8462 Chem. Commun., 2012, 48, 8462–8477 This journal is c The Royal Society of Chemistry 2012

Cite this: Chem. Commun., 2012, 48, 8462–8477

An indirect approach for anion detection: the displacement strategy and

its application

Xiaoding Lou,w Daxin Ou,w Qianqian Li and Zhen Li*

Received 26th January 2012, Accepted 14th June 2012

DOI: 10.1039/c2cc33158f

The development of new optical anion chemosensors with high sensitivity and selectivity is very

important, since anions possess some fundamental roles in a wide range of biological and

chemical processes. The displacement approach is a method using anion binding sites and

signaling subunits, which are not covalently attached but forming a coordination complex, in

which the presence of anions revives the noncoordinated spectroscopic behavior of the indicator.

In the past five years, according to the displacement strategy, many good optical anion

chemosensors have been successfully obtained. This paper reviews the recent progress in the field

of the fluorescent and colorimetric anion chemosensors designed according to the displacement

strategy (mainly from 2008 to 2011), and gives some outlooks for the further exploration of new

optical anion chemosensors.

Introduction

Nowadays, accompanying social development, people are

paying increasing attention to the living environment and

human health. As a result, it is imperative to obtain information

of analytes in some special samples to aid subsequent treatment.

Thus, chemosensors are useful tools for sensing various

analytes.1 Among all the important analytes, anions possess

some fundamental roles in a wide range of biological and

chemical processes, such as the transport of hormones, proteins

biosynthesis, DNA regulation, and the activity of enzymes.2

As typical examples, cyanide, sulfide, PPi and halogen ions have

attracted special interest in the research field of chemosensors.3–8

As is well known, cyanide is one of the most rapidly acting and

powerful poisons (for humans, 0.5–3.5 mg per kg of body

weight is lethal), with its toxicity derived from its propensity of

binding to the iron in cytochrome co-oxidase, interfering with

electron transport and resulting in hypoxia;3 while continuous

and high concentration exposure to sulfide would lead to

various physiological and biochemical problems.4 Also, because

PPi is the product of ATP hydrolysis under cellular conditions,

it is a biologically important target.5 In the case of iodide

anion, due to its biological activities (mental development,

growth, and basic metabolism), iodine deficiency can cause

serious diseases, however, increasing amounts of iodine and

its derivatives, will be harmful, for its hazardous radio-

active isotopes.6–8 Unfortunately, due to human activities,

Department of Chemistry and Hubei Key Lab on Organic andPolymeric Opto-Electronic Materials, Wuhan University,Wuhan 430072, China. E-mail: lizhen@whu.edu.cn,lichemlab@63.com; Fax: 86-27-68755363

Xiaoding Lou

Xiaoding Lou is a graduatestudent at Hubei KeyLaboratory on Organic andPolymeric Opto-ElectronicMaterials, Department ofChemistry, Wuhan University.She is currently pursuing herdoctor’s degree under thesupervision of Prof. Li.

Daxin Ou

Daxin Ou is a graduate studentat Hubei Key Laboratoryon Organic and PolymericOpto-Electronic Materials,Department of Chemistry,Wuhan University. She iscurrently pursuing her master’sdegree under the supervision ofProf. Li.

w Contributed equally to this paper.

ChemComm Dynamic Article Links

www.rsc.org/chemcomm FEATURE ARTICLE

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This journal is c The Royal Society of Chemistry 2012 Chem. Commun., 2012, 48, 8462–8477 8463

different anions, not limited to the ones mentioned above,

have been released into the biosphere and thus affected our

daily life. Thus, in recent years, chemists have devoted signi-

ficant efforts towards the design and synthesis of receptors and

chemosensors capable of binding and sensing anions, both

qualitatively and quantitatively.9

In all the reported anion chemosensors, the optical ones

(including fluorescent and colorimetric anion chemosensors),

especially fluorescent sensors, demonstrate many advantages,

such as easy and visual detection, high sensitivity, low back-

ground interference, convenient applications in bio-images.

Thus, optical chemosensors have attracted increasing interest.

Generally, there are three main approaches to design of

chemosensors or receptors for anions in the development of

optical signaling systems.10 Taking fluorescent chemosensors

as an example (Fig. 1), the first approach involves the use

of specific chemical reactions upon binding with anions,

i.e. chemodosimeters. The second one requires the covalent

introduction of binding sites and signaling subunits to the

chemosensors.1a,11 The third one uses a coordination complex

(displacement approach), in which the presence of anions

revives the noncoordinated spectroscopic behavior of the

indicator.12 In the second and third approaches, the change

of optical signaling is reversible, in principle, while in the

chemodosimeter approach, the objective should be specific

reactivity, since the goal in both the binding site and signaling

unit and displacement protocols is selective coordination.

By using any of these three approaches, a number of optical

sensors and reagents for anions have been reported.1a,9b,10,13,14

Unlike the first and second approaches, the displacement

approach is a method using anion binding sites and signaling

subunits, which are not covalently attached but forming a

coordination complex (one part of the host-indicator assem-

blies that are used in indicator displacement).12 An indicator is

displaced from the binding site upon the addition of anions,

resulting in a change from a coordinated to noncoordinated

state. If the spectroscopic characteristics of the signaling

subunit in the coordination complex are different from those

of the noncoordinated state, then the anion binding process is

coupled to a signal modulation. As it can be inferred, the

stability constant of the formed complex between the binding

site and the anions should be higher than that between the

binding site and the signaling subunits. There are many

advantages of the displacement approach. On the one hand,

it does not need to incorporate the indicator into the structures

of receptors or analytes, while on the other hand, the indicators

are exchangeable. Also, the detection mechanism of this method

is indepedent of the analyte structure.15a Considering that many

anions could form stable complexes with cations, scientists,

including us, were wondering if it was possible to probe anions

by utilizing good cation chemosensors. That is to say, the

anions might snatch cations from the formed complex of the

cations and their corresponding chemosensors, with a detect-

able optical signal. If the stability constant of the complex

formed by the anion and the cation is larger than that of the

complex of the cation and its chemosensor, the displacement

reaction will take place, hence, the signaling event indication of

the presence of the target anion will be observed.

