqueous ethanol medium (1:4 volume ratio).
the correlation of fluorescence intensity vs pH vs wavelength of the receptor 1. The plot illustrated the stable emission property of the receptor 1 within the pH 4 to 8 and distortion of the fluorescent stability in more acidic and basic pH range, owing to the protonation and deprotonation of hetero atoms of receptor 1. Hence the molecular aggregates were broken at low and high pH range and affected the intermolecular charge transfer during the excitation. The observed fluorescent stability of the receptor 1 in the wide range of pH (4e8) might be helpful to avoid the interference of induced pH changes during the biological stimulation [47]. 3.3. Metal binding analysis 3.3.1. Absorption and fluorescence binding studies The metal binding ability of the receptor 1 (0.3 104 M, HEPES-buffer, pH 7.4) was analyzed with different metal ions, i.e., Agþ, Ca2þ, Cd2þ, Co2þ, Cu2þ, Fe2þ, Fe3þ, Hg2þ, Kþ, Mg2þ, Mn2þ, Ni2þ, Pb2þ, and Zn2þ in aqueous ethanol medium (104 M with 1:4 volume ratio respectively) by absorbance spectral studies (Fig. 3a). The combined absorption spectrum of the receptor 1 predicted a hyperchromic shift specifically for the ferrous ion and none for
Fig. 1. Optical studies of the receptor 1 in different solvent medium (HEPES-buffer, pH 7.4). (a) UVevis absorption spectrum; (b) fluorescence spectrum (lex ¼ 754 nm).
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Fig. 3. Optical studies of the receptor 1 upon addition of different metal ions in aqueous ethanol medium (1:4 volume ratio) (HEPES-buffer, pH 7.4). (a) UVevis absorption spectrum (104 M); (b) emission spectrum (104 M) at lex ¼ 754 nm.
other metal ions (Fig. 3a). In emission studies (Fig. 3b), the metal binding property was analyzed by exciting the receptor 1 (0.3 106 M, HEPES-buffer, pH 7.4) at lex 754 nm [double excitation] and the resulting spectrum was monitored from the wavelength of 350e920 nm (Fig. 3b). In presence of ferrous ion, the receptor 1 showed an enhancement in the fluorescence intensity at lem 420 and 807 nm, while the other ions did not cause any significant variation under identical condition. In addition, the receptor 1 showed a small hypsochromic shift (Dlem z 20 nm) both in the short (350e500 nm) and longer wavelength (700e920 nm) regions in presence of ferrous ion. 3.3.2. Absorption and fluorescence titrations The combined spectrum of receptor 1 (0.3 104 M, HEPESbuffer, pH 7.4) absorption titrations with ferrous ion (0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 3.0, 5.0, 8.0 and 10 106 M) was depicted in Fig. 4a. The combined spectrum depicted a notable hyperchromic shift specifically at lmax 335 nm after addition of 0.4 104 M ferrous ion solution. The further increase in the concentration of ferrous ion did not show any remarkable enhancement in the intensity of absorbance, revealed the saturation limit of the receptor 1 with Fe2þ ion. In the fluorescence titration, the emission peaks of receptor 1 in the wavelength range of 350e550 nm was accounted for the metal binding study due to the small fluorescence intensity of the second
peak at the lem 700e900 nm. As shown in Fig. 4b, The free receptor 1 (0.3 106 M, HEPES-buffer, pH 7.4, lex 754 nm double excitation) showed an emission at lem 434 nm with a low fluorescence quantum yield (Fx ¼ 0.0574) whereas in presence of ferrous ion (0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 3.0, 5.0, 8.0 and 10.0 106 M) fluorescence intensity was doubled with blue shift (lem 434 to 423 nm). In addition, a pronounced increase in fluorescence quantum yield (Fx ¼ 0.167) was also noted after immediate addition of the Fe2þ ion. From the spectral studies, the observed physical change was plotted as a function of metal ion added to receptor system (Fig. 4bincerted). The plot illustrated the general binding isotherm with hyperbolic structure revealed the formation of simple 1:1 binding of the host with the guest [48]. The complexation mode of receptor 1 for Fe2þ was determined from a BenesieHildebrand plot analysis [49]. If the fluorescence change is only induced by the formation of a 1:1 complex between receptor 1 (L) and metal ion (M), the equilibrium can be expressed by the following equations:
L þ M#LM;
K ¼ ½LM=½L½M
(1)
The total receptor concentration and the fluorescence intensity are defined as [L]0 ¼ [L] þ [LM] and F ¼ fL [L] þ fML [ML], respectively, where [L]0 and [M]0 are the total concentration, [L] and [LM] are the equilibrium concentration of L and M, respectively,
Fig. 4. Optical titrations of the receptor 1 upon addition different concentration of Fe2þ (0e1.0 106 M) ion in aqueous ethanol medium (1:4 volume ratio) (HEPES-buffer, pH 7.4). (a) UVevis absorption spectrum; (b) emission spectrum at lex ¼ 754 nm.
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and fL and fML are the fluorescence quantum yields for free and complexed receptor. If [M]0 » [L]0, the BenesieHildebrand type equation can be derived as,
1 1 1 ¼ þ ðF F min Þ ðfML fL Þ½Lo K½Lo ðfML fL Þ½Mo
(2)
If a 1:1 metal-probe complex is formed between receptor 1 and metal ion Fe2þ, a BenesieHildebrand plot of the data according to Equation (2) should be linear [50] and present in Fig. 5. The calculated correlation coefficient of the linear plot was 0.989. The binding constant (Ka) and dissociation constant (Kd) of the receptor 1 were calculated from the intercept and the slope values (0.006 and 0.009 106 M respectively) and found to be 6.67 105 Me1 (±0.5%) and 1.50 106 M (±0.5%). This value is quite high compared to other reported ferrous ion receptors binding constant [51]. In all the reported receptors, the studies were influenced either by other charged species with similar ionic radius like Cr3þ and Co3þ or physical changes (pH and temperature) [39e42]. Hence, receptor 1 could be a promising candidate as fluorescent turn-on probe for ferrous ion.
