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Volume 41 | Number 8 | 21 April 2012 | Pages 30133432

ISSN 0306-0012

CRITICAL REVIEW Ha Na Kim, Wen Xiu Ren, Jong Seung Kim and Juyoung Yoon Fluorescent and colorimetric sensors for detection of lead, cadmium, and mercury ions

0306-0012(2012)41:8;1-P

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CRITICAL REVIEW

Fluorescent and colorimetric sensors for detection of lead, cadmium, and mercury ions
Ha Na Kim,wa Wen Xiu Ren,wb Jong Seung Kim*b and Juyoung Yoon*a
Downloaded by Korea University on 26 March 2012 Published on 19 December 2011 on http://pubs.rsc.org | doi:10.1039/C1CS15245A

Received 8th September 2011 DOI: 10.1039/c1cs15245a Exposure to even very low levels of lead, cadmium, and mercury ions is known to cause neurological, reproductive, cardiovascular, and developmental disorders, which are more serious problems for children particularly. Accordingly, great eorts have been devoted to the development of uorescent and colorimetric sensors, which can selectively detect lead, cadmium, and mercury ions. In this critical review, the uorescent and colorimetric sensors are classied according to their receptors into several categories, including small molecule based sensors, calixarene based chemosensors, BODIPY based chemosensors, polymer based chemosensors, DNA functionalized sensing systems, protein based sensing systems and nanoparticle based sensing systems (197 references).

Introduction
Among various heavy metal ions, lead, cadmium, and mercury ions are banned in electrical and electronic equipment by the European Unions Restriction on Hazardous Substances (RoHS) directive due to their hazardous nature.1 These three heavy metal ions are not biodegradable, and hence can accumulate in the environment, which results in contaminated food and water.2 Therefore, World Health Organization (WHO) and Environmental Protection Agency (EPA) have
a

Department of Chemistry and Nano Science and Department of Bioinspired Science (WCU), Ewha Womans University, Seoul 120-750, Korea. E-mail: jyoon@ewha.ac.kr; Fax: +82-2-3277-2384; Tel: +82-2-3277-2400 b Department of Chemistry, Korea University, Seoul 130-701, Korea. E-mail: jongskim@korea.ac.kr; Fax: +82-2-3290-3121; Tel: +82-2-3290-3143 w Contributed equally to this work.

strictly dened the concentration limits of these metal ions that are allowed in the drinking water.3 Lead is the most abundant and toxic substance of the three, it is often encountered in the environment due to its use in batteries, gasoline, and pigments, etc.4 Lead pollution is a persisting problem and a long-lasting danger to human health and the environment, as the 300 million tons of lead mined to date are still circulating mostly in soil and groundwater.5 Even very low levels of lead exposure can cause neurological, reproductive, cardiovascular, and developmental disorders, which introduce particularly serious problems in children including slowed motor responses, decreased IQs, and hypertension.6 Cadmium is also an extremely toxic and carcinogenic metal.7 A major exposure source is smoking and through food, but inhalation of cadmium-containing dust is the most dangerous route. Cadmium can be found in electroplated steel, pigments in plastics, electric batteries and so on.8 A high exposure level of

Ha Na Kim was born in Seoul, Korea, in 1980. She received BS degree from Department of Chemistry of Ewha Womans University and obtained MS degree in medical science from Seoul National University in 2006. She is on a doctoral course in Prof. Juyoung Yoons laboratory in Ewha Womans University.

Wen Xiu Ren was born in Changchun, China, in 1981. In 2009, he obtained his PhD from Kyungpook National University under the supervision of Prof. Sang Chul Shim and Prof. Chan Sik Cho. He now works as a postdoctoral fellow in Prof. Jong Seung Kims laboratory at Korea University.

Ha Na Kim
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Wen Xiu Ren


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cadmium is associated with increased risks of cardiovascular diseases, cancer mortality, and damage to liver and kidneys.9 Mercury is well known as one of the most toxic metals and is widespread in air, water, and soil, generated by many sources such as gold production, coal plants, thermometers, barometers, caustic soda, and mercury lamps.10 As it can cause strong damage to the central nervous system, accumulation of mercury in the human body can lead to various cognitive and motor disorders, and Minamata disease.11,12 A major absorption source is related to daily diet such as sh,13 and thus there are considerable eorts contributed to the development of the selective and sensitive detection methods. Currently, the most common methods to detect heavy metal ions include atomic absorption spectrometry,14 and inductively coupled plasma mass spectrometry,15 however these instrumentally intensive methods only measure the total metal ion content, and often require extensive sample preparation. Thus, a simple and an inexpensive method that not only detects but also quanties heavy metal ions is desirable for real-time monitoring of environmental, biological, and industrial samples. Among various detection techniques, optical detections (via uorescence changes or colorimetric changes) are the most convenient methods due to the simplicity and low detection limit.1619 The most important advantage of a uorescent probe would be the intracellular detection. During the last couple of decades, considerable eorts have been devoted to the development of uorescent and colorimetric sensors, which can selectively detect metal ions. To date there has been one review for lead analysis published in 1998,20 this review is the rst paper which systematically covers optical probes for lead, cadmium, and mercury ions. Since Nolans and Lippard have reviewed the optical detection of mercury ions in 2008,21 we particularly focus on the recent development of mercury detection between 2009 and 2011. In this critical review, the uorescent and colorimetric sensors are classied according to their receptors into several categories, including small molecule based sensors, calixarene based chemosensors, polymer based chemosensors, DNA

functionalized sensing systems and nanoparticle based sensing systems. Overall we would like to provide a general overview of the design and application of Pb2+, Cd2+, and Hg2+ selective chemosensors.

Fluorescent and colorimetric sensors for detection of lead ions


Chemosensors bearing heteroatom containing ligands Small molecule based chemosensors. Czarnik and coworkers reported a pioneering work regarding uorescent chemosensors for Pb2+ in 1996.22 Both 2- and 9-anthracene derivatives bearing the N-methylthiohydroxamate ligand (1 and 2) were prepared as shown in Fig. 1, which exhibited strongly quenched uorescence due to the photo-induced electron transfer (PET). Complexation of 2-derivative 1 with Pb2+ resulted in rapid metal ion-catalyzed hydrolysis. Whereas complexation of 9-derivative 2 with Pb2+ induced a 13-fold uorescence enhancement at pH 9, which can be attributed to the steric protection of the thiocarbonyl group by two peri hydrogens (Fig. 1). Even though there were few competitive metal ions such as Ag+, Co2+ and Hg2+, this is still one of the rst examples of uorescent chemosensors for Pb2+. Li et al. reported dibromo-p-methyl-methylsulfonazo (DBM-MSA, 3) as a sensitive and selective chromogenic

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Fig. 1 Structures of 2- and 9-anthracene derivatives (1 and 2) and the proposed binding mode of 2 with Pb2+.

Jong Seung Kim

Jong Seung Kim was born in Daejon, Korea, in 1963. He received PhD from Department of Chemistry and Biochemistry at Texas Tech University. After one-year postdoctoral fellowship at University of Houston, he joined the faculty at Konyang University in 1994 and transferred to Dankook University in 2003. In 2007, he then moved to Department of Chemistry at Korea University in Seoul as a Professor. To date, his research records 270 scientic publications and 25 domestic and international patents.

Juyoung Yoon

Juyoung Yoon was born in Pusan, Korea, in 1964. He received his PhD (1994) from The Ohio State University. After completing postdoctoral research at UCLA and at Scripps Research Institute, he joined the faculty at Silla University in 1998. In 2002, he moved to Ewha Womans University, where he is currently a Professor of Department of Chemistry and Nano Science and Department of Bioinspired Science. His research interests include investigations of uorescent chemosensors, molecular recognition and organo EL materials.
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Fig. 2 Structures of compounds 35.

Fig. 4 Structures of 7 and g-CyD and the proposed binding mode between 7/g-CyD with Pb2+.

reagent for Pb2+ (Fig. 2).23 In 0.24 M phosphoric acid medium, Pb2+ formed a 2 : 1 blue complex with 3, having a sensitive absorption peak at 642 nm. Under optimal conditions, Beers law was obeyed over the range 00.6 mg mL1 of Pb2+. The lower limit of detection was found to be 2.21 ng mL1. A similar approach was reported by Meng and coworkers. A sensitive and selective chromogenic reagent dibromop-methyl-carboxysulfonazo 4 (Fig. 2) was studied for the spectrophotometric determination of Pb2+.24 In 0.25 M phosphoric acid medium, Pb2+ formed a 2 : 1 blue complex with 4, having a sensitive absorption peak at 648 nm. Under optimal conditions, Beers law was obeyed over the range from 0 to 0.8 mg mL1 of Pb2+ with a detection limit of 2.14 ng mL1. This method was applied to determine the Pb2+ level in vegetables. Compound 5 (Fig. 2) showed selective uorescence enhancement (lmax = 492 nm) with K+ in a mixed solution of CHCl3 and CH3CN (9 : 1).25 However, it was reported that the mixed CH3CN/water solutions (510% H2O) of 5 exhibited an even larger uorescence enhancement in the presence of Pb2+. The emission intensity was increased by a factor of more than 20 and was accompanied by a shift in the emission maximum from 486 to 498 nm. The Pb2+ complex with 5 formed a unique structure involving a Pb2(CF3COO)4 unit sandwiched between two crown moieties of 5, which was conrmed by X-ray crystallography. Chen and Huang reported a new chemosensor 6 (Fig. 3), which can signal Pb2+ selectively and improve the uorescence intensity in CH3CN.26 In uorescence titration studies (lmax for emission = 491 nm), 6 displayed 40-, 12-, and 18-fold uorescence enhancements for Pb2+ (10 equiv.), Ba2+ (100 equiv.), and Cu2+ (100 equiv.), respectively, due to the photo-induced charge transfer (PCT) and metal binding-induced conformational restriction. As shown in Fig. 3, a 2 : 2 complex of Pb2+ and 6 was proposed since 6 had many advantages including remarkable selectivity, much improved emission and easy detection. However, when the aqueous solution of Pb(ClO4)2 was

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added to 6 in CH3CN, neither the binding strength nor the uorescence yield was aected. In another study, Hayashita et al. reported a supramolecular 7/g-cyclodextrin (g-CyD) complex sensor that exhibited the monomer/dimer emission ratio response with high selectivity for Pb2+ in 98% water/2% methanol (v/v) at pH 4.3 (Fig. 4).27 No obvious uorescence was observed in the absence of g-CyD. In contrast, signicant uorescence emission appeared in the presence of 12.0 mM g-CyD, indicating that 7 is dissolved in water by forming an inclusion complex with g-CyD, which also enhanced the uorescence quantum yield. Upon the addition of Pb2+, the broad emission observed in the longer wavelength region (471 nm) intensied whereas the pyrene monomer emission at 370410 nm decreased. The binding constant was calculated to be 1.17 0.75 109 M2 with the stoichiometry of 2 : 1. Kavallieratos et al. observed the ecient and selective ionexchange extraction of Pb2+ from water into 1,2-dichloroethane (DCE) with concurrent uorescence quenching using as an ionexchanger, the sulfonamide uorophore 8 (Fig. 5).28 This simple system did not require a secondary co-ligand in order to extract Pb2+ and showed remarkable extraction selectivity against other metals with DPb > 130 DCu and DPb > 1400 DZn. Fluorescence quenching was observed at 516 nm after the addition of Pb(NO3)2 into a solution of 8 and NH(i-Pr)2 in DCE. Specically, the uorescence intensity was reduced by as much as 29% upon mixing 8 (10 mM) and NH(i-Pr)2 (22 mM) with 5.5 mM Pb(NO3)2. Two TTF-pyridyl derivatives 9 and 10 (Fig. 5), in which the TTF moiety and pyridyl group are linked by a double bond,

Fig. 3

Structure of 6 and its proposed 2 : 2 binding mode with Pb2+.

Fig. 5

Structures of compounds 811.


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were studied as Pb2+ selective chemosensors in CH3CN.29 The interaction between the pyridyl group and Pb2+ improves the electron-accepting ability of the pyridyl group, which thus induces the color change of the solution from yellow to deep purple, the downeld shift of the proton peaks in 1H NMR, and the increase of the oxidation potentials E1ox and E2ox to more positive values. These dramatic changes were specic for Pb2+. The stoichiometry for the 9 complex was 2 : 1 (9/Pb2+), while that for the 10 complex was 1 : 1 (10/Pb2+) with the binding constants (log Ks) of 5.42 and 5.57 for 9 and 10, respectively. a,b,g,d-Tetrakis(3,5-dibromo-2-hydroxylphenyl)porphyrin (11) displayed the selective uorescence quenching eect on Pb2+ in the aqueous solution (pH 9.0) based on the chelation of porphyrin by b-cyclodextrin (b-CD) as reported by Yang et al. (Fig. 5).30 This caused a large increase of the porphyrin uorescence intensity (655 nm) and thus was sensitive to Pb2+ that displayed uorescence quenching of 11. The detection limit of this system was in the concentration range of 2.8 107 to 7.4 105 M of Pb2+. The organizing ability of the b-CD medium and the protection of the ligand from the micro-environment conferred increased sensitivity, selectivity and detection limit compared with those obtained in the absence of b-CD. The Yoon group reported rhodamine B derivative 12 as a uorescent and colorimetric chemosensor for Pb2+ (Fig. 6).31 Among the various metal ions, compound 12 showed signicant uorescent enhancement only with Pb2+ in CH3CN, despite relatively small uorescent enhancement with Cu2+ and Zn2+. From the uorescent titrations, the association constant for Pb2+ was calculated to be 1.95 105 M1. The spiro-carbon in compound 12 appeared at d 64.7 ppm in CD3CN : CDCl3 (9 : 1, v/v) and this peak disappeared upon the addition of Pb2+ or Zn2+ which suggested a reversible ring-opening mechanism as shown in Fig. 6. Additionally, the Teramae group reported that the 13/Triton X-100 complex (Fig. 7) formed below the critical micelle concentration (cmc) in water exhibited an amplied uorescence response for Pb2+.32 Dynamic light scattering and dark-eld microscope analyses revealed that the 13/Triton X-100 complex formed pseudo-micelle aggregates, which was triggered by selective Pb2+ binding with 13 and resulted in improved uorescence intensity with a distinct blue shift of the uorescence emission at pH 5.70. The uorescence color changed from green (lmax = 531 nm) to blue (lmax = 481 nm), which was easily conrmed by the naked eye. The standard conditions used for uorescence experiments employed 1.25 mM of 13 in 0.4% 1,4-dioxane/ 99.6% water (v/v) containing 0.08 mM Triton X-100 and 10.0 mM acetate buer (pH 5.70). The uorescent sensor (14) containing the bis(2-pyridylmethyl)amine group as a binding moiety for Pb2+ was developed by Hong and coworkers (Fig. 7).33 Compound 14 also showed

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Fig. 7

Structures of 1315 and Triton X-100.