In recent years, according to the simple displacement strategy

(Fig. 1c), many good anion chemosensors, derived from the

Fig. 1 The three main approaches for sensing anions: (a) chemo-

dosimeter; (b) chemosensor bearing a signaling subunit as well as a

binding site; (c) displacement approach.

Qianqian Li

Qianqian Li received her BScdegree from Hubei Universityin China in 2004, and thenobtained her PhD degree forWuhan University in 2009,under the supervision of Prof.Zhen Li. She is now a facultymember at Wuhan University,and her research interests arein the design and synthesisof new electric and opticalfunctional materials.

Zhen Li

Zhen Li received his BSc andPhD degrees from WuhanUniversity (WHU) in Chinain 1997 and 2002, respectively,under the supervision of Prof.Jingui Qin. In 2003–2004,he worked in the HongkongUniversity of Science andTechnology as ResearchAssociate in the group of Prof.Ben Zhong Tang. In 2010, heworked in Georgia Institute ofTechnology in the group ofProf. Seth Marder. He is afull professor at WHU from2006, and his research interests

are in the development of organic molecules and polymers with newstructure and new functions for organic electronics and photonics.

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8464 Chem. Commun., 2012, 48, 8462–8477 This journal is c The Royal Society of Chemistry 2012

corresponding cation ones, were successfully obtained as

probes of different anions, even in real samples from the

environment and cell images, with high sensitivity and selectivity.

The chance of the successful design of the anion chemosensor

by using the displacement strategy is much higher than those

following the first and second approaches.15b,c As is well

known, the key factors of the chemosensors are sensitivity

and selectivity. For the displacement strategy, the sensing

properties towards anions are mainly determined by the used

cation chemosensors. The selectivity can be achieved by

choosing an indicator (cation) binding site, which should

possess a larger stability constant with the cation rather than

other potential interfering anions. However, the stability con-

stant should be a little smaller than that between the cation

and the target anion.12a In order to achieve high sensitivity of

the anion chemosensors, the corresponding cation sensors

should have very high sensitivity. The higher the sensitivity

of the cation chemosensors, the better are the anion ones. That

is. the lower the amount of cations required to induce the

optical signal, the lower the amount of anions needed to

snatch the cations out from the chemosensor–cation complex,

for the recovery of the optical response. So far, the displace-

ment strategy has become more important for the further

development of new anion chemosensors with good perfor-

mance. Here, partially based on our recent systematic research

of chemosensors for cyanide and sulfide, this review mainly

focuses on recent advances in the design of fluorescent and

colorimetric anion chemosensors according to the displace-

ment strategy.

Chemosensors for cyanide ions

Cyanide is frequently used in many chemical processes, such as

electroplating, plastics manufacturing, gold and silver extrac-

tion, tanning and metallurgy.16 However, cyanide is toxic and

extremely harmful for humans and almost all other forms of

life, depending strongly on the form of exposure, absorption

and distribution. For humans, 0.5–3.5 mg per kg of body

weight is lethal.17 Thus, the exploration of new cyanide sensors

is always underway to obtain good ones with high sensitivity

and excellent selectivity. Since cyanide is a strong nucleophilic

reagent, many traditional cyanide probes have been reported

utilizing its nucleophilicity. Recently, the displacement

approach which utilizes affinity of cyanide towards certain

metal ions such as copper, cobalt and zinc, has attracted the

attention of many groups.

Cu complexes

Most of the reported systems involve the formation of an

ensemble between copper ion and polymer or molecule. The

addition of a target anion, for which the copper ion has a high

affinity, results in a displacement of the polymer or molecule.

Importantly, cyanide can react with copper ions to form very

stable [Cu(CN)x]n� species, thus, it is reasonable to design new

cyanide chemosensors by utilizing the affinity of this anion for

copper ions.

The first example in this section was reported in early 2008,

concerning the formation of the 1-Cu2+ complex (Scheme 1).

This represented a highly selective assay method to detect

cyanide using light-emitting imidazole-functionalized disubsti-

tuted polyacetylene 1 by Li et al.18 PA 1 could form a complex

with copper ion with imidazole groups as receptors, as a result,

the strong fluorescence of 1 was efficiently quenched by copper

ions (with a detection limit of 1.48 ppm) via an electron

transfer process selectively. Upon the addition of cyanide,

the copper ions were snatched from the 1-Cu2+ complex to

liberate free PA 1, and the fluorescence of 1 was recovered.

Therefore, the presence of cyanide induced an ‘‘off–on’’ type

change with an excitation wavelength of 335 nm, thus, the

sensing behavior of 1 toward copper ions, then to cyanide,

formed a reversible cycle. The 1-Cu2+ complex exhibited high

sensitivity of 1.82 ppm for cyanide, while other anions showed

nearly no disturbance to the selective sensing of CN�, except a

little influence from HPO42� and PO4

3�.

As mentioned in the introduction, the sensitivity of the

anion chemosensors is mainly determined by the corre-

sponding cation. Thus, to improve the sensitivity for cyanide,

it is needed to raise the sensitivity of the chemosensors towards

copper ions. With this aim, Li and co-workers also employed

the same strategy in the design of a new imidazole-fuctionalized

polyfluorene 2 (Scheme 2), since polyfluorenes generally

possess very high fluorescent quantum yields.19 As expected,

a selective fluorescent quenching effect was observed after the

addition of Cu2+ (3.2 � 10�6 mol L�1, ca. 0.2 ppm) among

various metal ions, with Ksv calculated to be 2.1 � 106 M�1.

The completely quenched fluorescence of 2 by Cu2+ was

turned on upon the addition of CN�, at very low concen-

tration (4.0 � 10�6 mol L�1). Since the lethal cyanide concen-

tration in the blood of fire victims is ca. 20 mM, 2 might be

utilized as sensitive chemosensor to probe trace CN� in

practical applications. In comparison with that of 1 (1.82 ppm),

2 exhibited a better detection limit of 0.31 ppm. The reason-

able big difference should be derived from the different detec-

tion limit of 1 (1.48 ppm) and 2 (0.2 ppm) toward copper ions.

In the detection process for CN�, Cu2+ ions were first added

to the diluted solution of the luminescent polymer to quench

its fluorescence completely due to the high affinity of imidazole

moieties toward the Cu2+ ions, then some CN� anions were

introduced to snatch the Cu2+ ions from imidazole moieties to

interrupt its interaction with the Cu2+ ions and hamper the

energy transfer from the conjugated polymer backbone to

the Cu2+ ions, leading to the quenched fluorescence of

Scheme 1 Proposed mechanism of 1 towards cyanide.