3.3.3. Selectivity and sensitivity of metal binding For practical application reversibility is a prerequisite need towards the efficient fluorescent chemosensors. The selectivity and reversibility of the receptor 1 towards ferrous ion was analyzed by comparing the changes in the fluorescence intensity of the host-guest system (receptor 1-ferrous ion) in presence of other metal ions (0.1 106 M) and ethylene diamine tetraacetic acid (EDTA, 0.3 106 M) (Fig. 6a). It observed spectral results revealed that the fluorescence profile of the host-guest system was not influenced by addition of other metal ions. The addition of complexing reagent EDTA to the host-guest system exhibited a reduction of fluorescence intensity at lem 423 nm. These studies clearly indicate that the receptor can be used for the selective detection of Fe2þ ion without interference from other metal ions. Furthermore, it was confirmed that the receptor 1 possessed a similar fluorescence behavior in presence of other Fe2þ salts (FeCl2, FeSO4, FeNO3 and (NH4)2Fe(SO4)2) (Fig. 6b), indicating that the counter anions of Fe2þ did not affect the fluorescence sensing property of the host.
Fig. 5. Benesi Hildebrand (BH) plot for the fluorescence titration of receptor 1 with ferrous solution.
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3.4. Cyclic voltammetric studies The cyclic voltammetric behavior of the free receptor 1 (0.3 106 M) in the HEPES-buffer (pH 7.4) medium was studied (Fig. 7a). The resulted cyclic voltammogram (CV) depicted the reversible reduction peaks with the cathodic potential (Epc) e 1.0066 V and the anodic potential (Epa) e 0.408 V. However, the similar peaks were not observed in the oxidation part of the cyclic voltammogram.
DEp ¼ ðEpc EpaÞ ¼ 1:0066 ð 0:408Þ ¼ 0:5986 V: The same solution of receptor 1 was used in the cyclic voltammetric titration with increasing concentration of the ferrous ion (0.5, 1.5, 2.5 5.0 and 7.5 106 M) (Fig. 7b). The initial addition of Fe2þ ion (0.5 106 M) resulted a notable difference in the appearance and position of peaks in the CV. Addition of 1.5 106 M ferrous solution illustrated both irreversible oxidation and reduction peaks with Epa 0.13978 V and Epc 0.3905 V respectively. In the case of 2.5 106 M addition, a new reduction peak appeared in the reductive anodic part at the Epa e 0.1586 V which is a reversible peak of the reductive cathodic peak Epc e 0.3905 V. The subsequent addition of Fe(II) ion (5.0 and 7.5 106 M) in the titration mixture resulted complete disappearance of reductive anodic peak Epa 0.1586 V. In addition, a shift of reduction part cathodic peak towards more negative potential and oxidation part of anodic peak towards more positive potential with a small raise in the intensity of the current were observed for the successive increase in the metal ion concentration. This describes a net one electron oxidation of the Fe2þ/Fe3þ couple of receptor 1 bound to Fe2þ cation. Further increase in the ferrous ion illustrated a saturation limit of receptor 1 in the CV titration mixture. Accordingly, the metal binding CV titration study supports the 1:1 binding of the receptor 1 with the ferrous ion [52]. 3.5. Computational studies 3.5.1. For free receptor system 1 In continuation of theoretical calculations on reaction mechanism [53], the present theoretical studies was planned to investigate the binding mode and affinity of the receptor 1 towards Fe2þ and Fe2þ ions. Initially the structure of the receptor 1 was optimized at B3LYP/6-311 þ G** level of theory. Three active binding modes A, B and C were proposed and illustrated in Scheme 2. First two modes of binding based on the binding of imidazole ring nitrogen atoms (eCeNHe and eC]Ne respectively), while the third mode C was the quinoline ring nitrogen in addition with the ethylene ether spacer linkage of the receptor 1. In order to understand the binding mode of receptor 1, DFT descriptors such as electronegativity, fukui functions and molecular electron density map were calculated for the receptor 1. 3.5.1.1. Electronegativity (c). It is the capacity of atoms to attract the electrons towards itself for binding. Physically negative c value of an atom in the molecule represents its more tendency to donate electrons and behaves as an efficient site for metal ion binding. The calculated c values for all the atoms in the receptor 1 revealed that the quinoline nitrogen atoms had more metal binding affinity since its c values were more negative (0.909 and 0.913 eV for Q1-N11 and Q-N39 respectively) (Fig. 8). In the imidazole rings of the receptor 1, a higher negative value was noted for the eC]N (0.868 and 0.870 eV for C]N24 and C]N52, respectively) rather than the -NH atom (0.847 and 0.850 eV for NH22 and NH50,
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Fig. 6. Changes in the fluorescence intensity of the free receptor 1, receptor 1 with different ions and Fe2þ (0.3 106 M) and receptor 1-Fe2þ with EDTA (0.3 106 M) in aqueous ethanol medium (1:4 volume ratio) (HEPES-buffer, pH 7.4) at lex ¼ 754 nm.
Fig. 7. Cyclic voltammetric titration of receptor 1 in aqueous ethanol medium containing Tris-HCl buffer medium. (a) Cyclic voltammogram of the dipodal receptor 1 alone; (b) changes in the cyclic voltammogram upon addition of Fe2þ (0.5, 1.5, 2.5 5.0 and 7.5 106 M).
respectively). It is also observed that the oxygen atom (O64) present in the middle of ethylene ether spacer linkage possess a high negative c value (0.513 eV) compared to the other oxygen atoms (0.488 and 0.510 eV for O57 and O78, respectively) in the receptor 1. The calculated c values of the receptor 1 illustrated that both QeN atoms and ethylene ether spacer linkage can form an electropositive cavity (binding mode C) to accommodate the
Scheme 2. Possible modes of metal binding of receptor 1 with Fe2þ and Fe3þ ion. (a) imidazole NeH mode A; (b). imidazole C]N mode B; (c). quinoline C]N mode C.
incoming metal ions than the other two proposed binding mode. 3.5.1.2. Fukui function. It is proposed by Parr and Yang, is one of the local reactivity indices specifying the response of any particular site of a chemical species in turn of electron density [54]. Table 1 showed the fukui function (FF) values for the receptor 1 calculated by Mulliken population analysis (MPA) and Hirshfeld
Fig. 8. Theoretically energy-minimized structure of the receptor 1 with electronegativity value (c).