Fig. 6 Structure of Pb2+ probe 12.

selective uorescence intensity enhancement (lmax for emission = 562 nm) with Pb2+ over other metal ions in pH 7.0 HEPES buer solution. This was ascribed to the complex formation between Pb2+ and 14 that blocked the photo-induced electron transfer process. A linear response as a function of Pb2+ concentration was obtained ranging between 1.9 107 and 6.0 106 M. The lower detection limit was found to be 1.9 108 M (3.9 mg L1) which is below the maximal allowed concentration of lead ions (10 mg L1) in drinking water. Therefore, this indicated the great potential of 14 to be employed as the sensor material for Pb2+ detection. A new type of synthetic uorescent sensor 15 has been studied for probing Pb2+ in living biological samples by the Chang group (Fig. 7).34 Under simulated physiological conditions (20 mM HEPES, buer pH 7), a desirable selective turn-on response for Pb2+ over competing metal ions was observed. Kd for Pb2+ coordination to 15 was reported as 23 4 mM. The addition of 15 ppb Pb2+, the maximum EPA limit for the allowable level of lead in drinking water, to a 5 mM solution of 15 induced a 15 2% increase in the uorescence intensity. This uorescent sensor 15 was hence successfully applied to track the changes in Pb2+ levels within living cells. Basu et al. have designed, synthesized, and characterized the new turn-on ratiometric uorescent lead sensor 16 (Fig. 8).35 Compound 16 exhibited an absorption band at 415 nm and an emission band at 465 nm. Upon incubation with lead acetate solution, the absorption band shifted to 389 nm and the emission band also shifted to 423 nm with a 5-fold increase in the uorescence intensity. Compound 16 was able to detect Pb2+ in aqueous solution over a wide pH range (410) and selectively in a mixture of several other metals at a concentration as low as 10 ppb. This sensor is advantageous because of its sensitivity for Pb2+ at concentrations below the limit set by the US Environmental Protection Authority (EPA). Additionally, the dissociation constant (Kd) of 16 was calculated as 23 mM. Guilard and coworkers reported a new colorimetric molecular sensor based on a 1,8-diaminoanthraquinone signaling subunit 17 (Fig. 8) as an ecient lead ion sensor in water at
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Fig. 8 Structures of compounds 1618.

neutral pH for naked-eye detection.36 The addition of Pb2+ (1 equivalent) induced a dramatic change in color (from violet to pink) that was blue-shifted by 47 nm and hence suggested a strong binding of Pb2+ by the triamide 17. In addition, the naked eye detection limit of Pb2+ was 23 ppm (1015 mM) in solution, which can be improved to 21 ppb (0.1 mM) by using a conventional spectrometer. A uoroionophore sensor, N-[4(1-pyrene)-butyroyl]-l-tryptophan (18), was reported as a Pb2+ selective chemosensor by Wu and colleagues (Fig. 8).37 In the aqueous solution, compound 18 exhibited a very high sensitivity (0.15 mM) and the 18Pb2+ complex showed a selective excimer peak at 465 nm. Both FT-infrared and Raman spectroscopy in addition to DFT calculations were employed to predict a characteristic interaction of lead ions with two carboxylate groups and two indole rings as well as the hydrogen bonding between two amide groups with a stiochiometry of 2 : 1 (Pb2+ : 18). Several years ago, a redox, chromogenic and uorescent chemosensor molecule based on a deazapurine ring 19 was rraga and Molina et al. (Fig. 9).38 Upon the reported by Ta addition of aqueous Pb2+, compound 19 in CH3CN showed a redox shift (DE1/2 = 0.15 V of the Fe(II)/Fe(III) redox couple), the colorless to orange color change and an emission change of 620-fold with a detection limit of 1.32 108 M. Compound 19 exhibited a very weak uorescence in CH3CN at 364 and 377 nm and a large chelation-enhanced uorescence (CHEF) eect only with aqueous Pb2+ even though there was a relatively

small CHEF eect with Zn2+. From the uorescence titrations, the association constants (Ka) for Pb2+ and Zn2+ were calculated to be 6.1 105 and 2.7 104 M1, respectively. The same group reported a series of ferrocenyl-containing imidazopyridine and imidazophenazine receptors 2022 as Pb2+ selective chemosensors (Fig. 9).39 Imidazophenazineferrocene dyad 20 has also demonstrated its ability for Pb2+ sensing through redox (DE1/2 = 120 mV), absorption (Dl = 23 nm, pale orange to red color), and emission (CHEF = 133) channels. The resulting Jobs plot suggested a 2 : 1 binding model between 20 and Pb2+, with the association constant being 3 108 M2 in CH3CN. The recognition properties of the two-armed imidazopyridine-ferrocene triad 21 were very similar to those exhibited by the parent monosubstituted receptor 19, and the most salient features were a strong perturbation of the redox wave (DE1/2 = 180 mV), the absorption wavelength (Dl = 23 nm, colorless to yellow color), a dramatic increase in the uorescent quantum yield (Fcomplex/Fligand = 890) in the presence of Pb2+, while the optical responses toward Zn2+ were silent. Binding assays using the continuous variation method (Jobs plot) suggest a 1 : 1 binding model with a Ka = 1.4 105 M1. The two-armed imidazophenazine-ferrocene triad 22 sensed Pb2+ through perturbation of the oxidation potential of the Fe(II)/Fe(III) redox couple (DE1/2 = 110 mV), the important blue shift (Dl = 160 nm) of the high energy band in the absorption spectrum, and a remarkable increase of the emission band (CHEF = 220), whereas smaller changes were observed in the presence of Zn2+. From the titration data, a 1 : 1 binding mode was deduced and the association constant Ka was found to be 3.5 103 M1 for Pb2+. The synthesis and electrochemical, optical, and ion-sensing properties of ferrocene-imidazophenazine dyads were also pre rraga and Molina et al.40 Compound 23 (Fig. 9) sented by Ta behaved as a highly selective redox/chromogenic/uorescent chemosensor molecule for Pb2+ in CH3CN/H2O (9 : 1). The emission spectrum illustrated a CHEF (47-fold) in the presence of Pb2+, a new low-energy band appeared at 502 nm in its UV/vis spectrum (yellow to orange color) and the oxidation redox peak was anodically shifted (DE1/2 = 230 mV). From the uorescence binding isotherm, the association constant was calculated to be 3.57 106 M1. Calixarene based chemosensors Quite a few examples of Pb2+ selective uorescent chemosensors utilized a unique calixarene template. Leray et al. reported a new uorescent molecular sensor 24 based on a calix[4]arene bearing four carboxydansyl groups as uorophores (Fig. 10).41 The complexation of Pb2+ to 24 in the CH3CN/H2O system induced a noticeable blue shift in the uorescence spectrum and an increase in the uorescence intensity with an unprecedented detection limit of 4 mg L1. Kim and coworkers developed a series of calix[4]arene-based uorescent chemosensors for Pb2+ detection in the past few years. In 2004, Kim and Lee et al. reported a new uorescent chemosensor with two dierent types of cation binding sites on the lower rims of a 1,3-alternate calix[4]arene (25) (Fig. 11).42 Two pyrene moieties linked to a cation recognition unit that is composed of two amide groups to form a strong excimer in
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Fig. 9 Structures of compounds 1923.

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Fig. 13 Structure of uorescent chemosensor 29 and its proposed binding models with Pb2+ and F ions. Fig. 10 Structure of the uorescent chemosensor 24.

Fig. 11 Structure of uorescent chemosensor 25 and its proposed binding models with Pb2+ and K+ ions.

solution. The excimer uorescence can be quenched by the addition of Pb2+ ions, and revived by further addition of K+ ions. Thus, metal ion exchange produced an OnOOn switchable uorescent chemosensor. Computational results revealed that the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) of the two pyrene moieties interact under UV irradiation of 25 and its K+ complex, while such HOMOLUMO interactions were absent in the Pb2+ complex. The Kim group also synthesized N-(1-pyrenylmethyl) amide-appended cone calix[4]crown-5 (26) and its structural analogue crown-6 (27) (Fig. 12).43 Judging from the uorescence changes upon the addition of cations, 27 having a crown-6 ring displayed the higher Pb2+ ion selectivity over other cations. Coordinating Pb2+ with two amide oxygen atoms with the aid of a crown ring, a reverse PET occurred in such a way that electrons transferred from the pyrene groups to the electron decient amide oxygen atoms resulting in a quenched uorescence. When diazo-phenyl units were modied to compound 27, new sensor 28 was formed which showed weak uorescence because of the energy transfer (ET) from the pyrene groups to the electron decient azo parts (Fig. 12).44 Upon the addition of Pb2+, compound 28 revealed the

uorescent and colorimetric dual changes, which arose from a hypsochromic shift of the azo units in the UV spectrum as well as the uorescence enhancement of the pyrenyl parts in the uorescence spectrum via a suppressed uorescence resonance energy transfer (FRET). Kim et al. also tried to replace the crown ring of 25 by a triazacrown ring to give a new uorescent chemosensor 29 (Fig. 13).45 When Pb2+ or Co2+ was bound to 29, both monomer and excimer emissions quenched due to the combination of heavy metal eect, reverse-PET, and conformational changes. The association constants (Ka) of 29 for Pb2+ and Co2+ were 4.65 107 and 4.95 106 M1 in CH3CN, respectively. On the other hand, 29 illustrated the ability to bind with anions, particularly F anions. Addition of F anions to 29 formed a selective complex through H-bonding and produced quenched monomer emission with little excimer emission change due to the PET eect. 1,3-Alternate calix[4]arene 30 bearing bispyrenylamide on the two lower rims and two carboxylic acids on the other two lower rims was also synthesized by the Kim group (Fig. 14).46 When the Pb2+ ion was bound to two amide oxygen atoms linked to pyrenylamide of 30, it exhibited a marked quenched excimer emission due to its geometrical change during the complexation. This excimer emission band revived with further addition of Ca2+ ions, indicating an interesting on/o switch process. As shown in Fig. 14, compound 31 responded to K+, Pb2+, or Cu2+ and revealed band shifting in both uorescence and absorption spectra with dierent binding modes.47 With K+, uorescence emissions of the ligand were barely aected, while addition of Pb2+ or Cu2+ produced a remarkable change in both excimer and monomer emissions. The observed data indicated that the metal cation was encapsulated by the crown-5 ring for K+ and by the two facing amide groups in the latter case, which was veried by a metal ion exchange experiment. The wavelength shifts in both uorescence and absorption spectra upon addition of Cu2+ showed that, in

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Fig. 12 Structures of the uorescent chemosensors 26, 27 and 28.

Fig. 14 Structures of uorescent chemosensors 30 and 31.

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Fig. 15 Structures of compounds 3234. Fig. 17 Structures of compounds 3638.

contrast to Pb , Cu interacted with the nitrogen atoms of the amide groups through the PCT mechanism. In 2006, Kim and Vicens et al. designed an unsymmetrical 1,3-alternate calix[4]biscrown-based chemosensor 32 having a 1,5-naphthalene unit (Fig. 15).48 The weak uorescence intensity of the naphthalene unit suggested that benzene rings of the calix[4]arene as well as the oxygen atoms of the crown-5 ring take part in PET. Complexation of Pb2+ caused uorescence quenching due to an inverse PET process. On the other hand, binding of two K+ ions to both crown-5 and 1,5naphthalene-crown-6 loops of 32 induced the uorescence enhancement of the naphthalene unit by CHEF (chelationenhanced uorescence). Kim, No and Ham et al. reported the syntheses of C-1,2alternate homodioxacalix[4]arene pyreneamides 33 and 34 (Fig. 15). With metal ion complexation, their emission bands and thermodynamic stabilities of the complexes were changed.49 Upon Pb2+ ion complexation, both 33 and 34 showed a quenched uorescence in both monomer and excimer bands. Upon the addition of Ca2+ ions, 33 gave no response while 34 provided enhanced excimer and declined monomer emission with ratiometric response. The excimer spectral changes were rationalized by the frontier molecular orbital in that the eective PyPy* interaction induced an emission intensity increase upon Ca2+ ion complexation, while in contrast there was no such interaction observed for Pb2+ binding. 1,3-Alternate calix[4]arene-based uorescent chemosensor 35 containing two-photon absorbing chromophores was reported by Kim and Cho et al. (Fig. 16).50 The sensing behaviors of 35 toward metal ions were investigated via absorption band shifts as well as one- and two-photon uorescence changes. Free ligands absorb light at 461 nm and weakly emit their uorescence at 600 nm when excited by UV-vis radiation at 461 nm, without any two-photon excited uorescence at 780 nm. Addition of Al3+ or Pb2+ ions to the ligand solution caused the blue-shifted absorption and enhanced uorescence due to a declined resonance energy transfer (RET) upon

2+

2+

excitation by one- and two-photon processes. Addition of the Pb2+ ion to a solution of 35K+ resulted in a higher uorescence intensity than the original 35Pb2+ complex regardless of the excitation pathway, due to the allosteric eect induced by the complexation of K+ with a crown loop. Huang and Chen et al. reported a new p-tert-butylcalix[4]arene-based chemosensor 36 with three N,N-diethylacetamide groups as the recognition site and one methyl 3-ethoxynaphthalene-2-carboxylate as the uorescent group, which exhibited a highly selective uorescent response to Pb2+ ions (Fig. 17).51 The association constant was 6.5 104 M1 in the CH3CN/H2O system. The Chung group reported a novel chromogenic calix[4]arene sensor 37 bearing bistriazoles and azophenols as binding sites and azo groups as signal transduction units, which displayed selective coloration with Ca2+ and Pb2+ addition (Fig. 17).52 The association constants for the 1 : 1 complex of 37 towards Ca2+ and Pb2+ ions were determined to be 7.06 104 M1 and 8.57 103 M1, respectively, resulting in a large bathochromic shift in the absorption spectrum. Talanova et al. described a new, ecient, and highly selective uorescent chemosensor 38 bearing two pendent proton-ionizable dansylcarboxamide groups to the calix[4]arene preorganized in the partial cone conformation for determination of Pb2+ ions (Fig. 17).53 Complexation of Pb2+ with 38 induces a blue shift as a result of the carboxydansyl uorophore deprotonation. In acidic CH3CN/H2O (1 : 1 v/v) solution, 38 allowed for the detection of Pb2+ at the levels as low as 2.5 ppb. New uorescent sensors 3941 based on calix[4]arenes have been synthesized by Kumar et al. (Fig. 18).54 Interaction between Pb2+ ions and imino nitrogen of ligands causes spectrouorometric changes in the pyrenyl group because of a reverse PET phenomenon. Compounds 39 and 40 in the cone conformation showed ratiometric sensing while 41 with the 1,3-alternate conformation exhibited OnO signalling

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Fig. 16 Structure of compound 35.

Fig. 18 Structures of the uorescent chemosensors 3941.

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with Pb2+ ions. Compounds 40 and 41 also showed a colour change from colourless to yellow upon the addition of Pb2+ ions. Peptide based chemosensors Deo and Godwin reported a ratiometric uorescent probe that is selective for Pb2+.55 This probe consists of a uorescent dye (dimethylamino)-naphthalene-1-sulfonamide (dansyl or dns) conjugated to the amino terminus of a tetrapeptide (ECEE) (glutamate, E, and cysteine, C). The specic amino acids within the rst generation ligand were chosen because their side chains contain functional groups (carboxylates and thiols) that are known to coordinate Pb2+ under biologically relevant conditions. Upon addition of Pb2+, the emission maximum of dns-ECEE shifts from 557 to 510 nm with the enhancement of intensity. By plotting the ratio of uorescence emission intensity at 510 nm versus the uorescence emission intensity at 557 nm (I510/I557), an EC50 for Pb2+ was obtained as B120 mM. Pb2+ induced hydrolysis A uorescent chemodosimeter 42 for Pb2+ was designed and synthesized by linking resorun (serving as a uorophore and electron acceptor) to p-nitrophenol (serving as a uorescence quencher and electron donor) through phosphodiester bonds (Fig. 19).56 Upon the addition of Pb2+, the phosphate ester bonds in the probe were cleaved and the uorophore was released, accompanying the retrievement of uorescence. Although the 5 h heating required for the reaction is its primary shortcoming, it is directly proportional to the Pb2+ concentration in a range of 50125 nM with a detection limit of 22 nM in phosphate buer (pH 8). Polymer based chemosensors Compared to small organic compounds, polymer based optical sensors displayed several important advantages.57 For instance, signal amplication could be one of the most important advantages. Bunz and coworkers reported the simple polymer 43 as a potent sensing platform for lead salts in the aqueous solution (Fig. 20).58 The polymer has a strong emission at Imax = 465 nm, typical for a dialkoxy-PPE. The uorescence of an aqueous PIPES-buered solution (pH 7.2) of 43 was eciently quenched by Pb2+ with a KSV = 8.8 105. 43 was by a factor of 1.5 103 more sensitive toward quenching than its model compound 44, which can be attributed to multivalent binding that is an important factor in the observed sensitivity.

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Fig. 20 Structures of 4347 and PCDA.

A series of ethylene glycol (45), triethylene glycol (46) and pentaethylene glycol (47) esters of 10,12-pentacosadiynoic acid (PCDA) (Fig. 20) were synthesized by Sukwattanasinitt and colleagues.59 Even though the glycol ester lipids could not form polydiacetylenes upon UV irradiation, they however could be mixed with PCDA up to 30 mol% and polymerized to form blue sols. The PDA sols with blue to red colorimetric response selectively to Pb2+ oered a method for the naked eye detection of Pb2+ at part per million levels. The color transition was induced by the selective binding between Pb2+ and carboxylate groups of PCDA causing vesicle aggregation and fusion. The dynamic range of 47/PCDA (30/70 mol%) sol for Pb2+ detection was determined by varying the concentration of Pb(NO3)2 solution from 5 to 100 mM. Linear colorimetric response was obtained with Pb2+ concentration in the range of 530 mM. Yoon et al. have developed a new PDA-based chemosensor system for the detection of Pb2+ in the aqueous solution.60 UV irradiation of the suspensions derived from both DA monomers (48a : PCDA = 1 : 9) resulted in the formation of stable and blue-colored PDA molecules (48b) (Fig. 21). 48b (200 mM) displayed a selective and clear blue-to-red transition only with Pb2+ in HEPES (10 mM, pH 7.4) among various metal ions tested, including Na+, K+, Ca2+, Cd2+, Co2+, Cu2+, Hg2+, Mg2+, Ni2+, Pb2+ and Zn2+. Since the blue-to-red transition of the PDAs is accompanied by the generation of uorescence, the lead-promoted transition was also monitored by uorescence spectroscopy. 48b (50 mM) produced a large uorescence

Fig. 19 Structure of the uorescent chemodosimeter 42 and its two possible hydrolytic routes.