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the polymer being turned on. Although the exact ratio between

the Cu2+ ions and CN� anions is unknown in the stable

complex of [Cu(CN)x]n� species, more CN� anions were

needed if a larger amount of Cu2+ ions was required for the

complete quenching of the fluorescence of the polymer. For

example, 1.48 ppm of the Cu2+ ions was used to quench the

fluorescence of 1, then the detection limit of CN� anions was

detected to be 1.82 ppm (70 mM); however, correspondingly,

the detection limit of CN� anions was found to be as low as

0.31 ppm (12 mM), while only 0.20 ppm of the Cu2+ ions were

needed to quench the fluorescence of 2 completely. Thus, if we

further improve the sensitivity of the chemosensors toward

CN� anions, we should develop new Cu2+ ion sensors with

even higher sensitivity. Also, we might claim that high sensi-

tive metal ion sensors (not only for Cu2+ ions) should be

developed to obtain better anion chemosensors (not only for

CN� anions). Furthermore, in 2010, Li et al. utilized a

copolymer of fluorene and triphenylamine bearing imidazole

groups as a turn-on fluorescent sensor for cyanide.20 This

sensor can detect cyanide at concentration as low as 0.47 ppm

by utilizing the strong affinity of cyanide towards copper ions.

Inspired by the pioneering work of Li et al., many other

good cyanide chemosensors were designed. The following

displacement example, reported by Yoon, Park and co-workers,

was based on the use of receptor 3, which, at pH 7.4 in 100%

aqueous system, showed an intense emission band at 522 nm.21

When 1 equivalent of Cu2+ was added, a nearly complete

fluorescent quenching was observed due to the formation of a

non-emissive 1 : 1 complex between Cu2+ and 3. The sub-

sequent addition of cyanide induced the ‘‘off–on’’ type fluores-

cence enhancement (Scheme 3). Other anions, such as CN�,

SCN�, AcO�, F�, Cl�, Br�, I�, H2PO4�, HSO4

�, NO3� and

ClO4�, gave essentially no interference at pH 7.4 (0.02 M pH

7.4 HEPES). Furthermore, this sensing system has been

successfully applied to a microfluidic platform: the fluorescent

sensor of 3-Cu2+ displayed green fluorescence enhancement,

which was assigned to a displacement of the Cu2+ ion and

formation of the corresponding Cu(CN)2, upon the addition

of cyanide. Also, studies of biological applications using

Caenorhabditis elegans demonstrated that this system could

be employed for the in vivo imaging of cyanide.

For the application in bioimaging, Yoon, Park and

co-workers devised a new near-infrared NIR fluorescent sensor

containing an amine-substituted heptamethine cyanine dye

and a copper complex moiety, which selectively sensed cyanide

in aqueous solution (Scheme 4).22 The emission at 748 nm was

completely quenched when 1 equiv. of copper ions was added

to 4, at the concentration of 5 mM. When CN� was added

gradually to a solution of 4-Cu2+, the peak intensity at 748 nm

apparently increased when the minimum cyanide concen-

tration was 50 mM, making the 4-Cu2+ complex a ‘‘turn-on’’

type sensor of cyanide. Owing to the high sensitivity of 4

toward copper ions, its detection limit for cyanide was as good

as 0.13 ppm. Various anions, such as F�, Cl�, Br�, I�, NO3�,

HSO4�, HCO3

�, CH3COO�, Pi (phosphate), PPi (pyro-

phosphate), SCN� and ClO4�, did not respond to the probe.

Scheme 3 Schematic illustration of ‘‘turn-on’’ fluorescence sensing mechanism of 3 for cyanide.

Scheme 2 Proposed mechanism of 2 towards cyanide.

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Excitingly, 4 was also successfully applied for the imaging of

anthropogenic and biogenic cyanide.

It was easy to expect that according to the displacement

strategy, there should be some examples dealing with the use

of the Cu2+ complex for the colorimetric detection of cyanide.

Also in 2008, applying the displacement strategy, Li et al.23

successfully reported the first example of a colorimetric

cyanide sensor by using a 50 year old, inexpensive, and

commercial available compound, zincon (2-carboxy-20-hydroxy-

50-sulfoformazylbenzene, 5, Scheme 5), which can probe

copper ions with high sensitivity and selectivity. When the

concentration of Cu2+ ions increased, the peak intensity of the

absorption maximum wavelength of 463 nm decreased with

the concurrent formation of a new peak at ca. 600 nm. In

the presence of cyanide, the demetalation of the complex

could be followed by a blue shift of the absorption maximum

(Dlmax = 137 nm) and a color change from blue to yellow.

Following this approach, cyanide could be detected by the

naked-eye in pure water with a detection limit as low as

0.13 ppm. Other anions, including Cl�, I�, IO3�, SO4

2�,

NO2�, Br�, H2PO4

�, SCN�, HSO4� and ClO4

�, did not cause

any disturbance.

A rhodamine hydrazone derivative complex 6-Cu2+ was

also utilized by Li et al. as a highly selective sensor for CN�

(Scheme 6).24 The interaction between Cu2+ ions and rhodamine

through the formation of an opened-spirolactam in 10 mM of

tris-HCl buffer–CH3CN (1 : 1 v/v) mixture at pH 7.0, gave a

graduated change from colorless to magenta accompanying

the increasing concentration of cyanide. The detection limit

was determined to be as low as 0.013 ppm, much lower than

the Maximum Contaminant Level for cyanide in drinking

water (0.20 ppm) set by the US Environmental Protection

Agency. Based on the colorimetric response of 6-Cu2+ to

CN�, test strips were fabricated, which also exhibited a good

sensitivity and selectivity to CN� as in solution. Other anions,

including Cl�, I�, IO3�, SO4

2�, NO2�, Br�, H2PO4

�, F�,

SCN�, HSO4�, and ClO4

�, had nearly no influence on the

probing behavior of 6 toward cyanide.