M. Mahalingam et al. / Journal of Molecular Structure 1099 (2015) 257e265 Table 1 Condensed Fukui function fk of the hero atoms in the receptor 1. Atoms
fk
fkþ
fk0
N11 N39 N22 N50 N52 N24 O71 O64 O57
0.021127 0.015303 0.010740 0.012000 0.001203 0.002334 0.001646 0.002808 0.002853
0.004578 0.009754 0.023299 0.019928 0.001852 0.000403 0.002020 0.003110 0.001620
0.0128525 0.0125285 0.0170195 0.0159620 0.0015275 0.0013685 0.0001850 0.0001520 0.0006155
population analysis (HPA) gross charges at B1/DZP level of theory. Both MPA and HPA schemes resulted that the quinoline nitrogen N11 and N39 had higher f k value revealed the feasibility of electrophilic attack than the imidazole azide nitrogen N24 and N52. The observed electrophilicity trend for the nitrogen and oxygen atoms present in the receptor 1 is in the following order of N11 > N39 > N50 > N22 > O57 > O64 > N24 > O71 > N52. The fukui calculations further supported the quinoline N-mode (C) of binding.
3.5.1.3. MEP. The molecular electron density difference map provides the information about accepting or releasing of electrons with the interacting molecules [55] thereby indicating the charge distribution in a molecule. In MEP surfaces, the negative and positive regions are the preferred site for electrophilic and nucleophilic attack which is denoted as red and blue color respectively. The significance of calculating MEP surface for a molecule is mainly due to the fact that it consequently picturizes the shape and size of molecular electronic charge density in terms of color grading. It is also reported that it is a useful tool in the molecular structural research to understand the physcicochemical property relationship [56]. In the present study, a MEP plot of the neutral receptor 1 in the three dimensional surface was calculated (Fig. 9). It exposed the negative potential represented as red color in all the hetero atoms of the receptor 1 except imidazole CeNH regions revealed unfeasibility of the first proposed binding modes A and B [Scheme 2A and B]. The MEP plot depicted that the electronegative potential of quinoline C]N with flexible ethylene glycol spacer can create a cavity feasible to hold the incoming positive charged species
Fig. 9. B3LYP/6-311G(d,p) calculated isosurface representation of electron density for the receptor 1.
263
[Scheme 2C]. However, such viable structural arrangement for the metal cation chelation was not possible in the case of other modes A and B. 3.5.2. Optimization of receptor 1 with Fe2þ and Fe3þ ions The structural optimization study for the proposed binding modes A, B and C were performed and compared with the host system 1 under B3LYP/6-311 þ G** level of theory (Table S2). The theoretical study predicted that the metal bound receptor systems A, B and C have more stability represented by the lower energy (2100 to 2200 a.u) in comparison with the free receptor system 1 (~1942 a.u). The calculated energy differences between the respective binding modes A, B and C with free receptor 1 are represented in Figs. 10 and 11 as downward arrow. The high energy difference for the ferrous ion complexes in each mode of binding (199.386, 199.489 and 278.181 a.u. respectively) revealed higher stability whereas the ferric ion exhibited small energy differences (198.967, 199.114 and 278.08 a.u. respectively) owing to the lower feasibility of the receptor 1 with ferric ion. In addition, the QeN binding mode C exhibited more feasibility of metal chelation through notable energy differences for ferrous and ferric ion respectively. 4. Conclusion A sensitive quinoline receptor 1 was synthesized and studied under the metal binding studies in the aqueous medium at higher excitation wavelength region (lexc 754 nm). In presence of ferrous
Fig. 10. B3LYP/6-311G(d,p) calculated energy-minimized structures of the receptorFe2þ complexes and the corresponding optimized energy differences with respect to the receptor 1. (A) imidazole NeH mode A; (B) imidazole C]N mode B; (C) quinoline C]N mode C.
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References
Fig. 11. B3LYP/6-311G(d,p) calculated energy-minimized structures of the receptorFe3þ complexes and the corresponding optimized energy differences with respect to the receptor 1. (A) imidazole NeH mode A; (B) imidazole C]N mode B; (C) quinoline C]N mode C.
ion, the receptor 1 shows an enhancement in the fluorescence intensity. The addition of EDTA to the receptor-Fe2þ mixture quenches the fluorescence intensity thereby enlightening the reversible sensing property of receptor 1. The binding affinity of the receptor 1 was also analyzed under electrochemical studies. In the theoretical illustration of metal binding mechanism, three binding modes A, B and C of receptor 1 were proposed. Quantum mechanical studies reveal that the QeN binding mode C of the receptor 1 must be an appropriate mode for the metal binding. Energy optimization of three binding modes A, B and C further establishes the ferrous ions sensing property of the receptor 1 and further supports the experimental observed metal binding results. Acknowledgments This work was supported under Fast-Track young scientist programme by Science and Engineering Research Board (SR/FT/CS51/2011) funded by the Indian Government. The NMR spectral data were obtained from the NMR research center, Indian Institute of Science, Bangalore, India. Mass spectral facility was provided by the Indian Institute of Technology, Chennai, India. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.molstruc.2015.06.070.