Fig. 21 Structure of monomer 48a and polymerization process of polymer 48b.

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enhancement with Pb2+. The uorescence spectra of the PDAs 48b showed a gradual increase in the presence of 09 mM Pb2+ with the detection limit of 0.8 ppm. Pb2+-dependent DNAzyme based sensing systems In 2000, Li and Lu reported a novel strategy to convert Pb2+ dependent DNAzyme (817 motif) into a highly selective and sensitive uorescence-based Pb2+ sensor.61 6-Carboxytetramethylrhodamine (TMR) was labelled to the substrate (17DS) containing a single RNA linkage (ribonucleoside adenosine, (rA)) as a uorophore. 4-(4 0 -Dimethylaminophenylazo)benzoic acid (Dabcyl) was labelled to the enzyme strand (17E-DY) as a uorescence quencher (Fig. 22(a)). When the substrate strand was annealed to the enzyme strand, the TMR uorescence was quenched by nearby Dabcyl (Fig. 22(a)). Upon the addition of Pb2+, the uorescence revived due to deoxyribozyme-catalyzed cleavage of the substrate. The biosensor had a quantiable detection range from 10 nM to 4 mM and a selectivity of >80-fold for Pb2+ over other metal ions at 4 1C. In 2003, Lu and co-workers optimized their sensing system by introducing both inter- and intramolecular quenchers to overcome the temperature limitation (Fig. 22(b)).62 More recently in 2009, introduction of the mismatches into the DNAzyme to resist temperature-dependent variations from 4 to 30 1C was explored (Fig. 22(c)).63 The new sensor was designed with the GR-5 DNAzyme base instead of 8-17 DNAzyme which oered higher selectivity and a slightly lower detection limit than previously reported (Fig. 22(d)).64 Moreover, Tan and co-workers linked an 817 DNAzyme sequence labelled with a quencher and a leaving substrate fragment labelled with a uorophore through a DNA hairpin structure. This modication can bring the quencher in close proximity to the uorophore ensuring ecient uorescence quenching.65 The new probe showed a selectivity for Pb2+ over other metal ions, where the quantiable detection range was from 2 nM to 20 mM. A similar work was reported by Zhang et al.66 The substrate strand of the Pb2+-dependent DNAzyme was designed as

a molecular beacon (MB) for highly ecient quenching. Upon the addition of Pb2+ ions, the DNAzyme catalyzed cleavage of the MB substrate could convert the intramolecularly stable hybridized MB stem into two much less stable intermolecularly hybridized DNA strands, thereby releasing the uorophorelabeled DNA strand and nally generated a uorescence signal enhancement. The Pb2+ detection limit was 600 pM. In addition, this strategy is applicable to detect the adenosine with similarly high sensitivity. He et al. reported a uorescent biosensor based on Pb2+regulatory protein in Ralstonia metallidurans CH34 with high selectivity and sensitivity for Pb2+ ions.67 A 25-mer duplex DNA containing the PbrR-binding sequence was prepared as a probe (Fig. 23). In the central base pair of this sequence, a uorescent base, 2-aminopurine (2AP), was incorporated as a messenger. Addition of Pb2+ ions and PbrR triggered a distortion of the duplex DNA to generate an unpaired 2-AP base, which would emit a strong uorescence. At room temperature, the detection limit can reach the nanomolar range (50 nM) for Pb2+ ions in solution. The probe was also highly selective towards Pb2+ ions over other metal ions (about 1000-fold) and could be reversed by the addition of ethylenediaminetetraacetate (EDTA). A new colorimetric and chemiluminescence detection system for Pb2+ was reported by the Willner group.68 The probe was constructed by hybridizing a nucleic acid containing Pb2+dependent cleaving DNAzyme and its substrate including horseradish peroxidase (HRP)-mimicking DNAzyme. Upon the addition of Pb2+ ions, the HRP-mimicking DNAzyme by the cleavage of the substrate assembled in the presence of hemin to a catalytic G-quadruplex. The catalytic G-quadruplex catalyzed the H2O2-mediated oxidation of 2,2 0 -azino-bis(3ethylbenzothiazoline)-6-sulfonate (ABTS2) or luminol, which results in a color change or generates chemiluminescence (CL), respectively. Furthermore, this method can be applied to L-histidine detection by using L-histidine cofactor-dependent nucleic acid cleaving DNAzyme instead of the Pb2+-dependent cleaving DNAzyme. Wang and Dong et al. designed another colorimetric and CL sensor for Pb2+ based on a similar concept. In the presence of K+, a common G-quadruplex DNAzyme PS2.M (with hemin as a cofactor) can eectively catalyze the H2O2-mediated

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Fig. 22 Predicted secondary structures of the uorescent DNAzyme lead sensors and schematic representation of the catalytic beacon sensor: (a) normal 817 DNAzyme sensor; (b) temperature independent 817 DNAzyme sensor; (c) 817 DNAzyme sensor with mismatches; (d) GR-5 DNAzyme sensor. F represents the uorophore, FAM, Q1 is the quencher DABCYL and Q2 is the quencher BHQ-1s. The single RNA base on the substrate arm is denoted by rA.

Fig. 23 Binding of Pb2+ ions to PbrR691 as revealed by a 2APmodied DNA probe. A# = 2-aminopurine = 2AP.

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Fig. 24 Schematic of utilizing Pb2+-induced allosteric G-quadruplex DNAzyme, PS2.M, for label-free colorimetric and CL detection of Pb2+.

Fig. 26 Schematic illustration of label-free uorescent detection of (a) Pb2+ and (b) adenosine.

oxidation of ABTS2 or luminol accompanied by color change or CL emission, respectively (Fig. 24).69 Addition of the Pb2+ ion induced a conformational change in the K+-stabilized PS2.M to Pb2+-stabilized structure which has a higher stability and a lower DNAzyme activity than the former. Thus, this system can be applied to colorimetric (ABTS2) and CL (luminol) detection of Pb2+ in aqueous solution. In addition, this sensing system provides good selectivity for Pb2+ with a low detection limit (32 nM per ABTS2 and 1 nM per luminol). The Chang group also developed a uorescence approach for Pb2+ ions detection based on another G-quadruplex DNAzyme, AGRO100.70 In the presence of hemin, addition of Pb2+ ions can increase DNAzyme activity of AGRO100 for H2O2-mediated oxidation of Amplex UltraRed (AUR). The AGRO100-AUR probe was highly sensitive (LOD = 0.4 nM) and selective (by at least 100-fold over other metal ions) toward Pb2+ ions, with a linear detection range from 0 to 1000 nM. A thrombin-binding aptamer (TBA) labelled with a uorophore and a quencher was reported by Chang et al. as a uorescent sensor for Pb2+ and Hg2+.71 As shown in Fig. 25, the TBA had a random coil structure that can be changed into a G-quartet structure in the presence of Pb2+ and into a hairpin-like structure in the presence of Hg2+ ions. Changes in the DNA strands conformation caused uorescence between the uorophore and the quencher to decrease via FRET. Pb2+ and Hg2+ ions can be selectively detected at concentrations as low as 300 pM and 5.0 nM in the presence of phytic acid and a random DNA/NaCN mixture, respectively. Wang et al. reported a recoverable DNA molecular device for the highly selective and sensitive uorescent detection of Pb2+ based on DNA duplexquadruplex exchange.72 T30695,

(GGGT)4, and its partly complementary strand were hybridized to form a DNA duplex. Addition of Pb2+ ions disrupted the duplex and stabilized the newly formed G-quadruplex. The Pb2+-stabilized G-quadruplex interacted with zinc protoporphyrin IX and enhanced its uorescence intensity. Further addition of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), a strong Pb2+ chelator, can reset this DNA molecular device. Lu and Tong et al. developed a new label-free method for uorescent detection of Pb2+ ions.73 They introduced an abasic site called dSpacer into the duplex regions of the 817 DNAzyme, which can bind to an extrinsic uorescent compound, 2-amino-5,6,7-trimethyl-1,8-naphthyridine (ATMND), and quench its uorescence (Fig. 26). Addition of Pb2+ ions enabled the DNAzyme to cleave its substrate and to release ATMND from the DNA duplex, recovering its uorescence. Similarly, this method was also used for the uorescent detection of adenosine by linking the dSpacer to the adenosine aptamer. The adenosine-induced structural switching of the aptamer led to the release of ATMND and subsequent uorescence enhancement. The detection limits of Pb2+ and adenosine were 4 nM and 3.4 mM, respectively. In 2010, the Lu group reported that DNA can hold ATMND and quench its uorescence by extending one end of DNA with a loop to generate a vacant site (Fig. 27).74 Either metal

Fig. 25 Representation of the sensing mechanism of the TBA probe for the detection of Hg2+ and Pb2+ ions.

Fig. 27 Fluorescence enhancement response of the functional DNA sensors specic to (a) Pb2+, (b) UO2 2+, (c) adenosine, and (d) Hg2+ using unmodied DNA via a vacant site.

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Nanoparticle based sensing systems Hupp et al. reported a simple colorimetric technique for the detection of aqueous heavy metal ions, such as Pb2+, Cd2+, and Hg2+. 13.6 0.4 nm diameter gold particles capped with 11-mercaptoundecanoic acid (MUA) were employed as chromophores (Fig. 29).80 Functionalized gold nanoparticles were aggregated in solution in the presence of divalent metal ions by an ion-templated chelation process as shown in Fig. 33, which induced an easily measurable change in the absorption spectrum of the particles. The aggregation also enhanced the hyper-Rayleigh scattering (HRS) response from the nanoparticle solutions, providing an inherently more sensitive method of detection. The chelation/aggregation process was reversible via the addition of a strong metal ion chelator such as EDTA. Thomas and colleagues reported Au and Ag nanoparticles that can be employed as Pb2+ selective colorimetric sensors, prepared by mixing the corresponding metal cations (Au3+ or Ag+) and a naturally occurring bifunctional molecule, gallic acid (Fig. 30).81 This system is known for its ability to detect micromolar quantities (ppm level) of Pb2+ ions even in the presence of other metal cations in water resulting in a visual color change from pink to blue for Au nanoparticles and yellow to red for Ag nanoparticles. Detailed mechanistic investigations indicated that the hydroxyl group of gallic acid (Fig. 30) is involved in the reduction of the Au3+/Ag+ ions and that the carboxylate group binds strongly to the surface of the nanoparticles. The newly synthesized nanoparticles are extremely stable in the pH range between 4.55.0. Under these pH conditions, it is dicult to bring nanoparticles in proximity due to strong interparticle electrostatic repulsion. However, the unique coordination behavior of Pb2+ ions (coordination number up to 12 with exible bond length and geometry) allows the formation of a stable supramolecular complex resulting in the plasmon coupling and a visual color change.

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Fig. 28 (a) Secondary structure of the DNAzyme. (b) Cleavage of 17DS by 17E in the presence of Pb2+. Pb2+-directed assembly of gold nanoparticles by the DNAzyme when nanoparticles are aligned in a head-to-tail (c) or a tail-to-tail manner (d). (e) For head-to-tail aligned aggregates, Pb2+ cannot induce DNAzyme cleavage and no color change can be observed. (f) For tail-to-tail aligned aggregates, Pb2+ can induce DNAzyme cleavage and color change can be observed. The rate of color change can be signicantly increased by adding invasive DNA.

ion-dependent cleavage by DNAzymes or analyte-dependent structural-switching by aptamers could release ATMND from the DNA duplex and recover its uorescence. As shown in Fig. 27, label-free uorescent sensors for Pb2+, UO22+, Hg2+, and adenosine were developed with high selectivity and sensitivity. The detection limits decreased to 3 nM, 8 nM, 30 nM, and 6 mM for UO22+, Pb2+, Hg2+ and adenosine, respectively. Recently, Liu and Lu reported highly sensitive and selective colorimetric sensing systems for Pb2+ detection by using Pb2+-dependent DNAzyme as a target recognition element and DNA-functionalized gold nanoparticles as a signaling element.7578 As shown in Fig. 28, the Pb2+-dependent DNAzyme was composed of an enzyme (17E) and a substrate strand (17DS) which was extended on both ends. Hybridization of the substrate with DNA attached nanoparticles induced aggregation of nanoparticles to provide a color change from red to blue.75 In addition, the nanoparticles could be aligned either in a head-to-tail manner or in a tail-to-tail manner according to the DNAs attached to the nanoparticles. In the former case, heating-and-cooling process (annealing) was required for the aggregation.76,77 However, in the presence of Pb2+, the substrate was cleaved by the enzyme, which inhibits the aggregation, and hence the color remains red. Furthermore, for the tail-to-tail aligned nanoparticles, the aggregation can be perturbed by further addition of Pb2+ to result in a blue-to-red color change, whereas the head-to-tail manner cannot.78 This process could be accelerated by using small pieces of DNA to invade the cleaved substrate of the DNAzyme. In 2008, Lu et al. reported a simple label-free colorimetric sensor for on-site and real-time Pb2+ detection.79 In the absence of Pb2+, the salt-induced aggregation of gold nanoparticles resulted in a color change from red to blue. This aggregation could be prevented by single-stranded DNA, which was released from the enzyme-complex by Pb2+ induced cleavage. The sensor exhibited a low detection limit of 3 nM and higher selectivity for Pb2+ over other metal ions.
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Fig. 29 Proposed process for the metal ion induced aggregation of Au-MUA.

Fig. 30 A general scheme for two electron oxidation of gallic acid to the corresponding quinine form and a representation of electrostatic interaction of carboxylic groups on the nanoparticle surface and the hydrogen bonding network formed between the surface capped molecules.

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Fig. 33 Strategy for the colorimetric detection of Pb2+ using GSH-GNPs.

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Fig. 31 (a) Schematic representation of the FRET donoracceptor assembly of positively charged CA-CdTe-QDs and negatively charged MUA-AuNPs; (b) schematic representation of the inhibition assay method for Pb2+ determination.

Positively charged CdTe-QDs capped with cysteamine (CA-CdTe-QDs) and negatively charged AuNPs capped with 11-mercaptoundecanoic acid (MUA-AuNPs) (Fig. 31) have been prepared and used for the determination of Pb2+ by Wang and Guo.82 These positively charged CACdTe-QDs formed FRET donoracceptor assemblies with negatively charged MUA-AuNPs due to electrostatic interactions, which eectively quenched the PL intensity of the QDs (Fig. 31). A novel inhibition assay method for Pb2+ detection was proposed based on the modulation eect of Pb2+ on the FRET eciency between QDs and AuNPs (Fig. 31). The response was linearly proportional to the concentration of Pb2+ in the range of 0.224.51 ppm, and the detection limit was calculated to be 30 ppb of Pb2+. Meanwhile, Huang and colleagues developed a colorimetric, label-free gold nanoparticle (Au NP) probe for the detection of Pb2+ in aqueous solution.83 The unique feature here is that this system is a nonaggregation-based nanoparticle sensor, in which Pb2+ ions accelerate the leaching rate of Au NPs by thiosulfate (S2O32) and 2-mercaptoethanol (2-ME) (Fig. 32). The formation of PbAu alloys accelerated the Au NPs rapid dissolution into solution, leading to dramatic decreases in the surface plasmon resonance (SPR) absorption. The 2-ME/ S2O32-Au NP probe was highly sensitive (LOD = 0.5 nM) and selective (by at least 1000-fold over other metal ions) toward Pb2+ ions, with a linear detection range (2.5 nM10 mM). Glutathione functionalized gold nanoparticles (GSH-GNPs) were reported by Su et al. as a facile, cost-eective and sensitive colorimetric detection method for Pb2+ (Fig. 33)84 which can potentially induce immediate aggregation of these nanoparticles.

Fig. 34 Schematic representation of the Pb2+-induced aggregation via sandwich complexation of azacrown ether-capped gold nanoparticles.