Similar to the above two successful cases, the coordination

of Cu2+ ions to the two carboxylates, the amino moiety and

the o-methoxy group of azobenzene acid 7 (Scheme 7), served

as the basis for a colorimetric chemosensor of cyanide.25 This

chemosensor displayed a reversible color change from pale

yellow to red under physiological pH conditions. Other anions

Scheme 4 The structure of 4 and its possible mechanism of sensing cyanide.

Scheme 5 Proposed mechanism of 5 towards cyanide. Inset: photographs of the corresponding color change; from left to right (�10�5 mol L�1):

0, 1.0, 2.0, 3.0, 4.0, 5.0, 6.0, 7.0, 8.0 and 9.0.

Scheme 6 The structure of 6 and photographs of the corresponding

absorption color change.

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including HSO4�, H2PO4

�, F�, SCN�, IO3�, I�, Br�, ClO4

�,

NO2�, Cl� and SO4

2� nearly gave no interference. Corre-

sponding to the high sensitivity of 7 for copper ions, the

complex of 7-Cu2+ demonstrated a good detection limit of

0.15 ppm.

Generally, fluorogenic chemosensors and colorimetric ones

possess different advantages. The fluorogenic sensors can

report the presence of the analytes more sensitively nearly

without the interference of the background noise; while the

colorimetric ones can be used without the aid of any apparatus,

but simply via visual detection. The above examples partially

confirmed this point. If some chemosensors could give both

fluorescence and color change signals, then, their potential

practical applications could surely be broadened. By intelli-

gently utilizing the displacement strategy, some dual chemo-

sensors have been designed to probe cyanide.

Kim et al. reported an ‘‘ensemble’’-based chemodosimeter

coumarin-Cu2+ for the detection of cyanide.26 In aqueous

system, 8 could be hydrolyzed after liberation from 8-Cu2+ by

cyanide with the aid of water, to yield the strong green

fluorescent species 8-1 (Scheme 8). Meanwhile, the addition

of CN� ions to 8-Cu2+ induced a hypsochromic shift as large

as 57 nm, with the absorption maximum wavelength changing

from 521 to 464 nm and a perceived color change from

orange–red to green. The complex of 8-Cu2+ showed good

selectivity toward cyanide, and no noticeable changes were

observed with other anions, such as F�, Cl�, Br�, I�, AcO�,

H2PO4�, HSO4

�, NO3�, ClO4

�, CO3�, SCN�, OH�, CO3

2�,

HPO42�, PO4

3�, adenosine monophosphate (AMP), adenosine

diphosphate (ADP) and adenosine triphosphate (ATP).

Biological application was also successfully performed in

HepG2 cells to show ‘‘off–on’’ fluorescence cellular images.

By linking di(2-picolyl)amine to boradiazaindacene (BODIPY),

Bozdemir group obtained a fluorogenic BODIPY derivative, 9.

With the aid of Cu2+, 9 showed a highly selective fluorescent

enhancement and colorimetric change upon the addition of

CN� in THF–water (98 : 2 v/v) mixtures, with a detection limit

of 0.66 mM (Scheme 9).27 Among other potentially interfering

anions including F�, Cl�, Br�, I�, AcO2�, NO3�, ClO4

�,

HSO4� and OH�, neither I� nor NO3

� interfered significantly

with the selective sensing of CN�, although they caused

emission recovery to some degree.

According to the displacement strategy, Yoon et al.

have prepared two fluorescent sensors, 4,5-disubstituted-

1,8-naphthalimide derivatives 10 and 11 for Cu2+, on the

basis of intramolecular charge-transfer (ICT) and deprotonation

mechanisms with high selectivity (Scheme 10).28 Moreover, they

successfully utilized 10-Cu2+ and 11-Cu2+ for the ratiometric

detection of cyanide via the fluorescent and colorimetric changes

in 100% aqueous solution with detection limits of 2.48 and

0.52 ppm, respectively. Other anions, including F�, Cl�, Br�,

I�, NO3�, SO4

2�, H2PO4� and CN�, could not induce the

revival of fluorescence of 10 and 11.

The displacement strategy for the development of cyanide

chemosensors, was not only applied to the above mentioned

organic molecules, but also utilized in quantum dots (CdSe,

Scheme 11) by Mareque-Rivas et al.29 [(bipy)CuCl2] was used

to completely quench the fluorescence of tri-n-octylphosphine

oxide (TOPO)-coated CdSe quantum dots (QDs), at a concen-

tration of 20 mM. The resultant copper-quenched CdSe nano-

crystal could detect cyanide in the range of 20–100 mM at a

physiological pH value (50 mMHEPES, pH 7.5). This was the

first time that a QD probe turned on its fluorescence in the

presence of anions. Following their work, Dong et al. also

utilized CdTe quantum dots as a ‘‘turn-on’’ fluorescent sensor

Scheme 7 Proposed mechanism of 7 towards cyanide.

Scheme 8 Schematic illustration of ‘‘turn-on’’ fluorescence sensing mechanism of 8. Inset: photographs of the corresponding absorption and

emission color change.

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8468 Chem. Commun., 2012, 48, 8462–8477 This journal is c The Royal Society of Chemistry 2012

for cyanide with a detection limit of 1.5 � 10�7 M at a

pH value of 7.0.30 Other anions, such as NO3�, AcO�,

SO42�, F�, Cl�, Br�, I�, ClO4

�, HCO3� and H2PO4

�, did

not apparently turn on the quenched fluorescence at pH 7.5

(50 mM HEPES).

Co complexes

All the above examples of cyanide chemosensors are based on

Cu2+ complexes, confirming that the displacement strategy

worked well. The key point is that cyanide could form a stable

complex with copper ions. Clearly if other metal ions could

yield stable complexes with cyanide, the displacement strategy

should still work. Considering Co(III)-cyano complexes exhibit

high thermodynamic stability, Zelder et al. designed a new

chemosensor for cyanide, by utilizing the ‘‘base on’’/‘‘base off’’

coordination of the intramolecular bound benzimidazole

nucleobase of vitamin B12 (Scheme 12).31 A switch from the

‘‘base on’’ form to the negatively charged ‘‘base off’’ form of

B12 was observed after the addition of cyanide, which led to a

bathochromic shift (Dlmax = 30 nm) accompanied with a

color change from red (lmax = 550 and 520 nm) to violet

(lmax = 579 and 542 nm). As a result, this system could be

used for the specific colorimetric detection of millimolar

concentrations of cyanide in water. Up to twelve different

anions as well as a 1000-fold excess of Cl� over CN� did

not interfere the sensing behavior, showing the excellent

selectivity. Unfortunately, the reaction time of 10 min at room

temperature was a drawback. Lately, they employed a similar

strategy in the design of modified corrinoid derivatives, which

overcame this limitation and enabled the rapid colorimetric

detection of micromolar amounts of cyanide.32 For further

application, they constructed a corrin-based chemosensor,

which allowed the rapid and selective colorimetric detection

of endogenous biological cyanide.33

Zn complex

Also by utilizing the displacement strategy, complex 12-Zn2+

could report the presence of cyanide as a fluorescent molecular

probe (Scheme 13).34 The replacement of the Zn2+ ions from

Scheme 9 Structure of 9 and its proposed mechanism towards cyanide. Inset: photographs of the corresponding emission change.