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Synthesis of bisbenzimidazo quinoline fluorescent receptor for Fe2þ ion in the aqueous medium e An experimental and theoretical approach Malathi Mahalingam a, *, Manikandan Irulappan a, Gayathri Kasirajan b, Mohan Palathurai Subramaniam b, Shankar Ramasamy c, Nusrath Unnisa a a b c
Department of Chemistry, Bannari Amman Institute of Technology, Sathyamangalam, India Department of Chemistry, Bharathiar University, Coimbatore, India Department of Physics, Bharathiar University, Coimbatore, India
a r t i c l e i n f o
a b s t r a c t
Article history: Received 31 August 2014 Received in revised form 23 June 2015 Accepted 23 June 2015 Available online 25 June 2015
Bisbenzimidazo quinoline receptor 1 bearing diethylene oxide spacer linkage was synthesized and characterized by spectral and analytical techniques. Metal binding properties of the receptor 1 in aqueous ethanol medium were studied through absorption, emission and electrochemical studies. Emission analyses were performed at higher excitation wavelength (lex 750 nm). Binding studies exhibited specific “turn-on-type” fluorescent enhancement character of the receptor 1 for the Fe2þ ion (Ka ¼ 6.67 105 Me1). The appreciable metal binding property of the receptor 1 was theoretically studied by the quantum mechanical calculation. In the illustration of metal binding mechanism three binding modes A, B and C for the receptor 1 with Fe2þ/Fe3þ ions were proposed and the active molecular sites were analyzed using DFT descriptors, fukui functions and molecular electron density map (MEP). Theoretically results were correlated to the experimentally observed results. © 2015 Elsevier B.V. All rights reserved.
Keywords: Bisbenzimidazo quinoline Fluorescence chemosensor Metal binding DFT Fugi function Molecular electron density map
1. Introduction Fluorometric analysis is the simplest method of detecting any charged species in solution by binding of fluorescent sensors with ions [1e5]. The principle behind the analysis involves either enhancement or diminishment of fluorescence intensity of the sensor in the contact with charged specie which in turn leads to the design and synthesis of suitable fluorescent sensors for the detection of ions [6,7] specifically essential traces of metallic minerals [8e12]. Iron is one of the most essential metals for human whose ionic state plays an important key role in human metabolism [13]. The lower content of iron in the human body leads to iron deficiency [14] in turn reduces the red blood cells or hemoglobin content [15]. If the deficiency becomes severe, the condition is diagnosed as iron-deficiency anemia. In contrast, the high content of iron in the human body has been considered as “iron overload” results liver
* Corresponding author. E-mail address: [email protected] (M. Mahalingam). http://dx.doi.org/10.1016/j.molstruc.2015.06.070 0022-2860/© 2015 Elsevier B.V. All rights reserved.
diseases [16], heart attack [17], diabetes mellitus [18], osteoarthritis [19], osteoporosis [20] and metabolic syndrome [21] etc., and the condition is diagnosed as hemochromatosis [22]. Fortunately, the human body can be able to maintain appropriate levels of available iron in the body, even if the iron consumption does not exactly match the body's iron loss ever. The regulation of blood-iron levels is mediated by the protein ferritin which hold the excess iron within the hollow sphere in the form of Fe(III) oxidation state [23]. It functions as a buffer against iron deficiency and, to lesser extent, against iron overload. In the case of iron deficiency, the protein releases the protein-bounded iron after the reduction of Fe(III) to Fe(II) oxidation state [24]. Accordingly, selective monitoring of Fe2þ/Fe3þ ions have become significant to understand the proteins and enzymes activities towards the medical diagnosis applications [25e27]. It fuel the need to develop fluorescence sensors that are capable of detecting the presence of Fe2þ or Fe3þ ions within the biological and environmental samples at various physiological pH value. Till date, few Fe2þ-selective fluorescent chemosensors have been achieved in aqueous medium [28e33]. All the reported fluorescence chemosensors show absorption and emission maxima in
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the region of lmax 300e400 nm range. Such a lower wavelength region of the UVevisible light can damage cellulose part of the living cell during in vivo biological studies [34e36]. The problem could be avoided if the synthesised sensors have long wavelength optical property with aqueous solubility, which allows visualization of ions, small molecules, or enzymes in the living cells under lower energy radiation [37,38]. In addition, the selective detection of Fe2þ ion is always accompanied by interference of Cu2þ and Fe2þ ions [39e41]. Liang et al. [42] reported a colorimetric receptor for ferric ion while a notable interference of ferrous ion was also accounted in the same study. In the search of new fluorophores, we have synthesized and studied the optical properties of the benzimidazo quinoline (BIQ) compounds and the structure-photo activity relationship [43] was also demonstrated. During the studies the higher wavelength excitation property of the BIQ compounds in the aqueous ethanolic environment was identified. The studied optical properties illustrates that the BIQ fluorescent probe can be suitable for the designing and synthesis of NIR-wavelength fluorescent receptors for the metal ions detection. With a view to develop BIQ based receptors, herein we report the synthesis and characterization of bisbenzimidazo quinoline receptor 1 and its metal binding behavior with a large number of cations [Agþ, Ca2þ, Cd2þ, Co2þ, Cu2þ, Fe2þ, Fe2þ, Hg2þ, Kþ, Mg2þ, Mn2þ, Ni2þ, Pb2þ, and Zn2þ]. Cation binding property has also determined from electrochemical studies. From the experimental results, we try to explain the metal binding mode of the receptor 1 with Fe2þ/Fe3þ ions by doing density functional theory (DFT) calculations. The theoretical energy calculations are compared with the experimentally observed results.
2. Experimental
2.2. Synthesis receptor 1 1:1 M ratio of 0.5 g (1.8 mmol) 3-(1H-benzo[d]imidazol-2-yl)-2chloroquinoline (BIQ) [43] and 0.1 mL (0.9 mmol) diethylene glycol with 0.1 g (1.8 mmol) KOH in 5 mL THF solvent were refluxed with constant stirring (45 min). The solvent was removed under reduced pressure and the crude was transferred to a beaker containing crushed ice and neutralized using dil. HCl solution. The white precipitate was filtered, dried and adsorbed for the silica (120e200 mesh) column chromatography. The pure product was isolated in the 5% petroleum ether and ethyl acetate medium. M.p ¼ 157 C. IR (cm1): 3340, 3070 (C ¼ N) 1611. 1H NMR (CDCl3, 400 MHz, TMS): 4.18e4.26 (m, 4H), 4.89e4.96 (m, 4H), 7.28e7.35 (m, 4H), 7.41e7.51 (m, 4H), 7.65e7.70 (m, 2H), 7.80e7.90 (m, 6H), 9.31 (s, 2H), 10.98 (bs, 2H). 13C NMR (CDCl3, 400 MHz) d 61.75, 68.85, 111.19, 114.09, 119.11, 122.71, 123.29, 125.09, 125.23, 126.63, 128.37, 130.90, 133.50, 139.36, 142.92, 146.02, 147.61, 161.96. HRMS (FAB) C36H28N6O3 ¼ 592.6492, found 592.6497.