Therefore the existence of Pb2+ was able to be detected by colorimetric response of GNPs monitored from a UV-vis spectrophotometer or even with the naked eye (red to blue color change), and the detection limit had the potential to reach 100 nM. The SPR of the GSH-GNPs solution at 700 and 520 nm are related to the quantities of dispersed and aggregated GSH-GNPs, respectively. Alkanethiol-bearing monoazacrown ethers were also used to modify gold nanoparticles (AuNPs) as a simple and fast colorimetric sensor to selectively detect Pb2+ in aqueous solutions (Fig. 34).85 These AuNPs selectively sensed Pb2+ through color change from brown to purple, which was visually discernible by an appearance of the surface plasmon band (SPB) at 520 nm. The recognition mechanism is attributed to the unique structure of the monoazacrown ether attached to AuNPs and the metal sandwich coordination between two azacrown ether moieties that are attached to separate the nanoparticles. Han et al. adopted 11-mercaptoundecyl phosphoric acid as a thiol ligand for AuNPs (Phos-AuNPs) based on the fact that alkyl phosphates are potentially good ligands for Pb2+ because Pb2+ easily forms solids with phosphates and approximately 95% of the body burden of lead is stored in the bones as lead phosphate derivatives.86 Phos-AuNPs were aggregated by Pb2+, which caused a dramatic red-to-blue color change. The detection limit of Phos-AuNPs for Pb2+ was reported as 1.637 mM from the titration results. Functional materials based sensing systems In 2007, the Crego-Calama group developed a new sensing material for the detection of heavy metal ions.87 The arrays of 21 dierent uorescent sensing monolayers, which were consisted of 3 dierent uorophores and 7 dierent ligands, were directly generated by combinatorial methods and immobilized on the wells surface of glass microtiter plates (Fig. 35).
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Fig. 32 Sensing mechanism of the 2-ME/S2O32-Au NP probe for the detection of Pb2+ ions.

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pressure, resulting in changes in the diracted wavelength. When acrylic acid (AAc) was copolymerized, the sensing system showed high pH dependence in a range of pH 3.22 to 7.91. Furthermore, copolymerization of 4-acryloylamidobenzo-18-crown-6 (4AB18C6) into the hydrogel produced a new sensing material which can detect less than 1012 mol of Pb2+.

Fluorescent and colorimetric sensors for detection of cadmium ions


Small molecule based chemosensors In 2001, Prodi and Savage et al. designed and synthesized 5-chloro-8-methoxyquinoline appended diaza-18-crown-6 (49) (Fig. 37) as a chemosensor for Cd2+ detection.89 Compound 49 exhibited extremely weak emission in methanol solution. The crown ring moiety can bind to various metal ions, including alkali and alkaline earth but with the exceptions of Mg2+, transition and post-transition metal ions. Among them only Cd2+ and Zn2+ could bind with 49 and give about 30 nm red shift of lem with high quantum yield. In addition, the enhancement factor for Cd2+ (94-fold) is larger than for Zn2+ (69-fold). Three mixed donor phenanthroline-containing macrocycles (5052) (Fig. 38) as uorometric chemosensors for toxic heavy metal ions were reported by Lippolis and coworkers.90 These macrocycles could interact with Pb2+, Cd2+, and Hg2+ to generate dierent complex species depending on the molar ratios of M/L. In CH3CN solution, addition of Pb2+ and Hg2+ induced a chelation enhancement of uorescence quenching (CHEQ) for all three ligands. In contrast, upon addition of Cd2+, the CHEQ eect could be observed with 50 and 52 in the low molar ratio range (Cd2+/50 o 1; Cd2+/ 52 o 0.5), and then the CHEF occurred in the higher molar ratios range (1 o Cd2+/50 o 2; 0.5 o Cd2+/52 o 1). For 51, the Cd2+ induced CHEF eect occurred in the whole range of molar ratios. Yoon et al. synthesized two anthracene derivatives bearing the iminomethyl diacetic acid moiety at 9,10-(53) and 1,8positions (54) for selective uorescent cadmium chemosensors (Fig. 39). Fluorescence studies of 53 indicated a selective and
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Fig. 35 (a) The self-assembled monolayers formed in each well of the glass microtiter plate (MTP); (b) the arrays of 21 dierent uorescent sensing monolayers (TM0-TM6, T0-T6, L0-L6) in MTP. (c) Chemical composition of each uorescent sensing monolayer.

Upon the addition of metal ions, such as Cu2+, Co2+, Pb2+, Ca2+ and Zn2+, the monolayers produced various responses by low selective interactions. These responses could be collected by laser confocal microscopy and microarray reader uorescence scanner and processed for each analyte as the characteristic uorescent pattern. The sensing systems can be recovered by washing with EDTA solution. As shown in Fig. 36, Asher and coworkers prepared twodimensional (2-D) polystyrene particle arrays with a high diraction ratio of incident light.88 These 2-D particle arrays can be immobilized on hydrogel thin lms containing dierent molecular recognition agents for chemical sensing by polymerization. In the presence of a special analyte, 2-D lattice spacing of the arrays can be changed by hydrogel swelling/shrinking caused by analyte-induced alterations of hydrogel osmotic

Fig. 37 Structure of compound 49 and its proposed binding mode with Cd2+.

Fig. 36 Fabrication of a 2-D photonic crystal for sensing applications.

Fig. 38 Structures of compounds 5052.

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Fig. 39 Structures of compounds 5356.

large CHEF eect by a PET mechanism with Cd2+ at pH 10, 0.1 M CAPS buer, even though there was a relatively small CHEF eect with Zn2+.91 The association constants for Cd2+ and Zn2+ were calculated to be 69 100 and 3200 M1, respectively. The stoichiometry with Cd2+ was 1 : 1 binding and the selectivity for Cd2+ was 20 times larger than that for Zn2+. In 100% aqueous solution, 54 was heavily quenched by metal ions via PET.92 Particularly, the Cd2+54 complex displayed a unique red-shifted broad band due to the chelatoselective uorescence perturbation resulted from electrophilic aromatic cadmiation. Gunnlaugsson et al. reported compounds 55 and 56 (Fig. 39) as uorometric chemosensors for Cd2+ based on the PET principle, using an anthracene uorophore, connected to either one or two iminodiacetate receptors by a methylene spacer.93 Both 55 and 56 have good water solubility and are pHindependent in the physiological pH range. Upon addition of Cd2+, the formation of charge-transfer complexes (exciplexes) induced uorescent enhancement at lmax = 506 and 500 nm for 55 and 56, respectively, whereas addition of Zn2+ only causes the increase of (monomeric) anthracene emission of 56 and a red-shifted emission (lmax = 468 nm) of 55. Thus, both 55 and 56 demonstrated sucient Cd2+ selectivity over Zn2+ under physiological conditions. Compound 57 (Fig. 40), a di-substituted bis(anthrylmethyl) derivative of 1,8-dimethylcyclam, was studied by Youn and Chang as a Hg2+- and Cd2+-selective uorogenic sensor in aqueous CH3CN solution.94 The water content of the aqueous CH3CN solution can dominate the signaling type of the recognition of Hg2+ and Cd2+. An OFFON type signaling was observed for Hg2+ and Cd2+ ions in low water content solutions (CH3CN : H2O = 90 : 10, v/v), while a selective ONOFF type signaling toward Hg2+ ions was observed in 50% aqueous CH3CN solution. Noveron and Stang et al. developed a new chromogenic phenanthroline-containing supramolecular optical sensor (58)

Fig. 41 Structure of compound 58 and its proposed binding mode with Cd2+.

Fig. 42 Structure of compound 59 and its proposed binding mode with M2+.

(Fig. 41) for transition metals such as Ni2+, Cd2+, and Cr3+.95 The 1 : 1 complexations of 58 with Ni2+, Cd2+, and Cr3+ in methanol solution induced dramatic changes in the UV-vis spectrum. The binding constants are calculated to be 2.01 0.05 107 M1, 3.39 0.5 104 M1 and 7.53 0.4 103 M1 for Ni2+, Cd2+, and Cr3+, respectively. Yuasa and coworkers designed and synthesized a carbohydratebased uorometric chemosensor (59) (Fig. 42) for Zn2+ and Cd2+.96 Two amino groups stayed at the 3 and 5 positions of the carbohydrate component as the recognition group and two pyrene groups were attached to 2 and 4 positions as the uorophore. In the absence of metal ions, the two pyrene groups were separated apart from each other and therefore only produced monomer emission. Addition of metal ions induced ring ip of the carbohydrate that led the pyrene groups to fold and thus to aord excimer emission. Overall, 59 also achieved high selectivity for Zn2+ and Cd2+ over other metal ions in acetone solution. Zhang and Yu et al. reported the design and synthesis of a porphyrin-appended terpyridine (60) (Fig. 43) as a uorometric chemosensor for recognition of Cd2+ ions.97 Upon addition of

Fig. 40 Structure of compound 57.

Fig. 43 Structure of compound 60.

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Fig. 44 Structures of compounds 61 and 62.

Cd2+, 60 displayed the CHEF eect via Cd2+ induced interruption of PET in EtOH/H2O (1 : 1, v/v) solution. It responded linearly to Cd2+ in the concentration of 3.2 106 to 3.2 104 M with a detection limit of 1.2 106 M. 60 provided good selectivity for Cd2+ ions with potential interference from Cu2+ and Zn2+. Machi et al. reported the chelating EDTA-based bichromophores (61 and 62) (Fig. 44) for uorometric detection of Cd2+.98 Compound 62 exhibited both intramolecular excimer emission (400 nm) and monomer emission (335 nm). Addition of Zn2+ induced formation of a [ZnL]0 type complex leading to the decrease of the excimer emission but enhancement in the monomer emission. Conversely, complexation with Cd2+ induced enhancement in the excimer emission and depression of the monomer emission. In addition, the ecient monomerexcimer interconversion was due to the formation of [CdL2]2 type complex. A uorescent sensor (63) containing a bis(2-pyridylmethyl)amine group as the binding moiety (Fig. 45) for the uorescent imaging of Cd2+ in living cells based on an internal charge transfer (ICT) mechanism was developed by Peng and Fan et al.99 Among the various metal ions, 63 showed high selectivity towards Cd2+ with blue shifted lmax, signicantly increased uorescence intensity and good cell permeability. The uorescent enhancement was observed after addition of Cd2+ into the medium and incubation for 0.5 h at 37 1C. Qian and Cui et al. reported a new ratiometric Cd2+ uorescent sensor 64 (Fig. 46), which can distinguish Cd2+ and Zn2+ by presenting dierent uorescent signals.100 Compound 64 showed high selectivity to Cd2+ over other metal ions, including Zn2+. Complexation of 64 with Cd2+ reduced the electron-donating ability of the naphthalimides nitrogen moiety, which induced the uorescent color change from green to blue. In contrast, the interaction between 64 and Zn2+ improved the electron-donating ability of the naphthalimides nitrogen moiety through a deprotonation process that led to a uorescence color change from green to yellow. The deprotonation process induced by Zn2+ was conrmed by HRMS.

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Fig. 46 Structure of compound 64 and the proposed binding mode of 65 with Cd2+.

A new water-soluble uorescent chemosensor 65 (Fig. 46) for detecting Cd2+ ions was designed by Li and Wang et al.101 Compound 65 was highly selective to Cd2+ over other metal ions with signicantly enhanced uorescence in HEPES buer solution. The complexation of 65 and Cd2+ was expected to prevent the rotation of acyclic CQN that induced the enhancement of uorescence, and this theory was conrmed by NMR and mass analysis. Lin et al. reported a coumarin pyridyl ketone 66 (Fig. 47) as a new chromogenic sensor for transition-metal ions.102 Compound 67 and 68 were also synthesized as reference compounds (Fig. 47). Compound 66 could eectively distinguish Cu2+, Ni2+, and Cd2+ in CH3CN/H2O (95%/5%, v/v) solution at dierent extents of bathochromic shifts. The pyridyl ketone moiety was supposed to be the metal-binding site according to the studies of reference compounds and their IR and NMR spectroscopy. The metal induced enhancement of ICT from the electron-donating diethylamino group to the pyridyl ketone moiety led to red shift in the visible region that could be easily spotted by the naked eye. A uorescent sensor 69 (Fig. 48) containing the 1,8naphthyridine moiety as a uorophore for Cd2+ detection based on a PET mechanism was developed by Qian and Xiao et al.103 Compound 69 exhibited selective uorescent enhancement

Fig. 47 Structures of compounds 6668.

Fig. 45 Structure of compound 63 and the proposed binding mode of 63 with Cd2+.

Fig. 48 Structures of compounds 6972.

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and red shift (Dlmax = 35 nm) with Cd2+ over other metal ions in a Tris-HCl (0.01 M) solution (ethanol/water = 7 : 3, v/v, pH = 7.00). Jobs plot suggested that 69 formed a 1 : 2 complex with Cd2+ ions and the association constants were calculated to be K1 = 0.75 105 M1 and K2 = 2.19 105 M1. Lee and coworkers prepared a ratiometric uorescence sensor 70 by linking 2,2 0 -bipyridyl moieties to an aryleneethynylene platform as a tight bischelator for recognizing metal ions.104 Compound 70 illustrated particularly high anity towards group 12 metal ions with binding constants of 1.7 (0.5) 107 M1, 1.5 (0.5) 106 M1 and 9.4 (0.9) 104 M1 for Zn2+, Cd2+ and Hg2+ in CH3CN, respectively. Upon addition of Zn2+, Cd2+ and Hg2+ ions, the CH3CN solution of 70 displayed ratiometric uorescence changes such as a signicant decrease in the free-ligand emission (lmax = 390 and 415 nm) and a concomitant increase of the complexation emission (lmax = 495 nm) with an isoemissive point at 433 nm. In addition, addition of other transition metal ions such as Ag+, Cu+, Cu2+, Fe2+, Mn2+, Co2+ or Ni2+ only introduced either complete quenching or negligible changes. In 2008, Thummel et al. synthesized and characterized 2,9di-(pyrid-2-yl)-1,10-phenanthroline (71) (Fig. 48).105 71 displayed high anity towards metal ions with an ionic radius close , particularly Cd2+, Gd3+, and Bi3+. Complexation to 1.0 A of 71 and Cd2+ induced a strong CHEF with a low detection limit (109 M). On the other hand, Ca2+ (103 M) and Na+ (1.0 M) only caused CHEF at extremely high concentrations, whereas other metal ions such as Zn2+, Pb2+, and Hg2+ caused no CHEF eect with 71. An acridine derivative bearing azathiacrown ligand 72 was synthesized by the Yoon group, as a selective Cd2+ chemosensor.106 72 exhibited a selective CHEF eect with Cd2+ and a relatively smaller CHEF eect with Hg2+ in 0.1 M HEPES (pH 7.4)-DMSO (95 : 5, v/v) solution. The CHEF eect could be explained by the blocking of the PET process from the benzylic nitrogens binding with the metal ion. The association constants were calculated to be >108 with Cd2+ and 3.28 104 M1 with Hg2+. A coumarin-based ratiometric chemosensor 73 (Fig. 49) containing a derivative of N,N,N 0 ,N 0 -tetrakis(2-pyridylmethyl) ethylenediamine (TPEN) as the chelator for uorescence imaging of intracellular Cd2+ was prepared by Taki and coworkers.107 73 presented good Cd2+ selectivity over other metal ions in aqueous media with a dissociation constant of 0.16 nM. Addition of Cd2+ ions to the HEPES buer solution of 73 induced ratiometric uorescence changes (decrease at 333 nm and increase at 356 nm) with a distinct isoemissive point at 340 nm. Some transition metal ions such as Cu2+, Zn2+, and Hg2+ can compete with Cd2+ for binding as well, however, only very small changes were observed in uorescence without the presence of Cd2+. 73 also had good cell

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Fig. 50 Structures of compounds 74, 75 and the proposed binding mode of 74 with Cd2+.

permeability and located within the acidic compartments of the cells. A BODIPY derivative 74 (Fig. 50) has been designed and synthesized as an OOn uorescent sensor based on the PET mechanism for the detection of Cd2+ in aqueous solution by the Qian and Xu group.108 When Cd2+ was added to the solution, the ecient PET quenching from polyamide to BODIPY uorophore was inhibited and a signicant increase in the uorescence intensity (195-fold) was observed. The nonlinear least-squares analysis and Jobs plot from uorescence spectra assumed a 1 : 2 stoichiometry for the 74Cd2+ complex with association constants of 7.2 103 M1 and 1.3 105 M1. In addition, Qian and Xu et al. also realized that the extension of 4-methoxyphenyl to the left arm of BODIPY skeleton with a vinyl linker caused a red shift of emission in the near-infrared region.109 Interestingly, 75 (Fig. 50) revealed dierent selectivity in various aqueous buer solutions. In MOPS (3-morpholinopropanesulfonic acid) buer solution (50 mM, 10% DMSO, pH = 7.0), 75 was highly selective toward Cd2+, Hg2+ and Pb2+ with signicant uorescence enhancement at 658 nm over other metal ions. In HEPES buer solution (10 mM, 10% DMSO, pH = 7.2, 10 mM NaCl), 75 preferred to bind to Cd2+ and Pb2+ resulting in turn-on uorescence. In addition, in 20 mM Tris-HCl (pH = 7.5, 10% DMSO, 0.1 mM sodium phosphate) buer solution, 75 only responded to Cd2+. Furthermore, 75 could selectively detect Hg2+ in 50 mM citratephosphate buer solution (pH = 7.0, 10% DMSO). Thus, multiple targets could be recognized with high selectivity by modulating the buer solutions. Ramaiah and coworkers reported the design and synthesis of quinaldine-based croconaine dyes (7679) (Fig. 51), which displayed the absorption maximum in the infrared region with high molar extinction coecients (15 105 M1 cm1) and low uorescence quantum yields in THF.110 Among these

Fig. 49 Structure of compound 73 and its proposed binding mode with Cd2+.