Scheme 10 Visible emissions and color changes observed from 10

and 11 upon the addition of Cu2+ and CN�, and the proposed

mechanism of 10 and 11 towards cyanide. Inset: photographs of the

corresponding absorption and emission color change.

Scheme 11 The structure ofMareque-Rivas’s cyanide QD-based probe.

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the complex by CN� shifted the emission maximum wave-

length from 530 (green emission) to the original 480 nm (blue

emission), thereby, allowing the ratiometric detection of

cyanide. Furthermore, this 12-Zn2+ complex was successfully

applied in the analysis of the cyanide concentrations in the

cultured plants, and gave satisfactory results. Other anions,

such as I�, Cl�, Br�, F�, N3�, HSO4

�, ClO4�, HPO4

2� and

OAc� did not give apparent interference.

Gold nanoparticles

In the displacement strategy, cyanide could snatch metal ions

from the complex of the metal ions and the corresponding

sensor, to form a more stable complex. Thus, the previously

quenched fluorescence or changed color caused by the metal

ions, could recover. The key point is that the metal ions are

liberated from the previous complex, and the complexes of the

metal ions and the corresponding chemosensors no longer

exist. In all the above cases, no matter whether for copper ions,

cobalt ions, or zinc ions, the working mechanisms are the

same. Since gold could be dissolved in the cyanide solution,

gold nanoparticles were studied as quencher for fluorophores

instead of the above three metal ions by Dong et al.

Fortunately, the displacement strategy worked. As shown in

Scheme 14, the quenched fluorescence of RB by Au NPs

turned on, upon the addition of cyanide, as a result of the

dissolution of fluorophore-coated gold nanoparticles by cyanide.35

This method allowed the selective detection of cyanide with a

detection limit as low as 8.0 � 10�8 M in aqueous solution

whereas negligible changes were observed upon addition of

other anions, including B4O72�, Br�, BrO3

�, Cl�, ClO4�,

CO32�, C2O4

2�, F�, IO3�, NO2

�, NO3�, PO4

3�, SO32�,

SO42� and S2O8

2�.

Li’s group also used a similar concept for the differential recogni-

tion of cyanide.36 For this task, on hybridization with Au NPs,

Scheme 12 Mechanism of the Vitamin B12-based cyanide sensor. Inset: photographs of the corresponding absorption color change.

Scheme 13 The possible mechanism of 12 towards cyanide and photographs of the corresponding absorption and emission color change.

Scheme 14 Schematic illustration of turn-on fluorescent cyanide

detection based on the dissolution of RB–Au NPs.

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the strong blue fluorescence of imidazole-functionalized poly-

fluorene P1 was completely quenched due to the coordination

of the imidazole groups in the side chain of P1 and the Au NPs

(Scheme 15), since the Au NPs are ultra-efficient fluorescent

quenchers. The resultant hybrid of P1 and Au NPs have

demonstrated highly sensitive and selective detection of cyanide

anion based on the dissolution of Au NPs. The experiments

conducted in various aqueous samples spiked with cyanide con-

firmed the potential practical application of this probe in real

samples. TheP1-AuNPs did not give an apparent response toward

physiologically and environmentally important anions, including

Cl�, CO32�, EDTA2� (EDTA = ethylenediaminetetraacetic

acid), F�, HCO3�, I�, NO2

�, NO3�, SCN�, SO3

2�, SO42�,

C2O42�, AC�, S2O8

2�, P2O74�, PO4

3�, H2PO42�and Br�,

indicating the high selectivity of this sensing system.

Chemosensors for pyrophosphate ions (PPi)

The key point of the displacement strategy is that the anions

could snatch the metal ions from the formed complex of the

metal ions and the corresponding sensors. Thus, if other

anions could also act in a similar way as cyanide in the above

examples, these anions should also be detected. Schanze et al.

reported the first application of a fluorescent conjugated

polyelectrolyte (CPE) for sensing pyrophosphate (PPi) in

HEPES buffer solution (pH 7.5).37 Phosphates are among

the most important anions in biological systems, as they play

significant roles in many biological processes, such as cellular

ATP hydrolysis, DNA and RNA polymerizations, and many

enzymatic reactions.13f,38 It was found that abnormal PPi

levels could lead to vascular calcification, resulting in severe

medical conditions.39 So, scientists have made enthusiastic

efforts to develop pyrophosphate sensors.

In Schanze’s system, an anionic CPE bearing carboxylate

side groups, PPE-CO2� (Scheme 16), exhibited a broad

fluorescence band with an emission maximum wavelength

of 530 nm, which was quenched by the added Cu2+ ions

(1 equiv.).40 The addition of pyrophosphate (PPi) into the

weakly fluorescent solution of PPE-CO2� and Cu2+ induced

the recovery of the fluorescence of the polymer, since PPi

complexed with Cu2+, effectively sequestering the copper ions

in the presence of PPi. This system could detect PPi at nanomolar

concentration (the detection limit is 80 nM) with high selectivity

over many other inorganic anions, including F�, Cl�, Br�, I�,

HSO4�, NO3

�, HCO3�, H2PO4

�, CH3CO2�, SO4

2�, CO32�

and HPO42�. Also, a real-time turn-off assay for alkaline

phosphatase was developed and tested under physiological

conditions. Based on the PPECO2-Cu2+ system, lately, they

developed a real-time fluorescence turn-off assay for the

enzyme alkaline phosphatase (ALP) using PPi as the substrate.41

Upon the addition of ALP, the fluorescence polymer recovered

by PPi would be quenched again. Recently, they have successfully

synthesized a cationic poly(phenylene–ethynylene) with branched

polyamine side chains, PPE-NH3Cl, which realized the direct

detection of PPi in aqueous solution.42 With the increasing

concentration of PPi, the maximum absorption wavelength of

PPE-NH3Cl in the MES buffered solution (pH = 6.5) was red-

shifted from 400 to 430 nm, corresponding to the aggregation-

induced planarization of the phenylene–ethynylene backbone.