2.3. Electrochemical study The electrochemical analyzer (CHI 1120A) equipped with a three electrode compartment consisting of platinum disc working electrode, platinum wire counter electrode and Ag/AgCl reference electrode was used to record the cyclic voltammograms of the receptor 1 in 0.1 M tetrabutylammonium perchloates with respective concentration of Fe(ClO4)2 salt. All the potential values were calibrated versus the ferrocene/ferrocenium redox couple and then corrected to the saturated calomel electrode (SCE) on the basis of an Fe/Feþ redox potential 0.28 V and 0.16 V versus SCE in Ethanol/ water (deionized) mixed solution. The potential scan rate was 0.1 V/ s.
2.1. General information and materials 2.4. Theoretical studies All of the materials for synthesis were purchased from commercial suppliers and used without further purification. All of the solvents used were analytical reagent grade. Thin-layer chromatography (TLC) was conducted using silica gel 60 F254 plates (Merck KGaA). Column chromatography was carried out using silica gel powder 60e120 mesh (Ranbaxy). IR spectra were recorded on a VERTEX 70 FT-IR (Bruker Optics) IR spectrophotometer. 1H NMR spectra were recorded on a Bruker Avance 400 (400 MHz) spectrometer, using CDCl3 as solvent and tetramethylsilane (TMS) as an internal standard. Melting points were determined on an XD-4 digital micro melting point apparatus. HRMS spectra were recorded on a Q-TOF6510 spectrograph (Agilent). UVevis spectra were recorded on a PerkineElmer Lambada-35 spectrophotometer. Fluorescence measurements were recorded on a Shimadzu RF5301PC spectrofluorometer. All pH measurements were made with a pH-10C digital pH meter. HEPES-buffer (5 mM, pH 7.4) were prepared in deionized water. The solution of metal ions was prepared from their perchlorate salts. All the measurements for metal binding studies were performed at room temperature (25 C) unless otherwise stated. Receptor 1 and various metal ions were dissolved in aqueous ethanol (1:4, EtOH:H2O, respectively) as a stock solution (1 103 M) respectively. In experiments, the required concentration of the receptor 1 with HEPES-buffer (5 mM, pH 7.4) and the various metal ions solutions were diluted in the same way. The excitation and emission slit widths were kept constant (5 nm) throughout the optical studies. The fluorescence quantum yields (FX) were determined by using 2-aminopyridine in 0.1 M sulfuric acid (Fstd) as standard and calculated by following the reported procedure [34].
The geometrical electronic structure of free receptor and metal chelated systems (LeFe2þ and LeFe3þ) were optimized using the B3LYP/6-311 þ G** basis set with Becke's three parameter exact exchange functional combined with the gradient corrected correlation functional of Lee, Yang and Parr represented as B3LYP [44] of the density functional theory (DFT) method. The vibrational frequency calculations were performed at the same level of theory, confirming that the structures were on real minima without imaginary frequencies. To study the physicochemical property relationships of the compound, electron density map analysis was carried out. The total electron density of the compounds was constructed by B3LYP/6-311G(d,p) method and viewed using Gauss View visualization program. All calculations were performed using the Gaussian 09 W program [45].
3. Results and discussion 3.1. Synthesis of the receptor 1 A condensation reaction of 3-(1H-benzoimidazol-2-yl)-2chloro-quinoline 2 with diethylene glycol (1:1 M ratio respectively) was performed in the THF solvent medium using potassium hydroxide as base [Scheme 1]. The pure product was isolated through silica column chromatography and the structure was characterized by spectral and analytical techniques. The 1H and 13C NMR spectral studies (Fig. S1 and S2), micro analytical and HRMS mass data confirmed the formation of the receptor 1.
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259
Scheme 1. Synthesis of dipodal receptor 1.
3.2. Optical properties of the receptor 1 3.2.1. Absorption and emission spectral studies The UVevis absorption spectrum of the receptor 1 in aqueous ethanol medium exhibited a peak at lmax 377 nm (Fig. S3). The emission spectrum of receptor 1 at the excitation wavelength lex 377 ± 5 nm (single excitation) illustrated two fluorescent peaks (Fig. S4). The first peak appears at shorter wavelength region with lem 436 nm and second peak at longer wavelength with lem 849 nm. However the same receptor 1 solution showed similar emission property with low fluorescence intensity at lex 754 nm (double excitation). 3.2.2. Solvent polarity study Optical studies of fluorescent molecule with respect to the solvent polarity are essential to optimize their applications in the opto-analytical studies [46]. Fig. 1 illustrated the absorbance and emission (lex 754 nm, double excitation) spectrum of the receptor 1 [0.5 106 M, HEPES-buffer, pH 7.4] under different solvent medium [petroleum ether, toluene, DCM, THF, ethyl acetate, ethanol, acetonitrile, acetic acid and DMSO]. In the combined spectra, shifting of absorption and emission wavelengths were observed within the range of lmax 280e390 nm and 370e470 nm respectively [Table S1] which clearly exhibited the bathochromic shifts in both studies with respect to solvent polarity. In absorbance, a pronounced shift in wavelength was noted with respect to the increase in solvent polarity from petroleum ether (0.1 p0 ) to toluene (2.4 p0 ) (Fig. 1a). 3.2.3. pH titration The pH titration was performed at lex 754 nm to find the fluorescence efficiency of the receptor 1 [0.3 106 M] in aqueous ethanol medium under a wide range of pH (Fig. S5). Fig. 2 showed
Fig. 2. The fluorescence stability of the receptor 1 upon pH titration at lex ¼ 754 nm in aqueous ethanol medium (1:4 volume ratio).