Fig. 51 Structures of compounds 7679 and their binding models with metal ions.

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Fig. 52 Structures of compounds 80 and 81.

dyes, dye 79, which substituted a cholesterol moiety to the quinaldine ring, had higher solubilities than other dyes in THF and CHCl3 and showed an absorption maximum at 871 nm in THF. Dye 79 preferred complexation with divalent metal ions, particularly Zn2+, Pb2+, and Cd2+, in a 2 : 1 stoichiometry, which led to signicant CHEF emission. The NMR and IR analysis of 79Zn2+ complex indicated that the Zn2+ ion was chelated with the carbonyl groups of the croconyl ring. Association constants were calculated to be 1.9 0.4 1014 M2, 1.0 0.3 1013 M2 and 5.2 0.4 1012 M2 for Zn2+, Pb2+, and Cd2+, respectively, based on the uorescence changes. Compound 80 (Fig. 52), with a specic semirigid framework, was synthesized by Liu and coworkers as a selective uorescent chemosensor for the recognition of Cd2+.111 In H2O/MeOH solution at pH 7.0, addition of Cd2+ caused a CHEF eect by inhibiting the intramolecular radiationless transitions from the np* state. The binding constant log b is 5.2 0.1 and Cd2+ could be detected at a very low concentration (9.0 106 M). Furthermore, the AcO anion can eciently enhance the uorescence intensity of 80Cd(ClO4)2 (ca. 3.5-fold) whereas other anions such as F, Cl, Br, I, NO3, or HSO3 cannot. In CH3CN solution, addition of Cd2+ induced a ratiometric uorescent change with a clear isoemissive point at 375 nm and 2.5-fold uorescence enhancement. Jobs plots from uorescence data suggest the formation of 80Cd2+ complex with a 1 : 2 stoichiometry. A sulfur-containing receptor 81 (Fig. 52) was synthesized via extending a lumazine ligand with a thiophene substituent as a water-soluble uorescent sensor for the detection of Cd2+, Hg2+ and Ag+ by Saleh.112 Probe 81 showed high selectivity towards Hg2+, Ag+ and Cd2+ over other metal ions with high sensitivity (a detection limit of about 10 nmol L1). In water solution at pH 5.1, an enhancement in uorescent intensity at 436 nm was observed with the addition of Cd2+ (log b = 2.79 0.08) while uorescence quenching was found in the presence of Hg2+ and Ag+ (log b = 5.42 0.1 and 4.31 0.15, respectively). The binding models were suggested to be 1 : 2 (M : L) for both Hg2+ and Cd2+ ions and 1 : 1 (M : L) for the Ag+ ion. In the past few years, Jiang et al. synthesized a series of uorescent sensors (8284) (Fig. 53) based on quinoline derivatives with DPA as a binding moiety for detecting Zn2+ and Cd2+ ions.113115 In aqueous buer solutions, compound 82, which contains an acetamidoquinoline moiety, exhibited Turn-On uorescence (about 40-fold) with a slight shift in emission in the presence of Cd2+ ions, based on the PET mechanism.111 In contrast, while binding to Zn2+ ions, 82 presented a red shifted emission with slightly enhanced emission intensity, based on the ICT mechanism. As shown in Fig. 53, these dierences are dependent on the dierent coordination conformations of 82Zn2+ and 82Cd2+ which were conrmed by 1H NMR studies. Probe 82 had high selectivity for Cd2+ over alkali and alkaline metal ions with a picomolar sensitivity
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Fig. 53 Structures of compounds 8284 and the proposed binding modes of 82 with Cd2+ and Zn2+.

(Kd = 0.25 0.03 pM). Compound 83, a chemosensor based on 8-methoxyquinoline, was also synthesized by the Jiang group.114 Addition of Zn2+ into the buer solution (10 mM Tris-HCl, 0.1 M KNO3, 50% CH3CN, pH = 7.4) of 83 induced ratiometric changes of uorescence whereas a decrease of emission at 405 nm and a signicant enhancement of emission at 458 nm with an isoemissive point at 400 nm, indicating that a promoted ICT process occurred with the complexation between Zn2+ and 83. Meanwhile, in the presence of Cd2+, 83 showed an enhancement of emission at 425 nm without an isoemissive point, which is attributed to the CHEF by the formation of 84Cd2+ complex. The titration curves of uorescence suggested the formation of 83Cd2+ and 83Zn2+complexes with a 1 : 1 stoichiometry. Moreover, because of the higher binding anity for Cd2+ than Zn2+, 83Zn2+ also can be used as uorescence chemosensor for Cd2+ detection with a gradual blue-shift from 458 to 425 nm. Recently, Jiang and He et al. developed 84 as a cadmium sensor. Probe 84 demonstrated high selectivity for sensing Cd2+ over other metal ions.115 In the aqueous buer (10 mM HEPES, 0.1 M NaCl, pH = 7.4) solution of 84, addition of Cd2+ induced a large blue shift in emission (Dl = 63 nm) with noticeable increase in the uorescence intensity. The ratiometric uorescent change is due to the inhibition of the resonance process via complexation of 84 with Cd2+. Probe 84 also presented high cell-permeability and noncytotoxicity in the confocal microscopy and cytotoxicity experiments. Yoon et al. reported few 7-hydroxycoumarin-based uorescent chemosensors bearing the iminodiacetic acid diethyl ester group at 8-position (85), iminodiacetic acid at 4-position (86), and the DPA unit (87) for Zn(II) and Cd(II) as shown in Fig. 54.116 The coumarin derivatives were compared by their selectivity for metal ions in terms of the uorescent changes in aqueous solutions. Particularly, compound 8587 oered large uorescence enhancements of Zn2+ and Cd2+ in DMSOHEPES buer (0.02 M, pH 7.4) (1 : 99, v/v) and Jobs plot study demonstrated 1 : 1 stoichiometry between 8587 and metal ions. The association constants with Cd2+ were calculated to be 1.4 103 M1, 1.3 104 M1 and 1.2 104 M1 for 85, 86, and 87, respectively. The Liu group linked 8-hydroxyquinoline uorophore to b-cyclodextrin using the triazole group as a linker to generate a uorescent Cd2+ sensor with good water solubility.117
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Fig. 54 Structures of compounds 8587.

Fig. 57 Structure of 92 and its binding mode with Cd2+.

Fig. 55 Structure of compound 88 and its proposed binding modes with Cd2+ and sodium adamantane carboxylate.

This new b-cyclodextrin derivative 88 (Fig. 55) showed very weak uorescence because of the intramolecular PET from N atom in the triazole moiety to the 8-hydroxyquinoline uorophore. Addition of Cd2+ can recover the uorescence by inhibiting the PET process. The Jobs plot analysis suggested a 1 : 1 stoichiometry of 88/Cd2+ complex. Moreover, the limit of detection (LOD) for 88 towards Cd2+ was found to be 1.89 103 M. In addition, using sodium adamantine carboxylate as a co-chelating agent, the binding constant (log Ks) increased from 2.10 0.23 to 3.38 0.09 without aecting the emission wavelength. A new uorescent Cd2+ sensor (89) (Fig. 56) based on 8-hydroxyquinoline containing a 2,8-dithia-5-aza-2,6-pyridinophane as an ionophore has been synthesized.118 This chemosensor exhibited a signicant CHEF response toward Cd2+ not only in aqueous solutions but also in sodium dodecyl sulfate micelles, liposomes, and living cells. The 1 : 1 stoichiometry of 89Cd2+ complex was conrmed by X-ray structure analysis. Probe 89 was proved to be a good choice for selective imaging of Cd2+ in living cells owing to its low cytotoxicity and low background uorescence. Li and coworkers reported dipyrrolylquinoxaline (DPQ) derivatives 90 and 91 as new uorescent sensors for transitionmetal ions.119 Both 90 and 91 showed good sensitivity toward

Cd2+, Zn2+ with turn-on uorescence based on the CHEF mechanism and Cu2+, Hg2+ turn-o uorescence based on the CHEQ mechanism. Jobs plot and crystal structure analysis indicated the formation of M90 (or 91) complex with 1 : 1 stoichiometry. Compound 92 (Fig. 57), containing a benzoimidazole moiety as a uorophore and DPA as an ionophore, was reported as a ratiometric uorescent Cd2+ sensor by Guo and He et al.120 In the HEPES buer solution (50 mM, 0.1 M KNO3, pH 7.2) of 92, addition of Cd2+ led to the co-planation of pyridine and benzoimidazole moieties and also enhanced electronwithdrawing ability of the acceptor resulting in both absorption spectra (red shift about 19 nm) and emission spectra changes (red shift about 53 nm). UV-vis and uorescence titrations indicated the 1 : 1 binding stoichiometry of 92Cd2+ complex with picomolar sensitivity. Metal-ion selectivity experiments indicated that probe 92 was unaected by other metal ions, except Zn2+. Although Zn2+ addition also induced a red shift in emission, it has little disturbance to the Cd2+ detection. Probe 92 also exhibited high cell membrane permeability and good reversibility with the metal ion chelator TPEN in HeLa cells. Yoon and co-workers designed a naphthalimide-based uorescent chemosensor 93 for ratiometric Zn2+ and Cd2+ detection (Fig. 58).121 Large uorescent enhancements were observed upon addition of Zn2+ (22-fold) and Cd2+ (21-fold). Notably Cd2+ induced a blue shift to 446 nm (blue uorescence), while Zn2+ caused a red shift to 514 nm (green uorescence) in the aqueous solution (CH3CN/0.5 M HEPES (pH 7.4) = 50 : 50) via amide tautomerization. The colorimetric changes could be distinguished by the naked eye and also Jobs plot study illustrated the 1 : 1 binding mode of 93Cd2+ and 93Zn2+ complexes. In 2011, Qian and Xu et al. investigated two near-infrared uorescent sensors 94 and 95 (Fig. 58) based on a tricarbocyanine uorophore for detecting Cd2+.122 Both 94 and 95 showed high selectivity and sensitivity to Cd2+ over other metal ions, in particular 95, which can even distinguish Cd2+ in Tris-HCl (12.5 mM) solution (containing 0.05 mM sodium

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Fig. 56 Structures of compounds 89, 90 and 91.

Fig. 58 Structures of compounds 93, 94 and 95.

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phosphate, pH 7.2). This is because addition of Cd2+ to the neutral buer solution of 94 and 95 resulted in a metalligand coordination, which inhibited the PET process from two aniline nitrogen atoms to tricarbocyanine and recovered the NIR uorescence. The nonlinear least-squares analysis of uorescence intensity and the data of Jobs plot indicated a 1 : 2 stoichiometry for the 95Cu2+ complex with association constants of 8.8 103 M1 and 1.9 105 M1. Although Zn2+ and Pb2+ can potentially interfere with sensors, the experimental results suggest that 94 is the better choice for imaging Cd2+ in living cells due to its strong cell permeability.
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Calixarene based chemosensors A novel calix[4]arene-based uorescent chemosensor 96 (Fig. 59) for the detection of Cd2+ and Zn2+ was reported by Kim, Matthews and Vicens et al.123 Compound 96 is highly selective for Cd2+ and Zn2+ over other metal ions. Addition of Cd2+ and Zn2+ to the CH3CN solution of 96 induced ratiometric changes of uorescence whereas a decrease of excimer emission and an increase of monomer emission can be observed. The association constants (Ka) were determined to be 5.18 104 M1 and 1.7 104 M1 for Cd2+ and Zn2+, respectively. Protein based chemosensors DAuria et al. reported a protein-based uorescence biosensor for an easy and rapid on-line detection of Cd2+ in water.124 The biosensor consisted of a column containing Chelex resin saturated with Zn2+ and a rhodamine-labeled metallothionein (MT). The column was washed several times until no uorescence was detected. When a water solution containing Cd2+ ows through the column, the uorescence was recovered because of the higher binding anity of Cd2+ with MT than Zn2+. Moreover, the detection limit was lower than 0.5 mM for Cd2+ in water. Functional materials based sensing systems El-Safty et al. developed the highly sensitive and selective chemical sensing systems for chromogenic detection of toxic ions at low-level concentrations.125 They immobilized hydrophilic and hydrophobic chromophores such as Dithizone, TMPyP, PR, and TPPS (Fig. 60) into the cubic Fm3m cage monoliths by direct and indirect postgrafting techniques. These generated a nanosensor that exhibits long-term stability, high adsorption capacity and high sensitivity for detection at low concentrations (subnanomolar range) of Pb2+, Cd2+, Sb3+, and Hg2+ ions. The color changes of the nanosensors

Fig. 60 Structures of the chromophores.

induced by target ions could be rapidly observed by the naked eye. The nanosensors could be easily recovered by using stripping agents, such as EDTA or Cl, SCN, and CN anions. The same group reported a series of Cd2+ selective nanosensors based on a similar methodology.126 Four chromophore molecules, including TMPyP, DTAR, DPAP, and DPC (Fig. 60), were labelled into spherical nanosized cavities and surfaces for the naked-eye detection of Cd2+. These nanosensors could colorimetrically recognize Cd2+ ions at a low concentration level in the range of 109 to 1010 M. Among them, the nanosensor, which immobilized the DPC probe molecules, exhibited the highest sensing utilities in terms of sensitivity, stability, and response time of Cd2+ ions. Matsunaga et al. designed and synthesized amphiphilic 4-ndodecyl-6-(2-thiazolylazo)resorcinol (DTAR) (Fig. 60) monolayers using the LangmuirBlodgett (LB) thin-lm technique as a potential solid-state chromoionophore sensor for Cd2+ detection.127 The sensors were selective and sensitive for Cd2+ ions over other metal ions and could resist interferences from other cationic and anionic species. The sensors could be recovered and reused for several times without losing sensing eciency and apparently they provided better mechanical stabilities when used in combination with polymer composites. Santra et al. appended diaza-18-crown-6 rings to the surface of QD (quantum dots) (Fig. 61) using the zero length coupling method to develop a new Cd2+ selective chemosensor.128 The electron transfer between the QD and the ligand caused luminescence quenching of QDL (ligand conjugated quantum dots). Such an electron transfer process could be prevented by complexation between Cd2+ and QDL that leads to luminescence enhancement. This is so because QDL showed high selectivity for Cd2+ over other metal ions.

Fig. 59 The proposed binding mode between 96 and Cd2+.

Fig. 61 Structure of QDL.

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Shi et al. described the complexation of cationic 5,10,15,20tetrakis(1-methyl-4-pyridinio)porphyrin (TMPyP) and negatively charged chemically converted graphene (CCG) sheets and utilized the TMPyP/CCG complex (Fig. 62) as an optical sensor for detecting Cd2+ ions in aqueous media.129 Addition of Cd2+ ions to the pure TMPyP solution exhibited a bathochromic shift of absorption band (ca. 22 nm). In the presence of CCG, the chelating reaction between TMPyP and Cd2+ ions was greatly accelerated from 20 h to 8 min under ambient conditions with a larger bathochromic shift (ca. 40 nm). Overall, the TMPyP/CCG complex displayed high selectivity towards Cd2+ ions over other metal ions, including Zn2+ ions. The design and synthesis of triazole-ester modied silver nanoparticles (TE-Ag NPs) (Fig. 63) was reported by the Li group.130 TE-Ag NPs showed high selectivity towards Cd2+ over other metal ions. Addition of Cd2+ ions into TE-Ag NPs solution induced a dramatic increase of the absorbance intensity at 550 nm resulting in a signicant color change from yellow to red, which can be observed by the naked eye. The TEM image indicated that the color change of TE-Ag NPs in the presence of Cd2+ is attributed to the Cd2+-induced assembly of TE-Ag NPs. The limit of colorimetric detection for Cd2+ is 2.0 105 M. Anzenbacher, Jr. et al. reported a uorescence sensor array, which was generated by dispersing 9 cross-reactive sensors (S1S9) (Fig. 64) in a hydrophilic polyurethane carrier.131 Based on the various anities and selectivities of the sensors,

Fig. 64 Structures of the chemosensors S1S9 used in the array.