Accompanying the absorption change, the emission spectra also

exhibited a large red-shift (B90 nm), due to the efficient inter-

molecular exciton coupling among polymer chains with close

proximity (leading to a lower energy ‘‘aggregate state’’).

In addition to completely snatching the metal ions from the

corresponding chemosensor–metal ion complex, the anions

coordinating to and sharing the metal ions with the original

chemosensor with some changed properties, should be another

kind of the displacement approach, to develop new chemo-

sensors for anions. For example, Jolliffe et al. utilized a

binuclear metal conjunction with bis(2-pyridylmethyl)amine

(DPA) ligands, in which two Zn2+-DPA units were intro-

duced onto a cyclic peptide (Scheme 17).43 The cyclic peptide

based receptor could bind pyrophosphate ions with high

affinity (logK = 8.0 � 0.1). With the aid of a water-soluble

fluorophore, this complex could detect PPi in water with a

selectivity two orders of magnitude over that of ADP and ATP

and complete selectivity over monophosphate anions.

Similarly, Kim et al. designed a new 1,8-naphthalimide-

based receptor (14) bearing two Zn2+ centers (Scheme 18),

which acts as a selective fluorescent chemosensor for PPi over

other anions in 95% aqueous solution.44 Large fluorescent

enhancements (59-fold) and a 29 nm red-shift were observed

upon the addition of Zn2+ to the solution of 14. Then, in the

presence of PPi, 23 nm blue-shift and a 52% fluorescence

quenching were observed. Other anions, including CN�, F�,

Br�, Cl�, I�, Pi, OH�, CH3CO2�, ClO4

�, NO3�, HCO3

�,

HPO4�, HSO4

�, and even ATP, nearly gave no interference.

Scheme 15 Schematic illustration of turn-on fluorescent cyanide

detection based on the dissolution of P1–Au NPs.Scheme 16 Structures of PPE-CO2

� and PPE-NH3Cl.

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By using the staining experiments in C2C12 cells, 14 could be

used as a fluorescent probe for monitoring Zn2+ ion and PPi

in living cells.

Coupled with the unique excited state intramolecular proton

transfer (ESIPT) turn-on mechanism, Pang et al. realized the

detection of PPi in a 2-(2-hydroxyphenyl)-1,3-benzoxazole

(HBO) derivative, with a very large Stokes shift (B100 nm

bathochromic shift).45 As shown in Scheme 19, in a buffered

aqueous solution (pH = 7.4), the two DPA-Zn2+ groups in

15-Zn2 with a suitable located distance, created a strong

binding environment to selectively recognize PPi over structurally

similar phosphate ATP and other anions. 15-Zn2 emitted strong

fluorescence centered at 420 nm, however, the presence of PPi

anions caused the emission band to shift to a much longer

wavelength (B518 nm), as a result of the keto emission arising

from ESIPT. This sensing system was further successfully

applied to the detection of PPi released from a DNA poly-

merase chain reaction (PCR) experiment, indicating that this

new probe could be a useful tool in bioanalytical applications.

Chemosensors for sulfide ions

Sulfide anion is not only widely used in industrial settings and

produced as a by-product, but also found in biosystems due to

microbial reduction of sulfate by anaerobic bacteria and

formation of sulfur-containing amino acids in meat proteins.46

Scheme 17 One of the possible bonding modes for the 13�Zn2 and 13�Zn2�PPi complex.

Scheme 18 Proposed binding modes of 14 and Zn2+ with PPi. Inset:

fluorescence and bright field images of C2C12 cells treated with 14

(a, e), 14 + Zn2+ (b, f), 14 + Zn2+ + PPi (c, g).

Scheme 19 Proposed binding modes of 15 and Zn2+ with PPi. Inset:

photographs of the corresponding emission color change.

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Nevertheless, sulfide anion is toxic to humans. Continuous

and high concentration exposure of sulfide can lead to irrita-

tion in mucous membranes, unconsciousness, and respiratory

paralysis. Once protonated, it becomes even more toxic.4,47

Thus, selective and sensitive sensors for the detection of sulfide

are needed.

Deeply thinking about the sensing mechanism of the

displacement strategy, the key point was that anions could

form very stable complexes and snatch metal ions from the

signaling unit–metal ion complex. Additionally, the selectivity

can be achieved by choosing metal ion and potential anion

coupled with a formation stability constant larger than that

between the signaling unit and the metal ion. Li et al. have

made some efforts on developing other anion chemosensors

besides cyanide. According to the displacement strategy, they

designed a DPA-containing polyacetylene (16, Scheme 20),

which could report the presence of sulfide anions with the aid of

copper ions, based on sulfide anion-induced demetallation.48

Interestingly, this sensing system eliminated the interference of

cyanide, since the constant of CuS (Ksp = 6.3 � 10�36) is much

lower than that of cyanide (3.2 � 10�20). The strong green

fluorescence of 16 could be completely quenched by Cu2+ ions

at concentration as low as 2.0 � 10�6 mol L�1, and the

quenched fluorescence could recover upon the addition

of trace S2� anions, with the detection limit as low as

5.0 � 10�7 mol L�1. No interference were observed from other

anions, including SO32�, HSO3

�, SO42�, ClO4

� , I�, Br�, Cl�,

F�, IO3�, HPO4

2�, PO43�, C2O4

2�, S2O32�, CO3

2�, AcO�,

CN� and P2O74�.

Similarly, the complex of macrocyclic compound and Cu2+

(17-Cu2+) could probe S2� anions selectively, with the detec-

tion limit of 7.0 � 10�7 mol L�1 in H2O–CH3OH (3 : 1, v/v,

Britton–Robinson buffer, pH = 7.1).49 Upon the addition of

some sulfide anion to the 17-Cu2+ complex, the disappeared

emission centered at 538 nm, recovered, and its intensity

increased with increased concentration of S2� (Scheme 21).