the correlation of fluorescence intensity vs pH vs wavelength of the receptor 1. The plot illustrated the stable emission property of the receptor 1 within the pH 4 to 8 and distortion of the fluorescent stability in more acidic and basic pH range, owing to the protonation and deprotonation of hetero atoms of receptor 1. Hence the molecular aggregates were broken at low and high pH range and affected the intermolecular charge transfer during the excitation. The observed fluorescent stability of the receptor 1 in the wide range of pH (4e8) might be helpful to avoid the interference of induced pH changes during the biological stimulation [47]. 3.3. Metal binding analysis 3.3.1. Absorption and fluorescence binding studies The metal binding ability of the receptor 1 (0.3 104 M, HEPES-buffer, pH 7.4) was analyzed with different metal ions, i.e., Agþ, Ca2þ, Cd2þ, Co2þ, Cu2þ, Fe2þ, Fe3þ, Hg2þ, Kþ, Mg2þ, Mn2þ, Ni2þ, Pb2þ, and Zn2þ in aqueous ethanol medium (104 M with 1:4 volume ratio respectively) by absorbance spectral studies (Fig. 3a). The combined absorption spectrum of the receptor 1 predicted a hyperchromic shift specifically for the ferrous ion and none for
Fig. 1. Optical studies of the receptor 1 in different solvent medium (HEPES-buffer, pH 7.4). (a) UVevis absorption spectrum; (b) fluorescence spectrum (lex ¼ 754 nm).
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Fig. 3. Optical studies of the receptor 1 upon addition of different metal ions in aqueous ethanol medium (1:4 volume ratio) (HEPES-buffer, pH 7.4). (a) UVevis absorption spectrum (104 M); (b) emission spectrum (104 M) at lex ¼ 754 nm.
other metal ions (Fig. 3a). In emission studies (Fig. 3b), the metal binding property was analyzed by exciting the receptor 1 (0.3 106 M, HEPES-buffer, pH 7.4) at lex 754 nm [double excitation] and the resulting spectrum was monitored from the wavelength of 350e920 nm (Fig. 3b). In presence of ferrous ion, the receptor 1 showed an enhancement in the fluorescence intensity at lem 420 and 807 nm, while the other ions did not cause any significant variation under identical condition. In addition, the receptor 1 showed a small hypsochromic shift (Dlem z 20 nm) both in the short (350e500 nm) and longer wavelength (700e920 nm) regions in presence of ferrous ion. 3.3.2. Absorption and fluorescence titrations The combined spectrum of receptor 1 (0.3 104 M, HEPESbuffer, pH 7.4) absorption titrations with ferrous ion (0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 3.0, 5.0, 8.0 and 10 106 M) was depicted in Fig. 4a. The combined spectrum depicted a notable hyperchromic shift specifically at lmax 335 nm after addition of 0.4 104 M ferrous ion solution. The further increase in the concentration of ferrous ion did not show any remarkable enhancement in the intensity of absorbance, revealed the saturation limit of the receptor 1 with Fe2þ ion. In the fluorescence titration, the emission peaks of receptor 1 in the wavelength range of 350e550 nm was accounted for the metal binding study due to the small fluorescence intensity of the second
peak at the lem 700e900 nm. As shown in Fig. 4b, The free receptor 1 (0.3 106 M, HEPES-buffer, pH 7.4, lex 754 nm double excitation) showed an emission at lem 434 nm with a low fluorescence quantum yield (Fx ¼ 0.0574) whereas in presence of ferrous ion (0.2, 0.4, 0.6, 0.8, 1.0, 1.5, 3.0, 5.0, 8.0 and 10.0 106 M) fluorescence intensity was doubled with blue shift (lem 434 to 423 nm). In addition, a pronounced increase in fluorescence quantum yield (Fx ¼ 0.167) was also noted after immediate addition of the Fe2þ ion. From the spectral studies, the observed physical change was plotted as a function of metal ion added to receptor system (Fig. 4bincerted). The plot illustrated the general binding isotherm with hyperbolic structure revealed the formation of simple 1:1 binding of the host with the guest [48]. The complexation mode of receptor 1 for Fe2þ was determined from a BenesieHildebrand plot analysis [49]. If the fluorescence change is only induced by the formation of a 1:1 complex between receptor 1 (L) and metal ion (M), the equilibrium can be expressed by the following equations:
L þ M#LM;
K ¼ ½LM=½L½M
(1)
The total receptor concentration and the fluorescence intensity are defined as [L]0 ¼ [L] þ [LM] and F ¼ fL [L] þ fML [ML], respectively, where [L]0 and [M]0 are the total concentration, [L] and [LM] are the equilibrium concentration of L and M, respectively,
Fig. 4. Optical titrations of the receptor 1 upon addition different concentration of Fe2þ (0e1.0 106 M) ion in aqueous ethanol medium (1:4 volume ratio) (HEPES-buffer, pH 7.4). (a) UVevis absorption spectrum; (b) emission spectrum at lex ¼ 754 nm.
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and fL and fML are the fluorescence quantum yields for free and complexed receptor. If [M]0 » [L]0, the BenesieHildebrand type equation can be derived as,
1 1 1 ¼ þ ðF F min Þ ðfML fL Þ½Lo K½Lo ðfML fL Þ½Mo
(2)
If a 1:1 metal-probe complex is formed between receptor 1 and metal ion Fe2þ, a BenesieHildebrand plot of the data according to Equation (2) should be linear [50] and present in Fig. 5. The calculated correlation coefficient of the linear plot was 0.989. The binding constant (Ka) and dissociation constant (Kd) of the receptor 1 were calculated from the intercept and the slope values (0.006 and 0.009 106 M respectively) and found to be 6.67 105 Me1 (±0.5%) and 1.50 106 M (±0.5%). This value is quite high compared to other reported ferrous ion receptors binding constant [51]. In all the reported receptors, the studies were influenced either by other charged species with similar ionic radius like Cr3þ and Co3þ or physical changes (pH and temperature) [39e42]. Hence, receptor 1 could be a promising candidate as fluorescent turn-on probe for ferrous ion.