Fig. 65 Structures of ve indicators and color-dierence maps of eight heavy-metal ions at standard concentrations of wastewater discharge. Fig. 62 Structure of the TMPyP/CCG complex.

this array can distinguish metal cations, such as Ca2+, Mg2+, Cd2+, Hg2+, Co2+, Zn2+, Cu2+, Ni2+, Al3+, Ga3+ at dierent ranges of pH and at dierent cation concentrations using linear discriminant analysis (LDA). This array was also used to identify samples from nine dierent mineral water brands without any pretreatment. Based on a similar concept, Feng and Guan et al. reported a solgel membrane array, which immobilized ve commercially available colorimetric indicators (Fig. 65) for the discrimination of trace heavy metal ions.132 Color-dierence maps were generated by comparing the digital red, green, and blue values in the presence and absence of analytes. Using this array, eight heavy metal ions, including Pb2+, Hg2+ and Cd2+, can be dierentiated at standard concentrations of wastewater discharge.

Fluorescent and colorimetric sensors for detection of mercury ions


Small molecule based chemosensors
Fig. 63 Structure of TE-Ag NPs.

rraga and Molina et al. Ferrocene based small molecules. Ta reported ferrocene-based multichannel molecular chemosensors
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bearing two pyridine rings which have Hg2+ selectivity through three dierent channels: the oxidation peak that is anodically higher shifted (DE1/2 = 300 mV for 97 and DE1/2 = 200 mV for 98), new low-energy bands that appear in the absorption spectrum at 483 nm and 485 nm, respectively. Also, the emission bands of 97 and 98 were red-shifted by 28 nm and 32 nm, respectively. Remarkable chelation-enhanced uorescent factors (CHEF = 227 for 97 and 165 for 98) were accompanied. The changes of compound 97 in absorption spectra are accompanied by the color change from yellow to orange, which allows the potential naked eye detection.40,133 The P. Ghosh group reported thiomethoxychalcone-based ligands 99 and 100 as Hg2+ selective chemodosimeters. In the acetonitrile solution, these two compounds showed selective color changes from orange to purple with Hg2+, and the UV/vis titration results indicated the formation of 2 : 1 (99 : Hg2+) and 1 : 1 (100 : Hg2+) complexes. X-ray crystal structure and cyclic voltammetric studies supported a selective chemodosimetric desulfurization between Hg2+ and 99 or 100.134 Kim et al. developed a ferrocene-based electrochemical chemodosimeter for Hg2+ recognition.135 Addition of Hg2+ induced cyclization and desulfurization as shown in Fig. 66. In addition, an anodic shift of 101s redox potential and a red shift in UV-vis spectroscopy were observed in CH3CN/H2O (9 : 1) solution with high selectivity among the various metal ions. Rhodamine based small molecules. Three sensors bearing the thiophene group and rhodamine, or thiospirolactam rhodamine, were synthesized for the selective detection of Hg2+ by Duan et al.136 Compared to compounds 102 and 103, compound 104 containing two rhodamine carbohydrazone arms exhibited better selectivity for Hg2+ in uorescent enhancement and absorption detection (Fig. 67). The ppb level uorescent detection limit of 102, 103 and 104 for Hg2+ oered their potential applications in the Hg2+ detection of drinking water. Recently, Yoon et al. described two rhodamine hydrazone derivatives bearing a thiol (105) and a carboxylic acid group (106) as selective uorescent and colorimetric chemosensors for Hg2+ (Fig. 68).137 Both the chemosensor samples containing Hg2+ in aqueous solution induced large uorescent enhancement and color change by the spirolactam ring-opening process of the rhodamine moiety. From the detection of Hg2+ in the microuidic channel, the linear responses of compounds 105 and

Fig. 67 Structures of compounds 102104.

Fig. 68 Structures of compounds 105 and 106.

Fig. 69 Proposed mechanism of 107 with Hg2+.

Fig. 66 Structures of compounds 97100 and Hg2+ induced intramolecular cyclic guanylation of 101.

106 were observed in the range of 1 nM1 mM Hg2+ concentration with the detection limit of 1 nM for 105 and 4.2 nM for 106, respectively. Both chemosensors were applied successfully to detect previously exposed nanomolar concentrations of Hg2+ in the C. elegans. Lin et al. reported new uorescence turn-on Hg2+ probe 107 considering the interaction of Hg2+ with both thiol and alkyne moieties.138 The probe exhibited large uorescence enhancement, high selectivity, low detection limit of 39 nM, and linear uorescent response to Hg2+ ranging from 5 108 to 4 106 M. Furthermore, the probe 107 is applicable for Hg2+ imaging in the living cells. The proposed mechanism is shown in Fig. 69. Lin and coworkers constructed a novel reversible uorescence turn-on Hg2+ sensor based on a new receptor composed of a thiol atom and an alkene moiety for living cell uorescent imaging.139 Compound 108 showed a 1000-fold uorescent enhancement with Hg2+ in PBS buer (25 mM, pH 7.0, containing 2.5% CH3CN) and is highly selective to Hg2+ with a detection limit of 27.5 nM. The S atom and the alkene moiety of compound 108 took part in the 1 : 1 stoichiometry binding with Hg2+ and the binding is reversible when excess EDTA was added under the neutral conditions (Fig. 70). A rhodamine B-based chemosensor containing NS2 for the reversible binding receptor of Hg2+ in aqueous media was introduced by Qian et al.140 Compound 109 exhibited quick uorescent and colorimetric response that allowed for the real-time detection.
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Fig. 70 Proposed binding mode of 108 with Hg2+.

Fig. 73 Structures of compounds 113 and 114.

Fig. 71 Proposed binding mode between 109/Hg2+.

The 1 : 1 stoichiometry 109/Hg2+ was conrmed by Jobs plot and the EDTA addition changed the color from pink to colorless and the uorescence was turned o (Fig. 71). The binding constant Ka was calculated to be (1.18 0.13) 106 M1 from the titration curve with Hg2+. Recently, Tang and Nandhakumar et al. reported rhodamine B hydrazide methyl 5-formyl-1H-pyrrole-2-carboxylate Schi base 110141 to detect both Cu2+ and Hg2+ using two dierent detection modes that are UV-vis spectroscopy for Cu2+ and selective uorescent recognition for Hg2+. Despite the copper ion induced color change with very weak uorescent emission, only Hg2+ exhibited uorescent enhancement by forming the open-ring form of rhodamine spirolactam in MeOH : H2O (3 : 1, v/v, HEPES 10 mM, pH 7.4). In addition, compound 110 for sensing Hg2+ is not inuenced under neutral pH conditions. Yu et al. reported compound 111 (Fig. 72) as a uorometric chemosensor for Hg2+ based on the rhodaminecoumarin conjugate.142 Probe 111 showed high sensitivity and selectivity for Hg2+ sensing with reversible dual-responsive colorimetric and uorescent response in 50% water/ethanol buered at pH 7.24. The probe 111 can be applied for the recognition of Hg2+ in both tap and river water samples, and the quantity of Hg2+ with a linear response ranged from 8.0 108 to 1.0 105 mol L1. The detection limit was 4.0 108 mol L1. A rhodamine based sensor containing a histidine group was synthesized for the detection of Hg2+ by the Yoon group.143 As shown in Fig. 72, compound 112 has two carbonyl oxygens as well as imidazole nitrogen that can provide a nice storage pocket for Hg2+. Addition of 100 equiv. Hg2+ caused the uorescence increase over 100-fold in 0.02 M, pH 7.4 HEPES : EtOH

(1 : 9, v/v) solution. From the uorescent titration study with Hg2+, the association constant of compound 112 was calculated to be 2.0 103 M1 and thus 112 was further applied to sense the intracellular Hg2+. Yoon et al. also reported two rhodamine derivatives bearing mono and bis-boronic acid groups (113 and 114) as uorescent and colorimetric sensors for Hg2+ (Fig. 73). These two rhodamine derivatives were the rst examples of reversible uorescent chemosensors, which utilized the boronic acid group as the binding ligand for metal ions.144 Through the uorescent titration with Hg2+ in CH3CNwater (9 : 1, v/v), the association constants of 114 and 114 with Hg2+ were calculated to be 3.3 103 M1 and 2.1 104 M1, respectively. Bis-boronic chemosensor 114 showed 9-fold tighter binding with Hg2+ than mono-boronic chemosensor 113, due to the additional boronic acid moiety, which plays an important role in the recognition of Hg2+. The Yoon group introduced rhodamine 6G thiolactone derivative 115 as a selective and colorimetric sensor for Hg2+ at pH 7.4.145 Oon type uorescent and colorimetric changes were observed in the presence of Hg2+ in CH3CNHEPES buer (0.01 M, pH 7.4) (1 : 99, v/v). X-Ray structure of 115Hg2+ exhibited the 1 : 2 stoichiometry of 115/Hg2+ and the sensor 115 could detect Hg2+ in the nanomolar range. In addition, compound 115 could be applied for in vivo imaging of C. elegans to detect Hg2+. Yoon and Shins group designed a selenolactone based uorescent probe 116 for the detection of inorganic mercury and methylmercury species with unique uorescence enhancement and UV-vis spectral change.146 Because of the extremely high anity between mercury and selenium, mercury and methylmercury species induced a deselenation reaction in compound 116 (Fig. 74). In the concentration range of Hg2+ (030 nM), the uorescent intensity displayed a linear response proportionally and the Jobs plot study demonstrated the binding mode of 1 : 1 stoichiometry between 116 and Hg2+. This sensing ability was hence successfully applied for the detection of inorganic mercury/methylmercury species in cells and zebrash. Compound 117 (Fig. 75), a tren-spaced rhodamine and pyrene uorophore, was reported by the Kim group as a Hg2+ and Cu2+-selective uorogenic sensor that modulated pyrene excimer emission.147 The complexation of 117 with Hg2+ induced the rhodamine spirolactam ring opening and exhibited dynamic excimer emission. The dierent binding mode between Hg2+ and Cu2+ was elucidated from DFT (density functional theory)

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Fig. 72 Structures of compounds 110112, and the proposed binding mode of 111 with Hg2+.

Fig. 74 Structures of compounds 115 and 116.

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Fig. 75 Schematics of the formation of dynamic excimers.

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Fig. 76 Proposed mechanism of compound 118 with Hg2+.

calculation and competition experiment. The encapsulating Cu2+ of the pyrene amide group induced a static excimer emission and the Hg2+117 complex can be replaced by Cu2+. Kumar and coworkers designed and synthesized a naphthalimide appended rhodamine based uorescent chemosensor (118) (Fig. 76) for Hg2+.148 Through the bond energy transfer (TBET), compound 118 showed selectivity for Hg2+ in mixed aqueous media and the detection limit of 2.0 106 mol L1 was suciently low to detect the submillimolar concentration range. The TBET system absorbs at a wavelength of naphthalimide donor then emits via a rhodamine receptor. The uorescence enhancement factor was far higher and the uorescence of 118 was much brighter than that of the rhodamine B ring opening. The 1 : 1 binding stoichiometry (host/guest) was reversible by decomplexation with addition of KI. In addition, 118 can be applied to sense Hg2+ in PC3 cell lines as a uorescent probe. Rao et al. reported a multi-measured sensing method based on rhodamine 6G as a chromo or uoro ionophore via visual detection and spectroscopic detection for heavy metal toxic ions such as Hg2+, Cd2+ and Pb2+.149 Novel colorimetric chemosensor 119 is based on the proposed sequential ligand exchange (SLE) mechanism as well as uorescent quenching (Fig. 77). The three metal toxins induced bathochromic shift from 530 nm of orange red to 575 nm of pink ternary ions. The formation of ternary ions with Cd, Pb or Hg resulted in uorescent quenching of rhodamine 6G. Furthermore, sequential ligand transfer of iodide with citrate or EDTA formed anionic complexes with Pb2+ and Cd2+, respectively. The uorescent quenching eect was proportional to a specic metal ion, so it can be applied to multi-measure quantication of mixtures of Pb2+, Cd2+ and Hg2+ by spectroscopic measurements. Naphthalimide based small molecules. Shanhgguan et al. reported that 1,8-naphthalimide derivatives 120 showed uorescent turn-o by imideHg2+imide complex formation (Fig. 78).150 The quenched uorescence was recovered by adding Na2S or HCl, which indicated that the binding of Hg2+ to the imide N-atom through imido protonHg exchange was
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Fig. 77 Schematic representation of uorescence quenching showing the competitive binding of ligands and the proposed sequential ligand exchange mechanism.

Fig. 78 Structures of compounds 120123.

reversible. In addition, the formation of 120aHg120a complex was induced by increasing the pH of the solution, since two protons were released when the complex formed. Based on the 1 H-NMR, mass, XPS, IR spectroscopy and uorescence results, it was suggested that N-unsubstituted cyclic imides reacted with Hg2+ selectivity and formed imideHgimide complexes. An alkyne conjugated 1,8-naphthalimide 121 was described as the ratiometric uorescent sensor for Hg2+ and Au3+ depending on the reaction conditions by the Peng group.151 At neutral pH, compound 121 exhibited highly selective ratiometric uorescence based on the naphthalimide uorophore tethered for Hg2+ in water via an alkyne moiety and the color of the Hg-containing solution changed from yellowish green to teal. After changing pH, the ratiometric selectivity switched to Au3+ in aqueous media and the colour change from green to blue in uorescence was also observed.
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A uorescent sensor (122) containing a thioether-rich crown group as the binding moiety (Fig. 78) exhibited dual signaling properties for Hg2+ and Ag+.152 Among the various metal ions, 122 showed high selectivity towards Hg2+ with uorescence enhancement and Ag+ ions induced a uorescent quenching eect because of the intramolecular dp interaction between the uorophore and Ag+. These turn-on and turn-o type signalling can be applied to distinguish Hg2+ and Ag+ and living cell imaging in the biological system for uorescent visualization of Hg2+. Zhang and coworkers reported a new ratiometric bioimaging probe based on naphthalimideporphyrin 123 (Fig. 78),153 which can avoid the emission spectra overlap problem and the emissions of two uorophores are well resolved with a 125 nm dierence between two maximum emission. Compound 123 containing two-independent Hg2+ sensitive uorophores, naphthalimide and porphyrin, showed high selectivity to Hg2+ over other metal ions, and the ratiometric uorescence signal was reversible. The detection limit was 2.0 108 M and the probe exhibited stable responses for Hg2+ concentration ranging from 1.0 107 M to 5.0 105 M. The ratiometric imaging of Hg2+ in living cells was eectively applied with good resolution without emission spectra overlap. Ho and Chou et al. synthesized 8,8 0 -(1,4,10,13-tetrathia7,16-diazacyclooctadecane-7,16-diyl)-bis(methylene)diquinolin7-ol 124 and proved to selectively recognize Hg2+ with Ka of B1.3 104 520 M1.154 X-Ray structural analyses revealed a 124/Hg2+ cage-like complex formation with thiol-crown and 7-hydroxyquinoline served as a signal transducer. When 124 was excited at 352 nm upon addition of Hg2+, a unique emission maximized at 520 nm was observed and the net uorescent result depended on specic proton tautomerization of 7-hydroxyquinoline as described in Fig. 79. The 3D-like structure caused 25-fold luminescence enhancement with Hg2+. Using the Hg2+ chelating agent, sodium-2,3-dimercapto-1-propanesulfonate (DMPS), it was found that the binding property of 124 with Hg2+ was the reversible response. Vaswani and Kera nen reported a 8-hydroxyquinoline derivative 125 (Fig. 80) as a new aqueous ono selective uorosensor for Hg2+.155 The detection limit of compound 125 in water at

Fig. 80 Structures of compounds 125127.