The higher stability of the complex of Cu2+ and sulfide ions

than that of 17-Cu2+, led to the release of free 17, as a result,

the fluorescence of 17 was fully revived by the transformation

from 17-Cu2+ (quenched, off) to free 17 (revived, on). The

sensing behavior was not affected by the presence of other

common interfering anions, such as SO32�, HSO3

�, SO42�,

ClO4� , I� , Br�, Cl�, F�, IO3

�, HPO42�, PO4

3�, C2O42�,

CO32�, AcO�, CN� and P2O7

4�.

Chang et al. synthesized a very simple fluorophore, 18,

which consisted of a fluorescein signaling moiety and a DPA

Scheme 20 Schematic representation of Cu2+ and S2� sensors based on the fluorescence ‘‘turn-off’’ and ‘‘turn-on’’ of 16.

Scheme 21 Proposed mechanism of 17 towards sulfide ions. Inset: photographs of the corresponding emission color change.

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binding unit (Scheme 22).50 With the aid of copper ions, 18

exhibited a selective off–on type signaling behavior towards

sulfide ions in 100% aqueous solution, with a detection limit of

420 nM. The presence of other common interfering anions

including cyanide, did not affect the sensing procedure.

Recently, Lin et al. reported the first NIR fluorescent sensor

for sulfide anions, according to the displacement strategy.51 As

shown in Scheme 23, the complex of 19-Cu2+ acts as a good

chemosensor for sulfide anions in pH 7.0 HEPES buffer–

ethanol (25 mM, 6 : 4 v/v). Upon treatment with sulfide, the

‘‘off–on’’ type emission change could be monitored at the

maximum wavelength of 794 nm, with up to a 27-fold fluores-

cence enhancement. The fluorescence intensities at 794 nm

showed an excellent linear relationship with concentration

of sulfide anions from 0.5–8 mM, and the detection limit

(S/N = 3) was calculated to be 280 nM. Other anions, such

as F�, Cl�, Br�, NO3�, NO2

�, N3�, SO4

2�, SO32�, CO3

2�,

PO43�, CH3COO�, I� and CN�, did not cause any detectable

interference.

Chemosensors for other anions

Apart from cyanide, pyrophosphate and sulfide ions, there

are many other anions involved in chemical, biological and

environmental processes of particular relevance. The above

text only summarizes some of the relatively systematically

studied chemosensors towards cyanide, PPi and sulfide reported

so far, by utilizing the displacement strategy. Partially inspired

by the successful examples mentioned above, some other good

chemosensors for other anions have been developed, according

to the displacement strategy.

Iodide plays an important role in several biological activities,

such as neurological activity and thyroid function.6b–c,52 This

necessitates the development of chemosensors for the selective

recognition of I�. Rao et al. reported an amido-benzothiazole

derivative 20 (Scheme 24),53 which showed the selective detec-

tion of Cu2+ among 11 different ions due to the formation of a

1 : 1 complex 20-Cu2+, as confirmed by electronic absorption

and ESI-MS. The complex of 20-Cu2+ could further recognize

iodide with a color change among the investigated 14 anions,

including F�, Cl�, Br�, I�, ClO4�, SCN�, AcO�, SO4

2�,

CO32�, NO3

�, HSO3�, HPO4

2�, NO2� and N3

�.

Jiang et al. also designed a metal-based complex for sensing

I� in aqueous media, according to the displacement strategy.54

It is well known that AgI is insoluble in water with a very low

soluble constant (Ksp = 1.5 � 10�16), thus, a silver complex or

sensor might be utilized to probe iodide anion by sequestrating

Ag+ from the complex to form the AgI precipitate in aqueous

media. As shown in Scheme 25, the Ag+-selective receptor

azacrown[N,S,O] was introduced to the 4-isobutoxy-

6-(dimethylamino)-8-methoxyquinaldine fluorophore, to yield

21, which provided ratiometric measurements for Ag+ with

high sensitivity and selectivity in MES buffer (pH = 6.0).

Upon the addition of I�, Ag+ was snatched from the 21-Ag+

complex and consequently reverted the resonance of quinoline

platform in the protonated 21, accompanied by a reversed

ratio signal output. The detection limit was determined to be

0.9 ppm. Other anions, including F�, Cl�, Br�, CO32�,

HSO4�, CN�, SCN�, H2PO4

�, S2�, and AcO�, did not give

apparent interference.

As we know, in addition to copper and silver ions, iodide

can also form a stable complex with mercury ions. Just utilizing

Scheme 22 The structure of the fluorescein–DPA chemosensor and the possible mechanism. Inset: photographs of the corresponding emission

color change.

Scheme 23 Proposed displacement mechanism of 19 towards sulfide anions.

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this property, recently, Wu et al. developed a fluorescence

turn-on sensing system for iodide.55 As shown in Scheme 26,

an anthracene–thymine dyad (22) could form a complex with

mercury(II) ion through the binding interaction between

thymine and mercury, which quenched the strong fluorescence

of the anthracene moiety. In the presence of iodide, the mercury(II)

ion was extracted from the complex, thus, the dyad was

released, accompanied with the recovery of the fluorescence

of the anthracene moiety. The detection limit was calculated to

be as low as 126 nM. Other anions, namely F�, Cl�, Br�,

HCO3�, SO4

2�, PO43�, NO3

�, CO32�, H2PO4

�, HPO42� and

CH3COO�, caused negligible changes of fluorescent signal.

Interestingly, this sensing system can be operated not only in

HEPES buffer solution, but also in tap-water and urine.

In the displacement strategy, metal ion complexes are

frequently used for the anion recognition, since we know more

about the coordination chemistry and the interactions between

the metal ions and anions. In addition to the above mentioned

Cu2+, Co3+, Zn2+, Ag+, Hg2+ ions, and Au nanoparticles,

Fe3+ was also utilized to design new anion chemosensors,

according to the displacement strategy. Hu et al. prepared a

rhodamine 6G-phenylurea derivative (23), which could selectively

detect Fe3+ in aqueous media.56 Moreover, in the presence of

Fe3+ ions, 23 showed high selectivity and sensitivity toward

AcO� in H2O–CH3CN (1 : 1, v/v) over other anions (including

F�, Cl�, Br�, I�, HSO4�, H2PO4

�, NO3� and CO3

2�), with

large change of the fluorescence intensity and also a clear color

change from pink to colorless (Scheme 27). The sensing

mechanism was proposed to be the displacement approach,

as proved by 1H NMR, i.e., the treatment of the 23-Fe3+

complex with AcO� prompted the dissociation of the 23-Fe3+

complex to release free 23.