3.3.3. Selectivity and sensitivity of metal binding For practical application reversibility is a prerequisite need towards the efficient fluorescent chemosensors. The selectivity and reversibility of the receptor 1 towards ferrous ion was analyzed by comparing the changes in the fluorescence intensity of the host-guest system (receptor 1-ferrous ion) in presence of other metal ions (0.1 106 M) and ethylene diamine tetraacetic acid (EDTA, 0.3 106 M) (Fig. 6a). It observed spectral results revealed that the fluorescence profile of the host-guest system was not influenced by addition of other metal ions. The addition of complexing reagent EDTA to the host-guest system exhibited a reduction of fluorescence intensity at lem 423 nm. These studies clearly indicate that the receptor can be used for the selective detection of Fe2þ ion without interference from other metal ions. Furthermore, it was confirmed that the receptor 1 possessed a similar fluorescence behavior in presence of other Fe2þ salts (FeCl2, FeSO4, FeNO3 and (NH4)2Fe(SO4)2) (Fig. 6b), indicating that the counter anions of Fe2þ did not affect the fluorescence sensing property of the host.
Fig. 5. Benesi Hildebrand (BH) plot for the fluorescence titration of receptor 1 with ferrous solution.
261
3.4. Cyclic voltammetric studies The cyclic voltammetric behavior of the free receptor 1 (0.3 106 M) in the HEPES-buffer (pH 7.4) medium was studied (Fig. 7a). The resulted cyclic voltammogram (CV) depicted the reversible reduction peaks with the cathodic potential (Epc) e 1.0066 V and the anodic potential (Epa) e 0.408 V. However, the similar peaks were not observed in the oxidation part of the cyclic voltammogram.
DEp ¼ ðEpc EpaÞ ¼ 1:0066 ð 0:408Þ ¼ 0:5986 V: The same solution of receptor 1 was used in the cyclic voltammetric titration with increasing concentration of the ferrous ion (0.5, 1.5, 2.5 5.0 and 7.5 106 M) (Fig. 7b). The initial addition of Fe2þ ion (0.5 106 M) resulted a notable difference in the appearance and position of peaks in the CV. Addition of 1.5 106 M ferrous solution illustrated both irreversible oxidation and reduction peaks with Epa 0.13978 V and Epc 0.3905 V respectively. In the case of 2.5 106 M addition, a new reduction peak appeared in the reductive anodic part at the Epa e 0.1586 V which is a reversible peak of the reductive cathodic peak Epc e 0.3905 V. The subsequent addition of Fe(II) ion (5.0 and 7.5 106 M) in the titration mixture resulted complete disappearance of reductive anodic peak Epa 0.1586 V. In addition, a shift of reduction part cathodic peak towards more negative potential and oxidation part of anodic peak towards more positive potential with a small raise in the intensity of the current were observed for the successive increase in the metal ion concentration. This describes a net one electron oxidation of the Fe2þ/Fe3þ couple of receptor 1 bound to Fe2þ cation. Further increase in the ferrous ion illustrated a saturation limit of receptor 1 in the CV titration mixture. Accordingly, the metal binding CV titration study supports the 1:1 binding of the receptor 1 with the ferrous ion [52]. 3.5. Computational studies 3.5.1. For free receptor system 1 In continuation of theoretical calculations on reaction mechanism [53], the present theoretical studies was planned to investigate the binding mode and affinity of the receptor 1 towards Fe2þ and Fe2þ ions. Initially the structure of the receptor 1 was optimized at B3LYP/6-311 þ G** level of theory. Three active binding modes A, B and C were proposed and illustrated in Scheme 2. First two modes of binding based on the binding of imidazole ring nitrogen atoms (eCeNHe and eC]Ne respectively), while the third mode C was the quinoline ring nitrogen in addition with the ethylene ether spacer linkage of the receptor 1. In order to understand the binding mode of receptor 1, DFT descriptors such as electronegativity, fukui functions and molecular electron density map were calculated for the receptor 1. 3.5.1.1. Electronegativity (c). It is the capacity of atoms to attract the electrons towards itself for binding. Physically negative c value of an atom in the molecule represents its more tendency to donate electrons and behaves as an efficient site for metal ion binding. The calculated c values for all the atoms in the receptor 1 revealed that the quinoline nitrogen atoms had more metal binding affinity since its c values were more negative (0.909 and 0.913 eV for Q1-N11 and Q-N39 respectively) (Fig. 8). In the imidazole rings of the receptor 1, a higher negative value was noted for the eC]N (0.868 and 0.870 eV for C]N24 and C]N52, respectively) rather than the -NH atom (0.847 and 0.850 eV for NH22 and NH50,
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Fig. 6. Changes in the fluorescence intensity of the free receptor 1, receptor 1 with different ions and Fe2þ (0.3 106 M) and receptor 1-Fe2þ with EDTA (0.3 106 M) in aqueous ethanol medium (1:4 volume ratio) (HEPES-buffer, pH 7.4) at lex ¼ 754 nm.