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20 C was 2.6 mM Hg2+ and a Job plot study indicated 1 : 1 stoichiometry in an aqueous system. Compound 126 was reported as a turn-on coumarin-based uorescent sensor for Hg2+ by the Katerinopoulos group.156 Through the PET mechanism, a water soluble, uorescent ion probe 126 could eectively detect Hg2+ in the environment and biological sample. DFT level of theory calculation also supported the PET process from a 15-crown-5 to a chromophore group, amino-coumarine nitrogen. A uorescent and colorimetric sensor 127 (Fig. 80) containing a pyrene moiety as a uorophore for Hg2+ and Cu2+ detection based on thiourea was developed by Yen et al. Compound 127 showed two selective color changes in aqueous solution (DMSO/H2O = 4/1, v/v, buered with HEPES, pH 7.8): a strong blue color for Cu2+ uorescent enhancement and an orchid color with Hg2+. When this compound was excited at 348 nm, two new emission peaks were evolved at 401/424 nm emission wavelengths upon addition of Hg2+ and 396/439 nm emission wavelengths with Cu2+. The colorimetric detection was possible in the 1.0 104 M range of two metal ions, and the uorescent detection limits of 127 were determined as 0.09 and 0.1 ppm for Hg2+ and Cu2+ respectively.157 BODIPY based small molecules. Atilgan and coworkers synthesized near-IR emitting 4,4-diuoro-4-bora-3a,4a-diazas-indacene(BODIPY)-based ratiometric chemosensor 128 by linking the BODIPY uorophore to dithia-dioxa-aza macrocycle moieties as a Hg2+ selective ligand.158 Compound 128 showed a band at 720 nm without the metal ion and a new band appeared upon addition of Hg2+ at 630 nm, blue-shifted region by 90 nm with strong uorescence emission intensity. Color change from green to blue was also observed with the naked eye. The binding mode was calculated to be 1 : 2 between 128 and Hg2+ with the dissociation constant of 1.8 106 M2. A BODIPY derivative 129 (Fig. 81) has been designed and synthesized as a molecular sensor based on the EET (excitation energy transfer) mechanism for the detection of Hg2+ in

Fig. 79 Proposed mechanism of 124 with Hg2+ in a neutral aqueous solution.

Fig. 81 Structures of compounds 128131.

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THF by the Akkaya group.159 Two emission peaks at 518 and 725 nm were observed without any metal ion, but addition of Hg2+ induced blue-shift with large enhancement in the emission intensity. The emission intensity of BODIPY (around 500 nm) was decreased and it indicated ecient energy transfer between the donor and acceptor chromophore after binding of Hg2+ to the dithiaazacrown ligand. The uorescent titration of compound 129 with Hg2+ exhibited the ratiometric emission result at 760723 nm and the intensity ratio demonstrated by the applicable measurements at various Hg2+ concentrations. Two BODIPY-triazine based tripod uorescent systems 130 and 131 were developed by Yoon et al., which bear a triazine core for combining three functional groups such as a uorophore (BODIPY), a ligand, and an auxiliary group.160 The quantum eciency for compound 130 was observed as 0.84 and the uorescent emission was quenched in the presence of Hg2+. On the other hand, compound 131 bearing the N,N-dimethylamine moiety on the phenyl ring exhibited an enhancement and a slight red shift upon the addition of Hg2+ by the large chelation enhanced uorescence (CHEF) eect of 131, because of the blocked PET mechanism process. Anthracene and acridine based small molecules. Rao et al. reported that a water soluble turn-on uorescent sensor for Hg2+, gluco-imino-anthracenyl derivative 132 (Fig. 82), has sensitivity for the recognition of Hg2+ in the presence of albumin proteins, human blood serum and milk.161 The binding mode between 132 and Hg2+ was studied with ESI MS and DFT computation modelling, the result indicated that compound 132 formed a 2 : 1 complex with Hg2+ through imine and aromatic moieties in the pH range 510. The reversibility was conrmed by the addition of Na2EDTA into the solution containing Hg2+. Even at 2 ppm of Hg2+ (the drinking water limit), 25 2% uorescent enhancement was observed and the sensitivity was not altered in the presence of several biologically relevant metal ions. A sugar-aza-crown ether (SAC) based uorescent sensor 133 (Fig. 82) was synthesized by coupling two anthracenetriazolym ethyl moieties by Wu et al., which showed high selectivity to Cu2+ and Hg2+ ions among various transition metal ions.162 The uorescent quenching mechanisms of 133 with Cu2+ and Hg2+ ions were explained by the reverse PET mechanism involving the anthracene group as an electron donor and the triazole group as an electron acceptor. The binding constants for 133Cu2+ and 133Hg2+ in methanol were calculated to be 4.0 105 M1 and 1.1 105 M1, respectively. An acridine derivative 134 (Fig. 82) bearing an immobilized azacrown ligand was introduced as a sensitive Hg2+ sensor by

Fig. 83 Structures of compounds 135 and 136.

Fig. 82 Structures of compounds 132134.

Yoon et al.163 Compound 134 displayed a large CHEF eect with Hg2+ among the various metal ions in 0.1 M HEPES (pH 7.4)DMSO = 95 : 5 (v/v). The association constants of 134 with Hg2+ and Cd2+ were calculated as 1.18 105 M1 and 4.48 103 M1, respectively. Cooperative binding of the immobilized ligand and the nitrogen atom on acridine may be attributed to the selectivity toward heavy metal ions. This acridine-based sensor 134 was applied for the detection of Hg2+ in mammalian cells. The Alizadeh group reported an optical sensor that was immobilized by Schis base 135 on an agarose membrane for Hg2+ determination (Fig. 83).164 The immobilization method of 2-[(2-sulfanylphenyl) ethanimidoyl]phenol on a transparent agarose lm as an optical sensor showed favorable properties such as low cost, low detection limit (1.0 106 M), simple fabrication and handling. The maximum absorbance of 135 showed a red shift after immobilization and contact with a sensing membrane to Hg2+ induced color change from yellow to green-blue. The membrane exhibited good reproducibility by soaking in EDTA solution and was successfully applied to determination of Hg2+ in amalgam alloys and spiked water samples. In addition, E. Cetinkaya et al. also reported the irreversible optical chemical sensor (optode) for Hg2+ using a plasticized PVC membrane with a long wavelength excitable uorophore, choloro phenyl imino propenyl aniline (CPIPA), 136.165 136 optode in the PVC membrane exhibited long-term photostability with excellent selectivity for Hg2+. The association constant was calculated to be 1.86 105 M1 in the formation of 1 : 1 complex with Hg2+ and the optode for the determination of Hg2+ was allowed in the working range of 1.0 109 1.0 105 M with the detection limit of 4.3 ppb. Compound 137 (Fig. 84), a squaraine containing dithiocarbamate moiety, was synthesized by Yuan and coworkers as a selective turn on uorescent chemosensor for the recognition of Hg2+.166 Jobs plot study from uorescence titration suggested the formation of 137Hg2+ complex with a 1 : 2 stoichiometry with the detection limit of 7.1 109 M as low as possible to detect Hg2+ in drinking water. The color change from a purple solution to blue was observed upon addition of Hg2+ ions in AcOH60% H2O, indicating that H-aggregates and the coordinated Hg2+ with the side dithiocarbamate arms induced steric hindrance, and nally resulted in deaggregation of H-aggregates with a 700-fold uorescence enhancement. In contrast, other metal ions (e.g., Pb2+, Cd2+, Cu2+, Zn2+, Al3+, Ni2+, Co2+, Fe3+, Ca2+, K+, Mg2+, Na+, and Ag+) did not induce these changes at all. A 3-oxo-2-{[4-(thiazol-2-ylsulfamoyl)-phenyl]-hydrazono}butyric acid ethyl ester (OSPBE) 138 (Fig. 85) was studied as a solvent assisted naked eye sensor for the detection of Hg2+ by the Upadhyay group.167 Compound 138 showed selectivity
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Fig. 86 Interaction mode of 139 with Hg2+, and structures of compounds 140 and 141.

Fig. 84 Process of sensing Hg2+ and proposed binding model of 137 with Hg2+.

Fig. 85 Structures of chelate formation between 138 and Hg2+.

toward Hg2+ with color change in some polar solvents like DMSO, DMF and acetone. UV and NMR experiment results in DMSO indicated that there was intermolecular hydrogen bonding between DMSO and compound 138, and this bonding caused switching on the intramolecular charge transfer (ICT) band at 489 nm. Addition of Hg2+ leads to the formation of six-membered chelate disturbing the hydrogen bonding, and nally the ICT band at 489 nm disappeared resulting in switching o. Verboom et al. reported a chemosensor (139) (Fig. 86), based on tris[2-(4-phenyldiazenyl)phenylaminoethoxy]cyclotriveratrylene as a chromophore, which was developed for the colorimetric and visual detection of Hg2+.168 In aqueous solutions, compound 139 exhibited the Hg2+ selectivity through a color change from yellow to red-orange which was easily detected visually and the detection limit was calculated to be 0.5 mM from the absorbance titration. Using 139 adsorbed silica, the visual detection of Hg2+ in water samples was carried out with the detection limit of 5 mM. In contrast, while binding with Zn2+ ions, 139 presented a red shifted emission with the slight enhanced emission intensity, based on the ICT mechanism. As shown in Fig. 86, compound 140, a uorogenic binary task-specic ionic liquid (IL), was specically designed by the
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Vaultier group.169 This ionic liquid 140 was prepared with an 8-hydroxyquinoline benzoate extracting/sensing unit for mercury cations, and to keep the 140Hg2+ complex in the IL phase, a very hydrophobic counteranion was selected and this detection method was based on both the transfer from a owing aqueous solution containing Hg2+ to a storage IL phase and uorescence emission. Addition of Hg(ClO4)2 into the ionic liquid (10 mM) induced a bathochromic shift resulting in a new emission band at 448 nm. The extraction of Hg2+ from aqueous solution was performed and the uorescence was observed in IL phase. Applying this method to the microsystem allowed for the real-time detection of Hg2+ in water, a high sensitivity with the detection limit of 50 ppb was achieved. Lee et al. demonstrated a ratiometric uorescent sensor 141 for Hg2+ based on dimerized Cys residues with two dansyl uorophores.170 Compound 141 showed good solubility in water, so Hg2+ detection in 100% aqueous solution via turn-on ratiometric response (I507/I583) was allowed with high sensitivity and selectivity. In the presence of other metal ions, the detection level was not interfered. The addition of EDTA to the solution sample containing the 141Hg2+ complex resulted in the original emission spectrum of 141, which indicates the reversibility of compound 141. A calix[4]arene derivative FRET chemosensor 142 based on pyrene excimer emission and rhodamine ring-opened absorption for selective detection of Hg2+ was synthesized by Kim et al.171 In the presence of Hg2+, 142 showed an enhancement of emission at B576 nm at the excitation wavelength of 343 nm, which was attributed to the ring opening of rhodamine moiety with a specic color change (Fig. 87). The intramolecular pp interaction forming the pyrene excimer exhibited a stronger FRET band and also the metal ion induced FRET from pyrene excimer emission to ring-opened rhodamine absorption was observed in the presence of Hg2+. The Bharadwaj group reported non-symmetric aza-oxa cryptand derivatives such as those bearing mono-, bis- and tris-7-nitrobenz-2-oxa-1,3-diazole (143ac) which are the electronwithdrawing uorophores, and those containing mono-, bisand tris-anthryl which are electron donating groups (143df in Fig. 88).172 In the presence of Hg2+, the large uorescent enhancements with high selectivity were observed by the electron-withdrawing ability of uorophore in CH3CN. This mechanism is based on the PET process from the donor N to the uorophore with low interaction between the metal and uorophore. The receptors with the electron-withdrawing
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Fig. 90 Structures of the uorescent sensors 146149. Fig. 87 Proposed binding mode of compound 142.

stoichiometry for 145/Hg2+ was observed with a detection limit of 2.2 108 M. Except for Cu2+ showing some quenching uorescence, 145 had good selectivity over transition metal ions. Polymer based chemosensors Leray et al. previously reported 146a based on a phosphane sulde derivative as a Hg2+ sensor. In the next paper published in 2009, they detailed the synthesis of compounds 146b148 (Fig. 90) and the inuence of steric hindrance was also investigated with respect to the length and the number of phenylethynyl arms.175 Chemosensors 146a, 147a and 147b exhibited remarkable selectivity and sensitivity for Hg2+ with a low detection limit; 3.8 nM for 146a, 23.9 nM for 147a and 8.9 nM for 147b in CH3CN/H2O = 8 : 2 at pH 4.0. Upon addition of Hg2+, strong uorescence quenching and the bathochromic shift in absorption spectra were observed in compounds 147a and 147b due to the electron-withdrawing properties of the phosphane sulde and oxide groups. Compound 146a was more exible but less eective in mercury complexation than compound 146b. Due to steric hinderance, the stoichiometries were dierent for dierent compounds. A complex of oligo(N1,N1,N1,N4,N4,N4-hexamethyl-2-(4(pyren-1-yl)butanoyloxy)butane-1,4-diaminium bromide) 149 and poly(dT), based on electrostatic and hydrophobic interactions, was prepared as a uorescent probe for the detection of Hg2+ in aqueous media by Shi et al.176 Addition of Hg2+ to the sample solution of 149 and oligothymine resulted in the formation of thymineHgthymine complex, which induced chain aggregation and uorescence quenching in the probe complex. The detection limit of this label-free system was measured to be as low as 5 109 M. Furthermore, the uorescent change can be observed by the naked eye in the presence of 5 106 M of Hg2+. b-Cyclodextrin based chemosensors Wu et al. designed a b-cyclodextrin (b-CD) based ratiometric sensor for Hg2+ detection in aqueous media, some biological uids, and live cells.177 As shown in Fig. 91, a thiocarbamido containing probe (acceptor) was linked onto the hydrophilic b-CD rim and the donor dye linked to the inside of the hydrophobic b-CD cavity, so the distance between the acceptor and donor was eective for Fo rster energy transfer. The b-CD accommodated to form the FRET system upon addition of Hg2+ as well as to increase the sensor water-solubility and
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Fig. 88 Chemical structures of 143af.

uorophores (143ac) exhibited higher uorescence increase with Hg2+ than the derivatives bearing electron-donating uorophores (143df). Porphyrin based chemosensors In 2009, Yu et al. reported two Hg2+ uorescent sensors based on porphyrin (Fig. 89). Compound 144 was utilized as an optical sensor for Hg2+ using the uorescent quenching system on a poly(vinyl chloride) (PVC) membrane coated with compound 144.173 The tetra(p-dimethylaminophenyl)porphyrin 144 showed decreased uorescence intensity in the presence of Hg2+ with reasonable reproducibility, reversibility and selectivity. The detection limit of 144 was 8.0 109 M1. Another porphyrin based ratiometric chemosensor 145 bearing a quinoline moiety was developed for uorescent recognition of Hg2+.174 Quinolin-8-ol p-[100 ,150 ,200 -triphenyl-50 -porphyrinyl]benzoate 145, which was complexed with Hg2+, exhibited the uorescent quenching eect at 646 nm and new uorescent enhancement at 603 nm caused by the binding of Hg2+ with the quinoline moiety in ethanol/water = 2 : 1 (v/v). The 1 : 1

Fig. 89 Structures of compounds 144 and 145.

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Fig. 91 Scheme of sensing system of 150 and structure of compound 151.

Fig. 92 (a) Structure of 152 and (b), (c) strategy for selective Hg2+ detection.

cell membrane permeability. With the increasing amount of Hg2+ added to compound 150 in pH 7.0 HEPES induced the enhancement of uorescent intensity at 586 nm and resulted in the red uorescence turn-on by the FRET based system with the detection limit of 10 nM and the turn-o uorescence at 518 nm. This sensor did not cause cytotoxicity or aect cell proliferation. A quinolinocyclodextrin, N-(2-methyl-8-amino-quinolyl)-paminobenzene sulfonamide) complexed with Zn2+ with 2 : 1 stoichiometric 151 was synthesized for Hg2+ uorescent sensing in aqueous solutions and thin lms by Lius group.178 The probe 151 indicated a unique uorescent response toward Hg2+ without any interference of other metal cations. Moreover, in water, 151 exhibited good sensing ability than in organic thin lm under the UV light. DNA functionalized chemosensors Deng and Zhou et al. reported a cationic water-soluble triazatetrabenzcorrole 152 for mercury detection by nucleic acidinduced aggregation (Fig. 92).179 152 was aggregated by single stranded nucleic acid via electrostatic binding, which resulted in uorescent quenching. In their previous report, the phosphorothioate DNA T4G4-S3(5 0 -TPSTPSTPSTGGGG-3 0 ) was designed and this sequence was able to form a G-quadruplex stabilized by SHgS pairs. The G-quadruplex did not cause the aggregation of 152 and hence strong uorescence was observed. Using this system, Hg2+ could be selectively detected with convenient, inexpensive, and label-free methods in aqueous solutions. Liu et al. developed a thymine rich DNA-functionalized polyacrylamide hydrogel-based sensor for ultrasensitive Hg2+ detection and the removal of mercury from water.180 Hg2+ between two thymine bases (Fig. 93(f)) formed a hairpin structure and then addition of SYBR dye 153 (Fig. 93(e)) showed green uorescence with the hairpin structure including Hg2+ (Fig. 93(a)). However, yellow uorescence was observed without Hg2+ in the presence of a thymine-rich DNA sequence (Fig. 93(h)). This DNA was immobilized within the polyacrylamide hydrogel, so the uorescence change caused by Hg2+ could be observed by
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the naked eye with the detection limit of 10 nM in 50 mL water. The hydrogel-based sensor was not only resistant to nuclease but also regenerative by acid treatment after Hg2+ exposure. Later, the same group reported an electrostatically directed optical sensor based on the previous study by replacing the gel backbone charge with polyacrylamide (neutral) (Fig. 93(g)), allylamine (positive), and 2-acrylamido-2-methyl1-propanesulfonic acid (AMPS, negative) (Fig. 93(b)(d)).181 Because of the repulsion between positively charged SYBR dye 153 and gel matrix containing allylamine, there was strong binding between NA and the gel backbone, which resulted in the signicantly reduced background uorescence and the improved detection limit by 9-fold (Fig. 93(i)).