Also, by using the Fe3+ chemosensors, Jiang et al. reported

a new sensing system for fluoride ions based on the thiosemi-

carbazone fragment.57 As shown in Scheme 28, 24 selectively

complexed with Fe3+ ions in neutral aqueous solution,

accompanied with a significant fluorescence quenching. Upon

the addition of F� anions, the blue emission revived immedi-

ately due to the liberation of 24 from the Fe3+-24 complex,

Scheme 25 Proposed bonding process of 21 in the presence of

Ag+ and I�.

Scheme 24 The structure of calix[4]arene-1,3-diamidobenzothiazole derivative 20, and its proposed sensing mechanism for iodide.

Scheme 26 The structure of 22 and the proposed mechanism of 22 towards iodide.

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with the detection limit as low as 2.66 ppm. Other anions, such

as AcO�, NO2�, NO3

�, I�, SCN�, ClO4�, N3

�, Br� and Cl�,

did not interfere in the sensing procedure.

Concluding remarks

In this Feature Article, recent progress of fluorescent and

colorimetric anion chemosensors (mainly from 2008 to 2011)

based on the displacement strategy, has been reviewed. Due to

the length limitation, we could not summarize all the related

work in this review. However, the selected examples could

demonstrate clearly how the combination of suitable binding

sites and metal ions can be coupled with the aim to obtain, in

certain cases, highly selective responses for target anions. We

classified these various probes by different kind of anions, such

as cyanide, pyrophosphate, sulfide and others. Li’s group

provided the pioneering work to detect cyanide by employing

Cu2+/polyacetylene complex, while Mareque-Rivas’s group

reported tri-n-octylphosphine oxide (TOPO)-coated CdSe

QDs as sensor for the highly selective detection of cyanide.

Besides, Schanze et al. gave the first example of metal complexes-

based PPi sensor. And thanks to the enthusiasm of scientists,

other anion chemosensors were successfully developed.

In the displacement strategy, it is the key point that the

stability constant of the complex formed by the anion and the

cation should be larger than that of the complex of the cation

and its chemosensor. Only in that case, will the displacement

reaction take place. However, at least three issues confuse

scientists for the further development of anion chemosensors

and their practical applications: the selectivity, the sensitivity,

and the formed stable complexes.

As illustrated in the above examples, copper complexes are

used to probe cyanide, sulfide, PPi and iodide anions in different

cases. Although, sometimes other anions do not cause interference,

in some cases they do. For some special real samples, the

possible interference could be ignored, for example, to monitor

the concentration of PPi in biological systems, the influence of

cyanide could be omitted, as the possibility of the presence of

cyanide is very low. However, for the pursuit of ideal chemo-

sensors, the response to a single analyte is always the goal of

scientists. Also, to deeply understand the mechanism of the

displacement strategy, more is needed to be known about the

selectivity. To achieve this, not only new anion chemosensors

should be explored, but also some work focused on reported

examples should be performed. For example, both 23 and 24

are good chemosensors towards Fe3+, but the Fe3+-23

complex can probe AcO� without any influence from F�,

while Fe3+-24 complex just responds to F�, and AcO� does

not cause interference. In principle, each anion, which could

form more stable complex with higher stability constant than

that of the complex of the cation and its chemosensor, should

be probed and give out optical signals. While it seems that the

cation chemosensor itself, essentially has nothing to do with

the sensing behavior of the formed complex toward anions, the

above cases of 23 and 24 would suggest otherwise. How

can we completely and systematically evaluate the role of

the cation chemosensors in the process of the displacement

reaction? To answer this question, there is still a long way

to go. However, undoubtedly, clarifying this point will help

scientists to design new anion chemosensors with good per-

formance, and especially high selectivity, according to the

displacement strategy.

The sensitivity is another important parameter for a good

chemosensor besides the selectivity. As mentioned in the

introduction, in order to achieve high sensitivity of the anion

chemosensors, the corresponding cation sensors should have

very high sensitivity. The higher sensitivity of the cation chemo-

sensors, the better of the anion ones. For example, as 2 possessed

Scheme 28 The proposed mechanism of 24 towards fluoride ions.

Scheme 27 The proposed mechanism of 23 towards acetate ions. Inset: photographs of the corresponding absorption color change.

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higher sensitivity toward copper ions (0.2 ppm) than 1 (1.48 ppm),

2 exhibited a better detection limit of 0.31 ppm for cyanide

(1.82 ppm of 1). Thanks to the great efforts of scientists, there

are many approaches to obtain good cation chemosensors

with very high sensitivity. From this point, the well-established

design rules of cation chemosensors will contribute to the

further development of anion sensors with high sensitivity,

based on the displacement strategy.

It should be considered fortunate that there is no apparent

disturbance from the formed stable complex of the anions and

the metal ions till now, even in cell imaging studies, though

there is no guarantee of this in future sensing systems or some

new practical analyzing samples. Thus, when we develop new

chemosensors according to the displacement strategy, the

effect of the stable complex or precipitant formed by the anion

and metal ion, should always be considered.

In summary, although it seems simple, it is still not an easy

task to develop new anion chemosensors with high selectivity

and sensitivity according to the displacement strategy. Excitingly,

the rapid progress of this field recorded so far is encouraging,

and indicates more success could be achieved. Thus, it is

reasonable to believe that many good cation chemosensors

could be explored to be ‘‘novel’’ selective and sensitive anion

chemosensors. Further, the displacement strategy might not be

limited to cation chemosensors, but also to other new chemo-

sensors towards different analytes besides anions.

Acknowledgements

We are grateful to the National Science Foundation of China

(no. 20974084), and the National Fundamental Key Research

Program (2011CB932702) for financial support. We acknowledge

the contributions from our students, whose names are given in

the references section.

Notes and references

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