Fig. 7. Cyclic voltammetric titration of receptor 1 in aqueous ethanol medium containing Tris-HCl buffer medium. (a) Cyclic voltammogram of the dipodal receptor 1 alone; (b) changes in the cyclic voltammogram upon addition of Fe2þ (0.5, 1.5, 2.5 5.0 and 7.5 106 M).
respectively). It is also observed that the oxygen atom (O64) present in the middle of ethylene ether spacer linkage possess a high negative c value (0.513 eV) compared to the other oxygen atoms (0.488 and 0.510 eV for O57 and O78, respectively) in the receptor 1. The calculated c values of the receptor 1 illustrated that both QeN atoms and ethylene ether spacer linkage can form an electropositive cavity (binding mode C) to accommodate the
Scheme 2. Possible modes of metal binding of receptor 1 with Fe2þ and Fe3þ ion. (a) imidazole NeH mode A; (b). imidazole C]N mode B; (c). quinoline C]N mode C.
incoming metal ions than the other two proposed binding mode. 3.5.1.2. Fukui function. It is proposed by Parr and Yang, is one of the local reactivity indices specifying the response of any particular site of a chemical species in turn of electron density [54]. Table 1 showed the fukui function (FF) values for the receptor 1 calculated by Mulliken population analysis (MPA) and Hirshfeld
Fig. 8. Theoretically energy-minimized structure of the receptor 1 with electronegativity value (c).
M. Mahalingam et al. / Journal of Molecular Structure 1099 (2015) 257e265 Table 1 Condensed Fukui function fk of the hero atoms in the receptor 1. Atoms
fk
fkþ
fk0
N11 N39 N22 N50 N52 N24 O71 O64 O57
0.021127 0.015303 0.010740 0.012000 0.001203 0.002334 0.001646 0.002808 0.002853
0.004578 0.009754 0.023299 0.019928 0.001852 0.000403 0.002020 0.003110 0.001620
0.0128525 0.0125285 0.0170195 0.0159620 0.0015275 0.0013685 0.0001850 0.0001520 0.0006155
population analysis (HPA) gross charges at B1/DZP level of theory. Both MPA and HPA schemes resulted that the quinoline nitrogen N11 and N39 had higher f k value revealed the feasibility of electrophilic attack than the imidazole azide nitrogen N24 and N52. The observed electrophilicity trend for the nitrogen and oxygen atoms present in the receptor 1 is in the following order of N11 > N39 > N50 > N22 > O57 > O64 > N24 > O71 > N52. The fukui calculations further supported the quinoline N-mode (C) of binding.
3.5.1.3. MEP. The molecular electron density difference map provides the information about accepting or releasing of electrons with the interacting molecules [55] thereby indicating the charge distribution in a molecule. In MEP surfaces, the negative and positive regions are the preferred site for electrophilic and nucleophilic attack which is denoted as red and blue color respectively. The significance of calculating MEP surface for a molecule is mainly due to the fact that it consequently picturizes the shape and size of molecular electronic charge density in terms of color grading. It is also reported that it is a useful tool in the molecular structural research to understand the physcicochemical property relationship [56]. In the present study, a MEP plot of the neutral receptor 1 in the three dimensional surface was calculated (Fig. 9). It exposed the negative potential represented as red color in all the hetero atoms of the receptor 1 except imidazole CeNH regions revealed unfeasibility of the first proposed binding modes A and B [Scheme 2A and B]. The MEP plot depicted that the electronegative potential of quinoline C]N with flexible ethylene glycol spacer can create a cavity feasible to hold the incoming positive charged species
Fig. 9. B3LYP/6-311G(d,p) calculated isosurface representation of electron density for the receptor 1.
263
[Scheme 2C]. However, such viable structural arrangement for the metal cation chelation was not possible in the case of other modes A and B. 3.5.2. Optimization of receptor 1 with Fe2þ and Fe3þ ions The structural optimization study for the proposed binding modes A, B and C were performed and compared with the host system 1 under B3LYP/6-311 þ G** level of theory (Table S2). The theoretical study predicted that the metal bound receptor systems A, B and C have more stability represented by the lower energy (2100 to 2200 a.u) in comparison with the free receptor system 1 (~1942 a.u). The calculated energy differences between the respective binding modes A, B and C with free receptor 1 are represented in Figs. 10 and 11 as downward arrow. The high energy difference for the ferrous ion complexes in each mode of binding (199.386, 199.489 and 278.181 a.u. respectively) revealed higher stability whereas the ferric ion exhibited small energy differences (198.967, 199.114 and 278.08 a.u. respectively) owing to the lower feasibility of the receptor 1 with ferric ion. In addition, the QeN binding mode C exhibited more feasibility of metal chelation through notable energy differences for ferrous and ferric ion respectively. 4. Conclusion A sensitive quinoline receptor 1 was synthesized and studied under the metal binding studies in the aqueous medium at higher excitation wavelength region (lexc 754 nm). In presence of ferrous
Fig. 10. B3LYP/6-311G(d,p) calculated energy-minimized structures of the receptorFe2þ complexes and the corresponding optimized energy differences with respect to the receptor 1. (A) imidazole NeH mode A; (B) imidazole C]N mode B; (C) quinoline C]N mode C.
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References
Fig. 11. B3LYP/6-311G(d,p) calculated energy-minimized structures of the receptorFe3þ complexes and the corresponding optimized energy differences with respect to the receptor 1. (A) imidazole NeH mode A; (B) imidazole C]N mode B; (C) quinoline C]N mode C.
ion, the receptor 1 shows an enhancement in the fluorescence intensity. The addition of EDTA to the receptor-Fe2þ mixture quenches the fluorescence intensity thereby enlightening the reversible sensing property of receptor 1. The binding affinity of the receptor 1 was also analyzed under electrochemical studies. In the theoretical illustration of metal binding mechanism, three binding modes A, B and C of receptor 1 were proposed. Quantum mechanical studies reveal that the QeN binding mode C of the receptor 1 must be an appropriate mode for the metal binding. Energy optimization of three binding modes A, B and C further establishes the ferrous ions sensing property of the receptor 1 and further supports the experimental observed metal binding results. Acknowledgments This work was supported under Fast-Track young scientist programme by Science and Engineering Research Board (SR/FT/CS51/2011) funded by the Indian Government. The NMR spectral data were obtained from the NMR research center, Indian Institute of Science, Bangalore, India. Mass spectral facility was provided by the Indian Institute of Technology, Chennai, India. Appendix A. Supplementary data Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.molstruc.2015.06.070.
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