Fig. 93 (a) DNA sequence of uorescent signal generation for Hg2+ detection. The molecular structures of (b) acrylamide, (c) allylamine, (d) AMPS, and (e) 153. Schemes of Hg2+ binding with (f) thymine base pairs, (g) polyacrylamide in hydrogel, and (h), (i) covalent DNA immobilization within hydrogels.

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Fig. 96 (a) The structure of [THg(II)T]. (b) The rationale of the prototype (F: uorescein; hnAbs: uorophore was excited at absorption wavelength; hnFlu: uorescence emission; PCT: photoinduced charge transfer).

Fig. 94 Schematic illustration of the sensing mechanism of the probing complex for the detection of Hg2+ and GSH.

Tang et al. developed a sensitive and selective Hg2+ and glutathione sensor based on the Hg2+DNA complex stimulating aggregation-induced emission (AIE) of tetraphenylethene derivative 154 (Fig. 94).182 Using electrostatic interaction between the ammonium cation of aptamer ssDNA at the AIE probe and the anionic phosphate backbone of DNA, a quaternized tetraphenylethene salt and an anti-Hg2+ aptamer ssDNA containing thymine rich sequence resulted in the aggregation of AIE probe and exhibited strong uorescence in the presence of Hg2+ by the conformational change of aptamer ssDNA. Furthermore, the addition of thiol containing molecules like GSH into the Hg2+AIE probe complex solution had decreased uorescence due to the destroyed structure. The probing method, based on the combination of the structural variations of aptamer, by binding to a specic target and AIE system represented rapid, simple, and easy detection. Shangguan et al. described a highly selective phthalocyaninethymine conjugate sensor, tetra-(thymin-1-yl-acetamido)-phthalocyanine Zn2+ 155 (Fig. 95(a)), for Hg2+ detection based on the target induced aggregation.183 Addition of Hg2+ ions to compound 155 solution in DMF/water = 7 : 3 (v/v) exhibited a split of Q-band (at 685 nm) and strong uorescence emission. In the presence of Hg2+, the formation of THgT complex induced aggregation of compound 155 which resulted in quenching of uorescence emission and decrease of the absorption Q-band (Fig. 95(b)). The Chen group also developed a highly selective uorescent sensor for Hg2+ using specic THgT binding interaction with the detection limit of 20 nM.184 A uorescein labelled

oligodeoxyribonucleotide poly(dT) formed a sandwich structure upon addition of Hg2+ and facilitated electron transfer via photo-induced charge transfer (PCT) resulting in uorescence quenching. In this turn-o sensor, p-stacked THg(II)T functioned not only as a Hg2+ recognition element but also as an electron acceptor to quench the donor, uorescein (Fig. 96). Xing et al. exploited a label free Hg2+ detection assay by polymerase assisted uorescence amplication with a high specicity and an enhanced sensitivity.185 As shown in Fig. 97, the single strand template containing a Hg2+ recognition sequence (MRS) was composed of thymine rich functional areas separated by a spacer of random bases. Addition of Hg2+ induced the complexation of MRS with Hg2+, and then a formed hairpin structure initiated the replication of the template probe in the presence of polymerase and dNTPs. The long duplex DNA, which is the replication product, was stained with SYBR Green I and a distinguishable uorescent enhancement was observed. Because of the amplication step and TT base pair in the template, this system could obtain a high sensitivity (40 pM) and eciency. Fig. 98 shows the chip-based scanometric detection of Hg2+ using DNA-functionalized gold nanoparticles developed by Mirkin and Lee.186 This assay utilized the chip based method for Hg(II) by using probes which can be hybridized with the immobilized oligonucleotides to form a duplex with THgT binding, and the duplex structure raised the temperature associated with dehybridization. The signal from amplication event of silver reduction, in the presence of hydroquinone, exhibited scattered light from the silver spot measured as the amount of an oligonucleotide binding selectively with Hg2+. The detection limit of this assay was 10 nM (2 ppb) for Hg2+ in 10 mM MOPS buer (pH 7.5) and natural media, which is the allowable level of Hg2+ in drinking water by EPA

Fig. 95 (a) Structure of 155 and (b) schematic representation of the aggregation of 155 induced by Hg2+.

Fig. 97 Schematic description of the polymerase-based uorescence amplication strategy for Hg2+ ions detection.

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Fig. 100 Structures of nanoparticles 156158.

Fig. 98 Depiction of the chip-based scanometric detection of Hg2+ using DNA-Au NPs.

regulation. Also, this result can be observed at the Hg2+ concentration higher than 600 nM with the naked eye, and is therefore possible to quantify and to detect with a simple light scattering device at a low Hg2+ concentration. The Kim group developed a sensitive polydiacetyleneliposome microarray for Hg2+ recognition.187 In the PCDAEpoxy/PCDA (4 : 1) liposome, epoxy units were used as the linkers to attach liposome onto the glass substrate and in posttethering of the thymine rich single stranded DNA aptamer (5 0 -TTCTTTCTTCCCCTTGTTT GTT-3 0 ) that formed a THgT complex. When the aptamer recognized Hg2+ and wrapped around Hg2+ by interacting with thymine, the steric repulsion perturbed the conjugated ene-yne backbone of PDA liposomes, causing the color change from blue to red that led to the red uorescence emission (Fig. 99). The detection limit of the PDA microarray was 5 mM (0.027 mg per 20 mL). Nanoparticle based sensing systems Jung et al. introduced nanoparticle based uorimetric and colorimetric sensors as shown in Fig. 100. Two azobenzenecoupled receptors were prepared by immobilization onto titanium oxide nanoparticles (156) and mesoporous silica (SBA-15) (157).188 Upon addition of Hg2+ in suspension, 156 changed its

color from yellow to deep red without any interference of metal ions and anions such as NO3, ClO4, Br, and I. The portable chemosensor lm coated with 156 was employed for the recognition of Hg2+ at pH 7.4 with a sensitivity of 28 nM. The absorbance and color change were almost reliable in the pH range 411 and the lm exhibited the same color change as 157. The hybridization between the inorganic support material and organic ligand takes the advantages of solubility and application, and therefore these heterogenous sensors are very useful. Sensor 158 was developed based on porphyrin functionalized Au@SiO2 core/shell nanoparticles that are suitable for the attachment of organic functional molecules, and has advantages such as high surface area and low in vivo toxicity.189 This sensor 158 exhibited decreased uorescence, color change from red to green in the presence of Hg2+, and also the reversible recognition upon addition of EDTA. The uorescence change showed a linear plot in the range 520 ppb of Hg2+ and the detection limit was 1.2 ppb in the aqueous solution of pH 7.4. A new uorescent surface sensor for Hg2+ was designed and prepared via the reaction of alkyne-functionalized naphthalimide derivative 159 with SBA-N3 to form a conjugated trizole linkage by the Zhang group (Fig. 101).190 The aminomethyl pyridine moiety of compound 159 could serve as the Hg2+ receptor, quench the PET process, and hence increase the uorescence of Hg2+. This was observed with a detection limit of 2.0 108 M for Hg2+, which was much improved in sensitivity and selectivity than the uoroionophore 159 alone in the solution phase. The eect of pH in the new surface sensor was also investigated and the result suggested that acidity did not aect the uorescent intensity of 159 onto SBA-15 in ethanol/water (1 : 1, v/v) solution. In addition, the stoichiometry was estimated to be 1 : 1 from the Jobs plot study. The SBA-15159 based surface sensor could therefore be applied to determine the Hg2+ level in tap and river water successfully.

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Fig. 99 (A) Chemical structure of the diacetylene monomers, PCDA and PCDA-Epoxy. (B) Schematic illustration of the PDA liposomebased microarray for mercury detection. (a) Surface modication of the glass substrate with amine functionality. (b) Immobilization of the epoxy liposomes onto the amine glass slide through epoxy-amine coupling. (c) Post-tethering of the ssDNA aptamer by means of a microarrayer. (d) Photopolymerization of the PDA liposomes using a 254 nm UV lamp. (e) Recognition of the target Hg2+ results in red uorescent emission.

Fig. 101 (a) Covalent grafting of a uoroionophore into the mesoporous SBA-15 silica by a two-step surface reaction involved click strategy to construct a uorescent surface sensor with a PET response mechanism and (b) chemical structure of compound 159.

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Fig. 104 Sensing mechanism of Hg2+. Fig. 102 Hybrid mesoporous material functionalized by 160.

Duan et al. also reported a hybrid mesoporous chemosensor for Hg2+, which was prepared by synthesizing 1,8-naphthalimide derivative 160 and immobilizing it onto the surface of mesoporous silica (SBA-15, Fig. 102).191 From the elemental analysis, X-ray powder diractometer (XRD) and spectroscopic methods, it was shown that compound 160 was successfully grafted onto the inner surface of SBA-15. The SBA-160 could detect Hg2+ with high selectivity and even catch absorbed Hg2+ in natural aqueous solution. In addition, the solid uorescent chemosensor was reversible for Hg2+ with the treatment of EDTA and base. El-Safty developed a highly sensitive organicinorganic hybrid mesoporous monoliths sensor for the simple and naked-eye detection and removal of Hg2+ from aqueous samples.192 The solid sensor was prepared by modication of disc-like monoliths with N-trimethoxysilylpropyl-N,N,N-trimethylammonium chloride (TMAC) and then by immobilizing the tetraphenylporphine tetrasulfonic acid (TPPS) probe for visual detection and facile signal handling (Fig. 103). During the recognition of Hg2+, a bathochromic shift from 410 to 450 nm was observed under the following sensing conditions of pH 9, 0.05 cm, and 25 1C. Addition of ClO4 anions induced decomplexation of the solid sensor and Hg2+, and the gradual color change from green to pale brown was observed with the naked eye. It was demonstrated that the disc-like sensor provided the reusability and regeneration/reuse cycle. Alginate stabilized silver nanocubes (alginate-Ag NCbs) were synthesized by reducing silver nitrate (AgNO3) in water and applied for sensing mercury using rhodamine 6G(Rh6G) by Tharmaraj and Pitchumani.193 As shown in Fig. 104, the Rh6G dye was bound to the Ag NCbs surface. After addition of Hg2+, there was a displacement of the bound Rh6G and the free Rh6G exhibited the emission and absorbance spectrum. In addition, only Hg2+ induced the color change from yellow to pink in aqueous solutions and the recognition of Hg2+ was as low as 1 1010 M.

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In 2011, Wu and Zeng et al. reported two FRET-based ratiometric detection systems for Hg2+ in water by using polymeric nanoparticles.194 The polymeric nanoparticle was prepared via miniemulsion polymerization to embed a hydrophobic dye NBD into the particle core as the FRET donor (Fig. 105(a)). For mercury detection, the rhodamine derivative 161 was linked covalently to the particle surface, and Hg2+ caused the spirolactam ring-opening of the rhodamine moiety. When it was excited at 420 nm by blue light irradiation, the donor NBD in the particle core transferred the excited energy to the ring-opened rhodamine derivative on the particle surface and then the emission was observed at 593 nm. This nanoparticle sensor could selectively detect Hg2+ in water with the detection limit of 100 nM (ca. 20 ppb) and was applicable in the pH range 48. In addition, the FRET-based system eciency in the point of energy transfer and ratiometric accuracy was higher with smaller particles. Based on the similar strategy, recognition of Hg2+ in water was studied with micelle nanoparticles composed of the poly(ethylene oxide)-b-polystyrene diblock copolymer.195 The nanoparticle incorporated with a more hydrophobic uorescein derivative (FLS-C12) than NBD, and the rhodamine derivative (RhB-CS) 162 as a probe for mercury was located at the micelle core interface (Fig. 105(b)). Upon addition of Hg2+, the ring opening of RhB-CS which acted as the energy acceptor generated the long wavelength emission at 588 nm. This micelle based nanoparticle sensor showed an improved detection limit (0.1 mM)

Fig. 103 Disk-like sensor for Hg2+ ion-sensing assay.

Fig. 105 Illustration for the FRET-based ratiometric detection of Hg2+ with the nanoparticle. (a) MMA-AA polymeric nanoparticle was used and the donor was nitrobenzoxadiazolyl derivative (NBD); (b) micelle nanoparticle composed of the poly(ethylene oxide)-b-polystyrene diblock copolymer was the core containing poly(ethylene oxide) and uorescein derivative FLS-C12 served as the energy transfer donor.

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analytes and modulators of the squaraine response allowing pattern-based discrimination. Hg2+, Pd2+, Cu2+, Fe2+, and Ni2+ were discriminated when combining 163 with ve thiols, such as propane thiol (PT), 3-mercaptopropionic acid (MPA), naphthalene-2-thiol (NT), 2,3-dimercaptopropanol (DMP), and 2-acetylamino-3-mercaptopropionic acid methyl ester (ACM). In this array analysis, squaraine, a single receptor, analyzes two dierent sets of analytes which are ve thiols and ve metal ions, and the array format generates patterns in a PC plot based on the uorescence data. Especially, Hg2+ was the only metal ion able to eect the discrimination of NT from PT and MPA, thus giving the best discrimination overall.
Fig. 106 Schematic diagrams of the proposed mechanism of detecting Hg2+ by IFP; (i) IFP added with BV (molar ratio: 1 : 2); (ii) IFP added with Hg2+ (molar ratio: 1 : 1); (iii) IFP added with a mixture of Hg2+ and BV (molar ratio: 1 : 1 : 2).

Concluding remarks
In this review, we covered the development and application of exciting uorescent and colorimetric sensors for Pb2+, Cd2+, and Hg2+ detection. The uorescent and colorimetric sensors were classied into several dierent categories according to their receptors, such as small molecule based sensors, calixarene based chemosensors, BODIPY based chemosensors, polymer based chemosensors, DNA functionalized sensing systems and nanoparticle based sensing systems. Most of the intelligently designed receptors fulll the required WHOs detection limit of 10 mg L1 for Pb2+, 3 mg L1 for Cd2+, and 1 mg L1 for Hg2+, and thus a few uorescent sensors were successfully applied to track the changes within living cells. DNA functionalized sensing systems are unique approaches for colorimetric and uorescent sensors along with clever utilizations of surface modied nanoparticles. We believe this research area will become more active due to the biological and environmental signicance of Pb2+, Cd2+, and Hg2+, and further investigations will continue to increase.

and could be applicable in biological uids such as human urine and fetal bovine serum because of the biocompatible poly(ethylene oxide) (PEO) as the corona of the micelle, which helped to penetrate cell membranes and then to detect intracellular Hg2+. Protein based sensing systems Gu and Tang et al. described a new strategy for the detection of Hg2+ with the combination of infrared uorescent protein (IFP) and cofactor biliverdin (BV) as the chromophore (Fig. 106).196 The IFP has a specic binding anity of a cysteine residue for Hg2+, which inhibits the conjugation of IFP chromophore biliverdin (BV), resulting in turning o the infrared emission of IFP. This IFP/BV sensor showed a favorable selectivity and sensitivity to Hg2+ in the broad pH range and the detection limit was determined as sub-50 nM in vitro. Also, a protein hydrogel based paper assay by immobilizing IFP onto the lter paper strip was developed for the detection of Hg2+ in a portable and robust fashion. Pattern based sensing systems Recently, Hewagw and Anslyn reported a pattern-based recognition strategy using a single squaraine/thiol complex depending on dierent responses by dierent metal ions and thiols.197 As shown in Fig. 107, the metal ions and thiols act as both

Acknowledgements
JY acknowledges National Research Foundation (NRF) grant (2011-0001334, 2011-0020450) and WCU (R31-2008-000-10010-0) and JSK acknowledges the CRI project (2011-0000420).

Notes and references


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